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939 Prolonged duration of succinylcholine in patients receiving anticonvulsants: evidence for mild up- regulation of Agi T. Melton Mr), Joseph E Antognini Mr), Gerald A. Gronert Mr) receptors?

Succinylcholine (SCh) normally causes a small increase in and 10.0 5:1.6 min in the control group, P = O.OOL The serum potassium concentration, but certain conditions may pre- recovery index (time for 25% to 75% recovery) was 2.6 5:0.9 dispose to severe hyperkalaemia. This is due to "up-regulation" min in the anticonvulsant group and L4 5:0.3 rain in the of acetylcholine receptors (AChR), which also control group, P < 0.01. The normal potassium response results in resistance to non-depolarizing muscle relaxants coupled with prolonged duration suggests a hypersensitivity to (NDMR). Anticonvulsant therapy causes NDMR resistance SCh that is consistent with an anticonvulsant-induced mild up- because of sub-clinical blockade, and diminished release, of regulation of AChR. acetylcholine. We studied nine patients chronically receiving an- ticonvulsants ( and/or ) and nine con- Normalement, la succinylcholine ne provoque qu'une l~gbre trol patients. Anaesthesia was induced typically with thiopen- augmentation du potassium s~rique, mais certaines conditions tone or propofol; isoflurane and N20 were used for peuvent favoriser une hyperkali~mie grave. Ceci est d~ it la maintenance. The ulnar nerve was supramaximally stimulated r~gulation ~ it la hausse ~ des r~cepteurs ac~tylcholinergiques and mechanical twitch height was measured with a force trans- des muscles squelettiques (AChR), qui produit aussi une r~sis- ducer at the adductor pollicis, before and after SCh 1 mg " kg -~, tance aux myo-relaxants non d~polarisants (MRND). Par un until return to baseline height. Plasma potassium concentration bloquage infraclinique, la thdrapie anticonvulsivante produit was measured before and at three, fwe, and ten minutes fol- une r~sistance aux MRND et une diminution de la liberation lowing SCh. Mean maximum potassium rise was 0.2 mEq " L -l d'ac~tylcholine. Nous avons ~tudi~ neuf patients sous th~rapie in each group. The time for return to baseline twitch height anticonvulsivante (du ph~nytoin ou de la carbamaz~pine) et was 14.3 5:2.3 rain (mean 5: SD) in the anticonvulsant group les avons compares it neuf contr6les. L'anesth~sie a ~td induite avec du thiopentone ou du propofol et maintenue it l~soflurane et au N20 Un stimulus supramaximal a dt~ appliqu~ au nerf cubital et la force du twitch mesur~e avec un transducteur it l'adducteur court du pouce, avant et apr~s SCh 1 mg" kg -j, jusqu'au retour it la ligne de base. La kali$mie a ~t~ mesur~e Key words avant, it trois, cinq, et dix minutes aprbs SCh. L'augmentation IONS: potassium; moyenne maxima& de potassium a ~t~ de 0,2 mEq" L -I dans NEUROMUSCULAR RELAXANTS: succinylcholine; chaque groupe. La dur~e de retour it la ligne de base a ~t~ : anficonvulsants, phenytoin, de 14,3 5:2,3 rain (moyenne 5: SD) dans le groupe anticon- carbamazepine; vulsivant et 10,0 5:1,6 dans le groupe contr6le, P = O,OOL RECEPTORS: acetylcholine. L'index de rdcup~ration (temps de rdcupdration h 25% h 75%) From the Department of Anesthesiology, University of a ~t~ de 2,6 + 0.9 min dans le groupe anticonvulsivant et de Califomia, Davis. 1,4 5:0,3 min clans le groupe contr~le, P < O,OL La normalit$ Address correspondence to: Dr. Joseph E Antognini, de la r~ponse kalidmique associ$e /1 une dur~e prolong~e sug- Department of Anesthesiology, TB-170, University of g~re une hypersensibilit~ h la SCh consistante avec une l~gbre California, Davis, Davis, California, USA 95616. r~gulation ~ it la hausse ~ induite par la thdrapie anticonvul- Accepted for publication 17th June, 1993. sivante.

CAN J ANAESTH 1993 / 40:10 / pp 939-42 940 CANADIAN JOURNAL OF ANAESTHESIA

Succinylcholine (SCh) is a depolarizing TABLE Potassiumconcentrations (mEq" L-l) beforeand after which normally causes a 0.2-0.5 mEq. L -I increase in succinylcholineinjection serum potassium concentration. ~.2 Succinylcholine use in Baseline 3 rain 5 rain 10 min certain clinical conditions (e.g., burns, denervation, mus- cle damage, etc.), may lead to a dramatic and sometimes Control 3.8 + 0.4 4.0 + 0.5 4.0 :L-0.5 4.0 + 0.5 Anticonvulsant 4.0 -I- 0.2 4.0 + 0.2 4.1 -t- 0.4 4.2 + 0.4 fatal increase in serum potassium. 3 This phenomenon is secondary to the development of new immature acetyl- ANOVA: no differences choline receptors (AChR) in skeletal muscle, and it also leads to resistance to non-depolarizing muscle relaxants induction, supramaximal stimulation (Digistim, II, Neu- (NDMR). 4 Anticonvulsants, such as phenytoin and car- rotechnology, Houston, TX) at 1 Hz was performed be- bamazepine, decrease acetylcholine release and produce fore and after SCh, until twitch height achieved pre-SCh a mild acetylcholine blockade at the neuromuscular junc- levels. Duration of twitch was the time in min- tion (NMJ). 5,6 While there is no evidence of clinical weak- utes from SCh injection until twitch height returned to ness, anticonvulsants do result in NDMR resistance, 7-~~ pre-SCh levels. Recovery index (time for recovery from and the mechanism has been related to increased 25% to 75% of twitch height) and time to 50% recovery AChR. t t To examine this issue, we analyzed potassium were also determined. changes and twitch responses to SCh in patients receiving Data are expressed as mean + SD. Changes in serum chronic anticonvulsant therapy. potassium and PaCO2 were evaluated using analysis of variance (ANOVA), and Student's t test was used to eval- Methods uate differences between the groups as regards twitch de- With approval by the Human Subjects Review Commit- pression durations and recovery index; significance was tee, informed consent was obtained from nine patients attained when P < 0.05. taking phenytoin and/or carbamazepine for at least one month and nine control patients. Patients with disorders Results associated with myopathies or up-regulation, e.g., neu- The anticonvulsant group included five men and four romuscular diseases and/or motor deficits, burns, and women, aged 41 + 11 yr and weight 79 + 16 kg. Four recent muscle trauma were excluded. Patients in the anti- men and five women, aged 40 + 12 yr and weight 76 convulsant group had therapeutic levels except for + 17 kg formed the control group. one patient whose phenytoin level was 8 mg- L -I (thera- The increase in potassium concentration after SCh was peutic range 10-20 mg. L-l). not different between the anticonvulsant group and the A radial arterial catheter was placed in each patient control group (Table). Potassium data from one control prior to induction. Anaesthetic management was left to patient were discarded due to clotting of the baseline sam- the attending anaesthetist. Patients were given fentanyl ple. Twitch recovery time was unobtainable in one patient 1-4 I~g-kg -I (five control, seven anticonvulsant), midaz- in the anticonvulsant group for technical reasons. Pro- olam 0.01-0.04 I~g"kg -I (four control, two anticonvul- found (98-100%) twitch depression occurred in all sant), I-1.4 mg. kg -~ (two control, two anti- patients. Recovery of baseline (pre-SCh) twitch height convulsant) followed by an induction dose of thiopen- following SCh administration was longer in the anti- tone 3.7-6.5 mg" kg-i (six control, seven anticonvulsant), convulsant group (14.3 + 2.3 min, n = 8) than in the propofol 2 mg. kg -I (one control, one anticonvulsant), control group (10.0 + 1.6 rain, n = 9), P = 0.001. Time or etomidate 0.34-0.46 mg. kg -I (two control, zero an- for recovery to 50% twitch height was 11.4 + 0.7 min ticonvulsant) followed by SCh 1 mg" kg -I. Nitrous oxide in the anticonvulsant group and 8.4 + 1.7 min in the and isoflurane (approximately 1%) were used for main- control group, P < 0.01. Corresponding recovery indexes tenance. Arterial samples were taken prior to and were 2.6 + 0.9 rain and 1.4 -t- 0.3 min, P < 0.01. The three, five, and ten minutes after SCh administration. PaCO2 was 43 + 4 mmHg prior to induction of anaes- These were analyzed for potassium (ion-specific electrode, thesia in the anticonvulsant group, and 43 + 6 mmHg accuracy + 0.1 mEq. L -l) and PaCO2 (Nova Stat Profde in controls. These did not change at three, five and ten 5, Nova Medical, Tewksbury, MA). minutes in either group. Prior to induction, the hand was stabilized and the thumb f~ed to an FT-10 transducer, with a resting ten- Discussion sion of approximately 200 g. The mechanical twitch of Acute effects of anticomqalsant therapy include a mild the adductor pollicis muscle was recorded (Model MT- neuromuscular blockade which potentiates d-tubo- 8500, Astro-Med, W. Warwick, RI). Skin electrodes were curarine and other NDMR. s,6 This mild neuromuscular placed over the ulnar nerve at the wrist, and following blockade is apparently not manifested clinically as Melton el al.: ANTICONVULSANTS AND SUCCINYLCHOLINE 941

~R MILD MARKED ~ RMAL EGULATION ~. REGULATION

FIGURE Schematicof a normal neuromuscularjunction, and changesassociated with mild and marked up-regulation.I"lMature receptor; Olmmature receptor; @Unconfirmedimmature receptor. See text for details. weakness due to the large amount of AChR available spread throughout the muscle membrane. Those in the in reserve-also known as the margin of safety of neu- perijunctional region cause NDMR resistance, while the romuscular transmission. 4 The neuromuscular blocking overall numerical increase results in hyperkalaemia after effect of anticonvulsants is due to a modest blockade SCh. Thus, in theory, up-regulation in response to anti- of acetylcholine effects and a decrease in acetylcholine convulsants, resulting in development of new receptors release, 5,6 which is thought to result in proliferation of only in the junctional and perijunctional areas, could rec- AChR, leading to up-regulation. Thus, chronic effects of oncile the similar degree of NDMR resistance compared anticonvulsants, seen after about two weeks, include re- with burns and UMNL, and the lack of hyperkalaemic sistance to competitive antagonists, e.g., NDMRs. 4.H For response to SCh. Our data are consistent with those of example, studies in rats have shown a modest elevation Platt et al., who found a normal potassium efflux fol- of AChR number and resistance to metocurine following lowing SCh in patients receiving anticonvulsants. ~6 Platt a two-week course of phenytoin, although part of this et al. also speculate that mild up-regulation of AChR resistance is possibly secondary to increased protein bind- could account for these data. ~6 ing. ,l The degree of resistance appears comparable to Studies in rats indirectly support the distinction be- that produced by an upper motor lesion tween mild and marked up-regulation. The proportional (UMNL), 12 thermal trauma, '3 or disuse atrophy, j4 al- increase in perijunctional AChR after thermal trauma 17 though specific direct comparisons have not been made. is similar to the increase in perijunctional AChR during To achieve 50% twitch depression, an UMNL patient re- anticonvulsant therapy: I I Since hyperkalaemia does not quires muscle relaxant blood levels 2-3 X normal; 12 for occur with the latter, these data suggest that the number thermal trauma, 2 • normal; ,3 for disuse atrophy, at least of receptors perijunctionally is similar for both conditions 2 X normal; 14 and for anticonvulsants, 1.7 • normal. 15 (e.g., resistance) and that total numbers are greatly in- Thus, for pharmacodynamic, and not pharmacokinetic creased only for thermal trauma. reasons, a similar increase in blood level and dose of Hypersensitivity to SCh and NDMR resistance follow- NDMR is required in all of these conditions. ing up-regulation of AChR is also due, in part, to the Up-regulation resulting from UMNL and thermal binding characteristics of the immature AChR. 4 These trauma is extensive as evidenced by potentially lethal hy- new receptors are more sensitive to agonists, e.g., SCh, perkalaemia in response to SCh, 4 whereas we believe up- and one-tenth to one-hundredth of normal doses can dep- regulation in response to anticonvulsants is mild. This olarize the end plate. 4 Binding of antagonists, e.g., is based on our data and is possibly explained by the NDMR, is decreased, resulting in resistance. Our data weak junctional blocking effects of anticonvulsants.4 This suggest increased sensitivity to SCh, in that the anticon- speculative difference between mild and marked up- vulsant group had a slight prolongation of action. This regulation is outlined in the Figure. Mild up-regulation prolongation is not likely due to alteration of pseudo- is thought to occur during anticonvulsant therapy, and cholinesterase activity, since carbamazepine and pheny- because the effect occurs at the endplate, new immature toin induce, not inhibit, pseudocholinesterase, is Likewise, receptors appear perijunctionally; the presence of new re- the varied induction agents would not be expected to ceptors actually within the NMJ is unconfu'rned. These have affected our results, since these agents, in the doses new AChRs increase the margin of safety, resulting in used, have no effect on SCh,19 and were fairly evenly NDMR resistance. However, there are insufficient distributed between the control and anticonvulsant numbers to result in hyperkalaemia. With marked up- groups. Last, we did not examine NDMR pharmaco- regulation, e.g., following thermal trauma, new receptors dynamics in our patients; however, that anticonvulsants 942 CANADIAN JOURNAL OF ANAESTHESIA consistently cause NDMR resistance is well estab- apy may be attributable to protein binding and acetylcho- fished. 7-~0 line receptor changes. Anesthesiology 1992; 77: 500-6. Other conditions which might have similar degrees of 12 Shayevitz JR, Matteo RS. Decreased sensitivity to meto- mild up-regulation include 2~ and disuse cufine in patients with upper motoneuron disease. Anesth atrophy of a single limb. 14,22 In these cases, NDMR re- Analg 1985; 64: 767-72. sistance occurs in the absence of hyperkalaemia: ,2~ 13 Martyn JAJ, Goudsouzian NG, Matteo RS, Liu LMP, The slight prolongation of SCh action in patients tak- Szyfelbein SK, Kaplan RE Metocufine requirements and ing anticonvulsants has few clinical implications. One, plasma concentrations in burned paediatric patients. Br J however, is the situation of an unanticipated difficult air- Anaesth 1983; 55: 263-7. way, where return of spontaneous breathing facilitates 14 Gronert GA, Matteo RS, Perkins S. Canine gastrocnemius airway management. disuse atrophy: resistance to paralysis by dimethyl tubocura- In summary, mild AChR up-regulation in response to fine. J Appl Physiol 1984; 57: 1502-6. chronic anticonvulsant therapy is a speculative and rea- 15 Ornstein E, Matteo RS, Young WL, Diaz J. Resistance to sonable pharmacodynamic explanation for the lack of hy- metocurine-induced neuromuscular blockade in patients re- perkalaemia in conjunction with prolonged twitch depres- ceiving phenytoin. Anesthesiology 1985; 63: 294-8. sion following SCh in humans taking antieonvulsants. 16 Platt PR, Thackray NM. Phenytoin-induced resistance to vecuronium. Anaesth Intensive Care 1993; 21: 185-91. References 17 Kim C, Fuke N, Martyn JAJ Bum injury to tat increases 1 Valentin N, Skovsted P, Danielsen B. Plasma potassium nicotine acetylcholine receptors in the diaphragm. Anesthe- following suxamethonium and electroconvulsive therapy. siology 1988; 68: 401-6. Acta Anaesthesiol Scand 1973; 17: 197-202. 18 Puche E, Garcia Morillas M, Garcia de la Serrana H, 2 Mazze R1, Escue HM, Houston JB. Hyperkalaemia and Mota C Probable pseudocholinesterase induction by val- cardiovascular collapse fo~owing administration of sue- proic acid, carbamazepine and phenytoin leading to in- cinylcholine to the traumatized patient. Anesthesiology creased serum aspirin-esterase activity in epileptics. Int J 1969; 31: 540-7. Clin Pharm Res 1989; 9: 309-11. 3 Gronert GA, Theye RA. Pathophysiology of hyperkalemia 19 Bevan DR, Bevan JC, Donati E Muscle Relaxants in induced by succinylcholine. Anesthesiology 1975; 43: 89-99. Clinical . Chicago: Year Book Medical Publish- 4 Martyn JAJ, White DA, Gronert GA, Jaffe RS, WardJM. ers Inc., 1988; 389-413. Up-and-down regulation of skeletal muscle acetylcholine re- 20 Moorthy SS, Krishna G, Dierdorf SF. Resistance to ve- ceptors. Effects on neuromuscular blockers. Anesthesiology curonium in patients with cerebral palsy. Anesth Analg 1992; 76: 822-43. 1991; 73: 275-7. 5 Norris FH Jr, Colella J,, McFarlin D. Effect of diphenylhy- 21 Dierdorf SF, McNiece WL, Rao CC, et aL Effect of sue- dantoin on neuromuscular synapse. Neurology 1964; 14: cinylcholine on plasma potassium in children with cerebral 869-76. palsy. Anesthesiology 1985; 62: 88-90. 6 Gray HStJ,, Slater RM, Pllard RI.. The effect of acutely 22 Fung DL, White DA, Jones BR, Gronert GA. The onset administered phenytoin on vecuronium-induced neuromus- of disuse-related potassium efflux to suceinylcholine. Anes- cular blockade. Anaesthesia 1989; 44: 379-81. thesiology 1991; 75: 650-3. 7 Tempelhoff R, Modica PA, Jellish WS, Spitznagel EL. Resistance to atracurium-induced neuromuscular blockade in patients with intractable disorders treated with anticonvulsants. Anesth Analg 1990; 71: 665-9. 8 Roth S, Ebrahim ZY. Resistance to pancuronium in pa- tients receiving carbamazepine. Anesthesiology 1987; 66: 691-3. 90rnstein E, Matteo RS, Schwartz AE, Silverberg PA, Young WL, Diaz J The effect of phenytoin on the magni- tude and duration of neuromuscular block following atra- curium or veeuronium. Anesthesiology 1987; 67: 191-6. 10 Ornstein E, Matteo RS, Young WI_, Diaz J. Resistance to metocufine-induced neuromuscular blockade in patients re- ceiving phenytoin. Anesthesiology 1985; 63: 294--8. 11 Kim CS, Arnold FJ,, ltani MS, Martyn JAJ Decreased sensitivity to metoeurine during long-term phenytoin ther-