We read with great interest the article by Rinaldi et al.1 describing the successful treatment of 5 liver transplant recipients suffering severe sepsis with recombinant human activated protein C (rhAPC). We would like to add our experience with rhAPC in a patient with septic shock 17 days after orthotopic liver transplantation. The patient was a 68-year-old man with a history of nonalcoholic steatohepatitis, cirrhosis, hypertension, hyperlipidemia, and type 2 diabetes. His postoperative course was complicated by hyperbilirubinemia (Table 1). The diagnostic workup revealed biliary strictures that required repeated instrumentation of the biliary tract, which resulted in biliary sepsis and multiple-organ system failure. His treatment consisted of the administration of broad-spectrum antibiotics (including linezolid) guided by bacterial culture results, intravenous fluids, norepinephrine and vasopressin, mechanical ventilation, withdrawal of immunosuppressive therapy, and continuous renal replacement therapy. rhAPC was started within 24 hours of severe sepsis at a dose of 24 μg/kg/hour. Five hours after the initiation of rhAPC treatment, the patient developed fixed, dilated pupils. Head computed tomography showed a large left intraparenchymal/intraventricular hemorrhage with a mass effect and uncal, subfalcine, and transtentorial herniation. He died several hours later. It is difficult to identify the differences between our patient who experienced an intracerebral hemorrhage and the patients in Rinaldi et al.'s case series.1 All but one of Rinaldi et al.'s patients exhibited some degree of liver dysfunction manifested by elevated liver enzymes, all were coagulopathic as evidenced by prolonged prothrombin and partial thromboplastin times, and all were septic. Therefore, it is unlikely that hepatic and/or septic encephalopathy with possible disruption of the blood-brain barrier could be a factor responsible for the intracranial bleed. However, none of the case series patients experienced the extent of hyperbilirubinemia seen in our patient (total and direct bilirubin ranged from 37.5 and 41.2 mg/dL and from 23.7 to 28.5 mg/dL, respectively). Could hyperbilirubinemia play a role in bleeding? There are 2 additional reports of the successful use of activated protein C in liver transplant recipients.2, 3 Patients in both case reports fulfilled the criteria of severe sepsis. No information about liver function was provided by Kulkarni et al.,2 but Browne et al.'s patient retained good graft function during a septic episode.3 Nevertheless, serious bleeding, particularly intracranial hemorrhage (ICH), is a feared complication of rhAPC administration and is more likely in patients predisposed to bleeding. Coagulation abnormalities are frequently present in septic patients, and coagulation screens do not accurately reflect the risk of bleeding. Lastly, ICH, even in the absence of anticoagulant treatment, is a well-known complication with a poor prognosis in liver transplant recipients. Bronster et al.4 reviewed central nervous system complications in 463 liver transplant recipients. The incidence of ICH was 1.5% with a mortality rate of 57%. Analyses by Estol et al.5 and Wang et al.6 indicated an even higher incidence of ICH (23.6% and 6.5%, respectively) in this patient population. Interestingly, in Estol et al.'s review, only 5 of 13 patients died because of intracranial bleeding. In the remainder, significant systemic and metabolic complications masked focal signs of the intracranial process. We believe that the administration of rhAPC was a major contributing factor to the bleeding complication in our patient. The challenge for future studies is to clarify an appropriate risk/benefit assessment for the administration of rhAPC in these severely ill patients. Jana Hudcova*, Roman Schumann , * Department of Surgical Critical Care Lahey Clinic Burlington, MA, Department of Anesthesia Tufts Medical Center Boston, MA.