BETA-ADRENOCEPTOR BLOCKADE, ALPHA-STIMULATION AND CHANGES IN PLASMA POTASSIUM CONCENTRATION AFTER SUXAMETHONIUM ADMINISTRATION IN DOGSf

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1 Br.J. Anaesth. (987), 59, 6-66 BETA-ADRENOCEPTOR BLOCKADE, ALPHA-STIMULATION AND CHANGES IN PLASMA POTASSIUM CONCENTRATION AFTER SUXAMETHONIUM ADMINISTRATION IN DOGSf D. R. GOLDHILL, J. A. J. MARTYN AND D. C. HOAGLIN Adrenoceptor activity has been shown to play a role in the extrarenal disposition of potassium. Evidence in animals and man indicates that beta (P)-adrenoceptor blockade (Rosa et al., 980) or alpha (a)-adrenoceptor stimulation (Williams et al., 984) prevents potassium from entering cells, whereas the reverse (P-stimulation or a-blockade) promotes cellular reuptake (Williams et al., 985). The effects appear to be P 2 -mediated (Brown, Brown and Murphy, 983). Serum potassium concentration increases after the administration of suxamethonium and may attain lethal values in association with denervation or burns (Gronert and Theye, 975). In the presence of either P-blockade or a-stimulation one might, therefore, expect the normal increase in potassium concentration after suxamethonium to be augmented and prolonged. To explore this possibility, we examined in dogs the effect of P-blockade or a-stimulation on the changes in plasma potassium concentrations after the administration of suxamethonium, and further examined the differential role of P r and p 2 -receptors in this process, using the selective P-adrenoceptor blocking drugs metoprolol (P,) and ICI 855 (p 2 ). D. R. GOLDHIIX,* M.B.B.S., F.P.A.R.C.S., J. A. J. MARTYN, M.D,, F.F.A.R.CS.; D. C. HOAGLIN, PH.D.; The Anesthesia Services of the Massachusetts General Hospital and Shriners Burns Institute, and the Department of Anaesthesiology, Harvard Medical School, Boston, Massachusetts 0244, U.S.A. Accepted for Publication: November 3, 986. Correspondence to J.M., Department of Anesthesia, Massachusetts General Hospital, Boston MA 024, U.S.A. *Present address: Department of Anaesthesia, The London Hospital, London El IBB. fpresented in part at the Annual Scientific Meeting of the Association of Anaesthetists of Great Britain and Ireland, September 985 and at the 60th Congress of the International Anesthesia Research Society, Las Vegas, March 986. SUMMARY A study involving 20 mongrel dogs tested the hypotheses that beta-adrenoceptor blockade or alpha-adrenoceptor stimulation may potentiate and prolong the increase in plasma potassium concentration after suxamethonium administration, and that the beta effect is beta 2 -receptor mediated. Propranolol 0.5 mg kg- altered the time to peak increase in plasma concentration of potassium after suxamethonium, but did not increase peak concentrations. In controls, the maximum change (0.83 mmol litre' ) occurred at 3 min, while in propranolol-treated dogs the peak change (0.96 mmol litre~ l occurred at 30 min. Similar results were obtained when metoprolol 0.25 mg kg- and ICI mg kg- were used, respectively, as selective beta x - and beta t -adrenoceptor blockers. The increases in potassium concentration following suxamethonium in the metoprolol group (0.98 mmol litre- ) and the ICI 855 group (0.82 mmol litre- ) reached maximum concentrations at 30 min compared with the controls (0.79 mmol litre- ) which achieved a maximum at 3 min. Phenylephrine was infused at 8 fig kg- min- to produce alpha stimulation. The infusion a lone altered plasma concentrations of potassium, but the haemodynamic changes were such that conclusions as to the effect of alpha-stimulation on release of potassium after suxamethonium could not be reached. MATERIALS AND METHODS Institutional approval was given for the study. Mongrel dogs ( kg) were anaesthetized with thiopentone mg kg" i.v. The trachea

2 62 BRITISH JOURNAL OF ANAESTHESIA was intubated and mechanical ventilation instituted. Anaesthesia was maintained with % halothane in oxygen. No neuromuscular blockers were administered before the suxamethonium, and there was no clinical evidence of inadequate anaesthesia. Catheters were placed percutaneously in a femoral artery and vein. Systemic arterial pressure was recorded continuously. Ventilation was adjusted to maintain the -Pa COt at kpa. Blood-gas tensions were measured throughout the study and ventilation adjusted, as necessary. Once stable anaesthesia was established, an infusion of 0.9 % saline 3 ml kg" was started and maintained throughout each investigation. All drugs except suxamethonium were diluted in saline, and administered via the infusion. All measurements were made from arterial blood samples which were drawn into pre-heparinized syringes, placed on ice and analysed for plasma potassium concentration with an ion-selective electrode (Nova ) (Ladenson, 979). The experiment was performed in two parts. Part The response to suxamethonium mg kg" was noted during the infusion of physiological saline for each dog. At intervals of at least 6 days, the dogs were re-anaesthetized and the responses to the administration of suxamethonium in the presence of phenylephrine or propranolol recorded. Controls (n = 8). The response to suxamethonium was noted during the infusion of saline in each dog. Of these eight dogs, two subsequently Control NaCI L Phenylephrine 8 pg kg' min" Y///////^///////////////^^^ Propranolol -+2 (jg kg" min" - Metoprolol 250 pgkg' -+pgkg' l min' - received phenylephrine but no propranolol, and two propranolol but no phenylephrine. The other four received on separate occasions either propranolol or phenylephrine. Only the six dogs that received the study drug acted as controls for their group. Phenylephrine infusion and suxamethonium (n = 6). Phenylephrine 8 ug kg" min" was infused from the start of the saline infusion. This dose was based on previous reports of the hyperkalaemic effect of phenylephrine (Todd and Vick, 97). Four of these dogs also received (on another occasion) an infusion of phenylephrine 8 ig kg" min", but no suxamethonium. Propranolol and suxamethonium (n = 6). Propranolol 0.5 mg kg" was given over 0 min from the start of the saline infusion, and maintained at 2 ug kg" min" thereafter. In all groups, apart from the group receiving phenylephrine without suxamethonium, suxamethonium mg kg" was given 30 min after the start of the infusion and blood was analysed for plasma potassium concentration at the following times: pre-infusion, infusion +0, + 25 (duplicate samples), and, 3, 5, 0, 5, 30, 60 and min after suxamethonium administration. Timing and dosage of drugs are shown infigure. Part 2 A further set of studies was performed to characterize the differential effect of P,- and P s -blockers. ICI 855 Sux. i i i i i i i i i i i i i i i i i i i Time (min) FIG.. Timing and doses of drugs administered.

3 ADRENOCEPTOR ACTIVITY, K + CONCENTRATION AND SUXAMETHONIUM 63 Controls (n = 8). These consisted of the same eight dogs for which data after saline infusion and suxamethonium were already available from Part. These were compared with two separate groups of dogs. Metoprolol (n = 6). Metoprolol 0.25 mg kg" was administered over 0 min, followed by ug kg~ l min~ l. ICI 855 (n = 6). ICI 855 O.lmgkg- was given over 0 min. This dose was chosen to give adequate P 2 -blockade without major P s effects in dogs (D. Riley, ICI Pharmaceuticals, England; persona] communication). As with propranolol, both metoprolol and ICI 855 were started 30 min before the administration of suxamethonium (fig. ). Blood was drawn for analysis of plasma potassium concentration as for Part. The effectiveness of P,-blockade was tested in the propranolol and metoprolol groups with a bolus of isoprenaline 0.5 ig kg" at the conclusion of the study. Since ICI 855 should have little PJ effect, the isoprenaline test was not performed in this group. Statistical analyses Statistical treatment of the data utilized analysis of variance, with allowance for repeated measures, on plasma potassium concentration and on the change in plasma potassium concentration after suxamethonium. The significance of comparisons of plasma potassium concentration with baseline within a treatment group and comparisons of change in plasma potassium concentration between groups was determined by t statistics, setting the critical value according to Bonferroni's inequality (Miller, 98) so that the simultaneous significance level would not exceed Thus, for example, to ensure that a set of five significance tests on the same data has, at most, a 0.05 probability of yielding one or more significant results by chance alone, the significance level for each of the five tests should be 0.05/5 = 0.0. RESULTS The suxamethonium-induced changes in plasma potassium concentration from baseline (5 min before administration of suxamethonium) for the P-blocked dogs are shown in tables I and II. There were no significant differences in the baseline values of potassium concentration between the groups. All groups experienced a significant increase in plasma potassium concentration by 3 min after suxamethonium. This increase persisted for min. In the control group, the potassium reached maximum concentration at 3 min and remained increased for 30 min before returning to baseline (tables I and II). The P-blocked groups also showed significant increases in potassium concentration at 3 min, but peak potassium concentrations occurred at 30 min. These reverted to baseline only at or after 60 min (tables I and II). There were no statistically significant differences between the maximum TABLE I. Changes (SD)from baseline in potassium concentration (mmol litre' ) after suxamethonium. * Significant changes from baseline within a group (P < 0.05, simultaneous) Time after sux. (min) Table II. Changes (SD)from baseline in potassium concentration (mmol litre' ) after tuxamethonium. Significant changes (P < 0.05, simultaneous): *from baseline within a group; \from control group Control 0.435(0.4) (0.234)* (0.208)* (0.248)* 0.762(0.3)* (0.65)* (0.44) -0.22(0.50) Propranolol (0.059) (0.09)* (0.223)* (0.32)* 0.772(0.30)* (0.375)* (0.344) (0.239) Time after sux. (min) Control Metoprolol ICI (0.46)* 0.7 (0.372)* (0.273)* (0.226)* (0.309)* (0.540)* (0.393) (0.204) 0.240(0.96) (0.275)* (0.25)* (0.246)* (0.283)* (0.488)* (0.408)*f (0.267) (0.29) (0.237)* (0.93)* 0.480(0.84)* 0.670(0.2)* 0.85 (0.9)* 0.482(0.72)* 0.077(0.3)

4 64 BRITISH JOURNAL OF ANAESTHESIA TABLE III. Changes (SD) from baseline in potassium concentration (mmol litre '). Control (sux. only) and phenylephrine with and without suxamethonium Time after sux. (min) Control (0.54) (0.40) (0.34) (0.254) (0.320) (0.439) (0.362) -0.28(0.26) concentrations obtained in each group. The time course of the change in potassium concentration, however, was altered by all of the P-blockers compared with their respective controls (P < 0.0). For the metoprolol group, the change in potassium value at 60 min was significantly greater than controls for the same time (P < 0.05) (table II). There was no difference between the metoprolol and ICI 855 groups in the changes in potassium concentration with time. After isoprenaline 0.5 ig kg", the average maximum increase in heart rate in propranolol-treated dogs was 6 beat min" and in die metoprolol group it was 35 beat min". Phenylephrine alone caused an increase in plasma potassium concentration after 0 min which returned to baseline after 25 min. If no suxamethonium was given, the plasma potassium concentration increased slowly subsequently. If suxamethonium was given, there was an immediate increase which was sustained (table III). These changes, however, were measured during a period of marked cardiovascular and metabolic derangements. Average arterial pressure for all dogs receiving phenylephrine (whether given suxamethonium or not) was 30/79 mm Hg before infusion and 278/62 mm Hg at 25 min of infusion. There was an associated metabolic acidosis which became increasingly pronounced over time. In two instances, frank pulmonary oedema necessitated termination of the study. DISCUSSION Adrenoceptor agents, probably acting via the Na + /K + pump (Clausen and Flatman, 977), play a role in the extrarenal disposition of potassium. Adrenaline leads to an increase in the extrarenal uptake of potassium, almost certainly mediated through P,-adrenoceptor stimulation (Brown, Phenylephrine 0.43 (0.49) (0.460) 0.444(0.48) (0.557) 0.62 (0.566) 0.65 (0.562) (0.467) (0.65) Phenylephrine without sux (0.4) 0.8(0.09) (0.87) (0.398) (0.243) Brown and Murphy, 983; De Fronzo, Bia and Birkhead, 98). This conclusion is reinforced by the observation that P 2 -stimulation can decrease plasma potassium concentrations arising from the hyperkalaemia secondary to familial periodic paralysis (Wang and Clausen, 976). Exercise leads to an increase in plasma potassium concentration. This is enhanced by P-blockade, especially when non-selective as opposed to P^selective blockade is induced (Carlsson et al., 978). P-Blockade has also been shown to impair the extrarenal disposition of a potassium load in some patients (Rosa et al., 980; Torretti et al., 986), although this has not always been confirmed (Rolf Smith et al., 984). Chronic P-blockade alone leads to a slight increase in plasma potassium concentration (Lundborg, 983). It has also been suggested that a-adrenoceptor stimulation impairs the extrarenal disposition of potassium, and that at least some of the increase in plasma potassium concentration seen in subjects receiving chronic P-blocker therapy may be secondary to the unopposed effects of a-stimulation (Williams et al., 984). Therefore, we might expect P-blocker or a-stimulation to have some effect on potassium release after suxamethonium. Our study examined this hypothesis and attempted to differentiate the PJ and P, effects using metoprolol (P t ) and ICI 855 (an experimental selective p s antagonist) as selective P-blockers. Our results demonstrate that P-blockade alters the time to peak potassium concentration after suxamethonium, and the duration of the increase, but does not significantly affect the magnitude of the response. Our data confirm the findings of Todd and Vick (97) that phenylephrine at an infusion rate of 8 ug kg" in the dog leads to an initial increase and subsequent reduction in plasma potassium concentration. We used this infusion rate since they

5 ADRENOCEPTOR ACTIVITY, K + CONCENTRATION AND SUXAMETHONIUM 65 concluded that the hyperkalaemic effect of phenylephrine was maximum at this dose. However, these authors failed to comment on the profound cardiovascular effects of this infusion. Arterial pressures were increased to non-physiological values, and profound metabolic acidosis developed, presumably secondary to extreme vasoconstriction and inadequate perfusion. In this situation, it is not possible to determine whether the changes in plasma potassium concentration were caused by the peripheral vascular effects, or by the direct cellular effects of phenylephrine. The same comments apply to the changes in plasma potassium concentration after suxamethonium in the presence of phenylephrine, in that the metabolic consequences of the cardiovascular effect were enough to mask and outweigh any direct effect at the cellular level. In dogs, an infusion of propranolol alone had no effect on plasma potassium concentration (Todd and Vick, 97). The dose of propranolol used in our study has been shown to have good blocking activity in the dog, and is similar to doses used by other workers (Harry et al., 973). The bolus of isoprenaline 0.5 ug kg" administered at the end of each investigation confirmed the efficacy of the blockade. We deliberately used a relatively small Pj-blocking dose of metoprolol because of a desire to avoid the P 2 effects seen with larger doses. This is reflected in the results of the isoprenaline challenge test. We found that both non-selective and selective P-blockade altered the time pattern of the release and re-uptake of potassium after suxamethonium. However, the peak concentrations were not increased significantly in the propranolol group. Only for metoprolol at 60 min were individual values significantly different from control. P-Blockade may effect the release of potassium from cells, thus explaining the later peak for the plasma potassium concentrations following suxamethonium (Carlsson et al., 978). Our results contrast with the findings of Mc- Cammon and Stoelting (984), who described a marked increased in plasma potassium concentration after suxamethonium in dogs given propranolol. The increase in potassium concentration in their propranolol-treated dogs appeared to be greater and more prolonged than ours. The increase in their controls seemed to be less than in our study. We can find no easy explanation for these differences. With the exception of the additional use of nitrous oxide, their anaesthesia was similar to ours. Their dogs received an initial bolus of 0.25 mg kg of propranolol, with subsequent increments of O.lmgkg". Suxamethonium was administered 0 min after the p- blocker. We cannot comment on their method of collecting, storing and evaluating potassium concentrations since this was not discussed; however, these factors could well affect the results (Hill et al., 980). Although Pfblockade, compared with P 3 selectively impairs extrarenal uptake of potassium, we found no difference between the predominantly PJ effect of metroprolol and the P t action of ICI 855 following suxamethonium. Metoprolol also has some P, activity, and it is possible that the doses we used were sufficient to unmask this effect. The dose of ICI 855 was chosen as adequate for a P,-block without significant P x effects. We are aware of no case reports in man implicating P-receptor blockade leading to hyperkalaemia following suxamethonium. It is reasonable to expect such blockade to have some effect on the release of potassium after suxamethonium. However, if these data can be extrapolated to man, it appears that lethal hyperkalaemia probably would not result from the use of suxamethonium in the presence of acute P-blockade. ACKNOWLEDGEMENTS We are grateful to ICI for the supply of ICI 855. The study was supported in part by grants from the Shriners Burns Institute and NIH GM 2700 and REFERENCES Brown, M. J., Brown, D. C, and Murphy, M. B. (983). Hypokalaemia from beta 2-receptor stimulation by circulating epinephrine. N. Engl.J. Mid,, 309, 44. Carlsson, E., Fellenius, E., Lundborg, P., and Svensson, L. (978). P-Adrenoceptor blockers, plasma-potassium, and exercise. Lancet, 2, 424. Clausen, T., and Flatman, J. A. (977). The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J. Physiol. (Land.), 270, 383. DeFronzo, R. A., Bia, M., and Birkhead, G. (98). Epinephrine and potassium homeostasis. Kidney Int., 20, 83. Gronert, G. A., and Theye, R. A. (975). Pathophysiology of hyperkalemia induced by succinylcholine. Anesthesiology, 43, 89. Harry, J. D., Kappagoda, C. T., Linden, R. J., and Snow, H. M. (973). Action of propranolol on the dog heart. Cardiovasc. Res., 7, 729. Hill, A. B., Nahrwold, M. L., Noonan, D., and Northrop, P. (980). A comparison of methods of blood withdrawal and sample preparation for potassium measurements. Anesthesiology, S3, 60.

6 66 BRITISH JOURNAL OF ANAESTHESIA Ladenson, J. H. (979). Evaluation of an instrument (Nova-) for direct potentiometric analysis of sodium and potassium in blood and their indirect potentiometric determination in urine. Clin. Chan., 25, 757. Lundborg, P. (983). The effect of adrenergic blockade on potassium concentrations in different conditions. Ada Med. Scand. (Suppl.), 672, 2. McCammon, R. L., and Stocking, R. K. (984). Exaggerated increase in serum potassium following succinylcholine in dogs with Beta blockade. Anesthesiotogy, 6, 723. Miller, R. G. jr (98). Simultaneous Statistical Inference, 2nd Edn, pp. 8, 67. New York: Springer-Verlag. Rolf Smith, S., Kendall, M. J., Ryder, C, and Laugher, S. (984). Lack of influence of beta adrenergic blockade on serum potassium during an infusion of potassium. Eur. J. Pharmacol., 26, 425. Rosa, R. M., Silva, P., Young, J. B., Landsberg, L., Brown, R. S., Rowe, J. W., and Epstein, F. H. (980). Adrenergic modulation of extrarenal potassium disposal. N. Engl. J. Med., 302, 43. Todd, E. P., and Vick, R. L. (97). Kalemotropic effect of epinephrine: analysis with adrenergic agonists and antagonists. Am. J. Physiol., 220, 964. Torretti, J., Gerson, J. I., Oates, R. P., and Lange, L. S. (986). P-Adrenoceptor blockade and tolerance to potassium. Anesthaiology, 64, 846. Wang, P., and Clausen, T. (976). Treatment of attacks in hyperkalaemic familial periodic paralysis by inhalation of sajbutamol. Lancet,, 22. Williams, M. E., Gervino, E. V., Rosa, R. M. Landsberg, L., Young, J. B., Silva, P., and Epstein, F. H. (985). Catecholamine modulation of rapid potassium shifts during exercise. N. Engl. J. Med., 32, 823. Rosa, R. M., Silva, P., Brown, R. S., and Epstein, F. H. (984). Impairment of extrarenal potassium disposal by a-adrcnergic stimulation. N. Engl.J. Med., 3, 45.