Nontechnical Skills for Surgeons as a Framework to Evaluate Cardiopulmonary Bypass Management Skills of Resident Trainees.

BACKGROUND: Nontechnical skills are critical in cardiac surgery but currently there is no formal paradigm to teach these in residency training. We investigated the use of the Nontechnical skills for surgeons (NOTSS) system as a framework to assess and teach nontechnical skills related to cardiopulmonary bypass (CPB) management. METHODS: Single-center retrospective analysis of Integrated and Independent pathway thoracic surgery residents who participated in dedicated nontechnical skills evaluation and training. Two CPB management simulation scenarios were utilized. All residents received a lecture on CPB fundamentals and then individually participated in the first simulation ("Pre-NOTSS"). Immediately following this, nontechnical skills were rated by self-assessment and by a NOTSS trainer. All residents then underwent group NOTSS training followed by the second individual simulation ("Post-NOTSS"). Nontechnical skills were rated as before. NOTSS categories assessed included Situation Awareness, Decision Making, Communication and Teamwork, and Leadership. RESULTS: Nine residents were divided into 2 groups: Junior (n = 4, PGY1-4) and Senior (n = 5, PGY5-8). Pre-NOTSS resident self-ratings were higher for Senior than Junior in the categories of Decision Making, Communication and Teamwork, and Leadership while trainer ratings were similar between the groups. Post-NOTSS, resident self-ratings were higher for Senior than Junior in Situation Awareness and Decision Making while trainer scores were higher for both groups in Communication and Teamwork and Leadership. CONCLUSIONS: The NOTSS framework in conjunction with simulation scenarios provides a practical framework to evaluate and teach nontechnical skills related to CPB management. NOTSS training can lead to improvements in both subjective and objective ratings of nontechnical skills for all PGY levels.

Enhanced recovery after cardiac surgery protocol reduces perioperative opioid use.

Objective: Enhanced Recovery After Surgery protocols are relatively new in cardiac surgery. Enhanced Recovery After Surgery addresses perioperative analgesia by implementing multimodal pain control regimens that include both opioid and nonopioid components. We investigated the effects of an Enhanced Recovery After Surgery protocol at our institution on postoperative outcomes with particular focus on analgesia. Methods: Single-center retrospective study comparing perioperative opioid use before and after implementation of an Enhanced Recovery After Surgery protocol at our institution. Subjects were divided into 2 cohorts: Enhanced Recovery After Surgery (study group from year 2020) and pre-Enhanced Recovery After Surgery (control group from year 2018). Baseline and perioperative variables including total opioid use from the day of surgery to postoperative day 5 were collected. Opioid use was calculated as morphine milligram equivalents and compared between the 2 cohorts. Results: A total of 466 patients were included: 250 in the Enhanced Recovery After Surgery group and 216 in the pre-Enhanced Recovery After Surgery group. Both groups had similar baseline characteristics, but the Enhanced Recovery After Surgery group had significantly more subjects with intravenous drug use history (P < .0001), endocarditis (P < .0001), and liver disease (P = .007) compared with the pre-Enhanced Recovery After Surgery group. Every day from the day of surgery to postoperative day 5, the Enhanced Recovery After Surgery group had significant reduction (57%) in opioid use compared with the pre-Enhanced Recovery After Surgery group. Total opioid use for the entire length of stay was 259 morphine milligram equivalents in the Enhanced Recovery After Surgery group versus 452 morphine milligram equivalents in the pre-Enhanced Recovery After Surgery group (P < .0001). Subgroup analysis of subjects with intravenous drug use history did not demonstrate a significant reduction in opioid use. Conclusions: Enhanced Recovery After Surgery protocols with an emphasis on multimodal pain management throughout perioperative care are associated with a significant reduction in the postoperative use of opioid analgesics.

Fifteen-year experience with pericardiectomy at a tertiary referral center.

PURPOSE: Pericardiectomy has traditionally carried relatively high perioperative mortality and morbidity, with few published reports of intermediate- and long- term outcomes. We investigated our 15-year experience performing pericardiectomy at our institution. METHODS: Retrospective study of all patients who underwent pericardiectomy at our institution between 2005 and 2019. Baseline demographics, intraoperative details, and postoperative outcomes including long-term survival were analyzed. RESULTS: Sixty-three patients were included in the study. 66.7% of subjects underwent isolated pericardiectomy while 33.3% underwent pericardiectomy concomitantly with another cardiac surgical procedure. The most common indications for pericardiectomy were constrictive (79.4%) and hemorrhagic (9.5%) pericarditis. Preoperatively, 76.2% of patients were New York Heart Association class II and III, while postoperatively, 71.4% were class I and II. One-, three-, five-, and ten- year overall mortality was 9.5, 14.3, 20.6, and 25.4%, respectively. Overall pericarditis recurrence rate was 4.8%. CONCLUSION: Pericardiectomy carries relatively high overall mortality rates, which likely reflects underlying disease etiology and comorbidities. Patients with prior cardiac intervention, history of dialysis, and immunocompromised state are associated with worse outcomes.

Preoperative stroke before cardiac surgery does not increase risk of postoperative stroke.

The optimal time when surgery can be safely performed after stroke is unknown. The purpose of this study was to investigate how cardiac surgery timing after stroke impacts postoperative outcomes between 2011-2017 were reviewed. Variables were extracted from the institutional Society of Thoracic Surgeons database, statewide patient registry, and medical records. Subjects were classified based upon presence of endocarditis and further grouped by timing of preoperative stroke relative to cardiac surgery: Recent (stroke within two weeks before surgery), Intermediate (between two and six weeks before), and Remote (greater than six weeks before). Postoperative outcomes were compared amongst groups. 157 patients were included: 54 in endocarditis and 103 in non-endocarditis, with 47 in Recent, 26 in Intermediate, and 84 in Remote. 30-day mortality and postoperative stroke rate were similar across the three subgroups for both endocarditis and non-endocarditis. Of patients with postoperative stroke, mortality was 30% (95% CI 4.6-66). Timing of cardiac surgery after stroke occurrence does not seem to affect postoperative stroke or mortality. If postoperative stroke does occur, subsequent stroke-related mortality is high.

Subxiphoid Endoscopic Epicardial Ventricular Tachycardia Ablation.

Ventricular tachycardia refractory to traditional therapies such as medical management and endocardial catheter ablation poses a risk for sudden cardiac death and poor quality of life. We describe a patient who was successfully treated for refractory symptomatic ventricular tachycardia using hybrid endocardial and minimally invasive epicardial ablation with a subxiphoid approach.

Impact of time between diagnosis to treatment in Acute Type A Aortic Dissection.

There is a paucity of data describing the effect of time interval between diagnosis and surgery for Acute Type A Aortic Dissection. We describe our 8-year experience and investigate the impact of time interval between symptom onset, diagnosis and surgery on outcomes. Retrospective single-center study utilizing our Society of Thoracic Surgeons registry and patient records. Subjects were grouped by time interval between radiographic diagnosis and surgical treatment: Group A (0-4 h), Group B (4.1-8 h), Group C (8.1-12 h), and Group D (12.1 + h). Data were analyzed to identify factors associated with mortality and outcomes. 164 patients were included. Overall mortality was 21.3%. Group C had the greatest intervals between symptom onset to diagnosis to surgery, and also the highest mortality (66.7%). Preoperative tamponade, cardiac arrest, malperfusion, elevated creatinine, cardiopulmonary bypass time, and blood transfusions were associated with increased mortality, while distance of referring hospital was not. Time intervals between symptom onset, diagnosis and surgery have a significant effect on mortality. Surgery performed 8-12 h after diagnosis carries the highest mortality, which may be exacerbated by longer interval since symptom onset. Time-dependent effects should be considered when determining optimal strategy especially if inter-facility transfer is necessary.

The Convergent Procedure: A Unique Multidisciplinary Hybrid Treatment of Atrial Fibrillation.

The convergent procedure is a hybrid ablation treatment for atrial fibrillation. It is increasingly considered as a management option for patients with persistent and long-standing atrial fibrillation. It consists of surgical ablation of the posterior left atrium through a minimally invasive closed-chest approach followed by endocardial catheter ablation. It is increasingly performed with concurrent epicardial occlusion of the left atrial appendage with a video-assisted thoracoscopic technique to physically and electrically isolate the left atrial appendage. This article provides an overview of a multidisciplinary approach to the convergent procedure, with concurrent thoracoscopic closure of the left atrial appendage, with an emphasis on perioperative management at a single institution. It provides a literature review of procedural outcomes, current data limitations, and future considerations.

An Emergent Nexus between Striae and Thoracic Aortic Dissection.

Current approaches to stratify the risk for disease progression in thoracic aortic aneurysm (TAA) lack precision, which hinders clinical decision making. Connective tissue phenotyping of children with TAA previously identified the association between skin striae and increased rate of aortic dilation. The objective of this study was to analyze associations between connective tissue abnormalities and clinical endpoints in adults with aortopathy. Participants with TAA or aortic dissection (TAD) and trileaflet aortic valve were enrolled from 2016 to 2019 in the setting of cardiothoracic surgical care. Data were ascertained by structured interviews with participants. The mean age among 241 cases was 61 ± 13 years. Eighty (33%) had history of TAD. While most participants lacked a formal syndromic diagnosis clinically, connective tissue abnormalities were identified in 113 (47%). This included 20% with abdominal hernia and 13% with skin striae in atypical location. In multivariate analysis, striae and hypertension were significantly associated with TAD. Striae were associated with younger age of TAD or prophylactic aortic surgery. Striae were more frequent in TAD cases than age- and sex-matched controls. Thus, systemic features of connective tissue dysfunction were prevalent in adults with aortopathy. The emerging nexus between striae and aortopathy severity creates opportunities for clinical stratification and basic research.

Combined epicardial and endocardial ablation for atrial fibrillation: Best practices and guide to hybrid convergent procedures.

The absence of strategies to consistently and effectively address nonparoxysmal atrial fibrillation by nonpharmacological interventions has represented a long-standing treatment gap. A combined epicardial/endocardial ablation strategy, the hybrid Convergent procedure, was developed in response to this clinical need. A subxiphoid incision is used to access the pericardial space facilitating an epicardial ablation directed at isolation of the posterior wall of the left atrium. This is followed by an endocardial ablation to complete isolation of the pulmonary veins and for additional ablation as needed. Experience gained with the hybrid Convergent procedure during the last decade has led to the development and adoption of strategies to optimize the technique and mitigate risks. Additionally, a surgical and electrophysiology "team" approach including comprehensive training is believed critical to successfully develop the hybrid Convergent program. A recently completed randomized clinical trial indicated that this ablation strategy is superior to an endocardial-only approach for patients with persistent atrial fibrillation. In this review, we propose and describe best practice guidelines for hybrid Convergent ablation on the basis of a combination of published data, author consensus, and expert opinion. A summary of clinical outcomes, emerging evidence, and future perspectives is also given.

Outcomes of Surgical Coronary Revascularization Performed Before Solid Abdominal Organ Transplants.

BACKGROUND: Cardiac risk stratification and coronary angiography are routinely performed as part of kidney and liver transplant candidacy evaluation. There are limited data on the outcomes of surgical coronary revascularization in this patient population. This study investigated outcomes in patients with end- stage renal or hepatic disease who were undergoing coronary artery bypass grafting (CABG) to attain kidney or liver transplant candidacy. METHODS: This study was a retrospective analysis of all patients who underwent isolated CABG at our institution, Indiana University School of Medicine (Indianapolis, IN), between 2010 and 2016. Patients were divided into 2 cohorts: pretransplant (those undergoing surgery to attain renal or hepatic transplant candidacy) and nontransplant (all others). Baseline characteristics and postoperative outcomes were compared between the groups. RESULTS: A total of 1801 patients were included: 28 in the pretransplant group (n = 22, kidney; n = 7, liver) and 1773 in the nontransplant group. Major adverse postoperative outcomes were significantly greater in the pretransplant group compared with the nontransplant group: 30-day mortality (14.3% vs 2.8%; P = .009), neurologic events (17.9% vs 4.8%; P = .011), reintubation (21.4% vs 5.8%; P = .005), and total postoperative ventilation (5.2 hours vs 5.0 hours; P = .0124). The 1- and 5-year mortality in the pretransplant group was 17.9% and 53.6%, respectively. Of the pretransplant cohort, 3 patients (10.7%) underwent organ transplantation (all kidney) at a mean 436 days after CABG. No patients underwent liver transplantation. CONCLUSIONS: Outcomes after CABG in pre-kidney transplant and pre-liver transplant patients are poor. Despite surgical revascularization, most patients do not ultimately undergo organ transplantation. Revascularization strategies and optimal management in this high-risk population warrant further study.

Intracardiac extension of chondroblastic osteosarcoma.

Intravascular tumour extension invading the intracardiac space is rarely seen with osteosarcoma. We present a patient with a history of previously resected pelvic osteosarcoma who was later found to have a local recurrence with continuous intravascular extension from the right femoral vein to the right atrium. Preoperative imaging studies initially described extensive thrombus burden, and a multidisciplinary approach involving open and percutaneous thrombectomy was planned. Intraoperative inspection and pathological analysis revealed unresectable malignant solid tumour rather than thrombus. Though exceedingly rare, the possibility of metastatic tumour must be considered when planning treatment strategies for these patients.

Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures.

Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood samples were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration-time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 < 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to individualized dosing.

Impact of troponin I level on coronary artery bypass grafting outcomes.

PURPOSE: The effect of preoperative cardiac troponin level on outcomes after coronary artery bypass grafting (CABG) is unclear. We investigated the impact of preoperative cardiac troponin I (cTnI) level as well as the time interval between maximum cTnI and surgery on CABG outcomes. METHODS: All patients who underwent isolated CABG at our institution between 2009 and 2016 and had preoperative cTnI level available were identified using our Society of Thoracic Surgeons registry. Receiver operating characteristic (ROC) analysis was performed to identify a cTnI threshold level. Subjects were divided into groups based on this value and outcomes compared. RESULTS: A total of 608 patients were included. ROC analysis identified 5.74 µg/dL as the threshold value associated with worse postoperative outcomes. Patients with peak cTnI >5.74 µg/dL underwent CABG approximately 1 day later, had twice the risk of adverse postoperative events, and had 2.8 day longer postoperative length of stay than those with peak cTnI ≤5.74 µg/dL. cTnI level was not associated with mortality or 30-day readmission. Time interval between peak cTnI and surgery did not affect outcomes. CONCLUSION: Elevated preoperative cTnI level beyond a certain threshold value is associated with adverse postoperative outcomes but is not a marker for increased mortality. Time from peak cTnI does not affect postoperative outcomes or mortality and may not need to be considered when deciding timing of CABG.

The presence of a dedicated cardiac surgical intensive care service impacts clinical outcomes in adult cardiac surgery patients.

BACKGROUND: Postoperative critical care management is an integral part of cardiac surgery that contributes directly to clinical outcomes. In the United States there remains considerable variability in the critical care infrastructure for cardiac surgical programs. There is little published data investigating the impact of a dedicated cardiac surgical intensive care service. METHODS: A retrospective study examining postoperative outcomes in cardiac surgical patients before and after the implementation of a dedicated cardiac surgical intensive care service at a single academic institution. An institutional Society of Thoracic Surgeons database was queried for study variables. Primary endpoints were the postoperative length of stay, intensive care unit length of stay, and mechanical ventilation time. Secondary endpoints included mortality, readmission rates, and postoperative complications. The effect on outcomes based on procedure type was also analyzed. RESULTS: A total of 1703 patients were included in this study-914 in the control group (before dedicated intensive care service) and 789 in the study group (after dedicated intensive care service). Baseline demographics were similar between groups. Length of stay, mechanical ventilation hours, and renal failure rate were significantly reduced in the study group. Coronary artery bypass grafting patients observed the greatest improvement in outcomes. CONCLUSIONS: Implementation of a dedicated cardiac surgical intensive care service leads to significant improvements in clinical outcomes. The greatest benefit is seen in patients undergoing coronary artery bypass, the most common cardiac surgical operation in the United States. Thus, developing a cardiac surgical intensive care service may be a worthwhile initiative for any cardiac surgical program.

Eleven-Year Experience Treating Blunt Thoracic Aortic Injury at a Tertiary Referral Center.

BACKGROUND: Blunt thoracic aortic injury treatment has evolved over the past decade particularly with respect to endovascular intervention options. We investigated the trends in blunt thoracic aortic injury management and outcomes over an 11-year span at the sole tertiary referral center in our state. METHODS: We retrospectively reviewed all patients who presented to our institution with blunt traumatic aortic injury between 2007 and 2017. Baseline demographics including aortic injury grade, injury severity score, and abbreviated injury scale were collected. Outcomes were compared by type and timing of treatment, which included either nonoperative management, endovascular repair, or open surgical repair. Bivariate and multivariable analyses were performed to examine treatment group differences and factors associated with 30-day mortality. RESULTS: In total, 229 patients were reviewed. The distribution of injury severity was grade 1 (30%), grade 2 (8%), grade 3 (30%), and grade 4 (31%). Overall, 27% of patients underwent endovascular repair, 29% open surgery, and 44% definitive nonoperative management. Over the study period, there was a dramatic decline in open surgery and a corresponding rise in endovascular treatment. Thirty-day mortality for the entire cohort was 22%. Mortality by treatment subgroup was 30% for nonoperative management, 8.2% for endovascular treatment, and 21% for open surgery. Delaying endovascular or open surgical treatment by at least 24 hours after admission was associated with significantly improved 30-day survival. CONCLUSIONS: Procedural intervention, whether endovascular or surgical, is associated with improved mortality compared with nonoperative treatment. Delayed intervention, particularly in the case of high-grade injuries, may allow for initial patient stabilization and improved outcomes.

Short and Intermediate Term Outcomes of the Convergent Procedure: Initial Experience in a Tertiary Referral Center.

PURPOSE: The Convergent procedure is a hybrid, multidisciplinary treatment for symptomatic atrial fibrillation (AF) consisting of minimally invasive surgical epicardial ablation and percutaneous/catheter endocardial ablation. We investigated outcomes following introduction of the Convergent procedure at our institution. METHODS: Retrospective study examining single-center outcomes. Demographic, procedural, and post-procedural variables were collected with follow-up data obtained at 3, 6, and 12 months. RESULTS: In all, 36 patients with paroxysmal (11%) or persistent/long-standing persistent (89%) AF underwent the Convergent procedure. 36% also underwent concomitant left atrial appendage (LAA) exclusion by thoracoscopic placement of an epicardial clip. Mean age 60.6 ± 8.0 years with mean arrhythmia burden of 3.9 ± 2.7 years. All patients had failed prior attempts at medical management, 81% had failed prior cardioversion, and 17% had failed prior catheter ablation. Convergent was performed successfully in all patients with no peri-procedural deaths or major complications. At 3 and 12 months, 77.8% and 77.3% of patients, respectively, were free from symptomatic arrhythmia. 65.8% were off anti-arrhythmic medication at 12 months. CONCLUSIONS: The Convergent procedure is safe and has good short- and intermediate-term clinical success rates. This unique hybrid approach combines strengths of surgical and catheter ablation and should be part of any comprehensive AF treatment program.

Current Management of Acute Pulmonary Embolism.

PURPOSE: Acute pulmonary embolism (PE) remains a significant cause of morbidity and requires prompt diagnosis and management. While non-surgical approaches have supplanted surgery as primary treatment, surgical pulmonary embolectomy (SPE) remains a vital option for select patients. We review the current management of acute PE, with a focus on surgical therapy. METHODS: A PubMed search was performed to identify literature regarding PE and treatment. Results were filtered to include the most comprehensive publications over the past decade. RESULTS: PE is stratified based on presenting hemodynamic status or degree of mechanical pulmonary arterial occlusion. Although systemic or catheter-guided fibrinolysis is the preferred first-line treatment for the majority of cases, patients who are not candidates should be considered for SPE. Studies demonstrate no mortality benefit of thrombolysis over surgery. Systemic anticoagulation is a mainstay of treatment regardless of intervention approach. Following surgical embolectomy, direct oral anticoagulants (DOACs) have been shown to reduce recurrence of thromboembolism. CONCLUSIONS: Acute PE presents with varying degrees of clinical stability. Patients should be evaluated in the context of various available treatment options including medical, catheter-based, and surgical interventions. SPE is a safe and appropriate treatment option for appropriate patients.

Induction of Human T-cell and Cytokine Responses Following Vaccination with a Novel Influenza Vaccine.

Cell mediated immunity plays a vital role in defense against influenza infection in humans. Less is known about the role of vaccine-induced cell mediated immunity and the cytokine responses elicited. We measured CD4+ and CD8+ T-cell reactivity in human subjects following vaccination with licensed trivalent influenza vaccine and a novel virus-like particle based vaccine. We detected influenza-specific CD4+ T-cell responses following vaccination with the licensed trivalent influenza vaccine and found that these correlated with antibody measurements. Administration of the novel virus-like particle based vaccine elicited influenza-specific CD4+ and CD8+ T-cell responses and the induction of the cytokines IFN-γ, IL-17A, IL17F, IL-5, IL-13, IL-9, IL-10 and IL-21. Pre-existing cytokine responses influenced the profile of the cytokine response elicited by vaccination. In a subset of individuals the VLP vaccine changed pre-vaccination production of type 2 cytokines such as IL-5 and IL-13 to a post-vaccination type 1 cytokine signature characterized by IFN-γ. A transcriptional signature to vaccination was found to correlate with antibody titer, IFN-γ production by T-cells and expression of a putative RNA helicase, DDX17, on the surface of immune cells.

HIV glycoprotein gp120 enhances mesenchymal stem cell migration by upregulating CXCR4 expression.

BACKGROUND: HIV infection and/or the direct pathogenic effects of circulating HIV proteins impairs the physiological function of mesenchymal stem cells (MSCs), and contribute to the pathogenesis of age-related clinical comorbidities in people living with HIV. The SDF-1/CXCR4 pathway is vital for modulating MSC proliferation, migration and differentiation. HIV glycoprotein gp120 inhibits SDF-1 induced chemotaxis by downregulating the expression and function of CXCR4 in monocytes, B and T cells. The influence of gp120 on CXCR4 expression and migration in MSCs is unknown. METHODS: We investigated CXCR4 expression and SDF-1/CXCR4-mediated MSC migration in response to gp120, and its effect on downstream signaling pathways: focal adhesion kinase (FAK)/Paxillin and extracellular signal-regulated kinase (ERK). RESULTS: Gp120 upregulated MSC CXCR4 expression. This potentiated the effects of SDF-1 in inducing chemotaxis; FAK/Paxillin and ERK pathways were over-activated, thereby facilitating actin stress fiber reorganization. CXCR4 blockage or depletion abrogated the observed effects. CONCLUSION: Gp120 from both T- and M- tropic HIV strains upregulated CXCR4 expression in MSCs, resulting in enhanced MSC chemotaxis in response to SDF-1. GENERAL SIGNIFICANCE: HIV infection and its proteins are known to disrupt physiological differentiation of MSC; increased gp120-driven migration amplifies the total MSC population destined for ineffective and inappropriate differentiation, thus contributing to the pathogenesis of HIV-related comorbidities. Additionally, given that MSCs are permissive to HIV infection, initial cellular priming by gp120 results in increased expression of CXCR4 and could lead to co-receptor switching and cell tropism changes in chronic HIV infection and may have implications against CCR5-knockout based HIV cure strategies.

Population Pharmacokinetics of Polymyxin B.

Polymyxin B is used as a last treatment resort for multidrug-resistant Gram-negative bacterial infections. The objectives of this study were to examine the population pharmacokinetics of polymyxin B and investigate factor(s) influencing pharmacokinetic variability. Four serial blood samples each were collected from 35 adult patients at steady state. The concentrations of individual polymyxin B components were analyzed using a validated liquid chromatography / tandem mass spectrometry assay and combined to derive total concentrations. A maximum likelihood expectation maximization approach was used to fit the data. Various demographic variables were investigated as potential covariates for clearance and volume of distribution (Vd ) using linear regression analysis. A one-compartment model fit to the data satisfactorily (r2 = 0.96). The best-fit mean ± SD for clearance and Vd were 2.5 ± 1.1 L/h and 34.3 ± 16.4 L, respectively. Creatinine clearance was found to be a statistically significant covariate of clearance, but the magnitude was deemed clinically insignificant.