Shaun Keegan

The incidence of seizures in patients undergoing therapeutic hypothermia after resuscitation from cardiac arrest

STUDY OBJECTIVE Non-convulsive seizures/status epilepticus occur in approximately 20% of comatose, non-cardiac arrest intensive care unit (ICU) patients, and are associated with increased mortality. The prevalence and clinical significance of seizures in comatose survivors of cardiac arrest undergoing therapeutic hypothermia is not well described. METHODS At this urban level I trauma center, every patient undergoing therapeutic hypothermia is monitored with continuous video encephalography (cvEEG). We abstracted medical records for all cardiac arrest patients treated with therapeutic hypothermia during 2010. Clinical data were extracted in duplicate. cvEEGs were independently reviewed for seizures by two board-certified epileptologists. RESULTS There were 33 patients treated with therapeutic hypothermia after cardiac arrest in 2010 who met inclusion criteria for this study. Median age was 58 (range 28-86 years), 63% were white, 55% were male, and 9% had a history of seizures or epilepsy. During cooling, seizures occurred in 5/33 patients (15%, 95%CI 6%-33%). 11/33 patients (33%, 95% CI 19%-52%) had seizures at some time during hospitalization. 13/33 (39%) survived to discharge and of these, 7/13 (54%) survived to 30 days. 9/11 patients with seizures died during hospitalization, compared with 11/22 patients without seizures (82% vs. 50%; difference 32%, CI 951%-63%). No patient with seizures was alive at 30 days. CONCLUSIONS Seizures are common in comatose patients treated with therapeutic hypothermia after cardiac arrest. All patients with seizures were deceased within 30 days of discharge. Routine use of EEG monitoring could assist in early detection of seizures in this patient population, providing an opportunity for intervention to potentially improve outcomes.

Effects of Critical Illness and Organ Failure on Therapeutic Argatroban Dosage Requirements in Patients with Suspected or Confirmed Heparin-Induced Thrombocytopenia

BACKGROUND Critically ill patients often require therapeutic argatroban dosages lower than those recommended in package labeling. The magnitude of dosage alteration in relation to severity of organ failure is unknown. OBJECTIVE To compare therapeutic argatroban dosages between critically ill and noncritically ill patients with confirmed or suspected heparin-induced thrombocytopenia and investigate the relationship between total Sequential Organ Failure Assessment (SOFA) score and therapeutic argatroban dosage. METHODS This retrospective cohort study was conducted at an urban academic medical center. Adults without Child-Pugh class C hepatic dysfunction who received argatroban for more than 24 hours over a 3-year period were included. Therapeutic argatroban dosage was that resulting in 2 consecutive activated partial thromboplastin time (aPTT) values 1.5–3 times the patient-specific baseline obtained at least 4 hours apart. Initial argatroban dosages were at the discretion of the managing service. RESULTS Fifty-three patients (critically ill, n = 34; noncritically ill, n = 19) were included. Critically ill patients had higher median [interquartile range] Acute Physiology and Chronic Health Evaluation (APACHE II) (17 [12–21] vs 10 [3.25–17.75]; p = 0.007) and SOFA (11 [7–13] vs 2 [0–2.75]; p < 0.001) scores. Critically ill patients required lower mean ± SD therapeutic argatroban dosage (0.6 ± 0.5 vs 1.4 ± 0.9 µg/kg/min; p < 0.001). There was no significant difference in time to therapeutic aPTT or proportion of aPTTs within therapeutic range. Argatroban dosage was inversely related to SOFA score tertiles (<6: 1.34 ± 0.82 µg/kg/min; 6–9: 0.93 ± 0.54; ≥10: 0.40 ± 0.27; p < 0.001). Total SOFA score at the time of argatroban initiation was independently associated with an argatroban dosage less than 0.75 µg/kg/min (OR 1.5, 95% CI 1.2 to 1.8; p < 0.001). Adverse events were similar between groups. CONCLUSIONS Critically ill patients with single or multiple organ failure require lower therapeutic argatroban dosages compared with noncritically ill patients. Because of an inverse relationship with SOFA score, initial argatroban dosage in critically ill patients should be based on the presence and magnitude of organ failure.

Effect of a dalteparin prophylaxis protocol using anti-factor Xa concentrations on venous thromboembolism in high-risk trauma patients

BACKGROUND Low anti-factor Xa (anti-Xa) concentrations with twice-daily enoxaparin are associated with venous thromboembolism (VTE) in high-risk trauma patients. Concerns have been raised with once-daily dalteparin regarding effectiveness and achievable anti-Xa concentrations. The purpose of this before-and-after study was to evaluate the effectiveness of a VTE prophylaxis protocol using anti-Xa concentrations and associated dalteparin dose adjustment in high-risk trauma patients. METHODS Adult trauma patients receiving VTE chemoprophylaxis and hospitalized for at least 3 days were prospectively followed during two 6-month epochs before (PRE) and after (POST) implementation of anti-Xa monitoring. In both groups, high-risk patients received dalteparin 5,000 U subcutaneously once daily; low-risk patients received subcutaneous unfractionated heparin. High-risk POST patients with anti-Xa less than 0.1 IU/mL 12 hours after initial dalteparin dose received dalteparin every 12 hours. All patients underwent routine VTE ultrasound surveillance of the lower extremities. The primary outcome was incidence of VTE. RESULTS A total of 785 patients (PRE, n = 428; POST, n = 357) were included. Demographics, injury patterns, Injury Severity Score (ISS), red blood cell transfusions, intensive care unit and hospital stays, and mortality did not differ between groups. Overall, POST patients had lower VTE (7.0% vs. 13%, p = 0.009) including acute VTE (6.4% vs. 12%, p = 0.01) and proximal deep vein thromboembolism (2.2% vs. 5.7%, p = 0.019). Between high-risk patients, VTE occurred in 53 (16.3%) PRE compared with 24 (9.0%) POST patients (p = 0.01); there was no difference in VTE between low-risk patients (PRE, 2.0% vs. POST, 1.1%; p = 0.86). Among 190 high-risk POST patients with anti-Xa, 97 (51%) were less than 0.1 IU/mL. Patients with low anti-Xa had higher rates of VTE (14.0% vs. 5.4%, p = 0.05) and deep vein thromboembolism (14.4% vs. 3.2%, p = 0.01). Younger age (odds ratio, 0.97; 95% confidence interval, 0.95–0.99) and greater weight (odds ratio, 1.02; 95% confidence interval, 1.00–1.03) predicted low anti-Xa on multivariate regression. CONCLUSION A VTE prophylaxis protocol using anti-Xa–based dalteparin dosage adjustment in high-risk trauma patients was associated with decreased VTE. Once-daily dalteparin 12-hour anti-Xa concentrations are suboptimal in a majority of patients and associated with VTE. LEVEL OF EVIDENCE Therapeutic study, level IV.

Prevention of perioperative venous thromboembolism.

Venous thromboembolism (VTE) is the most common preventable cause of morbidity and mortality in postoperative patients. Overall, VTE is the second-most-common medical complication, third-mostcommon reason for excess healthcare resource utilization, including prolonged hospital stay, and third-most-common cause of mortality in postoperative patients. Moreover, pulmonary embolism (PE) has been identified as the most common preventable cause of death in hospitalized patients. As supported by exhaustive reviews and evidence-based guidelines, as well as advocacy by United States and international healthcare policy groups, prevention of postoperative VTE is imperative to patient safety and necessary to decrease postoperative morbidity and mortality. Effective prevention also may limit the societal medical resource burden associated with VTE. Despite

Response to "Characterization of unbound phenytoin concentrations in neurointensive care unit patients using a revised Winter-Tozer equation" by Sean P. Kane, Adam P. Bress, and Eljim P. Tesoro.

TO THE EDITOR: We read with great interest the study by Kane et al evaluating multiple equations to correct total phenytoin levels in neurointensive care patients. This study is to be commended for its large sample size and focus on critically ill patients, who have multiple reasons for altered phenytoin concentrations. They found the traditional Winter-Tozer (WT) equation significantly underpredicted patients’ actual free phenytoin concentrations and concluded it is not appropriate to use in this population. They found greater correlation between predicted and actual free phenytoin concentrations with a modified WT equation and an equation developed through multivariate analysis. Previous studies evaluating the WT equation’s predictive ability have shown mixed results. We conducted an analysis of internal data in our neurointensive patient population to see how patient’s phenytoin binding changes throughout their stay. Our cohort included 100 patients and 556 paired total and free phenytoin concentrations. The average free fraction of phenytoin in our group was 18.8% and the average albumin was 2.7 g/dL. Following the results from Kane et al, we applied the 3 equations used (WT, multivariate liner regression model, and modified WT coefficient) to our data in an attempt to validate their results. We applied these equations to each patient’s first phenytoin concentrations and albumin level as Kane et al did (group 1, n = 92), then to the patient’s phenytoin concentrations and albumin levels throughout their entire intensive care unit stay (group 2, n = 312). Surprisingly, we found the traditional WT equation had the greatest correlation when compared with the other 2 equations, and overall, all 3 equations correlated poorly with actual free phenytoin concentrations (see Table 1). These markedly different results may be because of differences in study design and baseline demographics. Our data are from the patients’ entire stay in the neurointensive care unit (each patient had multiple phenytoin concentrations) versus within the first 24 hours of admission as Kane et al used. Also, our patients had a mean albumin of 2.7 g/ dL versus a mean albumin of 3.3 g/dL in Kane et al’s group. Overall, we agree with Kane et al’s idea of developing new predictive equations accounting for other variables in addition to albumin. Both our results have shown that the WT equation is not reliable in neurointensive patients. Future studies evaluating predictive phenytoin equations should include a variety of variables in their analysis.

995: METHADONE VERSUS SCHEDULED OPIOID THERAPY IN TIME TO CONTINUOUS INFUSION ANALGESIA DISCONTINUATION

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: Patients in the intensive care unit (ICU) routinely experience pain. Scheduled opioids may be employed to facilitate weaning of continuous infusion (CI) analgesia in mechanically ventilated (MV) patients to avoid withdrawal. However, an optimum strategy has not been identified. Methadone may be an optimal choice as it possesses a long duration of action and has the ability to be administered intravenously and enterally. Methods: This single center, retrospective, cohort study included adult ICU patients on MV for 48 hours that received CI analgesia plus concomitant methadone or scheduled, enteral immediate release opioids (IRO). The primary outcome was comparison of time to CI analgesia discontinuation. Secondary outcomes included comparison of initial, 96-hour, and final methadone or IRO dose in oral morphine equivalents (OME) at CI analgesia discontinuation and prolonged QTc interval incidence at 96 hours. Logistic regression analyses were performed to determine independent predictors of methadone response. Results: Seventy-four patients were included in the analysis. Time to CI analgesia discontinuation was similar between the two treatment groups (methadone, 69 hours vs IRO, 57.5 hours; p = 0.527). CI analgesia dose at study drug initiation and maximum dose were similar between the two groups. The methadone group received statistically more daily OME at all time points analyzed (initiation, 90 vs 60 mg, p = 0.009; 96 hours, 90 vs 45 mg, p < 0.001; CI analgesia discontinuation, 90 vs 30 mg, p < 0.001). No difference in prolonged QTc interval at 96 hours was observed (methadone, 445 vs IRO, 460 ms; p = 0.110). Patients that received methadone were significantly more likely to discharged with a long-acting opioid prescription (51.4 vs 2.7%, p < 0.001). No independent predictors for methadone response were identified. Conclusions: Methadone was not associated with a quicker time to CI analgesia discontinuation when compared to scheduled IRO. Patients that received methadone were more likely to be discharged with a prescription for a long-acting opioid and received significantly more opioid analgesia until CI analgesia was discontinued.

581: CLINICAL IMPACT OF HYPERCHLOREMIA SECONDARY TO HYPERTONIC SODIUM CHLORIDE ADMINISTRATION

Learning Objectives: Itravenous (IV) hypertonic sodium chloride (HTS) has multiple clinical indications. Isotonic sodium chloride and subsequent hyperchloremia have been associated with acute kidney injury (AKI), prolonged hospital length of stay (LOS), and increased mortality. These associations have not been evaluated with HTS use. The primary objective of this study is to compare the incidence of AKI among peak serum chloride concentrations in patients receiving HTS. Methods: This single-center, retrospective, observational study analyzed adult patients admitted >72 hr and reveiving ≥15 grams of sodium chloride via IV HTS. Patients were divided into tertiles based on peak serum chloride: tertile 1 (T1) ≤108 mmol/L; tertile 2 (T2) 109–116 mmol/L; tertile 3 (T3) ≥117 mmol/L. AKI and in-hospital mortality rates were compared among tertiles. Multivariate logistic regression was performed to identify factors associated with AKI development or mortality. Results: 136 patients were included (T1, 43 [32%]; T2, 52 [38%]; T3, 41 [30%]). Baseline characteristics were similar among tertiles with the exception of T1 including fewer traumatic admissions (19 v 52 v 42%;p=0.003) and more hyponatremia diagnoses (14 v 4 v 0%;p=0.018). Increase in serum chloride from baseline was different among tertiles (6 v 9 v 16%;p<0.001). Rate of AKI increased with peak serum chloride (2 v 10 v 22%;p=0.015). Multivariate logistic regression identified that peak serum chloride independently predicted AKI development (OR 7.1, 95% CI 1–50;p=0.049). Hospital (13 v 16 v 13;p=0.053) and ICU (8 v 11 v 11;p=0.124) LOS (days) were similar among groups. Mortality rate increased with peak serum chloride (5 v 14 v 32%;p=0.003). No factors were identified as independent predictors of mortality. Conclusions: After adjusting for concurrent nephrotoxins and other confounding variables, increasing magnitude of serum chloride was associated with AKI among patients who received HTS. Prospective, multicenter studies are needed to confirm this relationship.