John J. Radosevich

Emerging pharmacological agents to improve survival from traumatic brain injury.

Abstract Objective: To review emerging pharmacological agents for the treatment of traumatic brain injury with regard to survival outcomes and provide recommendations regarding their use. Methods: An Ovid MEDLINE (up to May 2013) and the Cochrane Central Register of Controlled Trials (up to May 2013) search was conducted to identify emerging pharmacological therapies for the treatment of traumatic brain injury. The search was limited to English language and humans. Pharmacological agents that were evaluated with respect to survival as an outcome were included. Main results: Based on the search, the investigators identified the following new therapies: beta-receptor antagonists, erythropoiesis stimulating agents, hydroxymethylglutaryl-CoA reductase inhibitors (statins) and progesterone. With the exception of progesterone, which was studied in several small, randomized, controlled trials, the remaining agents were primarily studied in observational retrospective cohorts. For each of the agents identified, a potential increase in survival was noted. Conclusions: Emerging pharmacological agents represent promising treatment options for traumatic brain injury to improve survival. Most of these agents are commercially available for other indications. However, limitations in study design, sample size, duration of treatment, timing of treatment and inclusion of heterogeneous patient populations make it difficult to draw definitive conclusions from the literature.

Hepatotoxicity in Obese Versus Nonobese Patients With Acetaminophen Poisoning Who Are Treated With Intravenous N-Acetylcysteine.

There is limited information regarding the outcomes associated with acetaminophen (APAP) poisoning in obese individuals. It is possible that patients who are obese are more susceptible to APAP-induced liver injury, thereby diminishing the efficacy of antidotes such as N-acetylcysteine (NAC). We evaluated the outcomes associated with APAP poisoning in obese versus nonobese adults who are treated with intravenous (IV) NAC. This was a retrospective cohort study conducted in a tertiary care, academic medical center. Adult patients with APAP toxicity, who were treated with IV NAC between June 2005 and August 2012, were included. The patients were categorized into 2 groups based on their body mass index (BMI): (1) obese (BMI ≥ 30.0 kg/m2) versus (2) nonobese (BMI 18.5–24.9 kg/m2). The primary outcome measure was the proportion of patients who developed hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >1000 IU/L). A total of 80 patients were included in the final cohort (40 in each group). The median BMI for the obese and nonobese groups was 34.5 kg/m2 [interquartile range (IQR) 31.4–40.2] and 22.4 kg/m2 (IQR 21.2–23.9), respectively (P < 0.001). Other than more white patients being present in the nonobese group, there were no other baseline differences between groups with regard to demographics, liver function tests, or coagulation studies. Obese patients received a median IV NAC dose of 291.5 mg/kg (IQR 270.8–300.7) compared with 300 mg/kg (IQR 287.8–301.9) in the nonobese group (P = 0.07). Hepatotoxicity occurred in 27.5% of the obese patients and 37.5% of the nonobese patients (P = 0.34). No adverse drug effects were noted in either group. Obese and nonobese patients being treated with IV NAC for APAP toxicity experienced similar rates of hepatotoxicity.

Evaluation of the treatment of candiduria at an academic medical center

To evaluate the epidemiology, management, and outcomes associated with candiduria in intensive care unit (ICU) and medical ward (MW) patients. This was a retrospective cohort study conducted in a tertiary care academic medical center. Adult patients aged between 18 and 75 years who were admitted for at least 5 days with a urinary culture that grew a Candida species between July 2010 and June 2011 were included. Medical records were retrospectively reviewed. Laboratory data, urinary symptoms, risk factors for urinary and invasive candidiasis, treatment, and patient outcomes were collected and evaluated. Sixty-seven ICU and 65 MW patients met the inclusion criteria. ICU patients were more likely to have risk factors for invasive candidiasis and candiduria. Candida albicans and Candida glabrata were the most frequently identified urinary isolates. Antifungal therapy was commonly initiated despite rapid replacement or removal of urinary drainage devices and a lack of patient reported symptoms. Fluconazole was the most commonly used antifungal agent, followed by micafungin. Hospital length of stay did not vary significantly between the ICU and MW groups (P = 0.0628). All-cause mortality was higher in the ICU patients compared with that of the MW patients (22.4% vs. 3.1%, P = 0.0012). Differences exist between ICU and MW patients that develop candiduria with respect to risk factors, and outcomes. Antifungals, including fluconazole and micafungin, were often used inappropriately (ie, asymptomatic patients) in this patient cohort. Efforts to improve healthcare provider awareness of the contemporary recommendations to manage candiduria are necessary to improve patient care and antifungal use.

Comparison of Ketamine- Versus Nonketamine-Based Sedation on Delirium and Coma in the Intensive Care Unit

Background: At this time, there are no studies evaluating the risk of delirium or coma with the use of ketamine in mechanically ventilated adult patients, compared to conventional therapies such as propofol or dexmedetomidine. Objective: The objective of this study was to evaluate the number of days alive without delirium or coma in mechanically ventilated patients in the intensive care unit receiving analgosedation infusions with ketamine versus without ketamine. Methods: This was a retrospective cohort study conducted at an academic medical center in the United States. Consecutive mechanically ventilated adult patients between November 2015 and April 2017 were evaluated. Patients were divided into 2 groups based on the sedative regimen used: ketamine based or nonketamine based. The primary outcome was the number of days alive without delirium or coma. The secondary outcomes were incidence of delirium, incidence of coma, and ventilator-free days at day 28. Results: The study cohort consisted of 79 patients, of which 39 received ketamine- and 40 received nonketamine-based sedation. The number of days alive without delirium or coma was 6 days (interquartile range [IQR]: 2-9 days) with ketamine and 4 days (IQR: 3-7 days) with nonketamine (P = .351). Delirium occurred in 29 (74%) of 39 patients with ketamine and 34 (85%) of 40 patients with nonketamine (P = .274). Coma occurred in 16 (41%) of 39 patients with ketamine and 6 (15%) of 40 patients with nonketamine (P = .013). The median ventilator-free days were 13 days (IQR: 0-23 days) with ketamine and 21 days (0-25 days) with nonketamine (P = .229). Conclusions: Sustained ketamine-based sedation in mechanically ventilated patients may be associated with a higher rate of observed coma but similar delirium- and coma-free days compared nonketamine-based regimens.

Catastrophic circulatory collapse after inadvertent subcutaneous injection of treprostinil

Purpose A case of life‐threatening cardiovascular collapse after inadvertent subcutaneous injection of undiluted treprostinil is reported. Summary A 29‐year‐old, 76‐kg woman with group 1 pulmonary arterial hypertension managed with subcutaneous treprostinil infusion arrived at the emergency department (ED) with headache, nausea, vomiting, and a syncopal episode. Her vital signs were stable on presentation. Admission orders were placed, and the appropriate 3‐mL syringe containing 7.5 mg of treprostinil intended for use with the patient’s home microinfusion pump was sent from inpatient pharmacy to the ED. The order in the electronic medical record stated to administer treprostinil as a subcutaneous injection rather than an infusion. The patient’s nurse transferred the 7.5 mg (3 mL) of undiluted treprostinil to a standard syringe and administered it as a single subcutaneous injection. Within minutes the patient experienced cardiovascular collapse, with a blood pressure nadir of 50/20 mm Hg. Aggressive resuscitation measures were immediately implemented. Initial management included fluids, bolus‐dose vasopressors, multiple high‐dose vasopressor infusions, ondansetron, acetaminophen, and loperamide. Hemodynamic stability was achieved, and vasopressors were discontinued 16 hours after the overdose event. Subcutaneous treprostinil was restarted at a reduced dose 12 hours after the overdose event and was adjusted to the patient’s home dose 24 hours after the initial event. She was discharged in stable condition 30 hours after the overdose event. Conclusion A patient who received an inadvertent overdose of subcutaneous treprostinil experienced cardiovascular collapse requiring aggressive resuscitation measures. Successful management of the patient was largely supportive, including fluids, bolus‐dose vasopressors, multiple high‐dose vasopressor infusions, ondansetron, acetaminophen, and loperamide.

Oral treprostinil in the treatment of pulmonary arterial hypertension

ABSTRACT Introduction: Pulmonary arterial hypertension (PAH) is a rare disease resulting in progressive remodeling of the pulmonary vasculature and eventual right ventricular failure. Despite the development of 13 therapies for PAH since 2000, the use of continuously infused prostanoids retains a special role. Infused medications present unique challenges, and the search for an efficacious oral prostanoid culminated in the FDA approval of oral treprostinil – a first in class oral prostanoid medication approved to treat pulmonary arterial hypertension (PAH). Areas covered: In this discussion, we review the pharmacologic properties of oral treprostinil, and discuss three original major registration studies that resulted in the approval and widespread use of the drug. We also review several post-approval analyses and transitional studies. We discuss administration issues including side effects, transitioning, cost, and comparative analysis with selexipag. Expert opinion: Though the prospects of harnessing the benefits of continuously infused prostanoid therapy in a pill form are tantalizing, the gap in efficacy between oral and infused treatment is substantial. Major side effects and exorbitant cost are further barriers to broad uptake. Competition from oral prostaglandin receptor agonist selexipag challenges the commercial success of oral treprostinil. The long-term viability of oral treprostinil rests largely on the outcome of the long-term event-driven study of the molecule added to background approved ERA or PDE5 inhibitor monotherapy.

1852: CATASTROPHIC CIRCULATORY COLLAPSE FOLLOWING AN INADVERTENT SUBCUTANEOUS INJECTION OF TREPROSTINIL

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) of meropenem in this case was 0.026 L/kg with a Clearance (Cl) of 0.051 mL/ kg/min. Results: This case demonstrates significant alterations in PK in patients receiving either ECMO or CRRT support from both standard drug references and published case reports. These supratherapeutic levels coupled with a significantly reduced clearance highlight the need for therapeutic drug monitoring and individualized, PK-based therapies in critically ill children as both the Vd and Cl may be hard to anticipate in these complex systems.

Higher insulin infusion rate but not 24-h insulin consumption is associated with hypoglycemia in critically ill patients☆

AIMSnTo assess the association between insulin infusion rates, and 24-h insulin consumption on hypoglycemia in the intensive care unit (ICU).nnnMETHODSnThis was a retrospective case-control study, conducted at an academic institution in the United States. Adult patients admitted to the ICU receiving intravenous insulin infusions for blood glucose control were included. Hypoglycemic (blood glucose <70 mg/dL) patients were matched 1:1 with non-hypoglycemic controls based on age, gender, and body mass index. Multivariable conditional logistic regression analyses were conducted to determine the effect of: (1) weight-adjusted insulin infusion rate (units/kg/h), (2) non-weight-adjusted insulin infusion rate (units/h), or (3) 24-h insulin consumption (units/day) on hypoglycemia.nnnRESULTSnA total of 122 patients were included in the study (61 cases, 61 controls). Compared to those patients who received <0.05 units/kg/h, the odds of hypoglycemia was higher in those who received was ≥0.1 units/kg/h (OR 4.57, 95% CI 1.45-14.41, p=0.010). Compared to those patients who received <4 units/h, the odds of hypoglycemia was higher in those who received was ≥8 units/h (4.17, 95% CI 1.18-14.75, p=0.027). The risk of hypoglycemia did not increase with higher 24-h insulin consumption.nnnCONCLUSIONSnHigher insulin infusion rates rather than 24-h insulin consumption may be associated with hypoglycemia in critically ill patients in the ICU.