Minimizing Shivering During Targeted Normothermia: Comparison Between Novel Transnasal and Surface Temperature-Modulating Devices.

BACKGROUND: Shivering is a common adverse effect of achieving and maintaining normothermia in neurocritical care patients. We compared the burden of shivering and shivering-related interventions between a novel transnasal temperature-modulating device (tnTMD) and surface cooling temperature-modulating devices (sTMDs) during the first 24 h of targeted normothermia in mechanically ventilated febrile neurocritical care patients. METHODS: This is a case-control study controlling for factors that impact shiver burden: age, sex, body surface area. All patients underwent transnasal cooling (CoolStat, KeyTech, Inc.) as part of an ongoing multicenter clinical trial (NCT03360656). Patients undergoing treatment with sTMDs were selected from consecutively treated patients during the same time period. Data collected included the following: core body temperature (every 2 h), bedside shivering assessment scale (BSAS) score (every 2 h), and administration of antishivering medication for a BSAS score > 1. Time to normothermia (≤ 37.5 °C), as well as temperature burden > 37.5 °C (°C × h), were compared between groups using Student's t-test for mean differences. The proportion of patients requiring interventions, as well as the number of interventions per patient, was compared using the χ2 test. Significance was determined based on a p value < 0.05. RESULTS: There were 10 tnTMD patients and 30 sTMD patients included in the analysis (mean age: 62 ± 4, 30% women, body surface area = 1.97 ± 0.25). There were no differences between groups in temperature at cooling initiation (tnTMD: 38.5 ± 0.2 °C vs. sTMD: 38.7 ± 0.5 °C, p = 0.3), time to ≤ 37.5 °C (tnTMD: 1.8 ± 1.5 h vs. sTMD: 2.9 ± 1.4 h, p = 0.1), or temperature burden > 37.5 (tnTMD: - 0.4 ± 1.13 °C × h vs. sTMD median [IQR]: - 0.57 ± 0.58 °C × h, p = 0.67). The number of tnTMD patients who received pharmacologic shivering interventions was lower than the number of controls (20 vs. 67%, p = 0.01). tnTMD patients also had fewer shivering interventions per patient (0 [range: 0-3] vs. 4 [range: 0-23], p < 0.001). CONCLUSIONS: A transnasal cooling approach achieved similar time to normothermia and temperature burden with less shivering than surface cooling. This approach may be a feasible option to consider for mechanically ventilated febrile neurocritical care patients.

Overlapping Physiologic Signs of Sepsis and Paroxysmal Sympathetic Hyperactivity After Traumatic Brain Injury: Exploring A Clinical Conundrum.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) occurs in a subset of patients with traumatic brain injury (TBI) and is associated with worse outcomes. Sepsis is also associated with worse outcomes after TBI and shares several physiologic features with PSH, potentially creating diagnostic confusion and suboptimal management of each. This is the first study to directly investigate the interaction between PSH and infection using robust diagnostic criteria. METHODS: We performed a retrospective cohort study of patients with TBI admitted to a level I trauma center intensive care unit with hospital length of stay of at least 2 weeks. From January 2016 to July 2018, 77 patients diagnosed with PSH were 1:1 matched by age and Glasgow Coma Scale to 77 patients without PSH. Trauma infectious diseases subspecialists prospectively documented assessments corroborating diagnoses of infection. Extracted data including incidence, timing, classification, and anatomical source of infections were compared according to PSH diagnosis. We also evaluated daily PSH clinical feature severity scores and systemic inflammatory response syndrome (SIRS) criteria and compared values for patients with and without confirmed infection, stratified by PSH diagnosis. RESULTS: During the first 2 weeks of hospitalization, there were no differences in rates of suspected (62%) nor confirmed (48%) infection between patients with PSH and controls. Specific treatments for PSH were initiated on median hospital day 7 and for confirmed infections on median hospital day 8. SIRS criteria could identify infection only in patients who were not diagnosed with PSH. CONCLUSIONS: In the presence of brain injury-induced autonomic nervous system dysregulation, the initiation and continuation of antimicrobial therapy is a challenging clinical decision, as standard physiologic markers of sepsis do not distinguish infected from noninfected patients with PSH, and these entities often present around the same time. Clinicians should be aware that PSH is a potential driver of SIRS, and familiarity with its diagnostic criteria as proposed by the PSH assessment measure is important. Management by a multidisciplinary team attentive to these issues may reduce rates of inappropriate antibiotic usage and misdiagnoses.

Development and Use of an Ex-Vivo In-Vivo Correlation to Predict Antiepileptic Drug Clearance in Patients Undergoing Continuous Renal Replacement Therapy.

OBJECTIVES: Results from previous ex-vivo continuous renal replacement therapy (CRRT) models have successfully demonstrated similar extraction coefficients (EC) identified from in-vivo clinical trials. The objectives of this study are to develop an ex-vivo in-vivo correlation (EVIVC) model to predict drug clearance for commonly used antiepileptics and to evaluate similarity in drug extraction across different CRRT modalities to extrapolate dosing recommendations. METHODS: Levetiracetam, lacosamide, and phenytoin CRRT clearance was evaluated using the Prismaflex CRRT system and M150 hemodiafilters using an albumin containing normal saline (ALB-NS) vehicle with 3 different albumin concentrations (2 g/dL, 3 g/dL, and 4 g/dL) and a human plasma vehicle at 3 different effluent flow rates (1 L/hr, 2 L/hr, and 3 L/hr). Blood and effluent/dialysate concentrations were collected after circuit priming. ECs were calculated for each drug, modality, vehicle, and experimental arm combination. RESULTS: The calculated average EC for levetiracetam and lacosamide was approximated to the fraction unbound from plasma protein. Human plasma and ALB-NS vehicles demonstrated adequate prediction of in-vivo CRRT clearance. Geometric mean ratios indicated similarity in extraction coefficients when comparing between hemofiltration and hemodiafiltration modalities and between filtration and dialysis modalities at effluent flow rates ≤ 2L/hr. Evaluation of phenytoin provided inconsistent findings with regards to extraction coefficient similarity across different CRRT modalities. CONCLUSION: The findings indicate that an ex-vivo study can be used as a surrogate to predict in-vivo levetiracetam and lacosamide clearance in patients receiving CRRT.

Admission Features Associated With Paroxysmal Sympathetic Hyperactivity After Traumatic Brain Injury: A Case-Control Study.

OBJECTIVES: Paroxysmal sympathetic hyperactivity occurs in a subset of critically ill traumatic brain injury patients and has been associated with worse outcomes after traumatic brain injury. The goal of this study was to identify admission risk factors for the development of paroxysmal sympathetic hyperactivity in traumatic brain injury patients. DESIGN: Retrospective case-control study of age- and Glasgow Coma Scale-matched traumatic brain injury patients. SETTING: Neurotrauma ICU at the R. Adams Cowley Shock Trauma Center of the University of Maryland Medical System, January 2016 to July 2018. PATIENTS: Critically ill adult traumatic brain injury patients who underwent inpatient monitoring for at least 14 days were included. Cases were identified based on treatment for paroxysmal sympathetic hyperactivity with institutional first-line therapies and were confirmed by retrospective tabulation of established paroxysmal sympathetic hyperactivity diagnostic and severity criteria. Cases were matched 1:1 by age and Glasgow Coma Scale to nonparoxysmal sympathetic hyperactivity traumatic brain injury controls, yielding 77 patients in each group. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Admission characteristics independently predictive of paroxysmal sympathetic hyperactivity included male sex, higher admission systolic blood pressure, and initial CT evidence of diffuse axonal injury, intraventricular hemorrhage/subarachnoid hemorrhage, complete cisternal effacement, and absence of contusion. Paroxysmal sympathetic hyperactivity cases demonstrated significantly worse neurologic outcomes upon hospital discharge despite being matched for injury severity at admission. CONCLUSIONS: Several anatomical, epidemiologic, and physiologic risk factors for clinically relevant paroxysmal sympathetic hyperactivity can be identified on ICU admission. These features help characterize paroxysmal sympathetic hyperactivity as a clinical-pathophysiologic phenotype associated with worse outcomes after traumatic brain injury.

A prospective, real-world, clinical pharmacokinetic study to inform lacosamide dosing in critically ill patients undergoing continuous venovenous haemofiltration (PADRE-02).

AIMS: Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH). METHODS: Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre-filter, post-filter and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling time points post-administration. Patient-specific flow rates and clinical measures were also collected simultaneously at the time of sampling. Plasma concentrations were measured using a validated high-performance liquid chromatography with ultraviolet radiation detection (HPLC-UV) bioanalytical method. Non-compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide. RESULTS: The observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5-12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was -2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate-based dosing regimens could be used to individualize lacosamide therapeutics. CONCLUSIONS: CVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.

Pain Trajectories Following Subarachnoid Hemorrhage are Associated with Continued Opioid Use at Outpatient Follow-up.

BACKGROUND: Subarachnoid hemorrhage (SAH) is characterized by the worst headache of life and associated with long-term opioid use. Discrete pain trajectories predict chronic opioid use following other etiologies of acute pain, but it is unknown whether they exist following SAH. If discrete pain trajectories following SAH exist, it is uncertain whether they predict long-term opioid use. We sought to characterize pain trajectories after SAH and determine whether they are associated with persistent opioid use. METHODS: We reviewed pain scores from patients admitted to a single tertiary care center for SAH from November 2015 to September 2019. Group-based trajectory modeling identified discrete pain trajectories during hospitalization. We compared outcomes across trajectory groups using χ2 and Kruskal-Wallis tests. Multivariable regression determined whether trajectory group membership was an independent predictor of long-term opioid use, defined as continued use at outpatient follow-up. RESULTS: We identified five discrete pain trajectories among 305 patients. Group 1 remained pain free. Group 2 reported low scores with intermittent spikes and slight increase over time. Group 3 noted increasing pain severity through day 7 with mild improvement until day 14. Group 4 experienced maximum pain with steady decrement over time. Group 5 reported moderate pain with subtle improvement. In multivariable analysis, trajectory groups 3 (odds ratio [OR] 3.5; 95% confidence interval [CI] 1.5-8.3) and 5 (OR 8.0; 95% CI 3.1-21.1), history of depression (OR 3.6; 95% CI 1.3-10.0) and racial/ethnic minority (OR 2.3; 95% CI 1.3-4.1) were associated with continued opioid use at follow-up (median 62 days following admission, interquartile range 48-96). CONCLUSIONS: Discrete pain trajectories following SAH exist. Recognition of pain trajectories may help identify those at risk for long-term opioid use.

Triage of Patients with Intracerebral Hemorrhage to Comprehensive Versus Primary Stroke Centers.

OBJECTIVES: The management of patients admitted with intracerebral hemorrhage (ICH) mostly occurs in an ICU. While guidelines recommend initial treatment of these patients in a neurocritical care or stroke unit, there is limited data on which patients would benefit most from transfer to a comprehensive stroke center where on-site neurosurgical coverage is available 24/7. As neurocritical units become more common in primary stroke centers, it is important to determine which patients are most likely to require neurosurgical intervention and transfer to comprehensive stroke centers. MATERIALS AND METHODS: This is a retrospective observational cohort study conducted at an academic comprehensive stroke center in the United States. Four-hundred-fifty-nine consecutive patients transferred or directly admitted to the neurocritical care unit from 2016-2018 with the primary diagnosis of ICH were included. Univariate statistics and multivariate regression were used to identify clinical characteristics associated with neurosurgical intervention, defined as undergoing craniotomy, ventriculostomy, or endovascular embolization of an arteriovenous malformation (AVM). RESULTS: The following variables were associated with neurosurgical intervention in multivariate analysis: age (OR 0.38, 95% CI 0.27-0.55), admission Glasgow Coma Scale (OR 0.29, 95% CI 0.18-0.48), the presence of intraventricular hemorrhage (OR 2.82, CI 1.71-4.65), infratentorial location of ICH (OR 2.28, 95% CI 1.20-4.31), previous antiplatelet use (OR 2.04, 95% CI 1.24-3.34), and an AVM indicated on CT Angiogram (OR 2.59, 95% CI 1.19-5.63) were independently associated with the need for neurosurgical intervention. This was translated into a scoring system to help make quick triage decisions, with high sensitivity (99%, 95% CI 97-99%) and negative predictive value (98%, 95% CI 89-99%). CONCLUSIONS: Using previously well described predictors of severity in ICH patients, we were able to develop a scoring system to predict the need for neurosurgical intervention with high sensitivity and negative predictive value.

Collaborative Management Strategies for Drug Shortages in Neurocritical Care.

Drug shortages have become all too familiar in the health care environment, with over 200 drugs currently on shortage. In the wake of Hurricane Maria in September 2017, hospitals across the USA had to quickly and creatively adjust medication preparation and administration techniques in light of decreased availability of intravenous (IV) bags used for compounding a vast amount of medications. Amino acid preparations, essential for compounding parenteral nutrition, were also directly impacted by the hurricane. Upon realization of the impending drug shortages, hospitals resorted to alternative methods of drug administration, such as IV push routes, formulary substitutions, or alternative drug therapies in hopes of preserving the small supply of IV bags available and prioritizing them for them most critical needs. In some cases, alternative drug therapies were required, which increased the risk of medication errors due to the use of less-familiar treatment options. Clinical pharmacists rounding with medical teams provided essential, patient-specific drug regimen alternatives to help preserve a dwindling supply while ensuring use in the most critical cases. Drug shortages also frequently occur in the setting of manufacturing delays or discontinuation and drug recalls, with potential to negatively impact patient care. The seriousness of the drug shortage crisis reached public attention by December 2017, when political and pharmacy organizations called for response to the national drug shortage crisis. In this article, we review institutional mitigation strategies in response to drug shortages and discuss downstream effects of these shortages, focusing on medications commonly prescribed in neurocritical care patients.

Control of Shivering During Targeted Temperature Management.

Targeted temperature management (TTM) is used frequently in patients with a variety of diseases, especially those who have experienced brain injury and/or cardiac arrest. Shivering is one of the main adverse effects of TTM that can often limit its implementation and efficacy. Shivering is the body's natural response to hypothermia and its deleterious effects can negate the benefits of TTM. The purpose of this article is to provide an overview of TTM strategies and shivering management.

Development and validation of a HPLC-UV assay for quantification of levetiracetam concentrations in critically ill patients undergoing continuous renal replacement therapy.

Limited clinical data exists on the effects of continuous renal replacement therapy (CRRT) on drug pharmacokinetics. A high-performance liquid chromatography with ultraviolet detection method was developed and validated to determine levetiracetam concentrations in human plasma and CRRT effluent samples. Five hundred microliters of human plasma and 250 µL effluent samples were used to quantify levetiracetam. Plasma samples were purified by protein precipitation, evaporated under nitrogen gas at room temperature and reconstituted in 50 mm potassium dihydrogen phosphate buffer (pH of 4.5). Reverse-phase chromatographic separation was achieved within 20 min using a mobile phase eluting gradient of 50 mm potassium dihydrogen phosphate and acetonitrile. UV detection was set at 195 nm. The calibration curve was found to be linear over the range of 2-80µg/mL. Inter- and intra-day precisions were < 8% for both plasma and effluent samples. The accuracy was determined to be within -12-10% of nominal concentrations. The method was selective and sensitive with a lower limit of quantification of 2 µg/mL. Overall recovery of levetiracetam from plasma was ~100%. The validated assay was successfully applied in a pharmacokinetic study to determine potential dose adjustments in patients undergoing CRRT and receiving levetiracetam.

Drug Class Combination-Associated Acute Kidney Injury.

OBJECTIVE: To evaluate the quality of available evidence of drug class combinations and their association with the development of acute kidney injury (AKI). DATA SOURCES: A search of MEDLINE and Embase databases was completed using the following terms: "risk factor AND (acute kidney injury or acute kidney failure) AND (drug or medication)." STUDY SELECTION AND DATA EXTRACTION: Inclusion criteria were the following: English language, full-text availability, and at least 1 drug-combination. Each citation was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. The literature was evaluated using the quality of evidence component of GRADE. No standardized definition of AKI was applied throughout.. DATA SYNTHESIS: Out of 2139 total citations, 151 were assessed for full-text review, with 121 citations (6%) meeting inclusion criteria, producing76 unique drug class combinations. Overall, 56 combinations (73.7%) were considered very low quality; 12 (15.8%) were considered low quality. There were 8 (10.5%) of moderate quality, and no combination was considered high quality. 58 (76%) combinations that had a single citation,with a mean of 1.6 citations per drug class combination. The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics was reported in 10 citations, the largest number of citations. CONCLUSIONS: Our study demonstrates a lack of well-designed studies addressing drug class combination-associated AKI. The combination of NSAIDs and diuretics with or without additional renin-angiotensin aldosterone agents had the strongest level of evidence. Despite limitations, the information included in this review may result in additional scrutiny about combining certain individual nephrotoxic drugs.

Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome.

BACKGROUND: Adjunctive medications to manage alcohol withdrawal syndrome (AWS) in patients not adequately responding to escalating doses of benzodiazepines (BZDs) are limited. The use of the N-methyl-d-aspartate antagonist ketamine, may serve as an effective adjunct agent; however, no published data currently exist for this practice. OBJECTIVE: To determine the safety and efficacy of adjunct ketamine for management of AWS. METHODS: The study was a retrospective review of adult patients from April 2011 to March 2014 who were administered ketamine specifically for management of AWS. Outcomes included changes in BZD requirements and ketamine-related adverse reactions. RESULTS: Of 235 patients screened, 23 patients met study eligibility. Ketamine was initiated primarily with toxicology consultation for significant BZD requirements or delirium tremens. The mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively. Mean initial infusion dose and median total infusion rate during therapy were 0.21 and 0.20 mg/kg/h, respectively. There was no change in sedation or alcohol withdrawal scores in patients within 6 hours of ketamine initiation. The median change in BZD requirements at 12 and 24 hours post-ketamine initiation were -40.0 and -13.3 mg, respectively. The mean time to AWS resolution was 5.6 days. There was one documented adverse reaction of oversedation, requiring dose reduction. CONCLUSIONS: Ketamine appears to reduce BZD requirements and is well tolerated at low doses. Prospective dose range evaluations in the management of AWS would be helpful in determining its place as an adjunctive agent.

Electrolyte considerations in targeted temperature management.

PURPOSE: Targeted temperature management (TTM), including normothermia and therapeutic hypothermia, is used primarily for comatose patients with return of spontaneous circulation after cardiac arrest or following neurological injury. Despite the potential benefits of TTM, risks associated with physiological alterations, including electrolyte shifts, may require intervention. SUMMARY: This review describes the normal physiological balance of electrolytes and temperature-related alterations as well as the impact of derangements on patient outcomes, providing general recommendations for repletion and monitoring of key electrolytes, including potassium, phosphate, and magnesium. CONCLUSION: Frequent monitoring and consideration of patient variables such as renal function and other risk factors for adverse effects are important areas of awareness for clinicians caring for patients undergoing TTM.

Adjunctive virtual reality pain relief after traumatic injury: a proof-of-concept within-person randomized trial.

ABSTRACT: In this study, we hypothesized that immersive virtual reality (VR) environments may reduce pain in patients with acute traumatic injuries, including traumatic brain injuries. We performed a randomized within-subject study in patients hospitalized with acute traumatic injuries, including traumatic brain injury with moderate pain (numeric pain score ≥3 of 10). We compared 3 conditions: (1) an immersive VR environment (VR Blu), (2) a content control with the identical environment delivered through nonimmersive tablet computer (Tablet Blu), and (3) a second control composed of donning VR headgear without content to control for placebo effects and sensory deprivation (VR Blank). We enrolled 60 patients, and 48 patients completed all 3 conditions. Objective and subjective data were analyzed using linear mixed-effects models. Controlling for demographics, baseline pain, and injury severity, we found differences by conditions in relieving pain (F 2,75.43 = 3.32, P = 0.042). VR Blu pain reduction was greater than Tablet Blu (-0.92 vs -0.16, P = 0.043), but VR Blu pain reduction was similar to VR Blank (-0.92 vs -1.24, P = 0.241). VR Blu was perceived as most effective by patients for pain reduction (F 2,66.84 = 16.28, P < 0.001), and changes in measures of parasympathetic activity including heart rate variability (F 2,55.511 = 7.87, P < 0.001) and pupillary maximum constriction velocity (F 2,61.41 = 3.50, 1-tailed P = 0.038) echoed these effects. There were no effects on opioid usage. These findings outlined a potential clinical benefit for mollifying pain related to traumatic injuries.

Steroids Provide Temporary Improvement of Refractory Pain Following Subarachnoid Hemorrhage.

Introduction: Evidence for optimal analgesia following subarachnoid hemorrhage (SAH) is limited. Steroid therapy for pain refractory to standard regimens is common despite lack of evidence for its efficacy. We sought to determine if steroids reduced pain or utilization of other analgesics when given for refractory headache following SAH. Methods: We performed a retrospective within-subjects cohort study of SAH patients who received steroids for refractory headache. We compared daily pain scores, total daily opioid, and acetaminophen doses before, during, and after steroids. Repeated measures were analyzed with a multivariable general linear model and generalized estimating equations. Results: Included 52 patients treated with dexamethasone following SAH, of whom 11 received a second course, increasing total to 63 treatment epochs. Mean pain score on the first day of therapy was 7.92 (standard error of the mean [SEM] .37) and decreased to 6.68 (SEM .36) on the second day before quickly returning to baseline levels, 7.36 (SEM .33), following completion of treatment. Total daily analgesics mirrored this trend. Mean total opioid and acetaminophen doses on days one and two and two days after treatment were 47.83mg (SEM 6.22) and 1848mg (SEM 170.66), 34.24mg (SEM 5.12) and 1809mg (SEM 150.28), and 46.38mg (SEM 11.64) and 1833mg (SEM 174.23), respectively. Response to therapy was associated with older age, decreasing acetaminophen dosing, and longer duration of steroids. Hyperglycemia and sleep disturbance/delirium effected 28.6% and 55.6% of cases, respectively. Conclusion: Steroid therapy for refractory pain in SAH patients may have modest, transient effects in select patients.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Analgosedation: a paradigm shift in intensive care unit sedation practice.

OBJECTIVE: To critically evaluate the use of analgosedation in the management of agitation in critically ill mechanically ventilated patients. DATA SOURCES: Literature was accessed through MEDLINE (1948-November 2011) and Cochrane Library (2011, issue 1) using the terms analgosedation, analgosedation, or analgesia-based sedation alone or in combination with intensive care unit or critically ill. Reference lists of related publications were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English were evaluated. Randomized controlled trials examining critically ill mechanically ventilated patients older than 18 years were included. DATA SYNTHESIS: Limitations of current sedation practices include serious adverse drug events, prolonged mechanical ventilation time, and intensive care unit (ICU) length of stay. Studies have demonstrated that analgosedation, a strategy that manages patient pain and discomfort first, before providing sedative therapy, results in improved patient outcomes compared to standard sedative-hypnotic regimens. Nine randomized controlled trials comparing remifentanil-based analgosedation to other commonly used agents (fentanyl, midazolam, morphine, and propofol) for ICU sedation and 1 trial comparing morphine to daily sedation interruption with propofol or midazolam were reviewed. Remifentanil is an ideal agent for analgosedation due to its easy titratability and organ-independent metabolism. When compared to sedative-hypnotic regimens, remifentanil-based regimens were associated with shorter duration of mechanical ventilation, more rapid weaning from the ventilator, and shorter ICU length of stay. Compared to fentanyl-based regimens, remifentanil had similar efficacy with the exception of increased pain requirements upon remifentanil discontinuation. Analgosedation was well tolerated, with no significant differences in hemodynamic stability compared to sedative-hypnotic regimens. CONCLUSIONS: Analgosedation is an efficacious and well-tolerated approach to management of ICU sedation with improved patient outcomes compared to sedative-hypnotic approaches. Additional well-designed trials are warranted to clarify the role of analgosedation in the management of ICU sedation, including trials with nonopioid analgesics.