Browsing by Author "Podgoreanu, Mihai V"
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Item Open Access A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting.(BMC Infect Dis, 2014-02-13) Nelson, Charlotte L; Pelak, Kimberly; Podgoreanu, Mihai V; Ahn, Sun Hee; Scott, William K; Allen, Andrew S; Cowell, Lindsay G; Rude, Thomas H; Zhang, Yurong; Tong, Amy; Ruffin, Felicia; Sharma-Kuinkel, Batu K; Fowler, Vance GBACKGROUND: Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena. METHODS: We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons. RESULTS: Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene (CDON, a member of the immunoglobulin family) and may warrant further study. CONCLUSIONS: The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated infection.Item Open Access Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.(Journal of cardiothoracic and vascular anesthesia, 2021-05) Manning, Michael W; Li, Yi-Ju; Linder, Dean; Haney, John C; Wu, Yi-Hung; Podgoreanu, Mihai V; Swaminathan, Madhav; Schroder, Jacob N; Milano, Carmelo A; Welsby, Ian J; Stafford-Smith, Mark; Ghadimi, KamrouzObjective
Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described.Design
Retrospective cohort.Setting
Single-center university hospital.Participants
A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015.Interventions
The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution.Measurements and main results
Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q3 = 32.6 v CUF < Q1 = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001).Conclusions
Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.Item Open Access Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci.(Kidney Int, 2015-10) Stafford-Smith, Mark; Li, Yi-Ju; Mathew, Joseph P; Li, Yen-Wei; Ji, Yunqi; Phillips-Bute, Barbara G; Milano, Carmelo A; Newman, Mark F; Kraus, William E; Kertai, Miklos D; Shah, Svati H; Podgoreanu, Mihai V; Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative TeamAcute kidney injury (AKI) is a common, serious complication of cardiac surgery. Since prior studies have supported a genetic basis for postoperative AKI, we conducted a genome-wide association study (GWAS) for AKI following coronary bypass graft (CABG) surgery. The discovery data set consisted of 873 nonemergent CABG surgery patients with cardiopulmonary bypass (PEGASUS), while a replication data set had 380 cardiac surgical patients (CATHGEN). Single-nucleotide polymorphism (SNP) data were based on Illumina Human610-Quad (PEGASUS) and OMNI1-Quad (CATHGEN) BeadChips. We used linear regression with adjustment for a clinical AKI risk score to test SNP associations with the postoperative peak rise relative to preoperative serum creatinine concentration as a quantitative AKI trait. Nine SNPs meeting significance in the discovery set were detected. The rs13317787 in GRM7|LMCD1-AS1 intergenic region (3p21.6) and rs10262995 in BBS9 (7p14.3) were replicated with significance in the CATHGEN data set and exhibited significantly strong overall association following meta-analysis. Additional fine mapping using imputed SNPs across these two regions and meta-analysis found genome-wide significance at the GRM7|LMCD1-AS1 locus and a significantly strong association at BBS9. Thus, through an unbiased GWAS approach, we found two new loci associated with post-CABG AKI providing new insights into the pathogenesis of perioperative AKI.Item Open Access Genome-wide association study of perioperative myocardial infarction after coronary artery bypass surgery.(BMJ Open, 2015-05-06) Kertai, Miklos D; Li, Yi-Ju; Li, Yen-Wei; Ji, Yunqi; Alexander, John; Newman, Mark F; Smith, Peter K; Joseph, Diane; Mathew, Joseph P; Podgoreanu, Mihai V; Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative TeamOBJECTIVES: Identification of patient subpopulations susceptible to develop myocardial infarction (MI) or, conversely, those displaying either intrinsic cardioprotective phenotypes or highly responsive to protective interventions remain high-priority knowledge gaps. We sought to identify novel common genetic variants associated with perioperative MI in patients undergoing coronary artery bypass grafting using genome-wide association methodology. SETTING: 107 secondary and tertiary cardiac surgery centres across the USA. PARTICIPANTS: We conducted a stage I genome-wide association study (GWAS) in 1433 ethnically diverse patients of both genders (112 cases/1321 controls) from the Genetics of Myocardial Adverse Outcomes and Graft Failure (GeneMAGIC) study, and a stage II analysis in an expanded population of 2055 patients (225 cases/1830 controls) combined from the GeneMAGIC and Duke Perioperative Genetics and Safety Outcomes (PEGASUS) studies. Patients undergoing primary non-emergent coronary bypass grafting were included. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome variable was perioperative MI, defined as creatine kinase MB isoenzyme (CK-MB) values ≥10× upper limit of normal during the first postoperative day, and not attributable to preoperative MI. Secondary outcomes included postoperative CK-MB as a quantitative trait, or a dichotomised phenotype based on extreme quartiles of the CK-MB distribution. RESULTS: Following quality control and adjustment for clinical covariates, we identified 521 single nucleotide polymorphisms in the stage I GWAS analysis. Among these, 8 common variants in 3 genes or intergenic regions met p<10(-5) in stage II. A secondary analysis using CK-MB as a quantitative trait (minimum p=1.26×10(-3) for rs609418), or a dichotomised phenotype based on extreme CK-MB values (minimum p=7.72×10(-6) for rs4834703) supported these findings. Pathway analysis revealed that genes harbouring top-scoring variants cluster in pathways of biological relevance to extracellular matrix remodelling, endoplasmic reticulum-to-Golgi transport and inflammation. CONCLUSIONS: Using a two-stage GWAS and pathway analysis, we identified and prioritised several potential susceptibility loci for perioperative MI.Item Open Access Interleukin-1β gene variants are associated with QTc interval prolongation following cardiac surgery: a prospective observational study.(Canadian journal of anaesthesia = Journal canadien d'anesthesie, 2016-04) Kertai, Miklos D; Ji, Yunqi; Li, Yi-Ju; Mathew, Joseph P; Daubert, James P; Podgoreanu, Mihai V; PEGASUS Investigative TeamBackground
We characterized cardiac surgery-induced dynamic changes of the corrected QT (QTc) interval and tested the hypothesis that genetic factors are associated with perioperative QTc prolongation independent of clinical and procedural factors.Methods
All study subjects were ascertained from a prospective study of patients who underwent elective cardiac surgery during August 1999 to April 2002. We defined a prolonged QTc interval as > 440 msec, measured from 24-hr pre- and postoperative 12-lead electrocardiograms. The association of 37 single nucleotide polymorphisms (SNPs) in 21 candidate genes -involved in modulating arrhythmia susceptibility pathways with postoperative QTc changes- was investigated in a two-stage design with a stage I cohort (n = 497) nested within a stage II cohort (n = 957). Empirical P values (Pemp) were obtained by permutation tests with 10,000 repeats.Results
After adjusting for clinical and procedural risk factors, we selected four SNPs (P value range, 0.03-0.1) in stage I, which we then tested in the stage II cohort. Two functional SNPs in the pro-inflammatory cytokine interleukin-1β (IL1β), rs1143633 (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.53 to 0.95; Pemp = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; Pemp = 0.04), remained independent predictors of postoperative QTc prolongation. The ability of a clinico-genetic model incorporating the two IL1B polymorphisms to classify patients at risk for developing prolonged postoperative QTc was superior to a clinical model alone, with a net reclassification improvement of 0.308 (P = 0.0003) and an integrated discrimination improvement of 0.02 (P = 0.000024).Conclusion
The results suggest a contribution of IL1β in modulating susceptibility to postoperative QTc prolongation after cardiac surgery.Item Open Access Intravenous Lidocaine Does Not Improve Neurologic Outcomes after Cardiac Surgery: A Randomized Controlled Trial.(Anesthesiology, 2019-06) Klinger, Rebecca Y; Cooter, Mary; Bisanar, Tiffany; Terrando, Niccolò; Berger, Miles; Podgoreanu, Mihai V; Stafford-Smith, Mark; Newman, Mark F; Mathew, Joseph P; Neurologic Outcomes Research Group of the Duke Heart CenterBackground
Cognitive decline after cardiac surgery occurs frequently and persists in a significant proportion of patients. Preclinical studies and human trials suggest that intravenous lidocaine may confer protection in the setting of neurologic injury. It was hypothesized that lidocaine administration would reduce cognitive decline after cardiac surgery compared to placebo.Methods
After institutional review board approval, 478 patients undergoing cardiac surgery were enrolled into this multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group trial. Subjects were randomized to lidocaine 1 mg/kg bolus after the induction of anesthesia followed by a continuous infusion (48 μg · kg · min for the first hour, 24 μg · kg · min for the second hour, and 10 μg · kg · min for the next 46 h) or saline with identical volume and rate changes to preserve blinding. Cognitive function was assessed preoperatively and at 6 weeks and 1 yr postoperatively using a standard neurocognitive test battery. The primary outcome was change in cognitive function between baseline and 6 weeks postoperatively, adjusting for age, years of education, baseline cognition, race, and procedure type.Results
Among the 420 allocated subjects who returned for 6-week follow-up (lidocaine: N = 211; placebo: N = 209), there was no difference in the continuous cognitive score change (adjusted mean difference [95% CI], 0.02 (-0.05, 0.08); P = 0.626). Cognitive deficit (greater than 1 SD decline in at least one cognitive domain) at 6 weeks occurred in 41% (87 of 211) in the lidocaine group versus 40% (83 of 209) in the placebo group (adjusted odds ratio [95% CI], 0.94 [0.63, 1.41]; P = 0.766). There were no differences in any quality of life outcomes between treatment groups. At the 1-yr follow-up, there continued to be no difference in cognitive score change, cognitive deficit, or quality of life.Conclusions
Intravenous lidocaine administered during and after cardiac surgery did not reduce postoperative cognitive decline at 6 weeks.Item Open Access Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery.(Anesth Analg, 2017-06-17) Karhausen, Jörn A; Smeltz, Alan M; Akushevich, Igor; Cooter, Mary; Podgoreanu, Mihai V; Stafford-Smith, Mark; Martinelli, Susan M; Fontes, Manuel L; Kertai, Miklos DBACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6 130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: ≥2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) × 10/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 × 10/L, 100 to 150 × 10/L, and <100 × 10/L, respectively. The risk for stroke increased by 12% on a given postoperative day for every 30 × 10/L decrease in platelet counts (adjusted hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01-1.24; P = .0255). On a given day, patients with moderate to severe thrombocytopenia were almost twice as likely to develop stroke (adjusted HR, 1.89; 95% CI, 1.13-3.16; P = .0155) as patients with nadir platelet counts >150 × 10/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (≥2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48.5.41; P = .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery.Item Open Access Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery.(Anesthesiology, 2016-02) Kertai, Miklos D; Zhou, Shan; Karhausen, Jörn A; Cooter, Mary; Jooste, Edmund; Li, Yi-Ju; White, William D; Aronson, Solomon; Podgoreanu, Mihai V; Gaca, Jeffrey; Welsby, Ian J; Levy, Jerrold H; Stafford-Smith, Mark; Mathew, Joseph P; Fontes, Manuel LBACKGROUND: Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. METHODS: The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. RESULTS: The median postoperative nadir platelet count was 121 × 10/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 × 10/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). CONCLUSION: The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery.Item Open Access Preoperative CYP2D6 metabolism-dependent β-blocker use and mortality after coronary artery bypass grafting surgery.(J Thorac Cardiovasc Surg, 2014-04) Kertai, Miklos D; Esper, Stephen A; Akushevich, Igor; Voora, Deepak; Ginsburg, Geoffrey S; Stafford-Smith, Mark; Grichnik, Katherine; Newman, Mark F; Fontes, Manuel L; Smith, Peter; Podgoreanu, Mihai V; Mathew, Joseph P; Cardiothoracic Anesthesia Research Endeavors (CARE) GroupOBJECTIVE: Recently, the role of β-blockers (BBs) in reducing perioperative mortality has been challenged. The conflicting results might have resulted from the extent of BB metabolism by the cytochrome P-450 (CYP2D6) isoenzyme. The purpose of the present study was to assess the association between the preoperative use of BBs dependent on metabolism of the CYP2D6 isoenzyme with operative mortality after coronary artery bypass grafting surgery. METHODS: We performed a retrospective study of 5248 patients who had undergone coronary bypass grafting surgery from January 1, 2001 to November 30, 2009 at Duke University Medical Center. The cohorts were defined by the preoperative use of BBs and BB type (non-CYP2D6_BBs, CYP2D6_BBs, or no BBs). Operative mortality was analyzed using inverse probability-weighted estimators with propensity score adjustment. RESULTS: Of the 5248 patients, 14% received non-CYP2D6_BBs, 43%, CYP2D6_BBs, and 43%, no BBs. The incidence of operative mortality was 0.8%, 2.1%, and 3.7% in the non-CYP2D6_BB, CYP2D6_BB, and no BB groups, respectively. Multivariable inverse probability-weighted-adjusted analyses showed that non-CYP2D6_BBs were associated with a lower incidence of operative mortality (odds ratio, 0.33; 95% confidence interval, 0.13-0.83; P = .02) compared with no BB use and a trend toward lower operative mortality (odds ratio, 0.44; 95% confidence interval, 0.16-1.07; P = .06) compared with CYP2D6_BBs. No significant decrease occurred in the risk of operative mortality between the CYP2D6_BB and no BB groups (odds ratio, 0.85; 95% confidence interval, 0.54-1.34; P = .48). CONCLUSIONS: Among these patients, preoperative non-CYP2D6_BB use, but not CYP2D6_BB use, was associated with a decreased risk of operative mortality.