HYPOTENSION, RENAL FAILURE, AND PULMONARY COMPLICATIONS IN LEPTOSPIROSIS

Abstract

During a recent outbreak of leptospirosis in northeastern Thailand, 148 patients with serologically diagnosed leptospirosis were seen in Loei hospital. The common serotypes were L. pyrogenes, and L. sejroe. Hypotension with a mean arterial pressure less than 70 mm Hg upon admission or within 24 h after admission was observed in 94 patients or 64%. 30 patients had normal renal function; 30 patients had prerenal azotemia with mild pulmonary complication in 2; and 34 patients had acute renal failure. 29 patients with acute renal failure had pulmonary complications including pulmonary hemorrhage in 8, pulmonary edema in 3, acute respiratory distress syndrome (ARDS) in 14 and interstitial pneumonitis in 4. 54 patients had normal blood pressure. In this group 5 patients had acute renal failure; 16 had prerenal azotemia and 33 had normal renal function. Interstitial pneumonitis was noted in one patient with prerenal azotemia. Less renal complication and minimal pulmonary complication were seen in leptospirosis patients with normal blood pressure. The patients with normal renal function had no pulmonary complication. Good association existed between hypotension, renal failure and pulmonary complications.

• Leptospirosis
• Hypotension
• Renal failure
• Pulmonary complications

INTRODUCTION

Leptospirosis is a common infectious disease in the tropics. The disease is characterized by fever with chills, myalgia and conjunctival injection. Renal failure, jaundice and pulmonary complications are seen when the disease is severe. Although hypotension can be observed in leptospirosis, it is mild and not a common finding.[[1]] During a recent outbreak of leptospirosis in northeastern Thailand hypotension of a significant degree early in the course of the disease was frequently observed. Its common association with renal failure and pulmonary complication is of clinical interest and deserves attention.

PATIENTS AND METHODS

From January 1999 to August 31, 2000, 148 patients with serologically diagnosed leptospirosis were admitted in Loei hospital 1 day to 14 days, averaging 4 days, after the onset of fever. The common serotypes were L. pyrogenes and L. sejroe. The other serotypes included bratislava, pomona, copenhageni, javanica, ballico, bangkok, wollfi and akiyami. 107 were male and 41 were female ranging in age from 8 to 76 averaging 36 years. The patients were farmers and fishermen.

Penicillin was given intravenously at a dose of 2,000,000 units every 6 h for 7 days. Ceftriaxone (2 g/day) was given if there was evidence of associated sepsis. The patients with hypotension (mean arterial pressure <70 mm Hg) received normal saline load with close observation of blood pressure, lung signs, the central venous pressure and the urine flow. If there was no rise in blood pressure and urine flow within 2 h dopamine (2 µg/kg/min) was started. Furosemide (40–120 mg) was given intravenously if the urine flow remained low despite correction of hypotension.

In the patient with pulmonary complication, acute respiratory distress syndrome (ARDS), pulmonary edema or hemorrhage intubation and ventilatory support, using positive end-expiratory pressure with 100% oxygen and pressure of 10 cm water, were instituted. Platelet transfusion was given to those with pulmonary hemorrhage and severe thrombocytopenia (platelets <50 000/mm³). Fluid intake was restricted in the patient with ARDS and pulmonary edema.

Either hemodialysis or peritoneal dialysis was performed in the patient with oliguric renal failure. In addition to dialysis, blood exchange (1.5 blood volume) was instituted in the patient with pulmonary complication or hyperbilirubinemia (total bilirubin >25 mg/dL).

Tumor necrosis factor alpha (TNFα) in the serum was determined by the enzyme-linked immunosorbent assay (Cytoscreen, Biosource International, Camarillo, CA) in 28 patients.

RESULTS

Clinical Data

More than 60% of the patients had fever, headache, myalgia, conjunctival suffusion and hypotension (mean arterial pressure <70 mm Hg). Decreased renal function (serum creatinine >1.5 mg/dL) was noted in 57% of the patients; jaundice in 41%; pulmonary complications in 22%; nausea and vomiting, 20%; abdominal pain, 12%; and diarrhea, 5%.

Hyperbilirubinemia (total serum bilirubin >25 mg/dL) was observed in 21 patients (14%); thrombocytopenia (platelet count <100 000/mm³) in 61 (41)%; hyponatremia (Na<125 mmol/L) in 13 (9%); hyperkalemia (K>5 mmol/L) in 9 (6)%; hypokalemia (K<3.5 mmol/L) in 38 (26%); and BUN/creatinine ratio>15 in 121 (82%). Mild proteinuria (trace to 1+) with red blood cells and white blood cells was observed in 61% of the patients. Relevant clinical data are shown in Table 1.

Table 1. Renal and Pulmonary Complications in Hypotensive and Normotensive Patients

	Normal Renal Function		Prerenal Azotemia		Acute Renal Failure
	HT (N = 30)	NT (N = 33)	HT (N = 30)	NT (N = 16)	HT (N = 34)	NT (N = 5)
Serum creatinine (mg/dL) on admission	0.9 ± 0.1	1.0 ± 0.1	3.0 ± 0.9	2.9 ± 0.9	8.2 ± 2.7	4.9 ± 1.7
Response to fluid load/dopamine
Blood pressure	↑		↑		↑
Urine flow	↑		↑
Pulmonary hemorrhage	0	0	1	0	8	0
Pulmonary edema	0	0	0	0	3	0
ARDS	0	0	0	0	14	0
Pneumonitis	0	0	1	1	4	0
TNFα (pg/mL)	12.8 ± 4.9	10.3 ± 2.6	172.6 ± 56.7	50.7 ± 13.2	677.8 ± 210.8	214.3 ± 84.5
Admission after onset (day)	2.8 ± 1.1	2.7 ± 1.1	3.2 ± 1.2	3.1 ± 1.2	4.4 ± 1.5	4.4 ± 1.4

HT: hypotension; NT: normotension.

Hypotension

94 patients or 64% had hypotension upon admission or within 24 h after admission. Hypotension was not specific for any serotype of leptospires. Among 94 hypotensive patients response to intravenous fluid either with or without dopamine with restoration of blood pressure, good urine flow and improved renal function was noted in 60 patients. Restoration of blood pressure but with impaired renal function, labeled as acute renal failure, was seen in 34 patients or 36% (Table 1). Pulmonary complications occurred in 31 patients (33%) with hypotension; 29 were associated with acute renal failure. Interestingly, most patients were clinically alert despite hypotension. The patients with hypotension had higher serum TNFα than normotensive patients (Table 1).

Renal Dysfunction

Decreased renal function with the serum creatinine level above 1.5 mg/dL was noted in 85 patients (57%). 64 patients were hypotensive and 21 were normotensive. 39 patients had acute renal failure, and 46 patients had prerenal azotemia (Table 1). 54 patients had normal blood pressure. In this group 5 patients had acute renal failure; 16 had prerenal azotemia and 33 had normal renal function.

Prerenal Azotemia

There were 46 patients with prerenal azotemia. The patients entered the hospital 3 days by average after the onset of fever. 30 patients were hypotensive on admission (Table 1); 16 were normotensive. The mean serum creatinine was 3.0 mg/dL and the mean BUN was 60 mg/dL. 28 patients were icteric while 18 patients were nonicteric. The urine specific gravity averaged 1.019. Response to intravenous fluid therapy was good with increased urine flow. The serum creatinine was decreased to less than 1.3 mg/dL within 48 h. Interstitial pneumonitis diagnosed by chest X-ray was observed in 2 patients; another patient had mild pulmonary hemorrhage (Table 1). The mean clinical course averaged 5 days.

Acute Renal Failure

39 patients had acute renal failure. They entered the hospital 2–7 days (averaging 4 days) after the onset of fever. 34 patients had hypotension upon admission; 5 were normotensive. The mean serum creatinine was 6.5 mg/dL; the mean BUN was 89 mg/dL. The urine specific gravity averaged 1.012. Renal failure was catabolic, and 50% were oliguric. 13 patients were nonicteric, and 26 were icteric. 20 patients were hyperbilirubinemic; the serum creatinine and BUN were higher in icteric leptospirosis than the nonicteric group. Pulmonary complications were common in the patients with renal failure. 29 patients had pulmonary complications including pulmonary hemorrhage in 8 patients, pulmonary edema in 3, ARDS in 14 and interstitial pneumonitis in 4. They were hypotensive upon admission (Table 1), 26 had thrombocytopenia. The duration of renal failure ranged from 4 to 40 days with a mean of 12 days.

Good association existed between hypotension, renal failure and pulmonary complications (Table 1). It started from hypotension followed by renal failure and pulmonary involvement. There was good positive correlation between the serum TNFα level and severity of the disease. Highest levels of serum TNFα were seen in the patients with renal failure and pulmonary complication.

Outcome

Recovery was complete in 143 patients. 5 patients died giving the mortality rate of 3.4%. The age varied from 42 to 70 years averaging 55 years. 3 died of pulmonary hemorrhage and severe thrombocytopenia (2 with renal failure); one had ARDS and one had pneumonia and septicemia. Both patients had renal failure and hyperbilirubinemia. Of the total 42 complicated patients consisting of 10 patients with only acute renal failure, 3 with only pulmonary complications and 29 with both renal failure and pulmonary involvement the mortality was 11.9%. Blood exchange performed in 9 patients gave dramatic clinical improvement. Of these 9 patients 5 had acute renal failure with ARDS; 3 had hyperbilirubinemic renal failure and one had acute renal failure with pulmonary hemorrhage. The serum TNFα level dropped from 412 ± 102 pg/mL to 92 ± 24 pg/mL.

DISCUSSION

Mild hypotension at subclinical level during the early phase of infectious disease including leptospirosis is not unusual. This is attributed to decreased systemic vascular resistance induced by vasodilating cytokines and mediators.[[2]], [[3]], [[4]] The vascular capacitance is increased while the renal blood flow is diminished. Significant hypotension, however, is not a common presentation of leptospirosis.[[1]] In this report hypotension with a mean arterial pressure less than 70 mm Hg upon admission or within 24 h after admission was observed in 94 patients or 64%. 60 patients responded to intravenous fluid administration with or without dopamine with increased blood pressure and urine flow. 30 patients in this group were presumed to have normal renal function based on normal serum creatinine; 30 patients had prerenal azotemia with mild pulmonary complication in 2 (Table 1). 34 patients had acute renal failure. The occurrence of acute renal failure was less in the patients with normal blood pressure. 29 patients with acute renal failure had pulmonary complications. Only 3 patients with prerenal azotemia had pulmonary involvement (Table 1). No complication was noted in the patients with normal renal function. There was good correlation between the serum TNFα levels and severity of the disease being in agreement with the findings in previous reports.[[5]], [[6]], [[7]] The highest levels of serum TNFα were seen in the patients with renal failure especially those with pulmonary complications. The patients with complications were admitted later after the initial symptom than those without complications (Table 1). Less renal complication and minimal pulmonary complication were seen in leptospirosis patients with normal blood pressure.

The high prevalence of hypotension could be related to the high bacterial virulence or the high bacterial load. The serum levels of TNFα were much higher than those ever reported.[[5]], [[6]] Interestingly, complications occurred in sequential order starting from hypotension followed by renal failure and pulmonary involvement. This triad of hypotension, renal failure and pulmonary complications deserves clinical attention. Although cellular injury in leptospirosis is due to the combination of hemodynamic factors, immunologic mechanism and direct cellular injury,[[1]], [[2]], [[8]], [[9]], [[10]] hemodynamic alteration seems to play an initiating role. Hypotension and renal failure led to pulmonary complication. Since renal and pulmonary complications often carry bad prognosis,[[11]], [[12]], [[13]] early stabilization of hemodynamics should be implemented. Shear stress in known to modulate adhesion molecule expression and shear stress bears good relationship with hemodynamics.[[14]], [[15]] Alterations of hemodynamics and shear stress may potentiate toxicity of bacterial products in causing renal and pulmonary injury through cytokines and mediators.[[8]], [[9]], [[10]], [[16]], [[17]] Further study in this area is warranted.

The management of severe leptospirosis with pulmonary involvement requires hemodynamic and ventilatory supports. Continuous venovenous hemofiltration (CVVH) which decreases circulating cytokines and mediators can be used.[[18]] Nitric oxide and CVVH have been reported to be useful in the treatment of pulmonary hemorrhage in leptospirosis.[[19]] These technologies are, however, costly and not available in the rural areas. Based on the principle of removing bacterial products, cytokines, chemokines, mediators, bilirubin and bile acids blood exchange can be performed at a less cost.[[20]], [[21]] The previous study has shown improvement of systemic and renal hemodynamics by blood exchange. In severe leptospirosis plasmapheresis increased the cardiac output and improved the renal blood flow and the glomerular filtration rate.[[22]] Clinical results have been encouraging. The overall mortality was 3.4% and the mortality among severe and complicated cases was 11.9% compared favorably with other reports in which the overall mortality ranged from 5 to 19%, and the mortality in complicated cases varied from 17 to 36%.[[11]], [[12]], [[13]] On the ground of low socioeconomy blood exchange or plasmapheresis should be considered as an adjunctive treatment of severe leptospirosis especially in the patient with pulmonary complications or hyperbilirubinemia.

ACKNOWLEDGMENT

The authors acknowledge the secretarial help of Miss Yuppayao Chiemrungsun.