Myocardial Failure With Altered Response to Adrenaline in Endotoxin Shock

Abstract

1 There is a growing concensus that myocardial performance in the early stages of experimental endotoxic and septic shock is relatively normal; however, recent reports have identified an intermediate phase of shock when myocardial dysfunction is clearly apparent. 2 The mechanism of dysfunction has become a subject of intense investigation. A current view is that altered myocardial responsiveness to circulating catecholamines may play an important role in the dysfunction observed after endotoxin administration. The present studies, in which an isolated working heart preparation of the dog was used, were designed to test this hypothesis. This particular experimental preparation was selected to provide an adequate interpretation of results; cardiac output, afterload, and concentrations of adrenaline reaching the coronary vascular bed were controlled in all experiments. Responses to infusions of adrenaline were recorded in the 'steady-state' condition. Control (non-shocked) heart responses to adrenaline were highly reproducible in terms of inotropic, chronotropic and coronary vascular behaviour. 3 Results from the study document myocardial dysfunction within 4-6 h following an LD70 endotoxin administration on the basis of increased left ventricular end diastolic pressure (LVEDP), decreased cardiac power and myocardial efficiency, and depressed negative and positive dP/dt parameters. 4 Findings suggest significantly altered responsiveness of the myocardium to infused adrenaline at rates of 1, 2, and 5 pg/min with concentrations between 10 and 1 ng/ml blood. LVEDP was elevated while calculated power and efficiency parameters remained significantly below control values during infusion of adrenaline in endotoxin-treated hearts. Depressions of responsiveness were interpreted to occur on the basis of failure to restore positive and negative dP/dt to normal values and depressed coronary blood flow responses during adrenaline administration. Increases in coronary flow were regularly less in experimental hearts than the controls. Heart rate responses to adrenaline in both failing and non-failing hearts were identical. 5 In conclusion, it is suggested that myocardial contractile and relaxation characteristics and coronary vascular responses to adrenaline infusion are depressed in endotoxin shock during the period of demonstrated myocardial dysfunction. No distinct causal relationships were observed between the ailtered myocardial responsiveness and pathogenesis of heart dysfunction since myocardial dysfunction and altered responsiveness to adrenaline were generally observed together. Myocardial oedema formation after endotoxin as previously reported by this laboratory may bear a relationship to the depressed negative dP/dt response to adrenaline.

RECRUITMENT OF FUNCTIONALLY ACTIVE HEART Β2-Adrenoceptors IN THE INITIAL PHASE OF ENDOTOXIC SHOCK IN PITHED RATS

“…The chronotropic response to adrenaline was reduced in endotoxintreated anesthetized cats (12) and not changed in hearts isolated from dogs treated with endotoxin (13). Moreover, the positive inotropic responses to ISO were attenuated in hearts or atria isolated from LPS-treated rats (14) or dogs (13) or in rabbit cardiac myocytes treated with endotoxin (15). A depression of the adrenaline-induced increase in myocardial contractility was also noticed in endotoxin-treated cats in vivo (12).…”

“…Thus, the chronotropic effect of ISO was decreased in cultured rat myocardial cells treated with human (10) or rat (11) serum sampled 1 or 24 h after the onset of septic shock. The chronotropic response to adrenaline was reduced in endotoxintreated anesthetized cats (12) and not changed in hearts isolated from dogs treated with endotoxin (13). Moreover, the positive inotropic responses to ISO were attenuated in hearts or atria isolated from LPS-treated rats (14) or dogs (13) or in rabbit cardiac myocytes treated with endotoxin (15).…”

Indications of Chlormethiazole as a Protective Agent in Experimental Endotoxemia

“…In a septic state the mobilization of the sympathetic neuroendocrine response seems to be one prerequisite for survival [1,[15][16][17]. Another 'defense' system which proba bly plays a role in survival in septic states is the reticuloendothelial system [7,14,18].…”

“…The primary strength of pigs as animal models is their anatomical and physiological similarity to humans with respect to cardiovascular and pulmonary functions [6,19]. One of many prerequisites for survival in sepsis is in creased activity in the reticuloendothelial system [14,18] and in the sympaticoadrenergic system [1,16,17]. Recently the impor tance of the adrenergic system was clearly indicated in our porcine septic model where two anesthetic agents were compared, namely metomidate with ketamine [15].…”

Circulatory Reflex Responses during the Initial Stage of Feline Endotoxin Shock

“…On the other hand, endotoxins have been proposed to be neurotoxic agents (Nagler and Levenson 1971) activating the sympathetic nervous system directly (Lillehei et al 1964). From the behaviour of the plasma catecholamines and heart rate, in turn, it has been concluded that endotoxins activate not only the sympathetic a and b, Nykiel and Glaviano 1961, Spink et al 1966, Levy and Blattberg 1967, Cavanagh et al 1970, Hall and Hodge 1971, Archer, Black and Hinshaw 1975 but also the vagal system (Chien et al 1966, Levy andBlattberg 1967). The validity of this latter concept has been substantiated by our recent studies on the effects of endotoxin on cardiovascular reflex functions and circulation in dogs (Halinen, Hakumaki andSarajas 1975, Halinen 1976).…”