Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest.


Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever.


In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale.


In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar.


In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C.

Source: NEJM


Vitamin D3 Supplements Do Not Lessen Cold, Influenza Risk.

Supplementation with vitamin D3 does not reduce the incidence or risk for upper respiratory tract infection (URTI) in adults, according to a new randomized controlled trial published onlineSeptember 6 and in the November 15 print issue of Clinical Infectious Diseases.

Judy R. Rees, MPH, PhD, from the Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, and colleagues enrolled 2259 participants (age, 45 – 75 years) who were also taking part in a colorectal adenoma chemoprevention trial. Participants were randomly assigned to receive 1000 IU/day of vitamin D3, 1200 mg elemental calcium/day, both, or placebo. All participants were in good health and had serum 25-hydroxyvitamin D levels of 2 ng/mL or higher.

Among the 759 participants who completed the study, the researchers found no significant decrease in the rate ratio (RR) of URTI episodes between the treatment groups (RR, 0.93; 95% confidence interval [CI], 0.79 – 1.09) or winter days of illness (RR, 1.13; 95% CI, 0.90 – 1.43). There was also no decrease noted in composite syndromes of influenza-like illness (ILI; RR, 0.95; 95% CI, 0.62 – 1.46) or colds (RR, 0.93; 95% CI, 0.78 – 1.10).

“Vitamin D supplementation conferred no significant protection against colds, ILI, or any URTI overall, nor among those with the lowest baseline serum 25(OH) vitamin D, although participants whose baseline concentration was <12 ng/mL were specifically excluded from our trial,” note Dr. Rees and colleagues.

Participants were recruited from 11 clinical centers, and the study was conducted November 2009 through March 2011. URTI was defined as either ILI (fever and 2 or more of the following: sore throat, cough, muscle aches, or headache) or a cold (absence of ILI, 2 or more of the following on a single day: runny nose, nasal congestion, sneezing, sore throat, cough, and swollen or tender neck glands).

Throughout the study period, researchers administered semiannual telephone surveys to 2228 participants and found no decrease in the odds ratio (OR) of ILI (OR, 1.14; 95% CI, 0.84 – 1.54) or colds (OR, 1.03; 95% CI, 0.87 – 1.23) among patients receiving vitamin D3 supplementation. Baseline vitamin D status, body mass index, adherence, or influenza vaccination also provided no significant benefit.

The researchers acknowledge that self-selection of the 759 participants from the parent trial may have influenced results if participants dropped out early because of a lack of treatment effect. The study authors also note that self-reported adherence to study protocol and lack of laboratory conformation of URTI may also have affected the results.

Michael Gleeson, PhD, from the School of Sport, Exercise and Health Sciences, Loughborough University, Leucestershire, United Kingdom, told Medscape Medical News, “Although participant numbers were large, I suspect that this dose of vitamin D3 is insufficient to affect respiratory illness incidence in individuals who are not vitamin D deficient,” and that “an effect might be seen in a more illness-prone population such as athletes.” Dr. Gleeson was not affiliated with the study.

“The effects on URTI of supplementation in adults with vitamin D deficiency (<12 ng/mL) should be addressed in future trials,” conclude the study authors. Studies should also address at what dose of vitamin D3 affects “markers of immune function that are important in defense against respiratory infections,” added Dr. Gleeson.

Inhaled corticosteroids in COPD and the risk of serious pneumonia


Background Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.

Methods We formed a new-user cohort of patients with COPD treated during 1990–2005. Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia. A nested case–control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.

Results The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year). Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75). The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17). The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).

Conclusions ICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials.


Using a large population-based cohort of over 160 000 patients with COPD followed for up to 18 years, we found that ICS use is associated with a significant 69% increase in the risk of serious pneumonia, requiring hospitalisation or fatal. This risk was particularly increased with fluticasone, with a doubling of the rate, and dose dependent with doses of 1000 μg of fluticasone per day associated with a 122% increase. The risk with budesonide was comparatively much lower with an increase of 17% and no dose–response effect. These elevated risks disappeared within a few months of stopping the use of ICS.

Systemic corticosteroids have been associated with increased risks of pneumonia in patients with rheumatoid arthritis.26 ,27 In these patients, a dose–response increase in the risk of pneumonia was seen with doses of prednisone as low as ≤5 mg/day (RR 1.4; 95% CI 1.1 to 1.6),26 and as low as 7.5 mg or less (RR 2.3; 95% CI 1.2 to 4.4).27 It is then not unexpected that high doses of ICS have similar effects on the incidence of pneumonia, as 1000 μg of inhaled fluticasone is estimated to be equivalent to 10 mg per day of prednisone with systemic effects evaluated by suppression of serum cortisol.7

Our findings confirm the observations of several randomised trials of varying durations and doses. The 2-year INSPIRE and 3-year TORCH trials both studied high doses of fluticasone (1000 μg per day) and found HRs of pneumonia of 1.94 (95% CI 1.19 to 3.17) and 1.64 (95% CI 1.33 to 2.02), respectively,3 ,4 ,13 ,14 A 1-year trial of fluticasone 1000 μg/day found a higher increase in the risk (RR 3.1; 95% CI 1.3 to 7.3; our calculation),15 which is consistent with our findings of a somewhat higher early risk. Our results confirm the subgroup analyses of the meta-analysis, suggesting that the risk is particularly elevated with high doses and start at short durations of use.12 With respect to the effect of dose, the two trials that evaluated a lower dose of fluticasone (500 μg per day) for 1 year also found a close to twofold higher incidence of pneumonia at 1 year with fluticasone.16–18This is also consistent with the dose–response curve from our study, which shows an increase in risk with lower doses and a RR of 1.6 at 500 μg/day of fluticasone.

The findings for budesonide confirm the pooled analysis of several trials of budesonide that found no increased risk of pneumonia over 1 year (RR 1.05; 95% CI 0·81 to 1·37),19 and a meta-analysis that suggests a lower risk with budesonide compared with fluticasone.20 Our finding of a more moderate 17% increase in the rate of serious pneumonia is concordant with these trial data. Moreover, the risk of pneumonia did not increase with the dose of budesonide. Nevertheless, a concern remains with budesonide as a recent 1-year trial in COPD found increases in pneumonia adverse events with daily doses of 640 μg (RR 2.3; 95% CI 1.2 to 4.7) and 320 μg (RR 1.7; 95% CI 0.8 to 3.6), equivalent to 400 μg and 200 μg of fluticasone, respectively.28 Since the fluticasone–salmeterol combination was approved and therefore promoted for COPD during the time period under study while the budesonide–formoterol combination was not, it remains possible that those receiving the budesonide combination were more likely to have asthma rather than COPD and be at lower risk of pneumonia compared with subjects receiving the fluticasone–salmeterol combination. Furthermore, since a higher dose formulation was only available for the fluticasone–salmeterol combination, patients with more severe disease may have been more likely to have received a combination therapy containing fluticasone rather than budesonide. Therefore, data on this question from countries where budesonide has a greater market share would be a valuable addition to this evidence.

There is good evidence supporting the effect of ICS on human pulmonary host defence, acting through several biological pathways, such as an inhibitory action on macrophage functions, a decrease in cytokine production and nitric oxide expression, which may lead to a failure to control infection.29 ,30 Although there have been no studies directly comparing the effects of fluticasone and budesonide on host defence, differences are likely related to their contrasting pharmacokinetic and pharmacodynamic properties. Fluticasone is known to be more potent (ie, greater effect on intracellular steroid receptors), more lipophilic and has a longer half life than budesonide.29Accordingly, fluticasone has a better penetration at the site of action and a more prolonged effect. It is therefore not surprising that a greater risk of oropharyngeal side effects is found with fluticasone compared with budesonide.31 While high potency and lipophilicity can be positive features allowing a lower dose to exert the desired effect, these characteristics may adversely affect drug safety. Indeed, a more prolonged corticosteroid effect in the lungs and greater pulmonary retention will facilitate the local immunosuppressive action.32 ,33 Budesonide enters the lungs with a lower lipophilicity, dissolves more quickly into pulmonary fluids, leading to a reduced local effect because of a more rapid cleavage and passage into the systemic circulation.30

This study has strengths and some limitations. The size of the population-based cohort of over 160 000 patients observed over 18 years permitted the identification of over 20 000 cases of serious pneumonia, allowing precise estimates of the risk associated with the different ICS at several doses. In this study, we defined serious pneumonia as a hospitalisation with a primary diagnosis of pneumonia or death from pneumonia, but did not have proof that the diagnosis was based on radiographic findings as these are not recorded in the RAMQ databases. However, it is most likely that as a primary inpatient diagnosis, it was in fact supported by a radiographic finding. To address confounding by COPD severity, we adjusted for the number of prescriptions for respiratory medications other than ICS, and for exacerbations as measured by prescriptions for oral corticosteroids, antibiotics, as well as prior hospitalisations for pneumonia and COPD exacerbation. Yet, residual confounding arising from unmeasured covariates can still be present. Of most concern is the possibility that budesonide may have been preferentially prescribed to patients with a lower risk of pneumonia, such as those with asthma or less severe COPD. In this specific study, however, our main results, adjusted for differences in severity, are consistent with those of several randomised trials which are inherently free of confounding, albeit less powerful with smaller study populations. Exposure to ICS was measured from dispensed prescriptions so that one must assume that the drugs were actually taken. However, not taking these medications would actually tend to underestimate the true risk increase. The definition of COPD used to identify the patients in our cohort was not based on a physician diagnosis of COPD or objective criteria for the diagnosis of COPD, but rather on including only subjects who started using respiratory medications at the age of 55 years or later and excluding subjects with a prior asthma hospitalisation or who used asthma-specific medications such as nedocromil, ketotifen, cromolyn or antileukotrienes. Nevertheless, our definition likely captured some patients with asthma. One can expect that this would reduce the estimate of risk of ICS since ICS do not appear to increase the risk of pneumonia in patients with asthma.34 Our sensitivity analysis within subjects previously hospitalised for COPD found practically the same differences in estimates of risk for fluticasone and budesonide.

The dose–response effect with fluticasone that we found on the incidence of serious pneumonia, sustained over a long time, is important in the risk–benefit balance for patients with COPD. While ICS are clearly effective for the treatment of asthma, their effectiveness in treating COPD is still controversial.1 ,2 The fact that ICS are now commonly combined in a single device with a long-acting bronchodilator, the latter recommended earlier in COPD, has resulted in ICS now being used by over 70% of patients with COPD.2 Moreover, these combined medications most often contain high doses of ICS, as high as 1000 μg of fluticasone per day.3 ,4 Consequently, the widespread use of ICS at higher doses in patients with COPD, along with the elevated incidence of pneumonia in this age group and their uncertain effectiveness, impact on the risk–benefit profile of ICS in COPD.

In conclusion, high and low doses of fluticasone in patients with COPD are associated with an important increase in the risk of serious pneumonia, while the risk with budesonide is comparatively low, even at high doses, though it needs further examination in light of recent data and the possibility that patients receiving budesonide are inherently at lower risk of pneumonia than those prescribed fluticasone. Further investigations into why the two popular ICS fluticasone and budesonide have such different effects on the risk of pneumonia are warranted.

Source: BMJ Thorax.

Colloids versus crystalloids for fluid resuscitation in critically ill patients.

Critically ill patients with trauma, burns, surgery or sepsis are often given intravenous fluids to expand intravascular volume. When it comes to selecting the resuscitation fluid, one of the choices is between using a colloid or a crystalloid solution. This choice has considerable cost implications, because volume replacement with colloids is much more expensive than with crystalloids. Clinical studies have shown that colloids and crystalloids have different effects on a range of physiological parameters. Because of these differences, all-cause mortality is arguably the most clinically relevant outcome measure for randomised trials comparing the two fluid types.

This review, which was updated for the sixth time in February 2013, assessed the effects on mortality of using colloids compared to crystalloids, during fluid resuscitation in critically ill patients. A systematic search was conducted for any controlled trial in which participants were assigned to treatment on the basis of random allocation. The interventions considered were colloids (dextran 70, hydroxyethyl starches, modified gelatins, albumin or plasma protein fraction) compared to crystalloid (isotonic or hypertonic) for fluid replacement. Studies needed to include critically ill patients (excluding neonates and pregnant women) who required volume replacement. The authors excluded trials of fluids used for other purposes, such as trials of pre-loading in preparation for elective surgery, and trials in patients undergoing fluid loading before cardiopulmonary bypass. Trials of total parenteral nutrition with or without albumin were also excluded, as were randomised cross-over trials.

A total of 78 eligible trials were identified, with mortality data available from 70 of these. The analyses were divided up on the basis of the types of intervention. Considering the basic comparison of colloids versus crystalloids, the largest number of randomized patients was in the studies of albumin or plasma protein fraction, with 24 trials that reported data on mortality (9920 patients). The pooled risk ratio (RR) from these trials was 1.01 (95% confidence interval (CI) 0.93 to 1.10). 25 trials compared hydroxyethyl starch with crystalloids (9147 patients), finding a pooled RR of 1.10 (95% CI 1.02 to 1.19). In the 11 trials of modified gelatin versus crystalloid, with 506 patients, the pooled RR was 0.91 (95% CI 0.49 to 1.72) and, for the 9 trials comparing dextran with a crystalloid (834 patients), the meta-analysis produced a RR of 1.24 (95% CI 0.94 to 1.65).

In other comparisons in the review, 9 trials compared dextran in hypertonic crystalloid with isotonic crystalloid (1985 patients), generating a pooled RR for mortality of 0.91 (95% CI 0.71 to 1.06). While there were three trials of colloids in isotonic crystalloid versus hypertonic crystalloid. In two of these trials, where the colloid was either gelatin or starch, there were no deaths in either group. In the third trial (38 patients), there were three deaths in the treatment group and none in the control group, giving a RR of 7.00 (95% CI 0.39 to 126.93).

In their summary, the authors of this updated Cochrane Review highlight that there is no evidence from randomised trials that resuscitation using colloids compared with crystalloids reduces the risk of death in patients with trauma, burns or following surgery. Their meta-analyses provide a precise estimate of hydroxyethyl starch effect on mortality, since it includes many thousands of patients and the number of deaths is large. Furthermore, the two studies that contribute 80% of the weight in the meta-analysis were of high methodological quality with a low risk of bias. The pooled relative risk of death (1.10 [95% CI 1.02 to 1.19]) suggests an increase in deaths in the colloids group, and makes it highly unlikely that there is a mortality reduction with these interventions. Therefore, since colloid use is not associated with improved survival and colloids are considerably more expensive than crystalloids, they conclude that it is difficult to see how their continued use in clinical practice can be justified.

Outcomes similar with different low-osmolar iodinated contrast agents.

Among patients undergoing coronary angiography or percutaneous coronary interventions with low-osmolar contrast media (LOCM), adverse outcomes are uncommon, with no advantage apparent between different agents.

That finding comes from a retrospective look at data on more than 100,000 patients, reported in theAmerican Journal of Cardiology online March 22 by Dr. James K. Min, with Cedars-Sinai Medical Center in Los Angeles, California, and colleagues.

“In contrast to previous studies that compared LOCM to iso-osmolar contrast media, our study directly compared alternate LOCM for differences in clinical outcomes,” the authors point out.

They note that previous reports have suggested that iohexol may be associated with increased rates of contrast-induced nephropathy (CIN) compared to an iso-osmolar contrast medium, whereas this has not been reported with other LOCM such as ioversol and iopamidol.

To determine if there is any difference between LOCMs, the team looked at outcomes in patients exposed to iohexol (n = 20,136), iopamidol (n = 21,539), or ioversol (n = 66,319) during invasive coronary procedures.

Propensity scoring generated 19,482 matched pairs of patients exposed to iohexol versus ioversol, and 10,204 pairs exposed to iohexol versus iopamidol.

The researchers found no significant difference between the iohexol-ioversol pairs in rates of new inpatient hemodialysis (relative risk 0.72; p = 0.05), inpatient mortality (RR 0.90; p = 0.42), or 30-day readmission for CIN (RR 0.81; p = 0.52).

Outcomes were also similar between the matched iohexol-iopamidol patients in terms of inpatient hemodialysis (RR 1.18; p = 0.45), inpatient mortality (RR 1.09; p = 0.60), or 30-day CIN readmission (RR 1.11; p = 0.82).

“Encouragingly, in this large dataset, even before matching, rates of in-hospital hemodialysis and mortality and 30-day readmission rates for CIN were low for all patients, irrespective of contrast medium used,” Dr. Min and colleagues comment.

“After matching,” they conclude, “we could not identify any significant differences in adverse events for patients who underwent ICA and/or PCI with different LOCM.”


Source: Am J Cardiol 


Ultrasonographically guided peripheral intravenous cannulation of children and adults: a systematic review and meta-analysis. .

Peripheral intravenous cannulation is procedurally challenging and painful. We perform a systematic review to evaluate ultrasonographic guidance as an aid to peripheral intravenous cannulation.

METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science,, and We included randomized trials evaluating ultrasonographically guided peripheral intravenous cannulation and reporting risk of peripheral intravenous cannulation failure, number of attempts, procedure time, or time from randomization to peripheral intravenous cannulation. We separately analyzed pediatric and adult data and emergency department (ED), ICU, and operating room data. Quality assessment used the Cochrane Risk of Bias Tool.
RESULTS: We identified 4,664 citations, assessed 403 full texts for eligibility, and included 9 trials. Five had low risk, 1 high risk, and 3 unclear risk of bias. A pediatric ED trial found that ultrasonography decreased mean difference (MD) in the number of attempts (MD -2.00; 95% confidence interval [CI] -2.73 to -1.27) and procedure time (MD -8.10 minutes; 95% CI -12.48 to -3.72 minutes). In an operating room pediatric trial, ultrasonography decreased risk of first-attempt failure (risk ratio 0.23; 95% CI 0.08 to 0.69), number of attempts (MD -1.50; 95% CI -2.52 to -0.48), and procedure time (MD -5.95; 95% CI -10.21 to -1.69). Meta-analysis of adult ED trials suggests that ultrasonography decreases the number of attempts (MD -0.43; 95% CI -0.81 to -0.05). Ultrasonography decreased risk of failure (risk ratio 0.47; 95% CI 0.26 to 0.87) in an adult ICU trial.
CONCLUSION: Ultrasonography may decrease peripheral intravenous cannulation attempts and procedure time in children in ED and operating room settings. Few outcomes reached statistical significance. Larger well-controlled trials are needed.

Source: Annals of Emergency Medicine.


Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis..


Cancer survival has improved in the past 20 years, affecting the long-term risk of mood disorders. We assessed whether depression and anxiety are more common in long-term survivors of cancer compared with their spouses and with healthy controls.


We systematically searched Medline, PsycINFO, Embase, Science Direct, Ingenta Select, Ovid, and Wiley Interscience for reports about the prevalence of mood disorders in patients diagnosed with cancer at least 2 years previously. We also searched the records of the International Psycho-oncology Society and for reports that cited relevant references. Three investigators independently extracted primary data. We did a random-effects meta-analysis of the prevalences of depression and anxiety in cancer patients compared with spouses and healthy controls.


Our search returned 144 results, 43 were included in the main analysis: for comparisons with healthy controls, 16 assessed depression and ten assessed anxiety; of the comparisons with spouses, 12 assessed depression and five assessed anxiety. The prevalence of depression was 11·6% (95% CI 7·7—16·2) in the pooled sample of 51 381 cancer survivors and 10·2% (8·0—12·6) in 217 630 healthy controls (pooled relative risk [RR] 1·11, 95% CI 0·96—1·27; p=0·17). The prevalence of anxiety was 17·9% (95% CI 12·8—23·6) in 48 964 cancer survivors and 13·9% (9·8—18·5) in 226 467 healthy controls (RR 1·27, 95% CI 1·08—1·50; p=0·0039). Neither the prevalence of depression (26·7% vs 26·3%; RR 1·01, 95% CI 0·86—1·20; p=0·88) nor the prevalence of anxiety (28·0% vs 40·1%; RR 0·71, 95% CI 0·44—1·14; p=0·16) differed significantly between cancer patients and their spouses.


Our findings suggest that anxiety, rather than depression, is most likely to be a problem in long-term cancer survivors and spouses compared with healthy controls. Efforts should be made to improve recognition and treatment of anxiety in long-term cancer survivors and their spouses.

Source: Lancet

Oral Apixaban for the Treatment of Acute Venous Thromboembolism.


Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.


In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.


The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.



A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding

Source: NEJM





Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.



Stroke is the major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression. Recently, small trials have demonstrated that SSRIs might improve recovery after stroke, even in people who are not depressed. Systematic reviews and meta-analyses are the least biased way to bring together data from several trials. Given the promising effect of SSRIs on stroke recovery seen in small trials, a systematic review and meta-analysis is needed.


To determine whether SSRIs improve recovery after stroke, and whether treatment with SSRIs was associated with adverse effects.


We searched the Cochrane Stroke Group Trials Register (August 2011), Cochrane Depression Anxiety and Neurosis Group Trials Register (November 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (from 1948 to August 2011), EMBASE (from 1980 to August 2011), CINAHL (from 1982 to August 2011), AMED (Allied and Complementary Medicine) (from 1985 to August 2011), PsycINFO (from 1967 to August 2011) and PsycBITE (Pyschological Database for Brain Impairment Treatment Efficacy) (March 2012). To identify further published, unpublished and ongoing trials we searched trials registers, pharmaceutical websites, reference lists, contacted experts and performed citation tracking of included studies.


We included randomised controlled trials that recruited stroke survivors (ischaemic or haemorrhagic) at any time within the first year. The intervention was any SSRI, given at any dose, for any period. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. In order to be included, trials had to collect data on at least one of our primary (dependence and disability) or secondary (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early) outcomes.


We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. For trials in English, two review authors independently extracted data. For Chinese papers, one review author extracted data. We used standardised mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous effects, with their 95% confidence intervals (CIs).


We identified 56 completed trials of SSRI versus control, of which 52 trials (4059 participants) provided data for meta-analysis. There were statistically significant benefits of SSRI on both of the primary outcomes: RR for reducing dependency at the end of treatment was 0.81 (95% CI 0.68 to 0.97) based on one trial, and for disability score, the SMD was 0.91 (95% CI 0.60 to 1.22) (22 trials involving 1343 participants) with high heterogeneity between trials (I(2) = 87%; P < 0.0001). For neurological deficit, depression and anxiety, there were statistically significant benefits of SSRIs. For neurological deficit score, the SMD was -1.00 (95% CI -1.26 to -0.75) (29 trials involving 2011 participants) with high heterogeneity between trials (I(2) = 86%; P < 0.00001). For dichotomous depression scores, the RR was 0.43 (95% CI 0.24 to 0.77) (eight trials involving 771 participants) with high heterogeneity between trials (I(2) = 77%; P < 0.0001). For continuous depression scores, the SMD was -1.91 (95% CI -2.34 to -1.48) (39 trials involving 2728 participants) with high heterogeneity between trials (I(2) = 95%; P < 0.00001). For anxiety, the SMD was -0.77 (95% CI -1.52 to -0.02) (eight trials involving 413 participants) with high heterogeneity between trials (I(2) = 92%; P < 0.00001). There was no statistically significant benefit of SSRI on cognition, death, motor deficits and leaving the trial early. For cognition, the SMD was 0.32 (95% CI -0.23 to 0.86), (seven trials involving 425 participants) with high heterogeneity between trials (I(2) = 86%; P < 0.00001). The RR for death was 0.76 (95% CI 0.34 to 1.70) (46 trials involving 3344 participants) with no heterogeneity between trials (I(2) = 0%; P = 0.85). For motor deficits, the SMD was -0.33 (95% CI -1.22 to 0.56) (two trials involving 145 participants). The RR for leaving the trial early was 1.02 (95% CI 0.86 to 1.21) in favour of control, with no heterogeneity between trials. There was a non-significant excess of seizures (RR 2.67; 95% CI 0.61 to 11.63) (seven trials involving 444 participants), a non-significant excess of gastrointestinal side effects (RR 1.90; 95% CI 0.94 to 3.85) (14 trials involving 902 participants) and a non-significant excess of bleeding (RR 1.63; 95% CI 0.20 to 13.05) (two trials involving 249 participants) in those allocated SSRIs. Data were not available on quality of life, fatigue or healthcare costs.There was no clear evidence from subgroup analyses that one SSRI was consistently superior to another, or that time since stroke or depression at baseline had a major influence on effect sizes. Sensitivity analyses suggested that effect sizes were smaller when we excluded trials at high or unclear risk of bias.Only eight trials provided data on outcomes after treatment had been completed; the effect sizes were generally in favour of SSRIs but CIs were wide.


SSRIs appeared to improve dependence, disability, neurological impairment, anxiety and depression after stroke, but there was heterogeneity between trials and methodological limitations in a substantial proportion of the trials. Large, well-designed trials are now needed to determine whether SSRIs should be given routinely to patients with stroke.

Source: PubMed


Still No Reason Not to Use Single-Dose Etomidate for RSI in Septic Patients.

This meta-analysis was flawed, and the authors’ conclusion that etomidate use is linked to increased mortality is faulty.

Researchers performed a meta-analysis to assess the effects of single-dose etomidate used for rapid sequence intubation (RSI) on the adrenal axis and mortality in septic patients. They included only studies that were randomized or prospective observational, had a control group, and reported data on mortality and adrenal insufficiency as determined by cosyntropin stimulation testing. Ten studies involving a total of 1623 patients were included in the analysis; of these, five evaluated mortality (865 patients) and seven evaluated adrenal insufficiency (1303 patients). Of the five mortality studies, only two included patients who were randomized to etomidate versus an alternative agent — neither showed a mortality difference. Of the three studies without etomidate randomization, only one reported a mortality difference.

The authors report that patients receiving etomidate had a higher risk of mortality (pooled relative risk, 1.20) and adrenal insufficiency (pooled RR, 1.33).

Comment: The entire mortality effect comes from a single study in which patients were not randomized for etomidate. We reviewed that secondary analysis of etomidate use previously and found it sorely lacking (JW Emerg Med Dec 18 2009). Four of the five mortality studies, including the three with the highest methodology scores, failed to show any effect of single dose etomidate on the primary outcome of mortality. The authors correctly note that “the quality of literature investigating etomidate in severe sepsis and septic shock is limited in both quantitative and qualitative fashions.”

Meta-analyses of methodologically flawed trials are no more valuable than the trials themselves. Until a sufficiently sized, properly randomized, controlled trial of single-dose etomidate shows harm, etomidate remains one of the safest options for RSI, particularly in patients at risk for hypotension.

Source:Journal Watch Emergency Medicine