Use and safety of aprotinin in routine clinical practice: A European postauthorisation safety study conducted in patients undergoing cardiac surgery.

BACKGROUND: Aprotinin has been used to reduce blood loss and blood product transfusions in patients at high risk of major blood loss during cardiac surgery. Approval by the European Medicines Agency (EMA) for its current indication is limited to patients at high risk of major blood loss undergoing isolated coronary artery bypass graft surgery (iCABG). OBJECTIVE: To report current real-world data on the use and certain endpoints related to the safety of aprotinin in adult patients. DESIGN: The Nordic aprotinin patient registry (NAPaR) received data from 83 European centres in a noninterventional, postauthorisation safety study (PASS) performed at the request of the EMA. SETTING: Cardiac surgical centres committed to enrolling patients in the NAPaR. PATIENTS: Patients receiving aprotinin agreeing to participate. INTERVENTION: The decision to administer aprotinin was made by the treating physicians. MAIN OUTCOME MEASURES: Aprotinin safety endpoints were in-hospital death, thrombo-embolic events (TEEs), specifically stroke, renal impairment, re-exploration for bleeding/tamponade. RESULTS: From 2016 to 2020, 5309 patients (male 71.5%; >75 years 18.9%) were treated with aprotinin; 1363 (25.7%) underwent iCABG and 3946 (74.3%) another procedure, including a surgical treatment for aortic dissection ( n  = 660, 16.7%); 54.5% of patients received the full-dose regimen. In-hospital mortality in iCABG patients was 1.3% (95% CI, 0.66 to 1.84%) vs. 8.3% (7.21 to 8.91%) in non-iCABG patients; incidence of TEEs and postoperative rise in creatinine level greater than 44 µmol l -1 2.3% (1.48 to 3.07%) and 2.7% (1.79 to 3.49%) vs. 7.2% (6.20 to 7.79%) and 15.5% (13.84 to 16.06%); patients undergoing re-exploration for bleeding 1.4% (0.71 to 1.93%) vs. 3.0% (2.39 to 3.44%). Twelve cases of hypersensitivity/anaphylactic reaction (0.2%) were reported as Adverse Drug Reactions. CONCLUSION: The data in the NApaR indicated that in this patient population, at high risk of death or blood loss undergoing cardiac surgery, including complex cardiac surgeries other than iCABG, the incidence of adverse events is in line with data from current literature, where aprotinin was not used. TRIAL REGISTRATION: EU PAS register number: EUPAS11384.

Cardiothoracic Anesthesia and Critical Care in the United Kingdom (UK) Part 1: Some Insights Into the History and Development.

This review is intended to highlight some of the historic events that contributed to the development of thoracic and cardiac anesthesia and surgery in Great Britain and Northern Ireland (UK). The aim of this first of two parts is to concentrate on the development of techniques, facilities, and pharmacology that allowed progress and advancement in patient management that were developed primarily in the UK. However, progress usually requires input from a wide variety of sources of knowledge, and cardiothoracic practice is no exception. Reference is, thus, made to sources outside of the UK that guided, influenced, or inspired changes in practice, such as the techniques of operating on the heart and great vessels in war casualties, developed by Dr. Dwight Harken, or the demonstration of the Blalock-Thomas-Taussig shunt by Alfred Blalock. In addition to advances in medical equipment, such as computed tomography, the UK contributed greatly to pharmacologic interventions that were unique at the time in such varied areas as nonflammable volatile anesthetic agents, heart failure treatments, and neuromuscular blocking agents for both cardiac and thoracic surgical practice.

Tranexamic acid in cardiac surgery: is there a cause for concern?

The withdrawal of marketing approval for aprotinin resulted in more clinicians administering tranexamic acid to patients at increased risk of bleeding and adverse outcome. The latest in a series of retrospective analyses of observational data is published in Critical Care and suggests an increase in mortality, when compared to data from the aprotinin era, in those patients having surgery when a cardiac chamber is opened. The added observation of an increase in cerebral excitatory phenomena (seizure activity) with tranexamic acid has a known mechanism and questions if such patients should be given this drug.

Aprotinin and renal dysfunction.

Aprotinin is a polypeptide serine protease inhibitor used to prevent bleeding and need for transfusions in patients having heart surgery. A recent analysis of an observational study data set suggested the use of aprotinin was associated with an increased risk of developing renal failure. The present article reviews the data from basic science studies in tissues, animals and man together with the data from observational studies and randomised controlled trials. The interpretation of the data is hampered owing to the use of different endpoints to describe mild/moderate renal impairment. Nonetheless, the evidence points to aprotinin use being associated with a transient small rise in plasma creatinine concentration in certain patients. There is no evidence for an increased risk of developing new renal failure requiring dialysis/renal replacement therapy.

Dynamics of nitroglycerin-induced exhaled nitric oxide after lung transplantation: evidence of pulmonary microvascular injury?

BACKGROUND: In search of real-time molecular correlates to ischemia-reperfusion-induced lung injury, we explored the hypothesis that liberation of nitric oxide (NO) into exhaled breath after pulmonary microvascular bioconversion of nitroglycerin (GTN) is attenuated in clinical lung transplantation. METHODS: Exhaled NO was measured under basal conditions and after intravenous administration of GTN in patients undergoing lung transplantation. Patients undergoing routine cardiac surgery served as controls. Basal and GTN-induced exhaled NO was also measured in donors before retrieval and after implantation in recipients. RESULTS: The characteristic GTN-induced exhaled NO response observed in cardiac surgical patients before cardiopulmonary bypass and in lung transplant and multiple-organ donors was nearly totally abolished in lung transplant recipients. This response was also attenuated to a lesser degree in the routine cardiac surgery patients after cardiopulmonary bypass. CONCLUSIONS: These results suggest a graded influence of time-factored complete and partial ischemia on GTN-induced evolution of NO into exhaled breath, providing biochemical evidence for a degree of microvascular injury, which can be monitored non-invasively at the bedside.

Long-term outcome of patients with perioperative myocardial infarction as diagnosed by troponin I after routine surgical coronary artery revascularization.

OBJECTIVE: Diagnosis of perioperative myocardial infarction (P-MI) after coronary artery bypass graft (CABG) surgery traditionally relied on a combination of electrocardiographic and enzyme assay changes. Patients with Q-wave P-MIs who survive to hospital discharge have a poorer long-term prognosis. Troponin assays are more sensitive and specific for detecting minor P-MI, with an increased incidence of P-MI being reported. This study investigated if P-MI after CABG surgery, as defined by troponin-I isozyme (cTn-I), correlated with long-term outcome. DESIGN: A prospective, observational study. SETTING: A single-institution, cardiothoracic specialty hospital. PARTICIPANTS: Seventy patients undergoing elective CABG surgery. INTERVENTIONS: Patients (n = 70) were stratified into low-risk and high-risk groups according to the absence (cTn-I <15 microg/L) or presence (cTn-I >or=15 microg/L) of P-MI after CABG surgery. Patients with (n = 24) and without (n = 46) P-MI were then followed for 3 years after CABG surgery to determine the impact of cTn-I-defined P-MI on long-term outcome. MEASUREMENTS AND MAIN RESULTS: Most patients felt that their quality of life and activity index had improved and that their symptoms of angina had lessened at 12-month follow-up. However, cardiovascular event-free survival was significantly less in patients with P-MI (p = 0.01) 3 years postoperatively. The incidence for cardiovascular events was 0.24 versus 0.65 (p = 0.049) in those patients without and with P-MI, respectively. The hazard ratio (2.9; 95% confidence interval, 1.3-9.4) for cardiovascular incidents was also significantly greater in patients with P-MI. More specifically, the incidence of arrhythmia was 2.4% versus 26.1% (p < 0.01), and the incidence of vascular events was 4.9% versus 26.1% (p = 0.02) in patients without and with P-MI, respectively. CONCLUSIONS: It was shown that P-MI as defined by cTn-I is associated with an increased long-term incidence of adverse cardiovascular events. An elevated peak cTn-I level (>or=15 microg/L) identified patients at increased risk but did not have a powerful positive predictive value for either cardiovascular (48%) or vascular (26%) complications. However, a peak cTn-I <15 microg/L was a negative predictor of adverse vascular outcome (95%). This may have implications for postoperative patient follow-up.

Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes.

BACKGROUND: Inappropriate activation of hemostasis and inflammation may contribute to postoperative morbidity and mortality. The serine protease inhibitor, aprotinin, has been shown to prevent tissue and organ injury in laboratory and animal studies. In this retrospective analysis, we evaluated the relationship of aprotinin therapy with organ dysfunction in humans undergoing coronary artery bypass graft surgery (CABG). METHODS: Data from prospective randomized, double-blind, placebo-controlled studies evaluating the safety and efficacy of full-dose aprotinin (2 million KIU load, 2 million KIU pump prime, and 0.5 million KIU/h continuous infusion) to reduce blood loss and transfusion requirements in patients undergoing CABG (placebo, n = 861; aprotinin, n = 862) were examined retrospectively. Primary end-points were death, adverse cerebrovascular outcome, myocardial infarction (MI), and pharmacological interventions (inotropic drugs, vasopressors, and antiarrhythmics). RESULTS: Univariate analysis showed that relative to placebo, full-dose aprotinin therapy was associated with significant effects on the incidence of adverse cerebrovascular outcome (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.19-0.93; P = 0.03) and use of inotropic drugs (OR 0.79, 95% CI 0.65-0.97; P = 0.02), vasopressors (OR 0.74, 95% CI 0.61-0.90; P < 0.01), and antiarrhythmics (OR 0.79, 95% CI 0.65-0.96; P = 0.02), but not death (OR = 1.00, 95% CI 0.54-1.85; P = 1.0) or MI (OR 0.92, 95% CI 0.64-1.31; P = 0.6). Multivariate analysis confirmed results of univariate analysis. CONCLUSIONS: This retrospective analysis of data collected from prospective, randomized, placebo-controlled studies in CABG shows that full-dose aprotinin use was associated with a lower risk of adverse cerebrovascular outcomes and a reduced need for use of vasoactive drugs; the risk of death and perioperative MI was not affected by aprotinin therapy.

Safety aspects of aprotinin therapy in cardiac surgery patients.

Aprotinin is the only agent with Class A Level 1 evidence for reduction in rates of transfusion and return to operating theatre to control bleeding after heart surgery. Principal on the list of safety issues raised over the years are increased risk for: a) thrombosis; and b) renal dysfunction. With multiple administrations, hypersensitivity reactions have emerged as a further safety concern. This review discusses these issues, based on the examination of > 500 published articles. The article also specifically places in context the data presented recently from the observational McSPI database analysis. This report suggested that aprotinin should be withdrawn from human use as serious safety issues have been ignored or missed, an inference not in agreement with the majority of the human safety literature.

Correlation between pulmonary gas exchange and basal and nitroglycerin (GTN)-induced exhaled nitric oxide (eNO) in patients undergoing cardiac surgery.

The relationship between eNO and events in the alveolar-capillary unit in acute lung injury remains to be established. Since endogenous eNO largely originates from the airway epithelium, but nitroglycerin (GTN)-induced eNO is due to microvascular/alveolar metabolism, we have proposed to use basal and GTN-induced eNO as metabolic markers of the airway--and microvascular/alveolar function, respectively. The current work investigates the relationship between basal and GTN-induced eNO and oxygenation parameters (PaO(2)/FiO(2) ratio) in patients undergoing cardiac surgery utilising cardiopulmonary bypass (CPB). Breath by breath eNO measurements were made in 10 patients before, and 1 and 3 h after CPB either under basal conditions or following intravenous administration of GTN (1, 2 and 3 microg/kg). Basal eNO remained unchanged, whereas GTN-induced eNO was reduced following CPB. Also, there was a transient reduction in PaO(2)/FiO(2) ratio 1 h after CPB (32+/-4 vs. 44+/-3 kPa). A negative correlation was found between oxygenation and basal eNO by Pearson's correlation test and linear regression analysis suggesting that decreased oxygenation was associated with increased basal eNO. In contrast, a decrease in GTN-induced eNO positively correlated with reduced oxygenation index (R=0.533, p=0.002). These data suggest that differential relationships exist between basal and nitrovasodilator-induced eNO and oxygenation indices during subclinical lung injury in patients following CPB and that GTN-induced eNO evolution may reflect better microvascular events and injury.

The comparison and validity of troponin I assay systems in diagnosing myocardial ischemic injury after surgical coronary revascularization.

OBJECTIVE: A prospective observational study was conducted to test the agreement between 2 commercially available automated cardiac troponin-I immunoassay systems (Opus Plus, Behring Diagnostics UK Ltd, Hounslow, UK; AxSYM, Abbott Laboratories, Abbott Park, IL) and to determine a normal reference range and threshold value indicative of perioperative myocardial infarction (PMI) after elective coronary artery bypass graft (CABG) surgery for the Opus Plus system. DESIGN: Prospective, observational study. Setting : Single institution, cardiothoracic specialty hospital. PARTICIPANTS: Seventy patients undergoing elective CABG surgery. INTERVENTIONS: After institutional review board approval, patients received standardized anesthetic, surgical, and myocardial preservation techniques. Serial electrocardiographs, creatine kinase-MB, troponin-I, and perioperative outcome data were collected. Correlation between the immunoassay systems was tested using 124 duplicate samples from the first 18 patients. The normal reference range and threshold value indicative of PMI were tested for the Opus Plus system using duplicate samples from all 70 patients. MEASUREMENTS AND MAIN RESULTS: Peak troponin-I concentrations (median [interquartile range]) differed significantly when measured by the Opus Plus and AxSYM immunoassay systems (5.61 [3.20-22.35] microg/L v 46.50 [14.55-70.95] microg/L, respectively; p < 0.001). There was clear proportional bias that was corrected with log transformation of the raw data. By using confidence interval and receiver operating characteristic curve analysis, the authors showed that a value > or =15 mug/L was indicative of PMI (Opus Plus system) and accordingly report a 35.7% (2.9% Q-wave) overall incidence of PMI in this study population (n = 70). CONCLUSIONS: These data highlight differences between commercially available troponin-I assay systems. The authors recommend that each institution establish a local reference range and threshold indicative of perioperative myocardial infarction for its specific patient population and assay system and provide sample methodology.

Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes.

BACKGROUND: Platelet (PLT) transfusions are administered in cardiac surgery to prevent or treat bleeding, despite appreciation of the risks of blood component transfusion. The current analysis investigates the hypothesis that PLT transfusion is associated with adverse outcomes associated with coronary artery bypass graft surgery (CABG). STUDY DESIGN AND METHODS: Data originally collected during double-blind placebo-controlled phase III trials for licensure of Trasylol (aprotinin injection) were retrospectively analyzed. Adverse outcome data of patients (n = 1720) that received, and did not receive, perioperative PLT transfusion were compared. Logistic regression analysis was used to assess the association of perioperative adverse events with PLT transfusion. Propensity scoring analysis was used to verify results of the logistic regression. RESULTS: Patients receiving PLTs were more likely to have prolonged hospital stays, longer surgeries, more bleeding, re-operation for bleeding, and more RBC transfusions, and less likely to have full-dose aprotinin administration. Adverse events were statistically more frequent in patients that received one or more PLT transfusion. Logistic regression analysis showed that PLT transfusion was associated with infection, vasopressor use, respiratory medication use, stroke, and death. Propensity scoring analysis confirmed the risk of PLT transfusion. CONCLUSIONS: PLT transfusion in the perioperative period of CABG was associated with increased risk for serious adverse events. PLT transfusion may be a surrogate marker for sicker patients and have no causal role in the outcomes observed. However, a direct contribution to outcomes remains possible.

Myocardial protection using fructose-1,6-diphosphate during coronary artery bypass graft surgery: a randomized, placebo-controlled clinical trial.

UNLABELLED: In vitro and in vivo studies suggest that fructose-1,6-diphosphate (FDP), an intermediary glycolytic pathway metabolite, ameliorates ischemic tissue injury through increased high-energy phosphate levels and may therefore have cardioprotective properties in patients undergoing coronary artery bypass graft (CABG) surgery. We designed a randomized, placebo-controlled, double-blinded, sequential-cohort, dose-ranging safety study to test 5 FDP dosage regimens in patients (n = 120; 60 FDP, 60 control) undergoing CABG surgery. Of these dosage regimens, 3 produced no benefit, 1 produced improved cardiac function, and 1 required adjustment as a result of metabolic acidosis. This suggests that we achieved the intended effect of a dose-ranging study. The expected response was observed in patients treated with 250 mg/kg FDP IV before surgery and 2.5 mM FDP as a cardioplegic additive (n = 15). These patients had lower serum creatine kinase-MB levels 2, 4, and 6 h after reperfusion (P < 0.05), fewer perioperative myocardial infarctions (P < 0.05), and improved postoperative cardiac function, as evidenced by higher left ventricular stroke work index (LVSWI) 6, 12, and 16 h (P < 0.01) and cardiac index (CI) at 12 and 16 h (P < 0.05) after reperfusion. Overall efficacy of FDP was tested across all regimens that included IV FDP (n = 88; 44 FDP, 44 control) using 2 (FDP versus placebo) x 3 (dose size) factorial analyses. Area-under-curve (AUC) analysis demonstrated a significant increase in CI (AUC-16h, P = 0.013) and LVSWI (AUC-16h, P = 0.003) and reduction in CK-MB levels (AUC-16h, P < 0.05) in FDP-treated patients. The internal consistency of this dataset suggests that FDP may provide myocardial protection in CABG surgery and supports previous laboratory and clinical studies of FDP in ischemic heart disease. IMPLICATIONS: Fructose-1,6-diphosphate (FDP) may increase high-energy phosphate levels under anaerobic conditions and therefore ameliorate ischemic injury. A dose-ranging safety study for FDP was conducted in patients undergoing coronary artery surgery. Preischemic provision of FDP significantly improved cardiac function and reduced perioperative ischemic injury. These myocardial protective effects may improve patient outcome after cardiac surgery.

Anaesthesia: the patient's point of view.

Patients scheduled for surgical procedures continue to express concerns about their safety, outcome, and comfort. All medical interventions carry risks, but the patient often considers anaesthesia as the intervention with the greatest risk. Many still worry that they will not wake up after their surgery, or that they will be awake during the operation. Such events have received attention from the media, but are very rare. Challenges to improve the comfort of patients continue, especially with regard to the almost universal problems of nausea, vomiting, and pain after surgery. A newer concern is that patients will develop some degree of mental impairment that may delay return to a full work and social lifestyle for days and weeks. Developments in technology, education, and training have had a major effect on anaesthetic practice, so that anaesthesia is increasingly regarded as safe for the patient. This article explores patients' concerns, and considers whether science and technology help to provide solutions to these complex difficulties.