Use of topical tranexamic acid or aminocaproic acid to prevent bleeding after major surgical procedures.

OBJECTIVE: To evaluate the literature describing topical use of tranexamic acid or aminocaproic acid for prevention of postoperative bleeding after major surgical procedures. DATA SOURCES: Literature was retrieved through MEDLINE (1946-September 2011) and International Pharmaceutical Abstracts (1970-September 2011) using the terms tranexamic acid, aminocaproic acid, antifibrinolytic, topical, and surgical. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All identified articles in English were evaluated. Clinical trials, case reports, and meta-analyses describing topical use of tranexamic acid or aminocaproic acid to prevent postoperative bleeding were included. DATA SYNTHESIS: A total of 16 publications in the setting of major surgical procedures were included; the majority of data were for tranexamic acid. For cardiac surgery, 4 trials used solutions containing tranexamic acid (1-2.5 g in 100-250 mL of 0.9% NaCl), and 1 trial assessed a solution containing aminocaproic acid (24 g in 250 mL of 0.9% NaCl). These solutions were poured into the chest cavity before sternotomy closure. For orthopedic procedures, all of the data were for topical irrigation solutions containing tranexamic acid (500 mg-3 g in 50-100 mL of 0.9% NaCl) or for intraarticular injections of tranexamic acid (250 mg to 2 g in 20-50 mL of 0.9% sodium chloride, with or without carbazochrome sodium sulfate). Overall, use of topical tranexamic acid or aminocaproic acid reduced postoperative blood loss; however, few studies reported a significant reduction in the number of packed red blood cell transfusions or units given, intensive care unit stay, or length of hospitalization. CONCLUSIONS: Topical application of tranexamic acid and aminocaproic acid to decrease postsurgical bleeding after major surgical procedures is a promising strategy. Further data are needed regarding the safety of this hemostatic approach.

A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.

BACKGROUND: Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences. METHODS: In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days. RESULTS: The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22). CONCLUSIONS: Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).

The effect of aprotinin on outcome after coronary-artery bypass grafting.

BACKGROUND: Aprotinin has recently been associated with adverse outcomes in patients undergoing cardiac surgery. We reviewed our experience with this agent in patients undergoing cardiac surgery at Duke University Medical Center. METHODS: We retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at Duke between January 1, 1996, and December 31, 2005. We fit data to a logistic-regression model predicting each patient's likelihood of receiving aprotinin on the basis of preoperative characteristics and to models predicting long-term survival (up to 10 years) and decline in renal function, as measured by increases in serum creatinine levels. RESULTS: A total of 1343 patients (13.2%) received aprotinin, 6776 patients (66.8%) received aminocaproic acid, and 2029 patients (20.0%) received no antifibrinolytic therapy. All patients underwent coronary-artery bypass grafting, and 1181 patients (11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic therapy (P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic acid (P=0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin use was also associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001) but not with a greater risk-adjusted incidence of dialysis (P=0.56). CONCLUSIONS: Patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who received aminocaproic acid or no antifibrinolytic agent.

[Aprotinin in cardiac surgery: more risks than usefulness?]. / Aprotinin in der Kardiochirurgie: Mehr Risiko als Nutzen?

Antifibrinolytic therapy with the serine protease inhibitor Aprotinin or the lysine analogues epsilon-aminocapronic acid or tranexamic acid is a therapeutic measure to reduce perioperative blood loss during cardiac surgery. In an international, prospective, non-randomised phase 4 observation study, Mangano et al. investigated the effectiveness and side-effects of Aprotinin, epsilon-aminocapronic acid and tranexamic acid in comparison to no antifibrinolytic therapy in a total of 4,374 patients who underwent cardiac surgery with extracorporeal circulation. In the opinion of Mangano et al. the results of this study question the safety and effectiveness of Aprotinin for reduction of perioperative blood loss by cardiac surgery patients. Despite a critical review of the study and results reported by Mangano et al., the authors of the present paper come to the conclusion that, in view of the availability of more reasonably priced alternatives in Germany, it appears to be sensible to give preference to tranexamic acid instead of aprotinin.

The risk associated with aprotinin in cardiac surgery.

BACKGROUND: The majority of patients undergoing surgical treatment for ST-elevation myocardial infarction receive antifibrinolytic therapy to limit blood loss. This approach appears counterintuitive to the accepted medical treatment of the same condition--namely, fibrinolysis to limit thrombosis. Despite this concern, no independent, large-scale safety assessment has been undertaken. METHODS: In this observational study involving 4374 patients undergoing revascularization, we prospectively assessed three agents (aprotinin [1295 patients], aminocaproic acid [883], and tranexamic acid [822]) as compared with no agent (1374 patients) with regard to serious outcomes by propensity and multivariable methods. (Although aprotinin is a serine protease inhibitor, here we use the term antifibrinolytic therapy to include all three agents.) RESULTS: In propensity-adjusted, multivariable logistic regression (C-index, 0.72), use of aprotinin was associated with a doubling in the risk of renal failure requiring dialysis among patients undergoing complex coronary-artery surgery (odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31). Similarly, use of aprotinin in the latter group was associated with a 55 percent increase in the risk of myocardial infarction or heart failure (P<0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P=0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. Adjustment according to propensity score for the use of any one of the three agents as compared with no agent yielded nearly identical findings. All the agents reduced blood loss. CONCLUSIONS: The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.

Predictors of pericardial effusion after orthotopic heart transplantation.

OBJECTIVES: Pericardial effusion occurs frequently after orthotopic heart transplantation, but the causes of this complication have not been well described. This study was designed to identify factors predisposing toward the development of significant postoperative pericardial effusions in a large, single-institution population of orthotopic heart transplant recipients. METHODS: A retrospective review of more than 90 preoperative, intraoperative, and postoperative variables was conducted for 241 patients undergoing orthotopic heart transplantation from September 1988 to December 1999. Patients who had significant postoperative pericardial effusions develop were identified from postoperative echocardiograms by standard criteria. Factors associated with the development of significant pericardial effusions were determined by multivariate logistic regression analysis. RESULTS: Echocardiographic data were available for 203 of 241 transplant recipients. Forty-two patients (21%) had significant effusions develop. According to multivariate analysis, pericardial effusions were less likely to occur in recipients with a history of previous cardiac surgery (odds ratio 0.13, 95% confidence interval 0.05-0.36, P <.0001) and with greater weight (odds ratio 0.96, 95% confidence interval 0.94-0.99, P <.0048). Pericardial effusions were more likely to occur in patients who had received aminocaproic acid during the operation (odds ratio 5.92, 95% confidence interval 2.23-15.72, P <.0008). Patient survival and hospital length of stay did not differ between patients with and without postoperative pericardial effusions. CONCLUSIONS: Postoperative pericardial effusions develop in approximately 20% of patients undergoing orthotopic cardiac transplantation. On the basis of the risk factors identified in this study, prevention may prove difficult, although avoidance of the intraoperative use of aminocaproic acid may be helpful.

High anion gap metabolic acidosis associated with aminocaproic acid.

OBJECTIVE: To report a case of high anion gap metabolic acidosis related to infusion of aminocaproic acid (ACA) that temporarily corrected during hemodialysis and resolved upon ACA discontinuation. CASE SUMMARY: A 65-year-old white woman with staphylococcal sepsis complicated by acute renal failure was treated with ACA to control a hemorrhagic coagulopathy. After receiving an initial 5-g bolus of ACA, she received a continuous intravenous infusion of 500 mg/h for just over 5 days, then 250 mg/h for a final 12 hours. Immediately after beginning ACA therapy, she developed a severe anion gap metabolic acidosis that briefly improved after hemodialysis. The condition resolved completely only after the discontinuation of ACA and therapy with a systemic alkalinizer. DISCUSSION: ACA is not among the previously identified causes of high anion gap metabolic acidosis. The temporal profile relating anion gap to ACA initiation, hemodialysis treatment, and ACA discontinuation supports causality in this case. The magnitude of increase in the anion gap appears to have been proportional to the dose of ACA. CONCLUSIONS: In patients with renal impairment, ACA administration may produce a dose-related, high anion gap metabolic acidosis that might be reversible during hemodialysis. Insufficient data are available, but when ACA must be used in such patients, a more conservative dosing of ACA should be coupled with close monitoring.

Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints.

BACKGROUND: Excessive bleeding may complicate cardiac surgery, and is associated with increased morbidity and mortality. Pharmacological strategies to decrease perioperative bleeding have been investigated in a large number of controlled trials, most of which have shown a decrease in blood loss. However, most studies lacked sufficient power to detect a beneficial effect on clinically more relevant outcomes. We did a meta-analysis of all randomised, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin). METHODS: Studies were included if they reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative myocardial infarction) in addition to perioperative blood loss. In addition, a separate meta-analysis was done for studies concerning complicated cardiac surgery. FINDINGS: We identified 72 trials (8409 patients) that met the inclusion criteria. Treatment with aprotinin decreased mortality almost two-fold (odds ratio 0.55 [95% CI 0.34-0.90]) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical re-exploration (0.37 [0.25-0.55], and 0.44 [0.22-0.90], respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion. By contrast, the use of desmopressin resulted in a small decrease in perioperative blood loss, but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2.4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results. INTERPRETATION: Pharmacological strategies that decrease perioperative blood loss in cardiac surgery, in particular aprotinin and lysine analogues, also decrease mortality, the need for rethoracotomy, and the proportion of patients receiving a blood transfusion.

Positivity of patch tests in cutaneous reaction to aminocaproic acid: two case reports.

We observed two cases of maculopapular eruption occurring 12-72 h after the administration of aminocaproic acid (ACA). Patch tests performed with ACA were positive. Clinical and allergologic patterns suggest the type IV mechanism of hypersensitivity. We present what we believe are the first two cases described of hypersensitivity to this drug.

Fibrel.

Fibrel is a useful product for the treatment of depressed cutaneous scars, facial lines, and wrinkles. There have been documented increases in collagen production and inflammatory response over time. Adverse reactions seem to be minimal. If a more user-friendly product can be used--no plasma, minimal inflammatory response, 30-gauge needle--Fibrel should be considered in all patients for soft tissue augmentation.

Vigabatrin: clinical evidence supporting rational polytherapy in management of uncontrolled seizures.

Monotherapy is the policy for management of patients with epilepsy. With increasing knowledge of the biology of epilepsy and of the modes of action of antiepileptic drugs (AEDs), this concept must be reevaluated. When monotherapy fails to control seizures, subsequent treatment should be based on "rational pharmacology," taking into consideration the mode of action of the drugs, to provide improved efficacy with maintained tolerance and ease of administration. Introduction of vigabatrin (VGB) as a new AED calls for just such a reevaluation. VGB is an enzyme-activated irreversible inhibitor of gamma-aminobutyric acid (GABA)-transaminase that increases brain and cerebrospinal (CSF) GABA concentrations in animals and humans. It has limited efficacy in the classic animal seizure screening tests, but in many clinical studies has halved the incidence of seizures in approximately 50% of patients, especially those with partial epilepsies. We evaluated the efficacy of VGB in "socially integrated and active outpatients" as a likely subset to demonstrate any advantage of rational polytherapy. The criteria for this evaluation included the effects on seizure frequency, patient tolerability, and cognitive performance in a battery of psychometric tests. Fourteen of the 19 patients (73%) completing the study had > 50% reduction in seizure frequency, and 10 of 19 (52%) had > 70% reduction in seizure frequency. Tolerability appeared good; somnolence was the most frequent adverse event. Three patients complained of a worsening of their seizures, 1 with an increase in frequency and 2 with development of myoclonic jerks not previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

[Allergic vasculitis caused by Vigabatrin]. / Allergische Vaskulitis durch Vigabatrin.

A patient with focal epilepsy that was resistant to medical treatment received add-on therapy with vigabatrin. Six months after commencement of vigabatrin therapy, allergic vasculitis caused by vigabatrin was diagnosed. The patient displayed unilateral anterior ischaemic optic neuropathy with impairment of vision and concentric loss of visual field. The diagnosis was based on the lymphocyte transformation test and the clinical course. The allergic vasculitis was healed by cortisone therapy.

Antiepileptic drugs in development: prospects for the near future.

Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.

Effect of vigabatrin on sedation and cognitive function in patients with refractory epilepsy.

Twenty-four patients with refractory epilepsy on one or more antiepileptic drugs were given additional vigabatrin (1 g twice daily for six weeks, followed by 1.5 g twice daily for a further six weeks) and matched placebo in a double blind, randomised, crossover study. A battery of neuropsychological tests was administered at baseline and at weeks two, six and 12 of both treatment periods. No significant differences were found between vigabatrin and placebo at any time point for any of the objective tests of cognitive function. Patients, however, reported a greater degree of sedation after two and six weeks on vigabatrin than during the equivalent placebo phase (p < 0.01), although no such difference was apparent at 12 weeks. Follow up over a mean of 14.75 months in 12 responders, who continued on vigabatrin, revealed a significant improvement (all p < 0.01) on each of three composite scales (three psychomotor tests, four memory tests, three self rating scales) compared with their scores during the double blind trial. Vigabatrin did not cause cognitive impairment either acutely or in the long term. Phased introduction, however, seems a prudent policy to allow tolerance to early subjective sedation.