Richard S. Slavik

Indomethacin: a review of its cerebral blood flow effects and potential use for controlling intracranial pressure in traumatic brain injury patients.

Traumatic brain injury (TBI) causes about 75,000 deaths and leaves approximately 200,000 people disabled in USA each year. Brain swelling and increased intracranial pressure (ICP) contribute to this morbidity and mortality. Aggressive management protocols, including ICP control, have been shown to reduce the overall mortality from 50% to 36% following severe head injury. Despite these encouraging results, new and improved pharmacologic strategies to control ICP are required. Indomethacin (IND) is a non-steroidal anti-inflammatory agent with unique effects on cerebral blood flow physiology which may be of benefit in reducing elevated ICP in TBI patients. Data from animal models and randomized, controlled studies with pre-term infants have shown that i.v. IND produces rapid, significant reductions in cerebral blood flow (CBF). Controlled studies of i.v. IND in normal volunteers show a reduction in CBF from 26%-40%. Case series involving severe TBI patients suggest that IND i.v. boluses of 30-50 mg reduce ICP by 37%-52%, reduce CBF by 22%-26%, with a modest 14% increase in cerebral perfusion pressure (CPP). Despite these encouraging results, i.v. IND should only be considered an experimental treatment for control of refractory ICP in TBI patients. Larger, well-designed randomized trials in TBI patients will provide more efficacy and safety data and delineate the effects of IND alone or in combination with other proven, effective, or experimental therapies. Once these concerns have been addressed, larger outcome studies will ultimately be needed to determine the role of IND for ICP control in TBI patients.

Selecting antibacterials for outpatient parenteral antimicrobial therapy: Pharmacokinetic-pharmacodynamic considerations

Some infectious diseases require management with parenteral therapy, although the patient may not need hospitalisation. Consequently, the administration of intravenous antimicrobials in a home or infusion clinic setting has now become commonplace. Outpatient parenteral antimicrobial therapy (OPAT) is considered safe, therapeutically effective and economical. A broad range of infections can be successfully managed with OPAT, although this form of treatment is unnecessary when oral therapy can be used. Many antimicrobials can be employed for OPAT and the choice of agent(s) and regimen should be based upon sound clinical and microbiological evidence. Assessments of cost and convenience should be made subsequent to these primary treatment outcome determinants. When designing an OPAT treatment regimen, the pharmacokinetic and pharmacodynamic characteristics of the individual agents should also be considered.Pharmacokinetics (PK) is the study of the time course of absorption, distribution, metabolism and elimination of drugs (what the body does to the drug). Clinical pharmacokinetic monitoring has been used to overcome the pharmacokinetic variability of antimicrobials and enable individualised dosing regimens that attain desirable antimicrobial serum concentrations. Pharmacodynamics (PD) is the study of the relationship between the serum concentration of a drug and the clinical response observed in a patient (what the drug does to the body). By combining pharmacokinetic properties (peak [Cmax] or trough [Cmin] serum concentrations, half-life, area under the curve) and pharmacodynamic properties (susceptibility results, minimum inhibitory concentrations [MIC] or minimum bactericidal concentrations [MBC], bactericidal or bacteriostatic killing, post-antibiotic effects), unique PK/PD parameters or indices (t > MIC, Cmax/MIC, AUC24/MIC) can be defined.Depending on the killing characteristics of a given class of antimicrobials (concentration-dependent or time-dependent), specific PK/PD parameters may predict in vitro bacterial eradication rates and correlate with in vivo microbiologic and clinical cures. An understanding of these principles will enable the clinician to vary dosing schemes and design individualised dosing regimens to achieve optimal PK/PD parameters and potentially improve patient outcomes. This paper will review basic principles of useful PK/PD parameters for various classes of antimicrobials as they may relate to OPAT.In summary, OPAT has become an important treatment option for the management of infectious diseases in the community setting. To optimise treatment course outcomes, pharmacokinetic and pharmacodynamic properties of the individual agents should be carefully considered when designing OPAT treatment regimens.

Etomidate for rapid sequence intubation in the emergency department: Is adrenal suppression a concern?

Etomidate has become one of the most commonly used induction agents in the United States during emergency department (ED) endotracheal intubation. While etomidate may be popular, concerns have been raised about possible adrenal suppression and subsequent adverse effects. In this paper we critically evaluate the recent literature and perspectives regarding the effect of etomidate on the adrenocortical system.

Corticosteroid Treatment of Severe Community-Acquired Pneumonia

Objective: To assess the evidence for adjunctive corticosteroids for severe community-acquired pneumonia (CAP). Data Sources: MEDLINE (1966–February 2007) and EMBASE (1980–February 2007) were searched to identify English- and French-language publications that evaluated the use of corticosteroids for CAP in adults. Major search terms included community-acquired pneumonia, intensive care unit, steroids, glucocorticoids, and adrenal cortex hormones. Study Selection and Data Extraction: Clinical studies that evaluated the use of corticosteroids for CAP in adults were included. Clinical and surrogate markers of pneumonia were evaluated. Data Synthesis: Severe CAP is associated with an increase in pulmonary and circulatory cytokines such as interleukin-6 and tumor necrosis factor-α that may be associated with higher mortality. Corticosteroids suppress inflammatory reactions and prevent migration of inflammatory cells from the circulation to tissues by suppressing the synthesis of chemokines and cytokines. One observational comparative study and 2 randomized, controlled studies examined the effects of corticosteroid therapy at various doses on endpoints of pulmonary and systemic inflammation and clinical outcomes. One small observational pilot study revealed that methylprednisolone blunted some of the pulmonary and systemic markers of inflammation. One small, randomized, placebo-controlled study revealed that hydrocortisone had no significant effects on markers of pulmonary and systemic inflammation or clinical outcomes. Another small, randomized, placebo-controlled preliminary study with methodological limitations revealed improvements in oxygenation, organ dysfunction score, and markers of inflammation favoring hydrocortisone over placebo. Conclusions: Given the lack of proven benefit on clinically meaningful endpoints and adverse events, corticosteroids cannot be recommended for adjunctive treatment of severe CAP.

Valproic Acid Management of Acute Alcohol Withdrawal

Objective: To review the clinical evidence to determine the efficacy and safety of valproic acid in the management of alcohol withdrawal syndrome (AWS). Data Sources: MEDLINE (1966–February 2006), EMBASE (1980–February 2006), and PubMed (1966–February 2006) searches identified pertinent studies that were conducted in humans and published in English. Key words used for identification of articles included valproic acid, ethanol, alcohol, alcoholism, alcohol withdrawal delirium, alcohol withdrawal seizures, and substance withdrawal syndrome. References of identified articles were manually searched. Study Selection and Data Extraction: All controlled clinical trials that evaluated the use of valproic acid for the management of AWS in humans were included. Data Synthesis: Comparisons were made among various regimens of valproic acid and traditional therapy with benzodiazepine or nonbenzodiazepine agents. Only 2 of 6 trials reported a statistically significant difference in favor of valproic acid on endpoints of AWS. However, these differences were of marginal clinical significance. The number of patients included in these studies did not allow for adequate evaluation of safety. Conclusions: The existing limited efficacy and safety data suggest that valproic acid should not replace conventional therapy or be used as adjunct therapy for management of mild-to-moderate AWS.

A Systematic Review of Randomized Controlled Trials Comparing Hypertonic Sodium Solutions and Mannitol for Traumatic Brain Injury Implications for Emergency Department Management

Objective: To comparatively evaluate hypertonic sodium (HTS) and mannitol in patients following acute traumatic brain injury (TBI) on the outcomes of all-cause mortality, neurological disability, intracranial pressure (ICP) change from baseline, ICP treatment failure, and serious adverse events. Data Sources: PubMed, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and WHO ICTRP (World Health Organization International Clinical Trials Registry Platform) were searched (inception to November 2015) using hypertonic saline solutions, sodium chloride, mannitol, osmotic diuretic, traumatic brain injury, brain injuries, and head injury. Searches were limited to humans. Clinical practice guidelines and bibliographies were reviewed. Study Selection and Data Extraction: Prospective, randomized trials comparing HTS and mannitol in adults (≥16 years) with severe TBI (Glasgow Coma Scale score ≤8) and elevated ICP were included. ICP elevation, ICP reduction, and treatment failure were defined using study definitions. Data Synthesis: Of 326 articles screened, 7 trials enrolling a total of 191 patients met inclusion criteria. Studies were underpowered to detect a significant difference in mortality or neurological outcomes. Due to significant heterogeneity and differences in reporting ICP change from baseline, this outcome was not meta-analyzed. No difference between HTS and mannitol was observed for mean ICP reduction; however, risk of ICP treatment failure favored HTS (risk ratio [RR] = 0.39; 95% CI = 0.18-0.81). Serious adverse events were not reported. Conclusions: Based on limited data, clinically important differences in mortality, neurological outcomes, and ICP reduction were not observed between HTS or mannitol in the management of severe TBI. HTS appears to lead to fewer ICP treatment failures.

Development of Clinical Pharmacy Key Performance Indicators for Hospital Pharmacists Using a Modified Delphi Approach

Background: Key performance indicators (KPIs) are quantifiable measures of quality. There are no published, systematically derived clinical pharmacy KPIs (cpKPIs). Objective: A group of hospital pharmacists aimed to develop national cpKPIs to advance clinical pharmacy practice and improve patient care. Methods: A cpKPI working group established a cpKPI definition, 8 evidence-derived cpKPI critical activity areas, 26 candidate cpKPIs, and 11 cpKPI ideal attributes in addition to 1 overall consensus criterion. Twenty-six clinical pharmacists and hospital pharmacy leaders participated in an internet-based 3-round modified Delphi survey. Panelists rated 26 candidate cpKPIs using 11 cpKPI ideal attributes and 1 overall consensus criterion on a 9-point Likert scale. A meeting was facilitated between rounds 2 and 3 to debate the merits and wording of candidate cpKPIs. Consensus was reached if 75% or more of panelists assigned a score of 7 to 9 on the consensus criterion during the third Delphi round. Results: All panelists completed the 3 Delphi rounds, and 25/26 (96%) attended the meeting. Eight candidate cpKPIs met the consensus definition: (1) performing admission medication reconciliation (including best-possible medication history), (2) participating in interprofessional patient care rounds, (3) completing pharmaceutical care plans, (4) resolving drug therapy problems, (5) providing in-person disease and medication education to patients, (6) providing discharge patient medication education, (7) performing discharge medication reconciliation, and (8) providing bundled, proactive direct patient care activities. Conclusions: A Delphi panel of hospital pharmacists was successful in determining 8 consensus cpKPIs. Measurement and assessment of these cpKPIs will serve to advance clinical pharmacy practice and improve patient care.

A critical appraisal of the quality of critical care pharmacotherapy clinical practice guidelines and their strength of recommendations

ObjectiveClinical practice guideline (CPG) quality assessment is important before applying their recommendations. Determining whether recommendation strength is consistent with supporting quality of evidence is also essential. We aimed to determine quality of critical care pharmacotherapy CPGs and to assess whether high quality evidence supports strong pharmacotherapy recommendations.MethodsMEDLINE (1966–February 2008), EMBASE (1980–February 2008), National Guideline Clearinghouse (February 2008) and personal files were searched to identify CPGs. Four appraisers evaluated each guideline using the appraisal of guidelines, research and evaluation (AGREE) instrument. AGREE assesses 23 items in six domains that include scope/purpose, stakeholder involvement, rigor of development, clarity, applicability and editorial independence. Standardized domain scores (0–100%) were determined to decide whether to recommend a guideline for use. One appraiser extracted strong pharmacotherapy recommendations and supporting evidence quality.ResultsTwenty-four CPGs were included. Standardized domain scores were clarity [69% (95% confidence interval (CI) 62–76%)], scope/purpose [62% (95% CI 55–68%)], rigor of development [51% (95% CI 42–60%)], editorial independence [39% (95% CI 26–52%)], stakeholder involvement [32% (95% CI 26–37%)] and applicability [19% (95% CI 12–26%)]. The proportion of guidelines that could be strongly recommended, recommended with alterations and not recommended was 25, 37.5 and 37.5%, respectively. High quality evidence supported 36% of strong pharmacotherapy recommendations.ConclusionVariation in AGREE domain scores explain why one-third of critical care pharmacotherapy CPGs cannot be recommended. Only one-third of strong pharmacotherapy recommendations were supported by high quality evidence. We recommend appraisal of guideline quality and the caliber of supporting evidence prior to applying recommendations.

Update on cardiopulmonary resuscitation and emergency cardiovascular care guidelines

PURPOSE The key changes included in the 2005 cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC) guidelines are reviewed. Advances since publication of the current guidelines are also discussed. SUMMARY The 2005 CPR and ECC guidelines include several key changes from the previous version published in 2000. The new guidelines place an increased emphasis on chest compressions and recommend a compression:ventilation (C:V) ratio of 30:2. Current knowledge on defibrillation has also been incorporated by recommending that Emergency Medical Service (EMS) rescuers give two minutes of CPR before defibrillation when the response interval is greater than four to five minutes and EMS responders did not witness the arrest. Another major change is the recommendation for a single shock to be administered followed immediately by CPR with no check of the cardiac rhythm until two minutes of CPR has been performed postdefibrillation. The 2005 guidelines recommend that an automated external defibrillator should be implemented in public locations where there is a relatively high likelihood of witnessed cardiac arrest. In addition, the most recent guidelines highlight the shift from primary-rhythm-based therapies and resuscitation to a focus on neurologic outcomes. CONCLUSION Several evidence-based changes were included in the 2005 CPR and ECC guidelines, including a C:V ratio of 30:2 and mitigation of hands-off time, early defibrillation, administration of a single shock versus a three-shock sequence, use of public-access defibrillators, and a shift from primary-rhythm-based therapies to a focus on neurologic outcomes.

Intravenous amiodarone for conversion of atrial fibrillation: misled by meta-analysis?

Therapeutic goals for atrial fibrillation (AF) include ventricular rate control, stroke prevention, conversion to normal sinus rhythm, and maintenance of normal sinus rhythm. The optimal strategy of rate versus rhythm control for acute management of patients with AF is a continuing debate. However, selected patients may require acute treatment with antiarrhythmic agents for conversion of symptomatic AF episodes to normal sinus rhythm. Recently published randomized controlled trials, qualitative systematic reviews, meta‐analyses, and evidence‐based international consensus guidelines have addressed the controversy regarding acute conversion of AF using antiarrhythmic therapy. Although meta‐analyses often provide the highest level of evidence, the validity and application of their results are based on the quality of their methodology and accuracy of reporting. Authors of the most recent meta‐analysis of amiodarone for conversion of AF state that the drug is effective and relatively rapid acting in converting AF to normal sinus rhythm in a wide range of patients, and they recommend it as a first‐line drug. We feel that these conclusions are overstated and potentially misleading due to methodologic limitations of the analysis. The results of this meta‐analysis and others concerning acute conversion of AF should be viewed as hypothesis generating and not the definitive answer to this question. Ultimately, well‐designed, adequately powered, randomized placebo‐ or rate‐controlled trials are needed in specific patient populations with AF to determine the absolute benefit of intravenous amiodarone for conversion of AF to normal sinus rhythm. Until more data are available, intravenous amiodarone cannot be promoted as a first‐line agent for this purpose.