Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials.

BACKGROUND: Few evidence-based treatment guidelines for tendinopathy exist. We undertook a systematic review of randomised trials to establish clinical efficacy and risk of adverse events for treatment by injection. METHODS: We searched eight databases without language, publication, or date restrictions. We included randomised trials assessing efficacy of one or more peritendinous injections with placebo or non-surgical interventions for tendinopathy, scoring more than 50% on the modified physiotherapy evidence database scale. We undertook meta-analyses with a random-effects model, and estimated relative risk and standardised mean differences (SMDs). The primary outcome of clinical efficacy was protocol-defined pain score in the short term (4 weeks, range 0-12), intermediate term (26 weeks, 13-26), or long term (52 weeks, ≥52). Adverse events were also reported. FINDINGS: 3824 trials were identified and 41 met inclusion criteria, providing data for 2672 participants. We showed consistent findings between many high-quality randomised controlled trials that corticosteroid injections reduced pain in the short term compared with other interventions, but this effect was reversed at intermediate and long terms. For example, in pooled analysis of treatment for lateral epicondylalgia, corticosteroid injection had a large effect (defined as SMD>0·8) on reduction of pain compared with no intervention in the short term (SMD 1·44, 95% CI 1·17-1·71, p<0·0001), but no intervention was favoured at intermediate term (-0·40, -0·67 to -0·14, p<0·003) and long term (-0·31, -0·61 to -0·01, p=0·05). Short-term efficacy of corticosteroid injections for rotator-cuff tendinopathy is not clear. Of 991 participants who received corticosteroid injections in studies that reported adverse events, only one (0·1%) had a serious adverse event (tendon rupture). By comparison with placebo, reductions in pain were reported after injections of sodium hyaluronate (short [3·91, 3·54-4·28, p<0·0001], intermediate [2·89, 2·58-3·20, p<0·0001], and long [3·91, 3·55-4·28, p<0·0001] terms), botulinum toxin (short term [1·23, 0·67-1·78, p<0·0001]), and prolotherapy (intermediate term [2·62, 1·36-3·88, p<0·0001]) for treatment of lateral epicondylalgia. Lauromacrogol (polidocanol), aprotinin, and platelet-rich plasma were not more efficacious than was placebo for Achilles tendinopathy, while prolotherapy was not more effective than was eccentric exercise. INTERPRETATION: Despite the effectiveness of corticosteroid injections in the short term, non-corticosteroid injections might be of benefit for long-term treatment of lateral epicondylalgia. However, response to injection should not be generalised because of variation in effect between sites of tendinopathy. FUNDING: None.

Aprotinin combined with nitric oxide and prostaglandin E1 protects the canine kidney from cardiopulmonary bypass-induced injury.

OBJECTIVE: Aprotinin is frequently used to reduce blood loss during cardiac surgery; however, it also causes renal injury. Since aprotinin reduces nitric oxide (NO) and prostaglandin I(2) (PGI(2)), and both cause vasodilation and inhibit activation of neutrophils and platelets, their reduction may be responsible for the injury. This study was to determine whether the combination of aprotinin with NO and prostaglandin E(1) (PGE(1), an analogue of PGI(2)) can attenuate renal injury associated with aprotinin during cardiopulmonary bypass (CPB). METHODS: Thirty mongrel dogs were equally divided into five groups, with each group receiving CPB and aprotinin, NO, PGE(1), a combination of the three or no treatment (control). Serum creatinine and creatinine clearance were determined. To elucidate the mechanism, neutrophil, platelet and thrombin activations were also assessed. RESULTS: After CPB, serum creatinine increased and creatinine clearance decreased in all dogs. These changes were similar among the NO, PGE(1), aprotinin and control groups, but were significantly smaller in the combination group. Similarly, myeloperoxidase activities in tissues, CD11b expression, plasma elastase, prothrombin fragment (PTF) 1+2 and platelet activation factor were lower, whereas neutrophil and platelet counts were higher in the combination group than in the other groups (P<0.05). CONCLUSIONS: Aprotinin combined with NO and PGE(1) produced synergistic protective effects and improved renal function, due partly to inhibition of platelet and neutrophil activation and suppression of thrombin formation.

[The "Seville" Consensus Document on Alternatives to Allogenic Blood Transfusion. Sociedades españolas de Anestesiología (SEDAR), Medicina Intensiva (SEMICYUC), Hematología y Hemoterapia (AEHH), Transfusión sanguínea (SETS) Trombosis y Hemostasia (SETH)]. / Documento «Sevilla¼ de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica.

The Consensus Document on Alternatives to Allogenic Blood Transfusion (AABT) has been drawn up by a panel of experts from 5 scientific societies. The Spanish Societies of Anesthesiology (SEDAR), Critical Care Medicine and Coronary Units (SEMICYUC), Hematology and Hemotherapy (AEHH), Blood Transfusion (SETS) and Thrombosis and Hemostasis (SETH) have sponsored and participated in this Consensus Document. Alternatives to blood transfusion have been divided into pharmacological and non-pharmacological, with 4 modules and 12 topics. The main objective variable was the reduction of allogenic blood transfusions and/or the number of transfused patients. The extent to which this objective was achieved by each AABT was evaluated using the Delphi method, which classifies the grade of recommendation from A (supported by controlled studies) to E (non-controlled studies and expert opinion). The experts concluded that most of the indications for AABT were based on middle or low grades of recommendation, "C", "D", or "E", thus indicating the need for further controlled studies.

Documento «Sevilla» de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica / The «Seville» Consensus Document on Alternatives to Allogenic Blood Transfusion

El Documento de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica (ATSA) ha sido elaborado por un panel de expertos pertenecientes a 5 sociedades científicas. Han participado y patrocinado las sociedades españolas de Anestesiología (SEDAR), Medicina Intensiva (SEMICYUC), Hematología y Hemoterapia (AEHH), Transfusión sanguínea (SETS) y Trombosis y Hemostasia (SETH). Las alternativas a la transfusión se han clasificado en farmacológicas y no farmacológicas, con un total de 4 módulos y 12 tópicos. La disminución de las transfusiones de sangre alogénica y/o el número de pacientes transfundidos fue la principal variable objetivo. El grado de cumplimiento de este objetivo, para cada ATSA, se llevó a cabo siguiendo la metodología Delphi, que clasifica el grado de recomendación desde «A» (apoyado por estudios controlados) hasta «E» (estudios no controlados y opinión de expertos). Los expertos concluyeron que la mayor parte de las indicaciones de las ATSA se sustentan en grados de recomendación medios y bajos, «C», «D» o «E», precisándose nuevos estudios controlados (AU)

The Consensus Document on Alternatives to Allogenic Blood Transfusion (AABT) has been drawn up by a panel of experts from 5 scientific societies. The Spanish Societies of Anesthesiology (SEDAR), Critical Care Medicine and Coronary Units (SEMICYUC), Hematology and Hemotherapy (AEHH), Blood Transfusion (SETS) and Thrombosis and Hemostasis (SETH) have sponsored and participated in this Consensus Document. Alternatives to blood transfusion have been divided into pharmacological and non-pharmacological, with 4 modules and 12 topics. The main objective variable was the reduction of allogenic blood transfusions and/or the number of transfused patients. The extent to which this objective was achieved by each AABT was evaluated using the Delphi method, which classifies the grade of recommendation from A (supported by controlled studies) to E (non-controlled studies and expert opinion). The experts concluded that most of the indications for AABT were based on middle or low grades of recommendation, «C», «D», or «E», thus indicating the need for further controlled studies (AU)

Safety and efficacy of methods for reducing perioperative allogeneic transfusion: a critical review of the literature.

A number of pharmacologic and nonpharmacologic technologies are in current use to minimize perioperative homologous blood use. Clinical trials, many of them randomized controlled trials, have been done evaluating these approaches and have demonstrated their efficacy. However, data on safety has relied mostly on case reports, uncontrolled studies, and, for the pharmacologic agents, extrapolation from the nonsurgical setting. In this review I analyze the data from the randomized trials and the lower-level evidence studies to provide the best estimates in safety with these alternatives. In general, these alternatives are safe with proper dosing and monitoring of effects. With aprotinin, the primary concern is anaphylaxis, and this predominantly with re-exposure. With aprotinin and with the anti-fibrinolytics, increased venous thromboembolic risk has not been a consistent finding. Tranexamic acid use intraoperatively is advantageous, but postoperative use appears to have no advantage and may be associated with renal dysfunction. DDAVP is low-risk, provided it is not overused, which can induce hyponatremia. Autologous predonation probably has similar risks as homologous blood with respect to transfusion errors and bacterial infection. As with most medical interventions, we must be vigilant to prevent human error.

High-dose epsilon-aminocaproic acid versus aprotinin: antifibrinolytic efficacy in first-time coronary operations.

BACKGROUND: The antifibrinolytic efficacy of a high-dose regimen of epsilon-aminocaproic acid (epsilon-ACA) was compared with aprotinin in first-time coronary operations. METHODS: In a prospective, double-blinded, randomized study, 20 patients received high-dose epsilon-ACA (10 g both as a loading and cardiopulmonary bypass priming dose, 2.5 g/h until 4 hours after protamine), and another 20 patients received aprotinin (2 x 10(6) KIU [280 mg] for loading and priming, 0.5 x 10(6) KIU/h [70 mg/h]). Ten untreated patients served as controls. RESULTS: Both agents reduced postoperative levels of thrombin/antithrombin III complexes, D-dimers, fibrin degradation products, free plasma hemoglobin (epsilon-ACA versus aprotinin, p = not significant; p < 0.05 versus controls), and amount of retransfused autologous blood (p < 0.001). Epsilon-ACA increased, aprotinin suppressed antiplasmin-plasmin complex generation (epsilon-ACA versus controls, p < 0.02; epsilon-ACA versus AP, p < 0.0001). For 4 hours after discontinuation, more chest drainage occurred with epsilon-ACA than aprotinin (137 +/- 90 mL versus 62 +/- 29 mL; means +/- standard deviation; p < 0.02). Cumulative 12-hour drainage was similar for aprotinin (391 +/- 220 mL) and epsilon-ACA (582 +/- 274 mL), but higher without inhibitor (1,091 +/- 541 mL; p < 0.001 versus drugs). Postoperatively, aprotinin was associated with the lowest autologous retransfusion incidence and highest hematocrits (p < 0.01 versus epsilon-ACA). Homologous transfusion exposures did not differ. CONCLUSIONS: In first-time coronary operations, higher postoperative hematocrit and less shed blood retransfusion constitute only subtle advantages of aprotinin over high-dose epsilon-ACA.

Proteinase inhibitors and pemphigus vulgaris. An in vitro and in vivo study.

The aim of this study was to determine the inhibitory effect of clinically usable proteinase inhibitors p-aminomethylbenzoic acid (PAMBA), and aprotinin on acantholysis in skin organ culture and in clinical trials with pemphigus patients. PAMBA added to the culture medium at a concentration of 1 mg/ml fully prevented the acantholysis, while Contrykal at 10 ATrE/ml reduced acantholysis. Subsequently, we treated 12 patients (groups 1) with PAMBA 100-200 mg daily for 7 to 26 days in combination with a moderate dose of corticosteroid (mean dose 36.1 mg prednisolone equivalent) or immunosuppressive drugs. A second group of 12 patients (group 2) were treated with a high dose of corticosteroid (mean 94.2 mg prednisolone equivalent) and immunosuppressive drugs. Evaluation was performed before treatment, after 3 weeks and on discharge using a clinical scoring system. The inclusion of PAMBA in the treatment protocol of group 1 resulted in active disease being brought under control with lower corticosteroid doses. As a result, fewer side effects were observed in group 1 than in group 2. In our opinion, protease inhibitors may be useful as adjuvant drugs in the combination therapy of pemphigus.

Recombinant aprotinin in coronary artery bypass graft operations.

OBJECTIVE: To evaluate the role of recombinant bovine aprotinin in reducing blood loss in coronary artery bypass graft surgery. DESIGN: An open-label, randomized, controlled study evaluating two dosage levels of recombinant aprotinin. SETTING: Two acute care hospitals (Northwestern Memorial Hospital, Chicago, Ill., and the Scott & White Memorial Hospital, Temple, Texas). PATIENTS: Patients undergoing primary and reoperation coronary artery bypass grafting were assigned to groups by means of a computer-generated table of random numbers. Treated (n = 48) and control (n = 36) patients did not differ significantly in age, sex, weight, number of grafts, or preoperative hemoglobin level. INTERVENTIONS: Recombinant aprotinin was given at two dosages. Dosage level 1 consisted of a bolus of 2 mg/kg intravenously immediately after the induction of anesthesia, 1 mg/kg added to each liter of the oxygenator prime, and 0.5 mg.kg-1.hr-1 infused continuously during operation. At dosage level 2, doses were doubled. Intraoperative monitoring of anti-factor Xa activity was performed, and additional doses of heparin were given on the basis of anti-factor Xa results. MAIN OUTCOME MEASURES: Preoperative and postoperative hemoglobin levels, amounts of autotransfusion device and chest tube drainage blood, and transfusions of allogeneic red blood cells. Adverse clinical events (alterations in renal function, graft thrombosis, myocardial infarction, and death) were recorded. RESULTS: Additional heparin was given to 48% patients in the aprotinin group and to 44% of control patients. Overall red blood cell loss (in milliliters, mean +/- standard deviation [SD]) was decreased with aprotinin at dosage level 1 for reoperations (1040 +/- 162 vs 1544 +/- 198, p < 0.01), and at dosage level 2 for all operations (primary operations, 886 +/- 362 vs 1333 +/- 618, p = 0.02; reoperations, 1191 +/- 560 vs 1815 +/- 1116, p = 0.2). Fewer patients in the aprotinin than in the control group had transfusions of donated blood (6/48 vs 12/36, p = 0.02) or reinfusion of chest tube drainage blood (12/48 vs 20/36, p < 0.01). Among patients receiving dosage level 1, there were no myocardial infarctions or deaths. At dosage level 2, one patient had profound bradycardia and died on day 12 and two patients had late graft closures. Two control patients had hypotension after bypass necessitating intraaortic balloon pumps, and one of these patients died. Postoperative increases in blood urea nitrogen and creatinine levels were small in both aprotinin and control groups. No hypersensitivity or other allergic reactions occurred. CONCLUSION: We conclude that, at the dosages given, recombinant bovine aprotinin decreases surgical blood loss and transfusion requirements in patients undergoing coronary artery bypass grafting, but its use requires appropriate monitoring of heparin use during bypass. Whether higher dosages of aprotinin increase the risk of graft thrombosis must be further assessed with a larger patient sample.

Intraoperative antifibrinolysis and blood-saving techniques in cardiac surgery. Prospective trial of 3 antifibrinolytic drugs.

Sixty consecutive patients undergoing elective open-heart surgery were prospectively enrolled in a study to compare the efficacy of 3 different antifibrinolytic drugs to reduce postoperative bleeding and to reduce homologous blood requirements in combination with blood-saving techniques and restrictive indications for blood transfusion. The patients were randomized to 1 of 4 intraoperative treatment regimens: 1) control (no antifibrinolytic therapy); 2) epsilon-aminocaproic acid (10 g IV at induction of anesthesia, followed by infusion of 2 g/h for 5 hours); 3) tranexamic acid (10 mg/kg IV within 30 minutes after induction of anesthesia, followed by infusion of 1 mg/kg per hour for 10 hours); or 4) high-dose aprotinin (2 million KIU IV at induction of anesthesia and 2 million KIU added to the extracorporeal circuit, followed by infusion of 500 thousand KIU/h during surgery). Hemoconcentration and reinfusion of blood drained from the operative field and the extracorporeal circuit after operation were used in all patients. Indications for blood transfusion were hypotension, tachycardia, or both, with hemoglobin values < 8.5 g/dL; or severe anemia with hemoglobin values < 7 g/dL. Compared with the blood loss in the control group, patients receiving aprotinin and epsilon-aminocaproic acid showed significantly less postoperative blood loss at 1 hour (control, 128 +/- 94 mL; aprotinin, 54 +/- 47 mL, p = 0.01; and epsilon-aminocaproic acid, 69 +/- 35 mL, p = 0.03); this trend continued at 24 hours after operation (control, 724 +/- 280 mL; aprotinin, 344 +/- 106 mL, p < 0.0001; and epsilon-aminocaproic acid, 509 +/- 148 mL, p = 0.01). Aprotinin was significantly more efficient than epsilon-aminocaproic acid (p=0.002). Tranexamic acid did not have a statistically significant effect on blood loss. Homologous blood requirements were not significantly different among the groups; postoperative hematologic values and coagulation times were also comparable. Despite the efficacy of aprotinin and epsilon-aminocaproic acid shown in the present study, the blood requirements were not significantly different from those that are found when transfusions are restricted, autotransfusions are used, and blood from the operative field and extracorporeal circuit is concentrated and reinfused. Therefore, intraoperative antifibrinolysis may not be indicated in routine cardiac surgery when other blood-saving techniques are adopted.

Fibrin glue for the treatment of persistent lymphatic drainage.

A 7-year-old girl underwent resection of an abdominal wall lymphangiomatous tumor. Postoperative serous drainage, up to 300 mL per day, developed despite application of external pressure to the wound. Thirty-three days after the initial procedure, fibrin glue was applied to the draining tract. Concentrated fibrinogen was prepared from one unit of blood donated by the patient's mother. Ten milliliters fibrinogen and 10 mL thrombin (1,000 U/mL) were injected simultaneously through the wound drain as it was slowly removed, and pressure was reapplied for 48 hours. No further drainage occurred, and at 2- and 14-week follow-up examinations the wound had healed normally without reaccumulation of fluid. Fibrin glue successfully sealed this persistently draining abdominal wall tract. It is a painless, safe, and effective biologic sealant, and when prepared from homologous plasma it carries a low risk of virus transmission.

Clinical application of inhibitors of fibrinolysis.

The basic proteinase inhibitor from bovine organs, aprotinin, was first identified in 1930 and its effect on enzyme and other biological systems has since been extensively studied. Aprotinin can only be administered intravenously and has a half-life of about 2 hours. Its administration at the start of cardiopulmonary bypass surgery appears to reduce blood loss and to protect against global myocardial ischaemia. Similarly, a smaller infarct size seems to result from early administration of aprotinin within the first hour after myocardial infarction, though further studies are needed to confirm this effect. A combination of aprotinin with tranexamic acid may be effective in preventing or delaying rebleeding after rupture of an intracerebral aneurysm; the addition of aprotinin seems to decrease the incidence of delayed cerebral vasospasm and ischaemic complications which are sometimes noted when tranexamic acid alone is used. Aprotinin is also effective as adjuvant treatment in traumatic haemorrhagic shock. The recommended loading dose is 15,000 to 20,000 KIU/kg bodyweight administered as a short intravenous infusion, followed by 50,000 KIU/hour by continuous infusion. Side effects of aprotinin are very rare. Epsilon-Aminocaproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and tranexamic acid are synthetic antifibrinolytic amino acids. Saturation of the lysine binding sites of plasminogen with these inhibitors displaces plasminogen from the fibrin surface. On a molar basis tranexamic acid is at least 7 times more potent that epsilon-aminocaproic acid and twice as potent as p-aminomethylbenzoic acid. All 3 compounds are readily absorbed from the gastrointestinal tract and excreted in active form in the urine. The plasma half-life of tranexamic acid is about 80 minutes. The main indications for tranexamic acid are the prevention of excessive bleeding after tonsillectomy, prostatic surgery, and cervical conisation, and primary and IUD-induced menorrhagia. It is possible that gastric and intestinal bleeding can also be reduced as well as recurrent epistaxis. Tranexamic acid could also be useful after ocular trauma. The value of fibrinolysis inhibitors in the prevention of bleeding after tooth extraction in patients with haemophilia is well documented, as is the treatment of hereditary angioneurotic oedema. The usual dose of tranexamic acid is 0.5 to 1g (10 to 15 mg/kg bodyweight) given intravenously 2 to 3 times daily, or 1 to 1.5 g orally 3 to 4 times daily. This dose needs to be reduced in patients with renal insufficiency. The main side effects of tranexamic acid are nausea or diarrhoea.