Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial

BACKGROUND: Prevention of bleeding episodes in noncirrhotic patients undergoing partial hepatectomy remains unsatisfactory in spite of improved surgical techniques. The authors conducted a randomized, placebo-controlled, double-blind trial to evaluate the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in major partial hepatectomy. METHODS: Two hundred four noncirrhotic patients were equally randomized to receive either 20 or 80 microg/kg rFVIIa or placebo. Partial hepatectomy was performed according to local practice at the participating centers. Patients were monitored for 7 days after surgery. Key efficacy parameters were perioperative erythrocyte requirements (using hematocrit as the transfusion trigger) and blood loss. Safety assessments included monitoring of coagulation-related parameters and Doppler examination of hepatic vessels and lower extremities. RESULTS: The proportion of patients who required perioperative red blood cell transfusion (the primary endpoint) was 37% (23 of 63) in the placebo group, 41% (26 of 63) in the 20-microg/kg group, and 25% (15 of 59) in the 80-microg/kg dose group (logistic regression model; P = 0.09). Mean erythrocyte requirements for patients receiving erythrocytes were 1,024 ml with placebo, 1,354 ml with 20 microg/kg rFVIIa, and 1,036 ml with 80 microg/kg rFVIIa (P = 0.78). Mean intraoperative blood loss was 1,422 ml with placebo, 1,372 ml with 20 microg/kg rFVIIa, and 1,073 ml with 80 microg/kg rFVIIa (P = 0.07). The reduction in hematocrit during surgery was smallest in the 80-microg/kg group, with a significant overall effect of treatment (P = 0.04). CONCLUSIONS: Recombinant factor VIIa dosing did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered. No safety issues were identified.     

Use of recombinant factor VIIa for adjunctive hemorrhage control in trauma and surgical patients

Recombinant factor VIIa (rFVIIa) has recently been described for patients with ongoing massive bleeding in a number of different clinical scenarios. A retrospective chart review was conducted at a public level I trauma center in order to describe the use of rFVIIa in trauma and surgical patients with massive bleeding despite surgical control. Fifteen trauma and general surgical patients underwent major operative procedures and developed coagulopathy requiring massive blood product transfusion. All patients had continued life-threatening hemorrhage despite surgical control of bleeding. The mean base deficit was 6 and arterial lactate was 9.0 mmol/L. An initial dose of rFVIIa was given intravenously, followed by a second dose if there was evidence of at least a partial response. Twelve of 15 patients who had been expected to die from hemorrhage survived for greater than 48 hours, and 7 survived to hospital discharge. A partial or complete hemostatic response to rFVIIa was noted in 12 of 15 patients. The number of blood products received after administration of rFVIIa was significantly reduced and the International Normalized Ratio (INR) decreased. Our experience demonstrates that rFVIIa may reduce or completely arrest coagulopathic bleeding in trauma and surgical patients after vascular control.     

Recombinant activated factor VII for adjunctive hemorrhage control in trauma

BACKGROUND: Recombinant activated factor VII (rFVIIa) was approved for treatment of hemorrhages in patients with hemophilia who develop inhibitors to factors VIII or IX. Conditions with increased thromboembolic risk, including trauma with or without disseminated intravascular coagulation, were considered a contraindication for the drug. The mechanism of action of rFVIIa suggests enhancement of hemostasis limited to the site of injury without systemic activation of the coagulation cascade. Therefore, use of the drug in trauma patients suffering uncontrolled hemorrhage appears to be rational. METHODS: Seven massively bleeding, multitransfused (median, 40 units [range, 25-49 units] of packed cells), coagulopathic trauma patients were treated with rFVIIa (median, 120 microg/kg [range, 120-212 microg/kg]) after failure of conventional measures to achieve hemostasis. RESULTS: Administration of rFVIIa resulted in cessation of the diffuse bleed, with significant decrease of blood requirements to 2 units (range, 1-2 units) of packed cells (p < 0.05); shortening of prothrombin time and activated partial thromboplastin time from 24 seconds (range, 20-31.8 seconds) to 10.1 seconds (range, 8-12 seconds) (p < 0.005) and 79 seconds (range, 46-110 seconds) to 41 seconds (range, 28-46 seconds) (p < 0.05), respectively; and an increase of FVII level from 0.7 IU/mL (range, 0.7-0.92 IU/mL) to 23.7 IU/mL (range, 18-44 IU/mL) (p < 0.05). Three of the seven patients died of reasons other than bleeding or thromboembolism. CONCLUSION: The results of this report suggest that in trauma patients rFVIIa may play a role as an adjunctive hemostatic measure, in addition to surgical hemostatic techniques, and provides the motivation for controlled animal and clinical trials.     

Recombinant factor VIIa for control of hemorrhage: early experience in critically ill trauma patients

STUDY OBJECTIVE: To examine our institutional experience with recombinant Factor VIIa (rFVIIa) as a treatment for exsanguinating hemorrhage in critically ill trauma patients. DESIGN: Retrospective case review. SETTING: A specialized trauma and critical care hospital, serving as the quaternary referral center for trauma and surgical shock in the state of Maryland. PATIENTS: All patients with diffuse coagulopathy and impending exsanguination, given rFVIIa in an effort to control life-threatening hemorrhage. Patients were in the intensive care unit (ICU) or operating room (OR) and included both acute admissions and late-stage patients with multiple organ system failure. INTERVENTIONS: Patients of interest were those that had received rFVIIa. MEASUREMENTS: Examination of medical records, including pharmacy data, laboratory results, and the institutional trauma registry. MAIN RESULTS: Administration of rFVIIa contributed to successful control of hemorrhage in three of five patients. Failure in two patients was mostly likely due to overwhelming shock and acidosis. CONCLUSIONS: Administration of rFVIIa shows promise in the treatment of exsanguinating hemorrhage. Prospective, controlled clinical trials of this therapy are strongly recommended.     

Recombinant factor VIIa in trauma patients without coagulation disorders

Recombinant activated factor VIIa (rFVIIa) has many clinical applications for patients with congenital bleeding disorders and in a variety of clinical settings. Additional studies in the future are ongoing and should provide the clinical anesthesiologist an additional option during certain bleeding states. Specific recommendations as to timing of administration and frequent monitoring of ionized calcium status are suggested at this time. Optimization of fibrinogen levels, platelet levels, pH, and body temperature will enhance efficacy of rFVIIa.     

Recombinant factor VIIa in trauma patients with the 'triad of death'

IntroductionThe use of recombinant factor VIIa (rFVIIa) in trauma patients is usually part of rescue therapy when haemorrhage and coagulopathy have not responded to conventional treatment. In this scenario, trauma patients are likely to have one or more components of the ‘triad of death’ (coagulopathy, acidosis and hypothermia). The aim of this study was to report on the outcome of trauma patients with the ‘triad of death’ immediately prior to receiving rFVIIa.Materials and methodsTrauma patients receiving rFVIIa with the ‘triad of death’ were identified from the Australia and New Zealand Haemostasis Registry (ANZHR) and included in the study. The ‘triad of death’ was defined as an INR of >1.5, serum pH of <7.2 and a core temperature of <35 °C. Pre-dose clinical signs, investigations, adverse events and outcomes were analysed.ResultsThere were 2792 patients in the ANZHR, of which 386 were trauma patients and 45 patients had the ‘triad of death’. Patients with the ‘triad of death’ were significantly older and had higher injury severity scores than other trauma patients, with a mortality of 68.9%. Survivors were significantly less acidaemic (p < 0.001) and had significantly less packed red blood cell (PRBC) transfusion prior to rFVIIa administration (p = 0.041) than non-survivors with the triad of death.DiscussionIn the face of refractory bleeding, coagulopathy, acidosis and hypothermia following conventional resuscitation, the use of rFVIIa in trauma patients was associated with survival in 31% of patients and may be considered as a management option. Administration of rFVIIa in patients with a pH of <6.91 appears futile.     

Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial.

BACKGROUND: Uraemic pruritus is a common and distressing symptom in patients on haemodialysis for chronic renal failure. Gabapentin is an anticonvulsant that alleviates neuropathic pain. We conducted a double-blind, placebo-controlled, crossover study to assess its effectiveness against renal itch. METHODS: We enrolled in the trial 25 adult patients on haemodialysis who were asked to daily record the severity of their pruritus on a visual analogue scale. The patients were randomly assigned to receive gabapentin for 4 weeks followed by placebo for 4 weeks or the reverse sequence. Gabapentin or placebo were administered thrice weekly, at the end of haemodialysis sessions. RESULTS: The mean pruritus score of the cohort before the study was 8.4 +/- 0.94. After placebo intake, it decreased to 7.6 +/- 2.6 (P = 0.098). The score of four patients decreased by >50% following placebo. After gabapentin administration, the mean score decreased significantly, to 1.2 +/- 1.8 (P = 0.0001), although one patient's symptoms did not improve significantly. No patient dropped out of the study due to adverse effects from gabapentin. CONCLUSIONS: Our study shows that gabapentin is safe and effective for treating uraemic pruritus in haemodialysis patients. Our results also support the neuropathic hypothesis of uraemic pruritus.     

Fibrinogen prophylaxis for reducing perioperative bleeding in patients undergoing radical cystectomy: A double-blind placebo-controlled randomized trial

ObjectiveExcessive bleeding is an important complication of radical cystectomy. We aimed to assess whether preoperative administration of fibrinogen decreases perioperative bleeding and improves the outcome of radical cystectomy.DesignDouble-blinded randomized trial with two parallel arms.SettingThe study was conducted in the department of surgery at a teaching hospital affiliated with a University of Medical Sciences.PatientsIn total, 70 men undergoing radical cystectomy were randomized to fibrinogen (n = 35) and placebo-control groups. Mean (SD) age was 64.7 (7.4) years.InterventionsThe intervention group received 2 g fibrinogen concentrate diluted in 100 ml distilled water, and the control group received 100 ml normal saline; both intravenously 15 ̶ 30 min before the start of the surgery.Outcome measuresThe primary outcome was the amount of perioperative blood loss. The secondary outcomes were hemodynamic features and vital signs.Main resultsFibrinogen significantly decreased the volume of blood loss (p < 0.001) and the total number of transfused packed-cell units per group (38 vs. 115 units); and compensated the decrease of HCO3 (p = 0.030), the mean arterial pressure (p < 0.001), hemoglobin O2 saturation (p = 0.001), heart rate (p < 0.001), and temperature (p < 0.001) throughout the surgery compared with the placebo. Patients in the fibrinogen group had shorter Intensive Care Unit (p = 0.001) and hospital (p < 0.001) stay. We did not find any adverse reaction in our patients receiving fibrinogen concentrate.ConclusionFibrinogen concentrate reduces perioperative bleeding and the need for blood transfusion in radical cystectomy. It improves the outcomes of the surgery and decreases patients' length of stay in the healthcare system following radical cystectomy.RegistrationIranian Registry of Clinical Trials (IRCT) http://www.irct.ir/, reference number: IRCT20191013045091N1.Ethics codeShahid Beheshti University of Medical Sciences, reference number: IR.SBMU.RETECH.REC.1398.033.     

Recombinant factor VIIa for life-threatening bleeding in high-risk cardiac surgery despite full-dose aprotinin

We report the case of an orthotopic heart transplant in a patient with multiple previous cardiac surgeries. The case was prolonged and complicated by severe coagulopathy and bleeding despite the use of full-dose aprotinin throughout. Bleeding was not controlled after 30 U of platelets, 20 U of fresh frozen plasma, and 10 U of cryoprecipitate. However, after the administration of recombinant factor VIIa 90 microg/kg, the rate of bleeding slowed dramatically and no further factor replacement was required. There was no evidence of unwanted clot formation within the newly transplanted heart or around the intraaortic balloon pump that remained in situ for 72 h postoperatively. With the combined risks of coagulopathy and bleeding as well as acute right ventricular failure with increases in pulmonary vascular resistance, the re-do sternotomy for heart transplant seems to be an ideal situation in which to consider the use of recombinant factor VIIa.     

Obesity is an independent risk factor of mortality in severely injured blunt trauma patients

HYPOTHESIS: Obesity is associated with increased morbidity and mortality in critically injured blunt trauma patients. DESIGN: Case-control study of all critically injured blunt trauma patients between January 2002 and December 2002. SETTING: Academic level I trauma center at a county referral hospital. PATIENTS: Two hundred forty-two consecutive patients admitted to the intensive care unit following blunt trauma. Patients were divided into 2 groups by body mass index. The obese group was defined as having a body mass index of 30 kg/m2 or higher, and the nonobese group was defined as having a body mass index lower than 30 kg/m2. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify risk factors for mortality. Complications and length of stay were also evaluated. RESULTS: Of the 242 patients, 63 (26%) were obese, and 179 (74%) were nonobese. The obese and nonobese groups were similar with regard to age (mean +/- SD, 49 +/- 18 years vs 45 +/- 22 years), male sex (63% vs 72%), Glasgow Coma Scale score (mean +/- SD, 11 +/- 5 vs 11 +/- 5), and injury severity score (mean +/- SD, 21 +/- 13 vs 20 +/- 14). The obese group had a higher body mass index (mean +/- SD, 35 +/- 7 vs 24 +/- 3; P<.001). Mechanisms of injury and injury patterns were similar between groups. The obese group had a higher incidence of multiple organ failure (13% vs 3%; P =.02) and mortality (32% vs 16%; P=.008). Obesity was an independent predictor of mortality with an adjusted odds ratio of 5.7 (95% confidence interval, 1.9-19.6; P=.003). CONCLUSIONS: Critically injured obese trauma patients have similar demographics and injury patterns as nonobese patients. Obesity is an independent predictor of mortality following severe blunt trauma.     

Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies

Uremic pruritus is a very common and frustrating condition for both patients and clinicians because no treatment has been demonstrated to be effective in relieving the itch. In this report, nalfurafine, a new kappa-opioid receptor agonist, was used to treat uremic pruritus in patients who were undergoing routine hemodialysis. Two multicenter, randomized, double-blind, placebo-controlled studies enrolled 144 patients with uremic pruritus to postdialysis intravenous treatment with either nalfurafine or placebo for 2 to 4 wk. A meta-analysis approach was used to assess the efficacy of nalfurafine. Statistically significant reductions in worst itching (P = 0.0212), itching intensity (P = 0.0410), and sleep disturbances (P = 0.0003) were noted in the nalfurafine group as compared with placebo. Improvements in itching (P = 0.0025) and excoriations (P = 0.0060) were noted for the nalfurafine-treated patients. Nalfurafine showed similar types and incidences of drug-related adverse events as did placebo. Nalfurafine was shown to be an effective and safe compound for use in this severely ill patient population.     

A trauma algorithm--a decision tool in first aid for severely injured patients

Treatment for severe multiple injuries has quite often been impeded by erroneous diagnostic assessment by inadequately experienced physicians in hectic situations. A trauma algorithm flow chart has been devised for due consideration of all important steps in decision-finding. The therapeutic process has thus been improved, as demonstrated by a prospective study.     

Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies

BACKGROUND: The incidence of adefovir dipivoxil (ADV) nephrotoxicity has been previously reported with the 60 and 120 mg daily dose in human immunodeficiency virus (HIV). We report a complete analysis on the renal tolerance of ADV at the currently approved dose of 10 mg daily for the treatment of chronic hepatitis B. METHODS: To investigate the efficacy, safety, and the tolerability of two dosing regimens of ADV (10 mg daily or 30 mg daily), two double-blind, placebo-controlled studies were performed in patients with chronic hepatitis B and compensated liver disease who were not undergoing current treatment and who had evidence of hepatitis B virus (HBV) replication. RESULTS: There was no overall median change from baseline at week 48 in serum creatinine or serum phosphorus levels in the ADV 10 mg group. In the ADV 30 mg group there was a slight increase of 0.2 mg/dL in median serum creatinine levels, and decrease of 0.1 mg/dL in serum phosphorus levels at week 48. Serum creatinine increase and hypophosphatemia were more frequently observed in patients receiving ADV 30 mg daily compared with ADV 10 mg and placebo. There were no grade 4 proteinuria, hematuria, or glycosuria events. CONCLUSION: Mild nephrotoxicity was demonstrated with the dose of 30 mg daily. Nephrotoxicity, as defined by an increase >/=0.5 mg/dL from baseline in serum creatinine or a serum phosphorus value of <1.5 mg/dL on two consecutive occasions, was not observed in patients treated with ADV 10 mg for a median follow-up period of approximately 64 weeks.     

Recombinant factor VIIa for intraoperative bleeding in a child with hepatoblastoma and review of recombinant activated factor VIIa use in children undergoing surgery

We report a case of a child with a large liver mass who underwent an open liver biopsy and had massive bleeding intraoperatively. Recombinant activated factor VII (rFVIIa) given intraoperatively was successful in stopping the bleeding. We also reviewed the literature on the use of rFVIIa in pediatric surgery.     

Efficacy of trospium chloride in patients with detrusor instability: a placebo-controlled, randomized, double-blind, multicentre clinical trial

OBJECTIVES: To assess the efficacy and safety of trospium chloride (TCl, 20 mg twice daily) in the treatment of detrusor instability, compared with placebo. PATIENTS AND METHODS: In all, 208 patients were allocated at random to either TCl or placebo in a double-blind clinical study; the patients were treated for 3 weeks. Urodynamic values were measured at the beginning and end of the treatment period. Adverse events were recorded on patient diary cards. A confirmatory adaptive procedure with one planned interim analysis was used to evaluate efficacy. RESULTS: Trospium chloride produced significant improvements in maximum cystometric bladder capacity (median treatment effect 22.0 mL, mean 37.3 mL, one-sided P = 0. 0054) and urinary volume at first unstable contraction (median treatment effect 45.0 mL, mean 63.6 mL, one-sided P = 0.0015). The patients' assessment of efficacy showed significantly greater clinical improvement in the TCl group than in the placebo group (two-sided P = 0.0047). Furthermore, TCl was well tolerated, with similar frequencies of adverse events reported in both groups (68% in the TCl and 62% in the placebo group). CONCLUSION: Trospium chloride (20 mg twice daily) is an effective and safe option for the treatment of detrusor instability.