qSOFA does not predict bacteremia in patients with severe manifestations of sepsis.

BACKGROUND: Bloodstream infections in septic patients may be missed due to preceding antibiotic therapy prior to obtaining blood cultures. We leveraged the FABLED cohort study to determine if the quick Sequential Organ Failure Assessment (qSOFA) score could reliably identify patients at higher risk of bacteremia in patients who may have false negative blood cultures due to previously administered antibiotic therapy. METHODS: We conducted a multi-centre diagnostic study among adult patients with severe manifestations of sepsis. Patients were enrolled in one of seven participating centres between November 2013 and September 2018. All patients from the FABLED cohort had two sets of blood cultures drawn prior to the administration of antimicrobial therapy, as well as additional blood cultures within 4 hours of treatment initiation. Participants were categorized according to qSOFA score, with a score ≥2 being considered positive. RESULTS: Among 325 patients with severe manifestations of sepsis, a positive qSOFA score (defined as a score ≥2) on admission was 58% sensitive (95% CI 48% to 67%) and 41% specific (95% CI 34% to 48%) for predicting bacteremia. Among patients with negative post-antimicrobial blood cultures, a positive qSOFA score was 57% sensitive (95% CI 42% to 70%) and 42% specific (95% CI 35% to 49%) to detect patients who were originally bacteremic prior to the initiation of therapy. CONCLUSIONS: Our results suggest that the qSOFA score cannot be used to identify patients at risk for occult bacteremia due to the administration of antibiotics pre-blood culture.

HISTORIQUE: Les infections sanguines peuvent rester non diagnostiquées chez les patients septiques avant l'obtention des cultures sanguines, en raison d'une antibiothérapie antérieure. Les chercheurs ont puisé dans l'étude de cohorte FABLED pour déterminer si le score rapide de l'évaluation séquentielle d'insuffisance des organes (Sequential Organ Failure Assessment, qSOFA) pourrait dépister les patients à plus haut risque de bactériémie avec fiabilité, malgré la possibilité de cultures sanguines faussement négatives en raison d'une antibiothérapie antérieure. MÉTHODOLOGIE: Les chercheurs ont réalisé une étude diagnostique multicentrique chez des patients adultes ayant de graves manifestations de sepsis. Les patients ont été inscrits dans l'un des sept centres participants entre novembre 2013 et septembre 2018. Tous les patients de l'étude de cohorte FABLED avaient subi deux séries de cultures sanguines avant de recevoir une thérapie antimicrobienne, de même qu'une autre série de cultures sanguines dans les quatre heures suivant le début du traitement. Les participants ont été classés en fonction de leur score de qSOFA, un score d'au moins 2 étant considéré comme positif. RÉSULTATS: Chez les 325 patients ayant de graves manifestations de sepsis, un score de qSOFA positif (défini comme un score d'au moins 2) à l'admission était sensible à 58 % (IC à 95 %, 48 % à 67 %) et spécifique à 41 % (IC à 95 %, 34 % à 48 %) pour prédire la bactériémie. Chez les patients dont les cultures sanguines étaient négatives après la prise d'antimicrobiens, un score de qSOFA positif était sensible à 57 % (IC à 95 %, 42 % à 70 %) et spécifique à 42 % (IC à 95 %, 35 % à 49 %) pour dépister les patients atteints d'une bactériémie avant le début du traitement. CONCLUSIONS: Selon les résultats, le score de qSOFA ne peut pas être utilisé pour dépister les patients à risque de bactériémie occulte à cause de l'administration d'antibiotiques avant la culture sanguine.

Neither Blood Culture Positivity nor Time to Positivity Is Associated With Mortality Among Patients Presenting With Severe Manifestations of Sepsis: The FABLED Cohort Study.

BACKGROUND: Sepsis is a leading cause of morbidity, mortality, and health care costs worldwide. METHODS: We conducted a multicenter, prospective cohort study evaluating the yield of blood cultures drawn before and after empiric antimicrobial administration among adults presenting to the emergency department with severe manifestations of sepsis. Enrolled patients who had the requisite blood cultures drawn were followed for 90 days. We explored the independent association between blood culture positivity and its time to positivity in relation to 90-day mortality. RESULTS: Three hundred twenty-five participants were enrolled; 90-day mortality among the 315 subjects followed up was 25.4% (80/315). Mortality was associated with age (mean age [standard deviation] in those who died was 72.5 [15.8] compared with 62.9 [17.7] years among survivors; P < .0001), greater Charlson Comorbidity Index (2 [interquartile range {IQR}, 1-3] vs 1 [IQR, 0-3]; P = .008), dementia (13/80 [16.2%] vs 18/235 [7.7%]; P = .03), cancer (27/80 [33.8%] vs 47/235 [20.0%]; P = .015), positive quick Sequential Organ Failure Assessment score (57/80 [71.2%] vs 129/235 [54.9%]; P = .009), and normal white blood cell count (25/80 [31.2%] vs 42/235 [17.9%]; P = .02). The presence of bacteremia, persistent bacteremia after antimicrobial infusion, and shorter time to blood culture positivity were not associated with mortality. Neither the source of infection nor pathogen affected mortality. CONCLUSIONS: Although severe sepsis is an inflammatory condition triggered by infection, its 90-day survival is not influenced by blood culture positivity nor its time to positivity. CLINICAL TRIALS REGISTRATION: NCT01867905.

Management of delirium in a medical and surgical intensive care unit.

WHAT IS KNOWN AND OBJECTIVE: Delirium has been associated with increased mortality and prolonged hospital length of stay among critical care patients. Furthermore, treatment of delirium remains variable amongst clinicians due to limited evidence. The objective of this study was to determine the local incidence of delirium and to characterize the effectiveness and safety of pharmacological therapy used to treat delirium. METHODS: A retrospective chart review evaluated patients diagnosed with delirium (Intensive Care Delirium Screening Checklist score ≥4) and requiring mechanical ventilation for ≥48 hours from January 2016 to June 2017. The primary outcomes included comparison of resolution, the time to first resolution and recurrence of delirium in patients prescribed pharmacological and/or pre-emptive therapy versus those who did not. Secondary outcomes included incidence of adverse effects of drug therapy and delirium attributable adverse events. RESULTS AND DISCUSSION: The incidence of delirium during our defined study period was 49%. Of the 178 patients included in the study, 136 (76%) received drug therapy for delirium. Agents used for treatment of delirium included dexmedetomidine (n = 90 [66%]), haloperidol (n = 77 [57%]), and quetiapine (n = 74 [54%]). Resolution of delirium occurred in 94 (52%) of patients and the difference was statistically significant favoring patients who did not receive pharmacological therapy. There was no difference in the median time to resolution of delirium (3 days) for patients who received pharmacological and/or pre-emptive therapy versus those who did not. Bradycardia and hypotension were the most frequently documented medication-related adverse events. Self-removal of an invasive line/catheter, was reported in 36 (26%) patients despite receiving pharmacological treatment. WHAT IS NEW AND CONCLUSION: Despite unclear evidence that pharmacological interventions help with delirium management, the majority of our patients received such interventions. To improve patient outcomes, we should shift focus towards non-pharmacological interventions for delirium.

Real-world Time to Positivity of 2 Widely Used Commercial Blood Culture Systems in Patients With Severe Manifestations of Sepsis: An Analysis of the FABLED Study.

BACKGROUND: Of all microbiological tests performed, blood cultures have the most impact on patient care. Timely results are essential, especially in the management of sepsis. While there are multiple available blood culture systems on the market, they have never been compared in a prospective study in a critically ill population. METHODS: We performed an analysis of the FABLED study cohort to compare culture results and time to positivity (TTP) of 2 widely used blood culture systems: BacT/Alert and BACTEC. In this multisite prospective study, patients with severe manifestations of sepsis had cultures drawn before antibiotics using systematic enrollment criteria and blood drawing methodology allowing for minimization of pre-analytical biases. RESULTS: We enrolled 315 patients; 144 had blood cultures (47 positive) with BacT/Alert and 171 with BACTEC (53 positive). Patients whose blood cultures were processed using the BacT/Alert system were younger (median, 64 vs 70 years; P = .003), had a higher proportion of HIV (9.03% vs 1.75%; P = .008) and a lower qSOFA (P = .003). There were no statistically significant differences in the most commonly identified bacterial species. TTP was shorter for BACTEC (median [interquartile range {IQR}], 12.5 [10-14] hours) compared with BacT/Alert (median [IQR], 17 [14-21] hours; P < .0001). CONCLUSIONS: In this large prospective multi-centre study comparing the two blood culture systems among patients with severe manifestations of sepsis, and using a rigorous pre-analytical methodology, the BACTEC system yielded positive culture results 4.5 hours earlier than BacT/Alert. These results apply to commonly isolated bacteria. However, our study design did not allow direct comparison of TTP for unusual pathogens nor of clinical sensitivity between systems. More research is needed to determine the clinical implications of this finding.

Use of fibrinogen concentrate for trauma-related bleeding: A systematic-review and meta-analysis.

BACKGROUND: Trauma-induced coagulopathy contributes to significant morbidity and mortality in patients who experience trauma-related bleeding. This study aimed to synthesize the evidence supporting the efficacy and safety of preemptive and goal-directed fibrinogen concentrate (FC) in the management of trauma-related hemorrhage. METHODS: PubMed, Medline, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform were systematically searched. All trial designs, except individual case reports, which evaluated the preemptive or goal-directed use of FC for trauma-related bleeding/coagulopathy, in patients older than 16 years, were included in the systematic review. For the included randomized controlled trials comparing FC with control, meta-analysis was performed and a risk-of bias-assessment was completed using the Cochrane Methodology and Preferred Reporting Items Systematic Reviews and Meta-analysis guidelines. RESULTS: A total of 2,743 studies were identified; 26 were included in the systematic review, and 5 randomized controlled trials (n = 238) were included in the meta-analysis. For the primary outcome of mortality, there was no statistically significant difference between the groups, with 22% and 23.4% in the FC and comparator arms, respectively (risk ratio, 1.00 [95% confidence interval, 0.39 to 2.56]; p = 0.99). In addition, there was no statistical difference between FC and control in packed red blood cell, fresh frozen plasma, or platelet transfusion requirements, and thromboembolic events. Overall, the quality of evidence was graded as low to moderate because of concerns with risk of bias, imprecision, and inconsistency. CONCLUSION: Further high-quality, adequately powered studies are needed to assess the impact of FC in trauma, with a focus on administration as early as possible from the point of entry into the trauma system of care. LEVEL OF EVIDENCE: Systematic review and Meta-analysis, level II.

Vasopressin for Septic Shock in a Medical-Surgical Intensive Care Unit.

BACKGROUND: Critically ill patients often need vasopressors to treat hypotension related to septic shock and to maintain adequate systemic perfusion. Although the 2017 guidelines of the Surviving Sepsis Campaign recommend norepinephrine as first-line therapy, they also state that vasopressin may be considered as an adjunctive agent for patients with refractory shock. Limited evidence is available for directing optimal administration of vasopressin. As such, prescribing practices are not standardized and may vary according to the particular clinician, the clinical scenario, and various patient-specific factors. OBJECTIVES: To review the current practice of administering concomitant norepinephrine and vasopressin therapy to patients with septic shock, to describe variability in vasopressin administration, and to evaluate effects on patient safety in a medical-surgical intensive care unit (ICU). METHODS: This single-centre retrospective chart review involved 100 adult patients admitted to the ICU who received vasopressin and norepinephrine for septic shock between April and December 2017. The data were analyzed with descriptive statistics. RESULTS: The mean time to initiation of vasopressin was 12.0 (standard deviation [SD] 21.6) h after initiation of norepinephrine. The mean dose of norepinephrine at the time of vasopressin initiation was 29.5 (SD 19.7) µg/min. The mean vasopressin dose prescribed was 0.04 (SD 0.03) units/min, with a range of tapering and discontinuation regimens. The mean duration of vasopressin therapy was 49.1 (SD 65.2) h, and vasopressin was discontinued before norepinephrine in 49 of the patients. A total of 60 hypotensive events occurred after vasopressor discontinuation and were more common when vasopressin was discontinued before norepinephrine. CONCLUSIONS: Vasopressin dosing was comparable to that reported elsewhere; however, discontinuation practices were inconsistent. These results show that variability in the literature supporting vasopressin use has led to variability in vasopressin administration and discontinuation practices; however, correlation with improvement in clinical outcomes, such as mortality or ICU length of stay, is unclear, and further research is required to determine the ideal approach to vasopressin use.

CONTEXTE: Les patients gravement malades nécessitent souvent un vasopresseur pour traiter l'hypotension liée au choc septique et pour préserver une perfusion systémique adéquate. Bien que les directives de 2017 de la campagne Surviving Sepsis recommandent la norépinephrine en guise de thérapie de première ligne, elles précisent également que la vasopressine pourrait être envisagée comme agent d'appoint pour les patients présentant des chocs réfractaires. Seules des données probantes limitées soutiennent l'administration optimale de la vasopressine. Les pratiques de prescription proprement dites ne sont pas standardisées et peuvent varier selon le clinicien, le scénario clinique et les divers facteurs particuliers au patient. OBJECTIFS: Examiner la pratique actuelle d'administration de la norépinephrine concomitante à la thérapie de vasopressine aux patients ayant subi un choc septique, décrire la variabilité d'administration de la vasopressine et évaluer les effets sur la sécurité du patient dans une unité de soins intensifs (USI) médicale-chirurgicale. MÉTHODES: Cet examen rétrospectif unicentrique des dossiers portait sur 100 patients adultes admis dans une USI, ayant reçu de la vasopressine et de la norépinephrine en réponse à des chocs septiques entre avril et décembre 2017. Les données ont été analysées à l'aide de statistiques descriptives. RÉSULTATS: Le temps moyen du début de l'administration de la vasopressine était de 12 h (écart type [É.T.] 21,6) après le début de l'administration de la norépinephrine. La dose moyenne de norépinephrine au moment du début de l'administration de la vasopressine était de 29,5 (É.T. 19,7) µg/min. La dose moyenne de vasopressine prescrite était de 0,04 (É.T. 0,03) unités/min, avec une gamme de posologies dégressives et d'abandons. La durée moyenne de la thérapie à la vasopressine était de 49,1 h (É.T. 65,2), et 49 patients ont abandonné la vasopressine avant l'abandon de la norépinephrine. Un total de 60 événements hypotenseurs se sont produits après l'abandon du vasopresseur et ils étaient plus fréquents lors de l'abandon de la vasopressine précédant celui de la norépinephrine. CONCLUSIONS: Le dosage de vasopressine était comparable à celui indiqué dans d'autres études; cependant, les pratiques d'abandon étaient incohérentes. Ces résultats démontrent que l'indétermination de l'information publiée dans la littérature soutenant l'utilisation de la vasopressine a entraîné une fluctuation dans l'administration de la vasopressine et des pratiques d'abandon; cependant, la corrélation entre l'usage de la vasopressine et l'amélioration des résultats cliniques, comme la mortalité ou la durée du séjour en USI, n'est pas claire, et davantage de recherches sont nécessaires pour déterminer l'approche idéale à adopter à l'égard de l'utilisation de la vasopressine.

Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis: A Diagnostic Study.

Background: Administering antimicrobial agents before obtaining blood cultures could potentially decrease time to treatment and improve outcomes, but it is unclear how this strategy affects diagnostic sensitivity. Objective: To determine the sensitivity of blood cultures obtained shortly after initiation of antimicrobial therapy in patients with severe manifestations of sepsis. Design: Patient-level, single-group, diagnostic study. (ClinicalTrials.gov: NCT01867905). Setting: 7 emergency departments in North America. Participants: Adults with severe manifestations of sepsis, including systolic blood pressure less than 90 mm Hg or a serum lactate level of 4 mmol/L or more. Intervention: Blood cultures were obtained before and within 120 minutes after initiation of antimicrobial treatment. Measurements: Sensitivity of blood cultures obtained after initiation of antimicrobial therapy. Results: Of 3164 participants screened, 325 were included in the study (mean age, 65.6 years; 62.8% men) and had repeated blood cultures drawn after initiation of antimicrobial therapy (median time, 70 minutes [interquartile range, 50 to 110 minutes]). Preantimicrobial blood cultures were positive for 1 or more microbial pathogens in 102 of 325 (31.4%) patients. Postantimicrobial blood cultures were positive for 1 or more microbial pathogens in 63 of 325 (19.4%) patients. The absolute difference in the proportion of positive blood cultures between pre- and postantimicrobial testing was 12.0% (95% CI, 5.4% to 18.6%; P < 0.001). Sensitivity of postantimicrobial culture was 52.9% (CI, 42.8% to 62.9%). When the results of other microbiological cultures were included, microbial pathogens were found in 69 of 102 (67.6% [CI, 57.7% to 76.6%]) patients. Limitation: Only a proportion of screened patients were recruited. Conclusion: Among patients with severe manifestations of sepsis, initiation of empirical antimicrobial therapy significantly reduces the sensitivity of blood cultures drawn shortly after treatment initiation. Primary Funding Source: Vancouver Coastal Health, St. Paul's Hospital Foundation Emergency Department Support Fund, the Fonds de recherche Santé-Québec, and the Maricopa Medical Foundation.

Eplerenone for hypertension.

BACKGROUND: Eplerenone is an aldosterone receptor blocker that is chemically derived from spironolactone. In Canada, it is indicated for use as adjunctive therapy to reduce mortality for heart failure patients with New York Heart Association (NYHA) class II systolic chronic heart failure and left ventricular systolic dysfunction. It is also used as adjunctive therapy for patients with heart failure following myocardial infarction. Additionally, it is indicated for the treatment of mild and moderate essential hypertension for patients who cannot be treated adequately with other agents. It is important to determine the clinical impact of all antihypertensive medications, including aldosterone antagonists, to support their continued use in essential hypertension. No previous systematic reviews have evaluated the effect of eplerenone on cardiovascular morbidity, mortality, and magnitude of blood pressure lowering in patients with hypertension. OBJECTIVES: To assess the effects of eplerenone monotherapy versus placebo for primary hypertension in adults. Outcomes of interest were all-cause mortality, cardiovascular events (fatal or non-fatal myocardial infarction), cerebrovascular events (fatal or non fatal strokes), adverse events or withdrawals due to adverse events, and systolic and diastolic blood pressure. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers up to 3 March 2016. We handsearched references from retrieved studies to identify any studies missed in the initial search. We also searched for unpublished data by contacting the corresponding authors of the included studies and pharmaceutical companies involved in conducting studies on eplerenone monotherapy in primary hypertension. The search had no language restrictions. SELECTION CRITERIA: We selected randomized placebo-controlled trials studying adult patients with primary hypertension. We excluded studies in people with secondary or gestational hypertension and studies where participants were receiving multiple antihypertensives. DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed the search results for studies meeting our criteria. Three review authors independently extracted data and assessed trial quality using a standardized data extraction form. A fourth independent review author resolved discrepancies or disagreements. We performed data extraction and synthesis using a standardized format on Covidence. We conducted data analysis using Review Manager 5. MAIN RESULTS: A total of 1437 adult patients participated in the five randomized parallel group studies, with treatment durations ranging from 8 to 16 weeks. The daily doses of eplerenone ranged from 25 mg to 400 mg daily. Meta-analysis of these studies showed a reduction in systolic blood pressure of 9.21 mmHg (95% CI -11.08 to -7.34; I2 = 58%) and a reduction of diastolic pressure of 4.18 mmHg (95% CI -5.03 to -3.33; I2 = 0%) (moderate quality evidence).There may be a dose response effect for eplerenone in the reduction in systolic blood pressure at doses of 400 mg/day. However, this finding is uncertain, as it is based on a single included study with low quality evidence. Overall there does not appear to be a clinically important dose response in lowering systolic or diastolic blood pressure at eplerenone doses of 50 mg to 400 mg daily. There did not appear to be any differences in the number of patients who withdrew due to adverse events or the number of patients with at least one adverse event in the eplerenone group compared to placebo. However, only three of the five included studies reported adverse events. Most of the included studies were of moderate quality, as we judged multiple domains as being at unclear risk in the 'Risk of bias' assessment. AUTHORS' CONCLUSIONS: Eplerenone 50 to 200 mg/day lowers blood pressure in people with primary hypertension by 9.21 mmHg systolic and 4.18 mmHg diastolic compared to placebo, with no difference of effect between doses of 50 mg/day to 200 mg/day. A dose of 25 mg/day did not produce a statistically significant reduction in systolic or diastolic blood pressure and there is insufficient evidence for doses above 200 mg/day. There is currently no available evidence to determine the effect of eplerenone on clinically meaningful outcomes such as mortality or morbidity in hypertensive patients. The evidence available on side effects is insufficient and of low quality, which makes it impossible to draw conclusions about potential harm associated with eplerenone treatment in hypertensive patients.

Garlic for the prevention of cardiovascular morbidity and mortality in hypertensive patients.

BACKGROUND: Garlic is widely used by patients for its blood pressure lowering effects. A meta-analysis published in 2008 concluded that garlic consumption lowers blood pressure in hypertensive and normotensive patients. Therefore, it is important to review the currently available evidence to determine whether garlic may also have a beneficial role in the reduction of cardiovascular events and mortality rates in patients with hypertension. OBJECTIVES: To determine whether the use of garlic as monotherapy, in hypertensive patients, lowers the risk of cardiovascular morbidity and mortality compared to placebo. SEARCH METHODS: A systematic search for trials was conducted in the Cochrane Hypertension Group Specialised Register, CENTRAL, MEDLINE, EMBASE, AGRICOLA, AMED, and CINAHL up to November 2011. A hand search of reference lists of identified reviews was conducted. Experts in the area were also contacted to identify trials not found in the electronic search. Clinicaltrials.gov was searched for ongoing trials. SELECTION CRITERIA: Randomized, placebo-controlled trials of any garlic preparation versus placebo for the treatment of hypertension were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality using the risk of bias tool. Data synthesis and analysis was performed using RevMan 5. MAIN RESULTS: The search identified two randomized controlled trials for inclusion. One trial included 47 hypertensive patients and showed that garlic significantly reduces mean supine systolic blood pressure by 12 mmHg (95% CI 0.56 to 23.44 mmHg, p=0.04) and mean supine diastolic blood pressure by 9 mmHg (95% CI 2.49 to 15.51 mmHg, p=0.007) versus placebo. The authors state that garlic was "free from side effects" and that no serious side effects were reported. There were 3 cases "where a slight smell of garlic was noted."The second trial could not be meta-analysed as they did not report the number of people randomized to each treatment group. They did report that 200 mg of garlic powder given three times daily, in addition to hydrochlorothiazide-triamterene baseline therapy, produced a mean reduction of systolic blood pressure by 10-11 mmHg and of diastolic blood pressure by 6-8 mmHg versus placebo.Neither trial reported clinical outcomes and insufficient data was provided on adverse events. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine if garlic provides a therapeutic advantage versus placebo in terms of reducing the risk of mortality and cardiovascular morbidity in patients diagnosed with hypertension. There is also insufficient evidence to determine the difference in withdrawals due to adverse events between patients treated with garlic or placebo.Based on 2 trials in 87 hypertensive patients, it appears that garlic reduces mean supine systolic and diastolic blood pressure by approximately 10-12 mmHg and 6-9 mmHg, respectively, over and above the effect of placebo but the confidence intervals for these effect estimates are not precise and this difference in blood pressure reduction falls within the known variability in blood pressure measurements. This makes it difficult to determine the true impact of garlic on lowering blood pressure.

Hydralazine for essential hypertension.

BACKGROUND: Hypertension is associated with an increased risk of stroke, myocardial infarction and congestive heart failure. Hydralazine is a direct-acting vasodilator which has been used for the treatment of hypertension since the 1950's. Although it has largely been replaced by newer antihypertensive drugs with more acceptable tolerability profiles, hydralazine is still widely used in developing countries due to its lower cost. A review of its relative effectiveness compared to placebo on surrogate and clinical outcomes is justified. OBJECTIVES: To quantify the effect of hydralazine compared to placebo in randomized controlled trials (RCTs) on all cause mortality, cardiovascular mortality, serious adverse events, myocardial infarctions, strokes, withdrawals due to adverse effects and blood pressure in patients with primary hypertension. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (2011, Issue 3), MEDLINE (1948-August 2011), International Pharmaceutical Abstracts (1970-June 2009) and EMBASE (1980-August 2011). Bibliographic citations from retrieved studies were also reviewed. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs studying the effect of oral hydralazine compared to oral placebo in patients with primary hypertension. We excluded studies of patients with secondary hypertension or gestational hypertension. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality using the risk of bias tool. Data synthesis and analysis was performed using RevMan 5. MAIN RESULTS: The search strategy did not yield any randomized controlled trials comparing hydralazine to placebo for inclusion in this review. There is insufficient evidence to conclude on the effects of hydralazine versus placebo on mortality, morbidity, withdrawals due to adverse effects, serious adverse events, or systolic and diastolic blood pressure. Some of the adverse effects related to hydralazine that have been reported in the literature include reflex tachycardia, hemolytic anemia, vasculitis, glomerulonephritis, and a lupus-like syndrome. AUTHORS' CONCLUSIONS: Hydralazine may reduce blood pressure when compared to placebo in patients with primary hypertension, however this data is based on before and after studies, not RCTs. Furthermore, its effect on clinical outcomes remains uncertain.

Extended-interval aminoglycoside therapy for adult patients with febrile neutropenia: a systematic review.

BACKGROUND: Although the efficacy and toxicity of extended-interval (once-daily) aminoglycoside regimens is well established for immunocompetent patients, there is clinical concern about using this regimen for patients with neutropenia. OBJECTIVE: To summarize and evaluate the literature reporting the clinical efficacy and safety of extended-interval aminoglycosides therapy in adults with febrile neutropenia. METHODS: A literature search was conducted within PubMed, Embase, and the Cochrane Database of Systematic Reviews to identify studies assessing the use of extended-interval aminoglycosides for treating febrile neutropenia in adults. Articles were categorized by quality of evidence, according to the rating scale of the US Preventive Services Task Force. RESULTS: TEN ARTICLES WERE IDENTIFIED: 5 with level I evidence, 1 with level II-2 evidence, and 4 with level III evidence. Review of the 5 studies with level I evidence (all open-label randomized controlled trials), which compared extended-interval dosing with multiple-daily dosing strategies, revealed no evidence to suggest superiority of one regimen over the other in terms of clinical outcomes. In the study with level II-2 evidence (a prospective comparative trial), the response rate was better in the extended-interval group than in the standard-therapy group. Two of the studies with level III evidence (both prospective noncomparative trials) also had acceptable response rates to extended-interval aminoglycoside therapy, with minimal associated nephrotoxicity. In this review, no major differences in rates of nephrotoxicity or ototoxicity were seen between the 2 dosing regimens. CONCLUSIONS: The use of extended-interval dosing for aminoglycosides, in combination with other recommended antibiotic therapy, is an effective and safe management strategy for immunocompromised patients with febrile neutropenia. In this population, the clinical efficacy and safety of extended-interval dosing does not appear to differ from those of standard dosing. Whether routine or selective pharmacokinetic monitoring in this patient subpopulation leads to improvements in outcomes is yet to be determined.

Hydralazine for essential hypertension.

BACKGROUND: Hypertension is associated with an increased risk of stroke, myocardial infarction and congestive heart failure. Hydralazine is a direct-acting vasodilator which has been used for the treatment of hypertension since the 1950's. Although it has largely been replaced by newer antihypertensive drugs with more acceptable tolerability profiles, hydralazine is still widely used in developing countries due to its lower cost. A review of its relative effectiveness compared to placebo on surrogate and clinical outcomes is justified. OBJECTIVES: To quantify the effect of hydralazine compared to placebo in randomized controlled trials (RCTs) on all cause mortality, cardiovascular mortality, serious adverse events, myocardial infarctions, strokes, withdrawals due to adverse effects and blood pressure in patients with primary hypertension. SEARCH STRATEGY: We searched the following databases: Cochrane Central Register of Controlled Trials (to Second Quarter 2009), MEDLINE (2005-June 2009), International Pharmaceutical Abstracts (1970-June 2009) and EMBASE (2007-June 2009). Bibliographic citations from retrieved studies were also reviewed. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs studying the effect of oral hydralazine compared to oral placebo in patients with primary hypertension. We excluded studies of patients with secondary hypertension or gestational hypertension. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality using the risk of bias tool. Data synthesis and analysis was performed using RevMan 5. MAIN RESULTS: The search strategy did not yield any randomized controlled trials comparing hydralazine to placebo for inclusion in this review. There is insufficient evidence to conclude on the effects of hydralazine versus placebo on mortality, morbidity, withdrawals due to adverse effects, serious adverse events, or systolic and diastolic blood pressure. Some of the adverse effects related to hydralazine that have been reported in the literature include reflex tachycardia, hemolytic anemia, vasculitis, glomerulonephritis, and a lupus-like syndrome. AUTHORS' CONCLUSIONS: Hydralazine may reduce blood pressure when compared to placebo in patients with primary hypertension, however this data is based on before and after studies, not RCTs. Furthermore, its effect on clinical outcomes remains uncertain.

Spironolactone for hypertension.

BACKGROUND: Spironolactone is an aldosterone antagonist, considered fourth line therapy for hypertension in patients already treated with multiple medications. OBJECTIVES: Primary: to determine the effect of spironolactone on patient mortality, morbidity, and to quantify the magnitude of blood pressure lowering effect of spironolactone monotherapy.Secondary: to determine the prevalence of adverse reactions observed with spironolactone monotherapy and to determine if there is a blood-pressure lowering dose response with spironolactone. SEARCH STRATEGY: We searched the following databases: Cochrane Central Register of Controlled Trials (3rd Quarter 2009), MEDLINE (2005 - Sept. 2009), and EMBASE (2007 - Sept. 2009). References from retrieved studies were reviewed to identify any studies missed in the initial search. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs studying patients with primary hypertension. We excluded studies of patients with secondary or gestational hypertension, and studies where patients were receiving multiple antihypertensives. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the search results for studies meeting our criteria. Three reviewers extracted data and assessed trial quality using a standardized data extraction form. Data synthesis and analysis was performed using RevMan 5. MAIN RESULTS: Meta-analysis of the 5 cross-over studies found a reduction in SBP of 20.09 mmHg (95%CI:16.58-23.06,p<0.00001) and a 6.75 mmHg (95%CI:4.8-8.69,p<0.00001) reduction in DBP. These results were statistically significant and there was no evidence of heterogeneity between the studies. There may be a dose response effect with spironolactone up to 50 mg/day, but the confidence intervals around the mean end-of-study blood pressure for doses ranging 25-500 mg/day all overlapped. In other words, it appears that doses >50mg/day do not produce further reductions in either SBP or DBP. One cross-over study found that spironolactone 25 mg/day did not statistically significantly change SBP or DBP compared to placebo, SBP: -9.9 (95%CI:-21.15,1.35); DBP -2.34 (95%CI:-7.92,3.06). AUTHORS' CONCLUSIONS: From the limited available evidence, spironolactone appears to lower blood pressure compared to placebo to a similar degree in patients with primary (essential) hypertension when doses of 100-500 mg/day are given. A dose of 25 mg/day did not statistically significantly reduce systolic or diastolic blood pressure, compared to placebo. Given the lack of a dose-response, coupled with a possible increased risk in adverse events with higher doses, doses of 25 to 100 mg/day are reasonable. There is no evidence of the effect of spironolactone on clinical outcomes in hypertensive patients.