Raymond M. Planinsic

Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose‐finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double‐blind trial, patients with end‐stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 μg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty‐three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895–900.)

Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome

In an attempt to more completely define the histopathologic features of the portal vein hyperperfusion or small-for-size syndrome (PHP/SFSS), we strictly identified 5 PHP/SFSS cases among 39 (5/39; 13%) adult living donor liver transplants (ALDLT) completed between 11/01 and 09/03. Living donor segments consisting of 3 right lobes, 1 left lobe, and 1 left lateral segment, with a mean allograft-to-recipient weight ratio (GRWR) of 1.0±0.3 (range 0.6 to 1.4), were transplanted without complications, initially, into 6 relatively healthy 25 to 63-year-old recipients. However, all recipients developed otherwise unexplained jaundice, coagulopathy, and ascites within 5 days after transplantation. Examination of sequential posttransplant biopsies and 3 failed allografts with clinicopathologic correlation was used in an attempt to reconstruct the sequence of events. Early findings included: (1) portal hyperperfusion resulting in portal vein and periportal sinusoidal endothelial denudation and focal hemorrhage into the portal tract connective tissue, which dissected into the periportal hepatic parenchyma when severe; and (2) poor hepatic arterial flow and vasospasm, which in severe cases, led to functional dearterialization, ischemic cholangitis, and parenchymal infarcts. Late sequelae in grafts surviving the initial events included small portal vein branch thrombosis with occasional luminal obliteration or recanalization, nodular regenerative hyperplasia, and biliary strictures. These findings suggest that portal hyperperfusion, venous pathology, and the arterial buffer response importantly contribute to early and late clinical and histopathologic manifestations of the small-for-size syndrome.

Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression.

Objective: To minimize maintenance immunosuppression in upper-extremity transplantation to favor the risk-benefit balance of this procedure. Background: Despite favorable outcomes, broad clinical application of reconstructive transplantation is limited by the risks and side effects of multidrug immunosuppression. We present our experience with upper-extremity transplantation under a novel, donor bone marrow (BM) cell-based treatment protocol (“Pittsburgh protocol”). Methods: Between March 2009 and September 2010, 5 patients received a bilateral hand (n = 2), a bilateral hand/forearm (n = 1), or a unilateral (n = 2) hand transplant. Patients were treated with alemtuzumab and methylprednisolone for induction, followed by tacrolimus monotherapy. On day 14, patients received an infusion of donor BM cells isolated from 9 vertebral bodies. Comprehensive follow-up included functional evaluation, imaging, and immunomonitoring. Results: All patients are maintained on tacrolimus monotherapy with trough levels ranging between 4 and 12 ng/mL. Skin rejections were infrequent and reversible. Patients demonstrated sustained improvements in motor function and sensory return correlating with time after transplantation and level of amputation. Side effects included transient increase in serum creatinine, hyperglycemia managed with oral hypoglycemics, minor wound infection, and hyperuricemia but no infections. Immunomonitoring revealed transient moderate levels of donor-specific antibodies, adequate immunocompetence, and no peripheral blood chimerism. Imaging demonstrated patent vessels with only mild luminal narrowing/occlusion in 1 case. Protocol skin biopsies showed absent or minimal perivascular cellular infiltrates. Conclusions: Our data suggest that this BM cell-based treatment protocol is safe, is well tolerated, and allows upper-extremity transplantation using low-dose tacrolimus monotherapy.

The impact of postreperfusion syndrome on short-term patient and liver allograft outcome in patients undergoing orthotopic liver transplantation†

The greatest part of liver allograft injury occurs during reperfusion, not during the cold ischemia phase. The aim of this study, therefore, was to investigate how the severity of postreperfusion syndrome (PRS) influences short‐term outcome for the patient and for the liver allograft. Over a 2‐year period, 338 consecutive patients who presented for orthotopic liver transplantation (OLT) were included in this retrospective study. They were divided into 2 groups according to the severity of the PRS they experienced. The first group comprised 152 patients with mild or no PRS; the second group comprised 186 patients with significant PRS. Perioperative hemodynamic parameters, coagulation profiles, blood product requirements, incidence of infection, incidence of rejection and outcome data for both groups were collected and analyzed. There was no demographic difference between the groups except for age; group 2 had older patients than group 1 (54.94 ± 9.07 versus 51.52 ± 9.91, P = 0.001). Compared to group 1, group 2 patients required more red blood cell transfusions (11.31 ± 10.90 versus 8.08 ± 7.89 units, P = 0.002), more fresh frozen plasma transfusions (10.25 ± 10.96 versus 7.03 ± 7.64 units, P = 0.002), more cryoprecipitate (1.88 ± 4.72 units versus 0.61 ± 1.80 units, P = 0.001), and were more likely to suffer from fibrinolysis (52.7% versus 41.4%, P = 0.041). Interestingly, group 2 had a shorter average warm ischemia time than group 1 (33.19 ± 8.55 versus 36.21 ± 11.83 minutes, P = 0.01). Group 2 also required longer, on average, mechanical ventilation (14.95 ± 29.79 versus 8.55 ± 17.79 days, P = 0.015), remained in the intensive care unit longer (17.65 ± 31.00 versus 11.49 ± 18.67 days, P = 0.025), and had a longer hospital stay (27.29 ± 32.35 versus 20.85 ± 21.08 days, P = 0.029). Group 2 was more likely to require retransplantation (8.6% versus 3.3%, P = 0.044). In conclusion, the severity of PRS during OLT appears to be related to the outcome of patient and liver allograft. Liver Transpl 14:504–508, 2008.

The incidence and outcome of perioperative pulmonary aspiration in a university hospital: a 4-year retrospective analysis.

We evaluated the current incidence and outcome of perioperative pulmonary aspiration (PPA) in the nonobstetric adult population at a tertiary university medical center. A 4-yr retrospective analysis (January 2001–December 2004) was conducted using both quality improvement data and the hospital-wide medical archive recording system. PPA was defined as either detection of nonrespiratory secretions from the tracheobronchial tree or development of new pulmonary symptoms and/or new abnormalities in chest radiographs within 24 hr postoperatively. Of 99,441 anesthetics, 14 cases had confirmed PPA. Seven of them (50%) occurred in connection with gastroesophageal procedures. All patients had one or more predisposing risk factors for PPA. PPA occurred under general anesthesia in 10 patients and under monitored anesthesia care in 4 patients. In general anesthesia cases, the aspiration was recognized immediately after induction in 5 patients and occurred during changing of the endotracheal tubes in 5. The PPA was detected during the surgical procedures in all the monitored anesthesia care cases. Six patients with confirmed PPA developed pulmonary complications, of which, one died. Ten of 14 (70%) cases of PPA were the result of improper anesthesia technique. The current incidence of PPA is 1 of 7103, with morbidity 1 of 16,573 and mortality 1 of 99,441.

Cerebral hemodynamic and metabolic profiles in fulminant hepatic failure: Relationship to outcome

The purpose of this retrospective study was to examine the potential role of cerebral hemodynamic and metabolic factors in the outcome of patients with fulminant hepatic failure (FHF). Based on the literature, a hypothetical model was proposed in which physiologic changes progress sequentially in five phases, as defined by intracranial pressure (ICP) and cerebral blood flow (CBF) measurements. Seventy‐six cerebral physiologic profiles were obtained in 26 patients (2 to 5 studies each) within 6 days of FHF diagnosis. ICP was continuously measured by an extradural fiber optic monitor. Global CBF estimates were obtained by xenon clearance techniques. Jugular venous and peripheral artery catheters permitted calculation of cerebral arteriovenous oxygen differences (AVDO2), from which cerebral metabolic rate for oxygen (CMRO2) was derived. A depressed CMRO2 was found in all patients. There was no evidence of cerebral ischemia as indicated by elevated AVDO2s. Instead, over 65% of the patients revealed cerebral hyperemia. Eight of the 26 patients underwent orthotopic liver transplantation—all recovered neurologically, including 6 with elevated ICPs. Of the 18 patients receiving medical treatment only, all 7 with increased ICP died in contrast to 9 survivors whose ICP remained normal (P < 0.004). Hyperemia, per se, was not related to outcome, although it occurred more frequently at the time of ICP elevations. Six patients were studied during brain death. All 6 revealed malignant intracranial hypertension, preceded by hyperemia. In conclusion, the above findings are consistent with the hypothetical model proposed. Prospective longitudinal studies are recommended to determine the precise evolution of the pathophysiologic changes. (Liver Transpl 2005;11:1353–1360.)

Pulmonary thromboembolism during adult liver transplantation: incidence, clinical presentation, outcome, risk factors, and diagnostic predictors

BACKGROUND Intraoperative pulmonary thromboembolism (PTE) is an often overlooked cause of mortality during adult liver transplantation (LT) with diagnostic challenge. The goals of this study were to investigate the incidence, clinical presentation, and outcome of PTE and to identify risk factors or diagnostic predictors for PTE. METHODS Four hundred and ninety-five consecutive, isolated, deceased donor LTs performed in an institution for a 3 yr period (2004-6) were analysed. The standard technique was a piggyback method with veno-venous bypass without prophylactic anti-fibrinolytics. The clinical diagnosis of PTE was made with (i) acute cor pulmonale, and (ii) identification of blood clots in the pulmonary artery or observation of acute right heart pressure overload with or without intracardiac clots with transoesophageal echocardiography. RESULTS The incidence of PTE was 4.0% (20 cases); cardiac arrest preceded the diagnosis of PTE [75% (15)] and PTE occurred during the neo-hepatic phase [85% (17)], especially within 30 min after graft reperfusion [70% (14)]. Operative and 60 day mortalities of patients with PTE were higher (P<0.001) than those without PTE (30% vs 0.8% and 45% vs 6.5%). Comparison of perioperative data between the PTE group (n=20) and the non-PTE group (n=475) revealed cardiac arrest and flat-line thromboelastography in three channels (natural, amicar, and protamine) at 5 min after graft reperfusion as the most significant risk factors or diagnostic predictors for PTE with an odds ratio of 154.32 [95% confidence interval (CI): 44.82-531.4] and 49.44 (CI: 15.6-156.57), respectively. CONCLUSIONS These findings confirmed clinical significance of PTE during adult LT and suggested the possibility of predicting this devastating complication.

Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes

BACKGROUND Liver transplant recipients frequently develop acute kidney injury (AKI), but the predisposing factors and long-term consequences of AKI are not well understood. The aims of this study were to identify predisposing factors for early post-transplant AKI and the impact of AKI on patient and graft survival and to construct a model to predict AKI using clinical variables. METHODS In this 5-year retrospective study, we analysed clinical and laboratory data from 424 liver transplant recipients from our centre. RESULTS By 72 h post-transplant, 221 patients (52%) had developed AKI [according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria]. Predisposing factors for development of AKI were female sex, weight (>100 kg), severity of liver disease (Child-Pugh score), pre-existing diabetes mellitus, number of units of blood or fresh frozen plasma transfused during surgery, and non-alcoholic steatohepatitis as the aetiology of end-stage liver disease (P≤0.05). Notably, preoperative serum creatinine (SCr) was not a significant predisposing factor. After fitting a forward stepwise regression model, female sex, weight >100 kg, high Child-Pugh score, and diabetes remained significantly associated with the development of AKI within 72 h (P≤0.05). The area under the receiver operator characteristic curve for the final model was 0.71. The incidence of new chronic kidney disease and requirement for dialysis at 3 months and 1 yr post-transplant were significantly higher among patients who developed AKI. CONCLUSIONS Development of AKI within the first 72 h after transplant impacted short-term and long-term graft survival.

Comparison of surgical methods in liver transplantation: retrohepatic caval resection with venovenous bypass (VVB) versus piggyback (PB) with VVB versus PB without VVB.

Use of piggyback technique (PB) and elimination of venovenous bypass (VVB) have been advocated in adult liver transplantation (LT). However, individual contribution of these two modifications on clinical outcomes has not been fully investigated. We performed a retrospective review of 426 LTs within a 3‐year period, when three different surgical techniques were employed per the surgeons’ preference: retrohepatic caval resection with VVB (RCR + VVB) in 104 patients, PB with VVB (PB + VVB) in 148, and PB without VVB (PB‐Only) in 174. The primary outcomes were intraoperative blood transfusion and the patient and graft survivals. Demographic profiles were similar, except younger recipient age in RCR + VVB and fewer number of grafts with cold ischemic time over 16 h in PB‐Only. PB‐Only required lesser intraoperative red blood cells (P = 0.006), fresh frozen plasma (P = 0.005), and cell saver return (P = 0.007); had less incidence of acute renal failure (P = 0.001), better patient survival (P = 0.039), and graft survival (P = 0.003). The benefits of PB + VVB were only found in shortened total surgical time (P = 0.0001) and warm ischemic time (P = 0.0001), and less incidence of acute renal failure (P = 0.001) than RCR + VVB. PB‐Only method seemed to provide the best clinical outcome. The benefit of PB was not fully achieved when it was used with VVB.

Initial experience using continuous intravenous treprostinil to manage pulmonary arterial hypertension in patients with end-stage liver disease.

Treprostinil is a prostacyclin analog and has been used on idiopathic pulmonary arterial hypertension (PAH). There is only limited clinical experience using treprostinil to manage PAH in patients with end‐stage liver disease (ESLD). We report three ESLD patients with PAH, who were treated with continuous intravenous treprostinil. A 59‐year‐old woman with ESLD secondary to alcoholic hepatitis had portopulmonary hypertension with mean pulmonary arterial pressure (mPAP) of 44 mmHg and transpulmonary gradient (TPG) of 23 mmHg. Treprostinil at 45 ng/kg/min for 6 months decreased mPAP to 23 (TPG to 8). A 53‐year‐old man had ESLD secondary to alcoholic hepatitis with PAH caused by multiple pulmonary embolisms (mPAP of 32 and TPG of 23). Treprostinil at 36 ng/kg/min for 3 months decreased mPAP to 23 and TPG to 14. Both patients underwent uneventful liver transplantation. A 48‐year‐old man had ESLD secondary to hepatitis C and portopulmonary hypertension with mPAP of 60 and TPG of 44. Two years after intravenous treprostinil at 106 ng/kg/min, his mPAP decreased to 44 and TPG to 30. These results demonstrate that for a selected group of ESLD patients with PAH, a continuous intravenous infusion of treprostinil appears to be safe and effective.