James M. Hollands

Comparison of Bivalirudin and Argatroban for the Management of Heparin-Induced Thrombocytopenia

Study Objectives. To compare the effectiveness of bivalirudin and argatroban in achieving anticoagulation goals and to compare clinical outcomes assessing the safety and efficacy in patients with known or suspected heparin‐induced thrombocytopenia (HIT).

Drug-induced arrhythmias.

The objective of this review is to characterize the mechanisms, risk factors, and offending pharmacotherapeutic agents that may cause drug-induced arrhythmias in critically ill patients. PubMed, other databases, and citation review were used to identify relevant published literature. The authors independently selected studies based on relevance to the topic. Numerous drugs have the potential to cause drug-induced arrhythmias. Drugs commonly administered to critically ill patients are capable of precipitating arrhythmias and include antiarrhythmics, antianginals, antiemetics, gastrointestinal stimulants, antibacterials, narcotics, antipsychotics, inotropes, digoxin, anesthetic agents, bronchodilators, and drugs that cause electrolyte imbalances and bradyarrhythmias. Drug-induced arrhythmias are insidious but prevalent. Critically ill patients frequently experience drug-induced arrhythmias; however, enhanced appreciation for this adverse event has the potential to improve prevention, treatment, patient safety, and outcomes in this patient population.

Optimizing antibiotic treatment for ventilator-associated pneumonia.

Ventilator‐associated pneumonia (VAP) is the most common infectious complication in patients receiving mechanical ventilation and accounts for exorbitant use of resources in the intensive care unit. Antimicrobial management of VAP incorporates an initial broad‐spectrum, empiric regimen to ensure appropriate coverage with deescalation of therapy after 48–72 hours based on culture results and sensitivities. When VAP clinically responds to treatment, antimicrobials should be discontinued after 7–8 days to reduce overall antibiotic consumption and the selection pressure on flora observed in the intensive care unit and thus minimize the development and spread of antimicrobial resistance.

Prolonged Infusion Antibiotics for Suspected Gram-Negative Infections in the ICU: A Before-After Study

BACKGROUND: β-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. OBJECTIVE: To determine whether prolonged infusion of β-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. METHODS: We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). RESULTS: A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). CONCLUSIONS: Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.

Identifying optimal initial infusion rates for unfractionated heparin in morbidly obese patients.

Background: Most literature available for unfractionated heparin (UFH) supports the use of actual body weight for dosing all patients, yet a small proportion of the patients in these studies were morbidly obese. The most appropriate dosing strategy for therapeutic UFH in this patient population is not clearly defined. Objective: To better define appropriate UFH dosing strategies in morbidly obese patients and to evaluate the safety of a weight-based heparin nomogram in this patient population. Methods: Patients with class III (morbid) obesity receiving therapeutic doses of a UFH infusion for greater than 24 hours were evaluated. Two comparator groups of overweight/class I–II obesity and normal/underweight patients were created by matching patients to the class III obesity group. Doses and times to therapeutic activated partial thromboplastin time (aPTT), bleeding rates, and mortality were assessed. Results: The mean infusion rate required to obtain a first therapeutic aPTT was 11.5 units/kg/h in the class III obesity group (n = 94) versus 12.5 units/kgm and 13.5 units/kg/h for the overweight/class I–II obesity (n = 92) and normal/underweight (n = 87) groups, respectively (p = 0.001). The mean times to a first therapeutic aPTT were 21.3, 22.1, and 29.9 hours, respectively (p = 0.421). There was a statistically significant difference in the infusion rate required to obtain 2 consecutive therapeutic aPTTs between groups (p = 0.016), with higher weight groups requiring smaller (per kilogram actual body weight) infusion rates, but there was no significant difference in the time to reach 2 consecutive therapeutic aPTTs (p = 0.776). There was no significant difference in bleeding (p = 0.517) or mortality (p = 0.475) among groups. Conclusions: Morbidly obese patients require smaller UFH infusion rates per kilogram actual body weight compared to patients with lower body mass indices. UFH dosing recommendations should be modified to reflect body mass index classification.

Role of corticosteroids in the management of acute respiratory distress syndrome

BACKGROUND Evidence exploring the use of corticosteroids for acute respiratory distress syndrome (ARDS) has targeted various stages of disease progression, from preventing ARDS in high-risk patients to halting disease evolution once ARDS has developed. OBJECTIVE The aim of this review was to evaluate randomized, controlled trials describing the role of corticosteroids in preventing and treating ARDS. METHODS English-language randomized, controlled trials were identified using MEDLINE via PubMed and EMBASE searches (key terms: acute respiratory distress syndrome, acute lung injury, and corticosteroids; years: 1968-January 2008). RESULTS A total of 10 trials were found and included in this analysis. Trials describing the role of high-dose corticosteroids compared with controls in preventing ARDS found no benefit, with the range of occurrence of ARDS in at-risk populations from 14% to 64% and absolute increases in mortality from 4% to 31%. Conflicting evidence was found for treating late-phase ARDS with corticosteroids, with 13% hospital mortality among patients receiving corticosteroids versus 63% with controls (P = 0.03) in one small study, but no significant difference was found when evaluating 60-day mortality (corticosteroid group, 29.2% vs control, 28.6%) in another investigation. The use of high-dose corticosteroids for the treatment of early phase ARDS was not associated with significant differences in 45-day mortality (methylprednisolone, 60% vs control, 63%). However, one trial found that methylprednisolone taper for early ARDS was associated with significant improvement in lung function or extubation (69.8% vs 35.7%; P = 0.002), fewer days on mechanical ventilation (median, 5.0 vs 9.5; P = 0.002), higher intensive care unit survival (79.4% vs 57.4%; P = 0.03), but similar rates of hospital survival (methylprednisolone, 76.2% vs control, 57.1%; P = NS). CONCLUSIONS Data from clinical trials did not support the use of short-course, high-dose corticosteroids for preventing ARDS or for the treatment of early ARDS. Longer-course corticosteroids have not conclusively been associated with improved survival in the treatment of late-phase ARDS but have provided some benefits in other markers of disease severity in this setting and in early phase ARDS. Published trials support the administration of low- to moderate-dose corticosteroids in the treatment of early (<7 days) and late-phase (days 7\2-14) ARDS, but this evidence is controversial.

Optimizing sustained use of sedation in mechanically ventilated patients: focus on safety.

Optimizing sustained use of ICU sedation in mechanically ventilated patients requires careful consideration of drug-specific characteristics (E.G. pharmacokinetics), consideration of potential adverse effects in susceptible patients, and utilization of sedation-minimizing strategies. In the era of anxiolytic dosing protocols adjusted to specific patient behaviors as defined by sedation scales in conjunction with daily interruption, midazolam is a reasonable option for long-term sedation. Propofol is an appealing agent for ICU sedation due to its pharmacokinetic profile and a reduced propensity to result in prolonged sedation. However, care should be taken to monitor for potential devastating adverse effects including hypertriglyceridemia and propofol-related infusion syndrome (PRIS). Dexmedetomidine unreliably provides adequate sedation at doses currently approved by the FDA, though upward titration of dexmedetomidine coupled with rescue benzodiazepines and/or fentanyl appears to be safe and comparable to benzodiazepines in the achievement of light to moderate Richmond Agitation Sedation Scale (RASS) goals. Clinicians should closely monitor patients receiving dexmedetomidine for hemodynamic-altering bradycardia. Strategies that promote frequent patient assessment with corresponding sedative dose minimization have demonstrated the benefits of limiting oversedation. Implementation of a sedation protocol requires careful consideration of ICU resources and staffing such that efforts made are sustainable and will be safe and effective for the patient population affected.

Assessment of Bleeding Events Associated With Short-Duration Therapeutic Enoxaparin Use in the Morbidly Obese:

Background: Enoxaparin dosing for patients with morbid obesity is uncertain, and therefore, an elevated incidence of bleeding may exist in this group. Objective: To determine if increased bleeding events occur in patients with morbid obesity (body mass index ≥ 40 kg/m2) compared with lower-weight patients with treatment doses of enoxaparin. Methods: Patients at a single, academic medical center receiving enoxaparin for at least 24 hours from July to December 2009 were retrospectively evaluated. Patients with morbid obesity were randomly selected among the total cohort and were matched with lower-weight controls (1:2 ratio) based on the presence of renal dysfunction (serum creatinine >1.4 mg/dL). Bleeding events, defined on the basis of laboratory changes, administration of blood products, or clinical data, occurring up to 24 hours after enoxaparin administration were evaluated. Independent risk factors for bleeding were assessed via multivariate analysis. Results: The maximum single dose administered throughout the study was 150 mg, and the largest patient enrolled weighed 175 kg. Final enoxaparin doses in morbidly obese (0.98 mg/kg) patients were lower compared with that in controls (1.04 mg/kg, P < .01). The proportion of patients with bleeding events was 29% in the morbidly obese and 23.5% in the control group (P = .30). Enoxaparin doses <0.9 mg/kg (adjusted odds ratio [AOR] = 2.35; 95% CI = 1.01-5.47; P = .04), durations of therapy beyond 48 hours (AOR = 2.42; 95% CI = 1.35-4.33; P < .01), and female gender (AOR = 2.05; 95% CI = 1.12-3.73; P = .02) were associated with bleeding, whereas warfarin use (AOR = 0.46; 95% CI = 0.26-0.81; P < .01) was associated with fewer bleeding events. Conclusions: Results suggest that dosing enoxaparin in morbidly obese patients (up to 175 kg in weight) with doses capped at 150 mg was not associated with increased bleeding incidence.

Characteristics of patients with morbid obesity at an academic medical center

Obesity is an epidemic in the United States, and its associated complications on health and health care utilization have been well described.[1][1]–[6][2] Obese patients are hospitalized longer once admitted to the hospital,[5][3],[7][4] and morbid obesity is associated with even larger increases

Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients With Class III Obesity

Background:A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent. Objective: To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients. Methods: This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] <25 kg/m2), obesity class I and II (BMI 30-39.9kg/m2), and obesity class III (BMI≥40 kg/m2) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated. Results: Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively (P=0.002). Longer durations of therapy (P<0.0001), higher initial maintenance doses in both total milligrams/day (P=0.0137) and milligrams/kilogram (P=0.0307), and any trough level >20 mg/L (P<0.0001) were identified as predictors of development of nephrotoxicity. Concomitant administration of piperacillin/tazobactam, diuretics, and IV contrast were associated with development of nephrotoxicity (P<0.005, all). Patients with class III obesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75). Conclusions: Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity.