Dependence of Defibrillation Threshold Upon Extracellular/Intracellular K+ Concentrations

Transcription

1 Purdue University Purdue e-pubs Weldn Schl f Bimedical Engineering Faculty Publicatins Weldn Schl f Bimedical Engineering 1980 Dependence f Defibrillatin Threshld Upn Extracellular/Intracellular K+ Cncentratins Charles F. Babbs Purdue University, babbs@purdue.edu S J. Whistler G Yim L A. Geddes Fllw this and additinal wrks at: Part f the Bimedical Engineering and Biengineering Cmmns Recmmended Citatin Babbs, Charles F.; Whistler, S J.; Yim, G; and Geddes, L A., "Dependence f Defibrillatin Threshld Upn Extracellular/Intracellular K+ Cncentratins" (1980). Weldn Schl f Bimedical Engineering Faculty Publicatins. Paper This dcument has been made available thrugh Purdue e-pubs, a service f the Purdue University Libraries. Please cntact epubs@purdue.edu fr additinal infrmatin.

2 Dependence f Defibrillatin Threshld Upn Extracellular/Intracellular K + Cncentratins C. F. Babbs, M.D., Ph.D., S. J. Whistler, M.S., G. K. W. Yim, PhD, and L. A. Geddes Ph.D. Bimedical Engineering Center and Department f Pharmaclgy and Txiclgy, Purdue University, West Lafayette, Indiana Abstract The effect f increasing extracellular ptassium cncentratin (K) upn electrical ventricular defibrillatin threshld was investigated in pentbarbital anesthetized dgs treated with intravenus ptassium chlride. Defibrillatin threshld fell during ptassium intxicatin. The percent decrease in defibrillatin threshld was linearly related t the lgarithm f K and t the ptassium equilibrium ptential, EK, calculated frm measured extracellular and intracellular ptassium cncentratins f ventricular muscle. In dgs supprted by left ventricular bypass in rder t maintain the circulatin during ptassium intxicatin, the values f K and EK required fr spntaneus, K + induced defibrillatin (electrical defibrillatin threshld = zer) were 16.6 meq/l and -46 mv cmpared t the nrmal values f 3.9 meq/l and -84 mv. Changes in defibrillatin threshld related t changes in EK may be significant events in digitalis intxicatin and in mycardial anxia during prlnged fibrillatin. Defibrillatin f the heart is ften discussed as a large scale analg f cardiac pacing. Terminatin f atrial r ventricular fibrillatin by a strng electric shck, applied with paddle electrdes acrss the chest r directly t the heart, is assumed t be the result f stimulatin f a diffuse mass f ptentially excitable cells (1, 2). The mechanism f defibrillatin is usually stated t be the cnsequent prductin f a simultaneusly refractry state in the entirety f a critical mass f the fibrillating mycardium (3, 4). Key wrds: cardiac muscle, equilibrium ptential, ptassium, Nernst equatin, transmembrane ptential. Intrductin The present reprt describes a pharmaclgic test f this hypthesis. If indeed the prcess f fibrillatin is analgus t electrical excitatin f a single resting mycardial cell, then the shck intensity required fr defibrillatin shuld decrease if cardiac cells are partially deplarized by pre-treatment with a drug such as ptassium chlride. In particular, the shck strength required fr defibrillatin shuld be prprtinal t the difference between the resting membrane ptential f nn-excited cells in the fibrillating mycardium and the firing r threshld ptential f these 1

3 cells. Defibrillatin shuld be accmplished with zer electric shck at a transmembrane ptential apprximately equal t the firing threshld mv in typical preparatins (5, 6). Indeed, befre the existence f electrical defibrillatrs, chemical defibrillatin, develped by Hker (7), was practiced at surgery by flushing the crnary vascular bed with ptassium slutin (8). The rati f intracellular ptassium cncentratin, Ki, t extracellular ptassium cncentratin, K, is a majr determinant f the resting transmembrane ptential. A first rder apprximatin f the transmembrane ptential is given by the Nernst equatin fr the ptassium equilibrium ptential, Under physilgic cnditins, measured resting transmembrane ptentials are slightly less negative than this value due t inward leakage f sdium ins (5, 9). Nte that because Ki is nrmally much greater than K ( meq/l vs. 2-5 meq/l) small abslute changes in K prduced by KCl infusin may cause relatively large changes in EK and transmembrane ptential, withut significantly altering intracellular r ttal bdy ptassium levels. Accrdingly, the bjectives f the studies here reprted were: 1) t investigate changes in the ventricular defibrillatin threshld prduced by changes in extracellular ptassium in cncentratin (K) in dgs; 2) t hld ttal bdy ptassium cntent essentially cnstant during these studies; 3) t measure the intracellular ptassium in cncentratin (Ki) f the ventricular mycardium; and 4) t plt defibrillatin threshld as a functin f EK = lg (Ki/K). If indeed defibrillatin is analgus t cardiac pacing, the defibrillatin threshld shuld be a decreasing functin f EK that appraches zer as EK appraches the cellular firing threshld (-50 t -60 millivlts). Methds Animal preparatin Healthy mngrel dgs weighing 7-20 kilgrams served as subjects. Anesthesia was induced with intravenus pentbarbital sdium (25-30 mg/kg) and maintained with additinal 2 mg/kg bluses as necessary. This anesthetic alne des nt alter the defibrillatin threshld (10). N ther drug except ptassium chlride was administered. Esphageal temperature, the ECG, artic bld pressure, respiratry minute vlume, and arterial bld ph, pco 2, and po 2 were mnitred as described previusly (11). One hur befre the beginning f defibrillatin threshld measurements, the right and left ureters were ligated thrugh a midline lapartmy t prevent rapid excretin f the infused ptassium.

4 Defibrillatin threshld was determined three times during the 120 min perid befre ptassium administratin, and three times during the 120 min perid after ptassium administratin. Details f the prcedure fr measuring defibrillatin threshld have been reprted previusly (11, 12). In brief, threshld was determined by repeated trials f fibrillatin and transchest defibrillatin, each with a damped sinusidal defibrillatr shck f peak current amplitude 10% less than the amplitude f the preceding shck. (The defibrillatr had a capacitance f 16 µf, an inductance f 44 mh and an internal-resistance f 7 (13).) A biplar catheter electrde was placed in the right ventricle via a jugular venus cut-dwn t initiate ventricular fibrillatin with 3 sec bursts f 60 Hz electrical stimuli. The lwest shck intensity able t achieve defibrillatin, and differing n mre than 10% in amplitude frm an intensity that did nt defibrillate was defined as threshld. The hearts f the animals were never permitted t fibrillate mre than 30 sec prir t defibrillatin and never refibrillated until arterial bld pressure had returned t a stable level. The peak vltage and peak current fr each shck were recrded n a strage scillscpe. Only data frm the first shcks applied after the nset f ventricular fibrillatin were used in the calculatin f threshld. Delivered energy was calculated as previusly described (13). Plasma levels f sdium and ptassium in arterial bld were mnitred at min intervals using an Instrumentatin Labratries Mdel 443 flame phtmeter. After the first three pre-drug threshld determinatins, intravenus ptassium chlride in a dse f 1.0 meq/kg was given slwly ver a perid f 5-10 min as the ECG was clsely mnitred fr arrhythmias. Fllwing this injectin, a slw infusin f ptassium chlride at 0.01 meq/kg/min was begun using a mtr driven syringe. After stable, elevated levels f plasma ptassium were attained, three mre measurements f the defibrillatin threshld were made during the 120 min fllwing the nset f ptassium administratin. This dsage regimen was selected because it prduced in preliminary experiments the greatest stable elevatins f serum ptassium that culd be tlerated during repeated episdes f ventricular fibrillatin and defibrillatin. With higher levels f ptassium intxicatin, sme animals did nt recver frm pst defibrillatin A-V blck and hyptensin. Measurement f intracellular ptassium cncentratin by a duble perfusin technique Because it is physically impssible t separate the intracellular and extracellular fluid cmpartments f slid tissues, intracellular ptassium cncentratin must be calculated indirectly. The calculatin can be made frm measurements f ttal tissue and extracellular ptassium cncentratin n the basis f the fllwing relatin: Kt = verall ptassium cncentratin f mycardial tissue, = vlume fractin f the 3

5 extracellular space, and i = vlume fractin f the intracellular space = (1- ) fr heart muscle. The intracellular ptassium cncentratin is calculated as prvided, the vlume fractin f the extracellular space, is knwn. Classically, is measured as the vlume f distributin f an indicatr substance which is permeable t capillaries, but which is excluded frm cells. 24Na, thisulfate, and mannitl have been used as indicatrs fr this purpse (14). The methd develped fr the present studies emplys nnistpic sdium as the indicatr substance. This indicatr is subtracted rather than added t the extracellular space as the mycardium is perfused with tw different istnic slutins, the first (lactated Ringer's slutin) cntaining physilgic sdium cncentratin and the secnd (5% dextrse in water) cntaining zer sdium cncentratin. Samples f tissue and perfusate are analyzed fr ttal sdium and ptassium cntent by flame phtmetry after each perfusin, permitting calculatin f. and Ki. Prcedure After cmpletin f the defibrillatin threshld measurements, the ptassium infusin was stpped and median sterntmy and pericarditmy were perfrmed. The heart was perfused first with lactated Ringer's slutin and then with 5% dextrse in water via a cannula placed in the left brachicephalic artery. All ther branches f the artic arch except the crnary arteries were ligated. Befre perfusin, the cavae and descending thracic arta were clamped; the atria were cut t prmte drainage f bld and perfusate. After perfusin with 500 ml f lactated Ringer's slutin, a 1 gram sample f right ventricular muscle nurished by the left anterir descending crnary artery was excised fr assay f sdium and ptassium cntent. Then perfusin with 500 ml f dextrse slutin was carried ut and a 1 gram sample f right ventricular muscle nurished by the right crnary artery was excised fr assay f tissue sdium and ptassium cntent. The assay prcedure emplyed vernight digestin f the tissue sample in 10 vlumes f 1 mlar H2SO4 at 80 C. Such digestin fr ne hur r lnger prduced maximal recvery f sdium and ptassium frm the pieces f mycardium. Assay f the supernatant slutin fr sdium and ptassium cncentratin was accmplished using the flame phtmeter, calibrated with slutins f 1 mlar H2SO4 cntaining knwn cncentratins f Na + and K + ins. Samples f crnary sinus effluent taken after perfusin with 400 ml f each slutin prvided a measure f extracellular sdium and ptassium cncentratins in each case. Perfusin pressure was always mmhg.

6 Calculatins Ttal tissue sdium cncentratin, Nat, is given by the expressin Na t Na Na, i i where, as befre, = vlume fractin f the extracellular space i = 1- = vlume fractin f the intracellular space, Nai = intracellular sdium cncentratin, and Na = extracellular sdium cncentratin. During the perfusin prcedure,, i, and Nai are cnstants. Therefre, was calculated frm measurable quantities as Nai Nat (Ringer 's) Nat (dextrse ), Na Na (Ringer 's) Na (dextrse ) assuming that sdium ins distributed nly t the extracellular space and did nt crss cell membranes significantly during the perid f perfusin. Intracellular ptassium cncentratin was then calculated frm ttal tissue and plasma ptassium cncentratins as K i K K 1 t. Investigatin f higher levels f K The ptassium treatment schedule fr the first ten animals just described was designed t prduce stable elevatins f extracellular ptassium cncentratin near the maximal levels tlerated by the animals, withut prfund hyptensin, depressin f the sinatrial r atriventricular ndes, r intractable tachyarrhythmias. In preliminary experiments such cmplicatins did ccur with mre rapid rates f ptassium infusin. Cnsequently, t elucidate the influence f high cncentratins f extracellular ptassium upn defibrillatin threshld, a secnd experiment was designed t determine at what cncentratin f extracellular ptassium the ventricles f dgs wuld spntaneusly defibrillate, that is, at what level f K defibrillatin threshld was zer. These studies were carried ut in pen chest dgs in whm cardiac utput was maintained by a left ventricular bypass pump. The prblem f circulatry cllapse prduced by very high levels f plasma ptassium was thus bviated. N defibrillatr was needed fr the study. Neither was it necessary t establish a cntrl level f the defibrillatin threshld, since zer threshld current is equivalent t zer percent f cntrl in any case. Nine pentbarbital anesthetized dgs served as subjects in this secnd experiment. After median sterntmy and pericarditmy had been perfrmed, surgical hemstasis secured, and heparin (2 mg/kg i.v.) administered, ventricular fibrillatin was initiated by 60 Hz stimulatin f the right ventricular surface. Each animal was immediately placed n 5

7 a La Farge-type left ventricular bypass system. Bld was withdrawn frm the left ventricle thrugh a large bre, multiple side-hle cannula inserted thrugh a small stab wund in the cardiac apex. Bld withdrawn frm the left ventricle was led thrugh a Travenl rller pump and re-infused int the animal via a large bre, right-angle cannula previusly placed in the abdminal arta. Prir t institutin f the bypass, the tubing was filled with warmed (30-40 C) Ringer's slutin. Care was taken t ensure that the left ventricular cannula was nt pushed thrugh the artic valve frm the left ventricle, since a shrt circuit wuld have been created. T remve venus return, the animal's hindquarters were elevated 30 degrees and up t 1000 ml f additinal Ringer's slutin infused as necessary t maintain a stable artificial cardiac utput. After the bypass system had been adjusted, ptassium chlride was infused via the femral vein at a rate f 0.2 meq/kg/min, calculated t raise the extracellular ptassium cncentratin by apprximately 1 meq/l/min. Esphageal temperature, the ECG, arterial bld pressure, and arterial bld ph, pco2, and po2 were mnitred. Tw arterial bld samples were taken at the time f spntaneus, chemical defibrillatin fr analysis f plasma ptassium cncentratin. The first sample was taken at the mment fibrillatin appeared t cease, as judged by the ECG and direct visual inspectin f the heart. The secnd sample was taken when defibrillatin was cnfirmed by electrical pacing f the ventricles by single 10 vlt, 2 msec stimulus applied t the ventricular surface with handheld biplar electrdes. Generatin f ventricular ectpic beats in the ECG was taken as cnfirmatin f ventricular defibrillatin. The average plasma ptassium cncentratin f the first and secnd samples was taken as the level required fr defibrillatin with zer current and energy. Results The elevatin f plasma ptassium cncentratin prduced by the "blus plus infusin" technique in ten dgs is illustrated in Figure 1. The technique described prduced a stable plateau f extracellular ptassium cncentratin fr defibrillatin studies. The verall mean cntrl ptassium level was 3.9 meq/l and the verall ptassium infusin level was 7.5 meq/l. Calculated levels f intracellular ptassium cncentratin in fur f these animals and in fur animals which did nt receive prir ptassium infusins are given in Table 1. The mean value fr intracellular ptassium was 91 meq/l and the standard errr f the mean was 3.6 meq/l. Intracellular ptassium cncentratins f dgs that received ptassium treatment were nt significantly different frm thse f dgs that did nt (t = 0.66, p = 0.53).

8 Figure 1. Elevatin f plasma ptassium in 10 dgs prduced by a slw intravenus injectin f ptassium chlride, 1.0 meq/kg, fllwed by a cnstant infusin f ptassium chlride, 0.01 meq/kg/min. Errr bars represent standard deviatins. 7

9 Table 1. Inic cncentratins in canine ventricular muscle. = vlume fractin f extracellular space; Nat = tissue sdium cncentratin; Kt tissue ptassium cncentratin; Nai, = intracellular sdium cncentratin; Ki intracellular ptassium cncentratin. Prir KCl = KCl 1.0 meq/kg i.v. slwly, fllwed by KCl 0.01 meq/kg/min fr 120 min. Student's t values (tw-tailed) test the null hypthesis that tabulated values fr dgs 1-4 (n prir KCl) are equal t tabulated values fr dgs 5-8 (prir KCl treatment). Prir KCl did nt cause significant changes in the tabulated values. Dg # Prir KCI Na 1 meq/l K, meq/l Na 1 meq/l Ki, meq/l n n n n yes yes yes yes Mean S.D t p

10 Figure 2 summarizes the effects f increased extracellular ptassium cncentratin n ventricular defibrillatin threshld. Defibrillatin threshld as percent f cntrl is pltted as a functin f plasma ptassium cncentratin and f calculated ptassium equilibrium ptential. The left-hand and middle data pints represent mean cntrl and mean pst-ptassium threshld values. The right-hand data pint represents the mean plasma ptassium cncentratin fr spntaneus defibrillatin with zer current r energy. The upper scale fr ptassium equilibrium ptential was calculated frm the Nernst equatin using the mean value f intracellular ptassium cncentratin reprted in Table 1. As extracellular ptassium cncentratin is increased, ventricular defibrillatin threshld dramatically decreased, reaching zer value when K was 16.6mEq/L and EK was -46mV. Figure 2. Effect f elevated extracellular ptassium cncentratin n ventricular defibrillatin threshld in dgs. Results frm bth experimental prtcls are cmbined. Errr bars represent 1 standard deviatins. The abscissa is brken t delineate standard deviatin f ptassium cncentratins fr spntaneus defibrillatin (hrizntal errr bars). Results are similar whether threshld shck strength was measured in terms f energy r current. 9

11 Discussin As the ptassium equilibrium ptential, EK, is made less negative by KCl infusin, the gap between the theretical equilibria fr resting membrane ptential and cellular firing threshld narrws. It is predicted that this change, in turn, will decrease the defibrillatin threshld. As indicated in Figure 2, the decrease in defibrillatin threshld is in fact related t the increase in EK, and defibrillatin threshld falls t zer nt far frm the expected value f cellular firing threshld. The fact that the bserved value f EK at zer defibrillatin threshld is smewhat less negative than the typically quted value f -60 mv fr cellular firing threshld f ventricular fibers may be related t the critical mass cncept f Zipes (3, 4). Accrding t this cncept, deplarizatin f a large critical mass f ventricular muscle is required fr defibrillatin, including cells with higher-than-average threshld. Hence, if cmplete defibrillatin is taken as the endpint, the calculated value f EK wuld be assciated with the cells in the critical mass with the highest threshlds. In additin, measured plasma levels f K in the secnd experiment were undubtedly slightly greater than tissue levels, since plasma cncentratins were increasing and cmplete equilibratin f plasma and interstitial cmpartments culd nt have ccurred. With these reservatins, the results btained are very clse t thse predicted by the hypthesis that defibrillatin is a large scale analg f cardiac pacing. Althugh ptassium cncentratins in circulating plasma cmparable t thse used in the present study are nt rutinely encuntered in the clinic, lcal tissue elevatins in extracellular ptassium may be quite significant in certain pathphysilgic states related t defibrillatin. Fr example, Tacker et al. (16) fund a dse-related decrease in defibrillatin threshld current and energy in dgs fllwing txic dses f the digitalis glycside, uabain. A dse f 50 µg/kg prduced an average maximum decrease in threshld energy f 20%, a finding virtually identical t that reprted earlier by Lwn et al. (17) These findings are cnsistent with the effects f ptassium reprted in this paper and may be explained as an indirect effect f the well-knwn inhibitin f membranebund sdium/ptassium ATPase by digitalis glycsides. This cellular effect f digitalis preparatins causes inhibitin f active transprt f sdium ins ut f and ptassium ins int mycardial cells. As a result, there is a net utward leakage f ptassium ins (18) which culd prduce lcal elevatins in extracellular ptassium cncentratin with resultant enhanced excitability and depressin f the defibrillatin threshld. These indirect alteratins in defibrillatin threshld by induced changes in lcal extracellular ptassium cncentratin may als explain the recent (unpublished) bservatin in ur labratries that defibrillatin threshld decreases fllwing duratins f fibrillatin and ttal circulatry arrest lasting mre than tw minutes.

12 In additin t depressin f defibrillatin threshld, we have fund in preliminary experiments that the ptassium cncentratin f bld recvered frm the crnary vascular bed increases prgressively as the duratin f fibrillatin and cardiac anxia is lengthened. This shift f ptassium frm intracellular t extracellular fluid cmpartments during ischemia has been demnstrated in several animal mdels (19, 20, 21). Hence, althugh elevatins f extracellular ptassium cncentratin as great as thse reprted in the present studies wuld never be prduced fr therapeutic reasns, the finding f threshld depressin by ptassium may be imprtant in understanding bth the mechanism f defibrillatin and changes in defibrillatin threshld during certain pathphysilgic states. References 1. GEDDES, L A: Electrical ventricular defibrillatin. In IEEE Medical Electrnics Mngraphs, D W HILL AND B W WATSON, eds. Peter Peregrinus Ltd, England, 1976, p LOWN, B: Cardiversin f arrhythmias. Md Cnc Cardivasc Dis 33:863, ZIPES, D P: Ventricular fibrillatin: Mechanisms f initiatin, maintenance, and terminatin. In Prceedings f the Cardiac Defibrillatin Cnference. Purdue University, West Lafayette, Indiana (Engineering Statin Dcument #00147), ZIPES, D P: Electrphysilgical mechanism invlved in ventricular fibrillatin. Circulatin 52:120, HOFFMAN, B F AND CRANEFIELD, P F: Electrphysilgy f the Heart. McGraw-Hill, New Yrk, WOODBURY, W J: Cellular electrphysilgy f the heart. In Handbk f Physilgy, Vl 1, Sectin 2 ("Circulatin"), W F HAMILTON, Ed. American Physilgical Sciety, Washingtn, DC, HOOKER, D R: On the recvery f the heart in electric shck. Am J Physil 91:305, PEIRCE, E C: Ptassium reversin f hypthermic ventricular fibrillatin. J Thracic and Cardivasc Surg 48:996, MUIRA, D S, HOFFMAN, B F AND ROSEN, M R: The effect f extracellular ptassium n the intracellular ptassium in activity and transmembrane ptentials f beating canine cardiac Purkinje fibers. J Gen Physil 69:463, BABBS, C F: Effect f pentbarbital anesthesia n ventricular defibrillatin threshld in dgs. Amer Heart J 95:331, BABBS, C F, WISTLER, S J, AND YIM, G K W: Tempral stability and precisin f ventricular defibrillatin threshld data. Amer J Physil, 4:H553,

13 12. GEDDES, L A, TACKER, W A, ROSBOROUGH, J, MOORE, A G AND CABLER, P S: Electrical dse fr ventricular defibrillatin f large and small animals using precrdial electrdes. J Clin Invest 53:310, BABBS, C F AND WHISTLER, S J: Evaluatin f the perating internal resistance, inductance, and capacitance f intact damped sine wave defibrillatrs. Med Instr 12:34, WELT, L G: Agents affecting vlume and cmpsitin f bdy fluids. In The Pharmaclgical Basis f Therapeutics, L S GOODMAN AND A GILMAN, Eds. The Macmillan Cmpany, New Yrk, SANO, T, TSUCHIHASHI, H, AND SIDMAMOTO, T: Ventricular fibrillatin studied by the micrelectrde methd. Circ Res 6:41, TACKER, W A, GEDDES, L A, KLINE, B AND BORTON, C: Alteratin f electrical defibrillatin threshld by the cardiac glycside, uabain. In Prceedings f the Cardiac Defibrillatin Cnference, Purdue University, West Lafayette, Indiana (Engineering Statin Dcument #00147), LOWN, B, KLEIGER, R, AND WILLIAMS, J: Cardiversin and digitalis drugs: Changed threshld t electric shck in digitalized animals. Circ Res 17:519, LANGER, G A AND SERENA, S D: Effects f strphanthidin upn cntractin and inic exchange in rabbit ventricular mycardium: Relatin t cntrl f active state. J Ml Cell Cardil 1:65, HOCHREIN, H, HUNSMANN, G AND STOEPEL, K: Changes f intracellular mycardial electrlytes in experimental hypertensin. Cardilgy 56:96, LEHR, D AND CHAU, R: Changes f the cardiac electrlyte cntent during develpment and healing f experimental mycardial infarctin. In Recent Advances in Studies n Cardiac Structure and Metablism, N S DHALLA, Ed. University Park Press, Baltimre, SINGH, C M, FLEAR, C T G, NANDRA, A AND ROSS, D N: Electrlyte changes in the human mycardium after anxic arrest. Cardilgy 56:128, 1971/72