TAPANI TAMMISTO AND MAUNO ATRAKSINEN Department of Pharmacology and the Eye Hospital, University of Helsinki, Finland SUMMARY

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1 Brit. J. Anaesth. (1966), 38, 510 INCREASE OF CREATINE KINASE ACTIVITY IN SERUM AS SIGN OF MUSCULAR INJURY CAUSED BY INTERMITTENTLY ADMINISTERED SUXAMETHONIUM DURING HALOTHANE ANAESTHESIA BY TAPANI TAMMISTO AND MAUNO ATRAKSINEN Department of Pharmacology and the Eye Hospital, University of Helsinki, Finland SUMMARY The serum creatine kinase (creatine phosphokinase) activity was determined immediately before anaesthesia and hours later in patients undergoing ophthalmic operations. Halothane widi nitrous oxide and oxygen was given. Suxamethonium was administered as a single dose, as a single dose followed by infusion, or in intermittent doses. Increased enzyme activity was found after intermittent administration; this increase was about seven times as great when halothane with nitrous oxide and oxygen was used, as when nitrous oxide and oxygen was given without halothane. After thiopentone induction there was less increase in activity than after gaseous induction. The increase in enzyme activity showed some correlation with the degree of visible fasciculations, whereas correlation with the occurrence of muscular pains could not be statistically ascertained. Muscular pains and stiffness which follow the use of suxamethonium are well known since 1952 (v. Dardel and Thesleff, 1952; Bourne, Collier and Somers, 1952) and constitute a drawback to the use of suxamethonium. Despite the fact that several factors predisposing to the complication have been suggested, the aetiology still is unknown. A correlation between the initial fasciculations and the pain has been assumed (Churchill- Davidson, 1954). Though the correlation is no simple one (Kreuscher et al., 1965) it was thought that the unco-ordinated fibrillations may overstrain muscular fibres and cause, among other effects, an outflow of muscular enzymes into the plasma. Creatine kinase (creatine phosphokinase) is rather specifically located in muscle cells, and greatly elevated activities are generally assumed to indicate muscular injury. We therefore found it interesting to investigate whether the use of suxamethonium causes elevation of creatine kinase activity in serum, and if so, whether the elevation can be correlated with the degree of visible fasciculations and with the subsequent development of muscular pain. MATERIAL AND METHODS The series comprised 60 patients ranging from 3 to 75 years of age who were anaesthetized for routine ophthalmic operations with minimal or no muscular involvement. Halothane and/or nitrous oxide with oxygen anaesthesia was used. According to the mode of administration of suxamethonium (suxamethonium chloride, Myolaxin Star) during halothane, nitrous oxide and oxygen anaesthesia the patients were divided into four groups: I No suxamethonium was given (8 patients). II Suxamethonium 1.0 mg/kg was given for intubation (12 patients). HI Suxamethonium 1.0 mg/kg was followed by 0.2 per cent suxamethonium infusion given up to a total dose of approximately 2.5 mg/kg (10 patients). IV The same amount of suxamethonium as was used in group III was given intermittently in four doses (1.0, 0.5, 0.5 and 0.5 mg/kg) at 5 to 10 minute intervals (24 patients). To investigate the role of halothane, this agent was omitted in some patients. V Nitrous oxide-oxygen anaesthesia was used without halothane and four to eight doses of suxamethonium (1.0 and 0.5 mg/kg) were given at 5 to 10 minute intervals (6 patients) The patients were selected at random, except in group V, which comprised only children and adult males.

2 INCREASE OF CREATINE KINASE ACnVITY IN SERUM 511 The anaesthetic technique was as follows. After intramuscular premedication with atropine (0.01 mg/kg), pethidine (1.5 mg/kg) and promethazine (1 mg/kg), anaesthesia was induced with intravenous thiopentone sodium or nitrous oxideoxygen and halothane (maximum 2.5 per cent; Fluotec Mark 2) or nitrous oxide and oxygen only. For maintenance nitrous oxide and oxygen (6:2) combined with halothane ( per cent) was used in all except the 6 patients in group V. These patients received only nitrous oxide and oxygen throughout the procedure. The Rees modification of Ayre's T-piece was used for patients weighing under 20 kg. For the other patients a nonrebreathing system with a Ruben valve was used. Respiration was controlled manually during suxamethonium relaxation. Creatine phosphokinase activity in serum was measured just before anaesthesia (but after premedication) and 24 to 28 hours later. Determinations were made at 25 C. A modification of the method of Tanzer and Gilvarg (1959) as recommended by the manufacturers (C. F. Boehringer & Soehne, 1962) was used. Student's "t" test was used in comparing two means. RESULTS Table I gives the means ± standard errors of serum creatine phosphokinase activities in the five groups immediately before anaesthesia and 24 to 28 hours later; the calculated mean elevations ± standard errors are included. The mean pre-operative values are of the same order in all groups except in group HI. The difference, however, is not statistically significant (P>0.05). The individual values show marked variation ( The mean elevation of creatine phosphokinase activity due to operative procedure (group I) was slight and statistically not significant (P>0.05). If suxamethonium was used for intubation (group H) the mean enzyme activity was about fourfold. The use of suxamethonium infusion (group III) did not cause any additional increase. Even in these groups the elevation of enzyme activity was not statistically significant. When suxamethonium was given intermittently during halothane anaesthesia (group IV) the postoperative mean activity was more than 25 times that of the control group. Of the patients in group IV, 25 per cent had an elevation of more than 50 i.u./l. As reported elsewhere (Airaksinen and Tammisto, in press) seven patients, all except one representing the highest values of creatine phosphokinase activity, had a positive Hemastix reaction* in the first urine sample voided after anaesthesia. Further analysis of the haeme pigment suggested that it was of muscular origin and in two cases the presence of myoglobin could be verified by immunochemical methods. Curiously enough, the increase in creatine phosphokinase activity after similar suxamethonium administration but without halothane was significantly lower (P<0.02), and only slightly higher than after a single administration during halothane anaesthesia. Serum glutamine oxalacetic acid transaminase activity (s.g.o.t.) was determined before and after anaesthesia in six patients. Pathological postoperative values were found in two patients (46 and 156 Wr6blewski units), both of whom had elevated creatine phosphokinase activities (54.06 and , respectively). * Hemastix test paper (Ames Co. Ltd.) containing o-toluidine and an organic peroxide for detection of peroxidase-like activity of haeme pigments. TABLE I The means and standard errors of serum creatine phosphokinase activities of ophthalmic patients before and hours after anaesthesia, and the calculated mean increases with standard errors. Group and mode of suxamethonium administration Creatine phosphokinase activity (/imol/min/1.) No. Before anaesthesia After anaesthesia Increase I. No suxamethonium ± ± ±0.88 II. One dose ± ± ±1.69 III. One dose + infusion ± ± ±1.12 IV. Four doses ± ± ±11.68 V. No halothane; 4-8 doses ± ± ±1.38

3 512 BRITISH JOURNAL OF ANAESTHESIA Scrutinizing group IV more closely it was found that the increase in enzyme activity depended upon the induction used. The mean increase in activity was significantly less (P<0.02) after thiopentone induction (8.45 ± 3.79 Lu./l.) than after halothane with nitrous oxide and oxygen induction (64.11 ±20.38 i.u./l.). The six highest values and all but one of the positive Hemastix reactions also were obtained when no thiopentone was used However, thiopentone was mainly used in adults, whereas children usually preferred the "gas". Therefore the possibility was considered that the difference observed reflects only the different age distribution in these groups. Indeed, when the postoperative creatine phospokinase activities of all 60 patients are plotted according to age (fig. 1), a tendency to higher activities is seen in children (under 15 years). On the other hand, the highest activities among the adults were measured in the two males who received halothane with nitrous oxide and oxygen for induction. The two highest values in adult females were also seen after similar induction. The postoperative creatine phosphokinase activity of the adult males seemed to be higher than that of the females (fig. 1). This statistically insignificant sex difference was not seen in the children, but it appeared in all the pre-operative so J OS SO M 70 W 15 FIG. 1 Creatine phosphokinase activities in children and adults after suxamethonium administration. The lines indicate the mean values as follows: x" Controls (group I). o o Four doses of suxamethonium during halothane (group IV). f Others (groups II, III and V).

4 INCREASE OF CREATINE KINASE ACTIVITY IN SERUM 513 TABLE II The occurrence of muscular pains in ophthalmic patients following various modes of suxamethonium administration. Group and mode of Muscular pain suxamethonium No. administration Mild Severe Total I. II. III. IV. V. No suxamethonium One dose One dose+infusion Four doses No halothane; 4-8 doses (8%) 1 (10%) 6 (25%) 1 (10%) 5 (21%) 2 (33%) 1 (8%) 2 (20%) 11 (46%) 2 (33%) values. The mean of the 32 males (0.94 ±0.18 i.u./l.) was significantly higher (P<0.05) than the mean (0.53 ±0.08 i.u,/l.) of the 28 females. In an attempt to correlate the degree of visible fasciculations to the increase in creatine phosphokinase activity the following basis of evaluation was used. No fasciculations, 0 point, and slight, moderate and vigorous fasciculations, 1, 2 and 3 points. When suxamethonium was given intermittently (groups IV and V) the points after each dose were added and a sum exceeding 4 points was graded as "marked" and a sum from 0 to 4 points as "slight". No correlation between the degree of fasciculations and the increase of creatine phosphokinase activity could be found when fibrillations occurred only once (groups II and HI). On the other hand, a correlation was found after intermittent administration. In group IV the mean increase of activity of the patients estimated to have "marked fasciculations" (68.39 ±21.83 Lu./l.) was significantly higher (P<0.02) than the value after "slight fasciculations" (9.11 ±3.55 i.u./l.). The same tendency was seen in group V. The fasciculations during nitrous oxide and oxygen anaesthesia seemed to be coarser and more co-ordinated than during halothane anaesthesia. Thiopentone induction weakened the visible fasciculations. In group IV all the patients were estimated to have "slight fasciculations" after induction with thiopentone. Muscular pain and/or stiffness were complained of postoperatively by 16 patients when asked (26.7 per cent). Table II shows the occurrence and severity of the pain in the different groups. Muscular pain was not reported by children under 9 years of age. Therefore, in an attempt to correlate the increase in enzyme activity to the pain, only adults (15 years and over) were included. This was done to minimize the role of unreliable information possibly given by children. The mean increase of creatine phosphokinase activity in the adults having pains was ± i.u./l., as compared to 2.76 ±1.47 i.u./l. in the patients without pains. However, some patients with low creatine phosphokinase activities complained of pain, owing to which this rather large difference was not statistically significant (P<0.12). DISCUSSION The intermittent administration of suxamethonium was found to increase creatine phosphokinase activities in serum during halothane anaesthesia. Grossly elevated activities (>50 i.u./l.) were found in 25 per cent of these patients. Obviously such pathological values, and the subsequent myoglobinuria, seen in some patients indicate some kind of muscle cell injury, or at least heavy muscular overactivity (Biorck, 1949; Colombo, Richterich and Rossi, 1962). The outflow of the enzymes and myoglobin from the muscle cells did not seem to depend on the degree and duration of the relaxation, since an equivalent amount of suxamethonium given by infusion caused only an insignificant elevation of the enzyme activity. Neither did one patient with prolonged apnoea (about 2 hours) after a single dose of suxamethonium show any elevation in creatine phosphokinase activity. On the other hand, the severity of the probable injury seems to depend somehow upon the degree of fasciculation since greatly increased values were seen only after repeated exposure and then mostly after vigorous fasciculations. The correlation, however, is not a simple one, since one patient developing myoglobinuria had only weak

5 514 BRITISH JOURNAL OF ANAESTHESIA fasciculations and two patients judged to have had vigorous fasciculations had no significant elevation of the postoperative enzyme activities. Constitutional factors may play a decisive role in the outflux of the enzymes and myoglobin. The marked deviation in the postoperative enzyme activities and the tendency to higher postoperative creatine phosphokinase activities in the patients with the highest pre-operative activities favour this assumption. Furthermore, Bennike and Jarnum (1964) have described the elevation of creatine phosphokinase activity and an attack of myoglobinuria with renal failure after a single dose of suxamethonium during halothane anaesthesia in a patient suffering from a syndrome of idiopathic myoglobinuria. Harrison has recently (1965) shown that visible fasciculations following a second dose of suxamethonium during halothane anaesthesia occur in 4 of 10 patients when the time interval between the administration is 5 minutes and in 9 of 10 when it is 10 minutes. We have also measured elevated creatine phosphokinase activities in cats but not in rats, in which suxamethonium does not exhibit a pure "acetylcholine-like" action (Zaimis, 1959). Halothane obviously plays an important role in the production of the assumed muscular injury since myoglobinuria and highly elevated creatine phosphokinase activities were not seen during nitrous oxide and oxygen anaesthesia, though this group (V) comprised only children and adult males, who in all other groups showed a tendency to higher activities than adult females. The mechanism of the action of halothane in this respect, however, is wholly unknown. It might be related to the fact that the twitches occurring during nitrous oxide with oxygen seemed to be briefer, coarser and more co-ordinated than the fasciculations during halothane anaesthesia. Halothane is also known to antagonize the neuromuscular effects of suxamethonium (Foldes, 1960). Craig (1964) has demonstrated the protective effect of thiopentone against the muscular pain that follows the use of suxamethonium. This agrees with our finding that thiopentone induction reduced the fasciculations and proteaed against an increase of creatine phosphokinase activity in serum. It seems reasonable to assume that if suxamethonium is able to damage the muscle cells the ensuing muscular pain is related to the injury. Such a tendency was observed in adults in the present study. However, despite their higher creatine phosphokinase activities children under 9 years denied the presence of pain. A similar observation was reported by Bush and Roth (1961). In general, pain is probably so complicated a sensation that direct correlation to the severity of muscular injury can hardly be obtained The presented series is relatively small and further studies are therefore required to confirm and explain the results obtained. The results however, suggest that the use of intermittent suxamethonium during halothane anaesthesia should be abandoned, particularly in patients with co-existing muscular lesions (crush injuries, major surgery, etc.). REFERENCES Airaksinen, M. M., and Tammisto, T. (1966). Myoglobinuria after routine intermittent administration of succinylcholine during halothane anesthesia. Clin. Pharmacol, (in press). Bennike, Kn.-A., and Jarnum, S. (1964). Myoglobinuria with acute renal failure possibly induced by suxamethonium. Brit. J. Anaesth., 36, 730. Biorck, G. (1949). On myoglobin and its occurrence in man. Acta med. scand. (SuppL 226), 133, 1. Boehringer, C. F., und Soehne G.m.b.H., Mannheim (1962). CPK-Test. Bestimmung der Aktivitat der Creatin-Phosphokinase im Serum (UV-Test mit DPNH), 3. (verdndene) Auflage. Delivered with the test reagents. Bourne, J. G., Collier, H. O. J., and Somers, C F. (1952). Succinylcholine; a muscle relaxant of short action. Lancet, 1, Bush, G. H., and Roth, F. (1961). Muscle pains after suxamethonium chloride in children. Brit. J. Anaesth., 33, 151. Churchill-Davidson, H. G. (1954). Suxamethonium (succinylcholine) chloride and muscle pains. Brit, med. % 1, 74. Colombo, J. P., Richterich, R., and Rossi, E. (1962). Serum-Kreatin-Phosphokinase. Bestimmung und diagnostische Bedeutung. Klin. Wschr., 40, 37. Craig, H. J. L. (1964). The protective effect of thiopentone against muscular pain and stiffness which follows the use of suxamethonium chloride. Brit. J. Anaesth., 36, 612. Dardel, O. v., and Thesleff, S. (1952). Succinylcholine iodide as a muscular relaxant A report of 500 surgical cases. Acta chir. scand., 103, 321. Foldes, F. F. (1960). The pharmacology of neuromuscular blocking agents in man Clin. Pharmacol. Ther., 1, 345. Harrison, G. A. (1965). The incidence of visible muscular fasciculations following a second dose of suxamethonium chloride. Brit. J. Anaesth., 37, 129. Kreuscher, H., Lange, H. J., Mutter, K. H., und Wengel, U. (1965). Untersuchungen fiber Fibrillationen und Muskelschmerz nach Succinylcholin und ihre Beeinflussung durch Gallamin. Der Anaesthesist, 14, 1.

6 INCREASE OF CREATINE KINASE ACnVITY IN SERUM 515 Tanzer, M. L., and Gilvarg, C. (1959). Creatine and creatine kinase measurement. J. biol. Chem., 234, Zaimis, E. (1959). Curare and Curare-like Agents, 1st ed., p Amsterdam: Elsevier. AUGMENTATION DE L'ACTTVITE DE LA CREATINE-KINASE DANS LE SERUM EN TANT QUE SIGNE DTINE LESION MUSCULAIRE CAUSEE PAR L'ADMINISTRA- TION INTERMITTENTE DE SUXA- METHONIUM AU COURS DE L'ANESTHESIE AU HALOTHANE SOMMAIRE L'activke de la creatine-kinase sdrique (creatine phosphokinase) a fti determinee imm&iiatement avant 1'anesthesie et heures plus tard chez des malades subissant des operations ophtalmiques. Ils recurent de l'halothane avec du protoxyde d'azote et de l'oxygene. Le suxam6thonium a iti administri comme dose unique, comme dose unique suivie de perfusion ou comme dose intermittente. On a constati une activity enzymatique accrue apres l'administration de doses intermittentes; cette augmentation 6tait a peu pres sept fois plus importante quand on utilisait l'halothane avec le protoxyde d'azote et l'oxygene que quand on utilisait le protoxyde d'azote et l'oxygene sans halothane. Apres une induction au thiopentone l'activit enzymatique augmentait moins qu'aprts une induction gazeuse. L'augmentation de l'activiti enzymatique presents quelques rapports avec le degr6 de fasciculations visibles, alors que les rapports eventuels avec la survenue de douleurs musculaires n'ont pu Stre confinnes par la statistique. DER ANSTIEG DER KREATINKINASE- AKTIVITAT IM SERUM ALS ZEICHEN EINER MUSKELSCHADIGUNG DURCH INTERMIT- TIEREND VERABFOLGTE GABEN VON SUXAMETHONIUM IM VERLAUF DER HALOTHAN-NARKOSE ZUSAMMENFASSUNG Bei Patienten zur Durchfuhrung von Augenoperationen wurde unmittelbar vor der Narkose und Stunden spater die Kreatinkinase (Kreatinphosphokinase)- Aktivitat im Serum bestimmt. Halothan wurde zusammen mit Lachgas und Sauerstoff verabfolgt. Suxamethonium wurde entweder als Einzeldosis, als Einzeldosis mit nachfolgender Infusion oder in mehreren Einzeldosen gegeben. Nach intermittierender Verabfolgung fand sich eine gesteigerte Enzymaktivitat, dieser Anstieg war bei Anwendung von Halothan mit Lachgas und Sauerstoff sieben Mai grofler als bei Anwendung von Lachgas und Sauerstoff ohne Halothan. Nach Narkoseeinleitung mit Thiopenton war der Aktivitatsanstieg geringer als nach Einleitung mit Narkosegasen. Der Anstieg der Enzymaktivitat zeigte eine gewifle Beziehung zu dem Ausmafi der sichtbaren Faszikulationen, dagegen konnte eine Beziehung zu dem Auftreten von Muskelschmerzen nicht statistisch gesichert werden. Clinical Anesthesia: Management of the Patient in Shock. Edited by Louis R. Orkin. Published by Blackwell, Oxford. Pp Price 40s. There has been an upsurge of interest in the management of surgical shock of late years. Unfortunately, however, no one has yet devised an effective definition of this condition and the term is used on the one hand by laboratory workers to describe a disease state which is already resistant to treatment by replacement of the lost fluid, and on the other hand by clinicians who use it very loosely indeed. To some, hypovolaemic hypotension is the essential disturbance of physiology; others are even less precise and mean little more than a patient who looks a bit pale and ill following an injury or surgical operation. In the face of such imprecision it is obviously impossible to oraculate about shock. The path of the author who sets out to write on the subject of shock is therefore very difficult indeed. The editor of this volume has concentrated mainly on the clinical management of patients in shock. In order to obtain the material for his manuscript, he asked a group of anaesthetists to describe and define their beliefs concerning the management of the shocked patient, beginning with a description of the condition and justifying their views in the course of the essay. The result is a series of papers dealing with the various forms of anaesthesia such as nitrous oxide/ oxygen, thiopentone, nerve block, cyclopropane, ether, halothane and neuroleptanalgesia as they are used in the management of the shocked patient. There are also essays on the changes during massive transfusion, BOOK REVIEW appropriate electrolyte therapy and on the effects of drugs in shock. Shock in the obstetric patient and shock following pulmonary embolism are also discussed and finally the editor pulls everything together in a chapter entitled "Critique". Perhaps it is a little surprising to find that no contribution deals specifically with the modern ideas concerning the use of alpha adrenergic blockers, the treatment of metabolic acidosis and the administration of isoprenaline, but in fact references to these points and to steroid therapy also, are plentifully scattered through the text The editor himself in his preface comments that he has been unable to find anyone to defend spinal anaesthesia, no one who thought he had sufficient knowledge available concerning methoxyflurane in shocked patients, nor yet anyone who knew the probable effects of anaesthetic agents on the subject of endotoxin shock. There is an inevitable risk in writing books dealing with a rapidly advancing field of medicine and Dr. Orkin chose such when he dealt with shock. Particularly in the field of endotoxin shock, things seem to have gone so rapidly ahead in the last twelve months or so that it would not be fair to suggest that the book was in any way deficient because this aspect of the subject is not dealt with specifically. In fact the editor of this book is to be congratulated on maintaining the high standard of the series and we recommend it most heartily to all who wish to learn something of the modern approaches to this most difficult subject. A. R. Hunter