Prediction models for development of retinopathy in people with type 2 diabetes: systematic review and external validation in a Dutch primary care setting.

AIMS/HYPOTHESIS: The aims of this study were to identify all published prognostic models predicting retinopathy risk applicable to people with type 2 diabetes, to assess their quality and accuracy, and to validate their predictive accuracy in a head-to-head comparison using an independent type 2 diabetes cohort. METHODS: A systematic search was performed in PubMed and Embase in December 2019. Studies that met the following criteria were included: (1) the model was applicable in type 2 diabetes; (2) the outcome was retinopathy; and (3) follow-up was more than 1 year. Screening, data extraction (using the checklist for critical appraisal and data extraction for systemic reviews of prediction modelling studies [CHARMS]) and risk of bias assessment (by prediction model risk of bias assessment tool [PROBAST]) were performed independently by two reviewers. Selected models were externally validated in the large Hoorn Diabetes Care System (DCS) cohort in the Netherlands. Retinopathy risk was calculated using baseline data and compared with retinopathy incidence over 5 years. Calibration after intercept adjustment and discrimination (Harrell's C statistic) were assessed. RESULTS: Twelve studies were included in the systematic review, reporting on 16 models. Outcomes ranged from referable retinopathy to blindness. Discrimination was reported in seven studies with C statistics ranging from 0.55 (95% CI 0.54, 0.56) to 0.84 (95% CI 0.78, 0.88). Five studies reported on calibration. Eight models could be compared head-to-head in the DCS cohort (N = 10,715). Most of the models underestimated retinopathy risk. Validating the models against different severities of retinopathy, C statistics ranged from 0.51 (95% CI 0.49, 0.53) to 0.89 (95% CI 0.88, 0.91). CONCLUSIONS/INTERPRETATION: Several prognostic models can accurately predict retinopathy risk in a population-based type 2 diabetes cohort. Most of the models include easy-to-measure predictors enhancing their applicability. Tailoring retinopathy screening frequency based on accurate risk predictions may increase the efficiency and cost-effectiveness of diabetic retinopathy care. REGISTRATION: PROSPERO registration ID CRD42018089122.

Artifact Processing Methods Influence on Intraoperative Hypotension Quantification and Outcome Effect Estimates.

BACKGROUND: Physiologic data that is automatically collected during anesthesia is widely used for medical record keeping and clinical research. These data contain artifacts, which are not relevant in clinical care, but may influence research results. The aim of this study was to explore the effect of different methods of filtering and processing artifacts in anesthesiology data on study findings in order to demonstrate the importance of proper artifact filtering. METHODS: The authors performed a systematic literature search to identify artifact filtering methods. Subsequently, these methods were applied to the data of anesthesia procedures with invasive blood pressure monitoring. Different hypotension measures were calculated (i.e., presence, duration, maximum deviation below threshold, and area under threshold) across different definitions (i.e., thresholds for mean arterial pressure of 50, 60, 65, 70 mmHg). These were then used to estimate the association with postoperative myocardial injury. RESULTS: After screening 3,585 papers, the authors included 38 papers that reported artifact filtering methods. The authors applied eight of these methods to the data of 2,988 anesthesia procedures. The occurrence of hypotension (defined with a threshold of 50 mmHg) varied from 24% with a median filter of seven measurements to 55% without an artifact filtering method, and between 76 and 90% with a threshold of 65 mmHg. Standardized odds ratios for presence of hypotension ranged from 1.16 (95% CI, 1.07 to 1.26) to 1.24 (1.14 to 1.34) when hypotension was defined with a threshold of 50 mmHg. Similar variations in standardized odds ratios were found when applying methods to other hypotension measures and definitions. CONCLUSIONS: The method of artifact filtering can have substantial effects on estimates of hypotension prevalence. The effect on the association between intraoperative hypotension and postoperative myocardial injury was relatively small. Nevertheless, the authors recommend that researchers carefully consider artifacts handling and report the methodology used.

Anaesthesia geriatric evaluation to guide patient selection for preoperative multidisciplinary team care in cardiac surgery.

BACKGROUND: A multidisciplinary approach to improve postoperative outcomes in frail elderly patients is gaining interest. Multidisciplinary team care should be targeted at complex patients at high risk for adverse postoperative outcome to limit the strain on available resources and to prevent an unnecessary increase in patient burden. This study aimed to improve patient selection for multidisciplinary care by identifying risk factors for disability after cardiac surgery in elderly patients. METHODS: This was a two-centre prospective cohort study of 537 patients aged ≥70 yr undergoing elective cardiac surgery. Before surgery, 11 frailty characteristics were investigated. Outcome was disability at 3 months defined as World Health Organization Disability Assessment Schedule 2.0 ≥25%. Multivariable modelling using logistic regression, concordance statistic (c-statistic), and net reclassification index was used to identify factors contributing to patient selection. RESULTS: Disability occurred in 91 (17%) patients. Ten out of 11 frailty characteristics were associated with disability. A multivariable model, including the European System for Cardiac Operative Risk Evaluation II and preoperative haemoglobin, yielded a c-statistic of 0.71 (95% confidence interval [CI]: 0.66-0.77). After adding pre-specified frailty characteristics (polypharmacy, gait speed, physical disability, preoperative health-related quality of life, and living alone) to this model, the c-statistic improved to 0.78 (95% CI: 0.73-0.83). The net reclassification index was 0.32 (P<0.001), showing improved discrimination for patients at risk for disability at 3 months. CONCLUSIONS: The addition of preoperative frailty characteristics to a multivariable model improved discrimination between elderly patients with and without disability at 3 months after cardiac surgery, and can be used to guide patient selection for preoperative multidisciplinary team care. CLINICAL TRIAL REGISTRATION: NCT02535728.

Patient and anesthesia characteristics of children with low pre-incision blood pressure: A retrospective observational study.

BACKGROUND: Intraoperative blood pressure has been suggested as a key factor for safe pediatric anesthesia. However, there is not much insight into factors that discriminate between children with low and normal pre-incision blood pressure. Our aim was to explore whether children who have a low blood pressure during anesthesia are different than those with normal blood pressure. The focus of the present study was on the pre-incision period. METHODS: This retrospective study included pediatric patients undergoing anesthesia for non-cardiac surgery at a tertiary pediatric university hospital, between 2012 and 2016. We analyzed the association between pre-incision blood pressure and patient- and anesthesia characteristics, comparing low with normal pre-incision blood pressure. This association was further explored with a multivariable linear regression. RESULTS: In total, 20 962 anesthetic cases were included. Pre-incision blood pressure was associated with age (beta -0.04 SD per year), gender (female -0.11), previous surgery (-0.15), preoperative blood pressure (+0.01 per mm Hg), epilepsy (0.12), bronchial hyperactivity (-0.18), emergency surgery (0.10), loco-regional technique (-0.48), artificial airway device (supraglottic airway device instead of tube 0.07), and sevoflurane concentration (0.03 per sevoflurane %). CONCLUSIONS: Children with low pre-incision blood pressure do not differ on clinically relevant factors from children with normal blood pressure. Although the present explorative study shows that pre-incision blood pressure is partly dependent on patient characteristics and partly dependent on anesthetic technique, other unmeasured variables might play a more important role.

Adjusting for Disease Severity Across ICUs in Multicenter Studies.

OBJECTIVES: To compare methods to adjust for confounding by disease severity during multicenter intervention studies in ICU, when different disease severity measures are collected across centers. DESIGN: In silico simulation study using national registry data. SETTING: Twenty mixed ICUs in The Netherlands. SUBJECTS: Fifty-five-thousand six-hundred fifty-five ICU admissions between January 1, 2011, and January 1, 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: To mimic an intervention study with confounding, a fictitious treatment variable was simulated whose effect on the outcome was confounded by Acute Physiology and Chronic Health Evaluation IV predicted mortality (a common measure for disease severity). Diverse, realistic scenarios were investigated where the availability of disease severity measures (i.e., Acute Physiology and Chronic Health Evaluation IV, Acute Physiology and Chronic Health Evaluation II, and Simplified Acute Physiology Score II scores) varied across centers. For each scenario, eight different methods to adjust for confounding were used to obtain an estimate of the (fictitious) treatment effect. These were compared in terms of relative (%) and absolute (odds ratio) bias to a reference scenario where the treatment effect was estimated following correction for the Acute Physiology and Chronic Health Evaluation IV scores from all centers. Complete neglect of differences in disease severity measures across centers resulted in bias ranging from 10.2% to 173.6% across scenarios, and no commonly used methodology-such as two-stage modeling or score standardization-was able to effectively eliminate bias. In scenarios where some of the included centers had (only) Acute Physiology and Chronic Health Evaluation II or Simplified Acute Physiology Score II available (and not Acute Physiology and Chronic Health Evaluation IV), either restriction of the analysis to Acute Physiology and Chronic Health Evaluation IV centers alone or multiple imputation of Acute Physiology and Chronic Health Evaluation IV scores resulted in the least amount of relative bias (0.0% and 5.1% for Acute Physiology and Chronic Health Evaluation II, respectively, and 0.0% and 4.6% for Simplified Acute Physiology Score II, respectively). In scenarios where some centers used Acute Physiology and Chronic Health Evaluation II, regression calibration yielded low relative bias too (relative bias, 12.4%); this was not true if these same centers only had Simplified Acute Physiology Score II available (relative bias, 54.8%). CONCLUSIONS: When different disease severity measures are available across centers, the performance of various methods to control for confounding by disease severity may show important differences. When planning multicenter studies, researchers should make contingency plans to limit the use of or properly incorporate different disease measures across centers in the statistical analysis.

Blood Pressure and End-tidal Carbon Dioxide Ranges during Aneurysm Occlusion and Neurologic Outcome after an Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Hypocapnia, hypotension, and hypertension during aneurysm occlusion in patients with an aneurysmal subarachnoid hemorrhage may lead to a poor prognosis, but evidence for end-tidal carbon dioxide (ETCO2) and mean arterial pressure (MAP) targets is lacking. Within the ranges of standardized treatment, the authors aimed to study the association between hypocapnia (PaCO2 < 35 mmHg), hypotension (MAP < 80 mmHg), and hypertension (MAP >100 mmHg) during general anesthesia for aneurysm occlusion and neurologic outcome. METHODS: This retrospective observational study included patients who underwent early aneurysm occlusion after an aneurysmal subarachnoid hemorrhage under general anesthesia. ETCO2 and MAP were summarized per patient as the mean and time-weighted average area under the curve for various absolute (ETCO2 < 30, < 35, < 40, < 45 mmHg; and MAP < 60, < 70, < 80, > 90, > 100 mmHg) and relative thresholds (MAP < 70%, < 60%, < 50%). Clinical outcome was assessed with the Glasgow Outcome Scale at discharge and at three months, as primary and secondary outcome measure, respectively. RESULTS: Endovascular coiling was performed in 578 patients, and 521 underwent neurosurgical clipping. Of these 1,099 patients, 447 (41%) had a poor neurologic outcome at discharge. None of the ETCO2 and MAP ranges found within the current clinical setting were associated with a poor neurologic outcome at discharge, with an adjusted risk ratio for any ETCO2 value less than 30 mmHg of 0.95 (95% CI, 0.81 to 1.10; P < 0.496) and an adjusted risk ratio for any MAP less than 60 mmHg of 0.94 (95% CI, 0.78 to 1.14; P < 0.530). These results were not influenced by preoperative neurologic condition, treatment modality and timing of the intervention. Comparable results were obtained for neurologic outcome at three months. CONCLUSIONS: Within a standardized intraoperative treatment strategy in accordance with current clinical consensus, hypocapnia, hypotension, and hypertension during aneurysm occlusion were not found to be associated with a poor neurologic outcome at discharge in patients with an aneurysmal subarachnoid hemorrhage.

Pulmonary Embolism After Endovascular Aortic Repair, a Retrospective Cohort Study.

OBJECTIVES: Endovascular aortic repair (EVAR) is associated with an increased risk of pulmonary embolism, which is often clinically silent and therefore difficult to recognise. The aim was to investigate the incidence of pulmonary embolism after EVAR using routinely performed pre- and post-operative aortic computed tomography angiography (CTA), and the association between pulmonary embolism and mortality. METHODS: This single centre retrospective cohort study included adult patients who underwent EVAR in the University Medical Centre Utrecht between January 2010 and July 2015 and who had a total aortic, thoracic aortic, or pulmonary CTA within one month post-operatively. Baseline and mortality data were obtained by reviewing hospital and general practitioner records. The primary outcome was pulmonary embolism within one month after surgery. Secondary outcomes were 30 day and six month mortality. RESULTS: During the study period, 526 EVARs were performed. Seventy-four of these procedures were included in the analysis of which there were 40 thoracic and 34 abdominal EVARs. In nine patients (12%, 95% CI 7-22) pulmonary embolism was observed of which one was central, two were segmental, and six were subsegmental. Seven were clinically silent and two were present on the pre-operative CTA. Thirty day mortality was significantly higher in patients with pulmonary embolism (relative risk 14.4, 95% CI 1.4-143, p = .037) though none of the deaths seemed directly attributable to it. CONCLUSIONS: This study, although preliminary, suggests that silent pulmonary embolism after EVAR occurs in approximately one in 10 patients, despite routine thrombo-embolism prophylaxis. Pulmonary embolism was associated with a higher 30 day mortality risk yet it was not the cause of death in any of these patients.

Incorporating repeated measurements into prediction models in the critical care setting: a framework, systematic review and meta-analysis.

BACKGROUND: The incorporation of repeated measurements into multivariable prediction research may greatly enhance predictive performance. However, the methodological possibilities vary widely and a structured overview of the possible and utilized approaches lacks. Therefore, we [1] propose a structured framework for these approaches, [2] determine what methods are currently used to incorporate repeated measurements in prediction research in the critical care setting and, where possible, [3] assess the added discriminative value of incorporating repeated measurements. METHODS: The proposed framework consists of three domains: the observation window (static or dynamic), the processing of the raw data (raw data modelling, feature extraction and reduction) and the type of modelling. A systematic review was performed to identify studies which incorporate repeated measurements to predict (e.g. mortality) in the critical care setting. The within-study difference in c-statistics between models with versus without repeated measurements were obtained and pooled in a meta-analysis. RESULTS: From the 2618 studies found, 29 studies incorporated multiple repeated measurements. The annual number of studies with repeated measurements increased from 2.8/year (2000-2005) to 16.0/year (2016-2018). The majority of studies that incorporated repeated measurements for prediction research used a dynamic observation window, and extracted features directly from the data. Differences in c statistics ranged from - 0.048 to 0.217 in favour of models that utilize repeated measurements. CONCLUSIONS: Repeated measurements are increasingly common to predict events in the critical care domain, but their incorporation is lagging. A framework of possible approaches could aid researchers to optimize future prediction models.

An observational study of end-tidal carbon dioxide trends in general anesthesia.

PURPOSE: Despite growing evidence supporting the potential benefits of higher end-tidal carbon dioxide (ETCO2) levels in surgical patients, there is still insufficient data to formulate guidelines for ideal intraoperative ETCO2 targets. As it is unclear which intraoperative ETCO2 levels are currently used and whether these levels have changed over time, we investigated the practice pattern using the Multicenter Perioperative Outcomes Group database. METHODS: This retrospective, observational, multicentre study included 317,445 adult patients who received general anesthesia for non-cardiothoracic procedures between January 2008 and September 2016. The primary outcome was a time-weighted average area-under-the-curve (TWA-AUC) for four ETCO2 thresholds (< 28, < 35, < 45, and > 45 mmHg). Additionally, a median ETCO2 was studied. A Kruskal-Wallis test was used to analyse differences between years. Random-effect multivariable logistic regression models were constructed to study variability. RESULTS: Both TWA-AUC and median ETCO2 showed a minimal increase in ETCO2 over time, with a median [interquartile range] ETCO2 of 33 [31.0-35.0] mmHg in 2008 and 35 [33.0-38.0] mmHg in 2016 (P <0.001). A large inter-hospital and inter-provider variability in ETCO2 were observed after adjustment for patient characteristics, ventilation parameters, and intraoperative blood pressure (intraclass correlation coefficient 0.36; 95% confidence interval, 0.18 to 0.58). CONCLUSIONS: Between 2008 and 2016, intraoperative ETCO2 values did not change in a clinically important manner. Interestingly, we found a large inter-hospital and inter-provider variability in ETCO2 throughout the study period, possibly indicating a broad range of tolerance for ETCO2, or a lack of evidence to support a specific targeted range. Clinical outcomes were not assessed in this study and they should be the focus of future research.

RéSUMé: OBJECTIF: Malgré une accumulation de données probantes suggérant des avantages de taux plus élevés de dioxyde de carbone en fin d'expiration (ETCO2) chez les patients chirurgicaux, nous ne disposons pas encore d'assez de données pour formuler des lignes directrices sur les cibles peropératoires idéales de l'ETCO2. Comme nous ne savons effectivement pas avec certitude quels taux peropératoires d'ETCO2 sont actuellement utilisés et si ces taux ont changé au fil du temps, nous avons étudié l'évolution de la pratique en utilisant la base de données du MPOG (Multicenter Perioperative Outcomes Group). MéTHODES: Cette étude multicentrique rétrospective observationnelle a inclus 317 445 patients adultes ayant reçu une anesthésie générale pour des procédures non cardiothoraciques entre janvier 2008 et septembre 2016. Le critère d'évaluation principal était une aire sous la courbe moyenne pondérée en fonction du temps (ASC-mT) pour quatre seuils d'ETCO2 (< 28, < 35, < 45 et > 45 mmHg). De plus, une ETCO2 médiane a été étudiée. Un test de Kruskal-Wallis a permis d'analyser les différences entre les années. Des modèles de régression logistique multifactorielle à effet aléatoire ont été construits pour étudier la variabilité. RéSULTATS: L'ASC-mT et l'ETCO2 médiane ont montré une augmentation minime de l'ETCO2 au fil du temps, avec une valeur médiane [plage interquartile] de l'ETCO2 de 33 [31,0 à 35,0] mmHg en 2008 et 35 [33,0 à 38,0] mmHg en 2016 (P < 0,001). Une grande variabilité entre les hôpitaux et prestataires de l'ETCO2 a été observée après ajustement pour les caractéristiques des patients, les paramètres de ventilation et la pression artérielle peropératoire (coefficient de corrélation intracatégorie : 0,36; intervalle de confiance à 95 % : 0,18 à 0,58). CONCLUSIONS: Entre 2008 et 2016, les valeurs peropératoires de l'ETCO2 n'ont pas varié d'une manière importante sur le plan clinique. Il est intéressant de noter que nous avons trouvé une grande variabilité de l'ETCO2 entre hôpitaux et prestataires tout au long de la période d'étude témoignant peut-être d'une vaste plage de tolérance de l'ETCO2 ou d'un manque de données probantes pour soutenir une valeur cible spécifique. L'évolution clinique n'a pas été analysée au cours de cette étude et elle devra être le centre d'intérêt de futures recherches.

Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study.

BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis. METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models. RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus -15% when compared with CMVs+ and +37% versus +4% when compared with CMVs-) and decreased IL-1RA (-41% versus 0% and -49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA. CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.

Unexpected Cardiac Computed Tomography Findings in Patients With Postoperative Myocardial Injury.

BACKGROUND: Postoperative myocardial injury (PMI) is a strong predictor of mortality after noncardiac surgery. PMI is believed to be attributable to coronary artery disease (CAD), yet its etiology is largely unclear. We aimed to quantify the prevalence of significant CAD in patients with and without PMI using coronary computed tomography angiography (CCTA). METHODS: This prospective cohort study included patients of 60 years or older without a history of cardiac disease and with and without PMI after intermediate- to high-risk noncardiac surgery. PMI was defined as any serum troponin I level ≥60 ng/L on the first 3 postoperative days. Main exclusion criteria were known cardiac disease and postoperative ischemic symptoms or electrocardiography abnormalities. Noninvasive imaging consisted of a postoperative CCTA. Main outcome was CAD defined as >50% coronary stenosis on CCTA. RESULTS: The analysis included 66 patients. Median peak troponin levels in the PMI (n = 46) and control group (n = 20) were 150 (interquartile range, 120-298) vs 15 (interquartile range, 10-31) ng/L (P < .01). CAD was found in 23 patients with PMI (50%) vs 3 without PMI (15%; relative risk, 3.3; 95% confidence interval, 1.1-9.8). Remarkably, pulmonary embolism was present in 15 patients with PMI (33%) versus in 4 without PMI (20%; relative risk, 1.6; 95% confidence interval, 0.6-4.3). None of the patients died within 30 days. CONCLUSIONS: In patients without a history of cardiac disease, PMI after noncardiac surgery was associated with CAD. In addition, a clinically silent pulmonary embolism was found in one-third of patients with PMI. This urges further research to improve clinical workup using imaging and may have important clinical implications.

Incidence, Predictors, and Outcomes of New-Onset Atrial Fibrillation in Critically Ill Patients with Sepsis. A Cohort Study.

RATIONALE: Patients admitted to intensive care units with sepsis are prone to developing cardiac dysrhythmias, most commonly atrial fibrillation. OBJECTIVES: To determine the incidence, risk factors, and outcomes of atrial fibrillation in a cohort of critically ill patients with sepsis. METHODS: We assessed the association between atrial fibrillation and mortality using time-dependent competing risks survival analysis. Subsequently, for development of a risk score estimating the probability of a first occurrence of atrial fibrillation within the following 24 hours, we performed logistic regression analysis. MEASUREMENTS AND MAIN RESULTS: Among 1,782 patients with sepsis admitted to two tertiary intensive care units in the Netherlands between January 2011 and June 2013, a total of 1,087 episodes of atrial fibrillation occurred in 418 (23%) individuals. The cumulative risk of new-onset atrial fibrillation was 10% (95% confidence interval [CI], 8-12), 22% (95% CI, 18-25), and 40% (95% CI, 36-44) in patients with sepsis, severe sepsis, and septic shock, respectively. New-onset atrial fibrillation was associated with a longer stay (hazard ratio [HR], 0.55; 95% CI, 0.48-0.64), an increased death rate (HR, 1.52; 95% CI, 1.16-2.00), and an overall increased mortality risk (subdistribution HR, 2.10; 95% CI, 1.61-2.73) when considering discharge as a competing event. A simple risk score for daily prediction of atrial fibrillation occurrence yielded good discrimination (C statistic, 0.81; 95% CI, 0.79-0.84) and calibration (chi-square, 9.38; P = 0.31), with similar performance in an independent validation cohort (C statistic, 0.80; 95% CI, 0.76-0.85). CONCLUSIONS: Atrial fibrillation is a common complication of sepsis and independently associated with excess mortality. A simple risk score may identify patients at high risk of this complication. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).

Accuracy of remote continuous respiratory rate monitoring technologies intended for low care clinical settings: a prospective observational study.

PURPOSE: Altered respiratory rate (RR) has been identified as an important predictor of serious adverse events during hospitalization. Introduction of a well-tolerated continuous RR monitor could potentially reduce serious adverse events such as opioid-induced respiratory depression. The purpose of this study was to investigate the ability of different monitor devices to detect RR in low care clinical settings. METHODS: This was a prospective method-comparison study with a cross-sectional design. Thoracic impedance pneumography (IPG), frequency modulated continuous wave radar, and an acoustic breath sounds monitor were compared with the gold standard of capnography for their ability to detect RR in breaths per minute (breaths·min-1) in awake postoperative patients in the postanesthesia care unit. The Bland and Altman method for repeated measurements and mixed effect modelling was used to obtain bias and limits of agreement (LoA). Furthermore, the ability of the three devices to assist with correct treatment decisions was evaluated in Clarke Error Grids. RESULTS: Twenty patients were monitored for 1,203 min, with a median [interquartile range] of 61 [60-63] min per patient. The bias (98.9% LoA) were 0.1 (-7.9 to 7.9) breaths·min-1 for the acoustic monitor, -1.6 (-10.8 to 7.6) for the radar, and -1.9 (-13.1 to 9.2) for the IPG. The extent to which the monitors guided adequate or led to inadequate treatment decisions (determined by Clarke Error Grid analysis) differed significantly between the monitors (P = 0.011). Decisions were correct 96% of the time for acoustic, 95% of the time for radar, and 94% of the time for IPG monitoring devices. CONCLUSIONS: None of the studied devices (acoustic, IPG, and radar monitor) had LoA that were within our predefined (based on clinical judgement) limits of ± 2 breaths·min-1. The acoustic breath sound monitor predicted the correct treatment more often than the IPG and the radar device.

The incidence of postoperative respiratory complications: A retrospective analysis of cuffed vs uncuffed tracheal tubes in children 0-7 years of age.

BACKGROUND: The use of cuffed vs uncuffed endotracheal tubes in pediatric anesthesia is widely debated. This study aimed to investigate whether the use of cuffed vs uncuffed tubes is associated with an increased incidence of acute postoperative respiratory complications. METHODS: We retrospectively studied all children aged 0-7 years in which the trachea was intubated between September 28, 2006 and August 26, 2016 in a pediatric university hospital. Logistic regression analysis was performed to estimate the association between tube design (cuffed vs uncuffed) and the incidence of acute postoperative respiratory complications (stridor, wheezing, or dyspnea; desaturations ≤90%) in need of intervention (epinephrine, dexamethasone, nebulizers, supplementary oxygen, or reintubation), adjusting for potential confounders. RESULTS: In 5247 of 6796 cases (77%), a cuffed tube was used. Acute postoperative respiratory complications in need of intervention occurred in 334 cases (4.9%) and were less common after cuffed than after uncuffed tubes (N = 236, 4.5% vs N = 98, 6.3%, respectively, odds ratio 0.70; 95%CI 0.55-0.89). Desaturation occurred less often after cuffed tubes (cuffed: N = 1365, 26.0%; uncuffed: N = 512, 33.1%; OR: 0.71 (0.61-0.84)). After adjusting for confounders, there was no difference in acute postoperative respiratory complications between cuffed tubes and uncuffed tubes (OR 0.74; 95%CI 0.55-1.01). Subgroup analyses in various age groups did not show significant differences between the use of cuffed or uncuffed tubes. CONCLUSION: After adjustment for multiple confounders, the use of cuffed tubes was not associated with an increased incidence of acute respiratory complications in postanesthesia care unit.

An Unbalanced Inflammatory Cytokine Response Is Not Associated With Mortality Following Sepsis: A Prospective Cohort Study.

OBJECTIVE: The prevailing theory of host response during sepsis states that an excessive production of pro-inflammatory mediators causes early deaths, whereas a predominantly anti-inflammatory response may lead to immunosuppression, secondary infection, and late deaths. We assessed inflammatory (im)balance by measuring pro-inflammatory interleukin-6 and anti-inflammatory interleukin-10 during three distinct time periods after sepsis, and assessed its association with mortality. DESIGN: Prospective observational cohort. SETTING: Two tertiary mixed ICUs in The Netherlands. PATIENTS: Consecutive patients presenting with severe sepsis or septic shock from 2011 to 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We repeatedly measured plasma interleukin-6 and interleukin-10 concentrations using cytometric bead array. Poisson regression was used to analyze the relation between inflammatory markers measured on 1) ICU admission and day 4 mortality, 2) day 4 and day 28 mortality, and 3) ICU discharge and 1-year mortality. Secondary outcome was development of ICU-acquired infections. Among 708 patients, 86 (12%) died within 4 days, 140 (20%) died between days 4 and 28, and an additional 155 (22%) died before 1 year. Interleukin-6 and interleukin-10 levels were both independently associated with mortality, but the balance of this response as modelled by an interleukin-6 and interleukin-10 interaction term was not (relative risk, 0.99; 95% CI, 0.95-1.04 on admission; relative risk, 1.02; 95% CI, 0.98-1.06 on day 4; and relative risk, 1.12; 95% CI, 0.98-1.29 at ICU discharge). However, inflammatory imbalance on day 4 was associated with development of ICU-acquired infections (subdistribution hazard ratio, 0.87; 95% CI, 0.77-0.98). CONCLUSIONS: Although both interleukin-6 and interleukin-10 productions are associated with death, the balance of these inflammatory mediators does not seem to impact either early, intermediate, or late mortality in patients presenting to the ICU with sepsis.

Accounting for treatment use when validating a prognostic model: a simulation study.

BACKGROUND: Prognostic models often show poor performance when applied to independent validation data sets. We illustrate how treatment use in a validation set can affect measures of model performance and present the uses and limitations of available analytical methods to account for this using simulated data. METHODS: We outline how the use of risk-lowering treatments in a validation set can lead to an apparent overestimation of risk by a prognostic model that was developed in a treatment-naïve cohort to make predictions of risk without treatment. Potential methods to correct for the effects of treatment use when testing or validating a prognostic model are discussed from a theoretical perspective.. Subsequently, we assess, in simulated data sets, the impact of excluding treated individuals and the use of inverse probability weighting (IPW) on the estimated model discrimination (c-index) and calibration (observed:expected ratio and calibration plots) in scenarios with different patterns and effects of treatment use. RESULTS: Ignoring the use of effective treatments in a validation data set leads to poorer model discrimination and calibration than would be observed in the untreated target population for the model. Excluding treated individuals provided correct estimates of model performance only when treatment was randomly allocated, although this reduced the precision of the estimates. IPW followed by exclusion of the treated individuals provided correct estimates of model performance in data sets where treatment use was either random or moderately associated with an individual's risk when the assumptions of IPW were met, but yielded incorrect estimates in the presence of non-positivity or an unobserved confounder. CONCLUSIONS: When validating a prognostic model developed to make predictions of risk without treatment, treatment use in the validation set can bias estimates of the performance of the model in future targeted individuals, and should not be ignored. When treatment use is random, treated individuals can be excluded from the analysis. When treatment use is non-random, IPW followed by the exclusion of treated individuals is recommended, however, this method is sensitive to violations of its assumptions.

Kinetics of troponin I in patients with myocardial injury after noncardiac surgery.

BACKGROUND: Myocardial injury after noncardiac surgery, as measured by troponin elevation, is strongly associated with mortality. However, it is unknown in which patients prognosis can be improved. The presence of kinetic changes of troponin may be associated with a worse prognosis and warrant more aggressive management. Therefore, we aimed to study the kinetics of troponin in patients with postoperative myocardial injury, and to determine the added predictive value of kinetic changes of troponin on mortality. METHODS: This cohort study included patients with myocardial injury after noncardiac surgery. Troponin I (TnI) was measured on the first three postoperative days. The primary outcome was all-cause 1-year mortality. We studied both absolute and relative TnI changes, and determined the delta TnI that was associated with mortality to distinguish a rise-and-fall TnI pattern from a stable TnI pattern. Next, we determined the added predictive value of a rise-and-fall TnI pattern for mortality. RESULTS: In total, 634 patients were included. The risk ratio (RR) for mortality increased significantly with an absolute delta TnI of ≥200 ng/L (RR 1.5, 99.4% CI 1.0-2.2, p=0.003). Using this delta TnI to define a rise-and-fall pattern, 459 patients (72%) had a stable TnI pattern and 175 patients (28%) had a rise-and-fall pattern. When added to a model including the highest TnI value and variables from the revised cardiac risk index (RCRI), the TnI pattern did not increase the predictive value for mortality. CONCLUSIONS: A postoperative TnI rise-and-fall pattern was associated with 1-year mortality, but had no added value in addition to the highest TnI level to predict 1-year mortality. Therefore, postoperative TnI kinetics are not useful for further mortality risk stratification in patients with myocardial injury after noncardiac surgery.

Relationship Between Preoperative Evaluation Blood Pressure and Preinduction Blood Pressure: A Cohort Study in Patients Undergoing General Anesthesia.

BACKGROUND: For outcomes research where changes in intraoperative blood pressure are a possible causative factor, it is important to determine an appropriate source for a reference value. We studied to what extent preinduction blood pressure values in the operating room differ from those obtained during preoperative evaluation outside the operating room. METHODS: Cohort study including 4408 patients aged 60 years or older undergoing noncardiac surgery. The outcome was the difference between the preinduction mean blood pressure (MBP) and the MBP obtained during preoperative evaluation. A difference of ≥10 mm Hg was considered clinically relevant. A paired samples t test was used to estimate the difference. Linear regression was used to obtain estimates adjusted for patient characteristics, comorbidity, medications, type of surgery, and preoperative blood pressure. RESULTS: Complete data were available for 3660 (83%) patients. There were 2228 (61%) patients with a difference of ≥10 mm Hg between the preinduction and preoperative MBP. The overall mean difference between both MBPs was 11 mm Hg (95% confidence interval, 10-11) with important variability among individuals. Patients with higher preoperative MBP values had smaller differences. After adjusting for patient characteristics, comorbidity, medications, type of surgery, and preoperative blood pressure, the difference decreased an estimated 5.0 mm Hg (95% confidence interval, 4.7-5.4) for every increase of 10 mm Hg in preoperative MBP. Patient characteristics, comorbidity, type of surgery, or medication were not strongly associated with the difference. CONCLUSIONS: The average preinduction blood pressure was higher than the preoperative blood pressure. This difference between the measurements can be explained by stress-induced effects and regression to the mean. To define an optimal reference value for research purposes or to arrive at a clinical perioperative blood pressure target, one should consider that there is important variability both within and between patients.

Impact of Intraoperative Hypotension During Cardiopulmonary Bypass on Acute Kidney Injury After Coronary Artery Bypass Grafting.

OBJECTIVE: The aim of this study was to investigate whether acute kidney injury (AKI) after coronary artery bypass grafting can be attributed to intraoperative hypotension during cardiopulmonary bypass (IOH-CPB). DESIGN: Retrospective analysis. SETTING: Tertiary-care hospital. PARTICIPANTS: Patients undergoing on-pump coronary artery bypass grafting from June 2011 to January 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: IOH-CPB was defined as blood pressure below several absolute and relative mean arterial pressure (MAP) thresholds and as the area under the curve for absolute MAP thresholds. AKI was defined as an absolute increase in serum creatinine of≥26 µmol/L within 48 hours or an increase to 150% or more within 7 days of surgery. Poisson regression with robust standard errors both before and after adjustment for confounders was used. Of the 1,891 patients included, 386 (20%) developed AKI. In univariable analysis, all IOH-CPB thresholds defined as a MAP of 50 mmHg or less and as a decrease in MAP of 60% from baseline were associated with a 1.07-to-1.11 times increased risk of AKI per 10 minutes of IOH-CPB (p<0.01). After adjustment for potential confounders, IOH-CPB, irrespective of the definition chosen, was not associated with an increased risk of AKI. CONCLUSIONS: In the authors' study population, univariable analysis showed an association of IOH-CPB with AKI in patients undergoing isolated CABG, but this relationship disappeared after correction for well-known risk factors for AKI.

The Effect of Dexamethasone on Symptoms of Posttraumatic Stress Disorder and Depression After Cardiac Surgery and Intensive Care Admission: Longitudinal Follow-Up of a Randomized Controlled Trial.

OBJECTIVE: Cardiac surgery and postoperative admission to the ICU may lead to posttraumatic stress disorder and depression. Perioperatively administered corticosteroids potentially alter the risk of development of these psychiatric conditions, by affecting the hypothalamic-pituitary-adrenal axis. However, findings of previous studies are inconsistent. We aimed to assess the effect of a single dose of dexamethasone compared with placebo on symptoms of posttraumatic stress disorder and depression and health-related quality of life after cardiac surgery and ICU admission. DESIGN: Follow-up study of a randomized clinical trial. SETTING: Five Dutch heart centers. PATIENTS: Cardiac surgery patients (n = 1,244) who participated in the Dexamethasone for Cardiac Surgery trial. INTERVENTIONS: A single intraoperative IV dose of dexamethasone or placebo was administered in a randomized, double-blind way. MEASUREMENTS AND MAIN RESULTS: Symptoms of posttraumatic stress disorder, depression, and health-related quality of life were assessed with validated questionnaires 1.5 years after randomization. Data were available for 1,125 patients (90.4%); of which 561 patients received dexamethasone and 564 patients received placebo. Overall, the prevalence of psychopathology was not influenced by dexamethasone. Posttraumatic stress disorder and depression were present in, respectively, 52 patients (9.3%) and 69 patients (12.3%) who received dexamethasone and in 66 patients (11.7%) and 78 patients (13.8%) who received placebo (posttraumatic stress disorder: odds ratio, 0.82; 95% CI, 0.55-1.20; p = 0.30; depression: odds ratio, 0.92; 95% CI, 0.64-1.31; p = 0.63). Subgroup analysis revealed a lower prevalence of posttraumatic stress disorder (odds ratio, 0.23; 95% CI, 0.07-0.72; p < 0.01) and depression (odds ratio, 0.29; 95% CI, 0.11-0.77; p < 0.01) in female patients after dexamethasone administration. Health-related quality of life did not differ between groups and was not associated with psychopathology. CONCLUSIONS: Overall, our findings suggest that exogenous administration of the glucocorticoid receptor agonist dexamethasone-compared with placebo-during cardiac surgery does not positively or negatively affect the prevalence of posttraumatic stress disorder and depression. However, in female patients, beneficial effects on the occurrence of posttraumatic stress disorder and depression may be present.