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Various metabolic, cellular, and subcellular alterations in cell function and morphology occur during shock or low-flow conditions. In attempting to find treatment programs that would be beneficial following shock, various substrates have been used. Infusion of hypertonic glucose during shock has been shown to improve survival; however, it is unlikely that the effect of glucose is by provision of energy until the circulation is restored. Infusion of glucose--insulin--potassium during shock has also been reported to be beneficial in certain clinical situations. Controversies exist concerning the efficacy of infusions of cyclic AMP, nicotinamide, and Krebs cycle intermediates during shock. Pretreatment of kidneys with inosine or raising glycogen stores of the myocardium have been shown to have protective effects of kidneys and myocardium during ischemia and these procedures may be suitable for organ preservation. Pretreatment with allopurinol has been shown to be beneficial in shock; however, it is unlikely that allopurinol by itself if given following shock would have any salutary effects. Treatment with ATP-MgCl2 has been shown to be beneficial following hemorrhagic shock, sepsis, endotoxin shock, burns, postischemic hepatic failure, and postischemic renal failure. Thus, provision of energy directly in the form of ATP during adverse circulatory conditions appears to be the most advantageous and direct method for the treatment of shock.

Gluconeogenic and oxidative capabilities with lactate as a substrate were studied in perfused livers isolated from rats in late sepsis. Glucose release in the presence of 5 mM lactate was significantly depressed in livers from septic rats. When gluconeogenesis was stimulated by phenylephrine, livers from septic rats exhibited both a decreased sensitivity and lower maximal rate of glucose release when compared with livers from sham-operated rats. Oxygen consumption (VO2) by perfused livers from septic rats was also depressed under the above conditions. The addition of lysine in concentrations greater than 0.5 mM restored glucose production in livers from septic rats to a rate not different from sham-operated controls but did not restore VO2. However, inclusion of lysine (5 mM) in the perfusate was not able to restore sensitivity to stimulation by phenylephrine in livers from septic rats. Although hepatic ATP levels were depressed in sepsis, the decrease was not sufficient to explain the decreased rates of glucose production. We conclude from these results that primary cellular defects in gluconeogenic and oxidative capabilities occur during sepsis that are independent of inadequate perfusion.

Although recent studies have shown that combined treatment with verapamil and ATP-MgCl2 (ATP) prevents cyclosporine (CyA)-induced nephrotoxicity, the mechanism of these effects remains unknown. To study this, rat kidneys were perfused at 100 mmHg for 100 minutes with Krebs buffer containing 7.5 g/dL of albumin and substrates. After an equilibration period of 30 minutes, 500 ng/mL CyA was added. In some experiments 1 microgram/mL verapamil was added 10 minutes prior to CyA and in others 2 mM ATP was added to CyA. At the end of the perfusion, cortical mitochondria (mito) were isolated and mito Ca2+ and Mg2+ (mumoles/g protein) and respiratory control ratios (RCR) were measured. In addition, total tissue Ca2+ and Mg2+ levels were measured. The results indicate that CyA treatment leads to an accumulation of mito Ca2+ and a decrease in ADP/O ratio. Simultaneous administration of ATP with CyA led to an increased mito Ca2+ accumulation and depressed RCR, which were corrected by verapamil pretreatment. The combination of verapamil pretreatment and ATP cotreatment with CyA increased tissue ATP levels from 0.8 +/- 0.4 (control) to 1.4 +/- 0.1 mumol/g. This pharmacologic regimen may prevent CyA-induced nephrotoxicity by preventing mito Ca2+ accumulation and by preserving mitochondrial respiratory function. This allows a more efficient generation of ATP and consequently preservation of renal function.

During the forty-month period ending July, 1976, intraaortic balloon counterpulsation was used as an adjunct to medical or surgical therapy in 273 patients. Thirty-seven developed complications. Limb ischemia occurred in 16; it resolved in 12, resulted in gangrene of the toes in 1 and leg gangrene in 2, and was the casue of death in 1 patient. Aortic dissection was confirmed in 7 patients and strongly suspected in another 4. Eight of the 11 patients with dissection underwent cardiac procedures with heparinization at two days to three months after balloon insertion with no untoward effects. Septicemia developed in 2 patients, 1 of whom died of cardiogenic shock. Localized groin sepsis occurred in 8 patients, 2 of whom required removal of infected Dacron graft material. Awareness of the complications of balloon insertion, proper attention to details of balloon management at the time of insertion and removal, and continuous monitoring through a central-lumen balloon should decrease the incidence of complications.

The effect of hemorrhagic shock, hypoxemia, and anoxia on the levels of adenine and pyridine nucleotides of liver and kidney was assessed. ATP levels in liver and kidney of animals in shock or animals subjected to 7 min of anoxia decreased by 85 and 73%, respectively. Under hypoxic conditions (arterial PO2 AT 18 MMHg), the decrease was only 62 and 48% in liver and kidney, respectively. Tissue NAD levels decreased and NADH levels increased during shock but were found to be essentially unaltered during experimental hypoxemia. Thus, shock produced greater alterations in adenine and pyridine nucleotides than did hypoxemia alone, indicating that stagnant hypoxemia due to shock is more deleterious to energy metabolism than is severe hypoxemia with an otherwise normal circulation. The results also suggest that if an anterial PO2 OF 18 MMHg represents the initial stages of tissue hypoxia, then tissue ATP levels are a more sensitive indicator of this than NAD levels.

High-amplitude peristaltic esophageal contractions, or the nutcracker esophagus, may be associated with chest pain or dysphagia. Medical treatment for this disorder is sometimes not satisfactory. We report the manometric and clinical effects of myotomy in four patients with high-amplitude peristaltic contractions who underwent surgery because of the severity of their symptoms and recalcitrance to various medical treatments. Manometry 1-5 years after surgery showed a reduction in amplitude, duration, and percent bipeaked waves at 5 and 10 cm above the lower esophageal sphincter. Peristalsis was abolished or decreased in the distal 10 cm of the esophageal body but was not affected more proximally. Lower esophageal sphincter pressure was decreased in all patients. The manometric changes were least marked in one patient, who was the only one who had some chest pain when last seen five years after myotomy. We conclude that in severely symptomatic patients with high-amplitude peristaltic contractions, myotomy results in marked manometric changes and marked clinical improvement. Patients with this disorder and whose chest pain is recalcitrant to extensive medical therapy may be successfully treated by surgical myotomy.

To determine whether hemorrhage without major tissue trauma can itself produce immunosuppression, the effect of hemorrhage on the lymphocyte response to T-cell mitogen in endotoxin-resistant C3H/HEJ mice was measured. The mice were bled to achieve a mean blood pressure of 35 mm Hg, maintained at that level for one hour, and then adequately resuscitated. On days 1 through 10 thereafter, the proliferative responses of the splenocytes to concanavalin A were measured and allogeneic mixed lymphocyte reaction was performed. The proliferative responses to mitogen stimulation as well as the results of mixed lymphocyte reaction studies indicated that marked immunosuppression occurred at day 1. Immunosuppression persisted for at least five days following hemorrhage, as evidenced by mitogen stimulation assay. Another group of mice was subjected to sepsis three days after hemorrhage and resuscitation. The mortalities in the sham-hemorrhage and hemorrhage groups following sepsis were 58% and 100%, respectively. Thus, a significant depression of cellular immunity occurred following simple hemorrhage despite adequate resuscitation, and this immunosuppression enhanced the susceptibility to sepsis.

To evaluate the role of thyroid hormones in sepsis, 250-400 g rats were surgically thyroidectomized and 2-6 weeks later sepsis was produced by cecal ligation and puncture (CLP). In normal rats, total body O2 consumption (VO2) increased by 12.8% (P less than 0.05) in early sepsis (6 hr after CLP) and decreased slightly in late sepsis (16 hr after CLP). In hypothyroid (HT) rats, VO2 was depressed by 19.8% (P less than 0.05) in early sepsis and further decreased to 46.7% (P less than 0.001) of preoperative levels in late sepsis. Hepatic blood flow increased in early sepsis in normal rats but was unchanged in HT rats. The normal hyperglycemic response to early sepsis was also absent in HT rats. The respiratory control ratio (RCR) of isolated mitochondria with succinate was not increased in HT rats in early sepsis. In late sepsis, hypothyroid animals showed further decreases in VO2 and mitochondrial RCR, and, in contrast to normal rats, showed no change in blood glucose levels. Survival (5 days) following late sepsis in normal, HT, and HT rats given daily ip injections of thyroxine (30 micrograms/kg) were 65.2% (15/23), 30% (6/20) (P less than 0.025), and 77.1% (14/18), respectively. Thus, absence of thyroid hormone abolishes the hyperdynamic phase of sepsis and significantly increases mortality in sepsis, and thyroxine replacement following thyroidectomy prevents the increased mortality from sepsis.

Hemorrhagic shock in rats was produced by bleeding them to a mean arterial blood pressure of 40 millimeters of mercury, which was maintained for two hours. After sacrifice, small pieces of liver, kidney, muscle and brain were quickly removed and frozen in liquid nitrogen. A protein-free extract of tissues was prepared, and cyclic adenosine monophosphate was measured by the radioimmunoassay procedure. Analysis os liver, kidney, muscle and brain showed that there were significant reductions in cyclic adenosine monophosphate and adenosine triphosphate levels. The decrease in cyclic adenosine monophosphate levels follow the same trend in the various organs as the decreases in adenosine triphosphate levels, suggesting that these two events are related. Infusion of adenosine triphosphate-magnesium chloride, 25 micromoles each, at the end of the shock period restored the cellular cyclic adenosine monophosphate and adenosine triphosphate levels. The precise mechanism for depletion and replenishment of cyclic adenosine monophosphate levels during shock is not now known.

This study was designed to test the hypothesis that infusion of ATP-MgCl2 during reperfusion following a prolonged period of hypothermic global ischemia would result in enhanced functional recovery of cardiac function. Two groups of dogs (n = 6 each) were placed on cardiopulmonary bypass (CP) with systemic hypothermia to 28 degrees C and subjected to 150 min of aortic cross-clamping. Crystalloid cardioplegia was infused every 20 min during ischemia. Reperfusion and rewarming were carried out for 20 min before discontinuation of CP bypass. During reperfusion, the experimental group received ATP-MgCl2(1.0 mg/kg/min ATP, 0.33 mg/kg/min magnesium). At 15 and 45 min following bypass, hemodynamic assessment was carried out for each animal by constructing Starling curves over a range of filling pressures at constant heart rate and comparing each animal to its own prebypass control level. The results indicated that ATP-treated animals exhibited complete functional recovery whereas control animals showed marked reduction in hemodynamic performance and myocardial compliance and had a higher myocardial water content (P less than 0.05). We conclude that infusion of ATP-MgCl2 during reperfusion following hypothermic ischemia may help ameliorate reperfusion injury.

The effects of prolonged starvation on reticuloendothelial system (RE) function and on the survival of animals following trauma were studied. Rats were fasted for 51/2 days (water ad lib) after which a two-cm midline incision was made and the cecum ligated (CL). Food and water were allowed 36 h after CL and survival was measured over 5 days. The mortality rate in these animals was 60% (15/25) compared to 0% (0/15) in CL rats fasted for 24 h. Starvation alone for 7 days did not produce any deaths but after 11 days of starvation mortality was 100%. Another group of animals were fasted for 51/2 days and were used to study RE function 10 h following CL. There was no significant difference in the intravascular clearance rates in injected lipid emulsion in various groups of animals, indicating that total phagocytic function was not changed by prolonged starvation plus CL (SCL). However, emulsion retention in the spleen, expressed as per cent injected dose per gm tissue, decreased by 53% and the lung retention increased by 988% following SLC. Serum GOT levels were not affected by prolonged starvation alone; however, SCL resulted in its elevation (37 vs. 82 IU/ml). Hepatic ATP levels (micromoles/g) decreased from 2.47 to 1.95 following 51/2 days starvation and following SCL, it decreased to 1.75. These results indicate that the increased metabolic demand following trauma (i.e., CL), coupled with prolonged starvation, altered RE function with splenic lipid emulsion uptake decreasing and pulmonary uptake increasing. The relationship of these findings to immune function remains to be determined. Although the precise cause of increased mortality is not known, altered metabolic and RE function may play a role.

Since plasma alanine concentrations are markedly elevated in late sepsis and alanine is an important gluconeogenic substrate, we investigated gluconeogenic activity in intra-abdominal sepsis. Sepsis in rats was produced by cecal ligation and puncture. After 17 to 21 hours (late sepsis, LS) livers from these and sham-operated rats were isolated and perfused at constant flow with Krebs buffer in the presence or absence of 10 mM alanine. Various phenylephrine (PE) concentrations were also used to measure gluconeogenic response to alpha-adrenergic stimulation. The results showed that glucose production from alanine by livers from LS rats was depressed in comparison to livers from sham rats (2.6 +/- 0.2 vs. 4.2 +/- 0.4 moles/gm/hr). Moreover, although livers from rats in LS responded to PE stimulation in a dose-dependent manner, the magnitude as well as the threshold of response was decreased in comparison to shams. In contrast to glucose production, VO2 of the sham and LS were not different under any conditions. Previous studies using lactate as a substrate, however, showed that both gluconeogenesis and oxidative responses were decreased in LS. Since hepatic gluconeogenic but not VO2 response was depressed with alanine, these results indicate that the decreased gluconeogenic capability precedes depressed oxidative capability in sepsis.

Functional residual capacity (FRC) of the lung was measured by the closed-circuit helium equilibration method before and for five days after upper abdominal operations in 28 patients (25 had cholecystectomies). Measurements in many were made with the patient both sitting in bed and sitting in a chair. Vital capacity (VC), residual volume (RV), and forced expiratory volume in one second (FEV1), as well as FRC, all decreased after operation, with the maximum decrease on days 1 and 2 and a gradual return toward preoperative values by day 5. Patients with 40% or less decrease in FRC after operation did not develop pulmonary complications. Change in position from bed to chair increased FRC 14.2% preoperatively and 17% postoperatively. The use of intermittent positive pressure breathing had no measurable effect on FRC. Similar changes in FEV1, VC, and RV also occurred, with maximum decreases on day 1.

Hemorrhagic shock in rats was produced by bleeding the animals to a mean arterial pressure of 40 mmHg, which was maintained for 2 h. Muscles from these animals ('shock' muscles) demonstrated basal glucose uptake values unchanged from control values but, unlike the control muscles, the "shock' muscles showed resistance to the stimulation of glucose uptake by insulin. Infusion of ATP-MgCl2, ADP-MgCl2, adenosine-MgCl2, or GTP-MgCl2 to animals following shock had no effect on basal glucose uptake; however, ATP-MgCl2 but not the other nucleotides permitted insulin to exert its stimulatory effect on such muscles. An optimal insulin effect in ATP-MgCl2 treated 'shock' muscles occurred at an insulin concentration of u.001 U/ml, which is also the concentration required to produce optimal insulin effect in control muscles. Following 1-h incubation in Krebs-HCO3 medium, intracellular ATP contents of 'shock' muscles were about 50% lower than in control muscles. Treatment with ATP-MgCl2 following shock, however, resulted in ATP contents in such muscles similar to those in control muscles. Possible mechanisms for this reversal of insulin resistance by in vivo infusion of ATP-MgCl2 in shock are discussed.

Drug-induced nephrotoxicity (NT) has become an increasingly significant clinical problem. An in vitro model of drug-induced NT was therefore developed using gentamicin and the effects of ATP-MgCl2 on reduction or prevention of NT were determined. To study this, non-pulsatile perfusion in isolated rat kidneys was maintained at 100 mm Hg during 2 hr of perfusion at 37 degrees C. The oxygenated Krebs-HCO3 perfusate contained 7.5 g/dl albumin as colloid, glucose, creatinine, amino acids, trace amounts of [3H]inulin and 125I-lysozyme, and either 0, 0.4, 0.8, or 1.2 mg/ml of gentamicin. In some studies, 2 mM ATP-MgCl2 was added with 0.8 mg/ml of gentamicin at 0 and 60 min of perfusion. During each 10-min clearance period, glomerular filtration rates, sodium absorption, water absorption, and fractional clearance of TCA-precipitable lysozyme were measured. The results indicate that renal perfusate flow, glomerular filtration rate, urinary flow and tubular absorption of protein (a sensitive indicator of tubular function), sodium, and water were affected by gentamicin in a dose-dependent manner. An isolated kidney preparation can therefore be used to study gentamicin-induced NT. Higher in vitro perfusate concentrations of the drug were needed, however, to acutely mimic the in vivo cumulative effects. Nonetheless, renal perfusate flow, glomerular filtration rate, and the depression in protein reabsorption which occurred with gentamicin treatment were markedly improved by simultaneous treatment with ATP-MgCl2. Thus, ATP-MgCl2 may be useful in reducing drug-induced nephrotoxicity.

It is well known that splenectomy causes immunologic impairment and increases susceptibility to infection; however, the time course of reticuloendothelial depression and of alterations in hepatic and pulmonary retention of injected lipid emulsion following splenectomy is not known. To determine this, rats were splenectomized and reticuloendothelial function evaluated at various intervals following splenectomy by measuring the intravascular clearance of 131I-triolein gelatinized lipid emulsion. The intravascular clearance (T/2) and lung uptake of the lipid emulsion increased and hepatic uptake of emulsion decreased 4 to 8 hours following splenectomy. One day followng splenectomy, although the T/2 appeared normal, the lung uptake was 1,123% higher and hepatic uptake was still 33% lower than control. The T/2 and hepatic retention returned to normal 2 days following splenectomy; however, the lung retention was higher than controls even 10 days following splenectomy. In another set of experiments, splenectomy was performed following which sepsis in rats was produced by cecal ligation and puncture. Ten hours following cecal ligation and puncture, the gangrenous cecum was removed and survival was measured over 5 days. The mortality rate in these animals was 57% (12/21) compared to 0% (0/8) in nonsplenectomized cecal ligated and punctured animals. These results suggest that splenectomy may not only have deleterious effects in terms of the host defense system, but may also cause prolonged pulmonary changes.

This study describes the experience in a major university hospital for a year before and a year after the institution of a trauma service. Demographic data and severity of injury were similar before and after the trauma service was instituted. Nonetheless, mortality for all trauma patients admitted to an intensive care unit decreased somewhat (from 16.1 to 11.8 percent) in the second period of study. When outcome for trauma patients admitted to the surgical intensive care unit was examined, the differences was more impressive, with a reduction in mortality from 27 percent to 6.1 percent. This reduction seemed to be due largely to a decrease in the number of patients who died from sepsis, multiple organ failure, or both. We suggest that trauma care can be significantly improved by an organized approach to the care of the multiply injured patient. A powerful argument can be made for organizing care of injured patients in major hospitals along the lines of a dedicated trauma service.

Mechanical ventilation with positive end-expiratory pre-sure (PEEP) is widely used to treat ventilatory failure complicating pulmonary infection. The present experiment was carried out to test the hypothesis that PEEP is beneficial in an experimental model of canine pneumonia studied for 24 hours. Sixteen mongrel dogs were assigned to ventilation with either zero end-expiratory pressure (ZEEP) or 10 cm H2O PEEP. Pneumonia was induced in half of each group by intratracheal inoculation with Pseudomonas. Tissues for quantitative bacteriology and pathology were obtained at the time of death at 24 hours. Three of four infected-ZEEP dogs died before 24 hours. The geometrical mean of quantitative bacterial counts from infected-ZEEP lobes was 2.0 X 10(6) (+/-3.9) (organisms/gm of tissue), while the mean of the infected-PEEP lobes was 1.7 X 10(4) (+/-3.6) (p less than 0.05). Semiquantitative pathology scores indicated greater injury to the ZEEP-infected than to the PEEP-infected lungs. Quantitative bacteriology and microscopic evidence of parenchymal injury were positively correlated. Thus PEEP-treated animals had lower quantitative bacterial counts, less microscopic pulmonary damage, and improved survival. The advantage conferred by PEEP may be due to facilitation of local mechanisms of pulmonary defense against infection, to increased systemic resistance to sepsis, or to both.

The aims of this study were to determine 1) the effects of anoxia and reoxygenation on electrolytes and ATP content of isolated hepatocytes and 2) whether exogenous ATP-MgCl2 has any beneficial effects on the cellular alterations that are produced during the reoxygenation period. After 90 min anoxia, intracellular Na and inorganic phosphate (Pi) increased, K and ATP decreased, whereas Ca and Mg did not change. After 60 min of reoxygenation, intracellular Mg and Na levels decreased, Ca increased, and Pi levels returned to normal, but ATP levels remained low. These results suggest that the plasma membrane is relatively impermeable to divalent ions such as Ca2+, Mg2+, and HPO2-4 during anoxia but becomes permeable to them after reoxygenation. When anoxic cells were treated with ATP-MgCl2 during reoxygenation, intracellular ATP and Mg levels increased, but accumulation of Ca and Pi was also observed. Thus enhancement of Mg transport and specific stimulation of Ca-Pi sequestration occurs with ATP-MgCl2 treatment. Na and K levels exhibited biphasic reciprocal dose-response changes to ATP-MgCl2 treatment; i.e., 0.1 mM ATP-MgCl2 (low-dose) treatment increased K and decreased Na, whereas 1 mM ATP-MgCl2 (high-dose) treatment decreased K and increased Na. These results indicate that although addition of a single high-dose ATP-MgCl2 was deleterious over a period of 60 min, low-dose ATP-MgCl2 accelerates the recovery of postanoxic cellular electrolyte homeostasis.

Hemorrhagic shock was produced in conscious rats by cannulating the subclavian arteries and bleeding the animals to a mean arterial pressure of 40 mm. Hg, which was maintained for one hour (early shock) or 2 hours (late shock). Analysis of diaphragm (working muscle) showed that there was a significant decrease in adenosine triphosphate (ATP), adenosine diphosphate (ADP), and creatine phosphate levels beginning with early shock, whereas in soleus muscle (resting muscle) these changes were not observed until late shock. Decreases in adenine nucleotides of diaphragm were less than in working organs such as liver and kidney in early shock. This suggests that the extent of decrease in adenine nucleotides during shock may be related to the metabolic activity of the organ.

The purpose of this study was to determine whether hepatocellular function is altered following hepatic ischemia and whether ATP-MgCl2 has any effect on it. To study this, total hepatic ischemia in rats was produced for 60 minutes by placing a ligature around the hepatic artery, portal vein, and the common bile duct. At the end of the ischemic period, the ligature was removed, reestablishing blood flow to the liver. The animals then received IV either 0.25 ml saline (nontreated) or 0.25 ml ATP-MgCl2 (12.5 mumoles each) (treated). Three hours following the end of ischemia, indocyanine green (ICG) clearance was determined by infusing ICG at a concentration of either 5 mg/kg body wt (low) or 25 mg/kg body wt (high). Following infusion of ICG blood samples were taken at five, six, eight, ten, 12, 15, 18, and 20 minutes thereafter to determine the ICG concentration. The clearance of ICG at low as well as at high ICG concentration was markedly depressed in the nontreated animals, suggesting that significant depression in hepatic blood flow as well as hepatocellular function was evident even three hours after ischemia. Administration of ATP-MgCl2 following hepatic ischemia, however, resulted in ICG clearance values similar to sham-operated animals when ICG was given at low as well as high concentration. Thus, ATP-MgCl2 treatment following hepatic ischemia not only seemed to restore hepatic blood flow but also active membrane transport toward normal.

Hemorrhagic shock was produced by bleeding rats to a mean arterial pressure of 40 mm Hg (1 mm Hg = 133 N/m2), which was maintained for 2 h. Muscles from these animals ('shock' muscles) showed resistance to the stimulation of glucose uptake by insulin. Addition of 1 mM ATP-MgCl2 to the medium had no effect on basal glucose uptake in either group of muscles, but it permitted insulin to exert its stimulatory effect in 'shock' muscles. An optimal insulin effect on glucose uptake in 'shock' muscles incubated without ATP was observed at an insulin concentration of 0.2 Unit/ml. When 1 mM ATP-MgCl2 was added to the medium, optimal insulin effect in 'shock' muscles was observed at an insulin concentration of 0.007 Unit/ml. Increasing the concentration of ATP-MgCl2 to 2.5 mM in the medium resulted in an optimal insulin effect at an insulin concentration of ATP-MgCl2 to 2.5 mM in the medium resulted in an optimal insulin effect at an insulin concentration of 0.001 Unit/ml in 'shock' muscles. Following 1 h cubation in Krebs-HCO3 medium, intracellular ATP contents of 'shock' muscles were approximately 50% lower than in control muscles. Addition of 1 mM ATP-MgCl2 to the incubation medium had no effect on the intracellular ATP contents of either group of muscles following incubation; however, 2.5 mM ATP-MgCl2 elevated intracellular ATP contents of 'shock' muscles but had no effect in control muscles. Possible mechanisms for this reversal of insulin resistance by ATP-MgCl2 in shock are discussed.

To determine limitations in survival and problems of single and multiple organ failure (SOF, MOF) following trauma in Bavaria, we reviewed 433 consecutive patients with multiple injuries treated at the Klinikum Grosshadern from 1978 through 1982. Most patients were young and were injured in traffic accidents. The overall mortality was 18% (78 deaths): 38 deaths were due to CNS injuries (49%), six from miscellaneous causes (7%), 15 associated with SOF (19%), and 19 associated with MOF (25%). There were 50 patients with SOF and 34 with MOF. Two MOF patterns were found: a rapid single-phase (15 patients) due to trauma and shock; and a delayed two-phase MOF (19 patients) due to trauma, shock, and sepsis. Mortality for the MOF group was 56%. The lung was the predominant organ to fail represented in all SOF and MOF cases. Cimetidine and pirenzipin prevented stress bleeding in all but four patients. Significant factors leading to MOF were shock, massive blood transfusions, sepsis, and errors in treatment. The temporal sequence of organ failure was lung, clotting system, kidney, and liver. Sepsis was ultimately the cause of death in eight MOF patients (42%). Earlier pulmonary and cardiovascular support beginning at the scene of the accident, and prevention and better treatment of head injury, respiratory failure, and sepsis are critical factors for increasing survival after injury.

Intact rat soleus muscles or hemidiaphragms were incubated at 37 degrees C for 1 h in 1.0 ml of Krebs-HCO3 buffer containing 10 mM glucose, 5 mM (8-14C)-labelled ATP and (alpha-32P)-labelled ATP together with 5 mM MgCl2 under an atmosphere of 95% O2-5% CO2. Samples of the incubation medium and tissue extract were subjected to electrophoretic separation and the radioactivity present as adenine nucleotides was counted. Extensive degradation of the added nucleotides was observed in the presence of both tissues. The concentrations of 14C-labelled and 32P-labelled ATP found in the muscle and diaphragm indicated that ATP was present within the muscle and diaphragm cells. By maintaining higher concentrations of ATP in the medium, ATP uptake in both tissues exhibited a saturation-type kinetics. These results provide further evidence for intracellular uptake of ATP and also suggest that the transport of ATP into the cell could be a carrier-mediated process.

Minipigs (20 to 25 kg.) were subjected to bilateral renal artery occlusion for 60 minutes. Renal blood flow was reduced to 65 per cent and glomerular filtration rate to 40 per cent of normal in control animals. Administration of adenosine triphosphate with magnesium chloride intravenously immediately after the period of ischemia resulted in restoration of renal blood flow to normal and glomerular filtration rate to 74 per cent of normal 24 hours later. Bilateral renal artery occulsion for 90 minutes resulted in a more severe impairment of renal function, which was not improved by the administration of adenosine triphosphate with magnesium chloride. Adenosine triphosphate with magnesium chloride may exert its effect by improving renal blood flow through inhibition of post-ischemic intrarenal vasoconstriction or possible by enhancing restoration of intracellular adenine nucleotides. The exact mechanism remains unclear.

A murine model was used to test the effects of various therapeutic modalities on the rate of death following intra-abdominal sepsis as produced by cecal ligation and puncture (CLP). There were no deaths among sham-operated control mice after ether anesthesia, whereas CLP produced a mortality rate of 100% by 24 hours. When CLP was followed at 16 hours by excision of the cecum and saline peritoneal lavage (CLPE), the mortality rate was 20% at 24 hours and 60% at 72 hours. The therapeutic modalities consisted of gentamicin (1.5 mg/kg) alone or in combination with methylprednisolone (50 mg/kg) or tuftsin (1 mg/kg) administered before CLP and at 16 and 24 hours after CLP. Separate groups of animals also received only methylprednisolone or tuftsin, a tetrapeptide produced by the spleen. Compared with the mortality rate in the CLPE group, mortality at 24 and 72 hours was decreased for gentamicin alone (0% and 10%, respectively), tuftsin alone (10%, 40%), or the two in combination (0%, 20%). As compared with CLPE, methylprednisolone led to increased mortality rates at 24 and 72 hours (70%, 80%). The data (significant at P less than 0.01, X2 analysis) suggest that gentamicin and tuftsin may improve the rate of early survival after intra-abdominal sepsis in this Model. Steroids do not seem to be beneficial and may, in fact, be harmful.

The present study was performed to determine whether insulin resistance, independent of the prevailing hormonal milieu, occurs in the liver during sepsis. To determine this, sepsis was produced in rats by cecal ligation and puncture (CLP). Six hours later, when the rats were in the early hypermetabolic phase of sepsis, the livers were isolated and perfused with Krebs-HCO3 buffer using a nonrecirculating system. The effects of various concentrations of insulin on the gluconeogenic response to lactate and phenylephrine stimulation were determined. In the absence of insulin and phenylephrine, there was no difference in the rates of glucose production from lactate between septic and sham-operated rats. The gluconeogenic response to phenylephrine stimulation was, however, significantly depressed in the livers from septic rats. Addition of 50 microU insulin/ml resulted in an inhibition of the phenylephrine-stimulated glucose release from livers from sham-operated rats. This inhibition was maximal at 100 microU insulin/ml. In contrast, significant inhibition of phenylephrine-stimulated glucose release from livers from septic rats was only observed in the presence of 2,000 microU insulin/ml. These results demonstrate that even during the early, hypermetabolic phase of sepsis, depressed hormonally stimulated hepatic gluconeogenic capability occurs. In addition, livers from septic rats exhibited a resistance to the effects of insulin on gluconeogenesis. This resistance may account, at least in part, for accelerated gluconeogenesis in spite of hyperinsulinemia in early sepsis.

This study examined a group of surgical patients with respect to the ability of their peripheral blood mononuclear cells to respond to phytohemagglutinin (PHA). Depression of the PHA response of more than 30% below baseline five to seven days after injury was found in 11 of 19 patients, and eight of them developed infectious complications. The addition of indomethacin to in vitro cultures resulted in an average enhancement of the PHA response of 37% baseline. Improvement at five to seven days with in vitro indomethacin was from 34% to 74% in infected patients. These data suggest that major injury can lead to depression of the PHA response, which correlates with the subsequent development of infectious complications. Indomethacin in vitro seems to be able to reverse or decrease this immunologic defect and deserves further study.

A prospective randomized trial of preoperative intratumoral therapy with Bacillus Calmette-Guérin (BCG) was conducted in non-small cell lung cancer patients. Eighty-eight patients (48 BCG-treated and 40 control subjects) were entered into the study; three control subjects were removed from data analysis because histology revealed pathology other than non-small cell lung cancer. There were no differences between BCG-treated and control patients in sex, age, cigarettes smoked per day, pack-years of cigarette smoking, white blood cell count, or number of peripheral blood lymphocytes. Toxicity of BCG was limited to transient malaise and fever (average peak temperature, 38.7 degrees C). There was no significant difference in outcome (recurrence or survival) between BCG-treated and control groups with Stage I or Stage III tumors; there were too few Stage II tumors for separate statistical analysis. Outcome was not affected within or between the two treatment groups by tuberculin skin test status. Combining both treatment groups, Stage III patients had a worse outcome than did Stage I-II patients, non-squamous cell tumor patients (large cell and adenocarcinoma) had worse outcomes than did squamous cell tumor patients, and men had a worse outcome than women. We conclude that, although preoperative intratumoral BCG therapy is safe, it does not lengthen disease-free interval or prolong survival in patients with non-small cell lung cancer.

During a 3 year period, direct myocardial revascularization was performed on an urgent basis in 48 patients with intermittent resting chest pain which persisted more than 24 hours despite in-hospital medical therapy and was accompanied by electrocardiographic changes representative of ischemia. Sixteen patients had saphenous vein (SV) grafts exclusively, and 32 patients each had one or two internal mammary artery (IMA) grafts with or without additional vein grafts. Follow-up ranges from 5 to 41 months (mean, 22 months). Twelve patients had single grafts to the left anterior descending coronary artery (LAD), 18 had double grafts, 16 had triple grafts, and 2 had quadruple grafts. The LAD required grafting in every patient. There was one operative death (2 per cent) and one late death from noncardiac causes. There were two (4 per cent) early postoperative myocardial infarcts and no late infarcts. Actuarial analysis projects a survival rate of 96 per cent 3 years postoperatively. Eighty-one per cent of the survivors are in Functional Class I, 17 per cent are in Class II, and 2 per cent are in Class III. All patients had postoperative angiography 2 weeks after operation. Eighty-six per cent of the SV grafts and all IMA grafts were open. No significant differences were observed between mean preoperative and postoperative left ventricular end-diastolic pressures or ejection fractions, but these parameters were noted to improve after operation in several patients. The remarkably high early and late survival rates, the low incidence of myocardial infarction, and the excellent functional results after rather long follow-up indicate that emergency coronary revascularization provides an effective therapy for unstable angina. The use of IMA grafts, when feasible, is a safe and possibly preferable approach in these patients.

In this study we investigated in vivo changes in hepatic cellular electrolytes and resting transmembrane potentials (Em) during hemorrhagic shock. Hepatic Na-K transport and cell volume regulation were assessed in vitro. Rats were bled and the ensuing hypotension (40 mmHg) was maintained by returning 25-30% (intermediate-shock, IS) or 55-60% (late-shock, LS) of the shed blood. We resuscitated IS rats by reinfusion of all of the remaining shed blood and Ringer's lactate solution. Hepatic cellular Na and Cl increased and K decreased progressively with shock. Resuscitation of IS rats restored cell K and Cl but not Na to preshock levels. Em decreased from the control average value of -40 (mV) to -31 in IS and -19 in LS. Em was partially restored (-36 mV) after resuscitation. We evaluated changes in relative membrane permeability to Na and K (PNa/PK) with shock by assuming Em either to be a Na-K exchange diffusion potential or due to an unequally coupled movement of Na and K. These evaluations show a lack of effect of shock (IS, with or without resuscitation) on PNa/PK. Our observations are compatible with failure of an electrogenic Na pump in shock. This may be related to loss of hepatic cell volume regulation in shock.