Postoperative troponin release is associated with major adverse cardiovascular events in the first year after noncardiac surgery.

INTRODUCTION: Troponin elevations after intermediate-to-high risk noncardiac surgery are common and can predict mortality. However, the prognostic value for early and late major adverse cardiovascular events (MACE) is less well investigated. The authors evaluated the relationship between postoperative troponin release and MACE in the first year after noncardiac surgery. METHODS: This observational cohort registry comprised data of patients aged ≥60 years undergoing intermediate-to-high risk noncardiac surgery between July 2012 and 2015, at the Erasmus University Medical Center, Rotterdam, the Netherlands. High-sensitivity troponin T was measured on day 1 to 3 after surgery. Peak troponin values were divided into four categories: <14 ng·L-1, 14-49 ng·L-1, 50-149 ng·L-1 and ≥150 ng·L-1. The primary endpoint MACE was defined as the occurrence of myocardial infarction, angina, revascularization therapy or cerebrovascular accident in the first year after surgery. The incidence of MACE and all-cause mortality was calculated using Kaplan-Meier estimates. Cox regression was used to estimate risks for both endpoints. RESULTS: In total, 3085 patients were included for analyses and peak troponin elevation above 14 ng·L-1 was present in 1678 (54.4%) patients. The overall incidence for one-year MACE was 5.8% (3.4%, 6.1%, 10.4% and 40.6% per increasing troponin category) with adjusted HR (95% CI) 1.32 (0.85-2.06), 2.53 (1.42-4.53) and 10.24 (5.91-17.75) for the consecutive increasing categories. One-year mortality occurred in 14.6% and showed a similar stepwise increase with adjusted HR (95% CI) 1.25 (0.98-1.60), 2.39 (1.72-3.32) and 3.79 (2.60-5.54). CONCLUSION: Our dataset demonstrates a graded relationship between postoperative troponin release and occurrence of MACE in the first year after intermediate-to-high risk noncardiac surgery.

Prognostic value of postoperative high-sensitivity troponin T in patients with different stages of kidney disease undergoing noncardiac surgery.

BACKGROUND: Emerging evidence suggests that postoperative troponin release is a strong and independent predictor of short-term mortality. However, evaluating elevated troponins in patients with chronic kidney disease (CKD) is still controversial and is often disregarded. This study examines morbidity along with short- and long-term mortality risk associated with elevated high-sensitivity troponin T (hsTnT) in patients with different stages CKD undergoing noncardiac surgery. METHODS: This observational cohort comprised 3262 patients aged ≥60 yr who underwent noncardiac surgery. Postoperative hsTnT concentrations were divided into normal [<14 ng l-1 (reference)], low (14-49 ng l-1), moderate (50-149 ng l-1), and high (≥150 ng l-1) groups. A threshold of 50 ng l-1 was used to dichotomize hsTnT. The study endpoints were 30-day and long-term all-cause mortality, and postoperative myocardial infarction. RESULTS: Postoperative hsTnT was associated with a stepwise increase in 30-day and long-term mortality risk: low hsTnT adjusted hazard ratio (HR) 1.4 [95% confidence interval (CI): 1.1-1.7], moderate hsTnT adjusted HR 3.1 (95% CI: 2.3-4.3), high hsTnT adjusted HR 5.5 (95% CI: 3.6-8.4). Postoperative hsTnT ≥50 ng l-1 was associated with 30-day and long-term mortality risk for each stage of CKD. Elevated troponin concentrations in severe CKD (estimated glomerular filtration rate <30 mL min-1 1.73 m-2), however, did not predict short-term death. CONCLUSIONS: Elevated postoperative hsTnT is associated with a dose-dependent increase in 30-day and long-term mortality risk in each stage of CKD with an estimated glomerular filtration rate ≥30 ml min-1 1.73 m-2.

Association between postoperative mean arterial blood pressure and myocardial injury after noncardiac surgery.

BACKGROUND: Myocardial injury after noncardiac surgery is common, although the exact pathophysiology is unknown. It is plausible that hypotension after surgery is relevant for the development of myocardial injury. The authors evaluated whether low mean arterial pressures (MAPs) after surgery are related to an increased incidence in postoperative cardiac-troponin elevation. METHODS: A prospective cohort of 2211 patients aged ≥60 yr, undergoing major or moderate noncardiac surgery in The Netherlands, was retrospectively analysed for the occurrence of postoperative cardiac-troponin elevation [high-sensitive troponin T (hsTnT) >14 ng L-1]. Blood pressures after surgery were recorded and divided into quartiles based on the lowest MAP prior to peak troponin recording. The association between MAP and extent of postoperative cardiac-troponin elevation was analysed. RESULTS: The patients were divided into quartiles based on their lowest MAP in the period preceding the peak hsTnT, ranging from a median of 62 in the lowest quartile to 94 in the highest quartile. Postoperative hsTnT elevation was present in 53.2% of the population. An association between MAP quartile and postoperative peak hsTnT was predominantly observed in the lowest quartile (P<0.001): median hsTnT 17.6 (10.3-37.3), 14.9 (9.4-24.6), 13.8 (9.1-22.5), and 14.0 (9.2-22.4). The multivariable logistic-regression analysis showed an increased risk for postoperative cardiac-troponin elevation with decreasing MAP thresholds. CONCLUSIONS: Lower postoperative blood pressure is associated with an increased incidence of postoperative cardiac hsTnT elevation, irrespective of pre- and intraoperative variables.

The preoperative cardiology consultation: indications and risk modification.

BACKGROUND: The cardiologist is regularly consulted preoperatively by anaesthesiologists. However, insights into the efficiency and usefulness of these consultations are unclear. METHODS: This is a retrospective study of 24,174 preoperatively screened patients ≥18 years scheduled for elective non-cardiac surgery, which resulted in 273 (1%) referrals to the cardiologist for further preoperative evaluation. Medical charts were reviewed for patient characteristics, main reason for referring, requested diagnostic tests, interventions, adjustment in medical therapy, 30-day mortality and major adverse cardiac events. RESULTS: The most common reason for consultation was the evaluation of a cardiac murmur (95 patients, 35%). In 167 (61%) patients, no change in therapy was initiated by the cardiologist. Six consultations (2%) led to invasive interventions (electrical cardioversion, percutaneous coronary intervention or coronary artery bypass surgery). On average, consultation delayed clearance for surgery by two weeks. CONCLUSION: In most patients referred to the cardiologist after being screened at an outpatient anaesthesiology clinic, echocardiography is performed for ruling out specific conditions and to be sure that no further improvement can be made in the patient's health. In the majority, no change in therapy was initiated by the cardiologist. A more careful consideration about the potential benefits of consulting must be made for every patient.

Postoperative hemoglobin levels and its association with myocardial ischemia in non-cardiac surgical patients.

BACKGROUND: Low hemoglobin (Hb) levels as well as cardiac complications are common conditions in postoperative surgical patients and both are associated with poor outcome. The aim of this study was to determine the influence of postoperative Hb levels on myocardial ischemia in high-risk patients who underwent non-cardiac surgery. METHODS: In this retrospective observational cohort study, we evaluated 3638 consecutive patients admitted to the 24-hour postoperative anesthesia care unit between 2006 and 2010; 273 (8%) high-risk patients, defined as three or more cardiac risk factors, were selected for analyses. Postoperative Hb levels were divided into tertiles (low, intermediate and high). The endpoint of this study was myocardial ischemia which was defined as new electrocardiographic abnormalities and/or elevated levels of troponin-T. The relationship between postoperative Hb levels and myocardial ischemia was assessed using logistic regression analyses stratified by gender. RESULTS: Postoperative myocardial ischemia was present in 73 (27%) of the 273 patients. After adjustment for significant pre-, intra- and postoperative risk factors, 4 independent risk factors remained for postoperative myocardial ischemia in male patients: age (OR 1.1; 95% CI: 1.0-1.1), a history of ischemic heart diseases (OR 4.2; 95% CI: 1.0-17.8), renal failure (OR 5.4; 95% CI: 2.1-13.9) and postoperative Hb levels: intermediate tertile (10.3-11.6 g/dL) (OR 5.8; 95% CI: 1.6-20.9) and lowest tertile (7.9-10.2 g/dL) (OR 12.9; 95% CI: 3.0-55.5). CONCLUSION: Postoperative Hb levels are independently associated with postoperative myocardial ischemia in high-risk patients undergoing non-cardiac surgery.

General anaesthesia is associated with adverse cardiac outcome after endovascular aneurysm repair.

OBJECTIVES: Endovascular aneurysm repair (EVAR) is associated with reduced cardiac stress compared with open repair and is an attractive therapeutic option, especially in cardiac fragile patients. General and locoregional anaesthesia differ regarding the stress response evoked by surgery. The aim of the study is to compare the incidence of cardiac events after EVAR under general or locoregional anaesthesia. METHODS: A total of 302 consecutive patients undergoing infrarenal EVAR between 2002 and 2011 were analysed in this retrospective cohort study. Selection of anaesthesia type was at the discretion of the treating physicians. Medical history, medication use, anaesthesia technique and follow-up were obtained. The study end point was 30-day cardiac complications, including cardiac death, non-fatal myocardial infarction, heart failure, ventricular arrhythmia and troponin T release. Multivariable analysis, adjusted for the propensity of receiving a locoregional technique and cardiac risk factors according to the Revised Cardiac Risk Index, was used to assess the association between cardiac events and anaesthesia type. RESULTS: A total of 173 patients underwent general anaesthesia and 129 locoregional anaesthesia. Obesity, aspirin use and therapeutic anticoagulation were more common in patients receiving general anaesthesia. Cardiac events were observed in 13.3% of patients receiving general anaesthesia and in 4.7% of patients receiving locoregional anaesthesia (P = 0.02), or 6.4% versus .8% (P = 0.02) when asymptomatic troponin release is excluded from the end point. In the general anaesthesia group, two cardiac deaths, six non-fatal myocardial infarctions, two cases of non-fatal heart failure, one non-fatal cardiac arrest and 12 cases of troponin T release were observed, compared with one myocardial infarction and five cases of troponin T release in the locoregional anaesthesia group. In multivariable analysis, general anaesthesia was associated with adverse cardiac events (odds ratio (OR) 3.8; 95%-confidence interval (CI) 1.1-12.9). Non-cardiac complications occurred in 11.6% of patients in both groups (P = 1.00). CONCLUSION: General anaesthesia was associated with an increased risk of cardiac events in EVAR, compared with locoregional anaesthesia.

Regulatory issues in the use of insect-cell culture.

CONCLUSION: The insect cell as host for protein production is relative new. Therefore few data are available. This creates a vicious circle because it makes the choice of insect cells as basis for a pharmaceutical process less attractive. There are three main issues when comparing insect-cells to "traditional" systems as mammalian and bacterial cells. First, since the expression vector is not incorporated in the cells, a virus stock similar to the cell bank system has to be laid down and tested. This will cost time and money. Secondly the vector is subject to mutation and therefore the decrease in infectivity has to be characterized and validated. Third, the post-translational modification of the protein may differ. None of the mentioned issues, however, forms an obstacle that can not be overcome.

Continuous beta-galactosidase production in insect cells with a p10 gene based baculovirus vector in a two-stage bioreactor system.

Continuous production of polyhedra or baculovirus-expressed proteins in insect cell cultures is limited to about 4 weeks. The decrease in production has been ascribed to the interference of defective deletion mutants with wild-type baculoviruses. The deleted genome sequences include the polyhedrin gene (or the heterologous gene of interest); in the remaining part, the major late p10 gene is always maintained. In the present study, the productivity of a recombinant baculovirus with the lacZ gene from Escherichia coli cloned downstream of the p10 promoter at the p10 locus was investigated. It was hypothesized that this p10 promoter driven gene is preserved over a longer period of time in a continuously operated two-stage bioreactor system than foreign genes behind the polyhedrin promoter at the polyhedrin locus. In two separate runs, beta-galactosidase production with the p10-lacZ recombinant reached quasi-steady-state levels of 30 and 60 units/cm3. Polyhedron production was about 3 x 10(6) and 6 x 10(6) polyhedra/cm3, respectively. However, both polyhedron and beta-galactosidase production decreased after about 30 days of relatively constant production. In the infection reactor, deletion mutants of the virus, which contained both the polyhedrin and lacZ gene, were predominant. Therefore, the presence of the polyhedrin or p10 gene alone in deletion mutants is not sufficient for prolonged expression; other genes involved in major late gene expression and not present in the deleted virus are probably necessary.

A structured dynamic model for the baculovirus infection process in insect-cell reactor configurations.

A mathematical description of the infection of insect cells with baculovirus in a continuously operated reactor configuration is presented. The reactor configuration consists of one bioreactor in which insect cells (Spodoptera frugiperda) are grown followed by one or two bioreactors in which cells are infected by a baculovirus (Autographa californica nuclear polyhedrosis virus). It was demonstrated that the so-called passage effect is responsible for the observed difference in run time between a configuration with one or with two infection vessels. Furthermore, a model is presented based on the hypothesis that the limited run time of series of continuously operated bioreactors is associated with the occurrence of a virus particle (so-called virion) that is defective and has interfering properties. With the assumption that not all nonoccluded virions are capable of establishing a correct infection leading to new virus production, infection levels in continuously operated reactor configurations could be described well with the model.

Continuous beta-galactosidase production with a recombinant baculovirus insect-cell system in bioreactors.

Insect cells were exploited to produce bacterial beta-galactosidase by infecting them with a recombinant nuclear polyhedrosis virus (baculovirus) of Autographa californica. The insect cells were cultured in a continuous stirred tank reactor (CSTR) and led to a second CSTR where they were infected with a recombinant virus in which the lacZ gene from Escherichia coli was inserted. In the effluent of the production reactor, maximum activities of 15 units beta-galactosidase per 10(6) cells were measured. For about 25 d beta-galactosidase production remained constant, but then rapidly declined. This drop was due to a decrease in production of active beta-galactosidase rather than to inactivation of this enzyme. It was concluded that the reduced production was due to reduced polyhedrin promoter-driven synthesis.

Detection and analysis of Autographa californica nuclear polyhedrosis virus mutants with defective interfering properties.

Defective interfering particles (DIPs) were generated upon continuous production of Autographa californica nuclear polyhedrosis virus (AcNPV) in bioreactors. This configuration mimicked the serial undiluted passaging of virus, which is known to result in plaque-morphology mutants. Restriction enzyme analysis of DIP-containing preparations of extracellular virus showed the presence of many DNA fragments in less than equimolar amounts. These fragments were colinear on the physical map of AcNPV and extended from map position 1.7 to 45. These DIPs thus lacked 43% of the genetic information of the standard virus, including the polyhedrin and DNA polymerase genes. The existence of DIPs was confirmed by electron microscopy, where virions were observed with reduced length. Among the less than equimolar fragments in DIP-containing preparations, fragments were observed linking sequences from map positions 1.7 and 45 via a TGTT linker of unknown origin. The DIPs could not be plaque-purified and needed standard (helper) virus to replicate; DIP-containing preparations interfered with standard virus replication in an interference assay, which explained the reduction in productivity of an AcNPV expression vector-insect cell system in continuous bioreactor operations. The origin of these DIPs and their possible generation mechanism are discussed.

Continuous production of baculovirus in a cascade of insect-cell reactors.

Insect cells (Spodoptera frugiperda) were cultured in a continuous stirred-tank reactor. The effluent was led to a cascade of another two reactors, each containing half the volume of the cell-growth reactor, where the cells were infected with Autographa californica nuclear polyhedrosis virus. For about 10 days production of 10(7) polyhedra (virus particles embedded in a protein capsule) per cm3 was achieved. This short production time compared to previous experiments involving an analogous system with a single infection vessel of equal volume to the cell-growth vessel is ascribed to the accelerated occurrence of the so-called passage effect (a decrease of infectious virus with time). From the results of a computer model it was concluded that this passage effect was accelerated by the change in residence time distribution as compared to the earlier experiments.