| Abstract|| |
Consensus on management of complicated cases of dengue infection is evolving. Dengue hemorrhagic fever (DHF) occasionally progress to fulminant liver failure with high fatality rate. Inadvertent use of blood products to control massive bleeding in dengue shock syndrome may worsen fluid overload and subsequently the multi-organ dysfunction. We report a case of 37-years-old Sri Lankan man who developed fulminant liver failure and massive bleeding associated with DHF, subsequently recovered completely with supportive measures including administration of N-acetyl cysteine and activated recombinant factor VII. In conclusion, prevention of ischemic injury to liver and adoption of early aggressive supportive measures in complicated cases of dengue hemorrhagic fever is crucial for a favorable outcome. Indications for rFVIIa to arrest uncontrolled internal bleeding and use of NAC in non-acetaminophen-induced acute liver failure in complicated DHF are a platform for discussion.
Keywords: Activated recombinant factor VII, dengue, fulminant hepatic failure, N-acetyl cysteine
|How to cite this article:|
Manoj EM, Ranasinghe G, Ragunathan M. Successful use of N-acetyl cysteine and activated recombinant factor VII in fulminant hepatic failure and massive bleeding secondary to dengue hemorrhagic fever. J Emerg Trauma Shock 2014;7:313-5
|How to cite this URL:|
Manoj EM, Ranasinghe G, Ragunathan M. Successful use of N-acetyl cysteine and activated recombinant factor VII in fulminant hepatic failure and massive bleeding secondary to dengue hemorrhagic fever. J Emerg Trauma Shock [serial online] 2014 [cited 2020 Feb 18];7:313-5. Available from: http://www.onlinejets.org/text.asp?2014/7/4/313/142771
| Introduction|| |
Dengue is an arboviral disease endemic in most of the tropical countries with recurrent epidemics. Although dengue is known to cause hepatic involvement commonly, it only occasionally results in fulminant liver failure (FLF), which has a high mortality.  N-acetyl cysteine (NAC), a precursor of glutathione, is an effective antioxidant scavenging for OH radicals have shown to be effective mainly in acetaminophen and even in non-acetaminophen-induced FLF.  Activated recombinant factor VII (rFVIIa) was initially developed to overcome the limitations of existing treatments for patients with congenital hemophilia and inhibitors. Clinical success in this arena led to experimental use in other coagulopathies as well. To the best of our knowledge, this is the first reported case of dengue hemorrhagic fever complicated by fulminant liver failure and massive hemorrhage successfully managed with NAC and rFVIIa.
| Case Report|| |
A 37-year-old previously healthy man who was a teetotaler admitted with fever, repeated vomiting, body aches, and fatigue for four days. Examination revealed a temperature of 100°F, tachycardia (106/min), normotension, and tachypnea (28/minute). He had a tender hepatomegaly and a right side pleural effusion. There were no signs of meningeal irritation. Investigations showed leukocyte count; 5.1 × 10 9 /L (neutrophils 53%, lymphocytes 41%), and platelets; 60 × 10 9 /L, hemoglobin; 14.1 g/dL with hematocrit of 43.4%, aspartate aminotransferase (AST); 220 U/L, alanine aminotransferase (ALT); 157 U/L on admission. Presumptive diagnosis of DHF was made considering the clinical picture and prevailing outbreak in the country. Close monitoring with replacement of maintenance volume of fluids was started in both oral and intravenous means. During next 36 hours, he had clinical and hematological evidence of ongoing plasma leakage but remained hemodynamically stable. Next day, he was shifted to intensive care unit due to agitation and drowsiness.
Platelet count dropped to less than 10 × 10 9 /L during day 5 and 6 of the illness and subsequently started rising gradually. Transaminases showed a marked rise (AST 12500 U/L and ALT: 2700 U/L) in seventh day of illness with prolongation of prothrombin time of 19.8s (INR; 1.7) activated partial thromboplastin time (89s), and elevated serum bilirubin. Chest X-ray and ultrasonography of abdomen showed bilateral pleural effusions and moderate ascites. Liver failure treatments started with intravenous vitamin K, thiamine, lactulose, and oral metronidazole. In the same day, worsening agitation and sensorium (Grade III hepatic encephalopathy) necessitated elective intubation and mechanical ventilation. Blood sugar was monitored, and his serum sodium levels maintained at 145-150 mmol/l range. An internal jugular central venous access was secured following transfusion of platelets and fresh frozen plasma (FFP). Twenty percent manitol infusion was administered 12 hourly for 48 hours, and NAC intravenous infusion was continued for 72 hours.
He developed massive hematemesis in the day 8 of the illness. Bleeding was difficult to control with transfusion of platelets, fresh frozen plasma, and pack red cells alone. This prompted us to administer him with 3 doses of rFVIIa following transfusion of cryoprecipitate to replenish fibrinogen levels in serum. Thereafter, his hemodynamic status became stable and coagulation parameters were gradually corrected. Patient's central venous pressure started rising (24-29 cmH 2 O) by ninth day with of illness necessitating a considerable dose of frusemide to achieve a safe level of CVP (8-12 cmH 2 O). Serum transaminases gradually came down over next few days [Table 1]. Dengue IgM and IgG (ELISA) were positive, while malarial smear, hepatitis panel, leptospira serology, and HIV ELISA became negative. However, the course of his illness was complicated initially by ventilator-associated pneumonia with Acenetobacter and later by Pseudomonas, necessitating antibiotic cover with Netilmycine and Ceftazidime. He was extubated following 7 days of ventilatory support and managed to be discharged after 18 days of hospital stay.
| Discussion|| |
Dengue hemorrhagic fever is defined as the presence of fever, thrombocytopenia, and evidence of capillary leak with serological evidence of acute infection by dengue virus.  Current management of DHF is mainly focused on meticulous fluid management during leakage phase of the illness. In DHF, an antibody-dependent immune mechanism is in play, by which non-neutralizing antibodies of previous dengue infection complexes with the new infecting serotype enhancing its uptake.  Liver damage is due to viral replication in hepatocytes, cytokine-related damage, and partly due to ischemic hepatitis. ,
Fulminant liver failure is defined as rapid onset of acute encephalopathy and coagulopathy (INR 1.5) in the setting of liver failure less than 6 weeks duration. Since the liver is capable of regenerating to a large extent as underlying cause of hepatocyte injury is controlled with supportive medical therapy, FHF in principle sustains potential for a complete recovery. Fulminant liver failure due to dengue infection with subsequent complete recovery has been reported rarely. ,,, FLF may be associated with changes in systemic hemodynamic, i.e., tissue hypoxia, which contributes to multiple-organ failure. Recent studies have shown that NAC administered to patients with FLF (non-paracetamol-induced) increases oxygen delivery and improves survival. ,
Morbidity and mortality in DHF is mainly associated with either prolonged shock or fluid overload. Activated recombinant factor VII is a coagulation protein that induces hemostasis by directly activating factor X. There were some evidences on safety and efficacy of rFVIIa for controlling hemorrhage in patients without hemophilia. ,,, Since inadvertent administration of blood products would worsen the fluid overload in DHF, the place for rFVIIa seems to be invaluable to arrest life-threatening bleeding as in our patient. So far, there was no clear information about the prophylactic or therapeutic use of rFVIIa in DHF. The use of NAC and rFVIIa despite limited evidence presumably had a greater impact on recovery of our patient. Therefore, this case highlights the potential use of rFVIIa and NAC along with aggressive supportive measures in cases of near-fatal DHF for a successful outcome.
| Conclusion|| |
Prevention of ischemic injury of liver by meticulous fluid resuscitation during the leakage phase of dengue fever is of paramount importance. Dengue may occasionally lead to FLF, has to be treated promptly with aggressive supportive measures. Indication of rFVIIa to arrest uncontrolled internal bleeding and the place of NAC in non-acetaminophen-induced FLF in complicated DHF is a platform for discussion.
| References|| |
Ling LM, Smith AW, Leo YS. Fulminant hepatitis in dengue hemorrhagic fever. J Clin Virol 2007;38:265-8.
Ben AZ, Vaknin H, Kaspa RT. N-acetylcysteine in acute hepatic failure (non-paracetamol-induced). Hepatogastroenterology 2000;47:786-9.
Meltzer E, Schwartz E. A travel medicine view of dengue and dengue hemorrhagic fever. Travel Med Infect Dis 2009;7:278-83.
Seneviratne SL, Malavige GN, De Silva HJ. Pathogenesis of liver involvement during dengue viral infections. Trans R Soc Trop Med Hyg 2006;100:608-14.
Gulati S, Maheshwari A. Atypical manifestations of dengue. Trop Med Int Health 2007;12:1087-95.
Wijeweera SC, Senevirathna K, Ragunathan MK. A case of fulminant liver failure in dengue haemorrhagic fever. Galle Med J 2009;14:1-2.
Gasperino J, Yunen J, Guh A, Tanaka KE, Kvetan V, Doyle H. Fulminant liver failure secondary to haemorrhagic dengue in aninternational traveller. Liver Int. 2007;27:1148-51.
Subhash G, Agrawal MP, Sharma V, Singh A. Acute hepatic failure due to dengue: A case report. Cases J 2008;1:202-4.
Subramanian V, Shenoy S, Joseph AJ. Dengue hemorrhagic fever and fulminant hepatic failure. Dig Dis Sci 2005;50:1146-7.
Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al.
Intravenous N-Acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137:856-64.
Chuansumrit A, Teeraratkul S, Wanichkul S, Treepongkaruna S, Sirachainan N. Recombinant-activated factor VII for control and prevention of hemorrhage in nonhemophilic pediatric patients. Blood Coagul Fibrinolysis 2010;21:354-62.
Mercier FJ, Bonnet MP. Use of clotting factors and other prohemostatic drugs for obstetric hemorrhage. Curr Opin Anaesthesiol 2010;23:310-6.
Yuan ZH, Jiang JK, Huang WD, Pan J, Zhu JY. A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. J Clin Neurosci 2010;17:685-93.
Rizoli SB, Boffard KD, Riou B, Warren B, Lau P. Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: Subgroup analysis from two randomized trials. Crit Care 2006;10:R178.
Dr. Edirisooriya Maddumage Manoj
Medical Department (Ward 42), National Hospital of Sri Lanka, Colombo
Source of Support: None, Conflict of Interest: None