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  1. New advisory board members, new guide for authors, and on-line access
  2. The effect of thoracic sympathectomy on baroreex control of circulation
  3. Endoscopic thoracic sympathectomy attenuates reex tachycardia during head-up tilt in lightly anesthetized patients with essential plamar hyperhidrosis
  4. Flumazenil reduces the hypnotic dose of propofol in male patients under spinal anesthesia
  5. Thoracoscopic sympathectomy: endobronchial anesthesia vs endotracheal anesthesia with intrathoracic CO2 insufation
  6. Renal function in surgical patients after administration of low-ow sevourane and amikacin
  7. Comparison of heart rate changes after neostigmine-atropine administration during recovery from propofol-N2O and isourane-N2O anesthesia
  8. The effect of propofol infusion on minimum alveolar concentration of sevourane for smooth tracheal intubation
  9. Anticonvulsant effects of sevourane on amygdaloid kindling and bicuculline-induced seizures in cats: comparison with isourane and halothane
  10. Comparison between sevourane and isourane anesthesia in pig hepatic ischemia-reperfusion injury
  11. Anesthesia and the gastrointestinal tract
  12. Education in anesthesiology for the twenty-rst century
  13. Malignant hyperthermia with normal calcium-induced calcium release rate of sarcoplasmic reticulum in skeletal muscle
  14. Accidental subarachnoid injection of atracurium: A case report
  15. An adult with ARDS managed with high-frequency oscillatory ventilation and prone position
  16. Blood component therapy guided by celite-activated thromboelastography for perioperative coagulopathy
  17. Post-herpetic neuralgia in a patient with congenital insensitivity to pain and anhidrosis
  18. Simple high-performance liquid chromatographic assay of propofol in human and rat plasma and various rat tissues
  19. Letters to the editor <LCT>Unexpectedly severe hypoxia during sprint swimming
  20. Perioperative coronary spasm reported in Japanese journals
  21. Obituary <CT>Akira Inamoto (19092001)

<JN>J Anesth (2002) 16:12
<PT>Editorials
<CT>New advisory board members, new guide for authors,
and on-line access
<CA>Hidenori Toyooka
<ADD>Department of Anesthesiology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
<para1>Since its foundation in 1954, the Japanese Society of Anesthesiologists has continued to grow steadily, and the number of Society members now is approaching 8600. In June 2001, the Society was approved by the Ministry of Education, Culture, Sports, Science and Technology of Japan as a legal entity, and it is now recognized as a corporate body. The name of the Society also underwent a slight modication, from the former Japan Society of Anesthesiologists to the current Japanese Society of Anesthesiologists. The Journal of Anesthesia, the ofcial journal of the Japanese
Society of Anesthesiologists, is in its 16th year of publication, and 9000 copies are distributed to Society members as well as to non-Society subscribers in Japan and in other parts of the world.
<para2>In this issue of the Journal of Anesthesia, readers will nd some minor but signicant changes. These changes include a listing of the new Advisory Board members and a revised version of the Guide for Authors. Instructions for accessing the Journal of Anesthesia on-line are also included, beginning with this issue.
<para2>The members of the International Advisory Board have long been a great guiding force for our journal. To join them, we recently have invited a considerable number of authorities from different elds of anesthesiology and related biomedical sciences from all over the world to become members of the Advisory Board. Two-thirds of these new members are from outside Japan. The majority of them are not only leading investigators
in our eld of specialization, they also have long-
established associations with members of our Society, including members of the Editorial Board of this journal. Many of the leading Japanese anesthesiologists have studied under these specialists in the early days of their education and still hold them in high esteem as mentors. The Editorial Board members are deeply grateful for their acceptance of our invitation to join
the Advisory Board of the Journal of Anesthesia. We believe that their valuable experience and expertise will be great assets to us.
<para2>Inside the back cover of the journal is the Guide for Authors, which has undergone some revision. The new Guide has been expanded to two full pages for easier reading but without major changes in our editorial
policies and principles. Contents of the previous
Prerequisites for Publication have been incorporated in the Guide for Authors. Thus, requests to conform to
the Uniform requirements for manuscript submitted to biomedical journals, including authorship and ethical issues, now appear in the Guide for Authors. Special Articles and Book and Multimedia Reviews have been added as new categories for submissions. The requirement of a cover page, specied in the old Guide, has been abolished. Instead of a cover page, a title page will carry essential information about the manuscript including names and afliations of all authors. The number of words permitted for the abstract of an original work has been increased from 200 to 250 words. The certication form to accompany all submissions has been simplied in format but still requires the signature of all authors. The Editorial Board has considered the possible adoption of a new system that will include
submissions and peer review on-line, but no decision on these procedures will be made at present. We hope that contributors will nd this new Guide for Authors much easier to refer to.
<para2>The importance of easy access to the contents of
the journal on the Internet has already been pointed out by the new members of the Advisory Board. Currently, we offer two ways to browse the Journal of Anesthesia on the Internet. One is by accessing the LINK
web site of our publisher, Springer-Verlag, at http://www.springer.de. Full access to an entire article in PDF format is limited to Society members and individual subscribers of the print version, but the table of contents and abstracts of articles are freely available. General instructions for accessing Springer-Verlags LINK
are found in each issue of the journal, with additional instructions for full on-line access to the Journal of
Anesthesia by individual Society members shown on a separate page. The alternative access to the Journal of Anesthesia is via the home page of the Japanese Society of Anesthesiologists at http://www.anesth.or.jp. Pages of the Journal of Anesthesia can be accessed easily by clicking the appropriate icons. Text les of entire articles excluding gures and tables will be freely available with no password required. The home page of the Japanese Society of Anesthesiologists is currently being reconstructed, and the procedure for accessing it will undergo some changes in the near future.
<para2>We believe that with these changes in our Advisory Board and in our Guide for Authors we enhance the contribution that the Journal of Anesthesia provides
to our profession. We hope that our members and
readers will join us in that belief with their continued support.
<para1> Hidenori Toyooka, M.D.
<para1> Editor in Chief

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<JN>J Anesth (2002) 16:3
<PT>
<CT>The effect of thoracic sympathectomy on baroreex control of circulation
<CA>Sumio Hoka
<ADD>Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara 228-8555, Japan
<para1>The sympathetic nervous system (SNS) comprises a
system of efferent nerves that regulate the voluntary functioning of most organs, including the heart and vasculature. The SNS works to minimize moment-to-
moment uctuations in the arterial blood pressure, mainly through baroreex modulation of its activity. We, anesthesiologists, manipulate the activity of the SNS in the operating room with the use of local and general anesthetics. Sympathomimetic drugs or adrenergic blocking agents are also frequently used to maintain hemodynamic stability during anesthesia. Thus, the integrity of the SNS is an important factor in the management of anesthesia, as well as being important in an individuals quality of daily life.
<para2>Anesthesiologists also manipulate the activity of the SNS as a tool of therapy in pain management. Sympathetic ganglion block is one of the most common techniques used in pain clinics. Thoracic sympathectomy
has been used as a treatment for palmar hyperhidrosis. Palmar hyperhidrosis usually appears at puberty and causes psychological, social, educational, and occupational problems for people who suffer from it. Although many treatments have been used, the only treatment that permanently eradicates the condition is sympathectomy. Transthoracic endoscopic sympathectomy (TES) seems to be accepted as an effective and simple modality for treating palmar hyperhidrosis. However, TES carries appreciable risks, including the possible occurrence of Horners syndrome, gustatory sweating,
neuralgia, and pneumothorax, in addition to the extraordinarily high incidence of postoperative compensatory hyperhidrosis.
<para2>TES can alter the autonomic function of the cardiovascular system. Two cases of cardiac arrest have been reported during TES [1]. Suzuki et al., [2], in their article in this issue of the Journal of Anesthesia, report
on their examination of the perioperative changes in baroreex-mediated circulatory control in patients with TES. Baroreex control of the circulatory system was assessed by head-up tilt. They showed that heart rate responses to head-up tilt were signicantly reduced
after TES, and that the prevalence of orthostatic hypotension was increased after TES. However, their study demonstrates only the short-term effects of TES. The detrimental effects of TES on SNS-mediated circulatory adjustments may be trivial or may disappear in the long term. Because TES is considered to be a highly effective treatment for palmar hyperhidrosis, the long-term side effects of this procedure should be vigorously examined.
<A>References
<REF>1. Lin CC, Mo LR, Hwang MH (1994) Intraoperative cardiac arrest: a rare complication of T2, 3-sympathectomy for treatment of
hyperhidrosis palmaris. Two case reports. Eur J Surg 160 (Suppl 572):4345
<REF>2. Suzuki T, Masuda Y, Nonaka M, Kadokura M, Hosoyanada A (2002) Endoscopic thoracic sympathectomy attenuates reex tachycardia during head-up tilt in lightly anesthetized patients with essential palmar hyperhidrosis. J Anesth 16:48

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<JN>J Anesth (2002) 16:48
<PT>Original articles
<CT>Endoscopic thoracic sympathectomy attenuates reex tachycardia during head-up tilt in lightly anesthetized patients with
essential plamar hyperhidrosis
<CA>Takashi Suzuki1, Yutaka Masuda1, Makoto Nonaka2, Mitsutaka Kadokura2, and Akiyoshi Hosoyamada1
<ADD>1 Department of Anesthesiology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
<ADD>2 First Department of Surgery, Showa University School of Medicine, Tokyo, Japan
<AB>Abstract
<AB>Purpose. Our purpose was to examine perioperative alterations in hemodynamic changes with head-up tilt (HUT) in patients undergoing endoscopic thoracic sympathectomy (ETS).
<AB>Methods. The subjects were 11 patients with essential
hyperhidrosis scheduled to undergo ETS (ETS group) and 9 age-matched volunteers undergoing minor surgery (control group). HUT was performed (40; 5 min) before and after the surgery, under nitrous oxide anesthesia. Orthostatic hypertension and hypotension in response to HUT were dened as changes of 10% or greater in systolic blood pressure.
<AB>Results. The increase in heart rate in response to HUT was signicantly reduced after surgery in the ETS group (from
34 6 18 to 14 6 11 beatsin21; P , 0.001), but not in the control group (from 23 6 18 to 22 6 12 beatsin21; P 5 0.911). Orthostatic hypertension disappeared completely after ETS (from 5 of 11 to none of 11 patients; P 5 0.035), whereas the prevalence of orthostatic hypotension increased signicantly after ETS (from 3 of 11 to 9 of 11 patients; P 5 0.030). In the control group, the prevalence of neither orthostatic hypertension nor orthostatic hypotension changed after
surgery.
<AB>Conclusions. ETS attenuates autonomic circulatory response under nitrous oxide anesthesia.
<KW>Key words Endoscopic thoracic sympathectomy Baroreex Essential palmar hyperhidrosis Head-up tilt Orthostatic change
<A>Introduction
<para1>Endoscopic thoracic sympathectomy (ETS) has become an accepted treatment for essential palmar hyperhidrosis (EPH) [1]. ETS satisfactorily abolishes palmar sweating and is minimally invasive. Recent studies suggest that ETS could also be used to treat other conditions that are resistant to standard therapy, including angina pectoris [2], vascular insufciency [3], sympathetically maintained pain [4], and social phobia [5]. Because sudomotor bers to the upper extremities are not selectively ablated in ETS, sympathetic ganglia that are in the pathways of the sympathetic innervation of the heart, the lungs, and the great vessels may be partially destroyed. Therefore, ETS is likely to change the autonomic regulation of the cardiovascular system. In fact, two cases of cardiac arrest of unknown etiology during ETS have been reported [6]. Although the anesthetic implications of ETS have been reviewed [7,8], little is known about the effects of ETS on the autonomic regulation of the cardiovascular system in the perioperative period. Conrmation of the safety of ETS for the treatment of EPH is essential, because EPH is a socially embarrassing, but not life-threatening, disorder. In addition, previous clinical studies have reported contradictory results concerning the effects on baroreex sensitivity of cardiac sympathectomy induced by cervicothoracic epidural analgesia (CTEA) [911]. We are particularly interested in the behavioral differences vesulting from the incomplete or partial sympathetic denervation induced by ETS compared with those
resulting from CTEA. The purpose of this study was
to obtain basic information about the hemodynamic changes in response to acute central hypovolemia induced by head-up tilt (HUT) before and after ETS.
<A>Methods
<para1>The study was approved by the ethics committee of our hospital, and informed consent was obtained from each patient. Patients who were receiving any long-term medications were excluded. Eleven consecutive ASA physical status classication I patients who had EPH and were scheduled to undergo ETS were enrolled (ETS group). Nine age-matched status I volunteers scheduled to undergo minor surgical procedures other than ETS were enrolled as control subjects (control group).
<para2>No premedication was given before surgery. General anesthesia was induced with propofol (2 mg/kg IV) and tracheal intubation was facilitated with vecuronium bromide (1.5 mg/kg IV). To facilitate surgery, patients undergoing ETS were intubated with an endobron-
chial tube for differential lung ventilation. After tracheal intubation, vecuronium bromide (approximately 0.15 mgg1) was continuously infused to immobilize the patients and to control ventilation during the study. In all subjects, anesthesia was maintained with sevourane and nitrous oxide in oxygen. Acetated Ringers solution was infused at 5 mlg2121. Heart rate (HR), percutaneous arterial oxygen saturation, end-tidal carbon dioxide tension, and end-tidal sevourane concentration were continuously monitored. Blood pressure was measured by the oscillometric method. All variables were measured with a patient monitoring system (model DC-5300; Fukuda Denshi, Tokyo, Japan).
<para2>After anesthesia had been induced and an indwelling Foley catheter had been placed, the inhalation of sevourane was discontinued. The patients were placed in the horizontal supine position and mechanically ventilated with 66% nitrous oxide in oxygen. The respiratory rate was xed at 10 breathsin21. Tidal volume was adjusted to maintain end-tidal carbon dioxide tension at approximately 35 mmHg. Rectal temperature was maintained at more than 36C with a uid warmer and a warming mattress. After the end-tidal sevourane concentration (less than 0.2%) was conrmed and hemodynamic stability was obtained, HR and arterial blood pressure were recorded at 1-min intervals for 10 min or more. Patients were then tilted to a 40 upright position (transit time, approximately 15 s) for 5 min by means of a motorized operating table with a foot board support. After 5 min of HUT, sevourane was administered again and ETS was performed in the following manner. The patient was placed in a half-sitting position. A small punch incision was made in the second or third intercostal space, and carbon dioxide was insufated to obtain a surgical view. The bilateral second and third thoracic sympathetic ganglia (T2
and T3) were ablated with a modied transurethral electroresectoscope. In patients with axillary hyperhidrosis, the fourth ganglia (T4) were also bilaterally ablated. For surgical procedures, a small amount (less than 2 ml) of 1% lidocaine with epinephrine (1 : 100 000) was injected into each incisional site. After ETS had been completed, the hemodynamic measurements associated with HUT were carried out in the same way as before HUT.
<para2>The mean values of three consecutive measurements immediately before HUT were dened as the pre-HUT values. The maximum change in HR was used to represent intra-HUT values. Orthostatic hypertension and hypotension in response to HUT were dened as an increase and a decrease, respectively, in systolic blood pressure (SBP) by 10% or greater from the pre-HUT values. Data values were compared by means of Students paired and unpaired t-tests and Fishers exact test. Differences with a P value of less than 0.05 were considered statistically signicant.
<A>Results
<para1>The ETS and control groups were similar in respect to age, sex, body weight, and height. The duration of surgery and anesthesia did not differ signicantly between the groups (Table 1). In the ETS group, 5 of 11 patients underwent ETS of T2 and T3 only, and 6 patients underwent ETS of T2, T3, and T4. Patients in the control group underwent minimally invasive procedures, mainly on the body surface (plastic, orthopedic, or otorhinolaryngological procedures and a mediastinoscopic biopsy). Intraoperative bleeding in the ETS group was insignicant, whereas that in the control group did not exceed 135 ml. In both groups, presurgical HUT was performed more than 30 min after the administration of propofol.
<para2>Pre-HUT HR and SBP before surgery did not differ signicantly between the groups (Table 1). However, the pre-HUT SBP after ETS was signicantly lower than that after the control surgeries (Table 1). The increase in HR in response to HUT was signicantly reduced after surgery in the ETS group (from 34 6 18 to 14 6 11 beatsin21; P , 0.001), but not in the control group (from 23 6 18 to 22 6 12 beatsin21; P 5 0.911). In contrast, SBP during the 5 min of HUT uctuated without an apparent trend (Fig. 1). Orthostatic hypertension completely disappeared after ETS (from 5 of
11 to none of 11 patients; P 5 0.035), but orthostatic hypotension was signicantly more prevalent after ETS (from 3 of 11 to 9 of 11 patients; P 5 0.030). After the minor surgeries, the prevalence of neither orthostatic hypertension (from 3 of 9 to 2 of 9 patients; P . 0.999) nor orthostatic hypotension (from 2 of 9 to 5 of 9 patients; P 5 0.335) increased signicantly in the control group. Hypotension/hypertension or bradycardia/
tachycardia requiring treatment did not occur during HUT. However, in 1 patient in the ETS group, frequent ventricular and atrial premature beats with moderately increased blood pressure (from 119 to 145 mmHg, SBP) were observed during presurgical HUT.
<A>Discussion
<para1>We found that ETS of the bilateral T2 to T3 ganglia, with or without T4 ganglia, attenuated the tachycardic response during HUT. Despite the lack of a standardized protocol, HUT has been used for several decades to detect the autonomic dysfunction seen in disorders such as orthostatic dysregulation, diabetic neuropathy, and Parkinsonism. Passive postural change to an upright position reduces venous return to the heart, and the body is able to compensate quickly for acute central hypovolemia by increasing HR, cardiac output, and
vascular tone. HUT may provoke the activation of
arterial and cardiopulmonary baroreceptor reexes and may initiate the aforementioned compensation. On the other hand, the Bainbridge reex, the existence of which remains controversial in humans, possibly results in a decrease in HR in response to acute central hypovolemia as a counterbalance to the baroreceptor reex [12]. Among the mechanisms of blood pressure con-
trol that respond to central hypovolemia, the arterial baroreceptor reex plays a major role, especially for instantaneous regulation.
<para2>Our method of HUT differed from more commonly used methods in several ways. First, our tests were performed with the subjects under controlled mechanical ventilation with muscle relaxation. Second, the subjects were lightly anesthetized with nitrous oxide and received a minimal concentration of sevourane. Third, the results of postsurgical HUT could have been affected by noxious stimuli of varying degree from the preceding surgery. Fourth, the trachea may have been stimulated by the tracheal (or endobronchial) tube accompanied by the tilting movement.
<para2>Mechanical lung ination can alter afferent dicharges from slowly adapting pulmonary stretch receptors and can thus modify baroreex function [13]. Positive intrathoracic pressure may reduce venous return to the right side of the heart. Skeletal muscle relaxation, especially in the lower part of the body, can impair the muscle pump that assists cardiac lling from the gravity pool [14]. Although volatile anesthetics in general, including sevourane, have been reported to depress baroreex sensitivity [1520], nitrous oxide has minimal effects in this regard [1517,21]. Furthermore, reex tachycardia in response to HUT has recently been reported to be better preserved with sevourane than with isourane or halothane [22]. Therefore, we believe that the minimum concentration of sevourane combined with nitrous oxide that we used has no signicant effects on the baroreex control of HR. On the other hand, the sympathomimetic action of nitrous oxide is well established [21,23]. Accordingly, the baseline sympathetic tone in the subjects was, presumably, augmented and possibly affected the results of HUT.
<para2>In addition, previous clinical studies have reported that baroreex control is affected by abnormal arterial blood gas levels [24], aging [25,26], sex [26,27], level of consciousness [28], mental state [29], and noxious stimuli [29]. However, we enrolled healthy young adults matched for age and sex as control subjects, and our experimental protocol provided adequate ventilation and allowed little or no variation in the subjects mental state.
<para2>Kohno and Taneyama [30] have recently shown that depression of the baroreex control of HR by surgical stimuli differs markedly depending on the location of surgery. They found that upper abdominal surgery signicantly depressed baroreex function, but that surgery of the lower abdomen, extremities, or chest wall had no effect on this function. Of the noxious stimuli produced by the preceding surgery, therefore, we believe that there were nonsignicant differences in the backgrounds for baroreex control of HR between
the chest wall punch incision resulting from ETS and the minor surgeries. Thus, various co-existing factors which may inuence hemodynamic regulation are unlikely to have signicantly affected the major ndings of the present study. However, as the trachea and bronchi are mechanosensitive, it is possible that a tilting movement could have provoked a pressor response although the subjects were fully paralyzed. If this had been so in the present study, both pressor and depressor responses may have been elicited by HUT.
<para2>The increased prevalence of orthostatic hypotension after ETS appears to be caused by sympathetic denervation. However, because our criterion for orthostatic change was rather modest, we do not beleive that this increase indicates that ETS is associated with an increased risk of clinically signicant orthostatic hypotension. However, severe orthostatic hypotension has been reported in a patient with EPH who underwent an extensive thoracic sympathectomy that affected splanchnic innervation [31]. Further study is needed to establish the incidence of such possible sequelae.
<para2>Unlike orthostatic hypotension, orthostatic hypertension is uncommon. In general, orthostatic hypertension most often occurs because of sympathetic overcompensation with an excessive release of catecholamines or because of nephroptosis with orthostatic activation of the renin-angiotensin system [32]. In our experimental setting, underlying sympathomimesis caused by nitrous oxide and the stress response to tracheal stimulation may have contributed to the increase in blood pressure and HR during HUT. Orthostatic hypertension with frequent premature beats occurred in one of our patients with EPH, but did not occur after ETS. We speculate that this event was, possibly, caused by transient, excessive catecholamine release, although we did not examine the possible involvement of humoral factors, and hemodynamic variables were not measured on a beat-by-beat basis. The disappearance of orthostatic hypertension after ETS was probably a result of sympathetic denervation and the subsequent decrease in the release of catecholamines.
<para2>Noppen et al. [33] found that ETS reduced plasma concentrations of norepinephrine, but not epinephrine, in patients with EPH. Their results indirectly support our ndings, in that the postsurgical, pre-HUT SBP in the ETS group was signicantly lower than that in the control group, whereas postsurgical, pre-HUT HRs were similar in both groups.
<para2>On the basis of our observations, we speculate that the hemodynamic response to acute central hypovolemia would be blunted in patients after ETS. A sufcient and instantaneous compensatory response by
the remaining innervated bers to the cardiovascular system may not always occur. Accordingly, we should be alert to the reduction in tachycardic response and
the severe hypotension that could be caused by possible postoperative complications, such as hemothorax [8].
<para2>Takeshima and Dohi [10] reported that baroreex sensitivity, as calculated with the depressor test (baroreex slope calculated with R-R interval change per decrease in systolic pressure change), was unchanged in a patient with cardiac sympathectomy induced by epidural anesthesia in whom sensory analgesia developed from C4 to T7. However, Goertz et al. [11] reported that epidural anesthesia producing analgesia above T1 reduced baroreex sensitivity, as calculated with the depressor test. The major differences between the two studies were that, in the study of Takeshima and Dohi [10], CTEA was performed with lidocaine, with the patient conscious, whereas, in the study of Goertz
et al. [11], CTEA was induced with bupivacaine during nitrous oxide-fentanyl anesthesia. Our present ndings are in contrast to those of Takeshima and Dohi [10], but are quite similar to those of Goertz et al. [11], although the scope of our study probably encompassed factors other than the depressor response. Therefore, we speculate that consciousness may help to preserve the tachycardic response evoked by acute central hypovolemia after the partial or incomplete denervation of cardiofugal sympathetic bers.
<para2>In conclusion, we found that the tachycardic response during HUT was reduced by ETS, but not by various types of minor surgery. Because of the safety concerns, physiologic implications, and increasing popularity of ETS, further studies are needed to evaluate its perioperative and long-term effects on the autonomic cardiovascular system, with and without underlying
anesthesia.
<A>References
<REF> 1. Drott C, Claes G (1996) Hyperhidrosis treated by thoracoscopic sympathicotomy. Cardiovasc Surg 4:788791
<REF> 2. Wettervik C, Claes G, Drott C, Emanuelsson H, Lomsky M, Rberg G, Tygesen H (1995) Endoscopic transthoracic sympathicotomy for severe angina. Lancet 345:9798
<REF> 3. Di Lorenzo N, Sica GS, Sileri P, Gaspari AL (1998) Thoracoscopic sympathectomy for vasospastic disease. J Soc Laparoendosc Surg 2:249253
<REF> 4. Samuelsson H, Claes G, Drott G (1994) Endoscopic electrocautery of the upper thoracic sympathetic chain: a safe and simple technique for treatment of sympathetically maintained pain.
Eur J Surg 160[Suppl] 572:5557
<REF> 5. Telaranta T (1998) Treatment of social phobia by endos-
copic thoracic sympathicotomy. Eur J Surg 164[Suppl] 580:27
32
<REF> 6. Lin CC, Mo LR, Hwang MH (1994) Intraoperative cardiac arrest: a rare complication of T2, 3-sympathicotomy for treatment of hyperhidrosis palmaris. Two case reports. Eur J Surg 160[Suppl] 572:4345
<REF> 7. Hartrey R, Poskitt KR, Heather BP, Durkin MA (1994) Anaesthetic implications for transthoratic endoscopic sympathectomy. Eur J Surg 160[Suppl] 572:3336
<REF> 8. Fredman B, Olsfanger D, Jedeikin R (1997) Thorascopic sympathectomy in the treatment of palmar hyperhydrosis: anaesthetic implications. Br J Anaesth 79:113119
<REF> 9. Dohi S, Tsuchida H, Mayumi T (1983) Baroreex control of heart rate during cardiac sympathectomy by epidural anesthesia in lightly anesthetized humans. Anesth Analg 62:815820
<REF>10. Takeshima R, Dohi S (1985) Circulatory responses to baroreexes, Valsalva maneuver, coughing, swallowing, and nasal stimulation during acute cardiac sympathectomy by epidural blockade in awake humans. Anesthesiology 63:500508
<REF>11. Goertz A, Heinrich H, Seeling W (1992) Baroreex control of heart rate during high thoracic epidural anaesthesia. A randomised clinical trial on anaesthetized humans. Anaesthesia 47:984987
<REF>12. Hakumi MOK (1987) Seventy years of the Bainbridge reex. Acta Physiol Scand 130:177185
<REF>13. Schelegle ES, Green JF (2001) An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors. Respir Physiol 125:1731
<REF>14. Raymond J, Davis GM, Bryant G, Clarke J (1999) Cardiovascular responses to an orthostatic challenge and electrical-stimulation-induced leg muscle contractions in individuals with paraplegia. Eur J Appl Physiol Occup Physiol 80:205212
<REF>15. Bristow JD, Prys-Roberts C, Fisher A, Pickering TG, Sleight P (1969) Effects of anesthesia on baroreex control of heart rate in man. Anesthesiology 31:422428
<REF>16. Duke PC, Trosky S (1980) The effect of halothane with nitrous oxide on baroreex control of heart rate in man. Can Anaesth Soc J 27:531534
<REF>17. Morton M, Duke PC, Ong B (1980) Baroreex control of heart rate in man awake and during enurane and enurane-nitrous oxide anesthesia. Anesthesiology 52:221223
<REF>18. Takeshima R, Dohi S (1989) Comparison of arterial baroreex function in humans anesthetized with enurane or isourane. Anesth Analg 69:284290
<REF>19. Tanaka M, Nishikawa T (1999) Arterial baroreex function in humans anaesthetized with sevourane. Br J Anaesth 82:350354
<REF>20. Tanaka M, Nishikawa T (1999) Sevourane speeds recovery of baroreex control of heart rate after minor surgical procedures compared with isourane. Anesth Analg 89:284289
<REF>21. Ebert TJ (1990) Differential effects of nitrous oxide on baroreex control of heart rate and peripheral sympathetic nerve activity in humans. Anesthesiology 72:1622
<REF>22. Adachi S (1996) Sevourane anesthesia maintains reex tachycardia on position change from supine recumbent to head-up tilt.
J Anesth 10:129132
<REF>23. Hohner P, Reiz S (1994) Nitrous oxide and the cardiovascular system. Acta Anaesthesiol Scand 38:763766
<REF>24. Bristow JD, Brown EB Jr, Cunningham DJ, Goode RC, Howson MG, Sleight P (1971) The effects of hypercapnia, hypoxia and ventilation on the baroreex regulation of the pulse interval.
J Physiol 216:281302
<REF>25. Duke PC, Wade JG, Hickey RF, Larson CP (1976) The effects of age on baroreceptor reex function in man. Can Anaesth Soc J 23:111124
<REF>26. Laitnen T, Hartikainen J, Vanninen E, Nisikanen L, Geelen G, Lansimies E (1998) Age and gender dependency of baroreex sensitivity in healthy subjects. J Appl Physiol 84:576583
<REF>27. Huikuri HV, Pikkujamsa SM, Airaksinen KE, Ikaheimo MJ, Rantala AO, Kauma H, Lilja M, Kesaenemi YA (1996) Sex-related differences in autonomic modulation of heart rate in middle aged subjects. Circulation 94:122125
<REF>28. Conway J, Boon N, Jones JV, Sleight P (1983) Involvement of the baroreceptor reexes in the changes in blood pressure with sleep and mental arousal. Hypertension 5:746748
<REF>29. Mini A, Rau H, Montoya P, Palomba D, Birbaumer N (1995) Baroreceptor cortical effects, emotions and pain. Int J Psychophysiol 19:6777
<REF>30. Kohno N, Taneyama C (1998) Surgical stress attenuates reex heart rate response to hypotension. Can J Anaesth 45:746752
<REF>31. van Lieshout JJ, Wieling W, Wesseling KH, Endert E, Karemaker JM (1990) Orthostatic hypotension caused by sympathectomies performed for hyperhidrosis. Neth J Med 36:5357
<REF>32. Streeten DH, Auchincloss JH Jr, Anderson GH Jr, Richardson RL, Thomas FD, Miller JW (1985) Orthostatic hypertension. Pathogenetic studies. Hypertension 7:196203
<REF>33. Noppen M, Sevens C, Gerlo E, Vincken W (1997) Plasma catecholamine concentrations in essential hyperhidrosis and effects of thoracoscopic D2D3 sympathicolysis. Eur J Clin Invest 27:202205

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<JN>J Anesth (2002) 16:912
<PT>
<CT>Flumazenil reduces the hypnotic dose of propofol in male patients under spinal anesthesia
<CA>Yushi U. Adachi1, Kazuhiko Watanabe1, Hideyuki Higuchi2, and Tetsuo Satoh1
<ADD>1Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
<ADD>2Department of Anesthesia, Japan Self-Defense Force Hanshin Hospital, 4-1-50 Kushiro, Kawanishi, Hyogo 666-0024, Japan
<AB>Abstract
<AB>Purpose. Flumazenil has been reported to produce a partial benzodiazepine-agonist-like effect in some psychopharmacological examinations. This study investigated the effect of umazenil on the hypnotic activity of propofol in 60 men scheduled for minor surgical procedures done under spinal anesthesia.
<AB>Methods. After a steady state of spinal anesthesia had been reached, patients were pretreated with saline or umazenil, 5 g21, followed by the administration of saline or midazolam, 10 g21. Then, 250 g21in21 of propofol was infused until hypnosis was achieved. Loss of response to a simple command with a slight stimulus, served as the end-point for hypnosis. Immediately after achievement of the end-point, propofol infusion was discontinued, and a 2-ml venous blood sample was obtained from the dorsal pedis vein to determine plasma propofol concentration.
<AB>Results. Flumazenil signicantly decreased the dose of propofol required and the time required to achieve hypnosis compared with values in the control group (55 6 10 [mean 6 SD] vs 71 6 14 mg and 212 6 42 vs 268 6 48 s, respectively;
P , 0.05), whereas umazenil attenuated the effect of midazolam in reducing the plasma concentration of propofol at hypnosis (2.9 6 0.5 and 2.5 6 0.6 l21, respectively;
P , 0.05).
<AB>Conclusion. These results suggested that umazenil may potentiate the hypnotic properties of propofol, despite umazenil having an antagonistic effect on the enhanced hypnotic activity of propofol induced by the coadministration of midazolam.
<KW>Key words Flumazenil Propofol Hypnotic dose
<A>Introduction
<para1>Flumazenil is the rst highly specic benzodiazepine antagonist, and, since its introduction, there have been many reports and publications dealing with its properties [1,2]. Flumazenil has been reported to reverse the hypnotic or anesthetic effect of benzodiazepine derivatives, e.g., midazolam [24]; however, umazenil was reported to have no effect in reversing propofol anesthesia [57]. In an experimental animal study, a high dose of umazenil showed a benzodiazepine-like hypnotic effect [7]. Recently, there have been some reports demonstrating that a clinical dose of umazenil had a partial benzodiazepine agonist-like effect in humans [8] and in experimental animals [913]. Because, from the viewpoint of psychopharmacology, the induction of
anesthesia typically causes a change in or a loss of
consciousness [11,12], we hypothesized that umazenil administration might have a potentiating effect on anesthetics at induction. In the present study, we investigated the effect of umazenil on the hypnosis induced by propofol in male patients who were scheduled for minor surgery under spinal anesthesia.
<A>Subjects and methods
<para1>After obtaining approval from the Department Ethics Committee and obtaining written informed consent from the patients, we studied 60 patients scheduled for surgery. All participants were male; they were aged
4585 years, of American Society of Anesthesiologists (ASA) physical status 1 or 2, and were undergoing minor surgery (mainly urological surgery) managed with spinal anesthesia. None of the patients had any psychological complications, and none were receiving medication. The participants were randomly assigned, using a computer-generated random-number sequence, to one of four treatment groups, of 15 patients each. From the beginning of anesthesia, heart rate, arterial blood pressure, and oxygen saturation were monitored non-
invasively with a pulse oxymeter. None of the patients received premedication. Spinal anesthesia was performed with the patients in the lateral position, at L3/4 with 2.02.3 ml of 0.3% dibucaine solution. Then the patients were returned to the supine position, and after conrmation that the level of anesthesia was below the dermatome of Th6-8, 3 lin21 of oxygen was administered, using a face mask.
<para2>After blood pressure, heart rate, and depth of anesthesia had reached a steady state, the 15 patients in each of the four groups were pretreated with: placebo and placebo (PP), umazenil and placebo (FP), umazenil and midazolam (FM), or placebo and midazolam
(PM). The PP and PM groups received 2 ml of saline intravenously administered, followed by saline or midazolam 10 g21, at a 2-min interval. The FP and FM groups received umazenil 5 g21, followed by saline or midazolam 10 g21, also at a 2-min interval. Propofol infusion to the patient was started through an antecubital venous line, at the rate of 250 g21in21, using an infusion pump (Terufusion; Terumo, Tokyo, Japan), with a maintenance dose of acetate Ringer solution, at about 2 mlin21. Loss of response to a simple command (open your eyes; breathe slowly), with a slight stimulus (shaking the patients shoulder) was dened as the end-point for hypnosis. Responses to verbal commands were evaluated by a blinded anesthesiologist at 10-s intervals [14]. Immediately after the end-point was achieved propofol infusion was discontinued, and a 2-ml venous blood sample was obtained from the dorsal pedis vein. The dose of propofol and the time required for establishment of hypnosis were recorded. All procedures were nished before the beginning of surgery. Blood samples were centrifuged for 15 min at 3500 rpm, and separated plasma was frozen until assayed.
<para2>Plasma concentrations of propofol were determined within a month, using high-performance liquid chromatography with uorescence detection at 310 nm and
after excitation at 276 nm (RF550; Shimadzu, Kyoto, Japan). The areas under the chromatographic peaks were calculated with an integrator (PowerChrom; ADInstrument, Tokyo, Japan). Propofol concentrations were estimated based on the peak-area ratio of propofol and the internal standard, thymol. Linear relationships were obtained between propofol and the internal standard peak-area ratios. The correlation coefcient was in excess of 0.997 in the range of 50 ngl21 to 10 l21 (seven points of concentration). The detection limit of propofol by this assay was 10 ngl21.
<para2>Analysis of variance was used to evaluate differences in results among groups. Determination of signicant difference (P , 0.05) was followed by Fishers least signicant difference multiple comparison post-hoc
test. All calculations were performed using a statistical software package (NCSS 2000; Number Crunchers, Kaysville, UT, USA).
<A>Results
<para1>There were no signicant differences in the background characteristics (age, weight, and height) among the four treatment groups (Table 1). There were no complaints of adverse effects of the administration of umazenil
or midazolam. No patient showed detectable signs or symptoms related to the pretreatment drugs. All patients emerged from anesthesia and were re-sedated before the surgery; however, after the surgery, none of them could recall this episode.
<para2>In the PP group, the values for mean dose and time
to achieve the end-point of hypnosis were signi-
cantly higher than those in the FP, FM, or PM groups (Table 2). The plasma concentrations of propofol
at hypnosis were signicantly lower in the FP, FM, and PM groups than in the PP group, and there were signicant differences between the FP or FM and PM groups.
<para2>The blood pressure and heart rate showed no signicant differences among the four groups at any measuring points (Table 3).
<A>Discussion
<para1>The results of the present investigation suggested that umazenil may have a potentiating effect on propofol anesthesia. Differences in the required dose of propofol and time to achieve hypnosis were found at the induction of anesthesia. The decreased plasma concentration of propofol observed with umazenil administration also supported the enhancing effect of umazenil on the hypnotic activity of propofol. The synergistic interaction of propofol and midazolam is well known [15,16]. Flumazenil may attenuate the interaction between midazolam and propofol, despite its potentiating effect on propofol. The results of the present study, in the clinical setting, were well consistent with those of our previous animal experiments in mice [11,12]. Because of ethical limitations, we could not demonstrate whether the effect of umazenil on the hypnotic activity of propofol was dose-dependent. However, the administration of 5 g21 umazenil clearly showed a potentiating effect on the hypnotic activity of propofol. The dose we studied is acceptable and is recommended for reversing the effect of benzodiazepine derivatives in operating rooms.
<para2>We have no clear explanation for the lack of consistency between the results of present study and those of prior investigations [57]. There are numerous studies of the interaction between propofol and umazenil. These investigations, however, focused on clarifying the reversal, or antagonistic effect, of umazenil on the hypnotic activity of anesthetics. In these investigations [5,6], umazenil was administered after a hypnotic or anesthetic state was reached. In such settings, it might be difcult to detect an interaction between umazenil and propofol. Recently, Maranets and Kain [17] reported that preoperative anxiety increased the dose of propofol required at induction and during anesthesia. Thus, if the administration of umazenil had a benzodiazepine agonist-like effect (this effect was reported by Smith and Bickel [8]), it would be acceptable that umazenil reduced the hypnotic dose of propofol required at the induction of anesthesia in the present investigation.
<para2>The limitations of the design in the present investigation should be addressed. In this study, we studied patients under spinal anesthesia. However, it is possible that local anesthetics may affect hypnosis [18,19]. Another limitation of the present study was that the participants consisted of only relatively elderly men. Gan and coworkers [20] reported that women emerged from general anesthesia faster than men. The population
in the present investigation, however, may have been more sensitive to the effect of anesthetics than another population consisting of both sexes. Further investigation is needed, including investigations of the effects
in different population, e.g., in young individuals, or women. Our investigation did not assess the dose-
dependency of each drug interaction [21]. Further pharmacological approaches may be required.
<para2>In conclusion, in male patients under spinal anesthesia, umazenil attenuated midazolams potentiation of the hypnotic effect of propofol, whereas umazenil
itself showed a potentiating effect on the hypnotic
activity of propofol.
<ACK>Acknowledgments. We would like to express our sincere thanks to Dr. Attila Kofalvi for the informative comments on this paper.
<A>References
<REF> 1. Amrein R, Hetzel W (1990) Pharmacology of Dormicum (midazolam) and Anexate (umazenil). Acta Anaesthesiol Scand 92:615
<REF> 2. Whitwam JG (1995) Flumazenil and midazolam in anaesthesia. Acta Anaesthesiol Scand (Suppl) 108:1522
<REF> 3. Ghouri AF, Ruiz MAR, White PF (1994) Effect of umazenil on recovery after midazolam and propofol sedation. Anesthesiology 81:333339
<REF> 4. Wilson E, David A, Mackenzie N, Grant IS (1990) Sedation during spinal anaesthesia: comparison of propofol and midazolam. Br J Anaesth 64:4852
<REF> 5. Fan SZ, Liu CC, Chao CC, Lin SM (1995) Lack of effect of umazenil on the reversal of propofol anaesthesia. Acta Anaesthesiol Scand 39:299301
<REF> 6. Fassoulaki A, Sarantopoulos C, Papilas K (1993) Flumazenil reduces the duration of thiopentone but not of propofol anaesthesia in humans. Can J Anaesth 40:1012
<REF> 7. Murayama T, Shingu K, Ogawa T, Tomoda K, Shindo K, Tamai S, Mori K (1992) Flumazenil does not antagonize halothane, thiamylal or propofol anaesthesia in rats. Br J Anaesth 69:61
64
<REF> 8. Smith BJ, Bickel WK (1999) Flumazenil discrimination by humans under a two-response and a novel-response procedure. J Pharmacol Exp Ther 291:12571268
<REF> 9. Izumi T, Inoue T, Tsuchiya K, Hashimoto S, Ohmori T, Koyama T (1999) Effects of the benzodiazepine antagonist umazenil on conditioned fear stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 23:12471258
<REF>10. Belzung C, LeGuisquet AM, Crestani F (2000) Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not C57BL/6 mice. Psychopharmacology 148:2432
<REF>11. Adachi Y, Watanabe K, Uchihashi Y, Higuchi H, Satoh T (2001) The effect of umazenil on the hypnotic dose of propofol in ddY mice. Masui (Jpn J Anesthesiol) 50:164167
<REF>12. Adachi YU, Watanabe K, Higuchi H, Satoh T (2001) High-dose umazenil potentiates the hypnotic activity of propofol, but not that of thiopental, in ddY mice. Acta Anaesthesiol Scand 45:848852
<REF>13. Schulze-Bonhage A, Elger CE (2000) Induction of partial epileptic seizures by umazenil. Epilepsia 41:186192
<REF>14. Adachi YU, Uchihashi Y, Watanabe K, Satoh T (2000) Small dose midazolam or droperidol reduces the hypnotic dose of propofol at the induction of anaesthesia. Eur J Anaesthesiol 17:126131
<REF>15. Short TG, Plummer JL, Chui PT (1992) Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth 69:162167
<REF>16. Teh J, Short TG, Wong J, Tan P (1994) Pharmacokinetic interactions between midazolam and propofol: an infusion study. Br J Anesth 72:6265
<REF>17. Maranets I, Kain ZN (1999) Preoperative anxiety and intraoperative anesthetic requirements. Anesth Analg 89:13461351
<REF>18. Tverskoy M, Fleyshman G, Bachrak L, Ben-Shlomo I (1996) Effect of bupivacaine-induced spinal block on the hypnotic
requirement of propofol. Anaesthesia 51:652653
<REF>19. Ben-Shlomo I, Tverskoy M, Fleyshman G, Cherniavsky G (1997) Hypnotic effect of i.v. propofol is enhanced by i.m. administration of either lignocaine or bupivacaine. Br J Anaesth 78:375377
<REF>20. Gan TJ, Glass PS, Sigl J, Sebel P, Payne F, Rosow C, Embree P (1999) Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 90:12831287
<REF>21. Minto CF, Schnider TW, Short TG, Gregg KM, Gentilini A, Shafer SL (2000) Response surface model for anesthetic drug interactions. Anesthesiology 92:16031616

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<JN>J Anesth (2002) 16:1316
<PT>
<CT>Thoracoscopic sympathectomy: endobronchial anesthesia vs endotracheal anesthesia with intrathoracic CO2 insufation
<CA>Abdelazeem El-Dawlatly1, Abdullah Al-Dohayan2, Walid Riyad3, Ahmed Thalaj3, Bilal Delvi3, and Salwa Al-Saud3
<ADD>1 Department of Anesthesia and ICU, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia
<ADD>2 Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
<ADD>3 Department of Anesthesia, King Khalid University Hospital, Riyadh, Saudi Arabia
<AB>Abstract
<AB>Purpose. To compare clinical advantages and hemodynamic and respiratory changes during one lung-collapsed ventilation (OLCV) using a double-lumen tube (DLT) or a single-lumen tube (SLT) with intrathoracic CO2 insufation, in patients undergoing thoracic sympathectomy (TS) under general
anesthesia.
<AB>Methods. One hundred and twenty-ve patients (94 men and 31 women) undergoing TS for the treatment of palmar hyperhidrosis (PH) were randomly allocated to two groups: group A (68 patients; age, 29 6 6 years) in whom DLT was used, and group B (57 patients; age, 32 6 3 years) in whom SLT with intrathoracic CO2 insufation at a rate of 0.51 lin21 and sustained intrathoracic pressure at 6 mmHg insufation were used. Anesthesia was maintained with 1 minimum alveolar concentration (MAC) isourane in 50% nitrous oxide in oxygen with incremental doses of sufentanil and atracurium when required. Arterial blood gases were measured in 10 patients in group B. Hemodynamic and respiratory parameters were obtained perioperatively.
<AB>Results. There were no signicant differences in hemodynamic and respiratory parameters between the two groups during the study phases, except for the arterial oxygen saturation (SpO2). The times required for anesthesia and surgery were signicantly shorter in the SLT group than in the DLT group. SpO2 during OLCV was 95 6 1% with DLT and 98 6 1% with SLT, with a signicant difference. Three patients had an SpO2 of less than 90% in the recovery room, where the chest tube position was readjusted, with no further sequelae.
<AB>Conclusion. General anesthesia with SLT and intrathoracic CO2 insufation provides optimal operating conditions, adequate oxygenation, and perfect hemodynamic stability
during TS.
<KW>Key words Thoracic surgery Anesthetic techniques Endotracheal intubation Endobronchial
<A>Introduction
<para1>Thoracoscopic sympathectomy (TS) for the treatment of palmar hyperhidrosis (PH) is gaining in popularity. In the past, surgical treatment of PH was invasive and had a high incidence of morbidity. Because TS provides detailed visualization of the surgical eld with minimal postoperative complications, most surgeons now prefer the thoracoscopic approach for the treatment of PH [1]. Anesthesia for TS is challenging. Establishing one-lung anesthesia is an essential part of the anesthetic technique to facilitate adequate surgical exposure. One lung-collapsed ventilation (OLCV) can be achieved
either by endobronchial anesthesia or by intrathoracic carbon dioxide (CO2) insufation combined with the use of an endotracheal tube [2]. In one report of 719 cases, single-lumen endotracheal tube (SLT) anesthesia was considered safe and economical for TS [3]. But in another report, the combination of balanced anesthesia and a double-lumen endobronchial tube (DLT) was considered an adequate technique for TS [4]. To evaluate the advantages and disadvantages of each technique, we conducted the present study. We investigated the hemodynamic and respiratory changes during general anesthesia for TS, using either DLT or SLT with an intrathoracic CO2 insufation technique.
<A>Patients and methods
<para1>After written informed consent was obtained, 125 adult patients (94 men and 31 women) scheduled to undergo elective TS for the treatment of PH under general anesthesia were randomly enrolled in the study. Patients with cardiorespiratory disease were excluded from the study. The physical status of the patients was American Society of Anesthesiologists (ASA) I or II. A preoperative chest X-ray was taken in all patients. Premedica-tion for all patients was achieved with oral diazepam 0.15 mgg21 2 h preoperatively. The patients were
randomly allocated to two groups: group A (n 5 68)
in whom DLT was used, and group B (n 5 57) in
whom the trachea was intubated with an SLT. Anesthesia in both groups was induced with sufentanil 0.1 g21 and thiopentone 4 mgg21, and intubation was accomplished with atracurium 0.5 mgg21. Endobronchial intubation was achieved with a left-
sided DLT (Mallinckrodt, Athlone, Ireland), size
3739 Fr. Correct placement was conrmed using a beroptic bronchoscope (FOB). Intraoperative monitoring consisted of electrocardiogram (ECG) lead II; heart rate; arterial oxygen saturation (SpO2) determined by pulse oximeter; blood pressure, determined by a non-invasive automated method; end-tidal carbon dioxide (EtCO2); and body temperature, determined
by rectal temperature probe. Anesthesia was maintained with 1 minimum alveolar concentration (MAC) isourane in 50% nitrous oxide in oxygen during OLCV. Incremental doses of sufentanil and atracurium were given if required. A radial artery cannula was inserted for arterial blood gas analysis in ten patients from group B.
<para2>Surgery was performed in all patients by the same surgeon. Patients were positioned supine, with a 30 higher tilt of the ipsilateral thorax. Group B patients were not ventilated during insertion of the Verres needle. The needle was inserted into the pleural space through a small incision in the third or fourth intercostal space, and CO2 was insufated at a rate of 0.51 lin21. Intrathoracic pressure was sustained at 6 mmHg. At the end of surgery, atropine 1.2 mg and neostigmine 2.5 mg were given intravenously and the trachea was extubated. All the patients were sent to the recovery room, where a chest X-ray was taken before they were transferred to the ward.
<para2>During the early phases of the study, a chest tube with a proper drainage system was routinely inserted in
every patient and remained until the rst postopera-
tive day. Later during the study period, a chest tube was inserted and connected to an under-water seal system at the end of surgery, and was removed in the recovery room after chest X-ray examination. Hemodynamic and respiratory data were obtained before, during, and after OLCV every 3 min and then averaged over the time of surgery in both groups A and B. The duration of anesthesia was dened as from the time of induction of anesthesia to extubation of the trachea, while the time of surgery was dened as from the time of skin incision until time of closure of the wound. The blood gas data for the ten patients in group B were also recorded
before, during, and after OLCV.
<para2>The results were expressed as mean 6 SD. The unpaired t-test was used for analysis of differences in the data between groups A and B, and one way analysis of variance (ANOVA) was used for analysis of differences in the data among group B patients before, during, and after OLCV. For all comparisons, P , 0.05 was considered statistically signicant.
<A>Results
<para1>There were no differences in the demographic data
between groups A and B (Table 1). There were no signicant differences in heart rate (HR) and mean blood pressure (mBP) before, during, and after
OLCV in either of the groups (Table 2). In groups
A and B, the mean EtCO2 values were signicantly higher during OLCV than before OLCV. In the ten patients in group B, orterial carbon dioxide pressure (PaCO2) was signicantly higher during OLCV than before OLCV. During OLCV, SpO2 in group A was signicantly lower than that in group B (Table 3). Times required for anesthesia and surgery in group B were both signicantly shorter than those in group A (Table 4). In the recovery room, two patients from group A and one patient from group B were desaturated, with SpO2 ,90%. The SpO2 was improved by adjusting the chest tube position, and there were no further episodes of desaturation.
<A>Discussion
<para1>Since the introduction of TS, the scope of treatment for PH has improved. The reported incidences of postoperative pneumothorax and hemothorax after TS were 0.4% and 0.15%, respectively. Minimal postoperative pain and a short period of hospital stay have been reported after TS [5]. Anesthesia for TS is technically demanding [6]. The use of a DLT provides excellent surgical conditions during TS and ensures OLCV if properly inserted [7]. However, placement of the DLT and conrmation of its correct position, using an FOB, needs clinical skill [8]. During endobronchial anesthesia, the use of intrathoracic CO2 insufation is rarely required for TS.
<para2>In contrast, anesthesia with SLT has certain advantages over DLT. Special skill is not required to conrm its correct position, and in the present study, there was a signicantly shorter duration of anesthesia in the SLT group than in the DLT group. However, intrathoracic CO2 insufation is an essential prerequisite for SLT to ensure adequate one-lung collapse throughout the procedure. During TS and OLCV, hypoxemia is a major concern. In the present study, a comparison of SpO2 values revealed that the tracheal anesthesia technique provided optimal oxygenation compared with oxygenation in the endobronchial technique. However, the lower SpO2 value in the endobronchial group of patients during OLCV was of no clinical signicance. It has been reported that the use of CO2 insufation in the closed chest cavity resembles tension pneumothorax, with a fall in the systolic blood pressure [9,10]. In one study, successful ipsilateral lung collapse was reported without unwanted adverse effects, using 1 lin21 CO2 insufation [11]. In another study, in 80 patients in whom intrathoracic CO2 insufation was used for TS for pH, postoperative complications included 1 with prolonged air leak, 1 with hemothorax, 2 with wound infections, and 15 cases of facial anhidrosis [12].
<para2>In the present study, we experienced three cases of transient postoperative desaturation; the chest tube
position was readjusted in these patients, and there were no further problems.
<para2>In conclusion, we believe that the combination of balanced anesthesia and SLT with intrathoracic CO2 insufation (at a rate of 0.51 lin21, with sustained intrathoracic pressure of 6 mmHg) provides optimal operating conditions, adequate oxygenation, and perfect hemodynamic stability during TS.
<ACK>Acknowledgments. The authors would like to thank Dr. Fayez Khan, Associate Professor of Anesthesia, for his valuable help in revising the manuscript. Also, we are grateful to Mr. S. Marghoub, Mr. M. Shah, and Mr. S. Najmuldin, anesthesia technicians at King Khalid University Hospital, for their technical assistance. Our thanks are also extended to Mr. Amir S. Marzouk for the statistical analysis of the data.
<A>References
<REF> 1. Johnson JP, Obasi C, Hahn MS, Glatleider P (1999) Endoscopic thoracic sympathectomy. J Neurosurg 91:9097
<REF> 2. Fredman B, Olsfanger D, Jedeiken R (1997) Thoracoscopic sympathectomy in the treatment of palmar hyperhidrosis: anesthetic implications. Br J Anaesth 79:113119
<REF> 3. Lee LS, Ng SM, Lin CC (1994) Single-lumen endotracheal intubated anesthesia for thoracoscopic sympathectomyexperience of 719 cases. Eur J Surg 572[Suppl]:2731
<REF> 4. Deloggu G, Marano M, Ciccioli T, Lombardi A, Costantini
D (1996) Thoracoscopic bilateral sympathectomy in Raynauds syndrome: anesthesiology problems. Ann Ital Chir 67:405
409
<REF> 5. Gothberg G, Drott C, Claes G (1994) Thoracoscopic sympathectomy for hyperhidrosissurgical technique, complications and side effects. Eur J Surg 572[Suppl]:5153
<REF> 6. Cunningham AJ (1993) Laparoscopic sympathectomy: anesthetic implications. Anesth Analg 76:11201130
<REF> 7. Jedeikin R, Olsfanger D, Shachor D, Mansoor E (1993) Transthoracic endoscopic sympathectomy. Br J Anaesth 70:491492
<REF> 8. Benumof JL, Partridge B, Salvatier C, Gibbins J (1987) Margin of safety in positioning modern double-lumen tubes. Anesthesiology 67:729738
<REF> 9. Jedeikin R, Olsfanger D, Shachor D, Mansoor K (1992) Anesthesia for transthoracic endoscopic sympathectomy in the treatment of upper limb hyperhidrosis. Anaesthesia 69:349351
<REF>10. Baraka A (1998) Hazards of carbon dioxide insufation during thoracoscopy. Br J Anaesth 81:100108
<REF>11. Olsfanger D, Jedeikin R, Fredman B, Shachor D (1995) Endotracheal anesthesia for transthoracic endoscopic sympathectomy. Br J Anaesth 74:141146
<REF>12. Hsu CP, Chen CY, Lin CT, Wang JH, Chen CL, Wang PY (1994) Video assisted thoracoscopic T2 sympathectomy for hyperhidrosis palmaris. J Am Coll Surg 179:5964

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<JN>J Anesth (2002) 16:1722
<PT>
<CT>Renal function in surgical patients after administration of low-ow sevourane and amikacin
<CA>Hideyuki Higuchi and Yushi Adachi
<ADD>Department of Anesthesia, Self Defense Force Hanshin Hospital, 4-1-50 Kushiro, Kawanishi, Hyogo 666-0024, Japan
<AB>Abstract
<AB>Purpose. Compound A, a degradation product of sevourane, is nephrotoxic in rats, while aminoglycosides induce nephrotoxic injury in humans. Combining an aminoglycoside with a known nephrotoxin can enhance nephrotoxicity. We investigated the effects of aminoglycosides on renal function in surgical patients anesthetized with low-ow sevourane.
<AB>Methods. We compared the urinary excretion of several
biochemical markers (such as total protein, albumin, -
microglobulin, glucose, and N-acetyl-glucosaminidase [NAG]) in an amikacin group (n 5 18) and a control group
(n 5 19) of surgical patients anesthetized with low-ow
anesthesia (1 lin21) with sevourane. All patients received cefotiam as an antibiotic perioperatively. In addition, the amikacin group received amikacin, an aminoglycoside, given intravenously twice a day (400 mg per day) from immediately after the induction of anesthesia to day 2 after anesthesia.
<AB>Results. Duration of anesthesia and mean compound A concentration were 5.2 6 1.4 h and 27.2 6 8.7 ppm (mean 6 SD) in the amikacin group, and 5.1 6 1.7 h and 27.1 6 7.8 ppm in the control group respectively (P . 0.05). The two groups did not differ in clinical laboratory baseline values (blood urea nitrogen and serum creatinine concentration). There were no signicant differences between the groups in either the maximum or the average values for the urinary excretion of biochemical markers after anesthesia.
<AB>Conclusion. Our study demonstrates that there is no synergic effect of compound A and amikacin on nephrotoxicity in humans.
<KW>Key words Anesthetics Volatile sevourane Degradation product: compound A Toxicity: renal Antibiotics: amikacin
<A>Introduction
<para1>Compound A is a degradation product of sevourane, produced by the action of carbon dioxide absorbents on sevourane [1]. Compound A is nephrotoxic in rats, producing transient swelling and/or necrosis and associated renal tubular epithelial hyperplasia in the corticomedullary junction [24]. Whether compound A is toxic in humans is still unclear [310]. Some studies have recently reported, however, that increased urinary excretion of protein and glucose, indicative of nephrotoxicity, was present in volunteers and surgical patients after prolonged low-ow sevourane anesthesia [7,9,10].
<para2>Aminoglycosides remain widely used for the treatment of gram-negative bacillary infections [11]. They also damage the proximal renal tubule in humans [11]. The combined nephrotoxicity of antibiotics and volatile anesthetics in humans has been reported [1214]. The present study investigated the effects of aminoglycosides on renal function in surgical patients anesthetized with low-ow sevourane.
<A>Methods
<para1>The study was conducted at the Self Defense Force Central Hospital (SDFCH) in Tokyo, Japan, and was approved by the hospital Ethics Committee. An informed consent form was signed by each patient prior to participation in the study. The patients were 37 men undergoing anesthesia for orthopedic surgery. Patients whose medical history, physical examination, or laboratory tests showed evidence of abnormal hepatic or renal function were excluded from the study. The sample size of the current study was determined by power analysis (5 0.05; 5 0.20) to reveal a signicant difference
in the excretion of protein. Power analysis indicated that 18 patients per group were required to obtain a signicant difference, assuming that the standard deviations were 160 and the difference between the groups was 150 mg/day.
<para2>Patients were randomly assigned to one of two groups: the amikacin group (n 5 18) and the control group (n 5 19). All patients received cefotiam as an antibiotic twice a day (2.0 g per day i.v.) from immediately after the induction of anesthesia to day 2 after anesthesia. Subsequently, 600 mg of cefotiam was given orally for 5 days. In addition, the amikacin group
received amikacin, an aminoglycoside, twice a day (400 mg per day i.v.) from immediately after the induction of anesthesia to day 2 after anesthesia.
<para2>Thirty minutes after receiving an intramuscular injection of atropine (0.5 mg) and midazolam (0.08 mgg21), each patient received an intravenous injection of thiopental (35 mgg21) and succinylcholine (1 mgg21) or vecuronium bromide (0.1 mgg21) to facilitate tracheal intubation. After tracheal intubation, anesthesia was maintained with sevourane, air, and oxygen (FiO2, 0.4) at a total ow of 6 lin21. After 5 min, the fresh gas
ow rate was reduced to 1 lin21. A semiclosed-circle system with a soda lime absorbent (Drersorb 800; Drer, Leck, Germany) was used to absorb CO2. The CO2 absorbent was changed before the administration of anesthetics to each patient. The anesthesia machine was a Narcomed IIB (North American Drer, Telford, PA, USA). A radial arterial catheter was inserted to monitor arterial blood pressure and to obtain blood samples for analysis of arterial blood gases and serum inorganic uoride concentrations. The lungs were ventilated mechanically with a tidal volume of
810 mlg21, and the ventilatory rate was adjusted to maintain an end-tidal CO2 partial pressure of 3540 mmHg. End-tidal concentrations of sevourane were analyzed with a Capnomac Ultima gas analyzer (Capnomac; Datex, Helsinki, Finland) that was calibrated immediately before each study. The anesthetic concentration was adjusted by the anesthesiologist to maintain the mean arterial blood pressure within 620% of baseline. No adjunct anesthetics or vasoactive drugs were used. A temperature probe (model DT-300; Intermedical, Tokyo, Japan) was inserted into the center of the upper absorbent canister, and the soda lime temperature was recorded at 5-min intervals. After postoperative X-ray lms of the surgical site were obtained, anesthetic administration was discontinued and the fresh gas inow rate was changed to 6 lin21 of oxygen. After the patient opened his eyes and took a deep breath on verbal command, the endotracheal tube was removed.
<para2>Lactated Ringers solution was administered at 56 mlg2121 during anesthesia and at 2 mlg2121 for 16 h after cessation of anesthetic exposure. Clinical laboratory studies of parameters such as serum uric acid, blood urea nitrogen (BUN), and serum creatinine concentrations were performed immediately before
anesthesia and repeated 1, 2, 3, 5, and 7 days after the initiation of anesthesia. Urine samples (24 h) were collected before anesthesia and for at least 7 days after anesthesia. These samples were used for the measurement of the urinary excretion of total protein, albumin, -microglobulin, glucose, N-acetyl-glucosaminidase (NAG), and creatinine. Urine collection after anesthesia began at the end of anesthesia and continued for each 24-h period from 0 to 168 h.
<para2>Gas samples were obtained from the inspiratory limbs of the anesthetic circuit distal to the one-way valves via a capped stopcock port, using gas-tight glass syringes for compound A analysis. Inspiratory limb gas samples were obtained from the inspiratory limb every 1 h after intubation and at the end of anesthesia, using a gas-tight locking syringe. The gas was injected into a gas chromatograph (GC-14A; Shimadzu, Kyoto, Japan). A glass column with a length of 5 m and an internal diameter of 3 mm packed with 20% dioctyl phthalate on a Chromosorb WAW (GL Science, Tokyo, Japan) 80/100 mesh was maintained at 110C in the gas chromatogram. The injection port was maintained at 130C. A carrier stream of nitrogen, owing at 30 mlin21, was delivered through the column to a hydrogen ame ionization detector. The gas chromatograph was calibrated by preparing standard calibration gases from stock solutions of compound A supplied by Maruishi Pharmaceutical (Osaka, Japan).
<para2>Routine laboratory tests such as BUN, urinary
protein, albumin, -microglobulin, glucose, and NAG concentrations, were measured at the Clinical Laboratories of SDFCH. The measurements were performed in a single-blinded manner. Urinary protein and glucose concentrations were measured with a Hitachi 7170 Auto Analyzer (Hitachi, Tokyo, Japan). Urinary albumin concentration was measured with a Nephrometer Analyzer II (Behring, Mrabury, Germany). Urinary -microglobulin was measured by radioimmunoassay (-Micro RIABEARS; Dainabot, Tokyo, Japan). Urinary NAG activity (24 h) was determined colorimetrically using a commercially available method (Shionogi, Osaka, Japan). Urinary excretion of NAG was expressed relative to creatinine concentrations.
<para2>The anesthetic dose was calculated as the product of end-tidal sevourane concentration (expressed as minimum alveolar concentration [MAC], where 1 MAC 5 2.4%) [15] and time, according to the equation [MAC-h 5 (end-tidal concentration %/2.4) 3 1/12 h]. Values taken at 5-min intervals were summed over the period of exposure to obtain the total delivered sevourane dose. Compound A exposure was calculated from the area under the curve (AUC) of compound A concentration versus time, using the trapezoid rule.
<para2>Values are expressed as means 6 SD. Inter- and
intragroup comparisons of laboratory data were performed using two-way repeated measures analysis of variance. Patient demographic data, and maximum
and average excretion data were analyzed by Students t-test or Welchs test. For variables that were not
normally distributed (e.g., urinary protein, albumin, -microgloblin, and glucose), Students t-test or Welchs test was conducted using log-transformed data. Differences were considered statistically signicant if the
P value was less than 0.05.
<A>Results
<para1>There were no differences between the groups in age, height, body weight, duration of anesthesia and surgery, MAC-h, the individual peak and mean compound A concentration, and compound A inspired AUC (Table 1). The two groups did not differ in clinical laboratory baseline values, and no abnormal changes in values in renal function studies were noted during the study period; neither elevated BUN and serum creatinine nor decreased creatinine clearances were observed in any patient (Table 2).
<para2>Urinary excretion of total protein was signicantly increased after anesthesia in both groups compared with values obtained before anesthesia (Fig. 1), but the amounts did not differ between the groups. There were no signicant differences in either the maximum or the average values for urinary excretion of total protein after anesthesia between the amikacin and control groups (Figs. 2A and 3A).
<para2>Changes over time in the urinary excretion of albumin, -microglobulin, glucose, and NAG were similar to the changes in the urinary excretion of total protein. There were no signicant differences between the two groups in either the maximum or average values for the urinary excretion of these biochemical markers (Figs. 2, 3).
<A>Discussion
<para1>The present study demonstrated that there were no signicant differences between our two groups in either the maximum or the average values for the urinary excretion of biochemical markers after anesthesia. In this study, we compared the urinary excretion of several biochemical markers in patients given cefotiam with the urinary excretion of these markers in patients given cefotiam plus amikacin. The amikacin group received amikacin so that the effects of amikacin on renal function could be investigated. Cefotiam was also administered to the amikacin group for prophylaxis, however, because amikacin is not effective for gram-positive
infections.
<para2>The renal tubule is the site of compound A nephrotoxicity in rats; in particular, the tubules in the outer strip of the outer medullary layer (corticomedullary junction) [3,4]. Aminoglycosides also injure the proximal tubules in rats and humans [11,16]. The combined use of aminoglycosides with a known nephrotoxin
that causes proximal tubule injury, such as cisplatin,
can enhance nephrotoxicity [11]. The combination of aminoglycosides and cephalosporin antibiotics does not seem to enhance nephrotoxicity, although this matter
is controversial [11,16]. In 1970, Kuzucu [12] demonstrated that tetracycline intensied the nephrotoxicity produced by methoxyurane administration in humans. Mazze and Cousins [13] and Barr et al. [17] reported the combined nephrotoxicity of gentamicin and methoxyurane in rats and humans, respectively. Motuz et al. [14] reported further increases in the urinary excretion of alanine aminopeptidase (AAP), a brush-border enzyme, associated with enurane after aminoglycoside administration. In contrast, Fish et al. [18] reported that anesthesia with either enurane or halothane in rats with chronic renal impairment treated with gentamicin did not result in additional renal damage. In contrast to the results of Motuz et al. [14], there was no synergic effect on the increase of urinary biochemical markers in the present study. This difference may have been caused by differences in the type of aminoglycoside examined, the patients ages, the low dose of amikacin in the present study, or the compound A-inspired AUC. In the present study, young healthy patients (mean age, 26 years) received amikacin as the aminoglycoside. In contrast, the patients in the study by Motuz et al. [14] (mean age, 63 years) received either gentamicin or tobramycin as the aminoglycoside. Age over 60 years is a clinical risk factor for aminoglycoside nephrotoxicity [11,16]. Amikacin is less nephrotoxic than gentamicin [19]. The dose of amikacin used in the present study was approximately 6 mgg21ay21: this dose was lower than that used in the study by Mondorf et al. [20], which reported increases in AAP in volunteers given 10 mgg21ay21. Furthermore, the compound A-inspired AUCs in the present study were relatively small, with the values both being below 150 ppm-h (137 ppm-h and 144 ppm-h,
respectively), in both groups. Compound A nephrotoxicity in rats is dose dependent [3,4], and the dose-
dependent effect may also be applicable to humans. Eger et al. [21] have contended that the threshold for compound A nephrotoxicity in humans is 150 ppm-h. Therefore, it is possible that larger doses of amikacin with more prolonged compound A inspiration than that used in the present study might cause renal damage.
<para2>The duration of amikacin treatment in the present study was relatively short. The percentage of patients who experience nephrotoxicity increases with duration of therapy [11]. Mondorf et al. [20], however, reported increases in AAP in volunteers given amikacin for
only 3 days. The investigation by Kosek et al. [22]
demonstrated the rapid formation of lysosomal cytosegresomes in Fischer 344 rats given gentamicin (1 mgg21ay21) for 2 days. Furthermore, synergic increases were induced by aminoglycosides and enurane in the urinary excretion of AAP on day 2 after anesthesia in the study by Motuz et al. [14]. Thus, the duration of treatment in the present study was probably not a factor.
<para2>The timing of administration of amikacin may also have affected the results. In the present study, amikacin administration began on the day of compound A inspiration. Barr et al. [17] reported that rats receiving
gentamicin beginning on the day of methoxyurane
administration had less nephrotoxicity than rats given gentamicin prior to methoxyurane administration. If the patients in the present study had been given amikacin prior to anesthesia, the results may have been different.
<para2>In conclusion, amikacin and low-ow sevourane
anesthesia had no synergic effect on nephrotoxicity in this study. The duration of amikacin treatment was short, however, and the doses of amikacin and compound A were relatively low. Further study with substantially higher doses of amikacin and compound A is required to establish the safety of low-ow sevourane with aminoglycoside denitively.
<A>References
<REF> 1. Hanaki C, Fujii K, Morio M, Tashima T (1987) Decomposition of sevourane by soda lime. Hiroshima J Med Sci 36:6167
<REF> 2. Morio M, Fujii K, Satoh N, Imai M, Kawakami U, Mizuno T, Kawai Y, Ogasawara Y, Tamura T, Negishi A, Kumagai Y, Kawai T (1992) Reaction of sevourane and its degradation products with soda lime: toxicity of the byproducts. Anesthesiology 77:11591164
<REF> 3. Gonowski C, Laster M, Eger EI II, Ferrell L, Kerschmann R (1994) Effect of a 3-h administration. Anesthesiology 80:556
565
<REF> 4. Gonowski C, Laster M, Eger EI II, Ferrell L, Kerschmann R (1994) Effect of increasing duration of administration. Anesthesiology 80:566573
<REF> 5. Eger EI II, Koblin DD, Bowland T, Ionescu P, Laster MJ, Fang Z, Gong D, Sonner J, Weiskopf RB (1997) Nephrotoxicity of sevourane versus desurane anesthesia in volunteers. Anesth Analg 84:160168
<REF> 6. Bito H, Ikeda K (1994) Closed-circuit anesthesia with sevourane in humans. Effects on renal and hepatic function and concentrations of breakdown products with soda lime in the circuit. Anesthesiology 80:7176
<REF> 7. Kharasch ED, Frink EJ Jr, Zager R, Bowdle TA, Artu A, Nogami WM (1997) Assessment of low-ow sevourane and isourane effects on renal function using sensitive markers of tubular toxicity. Anesthesiology 86:12381253
<REF> 8. Ebert TJ, Frink EJ, Kharasch ED. Absence of biochemical evidence for renal and hepatic dysfunction after 8 h of 1.25 minimum alveolar concentration sevourane anesthesia. Anesthesiology 1998;88:601610
<REF> 9. Higuchi H, Sumita S, Wada H, Ura T, Ikemoto T, Nakai T, Kanno M, Satoh T (1998) Effects of sevourane and isourane on renal function and possible markers of nephrotoxicity. Anesthesiology 89:307322
<REF>10. Goldberg ME, Cantillo J, Gratz I, Deal E, Vekeman D, McDougall R, Afshar M, Zafeiridis A, Larijani G (1988) Dose of compound A, not sevourane, determines changes in the biochemical markers of renal injury in healthy volunteers. Anesth Analg 88:437445
<REF>11. Bennett WM, Elzinga LW, Porter GA (1991) Tubulointerstitial disease and toxic nephropathy. In: Brenner BM (ed) The kidney, 4th edn. W.B. Saunders, Philadelphia
<REF>12. Kuzucu (1970) Methoxyurane, tetracycline, and renal failure JAMA 211:11621164
<REF>13. Mazze RI, Cousins MJ (1973) Combined nephrotoxicity of gentamicin and methoxyurane anaesthesia in man: a case report.
Br J Anaesth 45:394398
<REF>14. Motuz DJ, Watson WA, Barlow JC, Velasquez NV, Schentag JJ (1988) The increase in urinary alanine aminopeptidase excretion associated with enurane anesthesia is increased further by aminoglycosides. Anesth Analg 67:770774
<REF>15. Scheller MS, Saidman LJ, Partridge BL (1988) MAC of sevourane in humans and the New Zealand white rabbit. Can J Anaesth 35:153156
<REF>16. Rankin GO, Sutherland CH (1989) Nephrotoxicity of aminoglycosides and cephalosporins in combination. Adverse Drug React Acute Poisoning Rev 8:7388
<REF>17. Barr GA, Mazze RI, Cousins MJ, Kosek JC (1973) An animal model for combined methoxyurane and gentamicin nephrotoxicity. Br J Anaesth 45:306312
<REF>18. Fish K, Sievenpiper T, Rice SA, Wharton RS, Mazze RI (1980) Renal function in Fischer 344 rats with chronic renal impairment after administration of enurane and gentamicin. Anesthesiology 53:481488
<REF>19. Naruse T, Horokawa N, Oike S, Maekawa T (1981) Clinical evaluation of urinary N-acetyl-d-glucosaminidase activity in patients receiving aminoglycoside and cephalosporin drugs. Res Commun Chem Pathol Pharmacol 31:313329
<REF>20. Mondorf AW, Zegelman M, Klose J, Hendus J, Breier J (1978) Comparative studies on the action of aminoglycosides and cephalosporins on the proximal tubule of the human kidney. J Antimicrob Chemother 4:5357
<REF>21. Eger EI II, Gong D, Koblin DD, Bowland T, Ionescu P, Laster MJ, Weiskopf RB (1997) Dose-related biochemical markers of renal injury after sevourane vs desurane anesthesia in human volunteers. Anesth Analg 85:11541163
<REF>22. Kosek JC, Mazze RI, Cousins MJ (1974) Nephrotoxicity of gentamicin. Lab Invest 30:4857

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<JN>J Anesth (2002) 16:2327
<PT>
<CT>Comparison of heart rate changes after neostigmine-atropine administration during recovery from propofol-N2O and
isourane-N2O anesthesia
<CA>Tetsu Kimura, Makoto Tanaka, and Toshiaki Nishikawa
<ADD>Department of Anesthesia, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
<AB>Abstract
<AB>Purpose. Propofol augments the reduction of heart rate (HR) in combination with cholinergic agents and attenuates the HR response to atropine. We examined whether propofol anesthesia was associated with an increased incidence and extent of bradycardia after neostigmine-atropine administration compared with the effects of isourane anesthesia.
<AB>Methods. Thirty-six adult patients were randomly assigned to two groups (n 5 18 each): the propofol group patients were anesthetized with propofol (510 mgg2121)-N2O-fentanyl, and the isourane group patients were anesthetized with isourane (0.5%1.0%)-N2O-fentanyl. When surgery was completed, anesthetics were discontinued, and then a mixture of neostigmine 0.05 mgg21 and atropine 0.02 mgg21 was injected intravenously over 20 s. Blood pressure (BP) and HR were measured noninvasively at 1-min intervals for 10 min.
<AB>Results. At the completion of the surgery, the average infusion rate of propofol was 6.2 6 1.7 mgg2121, and the average inspired concentration of isourane was 0.73 6 0.15%. Immediately before the neostigmine-atropine injections, HR and mean BP were similar in the two groups. The maximum increase in HR after the neostigmine-atropine injections was signicantly less in the propofol group than in the isourane group (16 6 9 and 34 6 6 beatsin21, respectively, P , 0.01). The subsequent maximum decrease in HR was greater in the propofol group than in the isourane group (29 6 4 and 25 6 4 beatsin21, respectively; P , 0.01). The incidence of bradycardia (HR , 50 beatsin21) after neostigmine-atropine
injection was greater in the propofol group than in the isourane group (61% and 28%, respectively; P , 0.01).
<AB>Conclusion. We conclude that propofol anesthesia attenuates the initial increases in HR, enhances the subsequent decreases in HR, and increases the incidence of bradycardia after neostigmine-atropine injections compared with the effects of isourane anesthesia.
<KW>Key words Atropine Neostigmine Propofol Isourane Bradycardia
<A>Introduction
<para1>A neostigmine-atropine mixture may be used to antagonize nondepolarizing muscle relaxants. On the reversal of muscle relaxants when such drug combinations are used, heart rate (HR) changes are affected by the anesthetics administered to the patients [13], and moderate bradycardia has been reported to occur in some patients [1,35].
<para2>Propofol is reported to reduce parasympathetic tone to a lesser extent than sympathetic tone [6] and to
cause bradyarrhythmia in combination with various drugs and other factors that could potentially stimulate the parasympathetic nervous system [7,8]. Attenuated HR responses to intravenous atropine have also been reported in patients anesthetized with propofol [9]. Therefore, propofol may attenuate the initial increases and augment the subsequent decreases in HR after intravenous injections of a neostigmine-atropine mixture. To the best of our knowledge, however, the effects of propofol-based anesthesia on HR changes after the
administration of a neostigmine-atropine mixture have neither been examined, nor have they been compared with the changes that occur with other anesthetic techniques. Accordingly, this study was designed to test the hypothesis that the initial increase in HR is attenuated, whereas the subsequent decrease in HR is augmented, after a neostigmine-atropine injection during propofol anesthesia compared with the effects of isourane anesthesia. We also compared the incidence and degree of bradycardia with these two anesthetic techniques.
<A>Subjects and methods
<para1>The study protocol was approved by our local ethics committee, and informed consent was obtained from each patient. Thirty-six adult patients, American
Society of Anesthesiologists (ASA) I or II, scheduled for elective surgery under general anesthesia were
studied. The type of surgery was otolaryngeal, orthopedic, or minor supercial surgery. Patients with a history of cardiovascular disorders, diabetes mellitus, disorders known to affect autonomic function, and those taking medications known to affect cardiovascular function or whose resting HR was ,50 beatsin21 were excluded. All patients received oral famotidine (an H2-blocker) 20 mg 90 min before the induction of general anesthesia.
<para2>On the patients arrival in the operating room, a 20-gauge intravenous cannula was inserted, and acetated Ringers solution was administered at a rate of approximately 5 mlg2121 throughout the study period. Standard lead II electrocardiography (ECG; NEC San-ei Instrument, Tokyo, Japan) was performed and an automated blood pressure (BP) cuff (BP-308ET; Nippon Colin, Tokyo, Japan) was applied at the contralateral arm. HR, determined from the average R-R intervals every 4 s from the ECG monitor, and mean BP (MBP) were electronically calculated.
<para2>The patients were randomly assigned to either the isourane or propofol group (n 5 18 each). Random allocations to these groups were made according to a computer-generated number table. After the measurement of preinduction BP and HR, general anesthesia was induced with intravenous thiopental 5 mgg21 plus fentanyl 2 g21 in the isourane group, or with intravenous propofol 2 mgg21 plus fentanyl 2 g21 in the propofol group. Tracheal intubation was facilitated with intravenous vecuronium 0.1 mgg21. Then, the patients lungs were mechanically ventilated to maintain end-tidal CO2 tension at 3545 mmHg with a fresh gas ow of 6 lin21 throughout the study period. Anesthesia was maintained with 0.5%1.0% inspired concentra-tion of isourane and 70% nitrous oxide in oxygen in the isourane group, or with continuous infusion of propofol (510 mgg2121) and 70% nitrous oxide in oxygen in the propofol group. The inspired isourane concentration and the infusion rate of propofol were adjusted to maintain systolic BP and HR within the range of 620% of the preinduction values. All patients received fentanyl 0.5 g21 intravenously at 30-min
intervals from the induction of anesthesia to the end of the surgery. No additional vecuronium or other anesthetics was used.
<para2>At the completion of the surgery, all anesthetic agents were discontinued, while mechanical ventilation was continued with 100% oxygen. Immediately after the discontinuance of anesthetic agents, BP and HR were measured (preinjection BP and HR) and then a mixture of neostigmine 0.05 mgg21 and atropine 0.02 mgg21 was injected intravenously over 20 s. Measurements of BP and HR were made at 1-min intervals for 10 min after the neostigmine-atropine injections, and the highest HR value measured during this period was dened as the maximum HR in each patient. No stimulus, including intratracheal or oral suction, was given to the patients during this 10-min measurement period. Bradycardia was dened as HR ,50 beatsin21 after neostigmine-atropine injection. If HR decreased to ,45 beatsin21, additional atropine 0.01 mgg21 was administered repeatedly until a stable HR of .45 beatsin21 was obtained. Patients who received additional atropine administration were excluded from the subsequent analysis. After the completion of the 10-min measurement period, verbal commands to open their eyes were given to the patients at 1-min intervals. The patients tracheae were extubated after we conrmed that there were adequate responses to verbal commands, and that there was spontaneous respiration with end-tidal CO2 tension of ,45 mmHg.
<para2>For power analysis, we used data from our pilot study that examined HR changes after intravenous injections of the neostigmine-atropine mixture, which revealed that at least 16 patients in each group would provide a signicance ( of 0.05 and a power ( .0.9 for the detection of an approximately 30% difference in maximum HR changes between two groups [10]. All data values are expressed as mean 6 SD. Comparisons of patient characteristics and BP and HR between the groups were made using the unpaired Students t-test. Testing for differences in incidences between the groups was accomplished by analysis or Fishers exact test as appropriate. BP and HR responses to intravenous injections of the neostigmine-atropine mixture over time were analyzed by repeated-measures analysis of variance (ANOVA), followed by Fishers protected least-signicance method as a post-hoc test. Correlations between preinjection HR and minimum HR values after the neostigmine-atropine injections were analyzed by Pearsons correlation coefcient. A P value of ,0.05 was considered statistically signicant.
<A>Results
<para1>There were no signicant differences between the propofol and isourane groups in terms of age (44 6 4 and 49 6 18 years), height (162 6 9 and 159 6 9 cm), weight (58 6 10 and 58 6 13 kg), male/female ratio (8:10 and 12:6), anesthesia time (120 6 52 and 141 6 77 min), surgery time (89 6 49 and 112 6 71 min), average fentanyl dose (3.4 6 0.8 and 3.6 6 1.1 g21), pre-induction MBP (88 6 15 and 91 6 12 mmHg), and preinduction HR (67 6 11 and 69 6 13 beatsin21). Average durations from discontinuance of all anesthetics until eye opening (15 6 7 and 12 6 2 min) and tracheal extubation (18 6 7 and 15 6 2 min) were also similar in the two groups. The average infusion rates of propofol during the entire course of anesthesia and at the completion of the surgery were 6.6 6 1.3 and 6.2 6 1.7 mgg2121, respectively. The average inspired concentration of isourane at the completion of the surgery was 0.73% 6 0.15%.
<para2>Preinjection (i.e., immediately before the neostigmine-atropine injection) HR was similar in the two groups. Injections of the neostigmine-atropine mixture produced a similar hemodynamic pattern in both groups of initial increases and then subsequent decreases in HR (Fig. 1a). However, compared with the values in the isourane group, absolute HR values and changes in HR from preinjection values were less in the propofol group between 1 and 4 min after injections, and at 5 min after tracheal extubation (repeated-
measures ANOVA; P , 0.05). After the neostigmine-atropine injection, the mean maximum increase in HR from preinjection values was less in the propofol group than in the isourane group (16 6 9 and 34 6 6 beatsin21, respectively; P , 0.0001). Furthermore, the mean maximum decrease from preinjection values in HR was greater in the propofol group than in the isourane group (29 6 4 and 25 6 4 beatsin21, respectively; P , 0.01). The time until the maximum HR was attained after the neostigmine-atropine injection was 1 min in all patients in both groups, while the times until the minimum HR was attained were similar in the propofol and isourane groups (7.5 6 2.6 and 8.6 6 1.7 min, respectively; P 5 0.12). Absolute MBP values were lower in the propofol group than in the isourane group from 2 min after the neostigmine-atropine injection to 10 min after tracheal extubation, except at 5 min (Fig. 1b).
<para2>Eleven of the 18 patients (61%) in the propofol group and 5 of the 18 (28%) in the isourane group developed bradycardia, dened as HR ,50 beatsin21, after the neostigmine-atropine injection (P , 0.01). Additional intravenous atropine 0.01 mgg21 was required in 5 of the 18 patients (28%) in the propofol group, and in only 1 of the 18 (6%) patients in the isourane group to obtain HR values .45 beatsin21.
<para2>There were signicant correlations between the preinjection HR and the minimum HR values after the neostigmine-atropine injections in both groups (Fig. 2). The regression line in the propofol group was shifted toward the right compared with that in the isourane group. In the propofol group, all 10 patients (100%) whose preinjection HR values were ,60 beatsin21 eventually developed a minimum HR of ,50 beatsin21 after the neostigmine-atropine injections, while in the isourane group, 5 of 12 patients (42%) whose preinjection HR values were ,60 beatsin21 developed an ensuing minimum HR of ,50 beatsin21 (P , 0.01).
<para2>No patients showed dysrhythmias other than bradyarrhythmia after the neostigmine-atropine injections. Although one patient in each group spontaneously opened their eyes before the 10-min measurement interval was completed, BP and HR remained stable, and hence, their data were not excluded from the subsequent data analyses. All other patients in both groups did not open their eyes throughout the 10-min measurement period. In all patients, oxygen saturation values, measured by pulse oximeter, were more than 97%, end-tidal CO2 tension was ,45 mmHg, and rectal temperatures were between 37.5C and 36.5C during the 10-min observation periods.
<A>Discussion
<para1>Although several previous studies have reported
the effect of anesthetic agents on HR changes after neostigmine-atropine injections [13], to the best of our knowledge, the effects of propofol-based anesthesia on HR changes after intravenous injections of a neostigmine-atropine mixture have never been addressed. Our study demonstrated that propofol anesthesia attenuated the initial increases in HR, enhanced the subsequent
decreases in HR, and increased the incidence of bradycardia after intraveous neostigmine-atropine administration compared with the effects of isourane anesthesia.
<para2>HR responses to intravenous atropine may differ considerably depending on the anesthetic agents and techniques used [9,11,12]. Although the precise mechanism for the divergent HR responses is yet to be determined, it is considered to reect the effects of anesthetic agents on the balance between sympathetic and
parasympathetic inuence on the heart [9,11]. Cross
et al. [9] showed that atropine-induced HR increases were signicantly attenuated in patients anesthetized with propofol-fentanyl-N2O compared with these HR increases in patients anesthetized with enurane-
fentanyl-N2O, and they suggested that the attenuated HR increases during propofol-based anesthesia were associated with a relative predominance of vagal inuences. Indeed, such an autonomic milieu associated with propofol has been explained by a central sympatholytic/vagotonic mechanism and/or by parasympathetic tone being reduced to a lesser degree than sympathetic tone [6,13]. On the other hand, even though isourane depresses both the sympathetic and parasympathetic components of the autonomic nervous system equally, recovery of autonomic function is known to occur relatively quickly after isourane anesthesia [14,15]. Therefore, it is conceivable that the more suppressed initial increase in HR in the propofol group than in the isourane group in our study can be ascribed to the relatively depressed state of the sympathetic nervous system after propofol anesthesia and/or to the relatively well preserved state of the sympathetic nervous system after isourane anesthesia.
<para2>Our fundings of the enhanced HR reduction and the increased incidence of bradycardia after neostigmine-atropine injection in the propofol group are in accordance with previous ndings. Bradycardia during propofol anesthesia was reported in association with several drugs that can potentiate vagal tone, such as neostigmine and suxamethonium [7,8]. Deutschman et al. [6], by analyzing HR variability spectra, demonstrated that parasympathetic tone was reduced to a lesser degree than sympathetic tone throughout propofol anesthesia and they suggested that propofol anesthesia may predispose patients to develop bradycardia in response to parasympathetic stimuli.
<para2>The interpretation of our results should be conned to the combination doses used in our study. Mirakhur
et al. [4] reported a 30% incidence of bradycardia (HR ,50 beatsin21) when the combination of atropine 0.02 mgg21 and neostigmine 0.05 mgg21 was injected intravenously after halothane anesthesia. Naguib and Gomaa [16] reported that the atropine requirements to prevent neostigmine from lowering HR below baseline in 50% of patients were 0.031 mgg21 for neostigmine 0.04 mgg21, and 0.033 mgg21 for neostigmine 0.06 mgg21 under nitrous oxide-halothane anesthesia; these values suggest that atropine 0.02 mgg21, when combined with neostigmine 0.05 mgg21, would have been insufcient to prevent bradycardia in most patients anesthetized with isourane in our study. Because the incidence of bradycardia in the propofol group in our study was more than double that in the isourane group, it is possible that a larger dose of atropine may be required to prevent bradycardia in patients anesthetized with propofol.
<para2>We observed close positive correlations between
the preinjection HR and the minimum HR values after neostigmine-atropine injections in both groups in our study. The regression line in the propofol group
was shifted toward right compared with that in the isourane group, even though preinjection HR values were similar in the two groups. These results suggest that close attention should be paid to HR changes after neostigmine-atropine injection, especially in patients anesthetized with propofol whose preinjection HR value is low.
<para2>The results of our study should be interpreted with some constraints. First, in our study, no stimulus was given to the patients during the 10-min measurement period. However, in standard clinical practice, some stimuli, including oropharyngeal suction, may be given after neostigmine-atropine administration, and this
may prevent bradycardia during this period. Second, because the neostigmine-atropine mixture was injected immediately after the discontinuation of the anesthetic agents, the blood concentrations of the anesthetic agents must have been changing during the observation period. If the neostigmine-atropine mixture had been injected when anesthetic status was stable, the HR and BP changes could have been different from the present results. However, we intended to approximate the clinical situation, in which neostigmine-atropine mixture is injected when patients are about to emerge from general anesthesia. Third, fentanyl, with its intrinsic vagotonic activity, administered at induction and during anesthesia may have inuenced the hemodynamic
responses to the neostigmine-atropine mixture [17]. Fourth, because glycopyrrolate has been reported to provide a more stable HR than atropine when administered with neostigmine [1,4,5,18], the use of glycopyrrolate instead of atropine as an anticholinergic agent could have affected our results. Finally, because depth of anesthesia may affect the HR response to atropine via alterations in the vagal tone, it is imperative that
an equivalent depth of anesthesia should have been achieved in both our groups. Even though direct comparison of anesthetic levels between volatile and intravenous agents may be difcult, similar BP and HR values in the two groups before the administration of the neostigmine-atropine mixture, as well as similar times from discontinuance of anesthetics until eye-opening and tracheal extubation in the two groups do not suggest that one anesthetic technique resulted in a considerably deeper level of anesthesia than the other at the time of the hemodynamic determinations.
<para2>In conclusion, propofol anesthesia attenuates the initial increases in HR, enhances the subsequent decreases in HR, and increases the incidence of bradycardia associated with the intravenous injection of a neostigmine 0.05 mgg21-atropine 0.02 mgg21 mixture compared with the effects of isourane anesthesia. Close attention should be paid after neostigmine-atropine injection in patients anesthetized with propofol, especially if their preinjection HR value was low.
<A>References
<REF> 1. Heinonen J, Salmenpera M, Takkunen O (1982) Advantages of glycopyrrolate over atropine during reversal of pancuronium block. Acta Anaesthesiol Scand 26:147150
<REF> 2. Samra SK, Pandit UA, Pandit SK, Kothary SP (1983) Modication by halogenated anaesthetics of chronotropic response during reversal of neuromuscular blockade. Can Anaesth Soc J 30:4852
<REF> 3. Takkunen O, Salmenpera M, Heinonen J (1984) Atropine vs glycopyrrolate during reversal of pancuronium block in patients with halothane. Acta Anaesthesiol Scand 28:377380
<REF> 4. Mirakhur RK, Dundee JW, Jones CJ, Coppel DL, Clarke RS (1981) Reversal of neuromuscular blockade: dose determination studies with atropine and glycopyrrolate given before or in a mixture with neostigmine. Anesth Analg 60:557562
<REF> 5. Cozanitis DA, Dundee JW, Merrett JD, Jones CJ, Mirakhur RK (1980) Evaluation of glycopyrrolate and atropine as adjuncts to reversal of non-depolarizing neuromuscular blocking agents in a true-to-life situation. Br J Anaesth 52:8589
<REF> 6. Deutschman CS, Harris AP, Fleisher LA (1994) Changes in
heart rate variability under propofol anesthesia: a possible explanation for propofol-induced bradycardia. Anesth Analg 79:373377
<REF> 7. James MFM, Reyneke CJ, Whifer K (1989) Heart block following propofol: a case report. Br J Anaesth 62:213215
<REF> 8. Baraka A (1988) Severe bradycardia following propofol-suxamethonium sequence. Br J Anaesth 61:482483
<REF> 9. Cross G, Gaylard D, Lim M (1990) Atropine-induced heart rate changes: a comparison between midazolam-fentanyl-propofol-N2O and midazolam-fentanyl-thiopentone-enurane-N2O anaesthesia. Can J Anaesth 37:416419
<REF>10. Fisher DM (2000) Research design and statistics in anesthesia.
In: Miller RD (ed) Anesthesia (5th edn). Churchill Livingstone, New York, pp 753792
<REF>11. Yamaguchi H, Dohi S, Sato S, Naito H (1988) Heart rate response to atropine in humans anaesthetized with ve different techniques. Can J Anaesth 35:451456
<REF>12. Murray DJ, Forbes RB, Dillman JB, Mahoney LT, Dull DL (1989) Haemodynamic effects of atropine during halothane or isourane anaesthesia in infants and small children. Can J Anaesth 36:295300
<REF>13. Cullen PM, Turtle M, Prys-Roberts C, Way WL, Dye J (1987) Effect of propofol anesthesia on baroreex activity in humans. Anesth Analg 66:11151120
<REF>14. Kato M, Komatsu T, Kimura T, Sugiyama F, Nakashima K, Shimada Y (1992) Spectral analysis of heart rate variability during isourane anesthesia. Anesthesiology 77:669674
<REF>15. Takeshima R, Dohi S (1989) Comparison of arterial baroreex function in humans anesthetized with enurane and isourane. Anesth Analg 69:284290
<REF>16. Naguib M, Gomaa M (1989) Atropine-neostigmine mixture: a dose-response study. Can J Anaesth 36:412417
<REF>17. Reitan JA, Stengert KB, Wymore ML, Martucci RW (1978)
Central vagal control of fentanyl-induced bradycardia during
halothane anesthesia. Anesth Analg 57:3136
<REF>18. Mirakhur RK, Dundee JW, Clarke RSJ (1977) Glycopyrrolate-neostigmine mixture for antagonism of neuromuscular block: comparison with atropine-neostigmine mixture. Br J Anaesth 49:825829

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<JN>J Anesth (2002) 16:2833
<PT>
<CT>The effect of propofol infusion on minimum alveolar concentration
of sevourane for smooth tracheal intubation
<CA>Tsuyoshi Satsumae1, Seiji Watanabe1, and Hiroshi Yamaguchi2
<ADD>1 Department of Anesthesia, Pain Clinic, and Clinical Toxicology, Mito Saiseikai General Hospital, Mito, Ibaraki, Japan
<ADD>2 Department of Anesthesia and Critical Care Medicine, Iwaki Kyoritsu General Hospital, Iwaki, Fukushima, Japan
<AB>Abstract
<AB>Purpose. This study was conducted to determine the effect of propofol infusion on the minimum alveolar concentration necessary for smooth tracheal intubation (MACEI) of sevourane.
<AB>Methods. Sixty-nine patients, American Society of Anesthesiologists (ASA) status I, aged 3049 years, were randomly assigned to one of three groups according to the agents used for tracheal intubation (n 5 23 for each group): the SP group, in whom the intubation was attempted under sevourane plus propofol infusion; the S group, tracheal intubation under sevourane alone; and the P group, tracheal intubation under propofol infusion alone. Anesthesia was induced with propofol 2.5 mgg21 i.v. bolus. Prior to the tracheal intubation attempt, propofol infusion, 10 mgg2121, was given for 15 min in the SP and P groups, and sevourane equilibration was established in the SP and S groups. All tracheal intubation attempts were made 15 min after anesthetic induction. The end-tidal sevourane concentration at which tracheal intubation was attempted was predetermined by the up-and-down method (with 0.5% as a step size). MACEI was determined using a logistic regression test.
<AB>Results. The MACEI of sevourane was 1.73% in the SP group, and 2.99% in the S group. Laryngoscopy was not possible in the P group patients.
<AB>Conclusion. Propofol infusion reduced sevourane MACEI. This nding suggests that propofol would be an excellent
adjuvant to use with sevourane for tracheal intubation.
<KW>Key words Anesthetic techniques: tracheal intubation
Anesthetics, intravenous: propofol Anesthetics, volatile: sevourane
<A>Introduction
<para1>The plasma propofol concentration that resulted in a 95% probability of no response during tracheal intubation (Cp95 intubation) to be 34.8 l21. However, with this concentration, patients experienced severe hypotension and their systolic blood pressure decreased to 70.3 mmHg [1]. Moreover, a very large dose of propofol appeared to be required, which did not seem to be practical. It is assumed that smooth tracheal intubation cannot be achieved with propofol alone at a clinically acceptable dose.
<para2>In contrast, sevourane alone makes smooth tracheal intubation possible, without a muscle relaxant, at a clinically acceptable dose. Previously, we reported the minimum alveolar concentration necessary for smooth tracheal intubation (MACEI) of sevourane to be 4.52% [2]. However, with a high concentration of sevourane, it takes a long time to reach equilibration between cerebral and alveolar gas tensions.
<para2>In terms of upper airway integrity, propofol is an excellent agent [3]. However, tracheal intubation with a combination of sevourane and propofol, without a muscle relaxant, has not yet been tried. We hypothesized that a combination of sevourane plus propofol would allow smoother tracheal intubation without a muscle relaxant than either agent alone. In this study, we tested the effect of propofol infusion on the MACEI of sevourane in patients undergoing elective surgery under general anesthesia.
<A>Subjects and methods
<para1>The study protocol was approved by the Ethics Committee of Mito Saiseikai General Hospital, and written informed consent was obtained from each patient. Sixty-nine adult patients (American Society of Anesthesiologists [ASA] physical status I; age range, 30 to 49 years) who were undergoing elective surgery under general anesthesia were enrolled in this study. The patients were randomly assigned to one of three groups according to the agents used for tracheal intubation (n 5 23
for each group): the SP group, in whom tracheal intubation was attempted under sevourane plus propofol
infusion; the S group, in whom the intubation was
attempted under sevourane alone; and the P group, in whom the intubation was attempted under propofol
infusion alone.
<para2>Blood pressure was determined indirectly, and electrocardiogram, arterial hemoglobin oxygen saturation (SpO2), and rectal temperature were continuously monitored, using a patient monitor system (BP-508; Colin, Komaki City, Aichi, Japan). Acetated Ringers solution was infused intravenously, at the rate of 10 mlg2121 as a maintenance uid during the study period. In all the patients, anesthesia was induced using propofol, 2.5 mgg21, i.v. bolus, and a laryngeal mask airway (LMA) was inserted. In the SP and S groups, the patients were connected to an anesthesia ventilator, which delivered a tidal volume of 10 mlg21 at 12 bpm in a controlled ventilation mode, and they inhaled sevourane of a predetermined concentration in pure oxygen. The P group patients inhaled pure oxygen under manually assisted ventilation, which was provided because of the possibility of the patient ghting against the mechanical ventilator. Breath-by-breath inspired/end-tidal sevourane and carbon dioxide concentrations were measured with a gas monitor (RASCAL-1, Albion Instruments, Salt Lake City, UT, USA). We employed a semiclosed anesthetic breathing system with a fresh gas ow of 6 lin21. For the measurement of anesthetic concentration, respiratory gases were sampled from an angle piece tted at the distal end of the LMA. End-tidal sevourane concentration at laryngoscopy and tracheal intubation was predetermined by an up-and-down method (0.5% as the step size), starting with 2% (SP group) or 4% (S group). End-tidal CO2 and rectal temperature were maintained at around 30 mmHg and 35.5C or above, respectively.
<para2>In the SP and P groups, in addition to the induction dose, propofol, 10 mgg2121, was infused for 15 min prior to the tracheal intubation attempt. In the SP and S groups, when 90% or more of the predetermined end-tidal sevourane concentration had been achieved and maintained for at least 10 min under mechanical ventilation, the LMA was removed, and tracheal intubation, using a cuffed tracheal tube (Portex, 7.0-mm internal diameter [ID]), was attempted by conventional indirect laryngoscopy. The P group patients inhaled pure oxygen under manually assisted ventilation for the same period prior to the intubation attempt. All tracheal intubation attempts were made 15 min after anesthetic induction, using bolus propofol.
<para2>The patient were described as either unresponsive or responsive to laryngoscopy and tracheal intubation. When laryngoscopy was uneventful, and coughing and bucking did not occur after tracheal cuff ination, this was considered unresponsive. When we encountered difculty in mouth-opening, gross purposeful muscular movements, vocal cord movements during laryngoscopy, or bucking after cuff ination, this was considered responsive. A single anesthesiologist,
who was not blinded to the grouping, attempted all laryngoscopies and tracheal intubations, while another
anesthesiologist, who was blinded to the grouping, determined the presence or absence of any responses.
<para2>Arterial blood samples were taken from the radial artery, just after the intubation attempt, for the determination of blood propofol concentration in the ten unresponsive patients in the SP and S groups, and in ten patients who were randomly selected from the P group. Blood samples were stored at 5C until extraction and assay. Blood propofol concentration was determined using high-performance liquid chromatography.
<para2>Statistical analyses were done using analysis of variance (ANOVA) for differences in demographic data. Analysis of the probability of unresponsiveness versus end-tidal sevourane concentration, the maximum likelihood estimators of the model parameters, and goodness of t were tested using a logistic regression test (SAS proprietary software; SAS Institute, Chicago, IL, USA), which provided the best tting sigmoid curve. A probit test (SAS proprietary software, SAS Institute) was used to obtain 95% condence limits. Intraoperative awareness was recorded. P , 0.05 was considered statistically signicant. All values were expressed as means 6 SD.
<A>Results
<para1>There were no signicant differences in the demographic data among the three groups (Table 1). LMA was inserted smoothly in all the patients after induction with propofol, 2.5 mgg21 (i.v.). Arterial blood pressure and heart rate before induction, and before and after tracheal intubation attempts, in the SP and S groups, are shown in Fig. 1. The mean end-tidal CO2 value for all patients was 30 6 2 mmHg. Mean body temperature for all patients during the study was 36.1 6 0.6C.
<para2>The total amount of propofol administered before intubation attempts was 5.0 mgg21 in the SP and P groups, and 2.5 mgg21 in the S group. The responses in the 23 consecutive patients in each of the SP and S groups and the end-tidal sevourane concentration in oxygen are shown in Fig. 2. A nding of responsive was observed in all the patients in the P group. The reasons for responsiveness are listed in Table 1.
<para2>The dose-response curve based on the logistic regression test revealed that the median effective dose (ED50) of the end-tidal sevourane concentration necessary for smooth tracheal intubation was 1.73% (95% condence limits, 1.20%2.11%) in the SP group and 2.99% (95% condence limits, 0.28%3.94%) in the S group (Fig. 3). Propofol infusion reduced sevourane MACEI by 42%.
<para2>Mean blood propofol concentrations just after the intubation attempt were 4.18 6 0.37 l21, 0.70 6 0.09 l21, and 3.75 6 0.61 l21 for the SP, S, and P groups, respectively. There was no signicant difference in propofol concentrations between the SP and P groups, but the concentrations were greater than that in the S group.
<para2>One female patient in the SP group experienced
hypotension (,70 mmHg systolic blood pressure) and was successfully treated with bolus ephedrine (10 mg, i.v.). She was excluded from the study. No patient reported awareness during the study period.
<A>Discussion
<para1>The results of the present study show that when
identical doses of propofol are utilized for anesthetic induction and subsequently administered for 15 min,
the propofol reduces the MACEI of sevourane. Sevourane plus propofol infusion appears to be an appropriate combination that allows smooth tracheal intubation without a muscle relaxant.
<para2>The propofol dose in the present study maintained blood pressure and heart rate at an acceptable level prior to the intubation attempt in most patients, but kept no patients aware. In order to minimize the inhalation time to establish equilibration between cerebral and alveolar gas tensions, the anesthesia machine was primed with 1% sevourane prior to induction, and positive pressure ventilation was performed via an LMA in place in the SP and S groups. Manually assisted ventilation was performed in P group patients because patient ghting against the ventilator had been observed frequently in a preliminary study.
<para2>When interaction between volatile and intravenous anesthetic agents is dened, it is important that each agent has reached its steady-state concentration [4]. The conventional method of determining the MACEI of volatile anesthetics requires that a predetermined constant end-tidal concentration of the volatile anesthetic is maintained for at least 15 min to establish equilibration among cerebral, arterial blood, and alveolar gas tensions before tracheal intubation is attempted [2,58]. All determinations in this study were made at a slightly shorter time-phase than that used in previous studies. Because sevourane has a low blood-gas partition coefcient [9], the cerebral concentration of sevourane increases more rapidly than that of other volatile anesthetics. So, we believe that equilibration among cerebral, arterial blood, and alveolar gas tensions is established before tracheal intubation is attempted. Blood propofol concentration is known to reach a steady state quickly. When propofol was infused for 15 min after the bolus injection, blood propofol concentration rapidly reached a steady state [10,11]. It is probable that, in the present study, tracheal intubation was attempted after sevourane and propofol had reached their steady-state concentrations.
<para2>The plasma propofol concentration that facilitated smooth tracheal intubation (Cp95 intubation) was reported to be 34.8 l21 [1], which value was about ten times higher than that in our present study. Propofol, 500 mg, as a single bolus injection, supplemented by fentanyl and intravenous lidocaine, facilitated smooth tracheal intubation in only 15% of patients, but caused coughing and/or bucking in 70% of patients [12]. These ndings suggest that smooth tracheal intubation can be attained only when a large dose of propofol is administered, but in such circumstances, there is a risk of severe hypotension. As was seen in the P group in this study (blood propofol concentration, 3.75 6 0.61 l21), propofol alone did not even allow laryngoscopy. The results of the present study suggest that the inhalation of sevourane at low concentrations, in addition to the use of propofol, permits smooth tracheal intubation, and it is not necessary to treat the small hemodynamic changes that occur before and after intubation. Previously, we reported that, for sevourane, MACEI was greater than MAC [2]. However, in the present study, the sevourane MACEI in the SP group patients, 1.73%, was close to the sevourane MAC, 1.71%, reported by Katoh and Ikeda [13]. In the present study, the sevourane MACEI in the S group patients, 3.42%, was signicantly less than the sevourane MACEI, 4.52%, previously determined without adjuvant in our department [2]. This suggests that the propofol induction dose affects MACEI even 15 min after induction. These ndings conrm that propofol is not a strong analgesic, but that it is an excellent adjuvant for tracheal intubation.
<para2>There are some limitations to this study. First, arterial blood samples for the determination of blood propofol concentration were taken after the intubation attempt, and blood propofol concentration may be inuenced by the stress of the intubation attempt. Second, blood propofol concentration was determined only in those who were responsive, and it is possible that blood propofol concentration may differ between unresponsive and responsive patients. Finally, the step size for sevourane was 0.5%, and this may have affected the nal MACEI values. However, these limitations do not seem to have affected the principal results of this study; namely, the effect of propofol on MACEI reduction.
<para2>In conclusion, propofol infusion reduced the MACEI of sevourane in patients undergoing elective surgery. Propofol used for anesthetic induction reduced MACEI even 15 min after induction. These results of this study suggest that propofol would be an excellent adjuvant to use with sevourane for tracheal intubation.
<ACK>Acknowledgments. The authors are very grateful to the staff physicians and the nursing staff in the operating room, Mito Saiseikai General Hospital, for their help and cooperation, and for the assistance of Mr. Furuya, Maruishi Pharmaceutical Company, Osaka, Japan, for his statistical analysis work.
<A>References
<REF> 1. Kazama T, Ikeda K, Morita K (1997) Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. Anesthesiology 87:213227
<REF> 2. Kimura T, Watanabe S, Asakura N, Inomata S, Okada M, Taguchi M (1994) Determination of end-tidal sevourane concentration for tracheal intubation and minimum alveolar anesthetic concentration in adults. Anesth Analg 79:378381
<REF> 3. McKeating K, Bali IM, Dundee JW (1988) The effects of thiopentone and propofol on upper airway integrity. Anaesthesia 43:638640
<REF> 4. Smith C, McEwan AI, Jhaveri R, Wilkinson M, Goodman D, Smith LR, Canada AT, Glass PS (1994) The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 81:820828
<REF> 5. Yakaitis RW, Blitt CD, Angiulo JP (1977) End-tidal halothane concentration for endotracheal intubation. Anesthesiology 47:386388
<REF> 6. Yakaitis RW, Blitt CD, Angiulo JP (1979) End-tidal enurane concentration for endotracheal intubation. Anesthesiology 50:5961
<REF> 7. Inomata S, Watanabe S, Taguchi M, Okada M (1994) End-tidal sevourane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients. Anesthesiology 80:9396
<REF> 8. Taguchi M, Watanabe S, Asakura N, Inomata S (1994) End-tidal sevourane concentrations for laryngeal mask airway insertion and for tracheal intubation in children. Anesthesiology 81:628631
<REF> 9. Strum DP, Eger EI II (1987) Partition coefcients for sevourane in human blood, saline, and olive oil. Anesth Analg 66:654656
<REF>10. Gepts E, Camu F, Cockshott D, Douglas EJ (1987) Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg 66:12561263
<REF>11. Herregods L, Rolly G, Versichelen L, Rosseel MT (1987) Propofol combined with nitrous oxide-oxygen for induction and maintenance of anaesthesia. Anaesthesia 42:360365
<REF>12. Mingus ML, Shamsi AK, Recant JF, Eisenkraft JB (1996) Propofol permits tracheal intubation but does not affect postoperative myalgias. J Clin Anesth 8:220224
<REF>13. Katoh T, Ikeda K (1987) The minimum alveolar concentra-
tion (MAC) of sevourane in humans. Anesthesiology 66:301
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<JN>J Anesth (2002) 16:3443
<PT>
<CT>Anticonvulsant effects of sevourane on amygdaloid kindling and bicuculline-induced seizures in cats: comparison with isourane
and halothane
<CA>Kohei Murao, Koh Shingu, Etsuko Miyamoto, Sakahiro Ikeda, Shin-ichi Nakao, Munehiro Masuzawa,
and Makiko Yamada
<ADD>Department of Anesthesiology, Kansai Medical University, 10-15 Fumizono-cho Moriguchi, Osaka 570-8507, Japan
<AB>Abstract
<AB>Purpose. We compared the anticonvulsant effects of sevourane with those of isourane and halothane in amygdaloid kindling and bicuculline-induced seizures in cats.
<AB>Methods. In a crossover design, the effects of 70% nitrous oxide, and 0.3, 0.6, and 1.5 minimum alveolar concentration (MAC) of volatile anesthetics were studied in ve cats in which the amygdala was electrically stimulated at the current used for establishing the kindled state. The effects of 0.6 and 1.5 MAC of volatile anesthetics were studied in another ve cats, in which 0.2 mgg21 of bicuculline was administered IV.
<AB>Results. In the amygdaloid kindling model, all four anesthetics decreased the duration of after-discharge (AD), the rise of multiunit activity in midbrain reticular formation (R-MUA), and the behavior scores compared with ndings without
anesthetics. Halothane, at 1.5 MAC, signicantly decreased the number of cats showing AD (P , 0.05). In the bicuculline-induced seizure model, all ve cats showed repetitive spikes during 1.5 MAC of sevourane, whereas only two and three cats, respectively, showed the repetitive spikes during 1.5 MAC of isourane and halothane. All three volatile anesthetics decreased the rise of R-MUA, the duration of the repetitive spikes, and the behavior scores. The suppression
of the rise in R-MUA and the behavior scores with 1.5 MAC of sevourane was signicantly less than that with 1.5 MAC of isourane.
<AB>Conclusion. The anticonvulsant effects of sevourane were less potent than those of halothane in the amygdaloid kindling model and less potent than those of isourane in the bicuculline-induced seizure model.
<KW>Key words Amygdaloid kindling Bicuculline Halothane Isourane Sevourane
<A>Introduction
<para1>General anesthetics generally have anticonvulsant
effects, and a few volatile anesthetics also have proconvulsant effects [1,2]. The proconvulsant properties of enurane are well known, and its proconvulsant effects may counteract its anticonvulsant effects. However, Oshima et al. [3] showed that enurane signicantly depressed seizure in three different feline epileptic models, and they indicated that enurane could be used in patients with epileptic disorders. Sevourane is widely used, and has neurophysiological properties similar to those of enurane. Seizure shown on electroencephalograms (EEGs) can be induced by peripheral somatic stimulation performed in cats under sevourane anesthesia [4]. Further, there are a few case reports of the intraoperative occurrence of seizure under sevourane anesthesia [5,6]. Although Oshima et al. [3] showed enuranes anticonvulsant effects, they did not compare these effects of enurane with the anticonvulsant effects of other volatile anesthetics. Therefore, it is not clear whether the anticonvulsant effects of enurane or sevourane are less potent than those of other anesthetics.
<para2>We previously compared the anticonvulsant effects
of halothane, isourane, and sevourane on lidocaine- and penicillin-induced seizures in cats [7,8]. Sevourane and isourane showed more potent anticonvulsant
effects than halothane in lidocaine-induced seizure [7], whereas sevourane and halothane showed less potent effects than isourane in penicillin-induced seizure [8]. Therefore, the potency of anticonvulsant effects can be different when different epileptogenesis is involved, and anesthetics should be selected according to the type of epileptogenesis in the patient. The anticonvulsant effects of volatile anesthetics may not be mediated via an action that is common to different anesthetic agents. General anesthetics have many effects on the central nervous system (CNS), in which neuronal activities
are modulated by divergent neurotransmitters and neuromodulators. Different anesthetics would exert their anticonvulsant effects, mediating these divergent neuronal networks, in different ways.
<para2>In the present study, we compared the anticonvulsant effects of sevourane with those of isourane and halothane on another epileptic model, amygdaloid kindling, in cats; we also compared the anticonvulsant effects of these three anesthetics on bicuculline-induced seizures. Penicillin and bicuculline are antagonists of
aminobutyric acid (GABA)A receptors [9]. Volatile anesthetics potentiate GABAA receptor activities [10]. Therefore, the stimulatory effects of volatile anesthetics on GABAA receptors may explain the suppression of seizure induced by GABAA antagonists. The amygdaloid kindling model of epilepsy is used as a tool for investigating the mechanisms of epilepsy and the efciency of various anticonvulsant drugs, as well as being used as a model of complex partial epilepsy [11]. We selected these models of epilepsy, because these models are similar to those used in the study of Oshima et al. [3], and we could compare the anticonvulsant effects of sevourane with those of enurane, as well as those of isourane and halothane.
<A>Materials and methods
<para1>After our institutional committee on animal research had approved the study, we studied ten cats, each weighing 2.54.0 kg.
<B>Chronic placement of electrodes
<para1>Each animal was anesthetized by placing it in a 50-l plastic container that was lled with 5% sevourane in oxygen. Once the animal had lost consciousness, a catheter was inserted into the cephalic vein, and the trachea was intubated after the administration of 1 mg vecuronium IV; each cat was placed in the supine position, and anesthesia was maintained with 3.5% sevourane in oxygen. The lungs were mechanically ventilated using a nonrebreathing ventilator (Acoma Animal Respirator, AR-300; Acoma, Tokyo, Japan). A rectal thermistor was inserted, and the rectal temperature was maintained at 37C39C, using a warm-water mattress and a heating lamp. The animal was then placed on a stereotaxic apparatus. Stainless steel screws, 2.0 mm in diameter, were inserted in the frontal bone of the skull (reference electrode) and over the parietal and occipital cortex to record the cortical electroencephalogram (EEG). Parallel stainless steel wire electrodes (0.2 mm in diameter), which were insulated with epoxylite resin, except at the tips, with a vertical separation of 0.51.0 mm at the tips, were inserted in the bilateral midbrain reticular formation (A2; L3; H-2, according to the atlas of Snider and Niemer [12]) to record the reticular multi-unit activity (R-MUA). Wire electrodes of the same type were inserted into the bilateral dorsal hippocampus (A2; L8; H9) and the medial amygdala (A12; L9; H-6). The electrodes were connected to a socket that was xed to the skull with dental cement. The sevourane supply was turned off, and the cat was awakened. The experiment was done at least 1 week later. During the experiment, the socket was connected to the recording devices, and an electric stimulator, with a bundle of exible cables of 1.2 m length, was used to allow for the free movement of the animals.
<B>Administration of test anesthetics
<para1>To study the effects of 70% nitrous oxide, and 0.3 and 0.6 minimum alveolar concentration (MAC) of the volatile anesthetics, each cat was placed in a 50-l plastic container into which the study anesthetic gas in oxygen was delivered at 10 lin21. The inspired concentration of each anesthetic in the box was measured by placing the sampling port of an infrared anesthetic gas monitor (Capnomac Ultima, Datex, Finland) near the animals mouth. The anesthetic gas monitor was calibrated on each experimental day. To study the effects of 1.5 MAC of anesthetic agents, the cat was initially placed in the plastic container, which was lled with 2 MAC of the test agent, and a laryngeal mask airway was inserted
for deepening anesthesia [13], then the trachea was
intubated; no muscle relaxant was used. The lungs
were mechanically ventilated, using the nonrebreathing ventilator. The inspired concentrations of the test anesthetic and the end-tidal partial pressure of carbon
dioxide (ETCO2) under mechanical ventilation were measured, using the anesthetic gas monitor, and the ETCO2 was maintained at 3035 mmHg. The rectal temperature was maintained at 37C39C. One MAC was dened as 2.6% for sevourane [14], 1.6% for isourane, and 1.2% for halothane [15].
<B>Recording of CNS electrical activities
<para1>The cortical and subcortical EEGs were recorded on
an eight-channel polygraph (Nihon-Koden polygraph, AB621G; Nihon-Koden, Tokyo, Japan), and the reticular multiunit activity (R-MUA) was recorded on a straight writing oscillograph (Nihon-Koden; WT685G). The ring of a population of reticular neurons was measured using a MUA technique described previously [16]. In brief, the neuronal ring between the two active points of electrodes was obtained, amplied, and then sent to a high-pass lter. Because neuronal rings are high-frequency activities, the obtained signal was rectied and smoothed with an electronic circuit with a smoothing time constant of 50 ms and was expressed by the oscillation of dc voltage: the higher the dc level, the greater the ring of a population of units. The R-MUA level was measured as the height of the lower limit of the trace from the dc level obtained by input short instead of the animal. Neuronal discharges were picked up from an area of approximately 1 mm radius around the tip of the electrode. The R-MUA level was expressed as the percentage of that observed during the nonanesthetized state in each animal.
<B>Establishment of kindling model
<para1>Amygdaloid kindling was established, as described by Oshima et al. [3], in ve cats. Electric stimulation of 60 Hz and 1-s duration was given daily through either side of the amygdaloid electrodes, using a constant current stimulator (SEN 3301; Nihon-Koden) and an isolating unit (SS-104J; Nihon-Koden). On the rst day, the initial stimulating current was set at 200 and the current was increased by 50 every 15 min until local after-discharge was induced in the contralateral amygdaloid EEG (Fig. 1A). This current, which produced the local after-discharge in the contralateral amygdala, was used thereafter. From the second experimental day, the amygdala was stimulated once a day. This daily stimulation of the amygdala induced an after-discharge that initially developed in the contralateral amygdala and was propagated to the dorsal hippocampus (Fig. 1B) and then to the cerebral cortex, to form
a generalized seizure (Fig. 1C). The behavior also changed with the propagation of the after-discharge, and was scored according to seven stages of convulsion: no change (stage 0), unilateral facial twitching ipsilateral to the stimulation (stage 1), bilateral facial twitching (stage 2), head nodding (state 3), contralateral head turning with tonic extension of contralateral forepaw and circling (stage 4), generalized clonic jerking (stage 5), and, nally, generalized convulsion (stage 6). We dened that the so-called kindled state was established when this generalization of the after-discharge and convulsion were induced consistently on successive 5-day trials [3].
<B>Amygdaloid kindling model
<para1>Five kindled cats were used for comparing the anticonvulsant effects of 70% nitrous oxide, and 0.3, 0.6, and 1.5 MAC of sevourane, isourane, and halothane. After exposure to the test anesthetic agent for 30 min, the electrical stimulus was applied to the amygdala. The control response to stimulation was obtained during inhalation of room air. Anticonvulsant effects of the anesthetics were evaluated by the number of cats showing after-discharge, the duration of the after-discharge, the rise of R-MUA after stimulation, and the behavior of the animal, scored according to the seven stages of convulsion, as outlined for the process of establishing the kindling model. Each cat was tested to study the effects of 70% nitrous oxide and the three different concentrations of each of the three test anesthetics in a randomized, cross-over design with an interval of at least 7 days between each study.
<B>Bicuculline-induced seizure
<para1>In another ve cats with chronically implanted brain electrodes, we studied the effects of 0.6 and 1.5 MAC of the three anesthetics on a bicuculline-induced seizure. Each animal was anesthetized with 3% of sevourane, and a catheter was inserted in the cephalic vein. Sevourane was discontinued. One h later, full recovery from anesthesia was conrmed by CNS electric activities and behavior. A bicuculline solution, of 0.4 mgl21, was made each day by dissolving this agent in normal saline; the pH of the solution was adjusted to 5.3. A control response to intravenous bicuculline, 0.2 mgg21, was obtained during the inhalation of room air. For the study of the volatile anesthetics, the animal was exposed to the test agent for 30 min, and bicuculline, 0.2 mgg21, was administered IV. The anticonvulsant effects of the anesthetics were evaluated according to the number of cats showing repetitive spikes on the EEG after the injection of bicuculline, the duration of the repetitive spikes on the EEG, the rise of R-MUA after the administration of bicuculline, and the behavior of the animal. The behavior of the animal was scored as one of four stages: no change (stage 0), twitching (stage 1), convulsion restricted to the paws (stage 2), and generalized convulsion (stage 3). Each animal was used for studying the effects of the test anesthetics at two different concentrations, in a randomized, cross-over design with an interval of at least 7 days between each study.
<B>Correlations between EEG, R-MUA, and
behavior scores
<para1>Correlations between the maximum level of R-
MUA after electrical stimulation or bicuculline injection, EEG patterns, and behavior scores were
investigated.
<B>Statistical analysis [17]
<para1>The values are presented as means 6 SDs, except for the behavior scores, which are presented as medians and ranges. The spontaneous levels of R-MUA, rise
in R-MUA after stimulation, and duration of after-
discharge or repetitive spikes were tested with repeated measures analysis of variance (ANOVA), followed by the Newman-Keuls test. The occurrence of after-
discharge or repetitive spikes was tested by contingency table analysis. Behavior scores were tested using the Kruskal-Wallis test. Correlations between the rise of R-MUA and the behavior score were studied using Spearmans rank correlation. Differences were considered statistically signicant at P , 0.05.
<A>Results
<B>Amygdaloid kindled model
<para1>The kindling process was completed at 25 to 36 days (mean, 28 days). The duration of after-discharge ranged from 58 to 111 s (88 6 21 s) and the maximum level of R-MUA during after-discharge was 391 6 93% of that of the pre-stimulation period in the kindled state.
<para2>Before electrical stimulation, nitrous oxide did not alter the R-MUA level, whereas all volatile anesthetics depressed it (Table 1). The depression of R-MUA by sevourane and isourane was signicantly greater than that by halothane at 1.5 MAC (P , 0.05).
<para2>All test anesthetics suppressed the seizure in the amygdaloid kindled cats (Table 1). Although electrical stimulation induced the after-discharge in all cats with 70% nitrous oxide and 0.3 MAC of the volatile anesthetics, the after-discharge was not induced in several cats with 0.6 or 1.5 MAC of the volatile anesthetics,
and it was induced in only one cat with 1.5 MAC of halothane (P , 0.05). Both the duration of the after-discharge and the R-MUA rise after stimulation
were suppressed by all the anesthetics (P , 0.05). However, this suppression was not dose-dependent, and
no signicant difference between agents was shown. The behavior scores were also suppressed, and no convulsive behavior was observed (score 0) with 0.6 MAC of isourane or with 1.5 MAC of any of the volatile anesthetics in any cats (Table 1). Representative changes in EEGs and R-MUA induced by 1.5 MAC of each of the volatile anesthetics in same cat are shown in Fig. 2.
<B>Bicuculline-induced seizure model
<para1>Bicuculline induced repetitive spikes (seizures) on the EEG and a generalized convulsion (behavior score, 3) in all cats in the control state. The duration of seizure on the EEG was 283 6 42 s, and the maximum level of R-MUA after bicuculline administration was 436 6 155% of the pre-bicuculline level.
<para2>All the anesthetics signicantly suppressed the pre-bicuculline level of R-MUA (Table 2). At 0.6 MAC, there was no signicant difference in the effects between anesthetics, whereas at 1.5 MAC, sevourane and isourane depressed the R-MUA to a greater extent than halothane (P , 0.05).
<para2>All the anesthetics signicantly suppressed the bicuculline-induced seizure (Table 2). Bicuculline failed to induce seizure in several cats under anesthesia, except for that with 1.5 MAC sevourane. During the inhalation of 1.5 MAC sevourane, repetitive spikes appeared in all cats after the injection of bicuculline. In cats in which repetitive spikes did not appear, sporadic spikes were induced. Representative traces of EEGs and R-MUA in one cat during the inhalation of different anesthetics are shown in Fig. 3. The duration
of repetitive spikes was signicantly shortened by all anesthetics (P , 0.001); there was no signicant difference between the anesthetics. The R-MUA rise
after bicuculline was signicantly suppressed by all
anesthetics, and the suppression during inhalation of
1.5 MAC sevourane was less than that with 1.5
MAC isourane (P , 0.05). All anesthetics suppressed the behavior scores, and isouranes suppression at
1.5 MAC was greater than that of sevourane and
halothane.
<B>Correlations between EEG, R-MUA, and
behavior scores
<para1>The correlation between the maximum R-MUA and behavior scores is shown in Fig. 4. The behavior
scores were correlated with maximum R-MUA both in the amygdaloid kindling (R 5 0.888; P , 0.001) and in the bicuculline-induced seizure models (R 5 0.712; P , 0.001). In the amygdaloid kindling model, the correlation between the propagation of after-discharge on EEGs and behavior scores was the same as that shown during the process of establishing the kindling state.
In the bicuculline-induced seizure model, the follow-
ing correlations between behavior score and EEG
were shown: behavior score 0 was associated with no change or sporadic spikes on EEG; behavior score 1 was associated with sporadic spikes on EEG; and behavior score 2 or 3 was associated with repetitive spikes on EEG.
<A>Discussion
<para1>The present study showed that sevourane had anticonvulsant effects similar to those of halothane and isourane on both amygdaloid kindling and bicuculline-induced seizure models in cats. Differences between the volatile anesthetics in the anticonvulsant effects were shown in the occurrence of after-discharge in the kindling model, and in the suppression of the R-MUA rise after bicuculline, and in suppression of behavior scores in the bicuculline-induced seizure model. The most
potent anticonvulsant effects seemed to be exerted by halothane in the amygdaloid kindling model and by isourane in the bicuculline-induced seizure model.
<para2>In the amygdaloid kindling model of epilepsy, 1.5 MAC halothane had the greatest effect in decreasing the number of cats showing after-discharge. Halothane suppressed the background level of R-MUA with less potency than sevourane and isourane. This indicates that the potencies of the suppressive effect on neuronal ring in spontaneous ring and ring in response to a given stimulus are not correlated. Similar potent suppressive effects of halothane on the response capability of the brain were also shown in our prior study of responses to electrical sciatic nerve stimulation in cats [18]. Although in the present study, halothane suppressed the background EEGs and R-MUA with less potency than isourane and sevourane, in the previous study, halothane suppressed responses to electrical
sciatic nerve stimulation in terms of both R-MUA rise and arterial blood pressure, to a greater extent than isourane or sevourane [18]. In the present study,
nitrous oxide, at 70%, showed anticonvulsant effects similar to those seen with 0.3 MAC of the volatile
anesthetics. The MAC value of nitrous oxide in cats is reported to be 225% [19]. This indicates that the
anticonvulsant effects of nitrous oxide have a potency similar to those of volatile anesthetics in this epileptic model in cats.
<para2>In the bicuculline-induced seizure model, while increasing concentrations of isourane and halothane
decreased the number of cats showing repetitive spikes after bicuculline injection, all cats showed repetitive spikes after the injection of bicuculline during the inhalation of 1.5 MAC sevourane, and the suppression of the R-MUA rise after bicuculline during the inhalation of 1.5 MAC sevourane was less than that seen with isourane. These ndings indicate that sevourane has a proconvulsant effect, which partially masks the anticonvulsant effects. This result is consistent with
our previous report of the proconvulsant effects of large concentrations of sevourane in cats [4]. Isourane
also induced spontaneous sporadic spikes on EEGs
in cats [18,20], but it did not induce photic stimulation-induced spikes on EEG nor did it augment the photic stimulation-evoked potential in the visual cortex [20].
Therefore, sevourane, but not isourane, has a proconvulsant effect, and its proconvulsant effect may mask the anticonvulsant effects in this model of epilepsy. The potencies of the anticonvulsant effects of
the three anesthetics tested in the present study on
the bicuculline-induced seizure model were consistent with those in status epilepticus in cats induced by penicillin [8], which is also an antagonist for GABAA receptors. Although volatile anesthetics enhance GABAA receptor activities [10], we could not nd any report
that compared the enhancing potencies of halothane, isourane, and sevourane. Therefore, we could not investigate any correlation between the potency of the anticonvulsant effects and the potency of the GABAA receptor enhancing effects of volatile anesthetics.
<para2>Oshima et al. [3] demonstrated the anticonvulsant effects of enurane on penicillin- and bicuculline-
induced seizure models and an amygdaloid kindling model in cats. Enurane depressed seizures, even at
a convulsive dose (3.5%). However, the anticonvulsant effects on the amygdaloid kindling models were biphasic, and 1.5% enurane showed more potent
anticonvulsant effects than 3.5% enurane. The potency of the anticonvulsant effects of 1.5% enurane
in the study of Oshima et al. [3] were similar to the anticonvulsant effects of 0.6 MAC of sevourane in
our study, whereas 3.5% enurane in their study
was less potent than 1.5 MAC of sevourane in ours. These results suggest that 3.5% enurane produces a more potent proconvulsive effect (and counteracts the anticonvulsant effects) than 1.5 MAC sevourane. In fact, in another study, seizure was induced in all cats during deep enurane anesthesia, but in only 2 of 11 during sevourane anesthesia, with the augmenting
effects of sevourane on the somato-evoked potential being less than those of enurane [4]. Therefore, the proconvulsant effects of 1.5 MAC sevourane are less than those of 3.5% enurane, and the anticonvulsant effects of sevourane are greater than those of enurane.
<para2>In our study, the behavior scores were correlated
with the maximum levels of R-MUA (the level before electrical stimulation or bicuculline plus the rise in
R-MUA) in both seizure models. Anesthetics may suppress behavior not only by their effects on brain activities but also by suppressing motor systems. Although volatile anesthetics suppress activities in spinal motoneurons [2124], the present study showed that brain activities recorded by R-MUA correlated with behavior scores. Therefore, the neuronal ring level in the brain may be a major factor in affecting the behavior scores during convulsion. However, in the present study, we could not rule out the possibility that ascending volleys caused by muscle contraction could have affected the
R-MUA.
<para2>The present study was performed with animals under spontaneous respiration for the investigation of the effects of nitrous oxide and the effects of 0.3 and 0.6 MAC of volatile anesthetics, while the effects of 1.5 MAC of the volatile anesthetics were studied in animals under mechanical ventilation. Anesthetic suppression of respiration during 0.3 and 0.6 MAC may induce hypercapnia during spontaneous respiration, and hypercapnia has anticonvulsant effects [25]. Therefore, it is possible that, in our study, the anticonvulsant actions of the lower concentrations of volatile anesthetics, and these actions of nitrous oxide could have been overestimated, because hypercapnia could have been involved in these effects.
<para2>We investigated the effects of nitrous oxide in the amygdaloid kindling model, but not in the bicuculline-induced seizure model. In the amygdaloid kindling model, nitrous oxide showed an anticonvulsant potency similar to that of the volatile anesthetics. However, we can not conclude that our ndings on the anticon-vulsant potency of nitrous oxide would apply to other
seizure models, because nitrous oxide has recently been reported to have anti N-methyl-d-aspartate (NMDA)
receptor properties [26], which could affect its anticonvulsant effects in different seizure models. The anticonvulsant properties of nitrous oxide should be investigated in future studies.
<para2>The present study indicates that any of the three volatile anesthetics that we tested, including sevourane, can be used as anticonvulsants in patients with epileptic disorders. However, the proconvulsant effects of a large concentration of sevourane may partially counteract its anticonvulsant effects; the proconvulsant effects of sevourane are less potent than those of enurane and its counteracting effects may also be less potent than those of enurane.
<para2>In conclusion, sevourane has potent anticonvulsant effects in amygdaloid kindling and bicuculline-induced seizure models in cats. The anticonvulsant effects of sevourane were less potent than those of halothane in the amygdaloid kindling model and less potent than those of isourane in the bicuculline-induced seizure model.
<ACK>Acknowledgements. Supported in part by a Grant-in-Aid
for Scientic Research (no. 08457415) from the Ministry of Education, Science, and Culture of Japan.
<A>References
<REF> 1. Modica PA, Tempelhoff R, White PF (1990) Pro- and anticonvulsant effects of anesthetics (part I). Anesth Analg 70:303315
<REF> 2. Modica PA, Tempelhoff R, White PF (1990) Pro- and anti-
convulsant effects of anesthetics (part II). Anesth Analg 70:433
444
<REF> 3. Oshima E, Urabe N, Shingu K, Mori K (1985) Anticonvulsant actions of enurane on epilepsy model in cats. Anesthesiology 63:2940
<REF> 4. Osawa M, Shingu K, Murakawa M, Adachi T, Kurata J, Seo N, Murayama T, Nakao S, Mori K (1994) Effects of sevourane on central nervous system electrical activity in cats. Anesth Analg 79:5257
<REF> 5. Woodforth IJ, Hicks RG, Crawford MR, Stephen JPH, Burke DJ (1997) Electroencephalographic evidence of seizure activity under deep sevourane anesthesia in a nonepileptic patient. Anesthesiology 87:15791582
<REF> 6. Komatsu H, Taie S, Endo S, Fukuda K, Ueki M, Nogaya J, Ogli
K (1994) Electrical seizures during sevourane anesthesia in two pediatric patients with epilepsy. Anesthesiology 81:15351537
<REF> 7. Murao K, Shingu K, Tsushima K, Takahira K, Ikeda S, Nakao S (2000) The anticonvulsant effects of volatile anesthetics on lidocaine-induced seizure in cats. Anesth Analg 90:148155
<REF> 8. Murao K, Shingu K, Tsushima K, Takahira K, Ikeda S, Matsumoto H, Nakao S, Asai T (2000) The anticonvulsant effects of volatile anesthetics on penicillin-induced status epilepticus in cats. Anesth Analg 90:142147
<REF> 9. Antoniadis A, Mler WE, Wollert U (1980) Inhibition of GABA and bezodiazepine receptor binding by penicillins. Neurosci Lett 18:309312
<REF>10. Franks NP, Lieb WR (1994) Molecular and cellular mechanisms of general anesthesia. Nature 367:607614
<REF>11. McNamara JO, Bonhaus DW, Shin C (1993) The kindling model of epilepsy. In: Schwartzkroin PA (ed), Epilepsy: models, mechanisms, and concepts. Cambridge University Press, Cambridge, pp 2747
<REF>12. Snider RS, Niemer WT (1961) A stereotaxic atlas of the cat brain. Chicago, University of Chicago Press
<REF>13. Asai T, Murao K, Katoh T, Shingu K (1998) Use of the laryn-
geal mask airway in laboratory cats. Anesthesiology 88:1680
1682
<REF>14. Doi M, Yunoki H, Ikeda K (1988) The minimum alveolar concentration of sevourane in cats. J Anesth 2:113114
<REF>15. Drummond JC, Todd MM, Shapiro HM (1983) Minimum alveolar concentrations for halothane, enurane, and isourane in cat. J Am Vet Med Assoc 182:10991101
<REF>16. Mori K, Kawamata M, Mitani H, Yamazaki Y, Fujita M (1971) A neurophysiologic study of ketamine anesthesia in the cat. Anesthesiology 35:373383
<REF>17. Zar JH (1974) Biostatistical analysis. Prentice-Hall, Englewood Cliffs, NJ.
<REF>18. Tsushima K, Shingu K, Ikeda S, Kimura H, Yamada K, Murao K (1998) Suppressive actions of volatile anesthetics on the response capability in cats. Can J Anaesth 45:240245
<REF>19. Steffey EP, Gillespie JR, Berry JD, Eger II EI, Munson ES (1974) Anesthetic potency (MAC) of nitrous oxide in the dog, cat, and stump-tail monkey. J Appl Physiol 36:530532
<REF>20. Ogawa T, Shingu K, Shibata M, Osawa M, Mori K (1992) The divergent actions of volatile anesthetics on background neuronal activity and reactive capability in the central nervous system in cats. Can J Anaesth 39:862872
<REF>21. Rampil IJ (1994) Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 80:606610
<REF>22. Rampil IJ, King BS (1996) Volatile anesthetics depress spinal motor neurons. Anesthesiology 85:129134
<REF>23. Zhou HH, Mehta M, Leis AA (1997) Spinal cord motoneuron excitability during isourane and nitrous oxide anesthesia. Anesthesiology 86:302307
<REF>24. Antognini JF, Carstens E, Tabo E, Buzin V (1998) Effect of differential delivery of isourane to head and torso on lumbar dorsal horn activity. Anesthesiology 88:10551061
<REF>25. Crawford CD, Butler P, Froese A (1987) Arterial PaO2 and PaCO2 inuence seizure duration in dogs receiving electroconvulsive therapy. Can J Anaesth 34:437441
<REF>26. Jevtovic-Todorovic V, Todorovic SM, Mennerrick S, Powell S, Dilranian K, Benshoff N, Zorumski CF, Olney JW (1998) Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nature Medicine 4:460463

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<JN>J Anesth (2002) 16:4450
<PT>
<CT>Comparison between sevourane and isourane anesthesia in pig hepatic ischemia-reperfusion injury
<CA>Hiroshi Ishida1, Yoshitami Kadota1, Teruko Sameshima1, Atsushi Nishiyama1, Toshiyuki Oda2,
and Yuichi Kanmura1
<ADD>1 Department of Anesthesiology and Critical Care Medicine, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka,
Kagoshima 890-8520, Japan
<ADD>2 Department of Anesthesiology, Shonan Kamakura General Hospital, 1202-1 Yamasaki, Kamakura 247-0066, Japan
<AB>Abstract
<AB>Purpose. Sevourane and isourane have been reported to exert protective effects against ischemia-reperfusion injury (IRI) in various organs. To compare the effect of sevourane anesthesia on liver IRI with that of isourane anesthesia, we performed the present study in pigs.
<AB>Methods. Nineteen pigs were assigned to either the sevourane (n 5 9) or the isourane group (n 5 10). Hepatic warm ischemia was produced by 30-min hepatic artery and portal vein clamping beginning 90 min after the start of the inhalation anesthesia; this was followed by a 240-min reperfusion. To extend our evaluation, we evaluated the degree of IRI using various parameters (plasma glutathione-S-transferase [GST], lipid peroxide, and lactate concentrations), in addition to the conventionally used liver damage markers.
<AB>Results. The lactate level was signicantly higher under isourane than under sevourane at 120 min after reperfusion (4.0 6 0.4 mmol21 vs 2.5 6 0.3 mmol21; P , 0.05). How-
ever, this difference had disappeared after 240 min of reperfusion. No signicant differences between the two groups were observed in values for GST, lipid peroxides, aspartate aminotransferase, alanine aminotransferase, or
lactic dehydrogenase.
<AB>Conclusion. The extent of the hepatic IRI seen under sevourane anesthesia in pigs did not differ signicantly from that seen under isourane, as judged from measurements of a number of parameters over a 240-min reperfusion period.
<KW>Key words Ischemia-reperfusion injury (IRI) Sevourane Isourane GST Lipid peroxide
<A>Introduction
<para1>Intraoperative temporary interruption of liver blood ow sometimes occurs during various surgical procedures, including resection of hepatic tumor, repair of hepatic trauma, liver transplantation, and thoracic aortic surgery. This hepatic ischemia and the subsequent reperfusion can lead to liver dysfunction or severe hepatic failure, depending on the severity and duration of the ischemia. For some years, data have been accumulating from in vivo and in vitro experiments suggesting that inhalation anesthetics, including commonly used modern agents such as sevourane and isourane, exert protective effects against ischemia-reperfusion injury (IRI) in various organs [19]. In the liver, both isourane and sevourane are reported to protect against hepatic IRI in vitro [3]. However, Preckel et al. [5] and Schlack et al. [6] suggested that sevourane has more prominent protective effects than isourane on myocardial reperfusion injury (in vivo and in vitro investigations, respectively).
<para2>To our knowledge, no in vivo study has yet been done to compare the inuence of sevourane anesthesia
on liver IRI with that of isourane. In this study, we compared sevourane and isourane in terms of liver IRI in pigs. For this study, we used certain additional parameters besides the conventionally used liver damage markers to extend our evaluation of the injury. These parameters were: (1) plasma glutathione-S-
transferase (GST) concentration, (2) plasma lipid peroxide concentration, and (3) plasma lactate concentration. The plasma GST concentration provides a very sensitive index of liver damage [10,11], and the measurement of lipid peroxides has been used both to reveal the existence of oxidative stress, which is one of the mechanisms underlying IRI, and to enable the
inhibitory effect of anesthetics on this stress to be
evaluated [12,13].
<A>Materials and methods
<para1>The study was conducted following guidelines laid down by the Animal Care Committee of Kagoshima University School of Medicine. Nineteen male pigs (specic pathogen-free [SPF], weighing 2028 kg) were used.
<B>Surgical preparation
<para1>The pigs were anesthetized with ketamine 400 mg and atropine 0.5 mg, administered intramuscularly; a 24-gauge catheter was inserted into the ear vein, and tracheal intubation was performed. During the surgical preparation, including the catheterization and laparotomy, anesthesia and muscle paralysis were maintained with a continuous infusion of ketamine 20 mgg2121 and pancuronium 0.4 mgg2121, with local anesthesia achieved using 0.5% lidocaine. When needed (e.g.,
if there was an abrupt rise in arterial blood pressure
and heart rate), intravenous ketamine (50100 mg) was given to maintain adequate anesthesia during surgery. One catheter (Medicut-UK-II; outer diameter [OD], 16 G; length, 70 cm; Japan Sherwood, Tokyo, Japan) was inserted into the jugular vein for the administration of drugs and maintenance uids; another was inserted into the common carotid artery for blood sampling and measurement of arterial blood pressure. The liver was exposed via a midline incision, and both the hepatic artery and the portal vein were isolated. Ventilation was controlled to maintain PaCO2 and PaO2 at 35 6 5 mmHg and over 150 mmHg, respectively, using 40%50% oxygen in nitrogen (total ow, 56 l). During the experiment, acetated Ringers solution, containing 3% glucose, was infused via the venous catheter at a rate of 35 mlg2121. Arterial pressure and electrocardiogram were monitored, and body temperature, measured
with a thermistor probe inserted rectally, was kept
at 38 6 1C. The pigs were randomly assigned to
the sevourane group (n 5 9) or the isourane group
(n 5 10).
<B>Experimental protocol
<para1>After the surgical preparation, we allowed a no-
treatment time of 30 min for stabilization after the stress inherent in the surgery. After this stabilization period, there was a period of baseline inhalation anesthesia (90 min), during which there was no experimental intervention, such as hepatic warm ischemia. In newborn swine (12 weeks), the reported values for the 1.0 minimum alveolar concentration (MAC) of sevourane and isourane are 2.12% and 1.4%, respectively [14]. Our animals were anesthetized using these 1.0 MAC values (that is, sevourane 2.1% end-tidal concentration or isourane 1.4% end-tidal concentration) for the duration of the experiment. Hepatic warm ischemia was produced by 30-min clamping of the hepatic artery and portal vein beginning 90 min after the start of the inhalation anesthesia; this was followed by a 240-min period of reperfusion. The end-tidal concentration of sevourane or isourane was determined by infrared spectroscopy (Icorn Anesthetics Agent Monitor, Mera, Tokyo, Japan).
<B>Blood analysis
<para1>For the measurement of the liver enzymes GST,
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH), together with plasma lactate and lipid peroxides, and arterial blood gases, arterial blood samples (18 ml) were withdrawn before and at 90, 120, 122, 150, 180, 240, and 360 min after the start of the period of inhalation anesthesia. The anesthetic concentration in whole blood and the hemodynamic parameters were measured before and at 30, 60, 90, 100, 110, 120, 122, 135, 150, 165, 180, 240, and 360 min after the start of the inhalation anesthesia. Each blood sample was replaced with an equal volume of heparin-saline. The blood samples were centrifuged immediately, and the plasma was separated. The plasma for the measurement of GST, lactate, and lipid peroxide was stored at 280C until analysis. The GST concentration in plasma was measured using a Biotrin Hepkit-Alpha, Biotrin, Dublin, Ireland for
porcine GST (which is based on an enzyme immunoassay). The detection limit was 0.69 21. The intra- and interassay coefcients of variation were 1.83%5.69% and 4.02%11.0%, respectively. AST, ALT, and LDH activities in plasma were measured using a TBA-80FR self-analyzer (Toshiba, Tokyo, Japan). The lactate concentration in whole blood was measured by enzymatic analysis [15]. Lipid peroxides were evaluated by measuring malondialdehyde (end metabolite), with the plasma malondialdehyde concentration measured according to the method of Nielsen et al. [16], using high-performance liquid chromatography (HPLC). The
detection limit was 0.1 . The interassay coefcient
of variation was 3.50%. Arterial blood gases were
measured using a Stat prole 4 (Nova Biomedical,
Tokyo, Japan). The concentrations of sevourane and
isourane in whole blood were assayed by gas chromatography [17].
<B>Statistical analysis
<para1>Statistical analysis was performed using Stat-View
4.5 (Abacus Concepts, Berkeley, CA, USA). All data values are expressed as means 6 SE. One-way analysis of variance (ANOVA) for repeated measurements, followed by a post-hoc Fishers test, was used to compare values obtained from a given group at different times. For between-group comparisons, two-way ANOVA was performed. When signicant differences were
detected by ANOVA, a post-hoc Schefftest was used. Body weight was analyzed using one-way ANOVA. Statistical signicance was assumed at P values , 0.05.
<A>Results
<para1>No signicant difference in body weight was observed between the two groups (sevourane, 23.3 6 1.0 kg; isourane, 23.5 6 0.7 kg). Throughout the experiment, the blood concentration of each anesthetic was maintained at a level not signicantly different from that measured at 30 min after the start of the period of anesthesia (Table 1).
<para2>The GST concentration reached a maximum in both groups at 120 min after reperfusion (sevourane, 15.9 6 5.4 21; isourane, 10.2 6 3.3 21). Despite the tendency for a greater GST level in the sevourane group than in the isourane group from the start of reperfusion to 120 min after its start, no signicant difference was observed between the two groups over the entire experimental period (Fig. 1).
<para2>The lipid peroxide level rose to a maximum at 2 min after reperfusion and remained signicantly higher than the preischemia level until 60 min of reperfusion in both groups. No signicant differences were observed between the two groups in terms of lipid peroxide levels (Fig. 1).
<para2>In both groups, the plasma lactate level reached a maximum at 2 min after reperfusion and remained signicantly higher than the preischemia level until 60 min into the period of reperfusion. The lactate level was signicantly higher in the isourane group than in the sevourane group at only one sampling point: at 120 min into the reperfusion (Fig. 1).
<para2>No signicant differences were observed between the two groups in terms of AST, ALT, or LDH levels (Fig. 2). The AST level rose after reperfusion, and it showed a signicant elevation above the preischemia level at both 120 min and 240 min after the reperfusion in both groups. ALT increased signicantly in the isourane group, but not in the sevourane group at 240 min after the reperfusion. In each group, the LDH level was raised signicantly only at the sampling point at 2 min after reperfusion. There were no signicant differences between the two groups in terms of arterial blood gas analysis or hemodynamic changes after the start of
inhalation anesthesia (Table 1).
<A>Discussion
<para1>In the present study, we compared the degree of liver IRI between sevourane and isourane anesthesia using the following variables. (1) The plasma levels of the liver enzymes AST, ALT, LDH, and GST were measured. GST is primarily located in the centrilobular hepatocytes [10], which are considered to receive blood that is poorer in both oxygen and nutrients than the periportal hepatocytes, in which AST and ALT are mainly distributed. The half-life of GST in plasma is less than 90 min, which is considerably shorter than the half-lives of AST and ALT [10]. Therefore, GST is considered to be a more sensitive marker of acute hepatic damage and its recovery than either AST or ALT [10,11]. (2) Plasma lipid peroxides were measured both to evaluate oxidative stress, which is one of the underlying mechanisms for IRI, and to enable the inhibitory effect of anesthetics on this stress to be evaluated [12,13]. Oxygen radicals, which cause cell damage via lipid peroxidation, are considered to be generated
during liver ischemia-reperfusion [18,19]. (3) Plasma lactate was measured because this indicates not only
the degree of IRI (regional and systemic) but also the metabolic activity of the liver [20].
<para1>From the present experiments, the following conclusions can be drawn. (1) Liver damage in the periportal and centrilobular regions did not differ signicantly
between the two anesthetics over the time course of the experiment. Based on the GST level, the damage in the centrilobular region was recovered at 240 min after reperfusion in both groups, and the degree of recovery in the sevourane group was the same as that in the isourane group. (2) The degree of systemic lipid peroxidation after liver ischemia-reperfusion did not differ between the two groups. (3) The regional and systemic damage during and after liver ischemia-reperfusion, as shown by the peak plasma lactate concentration, did not differ between the two groups. The recovery in lactate metabolism after liver ischemia-reperfusion was somewhat faster in the sevourane group than in the isourane group. However, after 240 min of reperfusion, this difference between the two groups had disappeared, suggesting that the recovery in liver metabolic activity is not different between the two anesthetics over a 240-min period of reperfusion.
<para2>The above results showed that the liver IRI after
a 240-min reperfusion was not signicantly different between the two groups, suggesting that whether sevourane or isourane is chosen for surgery that involves a temporary interruption of the hepatic blood supply may not make a signicant difference in the early phase (240 min) of reperfusion.
<para2>Inhalation anesthetics have been shown to exert protective effects against IRI in various organs, including the heart [5,6,9], brain [7], lung [8], and liver [14]. Possible explanations for these protective effects of inhalation anesthetics [21] and the preservation of ATP levels during ischemia, reduced adhesion of polymorphonuclear neutrophils, increased nitric oxide production, inhibition of free radical production, or a reduction in calcium overloading. Both isourane [22] and sevourane [23] have been reported to mimic ischemia preconditioning effects in the heart, suggesting that the preischemic administration of these anesthetics may be protective against IRI. Imai et al. [3] showed that the reduction in IRI, assessed by measuring LDH release, was greater when isourane was administered during the reperfusion than when it was administered during the ischemia. This suggests that inhaled anesthetic administration is more important during the reperfusion phase than during the ischemic phase in terms of providing a protective effect against such injury. In the present experiment, we administered both agents before, during, and after the ischemic phase. Hence, our data suggest that the effects of sevourane on liver IRI throughout these three phases may be almost the same as the effects of isourane.
<para2>Although many in vivo and in vitro studies have suggested that inhalation anesthetics exert protective effects against IRI in various organs [19], few studies have compared the protective effects of isourane and sevourane. Imai et al. [3] reported that isourane and sevourane exerted protective effects of similar magnitude against IRI in a perfused rat liver model. Heindl
et al. [9] showed that both sevourane and isourane reduced the adhesion of polymorphonuclear neutrophils in the reperfused coronary system, and thereby helped to preserve cardiac function; the effects of these two agents were not signicantly different from each other. However, Preckel et al. [5] and Schlack et al. [6] both suggested that sevourane had more prominent protective effects than isourane on myocardial reperfusion injury (in vivo and in vitro investigations, respectively). In our in vivo experiment, the absence of a signicant difference between sevourane and isourane in terms of liver IRI at 240 min after reperfusion indicates that the two agents may have similar effects
on this injury. This conclusion is consistent with that obtained with a perfused rat liver in vitro [3].
<para2>Our experimental model has the following experimental limitations. (1) We assessed the extent of liver IRI by measuring various parameters in the 240 min after reperfusion. Hence, we cannot comment on
the inuence of the two anesthetics against IRI in the longer term. (2) Our main aim was to compare the effect of sevourane anesthesia on liver IRI with that of isourane anesthesia. For this reason, we did not create a control or reference group, such as an intravenous anesthetic group. Further detailed study will be necessary to clarify the full extent of the protective effect of the two inhalation anesthetics against liver IRI. (3) Our study revealed specically that the effects of 1.0 MAC sevourane anesthesia against liver IRI did not differ from those of 1.0 MAC isourane anesthesia in a 30-min hepatic ischemia model. However, for an understanding of the effects of the two anesthetics on liver IRI, we need to perform additional experiments using not only different concentrations of these anesthetics but different degrees of IRI. (4) To judge from the changes in GST level, the liver damage in the centrilobular regions after reperfusion was not signicantly different between the two anesthetics. However, we did observe a tendency for a higher GST level in the sevourane group than in the isourane group from 2 min after reperfusion to 120 min after its start. Because the sample size for the GST measurements was relatively small compared with those for the other parameters, we checked for a type II error ( in the GST measurements. The values calculated for the time points from 2 min after reperfusion to 120 min after its start were between 0.44 and 0.53, indicating that our sample size for the GST measurements was too small to allow denite conclusions to be reached in regard to liver damage in the centrilobular region. Consequently, we will need to do further experiments to clarify whether the damage in the centrilobular regions after reperfusion differs between the two anesthetics. (5) In this experiment, we did not actively treat conditions such as hypotension, hyperkalemia, and severe acidosis, which are observed during and after liver ischemia-reperfusion, all of which may have exacerbated the injury. Treatment of these conditions with appropriate uid and drug therapy may have reduced the hepatic IRI in our experiment. For this reason, the extent of the injury in the present experiment may differ from that experienced clinically.
<para2>In conclusion, the extent of hepatic IRI seen under sevourane anesthesia in pigs did not differ signicantly from that seen under isourane, when judged from a number of parameters over a 240-min reperfusion period in vivo. Further study will be necessary to assess more fully the inuence of these two anesthetics on such injury.
<ACK>Acknowledgments. The authors thank Dr. Etsurou Nagata, Ms. Masumi Inada, and Ms. Junko Miyao for their assistance in these experiments; and Dr. Robert Timms for his helpful advice on this manuscript.
<A>References
<REF> 1. Nagano K, Gelman S, Parks D, Bradley EL Jr (1990) Hepatic circulation and oxygen supply-uptake relationships after hepatic ischemia insult during anesthesia with volatile anesthetics and fentanyl in miniature pigs. Anesth Analg 70:5362
<REF> 2. Samuta T, Becker GL, Pohorecki R, Armstrong K, Landers DF (1993) Effect of isourane dose, duration of anoxia, and reoxygenation on isouranes preservation of energy balance in anoxic isolated hepatocytes. Anesth Analg 77:3843
<REF> 3. Imai M, Kon S, Inaba H (1996) Effects of halothane, isourane and sevourane on ischemia-reperfusion injury in the perfused liver of fasted rats. Acta Anaesthesiol Scand 40:12421248
<REF> 4. Kon S, Imai M, Inaba H (1997) Isourane attenuates early
neutrophil-independent hypoxia-reoxygenation injuries in the reperfused liver in fasted rats. Anesthesiology 86:128136
<REF> 5. Preckel B, Schlack W, Comfe T, Obal D, Barthel H, Ther V (1998) Effects of enurane, isourane, sevourane and desurane on reperfusion injury after regional myocardial ischemia in the rabbit heart in vivo. Br J Anaesth 81:905912
<REF> 6. Schlack W, Preckel B, Stunneck D, Ther V (1998) Effects of halothane, enurane, isourane, sevourane and desurane on myocardial reperfusion injury in the isolated rat heart. Br J Anaesth 81:913919
<REF> 7. Soonthon-Brant V, Patel PM, Drummond JC, Cole DJ, Kelly PJ, Watson M (1999) Fentanyl does not increase brain injury after focal cerebral ischemia in rats. Anesth Analg 88:4955
<REF> 8. Liu R, Ishibe Y, Ueda M, Hang Y (1999) Isourane administration before ischemia and during reperfusion attenuates ischemia/reperfusion-induced injury of isolated rabbit lungs. Anesth Analg 89:561565
<REF> 9. Heindl B, Reichle FM, Zahler S, Conzen PF, Becker BF (1999) Sevourane and isourane protect the reperfused guinea pig heart by reducing post ischemic adhesion of polymorphonuclear neutrophils. Anesthesiology 91:521530
<REF>10. Hayes PC, Bouchier IAD, Beckett GJ (1991) Glutathione S-transferase in humans in health and disease. Gut 32:813818
<REF>11. Van Wagensveld BA, Scheepers JJG, Gulik TM, Frederiks
WM, Bleeker WK, Obertop H, Gouma DJ (1997) Alpha glutathione S-transferase as novel parameter for hepatocellular damage in the isolated perfused rat liver. Transplant Proc 29:3449
3451
<REF>12. Kahraman S, KilinK, Dal D, Erdem K (1997) Propofol
attenuates formation of lipid peroxides in tourniquet-induced
ischaemia-reperfusion injury. Br J Anaesth 78:279281
<REF>13. De La Cruz JP, Sende G, Carmona JA, Sanchez de la Cuesta F (1998) The in vitro effects of propofol on tissular oxidative stress in the rat. Anesth Analg 87:11411146
<REF>14. Lerman J, Oyston JP, Gallagher TM, Miyasaka K, Volgyesi GA, Burrows FA (1990) The minimum alveolar concentration (MAC) and hemodynamic effects of halothane, isourane, and sevourane in newborn swine. Anesthesiology 73:717721
<REF>15. Gutmann I, Wahlefeld AW (1974) l-(1)-Lactate: determination with lactate dehydrogenase and NAD. In: Bergmeyer HU (ed) Methods in enzymatic analysis, vol 3. Verlag Chemie Weinheim and Academic Press, New York, pp 14651468
<REF>16. Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P (1997) Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clin Chem 43:12091214
<REF>17. Miller MS, Gandol AJ (1979) A rapid, sensitive method for quantifying enurane in whole blood. Anesthesiology 51:542544
<REF>18. Kurokawa T, Nonami T, Harada A, Nakao A, Takagi H (1996) Mechanism and prevention of ischemia-reperfusion injury of the liver. Semin Surg Oncol 12:179182
<REF>19. Jaeschke H (1998) Mechanisms of reperfusion injury after warm ischemia of the liver. J Hepatobiliary Pancreat Surg 5:402408
<REF>20. Nielsen VG, Tan S, Kirk KA, Baird MS, McCammon AT, Samuelson PN, Parks DA (1997) Halothane and xanthine oxidase increase hepatocellular enzyme release and circulating lactate
after ischemia-reperfusion in rabbits. Anesthesiology 87:908917
<REF>21. Ross S, Fo P (1999) Protective effects of anaesthetics in reversible and irreversible ischemia-reperfusion injury. Br J Anaesth 82:622632
<REF>22. Cason BA, Gamperl AK, Slocum RE, Hickey RF (1997)
Anesthetic-induced preconditioning. Previous administration of isourane decreases myocardial infarct size in rabbits. Anesthesiology 87:11821190
<REF>23. Novalija E, Fujita S, Kampine JP, Stowe DF (1999) Sevourane mimics ischemic preconditioning effects on coronary ow and nitric oxide release in isolated heart. Anesthesiology 91:701712

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<JN>J Anesth (2002) 16:5164
<PT>Review article
<CT>Anesthesia and the gastrointestinal tract
<CA>Alexander Ng and Graham Smith
<ADD>University Department of Anaesthesia, Critical Care and Pain Management, Leicester Royal Inrmary, Leicester LE1 5WW,
United Kingdom
<KW>Key words Gastrointestinal tract PONV
<A>Introduction
<para1>In this article, we have briey reviewed areas relating to the gastrointestinal (GI) tract of interest to the anesthesiologist; they include gastroesophageal reux and aspiration of gastric contents, postoperative nausea and vomiting (PONV), gastrointestinal ileus, and intestinal anastomotic leakages. These areas represent major causes of morbidity and delay in recovery from anesthesia and surgery. In addition, we have briey described the use of the GI tract for the purpose of drug administration in the perioperative period.
<para2>The subjects of regurgitation and aspiration have recently been reviewed by us in some detail [1]: so these areas are summarized only briey.
<A>Gastroesophageal reux and aspiration of gastric contents
<B>Incidence of aspiration and mortality attributable
to aspiration
<para1>The incidence of aspiration has remained relatively low over the past three decades. Data from several studies have shown that the incidence varies between 0.7 and 10.2 per 10 000 general anesthetics [28]. Over this same period, mortality attributable to aspiration during general anesthesia varied between 3.8% [9], 4.5% [3], and 4.6% [2].
<para2>In obstetric practice, however, mortality attributable to aspiration has declined over time. The triennial reports of the Condential Enquiry into Maternal Deaths in the United Kingdom have demonstrated that mortality attributable to aspiration has decreased from 52% to 65% 50 years ago, to 0% to 12% in the last 10 years [10]. Over the same period, there has been an increase in the total number of anesthetics administered, as a result of increasing instrumental rates and deliveries by cesarean section [10]. Therefore, the reduction in the proportion of anesthetic deaths is likely to be have been related not only to general improvements in anesthetic training and skills over time, but, more importantly, to the progressive move away from general anesthesia to epidural and spinal anesthesia.
<B>Anesthetic management of gastroesophageal reux and aspiration of gastric contents
<para1>Anesthetic management of gastroesophageal reux and aspiration of gastric contents requires the consideration of factors that predispose to aspiration pneumonitis and also methods to minimize regurgitation and aspiration (Table 1).
<C>Factors that predispose to aspiration pneumonitis
<E>Gastric contents. Gastric contents that are considered to increase the risk of aspiration pneumonitis are a pH less than 2.5 and gastric volume of 0.4 mlg21 and a composition comprising milk. While there is controversy over the minimum critical gastric volume [1113] above which the risk of aspiration pneumonitis is increased, there is concordance from animal studies that a very low pH (less than 1) [14], and breast milk or a dairy formula [15], predispose to an increased severity of aspiration pneumonitis compared with less acidic contents or a soya-based milk [16].
<E>Lower esophageal sphincter (LES) tone. Reduction in tone of the lower esophageal sphincter is an important physiological mechanism for reux of gastric contents. The factor which inhibits regurgitation is the barrier pressure, i.e., the difference between gastric pressure and LES pressure. During anesthesia, it has been
shown that LES pressure and also barrier are decreased by induction agents (thiopental), inhalation agents
(halothane and enurane), opioids, and anticholinergic drugs (glycopyrrolate, atropine) [1].
<E>Upper esophageal sphincter (UES) tone. UES tone is also reduced by induction agents (thiopental) [17], sedative agents [17], and muscle relaxants (succinylcholine [18], atracurium, pancuronium, and vecuronium [1922]).
<para2>However, the risk of aspiration depends not only on UES tone but also on coordination between the pharyngeal muscles and the UES during swallowing. It has been possible to study the deleterious effect of partial neuromuscular blockade on aspiration using video manometry. These studies have been conducted in healthy volunteers, and the extent of neuromuscular blockade adjusted according to the train-of-four (TOF) pattern of adductor pollicis during supramaximal stimulation of the ulnar nerve. Signicant delay in relaxation of the UES following contraction of the inferior constrictor muscle begins to occur at a TOF of 0.7 with atracurium [21] and 0.60 with vecuronium [20]. In 28%, 17%, 20%, and 13% of volunteers receiving atracurium, pharyngeal muscle dysfunction occurred at a TOF of 0.60, 0.70, 0.80 and $0.90, respectively. Of these swallows with pharyngeal dysfunction, 80% were misdirected, with contrast medium reaching the level of the vocal cords [21]. Although pharyngeal muscle dysfunction was demonstrated in patients given atracurium but not vecuronium, misdirected swallows still occurred in 6
of 14 volunteers at various levels of blockade with vecuronium [20]. These studies suggest that, even with clinically adequate neuromuscular transmission, conscious patients in the recovery room may still be at risk of aspiration.
<C>Protective airway reexes. Airway reexes are impaired by premedication with diazepam [23], by advancing age [24], and by incremental doses of fentanyl [25], in addition to progressively increasing depth of anesthesia. Loss of these reexes during anesthesia increases the risk of aspiration pneumonitis.
<C>Methods to minimize regurgitation and aspiration
<C>Methods to minimize regurgitation and aspiration
involve control of gastric contents, application of cricoid pressure, and control of the airway.
<E>Control of gastric contents and application of cricoid pressure. Preoperative starvation is a universal method for controlling gastric contents. Studies on gastric emptying demonstrate that clear uids, breast milk, non-human milk, and solids are emptied at correspondingly slower rates. From these studies involving paracetamol absorption [2632], electrical impedance tomography [3335], radiolabelled diet [32,34,3639] ultrasonography [4043], aspiration of gastric contents under direct vision with a gastroscope, polyethylene glycol dilution and blind aspiration of gastric contents, it is generally held that the preoperative starvation time should be 2 h for clear uids, 4 h for breast milk, and 6 h for nonhuman milk and solids [44].
<para2>Gastric emptying has been shown to be inhibited by atropine [45] and opioids [46], but facilitated by erythromycin [47], cisapride [48], and metoclopramide
[49]. The presence of a nasogastric tube may impair UES and LES tone [50], leading to gastroesophageal reux [51]. However, there is evidence from two cadaver studies that the efcacy of cricoid pressure is not diminished by the presence of a nasogastric tube [5253].
<para2>Evidence from clinical trials clearly shows that H2 antagonists and proton pump inhibitors (PPIs) are two drug groups that may signicantly lower gastric acidity [5456] and, hence, reduce the risk of aspiration pneumonitis. However, there is no available evidence to
support their routine use, probably because of the low incidence of aspiration and multiplicity of factors that are linked to this complication.
<para2>To minimize the passage of gastric contents through the esophagus, use of a nasogastric tube with an inatable balloon to occlude the gastric cardia has been
effective in a study involving pigs [57]. Application of cricoid pressure, however, is more usual in anesthetic practice, despite the lack of good evidence to demonstrate that it has reduced the incidence of aspiration or mortality. Recent studies have criticized cricoid pressure because of its effect in lowering LES tone [58], possible cricoid occlusion and vocal cord closure at a pressure of 44 N [59], occurrence of retching if applied too early [60], incorrect direction of application causing impaired laryngoscopy [61], variability in perceived force of application [62], and unsustainable force of application over time [63].
<C>Control of the airway. During general anesthesia,
an unobstructed airway is of paramount importance; this issue was highlighted by the Australian Incident Monitoring Study [9], in which the difcult airway was considered to predispose to regurgitation, vomiting, and aspiration.
<para2>Although tracheal intubation is considered to be the standard method for airway protection during general anesthesia, recent studies have challenged this view. The main issues are: rstly, whether tracheal intubation is effective; and secondly, whether aspiration is a problem if tracheal intubation is avoided. Clinical trials in the intensive care setting [64,65] have clearly demonstrated that high-volume, low-pressure cuffs do not
prevent passage of methylene blue between the longitudinal folds. In addition, a case series of patients anesthetized without tracheal intubation in the peripartum period did not show an increased incidence of aspiration [7]. There was one case of mild aspiration among 1870 patients anesthetized for obstetric procedures, except for cesarean sections.
<para2>The standard laryngeal mask airway (LMA) has been evaluated extensively in clinical trials. It appears to reduce barrier pressure [66] and, while promoting gastroesophageal reux of acid to the lower esophageal level, seems to spare the upper esophageal level [6769]. The ProSeal LMA (PLMA) is a recent modication of the standard LMA [70]. It has an esophageal vent that allows the passage of a nasogastric tube. Although this device allows the stomach to be emptied, it remains to be seen whether it will play an important role in minimizing the risk of aspiration pneumonitis.
<para2>The esophageal-tracheal combitube (ETC) is a double-lumen tube with a high-volume, low-pressure tracheoesophageal distal cuff and a proximal pharyngeal balloon. The ETC may protect against the risk of aspiration and has been given a role in the American Society of Anesthiologists (ASA) practice guidelines for the management of the difcult airway [71]. Complications of its use, such as esphageal lacerations, subcutaneous emphysema [72], sore throat, hematoma, and dysphagia, appear to have been related to blind insertions rather than insertions under direct vision [73,74].
<A>Postoperative nausea and vomiting (PONV)
<B>Clinical trials
<para1>Evidence on the outcome of different treatments
for PONV has been collated in quantitative systematic reviews (meta-analysis) of many double-blind randomized controlled trials (RCTs). Although these systematic reviews represent Level One Evidence, some assessment of the treatment effects of the individual trials must be made before a decision is made on whether the pooled results are valid. Overall, the applications of quantitative systematic reviews, as well as their limitations, have been discussed extensively in a recent article by Choi and Jadad [75].
<para2>Trials that have had event rates of 20% to 60% for early PONV (0 to 6 h) and 40% to 80% for late PONV (0 to 48 h) have been included in some systematic reviews, excluding studies with extreme values that were not deemed to reect the overall clinical situation. Treatment effect in many of these reviews has been quantied in terms of relative benet, relative risk, or odds ratio and also as absolute risk reduction. The relative benet, relative risk, or odds ratio allows a relative comparison of the outcome of one treatment over another, but does not take into account the magnitude of the problem. However, the absolute risk reduction does take into account the importance of the treatment effect, providing the clinician with more information from which to decide whether the treatment is worth administering. The reciprocal of the absolute risk reduction gives the term number needed to treat (NNT). The NNT is the number of patients who have to be treated to obtain one additional favorable outcome [76]. More efcacious treatments have a low NNT, while less useful treatments have a high NNT. All treatments have adverse effects, and in a similar way to the above consideration of benets, number needed to harm (NNH) can be obtained from the reciprocal of absolute risk increase.
<B>Factors that inuence the occurrence of PONV
<para1>PONV is more common in females and in patients
with a previous history of PONV or motion sickness.
It appears to be associated with strabismus surgery, adenotonsillectomy, orchidopexy, and prolonged surgery. Other factors predisposing to its occurrence are the use of etomidate, opioids, and pancuronium, and the use of atropine and neostigmine [77]. Propofol,
on the other hand, has the opposite effect, and in a systematic review of 84 RCTs involving 6069 patients, its effect on early and late PONV was assessed [78]. When used for maintenance instead of inhalation agents, propofol had an NNT (95% condence interval [CI]) of 4.9 (3.7 to 7.1), and 7.1 (3.4 to ) for early and late PONV, respectively, suggesting that any antiemetic advantage is short lived. Propofol used solely for induction did not confer an advantage over other intravenous agents. In a reassessment [79] of a systematic review of RCTs in which use of nitrous oxide was assessed [80], it was shown that omission of nitrous oxide had benecial effects on early (NNT 4.8 (3.6 to 7.3)) and late vomiting (NNT 5.6 (3.9 to 10)), but not early (NNT 9.1 (4.1 to )) or late nausea (NNT (80)).
<B>Methods to prevent and treat PONV
<para1>A management plan for the prevention of PONV has been summarized in Table 2. Techniques to minimize PONV may be classied into two categories, pharmacological agents and nonpharmacological methods. Studies on readily available pharmacological agents have compared the use of single agents versus placebo;
combination of agents versus single agents; and administration of an antiemetic with an opioid via a patient-
controlled analgesic device. In addition, data have been available concerning the possible antiemetic effect of 80% inspired oxygen compared with 30% [81]. In this RCT, oxygen was given intraoperatively and for the rst 2 h postoperative in patients undergoing colorectal surgery, and it has been found that the higher oxygen concentration had an antiemetic effect.
<C>Neurokinin (NK)-1 receptor antagonists
<C>NK-1 antagonists are thought to act by blocking the effect of substance P on NK-1 receptors [82]. For the prevention of PONV, evidence from a double-blind RCT of females listed for abdominal hysterectomy demonstrated that 100 mg or 200 mg of oral CP122721, administered 60 to 90 min preoperatively, was more effective than placebo for prevention of PONV within 8 h and 72 h into the postoperative period [83]. Within the rst 8 h, the higher dose of this NK-1 antagonist was more effective than the lower dose (the incidences of PONV being 10% and 33%, respectively). This benet was not demonstrable within 72 h. It is possible that further clinical studies may reveal a role for NK-1 antagonists in patients at high risk of PONV.
<C>5HT3 antagonists
<C>Although several 5HT3 antagonists have been evaluated, ondansetron has been studied most extensively. The efcacy of ondansetron has been assessed for both the prophylaxis and treatment of PONV. In a meta-analysis of 53 placebo-controlled RCTs involving 7177 patients, 24 different ondansetron regimens were evaluated [84] for the prevention of PONV. Although a broad range of NNTs were obtained, ondansetron showed treatment benet (NNT 5 to 6) at 8 mg i.v. and 16 mg orally, for prevention of early and late PONV. In addition, there was a signicant increased risk of elevated liver enzymes (NNH of 31) and headache (NNH of 36).
<para2>The issue of whether ondansetron is effective in preventing PONV in high-risk patients has been addressed. In a meta-analysis of RCTs, ondansetron 4 mg and 8 mg i.v. showed increased effectiveness for prevention of PONV in patients with motion sickness compared
with patients without this history [85]. The pooled odds ratios (95% CI) were 2.07 (1.692.52) and 2.19 (1.53.19) for the two respective doses. In another meta-analysis comparing patients with and without a previous history of PONV, there was no signicant difference in the effectiveness of ondansetron for vomiting within the rst 24 h postoperatively, at 4 mg i.v. [86]. There was a trend to effectiveness at 8 mg i.v., but this effect was not statistically signicant.
<para2>Ondansetron has been compared against other individual antiemetic drugs in addition to placebo. In a meta-analysis [87] of 23 RCTs with 3863 patients
comparing ondansetron with droperidol, and 19 RCTs of 2502 patients comparing ondansetron with metoclopramide, the pooled odds ratio (95% CI) for preven-tion of vomiting were 0.70 (0.52 to 0.94) and 0.43 (0.31 to 0.61), respectively. The corresponding odds ratios (95% CI) for prevention of nausea were 0.99 (0.66 to 1.47) and 0.70 (0.45 to 1.10), demonstrating that ondansetron was signicantly more effective than either droperidol or metoclopramide in preventing vomiting, but not nausea. Doses of all drugs varied: ondansetron
4 to 8 mg, and 0.10 mgg21 to 0.15 mgg21; droperidol 0.625 mg to 2.5 mg, and 20 g21 to 75 g21; metoclopramide 10 mg, and 0.25 mgg21 to 0.5 mgg21. This mixed effectiveness of ondansetron over droperidol contrasts with another quantitative systematic review, in which data in adults from 20 RCTs showed that the odds ratio (95% CI) was 0.56 (0.41 to 0.76) and NNT (95% CI) was 12 (7.32) in favor of ondansetron over droperidol. Data on doses used were not available for assessment [88].
<para2>The role of ondansetron lies not only in the prevention of PONV but also in the treatment of established PONV. In a quantitative systematic review [89] of seven RCTs, it was shown that intravenous ondansetron was effective compared with placebo for the treatment of established early and late PONV. For the treatment of early PONV, the NNT values (95% CI) were 3.8 (2.6 to 6.6), 3.2 (2.3 to 5.2), and 3.1 (2.4 to 4.5) with 1, 4, and 8 mg of ondansetron, respectively. The respective NNT values at the corresponding doses for the treatment of established late PONV were 4.8 (3.5 to 7.9), 3.9 (3.0 to 5.7), and 4.1 (3.1 to 6.2). Thus, at doses used clinically there is no additional benet in using higher doses of ondansetron for the treatment of established PONV. These results contrast with the situation in which ondansetron was used for the prophylaxis of PONV, when increased effectiveness was demonstrated at higher doses.
<C>Dexamethasone
<C>Dexamethasone, in doses of 8 mg to 10 mg, and 1 to 1.5 mgg21, has been evaluated in a quantitative systematic review [90]. Results from 15 placebo-controlled trials show that dexamethasone was effective for the prevention of early and late PONV. The NNT values (95% CI) for the prevention of early and late vomiting were 7.1 (4.5 to 18) and 3.8 (2.9 to 5.0), respectively, in data from children and adults. Data for nausea were available in adults but not children. The NNT values for early and late nausea were 5.0 (221 to 2.2) and 4.3 (2.3 to 26). Analysis of other trials in this review showed that antiemetics, such as ondansetron 4 mg i.v., granise-
tron 3 mg i.v., and perphenazine 70 g21 were more effective than dexamethasone for the prevention of PONV.
<para2>Other issues with dexamethasone concern the dose and timing of administration. In a double-blind placebo-controlled RCT of females undergoing thyroidectomy it was found that the minimum effective dose for the prevention of PONV was dexamethasone 5 mg i.v., given at induction of anesthesia [91]. Furthermore, in an RCT of 120 females undergoing hysterectomy, 10 mg of dexamethasone, given after induction anesthesia, signicantly reduced the incidence of PONV within the rst 2 h postoperatively, compared with administration at the end of the procedure, and rescue antiemetic consumption was signicantly reduced [92].
<C>Droperidol
<C>Droperidol is a butyrophenone that may cause dose-dependent sedation and drowsiness. Therefore, the main issue with its use concerns the minimum dose required to prevent PONV. In a systematic review [93], it was shown that 0.5 mg to 0.75 mg of droperidol was sufcient to prevent early nausea and that at least 1 mg to 1.25 mg was required for late nausea, in adults. For early vomiting, at least 1 mg to 1.25 mg i.v. of droperidol was required, compared with a lower dose of 0.5 mg to 0.75 mg i.v. for late vomiting, in adults. In children, there was a dose-dependent effect for early and late vomiting, and the relative risk was clearly in favor of droperidol compared with placebo, at doses of 50 g21 to 75 g21 compared with 10 g21 to 20 g21.
<C>Metoclopramide
<C>Metoclopramide is an antagonist at central dopaminergic receptors, central and peripheral 5HT3 receptors, and peripheral 5HT4 receptors. In a systematic review of 66 randomized placebo-controlled trials
involving 6266 patients, no antiemetic effect was
detected within 6 h postoperatively and at 48 h [94]. In adults, doses varied from 5 mg to 35 mg via i.v., i.m.,
oral and intranasal routes. In children, the doses were 0.1 mgg21 to 0.5 mgg21, given i.v. in all but one trial. Adverse reactions, such as extrapyramidal symptoms, sedation, drowsiness, dizziness, vertigo, and head-
ache were uncommon, even at higher doses of metoclopramide.
<C>Combination antiemetic therapy
<C>Combination antiemetic therapy or balanced antiemesis [95] is another technique that some investigators have been studying for the prevention of PONV. Combinations of a 5HT3 receptor antagonist (ondansetron 4 mg; granisetron 3 mg, or 20 g21 to 40 g21) with either dexamethasone 8 mg [90] or cyclizine 50 mg i.v. [96] have been shown to exhibit
increased effectiveness compared with the individual 5HT3 antagonist. Pueyo et al. [97] compared a combination of intravenous ondansetron 4 mg and droperidol 3.75 mg with ondansetron 4 mg, and found increased effectiveness, although Bugedo et al. [98] found no
advantages in a combination of ondansetron 4 mg
and droperidol 2.5 mg compared with ondansetron 4 mg. In a meta-analysis of RCTs, combinations of droperidol and a 5HT3 antagonist did not have any signicant advantages compared with individual agents [99].
<para2>Combination antiemetic therapy for PONV involving the administration of 200 mg of the oral NK-1 antagonist, CP1222721, and 4 mg i.v. of ondansetron has been compared with the individual drugs in a double-blind RCT [83]. There was a signicant improvement in
the median emesis-free time for 75% of patients in the
combination group compared with the ndings in the patients receiving CP1222721 or ondansetron separately. While there was no signicant difference in nausea scores between the three groups within 8 and 24 h. The incidence of emesis within 24 h was signicantly less with the combination compared with ondansetron but not with CP1222721. Another NK-1 antagonist has been assessed recently in patients receiving chemotherapy. The addition of the NK-1 antagonist, L754030, 300 to 400 mg, to granisetron 10 g21 i.v. and dexamethasone 20 mg orally was found to produce signicant antiemetic benets [100].
<para2>In summary, it appears that combination therapy involving the addition of some agents, such as dexamethasone, cyclizine, or an NK1 antagonist, to a 5HT3 antagonist provides additional prophylaxis against PONV compared with the individual 5HT3 antagonist.
<C>Prophylactic antiemetics during PCA opioids
<C>The effectiveness of administering an antiemetic to an opioid via a PCA device has been assessed in a quantitative systematic review of 14 eligible RCTs of 1117 patients [101]. Morphine was used in all but one RCT. Of the various antiemetic agents, such as hyoscine, propofol, metoclopramide, clonidine, promethazine, droperidol, ondansetron, and tropisetron, the most
frequently used were the latter three drugs. Although droperidol, with an NNT (95% CI) of 2.8 (2.1 to 3.9), was effective for the prevention of PONV, no dose-response effect could be identied. Ondansetron and tropisetron were administered in various doses, and both drugs were found to be effective for the prevention of PONV. Their respective NNTs (95% CI) were 2.9 (2.1 to 4.7) and 4.7 (3.0 to 11).
<C>Acupuncture
<C>The effect of the stimulation of the P6 acupuncture point on PONV was assessed in a meta-analysis of 19 RCTs involving 1679 patients undergoing tonsillectomy, laparoscopy, cesarean section, and gynecological and general surgery [102]. The acupuncture varied in terms of the type used, and its method, timing, and duration of administration. Manual acupuncture, electroacupuncture, transcutaneous electrical stimulation, and acupressure to P6 were given preoperatively, intraoperatively, and postoperatively, depending on the trial. In addition, the duration of treatment varied from 5 min to 7 days. It was found that this nonpharmacological technique had signicant benet compared with no treatment or sham treatment in adults for preventing nausea and vomiting, within 6 h. For early nausea, therefore, the relative risk (RR) (95% CI) was 0.34 (0.20 to 0.58) with an NNT (95% CI) of 4 (3 to 6). For early vomiting, the RR was 0.47 (0.340.64) and the NNT was 5 (48). There was no treatment benet
for late vomiting (048 h) in adults, or for early and
late vomiting in children. In seven trials within this meta-analysis, stimulation of P6 and antiemetics (metoclopramide, cyclizine, droperidol) were compared, and it was found that there was no signicant difference between these techniques in the prevention of early and late vomiting in adults.
<B>Scoring systems
<para1>In making a decision on whether to provide therapy to prevent the occurrence of PONV, assessment of factors that predict its occurrence is required. An ideal scoring system would be highly discriminative for all types of patients undergoing all forms of surgery, in any hospital, and be easy to apply. Some scoring systems have identied predictive factors by logistic regression analysis, and, to use such forms of evaluation, the physician must take into account the different weighting of each factor [103]. However, a simplied scoring, based on four
risk factors of equal weighting, has been evaluated in orthopedic, ophthalmic, otolaryngological, and general surgical patients. These factors comprised: female sex, history of motion sickness or PONV, nonsmoking, and use of intraoperative opioids. The ability of this scoring system to discriminate between patients who would and would not have PONV has been quantied by the area under the receiver operator curve, a plot of the true-positive rate against the false-positive rate. For a variety of operations, it was found that, in the presence of none, one, two, three, and four risk factors, the incidence of PONV was 10%, 21%, 39%, 61%, and 79% respectively [104]. In making a decision on whether to administer medication for the prevention of PONV, the use of
such a simple scoring system would be helpful to the anesthesiologist.
<A>Postoperative gastrointestinal motility
<para1>Ileus is a common problem occurring after major surgery and is caused by lack of motility of the left side of the colon. Its occurrence can delay the absorption of enteral nutrition and drugs, in addition to causing abdominal distension, patient discomfort, and prolonged hospital stay. Factors that have been shown to inhibit gastrointestinal motility include sympathetic reexes and also receptor agonists, nitric oxide, substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, and corticotrophin-releasing factor [105]. There is experimental evidence in rats that k opioid receptor agonists reverse the inhibition of gastrointestinal transit, in a dose-dependent fashion [106]. However, the administration of metoclopramide, cisapride, [107] and erythromycin [108] has not been found to be effective for the treatment of postoperative ileus.
<para2>Inhalation agents [77] and opioids [109] used in the intraoperative period for abdominal surgery cause a reduction in gastrointestinal motility. In addition, the type of analgesia employed in the postoperative period is a critical factor that affects the return of normal gastrointestinal motility. In current anesthetic practice, the main options available for providing postoperative analgesia for major abdominal surgery are systemic opioids and epidural analgesia. In a review of 16 studies, of which 10 were RCTs, it has been clearly demonstrated that return of gastrointestinal motility occurred earlier in patients who had epidural analgesia compared with ndings in those who had systemic opioids [110]. In these studies, a variety of end points were used, such as time to rst bowel sounds, time to rst passing of atus or feces, transit time of radio-opaque markers, and barium transit time. In addition, in three RCTs, it was found that return of gastrointestinal motility was delayed in patients receiving thoracic epidural morphine compared with ndings in those receiving thoracic epidural bupivacaine for postoperative analgesia [110]. It
is believed that the effectiveness of thoracic epidurals occurs because of blockade of inhibitory thoracolumbar sympathetic efferents, allowing unopposed parasympathetic activity via craniosacral efferents. In addition, there is blockade of nociceptive afferent neural impulses, decreased levels of endogenous circulating catecholamines, and a reduction in the administration of opioids. Despite some lack of evidence for efcacy in postoperative ileus [111], it is currently believed that epidural analgesia should be used as part of a multimodal care pathway of early nutrition, early mobilization [112], and minimally invasive surgery that facilitates postoperative recovery and minimizes morbidity and duration of hospital stay [113]. In addition there is clinical evidence that postoperative ileus following colorectal resection may be minimized by laparoscopic techniques compared with conventional surgery [114].
<A>Effect of postoperative analgesia on anastomotic leakage following colorectal surgery
<para1>The etiology of anastomotic leakage following colorectal surgery includes patient factors, such as
anemia and comorbidity; surgical factors, such as bowel preparation and operative expertise; and factors related to anesthesia and pain management. For anesthesiologists, the key clinical question is whether there is a relationship between postoperative analgesia and the development of anastomotic leakage. In this section, issues concerning the administration of systemic morphine vs systemic pethidine, in addition to epidural analgesia vs systemic opioid analgesia are examined.
<B>Systemic morphine vs systemic pethidine analgesia
<para1>There has been controversy on whether or not the
type of opioid used for postoperative analgesia affects the incidence of anastomotic dehiscence. Early studies [115,116], in which morphine and pethidine were administered by the i.m. route on demand, suggested that the incidence of anastomotic dehiscence was more common in patients who received morphine compared with those who received pethidine. Intravenous or intramuscular morphine has been shown to double the
frequency of colonic contractions [117] and to increase intraluminal pressure, especially in diverticular disease [118]. Pethidine, on the other hand, is associated with decreased colonic intraluminal pressure [118], and so there seems to be some theoretical grounds supporting these clinical ndings. However, in a recent trial in which equianalgesic doses of PCA morphine or PCA pethidine by the i.v. route were compared, it was found that there was no signicant difference in the incidence of anastomotic breakdown [119]. This nding may be explained on the basis that, in the earlier studies, the
use of i.m. morphine would have been associated with higher peak plasma concentrations of the drug than those occurring with the i.v. PCA method of administration, and, consequently, with this PCA method,
there may be a reduced tendency to the formation of contraction rings.
<B>Epidural analgesia vs systemic opioid analgesia
<para1>It has been speculated previously that epidural analgesia would be likely to increase the risk of anastomotic leakage following colorectal surgery, because of increased intestinal motility and intraluminal pressure, in addition to possible reduced anastomotic blood supply. This issue has been examined in a review of RCTs from 1966 to 2000, available on Medline [120]. In 11 RCTs of this review, epidural local anesthetic, with and without opioids, was compared with systemic opioids. Although the incidence of anastomotic leakage was 16/255 for epidurals compared with 9/252 for systemic opioids, there was no statistically signicant difference. In addition, data from 3 RCTs of this review comparing pure epidural opioid with epidural local anesthetic with and without an opioid did not demonstrate a signicantly increased risk of anastomotic leakage with the type of drugs administered.
<A>Alternative routes of drug administration
<para1>Gastrointestinal dysfunction impairs reliable drug absorption via the oral route, and in the immediate postoperative period after major surgery, it is mandatory to avoid oral administration of opioids for postoperative pain relief until it is clear that bowel motility has returned to normal. Otherwise, multiple doses which are not absorbed may be dumped suddenly into the upper GI tract when motility returns, leading to acute toxicity [121]. The presence of intestinal obstruction, abdominal pain, and PONV are common situations in which other methods of drug administration become necessary. In many instances, intravenous access is the standard alternative route. However, in specic situations, such as minor procedures or situations in which intravenous access can prolong hospital stay, other routes of drug administration would be highly desirable. In anesthetic practice, the administration of analgesics and sedative agents by intranasal, oral mucosal, transdermal, and rectal routes has been evaluated.
<B>Intranasal route
<para1>The nasal mucosa has a rich blood supply, allowing
rapid absorption of some drugs. For example, under optimal conditions, the administration of midazolam
via the nasal mucosa may lead to rapid and almost complete absorption. In a study of 14 adult patients
with neither rhinitis nor nasal obstruction, time (SD)
to peak arterial concentration of midazolam was 14 (2) min after the administration of midazolam 0.15 mgg21 by nasal spray. Bioavailability (SD) was 83 (15) % with minimal hydroxymidazolam concentrations, indicating minimal rst-pass metabolism from the swallowed drug [122]. However, despite these favorable pharmacokinetics, in a study of 44 children given intranasal midazolam 0.2 mgg21, Grifth et al. [123] did not recommend this route for premedication because of the unpleasant taste, and the complaints of stinging and crying.
<para2>The irritant effects observed with midazolam do not seem to occur with intranasal opioids [124]. In a recent study of patients with cancer pain it was found that intranasal fentanyl 20 , administered by spray, was tolerable and provided additional analgesia within 10 min [125]. In healthy volunteers [126], intranasal fentanyl 54 produced a maximum concentration within 5 min and a bioavailability of 71%. Although the nose is not the standard route for the administration of analgesics, there are plans to introduce a patient-controlled intranasal device [127].
<para2>Intranasal oxycodone has also been investigated recently in volunteers. It was found that with alternate sprays of 0.1 ml to each nostril, to a maximum dose of 0.1 mgg21, the values for mean time (95% CI) to peak concentration and bioavailability (95% CI) were 25(20240) min and 0.46 (0.250.67), respectively. Although oxycodone was absorbed rapidly, there were large interindividual differences, suggesting that careful titration would be required to avoid adverse effects [128].
<B>Oral mucosal route
<para1>Within the oral cavity, the sublingual and buccal mucosa are the main sites for drug absorption. Both sites are nonkeratinized, but the buccal mucosa is thicker, relatively immobile, and less permeable than the sublingual mucosa. The sublingual mucosa is relatively mobile and is constantly washed by saliva. Thus, the sublingual route would be appropriate for rapid but infrequent drug delivery, whereas the buccal route is better suited for sustained drug delivery [129].
<para2>Of the analgesic drugs administered via the buccal route, fentanyl has been studied in greatest detail. Oral transmucosal fentanyl has been advocated as a useful non-invasive method of providing analgesia for children undergoing painful procedures. In a clinical trial of 48 children receiving a lollipop of fentanyl 15 to 20 g21, Schechter et al. [130] found that pain scores were signicantly less during bone marrow aspiration or lumbar puncture performed 30 min after the lollipop was given. In another trial, in which oral transmucosal fentanyl 10 to 15 g21 was given to children aged 2 to 10 years, there was no evidence of improved cooperation at induction of anesthesia compared with the placebo group. Although patients receiving fentanyl were more sedated than those in the placebo group, there was no vomiting or desaturation in the preoperative period. From pharmacokinetic measurements, the bioavailability was 0.33 [131].
<para2>The effects of fentanyl administered via the oral transmucosal route have also been evaluated in healthy adult volunteers. With 800 of fentanyl consumed over 15 min, the median time (95% CI) to maximum concentration was approximately 24 (20 to 71) min, and the bioavailability (SE) was estimated to be 40 (11)% [132]. In addition, after three doses, at 6-h intervals, there was no evidence of signicant changes in pharmacokinetics, suggesting that alterations in drug prescribing are not required when multiple doses of transmucosal fentanyl are used [132]. Dose-proportional pharmacokinetics
are observed with oral transmucosal fentanyl, i.e., with increases in dose administered, there are proportional increases in maximum concentration, area under the concentration time curve, and adverse effects, such as respiratory depression [133].
<para2>In addition to opioids, the oral mucosal administrations of antiemetics and sedatives has been studied. Buccal prochlorperazine, at a dose of 6 mg, was found
to be effective in preventing PONV in patients receiv-ing PCA morphine after abdominal hysterectomy
[134]. In a study of buccal midazolam 10 mg in 2 ml for 5 min in adult volunteers, it was found that, although time (62 SD) to maximum venous concentration was
48 (28) min, electroencephalography (EEG) effects were evident within 5 min of administration [135]. In
a placebo-controlled RCT [136] in children (aged 12
to 129 months) of sublingual midazolam in thick
grape syrup, satisfactory sedation was evident in 52%
and 64%, 15 min after 0.5 mgg21 and 0.75 mgg21,
respectively.
<B>Transdermal route
<para1>In anesthetic practice, the transdermal route has been utilized mainly for the management of chronic pain. This route is particularly helpful for patients with cancer pain or chronic pancreatitis [137], when nausea, vomiting, and dysphagia may preclude oral drug administration. However, owing to its protective barrier functions, and variations in structure and perfusion, the skin
does present an obstacle to rapid reliable drug administration. Of all analgesics, fentanyl has been evaluated extensively and may be used to illustrate the pharmacokinetics of the transdermal route.
<para2>Transdermal therapeutic systems (TTS) of fentanyl consist of fentanyl dissolved in an enhancer of ethanol and a rate-controlling membrane of ethylene-vinyl acetate. Ethanol extracts lipids in the stratum corneum [138] and, hence, helps to achieve the target drug delivery rate. Variations in skin permeation are minimized by the rate-controlling membrane [139]. The rate of administration is proportional to the surface area of drug exposed to skin, and current patches can deliver fentanyl at rates of 25, 50, 75, and 100 21. The onset time for this route of administration is prolonged, and
is reected in the 17 to 48 h taken to reach maximum plasma concentration [140].
<para2>Age has no signicant effect on the pharmaco-
kinetics of TTS fentanyl. In a study of a transdermal patch delivering fentanyl at 50 21, for 72 h, it was found that the time to maximum plasma concentrations, elimination half-life, and area under the time concentration curve did not differ signicantly between elderly and young adults [141]. In children aged 18 to 60 months, time (SD) to reach maximum concentration was 18 (11) h with a patch designed to release fentanyl at 25 21 for 72 h. As would be expected, maximal fentanyl concentrations were higher in younger children [142].
<para2>The use of fentanyl delivered via the TTS is associated with delayed analgesic action, and the TTS is therefore unsuitable for acute pain management. However,
it has been possible to enhance transdermal administration by iontophoresis, in which the transport of an ionisable drug is facilitated by an external electric eld [143]. A PCA electrotransport therapeutic system (ETS) for fentanyl has been developed, delivering 80 boluses of 40 . Each bolus is administered over 10 min. In a clinical trial of 174 patients, it was found that ETS fentanyl seemed to provide satisfactory analgesia for acute pain after orthopedic and gynecological surgery [144].
<para2>Although TTS fentanyl has not been recommended for acute pain, transdermal ketamine has been found recently to be an effective adjuvant after abdominal gynecological surgery, when given at a rate of 25 mg per 24 h, without associated hallucinations or nightmares [145].
<B>Rectal route
<para1>Rectal drug administration is particularly useful when the oral route cannot be used. Recently, a new preparation of 30-mg morphine suppositories, given twice
daily for 5 days in patients with cancer, was reported to provide analgesia equivalent to the same oral dose [146]. In comparison with results with the oral morphine, the rectal route was associated with a higher bioavailability of morphine and lower plasma concentrations of morphine-6-glucuronide and morphine-3-glucuronide, indicating reduced rst-pass metabolism with rectal administration. Median time (range) to maximum plasma concentrations after the rectal administration of morphine was 4 (06) h.
<para2>The rectal route has been used extensively by anesthesiologists for the treatment of pain with simple
analgesics. In one study, involving children aged 9 weeks to 11 years, 25 mgg21 of paracetamol, given rectally at 6-h intervals for 5 days, was shown to be safe, with no evidence of supratherapeutic concentrations [147]. The mean time (SD) to reach maximum concentration in the rst dosing interval was 2.37 (1.10) h.
In adults, a higher single dose of rectal paracetamol,
of 40 g21, did not provide increased analgesia
compared with the lower dose of 20 g21, following vaginal or abdominal hysterectomy. Although the
maximum plasma concentration of paracetamol
was signicantly greater with the higher dose of paracetamol, there was no signicant difference in the time taken to reach this concentration. The mean times (SD) to reach maximum concentration were 4.2 (1.7) h and 3.6 (1.4) h for the higher and lower paracetamol doses, respectively [148].
<para2>Diclofenac suppositories are commonly used in acute and chronic pain management. In healthy male volunteers, it was found that 50 mg of rectal diclofenac exhibited a slightly increased bioavailability compared with that shown with the oral form. In addition, time to maximum plasma concentration for the rectal route was shorter, taking 0.62 6 0.06 h compared with 1.58 6 0.06 h for the oral route [149].
<A>Conclusion
<para1>In the perioperative period, impairment of gastrointestinal function can occur, causing increased morbidity and delayed recovery. Current evidence for the optimal management of gastroesophageal reux and aspiration of gastric contents, PONV, gastrointestinal ileus, and anastomotic leakage, as well as alternative routes of drug administration, have been discussed. Careful consideration of these factors and the application of appropriate treatments will go a long way to help our patients recover from surgery and anesthesia.
<A>References
<REF> 1. Ng A, Smith G (2001) Gastroesophageal reux and aspiration in anesthetic practice. Anesth Analg 93:494513
<REF> 2. Olsson GL, Hallen B, Hambraeus-Jonzon K (1986) Aspiration during anaesthesia: a computer-aided study of 185 358 anaesthetics. Acta Anaesthesiol Scand 30:8492
<REF> 3. Warner MA, Warner ME, Weber JG (1993) Clinical signicance of pulmonary aspiration during the perioperative period. Anesthesiology 78:5662
<REF> 4. Brimacombe JR, Berry A (1995) The incidence of aspiration associated with the laryngeal mask airway: a meta-analysis of published literature. J Clin Anesth 7:297305
<REF> 5. Mellin-Olsen J, Fastin S, Gisvold SE (1996) Routine preoperative gastric emptying is seldom indicated. A study of 85 594 anaesthetics with special focus on aspiration pneumonia. Acta Anaesthesiol Scand 40:11841188
<REF> 6. Borland LM, Sereika SM, Woelfel SK, Saitz EW, Carrillo PA, Lupin JL, Motoyama EK (1998) Pulmonary aspiration in pediatric patients during general anesthesia: incidence and outcome.
J Clin Anesth 10:95102
<REF> 7. Ezri T, Szmuk P, Stein A, Knoichezky S, Hagai T, Geva D (2000) Peripartum general anaesthesia without tracheal intubation:
incidence of aspiration pneumonia. Anaesthesia 55:421426
<REF> 8. Warner MA, Warner ME, Warner DO, Warner LO, Warner EJ (1999) Perioperative pulmonary aspiration in infants and children. Anesthesiology 90:6671
<REF> 9. Kluger MT, Short TG (1999) Aspiration during anaesthesia: a review of 133 cases from the Australian Anaesthetic Incident Monitoring Study (AIMS). Anaesthesia 54:1926
<REF> 10. Department of Health and Social Security (19571998) Deaths due to complications of anaesthesia. In: Report on condential enquiries into maternal deaths in England and Wales 19521994. Her Majestys Stationary Ofce, London
<REF> 11. Plourde G, Hardy JF (1986) Aspiration pneumonia: assessing the risk of regurgitation in the cat. Can Anaesth Soc J 33:345348
<REF> 12. Ingebo KR, Rayhorn NJ, Roxanne M, Shelton MT, Silber GH, Shub MD (1997) Sedation in children: adequacy of 2-hour fasting. J Pediatr 131:155158
<REF> 13. Schwartz DA, Connelly NR, Theroux CA, Gibson CS, Ostrom DN, Dunn SM, Hirsch BZ, Angelides AG (1998) Gastric contents in children presenting for upper endoscopy. Anesth Analg 87:757760
<REF> 14. James CF, Modell JH, Gibbs CP, Kuck EJ, Ruiz BC (1984) Pulmonary aspirationeffects of volume and pH in the rat. Anesth Analg 63:665668
<REF> 15. OHare B, Chin C, Lerman J, Endo J (1999) Acute lung injury after instillation of human breast milk into rabbits lungs. Anesthesiology 90:11121118
<REF> 16. Chin C, Lerman J, Endo J (1999) Acute lung injury after tracheal instillation of acidied soya-based or Enfalac formula or human breast milk in rabbits. Can J Anaesth 46:282286
<REF> 17. Vanner RG, Pryle BJ, ODwyer JP, Reynolds F (1992) Upper oesophageal sphincter pressure and the intravenous induction of anaesthesia. Anaesthesia 47:371375
<REF> 18. Vanner RG, Pryle BJ, ODwyer JP, Reynolds F (1992) Upper oesophageal sphincter pressure during inhalational anaesthesia. Anaesthesia 47:950954
<REF> 19. McGrath JP, McCaul C, Byrne PJ, Walsh TN, Hennessy TPJ (1996) Upper oesophageal sphincter function during general anaesthesia. Br J Surg 83:12761278
<REF> 20. Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, Kuylenstierna R (1997) Functional assessment of the pharynx at rest and during swallowing in partially paralysed humans. Anesthesiology 87:10351043
<REF> 21. Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna R, Eriksson LI (2000) The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralysed humans. Anesthesiology 92:977984
<REF> 22. Berg H (1997) Is residual neuromuscular block following pancuronium a risk factor for postoperative pulmonary complications? Acta Anaesth Scand 110:156158
<REF> 23. Murphy PJ, Langton JA, Barker P, Smith G (1993) Effect of oral diazepam on the sensitivity of upper airway reexes. Br J Anaesth 70:131
<REF> 24. Erskine RJ, Murphy PJ, Langton JA, Smith G (1993) Effect of age on the sensitivity of upper airway reexes. Br J Anaesth 70:574575
<REF> 25. Tagaito Y, Isono S, Nishino T (1998) Upper airway reexes during a combination of propofol and fentanyl anesthesia. Anesthesiology 88:14591466
<REF> 26. Nimmo WS, Wilson J, Prescott LF (1975) Narcotic analgesics and delayed gastric emptying during labour. Lancet I:890893
<REF> 27. Porter JS, Bonello E, Reynolds F (1997) The inuence of epidural administration of fentanyl infusion on gastric emptying in labour. Anaesthesia 52:11511156
<REF> 28. Marsh RH, Spencer R, Nimmo WS (1984) Gastric emptying and drug absorption before surgery. Br J Anaesth 56:161164
<REF> 29. Tarling MM, Toner CC, Withington PS, Baxter MK, Whelpton R, Goldhill DR (1997) A model of gastric emptying using paracetamol absorption in intensive care patients. Intensive Care Med 23:256260
<REF> 30. Lydon A, McGinley J, Cooke T, Duggan PF, Shorten GD (1998) Effect of anxiety on the rate of gastric emptying of liquids. Br J Anaesth 81:522525
<REF> 31. Hammas B, Hyarfner A, Thorn SE, Wattwil M (1998) Propofol sedation and gastric emptying in volunteers. Acta Anaesthesiol Scand 42:102105
<REF> 32. Naslund E, Bogefors J, Gryback H, Jacobsson H, Hellstrom PM (2000) Gastric emptying: comparison of scintigraphic, polyethylene glycol dilution and paracetamol tracer techniques. Scand
J Gastroenterol 35:375379
<REF> 33. Sandhar BK, Elliot RH, Windram I, Rowbotham DJ (1992) Peripartum changes in gastric emptying. Anaesthesia 47:196198
<REF> 34. Merio R, Festa A, Bergmann H, Eibl N, Stracher-Janotta G, Weber U, Budka C, Heckenberg A, Bauer P, Francesconi M, Schernthaner G, Stacher G (1997) Slow gastric emptying in type I diabetes: relation to autonomic and peripheral neuropathy, blood glucose and glycaemic control. Diabetes Care 20:419423
<REF> 35. Vaisman N, Weintrob N, Blumental A, Yosefsberg Z, Vardi P (1999) Gastric emptying in patients with type I diabetes mellitus. Ann N Y Acad Sci 873:506511
<REF> 36. Billeaud C, Guillet J, Sandler B (1990) Gastric emptying in infants with or without gastroesophageal reux according to the type of milk. Eur J Clin Nutr 44:577583
<REF> 37. Van Den Driessche M, Peeters K, Marien P, Ghoos Y, Devlieger H, Veereman-Wauters G (1999) Gastric emptying in formula-fed and breast-fed infants measured with the 13C-octanoic acid breath test. J Pediatr Gastroenterol Nutr 29:4651
<REF> 38. Caballero-Plasencia AM, Muros-Navarro MC, Martin-Ruiz JL, Valenzuela-Barranco M, De Los Reyes-Garcia MC, Vilchez-Joya R, Casado-Caballero FJ, Gil-Extremera (1994) Gastroparesis of digestible and indigestible solids in patients with insulin-dependent diabetes mellitus or functional dyspepsia. Dig Dis Sci 39:14091415
<REF> 39. Villanueva-Meyer J, Swischuk LE, Cesani F, Ali SA, Briscoe E (1996) Pediatric gastric emptying: value of right lateral and upright positioning. J Nucl Med 37:13561358
<REF> 40. Sethi AK, Chatterji C, Bhargava SK, Narang P, Tyagi A (1999) Safe pre-operative fasting times after milk or clear uid in children. Anaesthesia 54:5185
<REF> 41. McClure RJ, Newell SJ (1996) Effect of fortifying breast milk on gastric emptying. Arch Dis Child Fetal Neonatal Ed 74:60F62F
<REF> 42. Soreide E, Hausken T, Soreide JA, Steen PA (1996) Gastric emptying of a light hospital breakfast. A study using real time ultrasonography. Acta Anaesthesiol 40:549553
<REF> 43. Scrutton MJL, Metcalfe GA, Lowy C, Seed PT, OSullivan G (1996) Eating in labour. Anaesthesia 54:329334
<REF> 44. American Society of Anesthesiologists Task Force on Preoperative Fasting (1999) Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures. Anesthesiology 79:482485
<REF> 45. Parkman HP, Trate DM, Knight LC, Brown KL, Maurer AH, Fisher RS (1999) Cholinergic effects on human gastric motility. Gut 45:346354
<REF> 46. Crighton IM, Martin PH, Hobbs GJ, Cobby TF, Fletcher AJ, Stewart PD (1998) A comparison of the effects of intravenous tramadol, codeine and morphine on gastric emptying in human volunteers. Anesth Analg 87:445449
<REF> 47. Chapman MJ, Fraser RJ, Kluger MT, Buist MD, De Nichilo DJ (2000) Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Crit Care Med 23342337
<REF> 48. MacLaren R, Kuhl DA, Gervasio JM, Brown RO, Dickerson RN, Livingston TN, Swift K, Headley S, Kudsk KA, Lima JJ (2000) Sequential single doses of cisapride, erythromycin and metoclopramide in critically ill patients intolerant to enteral
nutrition: a randomized, placebo-controlled, crossover study. Crit Care Med 28:438444
<REF> 49. Jooste CA, Mustoe J, Collee G (1999) Metoclopramide improves gastric motility in critically ill patients. Intensive Care Med 25:464468
<REF> 50. Sellick BA (1961) Cricoid pressure to control regurgitation of stomach contents during induction of anaesthesia. Lancet II:404406
<REF> 51. Manning B, McGreal G, Winter DC, Kirwan WO, Redmond
HP (2000) Nasogastric intubation causes gastro-oesophageal reux in patients undergoing elective laparotomy. Br J Surg 87:637
<REF> 52. Vanner RG, Pryle BJ (1992) Regurgitation and oesophageal rupture with cricoid pressure: a cadaver study. Anaesthesia 47:732735
<REF> 53. Salem MR, Joseph NJ, Heyman HJ, Belani B, Paulissian R, Ferrara TP (1985) Cricoid compression is effective in obliterating the esophageal lumen in the presence of a nasogastric tube. Anesthesiology 63:443446
<REF> 54. Nishina K, Mikawa K, Takao Y, Shiga M, Maekawa N, Obara H (2000) A comparison of rabeprazole, lansoprazole and ranitidine for improving preoperative gastric uid property in adults undergoing elective surgery. Anesth Analg 90:717721
<REF> 55. Nishina K, Mikawa K, Maekawa N, Takao Y, Shiga M,
Obara H (1996) A comparison of lansoprazole, omeprazole and ranitidine for reducing preoperative gastric secretion in adult patients undergoing elective surgery. Anesth Analg 82:832
836
<REF> 56. Escolano F, Castano J, Lopez R, Bisbe E, Alcon A (1992)
Effects of omeprazole, ranitidine, famotidine and placebo on gastric secretion in patients undergoing elective surgery. Br J Anaesth 69:404406
<REF> 57. Roewer N (1995) Can pulmonary aspiration of gastric contents be prevented by balloon occlusion of the cardia? A study with a new nasogastric tube. Anesth Analg 80:378383
<REF> 58. Tournadre JP, Chassard D, Berrada KR, Bouletreau P (1997) Cricoid cartilage pressure decreases lower esophageal sphincter tone. Anesthesiology 86:79
<REF> 59. Palmer JH, MacG, Ball DR (2000) The effect of cricoid pressure on the cricoid cartilage and vocal cords: an endoscopic study in anaesthetised patients. Anaesthesia 55:263268
<REF> 60. Vanner RG (1992) Tolerance of cricoid pressure by conscious volunteers. Int J Obstet Anaesth 1:195198
<REF> 61. Vanner RG, Clarke P, Moore WJ, Raftery S (1997) The effect of cricoid pressure and neck support on the view at laryngoscopy. Anaesthesia 52:896900
<REF> 62. Meek T, Gittins N, Duggan JE (1999) Cricoid pressure: knowledge and performance amongst anaesthetic assistants. Anaesthesia 54:5185
<REF> 63. Meek T, Vincent A, Duggan JE (1998) Cricoid pressure: can protective force be sustained? Br J Anaesth 80:672674
<REF> 64. Young PJ, Basson C, Hamilton D, Ridley SA (1999) Prevention of tracheal aspiration using the pressure-limited tracheal tube cuff. Anaesthesia 54:559563
<REF> 65. Young PJ, Ridley SA (1999) Ventilator-associated pneumonia. Anaesthesia 54:11831197
<REF> 66. Rabey PG, Murphy PJ, Langton JA, Barker P, Rowbotham DJ (1992) Effect of the laryngeal mask airway on lower oesophageal sphincter pressure in patients during general anaesthesia. Br J Anaesth 69:346348
<REF> 67. Owens TM, Robertson P, Twomey C, Doyle M, McDonald M, McDonald N, McShane AJ (1995) The incidence of gastroesophageal reux with the laryngeal mask: a comparison with the face mask using esophageal lumen pH electrodes. Anesth Analg 80:980984
<REF> 68. Roux M, Drolet P, Girard M, Grenier Y, Petit B (1999) Effect
of the laryngeal mask airway on oesophageal pH: inuence of the volume and pressure inside the cuff. Br J Anaesth 82:566
569
<REF> 69. McCrory CR, McShane AJ (1999) Gastroesophageal reux
during spontaneous respiration with the laryngeal mask airway. Can J Anaesth 46:268270
<REF> 70. Brain AIJ, Verghese C, Strube PJ (2000) The LMA ProSealӎa laryngeal mask with an oesophageal vent. Br J Anaesth 84:650654
<REF> 71. American Society of Anesthesiologists Task Force (1993) Management of the difcult airway. Anesthesiology 78:597602
<REF> 72. Vezina D, Lessard MR, Bussieres J, Topping C, Trepanier CA (1998) Complications associated with the use of the Esophageal-Tracheal Combitube. Can J Anaesth 45:7680
<REF> 73. Urtubia RM, Aguila CM, Cumsille MA (2000) Combitube: a study for proper use. Anesth Analg 90:958962
<REF> 74. Hartmann T, Krenn CG, Zoeggeler A, Hoerauf K, Benumof JL, Krafft P (2000) The oesophageal-tracheal Combitube Small Adult. An alternative airway for ventilatory support during gynaecological laparoscopy. Anaesthesia 55:670675
<REF> 75. Choi PTL, Jadad AR (2000) Systematic reviews in anesthesia: should we embrace them or shoot the messenger? Can J Anesth 47:486493
<REF> 76. Sackett DL, Straus SE, Richardson WS, Rosenberg W, Haynes BR (2000) Therapy. In: Evidence based medicine. How to practice and teach EBM. Churchill Livingstone, London, pp 136
137
<REF> 77. Ogilvy AJ, Smith G (1995) The gastrointestinal tract after anaesthesia. Eur J Anaesthesiol 12:3542
<REF> 78. Tramer M, Moore A, McQuay H (1997) Propofol anaesthesia and postoperative nausea and vomiting: quantitative systematic review of randomized controlled studies. Br J Anaesth 78:247255
<REF> 79. Tramer M, Moore A, McQuay H (1997) Meta-analytic comparison of prophylactic antiemetic efcacy for postoperative nausea and vomiting: propofol anaesthesia vs omitting nitrous oxide vs total i.v. anaesthesia with propofol. Br J Anaesth 78:256
259
<REF> 80. Tramer M, Moore A, McQuay H (1996) Omitting nitrous oxide in general anaesthesia: meta-analysis of intraoperative awareness and postoperative emesis in randomized controlled trials. Br J Anaesth 76:186193
<REF> 81. Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI (1999) Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 91:12461252
<REF> 82. Otsuka M, Yoshioka K (1993) Neurotransmitter functions of mammalian tachykinins. Physiol Rev 73:229308
<REF> 83. Gesztesi Z, Scuderi PE, White PF, Wright W, Wender RH, DAngelo R, Black S, Dalby PL, MacLean D (2000) Substance P (neurokinin-1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 93:931937
<REF> 84. Tramer MR, Reynolds JM, Moore RA, McQuay HJ (1997) Efcacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting. A quantitative systematic review of randomized placebo-controlled trials. Anesthesiology 87:12771289
<REF> 85. Figueredo E, Canosa L (1999) Prophylactic ondansetron for post-operative emesis: meta-analysis of its effectiveness in
patients with and without a previous history of motion sickness. Eur J Anaesthesiol 16:556564
<REF> 86. Figueredo E, Canosa L (1999) Prophylactic ondansetron for postoperative emesis. Meta-analysis of its effectiveness in patients with previous history of postoperative nausea and vomiting. Acta Anaesthesiol Scand 43:637644
<REF> 87. Domino KB, Anderson EA, Polissar NL, Posner KL (1999) Comparative efcacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis. Anesth Analg 88:13701379
<REF> 88. Loewen PS, Marra CA, Zed PJ (2000) 5HT3 receptor antagonists vs traditional agents for the prophylaxis of postoperative nausea and vomiting. Can J Anaesth 47:10081018
<REF> 89. Tramer MR, Moore RA, Reynolds DJM, McQuay HJ (1997) A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting. BMJ 314:10881092
<REF> 90. Henzi I, Walder B, Tramer MR (2000) Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 90:186194
<REF> 91. Wang JJ, Ho ST, Lee SC, Liu YC, Ho CM (2000) The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg 91:14041407
<REF> 92. Wang JJ, Ho ST, Tzeng JI, Tang CS (2000) The effect of timing of dexamethasone administration on its efcacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 91:136139
<REF> 93. Henzi I, Sonderegger J, Tramer MR (2000) Efcacy, dose-
response, and adverse effects of droperidol for prevention of postoperative nausea and vomiting. Can J Anaesth 47:537551
<REF> 94. Henzi I, Walder B, Tramer MR (1999) Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomised, placebo-controlled studies.
Br J Anaesth 83:761771
<REF> 95. Heffernan AM, Rowbotham DJ (2000) Postoperative nausea and vomitingtime for balanced antiemesis? Br J Anaesth 85:675677
<REF> 96. Ahmed AB, Hobbs GJ, Curran JP (2000) Randomized, placebo-controlled trial of combination antiemetic prophylaxis for
day-case gynaecological laparoscopic surgery. Br J Anaesth 85:678682
<REF> 97. Pueyo FJ, Carrascosa F, Lopez L, Iribarren MJ, Garcia-Pedrajas F (1996) Combination of ondansetron and droperidol in the prophylaxis of postoperative nausea and vomiting. Anesth Analg 83:117122
<REF> 98. Bugedo G, Gonzalez J, Asenjo C, De la Cuadra JC, Gajardo A, Castillo L, Munoz H, Dagnino J (1999) Ondansetron and droperidol in the prevention of postoperative nausea and vomiting. Br J Anaesth 3:813814
<REF> 99. Eberhart LHJ, Morin AM, Bothner U, Georgieff M (2000) Droperidol and 5HT3 receptor antagonists, alone or in combination, for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomised controlled trials. Acta Anaesthesiol Scand 44:12521257
<REF>100. Navari RM, Reinhardt RR, Gralla RJ, Kris MG, Hesketh PJ, Khojasteh A, Kindler H, Grote TH, Pendergrass K, Grunberg SM, Carides AD, Gertz BJ (1999) Reduction of cisplatin-
induced emesis by a selective neurokinin-1 receptor antagonist. N Engl J Med 340:190195
<REF>101. Tramer MR, Walder BW (1999) Efcacy and adverse effects of prophylactic antiemetics during patient-controlled analgesia therapy: a quantitative systematic review. Anesth Analg 88:13541361
<REF>102. Lee A, Done M (1999) The use of nonpharmacologic techniques to prevent postoperative nausea and vomiting: a meta-analysis. Anesth Analg 88:13621369
<REF>103. Eberhart LHJ, Hogel J, Seeling W, Staack AM, Geldner G, Georgieff M (2000) Evaluation of three risk scores to predict postoperative nausea and vomiting. Acta Anaesthesiol Scand 44:480488
<REF>104. Apfel CC, Laara E, Koivuranta M, Greim C-A, Roewer N (1999) A simplied risk score for predicting postoperative
nausea and vomiting. Anesthesiology 91:693700
<REF>105. Holte K, Kehlet H (2000) Postoperative ileus. Br J Surg 87:14801493
<REF>106. Friese N, Chevalier E, Angel F, Pascaud X, Junien JL, Dahl SG, Riviere PJ (1997) Reversal by kappa-agonists of peritoneal
irritation-induced ileus and visceral pain in rats. Life Sci 60:625634
<REF>107. Bungard TJ, Kale-Pradhan PB (1999) Prokinetic agents for the treatment of postoperative ileus in adults: a review of the literature. Pharmacotherapy 19:416423
<REF>108. Smith AJ, Nissan A, Lanouette NM, Shi W, Guillem JG, Wong WD, Thaler H, Cohen AM (2000) Prokinetic effect of erythromycin after colorectal surgery: randomized, placebo-controlled, double-blind study. Dise Colon Rectum 43:333337
<REF>109. Cali RL, Meade PG, Swanson MS, Freeman C (2000) Effect of morphine and incision length on bowel function after colectomy. Dise Colon Rectum 43:163168
<REF>110. Steinbrook RA (1998) Epidural anesthesia and gastrointestinal motility. Anesth Analg 86:837844
<REF>111. Neudecker J, Schwenk W, Junghans T, Pietsch S, Bohm B, Muller JM (1999) Randomised controlled trial to examine the inuence of thoracic epidural analgesia on postoperative ileus after laparoscopic sigmoid resection. Br J Surg 86:1292
1295
<REF>112. Brodner G, Van Aken H, Hertle L, Fobker M, Von Eckardstein A, Goeters C, Buerkle H, Harks A, Kehlet H (2001) Multimodal perioperative managementcombining thoracic epidural analgesia, forced mobilisation and oral nutritionreduces hormonal and metabolic stress and improves convalescence after major urologic surgery. Anesth Analg 92:15941600
<REF>113. Basse L, Hjort Jakobsen D, Billesbolle P, Werner M, Kehlet H (2000) A clinical pathway to accelerate recovery after colonic resection. Ann Surg 232:5157
<REF>114. Schwenk W, Bohm B, Haase O, Junghans T, Muller JM (1998) Laparoscopic versus conventional colorectal resection: a prospective randomised study of postoperative ileus and early postoperative feeding. Langenbecks Arch Chir 383:4955
<REF>115. Aitkenhead AR, Wishart HY, Peebles-Brown DA (1978) High spinal block for large bowel anastomosis. Br J Anaesth 50:177183
<REF>116. Aitkenhead AR, Robinson S (1989) Inuence of morphine and pethidine on the incidence of anastomotic dehiscence after
colonic surgery. Br J Anaesth 63:230P231P
<REF>117. Painter NS (1963) The effect of morphine in diverticulosis of the colon. Proc R Soc Med 56:800802
<REF>118. Painter NS, Truelove SC (1964) The intraluminal pressure patterns in diverticulosis of the colon. Part II: the effect of morphine. Gut 5:201213
<REF>119. Armory P, Toogood L, Thomas M, Aitkenhead AR, Smith G (2000) Comparison of morphine and pethidine administered
by patient controlled analgesia systems for postoperative pain relief after large bowel anastomosis. Br J Anaesth 280P
281P
<REF>120. Holte K, Kehlet H (2001) Epidural analgesia and risk of anastomotic leakage. Reg Anesth Pain Med 26:111117
<REF>121. Pinnock CA, Derbyshire DR, Achola KJ, Smith G (1986) Absorption of controlled release morphine sulphate in the immediate postoperative period. Br J Anaesth 58:868871
<REF>122. Bjorkman S, Rigemar G, Idvall J (1997) Pharmacokinetics of midazolam given as an intranasal spray to adult surgical patients. Br J Anaesth 79:575580
<REF>123. Grifth N, Howell S, Mason DG (1998) Intranasal midazolam for premedication of children undergoing day-case anaesthesia: comparison of two delivery systems with assessment of intra-observer variability. Br J Anaesth 81:865869
<REF>124. Alexander-Williams JM, Rowbotham DJ (1998) Novel routes of opioid administration. Br J Anaesth 81:37
<REF>125. Seppetella G (2000) An assessment of the safety, efcacy and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain: a pilot study. J Pain Symptom Management 20:253258
<REF>126. Striebel HW, Kramer J, Luhmann I, Rohierse-Hohler I, Rieger A (1993) Pharmacokinetics of intranasal fentanyl. Der Schmerz 7:122125
<REF>127. Striebel HW, Toussaint S, Raab C, Klocker N (1999) Non-
invasive methods for PCA in pain management. Acute Pain 2:3640
<REF>128. Takala A, Kaasalainen V, Seppala T, Kalso E, Olkkola KT (1997) Pharmacokinetic comparison of intravenous and intranasal administration of oxycodone. Acta Anaesthesiol Scand 41:309312
<REF>129. Shojaei AH (1998) Buccal mucosa as a route for systemic drug delivery: a review. J Pharm Pharm Sci 1:1530
<REF>130. Schechter NL, Weisman SJ, Rosenblum M, Bernstein B, Conard PL (1995) The use of oral transmucosal fentanyl citrate for painful procedures in children. Pediatrics 95:335339
<REF>131. Dsida RM, Wheeler M, Birmingham PK, Henthorn TK, Avram MJ, Enders-Klein C, Maddalozzo J, Cote CJ (1998) Premedication of pediatric tonsillectomy patients with oral transmucosal fentanyl citrate. Anesth Analg 86:6670
<REF>132. Egan TD, Sharma A, Ashburn MA, Kievit J, Pace NL, Streisand JB (2000) Multiple dose pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers. Anesthesiology 665673
<REF>133. Streisand JB, Busch MA, Egan TD, Smith BG, Gay M, Pace NL (1998) Dose proportionality and pharmacokinetics of oral transmucosal fentanyl citrate. Anesthesiology 88:305309
<REF>134. Williams PI, Smith M (1999) An assessment of prochlorperazine buccal for the prevention of nausea and vomiting during intravenous patient-controlled analgesia with morphine following
abdominal hysterectomy. Eur J Anaesthesiol 638645
<REF>135. Scott RC, Besag FMC, Boyd SG, Berry D, Neville BGR (1998) Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics. Epilepsia 39:290294
<REF>136. Khalil S, Philbrook L, Rabb M, Wagner K, Jennings C,
Chuang AZ, Lemak NA (1998) Sublingual midazolam premedication in children: a dose response study. Paediatr Anaesth 8:461465
<REF>137. Niemann T, Madsen LG, Larsen S, Thorsgaard N (2000) Opioid treatment of painful chronic pancreatitis. Int J Pancreatol 27:235240
<REF>138. Sinha VR, Kaur MP (2000) Permeation enhancers for transdermal drug delivery. Drug Devel Industrial Pharmacy 26:11311140
<REF>139. Gupta SK, Southam M, Gale R, Hwang SS (1992) System functionality and physiochemical model of fentanyl transdermal
system. J Pain Symptom Management 7:S1726
<REF>140. Jeal W, Beneld P (1997) Trandermal fentanyl. A review of its pharmacological properties and therapeutic efcacy in pain
control. Drugs 53:109138
<REF>141. Thompson JP, Bower S, Liddle AM, Rowbotham DJ (1998) Perioperative pharmacokinetics of transdermal fentanyl in
elderly and young adult patients. Br J Anaesth 81:152154
<REF>142. Paut O, Camboulives J, Viard L, Lemoing JP, Levron JC (2000) Pharmacokinetics of transdermal fentanyl in the perioperative period in young children. Anaesthesia 55:12021207
<REF>143. Grond S, Radbruch L, Lehmann KA (2000) Clinical pharmacokinetics of transdermal opioids. Clin Pharmacokinet 38:5989
<REF>144. Dunn C (1997) Touch of a button delivers transdermal fentanyl. Inpharma 1087:1920
<REF>145. Azevedo VMS, Lauretti GR, Pereria NL, Reis MP (2000) Transdermal ketamine as an adjuvant for postoperative analgesia after abdominal gynaecological surgery using lidocaine epidural blockade. Anesth Analg 91:14791482
<REF>146. Moolenaar F, Meijler WJ, Frijlink HW, Visser J, Proost JH (2000) Clinical efcacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository
in patients with cancer pain. Eur J Clin Pharmacol 56:219
223
<REF>147. Hahn TW, Henneberg SW, Holm-Knudsen RJ, Eriksen K, Rasmussen SN, Rasmussen M (2000) Pharmacokinetics of rectal paracetamol after repeated dosing in children. Br J Anaesth 85:512519
<REF>148. Beck DH, Schenk MR, Hagemann K, Doepfmer UR, Kox WJ (2000) The pharmacokinetics and analgesic efcacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomised study. Anesth Analg 90:431436
<REF>149. Ramakrishna S, Fadnavis NW, Diwan PV (1996) Comparative pharmacokinetic evaluation of compressed suppositories of diclofenac in humans. Arzneimittelforschung 46:175177

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<JN>J Anesth (2002) 16:6569
<PT>Special article
<CT>Education in anesthesiology for the twenty-rst century
<CA>David E. Longnecker
<ADD>Robert D. Dripps Professor and Chair, Department of Anesthesia, University of Pennsylvania, 4 North Dulles, 3400 Spruce Street, Philadelphia PA 19104-4283, USA
<AB>Abstract The growth and development of anesthesiology in the twenty-rst century will likely depend on two major factors: our vision for the specialty in the future and our ability to implement an anesthesia education plan that will foster the achievement of that vision. The foundation of effective anesthesia education must be built on an understanding of the past and an analysis of the present but, most importantly, it must be shaped by our vision for the future. Focus on the future is essential, for it is remarkably easy to teach others as we were taught, or as we practice today. Unfortunately, the easy path will not foster the advancement of the specialty or develop the leaders for the future. The comments that follow are not a prescription for success. Rather, they are intended to stimulate discussion and planning regarding the future of anesthesiology, leading to a course of action that will enhance the development of the specialty. Long-term success for the
specialty will depend on our efforts in undergraduate and graduate medical education, whereas short-term success will depend on our efforts in the continuing medical education of current practitioners.
<KW>Key words Graduate medical education Workforce Perioperative medicine Critical care medicine Anesthesia research Nonphysician provider
<A>Introduction
<para1>Effective organizations of all types share one trait that seems to be universal: they plan their future steps carefully by establishing strategic directions and goals, and then implementing a series of steps that guide them towards those goals. The full potential of anesthesiology will likely not be realized by serendipity; rather, it will be accomplished by careful strategic planning. Medical specialties, like other organizations, can benet from thoughtful strategic planning. There are many reasons to adopt this approach for anesthesiology at this time. An overall global view for anesthesiology will be helpful, but that global vision will need much renement at the regional (e.g., Asia vs Europe vs North America, etc.) and national level, as the stages of evolution of the specialty are quite variable among the various countries and regions. Educational change, like overall planning, will inevitably proceed at various rates depending on the local circumstance, but a broad consensus on the long-term future will foster educational focus at all
levels.
<A>Background of the specialty
<para1>Anesthesiology is a relatively new medical specialty in most countries. In the United States, the importance of surgical anesthesia received special attention as a result of national and international armed conict. The benets of surgical anesthesia gained initial attention during the United States civil war (18601864, shortly after the introduction of ether anesthesia in the mid-1840s), and were further enhanced during World War I (19141918). However, World War II was the genesis of what many believe was the true evolution of the discipline as we now know it. Large numbers of generalist military physicians received brief focused training in basic anesthesia techniques for the care of combat casualties, and many of these individuals returned to civilian life in the late 1940s with a rm understanding of both the benets and limitations of then-current anesthesia practice. Many continued to practice anesthesia in community hospitals, while others entered graduate medical education (i.e., residency) programs to enhance their knowledge and basic skills; many from this latter group became the leaders of American academic anesthesia in the 1950s, 1960s, and 1970s. Although specic circumstances may differ depending on national events and needs, the time course of the emergence of anesthesia is relatively similar in most highly developed nations, including Great Britain [1]. Most importantly for our current considerations, the events of the twentieth century have brought anesthesia to a new threshold for the twenty-rst century [2]. Many academic medical centers have a cadre of highly trained and competent anesthesiologists; our challenges include dening the highest and best uses for this talent, and developing the leaders of tomorrow who will shape the specialty in the twenty-rst century. These goals can only be accomplished by a careful review of the current status of the specialty, for it is impossible to chart a course for the specialty without knowing the starting point, as well as the intended destination.
<A>Current status of anesthesiology
<para1>Anesthesiology can be evaluated in a variety of ways. Two useful approaches include an assessment of the stages of development of the discipline, and a review of the strengths, weaknesses and opportunities based on the stage of development in each region or nation.
<B>Stages of development
<para1>The stages of development might be subdivided into three categories: emerging, established, and comprehensive. For want of a better scheme, these might be dened according to the criteria given in Table 1.
<B>Strengths and weaknesses of anesthesiology
<para1>The strengths, weaknesses, and opportunities for the specialty vary depending on the stage of development, and, likely, each region and country can identify specic locales that are in various stages of development. However, for the purposes of this article, we will focus on the established and comprehensive environments, for these are the environments that provide global leadership for the discipline. (These leaders have, of course, an obligation to help their colleagues who are in the emerging stages of anesthesia development, but here again this help will often take the form of education if it is to have a lasting effect.)
<para2>The strengths of the specialty include a remarkably satisfying practice that requires broad-based knowledge in a variety of medical and surgical disciplines. Such broad-based knowledge leads to considerable intellectual satisfaction, and avoids the boredom and tedium of repetitive work that is accomplished by rote rather than by the application of professional knowledge and judgment to specic situations. Similarly, especially in the more advanced academic centers, anesthesiologists
often are recognized as balanced institutionally oriented leaders who are attuned more to overall institutional accomplishment than individual or departmental control or dominance. (Recently, an increasing number of anesthesiologists have been selected to lead academic medical centers in the United States, likely because of this broad-based knowledge and institutional orientation.) Much of anesthesia practice is associated with acute care, which provides access to high technology and immediate gratication for ones efforts. There is great satisfaction from the knowledge that ones
efforts truly make a difference, and not infrequently are directly responsible for survival in critically ill
patients [36]. Further, there are the nancial rewards of medical practice. (Although anesthesiologists are not as highly rewarded as some of the more prominent surgical specialties, the income and standard of living for anesthesiologists is far greater than that of the general population in nearly all countries.)
<para2>The weaknesses of the specialty include a narrow scope of practice (often a result of the desperate need for anesthesiologists in operating rooms), and a lack of public recognition for the role of anesthesia in overall health care; this lack of recognition does not foster prestige for the discipline. Another weakness is the willingness of some practitioners to readily accept these narrower denitions of anesthesia practice, thus inhibiting the potential scope of practice for those who seek to expand into perioperative care and pain medicine, for example.
<para2>The opportunities are many and they are attainable, for there are examples of outstanding comprehensive anesthesia programs in many institutions. The opportunities encompass both clinical practice and academic development. Clinical, research, and educational initiatives will be required to achieve a comprehensive anesthesia status more widely.
<A>Clinical initiatives
<para1>Extending the skills and talents of anesthesiologists from the operating rooms to the perioperative environment is a natural progression for the specialty, as the cadre of well-trained and dedicated anesthesiologists increases. These opportunities are especially attractive in areas such as the preoperative evaluation of surgical patients, postoperative acute pain management, and critical care medicine. Indeed, as medicine becomes more complex and as technology continues to develop, subdisciplines, such as critical care medicine, are logical areas for expanded anesthesia practice [7]. Extending practice into these areas improves patient outcomes [6,8] and reduces costs [5], and thus brings value to patients and to the health care system overall. Additionally, it brings increased public recognition to
anesthesiologists. In the more advanced centers, the development of subspecialization within the operating rooms (e.g., cardiac anesthesia, neuroanesthesia, thoracic anesthesia, etc.) leads to enhanced professional recognition, for these subspecialties are highly valued by our surgical and medical colleagues. The public
visibility of anesthesiologists is perhaps most apparent in areas such as acute pain management, chronic pain medicine, and critical care medicine. In each instance, the anesthesiologist is clearly identied and recognized by patients and families, leading to increased prestige for the specialty overall.
<A>Research initiatives
<para1>Research initiatives are vital to the image of the specialty and essential for its further development as a major medical discipline (the discovery of new knowledge is one of the factors that identies a profession rather than a trade). A recent new book described the public demonstration of ether anesthesia in 1846 as Americas greatest medical discovery [9]. Strangely, anesthesiologists have done little to capitalize on the contributions of our discipline to the advance in current health care, although these advances rely heavily on surgical care (an estimated 41 million surgical procedures are performed annually in the United States!). Outcomes research is vital to documenting our value, yet the most important outcome, survival, is rarely
studied by anesthesiologists. More often, anesthesia research examines intermediate outcomes, such as vital signs, cardiac output, muscle twitch tension, blood gas data, or other surrogates for improved care, whereas outcomes such as surgical mortality or return to full function remain the domain of other disciplines. There are fruitful opportunities here, as evidenced by recent publications which document that anesthesiologists
improve surgical outcomes [4,8]. More research of this type will demonstrate our value to health care, and will inuence both overall workforce policy and the appropriate development of subspecialty anesthesia practice.
<A>Education initiatives
<para1>Education is the means by which we build on the strengths, address the weaknesses, and achieve the vision of comprehensive anesthesiology in the twenty-rst century. Educational efforts will need to include all
aspects of the specialty, ranging from undergraduate recruitment to the education of nonphysician providers, but will necessarily focus especially on graduate medical education, which, clearly, is the single most effective site for assuring the success of the specialty in this century.
<para2>The graduate medical education programs are key
to the achievement of our goals for the specialty. The programs and faculty who are responsible for graduate medical education can either foster the development of comprehensive anesthesia care, or they can reinforce the status quo. Unfortunately, it is all too easy to confuse training with education, and workforce needs with essential clinical experience. There are subtle but very real distinctions between education and training. The core concept of education involves the imparting of knowledge, whereas the basis of training is the development of behavior patterns by experience and repetition. For example, one trains an animal to fetch an object or jump through a hoop, but no fundamental know-ledge or judgment is transferred in the process. In
contrast, a professional who is educated in a discipline (mathematics, physics, medicine, etc.) is able to reason and apply both knowledge and judgment to new situations. Simulators and multiple case experiences are valuable tools for training anesthesiologists in clinical skills (e.g., management of the difcult airway, etc.), but they do not replace comprehensive medical knowledge as the basis for effective judgment in overall anesthesia practice. In the nal analysis, high quality anesthesia care requires both education and training, and too often programs and faculty confuse or ignore these subtle distinctions. One cannot learn the management of complex anesthesia care from textbooks, lectures, video, or interactive computer programs alone, but neither can a trainee become a true professional by simple repetition of clinical experience. Quality graduate medical education requires an appropriate melding of education and training, and neither alone is sufcient. The pressures to substitute training for education must be managed if the specialty seeks to develop to its full potential. These pressures include busy operating schedules, limited
nancial resources, and multiple other demands on
faculty time that encourage educators to become
trainers. Succumbing to these pressures results in an inferior product from a training program, rather than a superior practitioner from a graduate medical education program. Similar pressures lead the program to limit educational experiences for the resident in areas such as chronic pain medicine or critical care medicine, again denying both the learner and the specialty of a practitioner who can participate in true comprehensive anesthesia practice. Training is easy for the faculty, whereas education is difcult, demanding, and often inconvenient. (Preparation of lectures or educational media is tedious and time-consuming, whereas training by experience is far easier for the faculty. Delivering personal anesthesia care to a busy surgical service is demanding, whereas reassigning residents from the
anesthesia consult service, the chronic pain clinic, or an intensive care unit is easier for faculty and often preferred by surgeons and hospital administrators.) The leaders of residency programs must review the curriculum regularly, in order to maintain the proper balance between education and training. Similarly, residents must learn the intellectual foundations of the discipline by participating in research conferences, morbidity and mortality conferences, and the development of practice guidelines and protocols. Experiences in these areas will foster some to seek careers in basic or patient-oriented research (including outcomes research), and will encourage all to recognize that high quality clinical care results from an iterative process involving an assessment of clinical experience combined with ongoing review of the scholarly literature.
<para2>Undergraduate medical education is the primary site for (a) exposing all medical students to the clinical challenges and strengths of our discipline, and (b) identifying interested students who may seek a career in anesthesiology. Some programs nd it difcult to achieve time in the medical school curriculum, owing to the multiple pressures from all services for time in the curriculum. Here again, those anesthesia programs that have achieved comprehensive anesthesiology status are far more likely to be included in the core curriculum, rather than being relegated to elective rotations only. Participating in the broader aspects of anesthesia practice (pain medicine, critical care medicine, etc.) provides further support for incorporating anesthesia education in the core medical school curriculum.
<para2>Postgraduate (continuing) medical education can be used to (a) seek support for a vision of the future of anesthesiology, and (b) impart knowledge that will help existing practitioners implement aspects of that vision in their local environments. Practicing anesthesiologists experience both the strengths and the weaknesses of
the specialty in their daily professional lives, and many are motivated to participate in the development of new opportunities. However, some lack the knowledge or skills to extend their practice beyond the operating rooms. Many academic anesthesia programs have the resources that can remedy these deciencies, and they should be encouraged to develop continuing education programs that address the needs of current practitioners, who can be valuable partners in developing the future of the specialty.
<para2>Some countries are exploring the role of nonphysician providers, such as advanced practice nurses
or anesthesia physician assistants, to supplement the anesthesia workforce in their health care systems. Experience can be gained from other countries (e.g., Sweden, the United States, etc.) where these provides form
a signicant component of the anesthesia workforce [10]. Although there can be no uniform policy that
applies to all countries, the experiences in Sweden
and the United States suggest that nonphysician providers can be valuable physician extenders for the delivery of anesthesia care. Data from the United States, however, show that surgical outcomes are improved when anesthesiologists direct the care provided by these physician extenders [4], and neither patients nor the profession are well served by allowing these groups to develop independently. Here again, the importance of education is a key aspect of this process. Thought leaders in anesthesiology have suggested that anesthesiologists should be responsible for the education of nonphysician providers [11], and this seems to
be prudent advice, based on experience in the United States.
<A>Summary and conclusions
<para1>Anesthesiology made great strides during the last half of the twentieth century. The specialty is now well positioned to develop in a variety of ways that will enhance patient care, discover new knowledge, and improve surgical outcomes. These advances will inevitably improve overall health care in the twenty-rst century, and achieve an enhanced status for anesthesiology and
anesthesia practitioners. However, achievement of these goals will require a clear vision and an intense commitment to anesthesia education in all its realms, but especially in graduate medical education.
<A>References
<REF> 1. Nunn JF (1999) Development of academic anaesthesia in the UK up to the end of 1998. Br J Anaesth 83:916932
<REF> 2. Longnecker DE (1997) Navigation in uncharted waters. Is anesthesiology on course for the twenty-rst century? Anesthesiology 86:736742
<REF> 3. Silber JH, Williams SV, Krakauer H, Schwartz JS (1992) Hospital and patient characteristics associated with death after surgery. Med Care 30:615629
<REF> 4. Silber JH, Kennedy SK, Even-Shoshan O, Chen W, Koziol LF, Showan AM, Longnecker DE (2000) Anesthesiologist direction and patient outcomes. Anesthesiology 93:152163
<REF> 5. Hanson CW, Deutschman CS, Anderson HL, Reilly PM, Behringer EC, Schwab CW, Price J (1999) Effects of an organized critical care service on outcomes and resource utilization. A cohort study. Crit Care Med 27:270274
<REF> 6. Pronovost PJ, Jenckes MW, Dorman T, Garrett E, Breslow MJ, Rosenfeld BA, Lipsett PA, Bass E (1999) Organization characteristics of intensive care units related to outcomes of abdominal aortic surgery. JAMA 281:13101317
<REF> 7. Willatts SM (2000) Opportunity knocks. Anaesthesia 55:11471148
<REF> 8. Gottschalk A, Smith DS, Jobes DR, Kennedy SK, Lally
SE, Noble VE, Grugan KF, Seifert HA, Cheung A, Malkowicz SB, Gutsche BB, Wein AJ (1998) Preemptive epidural analgesia and recovery from radical prostatectomy. JAMA 279:1076
1082
<REF> 9. Fenster JM (2001) Ether day. The strange tale of Americas
greatest medical discovery and the haunted men who made it. HarperCollins, New York
<REF>10. Vickers MD (2000) Non-physician anaesthetists. Can we agree on their role in Europe? Eur J Anaesthesiol 17:537541
<REF>11. James FM (1999) Rovenstine lecture. Who will lead us? Anesthesiology 90:17661772

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<JN>J Anesth (2002) 16:7071
<PT>Clinical reports
<CT>Malignant hyperthermia with normal calcium-induced calcium release rate of sarcoplasmic reticulum in skeletal muscle
<CA>Tetsuo Takaya1, Kenji Ito1, Mamoru Takiguchi1, Yasuko Ichihara2, Junji Sasaki2, and Hirosato Kikuchi2
<ADD>1 Department of Anesthesiology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan
<ADD>2 First Department of Anesthesiology, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan
<KW>Key words Malignant hyperthermia Muscle biopsy Ca-induced Ca release
<A>Introduction
<para1>Although the mortality rate of malignant hyperthermia (MH) has decreased dramatically in the past two decades, it remains one of the serious complications of anesthesia. An accelerated calcium-induced calcium
release (CICR) rate of sarcoplasmic reticulum (SR) is known to be a major causative factor of MH. Approximately 20% of fulminant MH cases, however, have other unexplained causes [14]. We report here a man who suffered from fulminant MH during general anesthesia 24 years ago at Kanto Teishin Hospital [5], but did not show any sign of MH in three recent operations at Tokai University Hospital. His muscle biopsy test revealed a normal CICR rate and a normal Ca uptake of SR.
<A>Case report
<para1>A 53-year-old man, weighing 55 kg, was admitted to Tokai University Hospital for acute appendicitis. He had a history of MH, diagnosed at Kanto-Teishin
Hospital, where he had undergone wide resection of
the stomach for duodenal ulcer 21 years before his
rst presentation to us. Anesthesia had been induced with thiamylal 300 mg after the administration of d-
tubocurarine 3 mg, and was maintained with N2OO2 halothane [5]. His trachea was intubated, with the assistance of suxamethonium 100 mg. Pancuronium was used as an intraoperative muscle relaxant. The surgery lasted approximately 2 h, 30 min. His rectal temperature increased from 37.8C just after the induction of anesthesia to 39C just before the end of surgery. His temperature increased further after the reversal of the pancuronium with atropine and neostigmine. He became tachypneic and his skin color revealed cyanotic change in the peripheral regions of his extremities and in his lips. His temperature transiently reached 40.5C, in spite of whole-body cooling carried out with a cooling mat and ethanol evaporation. Analysis of his arterial blood gas revealed pH 6.55, base excess (BE) 229.8 mEq/l. He showed almost complete recovery 7 h after whole-body cooling and the intravenous administration of bicarbonate (530 mEq in total).
<para2>In the recent series of operations, performed at our institution, an emergency appendectomy operation was performed (rst operation) without any problem, with the patient under spinal anesthesia combined with epidural anesthesia. Postoperative pathological examination diagnosed appendicular cancer.
<para2>Eighteen days after the rst operation, right hemicolectomy was performed (second operation). Anesthesia was induced with 120 mg of propofol, after the intravenous administration of dantrolene 60 mg, and was maintained with fentanyl, propofol, epidural block, and N2OO2. His airway was managed with a laryngeal mask. His rectal temperature decreased from 36C to 35.2C during the 2-h, 23-min operation. Results for serum electrolytes, serum creatine kinase (CK), arterial blood gas analysis, and urinary analysis were all normal. Two hours after the end of the operation, his temperature had increased to 38.2C in the intensive care unit (ICU), and this was associated with shivering. Intramuscular sulpyrine and intravenous urbiprofen decreased his temperature slightly. Sixty milligrams of dantrolene, however, was ineffective. His temperature had gradually returned to normal by day 6 after the operation.
<para2>Five months after the second operation, a skeletal muscle biopsy test was performed at Toho University Omori Hospital, and this revealed a normal CICR rate and normal Ca uptake in SR.
<para2>One year and 9 months after the rst operation, he was hospitalized again, for common bile duct cancer, and a choledochectomy with cholecystectomy (third operation) was scheduled. Anesthesia was induced with propofol, and then his trachea was intubated, with the assistance of vecuronium. An epidural block and the intravenous anesthetics, fentanyl and propofol, were used for the maintenance of anesthesia. Sixty milligrams of dantrolene was administered prophylactically during the operation. The 5-h, 15-min operation was completed without any particular problem. In the ICU, his temperature gradually increased from 36.6C to 38C. Forty milligrams of dantrolene was administered three times within 24 h after the operation. It was not, however, effective in reducing his temperature. However, urbiprofen 50 mg brought down his high body temperature, although its effect was transient. His temperature had gradually returned to normal by day 20 after the operation.
<A>Discussion
<para1>MH is a hereditary disease that is triggered by volatile anesthetics, which accelerate the CICR rate, and depolarizing muscle relaxants. Our patient had no particular family history suggestive of MH. The pathophysiology of MH is considered to be caused primarily by an abnormally high Ca level in skeletal muscle cytoplasm, and secondarily by such factors as the contracture of skeletal muscle, extreme energy production, and acidosis. Although almost 80% of fulminant MH patients have an accelerated CICR rate, the genesis of MH in the remainder of the patients is not certain. In our patient, at the end of the operation performed 24 years ago, his body temperature had increased to more than 40C, and tachypnea, cyanosis, and extreme metabolic acidosis were observed. Although it is difcult to analyze precisely the pathophysiology of the MH that occurred at that time, these signs and symptoms strongly suggest that he had the fulminant type, according to the clinical criteria of MH in Japan [6], and that MH was very likely, based on the MH clinical grading scale because his score was regarded as 40 [7]. Therefore, we did not use any triggering agent, such as depolarizing muscle relaxant or volatile anesthetic. We maintained the patients anesthesia basically with fentanyl, propofol, and epidural block in the last two operations. We did not reverse vecuronium after the third operation, as
we considered the possibility that an anticholines-
terase agent could be the causative agent of MH [5,8]. The intraoperative prophylactic administration of dantrolene in the last two operations may not have been necessary, because his muscle biopsy test revealed a normal CICR rate, and dantrolene is considered to be a specic suppressant of CICR [3,9,10].
<para2>In summary, we have experienced a 53-year-old male patient who suffered from fulminant MH 24 years ago, but did not show any sign of MH in recent operations, this being achieved by excluding the use of MH triggering agents. His muscle biopsy test revealed a normal CICR rate and a normal SR Ca uptake. We therefore consider that his MH was caused by factors other than an accelerated CICR rate.
<A>References
<REF> 1. Matsui K, Fujioka Y, Mukaida K, Takahashi M, Kikuchi H,
Fujii K, Morio M (1989) Comparative study of in vitro diagnosis by the skinned ber test and clinical diagnosis of malignant
hyperthermia (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 38:195201
<REF> 2. Kawana Y, Iino M, Horiuti K, Matsumura N, Ohta T, Matsui K, Endo M (1992) Acceleration in calcium-induced calcium release in the biopsied muscle bers from patients with malignant hyperthermia. Biomed Res 13:287297
<REF> 3. Matsui K, Kikuchi H (1994) Diagnosis of malignant hyperthermia by muscle biopsyCa-induced Ca release (in Japanese with English abstract). Nippon Rinsho Masui Gakkaishi (J Japan Soc for Clin Anesth) 14:5254
<REF> 4. Yuge O, Mukaida K, Ohsawa Y, Kawamoto M (1995) An update on malignant hyperthermia (I) (in Japanese). Rinsho Masui
(J Clin Anesth) 19:845854
<REF> 5. Nampo T, Kawashima Y, Meguro K, Aruga K, Yoshikawa H, Ohtani Y, Tanimura O, Takei H (1978) Malignant hyperpyrexia following the reversal of muscle relaxant: a case report of non-rigidity type (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 27:640646
<REF> 6. Morio M, Mori K (1988) Manual for the treatment of malignant hyperthermia (in Japanese). Kanehara, Tokyo, pp 3335
<REF> 7. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, rding H, Rosenberg H, Waud BE, Wedel DJ (1994) A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 80:771779
<REF> 8. Wohlfeil ER, Woehlck HJ, McElroy ND (1998) Malignant hyperthermia triggered coincidentally after reversal of neuromuscular blockade in a patient from the Hmong people of Laos. Anesthesiology 88:16671668
<REF> 9. Ohta T, Endo M, Nakano T, Morohoshi Y, Wanikawa K,
Ohga A (1989) Ca-induced Ca release in malignant hyperthermia-susceptible pig skeletal muscle. Am J Physiol 256:C358
C367
<REF>10. Fruen BR, Mickelson JR, Louis CF (1997) Dantrolene inhibition of sarcoplasmic reticulum Ca21 release by direct and specic
action at skeletal muscle ryanodine receptors. J Biol Chem 43:2696526971

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<JN>J Anesth (2002) 16:7274
<PT>
<CT>Accidental subarachnoid injection of atracurium: A case report
<CA>Ziya Salihoglu, Sener Demiroluk, and Yildiz Kose
<ADD>University of Istanbul, Cerrahpasa Medical School, Anaesthesia Department, Istanbul, Turkey
<KW>Key words Neuromuscular relaxant Atracurium Anesthetic technique Spinal Complication
<A>Introduction
<para1>Spinal anesthesia is a common method and is applied for a variety of surgical procedures. However, spinal anesthesia may be associated with the potential hazard that the wrong drugs may, accidentally, be administered into the subarachnoid space.
<para2>Although the pharmacological effects of neuromuscular blocking (NMB) drugs in the cerebrospinal uid (CSF) are unknown in humans, several observations suggest that NMB drugs are not inert when they have been injected into the CSF [1].
<para2>The present report describes a patient who developed weakness and generalized muscle hypotonia, tachycardia, hypotension, diplopia, and felt general discom-
fort after the accidental subarachnoid injection of atracurium.
<A>Case report
<para1>A 22-year-old man, weighing 70 kg, was scheduled for hemorrhoidectomy. Clinical and biochemichical tests showed normal values. We decided to use spinal anesthesia for his operation. Before spinal anesthesia, 0.03 mgg21 midazolam was given intravenously (IV) and 500 ml crystalloid uid was administered. Electro-cardiogram (ECG), mean arterial pressure (MAP), heart rate (HR), and arterial hemoglobin oxygen saturation (SpO2) were measured with a Millenia device (Millenia, Orlando, FL, USA). MAP and HR were 80 mmHg and 72 beatin21, respectively. A lumbar puncture was performed with the patient in the left lateral position. Under local anesthesia, a 22-gauge spinal needle was placed in the subarachnoid space at the L23 interspace, using a median approach. Its position was conrmed by the appearance of CSF oozing through the needle.
<para2>When the anesthetist performing the block needed to ll the syringe being used, the nurse, by mistake, passed him an ampule containing 5 ml (50 mg) of atracurium, instead of hyperbaric 1% bupivacaine solution. The content of the ampule was aspirated into the syringe and then 3 ml uid was injected into the subarachnoid space.
<para2>The patient was placed in the supine position with a pillow under his shoulders and head. This technique usually produces analgesia up to the T810 dermatomes. At this stage, the patient complained of diplopia and blurred vision, and then a general feeling of discomfort. Hypotension and tachycardia occurred. MAP and HR were 40 mmHg and 130 beatin21, respectively. All of these changes occurred after the administration of the drug into the subarachnoid space. Intravenous crystalloid infusion was restarted as soon as possible. Two minutes after the subarachnoid administration of the drug, MAP and HR were normalized, and the patients feeling of discomfort had disappeared. MAP and HR were 75 mmHg and 80 beatin21, respectively. The patient continued to complain of diplopia and blurred vision. When an assessment of the level of analgesia to the pinprick test was made 5 min later, it was apparent that there was no analgesia. At the same time, the patient showed progressive and generalized muscle hypotonia.
<para2>When the sudden hemodynamic occurred changes, SpO2 dropped to 94%. We started oxygen administration with a mask. Then, SpO2 was elevated to 100%. The fact that 30 mg of atracurium had been administered instead of hyperbaric 1% bupivacaine solution was noticed at this point, when the empty ampule was discovered.
<para2>The patients neuromuscular transmission was monitored with a Train of Four (TOF) guard device. When we applied a TOF stimulus, we found the TOF ratio to be 50% at the adductor pollicis muscle. The patients ability to breathe, to open and close his eyes, to protrude his tongue, and to swallow was not affected. Values for handgrip test and head-lift test were moderately diminished.
<para2>It was then decided not to reverse the neuromuscular blockade. We decided to wait for the neuromuscular blocking effect to subside spontaneously. A skin temperature probe was placed, and heat loss was prevented. The diplopia was attenuated 20 min after the accidental injection of atracurium. Forty minutes after the accidental injection of atracurium, the TOF response was restored to 100%. After approximately 1 h, vision was determined to be perfect. The operation was cancelled, and a neurological examination was performed. Sensory, motor, and reex ndings were normal. Neurological examinations were performed again 1 week and 1 month later, and results proved to be normal. Hemorrhoidectomy was then performed successfully, with the patient under general anesthesia.
<A>Discussion
<para1>There are several reports of the accidental injection of NMB agents into the subarachnoid space, but the acute or chronic sequelae of subarachnoid NMB injection are not clearly understood. NMBs may activate, rather than inhibit, particular subtypes of nicotinic acetylcholine receptors found in the central nervous system (CNS). This paradoxical effect may be the result of the substantial differences in subunit composition and pharmacology between central and neuromuscular nicotinic acetylcholine receptors. One important difference between these central and neuromuscular receptors is that the predominant brain subtype of nicotinic acetylcholine receptors, which consists of alfa-4 and beta-2 subunits, is seven times as permeable to calcium as the neuromuscular junction receptor. NMBs also interact with brain muscarinic acetylcholine receptors. For example, pancuronium appears to activate brain muscarinic receptors, because atropine inhibits the increase in calcium caused by this agent. It is possible that a given concentration of NMB could act simultaneously as an antagonist and an agonist in different subtypes of acetylcholine receptors, or in different brain regions expressing different subsets of receptors. It is clear that acetylcholine receptors are present on both pre and postsynaptic membranes, as well as on non-neuronal cells within the CNS [2].
<para2>Nondepolarizing NMB drugs are highly ionised. They have relatively low lipophilicity and normally do not cross the blood-brain barrier [1]. When an NMB is
administered intravenously in humans, a small quantity can be detectable in CSF [3]. In humans, accidental injection of small doses of gallamine or pancuronium into CSF has been reported to cause autonomic dysfunction and/or weakness [46]. Although our patient recovered with no neurological sequelae, there is both clinical and experimental evidence that convulsions and neuronal death ensue when NMB agents such as gallamine or tubocurarine are directly applied to the brain or accidentally injected into the lumbar CSF [710]. NMB causes excitement and seizures when introduced into the CNS [2,11]. In rats it was reported that acute intrathecal administration of NMB acted peripherally as a nicotinic receptor antagonist, leading to a dose-dependent CNS effect, culminateing in seizures [1]. The increase in Ca12 induced by NMB drugs may be relevant to the mechanism by which these drugs induce seizures [1]. Atracurium has a special feature in that laudanosine, its metabolite, may contribute to seizure activity, when atracurium is given intravenously. Our patient had general discomfort, but no seizure was observed. Our patients rst sign after the accidental injection of atracurium was the disturbance of vision such as blurring and diplopia.
<para2>Anesthetic agents generally disappear from the subarachnoid space through the arachnoid villi, and directly into the capillary or lymphatic channels of nerve bundles, or into capillaries of nerve tissue parenchyma. It has been determined that the greater portion of the drug leaves the subarachnoid space through venous drainage. The rate of elimination of agents injected into the subarachnoid space is regulated by diffusion [12]. The epidural space is rich in venous plexuses. Drugs administered into the epidural space are exposed to a large vascular surface. The absorption of local anesthetics from the peridural space occurs in a biphasic manner. The initial phase is characterized by short, rapidly reached high peak plasma times. As the peak levels decline, there is a slower, second phase, of absorption, lasting for up to 37 h [13]. These differences between subarachnoid and epidural injections could be helpful for the understanding of their pharmacokinetics.
<para2>Several studies suggest that NMB agents introduced into the CNS are pharmacologically active. Autonomic dysfunction, weakness, neuromuscular blockade, neuronal death, and seizures have been observed [2]. In our patient, we observed general discomfort, blurred vision, and diplopia, and transient hemodynamic changes. These observations may be associated with the autonomic dysfunction caused by NMBs when they are injected into the subarachnoid space. Atracurium has a molecular weight of 1243, with a low pH and plasma half-life of 20 min. Transient, severe hypotension is unlikely to be caused by systemic histamine release secondary to systemic absorption from the subarachnoid space. The brain and spinal cord have a complex
structure, with different receptor concentrations, and atracurium causes strong histamine releasing actions. So we think that histamine release caused by atracurium administration into the CSF may have been responsible for the hemodynamic changes in our patient. Hemodynamic changes such as hypotension and tachycardia occurred only in a period of 2 min. At rst, we thought this was due to the sympathetic block of spinal anesthesia. However, when we discovered that the wrong injection had been given, we thought that the hemodynamic changes were caused by direct histamine-releasing actions of the intrathecally injected atracurium. The
duration of the hemodynamic change was short. As a matter of fact, histamine has a short duration of action, and this supports our idea. There is some absorption of atracurium from the CSF into the systemic circulation, and this produces muscle weakness. Hemodynamic changes in our patient were observed shortly after the inadvertent injection of atracurium, but the neuromuscular abnormality lasted for longer. Peduto et al. [6] claimed that the intrathecal injection of hyperbaric 1% bupivacaine solution a few minutes after the accidental injection of an NMB into the subarachnoid space may help in limiting the diffusion of the NMB out of the lumbar area. We thought that this injection may be harmful, because the long stay of an NMB in the CSF may prolong the neural effects. The degradation of atracurium by Hoffman elimination, pH effects, and heat are very important in the pharmaco kinetics. Prevention of a fall in body temperature may be helpful in atracurium degradation. Warming with a blanket was thought to be helpful for the degradation of atracurium.
<para2>An accidental spinal injection of atracurium in this patient was, fortunately, devoid of neurological sequelae. This case demonstrates that there is some absorption of atracurium from the CSF into the systemic circulation, resulting in prolonged partial blockade of neuromuscular conduction.
<A>References
<REF> 1. Szenohradszky J, Trevor AJ, Bickler P, Caldwell JE, Sharma ML, Rampil IJ, Miller RD (1993) Central nervous system effects of intrathecal muscle relaxants in rats. Anesth Analg 76:1304
1309
<REF> 2. Cardone C, Szenohradszky J, Yost S, Bickler PE (1994) Activation of brain acetylcholine receptors by neuromuscular blocking drugs: a possible mechanism of neurotoxicity. Anesthesiology 80:11551161
<REF> 3. Matteo RS, Pua EK, Khambatta HJ, Spector S (1977) Cerebrospinal uid levels of d-tubocurarine in man. Anesthesiology 46:396399
<REF> 4. Goonewardene TW, Senthesmuganathan S, Kamalanathan S, Kanagasunderan R (1975) Accidental subarachnoid injection of gallamine. A case report. Br J Anaesth 47:889893
<REF> 5. Mesry S, Baradaran J (1974) Accidental intrathecal injection of gallamine triethiodide. Anesthesia 29:301304
<REF> 6. Peduto VA, Gungui P, di Martino MR, Napeolone M (1989) Accidental subarachnoid injection of pancuronium. Anesth Analg 69:516517
<REF> 7. Mc Donald JW, Garofalo EA, Hood T, Sackellares JC, Gilman S, McKeever PE, Troncoso JC, Johnston MV (1991) Altered excitory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann Neurol 29:529541
<REF> 8. Okutomi T, Hoka S (1998) Epidural saline solution prior to local anaesthetic produces differential nerve block. Can J Anaesth 45:10911093
<REF> 9. Morita T, Tsukagoshi H, Sugaya T, Shimada H, Sato H, Fujita T (1995) Inadequate antagonism of vecuronium induced neuromuscular block by neostigmine during sevourane or isourane anaesthesia. Anesth Analg 80:11751180
<REF>10. Morita T, Kurosaki D, Tsukagoshi, H, Shimada H, Sato H, Goto F (1997) Factors affecting neostigmine reversal of vecuronium block during sevourane anaesthesia. Anesthesia 52:538543
<REF>11. Scheepstra GL, Vree TB, Crul JF, van de Pol F, Reekers-Ketting J (1986) Convulsive effects and pharmocokinetics of laudanosine in the rat. Eur J Anaesthesiol 3:371383
<REF>12. Collins VJ (1993) Spinal anesthesia-principles. In: Collins VJ (ed) Principles of anesthesiology, general and regional anesthesia, third edn. Lea and Febiger, Philadelphia, pp 14541455
<REF>13. Collins VJ (1993) Epidural anesthesia. In: Collins VJ (ed) Principles of anesthesiology, general and regional anesthesia, third edn. Lea and Febiger, Philadelphia, p 1577

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<JN>J Anesth (2002) 16:7578
<PT>
<CT>An adult with ARDS managed with high-frequency oscillatory ventilation and prone position
<CA>Osamu Nagano1, Hiromi Fujii1, Hiroshi Morimatsu1, Satoshi Mizobuchi1, Keiji Goto1, Hiroshi Katayama1, Masahisa Hirakawa1, and Yoshitsugu Yamada2
<ADD>1 Department of Anesthesiology and Resuscitology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
<ADD>2 Department of Anesthesiology, Yokohama City University School of Medicine, Yokohama, Japan
<KW>Key words High-frequency oscillatory ventilation (HFOV) ARDS G-CSF
<A>Introduction
<para1>A protective strategy to prevent ventilator-induced lung injury has been proved to improve outcome in patients with acute respiratory distress syndrome (ARDS) [1,2]. With this strategy, low tidal volume is used to minimize alveolar stretch, resulting in various degrees of hypercapnia. High-frequency oscillatory ventilation (HFOV) is another mode of ventilation for lung protection. HFOV has been reported to improve the outcomes in neonates with respiratory distress syndrome [3] and
in pediatric patients with acute respiratory failure [4].
Recently, its clinical use has been increasing in adult patients [5,6].
<para2>We experienced an adult patient with ARDS managed with HFOV and prone position. Ventilation
improved immediately with HFOV, and oxygenation improved with prone position during HFOV. The duration of HFOV was about 38 h, and no adverse effects were observed.
<A>Case report
<para1>A 76-year-old male patient (body weight, 67 kg) underwent subtotal esophagectomy for esophageal cancer. After the operation he was mechanically ventilated with a PB-7200 ventilator (Puritan-Bennett, Carlsbad, CA, USA) in the intensive care unit. He had received chemotherapy (but no radiation therapy) before the operation. The preoperative chemotherapy had been started 11 days before the operation and had nished 9 days before the operation.
<para2>On the rst postoperative day, a chest radiograph revealed bilateral inltrates, and he was diagnosed as having acute lung injury (ALI), or ARDS, according to the denition of the American-European consensus conference on ARDS [7]. On the second postoperative day, marked neutropenia was observed (neutrophils, 200/; leukocytes, 1800/), and granulocyte colony-stimulating factor (G-CSF; 75 /day) was administered subcutaneously for 2 days. On the third postoperative day, oxygenation and hemodynamics deteriorated after the second administration of G-CSF. One hour before the second administration of G-CSF, arterial oxygen tension (PaO2) was 73.3 mmHg and arterial carbon
dioxide tension (PaCO2) was 39.6 mmHg with pressure support ventilation; fractional inspired oxygen (FIO2) was 0.7, positive end-expiratory pressure (PEEP) was 7 cmH2O, and pressure support, 18 cmH2O (PaO2/FIO2 (P/F) ratio, 104.7). Two hours after the second G-CSF, PaO2 was 47.6 mmHg and PaCO2 was 36.4 mmHg
with the same ventilator settings (P/F ratio, 68.0).
Arterial blood pressure was 75/45 mmHg, and central venous pressure was 15 mmHg with dopamine, 5 g21in21 and dobutamine, 4 g21in21. Although his hemodynamics improved with norepinephrine, 0.2 g21in21 and dopamine, 10 g21in21, urine output transiently decreased and continuous hemodialtration (CHDF) was started. Oxygenation did not improve and ventilation worsened in spite of the use of aggressive ventilator settings under conditions of sedation (continuous infusion of fentanyl and propofol) and muscle relaxation. PaO2 was 62.6 mmHg and PaCO2 was 52.4 mmHg (pH 7.28) with pressure-controlled ventilation (PCV); FIO2, 1.0; PEEP, 10 cmH2O; distending pressure, 25 cmH2O; respiratory frequency, 30/min. This resulted in a tidal volume of 0.35 l, minute volume of 10.5 l/min, mean airway pressure (MAP) of 22.5 cmH2O, and an oxygenation index (MAP 3 FIO2 3 100/PaO2; OI) of 35.9.
<para2>We decided to use HFOV for lung protection. We used a newly developed prototype HFO ventilator for adults (Suzuki-Metran, Tokyo, Japan). Informed consent was obtained from the patients family. The initial settings of the HFOV were: FIO2, 1.0; MAP, 20 cmH2O; frequency, 9 Hz; and stroke volume (SV), maximum. Although oxygenation did not improve with HFOV, ventilation improved immediately. Two hours after HFOV, PaO2 was 63.7 mmHg and PaCO2 was 37.0 mmHg (pH 7.32), with FIO2 1.0; MAP, 20 cmH2O; frequency, 9 Hz; and SV, 85% of maximum. Gas exchange did not change for the subsequent 9 h; the patient was then placed in the prone position for 6 h on
the fourth postoperative day. Twenty minutes after he had been placed in the prone position, oxygenation had improved (PaO2, 110.1 mmHg). Then FIO2 and MAP decreased, to 0.75 and 18 cmH2O, respectively. The placement in the prone position was repeated for 3 h on the fth postoperative day.
<para2>After the placement of the patient in the prone position for the second time, HFOV was switched to PCV. The duration of HFOV was about 38 h, and no adverse effects were observed. Before the switching to PCV, PaO2 was 84.2 mmHg and PaCO2 was 40.2 mmHg with HFOV; FIO2 was 0.7; MAP, 18 cmH2O; frequency, 9 Hz; and SV, 85% of maximum (P/F ratio, 120.4; OI, 14.9). Three hours after the switching to PCV, PaO2 was 84.9 mmHg and PaCO2 was 51.4 mmHg with conventional PCV; FIO2 was 0.65; PEEP, 10 cmH2O; distending pressure, 20 cmH2O; respiratory frequency, 20/min. This resulted in a tidal volume of 0.38 l, minute volume of 7.6 l/min, and MAP of 16.0 cmH2O (P/F ratio, 130.6; OI, 12.2).
<para2>Figure 1 shows the changes in laboratory data and Fig. 2 shows the changes in the P/F ratio, PaCO2, and OI. There were no apparent infections during the early postoperative period. On the seventh postoperative day, the P/F ratio exceeded 200 and FIO2 was decreased to 0.5. The patient was weaned from CHDF on the eighteenth postoperative day. Mechanical ventilation was needed until the forty-second postoperative day because of left phrenic nerve paralysis and bacterial pneumonia, and then the patient was transferred to a general ward.
<A>Discussion
<para1>In our patient, HFOV immediately improved ventilation, but not oxygenation. In HFOV, a high-lung
volume strategy, using a higher MAP than that of conventional mechanical ventilation, has proven to be effective and important in improving oxygenation [35]. Because of the patients unstable hemodynamics, we used a lower MAP than that of PCV. We performed sustained ination, using a pressure of 35 cmH2O for 30 s when starting HFOV. This pressure was same as the plateau pressure during PCV. As a result, oxygenation with HFOV was same as that with PCV (same level of P/F ratio, but lower OI). This means that the number of lung units that were open and ventilated was not increased with HFOV. A recent animal study, embracing the open lung concept, [8] has shown that HFOV and PCV had the same effect on oxygenation when an identical MAP was used after the same recruitment maneuver. This study well explains why oxygenation was not improved in our patient. To improve oxygenation with HFOV, not only a higher MAP but also sustained ination using higher pressure may be essential to recruit more lung units and keep them open.
<para2>Oxygenation was immediately improved with the rst trial of the prone position during HFOV. The effect of the prone position is generally thought to be brought about by better recruitment and/or better ventilation/perfusion matching [911]. Because improved oxygenation continued after the patient was returned to the supine position, it is conceivable that better recruitment was obtained with the prone position and was maintained with HFOV after the return to the supine position. This may explain why the second trial of the prone position was less effective in improving oxygenation than the rst trial. Three hours after the switching of HFOV to PCV, oxygenation had improved further. This may have occurred because we did not perform sustained ination periodically during HFOV. If sustained ination had been performed periodically, some further recruitment and further improvement of oxygenation may have been obtained. Although CHDF was performed during and after HFOV, the patients clinical course shows that CHDF had no direct relationship to the improvement of oxygenation during or immediately after HFOV.
<para2>With the changing of PCV to HFOV, ventilation
improved immediately. The prototype HFOV machine we used produces a maximum SV of 140 ml at 9 Hz and a maximum SV of 80 ml at 15 Hz with an 8-mm endotracheal tube. The reason that we used 9 Hz is that it is the lowest frequency in this machine. In HFOV, a frequency of 10 to 15 Hz has been used for neonates [3], 5 to 10 Hz for pediatric patients [4], and around 5 Hz for adults [5,6]. The reason that around 5 Hz has been used for adults [5,6] is that it was difcult to obtain enough ventilation at a higher frequency, because of the limited capacity of the machine used. In HFOV, the SV required to get the same alveolar ventilation becomes lower as the frequency becomes higher. On the other hand, the ventilatory capacity of the HFOV machine is reduced when a higher frequency is used because the SV produced by the machine becomes much lower with higher frequency. If a lower SV produces less ventilator-induced lung injury in HFOV, a higher frequency may be benecial for ARDS lungs.
<para2>Although G-CSF has been used safely in patients in intensive care units [12,13], there are a few reports
that suggest that G-CSF can induce ARDS [1416]. Takahashi et al. [16] showed that the use of G-CSF increased the incidence of ARDS caused by pulmonary infection in patients with hematological malignancy. In our patient, because the onset of ARDS occurred before the administration of G-CSF, the cause of ALI/ARDS was thought to be systemic inammatory response syndrome (SIRS) following surgical stress. However our patients status deteriorated rapidly after the second administration of G-CSF. Therefore, the G-CSF administered may have played a role as an exacerbating factor. We used methylprednisolone (1 g/day) for 3 days after the second administration of G-CSF. Steroid pulse therapy was reported to be very useful for the treatment of ARDS related to G-CSF administration [16], thus, the steroid treatment we employed may have contributed to the patients successful outcome.
<para2>In conclusion, we have reported an adult with ARDS that was successfully managed with HFOV and the prone position. We suggest that HFOV may be a useful new tool for adult patients with ARDS.
<A>References
<REF> 1. Amato MBP, Barbas CSV, Medeiros DM, Magaldi RB, De Paula Pinto Schettino G, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CRR (1998) Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347354
<REF> 2. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes for acute lung injury and acute respiratory distress syndrome. N Engl J Med 342:13011308
<REF> 3. Gerstmann DR, Minton SD, Stoddard RA, Meredith KS,
Monaco F, Bertrand JM, Battisti O, Langhendries JP, Francois A, Clark RH (1996) The provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory and clinical outcome in respiratory distress syndrome. Pediatrics 98:10441057
<REF> 4. Arnold JH, Hanson JH, Toro-Figuero LO, Gutirez J, Berens RJ, Anglin DL (1994) Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. Crit Care Med 22:15301539
<REF> 5. Fort P, Farmer C, Westerman J, Johannigman J, Beninati W, Dolan S, Derdak S (1997) High-frequency oscillatory ventilation for adult respiratory distress syndromea pilot study. Crit Care Med 25:937947
<REF> 6. Brambrink AM, Brachlow J, Weiler N, Eberle B, Elich D, Joost T, Koller M, Huth R, Heinrichs W (1999) Successful treatment of a patient with ARDS after pneumonectomy using high-frequency oscillatory ventilation. Intensive Care Med 25:11731176
<REF> 7. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R, and the Consensus Committee (1994) The American-European consensus conference on ARDS: denitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818824
<REF> 8. Vazquez de Anda GF, Hartog A, Verbrugge SJC, Gommers D, Lachmann B (1999) The open lung concept: pressure controlled ventilation is as effective as high frequency ventilation in improving gas exchange and lung mechanics in surfactant-decient animals. Intensive Care Med 25:990996
<REF> 9. Guerin C, Badet M, Rosselli S, Heyer L, Sab JM, Langevin B, Philit F, Fournier G, Robert D (1999) Effects of prone position on alveolar recruitment and oxygenation in acute lung injury. Intensive Care Med 25:12221230
<REF>10. Sinclair SE, Albert RK (1997) Altering ventilation-perfusion relationships in ventilated patients with acute lung injury. Intensive Care Med 23:942950
<REF>11. Walther SM, Domino KB, Glenny RW, Hlastala MP (1999) Positive end-expiratory pressure redistributes perfusion to dependent lung regions in supine but not in prone lambs. Crit Care Med 27:3745
<REF>12. Gross-Weege W, Weiss M, Schneider M, Wenning M, Harms B, Dumon K, Ohmann C, Rer H-D (1997) Safety of a low-dosage lgrastim (rhG-CSF) treatment in non-neutropenic surgical intensive care patients with an inammatory process. Intensive Care Med 23:1622
<REF>13. PettilV, Takkunen O, Varpula T, Markkola A, Porkka K, Valtonen V (2000) Safety of granulocyte colony-stimulating factor (lgrastim) in intubated patients in the intensive care unit: interim analysis of a prospective, placebo-controlled, double-blind study. Crit Care Med 28:36203625
<REF>14. White K, Cebon J (1995) Transient hypoxemia during recovery in febrile patients. Lancet 345:10221024
<REF>15. Schilero GJ, Oropello J, Benjamin E (1995) Impairment in gas exchange after granulocyte colony stimulating factor (G-CSF) in a patient with the adult respiratory distress syndrome. Chest 107:276278
<REF>16. Takahashi Y, Kobayashi Y, Chikayama S, Ikeda M, Kondo M (1999) Effect of granulocyte/colony-stimulating factor on the onset of the adult respiratory distress syndrome. Acta Hematol 101:124129

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<JN>J Anesth (2002) 16:7983
<PT>
<CT>Blood component therapy guided by celite-activated thromboelastography for perioperative coagulopathy
<CA>Jun Kawasaki1, Kenichi A. Tanaka2, Nobukazu Sato2, Toshie Saitoh1, Masahiro Shimizu1,
and Taro Kawazoe1
<ADD>1 Department of Anesthesiology, Saitama Medical Center, Saitama Medical School, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan
<ADD>2 Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Rd, NE, Atlanta, GA 30322, USA
<KW>Key words Thromboelastogram Platelet defects Fibrinoly-
sis Coagulopathy Intraoperative monitoring
<A>Introduction
<para1>Thromboelastography (TEG) is a viscoelastic measurement of clot formation, originally described by Hartert in 1948 [1]. Multiple parameters can be obtained from the TEG trace (Fig. 1c, Table 1). Clinically, TEG was shown to be effective in guiding transfusion therapy
in the early days of liver transplantation [2]. Further modications of TEG, including celite activation and heparinase, have been introduced, making TEG a point-of-care coagulation monitor in a wide variety of surgical procedures [37]. At our institution, TEG with celite activation is performed in the operating room by anesthesiologists. Briey, the blood sample is collected from the existing arterial line using a two-syringe technique. One milliliter of the whole blood sample is placed in a vial containing 90 of celite particles in normal saline (1% celite concentration), and, after being mixed by inversion ve times, 0.36 ml of the whole blood is pipetted into a prewarmed plastic cup (37C). With the use of celite as a coagulation activator, the blood is activated more rapidly and homogeneously, leading to a more rapid assessment of coagulation status. Reduced time for obtaining the maximum amplitude and lysis index is a clear advantage over the conventional TEG [7,8]. We report three patients in whom on-site TEG (C-TEG3000T; Haemoscope, Niles, IL, USA) was useful in monitoring coagulation status and guiding the blood component therapy.
<A>Case 1
<para1>Case 1 was a 54-year-old man (weight, 65 kg;
height, 160 cm), who while a bicycling was involved in
a head-on collision with a truck. He was brought to the emergency room with ndings of a slightly depressed level of consciousness (Glasgow Coma Scale [GCS]-
II score of 4). His abdomen was distended, and
computed tomography (CT) scanning revealed a high-
resolution lesion that was widespread throughout
the mesentery, consistent with intraabdominal bleeding. He was orally intubated, and 1800 ml of packed red blood cells (RBC) was administered in the emergency room.
<para2>Subsequently, he was brought to the operating
room for exploratory laparotomy. General anesthesia was maintained with O2 and sevourane. We were not able to detect any clot formation on celite-activated TEG immediately after induction of anesthesia
(Fig. 1A). The patient showed continuous bleeding, which required crystalloid 5700 ml; RBC 3600 ml; and fresh frozen plasma (FFP), 1200 ml. Tranexamic acid 1500 mg was given because increased brinolysis was also suspected from the minimal clot formation. Blood loss was estimated as 12 000 ml by the time surgical
hemostasis was established. Subsequent TEG showed near-normal reaction (R) time (8.3 min), but severely decreased angle and maximum amplitude (MA; 23 and 19 mm), suggesting decreased platelet count (Fig. 1B). It also showed hyperbrinolysis (Lysis index at 60 min [LY60], 17.5%). Platelet count was measured together with the second TEG, and it was 23 000/mm3, consistent with a reduced angle and MA. Thirty-ve units of platelets, FFP 560 ml, and tranexamic acid 1000 mg were given. At the end of the surgery, TEG showed near-normal values (Fig. 1C; R, 2.5 min; 54; MA, 47 mm; and LY60, 5.5%).
<para2>There was no increased bleeding from the drainage tube after the operation.
<A>Case 2
<para1>Case 2 was a 28-year-old woman, a primigravida (weight, 62.5 kg; height, 158 cm), at 41 weeks of gestation, who was admitted because of abdominal pain and dizziness. She had no signicant past medical history. Decreased fetal heart rate and placental hemorrhage were observed on an ultrasonogram, and abruptio
placentae with fetal distress was diagnosed. She was brought to the operating room for emergency cesarean section. The preoperative laboratory data were as
follows: WBC, 24 000/mm3; hemoglobin, 11.7 gl21; hematocrit, 35.1%; and platelet count, 96 000/mm3. Coagulation tests such as prothrombin time PT international normalized ratio [INR], 3.36; activated partial thromboplastin time (APTT), 77.6 s; and brinogen, less than 50 mgl21, suggested a consumptive coagulopathy. No marked changes in serum electrolyte values were noted.
<para2>The patient was orally intubated and general anesthesia was maintained with O2/N2O initially, and with O2/N2O with sevourane after the fetus was delivered dead. Massive hemorrhage occurred when the placenta was delivered. The initial celite-TEG suggested severe brinolysis (R, 17.5 min; MA, 1 mm; LY60, 100%) (Fig. 2A). Tranexamic acid 1500 mg was administered along with RBC 1680 ml, and FFP 1600 ml. Two hours after the initial treatment, vital signs were stabilized, and we measured the second TEG (Fig. 2B), which showed resolution of the hyperbrinolysis. However, the R time (15.3 min) was twice the normal level, and the angle (25.5) and MA (30.5 mm) were nearly half the normal values, suggesting deciencies of both coagulation factors and platelets. The platelet count, measured simultaneously with the second TEG, was 52 000/mm3. Based on these results, FFP 800 ml and 20 units of platelets were administered. A third TEG was obtained at the end of surgery (Fig. 2C). There were signicant improvements in the angle (57.5) and MA (53 mm) with a slight prolongation of R time (9.5 min). The patient was transferred to the intensive care unit (ICU) in stable condition. She did not require other blood products, except for RBC 720 ml for anemia while in the ICU.
<A>Case 3
<para1>Case 3 was a 48-year-old woman (weight, 125 kg; height, 165 cm), who was scheduled for coronary artery bypass graft surgery. She had a non-Q wave myocardial infarction 3 days prior to the surgery. Cardiac catheterization showed 70% stenosis of the proximal left anterior descending (LAD) artery, 60% stenosis of the mid right coronary artery (RCA), and an estimated ejection fraction of 25%. She had a history of noninsulin-dependent diabetes mellitus, obesity, and deep venous thromboses. Her preoperative medication included amlodipine, metformin, nitroglycerin, and coumadin. Coumadin was replaced with heparin 3 days prior to the surgery.
<para2>Laboratory data showed normal electrolyte values; hematocrit was 39.5%; platelet count, 245 000/mm3; and PT (INR), 1.30.
<para2>Anesthesia was induced with sodium thiopental,
fentanyl, and pancuronium, and was maintained with isourane/O2. The baseline celite-TEG was obtained with the addition of heparinase to the blood sample (4 Ul21) to neutralize preoperatively administered heparin (Fig. 3A). The normal R time (2.5 min) suggested no signicant residual effect of coumadin. The moderate reduction of MA (47 mm) suggested a dysfunction of brinogen-platelet interaction. Intraoperative heparin anticoagulation was monitored by the kaolin-activated coagulation time (ACT), using a Hemochron device (International Technodyne, Edison, NJ, USA). Baseline ACT was 297 s. After the administration of bovine-lung heparin 50 000 units, kaolin-ACT was more than 1000 s. Subsequently, high-dose aprotinin was administered throughout the surgery (2 3 106 KIU loading dose; 0.5 KIU21 infusion). Two-vessel coronary bypass was performed using saphenous venous grafts during moderate hypothermia (32C) on cardiopulmonary bypass (CPB). When the patient was rewarmed to 35.5C, blood samples for platelet count and brinogen level were sent to the laboratory, and
the celite-TEG with heparinase was repeated (Fig. 3B). The TEG result showed a further reduction in MA (38.0 mm), and a prolonged R time (11 min). At this point, 16 units of platelet concentrates and 2 units of FFP were ordered and thawed. The patient was weaned from the CPB with norepinephrine and milrinone infusion. Protamine 200 mg was administered to neutralize heparin, and the ACT returned to 134 s. RBC 350 ml were given for low hematocrit (23%). When the preordered blood products became available, the laboratory data were also returned, which conrmed the TEG results: platelet count, 79 000/mm3 and brinogen, 75 mgl21. After the transfusion of platelets and FFP, TEG was repeated (Fig. 3C; R, 7.3 min; 43; MA, 46 mm). In addition, cryoprecipitate 150 ml was given
to supplement brinogen. After the cryoprecipitate, the repeat TEG revealed full recovery of hemostatic function (R, 7 min; 57.5; MA, 52.5 mm) (Fig. 3D). The patient was transferred to the ICU in a stable condition. She required 1000 ml of RBC to replace the total chest tube drainage of 1315 ml over 24 h, but no other hemostatic products were necessary while she was in the ICU.
<A>Discussion
<para1>The three cases described here show the usefulness of TEG in the settings of massive hemorrhage, consumption coagulopathy, and CPB-induced coagulopathy. The conventional method for managing perioperative bleeding is the transfusion of uid and the empirical
use of blood products, with or without inotropic support to stabilize the hemodynamic parameters. Additional blood products are ordered when abnormal coagulation test results are reported. The standard laboratory coagulation tests are PT and APTT, which require citrate anticoagulation and blood centrifugation to obtain plasma. Because of their relatively long turn-around times (3040 min), these tests are not suitable for point-of-care coagulation monitoring. Several whole blood PT/APTT monitors are available for use at the bedside, but correlations with the standard PT/APTT are questionable in complex clinical situations [9]. Equivalent information on clotting factor activity can be obtained by celite-activated TEG within 1520 min (R time; Fig. 1), along with the quantitative measure of brin-platelet interaction (and MA; Fig. 1). Modied TEG with celite, a diatomaceous earth, provides several advantages over native (nonactivated) TEG. Celite-induced factor XII activation accelerates thrombin formation, leading to more rapid assessment of coagulation status. Sharma et al. [7] reported an up to fourfold reduction
in R time, and an up to 73% increase in angle when celite-activated TEG was compared with native TEG in pregnant women. Yamakage et al. [8] also reported that celite-activated TEG resulted in an approximately
50% reduction in R time and a 19% increase in MA when compared with native TEG. In addition, detec-tion of brinolysis was possible 30 min after MA with celite-activated TEG, in contrast to 60 min with native TEG.
<para2>We observed enhanced brinolysis in our cases 1 and 2. Systemic hyperbrinolysis may cause perioperative bleeding, such as that seen in liver transplantation,
cardiac surgery, or disseminated intravascular coagulopathy. It is not practical to order laboratory tests for brinolysis in acute settings, because the turn-around time for these tests (D-dimers and brin degradation products) is very long (several hours). On the other hand, hyperbrinolysis can be detected on TEG within 1 h, as seen in our cases [8]. The inappropriate use of antibrinolytic drugs, such as tranexamic acid, may
result in a thrombotic condition. Therefore, it is important to monitor coagulation before and after specic treatment. In cases 1 and 2, we were able to observe
the resolution of clinical brinolysis after the administration of tranexamic acid and FFP. Low platelet counts were observed in all three of our patientscases 1, 2, and 3 (platelet counts, 23, 52, and 79 3 1000/mm3,
respectively). The simultaneous TEG results were all abnormal: MA, 19; 30.5, and 38 mm, respectively.
Recently, Khurana et al. [10] reported that the clot strength on TEG (MA) was a function of platelet
concentration. They utilized various concentrations of glycoprotein (GP) IIb/IIIa inhibitor (c7E3 Fab) to block platelet function, delineating the contribution
of platelets to the clot formation. Platelet GP IIb/IIIa
is a site for brinogen binding, which plays a pivotal
role in the formation of the hemostatic plug. Platelets enhance clot strength by eightfold, relative to platelet-free brin clots seen on TEG. Platelet counts can be obtained in 3040 min in the laboratory, but this provides only quantitative information. Thus, the qualitative and quantitative information on platelet function provided by TEG seems more timely (15 min) and
practical.
<para2>The patients that we have described here required multiple blood products for hemostasis. Conventional blood product management has a long turn-around time: laboratory tests plus preparation of products by the blood bank. The bedside use of TEG enabled us to diagnose hemostatic abnormality and prepare blood products in a more timely manner. Lack of early detection of hemostatic abnormality and appropriate therapy can result in serious consequences: hemorrhage, and hemodynamic instability, followed by massive uid transfusion. The latter may lead to signicant hemodilution, worsening coagulation function. On the other hand, the administration of unnecessary hemostatic products may not only increase the risk of hypercoagulability but may also increase the chance of anaphylactic reactions or blood-borne infection. In our patients, the responses to blood products were monitored by repeated TEG, and we were able to guide our transfusion therapy. There was no indication of a hypercoagulable state. TEG is one of the coagulation tests that is useful for reducing the consumption of blood products during surgery [2,4,5].
<para2>In summary, we would like to recommend the use of celite-activated TEG in high-risk surgical patients as a point-of-care coagulation monitor.
<A>References
<REF> 1. Hartert H (1948) Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klin Wochenschr 26:577583
<REF> 2. Kang YG, Martin DJ, Marquez J, Lewis JH, Bontempo FA, Shaw BW Jr, Starzl TE, Winter PM (1985) Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 64:888896
<REF> 3. Sharma SK, Phillip J, Whitten CW, Padakandla UB, Landers DF (1999) Assessment of changes in coagulation in parturients with preeclampsia using thromboelastography. Anesthesiology 90:
385390
<REF> 4. Shore-Lesserson L, Manspeizer HE, DePerio M, Francis S, Vela-Cantos F, Ergin MA (1999) Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 88:312319
<REF> 5. Spiess BD, Tuman KJ, McCarthy RJ, DeLaria GA, Schillo R, Ivankovich AD (1987) Thromboelastography as an indicator of post-cardiopulmonary bypass coagulopathies. J Clin Monit 3:2530
<REF> 6. Moriwaki K, Sato N, Kubota M, Maekawa T, Maehara T, Nomura M, Sasaki H, Nakatani K, Yuge O (1992) Thrombelastography as a bedside monitor of coagulation and brinolysis during surgery. A report of three cases (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 41:11451150
<REF> 7. Sharma SK, Philip J, Wiley J (1997) Thromboelastographic changes in healthy parturients and postpartum women. Anesth Analg 85:9498
<REF> 8. Yamakage M, Tsujiguchi N, Kohro S, Tsuchida H, Namiki A (1998) The usefulness of celite-activated thromboelastography for evaluation of brinolysis. Can J Anaesthe 45:993996
<REF> 9. Werner M, Gallagher JV, Ballo MS, Karcher DS (1994) Effect
of analytic uncertainty of conventional and point-of-care assays
of activated partial thromboplastin time on clinical decisions in heparin therapy. Am J Clin Pathol 102:237241
<REF>10. Khurana S, Mattson JC, Westley S, ONeill WW, Timmis GC, Saan RD (1997) Monitoring platelet glycoprotein IIb/IIIa-brin interaction with tissue factor-activated thromboelastography. J Lab Clin Med 130:401411
<REF>11. von Kier S, Royston D (1998) Reduced hemostatic factor transfusion using heparinase-modied thromboelastography (TEG) during cardiopulmonary bypass (CPB). Anesthesiology 89:3A, A911

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<JN>J Anesth (2002) 16:8486
<PT>
<CT>Post-herpetic neuralgia in a patient with congenital insensitivity to pain and anhidrosis
<CA>Toshiya Tomioka1, Yutaka Awaya2, Kenji Nihei3, and Kazuo Hanaoka1
<ADD>1 Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, 3-1 Hongo 7-chome, Bunkyo-ku, Tokyo 113-8655, Japan
<ADD>2 Department of Pediatrics, Seibo International Catholic Hospital, 5-1 Naka-Ochiai 2-chome, Shinjyuku-ku, Tokyo 161-8521, Japan
<ADD>3 Department of Pediatric Neurology, National Pediatric Hospital, 35-31 Taishidou 3-chome, Setagaya-ku, Tokyo 154-8509, Japan
<KW>Key words Congenital insensitivity to pain and anhidrosis Post-herpetic neuralgia Itching
<A>Introduction
<para1>Congenital insensitivity to pain and anhidrosis (CIPA) is an inherited disease. CIPA is characterized by episodes of unexplained fever, systemic analgesia, anhidrosis, and mental distress. These symptoms occur because of an abnormality of the trkA gene, a receptor tyrosine kinase of nerve growth factor (NGF) [1]. Patients with CIPA often experience trauma, fracture, and even osteomyelitis because of their insensitivity to pain.
<para2>We experienced a patient who had been diagnosed with CIPA who complained of itching as a sequela of Herpes zoster infection. We believe that this itching was a symptom of post-herpetic neuralgia. Post-herpetic neuralgia is dened as persistent pain that follows a Herpes zoster infection; however, the mechanism of post-herpetic neuralgia is not known. We present a report of this patient and discuss the mechanism of post-herpetic neuralgia in this individual.
<A>Case report
<para1>The patient was a 27-year-old man who had had a fever of unknown cause at birth. He was diagnosed with CIPA at 6 months of age. He had systemic analgesia, and post-traumatic scars were found all over his body. He had anhidrosis, and showed little sweat with various sweat stimulus tests, such as thermal stimulus. In autonomic functional tests, he showed a normal cardiovascular reaction to norepinephrine and methacholine tolerance tests. He showed no reaction on the axon reex test. In the right ulnar nerve, the sensory nerve conduction velocity was 50 m/s, and the motor nerve conduction velocity was 36 m/s. The motor nerve conduction velocity was slighty delayed. Nerve biopsy had not been done. His intelligence was at the level of a
3-year-old boy.
<para2>On March 6, 1997, he experienced a Herpes zoster infection, at the Th 1012 levels, and complained of feeling uncomfortable and having a burning sensation. He could not sleep at night because of the burning sensation. His cutaneous symptoms showed the typical aspect of Herpes zoster infection. He had a slight fever, and his appetite was decreased. On March 8, 1997, he was taken to consult a dermatologist. He was treated intravenously with the antiviral drug, aciclovir, and
intradermally with the antiviral drug, vidarabine. No analgesics were prescribed by the dermatologist. He complained of pain in the involved cutaneous regions, but this complaint was not regarded as real pain by the parents, because he used to express discomfort as
pain. One week later, on March 14, 1997, when the dermal symptoms and the burning sensation had almost subsided, he began to complain of itching, and was treated orally with an antihistamines chlorpheniramine maleate. The itching increased in severity for about 3 months.
<para2>At follow-up in August, 1998, when he was brought to our department, he was still experiencing some itching, but it had mostly subsided. His clinical course is shown in Fig. 1. All the dermal symptoms had resolved, except for pigmentation. He had never complained of a sense of itching, and he had not scratched his body because of itching. Even when bitten by mosquitoes, he had never complained of itching.
<A>Discussion
<para1>Hereditary sensory and autonomic neuropathy (HSAN) is classied into ve types: I: sensory radicular neuropathy, II: congenital sensory neuropathy, III:
familial dysautonomia or Riley-Day syndrome, IV:
congenital insensitivity to pain with anhidrosis, and V hereditary sensory neuropathy with predominant loss
of small myelinated nerve bers. CIPA corresponds to type IV HSAN [2]. CIPA is characterized by insensitivity to pain, anhidrosis, and mental retardation. [3,4] Recently, Indo et al. [1] reported that a lack of the nerve growth factor (NGF) gene on chromosome 1 caused some cases of this disease. The insensitivity to pain is derived from a lack of the thin myelinated and unmyelinated nerve bers that conduct the pain impulse.
The sweat deciency results from a lack of the peripheral sympathetic end-bers that innervate the blood vessels surrounding the sweat glands. The case in our patient was classied as type IV HSAN from the clinical ndings, such as insensitivity to pain and anhidrosis at birth, and the mental retardation shown after growing up.
<para2>Post-herpetic neuralgia is dened as persistent pain subsequent to Herpes zoster infection. Histologically,
in this disorder, the peripheral nerves show greater
damage to the thick myelinated bers than to the thin myelinated and unmyelinated nerve bers [2,5]. The mechanism of post-herpetic neuralgia is not known; however, both an imbalance between the peripheral excitatory or inhibitory neurons, and/or the presence of spinal deafferented neurons may play a role [6,7]. The general mechanism of itching is twofold: there is a central mechanism via opioid receptors, and a peripheral mechanism via unmyelinated nerve bers. We speculate that the peripheral mechanism caused the itching in
our patient. A pattern theory and a specic receptor theory have been advanced to explain the peripheral mechanism of itching. According to the pattern theory, an increase in C-ber spikes causes not only itching but also pain.
<para2>Although CIPA is characterized by a marked decrease in thin myelinated and unmyelinated nerve bers, with normal thick myelinated bers, the Herpes zoster virus generally damages normal thick myelinated bers. While the mechanism of the itching in our patient remains unclear, it is possible that the Herpes zoster virus damaged the normal thick myelinated nerve bers, and the remaining few unmyelinated nerve bers temporarily predominated, resulting in this patient experiencing itching as a symptom of post-herpetic neuralgia. In other words, this patient did not have enough unmyelinated nerve bers to experience pain, and he therefore complained of itching.
<para2>In summary, we experienced a patient with CIPA who complained of itching as a sequela of Herpes zoster infection. We believe that this itching was a symptom of post-herpetic neuralgia.
<A>References
<REF>1. Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I (1996) Mutations
in the TRAK/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nature Genetics 13:485
488
<REF>2. Zacks SI, Langtt TW, Elliott FA (1964) Herpetic neuritis. A light and electron microscopic study. Neurology 14:744750
<REF>3. Dyck PJ, Mellinger JF, Regan TJ, Horowitz SJ, McDonald JW, Litchy WJ, Daube JR, Fealey RD, Go VL, Kao PC, Brimijoin WS, Lambert EH (1983) Not indifference to pain but varieties of hereditary sensory and autonomic neuropathy. Brain 106:373
390
<REF>4. Thrush DC (1973) Congenital insensitivity to pain. Brain 96:369386
<REF>5. Watson CPN, Morshead C, Van der Kooy D, Deck J, Evans RJ (1988) Post-herpetic neuralgia; post-mortem analysis of a case. Pain 34:129138
<REF>6. Cine MA, Ochoa J, Torebjork HE (1989) Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 112:621647
<REF>7. Rowbotham MC, Fields HL (1996) The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 119:347354

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<JN>J Anesth (2002) 16:8789
<PT>Short communication
<CT>Simple high-performance liquid chromatographic assay of propofol in human and rat plasma and various rat tissues
<CA>Hiroshi Seno1, Yan-Ling He1, Chikara Tashiro1, Hiroshi Ueyama2, and Takashi Mashimo2
<ADD>1 Department of Anesthesiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan
<ADD>2 Department of Anesthesiology, Osaka University Medical School, Osaka University, Suita 565-0871, Japan
<KW>Key words Propofol HPLC Tissue concentration
<para1>The use of propofol is becoming increasingly widespread as an intravenous anesthetic agent suitable for the induction and maintenance of anesthesia and for sedation in critically ill patients. The analysis and
monitoring of the concentrations of propofol aids in attempts to determine the minimal dose sufcient for an individual patient to maintain anesthesia and help to decrease the risk of drug-related complications and interactions. Recent studies have shown that the concentration of propofol at the effect site, estimated based on the effect-compartment model, was more accurate for predicting the onset of propofol effect than the plasma concentration [1,2]. Furthermore, the redistribution of propofol from various tissues has a more signicant impact on the time required for a patient to recover from propofol anesthesia than the elimination clearance of the drug in the awakening phase. To explore the implications of tissue distribution kinetics in the pharmacokinetics and pharmacodynamics of propofol,
measurement of the concentrations of propofol in various tissues is indispensable. The objective of the present study was to develop a simple method for the assay of propofol in plasma and tissues.
<para2>Propofol (2,6-diisopropylphenol) was purchased from Aldrich (Milwaukee, WI, USA). Acetonitrile and water of high-performance liquid chromatography (HPLC) grade were purchased from Wako Pure Chemical Industries (Osaka, Japan). The HPLC apparatus we used (LC-10AD; Shimadzu, Kyoto, Japan) is comprised of a uorimetric detector (RF-10AD; Shimadzu), degasser (DGU-14A; Shimadzu), autoinjector (SIL-10AD; Shimadzu), and column oven (CTO-10AS; Shimadzu). A Symmetry C18 column (3.5-, 4.6 3 100 mm; Waters, Tokyo, Japan) was selected for the separation of propofol. The temperature of the column oven was set at 40C. The mobile phase consisted of acetonitrile and water (60 : 40, vol/vol), which was equilibrated at 1.5 ml in21. The uorimetric detector was used for quantifying propofol, and the concentration of propofol was estimated based on the integrated peak area. The excitation and emission wavelengths for the uorescence detection of propofol were set at 276 and 310 nm, respectively [3].
<para2>Various rat tissues (brain, liver, kidney, and adipose and muscle tissues) harvested from rats anesthetized with pentobarbital (40 mgg21 i.p.) were rinsed with chilled saline to remove contamination with blood. The tissues were subdivided into small pieces with a scalpel and placed in homogenization vessels to prepare homogenates. The mobile phase, equal to nine times
the tissue weight, was then added, and the tissue was homogenized at 2000 rpm to a uniform slurry (Digital Homogenizer; Iuchi, Osaka, Japan). To 100 of plasma or 10% tissue homogenate, 1000 of acetonitrile was added and mixed thoroughly in a vortex mixer. The mixture was centrifuged at 15 000 g for 10 min at 4C. Then, 10 of the clear supernatant was directly injected onto the HPLC column. The samples for the calibration curves were prepared from an acetonitrile solution containing propofol at various concentrations. The acetonitrile solutions of propofol were diluted 50 times with plasma or 10% tissue homogenate to obtain the nal concentrations of 0, 0.05, 0.2, 1.0, 2.0, 5.0, and 10 l21 or per gram of wet tissue. The integrated peak area was plotted against the known concentrations of propofol, and calibration curves were constructed by linear regression (Microsoft Ofce 97 Excel; Tokyo, Japan). The slopes of calibration curves constructed with human plasma and various rat tissues were compared with one-way analysis of variance. If the analysis of variance showed a signicant difference, Bonferronis test was performed to compare the values for various tissues with that for human plasma. Differences were considered to be signicant when P , 0.05.
<para2>Figure 1 illustrates the chromatographs of human blank plasma, human plasma containing propofol 0.2 l21, rat brain blank homogenate, and rat brain homogenate containing propofol 0.2 21 wet tissue, respectively, following the deproteinization with acetonitrile. No interference peaks were observed around the retention time for propofol (4.7 min) for either plasma or tissues. As shown in Fig. 1, the areas (heights) of the propofol peaks were almost equal for human plasma and rat brain homogenate, suggesting that the extent
of coprecipitation of propofol with plasma and tissue homogenates was similar. Calibration curves were
constructed by increasing the sample concentrations
while maintaining the injection volume constant (10 ) over the range from 0.05 to 10 l21. The linear
regression characteristics of the calibration curves for propofol in human plasma and various rat tissue homogenates are summarized in Table 1. The slopes of calibration curves constructed with brain, liver, and kidney tissue homogenates showed signicantly different values as compared with that for human plasma (Table 1; P , 0.05), while no differences were observed for adipose and muscle tissues. The variations between
tissue and plasma samples can be attributed to the additional processes involved in the preparation of tissue homogenates. The correlation coefcients of the calibration curves for all rat tissues investigated were .0.999. The limit of quantication of propofol was 0.05 l21 in plasma when 10 of the supernatant was injected.
<para2>The intra- and interassay precision coefcients of variation for measuring propofol at a concentration of 0.2 l21 in human plasma were 1.38% and 1.72%, respectively (Table 2). A better intraassay precision (0.84%) was obtained when the concentration of propofol was increased to 10 l21. The interassay variation at 10 l21 (1.89%) was similar to that for 0.2 l21. The corresponding intra- and interassay precision coefcients of variation for propofol measurement in various rat tissues were ,4% and are summarized in Table 2.
<para2>A variety of HPLC methods for the assay of propofol in blood, plasma, and serum have been developed with UV, uorescence, or electrochemical detection techniques [315]. Most of the methods reported involve either liquid-liquid or solid-phase extraction, and a relatively large sample volume (0.5 to 1.0 ml) is necessary, which is not suitable for mechanism-based phar-
macokinetic and pharmacodynamic (PK/PD) studies
using small animals such as rats. Few methods for
the measurement of propofol reported so far have described the assay of propofol in tissue. Dowrie et al. [14] demonstrated an HPLC-electrochemical detection analytical method for determining the concentrations of propofol in human or rat plasma and a variety of rat tissues utilizing liquid-liquid extraction. In this study, we developed an HPLC method for determining the concentrations of propofol in human plasma and in various rat tissues with uorescence detection. This assay is very simple and has excellent reproducibility, while no extraction procedure is necessary. The plasma concentration can be measured within 20 min, including sample preparation, and only 10 of plasma is necessary for the determination of propofol concentration. Propofol was successfully separated and quantied by the present method, with uorescence detection; this was done
simply by deproteinization with acetonitrile before
injection onto the HPLC system. The limitation of quantication was 0.05 l21 in plasma or 10% tissue homogenate for a 10- injection volume, and this could be decreased to 0.01 l21 by increasing the injection volume. In comparison with the HPLC-UV detection method for determining the concentrations of propofol in plasma by direct injection of the deproteinized plasma onto HPLC developed by Vree et al. [5] and Pavan et al. [10], the present method with uorescence detection showed a much higher sensitivity. No internal standard was used in our assay, because we found excellent linear correlation coefcients for the calibration curves by plotting the integrated areas against the known concentrations of propofol (Table 1). Consistent with our observations, Yeganeh and Ramzan [15] also reported that they found no difference for the quantication of propofol using either the peak-area ratio of propofol to an internal standard (4-tert.-octylphenol) or using the area of propofol alone.
<para2>The currently developed assay is simple and does not need a procedure for extraction from biological uids. It is also sufciently sensitive for the determination of propofol concentrations in plasma and rat tissues for either clinical PK/PD studies or for basic tissue distribution kinetic studies using small volumes of plasma or tissue homogenate. This easy-to-use propofol assay is therefore suitable for routine studies in patients or in small animals.
<ACK>Acknowledgments. The source of nancial support was
two Grants-in-Aid (A-no.10770774 and B-no.11470330) for Scientic Research from the Ministry of Education, Science, Sports and Culture of Japan.
<A>References
<REF> 1. Wakeling HG, Zimmerman JB, Howell S, Glass PS (1999) Targeting effect compartment or central compartment concentration of propofol: what predicts loss of consciousness? Anesthesiology 90:9297
<REF> 2. Struys MM, De Smet T, Depoorter B, Versichelen LF, Mortier EP, Dumortier FJ, Shafer SL, Rolly G (2000) Comparison of plasma compartment versus two methods for effect compartment-controlled target-controlled infusion for propofol. Anesthesiology 92:399406
<REF> 3. Plummer GF (1987) Improved method for the determination
of propofol in blood by high-performance liquid chromato-
graphy with uorescence detection. J Chromatogr 421:171
176
<REF> 4. Adam HK, Douglas EJ, Plummer GF, Cosgrove MB (1981) Estimation of ICI 35,868 (Diprivan R) in blood by high-performance liquid chromatography, following coupling with Gibbs reagent.
J Chromatogr 223:232237
<REF> 5. Vree TB, Baars AM, de Grood PM (1987) High-performance liquid chromatographic determination and preliminary pharmacokinetics of propofol and its metabolites in human plasma and urine. J Chromatogr 417:458464
<REF> 6. Pullen RH, Kennedy CM, Curtis MA (1988) Direct plasma injection using internal surface reversed-phase high-performance
liquid chromatography: feasibility study using propofol as a model compound. J Chromatogr 434:271277
<REF> 7. Mazzi G, Schinella M (1990) Simple and practical high-
performance liquid chromatographic assay of propofol in human blood by phenyl column chromatography with electrochemical detection. J Chromatogr 528:537541
<REF> 8. Uebel RA, Wium CA, Hawtrey AO, Coetzee J (1990) Electrochemical determination of 2,6-diisopropylphenol after high-
performance liquid chromatography of extracts from serum.
J Chromatogr 526:293295
<REF> 9. Bailey LC, Tang KT, Rogozinski BA (1991) The determination
of 2,6-diisopropylphenol (propofol) in an oil in water emulsion dosage form by high-performance liquid chromatography and by second derivative UV spectroscopy. J Pharm Biomed Anal 9:501506
<REF>10. Pavan I, Buglione E, Massiccio M, Gregoretti C, Burbi L, Berardino M (1992) Monitoring propofol serum levels by rapid and sensitive reversed-phase high-performance liquid chromatography during prolonged sedation in ICU patients. J Chromatogr Sci 30:164166
<REF>11. Altmayer P, Buch U, Buch HP, Larsen R (1993) Rapid and sensitive pre-column extraction high-performance liquid chromatographic assay for propofol in biological uids. J Chromatogr 612:326330
<REF>12. Dawidowicz AL, Fijalkowska A (1995) Determination of propofol in blood by HPLC. Comparison of the extraction and precipitation methods. J Chromatogr Sci 33:377382
<REF>13. Knibbe CA, Koster VS, Deneer VH, Stuurman RM, Kuks PF, Lange R (1998) Determination of propofol in low-volume samples by high-performance liquid chromatography with uorescence detection. J Chromatogr B Biomed Sci Appl 706:305310
<REF>14. Dowrie RH, EblingWF, Mandama JW, Stanski DR (1996) High-performance liquid chromatographic assay of propofol in human and rat plasma and 14 rat tissues using electrochemical detection. J Chromatogr B Biomed Sci Appl 678:279288
<REF>15. Yeganeh MH, Ramzan I (1997) Determination of propofol in rat whole blood and plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 691:478482

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<JN>J Anesth (2002) 16:9091
<PT>Letters to the editor
<LCT>Unexpectedly severe hypoxia during sprint swimming
<LCA>Kiyoyuki William Miyasaka
<ADD>Swarthmore College, Swarthmore, PA, USA
<LCA>Yasuyuki Suzuki and Katsuyuki Miyasaka
<LA>Department of Anesthesia and ICU, National Childrens Hospital,
3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan
<para1>To the editor: The possibility of hypoxia during competitive swimming has been recognized for over a decade [1], yet, because of technical limitations, SpO2 has not previously been measured during swimming. We have succeeded in conrm-ing hypoxia during strenuous sprint swimming by using a new generation pulse oximeter (Masimo Set; Masimo, Irvine, CA, USA) [2], which is resistant to motion artifacts, to measure SpO2 from a nger probe. A surgical glove was worn over the hand the sensor was on and polyolen putty was used to make the sensor submersible.
<para2>Three well informed t male athletic swimmers did three 100-m sprints (four 25-m lengths; 28C) with rests between trials. SpO2 and pulse rate were recorded digitally every
second (Profox PFW; Profox Associates, Escondido, CA, USA). Each swimmer breathed into a standard capnometer without a nose clip for ten breaths immediately after nish-
ing the sprint, and the highest end-tidal CO2 values were
recorded.
<para2>A representative graph of the data acquired is presented
in Fig. 1. Unexpectedly signicant arterial hypoxemia, a 6%14% fall (median of 12%) in SpO2 from the baseline, was seen in all the trials, especially at the end of the sprint. Pulse rate
at that time reached as high as 182 per min, indicating how strenuous the trial was.
<para2>Exercise-induced arterial hypoxemia (EIAH) is recognized to occur in t subjects [3], but this is the rst objective report of its occurrence during sprint swimming. Among possible mechanisms that include ventilation-perfusion inequality and O2 diffusion limitation, inadequate compensatory hyperventilation to match the increased CO2 production caused by mechanical limitations during swimming has an important role.
<para2>In this study, the highest observed values of end-tidal CO2 at the end of swimming ranged from 58 to 96 mmHg. This estimated high level of PaCO2 might be characteristic of swimming sprints, as breathing may be sacriced for speed, especially in the nal stretch. We speculate that the combination of an increase in CO2 production and intentional breath-holding decreased alveolar oxygen, causing signicant hypoxia. A similar mechanism was suggested for synchronized swimming, but SpO2 was not measured [4].
<para2>The lowest SpO2 in our series was 83%, but it could be even lower in real sprint racing. The clinical signicance of this hypoxia could not be determined, but further research using this pulse oximeter with a larger number of subjects is warranted. Relative hypoventilation is believed to be the main mechanism for this hypoxemia, as end-tidal CO2 at the end of the sprint was extremely high. The highest end-tidal CO2 observed in this series (96 mmHg) may bring about an alveolar oxygen partial pressure that is as low as 30 mmHg. Because swimming is often recommended for medical reasons [5], it
is important to recognize the increased stress of restricted breathing in strenuous swimming compared with land-based exercises.
<para2>In summary, unexpectedly severe arterial desaturation
during strenuous sprint swimming was detected. Relative hypoventilation is believed to be the main mechanism for
this hypoxemia, as end-tidal CO2 at the end of the sprint was extremely high.
<A>References
<REF>1. Higgins P, Siminski J, Pearson RD (1986) Hypoxic lap swimminga cause of near-drowning. N Engl J Med 315:15521553
<REF>2. Barker SJ, Shah NK (1997) The effects of motion on the performance of pulse oximeters in volunteers. Anesthesiology 86:101108
<REF>3. Rice AJ, Thornton AT, Gore CJ, Scroop GC, Greville HW, Wagner H, Wagner PD, Hopkins SR (1999) Pulmonary gas
exchange during exercise in highly trained cyclists with arterial hypoxemia. J Appl Physiol 87:18021812
<REF>4. Davies N, Donaldson GC, Joels N (1995) Do the competition
rules of synchronized swimming encourage undesirable levels of hypoxia? Br J Sports Med 29:1619
<REF>5. Tanaka H, Bassett DR Jr, Howley ET, Thompson DL, Ashraf M, Rawson FL (1997) Swimming training lowers the resting blood pressure in individuals with hypertension. J Hypertens 15:651657
<FN>Address correspondence to: Katsuyuki Miyasaka
<FN>Received: March 5, 2001 / Accepted: May 15, 2001

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<JN>J Anesth (2002) 16:92
<LCT>Perioperative coronary spasm reported in Japanese journals
<LCA>Koh Mizutani
<LA>Department of Anesthesia, Fuchu Hospital, 1-10-17 Higo-cho, Izumi, Osaka 594-0076, Japan
<para1>To the editor: I read with interest the article by Drs. Koshiba and Hoka [1]. In their investigation, the contributing factors affecting perioperative coronary spasm were elucidated by a survey of the articles published in Japanese journals.
<para2>Why, though, were journals limited to those in Japan? There are many reports of perioperative coronary spasm in Japanese patients in the English-language literature worldwide, as the authors noted. Such reports should be included to elucidate the characteristics of perioperative coronary spasm in the Japanese as an ethnic group, or all reports worldwide should be surveyed to elucidate the general characteristics of this condition.
<A>Reference
<REF>1. Koshiba K, Hoka S (2001) Clinical characteristics of perioperative coronary spasm: reviews of 115 case reports in Japan. J Anesth 15:9399
<LFN>Address correspondence to: K. Mizutani
<LFN>Received: June 28, 2001 / Accepted: August 1, 2001
<LFN>
<LFN>
<LFN>Re: Clinical characteristics of perioperative coronary spasm: reviews of 115 case reports in Japan
<LCA>Kenichiro Koshiba and Sumio Hoka
<LA>Department of Anesthesiology, Kitasato University School of
Medicine, 1-15-1, Sagamihara 228-8555, Japan
<para1>In reply: We appreciate the letter from Dr. Mizutani who is interested in our article. He asked why our research survey did not include reports of perioperative coronary spasm in
Japanese patients that were published outside Japan. As described in the Methods section of our article, we did not limit the data to reports in journals published in Japan. We included reports found from searching Medline (19681998), as well as those in non-indexed Japanese journals. Thus, about 20 case reports in English on Japanese patients were found in citation-indexed journals from the Medline database.
<para2>As pointed out in the letter, there may be differences in the racial characteristics of perioperative coronary spasm. However, our study aimed to elucidate the clinical characteristics of perioperative coronary spasm only in Japanese patients. Therefore, racial characteristics, if any, remain to be
elucidated.
<LFN>Address correspondence to: K. Koshiba
<LFN>Received: August 21, 2001 / Accepted: September 24, 2001

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<JN>J Anesth (2002) 16:9394
<PT>Obituary
<CT>Akira Inamoto (19092001)
<para1>Professor Akira Inamoto died on May 29, 2001. His lovely wife, Hideko, died on February 2, 2000. They were inseparable for the 58 years of a superb, warm marriage. Hideko devoted her full energy to ensuring Dr. Inamotos professional success, nursing him when he suffered from tuberculosis, maintaining their home, and taking care of their two sons, Atsushi (who died in 1997) and Takashi. She was a typical Japanese wife in the best sense of the word. She, unfortunately, died 15 months before her husband. Professor Inamoto is the real founder of modern Japanese anesthesiology. He is mourned not only by family and friends both in Japan and overseas but also by all Japanese anesthesiologists and colleagues in the medical profession.
<para2>Akira Inamoto was born in Kyoto in 1909, and graduated from Hiroshima High School (in the city which, of course, gained notoriety as the rst city to suffer atomic bombing). He graduated from Kyoto University Faculty of Medicine and received his M.D. in 1933. He then undertook training in surgery, with a focus on neurosurgery, and researched the histopathology of brain tumors for his Doctorate of Medical Sciences. Upon completion of his training in neurosurgery and his dissertation, he was promoted to Lecturer of Surgery. His research activities ended when he was drafted into the army during World War II. He served as an Army surgeon in China. At the end of the war, he returned to Kyoto University Hospital as a lecturer. Several months later he developed lung tuberculosis and underwent thoracoplastic surgery. Three years later he dveloped tuberculosis in the spine and underwent laminectomy. He contracted these diseases before modern anesthesiology and pain management were introduced to Japan, and he suffered terrible pain during the intra- and postoperative periods. After recovery, he made up his mind to introduce and establish modern anesthesiology in Japan. At the time, very few physicians were eligible for teaching positions, and he was nominated to the departmental chair of Anesthiology at Kyoto University in 1956. He subsequently visited the United States and Canada to study modern anesthesiology, with nancial support from the Rockefeller Foundation. Before his trip to the United States, he called on Dr. Masao Fujita, who had nished resident training in anesthesiology at Albert Einstein Medical School Hospital and had a fellowship in pediatric anesthesia at Boston Childrens Hospital, to come back to Japan as his associate professor.
<para2>In the United States and Canada, Professor Inamoto visited Cornell University Hospital, Columbia University Presbyterian Hospital, Harvard Medical School Hospital, Boston Childrens Hospital, the Mayo Clinic, McGill University, and the University of Montreal
Hospital, during which trip he met with many world pioneers of anesthesiology, including Professors Artusio, Lund, and Grifth. He also met with young Japanese anesthesiologists studying in the United States who later served as professors of anesthesiology in Japan. He learned of the new anesthetic, halothane, during his visit to the United States, and was immensely impressed by its non-ammability, because during his past career in neurosurgery, electrocautery had been essential for operations. After returning to Kyoto, he extended his research eld to include a comparative study of the effects of halothane and diethyl-ether on the histopathology of the lungs, as well as studies of the neurophysiology of anesthetics, the use of gas chromatography for measuring inhalation anesthetics, and the use of hypothermia for brain protection.
<para2>Professor Inamoto was elected President of the Japan Society of Anesthesiology in 1960. He then hosted
the post-congress meeting of the second Asian and Australasian Congress of Anesthesiology in 1966. Another great contribution was as the Chairman of the Organizing Committee of the 5th World Congress of Anesthesiologists, held in Kyoto in 1972. He was subsequently elected Vice President of the World Federation of the Societies of Anesthesiologists, from 1972 to 1976.
<para2>In 1976, Professor Inamoto was admitted by election as a Fellow of the Faculty of Anaesthetists, Royal
College of Surgeons of the United Kingdom. Professor Inamoto was the rst Japanese anesthesiologist on whom this honor was bestowed. Of his students, nine became professors and departmental chairmen of anesthesiology in Japan. Professor Inamoto authored or co-authored 13 chapters in textbooks and handbooks of anesthesiology and 177 papers in Japanese and overseas journals, including Anesthesiology, the British Journal of Anaesthesia, and Anesthesia and Analgesia. He served for 17 years as a distinguished editor of the Japanese Journal of Anesthesiology. In addition, he served as a president of the Japanese Society of Dental Anesthesia, and as a president of the Japanese Society of Blood Transfusion.
<para2>After retirement from Kyoto University, Professor Inamoto established a new anesthesia department, at Aichi Medical School in Nagoya, in 1973. He then moved to Osaka Dental School in 1976 to inaugurate another department of anesthesiology, for dentistry. In 1981, in recognition of his successful academic career, he was honored by the Emperor, being bestowed with the Third Order of the Rising Sun, which he wears proudly in the photograph.
<para2>Professor Inamoto is survived by his son, Takashi, Professor of Surgery at the College of Medical Technology, Kyoto University. Encouraged by Takashi, both Professor and Mrs. Inamoto converted to Catholicism prior to their deaths, and were given the Christian names, Joseph and Maria.
<para1>Kenjiro Mori, M.D., D.Med.Sc., F.R.C.A.
<para1>Kyoto, August 22, 2001

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