Original Article
Brief Report
Shock and Multiple-Organ Dysfunction after Self-Administration of Salmonella Endotoxin
N Engl J Med 1993; 328:1457-1460May 20, 1993
- Article
Endotoxin, a lipopolysaccharide component of the outer membrane of gram-negative bacteria, is involved in the pathogenesis of septic shock, but it is unclear whether endotoxin alone is capable of causing all the manifestations of the septic shock syndrome. In animals, endotoxin causes many of the clinical features1 but produces a low-cardiac-output form of shock that is unlike the hyperdynamic cardiovascular profile of septic shock in humans2,3. In humans, the administration of endotoxin (4 ng per kilogram of body weight) triggers the release of cytokines,4 activates the coagulation and fibrinolytic systems,5,6 and causes a decrease in systemic vascular resistance and an increase in cardiac output7. At these low doses, however, endotoxin does not cause shock, disseminated intravascular coagulation, or clinically important organ dysfunction. A septic shock-like syndrome occurred in patients treated for cancer with crude preparations of endotoxin8 and in patients who received transfusions of blood products contaminated with gram-negative bacteria9. These reports, however, did not include detailed hemodynamic data, and other bacterial products may have contributed to the clinical signs and symptoms. We describe a patient who self-administered a single large dose of endotoxin and in whom the full clinical manifestations of septic shock syndrome developed.
Case Report
A middle-aged laboratory worker was brought to the emergency department because of malaise, headaches, nausea, and vomiting. The patient was awake but listless with a pulse of 114 per minute, a blood pressure of 42/20 mm Hg, and an oral temperature of 40 °C. The patient was treated with intravenous fluids, and a dopamine infusion was started at a dose of 5 μg per kilogram per minute. Blood cultures were obtained, and vancomycin and gentamicin were administered intravenously. The results of a urinalysis, chest roentgenography, and electrocardiography were normal. The patient was admitted to the medical intensive care unit with a presumptive diagnosis of septic shock.
A norepinephrine infusion was begun for persistent hypotension and titrated to maintain a mean arterial pressure of more than 60 mm Hg. Right ventricular catheterization revealed a form of shock in which there was low systemic vascular resistance (Table 1Table 1
Hemodynamic Measurements and Vasopressor Administration after the Injection of S. minnesota Endotoxin.). Eleven hours after admission, it was discovered that 2.5 hours before arriving at the emergency department, the patient had administered 1 mg of Salmonella minnesota endotoxin (Sigma, St. Louis), dissolved in sterile water, intravenously in an attempt to treat a recently diagnosed tumor. Consequently, a 100-mg dose of HA-1A antibody (Centoxin, Centocor, Malvern, Pa.) was administered 23 hours after the injection of endotoxin.Forty-four hours after the injection of endotoxin, the patient was alert, oriented, and afebrile. The respiratory rate was 30 per minute, and rales were audible bilaterally. A chest roentgenogram showed bilateral interstitial infiltrates consistent with the presence of pulmonary edema. Furosemide was administered, and a brisk diuresis followed. The norepinephrine infusion was discontinued 50 hours after the injection of endotoxin. All cultures (blood, urine, and stool) were negative for pathogens. The patient was sent home on the eighth hospital day.
Methods
Informed consent was obtained from the patient to transcribe relevant clinical data and draw blood specimens. Serum specimens were frozen at -20 °C until assayed. Before the specimens arrived at the research laboratory, no special precautions were taken to keep them free of pyrogens, with the exception of the use of sterile techniques. The specimens were thawed and kept at 4 °C before testing was conducted. Aliquots were assayed for endotoxin with a chromogenic limulus amebocyte lysate method (Whittaker M.A. Bioproducts, Walkersville, Md.) as previously described,11 but with the kinetic modification recommended by the manufacturer12. This assay was sensitive to a concentration of U.S. Standard Reference Endotoxin of 5 pg per milliliter (0.05 endotoxin units [EU] per milliliter).
Tumor necrosis factor-α (TNF-α) was measured at Centocor by enzyme-linked immunosorbent assay (ELISA) (Genzyme, Cambridge, Mass.) and by a bioassay method based on TNF-α-induced cytotoxicity in WEHI cells13. Interleukin-6 and granulocyte colony-stimulating factor concentrations were determined with double-ligand immunoassays (R & D Systems, Minneapolis) performed according to the manufacturer's instructions. Interleukin-8 concentrations were determined with a modified ELISA4.
Results
Initial measurements (Table 1)10 revealed hypotension with an elevated cardiac index and a low index of systemic vascular resistance. The pulmonary-capillary wedge pressure was low, and it rose slowly with fluid resuscitation to a peak of 21 mm Hg. While hypotensive, the patient received 14.9 liters of fluid in excess of the measured output and had clinical symptoms consistent with a generalized capillary-leak syndrome.
The patient's temperature and heart rate (Figure 1Figure 1
Serial Changes in Body Temperature and Heart Rate, Total White-Cell Count and Platelet Count, and Prothrombin Time (PT) and Partial-Thromboplastin Time (PTT) after the Intravenous Injection of Endotoxin.) did not return to normal until approximately 60 hours after the injection of endotoxin. The initial white-cell count of 1600 per cubic millimeter (Figure 1) was followed by progressive leukocytosis with increased band forms (up to 45 percent of the total count) that peaked at a count of 37,000 per cubic millimeter 24 hours after the injection of endotoxin. On admission, the patient had a normal platelet count, prothrombin time, and partial-thromboplastin time. The platelet count subsequently fell, reaching a nadir of 64,000 per cubic millimeter 74.5 hours after the injection (Figure 1). The prothrombin time and the partial-thromboplastin time (Figure 1) became prolonged and reached maximal values (14.6 and 59.6 seconds, respectively) 36 hours after the injection of endotoxin. The levels of fibrin split products were elevated at 44 hours to 64 μg per milliliter (normal, <10). Blood cultures were negative.Other abnormal findings included increased serum lactate dehydrogenase and aspartate aminotransferase values of 385 and 70 IU per liter, respectively. The serum creatinine concentration was 1.6 mg per deciliter (141.4 μmol per liter) 3.7 hours after the injection of endotoxin, and it returned to normal 24 hours later (0.9 mg per deciliter [79.5 μmol per liter]). A mild metabolic acidosis with an anion gap of 16 mmol per liter was present on admission, but the serum lactate concentration, measured 10 hours later, was only 2.0 mmol per liter. On admission, the patient had a partial pressure of arterial oxygen of 130 mm Hg while breathing room air. Forty-eight hours later, however, this value had decreased to 87 mm Hg while the patient received 4 liters of nasally administered oxygen per minute, and there was clinical and roentgenologic evidence of pulmonary edema.
The results of serial determinations of endotoxin, TNF-α, interleukin-6, interleukin-8, and granulocyte colony-stimulating factor are shown in Table 2Table 2
Serial Serum Concentrations of Endotoxin and Cytokines after the Injection of S. minnesota Endotoxin. 14. Since blood samples were not collected in a pyrogen-free manner, the possibility of exogenous contamination with endotoxin cannot be excluded. Although a positive endotoxin test is difficult to interpret in such a situation, the finding of an undetectable level suggests clearance of endotoxin from the circulation. The first serum sample without detectable endotoxin was obtained 11.5 hours after the endotoxin injection. The endotoxin level in an earlier sample, obtained 6.8 hours after the injection, was only 38 pg of U.S. Standard Reference Endotoxin per milliliter (0.38 EU per milliliter). The cytokine concentrations were highest at the first measurement and decreased thereafter.Discussion
The experience with this patient demonstrates that a single large intravenous dose of endotoxin reproduces all the manifestations of septic shock syndrome, including a high-cardiac-output form of hypotension, disseminated intravascular coagulation, abnormalities of hepatic and renal function, and noncardiogenic pulmonary edema. To maintain the blood pressure, the patient required therapy with norepinephrine for 50 hours after the injection of endotoxin. The coagulopathy and thrombocytopenia persisted for two and five days, respectively. Thus, endotoxin alone, in the absence of an ongoing infection, produced an inflammatory response that continued for days.
The precise role of endotoxin as a causative factor in septic shock remains controversial. Tolerance to endotoxin does not protect animals from lethal gram-negative bacillary infection,15 nor does it protect humans from experimental typhoid fever and tularemia16. Studies in animals17 and clinical studies18 have shown that microorganisms devoid of endotoxin can cause septic shock and that bacterial products other than endotoxin may contribute to mortality from gram-negative infections19. Finally, frequent serial determinations of endotoxin in 100 patients with septic shock revealed that 57 percent never had detectable endotoxemia11. The case reported here, however, shows that endotoxin alone is sufficient to trigger the endogenous inflammatory response that leads to septic shock in humans.
This patient injected 1 mg of purified endotoxin and survived. This dose, which is equal to 15,000 ng per kilogram, is 3750 times the dose of 4 ng per kilogram given to normal volunteers in experimental studies7. The apparently rapid clearance of endotoxin from the circulation in this patient is consistent with previous studies in animals20,21 and humans16. However, the detection of endotoxemia in this patient may have been hampered because only serum was available for testing22. Although some investigators have found that endotoxin is not trapped by clotted blood,23 others have reported the loss of endotoxin from serum after coagulation22. The serum TNF-α concentration was 9157 pg per milliliter by a cytotoxicity assay (14,630 pg per milliliter by ELISA) 3.6 hours after the injection of endotoxin, a concentration much higher than those measured in volunteers challenged with smaller doses of endotoxin4,7 or in patients with septic shock24. The level measured in this patient is in the range of the highest TNF-α levels reported among patients with fatal meningococcemia25,26.
The successful outcome and mild organ dysfunction observed in this patient, despite the occurrence of profound shock, may have been due to the limited nature of the insult, the absence of an active infection with the production of other microbial toxins, early intervention with fluid resuscitation and cardiovascular support, and the overall health of the patient. However, the role of other host-related factors, such as naturally occurring anti-endotoxin antibodies, cannot be excluded. It is possible that the administration of the HA-1A antibody affected the outcome in this patient, but it appears that endotoxin had already been cleared from the circulation before the dose was given. In conclusion, a single injection of endotoxin in the absence of infection can cause a syndrome of shock and organ injury that evolves over days and is similar to septic shock.
We are indebted to Patricia Madara, Renee Miller, and Jeanette M. Hosseini for their technical assistance, to Drs. Peter Daddona, Scott Siegal, and Richard McCloskey (all of Centocor) for performing the TNF-α assays, and to Dr. Ronald J. Elin for guidance and advice.
Source Information
From the Division of Pulmonary and Critical Care Medicine (A.M.T.S., F.S.C.) and the Department of Medicine (H.C.K., D.R.L.), Georgetown University, Washington, D.C., and the Critical Care Medicine Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Md. (A.F.S., R.L.D.).
Address reprint requests to Dr. Taveira da Silva at the Division of Pulmonary and Critical Care Medicine, Georgetown University Hospital, 3800 Reservoir Rd., NW, Washington, DC 20007.
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