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1 A new canine model of endotoxin shock has been developed in which spontaneous recovery of cardiovascular function is largely prevented, the haemodynamic effects of anaesthesia are minimized and intravascular volume replacement is given. 2 This model has been evaluated using two groups of five adult mongrel dogs anaesthetized with ca-chloralose and breathing spontaneously. Animals in one group were anaesthetized, instrumented and given Escherichia coli (E. coli) endotoxin intravenously, whilst those in the control group were subjected only to anaesthesia and instrumentation.3 E. coli endotoxin was given to dogs in the shock group as a bolus dose of 5 mg kg-lfollowed by a continuous infusion at 2 mg kg-1 h -1. This produced immediate, severe, cardiovascular depression, with precipitous falls in mean arterial pressure (MAP), cardiac index (CI), stroke index (SI) and left ventricular (LV) dp/dt max. There were associated increases in systemic and pulmonary vascular resistances. Arterio-venous oxygen content difference (C(a-v)O2) increased after induction of shock, and animals developed a progressive metabolic acidosis. Increasing haemoconcentration occurred, as evidenced by a rising haematocrit (PCV). Hypovolaemia was reflected by a concurrent fall in pulmonary capillary wedge pressure (PCWP). 4 One hour after induction of shock, intravascular volume replacement was given in the form of a colloidal gelatin solution, as a bolus dose of 10 ml kg-, followed by a continuous infusion at 10 ml kg-1 h-1. Volume replacement reversed haemoconcentration, restored PCWP and produced some haemodynamic improvement, although in general, severe cardiovascular depression persisted throughout a three hour observation period. 5 This severe endotoxin shock model has proved to be stable, reproducible and economical. It provides a useful preliminary test for new methods of treatment in hypodynamic endotoxin shock, as well as allowing investigation of acute metabolic and physiological changes. IntroductionAnimal models have been widely used for the investigation of septic shock, a condition which in man still carries a mortality of up to 50% (Schumer, 1979).Many workers have performed endotoxin-based experiments, and there is a wealth of literature describing the effects of endotoxin in different species of experimental animals (Halmagyi et al., 1963;Brockman et al., 1967; Kuida etal., 1971; Balis etal., 1978;Morris et al., 1979). This subject has been comprehensively reviewed by Gilbert (1960).However, concern has recently been expressed with regard to the clinical relevance of endotoxin models (Wichterman et al., 1980) and alternatives which attempt to represent more exactly the clinical situation have been suggested. These have included 1Correspondence. the intravenous infusion of live bacteria into mongrel dogs, sheep, pigs and rhesus monkeys (Pool et al., 1977;Hinshaw et al., 1979;Fairman & Glauser, 1980;Gahos et al., 1982). Other models have involved the induction of peritonitis, for example, by implantation of a septic sponge or ...

1 The specific opiate receptor antagonist, naloxone, can produce haemodynamic improvement and increased survival in experimental shock. The efficacy of naloxone therapy in a canine model of endotoxin shock has been evaluated both with and without intravascular volume replacement. 2 Animals were anaesthetized with cx-chloralose and allowed to breathe spontaneously. A large bolus dose of endotoxin was followed by a continuous infusion, and treatment was instituted one hour after the endotoxin bolus. 3 In the absence of volume replacement, naloxone caused only limited and transient increases in mean arterial pressure (MAP) and left ventricular (LV) dp/dt max, with little effect on cardiac index (CI). Total peripheral resistance index (TPRI) tended to rise in both control and naloxone-treated dogs. 4 In volume-replaced animals, naloxone produced substantial and sustained increases in the MAP and LV dp/dt max with an associated rise in the CI. TPRI rose initially in this series and then fell progressively. Further analysis of the improvements in the CI showed an increase in stroke index with a tendency for heart rate to fall. 5 These findings suggest a myocardial action of naloxone in endotoxin shock, which is augmented by volume replacement. An initial, transient vasoconstrictor effect cannot, however, be excluded. Further work is required to determine the mechanism of the effects described.

The possibility that nitrous oxide releases endogenous opioid peptides into the circulation has been tested in 10 pain-free, unstressed volunteers breathing 30% nitrous oxide in oxygen. Despite achieving plateau concentrations in venous blood, accompanied by subjective effects, there were no significant changes in plasma concentrations of immunoreactive beta-endorphin, methionine-enkephalin or ACTH. These results indicate that, in the absence of nociceptive input, the effects of the inhalation of nitrous oxide are unrelated to alterations in peripheral concentrations of these endogenous opioid peptides.