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Three young family members with recurrent arterial thrombosis underwent investigation for lipid or coagulation abnormalities. Lipoprotein electrophoresis, cholesterol, triglyceride levels, and routine coagulation studies were unremarkable. By contrast, testing of platelet function showed enhanced platelet aggregability to epinephrine and collagen in two of the subjects. In addition, release of 14C-serotonin by adenosine diphosphate and epinephrine was increased over control values in these same two patients. The third subject demonstrated decreased platelet aggregation and lowered 14C-serotonin release, but was symptomatic with rest pain at the time of testing. The ongoing in vivo thrombosis in the third subject may account for hypocoagulable platelets by in vitro testing. These abnormally sensitive platelets identified by platelet function testing may be associated with a familial "hypercoagulability" syndrome. Definition of the hemostatic abnormality in these individuals provided a rational basis for pharmacological therapy with antiplatelet drugs, which appeared to be successful.

Interleukin 1 (IL 1) is a product(s) of mononuclear phagocytes, and has multiple biologic activities that mediate several host responses to infection and inflammation. Highly purified IL 1 activates lymphocytes, induces fever, increases hepatic acute phase protein synthesis, and increases muscle protein degradation. A 4.2 kd peptide has been purified from plasma of febrile humans which also induces muscle proteolysis in vitro (termed proteolysis-inducing factor, PIF). Because IL 1 purified from activated human monocytes induces muscle proteolysis in vitro, studies were performed to determine the relationship of human monocyte-derived IL 1 to plasma-derived PIF. Purified PIF was highly active in the IL 1 thymocyte assay. After gel filtration of plasma from febrile patients, fractions with PIF activity also induced thymocyte proliferation and fever in mice. Thus, it seems likely that the plasma peptide PIF has IL 1 properties and probably represents a small m.w. cleavage product of IL 1. Further studies confirmed this finding. Highly purified 15 kd IL 1, rechromatographed over different gel filtration media, consistently fragmented into a 4 kd peptide with both muscle proteolysis-inducing and lymphocyte-activating properties. The breakdown of the 15 kd IL 1 into biologically active smaller fragments increased with time, and could be accelerated by trypsinization. The monocyte-derived IL 1 fragments were partially destroyed by heat. Highly purified 125I-labeled 15 kd IL 1 also fragmented into subunits, and these radioactive subunits produced fever in mice and were active in the thymocyte assay. Fragmentation of 125I-labeled 15 kd IL 1 was reduced by agents that inhibit proteases. These results indicate that some of the biologic activities of human IL 1 are conserved in small m.w. fragments. These studies also provide evidence that IL 1 may circulate in humans as a 4.2 kd peptide, and that this cleavage product can function as an active mediator of IL 1 effects in the host.

To measure the effects of cirrhosis on amino acid (AA) flux and to assess the value of the central plasma clearance rate of amino acids (CPCR-AA) as a hepatocyte function test, 35 patients with cirrhosis were studied before and after operation. Fourteen of these patients died after the operation. CPCR-AA measures the number of milliliters of plasma cleared of AA per minute by the liver and other visceral tissues. It is the ratio of AA entry rate into plasma (from peripheral tissues plus infusion) to the arterial AA plasma concentration. Preoperative CPCR-AA measurements in 21 fasted patients with cirrhosis who were not infected revealed a pattern of AA plasma concentration and exchange similar to that previously observed in patients with sepsis with normal liver function. Whereas the concentration of AA in both groups was slightly lower than normal, the CPCR-AA of each was more than four times that of normal postabsorptive people (p less than 0.01). However, preoperative values of CPCR-AA in patients with cirrhosis who survived was 220 +/- 26 ml/M2/min while that in those who died was 97 +/- 16 ml/M2/min (p less than 0.001). Postoperative measurements remained relatively unchanged: survivors 212 +/- 24 ml/M2/min and those who died 89 ml/M2/min (p less than 0.0005). Measurements in vitro of the hepatic protein synthetic rate in liver biopsy specimens taken at operation correlated well with CPCR-AA values obtained immediately before operation in 10 patients (r = 0.73; p less than 0.01). Thus in patients with cirrhosis visceral amino acid uptake and hepatic protein synthesis are maximally stimulated. Nevertheless, if the preoperative CPCR-AA does not approach the value of 284 +/- 76 ml/M2/min previously observed in patients with sepsis who recover, the patient with cirrhosis is prone postoperatively to die of overwhelming infection and multisystem failure.

Accelerated release of amino acids from muscle and their uptake for protein synthesis by liver and other visceral tissues are characteristic of trauma or sepsis. Experimentally, this response is induced by interleukin-1 (IL-1) generated by activated macrophages in vitro. However, IL-1 has not been demonstrated in human blood. A small 4000-dalton peptide recently isolated from plasma of patients with sepsis and trauma induces muscle proteolysis and is called "proteolysis-inducing factor" (PIF). To test whether this agent has the ability also to induce hepatic protein synthesis, a series of animal experiments and clinical observations were undertaken. The structural and secretory (acute-phase reactants) in vitro protein synthesis in livers of normal rats injected intraperitoneally with IL-1 or PIF was significantly greater than that of normal rats or those injected with Ringer's lactate (p less than 0.01). In patients with sepsis and trauma the central plasma clearance rate of amino acids, a measure of visceral (principally hepatic) amino acid uptake, was elevated and correlated with the rates of protein synthesis in incubated liver slices obtained by biopsy at operation from the same patients (p less than 0.05). Both in vivo measured central plasma clearance rate of amino acids and in vitro measured hepatic protein synthesis correlated with plasma levels of PIF in the same patients (p less than 0.01 and p less than 0.05, respectively). We conclude that since PIF, and not IL-1, is present in human plasma and both are produced by activated macrophages, PIF seems to be the stable circulating cleavage product of IL-1, which induces not only muscle proteolysis but also hepatic protein synthesis, principally in the form of acute-phase reactants during infection and other states in which inflammation is present.

The amino acid "central fractional clearance rate" (CFCR), the ratio of the rate of amino acid entry into the extracellular pool to the size of the pool, is a measure of amino acid uptake and clearance by liver and other visceral tissues. In nine normal postabsorptive persons, the mean CFCR was 5%, compared with 21% in 31 seriously infected patients. For comparative purposes, biopsy specimens of liver and muscle were obtained for incubation. In infected patients, the rate of hepatic incorporation of tyrosine into protein was three times that in noninfected patients and correlated well with the CFCR. There was no significant difference in hepatic tyrosine oxidation. In muscle from infected patients, net protein degradation was six times that in noninfected patients. Incubated tissues from rats behaved similarly. Thus, accelerated transfer of amino acid from muscle to viscera for protein synthesis occurs in humans with sepsis, as it does in animals. The CFCR demonstrated the importance to survival of visceral amino acid uptake; it was 35% in surviving patients, and only 19% in those who died.

Sixteen seriously septic patients were studied to determine whether proteolysis occurred to satisfy a deficit of peripheral fuel, as suggested by out previous experimental observations. Concentrations of glucose, lactate, free fatty acids,and alanine were measured in blood samples from the femoral artery and vein to determine extraction (+) and release (-) by the leg. Simultaneously, cardiac index (CI) was determined by thermal dilution, so that an estimate of uptake or production of fuel substrates could be made from the proportional relationship of cardiac index to peripheral blood flow. Due to the antilipolytic effect of elevated levels of insulin (42 +/- 4 muM per milliliter) in those patients with elevated cardiac indices (4.38 +/- 0.33 L. per square meter per minute), free fatty acid uptake (-0.59 +/- 0.021 mM.) was reduced. In low-flow septic shock (CI, 1.66 +/- .41 L. per square meter per minute), the majority of glucose taken up by the limb was converted to lactate (arterial lactate, 3.14 +/- 0.7 mM.; deltaA-V 0.68 +/- 0.17). Free fatty acid uptake also was impaired in low-flow sepsis. As opposed to fasting, arterial levels and uptake of ketone bodies were insignificant in sepsis. These findings suggest that there is a deficit of peripheral fuel with respect to glucose and fat. That protein is oxidized to fill this deficit is substantiated by the increased alanine release (-0.13 +/- 0.01, -0.33 +/- 0.12 mM.) in the high-flow and low-flow septic groups, respectively, whereas alanine production was three- and fourfold greater than that observed in fasting patients. Enhanced release of alanine reflects the magnitude of oxidation of branched-chain amino acids and accounts for the high rates of gluconeogenesis and proteolysis observed in sepsis.

Accelerated proteolysis of muscle is characteristic in patients with trauma or sepsis, but its cause is not well understood. Using rat muscle in vitro, we developed a bioassay to compare the proteolytic activity of plasma from 50 patients with trauma or sepsis with that of plasma from 14 normal volunteers and from 15 patients who had undergone "clean" elective surgical procedures. The mean proteolytic activity in the plasma of patients with trauma or sepsis was found to be 190 +/- 8.0 per cent of the control value (rat muscle incubated in medium alone), whereas the activity in normal plasma was 124 +/- 4.5 per cent (P less than 0.001). The activity in the plasma of patients who had undergone elective surgery was slightly elevated at 142 +/- 2.5 per cent (P less than 0.005). In 25 of the patients with trauma or sepsis the rate of amino acid release from one leg was measured by subtracting the concentration of tyrosine plus phenylalanine in the femoral artery plasma from that in the femoral vein; this rate correlated well with the bioactivity of the plasma in the bioassay system (r = 0.67, P less than 0.001). By means of ultrafiltration and chromatography, the plasma factor inducing proteolysis was isolated and found to be a peptide, probably containing sialic acid, with a chain of 33 amino acids and a molecular weight of approximately 4274 daltons.

Forty-five patients who underwent a 14 by 4 inch jejunoileal bypass for morbid obesity were studied before the operation and at periodic intervals after operation to determine the complications and changes in body composition resulting from this procedure. Body composition studies were determined using 3H2O and 42K. Rapid weight loss occurred in the first 3 months, with a mean loss of 30 percent of excess weight. This weight loss was accompanied by a decrease in exchangeable potassium (Ke) and total body water (TBW) during this interval by 14 and 10 percent, respectively. Although most patients continued to lose excess weight Ke and TBW stabilized at the end of the first year and returned to preoperative values in six patients at the end of 24 months. Analysis of the ratios of body cell mass and total body water to weight shows an improvement of body composition 12 months after operation. Body composition studies permit a quantitative assessment of the nutritional status in patients undergoing jejunoileal bypass. In spite of significant complications (23 percent), surgery for morbid obesity appears to satisfy the objective of allowing desirable loss of fat with relative sparing of muscle and other supporting tissues.

The adult pulmonary distress syndrome is a disease of many etiologies and significantly contributes to the post-traumatic and postsurgical mortality and morbidity. Pulmonary insufficiency associated with shock and hemorrhage is characterized by its relatively short duration, less severe alterations of pulmonary functions, and normal pulmonary vascular resistance. The judicious use of fluids and emphasis in the early use of blood during resuscitation will minimize the magnitude of the pulmonary insult. Severe changes in oxygenation and ventilation, increases in pulmonary vascular resistance, the need for long-term respiratory assistance, and an increase in mortality and morbidity are characteristic of the adult pulmonary distress syndrome that follows severe systemic sepsis. Early aggressive pulmonary support is required in all life-threatening surgical conditions. Endotracheal intubation is preferred to tracheostomy, and the use of a volume respirator will facilitate the control of ventilation and oxygenation. Significant decreases in the functional residual capacity are responsible for refractory hypoxemia and the use of high concentrations of oxygen can be circumvented by the use of positive end expiratory pressure. PEEP is sometimes associated with a decrease in cardiac output and an increase in the pulmonary shunt and occasionally pneumothorax. Continued hemodynamic and pulmonary monitoring of patients is mandatory when using PEEP. Discontinuance of ventilatory assistance is usually possible if the pulmonary shunts are less than 25 per cent, the tidal volumes greater than 5 cc per kg, and the vital capacity at least twice the tidal volume. Recovery from pulmonary insufficiency is predicated on adequate pulmonary management, nutritional support, and the control of the underlying contributory conditions.

Total hepatic and portal blood flow as well as hepatic and splanchnic oxygen consumption was measured in pigs in the normal fasted state and in the septic fasted state induced experimentally by cecal ligation. Pigs in the septic state were divided into two groupds, a septic high output state and a septic low output state, according to whether or not a pig showed a higher or lower cardiac output in the septic state than in the normal fasted state. In the septic high output state, the average cardiac output was 155 per cent of that during fasting; hepatic arterial flow increased 96 per cent, while portal flow decreased 19 per cent. Total hepatic blood flow increased slightly, 14 per cent. The ratio of total hepatic blood flow to cardiac output decreased from 42 per cent in the normal fasted state to 30 per cent. The total hepatic oxygen consumption increased 26 per cent because of significantly elevated oxygen transport by hepatic arterial flow. In the low output state, hepatic arterial flow significantly dropped, 74 per cent, while portal flow decreased slightly, 23 per cent, and total hepatic blood flow decreased 38 per cent. The decrease of cardiac output was less, 18 per cent. The ratio of total hepatic blood flow to cardiac output was 31 per cent. Total hepatic oxygen consumption decreased remarkably, 29.1 per cent, due chiefly to the decrease of hepatic arterial flow, and splanchnic oxygen consumption also decreased significantly, 22 per cent. Dissociation of hepatic arterial response to sepsis from the other gastrointestianl vessels caused a great difference in the hepatic oxygen consumption between the septic high output and the septic low output state, contributing in part to the difference in mortality between these two states.

The central plasma clearance rate of amino acids (CPCR-AA), the ratio of peripheral amino acid entry rate into blood plasma to arterial amino acid concentration, was measured preoperatively in 149 noninfected cirrhotic patients. In 50 survivors of shunting or general surgical procedures, the mean (+/- SEM) CPCR-AA was 201 +/- 17 mL/m2/min; in 39 subsequent deaths, the mean ratio was 87 +/- 14 mL/m2/min. Comparing Child's classification with CPCR-AA reveals the following values: class A (mortality, two of ten patients) survivors, 152 +/- 23 mL/m2/min; class A deaths, 96 +/- 54 mL/m2/min; class C (mortality, 13 of 19 patients) survivors, 214 +/- 47 mL/m2/min; class C deaths, 101 +/- 13 mL/m2/min. The preoperative CPCR-AA of 46 patients receiving liver transplants was 91 +/- 9 mL/m2/min; 69% of these patients survived. Preoperative CPCR-AA values correlated significantly with rates of hepatic protein synthesis in incubated liver slices obtained by biopsy at operation in 22 patients. Thus, CPCR-AA determination is a true liver function test, valuable in predicting surgical mortality and selecting transplantation or other operations for cirrhotic patients.

The metabolic responses associated with the tumor-bearing state, as compared to states of sepsis and prolonged starvation, were examined. Tumor-bearing rats manifested significant elevation of triglycerides, significant reduction of glucose and insulin levels, significantly increased plasma skeletal muscle proteolysis-inducing activity, and an unchanged hepatic protein synthetic activity compared to control rats. Prolonged starvation produced an adaptation characterized by significant hypoglycemia and hypoinsulinemia, reduced hepatic protein synthesis, and increased peripheral protolysis compared to controls. Septic animals had glucose, insulin, and lipid levels similar to control animals but had increased hepatic protein synthesis. Each state manifested its own unique metabolic response compared to controls. It appears that the metabolic consequences of cancer in this sarcoma rat model is different than septic and prolonged starvation states.

To determine whether or not kinin activation in the blood during severe infection with gram-negative bacteria may be related to hemodynamic abnormalities encountered, blood prekallikrein, kallikrein inhibitor and kinin values in 2l surgical patients with sepsis were compared with those in normotensive and hypotensive states. Because of reduced prekallikrein synthesis in patients with hepatic insufficiency, the normotensive and hypotensive groups were each subdivided according to the presence or absence of liver dysfunction, as indicated by elevated blood bilirubin, serum glutamic-oxalacetic transaminase or alkaline phosphatase levels. The mortality was zero in group 1, normotensive normal liver function; 80 per cent in group 2, hypotensive-normal liver function; 20 per cent in group 3, normotensive liver dysfunction, and 67 per cent in group 4, hypotensive liver dysfunction. Ultimately, the majority of deaths were due to respiratory failure. Although the blood prekallikrein level, was below normal in all groups and was significantly less in all patients with liver dysfunction, it was reduced proportionately in hypotensive patients to less than 30 per cent of the values noted in the two normotensive groups. This finding suggests prekallikrein consumption in the hypotensive groups to be the result of the process of activating kallikrein and bradykinin. This concept is supported by finding elevated kinin values, above 3 nanograms per milliliter of plasma, in only 28 per cent of those in group 1 and 12 per cent of those in group 3, while in the hypotensive patients, groups 2 and 4, the kinin level was elevated in 60 and 66 per cent, respectively.

Forty-one patients, all in end stage hepatic failure, underwent 46 liver transplantations with a long-term survival rate of 63%. Six patients died of uncontrollable bleeding due to primary graft malfunction at or immediately after operation. Nine died early or late with overwhelming infection. In addition to clinical assessment, needle liver biopsy, central plasma clearance rate of amino acids (CPCR-AA), and routine "liver function tests" were employed to aid in selection of patients for transplantation and for guidance in postoperative management. Although liver biopsies usually afforded an exact diagnosis, neither they nor the routine liver function tests quantitated the extent to which hepatocyte function was impaired. CPCR-AA, which measures the rate of amino acid uptake by the liver and other central tissues for oxidation, gluconeogenesis, and protein synthesis was 91 +/- 9 ml/M2/min in the preoperative transplant group. This compares with a value of 97 +/- 16 in a previously studied series of cirrhotics who died following other forms of surgery and a CPCR-AA of 220 +/- 26 ml/m2/min in those who survived. In addition, the preoperative CPCR-AA was found to correlate with the in vitro hepatic protein synthetic rate of slices from the resected recipient liver (r = 0.72, p less than 0.02). After operation, serial hepatic needle biopsies were classified by histology into four grades of injury, ranging from normal liver transplant (Grade I) to mild hypoxic or rejection injury (Grade II), viral hepatitis (Grade III), and severe hypoxic or rejection injury (Grade IV). Significant relationships of the histological grades to ultimate mortality, CPCR-AA, and prothrombin times were found. CPCR-AA and prothrombin time correlate inversely (r = 0.57, p less than 0.001), further demonstrating the relationship of CPCR-AA to protein synthesis of clotting factors. These patterns of posttransplant response were delineated by serial CPCR-AA values. "Early" responders had values over 290 ml/M2/min and all survived. Twelve patients with delayed response were characterized by values of 150 +/- 12, rising to over 200 ml/M2/min after 2 weeks. Two who failed to increase CPCR-AA died. In six "poor" responders, CPCR-AA with Grade IV injury remained below 110 ml/M2/min. All died except for one whose CPCR-AA subsequently rose following retransplantation. It is concluded that percutaneous hepatic needle biopsies and CPCR-AA measurements in combination are of proven value, not only in understanding the nature of injury and functional impairment of the liver, but are also important as guides to selection of patients and for their posttransplant management.

Natural killer cell (NK) activity was assessed in patients with nonthermal injury. NK activity was assessed employing a standard 4-hour 51Cr release. Peripheral mononuclear cells from healthy human donors and trauma ward patients served as effector cells at three effector/target ratios. Labeled K562 erythroleukemia cells were used as targets. Multiple dilutions of crude and purified proteolysis inducing factor (PIF), isolated from three septic patients, were evaluated in comparison with other adjuvants. Greater augmentation of anti-K562 activity was obtained in long-term pretreatment of effector cells with adjuvants present as opposed to immediate NK assay. Untreated effectors from trauma patients demonstrated the least amount of baseline NK activity; however, a combination of PIF and interferon showed the greatest cytotoxicity. Untreated healthy cells exhibited a significant (p less than 0.001), twofold greater amount of cytotoxicity than untreated trauma cells. PIF enhances NK activity and may be key to mobilization of host defense in trauma.

Two series of patients were studied by serial measurements of blood gas exchange and pulmonarmonary dysfunction and to evaluate the dangers of respiratory failure in post traumatic patients. There were 27 patients who had sustained profound hemorrhagic shock and massive blood replacement averaging 9.7 liters and 38 patients who suffered general peritonitis or other forms of fulminating nonthoracic sepsis. All were supported by endotrachael intubation and volume controlled ventilators. The overall mortality for the post shock patients without sepsis was 12% while in the septic patients it was 35%. The maximal pulmonary arteriovenous shunt encountered in the post hemorrhagic shock patients at 36 hours averaged 20 plus or minus 8% and was accompanied by high cardiac indices (average 5.1 plus or minus 1.3 L/M-2/min) but no significant rise of pulmonary arterial pressure or peak inspiratory pressure (PIP). Severe pulmonary dysfunction subsequently occurred only in those patients who later became septic. The studies on the septic patients were divided according to the magnitude of the cardiac indices (the high indices averaged 4.8 plus or minus 1.6L/M-2/min) and thelow indices averaged 1.9 plus or minus 1.0 L/M-2/min. In the former, the average maximal shunt of 30 plus or minus 6% was sustained for 4 or more days, accompanied by an elevation of PIP to 36 plus or minus 6 cm H2O and by Pa pressure of 28 plus or minus 5 mm Hg. The patients in low output septic shock usually had an associated bronchopneumonia and had an average venous admixture of 34 plus or minus 8% and PIP values of 41 plus or minus 8 cm H2O. The mean Pa pressure in this group was 29 plus or minus 6 mm Hg.

Thirty-five patients with occlusive disease of the arteries underwent metabolic studies. The arteriovenous differences of lactate, glucose and oxygen varied with the severity of the ischemic process, as assessed clinically. Lactate release and glucose extraction were significantly different from control values of patients with rest pain or with ischemic gangrene, while values in patients with claudication were comparable with those in the control group. Percutaneous muscle surface pH measurements, which reflect lactate release, decreased directly with diminished perfusion. Metabolic assessment of arterial occlusive disease may prove to be a useful clinical approach.

The relationship of glucogenesis and other energy-requiring functions of the liver to the proteolysis which is characteristic of trauma and sepsis was studied in conscious pigs following laporotomy and after the induction of intraperitoneal sepsis. By means of appropriately placed thermal dilution catheters, portal and hepatic arterial blood flows, hepatic oxygen consumption, glucogenesis, and uptake of the fuel, substrates were measured. No animal was in shock. Despite significant increases of lactate and aminoacids delivered to the liver, the blood concentrations were maintained in the normal range. The rate of glucogenesis was proportional (r equals 0.71) to the sum of the glucogenic precursors (lactate, pyruvate, glycerol, and alanine) taken up by the liver. Higher rates of glucose production were accompanied by elevated blood insulin values. Hepatic oxygen consumption and the uptake of free fatty acids also were related directly to the glucogenic rate, the correlation coefficients being 0.69 and 0.74, respectively. In the absence of shock, the liver function and hepatic energy production remained normal in post-traumatic and septic states. Under the conditions insulin-resistant muscle in the presence of reduced free fatty acid availability mobilize protein to satisfy local energy requirements. Skeletal muscle can oxidize only branch chain aminoacids; other aminoacids, including alanine, are transported to the liver for glucogenesis or other purposed. This concept accounted for failure of glucose infusion to eliminate post-traumatic and septic proteolysis, since alanine is cleared only from blood by conversion in the liver to glucose. Thus it is concluded that in sepsis the release of glucogenic substrates because of altered metabolism in peripheral tissues determines the rate of hepatic glucogenesis. This relationship constitutes an important metabolic homeostatic mechanism.

To assess the relationship of the high mortality of coma in cirrhotic surgical patients to defects in energy metabolism, reduced utilization of amino acids by the liver and other visceral tissues, oxygen consumption, central plasma clearance rate of amino acids (CPCR of amino acids), and the plasma concentrations of plasma inducing factors were measured in a series of 59 cirrhotic patients. They were classed as alert, encephalopathic, and comatose (Groups A, E, and C, respectively). The comatose group was set apart from the other two by a significantly higher mortality of 83 percent (p less than 0.005) combined with a lower whole body oxygen consumption of 103 +/- 6.8 ml/min per m2 compared with 135 +/- 10 ml/min per m2 in alert patients and 159 +/- 12 ml/min per m2 in the encephalopathic patients (p less than 0.01) and CPCR of amino acids of only 120 +/- 20 ml of plasma/min per m2 compared with 240 +/- 30 ml of plasma/min per m2 in the alert patients and 300 +/- 50 in the encephalopathic patients (p less than 0.01). An inverse correlation of tyrosine and phenylalanine concentrations existed with both whole body oxygen consumption (r = -0.56, p less than 0.01) and also with total amino acid clearance (r = -0.61, p less than 0.01). Tyrosine and phenylalanine concentrations also correlated directly with the octopamine concentration (r = 0.64, p less than 0.01). Thus, we conclude that coma is a symptom of hyperaminoacidemia, but that death is the result of impaired oxidative energy production and a deficiency of amino acid clearance for synthesis of proteins required for survival.

Sepsis, the commonest cause of late death following severe trauma, is related in part to inadequate uptake of amino acids (AA) and synthesis by the liver and other central tissues of proteins essential to immunological defense. Since 'central plasma clearance rate' of amino acids (CPCR-AA) has been found to reflect these functions, serial measurements of CPCR-AA were made in 32 seriously injured patients of whom ten died (31%), nine of sepsis. The mean Index Severity Score on admission for survivors was 31 +/- 1.8 and in deaths 34 +/- 3.9 (N.S.). The blood plasma AA concentrations were not significantly different. However, early in the course before the onset of infection, CPCR-AA in surviving patients was 227 +/- 30 and in those who ultimately died 83 +/- 24 ml/M2/min (p less than 0.001). Later during sepsis the values of CPCR-AA were 176 +/- 28 and 85 +/- 14 ml/M2/min, respectively (p less than 0.01). Thus CPCR-AA appears to be of value as an indicator of amino acid utilization by central tissues and as a predictor of survival or death following severe trauma.

Complement concentrations and blood cultures were compared in 58 patients within 24 hours of injury and weekly thereafter. Extensive amounts of nonviable tissue (n = 40) were associated with a mean depletion of C4, C3, and C5 by 56%, and minor injuries (n = 18) by 22% of normal concentration within 14 hours after injury. The C4, C3, and C5 concentrations returned to normal or above within a week after minor injuries, but not following major injuries. However, C4, c3, and C5 levels remained depressed after major injuries unless necrotic tissue was removed or abscesses were drained. If complement concentration was below 50% of normal for more than a week all patients developed bacteremia. Following debridement or drainage complement returned to normal in 11 patients and blood cultures became negative in seven. Possible consequences by activation and altered availability of complement for chemotaxis, opsonization, and lysis of bacteria have been analyzed and related to the development of bacteremia.

Amino acid (AA) arterial blood plasma concentrations, K1 (peripheral production + infusion rates), and central plasma clearance rates (K1 divided by arterial concentration) (CPCR-AA) were measured in 70 seriously septic patients. All of these people were in the "hyperdynamic" state at the time of observation. Thirty-seven recovered and 33 died. In addition, 10 noninfected, nontraumatized patients about to undergo laparotomy were studied. In 31 patients receiving parenteral alimentation, CPCR-AA was 326 +/- 38 in survivors and 160 +/- 17 ml/M2/min in the deaths (p less than 0.005). In 58 patients studied, while fasted with no intravenous amino acid infusion, values for CPCR-AA were: survivors 202 +/- 22 (28) and deaths 112 +/- 16 (30) ml/M2/min (p less than 0.002). The CPCR-AA in 10 noninfected patients was only 68 +/- 11 ml/M2/min. CPCR-AA in 19 patients correlated with hepatic protein synthetic rates in liver biopsies obtained simultaneously (r = 0.658, p less than 0.01), which shows that CPCR-AA is an indicator of visceral protein synthesis. To study the regulation of amino acid metabolism by synthesis. To study the regulation of amino acid metabolism by proteolysis inducing factor (PIF), the proteolysis inducing activity (PIA) of the plasma fraction (0-50,000 D) was measured 55 times in conjunction with metabolic studies. No significant differences existed in PIA between survivors and deaths. However, in those patients who recovered, PIA was significantly correlated to both peripheral amino acid production (r = 0.773, p less than 0.001) and to CPCR-AA (r = 0.721, p less than 0.001). This observation demonstrates the presence of one or more circulating agents affecting amino acid flux. PIA measured simultaneously in vivo correlated with in vitro protein synthetic rate in incubated liver biopsies (r = 0.653, p less than 0.01). PIF (4,000 D), isolated by chromatography, in patients without amino acid infusion was 35 +/- 3% in survivors and 33 +/- 6% in deaths (N.S.) and only 9 +/- 3% over control in noninfected patients. In patients who recovered, PIF titre was strongly correlated with peripheral amino acid production (r = 0.798, p less than 0.001) and with CPCR-AA (r = 0.835, p less than 0.001). However, values for patients who later died were significantly less for a given PIF titre. Thus, it is concluded that survival from sepsis is, in part, dependent on a significantly elevated CPCR-AA and hepatic protein synthesis, both of which appear to be related to the blood plasma PIF titre.

Liver blood flow and exchange of oxygen, glucose, lactate, and amino acids were measured in pigs at the same time as the peripheral arteriovenous (A-V) difference of these substances was determined. Four groups of animals were studied; they were normal postabsorptive, septic fasted, and septic infused either with complete parenteral nutrition (4.25% mixed amino acid solution with 25% glucose) or an isocaloric solution of 1.8% leucine with glucose. Sepsis in the pig caused a rise in arterial concentration of all essential amino acids except tryptophan and a decrease of most of the others. The liver uptake of the sum of all amino acids rose from nonsignificant values to 26.03 mumol/min/kg at the same time as the peripheral A-V difference changed from +20.4 to -678.0 mumol/l. Hyperalimentation increased arterial amino acid concentration, whereas peripheral A-V difference decreased to -132.3 mumol/l. The total liver uptake of amino acids was 24.80 mumol/min/kg but with a higher proportion of essential amino acids than in the fasted septic state suggesting increased liver protein synthesis. When leucine and glucose were infused the peripheral A-V difference of the sum of all amino acids was only -45.6 mumol/l indicating an almost complete cessation of muscle proteolysis. The arterial plasma concentration of all amino acids except leucine, glutamine, and glutamate were markedly reduced. Although hepatic clearance rate of amino acids fell only slightly, due to the low plasma concentrations, the liver uptake decreased substantially to 7.37 mumol/min/kg suggesting a decreased liver protein synthesis which could be deleterious in the presence of sepsis.

An isolated level model was used in 25-30 kg pigs to study the uptake and/or release of various energy substrates across the liver and splanchnic bed during trauma and sepsis. This was accomplished by bypassing the hepatic portion of the inferior vena cava (IVC) using a polytetrafluoroethylene (PTFE) (IMPRA, Inc.) graphite-impregnated graft, from above the renal veins to the right atrial junction. The IVC was then ligated between the distal anastomosis and the liver. Sampling was done from inlying catheters placed in the main portal vein, hepatic vena cava, and an artery. Total hepatic blood flow was determined by the dye dilution technique. Our data showed the same pattern of metabolic derangements in both the traumatized and the septic-starved animals, but differed significantly from the normal fed controls. The correlation between glucogenesis and other energy functions of the liver and the proteolysis in skeletal muscle seen in trauma and sepsis is demonstrated. This model is functional and is applicable to the study of various kinds of shock and/or liver failure.