Genetic predisposition may not improve prediction of cardiac surgery-associated acute kidney injury.

Background: The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury. Methods: Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models. Results: Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance (p < 5 × 10-8) threshold, however, six previously unreported variants exceeded the suggestive threshold (p < 1 × 10-6). Notable variants detected include: 1) rs74637005, located in the exonic region of NFU1 and 2) rs17438465, located between EVX1 and HIBADH. We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000-1.003, p = 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320-3.103, p = 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372-0.835, p = 0.005) were significant in the full model. Conclusion: Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors.

Comparison of static and rolling logistic regression models on predicting invasive mechanical ventilation or death from COVID-19-A retrospective, multicentre study.

INTRODUCTION: COVID-19 virus has undergone mutations, and the introduction of vaccines and effective treatments have changed its clinical severity. We hypothesized that models that evolve may better predict invasive mechanical ventilation or death than do static models. METHODS: This retrospective study of adult patients with COVID-19 from six Michigan hospitals analysed 20 demographic, comorbid, vital sign and laboratory factors, one derived factor and nine factors representing changes in vital signs or laboratory values with time for their ability to predict death or invasive mechanical ventilation within the next 4, 8 or 24 h. Static logistic regression was constructed on the initial 300 patients and tested on the remaining 6741 patients. Rolling logistic regression was similarly constructed on the initial 300 patients, but then new patients were added, and older patients removed. Each new construction model was subsequently tested on the next patient. Static and rolling models were compared with receiver operator characteristic and precision-recall curves. RESULTS: Of the 7041 patients, 534 (7.6%) required invasive mechanical ventilation or died within 14 days of arrival. Rolling models improved discrimination (0.865 ± 0.010, 0.856 ± 0.007 and 0.843 ± 0.005 for the 4, 8 and 24-h models, respectively; all p < 0.001 compared with the static logistic regressions with 0.827 ± 0.011, 0.794 ± 0.012 and 0.735 ± 0.012, respectively). Similarly, the areas under the precision-recall curves improved from 0.006, 0.010 and 0.021 with the static models to 0.030, 0.045 and 0.076 for the 4-, 8- and 24-h rolling models, respectively, all p < 0.001. CONCLUSION: Rolling models with contemporaneous data maintained better metrics of performance than static models, which used older data.

Limited clinical utility for GWAS or polygenic risk score for postoperative acute kidney injury in non-cardiac surgery in European-ancestry patients.

BACKGROUND: Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery. METHODS: We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center ("Vanderbilt" cohort) or Michigan Medicine, the academic medical center of the University of Michigan ("Michigan" cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants. RESULTS: The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971-1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability. CONCLUSION: The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.

Genetic variants associated with sepsis.

BACKGROUND: The variable presentations and different phenotypes of sepsis suggest that risk of sepsis comes from many genes each having a small effect. The cumulative effect can be used to create individual risk profile. The purpose of this study was to create a polygenic risk score and determine the genetic variants associated with sepsis. METHODS: We sequenced ~14 million single nucleotide polymorphisms with a minimac imputation quality R2>0.3 and minor allele frequency >10-6 in patients with Sepsis-2 or Sepsis-3. Genome-wide association was performed using Firth bias-corrected logistic regression. Semi-parsimonious logistic regression was used to create polygenic risk scores and reduced regression to determine the genetic variants independently associated with sepsis. FINDINGS: 2261 patients had sepsis and 13,068 control patients did not. The polygenic risk scores had good discrimination: c-statistic = 0.752 ± 0.005 for Sepsis-2 and 0.752 ± 0.007 for Sepsis-3. We found 772 genetic variants associated with Sepsis-2 and 442 with Sepsis-3, p<0.01. After multivariate adjustment, 100 variants on 85 genes were associated with Sepsis-2 and 69 variants in 54 genes with Sepsis-3. Twenty-five variants were present in both the Sepsis-2 and Sepsis-3 groups out of 32 genes that were present in both groups. The other 7 genes had different variants present. Most variants had small effect sizes. CONCLUSIONS: Sepsis-2 and Sepsis-3 have both separate and shared genetic variants. Most genetic variants have small effects sizes, but cumulatively, the polygenic risk scores have good discrimination.

Intraoperative risk factors of acute kidney injury after liver transplantation.

Acute kidney injury (AKI) is one of the most common complications of liver transplantation (LT). We examined the impact of intraoperative management on risk for AKI following LT. In this retrospective observational study, we linked data from the electronic health record with standardized transplant outcomes. Our primary outcome was stage 2 or 3 AKI as defined by Kidney Disease Improving Global Outcomes guidelines within the first 7 days of LT. We used logistic regression models to test the hypothesis that the addition of intraoperative variables, including inotropic/vasopressor administration, transfusion requirements, and hemodynamic markers improves our ability to predict AKI following LT. We also examined the impact of postoperative AKI on mortality. Of the 598 adult primary LT recipients included in our study, 43% (n = 255) were diagnosed with AKI within the first 7 postoperative days. Several preoperative and intraoperative variables including (1) electrolyte/acid-base balance disorder (International Classification of Diseases, Ninth Revision codes 253.6 or 276.x and International Classification of Diseases, Tenth Revision codes E22.2 or E87.x, where x is any digit; adjusted odds ratio [aOR], 1.917, 95% confidence interval [CI], 1.280-2.869; p = 0.002); (2) preoperative anemia (aOR, 2.612; 95% CI, 1.405-4.854; p = 0.002); (3) low serum albumin (aOR, 0.576; 95% CI, 0.410-0.808; p = 0.001), increased potassium value during reperfusion (aOR, 1.513; 95% CI, 1.103-2.077; p = 0.01), and lactate during reperfusion (aOR, 1.081; 95% CI, 1.003-1.166; p = 0.04) were associated with posttransplant AKI. New dialysis requirement within the first 7 days postoperatively predicted the posttransplant mortality. Our study identified significant association between several potentially modifiable variables with posttransplant AKI. The addition of intraoperative data did not improve overall model discrimination.

Airway driving pressure is associated with postoperative pulmonary complications after major abdominal surgery: a multicentre retrospective observational cohort study.

Background: High airway driving pressure is associated with adverse outcomes in critically ill patients receiving mechanical ventilation, but large multicentre studies investigating airway driving pressure during major surgery are lacking. We hypothesised that increased driving pressure is associated with postoperative pulmonary complications in patients undergoing major abdominal surgery. Methods: In this preregistered multicentre retrospective observational cohort study, the authors reviewed major abdominal surgical procedures in 11 hospitals from 2004 to 2018. The primary outcome was a composite of postoperative pulmonary complications, defined as postoperative pneumonia, unplanned tracheal intubation, or prolonged mechanical ventilation for more than 48 h. Associations between intraoperative dynamic driving pressure and outcomes, adjusted for patient and procedural factors, were evaluated. Results: Among 14 218 qualifying cases, 389 (2.7%) experienced postoperative pulmonary complications. After adjustment, the mean dynamic driving pressure was associated with postoperative pulmonary complications (adjusted odds ratio for every 1 cm H2O increase: 1.04; 95% confidence interval [CI], 1.02-1.06; P<0.001). Neither tidal volume nor PEEP was associated with postoperative pulmonary complications. Increased BMI, shorter height, and female sex were predictors for higher dynamic driving pressure (ß=0.35, 95% CI 0.32-0.39, P<0.001; ß=-0.01, 95% CI -0.02 to 0.00, P=0.005; and ß=0.74, 95% CI 0.63-0.86, P<0.001, respectively). Conclusions: Dynamic airway driving pressure, but not tidal volume or PEEP, is associated with postoperative pulmonary complications in models controlling for a large number of risk predictors and covariates. Such models are capable of risk prediction applicable to individual patients.

Volume of packed red blood cells and fresh frozen plasma is associated with intraoperative hypocalcaemia during large volume intraoperative transfusion.

BACKGROUND: Severe hypocalcaemia is associated with increased transfusion in the trauma population. Furthermore, trauma patients developing severe hypocalcaemia have higher mortality and coagulopathy. Electrolyte abnormalities associated with massive transfusion have been less studied in the surgical population. Here, we tested the primary hypothesis that volume of packed red blood cells and fresh frozen plasma transfused intraoperatively is associated with lower nadir ionised calcium in the surgical population receiving massive resuscitation. METHODS: We performed a retrospective observational study at an academic quaternary care centre to characterise hypocalcaemia following large volume (4 or more units packed red blood cells) intraoperative transfusion. We used multivariable linear regression to assess if volume of transfusion with packed red blood cells and fresh frozen plasma were independently associated with a lower ionised calcium. We then used multivariable logistic regressions to assess the association between ionised calcium and transfusion with: (i) mortality, (ii) acute kidney injury, and (iii) postoperative coagulopathy. RESULTS: Hypocalcaemia following large volume resuscitation in the operating room is a very frequent occurrence (70% of cases). After controlling for demographic variables and intraoperative variables, the volume transfused intraoperative was independently associated with hypocalcaemia on multivariable linear regression. Hypocalcaemia, intraoperative transfusion of packed red blood cells, and intraoperative transfusion of fresh frozen plasma were not shown to be associated with clinical outcomes. CONCLUSIONS: Hypocalcaemia was associated with increased transfusion volume in this single-centre study. Unlike the trauma population, hypocalcaemia was not associated with increased mortality during surgical care. Our findings suggest that despite improved practice patterns of calcium supplementation, intraoperative hypocalcaemia occurs with relatively high frequency following large volume intraoperative transfusion.

Genome-wide association study of cardiac troponin I in the general population.

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.

Exposure and risk factors for COVID-19 and the impact of staying home on Michigan residents.

COVID-19 has had a substantial impact on clinical care and lifestyles globally. The State of Michigan reports over 80,000 positive COVID-19 tests between March 1, 2020 and July 29, 2020. We surveyed 8,041 Michigan Medicine biorepository participants in late June 2020. We found that 55% of COVID-19 cases reported no known exposure to family members or to someone outside the house diagnosed with COVID-19. A significantly higher rate of COVID-19 cases were employed as essential workers (45% vs 19%, p = 9x10-12). COVID-19 cases reporting a fever were more likely to require hospitalization (categorized as severe; OR = 4.4 [95% CI: 1.6-12.5, p = 0.005]) whereas respondents reporting rhinorrhea was less likely to require hospitalization (categorized as mild-to-moderate; OR = 0.16 [95% CI: 0.04-0.73, p = 0.018]). African-Americans reported higher rates of being diagnosed with COVID-19 (OR = 4.0 [95% CI: 2.2-7.2, p = 5x10-6]), as well as higher rates of exposure to family or someone outside the household diagnosed with COVID-19, an annual household income < $40,000, living in rental housing, and chronic diseases. During the Executive Order in Michigan, African Americans, women, and the lowest income group reported worsening health behaviors and higher overall concern for the potential detrimental effects of the pandemic. The higher risk of contracting COVID-19 observed among African Americans may be due to the increased rates of working as essential employees, lower socioeconomic status, and exposure to known positive cases. Continued efforts should focus on COVID-19 prevention and mitigation strategies, as well as address the inequality gaps that result in higher risks for both short-term and long-term health outcomes.

Clinically applicable approach for predicting mechanical ventilation in patients with COVID-19.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) requiring mechanical ventilation have high mortality and resource utilisation. The ability to predict which patients may require mechanical ventilation allows increased acuity of care and targeted interventions to potentially mitigate deterioration. METHODS: We included hospitalised patients with COVID-19 in this single-centre retrospective observational study. Our primary outcome was mechanical ventilation or death within 24 h. As clinical decompensation is more recognisable, but less modifiable, as the prediction window shrinks, we also assessed 4, 8, and 48 h prediction windows. Model features included demographic information, laboratory results, comorbidities, medication administration, and vital signs. We created a Random Forest model, and assessed performance using 10-fold cross-validation. The model was compared with models derived from generalised estimating equations using discrimination. RESULTS: Ninety-three (23%) of 398 patients required mechanical ventilation or died within 14 days of admission. The Random Forest model predicted pending mechanical ventilation with good discrimination (C-statistic=0.858; 95% confidence interval, 0.841-0.874), which is comparable with the discrimination of the generalised estimating equation regression. Vitals sign data including SpO2/FiO2 ratio (Random Forest Feature Importance Z-score=8.56), ventilatory frequency (5.97), and heart rate (5.87) had the highest predictive utility. In our highest-risk cohort, the number of patients needed to identify a single new case was 3.2, and for our second quintile it was 5.0. CONCLUSION: Machine learning techniques can be leveraged to improve the ability to predict which patients with COVID-19 are likely to require mechanical ventilation, identifying unrecognised bellwethers and providing insight into the constellation of accompanying signs of respiratory failure in COVID-19.

Genetic mutations associated with susceptibility to perioperative complications in a longitudinal biorepository with integrated genomic and electronic health records.

BACKGROUND: Existing genetic information can be leveraged to identify patients with susceptibilities to conditions that might impact their perioperative care, but clinicians generally have limited exposure and are not trained to contextualise this information. We identified patients with genetic susceptibilities to anaesthetic complications using a perioperative biorepository and characterised the concordance with existing diagnoses. METHODS: Adult patients undergoing surgery within Michigan Medicine from 2012 to 2017 were consented for genotyping. Genotypes were integrated with the electronic health record (EHR). We retrospectively characterised frequencies of variants associated with butyrylcholinesterase deficiency, factor V Leiden, and malignant hyperthermia, three pharmacogenetic factors with perioperative implications. We calculated the percentage homozygous and heterozygous for each that had been diagnosed previously and searched for EHR findings consistent with a predisposition. RESULTS: Analysis of genetic data revealed that 25 out of 40 769 (0.1%) patients were homozygous and 1918 (4.7%) were heterozygous for mutations associated with butyrylcholinesterase deficiency. Of the homozygous individuals, 14 (56%) carried a pre-existing diagnosis. For factor V Leiden, 29 (0.1%) were homozygous and 2153 (5.3%) heterozygous. Of the homozygous individuals, three (10%) were diagnosed by EHR-derived phenotype and six (21%) by clinician review. Malignant hyperthermia was assessed in a subset of patients. We detected two patients with associated mutations. Neither carried clinical diagnoses. CONCLUSIONS: We identified patients with genetic susceptibility to perioperative complications using an open source script designed for clinician use. We validated this application in a retrospective analysis for three conditions with well-characterised inheritance, and showed that not all genetic susceptibilities were documented in the EHR.

Use of a Polygenic Risk Score Improves Prediction of Myocardial Injury After Non-Cardiac Surgery.

BACKGROUND: While postoperative myocardial injury remains a major driver of morbidity and mortality, the ability to accurately identify patients at risk remains limited despite decades of clinical research. The role of genetic information in predicting myocardial injury after noncardiac surgery (MINS) remains unknown and requires large scale electronic health record and genomic data sets. METHODS: In this retrospective observational study of adult patients undergoing noncardiac surgery, we defined MINS as new troponin elevation within 30 days following surgery. To determine the incremental value of polygenic risk score (PRS) for coronary artery disease, we added the score to 3 models of MINS risk: revised cardiac risk index, a model comprised entirely of preoperative variables, and a model with combined preoperative plus intraoperative variables. We assessed performance without and with PRSs via area under the receiver operating characteristic curve and net reclassification index. RESULTS: Among 90 053 procedures across 40 498 genotyped individuals, we observed 429 cases with MINS (0.5%). PRS for coronary artery disease was independently associated with MINS for each multivariable model created (odds ratio=1.12 [95% CI, 1.02-1.24], P=0.023 in the revised cardiac risk index-based model; odds ratio, 1.19 [95% CI, 1.07-1.31], P=0.001 in the preoperative model; and odds ratio, 1.17 [95% CI, 1.06-1.30], P=0.003 in the preoperative plus intraoperative model). The addition of clinical risk factors improved model discrimination. When PRS was included with preoperative and preoperative plus intraoperative models, up to 3.6% of procedures were shifted into a new outcome classification. CONCLUSIONS: The addition of a PRS does not significantly improve discrimination but remains independently associated with MINS and improves goodness of fit. As genetic analysis becomes more common, clinicians will have an opportunity to use polygenic risk to predict perioperative complications. Further studies are necessary to determine if PRSs can inform MINS surveillance.

Early Detection of Heart Failure With Reduced Ejection Fraction Using Perioperative Data Among Noncardiac Surgical Patients: A Machine-Learning Approach.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is a condition imposing significant health care burden. Given its syndromic nature and often insidious onset, the diagnosis may not be made until clinical manifestations prompt further evaluation. Detecting HFrEF in precursor stages could allow for early initiation of treatments to modify disease progression. Granular data collected during the perioperative period may represent an underutilized method for improving the diagnosis of HFrEF. We hypothesized that patients ultimately diagnosed with HFrEF following surgery can be identified via machine-learning approaches using pre- and intraoperative data. METHODS: Perioperative data were reviewed from adult patients undergoing general anesthesia for major surgical procedures at an academic quaternary care center between 2010 and 2016. Patients with known HFrEF, heart failure with preserved ejection fraction, preoperative critical illness, or undergoing cardiac, cardiology, or electrophysiologic procedures were excluded. Patients were classified as healthy controls or undiagnosed HFrEF. Undiagnosed HFrEF was defined as lacking a HFrEF diagnosis preoperatively but establishing a diagnosis within 730 days postoperatively. Undiagnosed HFrEF patients were adjudicated by expert clinician review, excluding cases for which HFrEF was secondary to a perioperative triggering event, or any event not associated with HFrEF natural disease progression. Machine-learning models, including L1 regularized logistic regression, random forest, and extreme gradient boosting were developed to detect undiagnosed HFrEF, using perioperative data including 628 preoperative and 1195 intraoperative features. Training/validation and test datasets were used with parameter tuning. Test set model performance was evaluated using area under the receiver operating characteristic curve (AUROC), positive predictive value, and other standard metrics. RESULTS: Among 67,697 cases analyzed, 279 (0.41%) patients had undiagnosed HFrEF. The AUROC for the logistic regression model was 0.869 (95% confidence interval, 0.829-0.911), 0.872 (0.836-0.909) for the random forest model, and 0.873 (0.833-0.913) for the extreme gradient boosting model. The corresponding positive predictive values were 1.69% (1.06%-2.32%), 1.42% (0.85%-1.98%), and 1.78% (1.15%-2.40%), respectively. CONCLUSIONS: Machine-learning models leveraging perioperative data can detect undiagnosed HFrEF with good performance. However, the low prevalence of the disease results in a low positive predictive value, and for clinically meaningful sensitivity thresholds to be actionable, confirmatory testing with high specificity (eg, echocardiography or cardiac biomarkers) would be required following model detection. Future studies are necessary to externally validate algorithm performance at additional centers and explore the feasibility of embedding algorithms into the perioperative electronic health record for clinician use in real time.

Association of Intraoperative Ventilator Management With Postoperative Oxygenation, Pulmonary Complications, and Mortality.

BACKGROUND: "Lung-protective ventilation" describes a ventilation strategy involving low tidal volumes (VTs) and/or low driving pressure/plateau pressure and has been associated with improved outcomes after mechanical ventilation. We evaluated the association between intraoperative ventilation parameters (including positive end-expiratory pressure [PEEP], driving pressure, and VT) and 3 postoperative outcomes: (1) PaO2/fractional inspired oxygen tension (FIO2), (2) postoperative pulmonary complications, and (3) 30-day mortality. METHODS: We retrospectively analyzed adult patients who underwent major noncardiac surgery and remained intubated postoperatively from 2006 to 2015 at a single US center. Using multivariable regressions, we studied associations between intraoperative ventilator settings and lowest postoperative PaO2/FIO2 while intubated, pulmonary complications identified from discharge diagnoses, and in-hospital 30-day mortality. RESULTS: Among a cohort of 2096 cases, the median PEEP was 5 cm H2O (interquartile range = 4-6), median delivered VT was 520 mL (interquartile range = 460-580), and median driving pressure was 15 cm H2O (13-19). After multivariable adjustment, intraoperative median PEEP (linear regression estimate [B] = -6.04; 95% CI, -8.22 to -3.87; P < .001), median FIO2 (B = -0.30; 95% CI, -0.50 to -0.10; P = .003), and hours with driving pressure >16 cm H2O (B = -5.40; 95% CI, -7.2 to -4.2; P < .001) were associated with decreased postoperative PaO2/FIO2. Higher postoperative PaO2/FIO2 ratios were associated with a decreased risk of pulmonary complications (adjusted odds ratio for each 100 mm Hg = 0.495; 95% CI, 0.331-0.740; P = .001, model C-statistic of 0.852) and mortality (adjusted odds ratio = 0.495; 95% CI, 0.366-0.606; P < .001, model C-statistic of 0.820). Intraoperative time with VT >500 mL was also associated with an increased likelihood of developing a postoperative pulmonary complication (adjusted odds ratio = 1.06/hour; 95% CI, 1.00-1.20; P = .042). CONCLUSIONS: In patients requiring postoperative intubation after noncardiac surgery, increased median FIO2, increased median PEEP, and increased time duration with elevated driving pressure predict lower postoperative PaO2/FIO2. Intraoperative duration of VT >500 mL was independently associated with increased postoperative pulmonary complications. Lower postoperative PaO2/FIO2 ratios were independently associated with pulmonary complications and mortality. Our findings suggest that postoperative PaO2/FIO2 may be a potential target for future prospective trials investigating the impact of specific ventilation strategies for reducing ventilator-induced pulmonary injury.

Intraoperative Mechanical Ventilation and Postoperative Pulmonary Complications after Cardiac Surgery.

BACKGROUND: Compared with historic ventilation strategies, modern lung-protective ventilation includes lower tidal volumes (VT), lower driving pressures, and application of positive end-expiratory pressure (PEEP). The contributions of each component to an overall intraoperative protective ventilation strategy aimed at reducing postoperative pulmonary complications have neither been adequately resolved, nor comprehensively evaluated within an adult cardiac surgical population. The authors hypothesized that a bundled intraoperative protective ventilation strategy was independently associated with decreased odds of pulmonary complications after cardiac surgery. METHODS: In this observational cohort study, the authors reviewed nonemergent cardiac surgical procedures using cardiopulmonary bypass at a tertiary care academic medical center from 2006 to 2017. The authors tested associations between bundled or component intraoperative protective ventilation strategies (VT below 8 ml/kg ideal body weight, modified driving pressure [peak inspiratory pressure - PEEP] below 16 cm H2O, and PEEP greater than or equal to 5 cm H2O) and postoperative outcomes, adjusting for previously identified risk factors. The primary outcome was a composite pulmonary complication; secondary outcomes included individual pulmonary complications, postoperative mortality, as well as durations of mechanical ventilation, intensive care unit stay, and hospital stay. RESULTS: Among 4,694 cases reviewed, 513 (10.9%) experienced pulmonary complications. After adjustment, an intraoperative lung-protective ventilation bundle was associated with decreased pulmonary complications (adjusted odds ratio, 0.56; 95% CI, 0.42-0.75). Via a sensitivity analysis, modified driving pressure below 16 cm H2O was independently associated with decreased pulmonary complications (adjusted odds ratio, 0.51; 95% CI, 0.39-0.66), but VT below 8 ml/kg and PEEP greater than or equal to 5 cm H2O were not. CONCLUSIONS: The authors identified an intraoperative lung-protective ventilation bundle as independently associated with pulmonary complications after cardiac surgery. The findings offer insight into components of protective ventilation associated with adverse outcomes and may serve as targets for future prospective interventional studies investigating the impact of specific protective ventilation strategies on postoperative outcomes after cardiac surgery.

Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection.

BACKGROUND: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. METHODS: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. RESULTS: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6-19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4-22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4-22.3, siblings: OR, 5.1; 95% CI, 1.1-23.9, children: OR, 6.0; 95% CI, 1.4-26.7). CONCLUSIONS: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

Postoperative continuous catheter-infused local anesthetic reduces pain scores and narcotic use after lower extremity revascularization.

Objective Postoperative pain following lower extremity revascularization procedures is traditionally controlled with narcotic administration. However, this may not adequately control the pain and puts the patient at risk for complications from opiate use. Here we report an alternative strategy for pain management using a continuous catheter-infused local anesthetic into the operative limb. Design Retrospective case-control study. Methods Patients undergoing lower extremity revascularization procedures using continuous catheter-infused local anesthetic were compared to similar patients undergoing similar procedures during the same time period who did not receive continuous catheter-infused local anesthetic. Records were reviewed for pain scores, narcotics consumption, length of stay, need for postoperative chest X-ray, supplemental oxygen use, wound complications, and 30-day readmission. Results There were 153 patients (mean age 69.5 years) from September 2011 to December 2014 who underwent common femoral artery procedures, femoral-popliteal bypass, femoral-tibial bypass, popliteal aneurysm repair, popliteal to pedal bypass, popliteal artery thrombo-embolectomy, sapheno-popliteal venous bypass, or ilio-femoral bypass. There were no significant differences between the continuous catheter-infused local anesthetic ( n=57) and control ( n=96) groups regarding age, body mass index, cardiac history, diabetes, hypertension, and procedures performed. The continuous catheter-infused local anesthetic group showed better cumulative average pain scores, better high pain scores on postoperative days 1-3, and better average pain scores on postoperative days 2-3 ( P<0.03). The continuous catheter-infused local anesthetic group had lower median narcotics consumption on postoperative days 1-2 ( P=0.02). No differences were found in postoperative length of stay, urinary catheter use, number of postoperative chest X-rays, oxygen use, mobilization, or fever. Wound complications occurred in 8.8% of the continuous catheter-infused local anesthetic group and in 11.5% of controls (P=0.79). Readmission rates were 23% (continuous catheter-infused local anesthetic) and 21% (controls; P=0.84). Conclusion Postoperative continuous catheter-infused local anesthetic reduces pain scores and pain medication use compared to standard opiate therapy in these patients, without increasing wound complication or readmission rates. Continuous catheter-infused local anesthetic appeared to have no effect on the incidence of pulmonary complications, mobilization, or fever.

Two cancers in one: breast carcinoma with underlying melanoma.

A 61-year-old woman presented with a diagnosis of metastatic invasive lobular carcinoma of the right breast, and after treatment it had regressed or was stable except for a scalp nodule. When biopsied, the outer edges of the scalp lesion had findings consistent with breast carcinoma; however, the bulk of the tumor's pathology was consistent with melanoma. It appeared that most of the tumor was a highly vascularized melanoma with lobular breast carcinoma noted at its edges.