Miodrag Filipovic

Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery : A randomized controlled trial

Objective:Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery. Design:Double-blind, randomized, placebo-controlled trial. Setting:One Swiss University Hospital. Patients:One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. Intervention:Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day. Measurements and Main Results:The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively. Conclusion:This negative or, because of methodologic issues, possibly failed trial does not support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass.

Prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis.

Background:There is uncertainty regarding the prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurements after noncardiac surgery. Methods:The current study undertook a systematic review and meta-analysis. The study used six search strategies and included noncardiac surgery studies that provided data from a multivariable analysis assessing whether a postoperative troponin or creatine kinase muscle and brain isoenzyme measurement was an independent predictor of mortality or a major cardiovascular event. Independent investigators determined study eligibility and abstracted data in duplicate. Results:Fourteen studies, enrolling 3,318 patients and 459 deaths, demonstrated that an increased troponin measurement after surgery was an independent predictor of mortality (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.2–5.2), but there was substantial heterogeneity (I2 = 56%). The independent prognostic capabilities of an increased troponin value after surgery in the 10 studies that assessed intermediate-term (≤ 12 months) mortality was an OR = 6.7 (95% CI 4.1–10.9, I2 = 0%) and in the 4 studies that assessed long-term (more than 12 months) mortality was an OR = 1.8 (95% CI 1.4–2.3, I2 = 0%; P < 0.001 for test of interaction). Four studies, including 1,165 patients and 202 deaths, demonstrated an independent association between an increased creatine kinase muscle and brain isoenzyme measurement after surgery and mortality (OR 2.5, 95% CI 1.5–4.0, I2 = 4%). Conclusions:An increased troponin measurement after surgery is an independent predictor of mortality, particularly within the first year; limited data suggest an increased creatine kinase muscle and brain isoenzyme measurement also predicts subsequent mortality. Monitoring troponin measurements after noncardiac surgery may allow physicians to better risk stratify and manage their patients.

Modifiable and Nonmodifiable Risk Factors for Postoperative Delirium After Cardiac Surgery With Cardiopulmonary Bypass

OBJECTIVES Postoperative delirium after cardiac surgery is associated with increased morbidity and mortality as well as prolonged stay in both the intensive care unit and the hospital. The authors sought to identify modifiable risk factors associated with the development of postoperative delirium in elderly patients after elective cardiac surgery in order to be able to design follow-up studies aimed at the prevention of delirium by optimizing perioperative management. DESIGN A post hoc analysis of data from patients enrolled in a randomized controlled trial was performed. SETTING A single university hospital. PARTICIPANTS One hundred thirteen patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS None. MEASUREMENTS AND MAINS RESULTS: Screening for delirium was performed using the Confusion Assessment Method (CAM) on the first 6 postoperative days. A multivariable logistic regression model was developed to identify significant risk factors and to control for confounders. Delirium developed in 35 of 113 patients (30%). The multivariable model showed the maximum value of C-reactive protein measured postoperatively, the dose of fentanyl per kilogram of body weight administered intraoperatively, and the duration of mechanical ventilation to be independently associated with delirium. CONCLUSIONS In this post hoc analysis, larger doses of fentanyl administered intraoperatively and longer duration of mechanical ventilation were associated with postoperative delirium in the elderly after cardiac surgery. Prospective randomized trials should be performed to test the hypotheses that a reduced dose of fentanyl administered intraoperatively, the use of a different opioid, or weaning protocols aimed at early extubation prevent delirium in these patients.

Genotyping the butyrylcholinesterase in patients with prolonged neuromuscular block after succinylcholine.

Background:Succinylcholine remains the standard neuromuscular blocking drug for tracheal intubation in emergency situations. The short duration of action is due to its rapid hydrolytic degradation by butyrylcholinesterase (plasmacholinesterase). Multiple variants of this enzyme are known (A, F, S, H, J, K variants) with different effects on enzyme activity. This study was undertaken to evaluate the use of molecular genetic methods in patients with clinically prolonged neuromuscular block. Methods:Nine patients with a neuromuscular block of 14 min to 5 h were selected. All four exons of the butyrylcholinesterase were amplified by polymerase chain reaction and analyzed by automated sequencing. Molecular genetic results were compared with clinical relaxation time and with biochemical test results (total butyrylcholinesterase activity, dibucaine and fluoride inhibition). Results:Seven of nine patients were mutation carriers. Five of these had more than one mutation. The A and K variants were the most frequent variations. Three of four patients who were homozygous for the A variant were also carriers of the K allele. The authors identified one novel mutation (G1294T) introducing a stop codon at amino acid position 432. The duration of neuromuscular block was substantially different between patients with identical butyrylcholinesterase genotypes. Conclusions:Variations in the genetic sequence of butyrylcholinesterase are frequent in patients with prolonged duration of action of succinylcholine. Direct sequencing of the whole butyrylcholinesterase gene is an appropriate method for genotyping and, accordingly, should be used in future clinical studies with drugs metabolized by this enzyme (e.g., succinylcholine, mivacurium).

The prognostic value of troponin release after adult cardiac surgery — a meta-analysis

To assess the accuracy of increased troponin (Tn) concentrations for the prediction of mid-term (> or = 12 months) mortality after coronary artery bypass graft (CABG) and valve surgery, we performed a systematic review identifying all studies reporting on the association between postoperative troponin release and mortality after cardiac surgery. Studies were identified through 30 April 2008 by electronic searches of the MEDLINE, EMBASE and BIOSIS databases. Two reviewers independently selected studies, assessed methodological quality and extracted the data. We primarily considered mid-term (> or = 12 months) and secondarily short-term (< or = 30 days) all-cause mortality. A bivariate random-effects model was used to study determinants and to pool measures of prognostic accuracy of Tn. Seventeen studies fulfilled the inclusion criteria with a total of 237 mid-term deaths in 5189 patients and 296 short-term deaths in 9703 patients. The diagnostic odds ratio of increased Tn concentrations was 5.46 (95% confidence interval (CI) 2.0-14.6) for mid-term mortality and 6.57 (95% CI 4.3-10.1) for short-term mortality after adult cardiac surgery. Alternatively expressed, for troponin elevation, the sensitivity was 0.45 (0.26-0.67) and the specificity 0.87 (0.73-0.90) to predict mid-term mortality. The sensitivity was 0.59 (0.48-0.69) and the specificity 0.82 (0.72-0.89) for short-term mortality. Between-study variability was high. In conclusion, this meta-analysis provides evidence for an association between postoperative Tn release with mid- and short-term all-cause mortality after adult cardiac surgery. However, differences in populations, timing of Tn testing, Tn subunit and Tn assays make definitive conclusions about effect size and cut-off values difficult.

A preliminary report on the prognostic significance of preoperative brain natriuretic peptide and postoperative cardiac troponin in patients undergoing major vascular surgery.

BACKGROUND: Associations between preoperative elevation of brain natriuretic peptide (BNP) or postoperative elevation of cardiac troponins (cTn) with major adverse cardiac events (MACE) after major surgery have been shown previously. In this study, we evaluated the added value of preoperative BNP with postoperative cTn levels for the prediction of MACE in patients undergoing major vascular surgery. METHODS: This is a prospectively prespecified, secondary analysis of data from a cohort of 133 clinically stable patients undergoing major vascular surgery enrolled in a clinical trial evaluating the effectiveness of the sympathetic nervous system-inhibiting drug moxonidine on reducing MACE. Concentrations of BNP and cTn were determined before surgery, and concentrations of cTn were measured immediately after surgery and on postoperative days 1, 2, 3, and 7. The primary end point was the occurrence of MACE (defined as any hospitalization for myocardial revascularization, acute coronary syndrome, acute congestive heart failure, or death by any cause) within 1 yr after surgery. Patients were evaluated for MACE by hospital chart review during hospitalization and by telephone interviews 12 mo after surgery. RESULTS: Within 1 yr after surgery, 19 patients (14%) had a MACE, including 14 patients (11%) who died. After adjustment for age, gender, and the revised cardiac risk index, preoperative BNP elevation ≥50 pg/mL was associated with MACE (adjusted hazard ratio [HR]: 6.5, 95% confidence interval [CI]: 1.4–29.5) regardless of the subsequent cTn I concentrations. The combination of preoperative BNP elevation ≥50 pg/mL and postoperative cTn I elevation ≥2 ng/mL was associated with MACE (adjusted HR: 25.2, 95% CI: 5.0–128.4) and all-cause mortality (adjusted HR: 18.7, 95% CI: 3.1–112.5). The negative predictive value of a normal preoperative BNP value for subsequent adverse events was 0.965 (95% CI: 0.879–0.996). CONCLUSION: These data suggest that measurement of preoperative BNP concentrations in addition to postoperative cTn concentrations provides additive prognostic information for MACE and mortality after major vascular surgery.

Pre-analytical effects of pneumatic tube transport on impedance platelet aggregometry.

Point-of-care platelet monitoring is increasingly used in cardiac patients treated with antiplatelet agents. The validity of a new assay needs to be evaluated not only for reproducible data in clinical samples, but also for other pre-analytical conditions that may influence measurements. The aim of this study was to evaluate the influence of a pneumatic tube system (PTS) for specimen transport on impedance platelet aggregometry. We evaluated 50 consecutive patients scheduled for coronary artery bypass surgery under oral therapy with 100 mg/d acetylsalicylic acid (aspirin). In each patient, three blood samples for platelet function analysis were taken before induction of anesthesia. The first sample was measured in the operating room (OR) area and designated as the reference value. The second sample was again measured by the same operator in the OR area using a random PTS transport. The third sample was sent to the central laboratory by PTS where it was measured by a local technician. Platelet function was assessed in whole blood by impedance aggregometry with a Multiplate™ analyzer using thrombin-related activation peptide (TRAP test) and arachidonic acid (ASPI test) (Dynabite GmbH, Munich, Germany). Mean ± SD for TRAP test was 1009 ± 196 in the reference measurement. Bias ± 95% limit of agreement between the reference measurement and a second measurement for TRAP test were 126 ± 284 (n = 25) for untransported and 181 ± 316 (n = 25) for PTS transported samples. In the reference measurements, 48/50 (96%) of TRAP values were within the normal range. After PTS transport, 35/50 (70%) of TRAP measurements in the central laboratory were within the normal range (p < 0.001). Mean ± SD for ASPI test was 175 ± 137. Bias ± 95% limit of agreement for ASPI test were 12 ± 109 (n = 25) for untransported and 68 ± 250 (n = 25) for PTS transported samples. In the reference measurements, 7/50 (14%) ASPI values were above the cut-off level and defined as reduced aspirin responsiveness. After PTS transport, only 1/50 (2%) of the patients showed reduced aspirin responsiveness in the central laboratory measurements (p = 0.031). In conclusion, PTS transport had a significant influence on platelet function testing by the Multiplate™ analyzer. Significantly fewer test results indicated normal platelet function in TRAP test and reduced aspirin responsiveness in ASPI test after PTS transport. Therefore, clinical decisions regarding platelet function and aspirin responsiveness should not be based on blood specimens transported by a PTS system.

The predictive value of preoperative natriuretic peptide concentrations in adults undergoing surgery: a systematic review and meta-analysis.

BACKGROUND: Several studies have evaluated preoperative B-type natriuretic peptides (NPs) for predicting mortality after surgery; however, the number of deaths in each study was small, limiting the power of these studies. We conducted a systematic review and meta-analysis of studies addressing preoperative NP levels to predict mortality after cardiac and noncardiac surgery. METHODS: We searched MEDLINE and EMBASE using the terms “natriuretic peptides,” “surgery or surgical procedures,” and a validated combination of prognostic and diagnostic terms. Two investigators independently assessed studies for eligibility and extracted data. The end points were all-cause mortality at ≥6 months and at ⩽90 days. We used a bivariate model to derive measures of prognostic accuracy and their heterogeneity. We calculated the pooled positive predictive value (PPV) and negative predictive value (NPV) by Bayesian Markov chain Monte Carlo methods. RESULTS: Of the 1558 retrieved articles, 23 studies satisfied the predefined eligibility criteria. After cardiac surgery, the diagnostic odds ratio of NP was 4.11 (95% confidence interval, 2.22–7.60) for ≥6-month mortality, the PPV 0.17 (95% Bayesian confidence interval, 0.07–0.36), and the NPV 0.96 (0.90–0.98). After noncardiac surgery, the diagnostic odds ratio of NP was 4.97 (3.06–8.07) for ≥6-month mortality. The corresponding PPV was 0.24 (0.14–0.38) and the NPV 0.94 (0.88–0.97). Results were similar for ⩽90-day mortality. CONCLUSIONS: Preoperative NP concentrations were associated with mortality after cardiac and noncardiac surgery. NP had high NPVs for both types of surgery suggesting that preoperative NP concentrations may be helpful in preoperative risk stratification.

Transesophageal Echocardiography for Monitoring Segmental Wall Motion During Off-pump Coronary Artery Bypass Surgery

In this prospective, observational study, we evaluated whether transesophageal echocardiography allows for monitoring left ventricular segmental wall motion during cardiac displacement for off-pump coronary artery bypass (OPCAB) surgery. On the basis of a pilot study that showed frequent loss of transgastric views during OPCAB surgery, we analyzed only midesophageal views. The midesophageal 4-chamber view, 2-chamber view, and long-axis view were recorded in 60 patients after opening the chest and placing an epicardial stabilizer on the displaced heart. Using the 16-segment model, 2 echocardiographers independently performed offline analysis of segmental wall motion. The percentage of patients in whom ≥14 left ventricular segments were readable was calculated at baseline and after cardiac displacement and placement of an epicardial stabilizer. At baseline, ≥14 segments were readable in 59 (98%) of 60 patients. After cardiac displacement, ≥14 segments were readable during 58 (76%) of 76 revascularizations of the left anterior descending coronary artery (P < 0.01 versus baseline), during 33 (83%) of 40 revascularizations of the left circumflex coronary artery (P < 0.01 versus baseline), and during 29 (94%) of 31 revascularizations of the right coronary artery (not significant). We conclude that the number of readable segments decreased after cardiac displacement but that availability of ≥14 readable segments allowed for reliable monitoring of segmental wall motion in 4 of 5 patients during OPCAB surgery.

Transfusion of allogeneic blood products in proximal aortic surgery with hypothermic circulatory arrest: effect of thromboelastometry-guided transfusion management.

OBJECTIVES Proximal aortic surgery with hypothermic circulatory arrest (HCA) commonly involves perioperative transfusion of allogeneic blood products, including red blood cells, plasma, and platelets. The authors hypothesized that surgery with HCA could be performed without allogeneic blood products and that a thromboelastometry-guided algorithm would reduce the transfusion of allogeneic blood products. DESIGN A retrospective analysis of prospectively collected data. Patients with and without thromboelastometry guidance were compared by case-control analysis (n = 62 matched patients) and multivariate regression (n = 194 patients). SETTING Single-center university hospital. PARTICIPANTS This study included 194 patients undergoing elective and emergent procedures with HCA involving the proximal aorta. INTERVENTIONS A thromboelastometry-guided treatment algorithm during surgery was used in 153 patients (79%), and conventional coagulation management was used in 41 patients (21%). MEASUREMENTS AND MAIN RESULTS During surgery and the following 24 hours, allogeneic blood products were transfused in 106 patients (55%). Median (interquartile range) number of allogeneic blood products transfused was 1 unit (0-6 units). Case-control analysis showed lower transfusion rates of red blood cells, plasma, and any allogeneic blood product (all p<0.050) in patients with thromboelastometry guidance. In the multivariate analysis, thromboelastometry guidance was associated with an odds ratio of 0.26 (95% confidence interval, 0.08-0.84; p = 0.025) for the transfusion of any allogeneic blood product. The use of thromboelastometry was not associated with adverse events (odds ratio 0.72; 95% confidence interval, 0.27-1.90; p = 0.507). CONCLUSIONS Allogeneic blood products were avoided in a proportion of patients. The findings further suggest that thromboelastometry-guided coagulation management promoting the use of coagulation factor concentrates decreased the use of allogeneic blood products during complex cardiac surgery.