Rewarming from hypothermia leads to elevated plasma lipopolysaccharide concentrations.

Rewarming victims of hypothermia such as divers or immersion victims, participants in winter sports and military operations, and surgical patients on cardiopulmonary bypass (CPB) may lead to vascular instability, multiorgan failure, shock, and even death. While the causes of these rewarming symptoms are unknown, they may be related to bacterial lipopolysaccharide (LPS) translocated from the intestines into the circulation due to splanchnic ischemia. We have determined LPS during the cooling (to 31.5 degrees-34.0 degrees C) and rewarming phases of hypothermic surgery in 11 patients at the Stanford University Medical Center. During rewarming, there was an LPS spike in 6/11, in one more patient there was an LPS spike during surgery but not during rewarming, and in 4/11 there was no rise in LPS, i.e., a temporary endotoxemia occurred in 7/11 (63.6%) patients, usually at the commencement of rewarming. All four patients with no LPS spike received dexamethasone for at least 7 days before surgery. We propose that hypothermia reduced splanchnic blood flow (BF), causing ischemic damage to the gut wall and translocation of LPS from the gut into the vascular space. Upon rewarming, splanchnic BF is restored, the translocated LPS transits from the splanchnic to the systemic circulations as a bolus, and the gut wall is healed. No sequelae occurred in these patients because of their adequately functioning immune systems. However, had they been immunocompromised, symptoms might have occurred. Rewarming of accident victims probably also incurs a similar risk of endotoxemia, and dexamethasone may have protected the gut wall. Further studies are indicated.

On the trail of potassium in heat injury.

In both classical and exertional heatstroke and in various animal models of human heat injury, clinical manifestations have included observations of normokalemia, hyperkalemia, and hypokalemia. This review attempts to address these observations as well as the role of potassium and potassium depletion in heat injury with an emphasis on the integration of information from the level of transmembrane potassium transport mechanisms to systems physiology. Under moderate conditions of passive heat exposure or exercise in the heat, the adaptive capacity of the Na-K pump (Na+-K+ ATPase activity) and cotransport mechanisms can ordinarily accommodate the attendant increased efflux of intracellular K+ and influx of extracellular Na+ to maintain ionic equilibrium. Several factors affecting transmembrane K+ kinetics include protracted K+ deficiency, extreme hyperthermia, dehydration, and excessive exertion. These could elicit reduced membrane potentials and conductance, futile cycling of the Na-K pump with concomitant energy depletion and greatly increased metabolic heat production, reduced arteriolar vasodilation, altered neurotransmitter release, or cell swelling, each of which could contribute to the pathophysiology of heat injury. This review represents a preliminary attempt to link transmembrane K+ pathophysiology with clinical heat injury.

Experimental approaches to therapy and prophylaxis for heat stress and heatstroke.

New developments in the fields of biochemistry, physiology, sepsis, cancer therapy, and molecular genetics have led to opportunities for the development of new therapies and prophylaxes for heat illnesses and for improving human performance during conditions of environmental stress. These include antilipopolysaccharide agents, anticytokines, potassium channel agents, a diet rich in omega-3 fatty acids, and psychological conditioning. This review summarizes the backgrounds and recent findings in the above fields and provides specific suggestions for potential therapy and prophylaxis for classic and exertional heatstroke and for improving athletic performance.

Anti-LPS antibodies reduce endotoxemia in whole body 60Co irradiated primates: a preliminary report.

Long periods in space may expose astronauts to the potentially harmful effects of ionizing radiation. We have used a primate model to evaluate any role of lipopolysaccharide (LPS, endotoxin) in radiation sickness. Vervet monkeys, which had been whole-body 60Co irradiated with an LD100 exposure, had periodic blood samples taken for the determination of LPS, anti-LPS IgG antibodies and bacteriological studies. On day 2 post-irradiation, primates were treated i.m. with either sterile 0.9% saline, or equine anti-LPS hyperimmune plasma (Anti-LPS), or orally with tripotassium-dicitrato-bismuthate ("Denol"). Gram positive bacteria were evident in blood samples of all animals as early as 2 d post-irradiation. Gram negative bacteria were found in the blood of saline- and Denol-treated primates by days 5 and 8, respectively, but first appeared on day 13 in the anti-LPS-treated animals. The saline controls and Denol-treated animals showed insignificant rises in plasma LPS on day 3, which increased further thereafter achieving significance on day 8 (p less than 0.01). These elevated levels persisted until death. However, in anti-LPS-treated monkeys, LPS concentrations remained below baseline until day 9, after which they rose significantly until death, but, were significantly less than the concentrations in both other groups (p less than 0.001). The anti-LPS-treated animals survived significantly longer than both the other groups (p less than 0.005). Since LPS may cause nausea, vomiting, diarrhea, anorexia and headaches, Anti-LPS administration may be of value in reducing plasma LPS concentration in humans and improving their performance and survivability.

Endotoxins and anti-endotoxins (their relevance to the anaesthetist and the intensive care specialist).

Endotoxins (lipopolysaccharides, LPS) are potent bacterial poisons always present within the intestines in considerable amounts. Several pathophysiological conditions such as hypovolaemia, hypoxia, intestinal ischaemia, burns and radiation lead to a breakdown in the barrier and depending upon the extent of the injury, endotoxins enter the systemic circulation in increasing amounts. Antibiotics do not inactivate the endotoxins which continue to exert their toxic effects leading to nausea, vomiting, diarrhoea, fever, disseminated intravascular coagulation, vascular collapse and organ failure. When nonabsorbable antibiotics are given prior to the insult, systemic endotoxaemia is prevented. Immunotherapy, using anti-lipopolysaccharide IgG, inactivates plasma endotoxins, destroys gram-negative bacteria and opsonises them and may become a major form of therapy. An outline of endotoxin and anti-lipopolysaccharide and its importance to the anaesthetist and intensive care specialist is presented.

Changes in lipopolysaccharide concentrations in hepatic portal and systemic arterial plasma during intestinal ischemia in monkeys.

The time course of changes in the level of plasma lipopolysaccharides (LPS) in both the hepatic portal and the systemic arterial circulations, together with changes in cardiovascular parameters, was ascertained during a 1 hr occlusion of the superior mesenteric artery (SMA) in six primates. The LPS concentrations before occlusion of the SMA in the hepatic portal and systemic arterial circulation were 0.051 +/- 0.009 and 0.065 +/- 0.011 ng/ml, respectively (NS). At the end of the occlusion period, there was no significant increase in either the hepatic portal or systemic arterial plasma LPS concentrations. Immediately on removal of the occlusion, however, the LPS concentration in the portal plasma increased and peaked at 0.431 +/- 0.124 ng/ml (P less than 0.01) within 17.5 +/- 1.71 min, whereas in the systemic arterial circulation the LPS concentration began to rise but only after a delay of approximately 10 min to peak at 0.287 +/- 0.126 ng/ml (P less than 0.05) within 32.5 +/- 4.23 min of reperfusion. The mean arterial pressure (MAP) declined during the reperfusion period from 98.6 +/- 6.89 to 65.0 +/- 9.5 mm Hg (P less than 0.05). The heart rate showed a small but not significant increase (P greater than 0.2) after about 80 min of reperfusion. These data indicate that the gut is the source of the increased plasma LPS concentration following occlusion of the SMA.

Oral administered nonabsorbable antibiotics prevent endotoxemia in primates following intestinal ischemia.

Plasma lipopolysaccharide (LPS) concentrations have been found to increase during a temporary occlusion of the superior mesenteric artery (SMA). We have attempted to show, by a prophylactic oral administration of a nonabsorbable antibiotic to monkeys subjected to an SMA occlusion shock, that the increased LPS is intestinal in origin. A total of eight monkeys were subjected to a temporary occlusion of the SMA. Four monkeys received prophylactic oral administration of a nonabsorbable antibiotic, while the rest acted as controls. The plasma LPS concentrations before occlusion in the control and the kanamycin group were 0.069 +/- 0.006 and 0.092 +/- 0.005 ng/ml, respectively. At the end of the 1-hr occlusion period the plasma LPS concentration in the controls increased to 0.09 +/- 0.009 ng/ml (P less than 0.1) and peaked to 0.378 +/- 0.103 ng/ml (P less than .001) within 20 min of reperfusion. Thereafter, the plasma LPS concentration returned slowly to baseline. In the kanamycin group the plasma LPS concentration remained at baseline throughout both the occlusion and reperfusion periods. These data suggest that the origin of the increased plasma LPS concentration seen following temporary occlusion of the SMA is from the gut, and is information of possible importance in patients about to undergo intestinal surgery.

Strenuous exercise causes systemic endotoxemia.

Eighteen triathletes were studied before and immediately after competing in an ultradistance triathlon. Their mean plasma lipopolysaccharide (LPS) concentrations increased from 0.081 to 0.294 ng/ml (P less than 0.001), and their mean plasma anti-LPS immunoglobulin G (IgG) concentrations decreased from 67.63 to 38.99 micrograms/ml (P less than 0.001). Both pretriathlon plasma LPS and anti-LPS IgG levels were directly related to the intensity of training (P less than 0.02 and P less than 0.01, respectively). It is possible that training-induced stress led to some leakage of LPS into the circulation, which, in turn, resulted in self-immunization against LPS. The effects on athletic performance in relation to exercise-induced changes in plasma LPS and anti-LPS IgG levels require further investigation.

Portal and systemic plasma lipopolysaccharide concentrations in heat-stressed primates.

Lipopolysaccharide (LPS) concentrations in hepatic portal and systemic arterial plasma were determined in five anesthetised monkeys heat-stressed by an environmental temperature of 41.0 +/- 0.3 degrees C and 100% relative humidity. As the rectal temperature (Tr) rose, the LPS concentrations in both the portal and systemic arterial plasma remained at the pre-heat-stress levels of 0.088 +/- 0.017 and 0.078 +/- 0.021 ng/ml (N.S.), respectively, until a Tr of 42.5-43.0 degrees C, when the LPS concentration increased slowly, first in the portal plasma and then in the systemic plasma. On the other hand, the concentration of plasma anti-LPS IgG antibodies began to decline at temperatures as low as 40 degrees C from 20.66 +/- 7.35 micrograms/ml (portal) and 22.14 +/- 7.43 micrograms/ml (arterial) to 5.51 +/- 1.28 micrograms/ml (portal) (P less than .05) and 4.6 +/- 1.69 micrograms/ml (arterial) (P less than .05) just prior to death. Above a Tr of 43 degrees C, the LPS concentration increased rapidly to a maximum of 0.244 +/- 0.05 ng/ml (portal) (P less than .01) and 0.224 +/- 0.06 ng/ml (arterial) (P less than .01). The mean arterial pressure remained more or less constant at 112 +/- 17.03 mm Hg until a Tr of 41.5 degrees C and then rapidly declined as Tr rose (P less than .01). The heart rate rose gradually from 154 +/- 14 min-1 as Tr increased and then rapidly after a Tr of 41.5 degrees C to a maximum of 307 +/- 13 min-1 at 43.0 degrees C. Thereafter it declined rapidly until death.(ABSTRACT TRUNCATED AT 250 WORDS)

Endotoxaemia in racehorses following exertion.

Endotoxins (lipopolysaccharides-LPS) and anti-endotoxin IgG antibodies were measured in racehorses before and after races of 1,000, 2,000 and 2,800 m. Results show that the mean plasma concentration of endotoxin increased significantly (p less than 0.02) while the anti-LPS IgG concentration decreased significantly (p less than 0.005) in all horses following the races. Pre-race and post-race anti-LPS IgG levels in racing-fit racehorses were significantly higher than in untrained horses (p less than 0.05). The possibility therefore exists that training-induced stress leads to leakage of LPS into the systemic circulation which results in self-immunisation against LPS. The effects of plasma LPS and anti-LPS IgG concentrations on performance of racehorses require further studies.

Plasma endotoxin concentration in healthy primates and during E. coli-induced shock.

The normal range for circulating plasma endotoxin concentration was determined in 62 healthy primates (vervet monkeys, Cerecopithecus aethiops) by the chromogenic substrate modification of the Limulus amoebocyte lysate test, and found to have a mean of 0.076 +/- 0.004 ng/ml (range 0.000 to 0.0127). Four anesthetized primates received an LD100 iv infusion of Escherichia coli over one hour. Plasma concentrations of endotoxin (lipopolysaccharide, LPS) and anti-LPS IgG, and viable E. coli colonies in circulating whole blood samples were determined at specified intervals. Plasma antiendotoxin IgG concentration was determined by an enzyme-linked immuno-absorbent assay, and viable bacterial counts were assayed by standard plate count techniques. LPS concentration increased during E. coli infusion to a mean of 1.13 +/- 0.068 ng/ml (p less than .001) with a concomitant decrease in the concentration of anti-LPS IgG to 59 +/- 5% of control values (p less than .005). Viable circulating E. coli colonies increased during the infusion to a maximum of 425 X 10(6) cfu/ml 10 min after the completion of the infusion, but fell precipitously 20 min later to 10.1 X 10(6) cfu/ml. When each animal succumbed, their respective plasma LPS concentrations were still raised, whereas no viable circulating E. coli colonies were present at a dilution of 10(2). Elevated plasma LPS could prove to be a significant circulating pathogen during Gram-negative bacterial shock and supports the possible association between plasma LPS and morbidity, and mortality in septic shock.

Endotoxaemia in exhausted runners after a long-distance race.

The extent to which plasma endotoxin concentrations increased was measured in 89 randomly selected exhausted runners who required admission to the medical tent for treatment in the 1986 Comrades Marathon (89,4 km). Eighty-one per cent had concentrations above the upper limit of 0,1 ng/ml ('endotoxaemic'), including 2% above 1 ng/ml (the reported lethal level in humans), and only 19% had normal levels. There was a negative correlation between plasma endotoxin and plasma anti-endotoxin IgG concentration (P less than 0,025). Those runners completing the race in less than 8 hours had a significantly lower average endotoxin value than those taking longer than 8 hours (P less than 0,025). Also 80,6% of runners (58/72) with high plasma endotoxin values reported nausea, vomiting and/or diarrhoea, compared with 17,7% (3/17; P less than 0,001) with low endotoxin values. Elevated plasma endotoxin concentrations of 32 randomly selected endotoxaemic runners had returned to normal 1-3 weeks later, and most of them (25/32) had increased anti-endotoxin IgG concentrations (P less than 0,02). Fifty-nine runners randomly selected in a short run (21,1 km) 3 weeks after the 89,4 km run completed the race without problems and none showed any increase in endotoxin levels. Further studies in this field are warranted, especially the measurement of endotoxin and anti-endotoxin values from commencement of training to full fitness. It is possible that these measurements may prove useful as predictors of an athlete's or combat soldier's performance.

Prophylactic corticosteroid increases survival in experimental heat stroke in primates.

It has been suggested that endotoxins or lipopolysaccharides (LPS), may contribute to heat stroke pathophysiology. In this study, 11 anesthetised monkeys were divided into 2 groups. The steroid group (n = 5) had received a dose of MPSS (30 mg.kg-1, i.v.) before being heat-stressed and the control animals (n = 6) received saline equivolumetrically. The animals were heat-stressed to a rectal temperature of 43.5 degrees C in an environmental temperature of 41 +/- 0.3 degrees C and 100% relative humidity and then allowed to recover at room temperature. Blood samples for LPS and anti-LPS IgG analyses were taken both before treatment and before and after heat-stress. The administration of prophylactic MPSS increased the survival rate significantly from 33% to 100% (p less than 0.05). The plasma LPS level in the steroid group showed very little change after heat-stress, whereas in the non-surviving controls there was a significant increase in plasma LPS level (from 0.089 +/- 0.007 to 0.257 +/- 0.031 ng.ml-1) (p less than 0.005). The control animals that survived showed very little increase in plasma LPS levels, but had about 300% greater plasma Anti-LPS IgG levels. We conclude that pretreatment with MPSS improves the survival rate during heat stroke, possibly by suppressing the rise in plasma LPS concentration.

Prophylactic corticosteroid suppresses endotoxemia in heat-stressed primates.

We previously found that lipopolysaccharides (LPS) leak from the gut lumen into the hepatic portal vein during heat stroke. Furthermore, we found that prophylactic corticosteroid administration could prevent a rise in plasma LPS concentration in superior mesenteric artery occlusion shock. In this study, we found that treatment prior to heat-stress with corticosteroids could prevent any rise in plasma LPS concentration in heat-stressed primates. Two groups of primates, one of which received a prophylactic dose of methylprednisolone sodium succinate (MPSS) (n = 4) were subjected to heat-stress (41 +/- 0.3 degrees C). Their arterial blood pressure, heart rate and rectal temperature (Tr) were continuously recorded. In the untreated control group (n = 8), the plasma LPS concentration tended to increase slowly at a Tr of 41.5 degrees C from an initial 0.06 +/- 0.013 ng.ml-1. Above a Tr of 43 degrees C, the plasma LPS level rose rapidly until at a Tr of 44.4 +/- 0.1 degrees C, the mean LPS level was 0.315 +/- 0.03 ng.ml-1 (p less than 0.001). Prophylactic treatment with MPSS suppressed the increase in plasma LPS levels to 0.066 +/- 0.01 ng.ml-1 before heat-stress and 0.03 +/- 0.01 ng.ml-1 at Tr 44.4 degrees C just before primate demise. The mean arterial pressure of the control group was lower than the treated group for any given Tr; between Tr 42-43 degrees this difference was significant (p less than 0.05). Moreover, the cardiovascular parameters began to deteriorate at a lower Tr in the control group.