Endotoxic Shock Part II: A Review of Treatment Elizabeth M. Hardie, DVM, PhD, and Kris Kruse-Elliott, DVM Treatment of endotoxemia is difficult because of the numerous mediators involved in the body’s response to endotoxin. There are three possible approaches in treating endotoxemia. The interaction of endotoxin with target cells can be blocked by inducing tolerance, decreasing plasma endotoxin concentrations, or interfering with endotoxin binding. Once endotoxin has interacted with target cells, endogenous mediators can be blocked with a huge variety of drugs. The effects of corticosteroids, cyclooxygenase blockers, leukotriene blockers, platelet activating factor blockers, tumor necrosis factor blockers, oxygen radical scavengers, opiate antagonists, antihistamines, calcium channel blockers are detailed. Supportive care of the endotoxemic patient continues to be a critical aspect of treatment. Controversies regarding solutions to use for volume support, vasoactive and cardiostimulant drugs, metabolic support, and treatment of disseminated intravascular coagulation are reviewed. (Journal of Veterinary Internal Medicine 1990; 4:306-314)

THE CLINICIAN faced with treating a patient with endotoxemia or gram-negative sepsis is currently limited primarily to the provision of supportive care. In part I of this review, we presented the cell types and mediators currently thought to be involved in the pathogenesis of endotoxic injury. Part I1 will review the numerous treatment methods under investigation and will indicate methods that are likely to become available in the future. A few cautions are in order when reviewing possible treatments for any shock condition, especially one as complex as endotoxemia. First, a vast number of treatments result in increased survival time, because they block one small part of the shock response, but do not prevent death. Most studies that report increased “survival” use the survival rate at one to three days as their end point. This end point is not really valid, because delayed deaths can occur up to at least seven days after the induction of shock.’ Finally, many studies use small numbers of animals because of constraints on survival studies. Before a treatment can truly be declared effective, it should result in a statistically significant increased survival rate at seven days (termed “increased long-term survival”). Second, the majority of treatments for endotoxemia involve modification of body defense systems in some

,

From the Departments of Companion Animal and Special Species Medicine (Hardie), and Anatomy, Physiology and Radiology (KruseElliott), North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina. Reprint requests: Elizabeth M. Hardie, DVM, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough Street, Raleigh, NC 27606.

manner. In the clinical patient, endotoxemia rarely occurs as an isolated condition, but often accompanies gram-negative sepsis. Treatments that are effective against endotoxemia may not be effective in sepsis if overwhelming infection occurs.’ Treatments should also, thus, be determined to be effective in sepsis models or in randomized, blinded clinical trials. All methods for treating endotoxic shock are more effective if treatment is begun before or coincident with the onset of endotoxemia, because many of the critical mediators are released within the first minutes. Many scoring system^^,^ for recognizing endotoxemia/sepsis are available for human patients. Modifications for species of interest to veterinarians have been suggested,’ but need to be validated with clinical studies. Endotoxemia has been proven to be a component of the following clinical syndromes: invasive gram-negative infection,6 vascular compromise of the intestine (equine colic, canine gastric dilatation-volvulous7), obstructive jaundice,8 liver disease,’ hemorrhagic diarrhea,” and heat stroke.“ Blocking the Interaction of Endotoxin and Target Cells

One approach to the treatment of endotoxemia is to prevent the interactions between endotoxin (LPS) and target cells that result in the production of endogenous mediators. This can be done by causing cells not to respond to LPS (tolerance), decreasing plasma LPS concentrations, or interfering with LPS binding. Tolerance to LPS can be induced through previous exposure to nonlethal doses of LPS.” Early tolerance lasts several days, is not 0-antigen specific, and appears to be due to nonresponsiveness of the macrophages.

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ment, lipid X improves long-term survival in several Late tolerance, which lasts several weeks, is 0-antigen specific, and is probably due to antitoxin action of spespecies.26-28In mice, lipid X treatment is also effective up to 6 hours after LPS administration.26 If mice are cific antibodies. Prophylactic “vaccination” against LPS sensitized to LPS with galactosamine, however, lipid X has not been widely used because it can be difficult to predict the time at which endotoxemia might occur, and is not effective if given after LPS administration.*’ These because exposure to even small amounts of LPS can results suggest that lipid X treatment might be effective have adverse effects. Early tolerance can now be inin less severe endotoxemic conditions. In all studies, the duced, however, with a nontoxic lipid-A derivative,12 effect of lipid X is highly dose-dependent. and has been shown to result in increased survival in Plasma exchange,29extracorporeal-activated charcoal endotoxic mice. Late tolerance has been exploited hemoperfu~ion,~~ and hemoperfusion or plasmapheresis mainly as a method of providing passive immunotherover polymyxin B linked to solid-phase supports3’have apy for endotoxic patients.’3”4 been used to lower LPS concentrations in the blood. The Whole bacteria, “core” glycolipid, lipid-A, and enplasmapheresis method avoids the complications of the terobacter common antigen fractions have been used to other methods, and has been shown to improve 24-hour induce anti-LPS antibodies, but only antibodies against survival in lead-acetate sensitized endotoxic rats.3’ whole bacteria or core glycolipid are pr~tective.’~ Typespecific antibodies are the most protective antibodies Blocking Endogenous Mediators against LPS from a given bacterium, but are impractical A second approach to the treatment of endotoxemia is as infection with a specific organism can rarely be preto block the endogenous mediators released in response d i ~ t e d . ’ ~Two . ’ ~ approaches have been used in order to to LPS. A vast array of blocking substances have been overcome this problem. The first approach is to pasused in studies focused on determining the role of spesively immunize patients with plasma that contains high cific mediators in endotoxemia. Some of these studies concentrations of specific IgG antibodies against a numhave examined survival statistics as well, allowing exber of different gram-negative organisms.I 3 Investigators trapolation to the clinical setting. have shown that this treatment lowers plasma LPS concentrations and decreases morbidity and mortality in a Corticosteroids variety of experimental and natural disease condiRandomized, double-blind clinical trials need tions. Numerous studies in mice, rats, dogs, and baboons indito be performed to confirm these results. cate that corticosteroids improve long-term survival in The second approach uses antisera prepared against endotoxemia, and when used in conjunction with antiwhole cells or core glycolipid from mutant gram-negabiotics, in ~ e p s i s . ~The .~~ major , ~ ~ actions of corticostetive bacteria (J5 Escherichia coli, Re mutant of Salrnoroids occur at the level of protein transcription and nella typhirnuriurn) that have core glycolipid exposed on translation. They block the synthesis of tumor necrosis their surface.18-20 These antisera cross-react with LPS factor (TNF),34and induce the synthesis (or release) of a from all gram-negative organisms. Administration of protein, lipocortin, that is proposed to inhibit phosphomutant bacterial antisera has resulted in decreased morlipase A2.35336 Because corticosteroids act through modibidity and mortality in some well-controlled experimenfications in protein synthesis, they are most effective if tal and clinical studies, but not in other^.'^,'^,'^-^' The administered prior to the onset of endotoxemia/sepsis. focus of current research in this field is to determine the Their effectiveness rapidly diminishes as the time from region of the core glycolipid with which the protective the onset of endotoxemia/sepsis to the time of initiation antibodies are reacting, and to determine which subclass of treatment increases.2316332 In most species, some beneof antibodies provide the most p r ~ t e c t i o n . ’ ~The , ~ ~ , ~fit~ of treatment can be detected for up to one to two hope is that a specific monoclonal antibody can be hours after the onset of sepsis/endotoxemia, but in sepfound that provides p r ~ t e c t i o n . ~ ~ . ~ ~ tic dogs, treatment could only be delayed 15 minutes.2 Some investigators have noted that when plasma is The dose of steroid administered has also been shown harvested for passive immunotherapy, it contains many to be critical, at least for methylprednisolone. A dose of acute phase reactants that aid in the clearance of LPS.24 30 mg/kg is optimal, as doses above and below this They indicate that some of the benefits derived from amount result in decreased efficacy in mice s t u d i e ~ . ’ ~ , ~ ~ passive immunotherapy may be due to these reactants. The questions of whether additional doses of steroid Current research is focusing on identifying these reacshould be administered, and at what intervals, have not tants and proving that they are deficient in septic pabeen well addressed. In septic mice, administration of t i e n t ~ Replacement .~~ therapy with individual composecond and third doses of methylprednisolone at 4-hour nents may be possible. intervals improved long-term survival, but with deLipid X, a nontoxic lipid-A precursor, can also be creasing efficacy.’6932 In septic dogs, a six hour infusion used to block the action of LPS, probably through interof methylprednisolone (0.9 mg/kg/min) resulted in infering with cellular binding. When used as a pretreatcreased long term survival, compared to multiple bolus “3”

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injections over the same time period.37Continuous addecrease due to inhibition of local vasodilatory prostaministration of steroids for days is not indicated in glandin~.~’ sepsis, because increased mortality (probably due to imLeukotriene Antagonists/Lipoxygenase Inhibitors munocompromise and overwhelming infection) occurs with this treatment.33 Little work is available on the effects of leukotriene There is disagreement over whether one corticosteblockers on survival in endotoxic shock. Treatment of roid is more effective than another. Most studies have endotoxic rats with the peptidoleukotriene receptor anutilized methylprednisolone. When dexamethasone tagonist SK+F 104353 increased 48-hr survival from 0% (6-8 mg/kg) and methylprednisolone were compared to In another study using an LD 100 (100%mordirectly, some investigators found an increased survival tality) LPS dose in galactosamine-sensitized rats, treatrate with methylpredni~olone,~~ while others found no ment with diethylcarbamazine (a lipoxygenase inhibidifference between the 2 compounds.16,39 tor) and FPL557 12 (a leukotriene receptor antagonist) Despite the experimental evidence documenting the resulted in 100%survival at 5 days.59In the same study, efficacy of corticosteroid treatment in endotoxemia/ indomethacin treatment resulted in 50% survival and sepsis, human clinical trials have not always demonibuprofen treatment in 0% survival. strated increased survival rates with steroid treatment.40,4’This disparity may arise because confirmed Cyclooxygenase/LipoxygenaseInhibitors sepsis had to be present before a patient could be entered Benoxaprofen and BW755C act as both cyclooxygenase into some protocols.33 Secondary infections are the major side effects of steroid treatment in p e ~ p l e . ~ ~ . ~ ’and lipoxygenase inhibitor^.^^ BW755C resulted in 100% survival in the above-mentioned rat study, but A special mention should be made regarding the use failed to improve survival in 2 other rat studies6’ In a of corticosteroids in equine endotoxemia. In this species study of LD 100 canine endotoxic shock, benoxaprofen corticosteroids appear to be of little benefit and may given 2 hours after LPS resulted in increased survival at actually increase morbidity.21 3 days6’ There is, thus, some indication that blocking both arachidonic acid pathways may be beneficial, but Cyclooxygenase Blockers more studies are needed. There is conclusive evidence that cyclooxygenase blockers prevent many early cardiovascular effects of Platelet Activating Factor Blockers LPS and delay death in severe acute endotoxemia Survival studies using the platelet activating factor models in a number of specie^.^^-^' Their effect on long blockers CV-3988,62BN-5202 1,63,64 and BN-5206364in term survival, however, is less well documented. In the rats demonstrated increased survival at 20 and 24 hours. dog, only aspirin and indomethacin have been shown to Only high doses were effective in improving survival, increase 72-hour survival in e n d ~ t o x e m i aIbuprofen .~~ but low doses reversed LPS-induced hypotension. Studdoes not improve survival.47The effect of flunixin megies on long-term survival have not been conducted. lumine on survival in canine endotoxemia has not been determined. In a study of rapidly fatal canine sepsis,48 Oxygen Radical Scavengers 5/8 dogs treated with fluids and gentamicin sulfate survived 7 days, while 8/8 dogs treated with fluids, gentaSurvival studies using several oxygen radical scavengers micin sulfate, and flunixin meglumine survived. These have been performed using LD 75-100 LPS doses in differences are not statistically significant. Long-term rats. Phenyl-t-butyl-nitrone improved 24- and 96-hour survival in 2 independent s t ~ d i e s .Allopurinol ~ ~ . ~ ~ and survival of endotoxic cats treated with cyclooxygenase blockers has not been assessed. The condition of cats at reduced glutathione failed to improve survival in another pair of s t ~ d i e s . ~Results ~ , ‘ ~ with other compounds the termination of 4- to 6-hr studies, however, indicated that long-term survival was unlikely to be improved.49 were less consistent. Superoxide dismutase (with or without catalase) improved 24-hour survival in 1 Flunixin meglumine has been shown to improve longbut did not improve 24- or 96-hour survival in term survival in equine end~toxemia.~’ another investigation.66Vitamin E had no effect in 1 Large numbers of rats have been used in survival studImproved 96-hour survival was found in a secies testing ibuprofen and indomethacin. Indomethacin ond study,66in which a higher dose of Vitamin E was improved 24-hr survival in some,’o,’’ but not all,’2.’3 rat used. Increased plasma concentrations of prostaglandins endotoxemia studies. Indomethacin and ibuprofen were were documented with the high dose vitamin E therapy, both ineffective in treatment of rat ~epsis.’~ but the addition of BW755C did not result in additional Two major side effects have been associated with the improvements in survival.66 use of potent cyclooxygenase blockers in the dog. First, A study of septic people68comparing three different potentially serious gastrointestinal ulceration and hemmixtures of antioxidants showed that all therapies were orrhage can O C C U ~ .Secondly, ~ ’ ~ ’ ~ renal blood flow may

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able to improve coagulation status and decrease measures of lipid peroxidation. Precise survival data was not reported, but a statement was made that the death rate was 40% lower than expected in the group receiving a mixture of ascorbic acid, alpha-tocopherol, propyl-gallate, butyl-hydroxytoluene, Na selinide, and alpha-mercatopropionylglycine.

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dogs,78and 48-hour survival in endotoxic rats.77When combined with gentamicin (which also has calcium channel blocking activity), verapamil improved 96-hr survival in septic mice.79This synergism was not seen with cefoxitin. In the rodent models, n i f e d i ~ i n eand ,~~ n i ~ a d i p i n were e ~ ~ even more effective than verapamil. Multiple Drug Therapy

Opiate Antagonists

Many researchers fail to believe that a single “silver bullet” will be found to treat endotoxemia and suggest that The mechanism of action of the opiate antagonist, nalof several key mediators may be necessary. A blockade oxone, in endotoxemia is not well understood. The most few studies have examined possible combinations. In accepted hypothesis is it acts to block central opiate reseptic rats, pretreatment with methylprednisolone, ibuceptors, where it reverses the autonomic effects of enprofen, and gentamicin improved long-term survival, dogenous opiates.69Other possible mechanisms include while combinations of 2 of these drugs did not.80 Inblockade of peripheral opiate receptors, effects on calcreased long-term survival was also demonstrated in encium flux, alterations in calcium flux, alterations of the dotoxic dogs treated with methylprednisolone, ibuproCAMPsystem, effects on the y-aminobutyric and dopafen, and naloxone.” In these dogs, the combination of minergic neurons, and scavenging of free radicals. methylprednisolone and ibuprofen also increased surThe original studies examining naloxone treatment of vival, while the combination of methylprednisolone and endotoxic animals demonstrated a number of positive naloxone delayed, but did not prevent, death. effects: improved cardiovascular status, decreased heThe problem with multiple drug therapy is that drug moconcentration, decreased acidosis, prevention of hyinteractions that are not apparent in experimental poglycemia, decreased pulmonary platelet trapping, immodels may occur in clinical patients. For example, the proved oxygenation, and increased survival time.69-72 authors have received reports of gastrointestinal hemorThese effects were only found with very high doses of rhage and perforation in dogs given combinations of naloxone and could be blocked by a number of condicorticosteroids and potent nonsteroidal anti-inflammations (low ambient temperature, acidosis, high concentory agents. trations of corticosteroids, hypophysectomy, adrenalectomy).69,72,73 When naloxone’s effect on long-term surFuture Drugs viva1 was examined (using both endotoxic and septic animals), very confusing results were ~ b t a i n e d .Nal~ ~ . ~ ~It is always risky to predict in which direction a field might move, but trials with certain therapies (antiprooxone was found to have no effect (septic baboons), to teases, specific eicosanoid blockers, interleukin- 1 increase mortality (septic rats, endotoxic pigs), or to inblockers, TNF blockers) appear to be warranted. If TNF crease survival (septic dogs). In human clinical trials, no proves to be an important mediator of endotoxic shock, improvement in survival was found. The value of naloxone as a treatment for clinical endotoxemia or sepsis, treatments that block this compound should improve survival. Passive immunotherapy with serum-containthus, remains to be documented. ing antibodies against TNF has been shown to improve long-term survival in endotoxic mice.82Therapy with Antihistamines monoclonal antibodies against TNF improved longHistamine has been proposed as a cause of hypotension term survival in baboons, however, only if given 2 hours and increased vascular permeability in endotoxemia. prior to induction of sepsis.83Because TNF is released Increased 24-hour and/or 96-hour survival has been early ( 1 Yz-2 hrs) in the course of e n d ~ t o x e m i a , ~ ~ - ~ ~ documented in endotoxic rats with various doses of ciblockade of this compound is likely to be most effective metadine, ranitidine, diphenhydramine, and with sevin the same “time window” as corticosteroids. ~ ~ . ~ on ~ eral combinations of H 1 and H2 b l o ~ k e r s .Effects Another approach is to use rapidly acting mediator long-term survival have not been studied. blockers with multiple actions. One such drug, lazaroid (U74006F), blocks both the arachidonic acid cascade Calcium Channel Blockers and iron-sensitive lipid peroxidation. This drug has shown beneficial effects in sublethal endotoxemia in Calcium channel blockers have been postulated to preneonatal calves87 and in canine gastric dilation-volvent intracellular calcium overload in endotoxemia, but vu1us.88 this effect could not be demonstrated. Anin 1 Supportive Care other possible mechanism of action is improved circulatory status secondary to vasodilation. Verapamil has been shown to improve 7-day survival in endotoxic

Practical clinical suggestions for the support of endotoxic and septic animal patients have been reviewed

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’

el~ewhere.~.~ 1.89-9 Many questions remain, however, as to what constitutes the best supportive regime. Antibiotics

Journal of Veterinary Internal Medicine

cular coagulation (DIC) are present, plasma would appear to be preferable to colloids. Administration of plasma prior to the administration of LPS has been shown to improve survival,’03an effect that is dependent on both volume and “heat labile factors.” Until those “factors” are identified and synthesized, plasma transfusion is the only method of supplementing them.

Antibiotic therapy does not alter the survival rate of endotoxic animals,92but endotoxemia has been proven to cause translocation of bacteria from the gut to other organs.93 Appropriate antibiotic therapy is the critical Vasoactive and Cardiostimulant Drugs factor in the survival of septic patient^.^^.^^ The selection of antibiotics to be used in the treatment of life-threatenThe effects of a number of vasoactive and cardiostimuing gram-negative infections should be based on knowllant drugs have been examined in endotoxemia modek5 edge of the probable organisms and site of i n f e ~ t i o n . ~ ’ , Alpha-adrenergic ~~ agonists decrease tissue perfusion in If the source of the infection is unknown, the usual reckey vascular beds and are ~ontraindicated.’~ Alphaommendation is to combine an aminoglycoside and a adrenergic blockers have been shown to result in inpenicillin, or to use a second-generation cephalosporin. creased tissue perfusion, increased cardiac index, imVolume Support The major question in volume support of endotoxic patients is what solution to use: isotonic crystalloid, colloid, plasma, hypertonic saline, or a hypertonic glucoseinsulin-potassium mixture? Lillehei’s original experiments on endotoxic dogs examined the effects of blood, plasma, dextran, or isotonic saline infusion on surin survival was noted with any ~ i v a lNo . ~ improvement ~ of these treatments, but if massive plasma transfusion was combined with phenoxybenzamine treatment, survival was improved. Administration of a glucose-potassium-insulin mixture has also been shown to increase survival in canine endotoxic Whether this represents a metabolic effect, a cardiovascular effect (secondary to hypertonicity), or both is not known. Hypertonic saline,97glucose,98and sorbito19*have similar beneficial cardiovascular effects to glucose-insulin-potassium in endotoxemia, suggesting that hypertonicity may be a key factor. The major problem with hypertonic solutions is how to extend their effect beyond the initial administration period. Glucose-insulin-potassium infusions have short duration hemodynamic effects,98and hypertonic saline cannot be administered indefinitely because of the development of severe hypernatremia and hyperosmolalit^.^' Current studies on resuscitation from hypovolemic shock suggest that cardiovascular status is optimized by using hypertonic saline with small amounts of colloid for initial resuscitation, and then continuing volume support with colloid or c r y ~ t a l l o i d .Whether ~ ~ ~ ’ ~ or not this regime is appropriate for endotoxemia (in which vascular permeability is marked increased) remains to be tested. The question of crystalloid vs. colloid also needs examining. Results from canine intestinal obstruction’” and rat superior mesenteric artery occlusionIo2shock models suggest that colloids are probably superior to crystalloids for the majority of acute endotoxic states. If severe hypoproteinemia and/or disseminated intravas-

proved metabolic status, and increased survival in laboratory animal^.^.^' Pulmonary edema and severe hypotension, however, have been observed in human clinical trial^.^ Directly acting vasodilators such as nitroprusside have received limited attention; they are of benefit in high resistance states when used after volume e~pansion.~ Calcium channel blockers, digitalis, glucagon, dopamine, dobutamine, and amrinone have been used to improve myocardial Calcium channel blockers have previously been discussed. Conflicting results concerning the beneficial effects of digitalis have been ~ b t a i n e d Glucagon .~ increased heart rate, cardiac output, and stroke volume in endotoxic dogs,Io4and increased survival in endotoxic pigs.’06Little effect on blood pressure was noted in either species. Dopamine and dobutamine both have beneficial cardiovascular effects in endotoxemia or sepsis, but improvements in survival have not been reported in either laboratory animals or human^.^-'^^ Dopamine has been directly compared to dobutamine in a canine endotoxemia model.’07Both drugs increased cardiac output. Dopamine increased and dobutamine decreased cardiac-filling pressure. When fluids were given to maintain a given cardiac-filling pressure, dobutamine-treated dogs required a significantly larger volume than dopamine-treated dogs. Cardiac performance and oxygen delivery, however, were maximized with the combination of volume loading and dobutamine. Dobutamine was recommended if increased cardiac output and improved oxygen delivery were of paramount importance. The investigators noted that if severe hypotension, hypoproteinemia, or oliguria were present, however, they would recommend dopamine. Amrinone,”’ a phosphodiesterase inhibitor, has been tested in the same canine endotoxemia model. Increased cardiac output and oxygen delivery (comparable to that achieved with dobutamine), without a change in cardiac-filling pressure, were found. Amounts of intravenous fluids required to maintain a given cardiac-filling

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pressure were not different from endotoxic controls. Amrinone, thus, shows promise as a replacement for or adjunct to catecholamines. Metabolic Support The complex metabolic response to infection has been well reviewed elsewhere.1089109The major question of interest to clinicians is whether or not nutritional support can alter this response, or alter the morbidity and mortality associated with endotoxemia/sepsis. A growing body of evidence suggests that malnourished patients have an increased risk of septic complications after surgery, and that preoperative nutritional support can lower the rate of complications."' What has been difficult to determine is how important nutritional supAn effect port is in the treatment of acute infe~ti0n.I'~ on mortality rates has yet to be demonstrated, and human clinical trials are difficult to perform because of the ethics of denying nutritional support to critical patients. Beyond the question of whether or not to support endotoxic patients is the question of what solutions to use.'09 Should fat or glucose be used as an energy source? Branched-chain amino acids improve nitrogen metabolism in septic rats, but have failed to have obvious benefits over regular amino acid mixtures in human surgical patients. Is there a defined group of septic patients in which branched chain solutions are indicated? Clear recommendations will be difficult to make until large-scale clinical trials are performed. Treatment of DIC The efficacy of systemic heparin therapy in treating DIC associated with endotoxemia is not well established.' ' I Most studies indicate benefit from heparin therapy, but reported effects on survival are variable. Survival was consistently improved, however, in experimental peritonitis in the cat, rabbit, and dog.'12 One human clinical trial demonstrated improvement in coagulation defects, but not in survival.l13 Randomized trials are needed to determine if heparin's beneficial effects (improved clotting function, improved bacterial clearance from the peritoneal cavity, decreased peritoneal fibrin formation, decreased abdominal abscess formation) outweigh its detrimental effects (thrombocytopenia, increased blood loss, red cell agglutination in horses)."'-' I 5 Antithrombin-I11 (AT-111) concentrations are low in septic human patients, and the degree of depression is directly correlated with mortality. I l 5 Studies in people using replacement therapy have concentrated on DIC, regardless of cause, rather than due to sepsis alone, and improved coagulation status is reported. 'I5 Survival, however, was not improved in 1 randomized human clinical study of AT-I11 therapy in DIC and shock."' In endotoxic rats, AT-111 praphylaxis ameliorated DIC and resulted in improved 7 day survival."' Improved clot-

31 1

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ting profiles resulted from AT-I11 prophylaxis of endotoxic dogs, while survival improved in endotoxic rabbits. I l 6 Clinical studies concentrating on endotoxic patients with DIC are needed to determine the efficacy of this therapy. Recently, streptokinase was shown to improve the coagulation status and survival of endotoxic rats."' The utility of this drug in the treatment of DIC associated with endotoxemia needs further work. ''3'

Support of Failing Organ Systems Multiple organ failure is common in septic people3 The need to provide respiratory support and to treat renal and hepatic failure are frequently emphasized. The effect of various supportive treatments on survival in multiple organ failure is difficult to evaluate, but one assumes that without such management, death is inevitable. Conclusion

It is probably appropriate to end this discussion with a note from the past. In 1979, an experiment was conducted using over 7000 septic mice.'6 A reproducible mortality rate of 50-70% was achieved by delaying antibiotic therapy several hours after the injection of bacteria. All major treatments shown to be effective in endotoxemia were tested to see if any of them could prevent mortality not preventable by antibiotic therapy alone. Heparin, ascorbic acid, aprotinin, phenoxybenzamine, glucagon, indomethacin, nicotinamide, nicotinic acid, glucose, a glucose-insulin-potassium mixture, and mutant bacterial antisera all failed the test. Only corticosteroids and specific antisera increased survival percentages beyond that seen in the antibiotic-treated mice, and large numbers of mice (50-150) were needed in each group before the effect reached statistical significance. When bone marrow suppression was added to the model, corticosteroids and specific antisera were no longer effective. Future therapies that increase longterm survival in small groups of animals will have to succeed in such rigorous test systems and in the clinic before they can truly be declared effective. References I. Hinshaw LB. Application of animal shock models to the human. Circ Shock 1985; 17:205-12. 2. Hinshaw LB, Beller-Todd BK, Archer LT. Current management of the septic shock patient: experimental basis for treatment. Circ Shock 1982; 9343-53. 3. Cons RJA, Nuytinck HKS, Redl H. Scoring systems and predictorsofARDSand MOF. ProgClin Biol Res 1987;236B:3-15. 4. Lehmkuhl P, Ludwig M, Pichlmayr I. The use of scoring systems as prognostic parameter after surgery and trauma. Prog Clin Biol Res 1987; 236B17-24. 5. Hardie EM, Rawlings CA. Septic shock. Part 11. Prevention, recognition, and treatment. Compend Contin Educ Pract Vet 1983; 5~483-9.

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6. Nitsche D, Kriewitz M, Rossberg A, et al. The quantitativedetermination of endotoxin in plasma samples of septic patients with peritonitis using the chromogenic substrate and its correlation with the clinical course of peritonitis. Prog Clin Biol Res 1987; 231:417-29. 7. Fessler JF, Bottoms GD. Plasma endotoxin concentrations in experimental and clinical equine and canine subjects. Vet Surg 1988; 17:32. 8. Cahill CJ, Pain JA, Bailey ME. Bile salts, endotoxin and renal function in obstructive jaundice. Surg Gynecol Obstet 1987; 165:519-22. 9. Gaeta GB, Perna P, Adinolfi LE, et al. Endotoxemia in a series of 104 patients with chronic liver diseases: prevention and significance. Digestion 1982; 23:239-44. 10. Wessel BC, Gaylin SL, Wells MT. Circulating plasma endotoxin (lipopolysaccharide) concentrations in healthy and hemorrhagic enteric endotoxemia. J Am Anim Hosp Assoc 1987; 23:291-5. 1 I . Gathirm P, Wells MT, Raidoo D, et al. Portal and systemic plasma lipopolysaccharide concentrations in heat stressed primates. Circ Shock 1988; 25:223-30. 12. Madonna GS, Peterson JE. Ribi E, et al. Early-phase endotoxin tolerance: Induction by a detoxified lipid A derivative, monophosphoryl lipid A. Infect Immun 1986; 52:6-11. 13. Cohen J. Anti-endotoxin immunotherapy in septic shock. J Antimicrob Chemother 1987; 19:436-49. 14. Clausner MP, Baumgartner JD. Letter to the editor. Antimicrob Chemother 1987; 19:551. 15. Girotti MJ, Moon B, Patterson GA, et al. Effect on cardiopulmonary changes of Gram-negative endotoxemia in sheep after type-specific, cross-reactive, and nonspecific immune stimulation. Circ Shock 1986: 18:171-8. 16. Greisman SE, DuBuy JB, Woodward CL. Experimental Gramnegative bacterial sepsis: Prevention of mortality not preventable by antibiotics alone. Infect lmmun 1979; 2553857. 17. Gathiram P, Gaffin SL, Wells.MT, et al. Superior mesenteric artery occlusion shock in cats: Modification of the endotoxemia by antilipopolysaccharide antibodies (anti-LPS). Circ Shock 1986; 19:231-7. 18. Ziegler EJ, McCutchan JA, Fierer J, et al. Treatment of Gramnegative bacteremia and shock with human antiserum to a mutant Escherichiu coli. N Eng J Med 1982; 20:1226-30. 19. Morris DD, Whitlock RH, Corbeil LB. Endotoxemia in horses; protection provided by antiserum to core lipopolysaccharide. Am J Vet Res 1986; 47344-9. 20. Spier S, Lavoie J, Cullor J, et al. Therapy for Gram-negative sepsis and endotoxemia using hyperimmune plasma to E. coli. Circ Shock 1988; 24:284. 2 I . Green EM, Gamer HE, Sprouse RF. Laminitis/endotoxemia: Pathophysiology and therapeutic strategy. Proceedings 6th Annual Veterinary Medical Forum. Am Coll Vet Intern Med 1988; 323-7. 22. Dunn DL, Bogard WC, Lena FB. Enhanced survival during murine Gram-negative sepsis by use of a murine monoclonal antibody. Arch Surg 1985; 120:50-3. 23. Miner KM, Manyak CL, Williams E, et al. Characterization of murine monoclonal antibodies to Escherichia coli J5. Infect Immun 1986; 5256-62. 24. Warren HS, Chedid LA. Strategies for the treatment of endotoxemia: Significance ofthe acute-phase response. Rev Infect Dis 1987; 9:S630-8. 25. Berger D, Berger HG. New aspects of the endotoxin (E) binding capacity of human serum: are there therapeutical approaches? Circ Shock 1988; 24:276. 26. Proctor RA, Will JA, Burhop KE, et al. Protection of mice against lethal endotoxemia by a lipid A precursor. Infect Immun 1986; 52:905-7. 27. Lam C, Schiitz E, Walzl H, et al. Protection of mice against lethal endotoxemia by lipid X is mediated through inhibition of neutrophil function. Circ Shock 1987; 22:311-21. 28. Golenbock DT, Will JA, Raetz CRH, et al. Lipid X ameliorates pulmonary hypertension and protects sheep from death due to endotoxin. Infect Immun 1987; 55:2471-6.

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