Multiple organ failure

Sepsis syndrome is characterized by evidence of an infectious process and a deleterious systemic response. One definition of the sepsis syndrome includes the following criteria: (1) fever or hypothermia; (2) leukocytosis or leukopenia, usually with a leftward shift in the differential cell count; (3) a systemic manifestation, such as hypotension, reduced SVR, metabolic acidosis, or multiple-system organ failure; and (4) a source of infection. [1] Although a diagnosis of sepsis syndrome requires that there be a source of infection, many patients with severe sepsis, including those with septic shock, [2] have neither positive blood cultures nor positive cultures from a closed space. [3] When the source of infection is unproven, the clinician may nonetheless remain confident in a diagnosis of sepsis syndrome if the clinical picture is very convicting. For example, a patient with fever, leukocytosis, hypotension with a low SVR and multiple-system organ failure may be presumed to have sepsis even though microbiologic proof of infection may be absent.

During the past 4 1/2 years, we have encountered five cases of an apparent sepsis syndrome that in fact resulted from chronic salicylate intoxication. In each case the clinical, hemodynamic and laboratory features strongly suggested overwhelming sepsis. Salicylate intoxication was recognized at the time of initial presentation in only one case. In the other four cases the presumptive diagnosis was bacterial sepsis, and in three of these cases a correct diagnosis of salicylate intoxication was established only retrospectively several days after admission to the hospital. Occult salicylate intoxication must be considered in the differential diagnosis of sepsis syndrome when an un-equivocal source of infection is not readily apparent.

Methods

The five patients who are the subject of this report were seen in consultation between October 1985 and June 1990. Each of these five patients had evidence of a "pseudo-sepsis" syndrome due to chronic salicylate intoxication, defined by the presence of each of the following criteria: (1) temperature greater than 38[degrees]C; (2) white blood cell count greater than 10 X [10.sup.9]/L or greater than 0.10 band cells or both; (3) reduced SVR; (4) failure of two or more organ systems; (5) salicylate level greater than 2.2 mmol/L (1 mmol/L = 13.5 mg/dl) in serum obtained at the time of admission (n = 4) or greater than 1.5 mmol/L in serum obtained 24 or more hours after admission (n = 1); (6) history of prior daily use of aspirin to treat chronic inflammatory disease or as analgesic therapy; and (7)

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inability to recover bacterial pathogens from blood, urine, or sputum to explain the septic illness and exclusion of an occult intra-abdominal abscess as the cause of sepsis by either clinical recovery (n = 3) or autopsy (n = 2).

Definitions of organ system failure (Table 1) were as follows:

1. ARDS - Presence of all of the following criteria: (a) [PaO.sub.2] less than 60 mm Hg on an [FIo.sub.2] greater than 0.6; (b) diffuse alveolar infiltrates involving four quadrants on an anteroposterior chest roentgenogram; (c) pulmonary artery wedge pressure less than 18 mm Hg; and (d) absence of pathogenic organisms by stain and culture of endotracheal tube secretions.

2. Acute renal failure -- Serum creatinine level greater than 180 [micrometer]mol/L/, with previously normal serum creatinine value, and a subsequent increase in serum creatinine level of at least 45 [micrometer]mol/L/d.

3. DIC -- Platelet count less than 100 X [10.sup.9]/L plus two or more of the following: (1) elevation in serum FDPs, (b) prolongation of the PT or PTT that was not reversed by vitamin K infusion; (c) prolongation of the TT; (d) moderate to marked red blood cell fragmentation on a peripheral blood smear; and (e) hypofibrinogenemia.

4. Encephalopathy -- Recent onset of confusion, lethargy, obtundation, or seizures not explained by factors other than salicylate intoxication.

Hemodynamic data included measurement of mean arterial pressure, pulmonary wedge pressure, right atrial pressure, cardiac output (thermodilution), and SVR. The normal range of values for SVR was taken from a standard reference source for hemodynamic data. [4] The hemodynamic data in patients 1, 2, 4, and 5 were obtained while dopamine was being infused by vein in a dose of 7 to 15 [micrograms]/kg/min. Patient 3 was receiving no vasoactive agents.

Salicylate levels were measured by the fluorescence polarization technique (Abbott TDX system) or spectrophotometrically (Sigma). Serum levels of TNF-[alpha], IL-1[beta], and IL-6 were measured by commercially available ELISAs (R&D Systems, Minneapolis). When normal sera were assessed with these assays, the average values for TNF-[alpha] and IL-1[beta] were 11.4 and 0.0 pg/ml, respectively. The maximum values found in normal sera were 25.8 pg/ml for TNF-[alpha] and 1.65 pg/ml for IL-1[beta]; IL-6 was detected in only 4 percent of normal sera, and the maximum value was 110 pg/ml (package insert, R&D Systems).

Case Reports

The clinical features at presentation and during the subsequent hospital course were similar in all five cases. Cardinal clinical and laboratory data are summarized in Table 1.

Case 1

A 50-year-old woman was admitted to the hospital because of progressive breathlessness during the previous 12 h. She was taking no prescribed medications. At the time of admission, the combination of fever, leukocytosis, and bilateral alveolar infiltrates evidenced on the chest roentgenogram led to a diagnosis of acute bacterial pneumonia. Blood cultures were obtained and cefotaxime was prescribed. The presence of mixed respiratory alkalosis and metabolic acidosis with an increased anion gap was not commented on by the admitting physician. A serum lactate value determined in the Emergency Department was 1.2 mmol/L (normal, < 2.0 mmol/L). The patient became progressively confused during the first 8 h in the hospital. During this time, she also developed increasing respiratory distress and hypotension, and mechanical ventilation was begun. At the time of initial consultation, 14 h after admission, the patient was found to be obtunded, hypotensive, and oliguric. Empiric intravenous crystalloid was given while a pulmonary artery catheter was inserted. After 2 L of a sodium chloride solution had been given, the wedge pressure was 7 mm Hg and low SVR was documented. Dopamine was given for hypotension. Sepsis was suspected, but review of the initial laboratory data showed an increased anion gap with a normal serum lactate value. This led to measurement of serum salicylate. The salicylate concentration was 3.9 mmol/L. Sodium bicarbonate was given to keep the serum pH above 7.45. Urgent hemodialysis was employed to eliminate salicylate. A prolonged PT was normalized with vitamin K administration. After discussion with family members, an acute intentional salicylate overdose seemed unlikely; the family was unaware that she had used aspirin on more than an occasional basis.

The patient's hospital course was complicated by severe ARDS and renal failure. She remained febrile and ceftazidime was given, although it was believed that persistent fever was possibly due to the initial salicylate poisoning. All cultures drawn on the first hospital day remained sterile. By day 4, she had developed severe thrombocytopenia (10 X [10.sup.9]/L). There was marked elevation in serum FDPs and mild prolongation of the PT and PTT. The fibrinogen was normal. A peripheral blood smear showed no microangiopathy. These changes were believed to be due to DIC. On day 6, she developed new right-sided weakness, and a CT scan showed an internal capsul infact.

The patient gradually improved. After a period of rehabilitation, mild right upper extremity weakness was the only residual abnormality from her illness. Once she recovered, the patient stated that she had consumed aspirin on a daily basis for several months prior to her illness because of chronic postsurgical foot pain.

Case 2

A 65-year-old woman with long-standing seropositive rheumatoid arthritis and pulmonary fibrosis was hospitalized because of the recent onset of increased breathlessness and confusion. Prescribed medications included aspirin, 325 mg (12 per day); methylprednisolone, 600 mg intravenously every week; and and monthly gold injections. At the time of hospital admission she was febrile, tachypneic, and confused. A chest roentgenogram showed bilateral interstitial-alveolar infiltrates and significant changes from the baseline film, which had demonstrated a honeycomb lung. A presumptive diagnosis of acute bacterial pneumonia was based on the presence of fever, leukocytosis with increased band forms, and the new infiltrates seen on the chest roentgenogram. The patient produced no sputum, but blood cultures were obtained and cefoxitin, gentamicin, tri-methoprim-sulfamethoxazole, and erythromycin were prescribed. Methylprednisolone (20 mg given intravenously every 6 h) and intravenously administered vitakin K (5 mg) also were prescribed. The latter was given because of a prolonged PT (18.6 s).

On the first hosital day, the patient became hypotensive and obtunded. Due to increasing respiratory distress and hypoxemia, the patient was placed on mechanical ventilation. A CT scan of the head and lumbar puncture were normal. A stain of secretions suctioned through the endotracheal tube showed no organisms. A grand mal seizure was observed, and diphenylhydantoin was prescribed. A pulmonary artery catheter was inserted. The initial wedge pressure was 30 mm Hg, but subsequent values were less than 18 mm Hg despite persistent oliguria. (The inial elevated value may have been in error or was perhaps due to transient myocardial ischemia.) Hypotension with a reduced SVR, together with the presence of fever, leukocytosis, ARDS, encephalopathy, and renal failure, supported a clinical diagnosis of overwhelming bacterial sepsis. Dopamine was required to manage hypotension. Broad-spectrum antibiotics were continued, but all cultures of blood, sputum, and urine proved sterile. Organ failure persisted, and on day 3 the patient was transferred to our institution for hemodialysis.

At the time of transfer, the patient was obtunded and severely ill with failure of multiple organs. The initial working diagnosis was nonbacteremic clinical sepsis, most likely of pulmonary origin. Bronchoscopy with lavage detected no pathogens. Coagulation studies drawn at the time of transfer included a PT of 15.4s (normal, 9.5 to 12 s); a PTT of 36.9 s (normal, 23.0 to 34.0 s); and a TT of 37.9 s (normal, 13.0 to 20.0 s). The platelet count was 116 X [10.sup.9]/L. Vitamin K and fresh-frozen plasma were given. Over the next two days, the platelet count fell to 11 X [10.sup.9]/L. Numerous fragmented red blood cells were seen on a peripheral blood smear, indicating a microangiopathic hemolytic process. At this time the fibrinogen level was 1.6 g/L (normal, 1.5 to 3.6 g/L); PT, 12.3 s; PTT, 26.1 s; and TT, 34.0 s. Serum FDPs could not be measured due to the presence of rheumatoid factor. The coagulation profile was believed to be consistent with DIC, but given the combination of fever, encephalopathy, ARDS, and renal failure, it was elected to perform empiric plasma exchange because of the possibility that TTP was responsible for these clinical features. There was no apparent benefit from this procedure. The patient died on day 16. An autopsy did not reveal a source for her apparent overwhelming sepsis, nor was there pathologic evidence to support a diagnosis of TTP. The lungs did contain focal areas of pneumonitis. Initially, it was believed that pulmonary abscesses might be present, but further review revealed that the observed changes represented preexisting cystic spaces from her honeycomb lung. All stains and cultures were negative for microorganisms. During the latter part of the patient's illness, the possibility of occult salicylate intoxication had been entertained. The referring hospital laboratory was able to retrieve a serum sample obtained at the time of admission; the salycylate concentration in this sample was 4.7 mmol/L.

Case 3

A 58-year old man presented to the Emergency Department with a complaint of progessive dyspnea during the previous 8 to 12 h. He was taking no prescribed medications. The patient produced no sputum, but the presence of fever, mild leukocytosis with increased band forms, and a chest roentgenogram that revealed bilateral infiltrates led to a presumptive diagnosis of pneumonia. On examination in the hospital, the patient was febrile, tachypneic, and confused. Several hours after admission, the patient had a grand mal seizure. This was attributed to alcohol withdrawal because the patient had a past history of alcohol abuse. A CT scan of the head and lumbar puncture disclosed no abnormalities. During the first hospital day, the patient developed progressive hypoxemia and required mechanical ventilation. A pulmonary artery catheter was inserted, revealing a wedge pressure of 12 mm Hg and a low SVR. The patient was not hypotensive. The working diagnosis was pneumonia, and broad-spectrum antibiotics, begun after cultures had been obtained at the time of admission, were continued. During the next several days, the patient had persistent ARDS and developed oliguric renal failure. Bronchoscopy with lavage failed to detect any pathogens. Dialysis was required for renal failure.

The patient had normal coagulation studies at the time of admission with the exception of a mildly prolonged PT (13.4 s). By day 4, he had developed marked thrombocytopenia (26 X [10.sup.9]/L) and had severe microangiopathic abnormalities of red blood cells seen on peripheral smear. The PT, PTT, and fibrinogen values at this time were normal, but serum FDPs were markedly increased and the TT was prolonged. This developed, together with the presence of fever, neurologic changes, renal failure, and ARDS, led to consideration of a diagnosis of TTP, and empiric plasma exchange was performed. It could not be determined that plasma exchange was of benefit. A kidney biopsy done on day 18 showed acute tubular necrosis. A repeat bronchoscopy with transbroncial lung biopsy on day 18 showed only interstitial fibrosis. A bone marrow biopsy revealed no pathogens, bud did show a fibrin thrombus in a small vessel. The patient gradually improved and fully recovery respiratory and neurologic function. Persistent renal failure required permanent dialysis. All cultures obtained during the hospitalization remained sterile. A family member provided the history on day 6 that the patient had not consumed alcohol for over a year, but that he had consumed large amounts of aspirin on a daily basis for several months because of chronic low-back pain. The hospital laboratory could not retrieve a serum sample from the time of admission. A sample drawn 24 h after admission had a salicylate concentration of 1.8 mmol/L, a value that would predict an admission salicylate level well within the toxic range ( > 2.2 mmol/L), given that the patient had normal renal function during the initial 24 h.

Case 4

A 40-year-old woman was seen in the Emergency Department with complaints of dyspnea and confusion. She had a past medical history that was significant for previous suicide attempts. On examination she was diaphoretic, agitated, and tachypneic. A chest roentgenogram showed bilateral symmetric alveolar infiltrates. Endotracheal intubation was performed and mechanical ventilation was instituted because of severe respiratory distress. The salicylate level was found to be 4.7 mmol/L. The patient was admitted with a diagnosis of salicylate intoxication. A companion did not believe that she had attempted suicide, but stated that she had been ingesting a large amount of aspirin on a daily basis for several weeks because of shoulder pain. Hemodialysis was begun within 1 h of admission to the intensive care unit, resulting in a postdialysis salicylate level of 0.4 mmol/L. Several hours after admission the patient became hypotensive and a dopamine infusion, 16 [micrograms/kg/min, was given. A pulmonary artery catheter was inserted. The pulmonary capillary wedge pressure was 16 mm Hg and reduced SVR was documented. Hypoxemia worsened and PEEP of 20 cm [H.sub.2.O] was required to maintain the [Po.sub.2] greater than 50 mm Hg on an FIo.sub.2] of 1.0. During the next 48 h the patient's cardiorespiratory status and mental status improved. Hypotension resolved, but a hyperdynamic hemodynamic state persisted. The mixed venous oxygen saturation was 70 percent and oxygen consumption calculated by the Fick method was 5.0 ml/kg/min (normal, 3.3 ml/kg/min). Persistent fever and leukocytosis led to continuation of broadspectrum antibiotic therapy that had been initiated soon after admission. Multiple cultures of blood, urine, and sputum were sterile. On day 3 the patient became oliguric, and the serum creatinine level had increased from 88 to 256 mmol/L. At this time there was laboratory evidence for DIC, including a platelet count of 29 X [10.sup.9]/L, markedly elevated FDPs in serum, and prolongation of the TT to 34.0 s (normal, 13.0 to 20.0 s). A peripheral blood smear showed no evidence of microangiopathy. The hemoglobin level had fallen by 50 g/L to a value of 86 g/L, and packed red blood cells were given. The patient developed rapidly worsening hypoxemia, leading to cardiac arrest and death. Postmortem examination revealed no evidence of infection at any site, including the lungs. Glomeruli contained abundant fibrin, and sterile vegetations were seen on the mitral valve. Both of these findings were interpreted as being due to fulminant DIC. Serum obtained at the time of admission and daily thereafter contained no detectable TNF-[alpha] or IL-1[beta]. However, serum IL-6 was markedly elevated at 813 pg/ml on admission and was still detectable at lower levels on days 2 to 4 (44, 182, and 58 pg/ml, respectively).

Case 5

A 68-year-old woman presented to her local hospital with complaints of severe dyspnea and dizziness. Past history included hypertension, atrial fibrillation, and osteoarthritis for which she took aspirin. At initial evaluation she was found to be febrile and was described as being drowsy and very breathless. Soon after admission to the hospital she was intubated and placed on mechanical ventilation because of progressive, severe respiratory distress. Examination revealed bilateral crackles. Neurologic status at this time was difficult to assess because intravenous sedation had been given following intubation. A chest roentgenogram showed minimal symmetric perihilar infiltrates. Laboratory studies included a normal white blood cell count with a marked increase in the number of bands, a mixed metabolic acidosis and respiratory alkalosis with a normal anion gap, an increase in the PT and PTT, and a serum creatinine value of 195 mmol/L. The presumptive diagnosis was sepsis of uncertain cause. Cultures of blod, urine, endotracheal tube secretions, and cerebrospinal fluid were obtained, and broadspectrum antibiotics were administered. During the first hospital day a pulmonary artery catheter was inserted because of hypotension that was unresponsive to volume infusion. Hemodynamic data recorded after volume infusion and while the patient received intravenously administered dopamine at 15 [micrograms]/kg/min revealed a wedge pressure of 16 mm Hg and a reduced SVR. Over the next few days the hemodynamic status improved, permitting discontinuation of dopamine. The temperature returned to normal, but no source for her apparent sepsis was identified. By day 4 the platelet count was 44 X [10.sup.9]/L, and the coagulation profile was consistent with DIC. She was transferred to our institution on day 5 for further evaluation and because of worsening renal function that might require dialysis. Because of our prior experience with patients 1 to 4 and the patient's prior history of salicylate use, the possibility of chronic salicylate intoxication was considered. A salicylate level at this time was .4 mmol/L. The referring hospital was contacted, and a serum sample obtained 12 h after initial admission was retrieved. The serum salicylate level in this sample was 3.7 mmol/L. The patient eventually recovered fully without the need for dialysis. All cultures proved to be sterile, and the entire clinical picture was believed to be secondary to salicylate intoxication. Serum obtained on the day of admission had no detectable IL-1[beta]. However, TNF-[alpha] was elevated at 215 pg/ml, and IL-6 was elevated at 7,100 pg/ml. None of these three cytokines was detected in serum obtained two, three, and five days after admission.

Discussion

Acute and chronic salicylate intoxication differ in several important respects. Acute intoxication typically results from intentional overdose by a young adult in a suicide attempt or through accidental poisoning by a child. This type of intoxication is usually recognized promptly, and the prognosis is directly related to the amount of drug ingested and the serum salicylate level. [5] The mortality and major morbidity associated with acute salicylate intoxication are ver low. [6] In contrast, chronic salicylate intoxication typically occurs in older adults who are taking aspirin as prescribed for a chronic inflammatory condition or as self-medication for chronic pain. [6] Chronic intoxication is associated with significant mortality and major morbidity, and the severity of illness does not bear a close relationship to the salicylate level.

One factor that may contribute to the severity of chronic salicylate intoxication is that diagnosis often is delayed. Anderson and associates [6] reviewed 73 salicylate-intoxicated adults and assessed eventual outcome in those diagnosed on admission as compared with those who were diagnosed 60 to 72 h after admission. Those patients who were diagnosed on admission had uniformly become intoxicated by intentional overdose and had a low rate of mortality (2

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percent) and major morbidity (16 percent). Patients who were diagnosed late were typically older individuals who had become intoxicated accidentally while ingesting salicylates on a chronic basis. The mortality (25 percent) and incidence of major complications (30 percent) in the latter group were considerable. [6]

Chronically intoxicated patients often do not offer a history of salicylate ingestion, and diagnosis therefore depends on the physician's ability to recognize pertinent clinical and laboratory manifestations of salicylate overdose. The importance of considering occult salicylate intoxication in the differential diagnosis of unexplained encephalopathy, permeability pulmonary edema, and certain acid-base disturbances previously has been emphasized. [6] In this article we have described an additional presentation of chronic salicylate intoxication. In the case described, the combination of fever, leukocytosis, a leftward shift in the differential cell count, hypotension, low SVR, and failure of multiple organ systems was highly suggestive of overwhelming bacterial sepsis (Table 2). However, infection could not be documented in any of our cases. We believe that chronic salicylate intoxication is the only logical explanation for the fulminant illnesses observed.

Certain aspects of our patients' illnesses are recognized features of salicylate intoxication. Fever, encephalopathy, acid-base disturbances, ARDS, and a prolonged PT are well-known complications of salicylate intoxication. [5-11] However, other prominent features that were observed have not been previously emphasized in reports of salicylate intoxication. These latter features included leukocytosis, leftward shift in the differential cell count, hypotension with a reduced SVR, and DIC.

A prominent and misleading feature in each of our cases was the presence of a reduced SVR. In four cases arterial vasodilation led to hypotension (mean arterial pressure less than 70 mm Hg despite infusion of dopamine at 7 to 15 [micgrograms]/kg/min). Hypotension with a reduced SVR is typical of septic shock, but is certainly not specific for sepsis. [12] This hemodynamic pattern has been previously documented in a single case of salicylate intoxication. [13] The mechanism of hyperdynamic shock during salicylate intoxication is not understood. Following our experience with patients 1 to 3, we had hypothesized that salicylate intoxication might have led to release of cytokines that would in turn be responsible for hemodynamic alterations and organ system failure. [14-16] In two subsequent cases (patients 4 and 5) we had the opportunity to determine whether certain cytokines (TNF-[alpha], IL-1[beta], IL-6) were detectable in serum at the time of salicylate intoxication. Neither patient had detectable levels of IL-1[beta] in serum. Patient 5 had markedly increased levels of both TNF-[alpha] and IL-6. Patient 4 also had very high levels of IL-6 in serum, but TNF-[alpha] was not detected. A role for TNF-[alpha] as a crucial mediator of shock and tissue injury in bacterial sepsis has been convincingly demonstrated in animal models. [14-15] Increased levels of TNF-[alpha] also have been demonstrated in serum obtained from humans with septic shock. [16] A pathogenetic role for IL-6 in sepsis is less well established. Increases in serum IL-6 have been found in both Gram-positive and Gram-negative sepsis, and when markedly elevated are highly predictive of a fatal outcome. [17] It is not clear, however, whether IL-6 is truly a proinflammatory mediator of tissue injury in sepsis or is merely an "alarm hormone" that reflects severe endothelial injury. [17] The relationship between the cytokines TNF-[alpha] and IL-6 and the salicylate-induced "sepsis syndrome" is uncertain.

Coagulation abnormalities observed in our patients were biphasic. Initially, the PT was prolonged, but the platelet count was normal. The prolonged PT responded to vitakin K infusion. This is consistent with the known inhibitory effects of salicylate intoxication on synthesis of vitakin K-dependent factors. [5] Subsequently, each patient developed laboratory evidence of DIC. the most prominent laboratory manifestation of DIC was severe thrombocytopenia, with nadir platelet counts ranging from 10 to 44 X [10.sup.9]/L. Neither thrombocytopenia nor DIC has been mentioned in most reviews of salicylate intoxication. [5,6,9] However, in a large Danish series both thrombocytopenia and DIC were listed as occasional complications of severe salicylate poisoning. [8] In one case (patient 4) the finding at autopsy of widespread fibrin deposition in glomeruli suggested that DIC could have played a contributory role to organ injury.

In summary, we have reported five cases of a sepsis-like syndrome due to chronic salicylate intoxication. Features of this syndrome included fever, leukocytosis, a leftward shift in the differential cell count, hypotension, reduced SVR, and multiple organ system failure (ARDS, acute renal failure, coagulopathy, and encephalopathy). Occult salicylate intoxication should be considered in the differential diagnosis of sepsis syndrome of uncertain origin.

(*) From the Department of Medicine, Pulmonary Division (Dr. Leatherman) and Nephrology Divison (Dr. Schmitz), Hennepin County Medical Center and University of Minnesota Medical School (Dr. Leatherman), Minneapolis.

Manuscript received February 7; revision accepted May 8.

Reprint requests: Dr. Leatherman, Department of Medicine, Hennepin County Medical Center, Minneapolis 55415

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