Faculty Bibliography

Venous thromboembolism (VTE) is a major health concern associated with significant morbidity and mortality. Critically ill patients are at an increased risk of VTE compared to general medical patients due to unique risk factors: prolonged immobilization, invasive lines and devices, certain medications, and acquired thrombophilia. Furthermore, VTE in the critically ill is associated with increased duration of mechanical ventilation, increased length of intensive care unit and hospital stay, and a trend toward increased mortality. Clinical practice guidelines therefore recommend VTE prophylaxis with either subcutaneous heparin or low-molecular-weight heparin for all critically ill patients without contraindication. Yet, many patients will develop VTE despite appropriate pharmacologic prophylaxis, which has led to interest in risk-stratifying critically ill patients for more aggressive prophylaxis strategies. Recent research identified patients at highest risk of failure of thromboprophylaxis and provided insight into the pathophysiologic mechanisms. Obesity and the receipt of vasopressors are 2 risk factors consistently identified in observational studies; further clinical data support decreased absorption of anticoagulant administered via the subcutaneous route as the likely mechanism behind thromboprophylaxis failure in these patient populations. Several studies have investigated novel thromboprophylaxis strategies to circumvent pharmacokinetic limitations in patients who are obese or on vasopressors: increased fixed-dose, weight-based subcutaneous, or continuous intravenous infusion of a prophylactic dose of anticoagulant has shown promise in limited studies; however, the results have yet to demonstrate superiority compared to current standard-of-care. This review discusses observational studies identifying patients at risk of thromboprophylaxis failure and critiques clinical studies evaluating novel thromboprophylaxis strategies in high-risk, critically ill patients with a focus on their limitations. Future studies are currently being conducted that will provide further guidance into the appropriate use of individualized thromboprophylaxis.

Nephrotoxicity is a known adverse effect of polymyxin B (PMB). Animal data suggests that once daily dosing may reduce the rate and delay the onset of acute kidney injury (AKI).In a multicenter, retrospective study, we evaluated adult patients with a creatinine clearance (CrCl) ≥30 mL/min who received ≥48h of PMB therapy. The primary endpoint was the difference in rate of AKI comparing once and twice daily PMB dosing. Secondary endpoints included time to AKI and recovery of renal function.Of 273 eligible patients, 100 from each group were matched based on propensity scores. In the matched groups, nephrotoxicity, defined according to RIFLE criteria, was more frequent with once versus twice daily dosing (47% vs. 17% P=0.0005). After adjusting for residual differences by multivariate conditional logistic regression, once daily dosing was more likely to result in nephrotoxicity (adjusted odds ratio 2.5, 95% CI 1.413-4.541, P=0.002). Among 64 patients who developed AKI, the median onset was similar between groups (7 days with once vs. 6 days with twice daily dosing, P=0.095). Of 37 patients who had their serum creatinine evaluated subsequently, 29/37 (78%) had recovery of renal function. No patient required renal replacement therapy.Our findings suggest that AKI is significantly more common with PMB once daily as compared to twice daily dosing with no difference in time to AKI. Prospective randomized study is warranted to validate these results.

BACKGROUND:There is little data guiding clinicians on how to discontinue vasopressors among septic shock patients on concomitant norepinephrine (NE) and vasopressin (VP). OBJECTIVE:To determine the incidence of hypotension within 24 hours of discontinuing NE (NE DC first) versus VP (VP DC first) first in septic shock patients. METHODS:This retrospective study evaluated septic shock patients admitted to the medical intensive care unit (MICU) and surgical ICU (SICU) receiving concomitant NE and VP. Receipt of additional vasopressors, mixed shock states, expired or care withdrawn, and NE and VP discontinued simultaneously were exclusion criteria. The primary outcome was incidence of hypotension within 24 hours of first vasopressor discontinuation. Secondary outcomes included time to hypotension, hospital length of stay (LOS), ICU LOS, and ICU mortality. RESULTS:A total of 80 patients were included (NE DC first [n = 35]; VP DC first [n = 45]), with a median age of 73 years and median modified Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores of 21 and 7, respectively. More patients in the NE DC first group were in the SICU (42.9% vs 20.0%; P = 0.048) with more intra-abdominal infections (40.0% vs 15.6%; P = 0.021) and fewer appropriate empirical antibiotics (62.9% vs 86.7%; P = 0.018). Hypotension within 24 hours of first agent discontinuation was higher in the VP DC first group (28.6% vs 62.2%; P = 0.004), with similar hospital LOS and ICU mortality. Multivariate analysis identified VP DC first as an independent predictor of hypotension (odds ratio = 7.2; CI = 2.3-22.7). CONCLUSION/CONCLUSIONS:Among septic shock patients on concomitant NE and VP, discontinuation of VP first was associated with an increased incidence of hypotension; future prospective control trials are warranted.

Background: Novoseven is a recombinant preparation of human factor VIIa (rFVIIa) indicated for the treatment of bleeding episodes and perioperative management. Aims: To evaluate the cost and utilization of rFVIIa at a large academic medical center. Methods: We performed a retrospective review. Data collection included baseline characteristics, past medical history, and antithrombotic use. Utilization of rVIIa included indication for use, number of doses, and blood product administration within 24 hours. Incidence of venous thromboembolism (VTE), stroke, transient ischemic attack (TIA), death from systemic embolism, myocardial infarction (MI), hypersensitivity, and disseminated intravascular coagulation (DIC) were also collected. The primary outcome was utilization and cost of rVIIa at NYULH. Secondary outcomes included compliance to NYULH off-label dosing guideline, blood product administration, adverse effects, and thromboembolic events. Results: The majority of rFVIIa use was for refractory bleeding after cardiac surgery. Dosing was according to NYULH guideline, lower, and higher than recommended in 76.5%, 3.9% and 17.6% of cases respectively. The costs of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous. Seventy percent of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. Conclusions: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced costs. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events and further literature is needed to determine the optimal use of rFVIIa or if other hemostatic agents may be warranted in this population

Extended infusion (EI) administration of β-lactams can improve target attainment in critically ill patients with altered pharmacokinetics/pharmacodynamics. To optimize meropenem dosing in patients with severe sepsis/septic shock, our Antimicrobial Stewardship Program implemented a EI meropenem (EIM) protocol in an 18-bed Medical Intensive Care Unit in March 2014. In this retrospective study, we compared intensive care unit (ICU) mortality and clinical response in patients who received meropenem for ≥72 hours administered per EIM protocol of 1 g over 3 hours every 8 hours versus intermittent infusion (IIM) protocol of 500 mg over 30 minutes every 6 hours. Age, weight, comorbidities, severity of illness, and vasopressor use were comparable between groups (EIM protocol n = 52, IIM protocol n = 96). The IIM protocol group had higher rates of renal dose adjustment at meropenem initiation. Among 56 identified gram-negative (GN) pathogens, 94% had meropenem minimal inhibitory concentration ≤0.25 mg/L. The ICU mortality was lower (19 vs 37%; P = .032) and clinical response was higher (83% vs 46%; P < .01) in the EIM protocol versus IIM protocol group. Total vasopressor days were shorter (2 vs 3 days; P = .038), and white blood cell normalization rate was higher (87% vs 51%; P < .01) in the EIM protocol versus IIM protocol group. There was no difference in days of mechanical ventilation, duration of therapy, and ICU stay. The IIM protocol was also identified as an independent risk factor associated with ICU mortality (hazard ratio: 3.653, 95% confidence interval: 1.689-7.981; P = .001) after adjusting for Sequential Organ Failure Assessment score. In this cohort of patients with severe sepsis/septic shock and highly susceptible GN pathogens, there was improved mortality and clinical response in the EIM protocol group.

Cancer is a known hypercoagulable state that leads to an increased risk of venous thromboembolism (VTE). Low molecular weight heparin remains the preferred anticoagulant for VTE in patients with cancer over vitamin K antagonist. However, the preferred anticoagulant in prevention of stroke and systemic embolism in atrial fibrillation (AF) in patients with cancer has yet to be determined. The direct oral anticoagulants (DOACs) are increasingly being utilized; however their role in cancer has only recently been investigated. The objective of this retrospective cohort was to describe real-world anticoagulation prescribing patterns in cancer patients at a large academic medical center between January 1, 2013 and October 31, 2016. We sought to assess the safety, tolerability, and efficacy of DOACs in patients with cancer for either VTE and/or AF. Patient demographic, clinical characteristics, as well as bleeding and thrombotic events were collected. There were 214 patients in our analysis, of which 71 patients (33%) received a DOAC [apixaban (n = 22), dabigatran (n = 17), and rivaroxaban (n = 32)]. There were fewer bleeding events and/or discontinuations in the DOAC group compared to enoxaparin (13 vs. 27, p = 0.022). There was no difference in major or minor bleeds or thromboembolic events in comparing DOAC to enoxaparin or DOAC to warfarin. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs compared to warfarin or enoxaparin in patients with cancer. DOACs may represent an alternative to warfarin or enoxaparin in patients with cancer for VTE and/or stroke reduction in AF.

PURPOSE: Traditionally, sodium chloride 3% has been administered via a central venous line (CVL) because of the perceived risk of infiltration and tissue injury due to its high osmolarity. In clinical practice, sodium chloride 3% is commonly administered through peripheral venous catheters (PVCs) given the necessity of timely administration. However, there is no published data on the safety of administering sodium chloride 3% through PVCs in the adult population. The objective of this study was to evaluate the safety of peripheral venous administration of sodium chloride 3%. MATERIALS AND METHODS: A retrospective review was conducted in patients who received sodium chloride 3% in the intensive care unit (ICU). Patients were excluded if they had a CVL for the entire duration of the infusion or younger than 18 years at the time of administration. Baseline patient and infusion characteristics were collected. Infusion-related adverse events (IRAEs) were recorded, graded, and interventions required were noted. RESULTS: A total of 66 patients were included in the analysis. The most common indication was hyponatremia and majority of the patients were managed in the neurosurgical ICU. The most common risk factor for IRAEs was the presence of altered mental status. Four patients experienced an IRAE at an event rate of 6.1%. Patients who experienced an IRAE ranged from 38 to 82 years old. The IRAEs were grade 1 in severity, managed conservatively with removal of the PVC, and 2 of the 4 patients had their infusions restarted peripherally. The time to initial IRAE ranged from 2 to 94 hours. For the entire cohort, hospital and ICU length of stay were 8 and 4 days, respectively. CONCLUSIONS: The rate of IRAEs related to the infusion of sodium chloride 3% through PVCs appears to be similar to those reported with other hyperosmotic agents and could be considered for patients who need time-sensitive therapy.

Purpose: Leveraging pharmacy personnel resources for the purpose of antimicrobial stewardship program (ASP) operations presents a challenging task. We describe our experience integrating all pharmacists into an ASP, and evaluate the impact on ASP interventions, antimicrobial utilization, rate of selected hospital-onset infections and readmission. Summary: During a study period (January 1 to December 31, 2015), a total of 14 552 ASP-related pharmacy interventions were performed (ASP clinical pharmacotherapy specialists [CPS] n = 4025; non-ASP CPS n = 4888; hospital pharmacists n = 5639). Sixty percent of interventions by ASP CPS were initiated utilizing the dedicated ASP phone, and 40% through prospective audit and feedback. Non-ASP CPS performed interventions during bedside rounds (dose adjustment 23%, initiate new or alternative anti-infective 21%, discontinue antibiotic(s) 12%, therapeutic drug monitoring 11%, de-escalation 4%), whereas hospital pharmacists participated at the point of verification (dose adjustment 75%, restricted antibiotic verification 15%, and reporting major drug-drug interactions 4%). The acceptance rate of interventions by providers and clinicians was >90% for all groups. Annual aggregate antimicrobial use decreased by 6.4 days of therapy/1000 patient-days (DOT/1000 PD; P = 1.0). Ceftriaxone use increased by 8.4 DOT/1000 PD (P = .029) without a significant compensatory increase in the use of antipseudomonal agents. Sustained low rates of hospital-onset Clostridium difficile (CDI) and carbapenem-resistant Enterobacteriaceae (CRE) infections were observed in 2015 compared with the prior year (1.1 and 1.2 cases/1000 PD, 0.2 and 0.1 cases/1000 PD, respectively). Thirty-day readmission rate decreased by 0.6% (P = .019). Conclusions: Integration of all pharmacists into ASP activities based on the level of patient care and responsibilities is an effective strategy to expand clinical services provided by ASP.

PURPOSE: Enteral nutrition (EN) is often held in patients receiving vasopressor support for septic shock. The rationale for this practice is to avoid mesenteric ischemia. The objective of this study is to evaluate the tolerability of EN in patients with septic shock who require vasopressor support and determine factors associated with tolerance of EN. MATERIALS AND METHODS: This was a single-center retrospective review of adult patients admitted to the intensive care unit with a diagnosis of septic shock and an order for EN. The primary outcome was EN tolerance. Secondary outcomes included time to initiation of EN from the start of vasopressor(s), length of stay, and mortality. RESULTS: A total of 120 patients were included. Sixty-two percent of patients tolerated EN. The most common reason for intolerance of EN was gastric residuals > 250 mL (74%). No reports of mesenteric ischemia were observed. A multivariate analysis demonstrated that patients with septic shock initiating EN within 48 hours and receiving norepinephrine-equivalent doses of 0.14 mug/kg/min or less were more likely to tolerate EN. CONCLUSION: Based on our observation, early EN may be tolerated and safely administered in patients with septic shock who are adequately fluid resuscitated and receive doses of < 0.14 mug/kg/min of norepinephrine equivalents.