Suresh Agarwal

The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients.

Objective:Previously, delirium has been identified as an independent risk factor for mortality in critically ill medical patients. We undertook this study to examine the relationships among medication usage, delirium, and clinical outcomes in a critically ill surgical/trauma population. Design:Prospective, multicentered, observational study. Setting:Two surgical intensive care units in level 1 trauma centers. Patients:One hundred thirty-four consecutive surgical adult patients requiring mechanical ventilation (MV) for greater than 24 hours. Interventions:Daily delirium assessment with the Confusion Assessment Method-Intensive Care Unit tool, outcomes assessment, and prospective data collection. Measurement and Main Results:Of the 134 patients who met inclusion criteria, 84 patients (63%) developed delirium at some point during their intensive care unit (ICU) stay. Delirium was associated with more MV days (9.1 vs. 4.9 days, p < 0.01), longer ICU stay (12.2 vs. 7.4 days, p < 0.01), longer hospital stay (20.6 vs. 14.7 days, p < 0.01). Additionally, greater cumulative lorazepam dose (p = 0.012), and higher cumulative fentanyl dose (p = 0.035) were administered in the delirium group. Conclusions:Delirium in the surgical/trauma ICU cohort is independently associated with more days requiring MV, longer ICU length of stay, and longer hospital length of stay. Additionally, greater amounts of lorazepam and fentanyl were administered to patients with delirium.

Adherence to Ventilator-Associated Pneumonia Bundle and Incidence of Ventilator-Associated Pneumonia in the Surgical Intensive Care Unit

OBJECTIVE To examine the impact of adherence to a ventilator-associated pneumonia (VAP) bundle on the incidence of VAP in our surgical intensive care units (SICUs). DESIGN Prospectively collected data were retrospectively examined from our Infection Control Committee surveillance database of SICU patients over a 38-month period. Cost of VAP was estimated at

Emergency general surgery: definition and estimated burden of disease.

30,000 per patient stay. SETTING Two SICUs at a tertiary care academic level I trauma center. PATIENTS Ventilated patients admitted to a SICU. INTERVENTION The Institute for Healthcare Improvement VAP bundle was instituted at the beginning of the study and included head-of-bed elevation, extubation assessment, sedation break, peptic ulcer prophylaxis, and deep vein thrombosis prophylaxis. A daily checklist was considered compliant if all 5 items were performed for each patient. MAIN OUTCOME MEASURES Patients were assessed for VAP. Staff were assessed for compliance with the VAP bundle. RESULTS Prior to initiation of the bundle, VAP was seen at a rate of 10.2 cases/1000 ventilator days. Compliance with the VAP bundle increased over the study period from 53% and 63% to 91% and 81% in each respective SICU. The rate of VAP decreased to 3.4 cases/1000 ventilator days. A cost savings of

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

1.08 million was estimated. CONCLUSIONS Initiation of the VAP bundle is associated with a significantly reduced incidence of VAP in patients in the SICU and with cost savings. Initiation of a VAP bundle protocol is an effective method for VAP reduction when compliance is maintained.

Successful Nonoperative Management of the Most Severe Blunt Liver Injuries: A Multicenter Study of the Research Consortium of New England Centers for Trauma

BACKGROUND Acute care surgery encompasses trauma, surgical critical care, and emergency general surgery (EGS). While the first two components are well defined, the scope of EGS practice remains unclear. This article describes the work of the American Association for the Surgery of Trauma to define EGS. METHODS A total of 621 unique International Classification of Diseases—9th Rev. (ICD-9) diagnosis codes were identified using billing data (calendar year 2011) from seven large academic medical centers that practice EGS. A modified Delphi methodology was used by the American Association for the Surgery of Trauma Committee on Severity Assessment and Patient Outcomes to review these codes and achieve consensus on the definition of primary EGS diagnosis codes. National Inpatient Sample data from 2009 were used to develop a national estimate of EGS burden of disease. RESULTS Several unique ICD-9 codes were identified as primary EGS diagnoses. These encompass a wide spectrum of general surgery practice, including upper and lower gastrointestinal tract, hepatobiliary and pancreatic disease, soft tissue infections, and hernias. National Inpatient Sample estimates revealed over 4 million inpatient encounters nationally in 2009 for EGS diseases. CONCLUSION This article provides the first list of ICD-9 diagnoses codes that define the scope of EGS based on current clinical practices. These findings have wide implications for EGS workforce training, access to care, and research.

Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study

BACKGROUND Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. FINDINGS Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. INTERPRETATION A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. FUNDING AbbVie Inc and Genentech Inc.

Pain as an indication for rib fixation: a bi-institutional pilot study.

HYPOTHESIS Grade 4 and grade 5 blunt liver injuries can be safely treated by nonoperative management (NOM). DESIGN Retrospective case series. SETTING Eleven level I and level II trauma centers in New England. PATIENTS Three hundred ninety-three adult patients with grade 4 or grade 5 blunt liver injury who were admitted between January 1, 2000, and January 31, 2010. MAIN OUTCOME MEASURE Failure of NOM (f-NOM), defined as the need for a delayed operation. RESULTS One hundred thirty-one patients (33.3%) were operated on immediately, typically because of hemodynamic instability. Among 262 patients (66.7%) who were offered a trial of NOM, treatment failed in 23 patients (8.8%) (attributed to the liver in 17, with recurrent liver bleeding in 7 patients and biliary peritonitis in 10 patients). Multivariate analysis identified the following 2 independent predictors of f-NOM: systolic blood pressure on admission of 100 mm Hg or less and the presence of other abdominal organ injury. Failure of NOM was observed in 23% of patients with both independent predictors and in 4% of those with neither of the 2 independent predictors. No patients in the f-NOM group experienced life-threatening events because of f-NOM, and mortality was similar between patients with successful NOM (5.4%) and patients with f-NOM (8.7%) (P = .52). Among patients with successful NOM, liver-specific complications developed in 10.0% and were managed definitively without major sequelae. CONCLUSIONS Nonoperative management was offered safely in two-thirds of grade 4 and grade 5 blunt liver injuries, with a 91.3% success rate. Only 6.5% of patients with NOM required a delayed operation because of liver-specific issues, and none experienced life-threatening complications because of the delay.

Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study.

BACKGROUND Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study. METHODS Previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy were enrolled into this non-randomised, open-label, phase 1b study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and either intermediate-risk or poor-risk cytogenetics. Patients were enrolled into one of three groups for the dose-escalation phase of this study: group A (venetoclax and intravenous decitabine 20 mg/m2 [days 1-5 of each 28-day cycle]), group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m2 [days 1-7 of each 28-day cycle]), and group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22-28, to assess its effect on venetoclax pharmacokinetics). Dose escalation followed a standard 3 + 3 design with at least three evaluable patients enrolled per cohort; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C. The primary endpoints were the safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included the preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival. We analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients who received one or more venetoclax doses. The expansion phase of the study is ongoing but is closed to accrual. This trial is registered with ClinicalTrials.gov, number NCT02203773. FINDINGS 57 patients were enrolled in the study. 23 patients in group A and 22 patients in group B were enrolled between Nov 19, 2014, and Dec 15, 2015, and 12 patients in group C were enrolled between June 14, 2015, and Jan 16, 2016. As of data cutoff on June 15, 2016, the most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; nine in group A, 13 in group B, and five in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, ten in group B, and three in group C), and neutropenia (23 [40%] of 57; 12 in group A, eight in group B, and three in group C). The most common serious treatment-emergent adverse event in groups A and B was febrile neutropenia (seven [30%] of 23 patients vs seven [32%] of 22), whereas in group C it was lung infection (four [33%] of 12 patients). 49 (86%) of 57 patients had treatment-related adverse events; the most common in groups A and B included nausea (12 [52%] patients vs seven [32%] patients), fatigue (six [26%] patients vs seven [32%]), and decreased neutrophil count (six [26%] patients vs six [27%]), whereas in group C the most common were nausea (seven [58%] of 12 patients), leucopenia (six [50%]), vomiting (five [42%]), and decreased platelet count (five [42%]). The maximum tolerated dose was not reached. The recommended phase 2 dose was 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion). In total, four (7%) of 57 patients had died within 30 days of the first venetoclax dose caused by sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A). Tumour lysis syndrome was not observed. Decitabine and azacitidine did not substantially affect venetoclax exposures. Overall, 35 (61%; 95% CI 47·6-74·0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery. In groups A and B, 27 (60%; 95% CI 44·3-74·3) of 45 patients had complete remission or complete remission with incomplete marrow recovery. INTERPRETATION Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population. Evaluation of expansion cohorts is ongoing at 400 mg and 800 mg doses using both hypomethylating agent combinations. FUNDING AbbVie and Genentech.

Effect of Low‐ and High‐Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First‐in‐Class BCL‐2 Inhibitor

BACKGROUND In trauma patients, open reduction and internal fixation of rib fractures remain controversial. We hypothesized that patients who have open reduction and internal fixation of rib fractures would experience less pain compared with controls and thus require fewer opiates. Further, we hypothesized that improved pain control would result in fewer pulmonary complications and decreased length of stay. METHODS This is a retrospective bi-institutional matched case-control study. Cases were matched 1:2 by age, injury severity Score, chest abbreviated injury severity score, head abbreviated injury severity score, pulmonary contusion score, and number of fractured ribs. The daily total doses of analgesic drugs were converted to equianalgesic intravenous morphine doses, and the primary outcome was inpatient narcotic administration. RESULTS Sixteen patients between July 2005 and June 2009 underwent rib fixation in 5 ± 3 days after injury using an average of 3 (1-5) metallic plates. Morphine requirements decreased from 110 mg ± 98 mg preoperatively to 63 ± 57 mg postoperatively (p = 0.01). There were no significant differences between cases and controls in the mean morphine dose (79 ± 63 vs. 76 ± 55 mg, p = 0.65), hospital stay (18 ± 12 vs. 16 ± 11 days, p = 0.67), intensive care unit stay (9 ± 8 vs. 7 ± 10 days, p = 0.75), ventilation days (7 ± 8 vs. 6 ± 10, p = 0.44), and pneumonia rates (31% vs. 38%, p = 0.76). CONCLUSION The need for analgesia was significantly reduced after rib fixation in patients with multiple rib fractures. However, no difference in outcomes was observed when these patients were compared with matched controls in this pilot study. Further study is required to investigate these preliminary findings.

Successful Nonoperative Management of the Most Severe Blunt Renal Injuries: A Multicenter Study of the Research Consortium of New England Centers for Trauma

Venetoclax is a selective, potent, first‐in‐class B‐cell lymphoma‐2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single‐dose and multiple‐dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax Cmax and AUC∞ by 106% (90%CI, 73%–145%) and 78% (90%CI, 50%–111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUC∞ by 42% (90%CI, 31%–52%) and 71% (90%CI, 66%–76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P‐glycoprotein (P‐gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P‐gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax.