Br.J. Anaesth. (1976), 48, 513
SUXAMETHONIUM-INDUCED PORCINE MALIGNANT HYPERTHERMIA G. A. GRONERT AND R. A. THEYE SUMMARY
Suxamethonium (SCh) is known to cause malignant hyperthermia (MH), particularly in the presence of other provocative agents (Relton, 1973; Ryan, 1973). To determine the effects of SCh per se, we have measured the metabolic, haemodynamic and neuroendocrine effects of SCh in malignant hyperthermiasusceptible (MHS) swine. These are compared with the previously reported effects of halothane (Gronert and Theye, 1976). The animals were identified as MHS by a screening test using halothane, in which a positive response included the development of limb rigidity (Gronert and Theye, 1976). MATERIALS AND METHODS
Five normal and five MHS 3O-50-kg Poland China swine were prepared according to a protocol (Gronert and Theye, 1976) for measurement of the oxygen consumption of the whole body ( KB 02 ) and hind limb ( KL OI! ), cardiac output (Q), arterial pH, Po 2 and Pco 2 , lactate, potassium (K+) and catecholamine concentrations, and temperature. Anaesthesia during these preparations included thiopentone, nitrous oxide, and controlled ventilation to maintain />aCOl! at 40 + 2 mm Hg. Control values were established in triplicate during a 15-min period. Suxamethonium 3 mg/kg was injected i.v. and all measurements were repeated after 5,10, 20,30,40, 50 and 60 min with unchanged ventilation and with no therapeutic intervention. The results are expressed as mean + SEM with comparison of means by Student's t test (P< 0.05 was considered significant).
RESULTS
Normal swine responded to SCh widi early small increases in the concentrations of lactate and K+ (not reported) and late increases in FB O 2 and VLOS (figs 1 and 2). In MHS swine (table I), SCh produced early transient changes in almost all of the measurements. Later, there were changes in KL O2 , lactate and K+ concentrations, heart rate, arterial pH and catecholamines. Both core and limb temperatures increased to plateau values, while the hind limb venous POi ( P L 0 2 ) and the mean arterial pressure decreased at a late stage. Muscle rigidity did not occur, although fasciculations were both marked and coarse. Figures 1-3 contrast SCh-induced changes in KBOa, VLOt and lactate, respectively with those of halothane in MHS 1% Halothane SCh, 3 mg/kg
(ml /min /kg
MHS D O
12
Body Weight)
1
20 40 MINUTES
60
Drug
GERALD A. GRONERT, M.D.J RICHARD A. THEYE, M.D.;
Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901, U.S.A.
FIG. 1. Whole body ^o 2 response to halothane or SCh in normal and MHS swine. Mean values: O significantly different from control value. Halothane data from Gronert and Theye (1976).
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on March 12, 2015
Metabolic, haemodynamic and neuroendocrine responses to suxamethonium (SCh) were measured in five normal swine and five swine susceptible to malignant hyperthermia (MH), to compare the responses with those previously reported for halothane. Following SCh, the onset of MH was sooner and more abrupt than following halothane. The maximal changes in aerobic metabolism and body temperature were similar, while the changes in lactate, potassium, hydrogen ion and catecholamine concentrations were smaller than those observed following halothane. These results are discussed in terms of the action of chemical depolarizing drugs such as suxamethonium and acetylcholine. The propagated muscle action potentials produce an increase in the free intracellular calcium concentration which may be self-regenerative, but which may become uncontrollable because of the peculiarities of MH that effect the calcium pump or storage areas.
Time after injection of suxamethonium (min) 0
Mean Lactate ((imol/ml) 1.3 Arterial 1.3 Limb vein K+ (mmol/litre) 3.9 Arterial 4.0 Limb vein 4.4 Limb 7o 2 (ml/ min/kg muscle
5
20
10
SEM
Mean
SEM
Mean
SEM
0.3 0.3
6.5* 7.5*
0.9 1.1
6.1* 6.8*
0.8 1.0
0.1 0.1 0.3
4.9* 4.9* 11.1*
0.1 0.1 1.0
5.0* 5.0* 13.7*
2.4 2.3
29.1* 30.0*
1.7 2.3
4
43
3
Mean
30
40
SEM
Mean
SEM
Mean
SEM
5.3 5.8
0.9 1.1
5.5 5.6
1.9 2.0
6.2* 6.7*
3.3 3.8
0.1 0.1 1.6
4.8* 4.9* 12.5*
0.2 0.2 1.5
5.2* 5.4* 11.3*
0.5 0.5 1.6
5.2* 5.5* 10.2*
0.4
31.5* 26.5*
2.4 2.1
28.6* 24.5*
3.6 2.5
30.0* 24.0*
9.3 6.2
36.8* 32.7*
18.4 15.8
35
2
30
3
29
5
25*
6
0.5 19
39.7* 214*
0.7 21
0.6 1.1
wt)
Lactate/pyruvate 10.1 Arterial Limb vein 11.1 P L 0 , (mm Hg) 46 Limb vein Temperature (°C) Limb vein 37.6 173 Heart rate (beat/min) Arterial pH 7.57 (units) Pa COj (mm Hg) 39 Pv c o , (mm Hg) 50 Adrenaline (ng/ml) 0.19 0.28 Noradrenaline (ng/ml) 8.0 Whole body VOa (ml/min/kg body wt) Temperature (°C) Right atrium 38.7 106 (Z (ml/min/kg body wt) Arterial pressure, 126 mean (mm Hg) 76 Limb flow (ml/min/kg muscle wt)
0.3 9
0.05 2 3
38.3* 210* 7.29* 62*
0.08 0.10
79* 0.59* 1.05*
0.5
14.6*
0.4 6
0.01 3 4
38.6* 226* 7.24* 67*
0.16 0.19
86* 0.43 1.53*
0.7
16.8*
0.4 7
0.02 3 4
0.12 0.21
39.0* 214* 7.29* 60* 84*
0.64* 2.06*
0.4 14
0.04 5 7
0.38 0.81
39.4* 218* 7.30* 58* 83*
2.03* 4.39*
0.07 6 12
1.75 3.17
7.30* 54* 82*
2.97* 3.98*
0.10 5 15
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on March 12, 2015
TABLE I. Effect of suxamethonium 3 mglkg on five MHS swine
50
60
Mean
SEM
Mean
SEM
7.1* 7.2*
4.4 4.5
9.2* 9.8*
5.9 5.8
5.5* 5.8* 9.7*
0.5
0.8 1.3
6.1* 6.4* 9.8*
1.1 1.2 1.2
45.2* 34.8*
24.9 18.4
53.3* 43.9*
29.9 23.5
23*
6
20*
5
39.7* 229*
0.7 12
39.7* 224*
0.7 11
7.30*
0.12
7.22*
0.14 W
49* 84*
3 16
47* 81*
1 14
2.63 2.31
4.44* 3.64*
2.35 1.54
3.16* 5.17*
2.33 1.99
1.3
9.1
0.7
7.8
1.0
H oo O
1.0
12.6*
0.8
12.3*
1.2
10.7
;> 0.5 10
39.0* 152*
0.4 15
39.3* 151*
0.4 16
5
117
13
111
7
112*
12
109*
118
0.4 15
116
0.5 13
7
105
5
113
9
102*
7
39.6*
39.8*
97*
99
0.6 12
83*
8
95*
13
89*
6
88*
5
80
40.0*
40.1*
r
64*
0.8 11
13
80*
18
o >
4
73
7
oo
0.6 8
40.1*
w
m • Different from control.
00
SUXAMETHONIUM AND MALIGNANT HYPERTHERMIA VMS n
Norual
1% Haloihcnt
SCh. 3 « | / l j
O
•
(ml/mln/kg 10 Muscle Weight)
T
20
40
MINUTES
FIG. 2. Hind limb £"o2 response to halothane or SCh in normal and MHS swine. Mean values: o significantly different from control values. Halothane data from Gronert and Theye (1976). Limb Vein O O Arterial U *
1% Halothant
SCh, 3 mg/ka
20 Drug
40
MINUTES
FIG. 3. Changes in lactate of MHS swine given halothane or SCh. Halothane data from Gronert and Theye (1976).
swine (Gronert and Theye, 1976). P&Ol remained greater than 120 mm Hg throughout the study in all animals. DISCUSSION
body weight (Allen, Thompson and Hegarty, 1974). Thus approximately 45% of the increase in F B 0 2 during MH is unaccounted for, a value similar to that calculated for halothane (Gronert and Theye, 1976). From this evidence we conclude that MH may not be solely a disorder of skeletal muscle and that other tissues may participate actively in the aerobic changes. However, there are errors of measurement and calculations associated with this evidence. The Fick relationship is qualitative when measurements are made during an unsteady state (Zierler, 1961). Some hind limb bloodflowwas not included in the measurements because of inaccessible collateral vessels, and different muscles may have varied responses in MH. Nevertheless, the time course of MH varied little, in these animals, as a result of the sudden onset following SCh, and the data were consistent, depicting accurately the changes that occur during SCh-induced MH. Increases in lactate following SCh, as with halothane (Gronert and Theye, 1976), occurred in the absence of signs of intracellular hypoxia; the common iliac venous flow remained stable or increased and PL O S showed no significant decreases until 40min after the injection of SCh. These apparently nonhypoxic increases in lactate may be related to changes in the metabolic control mechanism as discussed previously (Gronert and Theye, 1976). Hyperactive cellular functions deplete the concentrations of ATP (Plum, House and Duffy, 1974), with a resulting decrease in the ratio [ATP]/[ADP] [HPO 4 2 -]. This shifts the cytoplasmic redox state towards reduction, affecting the glyceraldehyde phosphate dehydrogenase system, thus maintaining a constant ratio of the cytoplasmic nicotinamide adenine dinucleotide (NAD) couple—free NAD+/free NADH. When free NADH tends to increase, thus altering this ratio, several systems respond. There is a rapid increase in lactate (Veech, Raijman and Krebs, 1970). Changes in lactate, K+, arterial pH and catecholamines during MH were smaller after SCh than after halothane (Gronert and Theye, 1976). There was, however, a severe biochemical disorder in the absence of rigidity.
These data demonstrate two apparent episodes of MH, the former a result of SCh, and the latter the stress of light anaesthesia. Suxamethonium produced an earlier onset of MH than did halothane (Gronert and Theye, 1976), with similar increases in aerobic metabolism. The increases in Vo2, both whole body The stress of light anaesthesia probably accounts and limb, began sooner after the administration of for the metabolic aberrations that occurred 30 or SCh because a bolus results in a more rapid increase in 40min after SCh. These animals were not given drug concentration at the muscle. Maximal increases supplementary thiopentone after muscle function in Vo2 may develop rapidly during MH and do not returned, and both normal and MHS swine moved, appear to be related to the type of provoking agent. shivered and reacted to the endotracheal tube during Calculated increases in skeletal muscle Vo2 may be 50% nitrous oxide in oxygen anaesthesia with conextrapolated from VtOi, assuming that the skeletal trolled ventilation. This accounts, in normal swine, muscle weight in muscular swine is 50% of the total for increases in Ko2 at 30 and 40 min. In MHS swine
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on March 12, 2015
Drug
515
516
impairs the calcium control mechanism, SCh and ACh increase the concentration of calcium. When both factors are combined, for example an excess release of calcium by depolarization plus inhibition of the calcium pump and storage mechanisms, fulminant MH may be expected. One example of this is the induction of anaesthesia with inhalation agents in an excited MHS pig. ACKNOWLEDGEMENT
Supported in part by Research Grant GM-21729 from NIH, PHS. REFERENCES
Allen, C. E., Thompson, E., and Hegarty, P. V. J. (1974). Physiological maturity of muscle and adipose cells in meat animals. Proc. Am. Meat Set. Assoc, p. 8. Britt, B. A., Endrenyi, L., and Cadman, D. L. (1975). Calcium uptake into muscle of pigs susceptible to malignant hyperthermia. Br. J. Anaesth., 47, 650. Ebashi, S., and Endo, M. (1968). Calcium ion and muscle contraction; in Progress in Biophysics and Molecular Biology (eds J. A. V. Butler and D. Noble), p. 123. Oxford: Pergamon Press. Ford, L. E., and Podolsky, R. J. (1972). Intracellular calcium movements in skinned muscle fibres. J. Physiol. {Lond.), 223, 21. Extradural anaesthesia has been reported to prevent Gronert, G. A., and Theye, R. A. (1975). Pathophysiology halothane-induced MH (Kerr, Wingard and Gatz, of hyperkalemia induced by succinylcholine. Anesthesiology, 43, 89. 1975). During extradural anaesthesia, ACh release (1976). Halothane-induced porcine malignant should virtually cease (Gronert and Theye, 1975); hyperthermia. Anesthesiology, 44, 36. free intracellular calcium should then be at a reduced Hall, L. W., Trim, C. M., and Woolf, N. (1972). Further concentration, as the affected muscles are relaxed in studies of porcine malignant hyperthermia. Br. Med. J., the absence of the usual tonic reflexes. Thus the 2, 145. contractile mechanism may be considered as "set" at Harrison, G. A. (1973). The effect of procaine and curare on the initiation of anaesthetic-induced malignant hypera level at which MH is not easily initiated. This may pyrexia; in International Symposium on Malignant also explain why thiopentone delays the onset of Hyperthermia (eds R. A. Gordon, B. A. Britt and W. halothane-induced MH (Gronert and Theye, 1976). Kalow), p. 271. Springfield: Thomas. Harrison (1973) has reported that tubocurarine may Kerr, D. D., Wingard, D. W., and Gatz, E. E. (1975). Prevention of porcine malignant hyperthermia by block SCh-induced MH, but not halothane-induced epidural block. Anesthesiology, 42, 307. MH. This observation seems to contradict Kerr's findings discussed above. This discrepancy is probably Nelson, T. E. (1973). Porcine stress syndromes; in International Symposium on Malignant Hyperthermia (eds related to the degree of paralysis with either technique. R. A. Gordon, B. A. Britt and W. Kalow), p. 191. Hall, Trim and Woolf (1972) noted that curare Springfield: Thomas. modified, but did not prevent, MH and Kerr observed Plum, F., House, D. C , and Duffy, T. E. (1974). Metabolic effects of seizures; in Brain Dysfunction in Metabolic that inadequate extradural anaesthesia was only Disorders. Research Publications, Association for Research partially protective. in Nervous and Mental Disease (ed. F. Plum), p. 141. Volatile agents, such as halothane, directly inhibit New York: Raven Press. abnormal MHS machinery (Ryan et al., 1974; Britt, Relton, J. E. S. (1973). Malignant hyperthermia—anesEndrenyi and Cadman, 1975). This results in poor thetic techniques and agents; in International Symposium on Malignant Hyperthermia (eds R. A. Gordon, B. A. clearance of free intracellular calcium, which inBritt and W. Kalow), p. 425. Springfield: Thomas. creases progressively. This increase begins almost as J. F. (1973). The early treatment of malignant soon as halothane is introduced, and the associated Ryan, hyperthermia; in International Symposium on Malignant metabolic and acid-base signs are initially subtle Hyperthermia (eds R. A. Gordon, B. A. Britt and W. (Gronert and Theye, 1976). Thus, while halothane Kalow), p. 430. Springfield: Thomas.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on March 12, 2015
this was apparently a sufficient stress to re-activate MH during the waning influence of SCh. This "re-activation" of MH was now related to increased stimulation and excitement similar to the porcine stress syndrome of awake swine (Nelson, 1973) and was, at least in part, a result of a greater release of acetylcholine (ACh) across neuromuscular junctions. ACh and SCh act similarly as chemical depolarizers (Gronert and Theye, 1975); the resulting action potentials are propagated to the muscle cell by the transverse tubules, causing a small release of calcium (Ebashi and Endo, 1968) which is increased further by self-regeneration (Ford and Podolsky, 1972). In MHS subjects, the abnormal intracellular machinery may be unable to clear the extra calcium, resulting in typical changes in metabolism (Harrison, 1973). These changes may be marked and unrecognized, for example, in patients receiving SCh during electroconvulsive therapy (Relton, 1973). In the present study the "re-activated" MH included continued increases in Vh02, lactate, K+ and catecholamines, and decreases in arterial pH and P\Oi. Thus it appears that the early episode of SCh-induced MH blended into a later episode of ACh-induced MH.
BRITISH JOURNAL OF ANAESTHESIA
SUXAMETHONIUM AND MALIGNANT HYPERTHERMIA Ryan, J. F., Donlon, J. V., Malt, R. A., Bland, J. H. L., Buckley, J. J., Sreter, F. A., and Lowenstein, E. (1974). Cardiopulmonary bypass in the treatment of malignant hyperthermia. N. Engl.J. Med., 290, 1097. Veech, R. L., Raijman, L., and Krebs, H. A. (1970). Equilibrium relations between the cytoplasmic adenine nucleotide system and nicotinamide adenine nucleotide system in rat liver. Biochem.J., 117, 499. Zierler, K. L. (1961). Theory of the use of arteriovenous concentration differences for measuring metabolism in steady and non-steady states. J. Clin. Invest., 40, 2111. HYPERTHERMIE MALIGNE DES PORCINS PROVOQUEE AU MOYEN DU SUXAMETHONIUM
44
SUXAMETHONIUM-EINGELEITETE MALIGNE HYPERTHERMIE BEIM SCHWEIN ZUSAMMENFASSUNG
Es wurden die metabolischen, haemodynamischen und neuroendokrinen Reaktionen nach Verabreichung von Suxamethonium (SCh) bei 5 normalen Schweinen gemessen und mit 5 auf maligne Hyperthermie empfindlichen Schweinen verglichen (MH) um sie mit denen auf Halothan zu vergleichen von denen friiher berichtet wurde. Nach Verabreichung von Suxamethonium erfolgte die maligne Hyperthermie schneller und war von kurzerer Dauer, als nach Halothan. Die maximalen Veranderungen im aerobischen Metabolismus und der Korpertemperatur waren ahnlich, wahrend Veranderungen im Laktat, Kalium und im Wasserstoff, sowohl wie den Katecholamin-Konzentraten kleiner waren als die nach Halothan ermessenen Werte. Die Ergebnisse werden in Bezug auf die Wirkung chemischer depolarisierender Praeparate wie Suxamethonium und Azetylcholin besprochen. Die Verbreitung der Muskelspannung verursachte einen Anstieg im freien intrazellularen Kalziumkonzentrat, das selbsterneuern sein mag, jedoch unkontrollierbar werden kann, aufgrund der besonderen Eigenschaften der malignen Hyperthermie durch die die Kalziumpumpe und Aufbewahrung beeintrachtigt werden. HIPERTERMIA MALIGNA PORCINA INDUCIDA POR SUXAMETONIO SUMARIO
Las respuestas metabolicas, hemodinamicas y neuroendocrinas a la succinilcolina (suxametonio) fueron medidas en cinco cerdos normales y cinco cerdos susceptibles a la hipertermia maligna (HM), para compararlas con las previamente comunicadas para el halotano. Los cambios maximos en metabolismo aerobico y temperatura corporal fueron parecidos, mientras que los cambios en las concentraciones de lactato, potasio, ion hidrogeno, y catecolaminas fueron menores que los observados tras el halotano. Se comentan estos resultados en t£rminos de la action de los compuestos quimicos despolarizantes tales como la succinilcolina y la acetilcolina. Los potenciales propagados de action muscular producen una elevacion de la concentration intracelular de calcio libre que pudiera ser autoregenerante, pero que pudiera volverse incontrolable debido a las peculiaridades de la HM que afectan las zonas de suministro o almacenamiento de calcio.
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on March 12, 2015
RESUME
Les reactions metaboliques, hemodynamiques et neuroendocriniennes au suxamethonium (Sch) ont ete mesurees sur cinq pores normaux et sur cinq pores predisposes a Phyperthermie maligne (HM), afin de les comparer a celles prealablement decrites pour l'halothane. Apres administration de Sch, l'apparition de l'HM a ete plus rapide et plus brutale qu'apres l'administration d'halothane. Les modifications maximales du metabolisme aerobie et de la temperature corporelle etaient analogues, alors que les changements de concentration des lactates, du potassium, des cations et des catecholamines etaient plus faibles que ceux observes apres administration d'halothane. Ces resultats sont discutes du point de vue de l'action des medicaments depolarisants chimiques tels que le suxamethonium et l'acetylcholine. La propagation des potentiels d'action dans les muscles produit une augmentation de la concentration du calcium intracellulaire libre qui peut etre auto-reg£nerant, mais qui peut aussi devenir incontrolable du fait des particularites de l'HM qui altere le pompage du calcium ou en affecte les reserves.
517
SUXAMETHONIUM-INDUCED PORCINE MALIGNANT HYPERTHERMIA G. A. GRONERT AND R. A. THEYE SUMMARY
Suxamethonium (SCh) is known to cause malignant hyperthermia (MH), particularly in the presence of other provocative agents (Relton, 1973; Ryan, 1973). To determine the effects of SCh per se, we have measured the metabolic, haemodynamic and neuroendocrine effects of SCh in malignant hyperthermiasusceptible (MHS) swine. These are compared with the previously reported effects of halothane (Gronert and Theye, 1976). The animals were identified as MHS by a screening test using halothane, in which a positive response included the development of limb rigidity (Gronert and Theye, 1976). MATERIALS AND METHODS
Five normal and five MHS 3O-50-kg Poland China swine were prepared according to a protocol (Gronert and Theye, 1976) for measurement of the oxygen consumption of the whole body ( KB 02 ) and hind limb ( KL OI! ), cardiac output (Q), arterial pH, Po 2 and Pco 2 , lactate, potassium (K+) and catecholamine concentrations, and temperature. Anaesthesia during these preparations included thiopentone, nitrous oxide, and controlled ventilation to maintain />aCOl! at 40 + 2 mm Hg. Control values were established in triplicate during a 15-min period. Suxamethonium 3 mg/kg was injected i.v. and all measurements were repeated after 5,10, 20,30,40, 50 and 60 min with unchanged ventilation and with no therapeutic intervention. The results are expressed as mean + SEM with comparison of means by Student's t test (P< 0.05 was considered significant).
RESULTS
Normal swine responded to SCh widi early small increases in the concentrations of lactate and K+ (not reported) and late increases in FB O 2 and VLOS (figs 1 and 2). In MHS swine (table I), SCh produced early transient changes in almost all of the measurements. Later, there were changes in KL O2 , lactate and K+ concentrations, heart rate, arterial pH and catecholamines. Both core and limb temperatures increased to plateau values, while the hind limb venous POi ( P L 0 2 ) and the mean arterial pressure decreased at a late stage. Muscle rigidity did not occur, although fasciculations were both marked and coarse. Figures 1-3 contrast SCh-induced changes in KBOa, VLOt and lactate, respectively with those of halothane in MHS 1% Halothane SCh, 3 mg/kg
(ml /min /kg
MHS D O
12
Body Weight)
1
20 40 MINUTES
60
Drug
GERALD A. GRONERT, M.D.J RICHARD A. THEYE, M.D.;
Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901, U.S.A.
FIG. 1. Whole body ^o 2 response to halothane or SCh in normal and MHS swine. Mean values: O significantly different from control value. Halothane data from Gronert and Theye (1976).
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on March 12, 2015
Metabolic, haemodynamic and neuroendocrine responses to suxamethonium (SCh) were measured in five normal swine and five swine susceptible to malignant hyperthermia (MH), to compare the responses with those previously reported for halothane. Following SCh, the onset of MH was sooner and more abrupt than following halothane. The maximal changes in aerobic metabolism and body temperature were similar, while the changes in lactate, potassium, hydrogen ion and catecholamine concentrations were smaller than those observed following halothane. These results are discussed in terms of the action of chemical depolarizing drugs such as suxamethonium and acetylcholine. The propagated muscle action potentials produce an increase in the free intracellular calcium concentration which may be self-regenerative, but which may become uncontrollable because of the peculiarities of MH that effect the calcium pump or storage areas.
Time after injection of suxamethonium (min) 0
Mean Lactate ((imol/ml) 1.3 Arterial 1.3 Limb vein K+ (mmol/litre) 3.9 Arterial 4.0 Limb vein 4.4 Limb 7o 2 (ml/ min/kg muscle
5
20
10
SEM
Mean
SEM
Mean
SEM
0.3 0.3
6.5* 7.5*
0.9 1.1
6.1* 6.8*
0.8 1.0
0.1 0.1 0.3
4.9* 4.9* 11.1*
0.1 0.1 1.0
5.0* 5.0* 13.7*
2.4 2.3
29.1* 30.0*
1.7 2.3
4
43
3
Mean
30
40
SEM
Mean
SEM
Mean
SEM
5.3 5.8
0.9 1.1
5.5 5.6
1.9 2.0
6.2* 6.7*
3.3 3.8
0.1 0.1 1.6
4.8* 4.9* 12.5*
0.2 0.2 1.5
5.2* 5.4* 11.3*
0.5 0.5 1.6
5.2* 5.5* 10.2*
0.4
31.5* 26.5*
2.4 2.1
28.6* 24.5*
3.6 2.5
30.0* 24.0*
9.3 6.2
36.8* 32.7*
18.4 15.8
35
2
30
3
29
5
25*
6
0.5 19
39.7* 214*
0.7 21
0.6 1.1
wt)
Lactate/pyruvate 10.1 Arterial Limb vein 11.1 P L 0 , (mm Hg) 46 Limb vein Temperature (°C) Limb vein 37.6 173 Heart rate (beat/min) Arterial pH 7.57 (units) Pa COj (mm Hg) 39 Pv c o , (mm Hg) 50 Adrenaline (ng/ml) 0.19 0.28 Noradrenaline (ng/ml) 8.0 Whole body VOa (ml/min/kg body wt) Temperature (°C) Right atrium 38.7 106 (Z (ml/min/kg body wt) Arterial pressure, 126 mean (mm Hg) 76 Limb flow (ml/min/kg muscle wt)
0.3 9
0.05 2 3
38.3* 210* 7.29* 62*
0.08 0.10
79* 0.59* 1.05*
0.5
14.6*
0.4 6
0.01 3 4
38.6* 226* 7.24* 67*
0.16 0.19
86* 0.43 1.53*
0.7
16.8*
0.4 7
0.02 3 4
0.12 0.21
39.0* 214* 7.29* 60* 84*
0.64* 2.06*
0.4 14
0.04 5 7
0.38 0.81
39.4* 218* 7.30* 58* 83*
2.03* 4.39*
0.07 6 12
1.75 3.17
7.30* 54* 82*
2.97* 3.98*
0.10 5 15
Downloaded from http://bja.oxfordjournals.org/ at University of Otago on March 12, 2015
TABLE I. Effect of suxamethonium 3 mglkg on five MHS swine
50
60
Mean
SEM
Mean
SEM
7.1* 7.2*
4.4 4.5
9.2* 9.8*
5.9 5.8
5.5* 5.8* 9.7*
0.5
0.8 1.3
6.1* 6.4* 9.8*
1.1 1.2 1.2
45.2* 34.8*
24.9 18.4
53.3* 43.9*
29.9 23.5
23*
6
20*
5
39.7* 229*
0.7 12
39.7* 224*
0.7 11
7.30*
0.12
7.22*
0.14 W
49* 84*
3 16
47* 81*
1 14
2.63 2.31
4.44* 3.64*
2.35 1.54
3.16* 5.17*
2.33 1.99
1.3
9.1
0.7
7.8
1.0
H oo O
1.0
12.6*
0.8
12.3*
1.2
10.7
;> 0.5 10
39.0* 152*
0.4 15
39.3* 151*
0.4 16
5
117
13
111
7
112*
12
109*
118
0.4 15
116
0.5 13
7
105
5
113
9
102*
7
39.6*
39.8*
97*
99
0.6 12
83*
8
95*
13
89*
6
88*
5
80
40.0*
40.1*
r
64*
0.8 11
13
80*
18
o >
4
73
7
oo
0.6 8
40.1*
w
m • Different from control.
00
SUXAMETHONIUM AND MALIGNANT HYPERTHERMIA VMS n
Norual
1% Haloihcnt
SCh. 3 « | / l j
O
•
(ml/mln/kg 10 Muscle Weight)
T
20
40
MINUTES
FIG. 2. Hind limb £"o2 response to halothane or SCh in normal and MHS swine. Mean values: o significantly different from control values. Halothane data from Gronert and Theye (1976). Limb Vein O O Arterial U *
1% Halothant
SCh, 3 mg/ka
20 Drug
40
MINUTES
FIG. 3. Changes in lactate of MHS swine given halothane or SCh. Halothane data from Gronert and Theye (1976).
swine (Gronert and Theye, 1976). P&Ol remained greater than 120 mm Hg throughout the study in all animals. DISCUSSION
body weight (Allen, Thompson and Hegarty, 1974). Thus approximately 45% of the increase in F B 0 2 during MH is unaccounted for, a value similar to that calculated for halothane (Gronert and Theye, 1976). From this evidence we conclude that MH may not be solely a disorder of skeletal muscle and that other tissues may participate actively in the aerobic changes. However, there are errors of measurement and calculations associated with this evidence. The Fick relationship is qualitative when measurements are made during an unsteady state (Zierler, 1961). Some hind limb bloodflowwas not included in the measurements because of inaccessible collateral vessels, and different muscles may have varied responses in MH. Nevertheless, the time course of MH varied little, in these animals, as a result of the sudden onset following SCh, and the data were consistent, depicting accurately the changes that occur during SCh-induced MH. Increases in lactate following SCh, as with halothane (Gronert and Theye, 1976), occurred in the absence of signs of intracellular hypoxia; the common iliac venous flow remained stable or increased and PL O S showed no significant decreases until 40min after the injection of SCh. These apparently nonhypoxic increases in lactate may be related to changes in the metabolic control mechanism as discussed previously (Gronert and Theye, 1976). Hyperactive cellular functions deplete the concentrations of ATP (Plum, House and Duffy, 1974), with a resulting decrease in the ratio [ATP]/[ADP] [HPO 4 2 -]. This shifts the cytoplasmic redox state towards reduction, affecting the glyceraldehyde phosphate dehydrogenase system, thus maintaining a constant ratio of the cytoplasmic nicotinamide adenine dinucleotide (NAD) couple—free NAD+/free NADH. When free NADH tends to increase, thus altering this ratio, several systems respond. There is a rapid increase in lactate (Veech, Raijman and Krebs, 1970). Changes in lactate, K+, arterial pH and catecholamines during MH were smaller after SCh than after halothane (Gronert and Theye, 1976). There was, however, a severe biochemical disorder in the absence of rigidity.
These data demonstrate two apparent episodes of MH, the former a result of SCh, and the latter the stress of light anaesthesia. Suxamethonium produced an earlier onset of MH than did halothane (Gronert and Theye, 1976), with similar increases in aerobic metabolism. The increases in Vo2, both whole body The stress of light anaesthesia probably accounts and limb, began sooner after the administration of for the metabolic aberrations that occurred 30 or SCh because a bolus results in a more rapid increase in 40min after SCh. These animals were not given drug concentration at the muscle. Maximal increases supplementary thiopentone after muscle function in Vo2 may develop rapidly during MH and do not returned, and both normal and MHS swine moved, appear to be related to the type of provoking agent. shivered and reacted to the endotracheal tube during Calculated increases in skeletal muscle Vo2 may be 50% nitrous oxide in oxygen anaesthesia with conextrapolated from VtOi, assuming that the skeletal trolled ventilation. This accounts, in normal swine, muscle weight in muscular swine is 50% of the total for increases in Ko2 at 30 and 40 min. In MHS swine
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Drug
515
516
impairs the calcium control mechanism, SCh and ACh increase the concentration of calcium. When both factors are combined, for example an excess release of calcium by depolarization plus inhibition of the calcium pump and storage mechanisms, fulminant MH may be expected. One example of this is the induction of anaesthesia with inhalation agents in an excited MHS pig. ACKNOWLEDGEMENT
Supported in part by Research Grant GM-21729 from NIH, PHS. REFERENCES
Allen, C. E., Thompson, E., and Hegarty, P. V. J. (1974). Physiological maturity of muscle and adipose cells in meat animals. Proc. Am. Meat Set. Assoc, p. 8. Britt, B. A., Endrenyi, L., and Cadman, D. L. (1975). Calcium uptake into muscle of pigs susceptible to malignant hyperthermia. Br. J. Anaesth., 47, 650. Ebashi, S., and Endo, M. (1968). Calcium ion and muscle contraction; in Progress in Biophysics and Molecular Biology (eds J. A. V. Butler and D. Noble), p. 123. Oxford: Pergamon Press. Ford, L. E., and Podolsky, R. J. (1972). Intracellular calcium movements in skinned muscle fibres. J. Physiol. {Lond.), 223, 21. Extradural anaesthesia has been reported to prevent Gronert, G. A., and Theye, R. A. (1975). Pathophysiology halothane-induced MH (Kerr, Wingard and Gatz, of hyperkalemia induced by succinylcholine. Anesthesiology, 43, 89. 1975). During extradural anaesthesia, ACh release (1976). Halothane-induced porcine malignant should virtually cease (Gronert and Theye, 1975); hyperthermia. Anesthesiology, 44, 36. free intracellular calcium should then be at a reduced Hall, L. W., Trim, C. M., and Woolf, N. (1972). Further concentration, as the affected muscles are relaxed in studies of porcine malignant hyperthermia. Br. Med. J., the absence of the usual tonic reflexes. Thus the 2, 145. contractile mechanism may be considered as "set" at Harrison, G. A. (1973). The effect of procaine and curare on the initiation of anaesthetic-induced malignant hypera level at which MH is not easily initiated. This may pyrexia; in International Symposium on Malignant also explain why thiopentone delays the onset of Hyperthermia (eds R. A. Gordon, B. A. Britt and W. halothane-induced MH (Gronert and Theye, 1976). Kalow), p. 271. Springfield: Thomas. Harrison (1973) has reported that tubocurarine may Kerr, D. D., Wingard, D. W., and Gatz, E. E. (1975). Prevention of porcine malignant hyperthermia by block SCh-induced MH, but not halothane-induced epidural block. Anesthesiology, 42, 307. MH. This observation seems to contradict Kerr's findings discussed above. This discrepancy is probably Nelson, T. E. (1973). Porcine stress syndromes; in International Symposium on Malignant Hyperthermia (eds related to the degree of paralysis with either technique. R. A. Gordon, B. A. Britt and W. Kalow), p. 191. Hall, Trim and Woolf (1972) noted that curare Springfield: Thomas. modified, but did not prevent, MH and Kerr observed Plum, F., House, D. C , and Duffy, T. E. (1974). Metabolic effects of seizures; in Brain Dysfunction in Metabolic that inadequate extradural anaesthesia was only Disorders. Research Publications, Association for Research partially protective. in Nervous and Mental Disease (ed. F. Plum), p. 141. Volatile agents, such as halothane, directly inhibit New York: Raven Press. abnormal MHS machinery (Ryan et al., 1974; Britt, Relton, J. E. S. (1973). Malignant hyperthermia—anesEndrenyi and Cadman, 1975). This results in poor thetic techniques and agents; in International Symposium on Malignant Hyperthermia (eds R. A. Gordon, B. A. clearance of free intracellular calcium, which inBritt and W. Kalow), p. 425. Springfield: Thomas. creases progressively. This increase begins almost as J. F. (1973). The early treatment of malignant soon as halothane is introduced, and the associated Ryan, hyperthermia; in International Symposium on Malignant metabolic and acid-base signs are initially subtle Hyperthermia (eds R. A. Gordon, B. A. Britt and W. (Gronert and Theye, 1976). Thus, while halothane Kalow), p. 430. Springfield: Thomas.
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this was apparently a sufficient stress to re-activate MH during the waning influence of SCh. This "re-activation" of MH was now related to increased stimulation and excitement similar to the porcine stress syndrome of awake swine (Nelson, 1973) and was, at least in part, a result of a greater release of acetylcholine (ACh) across neuromuscular junctions. ACh and SCh act similarly as chemical depolarizers (Gronert and Theye, 1975); the resulting action potentials are propagated to the muscle cell by the transverse tubules, causing a small release of calcium (Ebashi and Endo, 1968) which is increased further by self-regeneration (Ford and Podolsky, 1972). In MHS subjects, the abnormal intracellular machinery may be unable to clear the extra calcium, resulting in typical changes in metabolism (Harrison, 1973). These changes may be marked and unrecognized, for example, in patients receiving SCh during electroconvulsive therapy (Relton, 1973). In the present study the "re-activated" MH included continued increases in Vh02, lactate, K+ and catecholamines, and decreases in arterial pH and P\Oi. Thus it appears that the early episode of SCh-induced MH blended into a later episode of ACh-induced MH.
BRITISH JOURNAL OF ANAESTHESIA
SUXAMETHONIUM AND MALIGNANT HYPERTHERMIA Ryan, J. F., Donlon, J. V., Malt, R. A., Bland, J. H. L., Buckley, J. J., Sreter, F. A., and Lowenstein, E. (1974). Cardiopulmonary bypass in the treatment of malignant hyperthermia. N. Engl.J. Med., 290, 1097. Veech, R. L., Raijman, L., and Krebs, H. A. (1970). Equilibrium relations between the cytoplasmic adenine nucleotide system and nicotinamide adenine nucleotide system in rat liver. Biochem.J., 117, 499. Zierler, K. L. (1961). Theory of the use of arteriovenous concentration differences for measuring metabolism in steady and non-steady states. J. Clin. Invest., 40, 2111. HYPERTHERMIE MALIGNE DES PORCINS PROVOQUEE AU MOYEN DU SUXAMETHONIUM
44
SUXAMETHONIUM-EINGELEITETE MALIGNE HYPERTHERMIE BEIM SCHWEIN ZUSAMMENFASSUNG
Es wurden die metabolischen, haemodynamischen und neuroendokrinen Reaktionen nach Verabreichung von Suxamethonium (SCh) bei 5 normalen Schweinen gemessen und mit 5 auf maligne Hyperthermie empfindlichen Schweinen verglichen (MH) um sie mit denen auf Halothan zu vergleichen von denen friiher berichtet wurde. Nach Verabreichung von Suxamethonium erfolgte die maligne Hyperthermie schneller und war von kurzerer Dauer, als nach Halothan. Die maximalen Veranderungen im aerobischen Metabolismus und der Korpertemperatur waren ahnlich, wahrend Veranderungen im Laktat, Kalium und im Wasserstoff, sowohl wie den Katecholamin-Konzentraten kleiner waren als die nach Halothan ermessenen Werte. Die Ergebnisse werden in Bezug auf die Wirkung chemischer depolarisierender Praeparate wie Suxamethonium und Azetylcholin besprochen. Die Verbreitung der Muskelspannung verursachte einen Anstieg im freien intrazellularen Kalziumkonzentrat, das selbsterneuern sein mag, jedoch unkontrollierbar werden kann, aufgrund der besonderen Eigenschaften der malignen Hyperthermie durch die die Kalziumpumpe und Aufbewahrung beeintrachtigt werden. HIPERTERMIA MALIGNA PORCINA INDUCIDA POR SUXAMETONIO SUMARIO
Las respuestas metabolicas, hemodinamicas y neuroendocrinas a la succinilcolina (suxametonio) fueron medidas en cinco cerdos normales y cinco cerdos susceptibles a la hipertermia maligna (HM), para compararlas con las previamente comunicadas para el halotano. Los cambios maximos en metabolismo aerobico y temperatura corporal fueron parecidos, mientras que los cambios en las concentraciones de lactato, potasio, ion hidrogeno, y catecolaminas fueron menores que los observados tras el halotano. Se comentan estos resultados en t£rminos de la action de los compuestos quimicos despolarizantes tales como la succinilcolina y la acetilcolina. Los potenciales propagados de action muscular producen una elevacion de la concentration intracelular de calcio libre que pudiera ser autoregenerante, pero que pudiera volverse incontrolable debido a las peculiaridades de la HM que afectan las zonas de suministro o almacenamiento de calcio.
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RESUME
Les reactions metaboliques, hemodynamiques et neuroendocriniennes au suxamethonium (Sch) ont ete mesurees sur cinq pores normaux et sur cinq pores predisposes a Phyperthermie maligne (HM), afin de les comparer a celles prealablement decrites pour l'halothane. Apres administration de Sch, l'apparition de l'HM a ete plus rapide et plus brutale qu'apres l'administration d'halothane. Les modifications maximales du metabolisme aerobie et de la temperature corporelle etaient analogues, alors que les changements de concentration des lactates, du potassium, des cations et des catecholamines etaient plus faibles que ceux observes apres administration d'halothane. Ces resultats sont discutes du point de vue de l'action des medicaments depolarisants chimiques tels que le suxamethonium et l'acetylcholine. La propagation des potentiels d'action dans les muscles produit une augmentation de la concentration du calcium intracellulaire libre qui peut etre auto-reg£nerant, mais qui peut aussi devenir incontrolable du fait des particularites de l'HM qui altere le pompage du calcium ou en affecte les reserves.
517
