Sepsis

INFECTIOUS DISEASES

0749-0690/92 $0.00

+ .20

SEPSIS Bradley S. Bender, MD

Sepsis is a major cause of morbidity and mortality in the United States; there are between 300,000 and 500,000 cases annually (with about 30% mortalFurthermore, it appears that the number of cases is rising, resulting in ity).3,29,39,46 This increase may approximately $5 to $10 billion in medical costs each year.25,35,46 be a result of increased hospitalization, expanded use of invasive catheters, more intense management of medical problems, and the aging of the American population. The true magnitude and trends of this disorder, however, are difficult to determine. First, the terminology used to describe the clinical spectrum resulting from systemic infections (bacterernia, septicemia, sepsis, and septic shock) varies from author to author. An expert in the field has recommended that there be a uniform system for describing these disorders (Table Second, unlike infections such as gonorrhea or meningitis, sepsis is not a reportable disease. Third, only a small number of institutions have maintained long-term data. CLINICAL PRESENTATION

Sepsis is the clinical manifestations of the systemic response to infection It is frequently caused by bacteremia. Sepsis usually presents with the (Table sudden onset of chills, fever, and prostration. On examination, most patients have fever, tachycardia, and tachypnea. Often, signs and symptoms of underlying infections elsewhere (pneumonia, pyelonephritis, or infected intravenous catheter) can be detected. Sepsis syndrome occurs when there is evidence of altered organ perfusion, such as oliguria, elevated serum lactate, altered mental status, or cool, pale extremities. When hypotension (systolic blood pressure of less than 90 mm Hg or a 40 mm Hg or greater decrease below baseline systolic blood pressure) also occurs, the patient is said to have septic shock. If the hypotension lasts less than 1 hour and responds to either fluids or pharmacologic management, the term early

From the University of Florida College of Medicine; and the Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Gainesville, Florida

CLINICS IN GERIATRIC MEDICINE VOLUME 8 NUMBER 4 NOVEMBER 1992

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Table 1. RECOMMENDED CLASSIFICATION OF SEPSIS Disorder

Clinical Correlates*

Bacteremia Sepsis

Positive blood cultures Clinical evidence of infection plus signs of systemic response (tachypnea,tachycardia,

Sepsis syndrome

Diagnosis of sepsis plus evidence of altered organ perfusion (elevated lactate, oliguria, altered mental status) Diagnosis of sepsis syndrome plus hypotension lasting less than 1 hour and responsive to fluids or drugs Diagnosis of sepsis syndrome plus hypotension lasting more than 1 hour despite fluids and drugs

hyperthermia/hypothermia)

Early septic shock Refractory septic shock

*Except for bacteremia, positive blood cultures are not required for each disorder. Adapted from Bone RC: The pathogenesis of sepsis. Ann Intern Med 115:457,1991, with permission.

septic shock is used. If shock persists for more than 1 hour despite fluid resuscitation and administration of vasopressors, refractory septic shock is said to be present. Sepsis may result from infection with a variety of microbes, especially gramnegative and gram-positive bacteria and fungi; clinical studies have documented that clinical symptoms are essentially identical with all organism^.'^,^^,^^ Elderly persons tend to have atypical presentation of both gram-positive and gram-negative bacteremia, most commonly lower body temperatures (even hypothennia), change in functional capabilities, and altered mental status.11,13,31,33,64

PATHOPHYSIOLOGY

The complex topic of the pathogenesis of sepsis has been reviewed re~ently.~ Endotoxin, a liposaccharide that constitutes a major component of the cell wall of gram-negative bacteria, has traditionally been presumed to be responsible for most of the clinical manifestations of sepsis. Evidence for this comes primarily from studies showing that infusion of endotoxin into experimental animals or humans mimics the clinical features of sepsis, e.g., fever, tachycardia, tachypnea, hypotension, organ damage, and even death.3,20-23,39,43,45,57,67 More recently, the exact role of endotoxin has been questioned because of data showing that an identical clinical syndrome can be found with gram-positive bacteria or yeast (which lack end~toxin)~ and the lack of correlation between endotoxin levels and clinical illness.52Most experts believe that endotoxin or other external factors exert their effects by stimulating the release of inflammatory mediator^.^ The best studied of these mediators is tumor necrosis factor-a (TNF-a, also known as cachectin). Passive immunization against TNF-a protects mice subsequently challenged with a lethal dose of endot~xin.~ Furthermore, administration of TNF-a to humans causes fever, tachycardia, and h y p ~ t e n s i o n Other . ~ ~ mediators include interleukin (1L)-l, interleukin-6, interleukin-8, endothelial factors, and prostaglandin^.^^^^^^^^^^^^^^^ For example, IL-6 is detected in very high levels in patients with septic shock61 and is clearly p y r o g e n i ~ .All ~ ~ of , ~ these ~ mediators probably have multiple actions on different cells and interact with each other.6,22,23,61 Their major effect appears to occur through widespread endothelial damage, increased capillary permeability, and subsequent organ dysf~nction.~

FACTORS CONTRIBUTING TO THE SEVERITY OF SEPSIS IN ELDERLY PATIENTS

As with many infections, elderly patients are both at increased risk of developing sepsis and more likely to die after they acquire it. Nosocomial attack rates of gram-negative bacteremia are 0.2 to 1/100 and mortality rates are 5% to 35% for young adults and are 0.7 to 2/100 and 37% to 50% for older persons (Table 2).5,8,25,32 The well-documented, age-related decline in immune function probably plays only a small role in the severity of sepsis. Although antibody response to new antigens and to vaccines is somewhat less in elderly pers0ns,4~the humoral arm of the immune system is less important for defense against gram-negative bacteria. Aging adults have relatively major defects in cellular immunity, and this likely explains their increased susceptibility to some viral infections and tuberculosis, but not sepsis. The phagocytes (neutrophils, monocytes, and macrophages) have subtle abnormalities that can be detected only by quite sophisticated testing and thus, most likely have little impact on age-related severity of sepsis.36(See article on "Host Resistance and Immune System" elsewhere in this issue.) A major contributing factor to the higher frequency and mortality of sepsis in older patients, however, is the large number of anatomic and physiologic changes that occur with age. Impaired cough, decreased ciliary motion, benign prostatic hypertrophy, and skin thinning may contribute to pneumonia, urinary tract infections, and pressure sores. Increased gram-negative colonization of the oropharynx (which predisposes to gram-negative pneumonia) is more common in even healthy elderly persons.59When these persons are hospitalized, the frequency of colonization increases further.59Another "side-effect" of hospitalization is exposure of the patients to catheters, which serve as effective conduits for pathogenic microbes. Infections may not only result from many of the coexisting diseases of aging, but also may exacerbate other illnesses. Thus, it is not unusual to see a patient with congestive heart failure and a recent stroke develop an aspiration pneumonia, then sepsis, and further cardiac decompensation. - Lower body temperature with infection is strongly correlated with higher m~rtality.llJ~,~ There ~,~& are ~ ~several possible explanations for this. First, the lower temperatures may result in delayed diagnosis and initiation of appropriate antibiotics. Second, higher body temperatures may have benefits through either direct inhibition of microbial replication or enhanced immune function. Third, the lower temperature may be coincidental and only a marker for a poor host response. Elderly persons frequently have lower body temperatures with infections (Table 2).11,13,60 There are several reasons for this. The first has to do with basal temperatures. Body temperatures are normally maintained over a relatively narrow range. In young adults, studies have shown that although the mean body temperature is about 37"C, there is no single normal ~ a l u e . l ~Furthermore, ,'~ there is a notable diurnal variation so that early morning temperatures are about 1°C lower than evening temperature^.",^^,^^ Rectal temperatures are about 0.5"C higher than oral.19 Elderly persons, however, have basal temperatures that are about 0.3 to 0.5"C lower than in younger p e r ~ o n s , 9 . l ~ ,especially l ~ , ~ ~ when oral temperatures are recorded.18A British study showed that 10% of home-dwelling elders had deep body temperatures of less than 35.5"C.12One study showed no significant difference between nadir and peak temperatures for young and aged subjects; however, the older persons had significantly lower temperature amplit u d e ~ The . ~ ~clinical significance of lower basal temperatures was addressed recently in a retrospective chart review by Castle and colleague^.^ They found that

Table 2. BACTEREMIAS IN AGED PERSONS Author (~eference) Chattopadhyay et aP Meyers et aPi Madden et a128 van Dijk et aIe0 WindsoP6 Muder et aP5 Rudman et al" Setia et a P Total

Organisms (%)* Setting

Cases

Gram-Positive

Gram-Negative

Deaths (%)

Febrile (%) (T > 38°C)

638

38

63

30

88

Hospital Hospital Geriatric ward Geriatric ward Geriatric ward Nursing home Nursing home Nursing home

*Numbers do not always total to 100% because miscellaneousorganisms (anaerobes, fungi) were not included and multiple organisms were recovered from some patients. NS = not stated; T = temperature

the mean maximum temperature during an infection in elderly nursing home residents was 101.3"F and 47% (25/53) of the infected patients had temperatures of less than 101OF. Many of these patients had an adequate change in temperature from baseline (a change in temperature of more than 2.4"F) but failed to achieve a significant temperature (101°F) because of a low baseline value. Aged animals develop impaired fever responses following injection of either endotoxin, IL-1, or TNF,33,38,57 suggesting an age-related failure in pyrogenic mechanisms. Recent data suggest that this mechanism is a reduced capacity for thermogenesis in brown adipose tissue (BAT). BAT thermogenesis is mediated by catecholamine activation of adenylate cyclase through sympathetically innervated P-adrenergic receptors. This serves to increase lipolysis, and the free fatty acids serve as substrates for mitochondria1 oxidation and increased heat p r o d ~ c t i o n . ~ ~ Scarpace and colleagues demonstrated that following Escherichia coli peritonitis, aged rats had significantly less fever than younger rats and that this correlated ~~,~~ when the aged rodents were with decreased BAT a c t i ~ a t i o n . Furthermore, given CGP-12177A, a P-adrenergic agonist that specifically activates BAT, old rats had lower duration and amount of fever than young rats.50 An associated mechanism for the impaired febrile response in aging is increased heat loss following infection. It was demonstrated recently that low doses of E. coli induced a fever in young rats, whereas a large dose resulted in progressive hypothermia despite enhanced heat-generating mechanism.47Tocco-Bradley and colleagues demonstrated that with an environmental temperature of 26"C, Salmonella typhimurium-infected rats had a febrile response only slightly lower than young rats.57When the experiments were camed out at 15°C ambient temperature, there were significantly lower temperatures in the aged rodents.57Taken together, these experiments suggest that with more severe infections, heat-dissipating mechanisms dominate over heat-generating processes. These data are consistent with human studies showing that following cold exposure, older men showed little increase in metabolism and significant loss in body heat.62 MANAGEMENT OF SEPTIC SHOCK

Both gram-negative and gram-positive pathogens are important causes of sepsis in geriatric patients (Table 2). The primary sources of most of the gram-negative infections are the urinary tract, intra-abdominal sites (e.g., abscesses and cholecystitis), pneumonia, and infected intravenous catheters. Gram-positive bacteremia usually results from pneumonia, skin or soft tissue infection, an intravascular site (catheter, graft, or endocarditis), or urinary tract (enterococci). Overall mortality in older patients with bacteremia was 30% (Table 2) and although not stated, is probably at least 50% in patients. Mortality is higher in patients with ~ ~ ,likely ~ ~ reflects the nonurinary sources of infection, principally p n e u m ~ n i a .This severity of the underlying disease. universally endorsed recommendations for the management of sepsis include volume replacement with either crystalloid or colloid solutions, antibiotic therapy, and diligent monitoring of the patient's clinical course (vital signs, hourly urine output, serum electrolytes, and clotting parameters). The patient's central venous pressure or pulmonary capillary wedge pressure should be monitored, especially when septic shock is present. In these cases, a vasoactive agent is usually indicated. Most authorities regard dopamine as the preferred agent because unlike other vasoactive drugs, it increases renal blood flow. Old age alone is not a contraindication to placement in an intensive care unit. Even though older patients have higher mortality rates than their younger counterparts, other factors, such as the presence of multi-organ system failure, are more important in predicting outcome.58

There is a better prognosis if the initially selected antimicrobial agent(s)is(are) active in vitro against the isolated although one study showed that most patients died regardless of therapy.46Because a large variety of pathogens is possible (Table 2), broad-spectrum coverage is mandatory. Third-generation cephalosporins, imipenem/cilastin, ticarcillin/clavulanate, and antibiotic combinations such as a penicillin or cephalosporin with an aminoglycoside, aztreonam, or parenteral quinolone are probably equally efficacious in most patients. It is important to note that in one study of elderly persons with gram-negative bacteremia, patients older than age 70 given multiple antibiotics had a significantly higher mortality rate (30%) than those given one antibiotic (13?'0).~~ Even though aminoglycosides are generally thought to be more toxic in elderly patients, this has not been found in all ~ t u d i e s . ~ ~ , ~ ~ In certain clinical situations, use of particular antibiotics may be of benefit. For example, in a septic patient with fever, dysuria and flank pain, a urinary tract infection (pyelonephritis) is most likely and initial therapy with ampicillin and aztreonam, third-generation cephalosporin, parenteral quinolone, or an aminoglycoside (to cover enterococcus and gram-negative bacilli) is suggested. In patients with burns or neutropenia, Pseudomonas aeruginosa is common and needs coverage. Thus, the therapy should include either ceftazidime, a quinolone, or a combination of an antipseudomonal penicillin and an aminoglycoside. In institutions that have a relatively high prevalence of methicillin-resistant Sfaphylococcus aureus, vancomycin needs to be included in the initial regimen. It is important to adjust the antibiotic regimen as the clinical situation changes. When cultures return, more narrow spectrum or less toxic combinations can be used. Dosages of antibiotics may need to be adjusted with changes in renal function and changed if serious side effects, e.g., drug allergies or antibiotic-associated diarrhea, supervene. A major advance in the therapy of gram-negative sepsis is the introduction of monoclonal antibodies to the core region of e n d o t o ~ i n . Phase ~ ~ , ~ ~111 studies showed that two of these antibodies (HA-1A and E5) were safe and, for selected subgroups of patients, effective in reducing the mortality rate (Table 3). HA-1A and E5 are prepared from the same antigen (a mutant E. coli). HA-1A is mostly human, and E5 is 100% murine. Although increased adverse reactions might be expected with administration of E5, this was not found in the studies. In the HA-1A trial, patients with a clinical diagnosis of septic shock received a single 100-mg dose of HA-1A or placebo.68Overall mortality was not different between the placebo and therapy groups. There was a significant reduction in mortality (from 44% to 30%) in those patients with documented gram-negative bacteremia. This was particularly impressive in patients with gram-negative bacteremia and shock; mortality was reduced from 57% to 33%. The data from the E5 trial are more complicated.14In this study, patients with suspected gram-negative sepsis were randomized to receive either two doses of 2 mg/kg of E5 or placebo. As in the HA-1A trial, there was no overall reduction in mortality among the entire study population. A different subpopulation appeared to benefit, i.e., patients with gram-negative sepsis and without shock (mortality was 53% versus 30%). Further analysis of these studies reveals important similarities and differences. Pertinent to this review, most of the patients were relatively old (Table 3). Second, despite relatively stringent criteria, only 37% of the patients in both studies had documented gram-negative bacteremia. Overall mortality rates (about 40%) were remarkably similar. Next, the HA-1A study used one dose whereas the E5 study used two slightly higher doses 24 hours apart. Criteria were slightly different in the studies, Ziegler and c o l l e a g ~ e sfor , ~ ~example, focused on patients with documented gram-negative bacteremia, whereas Greenman and colleagues analyzed

Table 3. COMPARISON OF MONOCLONAL ANTIBODIES FOR GRAM-NEGATIVE SEPSIS

Manufacturer Source Clinical trial Centers Enrolled Gram-negative bacteremia Entry criteria

Dose Age (years) APACHE ll score Results (mortality) Total Gram-negative infections With shock Without shock

Centocor Human (98%)

Xoma Mouse

24 543 200 (37%) (1) Fever or hypothermia (2) Tachycardia and tachypnea (3) Hypotension or evidence of altered organ perfusion 100 mg 62.3 1.5$ 23.6 f 0.9 HA-1A 39% 30"/0(1 33v1 27%

+

33 468 171 (37%) (1) Fever or hypothermia (2) Leukocytosis, leukopenia, or left shift (3) Suspected gram-negative infection (4) Hypotension or evidence of altered organ perfusion 2 mg/kg X 2 doses 60.1 1.3 16.9 f 0.7 E5 Placebo 40% 41% 38% 41% 45% 40% 30w1 43%

+

Placebo 43% 49% 57% 40%

'Data from Ziegler EJ, Fisher CJ, Sprung CL, et al: Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. N Engl J Med 324:429, 1991 tData from Greenman RL, Schein RMH, Martin MA, et al: A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 266:1097, 1991 $Mean f standard error SBacteremia for HA-IA, sepsis for E5 lllndicates statistically significant difference

patients with gram-negative sepsis, i.e., patients with culture of gram-negative bacteria from either blood or other site.14It also appears, by Acute Physiology and Chronic Health Evaluation (APACHE) I1 test scores, that the patients in the HA-1A trial were somewhat sicker. It would be useful to see a direct comparison of HA-1A and E5 so that their efficacy can be better defined. There are other considerations that may further limit the use of these agents. These antibodies will likely be very expensive. The US price has not been announced, but HA-1A costs approximately $3700 per dose in Europe, and it seems very unlikely that the cost will be lower here. Next, even though these agents presumably work by binding endotoxin, not all experiments are consistent with this hypothesis. For example, the monoclonal antibody binds much more avidly to bacteria than endotoxin,' and Greisman and Johnston demonstrated that it failed to protect mice from a lethal dose of endotoxin.15Another limitation of the HA-1A study is that there may have been an inadvertent imbalance in randomization. Baumgartner has pointed out that in the 200 patients with gram-negative bacteremia, there were 101 serious complications present at entry in the 95 placebo recipients (a mean of 1,06/patients) compared with 85 in the 105 HA-1A recipients (O.Sl/patient) (P = 0.07).' The findings of a second trial of E5 were presented at a recent meeting41This study focused on those patients who were not in shock at the time of entry, i.e., the group of patients who benefited from the first trial.14 In this trial, however, there was no significant reduction in mortality. If the data from the two trials were combined, therapy with E5 was shown to significantly reduce only morbidity.41 Despite these limitations, both HA-1A and E5 will probably be approved for use. Therefore, it is necessary for physicians and pharmacy committees to develop guidelines for their use. It would be reasonable to use HA-1A in patients with septic shock and E5 in patients with sepsis (Table 4). The author's recommendations for limiting their use are given in Table 4. They are based on the criteria used in the two published studies. These could be included as a check list on the order form sent to the pharmacy. FUTURE THERAPEUTIC OPTIONS

There are several other agents currently being studied that may ultimately help in the management of sepsis.45The first of these is pentoxifylline, a phosphodiesterase inhibitor that is currently approved for use in patients with peripheral vascular disease. It has some anti-inflammatory effects, presumably through its actions of raising intracellular cyclic adenosine monophosphate (CAMP).In animal models of infection, it decreases end-organ damage and improves some hemodynamic m e a s ~ r e m e n t s . ' When ~ , ~ ~ administered to human volunteers who were also injected with endotoxin, it blocks the synthesis of TNF.67 It is well-known that nonsteroidal anti-inflammatory agents are effective antipyretics. When given to humans, ibuprofen blocks many of the systemic effects of endotoxin and also attenuates some of the neurohormonal response.43 Jacobs and colleagues reported that ibuprofen increased mean arterial pressure and cardiac index and improved acid-base status in a canine model of endotoxic In a further study the same group of investigators showed that it increased survival in sheep given live E. coli and antibiotics from 0% to 66%.4 Confirmation of these findings in human infections is clearly needed. Sepsis is associated with elevations of endogenous opiates, which have potent vasodilating and hypotensive effects. Peters and colleagues demonstrated that naloxone, an antagonist of P-endorphin, produced a rapid increase in blood pressure in patients with septic shock.4oMore recent studies have not demonstrated as

SEPSIS

921

Table 4. SAMPLE CRITERIA FOR USE OF ANTIENDOTOXIN MONCOLONAL ANTIBODIES IN SEPTIC SHOCK Inclusion Criteria Fever (T > 38.3"C) or hypothermia (T < 35.6%) Pulse > 90/min Respiratory rate > 2O/min or > 10 L/min if on ventilator Systolic BP 5 9 0 mm Hg or 240 mm Hg below baseline Evidence of end-organ dysfunction: Decreased renal function (urine output <30 mL/hr) Metabolic acidosis (pH 57.3) Thrombocytopenia (platelets < 1O0,000/mm3) CNS dysfunction Decreased systemic vascular resistance (<800 dyne*sec/cm5) Arterial hypoxemia (PaO, 5 7 5 mm Hg or PaOJFiO, <250 mm Hg) Disseminated intravascular coagulation Culture evidence or strong suspicion of gram-negative infection Failure to stabilize with appropriate fluid resuscitation (500 mL isotonic fluid) Exclusion Criteria Uncontrolled hemorrhage Granulocytopenia (<500/mm3) Burn wound sepsis Cardiogenic shock Use of intravenous immunoglobulin within 21 days T = temperature; BP = blood pressure; CNS = central nervous system; PaO, tension; FiO, = fraction inhaled oxygen

= arterial

oxygen

dramatic an effect, but this may be d u e to the investigators using lower doses or different administration schedules.45 Finally, a number of other monoclonal antibodies are undergoing evaluation. Three of t h e more promising agents a r e anti-IL-6, which protects against lethal E. coli challenge i n mice;53 antitissue factors (potent initiators of coagulation a n d possible initiators of disseminated intravascular coagulation in sepsis), which protect against lethal E. coli challenge i n baboons;55 and anti-TNF, which protects against lethal E. coli challenge i n pigs.*' ACKNOWLEDGMENT This work was supported by the Medical Research Service of the Department of Veterans Affairs.

References 1. Baumgartner J-D: Immunotherapy with antibodies to core lipopolysaccharide: A critical appraisal. Infect Dis Clin North Am 5:915, 1991 2. Beutler B, Milsark IW, Cerami AC: Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229:869, 1985 3. Bone RC: The pathogenesis of sepsis. Ann Intern Med 115:457, 1991 4. Bone RC, Jacobs ER, Wilson FJ: Increased hemodynamic and survival with endotoxin and septic shock with ibuprofen treatment. In First Vienna Shock Forum, Part A: Pathophysiological Role of Mediators and Meditator Inhibitors in Shock. New York, Alan R. Liss, 1987, p. 327 5. Bryan CS, Reynolds KL, Brenner ER: Analysis of 1,186 episodes of gram-negative

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BENDER

bacteremia in non-university hospitals: The effects of antimicrobial therapy. Rev Infect Dis 5:629, 1983 6. Cannon JG, Tompkins RG, Gelfand JA, et al: Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis 161:79, 1990 7. Castle SC, Norman DC, Yeh M, et al: Fever response in elderly nursing home residents: Are the older truly colder? J Am Geriatr Soc 39:853, 1991 8. Chattopadhyay B, Al-Zahawi M: Septicaemia and its unacceptably high mortality in the elderly. J Infect 7:134, 1983 9. Collins KJ, Dore C, Exton-Smith AN, et al: Accidental hypothermia and impaired temperature homoeostasis in elderly. Br Med J 1:353, 1977 10. Downton JH, Andrews K, Puxty JAH: "Silent" pyrexia in the elderly. Age Aging 16:41, 1987 11. Finkelstein MS, Petkun WM, Freedman ML, et al: Pneumococcal bacteremia in adults: Age-dependent differences in presentation and in outcome. J Am Geriatr Soc 31:19, 1983 12. Fox RH, Woodward PM, Exton-Smith AN, et al: Body temperatures in the elderly: A national study of physiological, social, and environmental conditions. Br Med J 1:200, 1973 geriatric patients. JAMA 13. Gleckman R, Hibert D: Afebrile bacteremia. A phenomenon in 248:1478, 1982 14. Greenman RL, Schein RMH, Martin MA, et al: A controlled clinical trial of E5 murine monoclonal IgM antibody to'endotoxin & the treatment of gram-negative sepsis. JAMA 266:1097, 1991 15. Greisman SE, Johnston CA. Failure of antisera to J5 and R595 rough mutants to reduce endotoxemic lethality. J Infect Dis 157:54, 1988 16. Harada H, Ishizaka A, Yonemaru M, et al: The effects of aminophylline and pentoxifylline on multiple organ damage after Escherichia coli sepsis. Am Rev Respir Dis 140:974, 1989 17. Horvath SM, Menduke H, Piersol GM: Oral and rectal temperatures of man. JAMA 144:1562, 1950 18. Howell TH: Normal temperatures in old age. Lancet 1:517, 1948 19. Ivy AC: What is the normal body temperature? Gastroenterology 5:326, 1945 20. Jacobs ER, Soulsby ME, Bone RC, et al: Ibuprofen in canine endotoxin shock. J Clin Invest 70:536, 1982 21. Jacobs RF, Kiel DP, Balk RA: Alveolar macrophage function in a canine model of endotoxin-induced lung injury. Am Rev Respir Dis 134:745, 1986 22. Kawasaki H, Moriyama M, Nariuchi H: Mechanism of augmentation of endotoxin fever by beta interferon in rabbits: Possible participation of tumor necrosis factor (cachectin). Infect Immun 60:933, 1992 23. Kawasaki H, Moriyama M, Tanaka A. Augmentation of endotoxin fever by recombinant human beta interferon in rabbits. Infect Immun 55:1121, 1987 24. Keilson L, Lambert D, Fabian D, et al: Screening for hypothennia in the ambulatory elderly. JAMA 254:1781, 1985 25. Kreger BE, Craven DE, Carling PC, et al: Gram-negative bacteremia. 111. Reassessment of etiology, epidemiology and ecology in 612 patients. Am J Med 68:344, 1980 26. Kreger BE, Craven DE, McCabe WR: Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med 68:344, 1980 27. Lindsey DC, Jesmok GJ, Duerr ML, et al: Dose dependent protection of TNF-alpha monoclonal antibody (TNF MAB) after a LD 100 E. coli challenge in pigs. Presented at the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, September 29-October 2, 1991, Chicago, IL 28. Madden JW, Croker JR,Beynon CPJ: Septicaemia in the elderly. Postgrad Med J 57:502, 1981 -.- -

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