Endotoxemia
Endotoxins--poisons released from the breakdown of bacterial cell walls from infection or antibiotic use--can cause symptoms (including death) misdiagnosed as SBS or additional signs of assumed but unproven abuse

en·do·tox·e·mi·a (nd-tk-sm-) n.
The presence of endotoxins in the blood, which, if derived from gram-negative rod-shaped bacteria, may cause hemorrhages, necrosis of the kidneys, and shock.

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=137306

Crit Care. 2002; 6(4): 289–290.
Published online 2002 June 20.
Copyright © 2002 BioMed Central Ltd

Endotoxemia in critically ill patients: why a reliable test could be beneficial
Robert A Balk corresponding author1
1Director, Section of Pulmonary & Critical Care Medicine, Rush Medical College and Rush-Presbyterian-St Luke's Medical Center and Voluntary Attending Cook County Hospital, Chicago, Illinois, USA
corresponding authorCorresponding author.
Robert A Balk: rbalk@rush.edu

Introduction
Potential benefits of reliable endotoxin detection
Targeted administration of anti-endotoxin therapy
Effective antibiotic therapy of Gram-negative infections
Predicting outcome
Conclusions
Competing interests
Abbreviations
References

Abstract
The detection of endotoxemia may provide a clue to the cause of sepsis or may indicate translocation of endotoxin from the gastrointestinal tract. A reliable endotoxin activity assay (EAA) offers the potential to determine Gram-negative infections in critically ill patients. In addition, a reliable EAA may indicate the adequacy of gastrointestinal tract perfusion, as well as potentially help to predict morbidity and mortality. A recent study by Marshall and colleagues, published in the present issue of Critical Care, evaluated the use of a whole blood EAA in a medical–surgical intensive care unit and found that 58% of the patients had positive endotoxin assays. However, only 13.5% of the population had a documented Gram-negative infection. This discrepancy and the observation that translocation and other causes of endotoxemia may not reflect true Gram-negative infection might severely limit the clinical utility of this EAA. Further study may better define the potential role of this technique in the diagnostic evaluation of the critically ill patient.
Keywords: endotoxemia, Gram-negative infection, prognosis, sepsis, translocation
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Introduction
In the present issue of Critical Care, John Marshall and colleagues report on a clinical trial designed to evaluate the use of an EAA in patients admitted to a medical–surgical intensive care unit [1]. Endotoxin plays a central role in sepsis [2,3]. The current 'gold standard' for the determination of endotoxemia is the limulus amebocyte lysate (LAL) assay, which requires specific expertise to perform and which is notorious for wide variability in results [4,5]. Would the EAA evaluated by Marshall and colleagues be more reliable? And what are the benefits of a reliable test to detect endotoxemia in critically ill patients?

Potential benefits of reliable endotoxin detection

Endotoxin, a lipopolysaccharide component of the cell wall of Gram-negative organisms, is a central component in the initiation and/or propagation of the septic cascade [2,3]. When endotoxin is administered to experimental animals or to human volunteers, a physiological and clinical picture resembling sepsis is produced [6,7].

There are several potential benefits of a reliable, reproducible, reasonably rapid endotoxin assay in the management of critically ill patients. The detection of circulating endotoxin in the blood of patients may signal the presence of a Gram-negative infection. This result could theoretically trigger the administration of antibiotic therapy directed against the Gram-negative bacteria. Also, endotoxemia can result from translocation of Gram-negative organisms and/or endotoxin from the terminal ileum and cecum in the setting of gastrointestinal tract mucosal barrier dysfunction that has been observed during hypoperfusion of the gastrointestinal tract [8]. In this setting, the detection of endotoxemia may signal the necessity for improved resuscitation and restoration of splanchnic perfusion. Third, some investigators have speculated that the level of endotoxin in the circulation may have prognostic ability for critically ill patients [9,10,11,12]. Finally, it has been suggested that the presence of endotoxemia may identify a population of patients who could benefit from the administration of antibodies against endotoxin [13].

Targeted administration of anti-endotoxin therapy

Endotoxemia has been the target of previous clinical trials evaluating the potential benefit of binding and/or neutralizing endotoxin in an attempt to improve the clinical outcome of patients with a presumed Gram-negative infection [13,14,15]. Unfortunately, these efforts have so far failed [13]. While this failure may reflect the inadequacy of the neutralizing agents, some have questioned whether the lack of efficacy reflected the variability in endotoxin levels or the actual presence of endotoxemia in the study population. These observations prompted speculation that a reliable, rapid endotoxin assay might identify a population of patients with circulating endotoxemia who could theoretically benefit from the administration of an anti-endotoxin treatment strategy. The current 'gold standard' for the determination of endotoxemia is the LAL assay, which requires specific expertise to perform and is notorious for a wide variability in results [4,5].


Effective antibiotic therapy of Gram-negative infections

John Marshall and colleagues showed an association between endotoxemia and Gram-negative infections in patients admitted to a medical–surgical intensive care unit [1]. They evaluated the use of an EAA and compared it with the 'gold standard' LAL assay in standardized whole blood samples, demonstrating a good correlation. Fifty-eight percent of the 74 patients studied had endotoxin levels >50 pg/ml. Proven infection was present in 26% of the patients on admission to the intensive care unit, while only 13.5% of the patients had culture-proven Gram-negative infections. These patients with documented Gram-negative infection had a significantly elevated mean EAA compared with the mean level in patients without a documented Gram-negative infection. There was an association between elevated EAA and Gram-negative infection, sepsis, and an elevated white blood cell count [1].

If endotoxemia could be reliably detected, it may serve as an indicator of a Gram-negative infection and may direct the clinician to administer effective antibiotic therapy directed against Gram–negative organisms. In an age of increasing resistance among the microorganisms encountered in the intensive care unit, it would be advantageous to only administer broad-spectrum antibiotics directed against Gram-negative bacteria to those patients who actually have a Gram-negative infection. Depending on the sensitivity of the test and the negative predictive value, there may be a potential to withhold Gram-negative antibiotic therapy in those patients who did not manifest a positive EAA.

Predicting outcome

There may also be a potential to use an EAA alone or in combination with other markers to prognosticate the outcome of patients with sepsis or the systemic inflammatory response syndrome. In Marshall and colleagues' small study, there was no statistically significant association between admission EAA and shock, mortality, APACHE II level, and length of stay [1]. Casey and colleagues, however, have previously demonstrated a greater risk of mortality among critically ill patients with a high lipopolysaccharide–cytokine score, in contrast to the lower mortality observed in those patients who had a lower lipopolysaccharide–cytokine score [9]. These observations are of interest and certainly merit further investigation.

Conclusions

The study by Marshall and colleagues was relatively small, with less than 30% of the study population having a documented infection. Less than one-half of these documented infections was caused by Gram-negative bacteria. Endotoxemia was found five times as often as documented Gram-negative infection. This demands further explanation. It may represent contamination of the assay technique, translocation from the gastrointestinal tract, or some other phenomenon. Such a large discrepancy indicates that the EAA tested by Marshall and colleagues may not be as valuable in detecting or directing antibiotic therapy as the rapid streptococcal test that is used by many pediatricians in the evaluation of children with sore throats. An EAA that could reliably differentiate between the presence and absence of Gram-negative infection would allow early initiation of empiric antibiotic therapy directed at the probable causative organisms. The reliable documentation of circulating endotoxemia could also help to determine whether there is a need for anti-endotoxin therapy or for improved splanchnic circulation. Further study is required before we can accept either of these conclusions.

Marshall and colleagues have presented us with a new test to detect endotoxin in the circulating blood. What we now need is a better definition of what endotoxemia signifies and how it can beneficially guide us to provide better care for our critically ill patients.

Abbreviations

EAA = endotoxin activity assay; LAL = limulus amebocyte lysate.

Notes

See related Research article: http://ccforum.com/content/6/4/342

References (active links on web page)

* Marshall JC, Walker PM, Foster DM, Harris D, Ribeiro M, Paice J, Romaschin AD, Derzko AN. Measurement of endotoxin activity in critically ill patients using whole blood neutrophil dependent chemiluminescence. Crit Care. 2002;6:342–348. doi: 10.1186/cc1522. [PubMed]
* Bone RC. Gram negative sepsis: background, clinical features, and interventions. Chest. 1991;100:802–808. [PubMed]
* Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goodard A, Wood WI, Gurney AL, Godowski PJ. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signaling. Nature. 1998;395:284–288. doi: 10.1038/26239. [PubMed]
* Scully MF. Measurement of endotoxaemia by the Limulus test. Intensive Care Med. 1984;10:1–2. [PubMed]
* Elin RJ, Robinson RA, Levine AS, Wolff SM. Lack of clinical usefulness of the limulus test in the diagnosis of endotoxemia. N Engl J Med. 1975;293:521–524. [PubMed]
* Natanson C, Eichenholz PW, Danner RL, Eichacker PQ, Hoffman WD, Kuo GC, Banks SM, MacVittie TJ, Parrillo JE. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989;169:823–832. [PubMed]
* Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovaco JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989;321:280–287. [PubMed]
* Fink, MP.; Aranow, JS. Gut barrier dysfunction and sepsis. In: Fein AM, Abraham ED, Balk RA, Bernard GR, Bone RC, Dantzker DR, Fink MP. , editor. In Sepsis and Multiorgan Failure. Baltimore, MD: Williams & Wilkins; 1997. pp. 383–407.
* Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Int Med. 1993;119:771–778. [PubMed]
* Exley AR, Leese T, Holliday MP, Swann RA, Cohen J. Endotoxemia and serum tumor necrosis factor as prognostic markers in severe acute pancreatitis. Gut. 1992;33:1126–1128. [PubMed]
* Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE. Endotoxemia in human septic shock. Chest. 1991;99:169–175. [PubMed]
* Guidet B, Barakett V, Vassal T, Petit JC, Offenstadt G. Endotoxemia and bacteremia in patients with sepsis syndrome in the intensive care unit. Chest. 1994;106:1194–1201. [PubMed]
* Bone RC. Monoclonal antibodies to endotoxin: new allies against sepsis? JAMA. 1991;266:1125–1126. [PubMed]
* Ziegler EJ, Fisher CJ Jr, Sprung CL, Straube RC, Sadoff JC, Foulke GE, Wortel CH, fink MP, Dellinger RP, Teng NN. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. N Engl J Med. 1991;324:429–436. [PubMed]
* Bone RC, Balk RA, Fein AM, Perl TM, Wenzel RP, Reines HD, Quenzer RW, Iberti TJ, Macintyre N, Schein RM. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. Crit Care Med. 1995;23:994–1006. [PubMed]

http://ajrccm.atsjournals.org/cgi/content/abstract/159/6/1710

Am. J. Respir. Crit. Care Med., Volume 159, Number 6, June 1999, 1710-1715
Abnormal Tissue Oxygenation and Cardiovascular Changes in Endotoxemia

PETER B. ANNING, MARK SAIR, C. PETER WINLOVE, and TIMOTHY W. EVANS

Unit of Critical Care, and Physiological Flow Studies Group, Imperial College of Science, Technology and Medicine, London, United Kingdom

Experimental sepsis induces disturbances in microcirculatory flow and nutrient exchange that may result in impaired tissue oxygenation. Volume resuscitation is a principal clinical intervention in patients with sepsis. Nitric oxide (NO) has been implicated in the pathophysiology of endotoxemia, but few data exist concerning the effects of either NO synthase inhibition (NOSi) or volume resuscitation on microvascular regulation and tissue oxygenation. Amperometric measurements were made of skeletal muscle (tissue) oxygen tension (PtO2) and its response to changes in fraction of inspired oxygen (FIO2) in rats rendered endotoxemic. Simultaneous measurements were made of systemic hemodynamic indices and arterial blood gas tensions. At normal PaO2, PtO2 in endotoxemic animals was significantly lower than in control animals, with marked attenuation of the response to increasing FIO2. These changes were associated with significant metabolic acidemia. In volume-resuscitated endotoxemic rats, PtO2 and blood pH were unchanged. A significant reduction in the PtO2 response to hyperoxia was observed in animals treated with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), an effect not reversed by fluid resuscitation. These data suggest that significant tissue hypoxia and abnormal microvascular control occur in endotoxemia. Volume resuscitation can reverse the changes in PtO2, whereas nitric oxide synthase (NOS) inhibition has deleterious effects on muscle PtO2 in both control and endotoxemic animals.

http://www.mycattle.com/health/updates/endotox.cfm

Veterinarians Say Treating for Endotoxemia in Cattle with BRD as Important as Using Antibiotics

Endotoxemia, a condition that often develops in cattle with bovine respiratory disease (BRD), can be "like a grenade going off in an ammunitions depot," according to a one veterinarian.

"It's sets off a chain reaction that ultimately destroys the entire facility," says Dr. Norman Stewart, a veterinarian with Schering-Plough Animal Health. "In cattle, the 'explosions' just go off at a slower pace. Treating for endotoxemia may be as important as providing antibiotics to combat the lung infection."

BRD, a bacterial lung infection often due to the pathogens Pasteurella multocida, Pasteurella haemolytica or Haemophilus somnus, remains a major economic problem in the cattle industry resulting in poor production, weight gain, feed conversion and, sometimes, death. In many cases, however, it's not only the infection making the animal ill. Endotoxemia can also reduce performance and prevent a speedy recovery.

Endotoxemia occurs both as the animal's immune system attacks bacteria and as antibiotics disrupt the ability of bacteria to repair themselves, Dr. Stewart explains. As a result, bacteria break up and fall apart, releasing cell wall "chunks" that contain endotoxins. Endotoxins cause inflammation and tissue damage in the lungs.

"Endotoxemia is part of the overall disease complex in BRD," says Dr. James S. Cullor, director of the Veterinary Medicine Teaching and Research Center, Tulare, Calif. "It's just part of what's making the animal with BRD sick. If we understand that, we can better diagnose, treat and, ultimately, prevent more serious illness and production losses."

Dr. Cullor, who has studied inflammation in cattle extensively, points out that some inflammation is good. "It's helps stimulate the immune system. It's the body's way of saying 'get going'," he says. "But after a certain point, inflammation causes a lot of trouble in the heart and lungs. The degree of trouble it causes varies among individual animals."

Signs of Illness

It's hard to miss cattle with endotoxemia. "They'll stop eating, act depressed and have a fever. Internally, a lot more is going on," Dr. Stewart says. "What appears at first to be slight illness can progress rapidly to a severe, life-threatening situation."

The heart rate may be weak and rapid and the respiratory rate fast and shallow. Normally pink tissues, such as the nose or gums, will be dark and muddy, indicating a lack of oxygen. "Without intervention that prevents further tissue damage, the animal will collapse to the ground and be unable to get up," he says.

Minimizing Damage

Veterinarians agree that the best way to prevent the devastating results that can occur as a result of endotoxemia is to treat promptly. "Get the infection under control as quickly as you can with antibiotics and good nursing care, Dr. Cullor says. It is important to control the effects of endotoxemia with anti-inflammatory therapy. "The sooner it's given, the better," he adds.

Dr. Stewart says, "Waiting too long to treat is like trying to fix the buildings in the ammunitions dump after they've been blown up. It's better to prevent their destruction in the first place by limiting the initial damage the grenade caused. Anti-inflammatories cannot neutralize endotoxins, but they do help block their effects," he adds. "They inhibit an enzyme that produces pain and inflammation."

First-Hand Experience

Based on first-hand experience, Dr. Doug Ford of Beaver Creek Veterinary Clinic, Brush, Colo., says that for reducing stress, vaccination and antibiotics are the first line of defense against BRD. "We also need to treat for endotoxemia with an anti-inflammatory," he agrees. "An anti-inflammatory isn't a silver bullet, but it is a useful tool. It can make animals with BRD feel better, so animals get back on feed. If cattle eat, they keep up their strength and will be find.

More on endotoxin: Ceftriaxone

http://www.wipo.int/pctdb/en/wo.jsp?IA=WO2007092427&wo=
2007092427&DISPLAY=DESC 
Endotoxin studies, poor results with treatment