1. Inhibitory effect of prostaglandin E1 on gastric secretion during general anesthesia in humans
2. Interactions of nicardipine to inhalation anesthetics sevoŽßurane and isoŽßuran
3. Total intravenous anesthesia combined with epidural eptazocine
4. Evaluation of a delivery system and monitors for ventilator administration of nitric oxide
5. Relationship between plasma neutrophil elastase and respiratory index of patients who had undergone cardiac surgery with cardiopulmonary bypass
6. Liver and renal functions following total intravenous anesthesia using midazolam and fentanylŽÑcomparison with enŽßurane-nitrous oxide anesthesia
7. Difference of train-of-four fade induced by nondepolarizing neuromuscular blocking drugs: a theoretical consideration on the underlying mechanisms
8. Effects of stellate ganglion block on cardiac coronary circulation
9. The dose-response relationship of amrinone in increasing the contractility of fatigued diaphragm in dogs
10. Anesthesia for laparoscopic cholecystectomy in an elderly patient with emphysematous bullaeŽÑcombined general and epidural anesthesia with spontaneous respiration and abdominal wall-left method
11. Cardiac arrest and rhabdomyolysis after succinylcholine in a healthy child
12. Fat embolism syndrome due to femoral shaft fracture during pregnancy
13. Intraperitoneum insufŽßation of carbon dioxide increases epidural pressure in laparoscopic cholecystectomy
14. Acute laryngeal trauma
15. Comparison of sevoŽßurane and other volatile anesthetics for cesarean section
16. Hemiparesis following carotid endarterectomy
17. A case of pulmonary arteriovenous ŽÞstula in which venous air embolism during cesarean section may have caused postoperative subendocardial infarction
18. A successful case in cancer pain management with high-dose intravenous morphine
19. Anesthetic management for an infant with mitochondrial cytopathy
20. Extracorporeal membrane oxygenation and tracheobronchial foreign body in an infant
21. The effects of graduated compression stocking on blood pressure and heart rate during spinal or epidural anesthesia
22. A simple method to advance a winged epidural needle
23. Reference citation accuracy in the Journal of Anesthesia
24. Report on the computer software contest at the 42nd Congress of the Japan Society of Anesthesiology

(JN)J Anesth (1996) 9:303 - 306
(PT)Original articles
(CT)Inhibitory effect of prostaglandin E1 on gastric secretion during general anesthesia in humans
(CA)Takashi Mashimo, Masaki Takashina, Yoshimi Inagaki, Tomoyoshi Seto, Yuri Tsuda, and Ikuto Yoshiya
(ADD)Department of Anesthesiology, Osaka University Medical School, 2-2 Yamadaoka, Suita-shi, Osaka, 565 Japan
(AB)Abstract: The present study was undertaken to clarify the effects of prostaglandin E1 (PGE1) on gastric secretion during general anesthesia. Thirty-three patients, 16 with (PGE1 group) and 17 without (control group) PGE1 administration, scheduled for selective surgery were studied during general anesthesia with nitrous oxide (67%) and enŽßurane (1%-
2% inspired). PGE1 was administered at a rate of 50-200 ngáÌg21áÎin21 when hypotensive medication was required. In the PGE1 group, gastric juice was collected serially three times before and during administration and 60 min after discontinuation of PGE1. In the control group, it was collected three times corresponding to those in the PGE1 group. The pH of gastric juice increased signiŽÞcantly, and the acidity and pepsin activity decreased after the beginning of the administration of PGE1, and these changes were observed even 1 h after discontinuation. There was signiŽÞcant differences in the pH, acidity, and pepsin activity between the two groups after administration of PGE1. The results indicate that PGE1
inhibits gastric secretion at doses that produce a sufŽÞcient hypotensive effect under general anesthesia.
(KW)Key words: Prostaglandin E1, Gastric secretion, General
anesthesia
(A)Introduction
(para1)Gastric stress ulcer is reported to occur sometimes in critically ill patients after surgery [1]. It was speculated to result from an imbalance between aggressive factors, including acid and pepsin, and defensive factors such
as mucosal resistance to ulcerogenic stimuli [2]. Drugs such as H2 antagonists were widely used to decrease
the secretion of gastric juice and its acidity during perioperative period [3,4].
(para2)Prostaglandin E1 (PGE1), which is used for hypotensive anesthesia and management of hypertension during anesthesia, has not only a hypotensive effect but also various other physiologic actions [5-7]. In 1967, Robert et al. [8] reported that PGE1 suppresses gastric secretion in dogs. Classen et al. [9] also reported that intravenous administration of PGE1 reduces the volume and acidity of gastric juice in humans when gastric secretion is enhanced by gastric stimulation. However, the effects of PGE1 on spontaneous gastric secretion during general anesthesia have not been clariŽÞed. Therefore, we evaluated changes in the gastric secretion in patients who underwent intravenous infusion of PGE1 during general anesthesia.
(A)Patients and methods
(para1)This study was approved by the Committee for Human Research at our institution and informed consent was obtained from all patients. Thirty-three ASA physical status I-II patients scheduled for elective surgery were studied. Gastric secretion was evaluated during anesthesia in 16 patients administered PGE1 (PGE1 group) and 17 controls.
(para2)Atropine sulfate (0.5 mg) and hydroxyzine (50 mg) were administered intramuscularly 30 min before
induction of anesthesia. Standard monitoring was
performed. Anesthesia was induced with thiamylal (4 mgáÌg21) and maintained with nitrous oxide (67%) and enŽßurane (1%-2% inspired). PGE1 was administered intravenously by continuous infusion at a rate
of 50-200 ngáÌg21áÎin21 in patients who required hypotensive medication. Saline as a placebo was administered in the control group.
(para2)A gastric tube was inserted immediately after induction of anesthesia. In the PGE1 group, gastric juice was collected serially three times before PGE1 administration, 60 min after the start of administration, and 60 min after discontinuation. In the control group, it was collected at the same times as in the PGE1 group. After ŽÞltering the gastric juice through absorbent cotton, the pH was determined using a pH tape (Neutralit, Merck, Rahway, NJ, USA), and the remaining sample was frozen until measurement of the acidity and pepsin activity. After the frozen gastric juice sample was thawed, the acidity and pepsin activity were measured in supernatant separated by centrifugation at 3000 rpm for 10 min. The acidity was determined by titration of a dilution of 0.1-1.0 ml of the sample with 50 ml of distilled water against 0.01 N NaOH to an end point of pH 7.0. Titration was made using an automatic titration system (GT-05, Mitsubishi Chemical Industries, Tokyo, Japan). Pepsin activity was determined by a hemoglobin digestion method [10] using 100-200 ùÍ of the sample diluted 3-50 times with 0.04 N HCl. Pepsin values are expressed as micrograms of tyrosine released from the hemoglobin substrate.
(para2)Values are expressed as mean 6 SD. Parametric data between groups were analyzed by one-way analysis of variance and assessed by ScheffeŽÕs test. Parametric data within each group were analyzed by two-way analysis of variance with repeated measures and assessed by paired t-test. A p value less than 0.05 was considered statistically signiŽÞcant.
(A)Results
(para1)Although there were no signiŽÞcant differences in the age or the male-female ratio, the control group showed a signiŽÞcantly lower body weight (Table 1). No signiŽÞcant difference between the two groups was observed in the duration of anesthesia or surgery. The infusion time of PGE1 was 113.8 6 47.9 min and the total administration dose was 483.8 6 232.0 ùÈ in the PGE1 group. The infusion time of saline was 120 min.
(para2)Figure 1A-C shows changes in the pH, acidity and pepsin activity of gastric juice during anesthesia, respectively. In the PGE1 group, the pH of gastric juice
increased signiŽÞcantly and the acidity decreased signiŽÞcantly after the beginning of PGE1 administration. These changes were observed 60 min after the discontinuation. The pepsin activity of gastric juice tended to decrease during the administration of PGE1 and
decreased signiŽÞcantly after the discontinuation. In
the control group, the pH showed as light increase
during the administration of saline but the acidity showed no signiŽÞcant change. In contrast, the pepsin activity increased signiŽÞcantly after the administration of saline.
(para2)There was no difference in the pH, acidity, or pepsin activity of gastric juice between the two groups before the administration of test drug. The pH was signiŽÞcantly higher in the PGE1 group than in the control group during the administration and after the discontinuation of PGE1 (Fig. 1A). The acidity in the PGE1 group was signiŽÞcantly less than that in the control group after the discontinuation (Fig. 1B). The pepsin activity in the PGE1 group after the discontinuation was signiŽÞcantly lower than that in the control group (Fig. 1C).
(A)Discussion
(para1)The pH, acidity, and pepsin activity of gastric juice were all suppressed by PGE1 at 50-200 ngáÌg21áÎin21, indicating that PGE1 inhibits gastric secretion under general anesthesia. The action of PGE1 to elevate the pH of gastric juice was comparable to that of 20 mg of famotidine, an H2 antagonist [4]. The inhibitory action of PGE1 on gastric secretion persisted for at least 60 min after the discontinuation. Goto et al. [11,12] and Takashina et al. [13] reported that the hypotensive
effect of PGE1 was sustained for more than 1 h after the discontinuation under general anesthesia. Since the blood concentration of PGE1 has been shown to decrease to the pre-administration level in about 10 min after the discontinuation [12], the reason for prolongation of the effects of PGE1 remains unclear.
(para2)Classen et al. [9] reported that the gastrin-enhanced increase in gastric secretion was suppressed by PGE1 in healthy adults. However, this result was obtained with
a very large dose of 5-7 ùÈáÌg21 administered over 30 min. They indicated that no effects on the cardiovascular system such as a reduction in blood pressure were noted at this concentration without anesthesia. Dajani [14] and Brand et al. [15] reported that a PGE1 analogue administered orally in humans suppressed gastric
secretion and was effective as a treatment for peptic
ulcer. They speculated that the anti-ulcer effect of PGE1 is derived from inhibition of gastric acid and pepsin secretion and increase in the gastric mucosal blood
Žßow.
(para2)The mechanism of the inhibition of gastric secretion by PGE1 remains obscure. Nevertheless, the presence of prostaglandins in the gastric mucosal cells has been demonstrated [16-18], and they may play an important physiological role in the mechanism of gastric secretion. Coceani et al. [19] clariŽÞed in rats that stimulation of the vagus nerve of the gastric wall promotes secretion of gastric juice as well as of PGE1. Baker et al. [20] reported that pentagastrin and histamine increase gastric acid secretion and promote the release of PGE2 into the gastric juice. Kobayashi et al. [21] also reported that endogenous prostaglandins inhibit acid secretion in humans. These ŽÞndings suggest that prostaglandins serve as mediators of the negative feedback in the regulatory mechanism of gastric secretion. Also, PGE2 is known to bind speciŽÞcally with porcine gastric wall cells and inhibits the increase in cyclic adenosine monophosphate due to histamine stimulation [22]. Therefore, PGE1 and PGE2 are considered to inhibit the H1 transport mechanism of gastric wall cells by reducing cyclic adenosine monophosphate and, thus, to suppress the secretion of gastric juice [23].
(para2)In conclusion, PGE1 suppressed the pH, acidity, and pepsin activity of gastric juice during general anesthesia. The gastric antisecretory effect of PGE1 may be promising for the prevention of gastric stress ulcer in the perioperative period.
(A)References
(REF) 1. Lucas CE, Sugawa C, Riddle J, Rector F, Rosenberg B, Walt AJ (1971) Natural history and surgical dilemma of ŽÒstressŽÓ gastric bleeding. Arch Surg 102:266-277
(REF) 2. Ahlquist DA, Dozois RR, Zinsmeister AR, Malagelada JR (1983) Duodenal prostaglandin synthesis and acid load in health and in duodenal ulcer disease. Gastroenterology 85:522-528
(REF) 3. Coombs DW, Hooper D, Colton T (1979) Preanesthetic cimetidine alteration of gastric Žßuid volume and pH. Anesth Analg 58:183-188
(REF) 4. Abe K, Shibata M, Demizu A, Hazano S, Sumikawa K, Enomoto H, Mashimo T, Tashiro C, Yoshiya I (1989) Effects of oral intramuscular famotidine on pH and volume of gastric contents. Anesth Analg 68:541-544
(REF) 5. Mills DCB, MacFarlane DE (1977) Prostaglandins and platelet adenylate cyclase. In: Silver MJ (ed) Prostaglandins in hematology, Spectrum, New York, pp 219-233
(REF) 6. Ueda Y, Matsuo K, Kamei T, Kayashima K, Konomi K (1989) Protective effect of prostaglandin E1 (PGE1) on energy metabolism and reticuloendothelial function in the ischemically damaged canine liver. Liver 9:6-13
(REF) 7. Anderson RJ, Berl T, McDonald KM, Schrier RW (1976) Prostaglandins: effects on blood pressure, renal blood Žßow, sodium and water excretion (Editorial). Kidney Int 10:205-215
(REF) 8. Robert A, Nezamis JE, Phillips JP (1967) Inhibition of gastric secretion by prostaglandins. Am J Digest Dis 12:1073-1076
(REF) 9. Classen M, Koch H, Bickhardt J, Topf G, Demling L (1971) The effect of prostaglandin E1 on the pentagastrin-stimulated gastric secretion in man. Digestion 4:333-344
(REF)10. Chiang L, Sanchez-Chiang L, Wolf S, Tang J (1966) The separate determination of human pepsin and gastricsin. Proc Soc Exp Biol Med 12:700-704
(REF)11. Goto F, Otani E, Kato S, Fujita T (1982) Prostaglandin E1 as a hypotensive drug during general anaesthesia. Anaesthesia 37:
530-535
(REF)12. Goto F, Otani E, Fujita T (1985) Antihypertensive activity and metabolic rate of prostaglandin E1 in surgical patients under general anesthesia. Prostaglandins Leukot Med 18:359-366
(REF)13. Takashina M, Kamada T, Sasaki S, Mashimo T, Yoshiya I (1990) Effect of prostaglandin E1 (PGE1) on skin blood Žßow and
thermoregulation during enŽßurane anesthesia. Anesthesiology 73:A59
(REF)14. Dajani EZ (1987) Perspective on the gastric antisecretory effects of misoprostal in man. Prostaglandins 33:68-77
(REF)15. Brand DL, Foufail WM, Thomson ABR, Tapper EJ (1985) Misoprostol, a synthetic PGE1 analog, in the treatment of duodenal ulcers. A multicenter double-blind study. Dig Dis Sci 30:147s-158s
(REF)16. Remwell PW, Shaw JE (1968) Prostaglandin inhibition of gastric secretion. J Physiol (Lond) 195:34-36
(REF)17. Bennett A, Friedmann CA, Vane JR (1967) Release of prostaglandin E1 from the rat stomach. Nature 216:873-876
(REF)18. Postius S, Ruoff H-J, Szelenyi I (1985) Prostaglandin formation by isolated gastric parietal and nonparietal cells of the rat. Br J Pharmacol 84:871-877
(REF)19. Coceani F, Pace-Ascia KC, Volta F, Worfe LS (1967) Effects of nerve stimulation on prostaglandin formation and release from the rat stomach. Am J Physiol 213:1956-1964
(REF)20. Baker R, Jaffe BM, Reed JD, Shaw B, Venables CW (1978) Endogenous prostaglandins and gastric secretion in the rat. J Physiol 278:451-460
(REF)21. Kobayashi K, Nakamura H, Arakawa T (1985) Does endogenous prostaglandins inhibit acid secretion? Gastroenterology 88:
1450
(REF)22. Tepperman BL, Soper BD (1980) Prostaglandin E2-binding sites and cAMP production in porcine fundic mucosa. Am J Physiol 242:G313
(REF)23. Butcher RW, Baird CE (1968) Effects of prostaglandins on adenosine 39-59-monophosphate levels in fat and other tissues. J Biol Chem 243:1713-1717 (MW)

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(JN)J Anesth (1996) 9:307 - 310
(PT)
(CT)Interactions of nicardipine to inhalation anesthetics sevoŽßurane and isoŽßurane
(CA)Tomoki Nishiyama and Masaki Nagase
(ADD)Department of Anesthesiology, JR Tokyo General Hospital, 2-1-3 Yoyogi, Shibuya-ku, Tokyo, 151 Japan
(AB)Abstract: The hemodynamic effects and pharmacokinetics of nicardipine under general anesthesia were compared between two different volatile anesthetics, sevoŽßurane and isoŽßurane. Sixteen adult neurosurgery patients were divided into sevoŽßurane and isoŽßurane groups. Anesthesia was maintained with either sevoŽßurane or isoŽßurane (0.5-1.5%) and nitrous oxide in oxygen. When the blood pressure was stabilized [0.5 minimum alveolar concentration (MAC) in both anesthetics] during surgery, nicardipine 1mg, i.v. was administered. Plasma catecholamines and nicardipine concentration were measured, and the pharmacokinetics of nicardipine were calculated. The decrease in blood pressure and the increase in heart rate 30min after nicardipine administration were signiŽÞcant in the isoŽßurane group but not in the sevoŽßurane group. Although plasma catecholamine levels increased after nicardipine administration in the isoŽßurane group, no signiŽÞcant changes were observed in the sevoŽßurane group. The sevoŽßurane group had a signiŽÞcantly longer elimination half-life, a larger area under the plasma concentration curve, and smaller clearance of nicardipine compared to the isoŽßurane group. In summary, the effects of nicardipine on blood pressure and heart rate were signiŽÞcantly longer under isoŽßurane anesthesia than under sevoŽßurane anesthesia. However, the metabolism and excretion of nicardipine were signiŽÞcantly delayed under sevoŽßurane anesthesia.
(KW)Key words: Nicardipine, Pharmacokinetics, Hemodynamics, SevoŽßurane, IsoŽßurane
(1)Introduction
(para1)Nicardipine is a calcium antagonist used for perioperative blood pressure control, however the effects of nicardipine administered in general anesthesia may be modiŽÞed because the anesthetic agent inŽßuences the pharmacokinetics of the agents. Although the effects of nicardipine administered under neurolept-
anesthesia [1], halothane [2], enŽßurane [3], and isoŽßurane [4] anesthesia have been reported, there are few reports on the comparison of the effects of nicardipine between different anesthetics and on sevoŽßurane anesthesia. We have already reported that the hemodynamic effects and pharmacokinetics of nicardipine under enŽßurane anesthesia are different from those under isoŽßurane anesthesia [5]. In the present study, the hemodynamic effects and pharmaco-kinetics of nicardipine under sevoŽßurane anesthesia were compared with those under isoŽßurane anesthesia.
(1)Patients and methods
(para1)Sixteen patients without liver or renal diseases and who were ASA Class 1 or 2 for elective neurosurgery were investigated. They were randomly divided into two groups of eight potients each by the envelope method: sevoŽßurane group and isoŽßurane group.
(para2)We obtained written informed consent from each patient and institutional approval from the Ethics Committee of our hospital.
(para2)As premedication, atropine 0.01mg?kg21 and hydroxyzine 1 mg?kg21 were injected intramuscularly 30 min before the patients arrived at the operating room.
Anesthesia was induced with thiamylal 2 mg?kg21, midazolam 0.1mg?kg21, and fentanyl 0.05 mg. Tracheal intubation was performed with vecuronium 0.15 mg?
kg21. Anesthesia was maintained with either sevoŽßurane or isoŽßurane 0.5 - 1.5% (end-tidal concentration measured with an Ultima Datex, Helsinki, Finland), 3 l?min21 of nitrous oxide in 2 l?min21 of oxygen and fentanyl. Pancuronium was administered for neuromuscular blockade during surgery. End-tidal CO2 concentration was adjusted to 30 -35 mmHg by artiŽÞcial ventilation. After the induction of anesthesia, a catheter was inserted into the dorsal pedal artery to measure blood pressure and to collect blood samples.
(para2)When the microsurgical procedure was started and blood pressure was stabilized, nicardipine 1 mg was
administered as a bolus. Blood pressure and the heart rate (by electrocardiogram) were measured im-mediately before and at 1, 3, 5, 10, 20, and 30 min after the nicardipine injection. Plasma epinephrine and norepinephrine levels were measured immediately before and at 5, 10, 20, and 30 min after the nicardipine injection with high-performance liquid chromatography (HPLC, NT detector, Yokohama Hewlett-Packard, Yokohama, Japan; detection limit 0.01ng?ml21). The plasma nicardipine level was also measured at 5, 10, 20, and 30 min after the injection by HPLC (UV detector SPD-2A, Shimadzu, Hamamatsu Japan; detection limit 3 ng?ml21) [6]. The pharmacokinetics of nicardipine were approximated by the trapezoidal method. For 30 min before and after nicardipine administration, the concentrations of inhalational anesthetics and the infusion rate (2 ml?kg21?h21) were constant and no other drugs were administered.
(para2)All values are expressed as mean 6 standard error. Statistical analysis consisted of the chi-square test for sex and kind of surgery, the Mann-Whitney U-test
for other parameters between the two groups, and analysis of variance (ANOVA) with repeated measures followed by StudentŽÕs t-test for blood pressure, heart rate, and plasma concentrations of nicardipine and
catecholamines. The value P , 0.05 was considered statistically signiŽÞcant.
(1)Results
(para1)The subjectsŽÕ backgrounds, doses of fentanyl and muscle relaxants, and minimum alveolar concentrations (MACs) of sevoŽßurane and isoŽßurane at the time of nicardipine administration (2.05% was calculated as 1 MAC for sevoŽßurane and 1.15% for isoŽßurane) showed no signiŽÞcant differences between the two groups (Table 1). The nicardipine dose per kilogram of body weight was not different between the two groups (0.018 mg?kg21).
(para2)Blood pressure and heart rate before nicardipine injection showed no signiŽÞcant differences between the two groups. Blood pressures that were signiŽÞcantly lower than preadministration levels continued for 30 min in the isoŽßurane group and for 20 min in the sevoŽßurane group. Although the heart rate measured 30 min after the administration still exceeded the preadministration value in the isoŽßurane group, those measured 10 min after the administration or later showed no differences from the preadministration value in the sevoŽßurane group (Fig. 1).
(para2)The plasma epinephrine and norepinephrine levels increased signiŽÞcantly after nicardipine administration in the isoŽßurane group while the sevoŽßurane group showed no signiŽÞcant changes. Epinephrine and norepinephrine in the isoŽßurane group (epinephrine: 30 min after nicardipine injection; norepinephrine: 20 and 30 min after nicardipine injection) demonstrated signiŽÞcantly higher levels than those in the sevoŽßurane group (Fig. 2).
(para2)Plasma nicardipine concentrations in the sevoŽßurane group 20 and 30 min after nicardipine injection were signiŽÞcantly higher than those in the isoŽßurane group (Fig. 3). Compared with the isoŽßurane group, the sevoŽßurane group showed a longer elimination half-life (T1/2¡¦, a larger area under the plasma concentration curve (AUC), and lower clearance of nicardipine (Table 2).
(1)Discussion
(para1)The important ŽÞndings in this study were that the effects of nicardipine on hemodynamics were signiŽÞcantly longer under isoŽßurane anesthesia than those under sevoŽßurane anesthesia, but the metabolism and excretion of nicardipine were signiŽÞcantly delayed under sevoŽßurane anesthesia.
(para2)Except as reported by Kishi et al. [1], nicardipine increased heart rate, as shown in the present study, by reŽßex sympathetic hypertonia due to hypotension under general anesthesia [2,5,7,8]. The results reported by Kishi et al. and by others might differ as a result of the effects of surgical stress, because Kishi et al. administered nicardipine when hypertension occurred by surgical stress. Therefore, we studied the changes during microscopic procedure in neurosurgery to minimize the inŽßuence of surgical stress in the present study.
(para2)EnŽßurane was reported to enhance the cardio-vascular depression by verapamil more signiŽÞcantly than halothane [9] and isoŽßurane [10]. Regarding the effects of nicardipine, we demonstrated that isoŽßurane enhanced the hemodynamic effects more signiŽÞcantly than enŽßurane [5].
(para2)The effects of isoŽßurane on hemodynamics were reported to be the same as those of sevoŽßurane[11]; however, the results of our study suggested that isoŽßurane had stronger effects than sevoŽßurane in accelerating hypotension and reŽßex sympathetic hypertonia by nicardipine. In the present study, the comparison between the two groups was not affected by fentanyl because the same amount of fentanyl was administered to the two groups before the study, and for 30min each before and after the nicardipine injection fentanyl was not administered. Therefore, the different effects were due to the interaction of inhalational anesthetics and nicardipine.
(para2)The larger T1/2¡¦and AUC of nicardipine and the smaller clearance of nicardipine in sevoŽßurane anesthesia than in isoŽßurane anesthesia was thought to be due to decreased blood Žßow or decreased liver function. Although Frink et al. [12] and Bernard et al. [13] reported that the effects of sevoŽßurane and isoŽßurane on hepatic blood Žßow were similar, Fujita et al. [14] demonstrated that sevoŽßurane decreased portal blood Žßow more signiŽÞcantly than isoŽßurane. In the present study, the decreases in blood pressure and catecholamine release were greater in the isoŽßurane group than in the sevoŽßurane group, while the metabolism of nicardipine was faster in the isoŽßurane group. This may have been because the decrease in hepatic blood Žßow or liver function under sevoŽßurane anesthesia was larger than those induced by decreased blood pressure and increased catecholamine release under isoŽßurane anesthesia.
(para2)In summary, hypotension and reŽßex sympathetic hypertonia induced by nicardipine were enhanced and prolonged signiŽÞcantly under isoŽßurane anesthesia compared with sevoŽßurane anesthesia; however, the metabolism and excretion of nicardipine was signiŽÞcantly slower under sevoŽßurane anesthesia than under isoŽßurane anesthesia.
(ACK)Acknowledgment. We thank Yamanouchi Pharmaceutical Co. Ltd. (Tokyo, Japan) for their kind cooperation in the measurement of plasma nicardipine and catecholamine concentrations.
(1)References
(REF) 1. Kishi Y, Okumura F, Furuya H (1984) Haemodynamic effects of nicardipine hydrochloride. Studies during its use to control acute hypertension in anaesthetized patients. Br J Anaesth 56:1003-1004
(REF) 2. Ray DC, Drummond GB (1989) Haemodynamic responses to nicardipine in humans anaesthetized with halothane. Anaesthesia 44:382-385
(REF) 3. Fukusaki M, Shimada M, Shibata O, Haseba S, Gotoh Y (1988) Hemodynamics during induced hypotension with continuous administration of nicardipine and enŽßurane (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 37:327-333
(REF) 4. Hysing ES, Chelly JE, Doursout MF, Hartley C, Merin RG (1986) Cardiovascular effects of an interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. Nicardipine and isoŽßurane. Anesthesiology 65:385-391
(REF) 5. Nishiyama T, Hirasaki A, Odaka Y, Toda N, Konishi H, Seto K (1992) Interaction of nicardipine and inhalational anestheticsŽÑComparison between enŽßurane and isoŽßurane (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 41:1237-1243
(REF) 6. Kobayashi S (1987) Simple method for the determination of nicardipine in plasma using high-performance liquid chromatography. J Chromatogr 420:439-444
(REF) 7. Fukusaki M, Miyako M, Fukui S, Haseba S, Gotoh Y (1986) Hemodynamics during induced hypotension with continuous administration of nicardipine (in Japanese with English abstract). Masui (Jpn J Anaesthesiol) 35:551-556
(REF) 8. Okamura A, Kemmotsu O, Morimoto Y, Yamamura T, Ishikawa T, Nakata F (1992) Hemodynamic effects of nicardipine-induced hypotension during enŽßurane/nitrous oxide anesthesia in man. J Anesth 6:401-406
(REF) 9. Kapur PA, Bloor BC, Flacke WE, Olewine SK (1984) Comparison of cardiovascular responses to verapamil during enŽßurane, isoŽßurane, or halothane anesthesia in the dog. Anesthesiology 61:156-160
(REF)10. Rogers K, Hysing ES, Merin RG, Taylor A, Hartley C, Chelly JE (1986) Cardiovascular effects of an interaction between calcium blocking drugs, and anesthetics in chronically instrumented dogs. Verapamil, enŽßurane, and isoŽßurane. Anesthesiology 64:568-575
(REF)11. Bernard JM, Wouters PF, Doursont MF, Florence B, Chelly JE, Merin RG (1990) Effects of sevoŽßurane and isoŽßurane on heart rate and coronary dynamics in chronically instrumented dogs. Anesthesiology 72:659-62
(REF)12. Frink EJ Jr, Morgan SE, Coetzee A, Conzen PF, Brown BB (1992) The effects of sevoŽßurane, halothane, enŽßurane, and isoŽßurane on hepatic blood Žßow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 76:85-90
(REF)13. Bernard JM, Doursout MF, Wouters P, Hartley CJ, Merin RG, Chelly JE (1992) Effects of sevoŽßurane and isoŽßurane on hepatic circulation in the chronically instrumented dogs. Anesthesiology 77:541-545
(REF)14. Fujita Y, Kimura K, Hamada H, Takaori M (1991) Comparative effects of halothane, isoŽßurane, and sevoŽßurane on the liver with hepatic artery ligation in the beagle. Anesthesiology 75:313-318 (MW)

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(JN)J Anesth (1996) 9:311 - 317
(PT)
(CT)Total intravenous anesthesia combined with epidural eptazocine
(CA)Sumihisa Aida1, Takemi Tomiyama2, and Koki Shimoji1
(ADD)1 Department of Anesthesiology and 2 Department of Surgery, Niigata University School of Medicine, 1 Asahimachi, Niigata, 951 Japan
(AB)Abstract: To reduce the doses of intravenous anesthetics (ketamine, diazepam, droperidol, and vecuronium) used in total intravenous anesthesia (TIVA), epidural administration of a ¡¦stimulating opioid, eptazocine, was combined with TIVA in 115 patients. Surgical procedures were uneventful under TIVA plus epidural eptazocine; signiŽÞcant depression of EEG and somatosensory-evoked potentials during anesthesia were observed without delay in recovery. The circulatory response and blood glucose level during and after anesthesia and surgery were stable, and there was no postanesthetic respiratory depression. On the other hand, in 46 patients given TIVA only, hypertension, tachycardia, and elevated blood glucose during and after anesthesia were observed: in 25 (54.3%) patients, a vasodepressor was required, and in 18 (39.1%) patients, nitrous oxide was needed. Therefore, epidural eptazocine may make it possible to use lower doses of anesthesia in TIVA, thus reducing the adverse effects associated with TIVA such as hypertension during surgery, intraoperative awareness, postanesthetic respiratory depression, delayed recovery from anesthesia, and neurological signs after anesthesia. This may be due to the ¡¦stimulating action of epidural eptazocine on the spinal cord and its ¡¦blocking action, as well as its lack of ¡¦action on the brain.
(KW)Key words: Eptazocine, Ketamine, TIVA, Epidural administration, ¡¦Action, ¡¦Action
(AB)
(1)Introduction
(para1)General anesthesia using a combination of intravenous anesthetics, so-called total intravenous anesthesia (TIVA), may have certain advantages over inhalation anesthesia in terms of disturbances of cardiovascular, respiratory, endocrine, metabolic and immune function [1,2]. TIVA using ketamine, fentanyl, and diazepam appears to be in widespread use [1]. However, TIVA has several drawbacks, such as hypertension during anesthesia, intraoperative awareness, delayed recovery from anesthesia, postanesthetic respiratory depression, dreaming, and extrapyramidal signs [1,2]. Large doses of opiates may also have an immunodepressant effect [3,4], and intravenous opiates including fentanyl have long-lasting effects [5].
(para2)Eliminating the need for an opiate and reducing
the dose of opioids may minimize these adverse
effects. A speciŽÞc opioid, eptazocine, provides ¡¦stimulating and ¡¦blocking action without a ¡¦effect [6]. Therefore, epidural administration of eptazocine was combined with TIVA, since a powerful analgesic effect of the epidural opioid, mediated by ¡¦stimulation in
the spinal cord without ¡¦and ¡¦stimulation was
expected [5].
(1)Patients and methods
(para1)The study was carried out after approval by the Institutional Committee for Human Investigation of this hospital. Informed consent was obtained from all 161 patients undergoing elective surgery. One hundred and ŽÞfteen patients were given TIVA plus epidural eptazocine (gastrectomy, 42; cholecystectomy, 31; mastectomy, 10; partial hepatectomy, 4; nephrectomy, 5; hemicolectomy, 18; other abdominal surgery, 5). Forty-six patients were given TIVA only (gastrectomy, 18; cholecystectomy, 13; mastectomy, 5; partial hepatectomy, 1; nephrectomy, 2; hemicolectomy, 4; other abdominal surgery, 3). The groups were matched statistically for surgery, age, sex, body weight (BW), ASA grade, and the duration of anesthesia and surgery (Table 1).
(2)Induction and maintenance of anesthesia
(para1)One hour before induction of anesthesia, patients were premedicated intramuscularly with atropine sulfate 0.01 mg?kg21 and hydroxyzine 1 mg?kg21. Anesthesia was started after setting up one or two intravenous infusion routes with lactated RingerŽÕs solution.
(para2)Before TIVA plus epidural eptazocine, patients were cannulated epidurally at the following levels: T3 - 4 (mastectomy), T7 - 8 (upper abdominal and retroperitoneal surgery), or T11 - 12 (lower abdominal surgery). After an induction dose of epidural eptazocine hydrobromide 7.5 mg (Nihon Iyakuhin Kogyo, Toyama, Japan) diluted in 2 ml, a maintenance dose of epidural eptazocine (1.2 mg?h21) was infused continuously by a balloon pump (SFA-0503D, Nipro, Tokyo, Japan).
Epidural eptazocine administration was continued throughout anesthesia and for 72 h thereafter for postoperative pain management. Patients given TIVA only were not canulated epidurally.
(para2)TIVA in both groups was induced and maintained as follows. Induction doses of 0.2 mg?kg21 diazepam (Yamanouchi Pharmaceutical, Osaka, Japan), and 0.05 mg?kg21 droperidol (Sankyo, Tokyo, Japan), were given intravenously. Thereafter, 0.16 mg?kg21 vecuronium bromide (Organon Tekniks, Amsterdam, Netherlands) was administered according to the time-principle method [7], and an induction dose of ketamine hydrochloride 1.0 mg?kg21 (Sankyo) was given intravenously. When muscle relaxation was achieved, patients were intubated and artiŽÞcially ventilated with an oxygen-air mixture (30% oxygen) at 4.5% - 5% of endtidal CO2 concentration. For maintenance of anesthesia, a mixed solution of ketamine (1.5 mg?kg21?h21) and vecuronium (0.08 mg?kg21?h21) was infused intravenously using an electrically driven syringe pump (SP-60, Nipro, Japan). Additional diazepam and droperidol were administered intermittently every 3 and 6 h in doses of 0.1 mg?kg21 and 0.025 mg?kg21, respectively. Doses of the drugs used are summarized in Table 2. When the depth of surgical anesthesia with TIVA alone was judged to be insufŽÞcient, an oxygen-nitrous oxide mixture (30% and 70%, respectively) was inhalated [8].
(para2)A vasopressor (¡¦adrenergic agent; etilefrine, 5 mg) and a vasodepressor (calcium antagonist; diltiazem, 5 mg) were given intravenously when the systolic blood pressure was less than 80 mmHg for 5 min and greater than 180 mmHg for 15 min, respectively. Approximately 5 min before the start of skin closure, intravenous infusion of the ketamine-vecuronium mixture was terminated. At the end of surgery, muscle relaxation was reversed with 0.5 mg atropine and 1.5 - 2.0 mg neostigmine. Patients were extubated when spontaneous respiration with endtidal CO2 concentration of ,6% had been established. Patients who had unbearable postoperative pain were given additional epidural eptazocine (3.8 mg) or intramuscular eptazocine (15 mg).
(2)Monitoring and laboratory measurements
(para1)Throughout anesthesia, the electrocardiogram, heart rate, noninvasive blood pressure (BP-308ET, Nippon Colin, Komaki, Japan), oxygen saturation, inspired oxygen concentration, endtidal CO2 concentration, minute ventilation volume and urine output were monitored. Arterial blood gases were measured at the start of surgery and 30 min after the termination of anesthesia. Serum electrolytes (Na, K, and Cl), blood urea nitrogen (BUN), serum creatinine, glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) were checked on the day before surgery and on the 3rd postoperative day. Blood glucose was measured before induction, at the start of surgery (skin incision), at 30 and 60 min after the skin incision, at the end of surgery, and 30 min after the termination of anesthesia.
(para2)In ŽÞve of the patients given TIVA plus epidural eptazocine, the electroencephalogram (EEG) and somatosensory-evoked potentials (SEPs) were monitored (Neuropack Four Mini, Nihon Kohden, Tokyo, Japan) with a recording and two reference electrodes (Ag-AgCl) placed at C49 and both earlobes, respectively. Electrical stimulation with a square pulse (20 mA, 2 ms) through a pair of Ag-AgCl electrodes (20 mm apart) was given to the left (contralateral) median nerve at the wrist.
(2)Statistical analysis
(para1)Data were analyzed using the chi-square test or by two- or three-way analyses of variance (ANOVA), and by DunnettŽÕs multiple comparison test or StudentŽÕs t-test when signiŽÞcant by the above tests. Values are shown as the mean and standard deviation (SD). P , 0.05 was considered signiŽÞcant.
(1)Results
(para1)During TIVA plus epidural eptazocine, blood pressure fell slightly but signiŽÞcantly (P , 0.05), while the heart rate did not change signiŽÞcantly (Fig. 1). None of the patients became hypertensive (systolic pressure .180 mmHg for more than 15 min) in the group undergoing TIVA plus epidural eptazocine. Hypotension due to hemorrhage occurred in 5 cases. Pre-existing arrhythmias (34 cases) did not become more frequent in any of the cases; and arrhythmias present before anesthesia became infrequent (23 of 34 cases) or disappeared (11 of 34 cases) during anesthesia without using anti-arrhythmic drugs. The depth of anesthesia was adequate and no nitrous oxide inhalation was required in patients given TIVA plus epidural eptazocine (Table 3).
(para2)In patients given TIVA only, blood pressure and heart rate were frequently elevated (P , 0.05), during anesthesia and surgery (Fig. 1), and a vasodepressor in 25 (54.3%) patients (P , 0.01), and an anti-arrythmic drug in one (2.2%) were required, respectively. Nitrous oxide was inhalated in 18 (39.1%) patients whose depth of anesthesia was judged to be insufŽÞcient (P , 0.01) (Table 3).
(para2)SEPs and EEGs were recorded in ŽÞve of the patients given TIVA plus epidural eptazocine. SEP latencies (N20, N32 and N60) in response to median nerve stimulation were signiŽÞcantly prolonged (P , 0.05), and the amplitudes were signiŽÞcantly (P , 0.05) decreased during anesthesia. EEGs showed a mixed pattern of slow waves (6 - 9 Hz) plus spiky fast waves (20 - 30 Hz) during anesthesia. These recovered within 10 min of reversal after muscle relaxation (Fig. 2).
(para2)Shortly (5 - 10 min) after reversal of muscle relaxation, all patients in both groups responded to verbal commands and regained spontaneous respiration. All patients were extubated in less than 30 min (10.0 6 5.9 min in patients given TIVA plus epidural eptazocine, and 12.8 6 13.3 in patients given TIVA only) after the termination of surgery (not signiŽÞcant). Arterial gases were normal during and 30 min after TIVA with and without eptazocine (Table 4). Neither airway stimulation nor postanesthetic respiratory depression occurred. Endtidal CO2 concentration was controlled between 4.5% and 5.0% during anesthesia. After anesthesia, oxygen, 3 l?min21, was insuflated under spontaneous respiration.
(para2)No signiŽÞcant changes in blood glucose levels were observed during anesthesia and surgery in patients given TIVA plus epidural eptazocine, although there was a slight increase 30 min after the termination of anesthesia (P , 0.05). In patients given TIVA only, however, a signiŽÞcant elevation (P , 0.01) of blood glucose level during and after surgery was observed (Fig. 3). Serum Na and Cl in both groups signiŽÞcantly
(P , 0.01) decreased 3 days after anesthesia in both groups. There were no signiŽÞcant changes in any other biochemical measurements (Table 5).
(para2)Sixty-one (53.0%) of the patients given TIVA plus epidural eptazocine and 22 (47.8%) of the patients given TIVA only reported that they dreamed during and after anesthesia, but were unable to recall whether this occurred during or after anesthesia. However, such patients stated that the content of the dreams either could not be recalled or was not unpleasant. Neither postanesthetic hypotension nor bradycardia was observed, and nausea, vomiting, headache, hallucination, and extrapyramidal signs did not occur. No adverse effects of long-term (72 h) opioid administration such as epidural infection were seen. Seventeen patients (14.8%) given TIVA plus epidural eptazocine and 45 (97.8%, P , 0.01) patients given TIVA only required additional analgesia postoperatively (Table 3).
(para2)Thus, in all 161 patients, surgical procedures were uneventful. It was later conŽÞrmed by interview that none of the patients in either group had been intra-operatively aware. There were no differences between the groups in infusion rate, urine output, blood loss, and blood transfusion during anesthesia (Table 1). The effect of the regime on urinary retention, if any, could not be assessed because all patients in both group were catheterized.
(1)Discussion
(para1)The present study demonstrated that analgesia of TIVA plus epidural eptazocine is more effective than TIVA only: the depth of surgical anesthesia was sufŽÞcient, a vasodepressor was used during anesthesia in only two patients, and the additional use of an analgesic for postoperative pain relief was infrequent (Table 3). The results also demonstrated that patients given TIVA plus epidural eptazocine had stable hemodynamics (Fig. 1) and glucose levels during and after surgery (Fig. 3). Postanesthetic respiratory disturbance was not noted (Table 4), and recovery from anesthesia was rapid in these patients. Furthermore, the SEP and EEG ŽÞndings suggest that central nervous system (CNS) function
during TIVA plus epidural eptazocine was stable and surgically deep (Fig. 2). Furthermore, the total doses
of intravenous anesthetics required were low during anesthesia compared with other authorŽÕs descriptions [1,2].
(para2)Eptazocine has been demonstrated to have ¡¦stimulating an ¡¦blocking action without a ¡¦effect (sodium index, 3.89) [6]. Most ¡¦receptors are found in the spinal cord, whereas ¡¦receptors are expressed widely in the brain and spinal cord [5]. Eptazocine is therefore a powerful analgesic when given epidurally with minimal effects on the brain via ¡¦receptors. Therefore, the effects of epidural eptazocine are considered to enhance anesthesia and reduce the does of anesthetic needed. These effects may account for the adequate anesthesia depth, stable hemodynamics and blood glucose level, rapid recovery from anesthesia, absence of respiratory depression, and neurological signs after anesthesia.
(para2)No anti-arrhythmic drugs were required during the study, and this is probably due to the anti-arrhythmic effect of ketamine [9 - 11]. On the other hand, the sympathomimetic action of ketamine is considered to be mediated via the CNS [9,12,13], which was blocked by the preceding administration of CNS depressants such as diazepam [14], droperidol [15,16], or opiates [15]. In the present study, the rise in blood pressure due to ketamine administration was thought to be blocked by the preceding administration of these drugs (Fig. 1). Thus, TIVA plus epidural eptazocine was uneventful even in 15 patients with complete right bundle branch block, 55 with coronary ischemia, 16 with atrial ŽÞbrillation, 2 with hypertrophic cardiomyopathy, and 2 patients over the age of 90 years, in patients given TIVA plus epidural eptazocine.
(para2)SEPs showed a signiŽÞcant prolongation of latency and a decrease in amplitude. However, the changes
in an early component, N20, were small, and were likely to be due to ketamine, since changes in early components of auditory evoked potential (AEP) during ketamine anesthesia have also been found to be small [17]. In the present study, we also observed a sustained depression in a later component, N60, and EEGs showed slow waves with spiky fast waves, another
characteristic of ketamine anesthesia (Fig. 2) [18]. Our regime of TIVA plus epidural eptazocine probably owes its effects to the balanced effects of ketamine, diazepam, droperidol, and eptazocine on N-methyl-d-aspartate (NMDA) receptors, ¡¦aminobutyric acid (GABA) receptors, catecholamine receptors, and ¡¦
receptors, respectively, with a dominant cortical effect of ketamine.
(para2)In the present study, muscle relaxation was achieved by a very low maintenance dose of vecuronium, 0.08 mg?kg21?h21 (Table 1). The need for such a low dose may be due to the fact that ketamine enhances the effect of nondepolarizing muscle relaxants [19 - 21]. No signiŽÞcant depression of respiration by ketamine [22,23], diazepam [23], droperidol [24] and eptazocine [25] in the respective clinical doses has been demonstrated. In addition, ketamine [26 - 29], opioids [5,30], diazepam [31], droperidol [24], and vecuronium [32] have been shown not to stimulate bronchial smooth muscle in the clinical doses used in this study, and
this accounts for the lack of signiŽÞcant effects on
respiration of our TIVA regime. In fact, a 72-year-
old woman with a recent history of several com-
plicated asthmatic attacks underwent uneventful
subtotal gastrectomy under TIVA plus epidural eptazocine.
(para2)No signiŽÞcant increases in blood glucose were found during anesthesia and surgery in patients given TIVA and epidural eptazocine (Fig. 3). A saline diuresis by ketamine, which is long-lasting and mild, has been suggested [33,34]. In the present study, urine output during anesthesia was also adequate in most cases, and signiŽÞcant falls in serum Na and Cl occurred after anesthesia. Other biochemical tests did not change signiŽÞcantly after anesthesia (Table 5), suggesting that TIVA plus epidural eptazocine does not disturb renal or hepatic function.
(para2)In conclusion, we suggest that TIVA plus epidural eptazocine has advantages, due to the balanced
effects of intravenous ketamine, diazepam and droperidol, and epidural eptazocine on the brain and spinal cord.
(1)References
(REF)1. Mallon JS, Edelist G (1990) Total intravenous anaesthesia. Can J Anaesth 37:279 - 281
(REF)2. Restall J, Tully AM, Kidd AG (1988) Total intravenous anaesthesia for military surgery. A techniques using ketamine, midazolam and vecuronium. Anaesthesia 43:46 - 49
(REF)3. Wybran J, Appelboom T, Famaey JP, Govaerts A (1979) Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J Immunol 123:1068 - 1070
(REF)4. McDonough RJ, Madden JJ, Falek A, Shafer DA, Pline M,
Gordon D, Bokos P, Kuehnle JC, Mendelson J (1980) Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: In vitro evidence for opiate receptor sites on T lymphocytes. J Immunol 125:2539 - 2544
(REF)5. Bailey PL, Stanley TH (1990) Narcotic intravenous anesthetics. In: Miller RD (ed) Anesthesia, 3rd edn., vol. 1. Churchill Livingstone, New York, pp 181 - 366
(REF)6. Nabeshima T, Matsuno K, Kamei H, Kameyama T (1985) The interaction of eptazocine, a novel analgesic, with opioid receptors. Res Commun Chem Pathol Pharmacol 48:173 - 181
(REF)7. Silverman SM, Culling RD, Middaugh RE (1990) Rapid-sequence orotracheal intubation: A comparison of three techniques. Anesthesiology 73:244 - 248
(REF)8. Wessels JV, Allen GW, Slogoff S (1973) The effect of nitrous oxide on ketamine anesthesia. Anesthesiology 39:382 - 386
(REF)9. Dowdy EG, Kaya K (1968) Studies of the mechanism of cardiovascular responses to CI-581. Anesthesiology 29:931 - 943
(REF)10. Hamilton JT, Bryson JS (1974) The effect of ketamine on transmembrane potentials of Purkinje ŽÞbers of the pig heart. Br J Anaesth 46:636 - 642
(REF)11. Koehntop DE, Liao JC, van Bergen FH (1977) Effects of pharmacologic alterations of adrenergic mechanisms by cocaine, tropolone, aminophylline, and ketamine on epinephrine-induced arrythmias during halothane-nitrous oxide anesthesia. Anesthesiology 46:83 - 93.
(REF)12. Byrne AJ, Tomlinson DR, Healy TEJ (1982) Ketamine and sympathetic mechanisms in cardiac and smooth muscle. Acta Anaesth Scand 26:479 - 484
(REF)13. Ivankovich AD, Miletich DJ, Reimann C, Albrecht RF, Zahed B (1974) Cardiovascular effects of centrally administered ketamine in goats. Anesth Analg 53:924 - 933
(REF)14. Zsigmond EK, Kothary SP, Matsuki A, Kelsch RC, Martinez O (1974) Diazepam for prevention of the rise in plasma catecholamines caused by ketamine. Clin Pharmacol Ther 15:223 - 224
(REF)15. Bovill JG, Clarke RSJ, Dundee JW, Pandit SK, Moore J (1971) Clinical studies of induction agents XXXIII: Effect of premedications and supplements on ketamine anaesthesia. Br J Anaesth 43:600 - 608
(REF)16. Becsey L, Malamed S, Randnay P, Foldes FF (1972) Reduction of the psychotomimetic and circulatory side-effects of ketamine by droperidol. Anesthesiology 37:536 - 543
(REF)17. Schwender D, Klasing S, Madler C, PÓÑpel E, Peter K (1993) Mid-latency auditory evoked potentials during ketamine anaesthesia in humans. Br J Anaesth 71:629 - 632
(REF)18. Domino EF, Chodoff P, Corssen G (1965) Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther 6:279 - 291
(REF)19. Johnston RR, Miller RD, Way WL (1974) The interaction of ketamine with d-tubocurarine, pancuronium, and succinylcholine in man. Anesth Analg 53:496 - 501
(REF)20. Amaki Y, Nagashima H, Randy PA, Foldes FF (1978) Ketamine
interaction with neuromuscular blocking agents in the phrenic nerve-hemidiaphram preparation of the rat. Anesth Analg 57:238 - 243
(REF)21. Tsai SK, Lee C (1989) Ketamine potentiates nondepolarizing neuromuscular relaxants in a primate. Anesth Analg 68:5 - 8
(REF)22. Kelly RW, Wilson RD, Traber DL, Priano LL (1971) Effects of new dissociative anesthetic agents, ketamine and CL-1848C, on
the respiratory response to carbon dioxide. Anesth Analg
50:262 - 269
(REF)23. Thompson GE, Moore DC (1971) Ketamine, diazepam and Innovar: a computerized comparative study. Anesth Analg 50:458 - 463
(REF)24. Reves JG, Glass PSA (1990) Nonbarbiturate intravenous anesthetics. In: Miller RD (ed) Anesthesia, 3rd edn., vol. 1. Churchill Livingstone, New York, pp 243 - 279
(REF)25. Mizobe T, Oda Y, Natsuyama T, Miyazaki M (1992) Anesthetic management with eptazocine hydrobromide in patients receiving long-termanti-psychotic medication. J Anesth 6:21 - 27
(REF)26. Hirsman CA, Downes H, Farbood A, Bergman NA (1979) Ketamine block of bronchospasm in experimental canine asthma. Br J Anaesth 51:713 - 718
(REF)27. Corssen G, Gutierrez J, Reves JG, Huber Jr FC (1972)
Ketamine in the anesthetic management of asthmatic patients. Anesth Analg 51:588 - 596
(REF)28. Fisher MM (1977) Ketamine hydrochloride in severe bronchospasm. Anaesthesia 32:771 - 772
(REF)29. Wilson LE, Hatch DJ, Rehder K (1993) Mechanisms of the relaxant action of ketamine on isolated porcine trachealis muscle. Br J Anaesth 71:544 - 550
(REF)30. Toda N, Hatano Y (1980) Contractile responses of canine tracheal muscle during exposure to fentanyl and morphine. Anesthesiology 53:93 - 100
(REF)31. Heinonen J, Muittari A (1972) The effect of diazepam on airway resistance in asthematics. Anaesthesia 27:37 - 40
(REF)32. Mitsuhata H, Matsumoto S, Enzan K, Yabe M, Terada H (1991) Changes in plasma histamine concentration after the administration of vecuronium bromide. J Anesth 5:24 - 29
(REF)33. Aida S (1979) Urinary output during and after ketamine anesthesia (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 28:50 - 55
(REF)34. Aida S, Fujihara H, Shimoji K (to be published) Ketamine increases urine output. Acta Med Biol (MW)

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(JN)J Anesyh (1996) 9:318 - 323
(PT)
(CT)Evaluation of a delivery system and monitors for ventilator administration of nitric oxide
(CA)Young-Kyoo Choi1, Hidekazu Yukioka2, Tokuhiro Yamada2, Masanori Hayashi2, and Mitsugu Fujimori2
(ADD)1 Department of Anesthesiology, Kyung Hee University Hospital, Seoul, 130-702 Korea
(ADD)2 Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, Osaka, 545 Japan
(AB)Abstract: The aim of this study was to compare nitric oxide (NO) and nitrogen dioxide (NO2) measurements obtained by chemiluminescence and electrochemical monitors using a delivery system for ventilator administration of NO. The formation of NO2 in this system and the efŽÞcacy of a soda-lime absorber to scavenge NO2 from inspiratory gas were also evaluated. Various concentrations of NO without and with soda lime were administered to a model lung via a Servo ventilator 900C with controlled ventilation by setting mass-Žßow regulators to maintain desired concentrations of NO in 80% O2. Close correlations were found between NO concentrations, as well as NO2 concentrations, measured using electrochemical monitors (TM100; 1002, PACII) and a chemiluminescence monitor (CLA-510SS). Soda-lime removed NO2 almost completely during administration of 0-25 p.p.m. NO, although a high concentration of NO2 appeared in the breathing circuit without soda lime. Four hundred grams of soda lime continued to absorb NO2 effectively during long-term administration of inhaled NO.
(AB)These ŽÞndings suggest that electrochemical monitoring is accurate and clinically useful for measurements of NO and NO2 concentrations, and that low doses of inhaled NO can be administered safely and reliably with the NO delivery system using a soda-lime absorber and mass-Žßow regulators.
(KW)Key words: Inhalation, Nitric oxide, Drug delivery, Monitor, Soda-lime absorber
(A)Introduction
(para1)Nitric oxide (NO) is of increasing clinical interest
because of its potential beneŽÞts as an endogenous nitrovasodilator. When administered in gaseous form, it has selective effects on the pulmonary vasculature owing to its rapid inactivation in blood by the formation of methemoglobin. It has the potential for wide use in intensive care units and other critical care facilities for the treatment of chronic severe pulmonary hypertension [1], adult respiratory distress syndrome (ARDS) [2], and neonatal persistent pulmonary hypertension [3,4].
(para2)However, administration of NO poses several clinical problems. It is reputed to be a toxic agent to the lungs, but the evidence for this is slim [5-7]. More importantly, it reacts with oxygen to form nitrogen dioxide (NO2), which is eventually transformed to nitrous and nitric acids, known to damage pulmonary epithelium and to cause pulmonary edema and acid pneumonitis in animals [6,8,9]. On the other hand, animal studies have revealed no major adverse effects of administration of 10-40 p.p.m. NO for periods ranging from 5 days to 6 months [7,10], and the Occupational Safety and Health Administration of USA permits exposure to NO for 8 h daily up to 25 p.p.m. [11]. The relatively low concentrations (6-20 p.p.m.) of NO that appear to be effective in clinical studies would thus be safe in normal lungs. However, the potential for induction of pulmonary toxicity (particularly with high FIO2) by NO in injured lungs with ongoing injury by oxidants or in newborn lung with altered oxidant defences is unknown.
(para2)Because of the potential toxicity of inhaled NO and the formation of NO2, which is more toxic than NO, it is mandatory that if NO is used as a therapeutic agent,
NO and NO2 concentrations be monitored very carefully. Although current recommendations from the Occupational Safety and Health Administration have set the upper limit for NO2 inhalation at 5 p.p.m. [12], Zapol et al. recommended 1 p.p.m. of NO2 as the limit for safety for patients with pulmonary hypertension [13]. When NO is mixed with ventilator gas, which often may have an oxygen concentration above 50%, rapid oxidation of NO to NO2 will occur, and therefore NO2 scavengers such as soda lime may be necessary to keep concentrations of NO2 low. However, little is known concerning the absorptive capacity of soda lime for NO or NO2 [14].
(para2)Currently used monitoring systems for NO and NO2 include chemiluminescence and electrochemical detection. The chemiluminescence technique is more accurate, but the equipment required can be difŽÞcult to set up and expensive to obtain. An alternative method of measuring NO and NO2 concentrations is electrochemical detection, the principle used in many fuel cell oxygen analyzers, although the reliability, reproducibility, and accuracy of the method in clinical studies have yet to be established [11].
(para2)The main objective of this study was to compare NO and NO2 measurements obtained by chemiluminescence and electrochemical monitors using a system for administration of NO in breathing gas with a Servo ventilator. The formation of NO2 in this system and the efŽÞcacy of the soda-lime absorber to scavenge NO2 from inspiratory gas were also evaluated.
(A)Methods
(B)NO/NO2 monitoring equipment
(para1)The most recent versions of three commercially available NO and NO2 monitoring systems were obtained from their respective manufacturers: (1) the SAAN TM 100 and TM 1002 gas monitors (SAAN Laboratories, Kyoto, Japan); (2) Dr³Èer Pac II NO and NO2 gas monitors (Dr³Èer AG, LÝÃeck, Germany); (3) the Horiba CLA-510SS NO and NOx (NO 1 NO2) gas monitor (Horiba, Osaka, Japan). The SAAN and Dr³Èer gas monitors were used for electrochemical detection, while the Horiba gas monitor was used for chemiluminescence measurements.
(para2)The performance of each instrument was evaluated by comparing the measurements of NO and NO2 obtained. Each instrument was maintained and calibrated in accordance with the manufacturerŽÕs speciŽÞcations. Yearly maintenance was performed by a factory representative before the start of the study. Prior to use, all monitoring equipment was allowed to stabilize for a period of 1-2 h and then placed within the breathing system.
(B)Gas delivery system
(para1)A gas delivery system was constructed with four parts: (1) one G-cylinder with an NO/N2 gas mixture (Taiyo Sanso, Osaka, Japan); (2) three mass-Žßow regulators (TGB-3C, Taiyo Sanso, Osaka, Japan) for O2, air and NO/N2 gas delivery; (3) a Servo Ventilator 900C
(Siemens-Elema AB, Solna, Sweden); (4) a breathing circuit with a model lung, humidiŽÞer with distilled
water, and three types of NO and NO2 monitoring equipment.
(para2)Since NO is toxic at high concentrations, 800 p.p.m. NO in N2 (NO2 , 4 p.p.m.) was chosen for use in the gas cylinders. The NO, O2 and air were mixed by the mass-Žßow regulators just in front of to the gas inlet of the ventilator. The ventilator was calibrated in accordance with the manufacturerŽÕs instructions, and ŽÞtted with a gas scavenging system. To study the efŽÞcacy of the soda-lime absorber in scavenging NO2, a soda-lime carbon dioxide absorber (Wako Lime-A, Wako Pure Chemical Industries, Osaka, Japan) with a canister volume of 900 ml and with 400 g absorber mass was inserted in the inspiratory limb of the breathing system immediately proximal to the humidiŽÞer. Inspired gas was passed through a canister containing soda lime to absorb NO2 or through a canister not containing soda lime, and NO and NO2 measurements were performed in the inspiratory limb immediately proximal to the model lung using the three types of NO/NO2 monitoring equipment
simultaneously.
(B)Experimental procedure
(para1)NO was administered via a Servo Ventilator 900C by setting three mass-Žßow regulators to maintain the
desired concentrations of NO and O2. In the present study, the ventilator was operated only in the volume-controlled mode. All experiments were performed
with a setting of 6 láÎin21 expiratory minute ventilation, since the chemiluminescence technique requires a 700 mláÎin21 aspiration volume from the inspiratory tube limb to measure NO and NO2. The ventilator was operated at 12 breathsáÎin21, with a peak pressure of 22.4-23.2 cmH2O. FIO2 was maintained at 0.8 during the experiment.
(para2)For comparison of NO and NO2 concentrations measured by chemiluminescence and electrochemical monitors, various concentrations of NO without and with soda lime were administered at a room temperature of 24Ž¡C. Absorption rates of NO and NO2 with soda lime were also calculated. Measurement of each concentration of NO and NO2 was performed after a steady state had been reached (normally more than 10 min).
(para2)In addition, in order to determine the maximum
recommended dose of inhaled NO in the NO delivery system, the relationship between NO and NO2 concentrations was studied using soda lime, since Zapol et al. [13] and the Occupational Safety and Health Administration [12] recommended 1 p.p.m. and 5 p.p.m. of NO2, respectively, as safety limits.
(para2)The capacity of the absorber to scavenge NO2 was tested for 4 and 7 days with NO (25 and 15 p.p.m., respectively) in 80% oxygen at the same ventilatory settings.
(B)Statistical analysis
(para1)All values are expressed as means 6 SD. Statistical analyses were performed by analysis of linear regression using the least-squares method, and analysis of variance was performed on a Macintosh llci computer using Statview 4.0 (FPU) software (Abacus Concepts, CA, USA). Probability values less than 0.05 were considered to indicate statistical signiŽÞcance.
(A)Results
(para1)In the studies without and with soda lime, a close correlation was found between NO concentrations measured using the TM 100 (electrochemical monitor) and the CLA-510SS (chemiluminescence monitor) (without soda lime, r2 5 0.97; with soda lime, r2 5 0.96). A close correlation was also found between NO2 concentrations measured using the TM 1002 (electrochemical monitor) and the CLA-510SS (without soda lime, r2 5 0.97; with soda lime, r2 5 0.84) (Fig. 1).
(para2)In measurements of NO and NO2 concentrations obtained using another electrochemical monitor (Dr³Èer Pac II), close correlations were found between measurements obtained with the Pac II and CLA-510SS (NO and NO2 concentrations measured without soda lime, r2 5 1.00, r2 5 0.99; NO and NO2 concentrations measured with soda lime, r2 5 0.98, r2 5 0.79) (Fig. 2).
(para2)For data analysis, absorption rates were stratiŽÞed into ŽÞve groups based on concentration of NO administered (0-5, 5-10, 10-15, 15-20, and 20-25 p.p.m.). High concentrations of NO2 (5-13 p.p.m.) appeared in the breathing circuit without soda lime during administration of 10-25 p.p.m. NO (Table 1). The absorption
rate of NO (30%-55%) with the soda-lime absorber increased depending on the NO concentration administered, ranging from 0 to 25 p.p.m.. The rates of absorption of NO2 with the soda-lime absorber were higher than 87% in all ŽÞve groups (Table 1, Fig. 3).
(para2)The relationship between NO and NO2 concentrations during use of soda lime is illustrated in Fig. 4. A close correlation was found between NO and NO2 concentrations (r2 5 0.89), and NO2 concentrations did not exceed 1.5 p.p.m. during inhalational administration of 0-30 p.p.m. NO.
(para2)During long-term administration of NO (25 p.p.m. for 4 days and 15 p.p.m. for 7 days), 400 g soda lime removed NO2 effectively, and NO2 concentrations were maintained below 1 p.p.m..
(A)Discussion
(para1)Despite the growing clinical use of NO inhalation, its potential toxicity should not be underestimated. Since NO and higher oxides such as NO2 are highly toxic in high doses [15,16], it is of vital importance to ensure safe and precise delivery of NO while delivering as little NO2 as possible. In maximizing safety, the ŽÞrst precaution is use of a primary NO concentration in the gas cylinders which would not pose a severe risk for the patient even if administered undiluted. In the present study, we used mass-Žßow regulators and a gas cylinder that contained 800 p.p.m. NO in N2 for safe and precise delivery of NO [12].
(para2)Since the most likely therapeutic level for inhaled NO is probably around 20 p.p.m. [17], and high FIO2 is required for patients with severe respiratory failure, and the rate of formation of NO2 from O2 and NO depends on the concentration of O2 and the square of the NO concentration, close monitoring of NO, NO2, and FIO2 is essential. They should be monitored close to the patient in the breathing circuit. However, relatively few monitors can be used clinically for measurements of NO and NO2 in a ventilatory circuit. The ideal monitor is small and quiet and provides precise, continuous real-time analysis with minimal sampling volumes. The monitor should be unaffected by water vapor, FIO2, CO2, or other compounds excreted by the lungs; it should function reliably, require minimal maintenance, and be easily calibrated and inexpensive, and it should monitor both NO and NO2 with a digital readout and have adjustable alarms that announce when safety limits have been exceeded [11].
(para2)The chemiluminescence device used was designed for industrial use in measuring atmospheric pollutants. It is extremely precise. However, in its current conŽÞguration, it is not ideally suited for bedside use. The large aspirating volumes (0.7 láÎin21) of this chemiluminescence device are associated with noisy aspirating pumps and loss of positive end-expiratory pressure. The water-vapor ŽÞlters that are inserted in the aspirating line of the device need to be replaced frequently unless sampl-
ing and monitoring are performed intermittently (e.g., hourly) rather than continuously. Quenching effects related to variable FIO2 necessitate accurate calibration data. In addition, the size of the device is relatively large [11].
(para2)Smaller, less expensive electrochemical monitoring devices which are free of the problems associated with large aspirating volumes are available. Although a separate device is needed for NO and NO2 measurements, and calibration is subject to drift and must be checked against a chemiluminescence measurement before use, the monitors, which are ŽÞtted with alarms, are less
cumbersome and are minimally affected by humidiŽÞcation of the inspired gas, may be more practical in
a clinical setting. Measurements obtained with two
electrochemical detectors, the Polytron (Dr³Èer AG, LÝÃeck, Germany) and the NO Sensor Stik (Environics Cerebus Ltd., Oldham, UK) have recently been compared with those obtained with a chemiluminescence monitor and found to be accurate [18,19]. In the present study, two electrochemical monitors (TM100, TM1002 and Pac II) were compared using the chemiluminescence monitor as a reference. NO and NO2 concentrations measured by electrochemical monitors were closely correlated with those measured by chemiluminescence, indicating that the electrochemical monitors are clinically useful.
(para2)In the present study, we attempted to evaluate the effects of a soda-lime absorber on removal of NO and NO2 during delivery of different NO concentrations (0-25 p.p.m.) in an FIO2 of 0.8. Soda lime removed NO2 almost completely during administration of 0-25 p.p.m. NO, and also removed between 30% and 55% of NO depending on the NO concentrations administered, although high concentrations of NO2 appeared in the breathing circuit without soda lime. Because Zapol et al. [13] and the Occupational Safety and Health Administration [12] recommended 1 p.p.m. and 5 p.p.m. of NO2, respectively, as safety limits, we determined the relationships between NO and NO2 concentrations following administration of various concentrations of NO using soda lime. NO2 concentrations did not exceed 1.5 p.p.m. during administration of inhaled 0-30 p.p.m. NO. In contrast, according to Pickett et al. [14], soda lime cannot be recommended for use as a NO2 scavenger during administration of inhaled NO. However, Kain [20] reported that 5-10 mesh soda lime with a green-to-brown color change (indicator 5 sodium manganate) was able to absorb higher oxides of N2 from a Žßowing gas stream. He calculated that each gram of soda lime was able to absorb 1.1 ml of the higher oxides. The reason for the difference between the ŽÞndings of our own study and those of the earlier one [14] is unclear.
(para2)In the present study, 400 g soda lime continued to absorb NO2 almost completely during long-term administration of inhaled NO (15-25 p.p.m.). These ŽÞndings indicate that the NO delivery system is suitable for long-term administration of inhaled NO. However, the
corrosion by NO of some plastics and metals in the ventilator might be of concern.
(para2)We conclude that electrochemical monitoring is accurate and useful for measurements of NO and NO2 concentrations, and that low doses of inhaled NO can be administered safely using a delivery system for Servo ventilator administration of NO with soda-lime and mass-Žßow regulators.
(A)Referenses
(REF) 1. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J (1991) Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 338:1173-1174
(REF) 2. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM (1993) Inhaled nitric oxide for adult respiratory distress syndrome. N Engl J Med 328:399-405
(REF) 3. Kinsella JP, Neish SR, Shaffer E, Abman SH (1992) Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:819-821
(REF) 4. Roberts JD, Polaner DM, Lang P, Zapol WM (1992) Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:818-819
(REF) 5. Tibballs J (1993) The role of nitric oxide (formerly endothelium-derived relaxing factorŽÑEDRF) in vasodilation and vasodilator therapy. Anaesth Intens Care 21:759-773
(REF) 6. Stavert DM, Lehnert BE (1990) Nitric oxide and nitrogen dioxide as inducers of acute pulmonary injury when inhaled at relatively high concentrations for brief periods. Inhalation Toxicol 2:53-
67
(REF) 7. Hugod C (1979) Effect of exposure to 43 p.p.m. nitric oxide and 3.6 p.p.m. nitrogen dioxide on rabbit lung. Int Arch Occup Environ Health 42:159-167
(REF) 8. Kawakami M, Yasui S, Yamawaki I, Katayama M, Nagai A, Takizawa T (1989) Structural changes in airways of rats exposed to nitrogen dioxide intermittently for seven days. Am Rev Respir Dis 140:1754-1762
(REF) 9. Man SFP, Williams DJ, Amy RA, Man GCW, Lien DC (1990) Sequential changes in canine pulmonary epithelial and endothelial cell functions after nitrogen dioxide. Am Rev Respir Dis 142:199-205
(REF)10. Oda H, Nogami H, Kusomoto S, Nakajima T, Kurata A, Imai K (1976) Long-term exposure to nitric oxide in mice. J Jpn Soc Air Pollut 11:150-160
(REF)11. Wessel DL, Adatia I, Thompson JE, Hickey PR (1994) Delivery and monitoring of inhaled nitric oxide in patients with pulmonary hypertension. Crit Care Med 22:930-938
(REF)12. Stenqvist O, Kjelltoft B, Lundin S (1993) Evaluation of a new system for ventilatory administration of nitric oxide. Acta Anaesthesiol Scand 37:687-691
(REF)13. Zapol WM, Rimar S, Gillis N, Marletta M, Bosken CH (1994) Nitric oxide and the lung. Am J Respir Crit Care Med 149:1375-1380
(REF)14. Pickett JA, Moors AH, Latimer RD, Mahmood N, Ghosh S, Oduro A (1994) The role of soda lime during administration of inhaled nitric oxide. Br J Anaesth 72:683-685
(REF)15. Frostell C, Fratacci M-D, Wain JC, Jones R, Zapol WM (1991) Inhaled nitric oxide: A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83:2038-2047
(REF)16. Clutton-Brock J (1967) Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anaesth 39:388-392
(REF)17. Falke K, Rossaint R, Pison U, Slama K, Lopez F, Santak B, Zapol WM (1991) Inhaled nitric oxide selectively reduces pulmonary hypertension in severe ARDS and improves gas exchange as well as right heart ejection fractionŽÑa case report. Am Rev Respir Dis (Suppl) 143:A248
(REF)18. Mercier JC, Zupan V, Dehan M, Renaudin MH, Bouchet M, Raveau C (1993) Device to monitor concentration of inhaled nitric oxide. Lancet 342:431-432
(REF)19. Petros AJ, Cox P, Bohn D (1994) A simple method for monitoring the concentration of inhaled nitric oxide. Anaesthesia 49:317-319
(REF)20. Kain ML (1967) Higher oxides of nitrogen in anaesthetic gas circuits. Br J Anaesth 39:382-387 (MW)

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(JN)J Anesth (1996) 9:324 - 328
(PT)
(CT)Relationship between plasma neutrophil elastase and respiratory index of patients who had undergone cardiac surgery with cardiopulmonary bypass
(CA)Toshiko Yusa1, Atsushi Nohara2, and Masahide Sunagawa2
(ADD)Department of Anesthesiology1 and Hyperbaric Medicine2, University of the Ryukyu, Faculty of Medicine, 207 Uehara, Nishihara, Okinawa, 903-01 Japan
(AB)Abstract: To evaluate the effects of cardiopulmonary by-
pass (CPB) on the release of polymorphonuclear leukocyte elastase (PMN-E) and postoperative pulmonary function, the perioperative plasma levels of PMN-E in ¡¦-antitrypsin complex (EAC) and hydrogen peroxide concentration in the expired breath were measured in eight patients who underwent cardiac surgery with CPB, and the relationship between EAC levels and the respiratory index (RI) was studied. Although PMN, EAC, and the ratio of EAC to neutrophil (E/N) were elevated signiŽÞcantly after surgery, alveolar-arterial oxygen difference (A-aDO2) and respiratory index (A-aDO2/PaO2) did not change when compared with those of the preopera-tive period. Hydrogen peroxide concentration in the expired breath also did not change (below 2.5 ùÎoláÍ-1) during the perioperative period. These results suggest that the elevation of EAC immediately after cardiac surgery using CPB, which lasted less than 2 h, was not a cause of postoperative pulmonary disorder. However, there was a signiŽÞcant positive correlation between E/N ratio and respiratory index (r 5 0.67, P , 0.01). Thus excessive release of PMN-E during CPB may
be implicated in the etiology of postoperative respiratory
dysfunction.
(KW)Key words: Neutrophil elastase, Elastase in ¡¦-antitrypsin complex, Cardiopulmonary bypass, Respiratory index, Expired breath hydrogen peroxide concentration
(A)Introduction
(para1)Neutrophil elastase, which is proteinase, is the quantitatively predominant constituent of azurophilic granules of polymorphonuclear leukocyte (PMN) and is known to possess elastinolytic and collagenolytic properties capable of causing major tissue destruction at sites
of inŽßammation [1]. Polymorphonuclear leukocyte elastase (PMN-E) is released from lysosomes, and an elevated level of PMN-E in plasma has been thought to be involved in pulmonary disorders, especially in adult respiratory distress syndrome (ARDS) [2]. Reduced oxygen species liberated by activated PMN are also involved in the injury process [3]. The hydrogen peroxide content of the expired breath from patients with ARDS was higher than that of other intensive care unit (ICU) patients [4].
(para2)During extracorporeal circulation such as hemodialysis and cardiac surgery with cardiopulmonary bypass (CPB), a marked increase of PMN-E in plasma was reported as a result of degranulation from mechanically traumatized blood [5]. In CPB, a post-bypass syn-
drome including pulmonary dysfunction (ŽÒpost-
perfusion lungŽÓ) has been reported, and was considered to be mediated by increased plasma PMN-E activity [6]. SigniŽÞcant positive correlations between the plasma level of PMN-E and alveolar-arterial oxygen difference (A-aDO2) [7,8], respiratory index (A-aDO2/PaO2) [9],
or oxygenation index (PaO2/FiO2) [10] during the perioperative period have also been reported.
(para2)To evaluate the effects of CPB on the release of PMN-E and postoperative pulmonary function, we measured the plasma level of PMN-E in ¡¦-antitrypsin complex (EAC) and the hydrogen peroxide concentration in the expired breath, and evaluated the relationship between these values and the respiratory index (RI) in patients who underwent cardiac surgery with CPB.
(A)Materials and methods
(B)Materials
(para1)Following approval by the Committee on Human Research of University of the RyukyuŽÕs, eight patients
who underwent elective cardiac surgery with CPB were included in this study. Six of these eight patients underwent aorto-coronary bypass and other two had aortic valve replacement. Their ages ranged from 32 to 70 years. Informed consent was obtained from each
patient.
(para2)All patients were premedicated with morphine and scopolamine. Anesthesia was induced and maintained with high-dose fentanyl and diazepam supplemented with enŽßurane as required. Pancuronium was used as a muscle relaxant. Patients were perfused with membrane oxygenators and received corticosteroid intravenously at the start of CPB. They had controlled or assisted ventilation through an endotracheal tube until an early postoperative period in the ICU.
(B)Methods
(para1)Heparinized and EDTA-anticoagulated arterial blood samples and expired breath samples were obtained before surgery (after induction of anesthesia; pre-op), at the end of the operation (post-op) and the following morning in the ICU when patients were breathing
100% O2.
(para2)Blood gas analysis, measurements of hemoglobin (Hb), and hematocrit (Hct) were done from a heparinized arterial blood sample (using the CIBA Corning 278 Blood Gas System and a Corning 2500 Co-oximeter, Ciba Corning Diagnostics Corp., Tokyo, Japan). White blood cell counts were also done from an arterial blood sample. EAC was measured by an enzyme-linked immunoassay using the technique of Neumann [11].
(para2)To collect the expired gas, the breath condensate
was obtained by passing the expired breath through 90 cm Tygon tubing submerged in an ice-water bath.
The tubing was connected to the expiratory limb of
a one-way exhalation valve. Expired gas was col-
lected until a condensate of approximately 1 ml had
formed (within 10 min). The condensate was then transferred to a polystyrene tube and immediately placed
on ice.
(para2)Hydrogen peroxide in the breath condensate was
assayed by the horseradish peroxide method (Sigma, Type II, SIGMA Chemical Company, MO, USA) using a spectrophotometer (Shimadzu UV 3000, Shimadzu Corporation, Kyoto, Japan) [12].
(para2)From the blood gas analysis data, the RI was calculated as the ratio of A-aDO2 to PaO2. The A-aDO2 was calculated as follows: A-aDO2 5 {(760 2 47)FiO2)} 2 PaCO2 R21 2 PaO2, where the respiratory exchange coefŽÞcient (R) is 0.8 and FiO2 is 1.0.
(para2)The ratio of EAC (fgáÎl21) to neutrophil (celláÎl21) (E/N ratio) was also calculated to eliminate the effect of hemodilution during CPB.
(B)Statistical analysis
(para1)Values were expressed as mean 6 SE. Statistical
analyses were performed using analysis of variance (ANOVA) with DunnettŽÕs test. The correlation was examined by a least-squares linear regression analysis. A P value of less than 0.05 was considered statistically signiŽÞcant.
(A)Results
(para1)There were no postoperative complications.
(para2)The durations of CPB, surgery, and anesthesia were 115.6 6 8.3 min, 343.8 6 23.4 min, and 425.0 6 28.4 min, respectively.
(para2)Hb and Hct values decreased signiŽÞcantly during surgery, indicating residual hemodilution during CPB immediately after surgery (Hb and Hct values were 13.4 6 0.5 gáÅl21 and 38.5 6 1.7%, respectively, in pre-op, and 10.7 6 0.5 gáÅl21 and 30.0 6 1.5%, respectively in post-op). Neutrophils (celláÎl21) increased signiŽÞcantly in the postoperative period (17.3 6 2.5 and 16.3 6 1.4 in post-op and ICU, respectively) compared with pre-op (4.0 6 0.5). Plasma levels of EAC rose above the normal range (21-165 ùÈ¡¦21) from 118.1 6 13.3 to 1118.1 6 267.1 and 491.4 6 55.8 in post-op and ICU, respectively. In post-op, the increase in EAC was signiŽÞcant compared with pre-op and ICU. Consequently, the E/N ratio increased signiŽÞcantly (74.8 6 19.8 fgáÄell21áÎl21) in post-op (Fig. 1).
(para2)Postoperative A-aDO2 and RI were not different from pre-op. A-aDO2 in post-op (304.8 6 50.3), however, was signiŽÞcantly higher than that (131.1 6 25.0) in the ICU (Fig. 2).
(para2)A signiŽÞcant positive correlation was found between RI and the E/N ratio during the perioperative period
(r 5 0.67, P , 0.01) with the exception of 2 points in post-op (because of extremely abnormal values in EAC, possibly caused by hemolysis during CPB) (Fig. 3).
(para2)The hydrogen peroxide content of expired breath condensate did not increase in the postoperative period compared with pre-op, and all values were below 2.5 ùÎoláÍ21 (Table 1).
(A)Discussion
(para1)In our study, immediately after cardiac surgery with CPB, neutrophil, EAC, and E/N ratio were signiŽÞcantly elevated (Fig. 1). A-aDO2 and respiratory index (RI) did not increase signiŽÞcantly compared with their preoperative level (Fig. 2) and hydrogen peroxide concentration of expired breath condensate also did not increase postoperatively (Table 1). However, there is
a signiŽÞcant correlation between RI and E/N ratio
(r 5 0.67, P , 0.01) (Fig. 3).
(para2)During extracorporeal circulation such as hemodialysis and cardiac surgery with CPB, blood is subjected to mechanical trauma [5]. As a result, PMN lysosomal enzymes are released and complements
are activated during CPB [13]. Complement-exposed PMNs are stimulated both to adhere to other surfaces and to aggregate. Complement conversion and pulmonary leukocytes sequestration were also observed
during CPB [14,15]. Furthermore, stimulated PMNs liberate a variety of highly reactive reduced oxygen species almost at the same time as the release of elastase [3]. Thus activated PMNs may play a causative or aggravating role in one of the most common side effects, postoperative pulmonary dysfunction known as post-perfusion lung, which is thought to fall under the category of ARDS. Therefore we measured PMNs, neutrophil EAC, RI, and hydrogen peroxide concentration in the expired breath, as an index of reactive reduced oxygen species released by sequestered pulmonary PMNs, in order to evaluate the effects of CPB on postoperative pulmonary function. The effect of EAC was evaluated as the E/N ratio to eliminate the effect of hemodilution during CPB.
(para2)Previously, a tremendous elevation in PMN and PMN-E was reported in patients who underwent cardiac surgery with CPB. There is also a positive correlation between levels of PMN or PMN-E and respiratory functions such as A-aDO2 [7,8], repiratory index [9], and oxygenation index [10]. Comparing our results, the temporal elevation of PMNs and EAC after CPB in our study would not contribute to postoperative pulmonary disorder such as is seen in ARDS, because the PMN and PMN-E in bronchoalveolar lavage Žßuid showed a signiŽÞcantly positive correlation to A-aDO2 only in patients with ARDS [7,8].
(para2)Hydrogen peroxide concentrations of expired breath condensate in our cases were below 2.5 ùÎoláÍ21, which was the highest normal range reported [4,16]. This result also indicates that pulmonary leukocyte sequestration during CPB in this study would be temporal. Elastases released by inŽßammatory stimuli such as endotoxin, complements, or immunocomplex are proteinases that can degrade almost all components of the extracellular matrix and cleave a variety of key plasma proteins and even attack intact cells [1]. How-
ever, plasma and interstitial Žßuid contain a series of powerful antiproteinases including ¡¦-proteinase (¡¦-antitrypsin), which irreversibly inhibits PMN-E by forming an enzyme-inhibitor complex; consequently, PMN-E levels have been measured in the form of the PMN elastase-¡¦-antitrypsin complex (EAC) by an enzyme-linked immunoassay such as we applied in this study. Thus measured EAC is inactive elastase. EAC itself, however, is a neutrophil chemoattractant [17], and therefore pulmonary leukocyte sequestration, which has been observed during CPB, is suggested as contributing to the pathogenesis of post-perfusion lung [6]. Activated PMNs release reduced oxygen species such as superoxide and hydrogen peroxide, but increased levels of hydrogen peroxide were only detected in the expired breath of ICU patients with focal lung inŽÞltration and in ARDS patients [4,16]. We also reported an increase in hydrogen peroxide concentration in the expired breath of one patient who had an excessive plasma EAC level after intraoperative blood transfusion [18]. Thus pulmonary PMN sequestration during CPB in this study is temporal and not sufŽÞcient to inactivate all ¡¦-antitrypsin and cause postoperative pulmonary dysfunction. Because the increase in PMN and PMN-E during CPB related to perfusion time [6], the relatively short time of CPB in our cases would affect our results.
(para2)The excess release of PMN-E, especially under conditions that compromise the function of their regulatory inhibitors, can lead to tissue damage in a broad spectrum of diseases such as endotoxin shock, septicemia, ARDS, and other inŽßammatory diseases [1]. By oxidatively inactivating a series of key proteinase inhibitors such as ¡¦-antitrypsin [19] and simultaneously activating latent proteinase, activated PMN can create an environment in which elastase, collagenase and gelatinase are able to exert destructive effects more effectively and with greater speciŽÞcity than could even enormous doses of oxidants [3]. In this study, there is a signiŽÞcant correlation between RI and E/N ratio (r 5 0.67, P , 0.01). Therefore the excessive elevation of PMN-E during cardiac surgery with prolonged CPB or in the patients with preoperative lung disease may be a factor of postoperative pulmonary disorder.
(A)References
(REF) 1. Janoff A (1985) Elastase in tissue injury. Annu Rev Med 36:207-216
(REF) 2. Ogawa M (1989) Neutrophil elastase and the lung, with special reference to the pathogenesis of ARDS (in Japanese with English abstract). Kokyu to Junkan (Respir Circ) 37:1258-1269
(REF) 3. Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320:365-376
(REF) 4. Baldwin SR, Simon RH, Grum CM, Ketai LH, Boxer LA, Devall LJ (1986) Oxidant activity in expired breath of patients with adult respiratory distress syndrome. Lancet 1:11-14
(REF) 5. HÓÓl WH, Jochum M, Heidland A, Fritz H (1983) Release of granulocyte proteinases during hemodialysis. Am J Nephrol 3:213-217
(REF) 6. Ratliff NB, Young WG Jr, Hackel DB, Mikat E, Wilson JW (1973) Pulmonary injury secondary to extracorporeal circulation. An ultrastructural study. J Thorac Cardiovasc Surg 65:425-432
(REF) 7. Idell S, Kucich U, Fein A, Kueppers F, James HL, Walsh PN, Weinbaum G, Colman RW, Cohen AB (1985) Neutrophil elastase-releasing factors in bronchoalveolar lavage from patients with adult respiratory distress syndrome. Am Rev Respir Dis 132:1098-1105
(REF) 8. Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE (1986) Lung neutrophils in the adult respiratory distress syndrome: Clinical and pathophysiologic signiŽÞcance. Am Rev Respir Dis 133:218-225
(REF) 9. Shimanuki K, Sakurabayashi I, Kanazawa K (1989) Perioperative Žßuctuation in plasma levels of granulocyte elastase and alpha-1-antitrypsin: The inŽßuence of the severity of surgical intervention and their effect on the respiratory index. Jpn J Surg 19:410-417
(REF)10. Mishima A, Takeuti Y, Usami S, Kotani H, Suzuki Y, Yura J (1990) Effects of ulinastatin on plasma polymorphonuclear leukocyte elastase activity and respiratory function in patients undergoing cardiopulmonary bypass (in Japanese with English abstract). Nihon Kyobu Geka Gakkai Zasshi (J Jpn Assoc Thorac Surg) 38:607-612
(REF)11. Neumann S, Gunzer G, Hennrich N, Lang H (1984) ŽÒPMN-elastase assayŽÓ: Enzyme immunoassay for human polymorphonuclear elastase complexed with ¡¦-proteinase inhibitor. J Clin Chem Clin Biochem 22:693-697
(REF)12. Gallati VH, Pracht I (1985) Peroxidase aus meerrettich: Kinetishe studien und optimierung der peroxidase-aktivitatsbestimmung mit den substraten H2O2 und 3,39,5,59-tetramethylbenzidin. J Clin Chem Clin Biochem 23:453-460
(REF)13. Antonsen S, Brandslund I, Clemensen S, SŽ¿feldt S, Madsen T, Alstrup P (1987) Neutrophil lysosomal enzyme release and complement activation during cardiopulmonary bypass. Scand J Thorac Cardiovasc Surg 21:47-52
(REF)14. Hammerschmidt DE, Stroncek DF, Bowers TK, Lammi-Keefe CJ, Kurth DM, Ozalins A, Nicoloff DM, Lillehei RC, Craddock PR, Jacob HS (1981) Complement activation and neutropenia occurring during cardiopulmonary bypass. J Thorac Cardiovasc Surg 81:370-377
(REF)15. Utoh J, Yamamoto T, Kambara T, Goto H, Miyauchi Y (1988) Complement conversion and leukocyte kinetics in open heart surgery. Jpn J Surg 18:259-267
(REF)16. Sznajder JI, Fraiman A, Hall JB, Sanders W, Schmidt G,Crawford G, Nahum A, Factor P, Wood LDH (1989) Increased hydrogen peroxide in the expired breath of patients with acute hypoxemic respiratory failure. Chest 96:606-612
(REF)17. Banda MJ, Rice AG, GrifŽÞn GL, Senior RM (1988) The inhibitory complex of human ¡¦-proteinase inhibitor and human leukocyte elastase is a neutrophil chemoattractant. J Exp Med 167: 1608-1615
(REF)18. Yusa T, Nohara A, Matayoshi K, Zukeran H (1994) Effect of intraoperative stored blood transfusion on plasma neutrophil elastase and its modiŽÞcation by ulinastatin (in Japanese with
English abstract). Masui (Jpn J Anesthesiol) 43:1486-1492
(REF)19. Matheson NR, Wong PS, Travis J (1979) Enzymatic inactivation of human alpha-1-proteinase inhibitor by neutrophil myeloperoxidase. Biochem Biophys Res Commun 88:402-409 (MW)

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(JN)J Anesth (1996) 9:329 - 332
(PT)
(CT)Liver and renal functions following total intravenous anesthesia using midazolam and fentanylŽÑcomparison with enŽßurane-nitrous oxide anesthesia
(CA)Tomoki Nishiyama1 and Tatsuo Iwasaki2
(ADD)1 Department of Anesthesiology, University of Tokyo, Faculty of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113 Japan
(ADD)2 Department of Anesthesiology, National Cardiovascular Center, Fujishirodai, Suita, Osaka, 565 Japan
(AB)Abstract: Thirty patients undergoing lower abdominal surgery were studied to compare liver and renal functions in total intravenous anesthesia (TIVA) using midazolam and fentanyl with those in enŽßurane-nitrous oxide anesthesia (GOE).
(AB)Patients were randomly divided into two groups of 15. In the TIVA group, anesthesia was induced with 0.3 mgáÌg21 midazolam and maintained with 0.68 mgáÌg21áÉ21 midazolam for 15 min followed by 0.125 mg ¡¦kg21áÉ21 midazolam and fentanyl. In the GOE group, anesthesia was induced with 5 mgáÌg21 thiamylal and maintained with enŽßurane-nitrous oxide in oxygen. Plasma levels of aspartate aminotransferase, alanine aminotransferase (ALT), lactate dehydrogenase, total bilirubin, alkaline phosphatase, ¡¦glutamyl transpeptidase (¡¦GTP), blood urea nitrogen (BUN), and creatinine (Cr) were measured before and at 1, 7, and 30 days after surgery. There were transient increases beyond the normal range in ALT and ¡¦GTP in both groups. BUN and Cr were within the normal range. There were no differences between the two groups regarding these parameters and the numbers with abnormally high levels of each parameter. In conclusion, liver and renal functions following TIVA using midazolam and fentanyl
were the same as those following enŽßurane-nitrous oxide
anesthesia.
(KW)Key words: Liver function, Renal function, Total intravenous anesthesia, Midazolam, EnŽßurane
(A)Introduction
(para1)Total intravenous anesthesia (TIVA) has been discussed in many reports because volatile anesthetics
produce problems of air pollution, bone marrow suppression, and possible toxicity to the liver and kidneys [1,2]. We also previously studied the hemodynamics, plasma levels of catecholamine, and postoperative analgesia in TIVA using midazolam and fentanyl [3,4]. It is well known that each of these two intravenous anesthetics has little effect on liver and renal functions. However, the elevated serum catecholamine levels during TIVA [5] will increase the metabolism and vascular resistance in the liver and kidney, which might affect liver and renal functions. No reports have appeared regarding postoperative liver and renal functions following TIVA. The aim of this study was to compare liver and renal functions after TIVA using midazolam and fentanyl with those following enŽßurane-nitrous oxide anesthesia (GOE).
(A)Methods
(para1)Following the approval of the Ethics Committee of the hospital and gaining informed consent, we studied 30 patients, aged 40-70 years with ASA class 1 or 2, scheduled for elective lower abdominal surgery. Those who had abnormally high plasma levels of liver enzymes, blood urea nitrogen (BUN), or creatinine (Cr), or were taking any drugs prior to surgery were excluded. They were divided into two groups according to a random-number table: a TIVA group and a GOE group of 15 patients each.
(para2)Atropine (0.5 mg) and hydroxyzine (50 mg) were injected intramuscularly as premedication 30 min before the patient entered the operating room. Prior to general anesthesia, an epidural catheter was inserted into a single interspace from Th10 to L2 for postoperative pain control.
(para2)In the TIVA group, anesthesia was induced with 0.3 mgáÌg21 midazolam, and tracheal intubation was performed with 1 mg pancuronium followed by 1 mgáÌg21 suxamethonium. Midazolam was infused at 0.68 mgáÌg21áÉ21 for 15 min followed by 0.125 mg¡¦ kg21áÉ21 according to the method of Persson et al. [6], with its infusion being stopped about 30 min before the end of surgery. Fentanyl and pancuronium were intermittently administered as necessary. Oxygen (6 l¡¦min21) was inhaled and no volatile anesthetics were used. Atropine (1 mg) and neostigmine (2 mg), naloxone (0.2 mg), and aminophylline (125 mg) were administered at the end of surgery to antagonize muscle relaxant, fentanyl, and midazolam, respectively.
(para2)In the GOE group, anesthesia was induced with 5 mgáÌg21 thiamylal and tracheal intubation was performed as in the TIVA group. Anesthesia was maintained with 1.0%-2.0% (end-tidal concentration) enŽßurane and 3 láÎin21 nitrous oxide in 2 láÎin21 oxygen. Atropine (1 mg) and neostigmine (2 mg) were administered at the end of surgery. An end-tidal concentration of 1.68% enŽßurane was calculated as 1 minimum alveolar concentration (MAC).
(para2)Postoperative pain control was performed with intermittent epidural injection of 0.25% bupivacaine and buprenorphine. Cefazolin was used as an antibiotic for
7 days after surgery in every case. Those who had apparent infection were excluded from this study.
(para2)Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total bilirubin (T.Bil), alkaline phosphatase (ALP), ¡¦glutamyl transpeptidase (¡¦GTP), BUN, and Cr were measured before surgery and at 1, 7, and 30 days after surgery. All parameters were measured at the hospitalŽÕs central laboratory according to standard procedures.
(para2)Data are given as mean 6 standard error. Statistical analysis consisted of an analysis of variance (ANOVA) with repeated measures for each parameter before
and after anesthesia, a ¡¦ test for sex, and the Mann-Whitney U-test for other parameters between groups.
A P value less than 0.05 was considered statistically signiŽÞcant.
(A)Results
(para1)There were no signiŽÞcant differences between the two groups for age, sex, body weight, duration of surgery, and anesthesia (Table 1), and blood pressure and heart rate (Table 2) during surgery. In the TIVA group, 48.5 6 4.1 mg (range 41.0-61.4 mg) midazolam and 717 6 60 ùÈ (range 600-900 ùÈ) fentanyl were administered. In the GOE group, 4.1 6 0.2 MACáÉ (range 3.1-4.7 MACáÉ) enŽßurane was used.
(para2)AST and ALT on the 7th day after surgery and T. Bil on the 1st day after surgery in the TIVA group, and LDH on the 1st and 7th days after surgery in both groups increased signiŽÞcantly compared to the presurgical values. However, they returned to the presurgical values on the 30th day after surgery. BUN and Cr were within the normal range in both groups. There were no signiŽÞcant differences in these parameters between the two groups. The numbers who had abnormally high levels in each parameter did not signiŽÞcantly differ between the two groups (Fig. 1).
(A)Discussion
(para1)Halothane [7] and enŽßurane [8] are known to cause liver dysfunction. Nitrous oxide is reported to depress bone marrow function [9]. Therefore, extended exposure to volatile anesthetics is dangerous not only to the patients, but also to the operating-room personnel [10]. The newly developed volatile anesthetics isoŽßurane [11] and sevoŽßurane [12] are also reported to cause liver dysfunction. However, no reports have indicated that midazolam or fentanyl alone cause liver or other organ dysfunction. In addition, intravenous anesthetics do not result in air pollution.
(para2)The TIVA method employed in the present study generated stable hemodynamics and postanesthetic
analgesia [3], although it produced higher serum
catecholamine levels than did enŽßurane-nitrous oxide anesthesia during surgery in our previous study [5]. In the present study, the TIVA group presented a transient but signiŽÞcant elevation in AST, ALT, LDH, and T.Bil following surgery, which might be due to increased metabolism or vascular resistance by catecholamine [13,14] in the liver during TIVA. However, these elevations did not differ signiŽÞcantly from those in the GOE group. The increases in liver enzymes were in part due to the abdominal surgical procedure employed, which unquestionably inŽßuenced liver blood Žßow and function.
(para2)Regarding the effect on renal function of anesthetics, methoxyŽßurane is well known to cause renal damage [15] and no other anesthetics are reported to cause renal dysfunction. The normal values of BUN and Cr in the present study indicate that renal function was not clinically affected by either TIVA or enŽßurane-nitrous oxide anesthesia.
(para2)In conclusion, the results of this study suggest that liver and renal functions following TIVA using midazolam and fentanyl are the same as those after enŽßurane-nitrous oxide anesthesia. To clarify this
problem, further studies are necessary in much larger populations.
(A)References
(REF) 1. Nilsson A, Tamsen A, Persson P (1986) Midazolam-fentanyl anesthesia for major surgery. Plasma levels of midazolam during prolonged total intravenous anesthesia. Acta Anaesthesiol Scand 30:66-69
(REF) 2. Reves JG, Glass P, Jacobs JR (1989) Alfentanyl and midazolam: New anesthetic drugs for continuous infusion and an automated method of administration. Mount Sinai J Med 56:99-107
(REF) 3. Nishiyama T, Odaka Y, Seto K (1990) Total intravenous anesthesia with continuous infusion of midazolam (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 39:1120-1125
(REF) 4. Nishiyama T, Odaka Y, Seto K (1990) Total intravenous anesthesia with continuous infusion of midazolam. Study on plasma levels of midazolam and catecholamines (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 39:1383-1387
(REF) 5. Nishiyama T, Odaka Y, Seto K (1990) Comparison between intravenous anesthesia and inhalation anesthesia (in Japanese). Rinsho Masui (Jpn J Clin Anesth) 14:1257-1260
(REF) 6. Persson P, Nilsson A, Hartvig P, Tamsen A (1987) Pharmacokinetics of midazolam in total I.V. anaesthesia. Br J Anaesth 59:548-556
(REF) 7. Subcommittee on the National Halothane Study of the Committed on Anesthesia, National Academy of SciencesŽÑNational Research Council (1966) Summary of the National Halothane Study. Possible association between halothane anesthesia and postoperative hepatic necrosis. JAMA 197:775-788
(REF) 8. Adams AP (1981) EnŽßurane in clinical practice. Br J Anaesth 53:s27-41
(REF) 9. Nunn JF, Sharer NW, Gorchein A, Jones JA, Wickramasinghe SN (1982) Megaloblastic haemopoiesis after multiple short-term exposure to nitrous oxide. Lancet 1379-1381
(REF)10. Report of an ad hoc committee on the effect of trace anesthetics on the health of operating room personnel, American Society of Anesthesiologists (1974). Occupational disease among operating room personnel: A national study. Anesthesiology 41:321-340
(REF)11. Hirakawa M (1993) Metabolism of volatile anesthetics and organ dysfunction (in Japanese). Rinsho Masui (J Jpn Soc Clin Anesth) 13:504-514
(REF)12. Ogawa M, Doi K, Mitsufuji T, Satoh K, Takatori T (1991) Drug-induced hepatitis following sevoŽßurane anesthesia in a child
(in Japanese with English abstract). Masui (Jpn J Anesthesiol) 40:1542-1545
(REF)13. Gelmans S (1987) General anesthesia and hepatic circulation. Can J Physiol Pharmacol 65:1762-1779
(REF)14. Hanson KM (1973) Response of intrahepatic vasculature to isoproterenol and epinephrine infusions. Angiologica 10:65-75
(REF)15. Mazze RI, Shue GL, Jackson SH (1971) Renal dysfunction associated with methoxyŽßurane anesthesia. A randomized, prospective clinical evaluation. JAMA 216:278-288 (MW)

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(JN)J Anesth (1996) 9:333 - 337
(PT)
(CT)Difference of train-of-four fade induced by nondepolarizing neuromuscular blocking drugs: a theoretical consideration on the underlying mechanisms
(CA)Takeshi Tajima, Junko Amaya, Kazunori Katayama, and Tamotsu Koizumi
(ADD)Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, 930-01 Japan
(AB)Abstract: Nondepolarizing neuromuscular blocking drugs induce train-of-four (TOF) fade, i.e., the reduction of the fourth to the ŽÞrst twitch height in a train under TOF stimulation. It has been observed that the degree of TOF fade varies with the drug used and is inversely correlated with the potencies of the drug. In this study, the cause of difference of TOF fade was considered using a dynamic model. The model was based on the following assumptions: (1) Twitch response is evoked by the binding of acetylcholine (ACh) molecules to the postsynaptic nicotinic receptors in a neuromuscular junction, (2) time-dependent ACh mobilization in a motor nerve terminal results in less ACh output at the fourth stimulus in a train than at the ŽÞrst stimulus, (3) the drugs compete with ACh for the postsynaptic receptors and inhibit the receptor-binding of ACh, and (4) the drugs have various afŽÞnities for the receptors. This study suggested that the difference of afŽÞnities
of the drugs for postsynaptic ACh receptors may cause the difference of TOF fade.
(KW)Key words: Train-of-four fade, Nondepolarizing neuromuscular blocking drugs, Acetylcholine, Mobilization, Model
(1)Introduction
(para1)Train-of-four (TOF) stimulation at frequencies lower than 4.0 Hz is used to monitor neuromuscular function [1 - 7]. The four successive twitch height responses (T1, T2, T3, and T4) evoked by the stimulation have similar height in the absence of relaxants. Nondepolarizing neuromuscular blocking drugs, however, induce fade in the series of four twitch heights as well as the depression of T1. The TOF ratio (T4/T1) at a certain degree of T1 depression varies depending on the drugs [3 - 5]. It has been considered that the difference of TOF fade among the drugs is due to the presynaptic action of the drugs [8 - 10]. Recently, it has been suggested that the TOF fade has no relation with the presynaptic action [11]. The mechanisms underlying the various TOF fade have not yet been fully elucidated. Careful survey of the reported data [3 - 5], however, indicated the existence of regularity: the degree of TOF fade is almost inversely related to the potencies of the drugs. TOF fade is a clinical index of the depth of neuromuscular blockade produced by the drugs. The clariŽÞcation of the difference of fade will help to achieve an appropriate dosage regimen. The magnitude of blockade is modulated by the afŽÞnities of drugs and the transmitter acetylcholine (ACh) for the postsynaptic receptors as well as the concentrations of the drugs and ACh. The purpose of this study is to propose an explanation of the relationship between the degree of TOF fade and the potencies of the drugs using a dynamic model based on the law of mass action.
(1)Theory
(para1)Because nondepolarizing neuromuscular blocking drugs compete with ACh for the postsynaptic nicotinic receptors, the concentrations of ACh-receptor complex (RA) and drug-receptor complex (RC) in a neuromuscular junction are written by Eqs. (1) and (2), respectively, applying expressions used in competitive enzyme
kinetics:
(para1)A
(para1)RA 5 RT A 1 KA(1 1 C/KC) (1)
(para1)C
(para1)RC 5 RT C 1 KC(1 1 A/KA) (2)
(para1)where RT is the total concentration of the receptor, and A and C are the unbound concentrations of ACh and drug, respectively. KA and KC are the dissociation constants for the receptor complex of ACh and the drug. The total concentration of ACh (AT, i.e., the concentration of released ACh) and drug (CT) are written by Eqs. (3) and (4), respectively:
(para1)AT 5 A 1 RA (3)
(para1)CT 5 C 1 RC. (4)
(para1)Substituting Eqs. (3) and (4) into Eqs. (1) and (2), RA and RC can be written as follows:
(para1)AT 2 RA
(para1)RA 5 RT AT 2 RA 1 KA(1 1 CT2 RC) (5)
(para1)KC
(para1)CT 2 RC
(para1)RC 5 RT CT 2 RC 1 KC(1 1 AT2 RA) (6)
(para1)KA
(para2)It was assumed that the concentration of ACh released by the fourth stimulus in a train (AT4) is lower than the concentration of ACh released by the ŽÞrst stimulus (AT1), irrespective of the presence or absence of a drug, because ACh mobilization in a motor nerve is time-dependent [12] and the ACh molecules released by each stimulus are immediately metabolized after binding to the receptors and causing a muscle contraction [13].
(para2)The receptor-binding of ACh evokes the twitch response of a muscle. In neuromuscular transmission, the margin of safety exists and the maximum twitch response is evoked at submaximal receptor occupancy by ACh [14]. HillŽÕs equation can accommodate such a nonlinear transduction of the receptor occupancy by an agonist into the pharmacological effect [15]. Hence, to describe the relationship between the receptor occupancy and twitch response, the twitch height (TW) is related to RA with HillŽÕs equation as follows:
(para2)RAS
(para1)TW 5 TWMAX RAS 1 RA50S (7)
(para1)where TWMAX is the physiological maximum twitch height, RA50 is the concentration of the ACh-receptor complex which causes 50% twitch height of TWMAX and s is HillŽÕs coefŽÞcient.
(1)Methods
(para1)Simulation with the model was carried out on a personal computer (PC-9801/RA, NEC, Tokyo, Japan). The inŽßuence of difference of KC on the T1-TOF ratio relationship as well as the drug concentration-muscle relaxation relationship was studied. The parameter values other than KC and CT were ŽÞxed to the reported values [6,7] shown in Table 1. For the simulation, RA and RC in Eqs. (5) and (6) were ŽÞrst solved numerically using NewtonŽÕs iterative method after speciŽÞc values of KC and CT were given. Then twitch heights in the presence or absence of a drug were obtained by using Eq. (7), and the twitch height ratio (the ratio of a twitch height to the control value) and the TOF ratio (the ratio of the fourth twitch height in a train to the ŽÞrst twitch height at a certain drug concentration) were calculated.
(1)Results
(para1)Relationships between drug concentration and twitch height ratios of T1 and T4 were simulated using various values of KC, the results of which are shown in Fig. 1. The T1-T4 relationship and the T1-TOF ratio relationship are also presented in Fig. 2. The TOF ratio in the absence of a drug was estimated to be almost 1.0. Irrespective of the value of KC, T4 at a certain drug concentration decreased more than T1 as shown in Fig. 1. As the value of KC increased, the drug concentration-twitch height curves of T1 and T4 shifted to the right (Fig. 1) and the T1-T4 ratio curves became concave (Fig. 2A). The characteristics of T1-T4 curves denoted that an increase of KC augments the degree of T4 depression at a ŽÞxed T1 depression. Consequently, an increase of KC reduced the TOF ratio as shown in Fig. 2B. It was predictable that the degree of fade is inversely correlated with the potencies of drugs.
(1)Discussion
(para1)Vecuronium (VEC), pancuronium (PAC), alcuronium (ALC), atracurium (ATR), d-tubocurarine (d-TC), fazadinium (FAZ), and gallamine (GAL) have been used as nondepolarizing neuromuscular blocking drugs for clinical and research purposes. The order of the in vivo potencies is VEC . PAC . ALC . ATR . d-TC . FAZ . GAL [16]. Williams et al. [3] compared the degree of TOF fade in human subjects and reported that the degree of fade was PAC , ALC , d-TC , FAZ , GAL. Gibson and Mirakhur [4] demonstrated that the degree of TOF fade in human subjects was VEC 5 PAC , ATR 5 d-TC. Klein et al. [5] found that the degree of fade in horses was VEC , PAC 5 GAL. These reported orders of the degree of TOF fade were almost in inverse relation to the order of the potencies of the drugs.
(para2)The difference of TOF fade induced by nondepolarizing neuromuscular blocking drugs has been attributed to a presynaptic action of the drugs [8 - 10]. At the presynaptic level, the drugs inhibit the feedback control of ACh release and reduce the ACh output at the fourth stimulus in a train in comparison with that at the ŽÞrst stimulus. However, it has been reported that d-TC fails to inhibit ACh output from a nerve terminal under train stimulations of 15 pulses at 5.0 Hz [11], suggesting that the presynaptic action is not operative under the TOF stimulations at usual frequencies lower than 4.0 Hz. A more feasible explanation of the difference of TOF fade is necessary.
(para2)Our previous work suggested that the time-dependent ACh mobilization results in less ACh output at the fourth stimulus than at the ŽÞrst stimulus [6,7]. The nondepolarizing neuromuscular blocking drugs share similar pharmacokinetic properties because of their similar physicochemical characteristics [17]. Thus, it is conceivable that the magnitude of the afŽÞnities for the postsynaptic receptors is responsible for the difference of TOF fade.
(para2)For a drug with a low afŽÞnity, a considerable amount is necessary to compete with ACh for the receptor and to depress twitch responses. It is assumed that the fraction of drug bound to the receptor is negligible with respect to the total concentration of the drug. Thus, C in Eq. (1) tends to be constant and the apparent afŽÞnity for the formation of ACh-receptor complex (RA) is hardly affected by the reduction of ACh output through the ŽÞrst to the fourth stimulus in a train. Subsequently, RA directly reŽßects the change of ACh output. The reduction of ACh output diminishes the receptor occupancy by ACh. In this way, the drug concentration-relaxation curves of T1 and T4 separate from each other and the TOF fade is observed (Figs. 1, 2).
(para2)On the other hand, the degree of TOF fade decreases in the presence of a drug with a high afŽÞnity. In this case, the fraction of drug bound to the receptor becomes nonnegligible with respect to the total drug, and then the unbound concentration of the drug is no longer proportional to the total concentration. When ACh output decreases, the resulting increase in receptor occupancy of the drug concurrently leads to a signiŽÞcant decrement of C relative to CT and augments the apparent afŽÞnity for the formation of RA, i.e., the inverse of KA (1 1 C/KC) in Eq. (1). This augmentation of the afŽÞnity counteracts the reduction of ACh output for the maintenance of receptor occupancy by ACh. Eventually, the difference in RA at both stimuli becomes smaller and the twitch heights of T1 and T4 become similar.
(para2)The pharmacological potency is generally assumed to be directly proportional to the afŽÞnity for the receptors associated with the drug effect. However, in neuromuscular transmission, the relation is not always valid. The potency ratio of PAN/GAL is reported to be 40 [16], whereas the examination of ACh-elicited currents for the mouse muscle ACh receptor [18] showed the afŽÞnity ratio of PAN/GAL to be about 400. The present results also account for the relationship between the potency and the afŽÞnity for the receptor. In Fig. 1, the EC50 of a drug with KC 5 1.0 ù® for T1 depression is about 10 ù®, whereas that with KC 5 0.001 ù® is 0.1 ù®. Then the 1000-fold difference in the afŽÞnity for the receptor would lead to a potency ratio of 100. If in all instances the unbound concentration of a drug adjacent to the receptor site is nearly equal to that of the total drug, these results could not be observed. The twitch response is evoked even at submaximal receptor occupancy by ACh and a drug must occlude a large portion of the receptors to block the muscle contraction. When the receptors densely exist on a motor end-plate, the formation of the drug-receptor complex would be accompanied by a decrease in the amount of the unbound drug available for promoting receptor occlusion. Subsequently, even when a drug has a fairly high afŽÞnity, a total drug concentration of at least more than the receptor concentration is necessary to exert the blockade effect. Thus, the discrepancy between the potency and the afŽÞnity for the receptors would be much greater for high-afŽÞnity drugs.
(para2)In previous reports, we showed that the maximum twitch responses at the ŽÞrst and fourth stimuli in the absence of a drug and the faint TOF fade by ¡¦bungarotoxin could be primarily explained in terms of the existence of the margin of safety [6,7]. Nondepolarizing neuromuscular blocking drugs competitively inhibit the ACh-receptor binding and produce the blockade effect. Therefore, in this study, we constructed a dynamic model including the receptor occupancy by ACh, the competitive inhibition of the receptor-ACh binding by drugs, the difference of afŽÞnities of the drugs for the receptors and the transduction of ACh-receptor binding to a muscle contraction. As a result, it was demonstrated that the pharmacological response mediated through the densely existing receptors would be modiŽÞed by the unbound fraction rather than the total drug amount.
(para2)To date, in researches on the difference of TOF fade induced by the drugs, the difference of afŽÞnities of the drugs for the postsynaptic receptors has not been taken into account. Additionally, although several kinetic studies on the pharmacological effect of non-de-
polarizing neuromuscular blocking drugs have been documented [19 - 21], the difference of TOF fade among the drugs has not been clariŽÞed. The present study, however, pointed out that TOF fade is not always an indicator of the presynaptic action of a drug. Rather, the afŽÞnity of the drug for the postsynaptic receptors may also govern the degree of TOF fade.
(1)References
(REF)1. Ali HH, Savarese JJ (1976) Monitoring of neuromuscular function. Anesthesiology 45:216 - 249
(REF)2. Jones RM (1985) Neuromuscular transmission and its blockade. Anaesthesia 40:964 - 976
(REF)3. Williams NE, Webb SN, Calvey TN (1980) Differential effects of myoneural blocking drugs on neuromuscular transmission. Br J Anaesth 52:1111 - 1115
(REF)4. Gibson FM, Mirakhur RK (1989) Train-of-four fade during onset of neuromuscular block with nondepolarizing neuromuscular blocking agents. Acta Anaesthesiol Scand 33:204 - 206
(REF)5. Klein L, Hopkins J, Rosenberg H (1983) Different relationship of train-of-four to twitch and tetanus for vecuronium, pancuronium and gallamine. Anesthesiology 59:A275
(REF)6. Tajima T, Kaneko K, Hatanaka T, Aiba T, Katayama K, Koizumi T (1994) Kinetic analysis of neuromuscular blockade. I. Rela-
tionship between twitch depression and stimulation frequency after d-tubocurarine administration. Biol Pharm Bull 17:1083 - 1088
(REF)7. Tajima T, Kato Y, Hatanaka T, Aiba T, Katayama K, Koizumi T (1994) Kinetic analysis of neuromuscular blockade. II. Train-of-four fade induced by d-tubocurarine and ¡¦bungarotoxin. Biol Pharm Bull 17:1089 - 1093
(REF)8. Cheah LS, Gwee MCE (1988) Train-of-four fade during neuromuscular blockade induced by tubocurarine, succinylcholine or ¡¦bungarotoxin in the rat isolated hemidiaphragm. Clin Exp Pharmacol Physiol 15:937 - 943
(REF)9. Gwee MCE, Cheah LS (1989) In vitro time course studies on train-of-four fade induced by hexamethonium, pancuronium and decamethonium in the rat isolated hemidiaphragm. Clin Exp Pharmacol Physiol 16:897 - 903
(REF)10. Bowman WC, Marshall IG, Gibb AJ, Harborne AJ (1988) Feedback control of transmitter release at the neuromuscular junction. Trends Pharmacol Sci 9:16 - 20
(REF)11. Wessler I, Rasbach J, Scheuer B, Hillen U, Kilbinger H (1987) Effect of (1)-tubocurarine on [3H]acetylcholine release from
the rat phrenic nerve at different simulation frequencies and
train lengths. Naunyn Schmiedebergs Arch Pharmacol 335:496 - 501
(REF)12. Wilson DF (1979) Depression, facilitation, and mobilization of transmitter at the rat diaphragm neuromuscular junction. Am J Physiol 237:C31 - C37
(REF)13. Namba T, Grob D (1968) Cholinesterase activity of the motor endplate in isolated muscle membrane. J Neurochem 15:1445 - 1454
(REF)14. Paton WDM, Waud DR (1967) The margin of safety of neuromuscular transmission. J Physiol (Lond) 191:59 - 90
(REF)15. Black JW, Leff P (1983) Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci 220:141 - 162
(REF)16. Miller RD, Savarese JJ (1986) Pharmacology of muscle relaxants and their antagonists. In: Miller RD (ed) Anesthesia. Churchill Livingstone, New York, p 897
(REF)17. Swerdlow BN, Holley FO (1987) Intravenous anaesthetic agents pharmacokinetic-pharmacodynamic relationships. Clin Pharmacokinet 12:79 - 110
(REF)18. Filatov GN, Alywin ML, White MM (1993) Selective enhancement of the interaction of curare with the nicotinic acetylcholine receptor. Mol Pharmacol 44:237 - 241
(REF)19. Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979) Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin Pharmacol Ther 25:358 - 371
(REF)20. Graham GG, Morris R, Pybus DA, Torda TA, Woodey R (1986) Relationship of train-of-four ratio to twitch depression during pancuronium-induced neuromuscular blockade. Anesthesiology 65:579 - 583
(REF)21. Parker CJR, Hunter JM (1992) A new four-parameter threshold model for the plasma atracurium concentration-response relationship. Br J Anaesth 68:548 - 554 (MW)

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(JN)J Anesth (1996) 9:338 - 342
(PT)
(CT)Effects of stellate ganglion block on cardiac coronary circulation
(CA)Iwao Sasaki, Tadanobu Kaneko, Naofumi Iwatsuki, and Yasuhiko Hashimoto
(ADD)Department of Anesthesiology, Tohoku University School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai, 980 Japan
(AB)Abstract: Since the stellate ganglion contains cardiac sympathetic nerves, stellate ganglion block (SGB) may inŽßuence cardiac and coronary hemodynamics. We investigated this inŽßuence of SGB by measuring the heart rate (HR), the left circumŽßex coronary artery blood Žßow (CBF), the maximum rate of increase of the left ventricular pressure (LV max dP/dt), the cardiac output (CO), the myocardial oxygen consumption (MVO2), and the myocardial oxygen extraction ratio (MOER) in nine dogs before and after performing SGB by means of injection of 2 ml 1% mepivacaine. Left SGB resulted in a decrease of 10% in CBF and a decrease of 15% in LV max dP/dt, but HR, CO, and MVO2 remained unchanged. On the other hand, right SGB resulted in a decrease of 30% in CBF and a decrease of 25% in LV max dP/dt, as well as a decrease of 20% in HR, 15% in CO, and 25% in MVO2. SGB on either side resulted in an increase in MOER that was slight but nonetheless signiŽÞcant (P , 0.05) in that it suggested a relative deŽÞcit in CBF with respect to MVO2. Inhalation of 100% oxygen decreased MOER to the pre-SGB level in either side, thus improving the myocardial oxygen supply-demand relationship. This study suggests the possibility that SGB has deteriorative effects on the myocardial oxygen supply-demand relationship. Those effects were counteracted by the inhalation of 100% oxygen.
(KW)Key words: Stellate ganglion block, Coronary blood Žßow, Myocardial oxygen consumption, Myocardial oxygen extraction ratio
(A)Introduction
(para1)Stellate ganglion block (SGB) is a reversible procedure that blocks the cervical sympathetic trunk, the inferior cervical ganglion, and the superior thoracic sympathetic ganglion by means of the injection of a local anesthetic into the fascia of the longus colli. SGB is the most frequently used therapy in the pain clinic ŽÞeld and is regarded as therapeutically signiŽÞcant in the treatment of such ailments as herpes zoster (upper thoracic, neck and face), circulatory disorders of the upper extremites and face, and pain-related disorders in which the sympathetic nerves are involved [1]. Since the cardiac sympathetic nerves pass through the stellate ganglion [2], SGB is expected to have an ameliorative effect on impaired coronary circulation and cardiac function and thus to be well suited to the treatment of angina pectoris and myocardial infarction [3]. However, some clinical reports have shown that SGB does not improve coronary spasm [4]. Moreover, research information concerning any precise study of the effects of SGB on coronary hemodynamics and the myocardial oxygen supply-demand relationship has been scarce. In an attempt to clarify the inŽßuence exerted by SGB on the myocardial oxygen supply-demand relationship, we have examined the effects of left and right SGB on cardiac coronary circulation as well as on cardiac function in dogs.
(A)Materials and methods
(para1)This study was conducted with the approval of the Animal Care Committee of the Tohoku University School of Medicine.
(B)Implantation of instruments
(para1)Nine dogs, weighing 8-11.5 kg, were anesthetized with intravenous pentobarbital at a rate of 25 mgáÌg21, and their tracheas were intubated. Anesthesia was then maintained with continuous infusion of pentobar-
bital at a rate of 2.0 mgáÌg21áÉ21 and pancuronium at 0.16 mgáÌg21áÉ21. Respiration was controlled with an animal ventilator (Aika R-60, Aika, Chiba, Japan) to maintain PaCO2 in the range 35-40 mmHg, and end-tidal CO2 was monitored (Model 78356A, Hewlett Packard. Boeblingen, Germany). A foreleg vein was cannulated for the infusion of lactated RingerŽÕs solution at a rate of 10 mláÌg21áÉ21 throughout the experiment. ECG and HR were continuously monitored with an oscilloscope. To monitor arterial blood pressure and to sample arterial blood, a catheter was placed in the right femoral artery. After thoracotomy on the left side, a catheter was placed, via the left external jugular vein, in the coronary sinus for the purpose of coronary sinus blood sampling. Electromagnetic Žßow probes (Nihon Kohden 1100, 2100 and 3100, Nihon Kohden, Tokyo, Japan) were placed on the ascending aorta, the left common carotid and the left circumŽßex coronary artery to measure Žßow at these locations. To measure the left ventricular pressure and its maximum rate of increase (LV max dP/dt) a catheter tip pressure transducer was inserted into the left ventricle through the femoral artery on the side not being used for the blood pressure measurement. Left and right SGB were performed by inserting two catheters, one into the left fascia and one into the right fascia of the longus colli just over the stellate ganglion.
(B)Experimental protocol
(para1)After baseline hemodynamic and blood gas data had been obtained in relation to inhalation of the room
air, left SGB was performed by injecting 2 ml 1% mepivacaine through the catheter and once again hemodynamics were measured and blood gas samples were taken. Then while left SGB was still effective (about 15 min after SGB) the animals were ventilated with 100% oxygen and measurements and sampling were repeated. About 2 h later, when hemodynamic data had returned to baseline and the effect of left SGB had disappeared, the same procedure was followed to investigate the effect of right SGB. The order of left and right SGB did not change their effects.
(para2)SGB was determined to have been effective when, in the case of left SGB, an increase in the left common carotid blood Žßow (L-CaBF) could be observed and when, in the case of right SGB, a decrease in HR could be observed [5,6]. Also, at the end of the experiment
the correct positioning of the SGB catheter was conŽÞrmed by observing the extent to which a dye injected through the catheter actually colored the stellate
ganglion area.
(para2)Myocardial oxygen consumption (MVO2) and the myocardial oxygen extraction ratio (MOER) were calculated by means of the following equations: MVO2 5 (CaO22CsO2) 3 CBF/100; MOER 5 (CaO22CsO2) 3 100/CaO2. In these equations MVO2 is expressed in mláÎin2 1, CaO2 is the oxygen content expressed in mláÅl21 arterial blood, CsO2 is the oxygen content expressed in mláÅl21 coronary sinus blood, CBF is coronary blood Žßow (left circumŽßex coronary artery blood Žßow) expressed in mláÎin21, and MOER is expressed as a percentage.
(para2)The experimental data were statistically analyzed
using analysis of variance (ANOVA), and StudentŽÕs paired t-test was used to test the difference between the other conditions of each group. Changes were considered to be signiŽÞcant when the probability (P) value was ,0.05. All data are expressed as the mean 6 standard deviation (SD).
(A)Results
(B)Effects of left SGB
(para1)Left SGB decreased cardiac output (CO) and systolic BP by 6 6 19% and 7 6 15%, respectively (P , 0.05). However, HR was unchanged. LV max dP/dt decreased by 15 6 11% (P , 0.01), and CBF decreased by 10 6 15% (P , 0.05). MVO2 did not change signiŽÞcantly. MOER increased from 65 6 12% to 67 6 11% (P , 0.05) (Tables 1 and 2; Figs. 1-3).
(B)Effects of right SGB
(para1)Right SGB decreased HR by 21 6 13%, CO by 15 6 32%, systolic BP by 6 6 18%, LV max dP/dt by 25 6 24%, and CBF by 30 6 22% (all P , 0.01). MVO2 decreased by 17 6 37%, while MOER increased from 66 6 13% to 70 6 14% (P , 0.05) (Tables 1 and 2; Figs. 1-3).
(B)Effects of inhalation of 100% oxygen
(para1)Following the inhalation of 100% O2 (without performing SGB), CBF decreased by 6 6 22% (P , 0.05), MVO2 decreased by 15 6 26% (P , 0.01), and MOER decreased by 12 6 21% (P , 0.01). BP, CO and LV max dP/dt were unchanged. These decreases in CBF, MVO2 and MOER were also observed when 100% O2 was inhaled while the effects of SGB on either side were present. Therefore the increased MOER that was induced by SGB was suppressed by the inhalation of 100% O2 (Table 2; Figs. 1-3).
(A)Discussion
(para1)The most signiŽÞcant ŽÞnding in our study is the fact that SGB on either side decreased CBF. Two explanations are under consideration about the main mechanisms contributing to this decrease in CBF. One is that SGB directly inŽßuences coronary vascular tone in a way that decreases CBF. The other is that coronary vascular tone is indirectly changed by SGB as a result of the fact that SGB decreases the heartŽÕs demand for oxygen by the decrease in HR, BP, and CO on right SGB, while there is a decrease in systolic BP and an increase in L-CaBF on left SGB. In the latter case, the decrease in CBF should correspond to the decrease in the operation of the heart (i.e., the heartŽÕs demand for oxygen), and this would indicate a balanced myocardial oxygen supply-demand relationship. However, in our study left SGB decreased CBF by 10% but did not change MVO2, while right SGB decreased CBF by 30% but decreased MVO2 by only 17%. Therefore, the decrease in CBF exceeded the decrease in MVO2. As a result, MOER increased slightly but signiŽÞcantly in response to SGB on either side. This suggests that the myocardial oxygen supply-demand relationship deteriorates with SGB. This unbalanced state further suggests that the decrease in CBF mediated by SGB is at least partially independent of myocardial metabolic change. The fact that
inhalation of oxygen decreased MOER, thereby improving the oxygen supply-demand relationship, was observed even in the presence of the effects of SGB on either side. Inhalation of oxygen may therefore be one of the ways to counteract the deleterious effect of SGB on the myocardial oxygen supply-demand relationship.
(para2)The possibility that the decrease in the activity of the heart may be contributing to the decrease in CBF deserves discussion. This hypothesis would similarly seem to require that the degree of decrease in CBF corresponds to the degree of decrease in the activity of the heart. However, in our study, the decrease in CBF was far greater than the decrease in the activity of the heart. Our results would thus seem to indicate that decreased activity of the heart cannot be viewed as the major contributor to the decrease in CBF. The depression of both HR and LV max dP/dt mediated by right SGB and the depression of LV max dP/dt and increase of L-CaBF mediated by left SGB in this study are consistent with previous reports [5,6] which demonstrated the effect of SGB on both sides. These results therefore prove that our procedure of SGB is acceptable.
(para2)In contrast with previous reports involving human subjects [7,8], our results would seem to question the value of using SGB on either side on patients with ischemic heart diseases because SGB on either side not only failed to improve but actually deteriorated coronary hemodynamics. Of course, extrapolation of our results to humans with ischemic heart problems is a matter requiring greater scrutiny. Our experiment was performed on dogs with normal coronary circulation (i.e., no ischemic heart problems), and the ways in which the canine coronary circulation and the human coronary circulation respond to SGB may differ. Moreover, the inŽßuence of general anesthesia on the effect of SGB on coronary circulation cannot be neglected. The next stage in the overall study should be an evaluation of the effects of SGB on coronary hemodynamics in a model of the ischemic heart.
(para2)In summary, SGB on either side decreased coronary blood Žßow and increased the MOER in a canine model with normal coronary circulation under general anesthesia. Inhalation of oxygen improved the deteriorated myocardial oxygen supply-demand relationship that was mediated by SGB.
(ACK)Acknowledgments. The authors would like to express their gratitude to Syoichi Obara for his expert technical assistance. This study was supported in part by a grant in aid for scientiŽÞc research from the Ministry of Education, Science, and Culture, Japan, #02670674.
(1)References
(REF)1. Bonica JJ (1990) Regional analgesia with local anesthetics. In: Bonica JJ (ed) The management of pain. Lea & Febiger, Philadelphia, PA, London, pp 1883-1966
(REF)2. White JC (1974) Sympathectomy for relief of pain. Adv Neurol 4:629-638
(REF)3. Klassen GA, Bramwell RS, Bromage PR (1980) Effect of acute sympathectomy by epidural anesthesia on the canine coronary circulation. Anesthesiology 52:8-15
(REF)4. Fukuuchi A, Fujita M, Suzuki H, Kawamata M, Mukubo Y, Yokoyama M (1990) Effects of stellate ganglion block on prevention of variant angina (in Japanese). Pein Kurinikku (Pain Clin) 11:214-218
(REF)5. Randall WC, Rohse WG (1956) The augmenter action of the sympathetic cardiac nerves. Circ Res 4:470-475
(REF)6. Inoue K (1984) Antiarrhythmic effects of stellate ganglion block (in Japanese). Masui (Jpn J Anesthesiol) 33:1187-1195
(REF)7. Tarazi RC, Estafanous FG, Fouad FM (1978) Unilateral stellate block in the treatment of hypertension after coronary bypass surgery. Am J Cardiol 42:1013-1018
(REF)8. Bidwai AV, Rogers CR, Pearce M (1979) Preoperative stellate ganglion blockade to prevent hypertension following coronary artery operations. Anesthesiology 51:345-347 (MW)

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(JN)J Anesth (1996) 9:343 - 347
(PT)
(CT)The dose-response relationship of amrinone in increasing the contractility of fatigued diaphragm in dogs
(CA)Yoshitaka Fujii1 and Hidenori Toyooka2
(ADD)1 Department of Anesthesiology, Toride Kyodo General Hospital, 2-1-1 Hongo, Toride, Ibaraki, 302 Japan
(ADD)2 Department of Anesthesiology and Critical Care Medicine, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113 Japan
(AB)Abstract: We studied the dose-related effects of amrinone on the contractility of a fatigued diaphragm in 16 anesthetized, mechanically ventilated dogs. The animals were divided into two groups: the control group (Group C, n 5 8) and the amrinone group (Group A, n 5 8). Diaphragmatic fatigue
was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. The contractility of the diaphragm was assessed from changes in transdiaphragmatic pressure (Pdi). After inducing fatigue, Pdi at low-frequency (20 Hz) stimulation decreased signiŽÞcantly compared with the pre-fatigue values (P , 0.05), whereas no change was observed at high-frequency (100 Hz) stimulation. In Group A, after producing fatigue, Pdi at 20 Hz stimulation increased signiŽÞcantly with a bolus injection (0.75 mgáÌg21) followed by continuous infusion of amrinone (2.5, 5 and then 10 ùÈáÌg21áÎin21) IV (P , 0.05). Pdi at 100 Hz
stimulation increased signiŽÞcantly with an administration of amrinone (10 ùÈáÌg21áÎin21) IV (P , 0.05). There was a signiŽÞcant positive correlation between Pdi at both stimuli and amrinone dose (P , 0.01). In Group C, the speed of recovery of Pdi at 20 Hz stimulation was relatively slower. The integrated electric activity of the diaphragam (Edi) in each group did not change at any frequency of stimulation throughout
the experiment. We conclude that amrinone exerts a dose-dependent enhancement of the contractility of a fatigued
diaphragm in dogs.
(KW)Key words: Amrinone, Diaphragmatic fatigue, Transdiaphragmatic pressure
(A)Introduction
(para1)Studies have shown that theophylline, ¡¦ agonists, digoxin, dopamine, and dobutamine may improve the contractility of a fatigued diaphragm [1-5]. Recently, we have also demonstrated that amrinone has a potent positive effect on the contraction of a fatigued diaphragm [6]. However, to our knowledge, the dose-related effects of amrinone on the strength of contraction in the fatigued diaphragm have not been reported. The purpose of the present study was to determine the dose-dependent effects of amrinone on experimentally induced diaphragmatic fatigue.
(A)Materials and methods
(para1)Institutional approval for the study was obtained from the Animal Care and Use Committee of Tokyo Medical and Dental University School of Medicine. We studied 18 healthy mongrel dogs (10-15 kg) anesthetized with pentobarbital sodium and mechanically ventilated. Animal preparation was similar to that described previously [6].
(para2)BrieŽßy, anesthesia was maintained with pentobarbital (2 mgáÌg21áÉ21 IV). No muscle relaxants were used. The animalŽÕs trachea was intubated, and ventilation was controlled with an oxygen-and-air gas mixture (FiO2 5 0.3-0.4) to maintain PaO2, PaCO2, and pH within normal ranges. A Swan-Ganz catheter was advanced via the right external jugular vein into the pulmonary artery to measure cardiac output by the thermodilution technique. Transdiaphragmatic pressure (Pdi) was measured by means of two thin-walled latex balloons, one positioned in the stomach, the other in the middle third of the esophagus. The balloons were connected to a differential pressure transducer (Pressure Head, Tokyo Keiki, Tokyo, Japan) and an ampliŽÞer (Type 1212, Nihondenki San-ei, Tokyo, Japan). The phrenic nerves were exposed bilaterally at the neck, and the stimulating electrodes were placed around them. Supramaximal electrical test stimuli of 0.1 ms duration were applied for 2 s at frequencies of 20 and 100 Hz with an electrical stimulator (Electronic Stimulator 3F37, Nihondenki San-ei). The contractility of the diaphragm was evaluated by measuring the maximal Pdi generated by test stimuli after airway occlusion at functional residual capacity (FRC) level. The electrical activity of the diaphragm was measured with needle electrodes inserted percutaneously into the diaphragm from the upper abdominal area, and was rectiŽÞed and integrated with a leaky integrator (Type 1310, Nihondenki San-ei) with a time constant of 0.1 s. This was regarded as the integrated electrical activity of the diaphragm (Edi). The experimental design is shown schematically in Fig. 1.
(para2)The dogs were randomly divided into two groups: the control group (Group C, n 5 8) and the amrinone group (Group A, n 5 8). After the pre-fatigue measurements of Pdi, Edi, and hemodynamic variables which included heart rate (HR), mean arterial pressure (MAP), and cardiac output (Qt), diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation applied for 30 min at a frequency of 20 Hz, an entire cycle of 4 s and a duty cycle of 0.5 (i.e. low-frequency fatigue) [7]. In Group A, after producing fatigue, a bolus injection (0.75 mgáÌg21) followed by continuous infusion of amrinone (2.5 ùÈáÌg21áÎin21) IV were administered with an electrical infusion pump (Terumo, Tokyo, Japan) for 10 min. Then administration of 5 and then 10 ùÈáÌg21áÎin21 amrinone (in this order) IV for 10 min was performed. Pdi, Edi, and hemodynamic parameters were measured every 10 min after the onset of amrinone infusion. In Group C, only maintenance Žßuid was administered, and the same measurements were performed as in Group A.
(para2)All values were expressed as mean 6 standard deviation (SD). Statistical analysis was performed using one-way analysis of variance (ANOVA) and StudentŽÕs t-test. P , 0.05 was considered statistically signiŽÞcant. Paired Pdi-amrinone dose determinations were ŽÞtted to both exponential and linear regression analyses to determine the best ŽÞt for the relationship. Because both analyses yielded almost identical correlation coefŽÞcients, linear regression analysis was used for comparisons.
(A)Results
(para1)Hemodynamic results in both groups are summarized in Table 1. There were no signiŽÞcant differences between the two groups in hemodynamic parameters during the pre-fatigue period. In Group A, with an infusion of
5 and 10 ùÈáÌg21áÎin21 amrinone, signiŽÞcant increases in HR and Qt (P , 0.05), and a signiŽÞcant decrease in MAP (P , 0.05) were observed compared with the pre-fatigue values. There were signiŽÞcant differences in these parameters between the two groups during amri-
(para1)none (5 and 10 ùÈáÌg21áÎin21) administration (P , 0.05).
(para2)All Pdi values are shown in Table 2. No signiŽÞcant differences in Pdi at either stimulus were observed
during the pre-fatigue period. In each group, after
producing fatigue, Pdi at 20 Hz stimulation decreased signiŽÞcantly from the pre-fatigue values (P , 0.05), whereas Pdi at 100 Hz stimulation did not change signiŽÞcantly. In Group A, Pdi at 20 Hz stimulation increased signiŽÞcantly compared with the fatigued values during amrinone (2.5, 5 and 10 ùÈáÌg21áÎin21) administration (P , 0.05). Pdi at 100 Hz stimulation increased signiŽÞcantly with administration of amrinone (10 ùÈáÌg21¡¦ min21) (P , 0.05). In Group C, the speed of recovery of Pdi at 20 Hz stimulation was relatively slower.
(para2)There was a signiŽÞcant positive correlation between Pdi at both stimuli and amrinone dose (Figs. 2 and 3), and the regression equations were: Pdi at 20 Hz stimulation (cmH2O) 5 0.69 3 amrinone (ùÈáÌg21áÎin21) 1 12.10 (r 5 0.65, n 5 32, P , 0.01); Pdi at 100 Hz stimulation (cmH2O) 5 0.33 3 amrinone (ùÈáÌg21áÎin21) 1 19.98 (r 5 0.50, n 5 32, P , 0.01).
(para2)No signiŽÞcant change in Edi was observed throughout the experiment in either group.
(A)Discussion
(para1)The major ŽÞnding of the present study was that administration of amrinone increased Pdi of a fatigued diaphragm in a dose-dependent manner.
(para2)It is known that low-frequency fatigue is of particular clinical importance because the spontaneous, natural rate of phrenic nerve discharge is believed to be mainly in the low-frequency range (5-30 Hz) [8]. Therefore, the effects of amrinone on contractility were examined in the fatigued diaphragm experimentally induced by 20 Hz stimulation.
(para2)The results of the present study showed that Pdi at 20 Hz stimulation decreased signiŽÞcantly after producing fatigue (P , 0.05), whereas Pdi at 100 Hz stimulation and Edi at any frequency stimulation did not change in Group C, in which amrinone was not administered. This was in agreement with our previous study [6].
(para2)The results in Group A demonstrated that Pdi at 20 Hz stimulation increased signiŽÞcantly compared with the fatigued values (P , 0.05) with an infusion of amrinone (.2.5 ùÈáÌg21áÎin21), while Pdi at 100 Hz stimulation increased signiŽÞcantly during 10 ùÈáÌg21¡¦ min21 amrinone administration (P , 0.05). Therefore, it is suggested that the high dose (.10 ùÈáÌg21áÎin21) of amrinone increases the contractility of a fatigued diaphragm at both stimuli, but the low dose (,10 ùÈáÌg21¡¦ min21) of this agent enhances fatigued diaphragmatic contraction only at 20 Hz stimulation. However, on the basis of our ŽÞndings that a relationship between Pdi
at both stimuli and amrinone dose was signiŽÞcantly positively different (P , 0.01), amrinone may improve the contractility of a fatigued diaphragm in a dose-
dependent manner.
(para2)Although the precise mechanism of improvement of the contractility in a fatigued diaphragm with an infusion of amrinone remains unclear, it has been suggested that this bipyridine derivative may have either a direct positive effect on diaphragmatic contractility, or an indirect effect on it through the increase in blood Žßow to the diaphragm [6].
(para2)Low-frequency fatigue is closely related to the impairment of excitation-contraction coupling [9]. This impairment is supposed to result from the alteration in movement of Ca21 from the sacroplasmic reticulum [7]. It is possible that amrinone may improve the impediment of Ca21 inŽßux in the fatigued diaphragm [6]. Therefore, the signiŽÞcant difference in the contractility between the two groups during amrinone infusion (P , 0.05) may be related to the difference in the inŽßux of Ca21 caused by administering amrinone.
(para2)The increase in blood Žßow to the diaphragm is known to be one of the major factors in improvement of the contractility of a fatigued diaphragm [4]. In the present study, the diaphragmatic blood Žßow was not measured. However, our previous study showed that Qt was an important factor in the regulation of blood Žßow to the diaphragm [10]. The increase in Qt observed in the present study may have led to an increase in diaphragmatic blood Žßow with an infusion of amrinone. The present study demonstrated that Qt increased signiŽÞcantly with an infusion of amrinone (P , 0.05), and Qt in Group A was signiŽÞcantly larger than that in Group C (P , 0.05). Therefore, the signiŽÞcant difference in the strength of contraction between the two groups during amrinone infusion (P , 0.05) may also be attributable to the difference in Qt which is related to diaphragmatic blood Žßow.
(para2)In conclusion, our results suggest that amrinone improves the contractility of a fatigued diaphragm, and this agent exerts a dose-dependent enhancement of its strength of contraction.
(ACK)Acknowledgments. The authors are very grateful to Prof. K. Amaha for his valuable comments, and to Mr. K. Yokoyama for his expert technical assistance.
(A)References
(REF) 1. Murciano D, Aubier M, Lecocguic Y, Pariente R (1984) Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 311:349-353
(REF) 2. Howell S, Roussos C (1987) Isoproterenol and aminophylline improve contractility of fatigued canine diaphragm. Am Rev Respir Dis 129:118-124
(REF) 3. Aubier M, Murciano D, Viires N, Lebargy F, Curran Y, Seta J-P, Pariente R (1987) Effects of digoxin on diaphragmatic strength generation in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 135:544-548
(REF) 4. Aubier M, Murciano D, Menu Y, Boczkowski, Boczkowski J, Mal H, Pariente R (1989) Dopamine effects on diaphragmatic strength during acute respiratory failure in chronic obstructive pulmonary disease. Ann Intern Med 110:17-23
(REF) 5. Fujii Y, Toyooka H, Ebata T, Amaha K (1993) Contractility of fatigued diaphragm is improved by dobutamine. Can J Anaesth 40:453-458
(REF) 6. Fujii Y, Toyooka H, Amaha K (1995) Amrinone improves contractility of fatigued diaphragm in dogs. Can J Anaesth 42:
80-86
(REF) 7. Aubier M, Farkas G, DeTroyer A, Mozes R, Roussos C (1981) Detection of diaphragmatic fatigue in man by phrenic nerve stimulation. J Appl Physiol 50:538-544
(REF) 8. Roussos C, Macklem PT (1982) The respiratory muscles. N Engl J Med 307:786-797
(REF) 9. Moxham J, Wiles CM, Newham D, Edwards RHT (1981) Contractile function and fatigue of the respiratory muscles in man. In: Human muscle fatigue: Physiological mechanics. Ciba Foundation Symposium, London. Pitman Medical 82:197-205
(REF)10. Fujii Y, Toyooka H, Amaha K (1991) Diaphragmatic fatigue and its recovery are inŽßuenced by cardiac output. J Anesth 5:17-23 (MW)

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(JN)J Anesth (1996) 9:348 - 350
(PT)Clinical reports
(CT)Anesthesia for laparoscopic cholecystectomy in an elderly patient with emphysematous bullaeŽÑcombined general and epidural anesthesia with spontaneous respiration and abdominal wall-left method
(CA)Yoshito Nagashima1, Song H. Kim1, and Tetsutaro Otagiri2
(ADD)1 Department of Anesthesiology, Matsushiro General Hospital, 183 Matsushiro, Nagano, 381-12 Japan
(ADD)2 Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390 Japan
(KW)Key words: Laparoscopic cholecystectomy, Barotrauma, Spontaneous respiration
(1)Introduction
(para1)Laparoscopic cholecystectomy is rapidly gaining popularity with surgeons and patients, but as the popularity of this technique increases and the selection of patients widens to older and sicker people, careful considerations in anesthetic management are required. We
recently experienced a case of laparoscopic cholecystectomy with emphysematous bullae. To avoid the risk of barotrauma, we adopted an abdominal wall-lift method without peritoneal insufŽßation, and maintained anesthesia with spontaneous respiration.
(1)Case report
(para1)An 81-year-old female, weighing 42 kg and 146 cm tall, was admitted with cholecystolithiasis and was scheduled for laparoscopic cholecystectomy. She had a 5-year history of pulmonary emphysema and emphysematous bullae. Her chest X-ray and computed tomography (CT) showed multiple bullae in the left lung ŽÞeld. It was also noted that one giant bulla in the left lower lobe had advanced in size over the last 5 years. The spirometric measurements were as follows: vital capacity was 2.22 l (111%) and forced expiratory volume in the 1st second was 1.66 l (74%). Analysis of arterial blood gases while breathing room air revealed a pH of 7.43, Paco2 of 41.9 mmHg, and Pao2 of 74.9 mmHg.
(para2)From these preoperative examinations, we judged that the patient should be able to tolerate general anesthesia, but an accidental rupture of bullae and concurrent pneumothorax were concerns. We could not neglect the hazard of pulmonary barotrauma in the presence of bullae, particularly if high positive airway pressure is required to provide adequate ventilation of the lungs during a pneumoperitoneum with carbon dioxide. We held a conference with surgeons and planned to perform a laparoscopic cholecystectomy without pneumoperitoneum according to the abdominal wall-lift method reported by Nagai et al. [1]. We also planned to maintain airway pressure as low as possible.
(para2)Preoperative medication consisted of atropine 0.3 mg and hydroxyzine 25 mg. Upon arrival in the operating room, her blood pressure (BP) was 120/70 mmHg and heart rate (HR) was 62 beats?min21. The left radial artery was cannulated for continuous blood pressure monitoring and blood sampling. An epidural catheter was inserted at the T8 - 9 intervertebral space, and 6 ml of 2% lidocaine was given. Fifteen minutes later, analgesia from T3 to T12 was conŽÞrmed by the pinprick method. Dopamine was continuously administered in addition to rapid infusion of lactated RingerŽÕs solution (approximately 500 ml in 30 min) to counter the decrease in blood pressure. Pure oxygen was given through a face mask. After midazolam 1 mg was given intravenously, isoŽßurane was administered with its concentration raised step by step. No assist ventilation was attempted throughout the procedure. Two milliliters of 4% lidocaine was injected into the trachea through the cricothyroid ligament to achieve surface anesthesia of the trachea. Inhalation of 1.5% isoŽßurane in oxygen
was continued for another 5 min and endotracheal intubation was performed without a muscle relaxant. Anesthesia was maintained with 1.0% - 1.5% isoŽßurane in oxygen and intermittent epidural administration of 2% lidocaine. Spontaneous respiration was reserved. The patientŽÕs respiratory rate was 20 - 25 times per minute and respiration was regular and stable. The patientŽÕs hemoglobin oxygen saturation was maintained around 99%. Analysis of arterial blood gases while breathing 100% oxygen revealed a pH of 7.39, Paco2 of 46.9 mmHg, and Pao2 of 367 mmHg.
(para2)Two wires were placed through the skin, one in
the upper portion of the umbilicus and the other in the midclavicular line at the right costal margin. Cholecystectomy was done in the same way with the peritoneal insufŽßation method. When the visibility of the operative ŽÞeld was not obtained sufŽÞciently and the surgeons asked that the abdominal muscles be relaxed more, 3 ml of 2% lidocaine was administered intermittently into the epidural space. Good visibility of the operative ŽÞeld was obtained immediately with the procedure. During the operation, it was necessary to increase the dose of lidocaine twice. The operation was performed within 1 h 25 min. IsoŽßurane was discontinued at the end of the operation and 30 min later the patient responded well to our verbal commands. Analysis of arterial bloodgases revealed a pH of 7.39, Paco2 of 43.2 mmHg, and Pao2 of 424 mmHg. Then, the endotracheal tube was extubated. The patientŽÕs postoperative course was uneventful.
(1)Discussion
(para1)Barotrauma is an inclusive term that may be classiŽÞed as pulmonary interstitial emphysema, pneumome-
diastinum, subcutaneous emphysema, and pneumotho-rax [2]. When pneumothorax occurs, failure to recognize it and to provide prompt treatment may cause be fatal [3]. Peak airway pressure is most frequently cited as the main risk factor that contributes to barotrauma [2,4].
(para2)An application of high pressure to the airway results in overdistention of the alveoli with subsequent leakage of gas into the surrounding tissues producing pulmonary interstitial emphysema. A perivascular spread of the small bubbles of gas to the hilum induces pneumomediastinum. Finally, the gas may pass through a tear of the mediastinal pleura into the pleural space, thus causing a pneumothorax [4,5]. A secondary cause of pneumothorax can occur by distal spread of the pulmonary interstitial emphysema to the surface of the lung where subpleural blebs or bullae exist. These blebs or bullae are apt to rupture and connect the peripheral airway to the pleural space [4,5]. In a patient with emphysematous bullae who requires positive pressure ventilation, both of these mechanisms can occur and the risk of pneumothorax is high [6].
(para2)The beneŽÞts of laparoscopic cholecystectomy, as opposed to the traditional open technique, include: (1) small incision, (2) less postoperative pain, and (3) less postoperative bed rest [7]. This technique is gaining popularity recently on account of these beneŽÞts. Generally, laparoscopic procedures are associated with the peritoneal insufŽßation of carbon dioxide. Absorption of carbon dioxide through the peritoneum causes hypercarbia, which must be managed by increasing minute ventilation [8]. The pneumoperitoneum also alters pulmonary mechanics. Respiratory impedance measurements have shown a marked elevation of the diaphragm [9]. Once the pneumoperitoneum is established, increased airway pressures are necessary to compensate for the fall in lung-thorax compliance resulting from the restriction of diaphragmatic movements [10]. Here precautions against barotrauma are critical.
(para2)Therefore, we reserved spontaneous respiration and tried to minimize the peak airway pressure, but when a patient is anesthetized under spontaneous respiration and the laparoscopic procedures are associated with
the pneumoperitoneum method, there is a high incidence of hypercarbia [11]. If an assist ventilation has to be applied to compensate for the rise in carbon dioxide tension, it should increase airway pressures as mentioned before. These problems may be resolved by adopting the abdominal wall-lift method [1]. Since this method requires no peritoneal insufŽßation, carbon
dioxide absorption may be excluded and the restriction of diaphragmatic movement is expected to be less
compared with the pneumoperitoneum method. Therefore, the risk of hypercarbia can be avoided even under spontaneous respiration. Another advantage of the
abdominal wall-lift method is that pneumothorax
induced by the existence of a congenital defect of the diaphragm can be avoided [12].
(para2)Another problem associated with the anesthetic
management is how to assure the visibility of the operative ŽÞeld. The patientŽÕs abdominal muscles need to
be completely relaxed to obtain a good exposure of
the operative ŽÞeld, but the need to reserve spontaneous respiration limits the use of muscle relaxants. In our case, the administration of regional anesthetics to
the epidural space provided a satisfactory operative ŽÞeld. We believe that epidural anesthesia is effective enough to achieve relaxation of the abdominal muscles, though it may be difŽÞcult in obese or sinewy patients.
(para2)In summary, we have described a case of anesthesia for laparoscopic cholecystectomy in an elderly patient with emphysema and multiple bullae. In managing
this patient with a high risk of pulmonary complications, special precautions against barotrauma were taken. First, we adopted the abdominal wall-lift method as
a laparoscopic technique. Secondly, we maintained
anesthesia with spontaneous respiration to minimize the peak airway pressure. Thirdly, we achieved abdominal muscle relaxation by the intermittent epidural
injection of regional anesthetics, and barotrauma was prevented.
(1)References
(REF) 1. Nagai H, Kondo Y, Yasuda T, Kasahara K, Kanazawa K (1993) An abdominal wall-lift method of laparoscopic cholecystectomy without peritoneal insufŽßation. Surg Laparosc Endosc 3:175 - 179
(REF) 2. Haake R, Schlichtig R, Ulstad DR, Henschen RR (1987) Barotrauma: Pathophysiology, risk factors, and prevention. Chest 91:608 - 613
(REF) 3. Nennhaus HP, Javid H, Julian OC (1967) Alveolar and pleural rupture. Arch Surg 94:136 - 141
(REF) 4. Newton NI, Adams AP (1978) Excessive airway pressure during anaesthesia: Hazards, effects and prevention. Anaesthesia 33:689 - 699
(REF) 5. Martin JT, Patrick RT (1960) Pneumothorax: Its signiŽÞcance to the anesthesiologist. Anesth Analg 39:420 - 429
(REF) 6. Mayo P, Saha SP, McElvein RB (1983) Spontaneous pneumothorax under anesthesia. Ala J Med Sci 20:84 - 85
(REF) 7. Marco AP, Yeo CJ, Rock P (1990) Anesthesia for a patient undergoing laparoscopic cholecystectomy. Anesthesiology 73:1268 - 1270
(REF) 8. Hall D, Goldstein A, Tynan E, Braunstein L (1993) Profound hypercarbia late in the course of laparoscopic cholecystectomy: Detection by continuous capnometry. Anesthesiology 79:173 - 174
(REF) 9. Alexander GD, Noe FE, Brown EM (1969) Anesthesia for pelvic laparoscopy. Anesth Analg 48:14 - 18
(REF)10. Hodgson C, McClelland RMA, Newton JR (1970) Some effects of the peritoneal insufŽßation of carbon dioxide at laparoscopy. Anaesthesia 25:382 - 390
(REF)11. Shantha TR, Harden J (1991) Laparoscopic cholecystectomy: Anesthesia-related complications and guidelines. Surg Laparosc Endosc 1:173 - 178
(REF)12. Whiston RJ, Eggers KA, Morris RW, Stamatakis JD (1991) Tension pneumothorax during laparoscopic cholecystectomy. Br J Surg 78:1325 (MW)

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(JN)J Anesth (1996) 9:351 - 353
(PT)
(CT)Cardiac arrest and rhabdomyolysis after succinylcholine in a healthy child
(CA)Shuya Kiyama1, Tamotsu Yoshikawa1, and Yoshiro Kobayashi2
(ADD)1Department of Anesthesia, Shizuoka Red Cross Hospital, 8-2 Otemachi, Shizuoka, 420 Japan
(ADD)2Department of Anesthesia, Kawasaki Municipal Hospital, 12-1 Shinkawa-dori, Kawasaki-ku, Kawasaki, 210 Japan
(KW)Key words: Cardiac arrest, Rhabdomyolysis, Malignant hyperthermia
(A)Introduction
(para1)Intractable, unexpected cardiac arrest following use
of succinylcholine has been reported in children who are apparently in good health preoperatively. Most
of these patients were boys who were subsequently found to have occult myopathies, primarily DuchenneŽÕs muscular dystrophy [1-7]. Some, if not most, of these patients developed clinical signs compatible with
malignant hyperthermia (MH). We report a case
of sudden cardiac arrest after administration of succinylcholine, followed by severe rhabdomyolysis without hyperthermia, in a healthy girl. Possible association with MH is discussed.
(A)Case report
(para1)A 9-year-old girl weighing 32 kg presented for adenoidectomy and myringotomy. The patient had had an inguinal hernia repair under halothane/N2O/O2 anesthesia without problems 2 years previously. The patient had no signs or symptoms of muscle diseases. There was no family history of muscle diseases or of adverse reactions to anesthesia. The results of preoperative laboratory examinations were all within normal limits: speciŽÞcally, creatine kinase (CK) was 159 IUáÍ21 (normal range, 0-180 IUáÍ21).
(para2)Atropine (0.5 mg) was given intramuscularly 60 min prior to induction. Monitoring of noninvasive blood pressure, electrocardiogram (ECG) and oxygen saturation was started. Anesthesia was induced with
intravenous midazolam (3 mg) and inhalation of 3% sevoŽßurane in oxygen for 3 min. Succinylcholine (30 mg) was given intravenously (i.v.) to facilitate tracheal intubation. Masseter as well as generalized muscle rigidity occurred and the mouth was opened with considerable difŽÞculty. A tracheal tube was put in position. Two minutes after administration of succinylcholine, ECG showed a peaked T-wave immediately followed by
ventricular ŽÞbrillation. External cardiac massage was started, and an i.v. bolus of 60 mg lidocaine and 50 ùÈ adrenaline were given. Cardiac activity was restored in less than 10 min. Stat arterial blood gas and electrolytes results taken approximately 5 min after cardiac arrest were as follows: pH, 7.14; PaCO2, 47 mmHg; PaO2, 342 mmHg (FIO2 5 1.0); base excess, 28.5 mM; potassium, 7.16 mEqáÍ21. Suspecting MH, 20 mg dantrolene was also given i.v. during cardiac resuscitation. Twenty milliliters of 50% dextrose with 4 units of insulin, as well as 5 ml of 2% calcium chloride, were given to treat hyperkalemia. Cola-colored urine was noted, which was later found to be myoglobinuria. Urine output
(.1 mláÌg21áÉ21) was maintained with furosemide and mannitol. During this acute episode, creatine kinase was 5210 IUáÍ21. Throughout the episode, rectal temperature was between 36.2 and 36.4Ž¡C.
(para2)The patient was transferred to the intensive care unit (ICU) in a stable cardiorespiratory condition. She was awake and neurologically intact upon admission to ICU, and was extubated. To prevent a return of symptoms, four doses of 20 mg dantrolene were given every 6 h. Her maximal temperature while in ICU was 37.9Ž¡C within 3 h from induction. She did not develop cardiac or renal failure, or coagulopathy. The patient also did not show metabolic or respiratory acidosis, or cardiac arrhythmia in ICU. CK values increased to a maximum of 57 000 IUáÍ21 within 24 h and 98 000 IUáÍ21 within 48 h, and then decreased over 5 days. She made an uneventful recovery and was discharged to the pediatric ward on the fourth postoperative day. Two weeks later, she had myringotomy under local anesthesia with lidocaine. Muscle biopsy under general anesthesia with non-triggering agents was performed 3 months later. No problems were encountered during these two anesthesias. Histological examination, as well as the result of a calcium-induced calcium release (CICR) test, was normal. Other members of her family were not tested for MH susceptibility.
(A)Discussion
(para1)Although the clinical manifestations of fulminant MH are quite dramatic, most of the signs are not unique to MH and are of variable intensity and time course, and therefore early diagnosis during anesthesia is often difŽÞcult [8]. Another cause of diagnostic difŽÞculty might be the early use of dantrolene, which can halt the hypermetabolic process in the muscles before full-blown MH develops. Lack of internationally accepted clinical diagnostic criteria also leaves clinicians puzzled when attempting to diagnose equivocal cases.
(para2)According to the recently published clinical grading scale of MH [9], the initial score of the patient in this case was 33 (15 points for generalized muscular rigidity, 15 points for elevated CK (.20 000 IUáÍ21), and 3 points for ventricular ŽÞbrillation), and her MH rank was 4, i.e., the likelihood of MH was somewhat greater than
normal.
(para2)The caffeine halothane contracture test (CHCT) has previously been the ŽÒgold standardŽÓ for diagnosing MH susceptibility in North America and Europe. However, four false-negative results of CHCT have been documented in patients who were almost certain to be
MH-susceptible [10]. In Japan, however, CICR from sarcoplasmic reticulum using skinned muscle ŽÞber has been studied as a diagnostic test of MH-susceptibility [11].
(para2)The major clinical difference between fulminant and abortive MH is that the maximal temperature is above 40Ž¡C or the rate of temperature increase is more than 2Ž¡CáÉ21 in the former, while the latter does not fulŽÞll this criteria of hyperthermia. Results of CICR also differ signiŽÞcantly between fulminant and abortive MH; 87% of fulminant MH cases had accelerated CICR, while 82% of abortive MH had normal CICR [12]. This is a striking difference, and it is not yet clear if these two types of MH should be considered clinically different entities, or whether both types just lie in the wide spectrum of a single clinical entity. Increased recognition of this potentially fatal disorder and early initiation of speciŽÞc treatment, i.e., the use of dantrolene, may have led to an increase in the number of abortive cases of MH being reported rather than unequivocal cases.
(para2)Dantrolene is effective for MH because it inhibits CICR. It is not known whether dantrolene is also
effective for MH cases in which the rate of CICR is
not accelerated. Although it is difŽÞcult to know if dantrolene had any effect on this patientŽÕs favorable outcome, it would be both reasonable and practical to administer dantrolene during an acute MH-like episode even when the patient is subsequently found to have normal CICR. Dantrolene is not acutely toxic, and might be helpful after sudden cardiac arrest following succinylcholine, as the clinical differentiation from
MH is often difŽÞcult. However, the effectiveness of dantrolene under life-threatening circumstances does not necessarily imply that the situation is due to
MH. Dantrolene has been used effectively to treat neuroleptic malignant syndrome and thyrotoxic crisis [13].
(para2)Most cases of cardiac arrest after succinylcholine
in pediatric patients have occurred in boys affected
with DuchenneŽÕs muscular dystrophy. However, there
is a report of a patient who developed masseter
muscle rigidity and increased CK after succinylcholine without muscle disease or MH-susceptibility as evidenced by a normal muscle biopsy specimen and a
normal CHCT [14]. The case in our report is another patient who had a cardiac arrest following sevo-
Žßurane and succinylcholine, but who did not show
any abnormality with muscle biopsy and CICR. As
the prevalence of MH in Japan is unknown, the predictive value of negative CICR cannot be calculated.
Although the present patient did not fulŽÞll the clinical criteria of fulminant MH, we believe that when the clinical (cardiac arrest, rhabdomyolysis) and biochemical (hyperkalemia, increase in CK) ŽÞndings occur
in reaction to anesthetic drugs, patients should
be managed clinically as MH-susceptible in future
anesthesia.
(para2)The case reports available to the MH Hotline in the United States suggest that sudden unexpected cardiac arrest in reaction to succinylcholine occurs about ŽÞve to six times per year across the U.S. In view of the lack
of an effective way to recognize patients at risk of a hyperkalemic response to succinylcholine, the Food
and Drug Administration in the U.S. determined to contraindicate succinylcholine except in cases for which it is clearly indicated [15]. At the moment, the situation regarding the use of succinylcholine in pediatric as well as adult patients in Japan is quite different from that in the U.S. The authors are of the opinion that the decision of indication or contraindication should be left to clinicians and not to pharmaceutical companies. How-
ever, the report of this case may prompt reconsider ation of the use of succinylcholine in elective pediatric anesthesia [16].
(1)References
(REF) 1. Rosenberg H, Gronert GA (1992) Intractable cardiac arrest in children given succinylcholine. Anesthesiology 77:1054
(REF) 2. Miller ED, Sanders DB, Rowlingson JC, Miller ED, Sanders DB, Rowlingson JC, Berry FA, Sussman MD, Epstein RM (1978) Anesthesia-induced rhabdomyolysis in a patient with DuchenneŽÕs muscular dystrophy. Anesthesiology 48:146-148
(REF) 3. Wang JM, Stanley TH (1986) Duchenne muscular dystrophy and malignant hyperthermiaŽÑtwo case reports. Can Anaesth Soc J 33:492-497
(REF) 4. Henderson WAV (1984) Succinylcholine-induced cardiac arrest in suspected Duchenne muscular dystrophy. Can Anaesth Soc J 31:444-446
(REF) 5. Mehler J, Bachour H, Simons F, Mehler J, Bachour H, Simons F, Wolpers K (1991) Cardiac arrest during induction of anesthesia with halothane and succinylcholine in an infant. Anaesthetist 40:497-501
(REF) 6. Stelzner J, Kretz FJ, Rieger A, Stelzner J, Kretz FJ, Rieger A, Reinhart K (1993) Anaesthesia-induced cardiac arrest in two infants with unsuspected muscular dystrophy. Anaesthetist 42:44-46
(REF) 7. Solares G, Herranz JL, Sanz MD (1986) Suxamethonium-induced cardiac arrest as an initial manifestation of Duchenne muscular dystrophy. Br J Anaesth 58:576
(REF) 8. Rosenberg H (1988) Clinical presentation of malignant hyperthermia. Br J Anaesth 60:268-273
(REF) 9. Larach MG, Localio AR, Alloen GC, Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H, Rosenberg H, Waud BE, Wedel DJ (1994) A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 80:771-779
(REF)10. Isaacs H, Badenhorst M (1993) False-negative results with muscle caffeine halothane contracture testing for malignant hyperthermia. Anesthesiology 79:5-9
(REF)11. Endo M, Yagi S, Ishizuka T, Endo M, Yagi S, Ishizuka T, Horiuti K, Koga Y, Amaha K (1983) Mechanism in the sarcoplasmic reticulum of the muscle from a patient with malignant hyperthermia. Biochem Res 4:83-92
(REF)12. Matsui K, Kikuchi H (1994) Diagnosis of malignant hyperthermia by muscle biopsyŽÑCa-induced Ca release. J Jpn Soc Clin Anesth 14:402-404
(REF)13. Bennett MH, Wainwright AP (1989) Acute thyroid crisis on induction of anaesthesia. Anaesthesia 44:28-30
(REF)14. Kaplan RF, Rushing E (1992) Isolated masseter spasm and increased creatine kinase without malignant hyperthermia susceptibility or other myopathies. Anesthesiology 77:820-822
(REF)15. Katz L, Wright C, Harter J, Katz L, Wright C, Harter J, Zung M, Scally D, Spyker D (1994) Revised label regarding use of succinylcholine in children and adolescents. Anesthesiology 80:243-244
(REF)16. Delphin E, Jackson D, Rothstein P (1987) Use of succinylcholine during elective pediatric anesthesia should be reevaluated. Anesth Analg 66:1190-1192 (MW)

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(JN)J Anesth (1996) 9:354 - 356
(PT)
(CT)Fat embolism syndrome due to femoral shaft fracture during pregnancy
(CA)Tae-Yool Chun, Munetaka Hirose, and Masao Miyazaki
(ADD)Department of Anesthesia, National Maizuru Hospital, 2410 Yukinaga, Maizuru, Kyoto, 625 Japan
(KW)Key words: Fat embolism syndrome, Pregnancy, Bone fracture
(A)Introduction
(para1)We report herein a rare case of fat embolism syndrome during pregnancy and discuss the effect of the pregnant state on this syndrome.
(A)Case report
(para1)A 31-year-old female, 30 weeksŽÕ gestation, para 1, was scheduled to undergo an operation for left femoral shaft fracture sustained in a trafŽÞc accident. At admission, her consciousness was clear, and no other signiŽÞcant wound was recognized. She had no medical history and the course of pregnancy had been fair until the accident. Ritodrine (100 ùÈáÎin21) had been continuously administered for uterine tocolysis because of an increase in uterine tone since admission. On the second day after admission, profound respiratory failure developed
suddenly in association with severe hypoxia (PaO2 28 mmHg, PaCO2 28 mmHg at room air). Her consciousness level decreased, and she showed delirium. Bloody sputum, tachypnea (respiratory rate [RR] 45 breaths¡¦min21), tachycardia ([HR] 146 beatsáÎin21), and diffuse inŽÞltrates demonstrated by chest radiogram indicated that the patientŽÕs condition was critical. We suspected that our patient had fat embolism syndrome (FES) because she exhibited many features of GuardŽÕs diagnostic criteria [1], including two of the major
features (diffuse pulmonary inŽÞltrates and loss of
consciousness with deepening coma), one of the intermediate features (severe hypoxemia), and three of the minor features (tachycardia, elevation of body temperature and elevated erythrocyte sedimentation rate). We decided to perform an emergency cesarean section. The maternal vital signs at this time were blood pressure (BP) 120/50 mmHg, HR 160 beatsáÎin21, and body temperature (BT) 38.0Ž¡C, although the basal fetal heart rate was almost normal (fetal heart rate: 160 beatsáÎin21). The patient underwent a rapid-sequence induction with 250 mg thiopental and 7 mg vecuronium bromide intravenously. After tracheal intubation, anesthesia was maintained with isoŽßurane (0.6%) in oxygen under 8 cmH2O positive end-expiratory pressure (PEEP) throughout the operation. Pulse oximetry showed 48% of SpO2 just after induction. The premature baby (1790 g, Apgar score 4/7) was delivered, but died during severe idiopathic respiratory distress syndrome 12 h after the cesarean section, despite all attempts at treatment. The obstetricians found abruptio placenta during the operation. The induction-delivery time was about 3 min. SpO2 increased gradually to 70%-80% soon after the delivery, and to 96% by the end of the operation. The data acquired via a Swan-Ganz catheter, which had been inserted during the operation, were 37 mmHg mean pulmonary artery pressure (MPAP) and 9 mmHg mean pulmonary capillary wedge pressure (PCWP), and arterial blood gas analysis revealed pH 7.12,
PaCO2 62.2 mmHg, PaO2 60.5 mmHg, BE 210, and SaO2 79.2%. Medication after the delivery consisted of dobutamine (3 ùÈáÌg21áÎin21), prostaglandin E1 (0.05 ùÈáÌg21áÎin21), and 1 g methylpredonisolone sodium succinate. The acidosis was partially compensated by injection of 60 ml of 7% sodium bicarbonate and hyperventilation. At the end of the operation, arterial blood gas analysis data were improved to pH 7.29, PaCO2 54.2 mmHg, PaO2 69.4 mmHg, BE 21.1, and SaO2 90.7%. The ŽÞnal operating room vital sign values were BP 100/60 mmHg, HR 163 beatsáÎin21, and BT 37.7Ž¡C. S-T segment depression, shown on the electrocardiogram, had continued since the operation. Administration of diltiazem (1.5 ùÈáÌg21áÎin21) and digoxin (0.25 mgáÅay21) was started to improve myocardial ischemia and sustained tachycardia, respectively. On postoperation day (POD) 10, echocardiogram and radionuclide studies (9 mTc and 201Tl) were performed. Hypokinesis of the left ventricle wall and 55% ejection fraction were noted, and the ŽÞndings of the radionuclide studies were consistent with typical myocardial ischemia. The patient was also under mechanical ventilation (SIMV, FIO2 1.0-0.6; PEEP 8-5 cmH2O) until extubation on POD 4. On POD 13, her general condition was improved with fairly reversed respiratory
state and ischemic heart, and the operation for left femoral bone fracture was performed under general anesthesia (isoŽßurane with nitrous oxide and 200 ùÈ fentanyl). The anesthetic course was uneventful, and the intraoperative blood gas analysis ŽÞndings were
fair.
(A)Discussion
(para1)Although the mechanism of FES has not yet been clariŽÞed, two hypotheses regarding this mechanism have been presented. Fat emboli may mechanically block capillaries in the lungs. However, the medullary bone content is of insufŽÞcient volume to produce widespread pulmonary microvascular embolization. An alternate hypothesis is that fatty acids, especially oleic acid, derived from fat emboli are toxic to the parenchyma of the lung and may lead to disruption of its capillary network [1-3].
(para2)In pregnancy, we believe, two factors could worsen the respiratory state of a patient with FES. One is the maternal hormonal and metabolic state. It is known that human placental lactogen (hPL), which is produced at the syncytium of the placenta, enhances lipolysis and increases the free fatty acid level in the maternal blood. The hPL concentration in the blood increases in proportion to the enlargement of the placenta [4], and is highest at term. At that time the serum total lipid level is elevated by as much as 50% and the serum level of free fatty acids by 60% compared with those in the non-pregnant state [5]. The hPL level declines rapidly after the birth and is not detectable 7 h after the end of labor. Furthermore, lipoprotein lipase activity, which transfers free fatty acids in the bloodstream into the tissues, is lower in pregnant women. The hormones and enzymes released from the placenta (hPL, insulinase and progesterone) also have an antagonistic effect on insulin, and this decreases the rate of removal of fatty acids into the extrahepatic tissues [6,7]. Also, blood in a parturient is apt to coagulate and lead to disseminated intravascular coagulation. Therefore once FES was established a
parturient could deteriorate very rapidly. A pregnant woman is also disadvantaged by the effect of pregnancy on her lungs. It is generally recognized that in a parturient, functional residual capacity (FRC), expiratory re-
(para2)serve volume, and residual volume are decreased. These
(para2)changes are related to the cephalad displacement of the diaphragm by the large gravid uterus. The respiratory mucous membrane also becomes more congested, edematous, and friable. These changes in the lungs of a pregnant woman will tend to weaken her respiratory system, and under the above-mentioned conditions she might be at high risk of respiratory failure.
(para2)In our case, the parturientŽÕs respiratory state had deteriorated suddenly at midnight. We tried to improve here condition by the cesarean section prior to the
orthopedic operation. Delivery would reduce her
enlarged uterus and stop the release of placental substances. Her fractured left leg was thought not to be contributing to her worsening condition because FES was almost established. Therefore, repairing the fracture seemed to be of secondary importance in her critical condition. In general, a fractured shaft should be set very exactly, and an emergency orthopedic repair is controversial [8-10]. Repair surgery may release a large quantity of fatty acids all at once on deŽßation of the tourniquet. Case reports concerning FES during pregnancy are rare [3]. The relation between FES and pregnancy should be examined in detail.
(para2)FES must also have had some inŽßuence on the infantŽÕs respiratory distress. The mother had had an uneventful pregnancy, but the obstetricians found abruptio placenta after the delivery. One-third of the placenta on the motherŽÕs side showed infarction or necrosis. The infant failed to respond to any treatment, including surfactant therapy. We suspected that FES, not transient hypoxia, was responsible. In studies on normal fetal heart rate just before cesarean section, it has been shown that a fetus occasionally shows a normal fetal heart rate pattern when it has adapted itself to hypoxia.
(para2)We administered dobutamine and prostaglandin E1, both to reduce pulmonary hypertension, and methylpredonisolone sodium succinate to improve the ventilation-perfusion ratio, decrease shunt, and increase PO2 [11].
(para2)In summary, we report a rare case of FES in a pregnant woman involved in a trafŽÞc accident. FES has graver consequences in a pregnant patient than in a non-pregnant patient. It is not clear why the incidence of FES is rare in pregnant women. Detailed examination of parturients with a long bone fracture is needed. However, prompt and careful therapy, including
emergency delivery, is required for pregnant patients with FES because of their hormonal and respiratory
state.
(A)References
(REF) 1. Guard AR, Wilson RI (1974) The fat embolism syndrome. J Bone Joint Surg 56B:408-416
(REF) 2. Peltier LF (1988) Fat embolism. Clin Orthop 232:263-270
(REF) 3. Moore P, James O, Saltos N (1981) Fat embolism syndrome. Aust N Z J Surg 6:546-551
(REF) 4. Singer W, Desjardins P, Friesen HG (1970) Human placental lactogen. Obstet Gynecol 36:222-232
(REF) 5. Potter JM, Nestel PJ (1979) The hyperlipemia of pregnancy
in normal and complicated pregnancies. Am J Obstet Gynecol 133:165-170
(REF) 6. Fabian E, Stork A, Kucerova L, Sponarova J (1968) Plasma levels of free fatty acids, lipoprotein lipase, and postheparin esterase in pregnancy. Am J Obstet Gynecol 7:904-907
(REF) 7. Biale Y (1985) Lipolytic activity in the placentas of chronically deprived fetuses. Acta Obstet Gynecol Scand 64:111-114
(REF) 8. Sugai K, Sugai Y, Aoki H, Honjo M (1991) A case of fat embolism syndrome after femoral shaft fracture (in Japanese). Seikeigeka (Orthop Surg) 42:391-394
(REF) 9. Shibata S, Yoshioka T (1992) Fat embolism syndrome after the fracture of the femoral neck (in Japanese). Seikeigeka (Orthop Surg) 43:532-534
(REF)10. Talucci RC (1983) Early intramedullary nailing of femoral shaft fracture; a cause of fat embolism syndrome. Am J Surg 146:107-111
(REF)11. Fischer JE, Turner RH, Herndon JH, Riseborough EJ (1971) Massive steroid therapy in severe fat embolism. Surg Gynecol Obstet:667-672 (MW)

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(JN)J Anesth (1996) 9:357 - 359
(PT)
(CT)Intraperitoneum insufŽßation of carbon dioxide increases epidural pressure in laparoscopic cholecystectomy
(CA)Hong-Lin Du, Masakazu Hayashita, and Kazuo Hanaoka
(ADD)Department of Anesthesiology, University of Tokyo, 7-3-1 Hongo, Tokyo, 113 Japan
(KW)Key words: Laparoscopic cholecystectomy, Epidural space, Cerebrospinal Žßuid pressure
(A)Introduction
(para1)Laparoscopic cholecystectomy is being performed with increasing frequency because of its low level of postoperative pain, faster recovery, and shorter hospitalization [1], but data recorded during this procedure indicate that it affects some physiologic functions. For example, intraperitoneum insufŽßation with carbon dioxide (CO2) often has a depressive effect on circulation and respiration [2, 3]. However, little is known about the effect of CO2 pneumoperitoneum on intracranial pressure or cerebrospinal Žßuid pressure, partly because of the difŽÞculty in measuring these parameters. In this study, we continuously measured epidural pressure after injecting a known volume of local anesthetic at a ŽÞxed speed. We used epidural pressure as an indirect measure of cerebrospinal Žßuid pressure when it was relatively stable after epidural injection [4-6]. The inŽßuence of CO2 pneumoperitoneum on epidural pressure in laparoscopic cholecystectomy was evaluated.
(A)Materials and methods
(para1)Eight patients (four men and four women) were involved in the study. They all had chronic cholecystitis and/or gallbladder stone, and were scheduled for laparoscopic cholecystectomy. Their mean age was 35 6 12 (SD) years, and mean weight was 58 6 11 kg, ASA I or II. Informed consent was obtained from each pa-
tient on the day before surgery. All patients were premedicated with intramuscular atropine (0.01 mgáÌg21) and hydroxyzine (1 mgáÌg 21) 30 min before arriving in the operating room. Before the induction of general anesthesia, epidural puncture was performed at the T8-T9 interval with a 17 G Tuohy needle. That the epidural space had been entered was conŽÞrmed by loss of resistance to normal saline injection. An 18 G epidural catheter (Terumo, Tokyo, Japan; 0.985 mm inner diameter, 953 mm length) was advanced 3 cm cephalad. A 25 G needle (20 mm length) was connected to the outer end of the epidural catheter. A pressure transducer was then connected with the 25 G needle through a three-way stopcock. Using this stopcock, the epidural catheter could be connected either to the transducer for monitoring epidural pressure or to the local anesthetic injector for injecting anesthetic. General anesthesia was induced with thiopentone (5 mgáÌg21 i.v.) and endotracheal intubation was performed with the facilitation of intravenous vecuronium (0.2 mgáÌg21). The patientŽÕs respiration was mechanically controlled with a tidal volume of 12 mgáÌg 21 at a rate of 10 breathsáÎin21. General anesthesia was maintained by 0.5%-1.5% isoŽßurane with 40% oxygen in nitrogen. One per cent mepivacaine was injected into the epidural space when necessary.
(para2)After anesthesia induction, the operating table was adjusted to the horizontal position. The ŽÞrst 5 ml mepivacaine was injected into the epidural space at 0.5 mláÔ21. Epidural pressure was monitored continuously. It increased immediately after epidural injection and then decreased gradually. It remained relatively stable from 3-5 min to 20 min after the injection. Epidural pressure was sampled every minute from 6 min to 20 min after epidural injection to calculate its coefŽÞcient of variation.
(para2)The second 5 ml mepivacaine was injected into the epidural space at 0.5 mláÔ21 6 min before intraperitoneum insufŽßation. Epidural pressure was monitored continuously for 20 min after the injection. The peritoneal cavity was insufŽßated with CO2 and intraperitoneal pressure was maintained at 12-15 mmHg throughout the procedure. For statistical comparison between epidural pressure and intraperitoneal pressure, the values immediately before and 5 min after the
start of the insufŽßation were used. Arterial blood was sampled and PaCO2 was measured immediately before and 5 min after the start of intraperitoneum insufŽßation.
(para2)Epidural pressure was referenced at the level of the outer ear tract. Intraperitoneal pressure was measured with a differential pressure transducer. Both pressures were read at the end of expiration. Data were presented as mean 6 SD. Comparison between before and 5 min after the start of intraperitoneum insufŽßation was conducted by paired t-test. Statistical signiŽÞcance was
accepted at P , 0.05.
(A)Results
(para1)The coefŽÞcient of variation of epidural pressure sampled every minute from 6 min to 20 min after the ŽÞrst epidural injection was 2.4 6 0.3%. Intraperitoneum insufŽßation with CO2 resulted in simultaneous increases in epidural pressure and intraperitoneal pressure (Fig. 1). Epidural pressure remained elevated during the 15 min of CO2 pneumoperitoneum when it was being monitored. When we compared the increases in intraperitoneal and epidural pressure 5 min after the start of CO2 pneumoperitoneum, it was found that the increase in epidural pressure was about one-third of the increase in intraperitoneal pressure (Table 1). PaCO2 did not change signiŽÞcantly 5 min after the start of CO2 pneumoperitoneum when compared with that before CO2 pneumoperitoneum.
(A)Discussion
(para1)This study showed that the increase in intraperitoneal pressure caused by intraperitoneum insufŽßation with CO2 resulted in a simultaneous increase in epidural pressure. The increase in epidural pressure was about one-third of the increase in intraperitoneal pressure.
(para2)Epidural pressure after epidural injection may be affected by factors such as the volume injected and the injecting speed. By controlling these factors, epidural pressure can be measured with good reproducibility and may remain stable for several minutes [4-6]. Then as the injected Žßuid is absorbed or Žßuxes out of the epidural space, the epidural pressure gradually decreases. In this study, we found that by controlling the volume injected and the injecting speed, the epidural pressure remained relatively stable from 6 min to 20 min after injection of local anesthetic into the epidural space (coefŽÞcient of variation 2.4 6 0.3%). InŽßuence of intraperitoneum insufŽßation with CO2 on epidural pressure could therefore be investigated during this period.
(para2)This stable epidural pressure has been shown to have a good relationship with cerebrospinal Žßuid pressure in both humans and animals [4-6]. This ŽÞnding is acceptable because there is only elastic dura mater between the epidural space and the subarachnoid space. Epidural pressure and cerebrospinal Žßuid pressure may reach equilibration through the dura mater under stable
conditions when Žßuid exists in the epidural space to transmit pressure [4]. Therefore, our results suggest
that caution should be taken when CO2 pneumoperitoneum is conducted in patients with low intracranial compliance.
(para2)The reason for the increase in epidural pressure caused by CO2 pneumoperitoneum is not well known. The elevated intraperitoneal pressure produced by intraperitoneum insufŽßation with CO2 may transmit directly to the epidural space through intervertebral foramina, and/or indirectly increase the epidural pressure by interfering with the venous return of the epidural space vein [7]. As PaCO2 did not change signiŽÞcantly 5 min after the start of insufŽßation, the increase in
epidural pressure cannot be attributed to the PaCO2 change.
(para2)In summary, we have found that the increase in
intraperitoneal pressure caused by intraperitoneum insufŽßation with CO2 resulted in a simultaneous increase in epidural pressure. Since epidural pressure reŽßects cerebrospinal Žßuid pressure, it is suggested that caution should be taken when CO2 pneumoperito-
neum is conducted in patients with low intracranial
compliance.
(1)References
(REF)1. Wolfe BM, Gardiner B, Frey CF (1991) Laparoscopic cholecystectomy. A remarkable development (Editorial). JAMA 265:
1573-1574
(REF)2. Critchley LAH, Critchley JAJH, Gin T (1993) Haemodynamic changes in patients undergoing laparoscopic cholecystectomy: Measurement by transthoracic electrical bioimpedance. Br J Anaesth 70:681-683
(REF)3. Nyarwaya JB, Mazoit JX, Samii K (1994) Are pulse oximetry
and end-tidal carbon dioxide tension monitoring reliable during laparoscopic surgery? Anaesthesia 49:775-778
(REF)4. Du HL, Suwa K, Hanaoka K (1994) Estimation of cerebrospinal Žßuid pressure via the lumbar epidural space by the equilibration method. J Anesth 8:182-187
(REF)5. Asano M, Kosaka Y (1986) Changes of epidural pressure and cerebrospinal Žßuid pressure during abdominal surgery (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 35:1694-1700
(REF)6. Asano M, Oh-Oka T, Kosaka Y (1987) Relation between epidural pressure and cerebrospinal Žßuid pressure in dogs (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 36:89-93
(REF)7. Usubiaga JE, Moya F, Usubiaga LE (1967) Effect of thoracic and abdominal pressure changes on the epidural space pressure. Br J Anaesth 39:612-618 (MW)

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(JN)J Anesth (1996) 9:360 - 362
(PT)
(CT)Acute laryngeal trauma
(CA)Keng Fatt Cheong and Gordon Hok Man Yau
(ADD)Department of Anaesthesia, National University Hospital, 5 Lower Kent Ridge Road, Singapore
(KW)Key words: Blunt injury, Laryngeal trauma, Fiberoptic endoscopy
(A)Introduction
(para1)Acute blunt injuries to the larynx are rare and
potentially life-threatening. The aim of initial management is to relieve any upper-airway obstruction and to protect the airway in the least traumatic manner. Fiberoptic endoscopy and computed tomography are invaluable aids in the management of patients. Early recognition is vital to prevent residual impairment of the laryngeal functions. We report two cases of such injuries with a brief review on recent management of these patients.
(B)Case 1
(para1)A 31-year-old motorcyclist was admitted after a road trafŽÞc accident. He sustained massive soft-tissue injuries of the face and neck, a LeFort II fracture of the maxilla, and fractures of the body and angle of the mandible. A large transverse bruise was present across the neck with loss of laryngeal prominence. Crepitus was palpable across the front of the neck. He was mildly dyspneic although pulse oximetry did not show any period of desaturation.
(para2)In view of the imminent danger of airway obstruction, he was brought into the operating theater to secure the airway by means of a tracheostomy and for exploration of the face and neck injuries. After the tracheostomy was done, laryngoscopy showed that visualization of the glottis was not possible because of the distortion from the injuries and profuse bleeding. An open reduction and internal ŽÞxation of the maxillofacial fractures was done. A subsequent computed tomograph (CT) showed signiŽÞcant endolaryngeal edema (Fig. 1), as well as fractures of the anterior arch of the cricoid cartilage.
(para2)The fractured larynx was electively operated on 1 week after the accident. The supraglottic mucosa was edematous and traumatized. The cricoid fragments were ŽÞxed with prolene, the vocal cords anchored to the perichondrium of the thyroid cartilage, and a laryngeal stent inserted. The patient was discharged 1 week postoperatively with removal of the laryngeal stent 6 weeks later.
(B)Case 2
(para1)A 19-year-old motorcyclist sustained trauma to the neck after his motorcycle skidded. On arrival at the casualty department, he was confused, stridorous, and cyanosed, with extensive neck swelling. Endotracheal intubation was successful after several attempts as visualization of the larynx was difŽÞcult owing to bleeding. A subsequent cervical spine X-ray and CT scan of the head showed no abnormalities.
(para2)Seven hours after admission, the patient was awake and orientated, and vital signs were stable. Immediately after extubation, he developed airway obstruction
and was reintubated. During laryngoscopy, no abnormalities were seen and vocal cord movements were
normal.
(para2)A subsequent X-ray showed subcutaneous emphysema over the neck region. A CT examination showed laryngeal fractures. A microlaryngoscopy and esophagoscopy examination was found to be normal. Subsequent exploration of the neck revealed fractures of the cricoid cartilage. Repair of the fractures was performed and a laryngeal stent insertd to maintain airway patency. A tracheostomy was also fashioned. Subsequent recovery was uneventful.
(A)Discussion
(para1)Acute blunt tracheolaryngeal injuries are rare [1], and they usually occur as a result of vehicular accidents, close-contact sports, or strangulation attempts. Commonly during a vehicular accident where the unrestrained driver or the front passenger is thrown forward, extension of the neck would result in the trachea or larynx being compressed between the steering wheel or the dashboard and the vertebral bodies. Ligamentous membrane rupture or fractures of the laryngotracheal cartilages may result. Other associated injuries involving the head, cervical spine, chest, and esophagus are common [2].
(para2)A signiŽÞcant number of these patients die at the scene of the accident after airway obstruction. Of those who survive, some will present with signs of upper-airway obstruction, as seen in our ŽÞrst patient, while others remain undetected owing to the presence of other more obvious major injuries.
(para2)Airway obstruction may result from avulsion, fracture, or dislocation of the thyroid, cricoid, or tracheal cartilages. In addition, accumulation of edema Žßuid or hematoma in the subglottic and supraglottic mucosa may occur. Air dissecting into the submucosa planes from the disrupted airway may also reduce the lumen of the trachea or larynx, contributing to the symptoms.
(para2)The most important clinical sign of blunt injury to the neck is bruising and swelling. The neck contour may appear Žßattened owing to the loss of the thyroid cartilage prominence. Surgical emphysema over the neck usually signiŽÞes that the laryngotracheal complex is
ruptured.
(para2)If the head trauma or the maxillofacial injuries are severe or the patient is unconscious, the laryngotracheal fractures may be missed altogether. Hurried and inexperienced intubation may then further exacerbate an already precarious airway. Even if the patient
survives the initial injuries, missed laryngeal fractures may result in respiratory distress when the patient is extubated, and this is illustrated in our second patient.
(para2)DeŽÞnitive diagnosis of the level and extent of
suspected laryngotracheal injury is made by radiographic and endoscopic examinations. X-rays of the neck are essential to assess the cervical spine and to demonstrate injuries to the laryngotracheal complex indicated by the presence of swelling or shift in the position of the epiglottis, an abnormally shaped column of air in the tracheal outline, or subcutaneous emphysema. Cricotracheal separation may be present if the hyoid bone is found to be shifted upward above the upper level of the third cervical vertebra [3].
(para2)A computed tomographic scan is an excellent diagnostic tool to conŽÞrm the diagnosis of laryngotracheal fracture and detect unsuspected injuries, and it may be done before or after the airway is secured [4,5]. Some trauma centers routinely perform a CT scan in all cases of suspected laryngeal trauma, whereas others [6-8] suggest that it should be reserved only for those cases where the radiographic results may determine subsequent management.
(para2)Indirect laryngoscopy is often used to assess the
degree of damage and the integrity of the glottis.
However, in uncooperative patients or where mouth opening is limited owing to concomitant maxillofacial injuries, this could be difŽÞcult. Recently, ŽÞberoptic nasoendoscopy and bronchoscopy [9-11] were used with success to assess the airway with minimal manipulation of the cervical spine. Furthermore, immediate airway control is possible, if required, by railroading an endotracheal tube over the instrument.
(para2)In the management of blunt trauma to the neck, the integrity of the airway takes precedence. Cervical spine protection measures should be undertaken until the integrity of the spine is assured. Measures to secure the airway and the timing of surgical intervention will be determined by the level and severity of the injury, and the degree of the airway compromise. Mild cases with minimal symptoms may be managed conservatively with close observation and humidiŽÞed air. However, progressive edema of the glottis may occur and the airway may be compromised rapidly. When the initial assessment indicates that airway control is necessary, the airway should be secured as rapidly and in the least traumatic manner possible. The manner in which the airway is secured remains controversial. Tracheostomy is preferred, as endotracheal intubation carries the risk of disruption of the fractured sites or tears of the mucosa [1,8,12]. False passages and total separation of the transected ends may result. Tracheostomy may, however, be extremely difŽÞcult in the confused, hypoxic, or uncooperative patient, or in those with gross distortion of the cervical anatomy from the trauma. Endotracheal intubation, with or without the aid of ŽÞberoptic endoscopy, has been shown to be safe [13,14]. Under direct vision, the risk of creating a false passage is minimized. However, blood in the tracheobronchial tree may
impair the visibility of the scope. If endotracheal intubation is deemed impossible, ventilation via cricothyroidotomy may be employed while tracheostomy is being prepared.
(para2)In summary, a high index of suspicion for laryngeal trauma should be maintatined in all cases of multiple injuries involving the head and neck regions. In those patients where immediate airway control is required, most authors recommend a tracheostomy. Endotracheal intubation by an experienced anesthetist is an alternative, but extreme caution should be exercised. A CT scan and endoscopic examination of the larynx should be performed to determine the extent of injury. Early diagnosis and proper management are essential for a successful outcome and preservation of laryngeal functions.
(A)References
(REF) 1. Schaefer SD (1992) The acute management of external laryngeal trauma. Arch Otolaryngol Head Neck Surg 118:598-604
(REF) 2. Capan LM, Miller SM, Turndof H (1991) Management of neck injuries. In: Capan LM, Miller SM, Turndof H (eds) TraumaŽÑanaesthesia and intensive care. Lippincott, Philadephia, PA, pp 409-446
(REF) 3. Polansk A, Resnick D, Soffereman RA, Davidson TM (1984) Hyoid bone elevation: a sign of tracheal transection. Radiology 150:117-120
(REF) 4. Gussack GS, Jurkovich GJ (1986) Laryngotracheal trauma: a protocol approach to a rare injury. Laryngoscope 96(6):660-665
(REF) 5. Stanley RB (1984) Value of computed tomography in the management of acute laryngeal injury. J Trauma 24:359-362
(REF) 6. Gussack GS, Jurkovich GJ (1988) Treatment dilemmas in laryngotracheal trauma. J Trauma 28:1439-1444
(REF) 7. Schaefer SD, Brown OE (1983) Selective application of computed tomography in the management of laryngeal trauma. Laryngscope 93:1473-1475
(REF) 8. Fuhrman GM, Steig FH, Buerk CA (1990) Blunt laryngeal trauma: classiŽÞcation and management protocol. J Trauma 30(1):87-92
(REF) 9. Goodie G, Patton P (1991) Acute management of the blunt airway trauma. Anaesth Intensive Care 19:271-274
(REF)10. Flynn AE, Thomas AN, Schecter WP (1989) Acute tracheobronchial injury. J Trauma 29:1326-1330
(REF)11. Hara KS, Prakash UB (1989) Fiberoptic bronchoscopy in the evaluation of acute chest and upper airway trauma. Chest 96(3):
627-630
(REF)12. Schaefer SD, Close LG (1989) Acute management of laryngeal traumaŽÑupdate. Arch Otol Rhinol Laryngol 98:98-104
(REF)13. Gussack GS, Jurkovich GJ, Luterman A (1986) Laryngotracheal trauma: a protocol approach to a rare injury. Laryngoscope 96:660-665
(REF)14. Yarington CT (1979) Trauma involving air and food passages. Otolaryngol Clin North Am 12:321-327 (MW)

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(JN)J Anesth (1996) 9:363 - 365
(PT)
(CT)Comparison of sevoŽßurane and other volatile anesthetics for cesarean section
(CA)Keiichi Kan, Akira Shigihara, Choichiro Tase, and Akira Okuaki
(ADD)Department of Anesthesiology, Fukushima Medical College, 1 Hikarigaoka, Fukushima-city, Fukushima Prefecture, 960-12 Japan
(KW)Key words: SevoŽßurane, Halothane, EnŽßurane, IsoŽßurane, Cesarean section
(A)Introduction
(para1)Low-concentration halothane or enŽßurane is generally used for a cesarean section. SevoŽßurane is a new volatile anesthetic and its blood/gas partition coefŽÞcient is very low. It seems to be suitable for anesthesia that requires rapid induction and emergence, such as cesarean section. In this study sevoŽßurane was evaluated during
anesthesia for cesarean section and compared with halothane, enŽßurane, and isoŽßurane.
(A)Material and methods
(para1)With informed consent from the subjects, we studied 60 healthy mothers who were to have elective cesarean section under general anesthesia. Premedication consisted of atropine 0.5 mg injected intramuscularly. The patients were randomly allocated into four groups receiving halothane, enŽßurane, isoŽßurane, or sevoŽßurane. Each group had 15 patients.
(para2)After preoxygenation, 4 mgáÌg21 thiopental and 40 mg succinylcholine chloride were administered intravenously. Following endotracheal intubation, 2 láÎin21 oxygen, 4 láÎin21 nitrous oxide and one of the volatile anesthetics halothane (0.5%), enŽßurane (1%), isoŽßurane (0.7%), or sevoŽßurane (1%) were used. Then the operation was started. During the incision of the peritoneum, the volatile anesthetic was discontinued. At the time of incision of the uterine serosa, the nitrous oxide was turned off. After the fetus was delivered and the umbilical cord was clamped, 150 mg thiopental
and 0.2 mg buprenorphine were administered. Nitrous oxide and one of the volatile anesthetics (0.5% halothane, 1% enŽßurane, 0.7% isoŽßurane, or 1% sevoŽßurane) were added again. At the same time prostaglandin F2¡¦(PGF2¡¦ was injected into the uterine muscle and methylergometrine maleate was injected intravenously.
(para2)Blood pressure, heart rate, EKG and SpO2 were monitored. End-tidal concentrations of the inhalation anesthetics were measured by anesthetic gas monitor (BrÝÆl KjŽ¾r, NŽ¾rum, Denmark). Apgar score was estimated by pediatricians. Blood loss was estimated by counting the volume in the suction bottle and the weight of the swabs. After the delivery the obstetricians were asked to assess uterine contractility condition as follows:
(para1)1. Good, no additional treatment
(para1)2. Fair, contraction recovered with uterine massage
(para1)3. Poor, additional drugs were necessary
(para2)Blood gas of maternal arterial and umbilical venous blood were measured by ABL-3 (Radiometer, Copenhagen, Denmark). Recovery from anesthesia was assessed as follows:
(para1)1. Good, less than 10 min from the end of the operation to extubation
(para1)2. Fair, from 10 to 20 min from the end of the operation to extubation
(para1)3. Poor, over 20 min from the end of the operation to extubation
(para2)The patients were interviewed about intraoperative awareness the day after the operation. Routine blood examinations for liver and kidney function, blood cell count, and blood gas were checked during the 7 days after surgery. Values were shown as the means 6 SD. Data were analyzed using one-way analysis of variance (ANOVA) and the Mann-Whitney U-test, and a P-value less than 0.05 was considered signiŽÞcant.
(A)Results
(para1)There was no signiŽÞcant difference among the groups
in regard to mean age, height, weight, and gestational age.
(para2)The changes in mean blood pressure and heart rate are shown in Fig. 1. The mean blood pressure in the enŽßurane, isoŽßurane, and sevoŽßurane groups and heart rate in the enŽßurane and sevoŽßurane groups increased signiŽÞcantly at the beginning of the operation compared with the values before anesthesia.
(para2)It took 5 6 2.5 min from the beginning of the operation to delivery for all groups, and the concentrations of the agents at delivery were 0.07 6 0.05% (halothane), 0.03 6 0.06% (enŽßurane), 0.03 6 0.05% (isoŽßurane), 0.03 6 0.05% (sevoŽßurane). There was no signiŽÞcant difference among the groups.
(para2)The mean values of the Apgar score at 1 and 5 min were over 8 and 9, respectively, and no baby needed resuscitation.
(para2)The average blood loss during the operation was 650 6 231 ml in the halothane group, 688 6 368 ml in the enŽßurane group, 731 6 410 in the isoŽßurane group, and 796 6 276 ml in the sevoŽßurane group. There was no signiŽÞcant difference among these groups. During and after the operation there was no abnormal hemorrhage and no patient needed blood transfusion.
(para2)The obstetrician assessed the uterine contractility. The contractility was good in all cases except one in the enŽßurane group, whose contractility was fair, but that patientŽÕs uterine contractions gradually improved with uterine massage.
(para2)The blood gas of maternal arterial and umbilical venous blood at delivery is shown in Table 1. There was no signiŽÞcant difference among these groups.
(para2)The anesthesiologist assessed recovery from anesthesia. In two cases in the halothane group and one in the enŽßurane group the recovery was considered to be fair, but even in these three cases no additional treatment was necessary.
(para2)The patients were interviewed about intraoperative awareness the day after the operation. None of them reported awareness during the operation.
(para2)Transient premature ventricular contraction and premature atrial contraction were seen in some patients in the halothane, enŽßurane, and isoŽßurane groups soon after the injection of PGF2¡¦and methylergometrine maleate, but none of the patients needed treatment for arrhythmia.
(para2)Routine blood examination for liver and kidney function, blood cell count, and blood gas during the 7 days after the operation indicated no abnormal data that suggested the need for treatment.
(A)Discussion
(para1)Low doses of volatile anesthetics have been used for cesarean section because they decrease the likelihood of maternal postoperative recall and awareness of intraoperative events, may improve uterine blood Žßow, do not result in increased uterine bleeding, do not induce abnormal hypotension, and do not depress the newborn [1,2].
(para2)SevoŽßurane is a new volatile anesthetic, and its alveolar concentration rises more rapidly than that of other presently available, potent inhalation anesthetic [3].
We evaluated low concentration (1%) sevoŽßurane for cesarean section. Although Asada et al. [4] used sevoŽßurane for cesarean section, the concentration range was from 3% to 4% at the start of anesthesia and from 0.5% to 4% after delivery. He reported that uterine contractions were fair in 2 and poor in 2 of 12 patients. In our experiment uterine contractions were good in all the patients in the sevoŽßurane group. The reason is that 1% sevoŽßurane alone has no muscle
relaxant effect, although sevoŽßurane has a strong
potentiation effect on neuromuscular block by relaxants [5].
(para2)The minimum alveolar concentration (MAC) for sevoŽßurane is reported to be 1.71% for healthy Japanese (mean age 48) [6] or 2.05% for North Americans (mean age 38) [7]. One percent sevoŽßurane would be equivalent to 0.49%-0.58% MAC according to previous reports. This might be a little lower than the other volatile anesthetics in this study. SevoŽßurane has the characteristic of more rapid induction and recovery than other agents, and in our anesthesia technique nitrous oxide and volatile anesthetics were discontinued prior to the delivery so that maternal recall might occur. However, there was no patient in this study who was conscious during the operation and had postoperative recall. Buprenorphine might contribute to loss of awareness during an operation.
(para2)In this study there was no apparent difference between sevoŽßurane and the other volatile anesthetics with regard to blood pressure, heart rate, Apgar score, blood loss, uterine contractility, blood gas of maternal artery and umbilical vein, recovery from anesthesia, and intraoperative awareness.
(para2)There were some patients who had transient arrhythmia after delivery in the halothane, enŽßurane, and isoŽßurane groups. The arrhythmia might be connected with the PGF2¡¦injected into the uterine muscle and methylergometrine maleate injected intravenously after delivery [8,9]. On the other hand, no patient had arrhythmia in the sevoŽßurane group. SevoŽßurane dose not appear to be arrhythmogenic in dogs, and the arrhythmogenic dose of epinephrine exceeds that found during anesthesia with isoŽßurane [10]. This is an advantage during anesthesia for cesarean section.
(para2)This investigation showed that low-dose sevoŽßurane has the same advantages as the other three anesthetics in that it does not induce hypotension, depress uterine contractility, result in increased uterine bleeding, or depress the newborn; neither does it induce maternal post-operative recall or awareness of intraoperative events, and no arrhythmia was seen during anesthesia. Therefore sevoŽßurane is a useful anesthetic agent for cesarean section.
(1)References
(REF) 1. Moir DD (1970) Anaesthesia for caesarean section: an evaluation of a method using low concentrations of halothane and 50 percent oxygen. Br J Anaesth 42:136-142
(REF) 2. Waren TM, Datta S, Ostheeimer GW, Naulty JS, Weiss JB, Morrison JA (1983) Comparison of maternal and neonatal effects of halothane, enŽßurane and isoŽßurane for cesarean delivery. Anesth Analg 62:516-520
(REF) 3. Yasuda N, Lockhart SH, Eger EI II, Weiskopf RB, Liu J, Laster M (1991) Comparison of kinetics of sevoŽßurane and isoŽßurane in humans. Anesth Analg 72:316-324
(REF) 4. Asada A, Fujimori M, Tomoda S, Hidaka A (1990) SevoŽßurane anesthesia for elective cesarean section. J Anesth 4:66-72
(REF) 5. Itagaki T, Tai K, Katsumata N, Tai K, Suzuki H (1988) Potentiation with sevoŽßurane of neuromuscular blocking effects of vecuronium and pancuronium (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 37:943-954
(REF) 6. Katoh T, Ikeda K (1987) The minimum alveolar concentration (MAC) of sevoŽßurane in humans. Anesthesiology 66:301-303
(REF) 7. Scheller MS, Saidman LJ, Partridge BL (1988) MAC of sevoŽßurane in humans and the New Zealand white rabbit. Can J Anaesth 35:153-156
(REF) 8. Kan K, Hiruta Y, Okazaki M, Kawamae K, Otsuki M, Okuaki A (1990) Three cases of multifocal premature ventricular contraction during anesthesia for cesarean section (in Japanese). Rinshomasui (J Clin Anesth) 14:723-724
(REF) 9. Kabutan K, Satou K, Ono J, Ono J, Sugimoto S, Tsuji F, Taniguchi M (1994) Ventricular arrhythmia during cesarean section due to intramyometrically administered prostaglandin PGF2¡¦ Report of two cases (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 43:392-394
(REF)10. Imamura S, Ikeda K (1987) Comparison of the epinephrine-induced arrhythmogenic effect of sevoŽßurane with isoŽßurane and halothane. J Anesth 1:62-68 (MW)

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(JN)J Anesth (1996) 9:366 - 369
(PT)
(CT)Hemiparesis following carotid endarterectomy
(CA)Yuji Kadoi1, Nao Fujita1, Shigeru Saito2, and Tatsushi Fujita2
(ADD)1 Department of Anesthesiology, Saitama Prefectural Ohara-Cardiovascular Center, 1696 Itai Kounancho, Osato-gun, Saitama, 360-01 Japan
(ADD)2 Department of Anesthesiology and Reanimatology, Gunma University, School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371 Japan
(KW)Key words: Hemiparesis, Carotid endarterectomy, Electroencephalography
(A)Introduction
(para1)Many monitors have been designed for use during carotid endarterectomy (CEA) surgery to detect cerebral ischemia during carotid artery clamping [1]. Electroencephalography (EEG) is one of the monitors often used during CEA surgery. EEG is a useful system for the detection of cerebral ischemia, but it does not detect all cases of cerebral ischemia.
(para2)We report a case of hemiparesis following CEA surgery where the EEG indicated an improvement in the pattern of ischemic irregularities after surgery compared with the preoperative EEG pattern. In this case, we could not detect cerebral ischemia during CEA
surgery.
(A)Case report
(para1)A 67-year-old man, who had had a thoractomy 25 years previously due to tuberculosis, experienced transient ischemic attacks consisting primarily of weakness in the right arm and leg. The patientŽÕs body weight was 67 kg and his height was 170 cm. His Arterial blood pres-
sure was 125/57 mmHg, and his heart rate was 65 beats ¡¦min21. Brain computed tomography (CT) indicated no irregularities, but angiography indicated approximately 99% stenosis at the bifurcation of the left carotid artery. The left middle cerebral artery (MCA) was shown slightly by angiography. The results of neurological examination were normal. He underwent an emergency operation.
(para2)No premedication was performed. Prior to anesthetic induction in the operating room, the patientŽÕs arterial blood pressure was 120/63 mmHg and his heart rate
was 64 beats ¡¦min21. Anesthesia was induced with an intravenous administration of 0.2 mg fentanyl, 200 mg thiopental, and 8 mg vecuronium, and the trachea was intubated. Anesthesia was maintained with nitrous oxide-oxygen-isoŽßurane (0.8-1.0MAC). The concentrations of expired isoŽßurane and end-tidal CO2 tension (ETCO2) were monitored using a Capnomac Ultima (Datex, Helsinki, Finland) and ETCO2 was maintained within 40-45 mmHg. During the CEA operation, the arterial systolic blood pressure was maintained between 120 and 150 mmHg.
(para2)After the induction of anesthesia, EEG was monitored using a Lifescan (NeurometricsTM, San Diego, CA) monitor [2]. The ŽÞve Lifescan electrodes were placed bilaterally with one over the frontal and mastoid areas and a reference electrode attached to the middle of the frontal region.
(para2)Figure 1 shows the recording produced by the Lifescan monitor during CEA surgery. Figure 1(a) shows the recording obtained after the induction of
anesthesia. The left-hand EEG panel indicates the
presence of ischemic irregularities compared with the right-hand EEG panel, and the activity edge shows asymmetry. Figure 1(b) shows the recording obtained during carotid artery occlusion. The arrow indicates the time when the carotid artery was clamped. The carotid artery was clamped at 7 cm proximal from MCA bifurcation. The endarterectomy was 5 cm in length in the left carotid artery. Figure 1(c) shows the recording obtained after the carotid artery was declamped. Figure 1(b) and (c) also show ischemic irregularities and the activity edge shows asymmetry. Figure 1(d) shows the recording obtained at the end of surgery during anesthesia. This ŽÞgure shows that there are no ischemic irregularities and the activity edge shows symmetry. The carotid artery occlusion time was 27 min. Thirty minutes after all anesthetic agents were stopped, the patient had a weak reaction to command and pain responses, and his consciousness level was drowsy. Therefore, brain CT was performed immediately, and this suggested that a new, low-density area had formed in the middle cerebral artery. Several hours after the operation, 16-lead EEG was performed, and this showed no remarkable change except for the global low voltage amplitudes (Fig. 2). One day after surgery, the patient developed right hemiparesis.
(A)Discussion
(para1)During CEA surgery, the carotid artery was temporarily occluded, so that the brain was in an ischemic condition during carotid artery occlusion. During that period, the brain blood Žßow was dependent upon the opposite internal carotid and vertebral arteries. The new neurological complications which occur in 1%-2% of cases after a CEA operation are caused by the decrease in brain blood Žßow during carotid artery occlusion [1]. To prevent the occurrence of new neurological complications, certain strategies are used: (1) reduction of the carotid artery occlusion time; (2) avoidance of the reduction of brain blood Žßow by making an intracarotid bypass shunt; (3) drug therapies such as barbiturates; (4) the use of monitors for indicating brain ischemia [1,3,4].
(para2)Many monitors are used today to detect brain ischemia; examples include stump pressure, EEG, hemoglobin oxygen saturation of the internal jugular vein, and somatosensory evoked potential (SEP) [1,3,4]. The Lifescan uses aperiodic analysis, which maps each waveform in relation to its frequency, amplitude, and time of occurrence rather than averaging a large number of waveforms over a given period. The frequency is displayed on the X-axis, the amplitude of each mapped EEG wave is a vertical ŽÒpole,ŽÓ and time is displayed on the diagonal axis. The activity edge is also displayed by the line on the box in order to determine the electrical activity of EEG more easily. The activity edge is indicated as the 80% point of sum of all amplitudes from the slow wave side. The refore 80% of all amplitudes are under the activity edge, and this represents the global activity of the whole brain. For example, the event of brain ischemia or brain hypothermia induces the activity edge line to shift to the left, and a sudden decrease in the activity edge indicates that the EEG monitor has detected ischemic irregularities [2,5,6].
(para2)In this case, ischemic irregularities occurred before and during carotid artery occlusion according to the activity edge, which showed an asymmetric pattern. However, these ischemic irregularities were improved after the declamping of the carotid artery.
(para2)Stump pressure was always maintained at more than 50 mmHg during the CEA operation. The stump pressure is one criterion for determining the necessity of an intracarotid bypass shunt during carotid artery occlusion. It is advisable to make an intracarotid bypass shunt when the stump pressure is less than 50 mmHg in order to maintain brain blood Žßow [1,3,4]. In this patient, stump pressure was maintained above 50 mmHg during carotid artery occlusion. As making an intracarotid bypass shunt may induce thrombosis, we did not carry out that procedure. However, some reports have suggested that there is no relation between the brain blood Žßow and stump pressure [7]. Furthermore, an appropriate brain blood Žßow is not always maintained with a stump pressure of greater than 50 mmHg.
(para2)During the CEA operation, ETCO2 was kept within 40-45 mmHg and the systolic blood pressure was maintained at 120-150 mmHg. Nevertheless, the patient suffered cerebral infarction in the region of the middle cerebral artery. It may be that air or thrombus entered the carotid artery when it was declamped. This phenomenon was not detected using the Lifescan monitor. It has been reported that hemiparesis occurred after a CEA operation, but that the EEG, consciousness, and motor disturbance did not indicate any irregularities during the operation, which was with local anesthesia [8]. Therefore, the EEG monitor may not be capable of detecting all types of ischemic irregularities.
(para2)In conclusion, a case of hemiparesis occurred following a CEA operation where the post-CEA EEG indicated improvement in the pattern of ischemic irregularities compared with the preoperative EEG. We were unable to detect the occurrence of cerebral ischemia during CEA surgery using a Lifescan EEG monitor.
(A)References
(REF)1. Banoub M, Nugent M (1993) Concomitant cardiac and non-cardiac procedure. In: Estafanous FG, Barash PG, Reves JG (eds) Cardiac anesthesia: Principles and clinical practice. Lippincott, Philadelphia, pp 682-693
(REF)2. Kikura M, Imamura S, Ikeda K (1991) LifescanTM EEG monitor during carotid endarterectomy (in Japanese). Rinshiyou Masui (Jpn J Clin Anesth) 15:33-39
(REF)3. Moorthy SS, Markand ON, Dilley RS, McCammon RL, Warren CH (1982) Somatosensory evoked responses during carotid endarterectomy. Anesth Analg 61:879-883
(REF)4. Kearse LA, Mcpeck K (1989) Comparison between electroencephalography and somatosensory evoked potentials during carotid endarterectomy. Anesthesiology 71(3A):A393
(REF)5. Spackman TN, Faust RJ, Cucchiara RF, Sharbrough FW (1987) A comparison of aperiodic analysis of EEG with standard EEG and cerebral blood Žßow for detection of ischemia. Anesthesiology 66:229-231
(REF)6. Yoshiyama T, Chuma R, Mori M, Kiichi Y, Obara H, Takao Y (1994) Monitoring of cerebral electrical activity using aperiodic analysis during general anesthesia (in Japanese with English abstract). Rinshiyou Masui (Jpn J Clin Anesth) 18:893-898
(REF)7. Mckay RD, Sundt TM, Michenfelder JD, Gronert GA, Messick JM, Sharbrough FW, Piepgras DG (1976) Internal carotid artery stump pressure and cerebral blood Žßow during carotid endarterectomy. Anesthesiology 45:390-399
(REF)8. Grundy BL, Sanderson AC, Webster MW, Richey ET, Procopio P, Karanjia PN (1981) Hemiparesis following carotid endarterectomy: Comparison of monitoring methods. Anesthesiology 55:462-466 (MW)

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(JN)J Anesth (1996) 9:370 - 373
(PT)
(CT)A case of pulmonary arteriovenous ŽÞstula in which venous air embolism during cesarean section may have caused postoperative subendocardial infarction
(CA)Shinji Kawahito, Hiroshi Kitahata, Hideyuki Kimura, Arifumi Kohyama, and Takao Saito
(ADD)Department of Anesthesiology, Tokushima University School of Medicine, 2-50-1 Kuramoto-cho, Tokushima, 770 Japan
(KW)Key words: Cesarean section, Venous air embolism, Pulmonary arteriovenous ŽÞstula
(1)Introduction
(para1)A high incidence of venous air embolism (VAE) has been reported during cesarean section, but serious cases of this complication are comparatively few [1 - 4]. In the present report, we describe a case of pulmonary arteriovenous ŽÞstula complicated by possible postoperative subendocardial infarction due to VAE during cesarean section.
(1)Case report
(para1)The patient was a 30-year-old woman in her 38th week of pregnancy, who was 156 cm tall and weighed 58 kg. She had shown cyanosis since 6 years of age. At the age of 8, dyspnea on exertion developed, and cardiac disease was suspected. At the age of 14, she was examined by cardiac catheterization, but no abnormalities were found. No special therapy was performed. In the present pregnancy period, polycythemia [red blood
cell count (RBC) 533 3 104 ¡¦ùÍ21, hemoglobin concentration (Hb) 17.1 gáÅl21, and hematocrit (Ht) 51.6%] were observed. Although she underwent further
examinations such as computed tomography (CT), magnetic resonance imaging (MRI), radioisotope (RI)-angiography, and chest X-ray, no abnormal ŽÞndings other than hypoxemia and right aortic arch were observed. No abnormalities of hemoglobin were found either. She was diagnosed as having secondary polycythemia of unknown origin. Because of intrauterine growth retardation, cesarean section was scheduled. Upon physical examination, blood pressure was 96/66 mmHg and the pulse rate was 104 beatsáÎin21 and regular. Cyanotic lips, clubbed ŽÞngers, and pretibial edema were observed. The results of peripheral blood examination were: white blood cell (WBC) 7300 ¡¦ùÍ21, RBC 476 3 104 ¡¦ùÍ21, Hb 11.6 gáÅl21, Ht 39.3%, and platelets (Plt) 16.8 3 104 ¡¦ùÍ21. No polycythemia was observed because of dilution anemia in pregnancy. Although no abnormalities were seen in hepatic or renal function, decreases in serum cholinesterase (ChE) 0.34 Ž¢pH, plasma total protein (TP) 5.2 gáÅl21, and albumin (Alb) 3.1 gáÅl21 were observed. Pulmonary function and electrocardiogram (ECG) were normal, and only the right aortic arch was found to be abnormal by chest X-ray. The values of arterial blood gas analysis under breathing room air were: pH 7.437, partial arterial pressure of CO2 (Paco2) 25.3 mmHg, and O2 (Pao2) 56.2 mmHg, and base excess (BE) 24.5 mM. Since the data indicated hypoxemia, oxygen was supplied at 4 láÎin21 through a nasal cannula. However, Pao2 increased to only 73.2 mmHg.
(2)Anesthetic procedure
(para1)The anesthesia record is shown in Fig. 1. The patient was premedicated with atropine sulfate 0.5 mg intramuscularly 30 min prior to arrival in the operating room. The radial artery was cannulated under local anesthesia for continuous monitoring of arterial blood pressure. Pao2 in the supine position while breathing room air was 59.7 mmHg and was raised to 100.4 mmHg by oxygen inhalation at 6 láÎin21 using a mask. Anesthesia was induced with thiamylal and muscle relaxation was obtained with succinylcholine. After induction of anesthesia and tracheal intubation, a probe of transesophageal echocardiography (TEE) for child (5 MHz, UST-5234S-5, Aloka, Tokyo, Japan) was inserted into the esophagus and attached to a color Doppler imaging system (SSD-830, Aloka). Anesthesia was maintained with oxygen and sevoŽßurane, and muscle relaxation was obtained with vecuronium. After delivery of the neonate (1 min after, the Apgar score was 8 points), marked VAE, rated grade 2 by the scoring system of Rodigas et al. [5], was observed with the TEE (Fig. 2). Since air emboli were also detected in the left atrium and ventricle through the left upper pulmonary vein, the presence of a shunt in the left lung was suspected. VAE was transient and was not accompanied by hemodynamic changes. After delivery, anesthesia was maintained with fentanyl and diazepam. After operation, oxygen saturation was good with a pulse oximeter, then extubation was performed and anesthesia was concluded.
(2)Postoperative procedure
(para1)After transfer into the intensive care unit, no marked changes in the patientŽÕs general condition were observed; nevertheless she complained of chest pain the next day. Although no ST changes were detected
on the ECG, creatine kinase (CK) and isoenzyme CK-MB were increased (526 IUáÍ21 and 125 IUáÍ21, respectively). Echocardiography showed no wall motion abnormality, therefore, subendocardial infarction caused by VAE was suspected. Later, CK and CK-MB decreased gradually, and on the 4th day after operation, returned to normal levels of 121 IUáÍ21 and 15 IUáÍ21, respectively. Two weeks later, two-dimensional echocardiography was performed. When 10 ml of normal saline was rapidly injected into the left cubitus vein, contrast echo appeared in the right ventricle followed by the left atrium with a delay of 1.5 - 2.0 s. Hence, arteriovenous ŽÞstula was diagnosed. Although cyanosis
developed during physical exercise thereafter, no signiŽÞcant changes in the ECG and no symptoms such as chest pain were observed. The mother and the child were discharged without other complications.
(1)Discussion
(para1)The incidence of VAE during cesarean section is high, and a 25% incidence was observed in our study using TEE [1]. Various incidences from 11% to 65% have been reported elsewhere [2,3], and a high incidence of 97% has been observed by monitoring the expired nitrogen concentration [4]. Generally, VAE is slight and its effects on respiration and circulation are limited. However, hypoxemia [3,6] or hemodynamic changes could be induced at times, and serious complications such as cardiac arrest have been reported [7]. The risk is especially high in patients with a right-to-left shunt as in the present case [8]. In the present patient, subendocardial infarction seems to have been caused by air emboli. It has been reported that no statistical difference related to the type of anesthesia existed in the incidence of VAE [2], but in this case we selected general anes-
thesia suitable for the inhalation of oxygen with a high concentration.
(para2)Arteriovenous ŽÞstula is a relatively rare disease, and shows no abnormalities in routine examinations for cardiac or respiratory function and, therefore, can easily be overlooked. Although pulmonary angiography is usually required for a deŽÞnite diagnosis, the recent development of contrast echocardiography makes it possible to diagnose deŽÞnitively. In comparison with the conventional M-mode contrast echocardiography [9], two-
dimensional contrast echocardiography can achieve more accurate diagnosis and is useful for postoperative follow-up examinations [10]. The present case is a very rare one in which intraoperative diagnosis was made by TEE. Our results indicate the usefulness of TEE monitoring during operation.
(para2)It has been reported that about 50% of arteriovenous ŽÞstula cases are complicated with Rendu-Osler-Weber disease [11]. This disease, a so-called hereditary hemorrhagic telangiectasis (HHT), is attributed to a dominant gene located on a autosome. A characteristic of this disease is thinning of the skin, conjunctiva, and ŽÞne veins and capillaries in various organs. Since only the endothelium is found in the affected regions, hemorrhage occurs easily by an even weak external force [12]. In Japan, 141 family lines of this disease have been reported [13]. Although no hemorrhagic tendency was observed in the present patient, her sister showed similar symptoms suggesting an intra-family disease. Consequently, it is possible that she is suffering from Rendu-Osler-Weber disease.
(para2)In summary, we reported a case of arteriovenous ŽÞstula complicated with possible postoperative subendocardial infarction caused by VAE during cesarean section. For patients with a right-to-left shunt, prevention and early diagnosis of VAE during operation are of great importance. TEE was useful in the detection of VAE during cesarean section and the diagnosis of pulmonary arteriovenous ŽÞstula.
(1)References
(REF)1. Kawahito S, Kitahata H, Kimura H, Kohyama A, Saito T (1995) Hypoxemia during cesarean sectionŽÑEvaluation of venous air embolism by transesophageal echocardiography (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 44:10 - 14
(REF)2. Fong J, Gadalla F, Pierri MK, Druzin M (1990) Are Doppler-detected venous emboli during cesarean section air emboli? Anesth Analg 71:254 - 257
(REF)3. Vartikar JV, Johnson MD, Datta S (1989) Precordial Doppler monitoring and pulse oximetry during cesarean delivery: detection of venous air embolism. Reg Anesth 14:145 - 148
(REF)4. Lew TWK, Tay DHB, Thomas E (1993) Venous air embolism during cesarean section: more common than previously thought. Anesth Analg 77:448 - 452
(REF)5. Rodigas PC, Meyer FJ, Haasler GB, Dubroff JM, Spotnitz HM (1982) Intraoperative 2-dimensional echocardiography: ejection of microbubbles from the left ventricle after cardiac surgery. Am J Cardiol 50:1130 - 1132
(REF)6. Kawahito S, Kitahata H, Yasumoto S, Tomiyama Y, Kohyama A, Saito T (1994) Severe hypoxemia during cesarean section (in Japanese with English abstract). Masui (Jpn J Anesthesiol) 43:927 - 930
(REF)7. Younker D, Rodriguez V, Kavanagh J (1986) Massive air embolism during cesarean section. Anesthesiology 65:77 - 79
(REF)8. Cucchiara RF, Seward JB, Nishimura RA, Nugent M, Faust RJ (1985) IdentiŽÞcation of patent foramen ovale during sitting position craniotomy by transesophageal echocardiography with positive airway pressure. Anesthesiology 63:107 - 109
(REF)9. Meltzer RS, Vered Z, Roelandt J, Neufeld HN (1983) Systematic analysis of contrast echocardiograms. Am J Cardiol 52:375 - 380
(REF)10. Barzilai B, Waggoner AD, Spessert C, Picus D, Goodenberger D (1991) Two-dimensional contrast echocardiography in the detection and follow-up of congenital pulmonary arteriovenous malformations. Am J Cardiol 68:1507 - 1510
(REF)11. Dines DE, Seward JB, Bernatz PE (1983) Pulmonary arteriovenous ŽÞstulas. Mayo Clin Proc 58:176 - 181
(REF)12. Osler W (1901) On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes. Bull Johns Hopkins Hosp 12:333 - 337
(REF)13. Maruyama J, Watanabe M, Onodera S, Hasebe N, Yamashita H, Tobise K (1989) A case of Rendu-Osler-Weber disease with cerebral hemangioma, multiple pulmonary arteriovenous ŽÞstulas and hepatic arteriovenous ŽÞstula. Jpn J Med 28:651 - 656 (MW)

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(JN)J Anesth (1996) 9:374 - 375
(PT)
(CT)A successful case in cancer pain management with high-dose intravenous morphine
(CA)Teruhiko Ishikawa and Kazuaki Hiraga
(ADD)Department of Anesthesiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104 Japan
(KW)Key words: Cancer pain management, High-dose morphine, PCA
(A)Introduction
(para1)Patients with cancer pain sometimes experience so-called crescendo pain which escalates in intensity within short periods of time. Physicians who are not very familiar with morphine treatment may hesitate in such cases to increase the dose, probably because of a ŽÞrm opposition to ŽÒmorphinism.ŽÓ
(para2)We present a case in which a high dose of intravenous morphine (300 mg/h) was necessary to control severe cancer pain. In this case, rapid increase and high-dose morphine resulted in adequate pain relief without undesirable side effects such as addiction, respiratory depression, or a higher tolerance for morphine.
(A)Case report
(para1)A 36-year-old woman with recurrent rectal cancer was referred to our clinic for uncontrollable severe pain in her left femoral region. Previous palliative treatment such as radiotherapy and oral morphine (240 mg/day) could not achieve sufŽÞcient pain relief. Evaluation of the pain revealed a vertebral metastasis. A trial of morphine infusion (200 mg/day) resulted only in nausea and drowsiness, but epidural morphine (150-200 mg/day) in combination with lidocaine (90-120 mg/day) by the patient controlled analgesia (PCA) system achieved good control without the major side effects related to narcotics use. Two months later, tumor invasion to the epidural space made epidural injection impossible. We therefore changed from epidural morphine to 500 mg/day i.v. morphine (bolus and background infusion by the PCA system) in combination with intravenous dexamethasone (0.5 mg/day), oral imipramine (50 mg/day) and carbamazepine (200 mg/day). However, the pain increased abruptly, which might be attributed to involvement of the spinal cord or roots by the tumor, so that the dose of morphine had to be increased rapidly to 300 mg/h, with which adequate pain relief was ŽÞnally achieved. Within a week, her requests for analgesics declined dramatically, and the dose of morphine was tapered off gradually. She reported that numbness had replaced her pain, and paralysis was also clinically observed in her legs. Three weeks after the peak running dose, pain management was carried out satisfactorily with continuous infusion of morphine 200-300 mg/day. During the course of tapering off the dosage, she showed no withdrawal symptoms such as perspiration, tachypnea, or loss of pain control.
(A)Discussion
(para1)Despite the wide acceptance of WHO methods for cancer pain relief [1,2], the pharmacological properties of morphine do not seem to be sufŽÞciently understood. According to a report, only 13.8% of physicians who responded to a questionnaire would have clearly informed their patients of the fact that they were receiving morphine, and the rate of complete pain relief remained at less than 40% [1]. It is also worth noting that the amount of morphine consumed per capita in Japan is still less than one-ŽÞfth of that consumed in the United States and Great Britain [2]. These ŽÞndings imply that many doctors tend to correlate morphine use with narcotic abuse. They relate increasing morphine doses to a higher tolerance and a consequent dependence on the drug.
(para2)In these circumstances, Hayashi et al. reported two cases of high-dose morphine administered orally. They positively titrated the dose to the patientsŽÕ pain
intensities and ŽÞnally adequate pain relief was achieved by the administration of more than 5000 mg/day of morphine [3]. Since they did not measure the serum or cerebrospinal Žßuid concentration of morphine, the optimal doses could be smaller than 5000 mg/day. Oral administration did not always conŽÞrm the minimum dosage necessary for the patients, especially in cases of digestive cancer due to malabsorption. Hashimoto et al., on the other hand, reported two cases of continuous intravenous infusion of high-dose morphine [4]. They suggested that the third step of the WHO analgesic ladder had been mostly inadequate for their terminal cancer patients and recommended continuous infusion of morphine, though the doses they used were still
only 12 mg/h and 20 mg/h, which were far smaller than ours.
(para2)In our case, a high dose of morphine was necessary to obtain adequate pain relief. Two reasons for our employing high-dose morphine are suggested: (1) severe neuropathic pain caused by tumor involvement, and (2) the possibility of a lower serum concentration of morphine than would be expected considering the high dose.
(para2)In general, the compression of the spinal cord or roots can cause severe pain, and this pain tends to increase rapidly. Anticonvulsants, antidepressants, and corticosteroids are usually recommended as adjuvant drugs of analgesics [5]. Despite administering all of the above drugs to the patient, we could not achieve adequate pain relief in our case without increasing the morphine dose. Systemic administration of local anesthetics has been reported to provide an analgesic effect on neuropathic pain [6], so it may be possibile to reduce the dose with intravenous lidocaine.
(para2)When an opioid is administered intravenously, the serum concentration of the drug is predictable to a certain extent. It has been reported, however, that a patient with chronic cancer pain requiring high-dose intravenous hydromorphone exhibited a far lower serum concentration than anticipated [7]. The etiology of these confusing results can still only be speculative; an accumulation of morphine in the abdominal or pleural effusion, or interstitial edema could account for the low serum concentration [8]. Though we did not measure the morphine serum concentration in our case,
there was no clinical evidence of abdominal or pleural effusion, except mild edema observed in the lower limbs.
(para2)Also a morphine metabolite, morphine-3-glucuronide (M3G) has been shown to be an antagonist of the opiate receptor for both morphine and morphine-6-glucuronide (M6G) [9,10]. Therefore, the overall analgesic effect may be inŽßuenced not only by the serum or CSF concentration of morphine but by the ratio of M3G to M6G [11]. The reason for the high morphine dose in our case may be speculative, however, since no concentrations of analgesics were measured.
(para2)Tolerance could also be a factor in the high-dose morphine. Arn»Ó et al. reported that the development of tolerance was considered a signiŽÞcant problem in spinal morphine treatment for cancer pain [12]. In
our case, however, tolerance did not seem important
because a small supplemental rescue dose proved to
be effective and the dose was tapered without any
problems.
(para2)In summary, we successfully managed a patient with severe cancer pain with an initially high morphine dose and a subsequent reduction of this dose without any undesirable side effects.
(A)References
(REF) 1. Hiraga K, Mizuguchi T, Takeda F (1991) The incidence of cancer pain and improvement of pain management in Japan. Postgrad Med J 67[Suppl 2]:S14-S25
(REF) 2. Takeda F (1993) Japan: Status of Cancer Pain and Palliative Care. J Pain Symptom Manage 8:425-426
(REF) 3. Hayashi A, Tsuneto S, Yamamoto K, Kashiwagi T (1990) High dose morphine for cancer pain treatment: two cases needed more than 5000 g/day morphine (in Japanese). Chiryogaku 24:984-986
(REF) 4. Hashimoto Y, Takarada M, Tanioka H, Rigor BM (1990) Treatment of cancer pain of the head and neck by continuous intravenous infusion of high-dose morphine: report of two cases. J Oral Maxillofac Surg 48:398-400
(REF) 5. World Health Organization (WHO) (1986) Cancer Pain Relief. WHO, Geneva
(REF) 6. Brose WG, Cousins MJ (1991) Subcutaneous lidocaine for treatment of neuropathic cancer pain. Pain 45:145-148
(REF) 7. Hays H, Mayo P (1993) A single case study using high-dose hydromorphone to control severe pain and serial psychometric testing to assess effects. J Pain Symptom Manage 8:173-176
(REF) 8. Yokokawa N, Hiraga K, Oguma T, Konishi M (1991) Relationship between plasma concentration of morphine and analgesic effectiveness. Postgrad Med J 67[Suppl 2]:S50-S54
(REF) 9. Smith MT, Watt JA, Crammond T (1990) Morphine-3-glucuronideŽÑa potent antagonist of morphine analgesia. Life Sci 47:579-585
(REF)10. Gong QL, Hedner J, Bjorkman R, Hedner T (1992) Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide
induced antinociception and ventilatory depression. Pain 48:
249-255
(REF)11. Bowsher D (1993) Paradoxical Pain. When metabolites of morphine are in the wrong ratio. Br Med J 306:473-474
(REF)12. Arn»Ó S, Rawal N, Gustafsson L (1988) Clinical experience of long-term treatment with epidural and intrathecal opioidsŽÑa
nationwide survey. Acta Anaesthesiol Scand 32:253-259 (MW)

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(JN)J Anesth (1996) 9:376 - 379
(PT)
(CT)Anesthetic management for an infant with mitochondrial cytopathy
(CA)Yasuyo Maegawa, Hiromi Nakagawa, Toyoshi Hosokawa and Yoshifumi Tanaka
(ADD)Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto, 602 Japan
(KW)Key words: Mitochondrial cytopathy, Anesthetic management
(A)Introduction
(para1)Mitochondrial cytopathy [1] is a rare congenital disorder characterized by progressive multiple-organ dysfunction due to impaired production and conversion of adenosine triphosphate (ATP) in mitochondria. The main target organs are the muscle and encephalon which characteristically require a large amount of energy. The heart, liver, and pancreas are sometimes
involved.
(para2)Although the clinical features of this disease are well described in the literature of pediatrics and general medicines, there are few reports about the management of anesthesia in patients with mitochondrial cytopathy. We report a case of general anesthesia for a 5-month-old infant with convulsion, difŽÞculty in breathing, and uncontrollable diabetes resulting from severe mitochondrial cytopathy who underwent tracheotomy, and we discuss the problems of the anesthetic management for mitochondrial cytopathy.
(A)Case report
(para1)A 5-month-old male Japanese infant was admitted to our hospital for failure to thrive. He had been normal at birth and his family history was noncontributory. On admission, he had stopped breathing and required controlled mechanical ventilation. He exhibited convulsions, increased deep tendon reŽßexes, and solid edema in all limbs. Biochemical testing revealed diabetes [blood sugar 277 mg ¡¦dl21, HbA1c 4.1% (normal range: 3.8%-5.3%), HbA1 8.1% (normal range: 5.3%-7.1%), insulin 1.5 ù¶ ¡¦ml21 (normal range: 5-12 ù¶ ¡¦ml21)], hyperlactemia 21.7 mg ¡¦dl21 (normal range: 4-16 mg ¡¦ dl21) and hyperpyruvemia 1.9 mg ¡¦dl21 (normal range: 0.3-0.9 mg ¡¦dl21) and increased urinary excretion of 2-OH-n-butyrate, fumarate, and 2-ketoglutalate. The latter are intermediates of the tricarboxylic acid (TCA) cycle which are not normally observed in the urine. An electroencephalograph showed multiple focal spikes. Computed tomography (CT) revealed atrophy of the frontal lobe. Mitochondrial encephalomyopathy was diagnosed. He was administered the following medications: for convulsions, phenobarbital 40 mg ¡¦day21,
sodium valproate 140 mg ¡¦day21, and carbamazepine 10 mg ¡¦day21; for diuresis, furosemide 4 mg ¡¦day21; and for hyperglycemia 0.08 U ¡¦kg21 ¡¦h21 of insulin by continuous subcutaneous infusion. Although chest X-rays showed small granulomatous shadows in both lung ŽÞelds due to prolonged administration of controlled mechanical ventilation, the blood gases were well controlled: pH 7.42, partial arterial pressure of CO2 (Paco2) 36 mmHg, and O2 (Pao2) 134 mmHg and base excess (BE) 20.1 at an inspired oxygen fraction (Fio2) 0.35. At the age of 5 months he weighed 7.1 kg and was 72 cm tall. Tracheotomy was scheduled for prolonged controlled ventilation under general anesthesia.
(para2)No premedication was given. The infant was too small to monitor the level of neuromuscular blockade. Anesthesia was induced with diazepam 1 mg, fentanyl 30 ùÈ, and vecuronium 1 mg was administered for
immobilization. However, muscle relaxation was not
sufŽÞcient and a total dose of 2.2 mg (0.3 mg ¡¦kg21) vecuronium was necessary for complete paralysis.
Anesthesia was maintained with fentanyl using air
and oxygen. As Žßuid management, we administered 95 ml of Solita T1 (Shimizu pharmacy corporation,
Japan) (Na 90, Cl 70, lactate 20 mEq ¡¦l21 and glucose 26 g ¡¦l21). He developed hyperkalemia (6.1 mEq ¡¦l21) intraoperatively due to the suspension of insulin infusion and furosemide. The potassium level decreased to 5.2 mEq ¡¦l21 following the induction of diuresis by furosemide 0.5 mg. The anesthetic time was 140 min, blood loss was 2 g, and urine volume was 38 ml. All cardiovascular, respiratory, and temperature measurements stayed within the normal ranges, and no metabolic acidosis occurred perioperatively.
(A)Discussion
(para1)Mitochondrial myopathy is a group of disorders with
a variable clinical picture and an underlying mitochondrial metabolic defect due to mutation of mitochondrial genes. Although mitochondrial myopathy had ever been classiŽÞed as Kearns-Sayre syndrome (KSS), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and
so on according to clinical symptoms, it has been classiŽÞed into ŽÞve categories according to deŽÞciency of enzymes [2,3] (Table 1). Our patient was diagnosed
with acute encephalomyopathic type in complex IV
deŽÞciency, which is characterized as remarkable brain atrophy, muscle weakness, and multisystem involvement. Such patients present several challenges to
anesthesiologists.
(para2)DŽÕAmbra et al. ŽÞrst referred to the anesthetic management of patients with mitochondrial cytopathy in 1979 [4]. Since then, several additional cases have been reported [5-13] (Table 2). Although these reports mention various types of mitochondrial cytopathies, metabolic disorder and myopathy are common anesthetic problem in all types of this disease.
(para2)Metabolic disorders such as hyperlactemia or hyperpyruvemia due to a greater oxygen demand than supply in peripheral tissue lead to metabolic acidosis [7,9,11]. To avoid metabolic acidosis, the anesthetic level, ventilation, heart rate and blood pressure (cardiac output), Sao2, and hemoglobin level should be monitored and enough oxygen delivery should be maintained [8-11]. Go et al. reported intraoperative metabolic acidosis induced by hyperlactemia due to depression of lactate resolution in spite of good oxygen delivery [7]. Therefore, it might be better to avoid large amounts of lactated RingerŽÕs infusion in cases with mitochondrial cytopathies, though no metabolic disorder was recognized in our case.
(para2)Myopathy is a second common anesthetic problem. Patients with mitochondrial cytopathy have an increased susceptibility to malignant hyperthermia (MH) [14]. One child with mitochondrial myopathy developed signs of MH after the induction of general anesthesia [5]. As the relationship between MH and this disorder has not been clariŽÞed, it is wise to select neuroleptanesthesia and nondepolarizing muscle relaxants to avoid MH [14].
(para2)In patients with mitochondrial myopathy, muscle relaxants should be used cautiously because of muscle weakness. Although DŽÕAmbra et al. [4] reported that responses to depolarizing and nondepolarizing muscle relaxants were normal in cases of Kearns-Sayre syndrome, it is preferable to avoid them [8-10]. If these agents are required during surgery, a minimal dose of a nondepolarizing muscle relaxant should be administered under careful monitoring of neuromuscular blockade, especially in patients with severe muscle weakness, as seen in our case [6,7,10]. However, a large dose of vecuronium (0.3 mg ¡¦kg21) was ultimately required to induce muscle relaxation in the present case compared with the dose used for intubating a healthy man:
0.07-0.1 mg ¡¦kg21 [15]. Since any drug that can inŽßu-ence the central nervous system can also inŽßuence the neuromuscular junctions, anticonvulsants given as preoperative medication might modify the neuromuscular blockade. Phenytoin produces resistance to neuromuscular blocking drugs by antagonizing acetylcholine at the prejunctional receptors [16]. Pancuronium and carbamazepine compete for the same site at the neuromuscular junction [17]. The numerous anticonvulsants administered to this patient might make him resistant to the competitive neuromuscular blockers. Since patients with mitochondrial cytopathies often receive anticonvulsants, the possibility of the development of resistance to neuromuscular blockade must be kept in mind.
(para2)Cardiomyopathy is another possible lethal complication of this disease [12,18]. Although no cardiac event occurred in the present case, the heart must
be carefully monitored perioperatively, and temporary pacing might be necessary in the event of a sudden A-V block.
(para2)Diabetes mellitus is commonly accompanied by
mitochondrial cytopathy and is sometimes uncontrollable for insufŽÞcient insulin secretion as seen in our case [19]. Hypoglycemia induces lipolysis and hyperglycemia induces activation of phosphofructokinase leading to hyperlactemia due to increased glycolysis. Although blood sugar was maintained at a normal level in our case, hyperkalemia was observed, which might be a
rebound reaction to the infusion of the insulin suspension. Control of blood sugar and electrolytes was
essential for the perioperative management of this
disease.
(para2)In conclusion, prevention of metabolic acidosis,
control of blood sugar and electrolytes, monitoring
for the possibility of MH, cardiac failure due to cardiomyopathy, and administration of adequate
doses of muscle relaxants are the major considera-
tions for anesthesia in patients with mitochondrial
cytopathy.
(A)References
(REF) 1. Egger J, Lake BD, Wilson J (1981) Mitochondrial cytopathy. A multisystem disorder with ragged red ŽÞbers on muscle biopsy. Arch Dis Child 56:741-751
(REF) 2. Rowland LP (1983) Molecular genetics and clinical neurology. Neurology 33:1179-1191
(REF) 3. Dimauro S, Bonilla E, Zeviani M, Servidei S, DeVivo DC, Schon EA (1987) Mitochondrial encephalomyopathies. J Inher Metab Dis 10:113-128
(REF) 4. DŽÕAmbra MN, Debrick D, Savarese JJ (1979) Kearns-Sayre syndrome and pancuronium-succinylcholine-induced neuromuscular blockade. Anesthesiology 51:343-345
(REF) 5. Ohtani Y, Miike T, Ishitsu T, Matuda I, Tamari H (1985) A case of malignant hyperthermia with mitochondrial dysfunction. Brain Dev 7:249
(REF) 6. Nogata S, Morooka H, Kawahara K, Ariyoshi S, Haseba J, Gotou H (1986) Anesthesia for a patient with Kearns-Sayre syndrome (in Japanese with English abstract). Nippon Rinshou Masui Gakkaishi (J Jpn Soc Clin Anesth) 6:69-72
(REF) 7. Go R, Sakata M, Kato M, Arase T, Saitou T (1987) Anesthetic management of mitochondrial encephalomyopathy (in Japanese). Rinshou Masui (J Clin Anesth) 11:57-61
(REF) 8. Kameumi A, Komura Y, Mishima S (1987) Anesthetic management of mitochondrial myopathy (in Japanese). Rinshou Masui
(J Clin Anesth) 11:1377-1378
(REF) 9. Shimizu H, Suzuki H, Fujita M, Kitano S, Hayashi K, Fukayama Y (1988) Anesthetic management of a child with mitochondrial encephalomyopathy (in Japanese). Tokyo Jyoshi Ika Daigaku Zasshi (J Tokyo WomenŽÕs Med Coll) 58:1132-1134
(REF)10. Burns AM, Shelly MP (1989) Anaesthesia for patients with mitochondrial myopathy. Anaesthesia 44:975-977
(REF)11. Moritsune O, Horibe M, In-nami H, Okada K, Ochiai S, Gotou S (1992) Anesthetic management of mitochondrial encephalomyopathy (in Japanese with English abstract). Nippon Rinshou Masui Gakkaishi (J Jpn Soc Clin Anesth) 12:83-87
(REF)12. Klockgether-Radke A, Henze T, Braun U, Kettler D (1993) Anesthesia in two patients with mitochondrial myopathy. Anaesthesist 42:111-114
(REF)13. Breucking E, Mortier W, Lampert R, Brandt L (1993) Anaesthesia and intensive care for a patient with mitochondrial myopathy and a general condition similar to that seen with malignant hyperthermia. Anaesthesist 42:719-723
(REF)14. Figarella Branger D, Kozak Ribbens G, Rodet L, Aubert M, Borsarelli J, Cozzone PJ, Pellissier JF (1993) Pathological ŽÞndings in 165 patients explored for malignant hyperthermia susceptibility. Neuromuscul Disord 3:553-556
(REF)15. Miller RD, Savarese JJ (1990) Pharmacology of muscle relaxants and their antagonists. In: Miller RD (ed) Anesthesia. Churchill Livingstone New York, pp 389-435
(REF)16. Ornstein E, Matteo RS, Schwartz AE, Silverberg PA, Young WL (1987) The effects of phenytoin on the magnitude and duration of neuromuscular block following atracurium or vecuronium. Anesthesiology 67:191-196
(REF)17. Roth S, Ebrahim ZY (1987) Resistance to pancuronium in
patients receiving carbamazepine. Anesthesiology 66:691-
693
(REF)18. Anan R (1991) Cardiac involvement in mitochondrial disease: a clinical study of 38 patients (in Japanese with English abstract). Igaku Kenkyu (Acta Medica) 61:49-59
(REF)19. Piccolo G, Aschei M, Ricordi A, BanŽÞ P, Curto FL, Fratino P (1989) Normal insulin receptors in mitochondrial myopathies with ophthalmoplegia. J Neurol Sci 94:163-172 (MW)

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(JN)J Anesth (1996) 9:380 - 382
(PT)
(CT)Extracorporeal membrane oxygenation and tracheobronchial foreign body in an infant
(CA)Yoshimi Inagaki1, Toshiko Hamanaka2, Makoto Takenoshita1, Takashi Mashimo1, and Ikuto Yoshiya1
(ADD)1 Department of Anesthesiology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, 565 Japan
(ADD)2 Department of Anesthesia, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565 Japan
(KW)Key words: Tracheobronchial foreign body, Extracorporeal membrane oxygenation, Infant
(A)Introduction
(para1)Inadvertent aspiration of foreign bodies into the tracheobronchial region occurs most often in children
between 1 and 3 years old [1,2]. In the anesthetic
management of removal of a tracheobronchial foreign body, difŽÞculty arises when the ventilation route coexists with the surgical ŽÞeld in the narrow lumen of
the tracheobronchial tree. It is most important to choose a ventilation technique which does not disturb the surgical procedure, because lethal asphyxia may occur if the foreign body occludes the trachea or main bronchus.
(para2)We report the successful use of extracorporeal membrane oxygenation (ECMO) for the removal of a
tracheal foreign body which led to severe hypoxia.
(A)Case report
(para1)A 1-year-old boy, weighing 10.1 kg, who had sudden but temporary cyanosis and weak respiratory sound of the right lung for 3 days, was transferred to the Department of Otolaryngology at our university hospital under the diagnosis of obstruction of the right main bronchus. On arrival, he was not cyanotic but the respiratory sound of the right lung ŽÞeld was not audible at all. A plain chest X-ray revealed slight inŽßammatory changes in the right lower lung ŽÞeld and the rightward deviation of the
mediastinum at the inspiratory phase. No pulmonary atelectasis was detected. Computed tomography showed no sign of foreign bodies in the right main
bronchus. Arterial blood gas analysis under room air was pH 7.395, partial arterial pressure of CO2 (Paco2) 35.3 mmHg, and O2 (Pao2) 86.5 mmHg, and arterial oxygen saturation (Sao2) 96.3%. Routine laboratory tests, including blood chemistry and blood cell counts were within normal limits.
(para2)An emergency bronchoŽÞberscopic examination to detect a foreign body was performed. Atropine sulfate (0.2mg) was intravenously injected as an anesthetic premedication. The patient was anesthetized with an intravenous injection of 2 mg ¡¦kg21 of sodium thiamylal. Then we assisted respiration with manual ventilation via an anesthetic mask. Thereafter, he was intubated with an endotracheal tube 4.5 mm inside diameter (i.d.) with the aid of additional thiamylal (2 mg ¡¦kg21) intravenously and vecuronium bromide (0.15 mg ¡¦kg21)
intravenously. Electrocardiography (ECG) was carried out and pulse oximetry peripheral oxygen saturation, (Spo2), end-expiratory carbon dioxide tension (PETCO2), osillometric blood pressure, and respiratory sounds of the left lung were monitored, the latter by a precordial stethoscope. Spo2 before anesthetic induction was 92% (room air). Anesthesia was maintained with 1%-2% sevoŽßurane in oxygen, and the lungs were ventilated manually to keep Spo2 between 97% and 100% and PETCO2 between 35 and 45 mmHg.
(para2)The bronchoŽÞberscopic examination disclosed a foreign body, a plastic cap, in the right main bronchus. The endotracheal tube was replaced with a rigid type ventilating bronchoscope (VBS) with a side port for ventilation. The patient was ventilated manually and Spo2 was maintained at 98% or more. An attempt was made to remove the foreign body using an alligator forceps through the VBS, but the foreign body was too big to pass the vocal cords, and fell out of the forceps. Suddenly, manual ventilation became impossible and PETCO2 was no longer detectable. We immediately removed the VBS, discontinued sevoŽßurane, and ventilated manually via an anesthetic mask with pure oxygen. Spo2 decreased to less than 30% and the heart rate (HR) decreased from 150 beats per minute (bpm) to 50 bpm.
We intubated the trachea with an endotracheal tube 4.5 mm i.d. but the foreign body seemed to completely obstruct the trachea. We then pushed the foreign body further down the trachea by means of the endotracheal tube with a stylet. Ventilation suddenly became easy. Spo2 returned to 99%, and HR increased to 130 bpm. However, there was alternating diminution of the breath sound on either side of the lung ŽÞeld. The foreign body was found riding on the bifurcation of the trachea by bronchoŽÞberscopic examination. Tracheostomy was proposed but was rejected because of the possibility of difŽÞcult airway management.
(para2)We therefore decided to use ECMO to make removal of the foreign body easier while maintaining adequate oxygenation and ventilation. Informed consent was obtained from the parents prior to ECMO. The equipment for ECMO consisted of an oxygenator (MENOX EL-2000: membrane area 5 0.4 m2, Kuraray, Kurashiki,
Japan), a centrifugal pump (HCV-11, Nikiso, Tokyo, Japan), and an ECMO circuit for children (Kuraray). The ECMO circuit was primed with 250 ml of lactated RingerŽÕs solution containing 500 IU of heparin. After 100 IU ¡¦kg21 of heparin was injected as a bolus, a 14 Fr catheter was inserted via the right internal jugular vein into the right atrium and a 12 Fr catheter was inserted into the right common carotid artery through the Gortex graft. Anesthesia was maintained with 0.5% sevoŽßurane in air and fentanyl (5 ùÈ ¡¦kg21). Activated clotting time (ACT) was monitored for control of blood coagulation. We started ECMO and maintained the centrifugal pump at 3900 rpm to obtain an output of 1-1.2 l ¡¦min21 with a constant Žßow of oxygen at 1 l ¡¦min21 (inspired oxygen fraction; Fio2 5 0.5). During ECMO, the patientŽÕs hemodynamics were stable and Spo2 was kept at 99% or more. ACT was maintained at over 200 s. When stable ECMO Žßow was obtained, arterial blood gas analysis was as follows: pH 7.49, PaCO2 33.0 mmHg, PaO2 204 mmHg, SaO2 99.3%. Thereafter, we discontinued ventilation, and removal of the foreign body using the VBS was restarted. The foreign body, a plastic cap 6 mm in diameter and 6 mm in length, was successfully removed from the trachea using alligator forceps. The duration of ECMO was 39 min.
(para2)Postoperative bronchoŽÞberscope and chest X-ray ŽÞlm revealed no abnormal ŽÞndings. The patient was extubated 18 h after the operation and left the hospital
2 days later without sequela.
(A)Discussion
(para1)In the anesthetic management of the removal of tracheobronchial foreign bodies in infants or children, it is most important to prevent hypoxia due to inadequate ventilation. Although the VBS has improved the safety of the operation [2], other methods should be considered in the event of insufŽÞcient ventilation through the side port of the VBS. These include high-frequency
jet ventilation (HFJV) through the VBS [3] or the bronchoŽÞberscope [4]. However, HFJV is as ineffective as VBS in case of complete tracheal occlusion. In the current situation, it was essential to push the foreign body into one of the main bronchi using an endotracheal tube with a stylet.
(para2)In the present case, we rapidly induced anesthesia with thiamylal and then conŽÞrmed the ability to
manually ventilate because we believed that the foreign body was located in the right main bronchus from
radiographic ŽÞndings. The slow induction of anesthesia with inhalation anesthetics is generally used for the
removal of a tracheobronchial foreign body in the case of sudden obtruction of the airway by the foreign
body.
(para2)When the foreign body could not be removed during the ŽÞrst trial, we had four options: (1) use a Fogarty catheter, (2) tracheostomy, (3) open chest surgery and (4) ECMO. First, the use of a Forgarty catheter and tracheostomy were proposed but were rejected because of difŽÞcult airway management during the surgical procedure including critical sudden airway obstruction in our ŽÞrst attempt. Furthermore, we were not sure whether the foreign body could pass the tracheostomy stoma and we were concerned about postoperative tracheal stenosis in the infant. Second, open chest surgery is much more invasive than ECMO and would require more difŽÞcult respiratory management during anesthesia due to bronchostomy at the level of the main bronchi, including one-lung ventilation with or without HFJV. We, therefore, did not employ open chest
surgery.
(para2)The use of ECMO in children has become popular recently because of improved safety and availability [5]. On the other hand, there are several physiologic complications in the use of ECMO. Of these complications, hemorrhage occurs most frequently (36%): intracranial hemorrhage (17%), surgical site (14%), and gastrointestinal hemorrhage (5%). The incidence of neurological complication is 27%: severe neuroimpairment (3%), seizures (20%), and others (4%), while that of pulmonary complications including pulmonary artery embolism by thrombus or air are less than 5% [6]. By utilizing ECMO, we could separate the ventilating route from the surgical ŽÞeld, thereby allowing sufŽÞcient time for removal of the foreign body. For removal of fragile foreign bodies such as a swollen peanut, the time for the procedure is an important consideration. To facilitate respiratory management during surgical procedure and to prevent life-threatening hypoxia, we decided to use ECMO after we had explained to his parents the incidence of physiologic complications in the use of ECMO, his life-threatening hypoxic situation, and other options and obtained their informed consent. We have recognized that using ECMO for a healthy patient who may be put in a life-threatening situation is acceptable, as well as use for a patient suffering from severe respiratory failure.
(para2)In summary, we experienced a life-threatening hypoxic event during bronchoscopic removal of a foreign body in the trachea in a 1-year-old infant. The patient was successfully treated by clearing the occluded airway by pushing the foreign body down into a main bronchus followed by bronchoscopic removal under ECMO. ECMO may become a useful methods for tracheobronchial foreign body removal at hospitals that are accustomed to dealing with ECMO.
(A)References
(REF)1. Weissberg D, Schwartz I (1987) Foreign bodies in the tracheobronchial tree. Chest 91:730-733
(REF)2. McGuirt WF, Holmes KD, Feehs R, Browne JD (1988) Tracheo bronchial foreign bodies. Laryngoscope 98:615-618
(REF)3. Lee ST (1973) A ventilating bronchoscope for inhalation anesthesia and augmented ventilation. Anesth Analg 52:89-93
(REF)4. Satyanarayana T, Capan L, Ramanathan S, Chalon J, Turndorf H (1980) BronchoŽÞberscopic jet ventilation. Anesth Analg 59:350-354
(REF)5. Trento A, Thompson A, Siewers RD, Orr RA, Kochanek P, Fuhrman B, Frattallone J, Beerman LB, Fischer DR, GrifŽÞth BP, Hardesty RL (1988) Extracorporeal membrane oxygenation in children. New trends. J Thorac Cardiovasc Surg 96:542-547
(REF)6. Toomasian JM, Snedecor SM, Cornell RG, Cilley RE, Bartlett RH (1988) National experience with extracorporeal membrane oxygenation for newborn respiratory failure. Data from 715 cases. Trans Am Artif Intern Organs 34:140-147 (MW)

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(JN)J Anesth (1996) 9:383 - 384
(PT)Short communication
(CT)The effects of graduated compression stocking on blood pressure and heart rate during spinal or epidural anesthesia
(CA)Hiroshi Iwama
(ADD)Department of Anesthesiology, Central Aizu General Hospital, 1-1 Tsuruga-machi, Aizuwakamatsu, Fukushima, 965 Japan
(KW)Key words: Graduated compression stocking, Spinal anesthesia, Epidural anesthesia
(para1)Hypotension occurring during spinal or epidural
anesthesia is commonly treated by Žßuid loading, adminstration of vasopressor agents, or compression bandaging after elevation of the legs. However, these methods are potentially harmful. Thigh-length graduated compression stockings (TED stocking, Kendall, London, UK) ŽÞtted on both legs, and correctly measured, increase the femoral vein blood Žßow velocity to 138.4% of the base line, and thereby prevent deep venous thrombosis [1]. This study was designed to ŽÞnd out if a simpler method using the present stock-
ing would be prophylactic for spinal or epidural hypotension.
(para2)Eighty adult patients from elective surgery (Table 1) (except cesarean section) under spinal (n 5 40) or epidural (n 5 40) anesthesia were randomly divided into a TED(1) group (TED stockings of thigh length on both legs) and a TED(2) group (no ŽÞtting) after informed consent had been obtained. Spinal anesthesia was performed by injecting 0.3% dibucaine 2.0 ml in the 4th-5th lumbar interspace in the lateral position, immediately followed by the supine position. Epidural anesthesia was performed by injecting 2% mepivacaine 0.2 mláÌg21 in the supine position through an 18 G epidural catheter inserted in the 4th-5th lumbar interspace. Lactated RingerŽÕs solution was administered at 10 mláÌg21áÉ21 Žßow rate during anesthesia. Systolic blood pressure and heart rate were measured pre-anesthesia and 5, 10, 15, and 20 min after injecting local anesthetic. Data were expressed as mean 6 standard deviation. Statistical analysis was done using Stat View SE1 (Abacus Concepts Inc., USA) employing the Wilcoxon signed-rank test for paired data and the Mann-Whitney U test for unpaired data. Statistical signiŽÞcance was indicated as
P , 0.05.
(para2)There were no statistically signiŽÞcant differences between TED(1) and TED(2) groups with regard to
age, height, weight, and anesthetized spinal segments achieved 20 min later in spinal or epidural anesthesia (Table 2). In spinal anesthesia, systolic blood pressures and heart rates showed no statistical differences between the groups in the pre-anesthesia period. Systolic blood pressure decreased signiŽÞcantly after injecting local anesthetic in both groups, but at 10, 15, and 20 min after injection the TED(1) group showed signiŽÞcantly higher values compared with the TED(2) group. Although heart rate in the TED(1) group decreased 15 and 20 min later, while in the TED(2) group it decreased only 20 min later, there were no statistical differences in heart rate between the groups. In epidural anesthesia also, systolic blood pressures and heart rates showed no statistical differences between the groups in the pre-anesthesia period. Although systolic blood pressures in both groups signiŽÞcantly decreased after injecting local anesthetic, there were no statistical differences between the groups. Heart rates showed no statistical differences, either compared with pre-anesthesia values or between groups (Fig. 1).
(para2)The present study suggests that a graduated compression stocking seems to maintain blood pressure during spinal anesthesia, although it is not effective under epidural anesthesia. The mechanism for preventing spinal hypotension is believed to be restraint of cutaneous venous dilatation of the lower extremities and an increment in femoral vein blood Žßow. While a graduated compression stocking is reported not to prevent spinal or epidural hypotension in cesarean section without left uterine displacement [2,3], it seems that a gravid uterus suppresses the venous return from the lower extremities. Moreover, the stocking used in this study does not impair the peripheral circulation of the legs and is safe for long-term ŽÞtting [4]. Consequently, it is concluded that ŽÞtting graduated compression stockings on both legs seems to be a noninvasive, simple and safe procedure to prevent hypotension during spinal anesthesia, except for cesarean section.
(1)References
(REF)1. Sigel B, Edelstein AL, Savitch L, Hasty JH, Felix WR Jr (1975) Type of compression for reducing venous stasis. Arch Surg 110:171-175
(REF)2. James FM, Greiss FC (1973) The use of inŽßatable boots to prevent hypotension during spinal anesthesia for cesarean section. Anesth Analg 52:246-251
(REF)3. Lee A, McKeown D, Wilson J (1987) Evaluation of the efŽÞcacy
of elastic compression stockings in prevention of hypotension
during epidural anaesthesia for elective cesarean section. Acta Anaesthesiol Scand 31:193-195
(REF)4. Lawrence D, Kakkar VV (1980) Graduated, static, external compression of the lower limb. Br J Surg 67:119-121 (MW)

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(JN)J Anesth (1996) 9:385 - 386
(PT)Letter to the editor
(CT)A simple method to advance a winged epidural needle
(CA)Shamsul Alam, Shinichi Sakura, and Yoshihiro Kosaka
(ADD)Department of Anesthesiology, Shimane Medical University, 89-1 Enya-cho, Izumo, Shimane, 693 Japan
(A)To the editor:
(para1)Despite numerous publications concerning techniques for identiŽÞcation of the epidural space, little interest has been focused on the control of the advance of the epidural needle, which we believe is the most difŽÞcult part to learn and seems daunting to the beginner. The following technique with a standard winged Touhy epidural needle has been employed in our institution. We have found it to be satisfactory for controlling the needle and preventing sudden forward movement that can result in inadvertent dural puncture.
(para2)The prominent feature of our technique is the position of the ŽÞnger(s), placed on the shaft of the needle throughout the procedure. Fig. 1 shows the grip
during the procedure of ŽÞxing the needle in the interspinous ligament. While advancing the needle with the stylet in place, the index ŽÞnger of the operatorŽÕs dominant hand provides steady support to the long axis of the shaft, leading it in the right direction. The needle, without the stylet, is then advanced steadily using either of the following techniques until it reaches its ŽÞnal destination. Fig. 2 shows the grip for the loss of resistance technique. The thumb and the index ŽÞnger of the operatorŽÕs non-dominant hand that grasp the wing impart constant forward motion to the needle, while the middle ŽÞnger on the shaft controls the advance of the needle against the patientŽÕs back. The other hand applies constant pressure on the plunger. The grip for the hanging drop technique, where the needle is advanced with both hands, is shown in Fig. 3. The palmar surfaces of the middle ŽÞngers are braced against the shaft of the needle and the tips against the patientŽÕs back. Every millimeter of the advance and direction of the needle can be easily controlled.
(para2)The ŽÒBromageŽÓ grip [1] is ideal for wingless needles. We believe, however, that our technique with a winged needle also helps precise positioning and a gradual and controlled advance with little risk of unintentional dural puncture, providing a high success rate.
(A)Reference
(REF)1. Bromage PR (1978) Epidural analgesia. Saunders, Philadelphia, pp 176-214 (MW)

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(JN)J Anesth (1996) 9:387 - 389
(PT)The others
(CT)Reference citation accuracy in the Journal of Anesthesia
(CA)Kahoru Nishina, Katsuya Mikawa, Migiwa Asano, Nobuhiro Maekawa, and Hidefumi Obara
(ADD)Department of Anaesthesiology, Kobe University School of Medicine, 7 Kusunoki-cho, Chuo-ku, Kobe, 650 Japan
(AB)Abstract: To determine the accuracy of the bibliographic citations in the Journal of Anesthesia, all references appearing the years 1987 (Vol. 1; n 5 548) and 1994 (Vol. 8; n 5 1839) were sequentially numbered and 100 references from each year were randomly selected. After citations of non-journal articles were excluded (n 5 8 in 1987; n 5 7 in 1994), the remaining 185 citations were scrutinized. The authorsŽÕ names, article title, journal title, volume number, page numbers, and year were examined for each reference. A reference was deemed correct if each clement of the citation was identical to its source. Of the references examined, 41% and 42% in 1987 and 1994, respectively, contained one or more errors. The elements that were inaccurate most often were, in descending order of frequency, article title, author, and page number. No signiŽÞcant differences existed in the error rate between the two years. We have demonstrated a considerable level of citation error in the reference lists of the Journal of Anesthesia articles, and no improvement over the last seven years. We recommend that contributors to the Journal of Anesthesia should carefully check the accuracy of their reference listings.
(KW)Key words: Publications, Documentation, Journal of
Anesthesia
(A)Introduction
(para1)The accuracy of reference lists is one criterion of a good scientiŽÞc journal. A report published in 1992 indicated that four anesthesia journals with established worldwide reputations had many citation errors in the
reference lists. The journals were Anesthesiology, the Canadian Journal of Anaesthesia, Anesthesia and Analgesia, and the British Journal of Anaesthesia [1]. However, no report has been published on the accuracy of reference lists in the Journal of Anesthesia, which is the ofŽÞcial journal of the Japan Society of Anesthesiology. Thus, we conducted the present study to examine and compare the variety and frequency of citation errors in this journal, based on volumes published in 1987 and 1994.
(A)Materials and methods
(para1)The Journal of Anesthesia was ŽÞrst published in 1987. We chose this as the ŽÞrst year for our study and, beginning with the ŽÞrst reference in the ŽÞrst issue (issue No. 1) and ending with the last reference in the last issue (issue No. 2), numbered every citation sequentially (n 5 548). Using a random number generator (PC-G801, Sharp, Osaka, Japan), we chose 100 references. References to nonjournal items, such as books and book chapters, were excluded from the analysis, leaving a total of 92 references for scrutiny.
(para2)A reference form was prepared, which helped identify any citation by its sequential number and the journal issue in which it appeared. Data ŽÞelds for the cited references corresponded to six standard elements of bibliographic citation: authors (including correct number, order, initials, and spelling), article title, journal title (including proper Index Medicus abbreviation), volume number, page number, and year.
(para2)Citations were veriŽÞed by comparison with the original publication (primary source). If our institution did not own the source, it was obtained through the interlibrary loan system.
(para2)Citations containing no errors were classiŽÞed as ŽÒcorrect.ŽÓ If an error existed in any element, the citation was classiŽÞed as ŽÒincorrect.ŽÓ We deŽÞned a citation that contained more than one error as having ŽÒtwo or more errors.ŽÓ If the citation contained two or more mistakes in one element only, it was assigned to the category of ŽÒone error.ŽÓ
(para2)An error that would potentially impede retrieval of the original paper was regarded as ŽÒmajor.ŽÓ This included (1) errors that were completely different from the original (not typographic errors), and (2) typographic errors in the ŽÒvolume,ŽÓ ŽÒyear,ŽÓ or ŽÒpageŽÓ (the ŽÞrst page of a reference) ŽÞelds. If only the last page was different, it was regarded as a minor error. In contrast, punctuation errors and typographic errors in other ŽÞelds (author, title, journal, or the last page of a reference) were regarded as minor. These errors probably
do not prevent readers from retrieving the original manuscript.
(para2)Similarly, we identiŽÞed 100 references from 1994
issues (issue Nos. 1-4; n 5 1839) of the journal, and analyzed 93 of those references; the other seven references pertained to non-journal items.
(para2)Data are presented as frequency or percent, overall and by element, for each year. Differences in frequency and percent of errors between the years 1987 and 1994 were tested for statistical signiŽÞcance using the x2 test. FisherŽÕs exact test with an r 3 c contingency table was used when assumptions underlying the x2 method were not met. P , 0.05 was deemed signiŽÞcant.
(A)Results
(para1)As shown in Table 1, many references contained an error in at least one element of the citation (41% in 1987 and 42% in 1994). In 1987, 8.7% of references contained two or more errors. In 1994, this ŽÞgure was 7.5%. Error rates did not differ between the two years.
(para2)Table 2 shows the distribution of errors in the six chosen bibliographic elements. ŽÒTitleŽÓ errors were the most common in both years, occurring in nearly 36% of the incorrect references. Errors in the authorsŽÕ names was the second most common fault, followed by page number errors. Errors in journal title, volume number, and year were less frequent. The distribution of errors was similar in the two years.
(para2)Most of the citation errors were minor. However, four of the references from 1987 and 1994 had major errors such as incorrect page numbers, volume, or year. Two references in 1994 had serious errors: in one case, only ŽÒtitleŽÓ and ŽÒauthorŽÓ ŽÞelds were correct; the other four elements were incorrect. In another, the ŽÒvolumeŽÓ, ŽÒpageŽÓ, and ŽÒyearŽÓ were missing. We had great
difŽÞculty in retrieving these references and had to
use computer retrieval (MEDLINE, IGAKU-CHUO-
ZASSHI) to ŽÞnd them. We show the two references as printed in the Journal, and the corrections necessary,
in the appendix.
(A)Discussion
(para1)Accurate reference lists provide readers with useful information for their studies. Nothing could be more frustrating for readers than to uncover an unidentiŽÞable reference. Reference lists with which care has obviously been taken prevent this sort of frustration. Thus, reference accuracy in a paper is essential. We believe that the correct citation of references will upgrade the quality of a journal. Although contributors to any journal have an obligation to cite references accurately, many of them fail to do so.
(para2)In 1992, McLellan et al. [1] called the attention of authors and readers in the ŽÞeld of anesthesiology to the inaccuracy of the reference lists observed even in the aforementioned esteemed journals. Thus, we compared the frequency of citation errors in the Journal of Anesthesia between 1987 and 1994 to determine whether or not the accuracy of the reference lists had improved after the study by McLellan et al. We found many citation errors in both years. Between the two years, there were no differences in the frequency (41% and 42%) and variety of the errors. However, the error rates in the Journal of Anesthesia seem no higher than those in the four anesthesia journals examined previously (44%-56%) [1].
(para2)We conducted a similar study for the years 1990
and 1994 on the Canadian Journal of Anaesthesia,
Anesthesia and Analgesia, and the British Journal of Anaesthesia. In the Canadian Journal of Anaesthesia, the error rate has decreased from 48% to 22% (P , 0.05) [2]. After McLellanŽÕs report, the editors of the Canadian Journal of Anaesthesia began to ask contributors to verify reference citation accuracy and submit photocopies of the ŽÞrst page of each of the references quoted when they were requested to revise their manuscripts. In the other journals, which did not change their editorial policy after the warning, the rate of citation errors did not decrease signiŽÞcantly (from 36% to 38% in Anesthesia and Analgesia [3] and from 47% to 36% in the British Journal of Anaesthesia, P . 0.05). Thus, this improvement of citation accuracy in the Canadian Journal of Anaesthesia may be due to the reference check system now used by editors and contributors. Such an editorial strategy may be necessary to decrease the citation errors in the Journal of Anesthesia. Furthermore, contributors should check the accuracy of the reference lists thoroughly, especially of the ŽÒtitleŽÓ and ŽÒauthorŽÓ elements, because errors in these ŽÞeld seem particularly common.
(para2)In conclusion, we found many citation errors in the reference lists of the Journal of Anesthesia and no reduction in this carelessness in the last seven years. Any contributors to the Journal of Anesthesia should carefully check the accuracy of their reference lists so that the value of the journal may be further enhanced.
(A)Appendix
(para1)The underlined parts in (a) are incorrect; corrections are shown in square brackets.
(para1)(a) Owen H, McMillan V, Rogowski D (1989) Postoperative pain therapy: a survey of patientsŽÕ expectations and experiences. Anesth Analg 68:645-648 [1990, Pain, 41:303-307]
(para1)(b) Sakura S, Nonoue T, Nomura T, et al. Differences in the assessment of postoperative pain when evaluated by patients and doctors. J Anesth [(1993), 7:287-292]
(1)References
(REF)1. McLellan MF, Case LD, Barnett MC (1992) Trust, but verify: The accuracy of references in four anesthesia journals. Anesthesiology 77:185-188
(REF)2. Asano M, Mikawa K, Nishina K, Maekawa N, Obara H (1995) Improvement of the accuracy of references in Canadian Journal of Anaesthesia. Can J Anaesth 42:370-372
(REF)3. Nishina K, Asano M, Mikawa K, Maekawa N, Obara H (1995) Accuracy of reference in Anesthesia and Analgesia does not
improve. Anesth Analg 80:641-642 (MW)

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(JN)J Anesth (1996) 9:390 - 391
(PT)
(CT)Report on the computer software contest at the 42nd Congress of the Japan Society of Anesthesiology
(CA)Kunio Suwa, Masatsugu Echikawa, Yoshito Nakayama, Yoshinori Iwase, Takahiko Mori, Makoto Ozaki, Youichi Kondo, and Yoshifumi Tanaka
(ADD)Executive Committee of the Computer Software Contest at the 42nd Congress of the Japan Society of Anesthesiology
(ADD)Department of Anesthesia, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113 Japan
(KW)Key words: Free software, JSA, CD-ROM, MS-Windows
(para1)We held another computer software contest at the 42nd Congress of the Japan Society of Anesthesiology (JSA), held in Hamamatsu in April 1995. This is a brief report of the contest from the members of the executive committee. The aim and procedures have been explained in the previous four reports [1 - 4]. This report will be limited only to what differs from those of the previous four events.
(para2)We recruited another member (ME) to the Executive Committee, who belongs to the Department of Anesthesiology at Hamamatsu Medical School. He arranged most of the practical aspects of the contest.
(1)Results
(para1)We received 22 entries for the contest. The spectrum of personal computers and operating systems (OS) for which the software was intended showed a marked shift from NEC PC9801 and Macintosh to various other types of platforms/OS (Table 1). Only one program was entered solely for the NEC PC9801 series, while six were entered solely for Macintosh, including one which was translated from that originally developed for MS-DOS. Eight programs were intended for MS-Windows. Many programs and data were intended for various platforms/machines including those mentioned above plus AT-compatibles and UNIX systems. This trend was especially marked when the software receiving prizes was considered. Out of seven, three were for MS-Windows while the remaining four were shared by PC9801, Macintosh, HP200LX, and Unix. The total number of co-workers for all these 22 programs was 64.
(para2)We received monetary donations from various sources plus one million yen worth of instruments and goods for prizes. Examples of prizes were a pulse-oximeter, a TFT-display note-type PC, four HP200LX palm-top computers, three multisession CD-ROM drives and two MIDI-sound instruments.
(para2)The grand prize was withheld again this year, because no entry reached the high standards of quality required for this prize. The authors and titles of the top ŽÞve prizes for excellence, and of the two extra prizes are listed in Table 2. All entries were awarded prizes. All programs are free software although a few may be difŽÞcult to distribute for technical reasons.
(para2)We held a special lecture session by Dr. Ken Sakamura, the promoter of the TRON project, who talked on the future perspective of computers, including the concept of a computer-augumented environment. Attendance increased markedly, reaching as many as 200.
(1)Discussion
(para1)The number of entries remained at the same level, but the attendance increased substantially this year over the previous 4 years. We interpret this to indicate that the contest is now gaining popularity among the members of the Society as well as to an increased interest in computers in general.
(para2)The software by Dr. Enomoto may deserve special mention. It is a group of small programs developed over a span of more than a decade, to be used mostly at the bedside in the operating room. It uses a standard language (MS-BASIC), and no new technology such as GUI or video data. With its high quality and wide applicability, it is an impressive achievement and a useful program.
(para2)The size of programs has again grown markedly over previous years. It is now common to use visual and auditory data, which can increase the size of data to the order of 100 megabytes. We have been discussing the possibility of making a CD-ROM for distributing these programs. It has been delayed for both technical and economic reasons. It appears that even a single CD-ROM may not have the capacity to incorporate the many programs provided.
(para2)It has already been arranged that both the 43rd (1996) and the 44th (1997) Congresses of the JSA are to hold a similar software contest. While we had no programs entered from abroad this year, we at least received one program in English aiming at international use, to be used on AT-compatibles. The same policy shall be maintained for the coming years. The English version of the OS for both Macintosh and MS-Windows will be available if we receive entries which require them.
(para2)For the contest, we maintain a policy that all programs entered must be distributed as free software with all the supporting documentation available to the users. Under this condition, we welcome entries from abroad to the contest. The authors of the software are free to revise and to distribute them independently, even via commercial routes.
(ACK)Acknowledgments. We wish to acknowledge President Kazuyuki Ikeda and the Executive staff of the 42nd Congress of the Japan Society of Anesthesiology for making it possible to hold this contest. We also wish to gratefully acknowledge the following companies who made generous donations and supplied prizes for the contest. Their Japanese names were translated into English somewhat arbitrarily by the authors.
(para1)Sponsoring companies (in alphabetical order): Baxter, Ltd.; Ciba-Corning Diagnostics, Inc.; Dainabot Pharmaceutical Company, Inc.; Fuji R-C, Inc.; Kayaku Pharmaceutical Company, Inc.; Kyoudou Oxygen Company, Inc.; Nihon Kohden Corporation, Ltd.; Nikken Chemical Company, Inc.; Nissan Chemical Industries, Inc.; Plat-home, Inc.; Radiometer Trading K.K.; Ricoh Co, Inc.; Yokogawa-Hewlett-Packard, Inc.
(1)References
(REF)1. Suwa K, Miyasaka K, Tanaka Y, Ozaki M, Mori T, Iwase Y, Nishi S (1991) Report on the Computer Software Contest at the 38th Congress of the Japan Society of Anesthesiology. J Anesth 5:441 - 444
(REF)2. Suwa K, Watanabe R, Iwase Y, Mori T, Ozaki M, Tanaka Y, Miyasaka K (1993) Report on the computer software contest at the 39th Congress of the Japan Society of Anesthesiology. J Anesth 7:124 - 126
(REF)3. Suwa K, Harada K, Watanabe R, Iwase Y, Mori T, Ozaki M, Tanaka Y, Miyasaka K (1994) Report on the computer software contest at the 40th Congress of the Japan Society of Anesthesiology. J Anesth 8:250 - 251
(REF)4. Suwa K, Uchida T, Nakayama Y, Watanabe R, Iwase Y, Mori T, Ozaki M, Kondo Y, Tanaka Y (1994) Report on the computer software contest at the 41st Congress of the Japan Society of Anesthesiology. J Anesth 8:508 - 509 (MW)

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