Douglas Campbell

Rationale and Design of the Balanced Anesthesia Study: A Prospective Randomized Clinical Trial of Two Levels of Anesthetic Depth on Patient Outcome After Major Surgery.

BACKGROUND:An association between relatively deep anesthesia, as guided by the bispectral index (BIS), and increased postoperative mortality has been demonstrated in 6 of 8 published observational studies, but association does not necessarily mean causality. Small clinical trials of anesthetic depth have demonstrated increased delirium and postoperative cognitive dysfunction in patients who were relatively deeply anesthetized, but have been inadequately powered to study mortality. A large-scale randomized study is required to determine whether causality exists. METHODS:The primary hypothesis of our study is that “light” anesthesia, defined as a BIS target of 50, will reduce all-cause mortality within 1 year of surgery in comparison with “deep” anesthesia, defined as a BIS target of 35, in patients aged ≥60 years presenting for major surgery under general anesthesia. The trial is an international multicenter, randomized, parallel-group, double-blind (patients and investigators) prospective, intention-to-treat, safety and efficacy study. The relative reduction in mortality in the light anesthesia group is expected to be 20%, giving an absolute risk reduction from 10% to 8%. Power analysis using a = 0.049 and b = 0.2 indicates that 3250 patients are required in each group. RESULTS:The study is underway, and 1325 patients have been recruited in 40 centers in 5 countries. It is anticipated that the study will be completed in 3 years. CONCLUSIONS:This randomized controlled trial should definitively answer the question of whether titrating anesthetic depth makes a difference to patient outcome in a vulnerable patient group.

A Pilot Study for a Prospective, Randomized, Double-blind Trial of the Influence of Anesthetic Depth on Long-term Outcome

BACKGROUND:Deep general anesthesia has been associated with increased mortality in 5 observational studies. The association may be causal or an epiphenomenon due to increased anesthetic sensitivity in high-risk patients. We conducted a pilot study to assess the feasibility of performing a definitive randomized controlled trial. The aims of the study were to determine whether anesthetic depth targeting in a high-risk group was feasible and to document anesthetic doses and arterial blood pressures associated with “deep” and “light” general anesthesia. METHODS:ASA physical status III and IV patients, aged ≥60 years, having surgery lasting ≥2 hours, with expected hospital stay ≥2 days, and receiving general anesthesia were randomly allocated to a Bispectral Index (BIS) or spectral entropy (SE) target of 35 (“low” group) or 50 (“high” group). The primary end point was mean BIS or SE. Secondary end points were postanesthesia care unit length of stay and pain scores, quality of recovery score, hospital length of stay, postoperative complications, and death. A composite end point of postoperative complications (pneumonia, myocardial infarction, stroke, pulmonary embolism, heart failure, and death) was determined at 1 year. RESULTS:One hundred twenty-five patients were recruited. The mean of the median BIS/SE values for each patient during the maintenance phase of anesthesia in the low and high groups was significantly different: 39 vs 48 (mean difference 8 [95% confidence interval {CI95}, 6 to 10], P < 0.001). There was also a significant difference in mean volatile anesthetic administration (minimum alveolar concentration): 0.98 vs 0.64 (mean difference −0.35 [CI95, −0.44 to −0.26], P < 0.001) and target propofol concentrations: 4.0 vs 3.1 &mgr;g/mL (mean difference −0.8 [CI95, −1.2 to −0.3], P = 0.004). Intraoperative mean arterial blood pressures were similar (85 vs 87 mm Hg; mean difference 2 [CI95, −2 to 6], P = 0.86), and there were no differences in short-term recovery characteristics or hospital length of stay. There was a significant difference in the incidence of wound infection at 30 days (13% vs 3%; risk difference −10% [CI95, −21 to −0.1], P = 0.04). At 1 year, the composite rates of complications in the low and high groups were 28% and 17% (risk difference −11 [CI95, −25 to 4], P = 0.15) and mortality rates were 12% and 9%, respectively (risk difference −2 [CI95, −14 to 9], P = 0.70). CONCLUSIONS:This pilot study demonstrated that depth of anesthesia targeting with BIS or SE was achievable in a high-risk population with adequate separation of processed electroencephalogram monitor targets. The expected incidence of postoperative complications and mortality occurred. We conclude that a large, multicenter, randomized controlled trial is feasible.

Refining Target-Controlled Infusion: An Assessment of Pharmacodynamic Target-Controlled Infusion of Propofol and Remifentanil Using a Response Surface Model of Their Combined Effects on Bispectral Index

BACKGROUND:Propofol and remifentanil are commonly combined for total IV anesthesia. The pharmacokinetics (PK), pharmacodynamics (PD), and drug interactions of the combination are well understood, but the use of a combined PK and PD model to control target-controlled infusion pumps has not been investigated. In this study, we prospectively tested the accuracy of a PD target-controlled infusion algorithm for propofol and remifentanil using a response surface model of their combined effects on Bispectral Index (BIS). METHODS:Effect-site, target-controlled infusions of propofol and remifentanil were given using an algorithm based on standard PK models linked to a PD response surface model of their combined effects on BIS. The combination of a targeted BIS value and adjustable ratio of propofol to remifentanil was used to adjust infusion rates. The standard model performance measures of median performance error (bias) and median absolute performance error (inaccuracy), expressed as percentages, were used to assess accuracy of the infusions in a convenience sample of 50 adult patients undergoing surgery with general anesthesia. The influence of age and weight on the performance of the model was also assessed. RESULTS:Patients had a mean (range) age of 48 (19–73) years, weight of 80 (45–169) kg, and body mass index of 28 (19–45) kg/m2. The overall model had a bias of 8% (SD 24%) and inaccuracy of 25% (SD 13%). Performance was least accurate during the early induction phase of anesthesia. There was no significant bias in BIS predictions with increasing age (P = 0.44) or weight (P = 0.56). CONCLUSIONS:The algorithm performed adequately in a clinical setting. The algorithm could be further refined, and assessment of its accuracy and utility in comparison to current clinical practice for giving IV anesthesia is warranted.

Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial.

BACKGROUND: Globally, >300 million patients have surgery annually, and ⩽20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55–4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26–3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89–6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

Rationale and design for the detection and neurological impact of cerebrovascular events in non-cardiac surgery patients cohort evaluation (NeuroVISION) study: a prospective international cohort study

Objectives Covert stroke after non-cardiac surgery may have substantial impact on duration and quality of life. In non-surgical patients, covert stroke is more common than overt stroke and is associated with an increased risk of cognitive decline and dementia. Little is known about covert stroke after non-cardiac surgery. NeuroVISION is a multicentre, international, prospective cohort study that will characterise the association between perioperative acute covert stroke and postoperative cognitive function. Setting and participants We are recruiting study participants from 12 tertiary care hospitals in 10 countries on 5 continents. Participants We are enrolling patients ≥65 years of age, requiring hospital admission after non-cardiac surgery, who have an anticipated length of hospital stay of at least 2 days after elective non-cardiac surgery that occurs under general or neuraxial anaesthesia. Primary and secondary outcome measures Patients are recruited before elective non-cardiac surgery, and their cognitive function is measured using the Montreal Cognitive Assessment (MoCA) instrument. After surgery, a brain MRI study is performed between postoperative days 2 and 9 to determine the presence of acute brain infarction. One year after surgery, the MoCA is used to assess postoperative cognitive function. Physicians and patients are blinded to the MRI study results until after the last patient follow-up visit to reduce outcome ascertainment bias. We will undertake a multivariable logistic regression analysis in which the dependent variable is the change in cognitive function 1 year after surgery, and the independent variables are acute perioperative covert stroke as well as other clinical variables that are associated with cognitive dysfunction. Conclusions The NeuroVISION study will characterise the epidemiology of covert stroke and its clinical consequences. This will be the largest and the most comprehensive study of perioperative stroke after non-cardiac surgery. Trial registration number NCT01980511; Pre-results.

Response of bispectral index to neuromuscular block in awake volunteers

the Critically Ill Adult. 3rd Edn. London: Intensive Care Society, 2011 6. Vos G, Nissen A, Nieman F, et al. Comparison of interhospital pediatric intensive care transport accompanied by a referring specialist or a specialist retrieval team. Intensive Care Med 2004; 30: 302–8 7. Forrest P, Ratchford J, Burns B, et al. Retrieval of critically ill adults using extracorporeal membrane oxygenation: an Australian experience. Intensive Care Med 2011; 37: 824–30 8. Haites E, Turner S. Are CCAST patients developing ametabolic acidosis in-flight and if so is lactate monitoring necessary. J R Army Med Corps 2010; 156: (4 Suppl 1):404. 9. Wiegersma JS, Droogh J, Zijlstra J, Fokkema J, Ligtenberg J. Quality of interhospital transport of the critically ill: impact of a Mobile Intensive Care Unit with a specialized retrieval team. Published online Feb 28, 2011. doi:10.1186/cc10064 10. Bellingan G, Olivier T, Batson S,WebbA. Comparison of a specialist retrieval team with current United Kingdom practice for the transport of critically ill patients. Intensive Care Med 2000; 26: 740–4

Errors in assessment of resident performance.

To the Editor: I read with interest the recent article by Baker regarding the value of normalizing resident evaluation scores to eliminate individual faculty evaluator bias. Without unduly undermining the importance of this study, I have concern about the statistical handling of Likert scores. Likert scores were used to create individual faculty member mean scores, faculty score standard deviations, and average resident scores when more than one core competency section was included. The central issue is that Likert scales involve ordinal data, or categories falling in a hierarchy. Because the numbers in a Likert scale represent verbal statements of rank order (e.g., 5 distinctly above peer level), summarizing such ordinal data with a mean value is inappropriate by strict statistical methodology. Moreover, the intervals between data points on a Likert scale are not necessarily equal or even certain. To put this in the context of the study, consider this example from the relative performance designation used in the study: a score of “4” is “somewhat above peer level” and a score of “5” is “distinctly above peer level”; however, an average score of “4.5” cannot be said to represent “somewhat-above-peerlevel-and-a-half.” Similarly, on the absolute/anchored competency designation, the difference between a score of “5” (performed in a fully independent manner) and a score of “6” (able to serve as a consultant to other physicians) is not necessarily equivalent to the difference between a score of “2” (needed moderate assistance) and a score of “3” (needed only minimal assistance). It is difficult to determine what, if any, limitation was imposed on the study as a result of this violation of statistical propriety. Nevertheless, although a purist may pine for cleaner data and analysis, this distraction can be mitigated by considering what Stevens wrote in 1946: “for this ‘illegal’ statisticizing there can be invoked a kind of pragmatic sanction: In numerous instances it leads to fruitful results.” I look forward to future contributions from Baker. When I was a fellow his efforts sparked my interest in resident education and continue to do so now.