Association between Complications and Death within 30 days after General Surgery: A Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) substudy.

OBJECTIVE: To determine the epidemiology of post-operative complications among general surgery patients, inform their relationships with 30-day mortality, and determine the attributable fraction of death of each postoperative complication. BACKGROUND: The contemporary causes of post-operative mortality among general surgery patients are not well characterized. METHODS: VISION is a prospective cohort study of adult non-cardiac surgery patients across 28 centres in 14 countries, who were followed for 30 days after surgery. For the subset of general surgery patients, a cox proportional hazards model was used to determine associations between various surgical complications and post-operative mortality. The analyses were adjusted for preoperative and surgical variables. Results were reported in adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Among 7950 patients included in the study, 240 (3.0%) patients died within 30 days of surgery. Five post-operative complications (myocardial injury after non-cardiac surgery [MINS], major bleeding, sepsis, stroke, and acute kidney injury resulting in dialysis) were independently associated with death. Complications associated with the largest attributable fraction (AF) of post-operative mortality (i.e., percentage of deaths in the cohort that can be attributed to each complication, if causality were established) were major bleeding (n=1454, 18.3%, HR 2.49 95%CI 1.87-3.33, P<0.001, AF 21.2%), sepsis (n=783, 9.9%, HR 6.52, 95%CI 4.72-9.01, P<0.001, AF 15.6%), and MINS (n=980, 12.3%, HR 2.00, 95%CI 1.50-2.67, P<0.001, AF 14.4%). CONCLUSION: The complications most associated with 30-day mortality following general surgery are major bleeding, sepsis, and MINS. These findings may guide the development of mitigating strategies, including prophylaxis for perioperative bleeding.

One-year Outcomes after Discharge from Noncardiac Surgery and Association between Predischarge Complications and Death after Discharge: Analysis of the VISION Prospective Cohort Study.

BACKGROUND: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery. METHODS: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis. RESULTS: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr). CONCLUSIONS: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge.

Myocardial Injury After Noncardiac Surgery in Major General Surgical Patients a Prospective Observational Cohort Study.

OBJECTIVE: The objective of this study was to determine the prognostic relevance, clinical characteristics, and 30-day outcomes associated with myocardial injury after noncardiac surgery (MINS) in major general surgery patients. BACKGROUND: MINS has been independently associated with 30-day mortality after noncardiac surgery. The characteristics and prognostic importance of MINS in major general surgical patients have not been described. METHODS: This was an international prospective cohort study of a representative sample of 22,552 noncardiac surgery patients 45 years or older, of whom 4490 underwent major general surgery in 24 centers in 13 countries. All patients had fifth-generation plasma high-sensitivity troponin T (hsTnT) concentrations measured during the first 3 postoperative days. MINS was defined as a hsTnT of 20-65 ng/L and absolute change >5 ng/L or hsTnT ≥65 ng/L secondary to ischemia. The objectives of the present study were to determine (1) whether MINS is prognostically important in major general surgical patients, (2) the clinical characteristics of major general surgical patients with and without MINS, (3) the 30-day outcomes for major general surgical patients with and without MINS, and (4) the proportion of MINS that would have gone undetected without routine postoperative monitoring. RESULTS: The incidence of MINS in the major general surgical patients was 16.3% (95% CI, 15.3-17.4%). Thirty-day all-cause mortality in the major general surgical cohort was 6.8% (95% CI, 5.1%-8.9%) in patients with MINS compared with 1.2% (95% CI, 0.9%-1.6%) in patients without MINS ( P <0.01). MINS was independently associated with 30-day mortality in major general surgical patients (adjusted odds ratio 4.7, 95% CI, 3.0-7.4). The 30-day mortality was higher both among MINS patients with no ischemic features (ie, no ischemic symptoms or electrocardiogram findings) (5.4%, 95% CI, 3.7%-7.7%) and among patients with 1 or more clinical ischemic features (10.6%, 95% CI, 6.7%-15.8%). The proportion of major general surgical patients who had MINS without ischemic symptoms was 89.9% (95% CI, 87.5-92.0). CONCLUSIONS: Approximately 1 in 6 patients experienced MINS after major general surgery. MINS was independently associated with a nearly 5-fold increase in 30-day mortality. The vast majority of patients with MINS were asymptomatic and would have gone undetected without routine postoperative troponin measurement.

Intrapulmonary and Intracardiac Shunts in Adult COVID-19 Versus Non-COVID Acute Respiratory Distress Syndrome ICU Patients Using Echocardiography and Contrast Bubble Studies (COVID-Shunt Study): A Prospective, Observational Cohort Study.

OBJECTIVES: Studies have suggested intrapulmonary shunts may contribute to hypoxemia in COVID-19 acute respiratory distress syndrome (ARDS) with worse associated outcomes. We evaluated the presence of right-to-left (R-L) shunts in COVID-19 and non-COVID ARDS patients using a comprehensive hypoxemia workup for shunt etiology and associations with mortality. DESIGN: Prospective, observational cohort study. SETTING: Four tertiary hospitals in Edmonton, Alberta, Canada. PATIENTS: Adult critically ill, mechanically ventilated, ICU patients admitted with COVID-19 or non-COVID (November 16, 2020, to September 1, 2021). INTERVENTIONS: Agitated-saline bubble studies with transthoracic echocardiography/transcranial Doppler ± transesophageal echocardiography assessed for R-L shunts presence. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were shunt frequency and association with hospital mortality. Logistic regression analysis was used for adjustment. The study enrolled 226 patients (182 COVID-19 vs 42 non-COVID). Median age was 58 years (interquartile range [IQR], 47-67 yr) and Acute Physiology and Chronic Health Evaluation II scores of 30 (IQR, 21-36). In COVID-19 patients, the frequency of R-L shunt was 31 of 182 COVID patients (17.0%) versus 10 of 44 non-COVID patients (22.7%), with no difference detected in shunt rates (risk difference [RD], -5.7%; 95% CI, -18.4 to 7.0; p = 0.38). In the COVID-19 group, hospital mortality was higher for those with R-L shunt compared with those without (54.8% vs 35.8%; RD, 19.0%; 95% CI, 0.1-37.9; p = 0.05). This did not persist at 90-day mortality nor after adjustment with regression. CONCLUSIONS: There was no evidence of increased R-L shunt rates in COVID-19 compared with non-COVID controls. R-L shunt was associated with increased in-hospital mortality for COVID-19 patients, but this did not persist at 90-day mortality or after adjusting using logistic regression.

In COVID-19 with hypoxemia, 12 vs. 6 mg/d of dexamethasone did not increase days alive without life support.

SOURCE CITATION: Munch MW, Myatra SN, Vijayaraghavan BK, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326:1807-17. 34673895.

Persistent Incisional Pain after Noncardiac Surgery: An International Prospective Cohort Study.

BACKGROUND: The purpose of this study was to determine the incidence, characteristics, impact, and risk factors associated with persistent incisional pain. The hypothesis was that patient demographics and perioperative interventions are associated with persistent pain. METHODS: This was a secondary analysis of an international prospective cohort study from 2012 to 2014. This study included patients who were 45 yr of age or older who underwent major inpatient noncardiac surgery. Data were collected perioperatively and at 1 yr after surgery to assess for the development of persistent incisional pain (pain present around incision at 1 yr after surgery). RESULTS: Among 14,831 patients, 495 (3.3%; 95% CI, 3.1 to 3.6) reported persistent incisional pain at 1 yr, with an average pain intensity of 3.6 ± 2.5 (0 to 10 numeric rating scale), with 35% and 14% reporting moderate and severe pain intensities, respectively. More than half of patients with persistent pain reported needing analgesic medications, and 85% reported interference with daily activities (denominator = 495 in the above proportions). Risk factors for persistent pain included female sex (P = 0.007), Asian ethnicity (P < 0.001), surgery for fracture (P < 0.001), history of chronic pain (P < 0.001), coronary artery disease (P < 0.001), history of tobacco use (P = 0.048), postoperative patient-controlled analgesia (P < 0.001), postoperative continuous nerve block (P = 0.010), insulin initiation within 24 h of surgery (P < 0.001), and withholding nonsteroidal anti-inflammatory medication or cyclooxygenase-2 inhibitors on the day of surgery (P = 0.029 and P < 0.001, respectively). Older age (P < 0.001), endoscopic surgery (P = 0.005), and South Asian (P < 0.001), Native American/Australian (P = 0.004), and Latin/Hispanic ethnicities (P < 0.001) were associated with a lower risk of persistent pain. CONCLUSIONS: Persistent incisional pain is a common complication of inpatient noncardiac surgery, occurring in approximately 1 in 30 adults. It results in significant morbidity, interferes with daily living, and is associated with persistent analgesic consumption. Certain demographics, ethnicities, and perioperative practices are associated with increased risk of persistent pain.

Association between complications and death within 30 days after noncardiac surgery.

BACKGROUND: Among adults undergoing contemporary noncardiac surgery, little is known about the frequency and timing of death and the associations between perioperative complications and mortality. We aimed to establish the frequency and timing of death and its association with perioperative complications. METHODS: We conducted a prospective cohort study of patients aged 45 years and older who underwent inpatient noncardiac surgery at 28 centres in 14 countries. We monitored patients for complications until 30 days after surgery and determined the relation between these complications and 30-day mortality using a Cox proportional hazards model. RESULTS: We included 40 004 patients. Of those, 715 patients (1.8%) died within 30 days of surgery. Five deaths (0.7%) occurred in the operating room, 500 deaths (69.9%) occurred after surgery during the index admission to hospital and 210 deaths (29.4%) occurred after discharge from the hospital. Eight complications were independently associated with 30-day mortality. The 3 complications with the largest attributable fractions (AF; i.e., potential proportion of deaths attributable to these complications) were major bleeding (6238 patients, 15.6%; adjusted hazard ratio [HR] 2.6, 95% confidence interval [CI] 2.2-3.1; AF 17.0%); myocardial injury after noncardiac surgery [MINS] (5191 patients, 13.0%; adjusted HR 2.2, 95% CI 1.9-2.6; AF 15.9%); and sepsis (1783 patients, 4.5%; adjusted HR 5.6, 95% CI 4.6-6.8; AF 12.0%). INTERPRETATION: Among adults undergoing noncardiac surgery, 99.3% of deaths occurred after the procedure and 44.9% of deaths were associated with 3 complications: major bleeding, MINS and sepsis. Given these findings, focusing on the prevention, early identification and management of these 3 complications holds promise for reducing perioperative mortality. Study registration: ClinicalTrials.gov, no. NCT00512109.

Myocardial Injury After Noncardiac Surgery (MINS) in Vascular Surgical Patients: A Prospective Observational Cohort Study.

OBJECTIVE: To determine the prognostic relevance, clinical characteristics, and 30-day outcomes associated with myocardial injury after noncardiac surgery (MINS) in vascular surgical patients. BACKGROUND: MINS has been independently associated with 30-day mortality after noncardiac surgery. The characteristics and prognostic importance of MINS in vascular surgery patients are poorly described. METHODS: This was an international prospective cohort study of 15,102 noncardiac surgery patients 45 years or older, of whom 502 patients underwent vascular surgery. All patients had fourth-generation plasma troponin T (TnT) concentrations measured during the first 3 postoperative days. MINS was defined as a TnT of 0.03 ng/mL of higher secondary to ischemia. The objectives of the present study were to determine (i) if MINS is prognostically important in vascular surgical patients, (ii) the clinical characteristics of vascular surgery patients with and without MINS, (iii) the 30-day outcomes for vascular surgery patients with and without MINS, and (iv) the proportion of MINS that probably would have gone undetected without routine troponin monitoring. RESULTS: The incidence of MINS in the vascular surgery patients was 19.1% (95% confidence interval (CI), 15.7%-22.6%). 30-day all-cause mortality in the vascular cohort was 12.5% (95% CI 7.3%-20.6%) in patients with MINS compared with 1.5% (95% CI 0.7%-3.2%) in patients without MINS (P < 0.001). MINS was independently associated with 30-day mortality in vascular patients (odds ratio, 9.48; 95% CI, 3.46-25.96). The 30-day mortality was similar in MINS patients with (15.0%; 95% CI, 7.1-29.1) and without an ischemic feature (12.2%; 95% CI, 5.3-25.5, P = 0.76). The proportion of vascular surgery patients who suffered MINS without overt evidence of myocardial ischemia was 74.1% (95% CI, 63.6-82.4). CONCLUSIONS: Approximately 1 in 5 patients experienced MINS after vascular surgery. MINS was independently associated with 30-day mortality. The majority of patients with MINS were asymptomatic and would have gone undetected without routine postoperative troponin measurement.

Age Does Not Affect Metoprolol's Effect on Perioperative Outcomes (From the POISE Database).

BACKGROUND: Perioperative ß-blockade reduces the incidence of myocardial infarction but increases that of death, stroke, and hypotension. The elderly may experience few benefits but more harms associated with ß-blockade due to a normal effect of aging, that of a reduced resting heart rate. The tested hypothesis was that the effect of perioperative ß-blockade is more significant with increasing age. METHODS: To determine whether the effect of perioperative ß-blockade on the primary composite event, clinically significant hypotension, myocardial infarction, stroke, and death varies with age, we interrogated data from the perioperative ischemia evaluation (POISE) study. The POISE study randomly assigned 8351 patients, aged ≥45 years, in 23 countries, undergoing major noncardiac surgery to either 200 mg metoprolol CR daily or placebo for 30 days. Odds ratios or hazard ratios for time to events, when available, for each of the adverse effects were measured according to decile of age, and interaction term between age and treatment was calculated. No adjustment was made for multiple outcomes. RESULTS: Age was associated with higher incidences of the major outcomes of clinically significant hypotension, myocardial infarction, and death. Age was associated with a minimal reduction in resting heart rate from 84.2 (standard error, 0.63; ages 45-54 years) to 80.9 (standard error, 0.70; ages >85 years; P < .0001). We found no evidence of any interaction between age and study group regarding any of the major outcomes, although the limited sample size does not exclude any but large interactions. CONCLUSIONS: The effect of perioperative ß-blockade on the major outcomes studied did not vary with age. Resting heart rate decreases slightly with age. Our data do not support a recommendation for the use of perioperative ß-blockade in any age subgroup to achieve benefits but avoid harms. Therefore, current recommendations against the use of ß-blockers in high-risk patients undergoing noncardiac surgery apply across all age groups.

Troponin T monitoring to detect myocardial injury after noncardiac surgery: a cost-consequence analysis.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is a mostly asymptomatic condition that is strongly associated with 30-day mortality; however, it remains mostly undetected without systematic troponin T monitoring. We evaluated the cost and consequences of postoperative troponin T monitoring to detect MINS. METHODS: We conducted a model-based cost-consequence analysis to compare the impact of routine troponin T monitoring versus standard care (troponin T measurement triggered by ischemic symptoms) on the incidence of MINS detection. Model inputs were based on Canadian patients enrolled in the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study, which enrolled patients aged 45 years or older undergoing inpatient noncardiac surgery. We conducted probability analyses with 10 000 iterations and extensive sensitivity analyses. RESULTS: The data were based on 6021 patients (48% men, mean age 65 [standard deviation 12] yr). The 30-day mortality rate for MINS was 9.6%. We determined the incremental cost to avoid missing a MINS event as $1632 (2015 Canadian dollars). The cost-effectiveness of troponin monitoring was higher in patient subgroups at higher risk for MINS, e.g., those aged 65 years or more, or with a history of atherosclerosis or diabetes ($1309). CONCLUSION: The costs associated with a troponin T monitoring program to detect MINS were moderate. Based on the estimated incremental cost per health gain, implementation of postoperative troponin T monitoring seems appealing, particularly in patients at high risk for MINS.

CONTEXTE: Les lésions myocardiques après chirurgie non cardiaque (CNC) sont majoritairement asymptomatiques et fortement associées au risque de mortalité dans les 30 jours; toutefois, dans la plupart des cas, elles ne sont pas détectées en l'absence d'une surveillance systématique de la troponine T. Nous avons évalué les coûts et les conséquences d'une telle surveillance pour détecter les lésions myocardiques après CNC. MÉTHODES: Nous avons mené une analyse coût-conséquence modélisée pour comparer la surveillance systématique de la troponine T aux soins habituels seuls (mesure de la troponine T seulement s'il y a présence de symptômes d'ischémie) sur la fréquence de détection de lésions myocardiques après CNC. Les données ayant servi à l'analyse provenaient des patients canadiens ayant participé à l'étude de cohorte VISION, qui visait à évaluer les complications vasculaires chez les patients de 45 ans et plus ayant subi une CNC. Nous avons mené des analyses de probabilité avec 10  000 itérations et des analyses de sensibilité approfondies. RÉSULTATS: Les données portaient sur 6021 patients (48 % du sexe masculin; âge moyen de 65 ans [écart-type de 12 ans]). Le taux de mortalité dans les 30 jours associé à une lésion myocardique après CNC était de 9,6 %. Nous avons déterminé que le coût marginal de la détection de la présence d'une lésion par surveillance de la troponine T était de 1632 $ (dollars canadiens en 2015). Le rapport coût-efficacité était plus bas pour les sous-groupes de patients à risque élevé de lésion myocardique après CNC, comme les patients de 65 ans et plus ou ceux ayant des antécédents d'athérosclérose ou de diabète (1309 $), que pour leurs pairs. CONCLUSION: Les coûts associés à un programme de surveillance de la troponine T pour détecter les lésions myocardiques après CNC étaient modérés. Le coût marginal estimé par gain de santé indique que la mise en œuvre de ce type de programme pourrait être une option intéressante, surtout pour les patients à risque élevé de lésion myocardique après CNC.

Combined Stump Pressure and Oximetry for Shunt Use During Carotid Endarterectomy.

BACKGROUND: Cross-clamp ischemia during carotid endarterectomy can be prevented with carotid bypass shunts in vulnerable patients identified by cerebral monitoring for ischemia. We compared transcranial cerebral oximetry (TCO) with carotid stump pressure measurements for selective shunt use. METHODS: We prospectively collected data on 300 consecutive patients operated on under general anesthesia between 2009 and 2016. Shunts were inserted for a 10% or greater drop in cerebral saturations and/or a mean stump pressure less than 40 mmHg. RESULTS: Seventy-five patients, 25% of the study population, were shunted. The indication was a combined desaturation and stump pressure in 38 (50% of the shunted group), desaturation alone in 11 patients (15%), and a low stump pressure alone in 26 patients (35%). There were no significant differences in baseline characteristics between those patients who were or were not shunted, except angiographic collateral blood supply, which was more commonly identified in patients who were not shunted. A watershed infarct occurred in just one patient with borderline TCO and stump pressure measurements in whom a shunt was not used. CONCLUSIONS: There was poor concordance between TCO and stump pressures, but using both in determining the need for shunt use almost eliminated cross-clamp ischemia in this series of 300 carotid endarterectomy patients.

Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery.

IMPORTANCE: Little is known about the relationship between perioperative high-sensitivity troponin T (hsTnT) measurements and 30-day mortality and myocardial injury after noncardiac surgery (MINS). OBJECTIVE: To determine the association between perioperative hsTnT measurements and 30-day mortality and potential diagnostic criteria for MINS (ie, myocardial injury due to ischemia associated with 30-day mortality). DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of patients aged 45 years or older who underwent inpatient noncardiac surgery and had a postoperative hsTnT measurement. Starting in October 2008, participants were recruited at 23 centers in 13 countries; follow-up finished in December 2013. EXPOSURES: Patients had hsTnT measurements 6 to 12 hours after surgery and daily for 3 days; 40.4% had a preoperative hsTnT measurement. MAIN OUTCOMES AND MEASURES: A modified Mazumdar approach (an iterative process) was used to determine if there were hsTnT thresholds associated with risk of death and had an adjusted hazard ratio (HR) of 3.0 or higher and a risk of 30-day mortality of 3% or higher. To determine potential diagnostic criteria for MINS, regression analyses ascertained if postoperative hsTnT elevations required an ischemic feature (eg, ischemic symptom or electrocardiography finding) to be associated with 30-day mortality. RESULTS: Among 21 842 participants, the mean age was 63.1 (SD, 10.7) years and 49.1% were female. Death within 30 days after surgery occurred in 266 patients (1.2%; 95% CI, 1.1%-1.4%). Multivariable analysis demonstrated that compared with the reference group (peak hsTnT <5 ng/L), peak postoperative hsTnT levels of 20 to less than 65 ng/L, 65 to less than 1000 ng/L, and 1000 ng/L or higher had 30-day mortality rates of 3.0% (123/4049; 95% CI, 2.6%-3.6%), 9.1% (102/1118; 95% CI, 7.6%-11.0%), and 29.6% (16/54; 95% CI, 19.1%-42.8%), with corresponding adjusted HRs of 23.63 (95% CI, 10.32-54.09), 70.34 (95% CI, 30.60-161.71), and 227.01 (95% CI, 87.35-589.92), respectively. An absolute hsTnT change of 5 ng/L or higher was associated with an increased risk of 30-day mortality (adjusted HR, 4.69; 95% CI, 3.52-6.25). An elevated postoperative hsTnT (ie, 20 to <65 ng/L with an absolute change ≥5 ng/L or hsTnT ≥65 ng/L) without an ischemic feature was associated with 30-day mortality (adjusted HR, 3.20; 95% CI, 2.37-4.32). Among the 3904 patients (17.9%; 95% CI, 17.4%-18.4%) with MINS, 3633 (93.1%; 95% CI, 92.2%-93.8%) did not experience an ischemic symptom. CONCLUSIONS AND RELEVANCE: Among patients undergoing noncardiac surgery, peak postoperative hsTnT during the first 3 days after surgery was significantly associated with 30-day mortality. Elevated postoperative hsTnT without an ischemic feature was also associated with 30-day mortality.

Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol alone or a sedation protocol and daily interruption.

BACKGROUND: Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation. METHODS: This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation. RESULTS: Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356 mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, and was at target (3.2 vs 3.3, 95 % CI -0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the night and day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were more unintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases in nighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and the decision not to extubate the patient despite successful SBT. CONCLUSION: Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses were associated with SBT failure and delayed extubation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00675363 . Registered 7 May 2008.

The unmet need for addressing cardiac issues in intensive care research.

OBJECTIVE: Patients with primary cardiovascular disorders and comorbidities are commonly admitted to ICUs; however, little is known about the current state of cardiac research being conducted in these adult ICU patients. DESIGN: Retrospective analysis. PATIENTS OR SUBJECTS: None. SETTING: In separate searches of ongoing phase II-IV clinical trials registered with ClinicalTrials.gov and funding grants available in the Canadian Institutes for Health Research funding decision database between 1999 and 2012, we identified all research initiatives focused on adult ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome of interest was the proportion of cardiac-specific ICU studies, defined as any involving a cardiac population with a cardiac intervention (or observation for observational analyses) and/or a cardiac outcome. A total of 192 unique studies including adult ICU patients were identified from the ClinicalTrials.gov database. These were most commonly classified as respiratory or ventilation (19%), infectious (14.1%), or neurologic (12.0%) in focus. A total of 105 grants were identified in the Canadian Institutes for Health Research database. Funded studies most commonly addressed respiratory or ventilator questions (18.1%), infectious disease issues (12.4%), or hematological/thrombosis questions (9.5%). Only 4.6% of all ICU studies in ClinicalTrials.gov and 1.9% of all Canadian Institutes for Health Research grants could be considered cardiac. CONCLUSIONS: These findings highlight the relative paucity of cardiac-specific research in the intensive care setting relative to the high prevalence of acute cardiac diseases and comorbidities. This observed disparity warrants timely attention and should lead to meaningful research opportunities aimed at improving the outcomes of critically ill cardiac patients.

Recall of ICU Stay in Patients Managed With a Sedation Protocol or a Sedation Protocol With Daily Interruption.

OBJECTIVES: To 1) describe factual, emotional, and delusional memories of ICU stay for patients enrolled in the SLEAP (Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol) trial; 2) compare characteristics of patients with and without ICU recall, and patients with and without delusional memories; and 3) determine factors associated with delusional memories 28 days after ICU discharge. DESIGN: Prospective cohort. SETTING: Sixteen North American medical and surgical ICUs. PATIENTS: Critically ill, mechanically ventilated adults randomized in the SLEAP trial. INTERVENTIONS: Post-ICU interviews on days 3, 28, and 90 using the validated ICU Memory Tool. MEASUREMENTS AND MAIN RESULTS: Overall, 289 of 297 ICU survivors (97%) (146 protocolized sedation and 143 protocolized sedation plus daily interruption patients) were interviewed at least once. Because there were no differences in recall status or types of memories between the two sedation groups, we present the findings for all patients rather than by study group. On days 3, 28, and 90, 28%, 26%, and 36% of patients, respectively, reported no recall of being in the ICU (overall perception, self-reported) (p = 0.75). Mean daily doses of benzodiazepines and opioids were lower in patients with no ICU recall than those with recall (p < 0.0001 for both). Despite one third of patients reporting no recall of ICU stay on day 3, 97% and 90% reported at least one factual and one emotional memory from ICU, respectively. Emotional memories declined with time after ICU discharge, particularly panic and confusion. Delusional memories 28 days after discharge were common (70%) yet unrelated to delirium (p = 0.84), recall status (p = 0.15), total dose of benzodiazepine (p = 0.78), or opioid (p = 0.21). Delusional memories were less likely with longer duration of mechanical ventilation (odds ratio, 0.955; 95% CI, 0.91-1.00; p = 0.04). CONCLUSIONS: Recall of ICU stay and types of memories reported were not influenced by the trial sedation strategy. Lack of ICU recall and delusional memories were common after ICU discharge despite the use of sedation strategies that promoted wakefulness.

Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults.

OBJECTIVE: Delirium is common during critical illness and associated with adverse outcomes. We compared characteristics and outcomes of delirious and nondelirious patients enrolled in a multicenter trial comparing protocolized sedation with protocolized sedation plus daily sedation interruption. DESIGN: Randomized trial. SETTING: Sixteen North American medical and surgical ICUs. PATIENTS: Four hundred thirty critically ill, mechanically ventilated adults. INTERVENTIONS: All patients had hourly titration of opioid and benzodiazepine infusions using a validated sedation scale. For patients in the interruption group, infusions were resumed, if indicated, at half of previous doses. Delirium screening occurred daily; positive screening was defined as an Intensive Care Delirium Screening Checklist score of 4 or more at any time. MEASUREMENTS AND MAIN RESULTS: Delirium was diagnosed in 226 of 420 assessed patients (53.8%). Coma was identified in 32.7% of delirious compared with 22.7% of nondelirious patients (p = 0.03). The median time to onset of delirium was 3.5 days (interquartile range, 2-7), and the median duration of delirium was 2 days (interquartile range, 1-4). Delirious patients were more likely to be male (61.1% vs 46.6%; p = 0.005), have a surgical/trauma diagnosis (21.2% vs 11.0%; p = 0.030), and history of tobacco (31.5% vs 16.2%; p = 0.002) or alcohol use (34.6% vs 20.9%; p = 0.009). Patients with positive delirium screening had longer duration of ventilation (13 vs 7 d; p < 0.001), ICU stay (12 vs 8 d; p < 0.0001), and hospital stay (24 vs 15 d; p < 0.0001). Delirious patients were more likely to be physically restrained (86.3% vs 76.7%; p = 0.014) and undergo tracheostomy (34.6% vs 15.5%; p < 0.0001). Antecedent factors independently associated with delirium onset were restraint use (hazard ratio, 1.87; 95% CI, 1.33-2.63; p = 0.0003), antipsychotic administration (hazard ratio, 1.67; 95% CI, 1.005-2.767; p = 0.047), and midazolam dose (hazard ratio, 0.998; 95% CI, 0.997-1.0; p = 0.049). There was no difference in delirium prevalence or duration between the interruption and control groups. CONCLUSION: In mechanically ventilated adults, delirium was common and associated with longer duration of ventilation and hospitalization. Physical restraint was most strongly associated with delirium.

Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*.

OBJECTIVES: To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU. DESIGN: Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial. SETTING: Sixty-seven medical-surgical ICUs in six countries. PATIENTS: Three thousand seven hundred forty-six medical-surgical critically ill patients. INTERVENTIONS: All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses. MEASUREMENTS AND MAIN RESULTS: Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004). CONCLUSIONS: Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.

Thromboprophylaxis patterns and determinants in critically ill patients: a multicenter audit.

INTRODUCTION: Heparin is safe and prevents venous thromboembolism in critical illness. We aimed to determine the guideline concordance for thromboprophylaxis in critically ill patients and its predictors, and to analyze factors associated with the use of low molecular weight heparin (LMWH), as it may be associated with a lower risk of pulmonary embolism and heparin-induced thrombocytopenia without increasing the bleeding risk. METHODS: We performed a retrospective audit in 28 North American intensive care units (ICUs), including all consecutive medical-surgical patients admitted in November 2011. We documented ICU thromboprophylaxis and reasons for omission. Guideline concordance was determined by adding days in which patients without contraindications received thromboprophylaxis to days in which patients with contraindications did not receive it, divided by the total number of patient-days. We used multilevel logistic regression including time-varying, center and patient-level covariates to determine the predictors of guideline concordance and use of LMWH. RESULTS: We enrolled 1,935 patients (62.3 ± 16.7 years, Acute Physiology and Chronic Health Evaluation [APACHE] II score 19.1 ± 8.3). Patients received thromboprophylaxis with unfractionated heparin (UFH) (54.0%) or LMWH (27.6%). Guideline concordance occurred for 95.5% patient-days and was more likely in patients who were sicker (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.17, 1.75 per 10-point increase in APACHE II), heavier (OR 1.32, 95% CI 1.05, 1.65 per 10-m/kg2 increase in body mass index), had cancer (OR 3.22, 95% CI 1.81, 5.72), previous venous thromboembolism (OR 3.94, 95% CI 1.46,10.66), and received mechanical ventilation (OR 1.83, 95% CI 1.32,2.52). Reasons for not receiving thromboprophylaxis were high risk of bleeding (44.5%), current bleeding (16.3%), no reason (12.9%), recent or upcoming invasive procedure (10.2%), nighttime admission or discharge (9.7%), and life-support limitation (6.9%). LMWH was less often administered to sicker patients (OR 0.65, 95% CI 0.48, 0.89 per 10-point increase in APACHE II), surgical patients (OR 0.41, 95% CI 0.24, 0.72), those receiving vasoactive drugs (OR 0.47, 95% CI 0.35, 0.64) or renal replacement therapy (OR 0.10, 95% CI 0.05, 0.23). CONCLUSIONS: Guideline concordance for thromboprophylaxis was high, but LMWH was less commonly used, especially in patients who were sicker, had surgery, or received vasopressors or renal replacement therapy, representing a potential quality improvement target.

Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients.

IMPORTANCE: Venous thromboembolism (VTE) is a common complication of acute illness, and its prevention is a ubiquitous aspect of inpatient care. A multicenter blinded, randomized trial compared the effectiveness of the most common pharmocoprevention strategies, unfractionated heparin (UFH) and the low-molecular-weight heparin (LMWH) dalteparin, finding no difference in the primary end point of leg deep-vein thrombosis but a reduced rate of pulmonary embolus and heparin-induced thrombocytopenia among critically ill medical-surgical patients who received dalteparin. OBJECTIVE: To evaluate the comparative cost-effectiveness of LMWH vs UFH for prophylaxis against VTE in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: Prospective economic evaluation concurrent with the Prophylaxis for Thromboembolism in Critical Care Randomized Trial (May 2006 to June 2010). The economic evaluation adopted a health care payer perspective and in-hospital time horizon; derived baseline characteristics and probabilities of intensive care unit and in-hospital events; and measured costs among 2344 patients in 23 centers in 5 countries and applied these costs to measured resource use and effects of all enrolled patients. MAIN OUTCOMES AND MEASURES: Costs, effects, incremental cost-effectiveness of LMWH vs UFH during the period of hospitalization, and sensitivity analyses across cost ranges. RESULTS: Hospital costs per patient were $39,508 (interquartile range [IQR], $24,676 to $71,431) for 1862 patients who received LMWH compared with $40,805 (IQR, $24,393 to $76,139) for 1862 patients who received UFH (incremental cost, -$1297 [IQR, -$4398 to $1404]; P = .41). In 78% of simulations, a strategy using LMWH was most effective and least costly. In sensitivity analyses, a strategy using LMWH remained least costly unless the drug acquisition cost of dalteparin increased from $8 to $179 per dose and was consistent among higher- and lower-spending health care systems. There was no threshold at which lowering the acquisition cost of UFH favored prophylaxis with UFH. CONCLUSIONS AND RELEVANCE: From a health care payer perspective, the use of the LMWH dalteparin for VTE prophylaxis among critically ill medical-surgical patients was more effective and had similar or lower costs than the use of UFH. These findings were driven by lower rates of pulmonary embolus and heparin-induced thrombocytopenia and corresponding lower overall use of resources with LMWH.