Current management of the septic shock patient: experimental basis for treatment.

Experimental research has shown that following the intravenous infusion of animals with bacteria or endotoxin a myriad of adverse vascular events occur resulting in deficient organ perfusion and cell death. The primary goals of therapy for sepsis and septic shock, therefore, should include elimination of the source of infection and/or infectious agents and prevention or reversal of adverse vascular events. The following review describes the evolution of an effective therapy for shock consisting of steroid in combination with antibiotic and discusses its relevance and application for humans in severe sepsis or septic shock.

Hematologic disturbances during sepsis: platelets and leukocytes.

This brief review summarizes recent observations about leukocyte and platelet involvements during sepsis and septic shock. Endotoxins are known to exert significant effects on leukocytes and platelets as well as monocytes, macrophages, endothelial, and mast cells. The presence of endotoxin itself is reported to enhance the phagocytic and killing capacity of neutrophils. Transfusion of additional white blood cells has been shown to increase the probability of recovery from sepsis. Defects in neutrophil function, impaired opsonization, sequestration of neutrophils in pulmonary capillaries, and depressed metabolic states adversely affecting neutrophils may significantly contribute to the lethal outcome of septic shock. Platelet responses in septic shock are reported to include aggregation accompanied by release of several agents, including vasoactive amines, ADP, and platelet factor 3. In summary, leukocytes and platelets are known to perform significant roles in sepsis and septic shock although the precise mechanisms of their involvement remain to be clearly defined.

Survival characteristics during septic shock in 39 baboons.

In septic shock nonsurvival is characterized by failure of multiple organ systems. The design of therapeutic measures to increase survival would be enhanced if critical responses could be identified early. Escherichia coli LD100 was given to 39 baboons by IV infusion over two hours followed by different therapy regimens in 31 [2--4]. There were 18 permanent survivors (seven days or more), all receiving antibiotic/steroid combination therapy. Responses of survivors and nonsurvivors were measured and compared during the first 12 hours from onset of infusion. Changes in blood pressure and acid-base parameters were not significantly different between groups. Five responses indicative of permanent survival were lower heart rates, less elevation of blood urea nitrogen, normal blood glucose at eight hours, hyperglycemia with normal insulin at 12 hours, and lower plasma lactate concentrations beginning at four hours.

Does LD100 E coli shock cause myocardial failure?

We have documented that myocardial dysfunction occurs in canine endotoxin shock and have designed this study to determine the effect of lethal live E coli-induced shock on the myocardium. Small adult heart "donor" dogs (wt range 6-9 kg) were infused with LD100 E coli (N = 12) or saline (N = 16) for 30 minutes. Two hours later, heart transfer surgery was initiated and once completed the isolated working left ventricle was allowed to equilibrate in the extracorporeal circuit of a "support" dog (wt range 22-32 kg). Myocardial performance was then evaluated by changing mean aortic pressure while controlling cardiac output. Three to five hours after E coli infusion, marked myocardial dysfunction occurred in 75% of the hearts as evidenced by increased left ventricular and diastolic pressures and depressed peak positive and negative dP/dt at every mean aortic pressure tested compared with control hearts. Myocardial efficiency and power were depressed, oxygen uptake was elevated, and coronary blood flow was unchanged in E coli-treated compared with control hearts. Data support the presence of heart dysfunction in gram-negative septic shock.

Effectiveness of steroid/antibiotic treatment in primates administered LD100 Escherichia coli.

Early aggressive therapy with maintenance infusions of methylprednisolone sodium succinate and gentamicin sulfate significantly increases the probability for survival of baboons given LD100 Escherichia coli. The present study was designed to determine if baboons would recover when initiation of treatment was delayed until they had sustained E. coli-induced systemic hypotension for a period of approximately three hours. Sixteen adult baboons were each administered a two-hour infusion of LD100 E. coli. All eight untreated animals died within 42 hours. Five of the eight baboons treated after approximately three hours of hypotension with methylprednisolone sodium succinate and gentamicin sulfate survived. Treated animals had significantly higher blood glucose and insulin levels and lower blood urea nitrogen concentrations than baboons receiving E. coli alone. E. coli blood concentrations were lower in the treated than in the untreated baboon group by the sixth hour (less than 0.02). Heart rates increased in all animals but were not as high in the treated baboons. Both groups experienced similar decreases in mean systemic arterial pressure, PCO2, base excess, leukocyte, lymphocyte, and platelet concentrations, and increases in creatinine and lactate concentrations. Data from the present study indicate that the probability of recovery from shock is significantly increased even when initiation of steroid/antibiotic therapy is postponed until baboons have experienced sustained systemic hypotension.

Survival of primates in lethal septic shock following delayed treatment with steroid.

We recently developed a methylprednisolone sodium succinate (MPSS)/gentamicin sulfate (GS) regimen that prevented death in baboons given a 2-hour infusion of LD100 E coli (J. Surg. Res. 28:151, 1980). Steroid treatment was begun in that study 30 minutes after initiation of E coli. Our current aim was to determine if baboons would survive if MPSs treatment was delayed until all E coli were infused and severe hypotension had ensued. Fourteen lightly anesthetized baboons (P.c. cynocephalus) were administered E. coli and seven were then treated with MPSS and GS for 10 hours. All nontreated baboons died, while six of seven treated animals survived. In the treated group, hypoglycemia and hypoinsulinemia were reversed, tachycardia was reduced and neutrophil recovery was improved. Baboons with delayed MPSS, however, evidenced diminished perfusion and recovered more slowly than those with earlier MPSs treatment. In conclusion, primates in septic shock are clearly protected with delayed steroid/antibiotic therapy.