Terlipressin

Massive hemoptysis in patients with severe leptospirosis is often resistant to conventional therapies and can rapidly become fatal. Desmopressin is a fast-acting blood-saving agent used in various hereditary and acquired clotting disorders. We used desmopressin infusions to treat massive pulmonary hemorrhage in six leptospirosis patients with respiratory failure, shock, and multiple organ dysfunction. Hemoptysis ceased rapidly in every case, and five patients finally recovered. Two additional patients with less severe hemoptysis were also successfully treated.

Keywords: Weil's disease; respiratory distress syndrome, hemorrhage; hemostatics; receptors, vasopressin

The severe forms of leptospirosis usually combine septic shock, hepatorenal dysfunction, rhabdomyolysis, and bleeding frequently exacerbated by thrombocytopenia. Recent outbreaks of pulmonary forms have drawn attention, mainly in tropical countries (1), and respiratory distress or hemoptysis emerge here as lethal complications. In India, the fatality rate of complicated pulmonary forms reached 43% (2). In Brazil, 55% of patients mechanically ventilated for acute lung injury died (3). In Seychelles (4), Thailand (5), and Argentina (6), rapidly progressive pulmonary hemorrhage was the main cause of death. Hemoptysis originates in alveolar hemorrhage, whose primary cause is diffuse vasculitis with endothelial damage in the septal capillary bed, leading to alveolar flooding and asphyxiation (7, 8). The lesions are widespread and cannot be cured by surgery or embolization. In such patients with pulmonary hemorrhage, acute respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction, the priorities are to stop alveolar bleeding, restore gas exchanges, and provide hemodynamic support.

Platelet transfusions contribute to controlling the bleeding but may fail. Vasopressin was formerly used to treat hemoptysis. Vasopressin derivatives such as terlipressin or 1-deamino-8-D-- arginine vasopressin (desmopressin [DDAVP]) (9) that induces less adverse effects have been also used. DDAVP, a selective vasopressin V2 receptor agonist, has been used successfully for more than 25 years to improve hemostatic deficiencies in hereditary disorders such as, mild hemophilia A, Type I von Willebrand disease, platelet disorders, and also in acquired bleeding due to renal failure, hepatic cirrhosis, and drug-induced platelet dysfunction (10). Its effects appear within minutes and last for several hours. Its side effects are known (11) and can be controlled in a monitored environment.

In view of poor outcomes and considering the limited efficacy of conventional therapy, we used DDAVP to contain alveolar bleeding in patients admitted to our intensive care unit for severe leptospirosis and massive pulmonary hemorrhage.

CASE REPORTS

In 2001, 10 patients with leptospirosis were referred to our intensive care unit. The diagnoses were confirmed by using IgM serology and, in three cases, by blood and bronchoalveolar fluid cultures. Six patients, 13 to 34 years of age, had respiratory distress with massive pulmonary hemorrhage. The Simplified Acute Physiology Score II severity score (12) and the Multiple Organ Dysfunction Score (13) were determined on admission (Tables 1 and 2). Chest radiography showed bilateral patchy alveolar infiltrates with condensation. The patients had oligoanuria, and hepatic dysfunction was confirmed by elevated bilirubin or alanine aminotransferase levels. Prothrombin time ratios ranged from 1.0 to 1.2, fibrinogen from 5.3 to 11.9 giL, and partial thromboplastin times were within normal range.

DDAVP was administered 0.3 (mu)g/kg in 30 ml of saline, as a 30-minute infusion. This treatment could be repeated two or three times at 12- or 24-hour intervals when minor bleeding occasionally persisted. The decision to administer DDAVP was based on knowledge of published information regarding mortality in such cases, its use in hemoptysis, and its beneficial and potential side effects. As soon as was allowed by the resuscitation process, informed consent was obtained from the patients or their next of kin.

Apart from antibiotics, other supportive measures included mechanical ventilation with vecuronium-induced neuromuscular block (VT 6.5-9 ml/kg), positive end-expiratory pressure (5-15 cm H^sub 2^O), oxygen supplementation (initial FI^sub o^^sub 2^, 1), and prone position. Hemodynamic support consisted of vascular filling, noradrenaline, and dopamine or dobutamine. On the first day, two patients who had platelet counts below 20 x 10^sup 9^/L received one platelet concentrate and two patients received nitric oxide that was discontinued, as the pulse oximeter saturation remained unchanged.

Patients 1, 2, and 3 were admitted with acute respiratory distress and were mechanically ventilated within 2 hours of entry in the intensive care unit. Patients 4, 5, and 6 developed rapidly progressive respiratory distress and were ventilated 10, 7, and 20 hours later, respectively. Patient 1 had pulmonary hemorrhage discovered at intubation. Patients 2, 3, 5, and 6 had hemoptysis when they were admitted, and Patient 4 developed hemoptysis 5 hours later (Table 2). The volume of hemoptysis was not measured because in alveolar hemorrhage most of the blood remains trapped in the lungs, and the volume of hemoptysis is not a reliable measure with which to help guide the resuscitation process. Patients 1, 2,3, and 4 received the first DDAVP infusion simultaneously with the initiation of mechanical ventilation. Profuse blood had to be aspirated repeatedly. The ongoing pulmonary bleeding ceased within the next hour. Aspirations were later performed in progressive intervals of 1 to 4 hours, and some blood mixed with secretions was drawn up to 3 days after the acute episode. Patient 4 had recurrent hemoptysis on Day 3 and died the next day of refractory septic shock. Patients 5 and 6 received a first course of DDAVP before intubation. Hemoptysis abated but they nonetheless proceeded to develop acute respiratory distress and required mechanical ventilation (Table 2). At that time aspirations were still bloody but cleared progressively. During treatment with DDAVP, levels of fibrin split products and D-dimers remained below 20 and 2 mg/L, respectively, and fibrin-soluble complexes assays were negative. One patient developed melena the day after admission, but no other bleeding was observed. The patients also presented cardiac, renal, and infectious complications. Patients 4 and 5 developed atrial fibrillation on the day of admission, reduced by amiodarone. The cardiac echography of Patient 4 was normal, and invasive procedures were avoided. Patient 5 also developed hemodynamic failure that was resistant to amines, and a Swan-- Ganz catheter was inserted. The patient's pulmonary-artery wedge pressure, 21 mm Hg, was attributable to leptospirosis myocarditis. No clinical evidence of left atrial hypertension was found in the other patients. Renal function was closely monitored, and oliguria regressed in three patients with appropriate hemodynamic support. The others three patients received furosemide on the first day, but one patient nonetheless required continuous venovenous hemodiafiltration. Nosocomial pulmonary infections developed in three patients who required ventilation support up to 9, 11, and 22 days, respectively. Five of the patients finally recovered, resulting in a mortality rate of 17% (1/6).

During the same period, four other patients were admitted to the intensive care unit for leptospirosis. Two had mild hemoptysis, one of them with 20 x 10^sup 9^ platelets/L and borderline ARDS (Pa^sub o^^sub 2^/FI^sub o^^sub 2^: 202), and the other with 30 x 10^sup 9^ platelets/L and no respiratory distress. Their hemoptysis regressed with two DDAVP infusions. The other two patients had no hemoptysis and did not receive DDAVP. All four patients recovered.

DISCUSSION

Treatments of severe pulmonary hemorrhaging due to leptospirosis are rarely proposed: corticosteroid boluses (14,15) and nitric oxide inhalation (16) have been claimed to be beneficial. In this context, DDAVP displays a range of potentially favorable effects: it triggers the release of endothelial hemostatic factors, shortens prolonged bleeding times, and enhances platelet adhesiveness to injured vessels (10). DDAVP induces von Willebrand factor secretion by activating endothelial cell V2 receptors. Interestingly, these receptors have been recently identified in human lung tissues and cultured human lung microvascular endothelial cells (17). Although pulmonary endothelial V2 receptors may promote local hemostasis, the possible effects of the receptors on interstitial edema associated with ARDS and pulmonary hemorrhage deserves further studies. DDAVP has also proved to be effective in the bleeding associated with hepatic and renal failure (10), and this also supports its use in patients with leptospirosis.

The main side effect of DDAVP is water retention. An intravenous dose of 0.3 (mu)g/kg does not induce significant changes in serum sodium concentration and its antidiuretic effects last for about 24 hours (18). However, if doses are repeated, the risk of water overload and hyponatremia must be considered, especially in patients with renal failure: fluid administration and serum sodium concentration must be strictly controlled.

Another concern about the use of DDAVP in patients with leptospirosis involves aggravating an underlying disseminated intravascular coagulation. DDAVP does not induce platelet aggregation or surface expression of activation-dependent platelet antigens (19). Disseminated intravascular coagulation has been occasionally reported in patients with severe leptospirosis, but other pathologic, ultrastructural, and blood coagulation studies have not shown its occurrence (8, 20). In our patients, daily assays of coagulation in conjunction with clinical observation raised no suspicion of induced or promoted disseminated intravascular coagulation.

DDAVP efficacy is controversial in patients with thrombocytopenia (11), but seven of our eight patients treated with DDAVP had thrombocytopenia and pulmonary hemorrhage ceased after DDAVP infusions. In our patients who were receiving catecholamines, we did not observe the mild fall in diastolic blood pressure attributable to DDAVP. Finally, rare reports of cerebral or myocardial infarction imply its cautious use in elderly patients with atherosclerosis.

The optimal DDAVP schedule in this setting remains to be determined. The daily dosing schedule used here was derived from the use of DDAVP in mild hemophilia or in von Willebrand disease, in which tachyphylaxis occurs after three or four doses. However, in healthy volunteers, the kinetics of platelet adhesiveness stimulated by DDAVP does not match that of Factor VIII and von Willebrand factor release (21). Thus, the protocol may be optimized.

In this series, DDAVP proved to be an effective adjunct to the treatment of massive pulmonary hemorrhage in patients with leptospirosis. Future randomized studies in major centers recruiting additional patients are required to confirm these results and to define the optimal protocol in this setting.

Acknowledgment: The authors thank Coleen Baik and Thomas Gueguen for editing assistance.

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Laurent Pea, Laurent Roda, Veronique Boussaud, and Bernard Lonjon

Critical Care and Clinical Biology Units, Centre Hospitalier Territorial, Papeete, Tahiti

(Received in original form May 22, 2002; accepted in final form December 8, 2002) Correspondence and requests for reprints should be addressed to Laurent Roda, Clinical Biology Unit, Centre Hospitalier Territorial, BP1 640, Papeete, Tahiti, Polynesie Francaise. E-mail: rodal@mail.pf

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