William Schumer

Pathophysiology and treatment of septic shock

Shock is defined as inadequate circulating blood volume producing decreased peripheral vascular perfusion and cellular metabolic derangements, first in the nonvital tissues (the gastrointestinal tract, muscle, connective tissue, and skin) and later in the vital tissues (the brain, heart, lung, liver, and kidneys). This inadequate microcirculatory perfusion is the common denominator of all types of shock. Septic shock is caused by an immunologic reaction characterized by a hyperdynamic state, which produces increased cardiac output and decreased peripheral resistance. This reaction is secondary to endotoxin-antibody-complement complexing and leukocyte lysis that results in the production of histamine, serotonin, super-radicals, lysosomal enzymes, and kinins. These substances induce a marked capillary permeability and a third space loss, leading to hypovolemia. This is the hypodynamic state of septic shock, which is characterized by decreased cardiac output and increased peripheral resistance. Diagnosis should be established in the hyperdynamic state of septic shock. Monitoring of the patient in septic shock requires continuous evaluation of the status of clinical signs, peripheral perfusion, vital organ function, and volume requirements. There are four principal and equally important objectives in the treatment of septic shock: treatment of sepsis, management of the hypovolemic state, reparation of the metabolic acid-base imbalance, and correction of the nutritional deficit. There are no priorities; all aspects of treatment must be rendered concomitantly and rapidly. It is essential that the septic and hypovolemic processes be treated concomitantly, since preventing the complexing of antigen-antibody and complement will deter vascular permeability and its consequent hypovolemia. Prompt and adequate treatment of hypovolemia prevents the development of attendant cellular metabolic derangements.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic glycolytic intermediates in fed and fasted rats after severe hemorrhage.

The responses of key liver carbohydrate intermediates to severe hemorrhage were investigated in fed and fasted young adult male rats. Forty per cent of intravascular blood was withdrawn and liver was sampled by freeze-clamp at 0, 0.25, 1.0, 3.0, and 4.0-5.0 hours. Fed rats with abundant glycogen showed a threefold increase in glucose-6-phosphate (G6P) concentration, and fasted rats showed a 75% decline in G6P immediately after hemorrhage. This significant difference in response traces to the fact that G6P is one of the first catabolites in fed liver formed by glycogenolysis but is the last intermediate of the gluconeogenic pathway in fasted animals. Phosphoenolpyruvate (PEP), the high-energy intermediate, was markedly depleted in both fed and fasted rats at zero time. In the fasted animal, however, the PEP was rapidly restored, and by 1.0 hour was threefold above normal. The ability of fasted rats to rapidly synthesize glucose from accumulated lactate is attributed to increased amount of gluconeogenic enzymes induced by fasting. In prolonged shock states, this synthetic capacity plays a protective role. Contrariwise, in brief shock states such as hemorrhage, the immediate availability of glucose from stored glycogen appears to be a more important determinant of survival. In the present experiments, fed rats were more resistant to the hemorrhage protocol.

Antiendotoxic effect of water-soluble analogs of glucocorticoids

Abstract The results of this study indicate that in the rat the antiendotoxic action of hydrocortisone, methylprednisoline, or dexamethasone is not affected by the nature of the salt radical employed to render these steroids water soluble. Also, the administration of methylprednisolone succinate and dexamethasone phosphate in concert protects in a simple additive manner.

Effect of severe hemorrhage on rat hepatic glycolytic intermediates

Abstract The concentrations of key hepatic glycolytic intermediates were determined at different time intervals in fasted adult male rats following the removal of 40% of the estimated blood volume. This procedure lowered arterial pressure to 40–45 mm Hg. Frozen liver samples taken immediately after bleeding showed an 87% decrease of phosphoenolpyruvate (PEP), a critical high-energy metabolite, while glucose 6-phosphate (G6P) was reduced 67% compared to controls. Liver lactate increased 2.5-fold and fructose 1,6-diphosphate (FDP) was doubled, indicating the rapid onset of hypoxic conditions and the simultaneous decline of gluconeogenesis. Within 15 min, however, homeostatic mechanisms had restored PEP levels to normal and at 1 hr to supernormal concentrations. G6P rose almost to the control range in 1 hr and was 100% overcompensated at 3 and 5 hr. Liver lactate and FDP were normalized at 3 and 5 hr. The data reveal the great sensitivity of the glycolytic cycle to the hypovolemia and hypoxia of severe hemorrhage and, additionally, the remarkable capacity of the liver to promptly restore depleted substrates. Theoretically significant was the fact that the hepatic metabolite pattern differed completely from previous findings on endotoxic and septic livers studied at 5 hr. This difference in metabolic pattern suggests that the changes in endotoxemic and septic liver are not caused by circulatory deficits and that the hypoglycemia of terminal infective states results from some other factor.

REGULATION OF GLUCONEOGENIC INTERMEDIATES IN ENDOTOXIC AND SEPTIC RAT LIVERS

Publisher Summary This chapter describes the regulation of gluconeogenic intermediates in endotoxic and septic rat livers. In a study described in the chapter, fasted adult albino male rats were made septic by cecal incision. Livers were sampled at 5 h by liquid nitrogen cooled tongs. Perchloric acid extracts were assayed by standard enzymatic spectrophotometric methods. Peritonitis elevated lactate 2- to 3-fold in all groups, and this was not reversed by glucocorticoids. Glucocorticoids promote gluconeogenesis by inducing the formation of phosphoenolpyruvate (PEP) carboxykinase. Glucocorticoid raised PEP plus 70% despite sepsis. In the fed peritonitis group, PEP fell drastically compared to sham-operated controls. Without fasting or hormone, PEP carboxykinase cannot be induced and PEP production is not maintained. As adequate glycogen is available in fed rats, hexose monosphosphates (HMP) values are supernormal at 5 h even in sepsis. Well-fed rats do not suffer decreases in hexose monophosphates during sepsis, while glucocorticoid treatment supports the synthesis of high-energy phosphoenolpyruvate in fasted rats. Restoring a normal pattern of glycolytic intermediates in sepsis might require both hormones and nutritional repletion.

Indications for Use of Corticosteroid Agents in Treatment of Shock

The use of steroids in the treatment of shock is indicated in early septic shock, in late refractory hypovolemic shock, and in post-traumatic pulmonary insufficiency.

Nutrition of the Critically Ill and Traumatized Patient: Parenteral Alimentation

The human organism responds to trauma or disease by stimulating the hypothalamus, the pituitary gland, and the adrenal cortex. The hypothalamopituitary complex secretes somatotropic, adrenocorticotropic, thyrotropic, and antidiuretic (ADH) hormones. This endocrine response has two major consequences: (a) the combined effect of ADH and adrenal mineralocorticoid hormones conserving water to maintain blood volume and (b) the pituitary-adrenal axis secreting glucocorticoids to mobilize amino and fatty acids for sugar production, stimulating the adrenal medulla to secrete epinephrine for the catabolism of glycogen to sugar, and aiding the induction of lipid and protein catabolism. This accelerated breakdown of fats and proteins is the main cause of weight loss during disease and trauma. The secretion of somatotropic hormones, which usually begins on the third day of disease or trauma, increases the serum concentration of glucose by mobilizing additional fats and proteins. At the same time, the stimulated thyroid accelerates metabolism and the utilization of glucose.

Influence of pharmacologic agents on tissue metabolism in circulatory shock.

Our research activities have been oriented to the effect of pharmaeologic agents on tissue metabolism in the low flow state of circulatory shock. Specifically, we have been most interested in the effect of glucocorticoids on cellular metabolism because these agents exert a reproducible protective effect during septic and endotoxic shock in rats and monkeys. Further, we have studied the differences between untreated animals in shock and those treated with pharmaeologic agents in an attempt to determine which cellular metabolic changes are critical to survival. This paper will present our studies as well as those of other laboratories, which have defined the effects on tissue metabolism of certain pharmaeologic agents: those which stimulate cyclic adenosine monophosphate (AMP) (epinephrine, norepinephrine, glucagon, and prostaglandin) and those which do not (the glucocorticoids).