Substandard and Falsified Medications: A Barrier to Global Health Equity Exemplified in Ecuador.

Medicines have been developed and have become globalized at a pace faster than traditional medical education can keep up. Physicians, pharmacists, nurses, and advanced practice providers learn the names and functions of these medications, but not how they are made and how they get to the bedside. The often economically driven intricacies behind these processes have a dramatic effect on patient care and outcomes. A staggering proportion of medications worldwide are reported to be substandard or falsified. This article explores one country's story of how medication gets to the bedside, describes how this process can go wrong, and outlines what providers can do to work toward the goal of equitable access to quality medications for all.

Pentobarbital Removal During Continuous Venovenous Hemofiltration: Case Report and Review of the Literature.

BACKGROUND:: Renal replacement therapy may enhance the elimination of barbiturates. Pentobarbital clearance during continuous venovenous hemofiltration (CVVH) has not been described previously. We report a patient case involving the measurement of serial pentobarbital levels during CVVH and review relevant literature characterizing extracorporeal pentobarbital elimination. METHODS:: The following is a retrospective report of a previously healthy 26-year-old woman who sustained a severe traumatic brain injury (TBI) and required administration of pentobarbital on hospital day 0 for intracranial pressure (ICP) control. Given concern for interference with the patient's ongoing neurologic assessments, pentobarbital was discontinued on hospital day 4. The patient's hospital course was complicated by acute kidney injury (AKI), requiring initiation of CVVH on hospital day 5. Daily serum pentobarbital levels were obtained during CVVH. RESULTS:: While on CVVH, the patient's estimated pentobarbital clearance ranged from 6 to 44 mL/min and the elimination half-life ranged from 17.7 to 65.9 hours. Based on reductions in pentobarbital clearance during CVVH interruption, the elimination of drug was dependent upon extracorporeal removal in this patient. CVVH facilitated pentobarbital elimination in a manner approaching endogenous clearance in healthy individuals. CONCLUSION:: We report clinically significant pentobarbital removal by CVVH in a patient with severe TBI. Application of CVVH may expedite reliable neurologic assessments and facilitate the application of clinical brain death examination following pentobarbital exposure.

Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban.

PURPOSE OF REVIEW: We summarize the available data related to reversing the anticoagulant effect of the oral direct thrombin and factor Xa inhibitors and provide our opinion on treating patients presenting with severe and life-threatening hemorrhage related to these agents. RECENT FINDINGS: No specific antidotes are currently available for the oral direct thrombin and factor Xa inhibitors but two promising agents are under investigation in phase 3 trials. No data are available on reversing these agents in bleeding patients. Activated charcoal may be effective in reducing factor Xa inhibitor absorption up to 6 h after ingestion. Animal models suggest that unactivated 4-factor prothrombin complex concentrate may be an effective reversal agent. Recent data in warfarin-treated patients suggest that 4-factor prothrombin complex concentrate may provide more rapid and effective hemostasis than fresh frozen plasma. SUMMARY: In the absence of evidence in bleeding patients, animal models and ex-vivo studies suggest administration of coagulant factors in the form of hemostatic agents may be of benefit in reversing the effect of direct thrombin and factor Xa inhibitors. Specific reversal agents and clinical data in patients with hemorrhage remain an unmet need.

Desmopressin improves platelet activity in acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Minimizing hematoma growth in high-risk patients is an attractive strategy to improve outcomes after intracerebral hemorrhage. We tested the hypothesis that desmopressin (DDAVP), which improves hemostasis through the release of von Willebrand factor, improves platelet activity after intracerebral hemorrhage. METHODS: Patients with reduced platelet activity on point-of-care testing alone (5), known aspirin use alone (1), or both (8) received desmopressin 0.4 µg/kg IV. We measured Platelet Function Analyzer-epinephrine (Siemens AG, Germany) and von Willebrand factor antigen from baseline to 1 hour after infusion start and hematoma volume from the diagnostic to a follow-up computed tomographic scan. RESULTS: We enrolled 14 patients with of mean age 66.8±14.6 years, 11 (85%) of whom were white and 8 (57%) were men. Mean Platelet Function Analyzer-epinephrine results shortened from 192±18 seconds pretreatment to 124±15 seconds (P=0.01) 1 hour later, indicating improved plate activity. von Willebrand factor antigen increased from 242±96% to 289±103% activity (P=0.004), indicating the expected increase in von Willebrand factor. Of 7 (50%) patients who received desmopressin within 12 hours of intracerebral hemorrhage symptom onset, changes in hematoma volume were modest, -0.5 (-1.4 to 8.4) mL and only 2 had hematoma growth. One patient had low blood pressure and another had a new fever within 6 hours of desmopressin administration. CONCLUSIONS: Intravenous desmopressin was well tolerated and improved platelet activity after acute intracerebral hemorrhage. Larger studies are needed to determine its potential effects on reducing hematoma growth versus platelet transfusion or placebo. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00961532.

Preadmission statin use does not improve functional outcomes or prevent delayed ischemic events in patients with spontaneous subarachnoid hemorrhage.

STUDY OBJECTIVE: To determine whether preadmission statin use in patients with spontaneous subarachnoid hemorrhage (SAH) is associated with improved functional outcomes and a lower incidence of delayed cerebral ischemic events compared with statin-naive patients with SAH. DESIGN: Prospective cohort study. SETTING: Neurosciences intensive care unit of a tertiary care hospital. PATIENTS: A total of 295 consecutive patients with SAH admitted between March 2006 and May 2013 who had complete medication histories; of these patients, 41 reported taking a statin prior to admission, and 254 were statin naive. INTERVENTION: All patients received clinical management for SAH according to hospital protocol for standard care that included acute statin therapy with enteral pravastatin 40 mg/day on hospital day 1 for up to 21 days. MEASUREMENTS AND MAIN RESULTS: Functional outcomes were assessed by using the modified Rankin Scale (mRS) at 14 days, 28 days, and 3 months. Delayed cerebral ischemia was assessed by using clinical evaluation and computed tomography. Patients taking statins prior to admission were more likely to have a history of diabetes mellitus, hypertension, coronary artery disease, and stroke. No significant difference in favorable neurologic outcome (mRS score 0-3) at 3 months was observed between the preadmission statin group compared with the statin-naive group (56.3% vs 72.4%, p=0.095). In multivariate logistic regression analysis, only age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome. No significant difference in the development of delayed cerebral ischemic events was observed between groups (p=0.48). CONCLUSION: Statin use prior to admission did not improve functional outcomes or prevent delayed cerebral ischemic events in patients with SAH. Age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome at 3 months after discharge.

Introduction to drug pharmacokinetics in the critically ill patient.

Despite regular use of drugs for critically ill patients, overall data are limited regarding the impact of critical illness on pharmacokinetics (PK). Designing safe and effective drug regimens for patients with critical illness requires an understanding of PK. This article reviews general principles of PK, including absorption, distribution, metabolism, and elimination, and how critical illness can influence these parameters. In the area of drug absorption, we discuss the impact of vasopressor use, delayed gastric emptying and feeding tubes, and nutrient interactions. On the topic of drug distribution, we review fluid resuscitation, alterations in plasma protein binding, and tissue perfusion. With drug metabolism, we discuss hepatic enzyme activity, protein binding, and hepatic blood flow. Finally, we review drug elimination in the critically ill patient and discuss the impact of augmented renal clearance and acute kidney injury on drug therapies. In each section, we highlight select literature reviewing the PK impact of these conditions on a drug PK profile and, where appropriate, provide general suggestions for clinicians on how to modify drug regimens to manage PK challenges.