Prophylactic magnesium for improving neurologic outcome after aneurysmal subarachnoid hemorrhage: Systematic review and meta-analysis

Purpose

Neurologic disability is common after aneurysmal subarachnoid hemorrhage (aSAH). Our objective was to systematically review the prophylactic use of magnesium to improve neurologic outcomes in these patients.

Methods

We searched MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials to June 2012 for randomized and quasi-randomized controlled trials of intravenous magnesium in adults after aSAH, given before radiologic vasospasm or delayed cerebral ischemia (DCI) and compared with any control group. Two reviewers independently extracted data on study population, interventions, and outcomes (good neurologic outcome [primary outcome], cerebral infarction, DCI, radiographic vasospasm, mortality, adverse events). Analyses used random-effects models.

Results

Of 702 citations, 13 trials (n = 2401) met the selection criteria. Meta-analyses showed that magnesium did not increase the probability of good neurologic outcome (risk ratio [RR], 1.02; 95% confidence interval [CI], 0.97-1.07; P = .49; 12 trials, n = 2345) or decrease the risks of cerebral infarction (RR, 0.69; 95% CI, 0.46-1.05; P = .08; 5 trials, n = 572), radiographic vasospasm (RR, 0.86; 95% CI, 0.71-1.04; P = .13; 7 trials, n = 438), or mortality (RR, 0.98; 95% CI, 0.80-1.20; P = .86; 11 trials, n = 2092). Magnesium did reduce the risk of DCI (RR, 0.73; 95% CI, 0.56-0.96; P = .02; 10 trials, n = 1095). Data on adverse events were generally sparse.

Conclusions

Despite decreasing the incidence of DCI in patients with aSAH, prophylactic intravenous magnesium does not improve neurologic outcome or decrease cerebral infarction, radiographic vasospasm, or mortality.     

Endothelin antagonists in subarachnoid hemorrhage: what next?

In the previous issue of Critical Care, Ma and colleagues perform a meta-analysis of five randomized, clinical trials of endothelin antagonists in patients with aneurysmal subarachnoid hemorrhage. There are four trials using clazosentan and one trial with TAK-044. These studies show that endothelin plays an important role in the genesis of angiographic vasospasm. The benefit of these drugs is less on delayed cerebral ischemia and nonexistent on overall clinical outcome. Why the drugs reduce vasospasm but do not improve outcome could be because of side effects such as hypotension and pulmonary complications that are more common in patients treated with endothelin antagonists or because rescue therapy, which is used more in the placebo groups, improves outcome in these patients to the same extent as the endothelin antagonists. As the authors conclude, future studies of these drugs will need to consider these and other factors in their design.In the previous issue of Critical Care, Ma and colleagues report a meta-analysis of the randomized, clinical trials of clazosentan and TAK-044 in patients with aneurysmal subarachnoid hemorrhage (SAH) [1]. The endothelins (ETs) are a family of three (ET-1, ET-2 and ET-3) 21-amino-acid peptides that act on several receptors, principally ET_A and ET_B receptors in the vasculature. The main effect is to cause vasoconstriction. Experimental data as well as the results of this meta-analysis show that this system is important in the pathogenesis of angiographic vasospasm after SAH [2]. A variety of ET receptor antagonists have been developed. Clazosentan is a heteroarylsulfonamido pyrimidine that was specifically developed to be a relatively water-soluble, small-molecule, highly-selective ET_A receptor antagonist for prevention of angiographic vasospasm [3]. TAK-044 is a relatively nonselective antagonist of ET_A and ET_B receptors [4].Ma and colleagues identified five randomized clinical trials of ET antagonists for SAH. Their meta-analysis gives the same results as the trials, which at least for the four largest studies all had basically the same results. The pooled relative risk (RR) of angiographic vasospasm with ET antagonist treatment was 0.66 (95% confidence interval (CI) = 0.57 to 0.77), so these drugs effectively reduce vasospasm. The main consequence of vasospasm, delayed cerebral ischemia (DCI), was defined in the last three clazosentan studies as delayed ischemic neurological deficit. The current meta-analysis reports delayed ischemic neurological deficit and DCI, but DCI is defined as infarction on computed tomography ''only attributable to cerebral vasospasm and DCI'' [1], which is a partly circular definition. These varied definitions lead to confusion since the definitions vary in the studies and the terminology of Ma and colleagues does not match that recommended by Vergouwen and colleagues [5]. Interestingly, and not unexpectedly, there was a significant reduction in delayed ischemic neurological deficit (RR = 0.77, 95% CI = 0.66 to 0.90) and a trend towards reduction in DCI (RR = 0.87, 95% CI = 0.74 to 1.03). Despite these improvements, there was no effect on mortality and unfavorable outcome. Thus, considering the pathway from angiographic vasospasm to ischemia (DCI by most definitions), to infarction, and to poor outcome, the benefits of ET antagonists diminish at each step.The findings of Ma and colleagues are virtually identical to a meta-analysis conducted by Vergouwen and colleagues [6]. Vergouwen and colleagues, however, also reported data from a subset of the studies showing that there was no significant reduction in vasospasm-related cerebral infarction (RR = 0.76, 95% CI = 0.53 to 1.11) although the RR is reduced, in keeping with the analysis of Ma and colleagues. ET antagonists did not seem to have any effect on all new cerebral infarction (RR = 1.04; 95% CI = 0.91 to 1.19). This is an important finding since cerebral infarction is one of the most important prognostic factors for outcome after SAH. The odds ratios show the same pattern as mentioned above.Why is there a substantial effect on angiographic vasospasm, less effect on infarction judged to be due to vasospasm and no effect on all delayed infarcts and clinical outcome? One theory is that the delayed infarctions are not due solely to angiographic vasospasm. This theory predicts that reducing angiographic vasospasm may not be adequate to reduce infarction and improve outcome. Under this theory, the vasospasm-related and any new infarction incidences should be the same. Strictly speaking, they are the same - although, as noted above, the trends in the odds ratios seem different. One alternative theory is that side effects of the drugs, such as hypotension and pulmonary complications, counteract the beneficial effects of reducing vasospasm so that there is no overall beneficial effect on outcome. Indeed, both meta-analyses report virtually identical and significant increases in lung complications, hypotension and anemia in the patients treated with ET antagonists. To fit the data, this theory would require those side effects being sufficient to cause infarctions so that the overall infarction rate is about the same. One could argue that the data, while not conclusive, favor the second theory. Another fundamental issue is that patients in the placebo groups of these studies are administered rescue therapies for DCI in a higher percentage of cases than in the drug-treated groups. If rescue therapy is efficacious, then this also could reduce the difference between the groups in cerebral infarction and overall clinical outcome.What are some of the limitations of Ma and colleagues'' meta-analysis? The strengths of the current analysis are that it is rigorous and follows preferred reporting items for systematic review and meta-analysis (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines [7]. The results of this meta-analysis are not surprising, given that the results for all of the individual studies are the same - which is not a weakness but a comment. Another issue is the inclusion of drugs of different chemical classes and with different known pharmacologic actions in these sorts of meta-analyses. Multiple doses and methods and timing of administration of different drugs are combined into single treatment groups, which makes no sense biologically.What does the future hold for ET antagonists in SAH? Since all of the studies are only recently completed, obtaining the individual patient data from the sponsors may allow further analysis to guide further studies. This collation is obviously being done, since Actelion (Allschwill, Switzerland) sponsored all of the clazosentan studies, have the data and have invested heavily in clazosentan. According to Vergouwen and colleagues, Actelion did not provide individual patient data or data that would enable an intention-to-treat analysis [6]. The former omission is an issue. The latter missing data, however, given the small number of patients involved, are not going to change the overall findings. Actelion, however, must be complimented for supporting development of clazosentan and for conducting these studies that would not have occurred if we waited for funding from peer-reviewed granting agencies. The studies they have conducted have been fundamentally directed at improving the outcome of patients with SAH and there cannot be any question about their motivation to develop a drug that will address this.In summary, the authors'' conclusion is that future studies of ET antagonists should be ''more carefully formulated and designed''. Input into the design of these studies would be welcome, given that all of these studies were already very carefully formulated and designed. My opinion is that some method of reducing the side effects of ET antagonists, primarily hypotension and pulmonary complications, is the key to the future of these drugs.     

The effect of goal-directed therapy on mortality in patients with sepsis - earlier is better: a meta-analysis of randomized controlled trials

Introduction

The Surviving Sepsis Campaign guidelines recommend goal-directed therapy (GDT) for the early resuscitation of patients with sepsis. However, the findings of the ProCESS (Protocolized Care for Early Septic Shock) trial showed no benefit from GDT for reducing mortality rates in early septic shock. We performed a meta-analysis to integrate these findings with existing literature on this topic and evaluate the effect of GDT on mortality due to sepsis.

Methods

We searched the PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) databases and reference lists of extracted articles. Randomized controlled trials comparing GDT with standard therapy or usual care in patients with sepsis were included. The prespecified primary outcome was overall mortality.

Results

In total, 13 trials involving 2,525 adult patients were included. GDT significantly reduced overall mortality in the random-effects model (relative risk (RR), 0.83; 95% confidence interval (CI), 0.71 to 0.96; P =0.01; I² = 56%). Predefined subgroup analysis according to the timing of GDT for resuscitation suggested that a mortality benefit was seen only in the subgroup of early GDT within the first 6 hours (seven trials; RR, 0.77; 95% CI, 0.67 to 0.89; P =0.0004; I² = 40%), but not in the subgroup with late or unclear timing of GDT (six trials; RR, 0.92; 95% CI, 0.69 to 1.24; P =0.59; I² = 56%). GDT was significantly associated with the use of dobutamine (five trials; RR, 2.71; 95% CI, 1.20 to 6.10; P =0.02).

Conclusions

The results of the present meta-analysis suggest that GDT significantly reduces overall mortality in patients with sepsis, especially when initiated early. However, owing to the variable quality of the studies, strong and definitive recommendations cannot be made.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0570-5) contains supplementary material, which is available to authorized users.     

Intravenous magnesium therapy in adult patients with an aneurysmal subarachnoid haemorrhage: A systematic review and meta-analysis

BackgroundThe value of magnesium for the prevention of cerebral arterial vasospasm in patients with aneurysmal subarachnoid haemorrhage (SAH) is debatable. We performed a systematic review to collate the available evidence to evaluate the effects of intravenous magnesium for the prevention of cerebral arterial vasospasm.Materials and methodsAn electronic search of MEDLINE (Ovid), ProQuest, CINAHL and the Cochrane Database of Systematic Reviews was undertaken up to 1st October 2012 for randomised controlled trials (RCTs) of intravenous magnesium for the prevention of vasospasm in adult patients with aneurysmal SAH. Primary outcome measures were risk of vasospasm, functional outcomes and mortality. Results are presented as risk ratios (RR) and 95% confidence intervals (CI).ResultsNine of 38 trials were included in this review. Not all trials could be combined for analyses due to differences in reported outcomes and outcome definitions. Of the trials that could be combined we found a statistically significant reduction on the incidence of vasospasm with magnesium (RR 0.83; 95% CI 0.71, 0.98; P = 0.03). No statistical difference for the last reported favourable functional outcome (RR 1.00; 95% CI 0.96, 1.05; P = 0.84); or mortality (RR 0.95; 95% CI 0.77, 1.18; P = 0.67) between magnesium treated and standard care/control groups was found.ConclusionWe identified a benefit in the role of magnesium to reduce the incidence of cerebral vasospasm in patients with an aneurysmal SAH. However no benefit was found regarding improved favourable functional outcome or a reduction of mortality.     

Impact of oral care with versus without toothbrushing on the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis of randomized controlled trials

Introduction

Ventilator-associated pneumonia (VAP) remains a common hazardous complication in mechanically ventilated patients and is associated with increased morbidity and mortality. We undertook a systematic review and meta-analysis of randomized controlled trials to assess the effect of toothbrushing as a component of oral care on the prevention of VAP in adult critically ill patients.

Methods

A systematic literature search of PubMed and Embase (up to April 2012) was conducted. Eligible studies were randomized controlled trials of mechanically ventilated adult patients receiving oral care with toothbrushing. Relative risks (RRs), weighted mean differences (WMDs), and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with the I² test.

Results

Four studies with a total of 828 patients met the inclusion criteria. Toothbrushing did not significantly reduce the incidence of VAP (RR, 0.77; 95% CI, 0.50 to 1.21) and intensive care unit mortality (RR, 0.88; 95% CI, 0.70 to 1.10). Toothbrushing was not associated with a statistically significant reduction in duration of mechanical ventilation (WMD, -0.88 days; 95% CI, -2.58 to 0.82), length of intensive care unit stay (WMD, -1.48 days; 95% CI, -3.40 to 0.45), antibiotic-free day (WMD, -0.52 days; 95% CI, -2.82 to 1.79), or mechanical ventilation-free day (WMD, -0.43 days; 95% CI, -1.23 to 0.36).

Conclusions

Oral care with toothbrushing versus without toothbrushing does not significantly reduce the incidence of VAP and alter other important clinical outcomes in mechanically ventilated patients. However, the results should be interpreted cautiously since relevant evidence is still limited, although accumulating. Further large-scale, well-designed randomized controlled trials are urgently needed.     

Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials

Introduction

The ideal measures to prevent postoperative delirium remain unestablished. We conducted this systematic review and meta-analysis to clarify the significance of potential interventions.

Methods

The PRISMA statement guidelines were followed. Two researchers searched MEDLINE, EMBASE, CINAHL and the Cochrane Library for articles published in English before August 2012. Additional sources included reference lists from reviews and related articles from ''Google Scholar''. Randomized clinical trials (RCTs) on interventions seeking to prevent postoperative delirium in adult patients were included. Data extraction and methodological quality assessment were performed using predefined data fields and scoring system. Meta-analysis was accomplished for studies that used similar strategies. The primary outcome measure was the incidence of postoperative delirium. We further tested whether interventions effective in preventing postoperative delirium shortened the length of hospital stay.

Results

We identified 38 RCTs with interventions ranging from perioperative managements to pharmacological, psychological or multicomponent interventions. Meta-analysis showed dexmedetomidine sedation was associated with less delirium compared to sedation produced by other drugs (two RCTs with 415 patients, pooled risk ratio (RR) = 0.39; 95% confidence interval (CI) = 0.16 to 0.95). Both typical (three RCTs with 965 patients, RR = 0.71; 95% CI = 0.54 to 0.93) and atypical antipsychotics (three RCTs with 627 patients, RR = 0.36; 95% CI = 0.26 to 0.50) decreased delirium occurrence when compared to placebos. Multicomponent interventions (two RCTs with 325 patients, RR = 0.71; 95% CI = 0.58 to 0.86) were effective in preventing delirium. No difference in the incidences of delirium was found between: neuraxial and general anesthesia (four RCTs with 511 patients, RR = 0.99; 95% CI = 0.65 to 1.50); epidural and intravenous analgesia (three RCTs with 167 patients, RR = 0.93; 95% CI = 0.61 to 1.43) or acetylcholinesterase inhibitors and placebo (four RCTs with 242 patients, RR = 0.95; 95% CI = 0.63 to 1.44). Effective prevention of postoperative delirium did not shorten the length of hospital stay (10 RCTs with 1,636 patients, pooled SMD (standard mean difference) = -0.06; 95% CI = -0.16 to 0.04).

Conclusions

The included studies showed great inconsistencies in definition, incidence, severity and duration of postoperative delirium. Meta-analysis supported dexmedetomidine sedation, multicomponent interventions and antipsychotics were useful in preventing postoperative delirium.     

Effect of statin therapy on mortality from infection and sepsis: a meta-analysis of randomized and observational studies

Introduction

Observational data have suggested that statin therapy may reduce mortality in patients with infection and sepsis; however, results from randomized studies are contradictory and do not support the use of statins in this context. Here, we performed a meta-analysis to investigate the effects of statin therapy on mortality from infection and sepsis.

Methods

We searched electronic databases (PubMed and Embase) for articles published before November 2013. Randomized or observational studies reporting the effects of statin therapy on mortality in patients with infection or sepsis were eligible. Randomized and observational studies were separately pooled with relative risks (RRs) and random-effects models.

Results

We examined 5 randomized controlled trials with 867 patients and 27 observational studies with 337,648 patients. Among the randomized controlled trials, statins did not significantly decrease in-hospital mortality (RR, 0.98; 95% confidence interval (CI), 0.73 to 1.33) or 28-day mortality (RR, 0.93; 95% CI, 0.46 to 1.89). However, observational studies indicated that statins were associated with a significant decrease in mortality with adjusted data (RR, 0.65; 95% CI, 0.57 to 0.75) or unadjusted data (RR, 0.74; 95% CI, 0.59 to 0.94).

Conclusions

Limited evidence suggests that statins may not be associated with a significant reduction in mortality from infection and sepsis. Although meta-analysis from observational studies showed that the use of statins was associated with a survival advantage, these outcomes were limited by high heterogeneity and possible bias in the data. Therefore, we should be cautious about the use of statins in infection and sepsis.     

Non-invasive assessment of vasospasm following aneurysmal SAH using C-arm FDCT parenchymal blood volume measurement in the neuro-interventional suite: Technical feasibility

Introduction

Cerebral vasospasm is the leading cause of morbidity and mortality in patients with aneurysmal subarachnoid haemorrhage (SAH) surviving the initial ictus. Commonly used techniques for vasospasm assessment are digital subtraction angiography and transcranial Doppler sonography. These techniques can reliably identify only the major vessel spasm and fail to estimate its haemodynamic significance. To overcome these issues and to enable comprehensive non-invasive assessment of vasospasm inside the interventional suite, a novel protocol involving measurement of parenchymal blood volume (PBV) using C-arm flat detector computed tomography (FDCT) was implemented.

Materials and methods

Patients from the neuro-intensive treatment unit (ITU) with suspected vasospasm following aneurysmal SAH were scanned with a biplane C-arm angiography system using an intravenous contrast injection protocol. The PBV maps were generated using prototype software. Contemporaneous clinically indicated MR scan including the diffusion- and perfusion-weighted sequences was performed. C-arm PBV maps were compared against the MR perfusion maps.

Results

Distribution of haemodynamic impairment on C-arm PBV maps closely matched the pattern of abnormality on MR perfusion maps. On visual comparison between the two techniques, the extent of abnormality indicated PBV to be both cerebral blood flow and cerebral blood volume weighted.

Conclusion

C-arm FDCT PBV measurements allow an objective assessment of the severity and localisation of cerebral hypoperfusion resulting from vasospasm. The technique has proved feasible and useful in very sick patients after aneurysmal SAH. The promise shown in this early study indicates that it deserves further evaluation both for post-SAH vasospasm and in other relevant clinical settings.     

Antiarrhythmia drugs for cardiac arrest: a systemic review and meta-analysis

Introduction

Antiarrhythmia agents have been used in the treatment of cardiac arrest, and we aimed to review the relevant clinical controlled trials to assess the effects of antiarrhythmics during cardiopulmonary resuscitation.

Methods

We searched databases including Cochrane Central Register of Controlled Trials; MEDLINE, and EMBASE. Clinical controlled trials that addressed the effects of antiarrhythmics (including amiodarone, lidocaine, magnesium, and other new potassium-channel blockers) on the outcomes of cardiac arrest were included. Data were collected independently by two authors. The risk ratio of each outcome was collected, and meta-analysis was used for data synthesis if appropriate. Heterogeneity was assessed with the χ² test and the I² test.

Results

Ten randomized controlled trials and seven observational trials were identified. Amiodarone (relative risk (RR), 0.82; 95% confidence interval (CI), 0.54 to 1.24), lidocaine (RR, 2.26; 95% CI, 0.93to 5.52), magnesium (RR, 0.82; 95% CI, 0.54 to 1.24) and nifekalant were not shown to improve the survival to hospital discharge compared with placebo, but amiodarone, lidocaine, and nifekalant were shown to be beneficial to initial resuscitation, assessed by the rate of return of spontaneous circulation and survival to hospital admission, with amiodarone being superior to lidocaine (RR, 1.28; 95% CI, 0.57 to 2.86) and nifekalant (RR, 0.50; 95% CI, 0.19 to 1.31). Bretylium and sotalol were not shown to be beneficial.

Conclusions

Our review suggests that when administered during resuscitation, antiarrhythmia agents might not improve the survival to hospital discharge, but they might be beneficial to initial resuscitation. This is consistent with the AHA 2010 guidelines for resuscitation and cardiovascular emergency, but more studies with good methodologic quality and large numbers of patients are still needed to make further assessment.     

Efficacy of ultrasound-guided radial artery catheterization: a systematic review and meta-analysis of randomized controlled trials

Introduction

Ultrasound guidance has emerged as an adjunct for central vein catheterization in both adults and children. However, the use of ultrasound guidance for radial arterial catheterization has not been well established. We conducted a systematic review and meta-analysis to evaluate the efficacy of ultrasound guidance for radial artery catheterization.

Methods

PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials (RCTs) comparing ultrasound guidance with other techniques (palpation or Doppler) in adult or pediatric patients requiring radial artery catheterization were included. The primary outcome was first-attempt success.

Results

Seven RCTs enrolling 546 patients met the inclusion criteria, and all the selected trials were considered as at high risk of bias. Ultrasound-guided radial artery catheterization was associated with an increased first-attempt success (relative risk (RR) 1.55, 95% confidence interval (CI) 1.02 to 2.35). There was significant heterogeneity among the studies (I² = 74%). Ultrasound-guided radial artery catheterization in small children and infants also provided an increased chance for first-attempt success (RR 1.94, 95% CI 1.31 to 2.88). Ultrasound guidance further significantly reduced mean attempts to success (weighted mean difference (WMD) −1.13, 95% CI −1.58 to −0.69), mean time to success (WMD −72.97 seconds, 95% CI −134.41 to −11.52), and incidence of the complication of hematoma (RR 0.17, 95% CI 0.07 to 0.41).

Conclusions

Ultrasound guidance is an effective and safe technique for radial artery catheterization, even in small children and infants. However, the results should be interpreted cautiously due to the heterogeneity among the studies.     

Nasogastric or nasojejunal feeding in predicted severe acute pancreatitis: a meta-analysis

Introduction

Enteral feeding can be given either through the nasogastric or the nasojejunal route. Studies have shown that nasojejunal tube placement is cumbersome and that nasogastric feeding is an effective means of providing enteral nutrition. However, the concern that nasogastric feeding increases the chance of aspiration pneumonitis and exacerbates acute pancreatitis by stimulating pancreatic secretion has prevented it being established as a standard of care. We aimed to evaluate the differences in safety and tolerance between nasogastric and nasojejunal feeding by assessing the impact of the two approaches on the incidence of mortality, tracheal aspiration, diarrhea, exacerbation of pain, and meeting the energy balance in patients with severe acute pancreatitis.

Method

We searched the electronic databases of the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We included prospective randomized controlled trials comparing nasogastric and nasojejunal feeding in patients with predicted severe acute pancreatitis. Two reviewers assessed the quality of each study and collected data independently. Disagreements were resolved by discussion among the two reviewers and any of the other authors of the paper. We performed a meta-analysis and reported summary estimates of outcomes as Risk Ratio (RR) with 95% confidence intervals (CIs).

Results

We included three randomized controlled trials involving a total of 157 patients. The demographics of the patients in the nasogastric and nasojejunal feeding groups were comparable. There were no significant differences in the incidence of mortality (RR = 0.69, 95% CI: 0.37 to 1.29, P = 0.25); tracheal aspiration (RR = 0.46, 95% CI: 0.14 to 1.53, P = 0.20); diarrhea (RR = 1.43, 95% CI: 0.59 to 3.45, P = 0.43); exacerbation of pain (RR = 0.94, 95% CI: 0.32 to 2.70, P = 0.90); and meeting energy balance (RR = 1.00, 95% CI: 0.92 to 1.09, P = 0.97) between the two groups. Nasogastric feeding was not inferior to nasojejunal feeding.

Conclusions

Nasogastric feeding is safe and well tolerated compared with nasojejunal feeding. Study limitations included a small total sample size among others. More high-quality large-scale randomized controlled trials are needed to validate the use of nasogastric feeding instead of nasojejunal feeding.     

Exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome: a systematic review and meta-analysis

Introduction

The effectiveness of corticosteroid therapy on the mortality of acute respiratory distress syndrome (ARDS) remains under debate. We aimed to explore the grounds for the inconsistent results in previous studies and update the evidence.

Methods

We searched MEDLINE, Cochrane Central Register of Controlled Trials and Web of Science up to December 2013. Eligible studies included randomized clinical trials (RCTs) and cohort studies that reported mortality and that had corticosteroid nonusers for comparison. The effect of corticosteroids on ARDS mortality was assessed by relative risk (RR) and risk difference (RD) for ICU, hospital, and 60-day mortality using a random-effects model.

Results

Eight RCTs and 10 cohort studies were included for analysis. In RCTs, corticosteroids had a possible but statistically insignificant effect on ICU mortality (RD, −0.28; 95% confidence interval (CI), −0.53 to −0.03 and RR, 0.55; 95% CI, 0.24 to 1.25) but no effect on 60-day mortality (RD, −0.01; 95% CI, −0.12 to 0.10 and RR, 0.97; 95% CI, 0.75 to 1.26). In cohort studies, corticosteroids had no effect on ICU mortality (RR, 1.05; 95% CI, 0.74 to 1.49) but non-significantly increased 60-day mortality (RR, 1.30; 95% CI, 0.96 to 1.78). In the subgroup analysis by ARDS etiology, corticosteroids significantly increased mortality in influenza-related ARDS (three cohort studies, RR, 2.45, 95% CI, 1.40 to 4.27).

Conclusions

The effects of corticosteroids on the mortality of ARDS differed by duration of outcome measures and etiologies. Corticosteroids did not improve longer-term outcomes and may cause harm in certain subgroups. Current data do not support routine use of corticosteroids in ARDS. More clinical trials are needed to specify the favorable and unfavorable subgroups for corticosteroid therapy.     

Efficacy and adverse events of high-frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome: a meta-analysis

Introduction

Theoretically, high-frequency oscillatory ventilation (HFOV) achieves all goals of a lung-protective ventilatory mode and seems ideal for the treatment of adult patients with acute respiratory distress syndrome (ARDS). However, its effects on mortality and adverse clinical outcomes remain uncertain given the paucity of high-quality studies in this area. This meta-analysis was performed to evaluate the efficacy and adverse events of HFOV in adults with ARDS.

Methods

We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials through February 2014 to retrieve randomized controlled trials of HFOV in adult ARDS patients. Two independent reviewers extracted data on study methods, clinical and physiological outcomes and adverse events. The primary outcome was 30-day or hospital mortality. Risk of bias was evaluated with the Cochrane Collaboration’s tool. Mortality, oxygenation and adverse effects of HFOV were compared to those of conventional mechanical ventilation. A random-effects model was applied for meta-analysis.

Results

A total of five trials randomly assigning 1,580 patients met inclusion criteria. Pooled data showed that HFOV significantly improved oxygenation on day one of therapy (four studies; 24% higher; 95% confidence interval (CI) 11 to 40%; P <0.01). However, HFOV did not reduce mortality risk (five studies; risk ratio (RR) 1.04; 95% CI 0.83 to 1.31; P = 0.71) and two early terminated studies suggested a harmful effect of HFOV in ARDS (two studies; RR 1.33; 95% CI 1.09 to 1.62; P <0.01). Safety profiles showed that HFOV was associated with a trend toward increased risk of barotrauma (five studies; RR 1.19; 95% CI 0.83 to 1.72; P = 0.34) and unfavorable hemodynamics (five studies; RR 1.16; 95% CI 0.97 to 1.39; P = 0.12).

Conclusions

HFOV improved oxygenation in adult patients with ARDS; however, it did not confer a survival benefit and might cause harm in the era of lung-protective ventilation strategy. The evidence suggests that HFOV should not be a routine practice in ARDS and further studies specifically selecting patients for this ventilator mode should be pursued.     

Efficacy of the Pilates method for pain and disability in patients with chronic nonspecific low back pain: a systematic review with meta-analysis

Objective

To systematically review the available evidence on the efficacy of the Pilates method in patients with chronic nonspecific low back pain.

Method

Searches were performed in MEDLINE, EMBASE, PEDro, SciELO, LILACS, CINAHL and CENTRAL in March 2013. Randomized controlled trials that tested the effectiveness of the Pilates method (against a nontreatment group, minimal intervention or other types of interventions) in adults with chronic low back pain were included regardless the language of publication. The outcome data were extracted from the eligible studies and were combined using a meta-analysis approach.

Results

The searches identified a total of 1,545 articles. From these, eight trials were considered eligible, and seven trials were combined in the meta-analysis. The comparison groups were as follows: Pilates versus other types of exercises (n=2 trials), and Pilates versus no treatment group or minimal intervention (n=4 trials) for short term pain; Pilates versus minimal intervention for short-term disability (n=4).We determined that Pilates was not better than other types of exercises for reducing pain intensity. However, Pilates was better than a minimal intervention for reducing short-term pain and disability (pain: pooled mean difference=1.6 points; 95% CI 1.4 to 1.8; disability: pooled mean difference=5.2 points; 95% CI 4.3 to 6.1).

Conclusions

Pilates was better than a minimal intervention for reducing pain and disability in patients with chronic low back pain. Pilates was not better than other types of exercise for short-term pain reduction.     

Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis

Introduction

Hyper- and hypoglycemia are strongly associated with adverse outcomes in critical care. Neurologically injured patients are a unique subgroup, where optimal glycemic targets may differ, such that the findings of clinical trials involving heterogeneous critically ill patients may not apply.

Methods

We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing intensive insulin therapy with conventional glycemic control among patients with traumatic brain injury, ischemic or hemorrhagic stroke, anoxic encephalopathy, central nervous system infections or spinal cord injury.

Results

Sixteen RCTs, involving 1248 neurocritical care patients, were included. Glycemic targets with intensive insulin ranged from 70-140 mg/dl (3.9-7.8 mmol/L), while conventional protocols aimed to keep glucose levels below 144-300 mg/dl (8.0-16.7 mmol/L). Tight glycemic control had no impact on mortality (RR 0.99; 95% CI 0.83-1.17; p = 0.88), but did result in fewer unfavorable neurological outcomes (RR 0.91; 95% CI 0.84-1.00; p = 0.04). However, improved outcomes were only observed when glucose levels in the conventional glycemic control group were permitted to be relatively high [threshold for insulin administration > 200 mg/dl (> 11.1 mmol/L)], but not with more intermediate glycemic targets [threshold for insulin administration 140-180 mg/dl (7.8-10.0 mmol/L)]. Hypoglycemia was far more common with intensive therapy (RR 3.10; 95% CI 1.54-6.23; p = 0.002), but there was a large degree of heterogeneity in the results of individual trials (Q = 47.9; p<0.0001; I² = 75%). Mortality was non-significantly higher with intensive insulin in studies where the proportion of patients developing hypoglycemia was large (> 33%) (RR 1.17; 95% CI 0.79-1.75; p = 0.44).

Conclusions

Intensive insulin therapy significantly increases the risk of hypoglycemia and does not influence mortality among neurocritical care patients. Very loose glucose control is associated with worse neurological recovery and should be avoided. These results suggest that intermediate glycemic goals may be most appropriate.     

Small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials

Introduction

This systematic review and meta-analysis aimed to evaluate the effect of small bowel feeding compared with gastric feeding on the frequency of pneumonia and other patient-important outcomes in critically ill patients.

Methods

We searched EMBASE, MEDLINE, clinicaltrials.gov and personal files from 1980 to Dec 2012, and conferences and proceedings from 1993 to Dec 2012 for randomized trials of adult critically ill patients in the intensive care unit (ICU) comparing small bowel feeding to gastric feeding, and evaluating risk of pneumonia, mortality, length of ICU stay, achievement of caloric requirements, duration of mechanical ventilation, vomiting, and aspiration. Independently, in duplicate, we abstracted trial characteristics, outcomes and risk of bias.

Results

We included 19 trials with 1394 patients. Small bowel feeding compared to gastric feeding was associated with reduced risk of pneumonia (risk ratio [RR] 0.70; 95% CI, 0.55, 0.90; P = 0.004; I² = 0%) and ventilator-associated pneumonia (RR 0.68; 95% CI 0.53, 0.89; P = 0.005; I² = 0%), with no difference in mortality (RR 1.08; 95% CI 0.90, 1.29; P = 0.43; I² = 0%), length of ICU stay (WMD -0.57; 95%CI -1.79, 0.66; P = 0.37; I² = 0%), duration of mechanical ventilation (WMD -1.01; 95%CI -3.37, 1.35; P = 0.40; I² = 17%), gastrointestinal bleeding (RR 0.89; 95% CI 0.56, 1.42; P = 0.64; I² = 0%), aspiration (RR 0.92; 95% CI 0.52, 1.65; P = 0.79; I² = 0%), and vomiting (RR 0.91; 95% CI 0.53, 1.54; P = 0.72; I² = 57%). The overall quality of evidence was low for pneumonia outcome.

Conclusions

Small bowel feeding, in comparison with gastric feeding, reduces the risk of pneumonia in critically ill patients without affecting mortality, length of ICU stay or duration of mechanical ventilation. These observations are limited by variation in pneumonia definition, imprecision, risk of bias and small sample size of individual trials.     

Vitamin D deficiency as a risk factor for infection,sepsis and mortality in the critically ill: systematic review and meta-analysis

Introduction

In Europe, vitamin D deficiency is highly prevalent varying between 40% and 60% in the healthy general adult population. The consequences of vitamin D deficiency for sepsis and outcome in critically ill patients remain controversial. We therefore systematically reviewed observational cohort studies on vitamin D deficiency in the intensive care unit.

Methods

Fourteen observational reports published from January 2000 to March 2014, retrieved from Pubmed and Embase, involving 9,715 critically ill patients and serum 25-hydroxyvitamin D₃ (25 (OH)-D) concentrations, were meta-analysed.

Results

Levels of 25 (OH)-D less than 50 nmol/L were associated with increased rates of infection (risk ratio (RR) 1.49, 95% (confidence interval (CI) 1.12 to 1.99), P = 0.007), sepsis (RR 1.46, 95% (CI 1.27 to 1.68), P <0.001), 30-day mortality (RR 1.42, 95% (CI 1.00 to 2.02), P = 0.05), and in-hospital mortality (RR 1.79, 95% (CI 1.49 to 2.16), P <0.001). In a subgroup analysis of adjusted data including vitamin D deficiency as a risk factor for 30-day mortality the pooled RR was 1.76 (95% CI 1.37 to 2.26, P <0.001).

Conclusions

This meta-analysis suggests that vitamin D deficiency increases susceptibility for severe infections and mortality of the critically ill.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0660-4) contains supplementary material, which is available to authorized users.     

Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials

Introduction

Randomized trials investigating neuromuscular blocking agents in adult acute respiratory distress syndrome (ARDS) have been inconclusive about effects on mortality, which is very high in this population. Uncertainty also exists about the associated risk of ICU-acquired weakness.

Methods

We conducted a systematic review and meta-analysis. We searched the Cochrane (Central) database, MEDLINE, EMBASE, ACP Journal Club, and clinical trial registries for randomized trials investigating survival effects of neuromuscular blocking agents in adults with ARDS. Two independent reviewers abstracted data and assessed methodologic quality. Primary study investigators provided additional unpublished data.

Results

Three trials (431 patients; 20 centers; all from the same research group in France) met inclusion criteria for this review. All trials assessed 48-hour infusions of cisatracurium besylate. Short-term infusion of cisatracurium besylate was associated with lower hospital mortality (RR, 0.72; 95% CI, 0.58 to 0.91; P = 0.005; I² = 0). This finding was robust on sensitivity analyses. Neuromuscular blockade was also associated with lower risk of barotrauma (RR, 0.43; 95% CI, 0.20 to 0.90; P = 0.02; I² = 0), but had no effect on the duration of mechanical ventilation among survivors (MD, 0.25 days; 95% CI, 5.48 to 5.99; P = 0.93; I² = 49%), or the risk of ICU-acquired weakness (RR, 1.08; 95% CI, 0.83 to 1.41; P = 0.57; I² = 0). Primary studies lacked protracted measurements of weakness.

Conclusions

Short-term infusion of cisatracurium besylate reduces hospital mortality and barotrauma and does not appear to increase ICU-acquired weakness for critically ill adults with ARDS.     

Is high-frequency oscillatory ventilation more effective and safer than conventional protective ventilation in adult acute respiratory distress syndrome patients? A meta-analysis of randomized controlled trials

Introduction

Comprehensively evaluating the efficacy and safety of high-frequency oscillatory ventilation (HFOV) is important to allow clinicians who are using or considering this intervention to make appropriate decisions.

Methods

To find randomized controlled trials (RCTs) comparing HFOV with conventional mechanical ventilation (CMV) as an initial treatment for adult ARDS patients, we searched electronic databases (including PubMed, MedLine, Springer Link, Elsevier Science Direct, ISI web of knowledge, and EMBASE) with the following terms: “acute respiratory distress syndrome”, “acute lung injury”, and “high frequency oscillation ventilation”. Additional sources included reference lists from the identified primary studies and relevant meta-analyses. Two investigators independently screened articles and extracted data. Meta-analysis was conducted using random-effects models.

Results

We included 6 RCTs with a total of 1,608 patients in this meta-analysis. Compared with CMV, HFOV did not significantly reduce the mortality at 30 or 28 days. The pooled relative risk (RR) was 1.051 (95% confidence interval (CI) 0.813 to 1.358). ICU mortality was also not significantly reduced in HFOV group, with a pooled RR of 1.218 (95% CI 0.925 to 1.604). The pooled effect sizes of HFOV for oxygenation failure, ventilation failure and duration of mechanical ventilation were 0.557 (95% CI 0.351 to 0.884), 0.892 (95% CI 0.435 to 1.829) and 0.079 (95% CI −0.045 to 0.203), respectively. The risk of barotrauma and hypotension were similar between the CMV group and HFOV group, with a RR of 1.205 (95% CI 0.834 to 1.742) and a RR of 1.326 (95% CI 0.271 to 6.476), respectively.

Conclusions

Although HFOV seems not to increase the risk of barotrauma or hypotension, and reduces the risk of oxygenation failure, it does not improve survival in adult acute respiratory distress syndrome patients.     

Depression and use of health care services in patients with advanced cancer

Objective

To examine whether depression in patients with advanced cancer is associated with increased rates of physician visits, especially to primary care.

Design

Retrospective, observational study linking depression survey data to provincial health administration data.

Setting

Toronto, Ont.

Participants

A total of 737 patients with advanced cancer attending Princess Margaret Hospital, who participated in the Will to Live Study from 2002 to 2008.

Main outcome measures

Frequency of visits to primary care, oncology, surgery, and psychiatry services, before and after the depression assessment.

Results

Before the assessment, depression was associated with an almost 25% increase in the rate of primary care visits for reasons not related to mental health (rate ratio [RR] = 1.23, 95% CI 1.00 to 1.50), adjusting for medical morbidity and other factors. After assessment, depression was associated with a 2-fold increase in the rate of primary care visits for mental health–related reasons (RR = 2.35, 95% CI 1.18 to 4.66). However, depression was also associated during this time with an almost 25% reduction in the rate of oncology visits (RR = 0.78, 95% CI 0.65 to 0.94).

Conclusion

Depression affects health care service use in patients with advanced cancer. Individuals with depression were more likely to see primary care physicians but less likely to see oncologists, compared with individuals without depression. However, the frequent association of disease-related factors with depression in patients with advanced cancer highlights the need for communication between oncologists and primary care physicians about the medical and psychosocial care of these patients.