In the following experiments we attempt to quantitate the range of plasma catecholamine levels during canine endotoxin shock and to clarify some of the mechanisms involved in the changes. Basic to these investigations was a sensitive and reliable method for recovering the amines in plasma, a need that had been reflected in other studies (1-4).The availability of such an assay permitted a series of comparative studies on normal anesthetized animals, on those given varying doses of endotoxin at different rates of administration, on dogs subjected to adrenalectomy and high cervical cord section and then given endotoxin, and on the effects of endotoxin on catecholamine levels in endotoxin-resistant dogs.It was observed that the plasma concentrations of epinephrine were related to the level of the systemic arterial blood pressure although other factors also appeared to affect the amounts. Changes in blood pressure were not correlated with variations in the plasma content of norepinephrine. Repeated challenge with large doses of endotoxin conferred resistance to its lethal action, but this effect was not associated with an alteration in the pattern of the plasma catecholamine response. After cervical cord section shock could be induced in the absence of detectable plasma catecholamine, and under these conditions shock was significantly accelerated.* Submitted for publication June 25, 1965; accepted September 30, 1965. Supported by U. S. Public Health Service research grant AI-04415-04.

A B S T R A C T Myocardial function and peripheral hemodynamic alterations were measured through the late stages of canine endotoxin shock. 60 min postendotoxin paired animals were given infusions of either 5 ml/kg per hr of 5%o dextrose or dextrose plus isoproterenol (0.25 pg/kg per min). Comparable blood lactic and pyruvic acid levels were determined, the excess lactic acid calculated, and pH values were obtained. During the initial stages the classic pattern of hemodynamic alterations was observed; an excess of lactic acid appeared and the pH decreased. Outstanding was evidence of markedly reduced myocardial function in the late stages of shock with progressive rise in left ventricular end diastolic pressure (LVEDP), low cardiac index, rise of central venous pressure, increased central blood 'volume, tachycardia, and declining arterial pressure. Analyses of left ventricular function curves also indicated myocardial failure.Infusion of dextrose alone failed to decrease mortality rate (10 of 18 dying), whereas the rate was significantly decreased with isoproterenol (2 of 18). Dextrose infusion did not benefit myocardial function. Isoproterenol resulted in a marked improvement in myocardial action with a significant increase in heart work associated with, yet very minor, increments of LVEDP. In addition, tachycardia subsided, peripheral resistance decreased, and the blood pressure stabilized. The Address requests for reprints to Dr.

ATIEMPTS to evaluate therapy in patients having shock due to gram-negative microorganisms (endotoxin shock) are obscured by the lack of quantitative data on the natural course of human shock. The canine experimental model for studying endotoxin shock has provided basic information on the pathophysiology of this disorder.6 11,22,23 Agents that have altered the progress of canine endotoxin shock favorably have at timnes been beneficial in human subjects.17' 23 However, the management of human endotoxin shock still constitutes a major therapeutic problem.Isoproterenol, a synthetic catecholamine, structurally similar to the endogenous catecholamines norepinephrine and epinephrine appears to be a promising adjunct in the management of patients with endotoxin shock. 3' 4, 13, 16 Studies have indicated that isoproterenol can partially reverse the undesirable hemodynamic effects of endotoxin shock in sheep and in dogs.4 10,26 But, because of experimental design, lack of proper controls, or insufficient numbers, proper assessment of isoproterenol in survival is lacking.Extensive observations on canine endotoxin shock in our laboratory have demonstrated that significant survival or mor-

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