Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials

BACKGROUND: Uncontrolled bleeding is a leading cause of death in trauma. Two randomized, placebo-controlled, double-blind trials (one in blunt trauma and one in penetrating trauma) were conducted simultaneously to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma. METHODS: Severely bleeding trauma patients were randomized to rFVIIa (200, 100, and 100 microg/kg) or placebo in addition to standard treatment. The first dose followed transfusion of the eighth red blood cell (RBC) unit, with additional doses 1 and 3 hours later. The primary endpoint for bleeding control in patients alive at 48 hours was units of RBCs transfused within 48 hours of the first dose. RESULTS: Among 301 patients randomized, 143 blunt trauma patients and 134 penetrating trauma patients were eligible for analysis. In blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (estimated reduction of 2.6 RBC units, p = 0.02), and the need for massive transfusion (>20 units of RBCs) was reduced (14% vs. 33% of patients; p = 0.03). In penetrating trauma, similar analyses showed trends toward rFVIIa reducing RBC transfusion (estimated reduction of 1.0 RBC units, p = 0.10) and massive transfusion (7% vs. 19%; p = 0.08). Trends toward a reduction in mortality and critical complications were observed. Adverse events including thromboembolic events were evenly distributed between treatment groups. CONCLUSION: Recombinant FVIIa resulted in a significant reduction in RBC transfusion in severe blunt trauma. Similar trends were observed in penetrating trauma. The safety of rFVIIa was established in these trauma populations within the investigated dose range.     

Recombinant factor VIIa in major abdominal surgery and liver transplantation

The author reviewed the literature regarding recombinant activated Factor VII (rFVIIa) in major abdominal surgery and liver transplantation and concluded that, on the basis of evidence-based medicine, there is no evidence to support an extensive use of rFVIIa. Nevertheless, various case reports suggest the usefulness of rFVIIa to treat life-threatening bleeding after failure of conventional therapies. It appears that there is a consensus that rFVIIa can be used with good results as a rescue therapy in extremely severe situations. Economic cost and potential thrombosis risk remain arguments against more widespread use of rFVIIa. Doses from 5 to 120 kg/kg in each administration have been reported without clear evidence to support a specific protocol. Efficacy of 15 to 20 kg/kg in surgical settings has been reported, but higher doses are more frequently used. The majority of the reviewed investigators accepted the use of rFVIIa after or simultaneously with the use of aprotinin; no data refute the safety of this association.     

Prophylactic fluconazole in liver transplant recipients: A randomized,double-blind,placebo-controlled trial

Background:Among persons who receive solid organ 0842 transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective.Objective:To evaluate the efficacy and safety of prophylactic0842 fluconazole in liver transplant recipients.Design:Randomized, double-blind, placebo-controlled trial. 0842Setting:University-affiliated transplantation center.0842Patients:212 liver transplant recipients who received fluconazole0842 (400 mg/d) or placebo until 10 weeks after transplantation.Measurements:Fungal colonization, proven superficial 0842 or invasive fungal infection, drug-related side effects, and death.Results:Fungal colonization increased in 0842 patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003).Conclusions:Prophylactic 0842 fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.     

PORTAL: Pilot study on the safety and tolerance of preoperative melatonin application in patients undergoing major liver resection: a double-blind randomized placebo-controlled trial

Background  

Major surgical procedures facilitate systemic endotoxinemia and formation of free radicals with subsequent inflammatory changes that can influence the postoperative course. Experimental data suggest that preoperative supraphysiological doses of melatonin, a potent immuno-modulator and antioxidant, would decrease postoperative infectious and non-infectious complications induced by major abdominal surgery.     

Recombinant human coagulation factor VIIa in Jehovah's Witness patients undergoing liver transplantation

Indisputably, liver transplantation is among the most technically challenging operations in current practice and is compounded by significant coagulopathy and portal hypertension. Recombinant human coagulation factor VIIa (rFVIIa) is a new product that was initially described to treat bleeding in hemophilia patients. We present in this paper 10 liver transplants in Jehovah's Witness patients using this novel product at University of Southern California-University Hospital. The subject population included nine males and one female with an average age of 50 years. Six patients underwent cadaveric and four live donor liver transplantation. Surgeries were conducted following our established protocol for transfusion-free liver transplantation, which includes preoperative blood augmentation, intraoperative blood salvage, acute normovolemic hemodilution, and postoperative blood conservation. Factor rFVIIa was used at a dose of 80 microg/kg intravenously just prior to the incision in all patients, and a second intraoperative dose was used in 3 patients. All living donor liver transplantation (LDLT) recipients did well and were discharged uneventfully with normal liver functions. Two of the six cadaveric recipients died. One patient died intraoperatively from acute primary graft nonfunction, and the other died 38 hours postoperatively from severe anemia. This report suggests factor rFVIIa might have a much broader application in surgery in the control of bleeding associated with coagulopathy.     

Alpha-blockers impact stent-related symptoms: a randomized, double-blind, placebo-controlled trial

Abstract Background and Purpose: Ureteral stents are indispensable tools in endourology, although they often are associated with bothersome lower urinary tract symptoms. This study was conducted to evaluate the effect of alfuzosin on urinary symptoms, quality of life, and pain in patients after Double-J ureteral stent placement in a randomized, placebo-controlled trial. Patients and Methods: This study was conducted from July 2008 to May 2009. A total of 130 patients underwent placement of a Double-J stent after retrograde semirigid ureteroscopy for ureteral stones. They were randomized in two groups. Group 1 (n=65) received alfuzosin 10?mg once daily and group 2 (n=65) received placebo for 1 week. Both groups also received standardized analgesia. The stent symptoms were measured and recorded 1 week after the procedure. Statistical analyses were performed using the chi-square test and Student t test with P<0.05 considered significant. Results: The demographic profile including patient and stone-related parameters were comparable. Group 1 had significantly less urinary symptoms (P<0.05). The quality-of-life assessment was better in the alfuzosin arm than in the placebo arm (P<0.001). The mean pain score was 1.15 in group 1 and 3.89 in the placebo group (P<0.001). None of the patients in either of the arms withdrew from treatment; there were minimal adverse effects in the treatment arm. The limitation of the current work includes relatively smaller sample size and use of single type of stent. Conclusions: Alfuzosin 10?mg once daily in patients with a Double-J stent significantly decreases the bothersome urinary symptoms, besides decreasing significantly the pain associated with the stent.     

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.     

Effects of different photobiomodulation dosimetries on temporomandibular dysfunction: a randomized,double-blind,placebo-controlled clinical trial

Changes involving temporomandibular joint, masticatory musculature, and associated structures characterize temporomandibular dysfunction (TMD). The analgesic and anti-inflammatory effect produced by photobiomodulation has contributed to pain relief and functional improvement. However, the parameters to be used have not yet been well established. The aim of this study is to compare the efficacy of three different photobiomodulation dosimetries in the treatment of patients with TMD. A randomized, double-blind, placebo-controlled clinical trial with 44 subjects divided into the groups 8 J/cm² (n?=?11), 60 J/cm² (n?=?11), 105 J/cm² (n?=?11), and control (n?=?11). Pain, symptom severity, and joint mobility were evaluated before and after a ten-session protocol of photobiomodulation with AlGaAs laser (830 nm), at a power density of 30 mW/cm². The mouth opening increased in the 8-J/cm² group from 10.49?±?4.68 to 15.40?±?6.43 degrees, and in the right protrusion from 9.80?±?4.2 to 12.56?±?5.40 degrees after the intervention protocol (p?<?0.05). All groups significantly decreased pain (p?<?0.05). 830-nm laser photobiomodulation was effective in reducing TMD pain and symptoms at all doses tested. Only the doses of 8 J/cm² were effective regarding maximal opening and protrusion of the mandible.     

Cardioprotective effects of carnitine in extensive aortocoronary bypass grafting: a double-blind, randomized, placebo-controlled clinical trial

The cardioprotective effects of carnitine were tested in patients undergoing multiple aortocoronary bypass grafting. Intermittent aortic cross-clamping at 28 degrees C was used. Mean total cross-clamping time was 30 +/- 11 min. Patients were randomized into three groups: a control group receiving placebo (group 1), a group pretreated with 3 g carnitine intravenously before cardiopulmonary bypass (CPB) (group 2), and a group pretreated with 6 g carnitine intravenously (group 3). The markers of myocardial ischemia included levels of adenosine triphosphate, its catabolites, and creatine phosphate in transmural left ventricular biopsy specimens taken at the beginning and end of CPB, as well as hemodynamic recovery during weaning from CPB and for the next 24 h. The intravenous infusion of carnitine (3 or 6 g) had no hemodynamic effect. At the end of CPB myocardial tissue levels of adenosine triphosphate and creatine phosphate did not differ significantly among the groups (P greater than 0.05). Recovery of cardiac function during weaning from CPB and for the following 24 h was similar in all three groups (P greater than 0.05). It is concluded that pretreatment with carnitine neither facilitates weaning from cardiopulmonary bypass in patients undergoing aortocoronary bypass surgery nor favorably affects hemodynamic function during the next 24 h.     

Dexamethasone in preventing post-dural puncture headache: a randomized, double-blind, placebo-controlled trial

Spinal anesthesia is major complication is Post-Dural Puncture Headache (PDPH) which is an intense and debilitating event. We decided to assess if intravenous administration of dexamethasone can decrease the incidence and/or intensity of this kind of headache. For this purpose 178 patients, who were supposed to undergo lower extremity orthopedic surgery, were enrolled in the study . Before spinal anesthesia was initiated, the first group (DXM-group) received 2 mL intravenous (i.v) dexamethasone whereas the second group (PCB-group) received 2 mL i.v. normal saline. After termination of surgery, a 7 days follow-up started to observe the possible occurrence and intensity of PDPH. There was no statistically significant difference between DMX and PCB groups regarding the incidence of PDPH. However, the intensity of headache differed between the two groups being less severe if IV dexamethasone had been given prophylactically. Dexamethasone can be used to decrease the severity of PDPH in patients who receive spinal anesthesia.     

Homeopathic treatment of mild traumatic brain injury: A randomized, double-blind, placebo-controlled clinical trial

BACKGROUND: Mild traumatic brain injury (MTBI) affects 750,000 persons in the United States annually. Five to fifteen percent have persistent dysfunction and disability. No effective, standard pharmacological treatment exists specifically for this problem. We designed a pilot research project to study the clinical effectiveness of homeopathic medicine in the treatment of persistent MTBI. METHOD: A randomized, double-blind, placebo-controlled trial of 60 patients, with a four-month follow-up (N = 50), was conducted at Spaulding Rehabilitation Hospital (SRH). Patients with persistent MTBI (mean 2.93 years since injury, SD 3.1) were randomly assigned to receive a homeopathic medicine or placebo. The primary outcome measure was the subject-rated SRH-MBTI Functional Assessment, composed of three subtests: a Difficulty with Situations Scale (DSS), a Symptom Rating Scale (SRS), and a Participation in Daily Activities Scale (PDAS). The SRH Cognitive-Linguistic Test Battery was used as the secondary measure. RESULTS: Analysis of covariance demonstrated that the homeopathic treatment was the only significant or near-significant predictor of improvement on DSS subtests (P =.009; 95% CI -.895 to -.15), SRS (P =.058; 95% CI -.548 to.01) and the Ten Most Common Symptoms of MTBI (P =.027; 95% CI -.766 to -.048). These results indicate a significant improvement from the homeopathic treatment versus the control and translate into clinically significant outcomes. CONCLUSIONS: This study suggests that homeopathy may have a role in treating persistent MTBI. Our findings require large-scale, independent replication.     

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.     

Effect of homeopathic Arnica montana on bruising in face-lifts: results of a randomized, double-blind, placebo-controlled clinical trial

OBJECTIVES: To design a model for performing reproducible, objective analyses of skin color changes and to apply this model to evaluate the efficacy of homeopathic Arnica montana as an antiecchymotic agent when taken perioperatively. METHODS: Twenty-nine patients undergoing rhytidectomy at a tertiary care center were treated perioperatively with either homeopathic A. montana or placebo in a double-blind fashion. Postoperative photographs were analyzed using a novel computer model for color changes, and subjective assessments of postoperative ecchymosis were obtained. RESULTS: No subjective differences were noted between the treatment group and the control group, either by the patients or by the professional staff. No objective difference in the degree of color change was found. Patients receiving homeopathic A. montana were found to have a smaller area of ecchymosis on postoperative days 1, 5, 7, and 10. These differences were statistically significant (P<.05) only on postoperative days 1 (P<.005) and 7 (P<.001). CONCLUSIONS: This computer model provides an efficient, objective, and reproducible means with which to assess perioperative color changes, both in terms of area and degree. Patients taking perioperative homeopathic A. montana exhibited less ecchymosis, and that difference was statistically significant (P<.05) on 2 of the 4 postoperative data points evaluated.     

No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial

OBJECT: From the moment an intracranial aneurysm ruptures, cerebral blood flow is impaired, and this impairment mainly determines the outcome in patients who survive after the initial bleeding. The exact mechanism of impairment is unknown, but activation of coagulation and fibrinolysis correlate with clinical condition and outcome after aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to determine whether enoxaparin, a low-molecular-weight heparin, which is a well-known anticoagulating agent, has any effect on the outcome of aneurysmal SAH postoperatively. METHODS: In this randomized, double-blind, single-center clinical trial, 170 patients (85 per group) with aneurysmal SAH were randomly assigned to receive either enoxaparin (40 mg subcutaneously once daily) or a placebo, starting within 24 hours after occlusion of the aneurysm and continuing for 10 days. Analysis was done on an intention-to-treat basis. Outcome was assessed at 3 months on both the Glasgow Outcome and modified Rankin Scales. Patients were eligible for the study if surgery was performed within 48 hours post-SAH, and no intracerebral hemorrhage was larger than 20 mm in diameter on the first postoperative computerized tomography scan. At 3 months, there were no significant differences in outcome by treatment group. Of the 170 patients, 11 (6%) died, and only 95 (56%) had a good outcome. Principal causes of unfavorable outcome were poor initial condition, delayed cerebral ischemia, and surgical complications. There were four patients with additional intracranial bleeding in the group receiving enoxaparin. The bleeding was not necessarily associated with the treatment itself, nor did it require treatment, and there were no such patients in the placebo group. CONCLUSIONS: Enoxaparin seemed to have no effect on the outcome of aneurysmal SAH in patients who had already received routine nimodipine and who had received triple-H therapy when needed. Routine use of low-molecular-weight heparin should be avoided during the early postoperative period in patients with SAH, because this agent seems to increase intracranial bleeding complications slightly, with no beneficial effect on neurological outcome.     

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.     

Multimodal analgesia for arthroscopic rotator cuff repair: a randomized,placebo-controlled,double-blind trial

Background

The aim of the study was to investigate whether a multimodal analgesia (MMA) protocol reduces postoperative pain and opioids consumption in patients undergoing arthroscopic rotator cuff repair.

Methods

Fifty-four patients scheduled for arthroscopic rotator cuff repair were randomly assigned to either the MMA group or the control group. The primary outcome was visual analog scale (VAS) for pain. Secondary outcome measures included the time required for the VAS pain to reduce to that of a blood draw, (PCA) consumption, rescue morphine consumption, night awakening, and opioid-related side effects.

Results

The MMA group showed significantly less postoperative pain at postoperative 5 h, and 9 a.m. and 5 p.m. at 4th postoperative day (P < 0.001, = 0.040, and 0.013, respectively). MMA also shortened the time for postoperative pain to reduce down to the blood draw pain level from 5 days in the control group to 2 days in the MMA group. MMA also significantly reduced PCA consumption for up to 24 h postoperatively (P = 0.038) and rescue morphine consumption during the first 6 h and between 48 and 60 h postoperatively (P = 0.036 and 0.044, respectively). No significant differences were observed between the MMA and control groups with respect to side effects.

Conclusion

The MMA protocol used in this study was found to reduce postoperative pain and opioid consumption during the acute postoperative period after arthroscopic rotator cuff repair without increasing side effects after arthroscopic rotator cuff repair.