1401

Adrenaline and Potassium:

Everything in Flux

THE LANCET

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WE are all acquainted with the rigorous controlsystems governing the plasma K concentration-orare we? Certainly, we know the potentially disastrousconsequences of both hypokalaemic and hyper-kalaemic arrhythmias, and the body’s efforts to steer acourse between these hazards. But is it not the truththat the plasma K concentration is less buffered thanthat of any other major ion; and that it is preciselybecause this concentration can change rapidly and(usually) with impunity through a 3-fold range that thesafety limits are sometimes breached? (Patients may besubmitted to parathyroidectomy to alleviate a 5-10070increase in serum Ca", while 10 minutes’ hardexercise can raise plasma K by 50%.)Long-term control of plasma K is effected by the

kidneys with the aid of aldosterone secretion; and,except in addisonian crisis, life-threateninghyperkalaemia seldom arises in the presence of normalrenal function. However, only a fraction of the body’sK is present in the circulation and handled by thekidney; acute rises in plasma K can therefore occurwhen even small amounts of K leak out of cells-for

instance, during heavy exercise or in diabeticketoacidosis. Conversely, while diuretics are thecommonest cause of chronic hypokalaemia, the

quickest method of reducing plasma K is to "push"K into cells, usually by intravenous administration ofinsulin. The accumulation and retention ofK in cellsagainst its concentration gradient requires the activityof the Na+/K+-ATPase enzyme; and the extendedunfolding of a story in adrenergic pharmacology hasshown how the deliberate stimulation of this enzyme

offers a simple emergency treatment of

hyperkalaemia. IAlmost fifty years ago D’Silva2 reported that

adrenaline, when given to animals, lowers plasma K.The observation passed, unexplained, into the smallprint of textbook pharmacology,3 until thirty yearslater when the first clue was provided by measurementsofNa+ and K+ flux in the frog atrium. Subsequentlyadrenaline was found to increase K + flux intomammalian skeletal muscle.5 The suspicion that thehypokalaemic effect of adrenaline was in some waysecondary to its other actions (eg, stimulation of reninrelease) was finally dispelled a few years ago whenadrenaline was shown to induce hypokalaemia in theabsence of kidneys, pancreas, adrenals, and

sympathetic nerves.6-9 At the same time, Flatman andClausen showed in isolated rat skeletal muscle thatadrenaline stimulation of K transport is inhibitedboth by ouabain and by 02 -receptorblockade-suggesting the existence of a -receptorlinked ATPase. 10-12

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What are the clinical implications of these findings?Is adrenaline of importance in the physiological controlof plasma K’? Can excessive release of adrenaline everbe responsible for hypokalaemia? And can, reversely,(3-adrenoceptor stimulation be used to therapeuticadvantage in the emergency treatment of

hyperkalaemia? f3-blocking drugs exaggerate the

hyperkalaemia of exercise, and the main physiologicalrole of adrenaline in this respect may well be to

antagonise the leak of intracellular K during muscleactivity.13,14 It is less certain-that hyperkalaemia itselfstimulates’ adrenaline release (as is the case, for

instance, with aldosterone). But high K +

concentrations are a standard means of stimulatingcatecholamine release in vitro;15 and adrenalinesecretion is above normal in some patients with severe

1. Wang P, Clausen T. Treatment of attacks in hyperkalaemic familial periodic paralysisby inhalation of sulbutamol. Lancet 1976; i: 221-23

2. D’Silva JL The action of adrenaline on serum potassium J Physiol 1934; 82: 393-98.3 Innes IR, Nickerson M Drugs acting on postganglionic adrenergic nerve endings and

structures innervated by them (sympathomimetic drugs). In: Goodman LS, GilmanA, eds. The pharmacological basis of therapeutics, 3rd ed. London: Collier-Macmillan, 1965· 493.

4. Glitsch HG, Haas HG, Trautwein W. The effect of adrenaline on the K and Na fluxesin the frog’s atrium. Naunyn Schiedebergs Arch Exp Pathol 1965; 250: 59-71

5. Vick RL, Todd EP, Ludke DW Epinephrine-induced hypokalemia: relation to liverand skeletal muscle. J Pharmacol Exp Ther 1972; 181: 139-46.

6. Olsson AM, Persson S, Schroder R. Effects of terbutaline and isoproterenol onhyperkalemia in nephrectomized rabbits. Scand J Urol Nephrol 1978; 12: 35-39.

7. Bia MJ, DeFronzo RA. Extrarenal potassium homeostasis. Am J Physiol 1981; 240:F257-68.

8. Rosa RM, Silva P, Young JB, et al. Adrenergic modulation of extrarenal potassiumdisposal N Engl J Med 1980, 302: 431-34

9. Pettit GW, Vick RL. An analysis of the contribution of the endocrine pancreas to thekalemotropic actions of catecholamines. J Pharmacol Exp Ther 1974; 190: 234-42.

10. Clausen T, Flatman JA. The effect of catecholamines on Na-K transport andmembrane potential in rat soleus muscle. J Physiol 1977; 270: 383-414

11. Clausen T, Flatman JA Beta 2-adrenoceptors mediate the stimulating effect ofadrenaline on active electrogenic Na-K-transport in rat soleus muscle. Br JPharmacol 1980; 68: 749-55.

12. Clausen T. Adrenergic control of Na+-K+-homeostasis. Acta Med Scand 1983; suppl672· 111-15.

13 Carlsson E, Fellenius E, Lundborg P, Svensson L &bgr;-adrenoceptor blockers, plasma-potassium and exercise Lancet 1978, ii: 424-25

14. Lundborg P, Astrom H, Bengtsson C, et al. Effect of &bgr;-adrenoceptor blockade onexercise performance and metabolism. Clin Sci 1981; 61: 299-305.

15. Douglas WW Stimulus-secretion coupling: the concept and clues from chromaffin andother cells. Br J Pharmacol 1968; 34: 451-74.

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familial hyperkalaemic periodic paralysis.’6 There ismore certainty about the clinical reality of adrenaline-induced hypokalaemia. Man seems to be more

sensitive than other species to this effect, and falls ofalmost 1 mmol/1 are observed after infusions that causea 20-30-fold rise in plasma adrenaline. "-19 Rapidincreases of this order are not merely a laboratoryextravagance: they can arise in sick patients (eg, aftermyocadial infarction20,21) and even in frightenedhealthy subjects.22 Indeed, the transient hypokalaemianoted in inpatients immediately after admission tohospital may be a marker of their apprehension. 23There is little doubt that the mechanism of

hypokalaemia in man is a (32-receptor-mediated influxof K into cells, although necessarily the evidence isless direct than in animals. Thus the effect is blocked by(32 (or non-selective &bgr;)-antagonists, but less effectivelyby -antagonists’’—the converse of the effect of

(3-blockers on renin release.25 Reduction of plasma K +

has also been noted, and employed therapeutically,with usual doses of many of the selective &bgr; -receptorpartial agonists, such as salbutamol and terbutaline, 2 6, 27whereas only high doses of isoprenaline (a non-

selective &bgr;-receptor agonist) reduce plasma K + .19Furthermore, urine K excretion is actually reducedby adrenaline; 18,19,28 whereas the opposite tendency isseen with 0-receptor blockade, in which the shift ofK

+

to the extracellular compartment presents an increasedK + load to the kidneys.29,30 Stimulation of Na’K + -ATPase by adrenaline is less easy to demonstrate invivo. In the rabbit, therapeutic doses of digoxin do notinhibit adrenaline-induced hypokalaemia:3’ perhaps

16. Clausen T, Wang P, Orskov H, Kristensen O. Hyperkalemic periodic paralysis.Relationships between changes in plasma water, electrolytes, insulin andcatecholamines during attacks. Scand J Clin Lab Invest 1980; 40: 211-20.

17. Brown MJ, Macquin I. Catecholamine neurotransmitters and the heart. Acta MedScand 1982; suppl 660: 34-39.

18. Struthers AD, Reid JL, Whitesmith R, Rodger JC. Effect of intravenous adrenaline onelectrocardiogram, blood pressure, and serum potassium. Br Heart J 1983; 49:90-93.

19. Brown MJ, Brown DC, Murphy MB Beta2-receptor stimulation by circulatingepinephrine causes prolonged hypokalemia. N Engl J Med 1983; 309: 1414-19.

20. Karlsberg RP, Cryer PE, Roberts S. Serial plasma catecholamine response early in thecourse of clinical acute myocardial infarction: relationship to infarct extent andmortality. Am Heart J 1981; 102: 24-29.

21. Mueller HS, Ayres SM. Propranolol decreases sympathetic nervous activity reflectedby plasma catecholamines during evolution of myocardial infarction man. J ClinInvest 1980; 65: 338-46.

22. Dimsdale JE, Moss J. Short-term catecholamine response to psychological stressPsychosom Med 1980; 42: 493-97

23. Morgan DB, Young RM. Acute transient hypokalaemia new interpretation of acommon event. Lancet 1982, ii: 751-52.

24. Struthers AD, Reid JL, Whitesmith R, Rodger JC The effects of cardioselective andnon-selective &bgr;-adrenoceptor blockade on the hypokalaemic and cardiovascularresponses to adrenomedullary hormones in man. Clin Sci 1983; 65: 143-47

25. Buhler FR, Burkart F, Lutold BE, Kung M, Marbet G, Pfisterer M. Antihypertensivebeta blocking action as related to renin and age: a pharmacologic tool to identifypathogenetic mechanisms in essential hypertension. Am J Cardiol 1975; 36:652-69.

26. Leitch AG, Clancy LJ, Costello JF, Flenley DC. Effect of intravenous infusion ofsalbutamol on ventilatory response to carbon dioxide and hypoxia on heart rate andplasma potassium in normal men. Br Med J 1976, i: 365-67.

27 Moravec MA, Hurlbert BJ. Hypokalemia associated with terbutaline administration inobstetrical patients. Anesth Analg 1980; 59: 917-20.

28. DeFronzo RA, Bia M, Birkhead G. Epinephrine and potassium homeostasis. KidneyInt 1981; 20: 83-91

29. Steiness E. Negative potassium balance during beta-blocker treatment of hypertension.Clin Pharmacol Ther 1982, 31: 691-94.

30. Pedersen G, Pedersen A, Pedersen EB. Effect of propranolol on total exchangeablebody potassium and total exchangeable body sodium in essential hypertension.Scand J Clin Lab Invest 1979; 39: 167-70.

31. Price JS, Struthers AD, Brown MJ. The effect of digoxin on adrenaline inducedhypokalaemia in rabbits. Clin Sci 1984; 66: 68P

this reflects the inefficacy of digoxin as an ATPaseinhibitor outside the heart-and the danger of

extrapolating from in vitro studies when studyingputative Na+/K+-ATPase inhibitors.32There is considerable evidence linking

hypokalaemia with an increased incidence ofventricular arrhythmias and death after myocardialinfarction.33-35 Although the contribution of diureticsto this has been questioned,36 it may be important thatadrenaline and thiazide-induced hypokalaemia are

additive: Struthers et al37 recorded plasma K values aslow as 2’ 4 mmol/1 in volunteers receiving both drugs.37It remains possible that the sinister reputation ofhypokalaemia in such patients merely reflects the

greater release of adrenaline in patients with the moresevere infarcts, 38 and the answer can come only from atrial of selective blockade of adrenaline-induced

hypokalaemia after myocardial infarction. Meanwhile,we can speculate that some of the recentlydemonstrated benefit from &bgr;-blockade in myocardialinfarct patients is due to an inhibition of adrenaline-induced hypokalaemia.39 Brown et all9 report thatselective &bgr;2-adrenoceptor blockade in normalvolunteers can abolish adrenaline-induced

hypokalaemia without loss of the inotropic effect ofadrenaline (essential to patients with severelycompromised myocardial function).19 The use of

&bgr;2-receptor blockade alone in infarct patients might beunwise without simultaneous a-receptor blockade to

prevent the rises in arterial pressure and plasma K thatresult from unopposed a-receptor stimulation byadrenaline4O; but, with this caveat, it would seem ofinterest to investigate the clinical use of P2 -receptorblockade in prevention of post-infarct arrhythmias.Another group in whom such a drug (if available) couldbe prophylactic is those at risk from sport-assistedarrhythmias.41 Whereas plasma K

+

rises duringmuscular activity, it falls sharply after exercise orbetween bouts of activity, as in squash, and it may bethese rapid fluxes of K+ that are dangerous.The adrenergic influence on Na + /K homoeostasis

is not confined to plasma K. One of the most potentchronic stimuli of the sympathetic nervous system is

32. Poston L, Sewell RB, Wilkinson SP, et al. Evidence for a circulating sodium transportinhibitor in essential hypertension. Br Med J 1981, i: 847-49.

33. Dyckner T, Helmers C, Lundman T, Wester PO. Initial serum potassium level inrelation to early complications and prognosis in patients with acute myocardialinfarction. Acta Med Scand 1975; 197: 207-10.

34. Johansson BW, ed. Electrolytes and cardiac arrhythmias. Acta Med Scand 1981; suppl647: 1-177.

35. Duke M. Thiazide-induced hypokalemia associated with acute myocardial infarctionand ventricular fibrillation. JAMA 1978; 239: 43-45.

36. Medical Research Council Working Party on Mild to Moderate HypertensionVentrular extrasystoles during thiazide treatment: substudy of MRC mildhypertension trial. Br Med J 1983; 287: 1249-53.

37. Struthers AD, Whitesmith R, Reid JL. Prior thiazide diuretic treatment increasesadrenaline-induced hypokalaemia. Lancet 1983; i: 1358-60.

38. Harrington JT, Isner JM, Kassirer JP Our national obsession with potassium. Am JMed 1982; 73: 155-59.

39 Yusuf S, Ramsdale D, Peto R, et al. Early intravenous atenolol treatment in suspectedacute myocardial infarction. preliminary report of a randomised trial. Lancet 1980,ii. 273-76.

40. Struthers AD, Whitesmith R, Reid JL. Metabolic and haemodynamic effects ofincreased circulating adrenaline in man. Effect of labetalol, an alpha and betablocker. Br Heart J 1983, 50: 277-81.

41. Northcote RJ, Ballantyne D Sudden cardiac death in sport Br Med J 1983; 287:1357-59.

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Na+ depletion.42 The importance of this is, however,questionable since drugs that reduce or antagonisesympathetic activity do not have a pronouncednatriuretic effect; indeed the opposite occurs withguanethidine. Nevertheless, catecholamines can greatlyaffect Na+ and water transport, as illustrated by thework of Walters et al43 in fetal lambs. One of the moststressful periods of our life is its beginning; and thehighest recorded values of plasma adrenaline have beenin umbilical cord arterial blood drawn during vaginaldelivery.44 After birth, babies delivered by caesareansection have lower adrenaline levels but wetter lungsthan those delivered vaginally.45,46 The surge ofadrenaline during vaginal delivery was shown, inWalters’ experiments, to stimulate the rapidreabsorption of sodium and water from the lungsimmediately after birth.43 Again this seems to be a&bgr;2-receptor-mediated effect, caused by adrenaline butnot noradrenaline, and again we may speculate that the&bgr;2-partial agonists could be therapeutically useful in adisease such as the adult respiratory distress syndromein which the lungs become overwhelminglywaterlogged. In the hierarchy of hormones, adrenalineis usually subordinate to its neuronally released parent,noradrenaline. But in the case of ionic flux the roles arereversed.

Payment by DiagnosisOcT 1, 1983, marked a turning-point in American

health care. That day saw the beginning of a big effortto contain health costs-the introduction of "diagnosisrelated groups" as a means of determiningreimbursements to hospitals.’ The consequences forthe practice of medicine and the delivery of health carecould be far-reaching.The rising cost of health care has become a major

political issue in the United States. Through a

combination of factors-increased use of new and

existing tests, widespread availability of expensivetechnology, and world-wide inflation-the average billfor a day’s hospital care increased by almost 18% a yearfrom 1979 to 1982.2 Financial disaster was predicted

42. Nicholls MG, Kiowski W, Zweifler AJ, Julius S, Schork MA, Greenhouse J. Plasmanorepinephrine variations in dietary sodium intake. Hypertension 1980; 2: 29-32.

43. Brown MJ, Olver RE, Ramsden CJ, Strang LB, Walters DV. Effects of adrenaline andof spontaneous labour on the secretion and absorption of lung liquid in the fetallamb. J Physiol 1983; 344: 137-52.

44 Lagercrantz H, Bistoletti P. Catecholamine release in the new-born infant at birth.Pediatr Res 1977; 11: 889-93.

45. Bland RD, Macmillan DD, Bressack MA. Labour decreases lung water content of new-born rabbits. Am J Obstet Gynecol 1979; 134: 364-67.

46. Milner AD, Saunders RA, Hopkin IE Effects of delivery by caesariean section on lungmechanics and lung volume in the human neonate. Arch Dis Childh 1978; 53:545-48.

1. Medicare Program: Prospective Payments for Medicare Inpatient Hospital Services.Federal Register Sept 1, 1983.

2. Diagnosis related groups (DRGs) and the Medicare program: implications for medicaltechnology. Technical Memorandum. Washington, DC: Office of TechnologyAssessment, Congress of the United States, July, 1983.

for the Medicare system ifhealth care costs could not becontained. It became clear that this could not beachieved on a voluntary basis either by medical

practitioners or by hospitals, and the federal

government finally took the initiative. The Medicaresystem pays the hospital expenses of people aged 65years and older, and its resources were under pressurenot only from ever-increasing health care costs but alsofrom the rapid expansion of the eligible population.Medicare payments for inpatient hospital servicesincreased from$3 billion a year when the programmewas initiated in 1967, to$33 billion a year in 1982,2 2while the number of people over the age of 65, at

present 25’ 5 million, is projected to increase to 45million by the year 2020.3 3

In the past, Medicare and all of the major insurancecompanies have based their payments to hospitals on"reasonable" costs incurred in caring for the patient,with no set limits. Under this system hospitals had noincentive to contain costs: the longer that a patientstayed in hospital and the more tests that could be done,the higher were the payments to the hospital. Facedwith the prospect of bankruptcy in the federally fundedMedicare system, Congress authorised HCFA (theHealth Care Financing Administration which runsMedicare) to develop a system of prospectivepayment-in effect, a specific price list for all diseases.Hospitals exceeding these prices would no longer berewarded for their therapeutic zeal but instead wouldhave to absorb the losses, while those that could treatthe patient for less than the fixed reimbursement couldkeep the difference. Under the new system, all patientsare classified into one- of the 470 diagnosis relatedgroups (DRGs), according to their age, whether thetreatment is medical or surgical, and other factors. Acomplex methodology has been developed to weightthe reimbursement rates to hospitals according to theirlocation in urban or rural areas, local wage rates, and acase-mix index that distinguishes community hospitalsfrom acute-care tertiary referral centres.

Reimbursement rates will be adjusted annually toreflect inflation and changes in medical managementpatterns.Hospital administrators are now working with

unprecedented enthusiasm to learn how to monitortheir costs so that they can keep them at or below thereimbursement rates. The prospective payment systemwill be phased in over three years to allow hospitalstime to adjust. (Psychiatric hospitals, long-term carefacilities, children’s hospitals, and rehabilitationcentres are exempt from the new regulations, as arehospitals in Maryland, New York State, New Jersey,and Massachusetts that already operate under cost-containment programmes.) The DRG payment systemwill apply to about 5500 US hospitals and, according tosome forecasters, as many as one-sixth of them may be

3. Provisional Projections of the Population of the States by Age and Sex, 1980-2020.Washington, DC: US Department of Commerce, Bureau of the Census. August,1983.