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BMJ Open Sep 2020To integrate evidence from randomised controlled trials (RCTs) and observational studies on the efficacy of inhaled treatments for chronic obstructive pulmonary disease... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To integrate evidence from randomised controlled trials (RCTs) and observational studies on the efficacy of inhaled treatments for chronic obstructive pulmonary disease using network meta-analyses.
METHODS
Systematic searches MEDLINE and Embase based on predetermined criteria. Network meta-analyses of RCTs investigated efficacy on exacerbations (long-term: ≥20 weeks of treatment; short-term: <20 weeks), lung function (≥12 weeks), health-related quality of life, mortality and adverse events. Qualitative comparisons of efficacies between RCTs and observational studies.
RESULTS
212 RCTs and 19 observational studies were included. Compared with combined long-acting beta-adrenoceptor agonists and long-acting muscarinic antagonists (LABA+LAMA), triple therapy (LABA+LAMA+inhaled corticosteroid) was significantly more effective at reducing exacerbations (long-term 0.85 (95% CI: 0.78 to 0.94; short-term 0.67 (95% CI: 0.49 to 0.92)) and mortality (0.72 (95% CI: 0.59 to 0.89)) but was also associated with increased pneumonia (1.35 (95% CI: 1.10 to 1.67)). No differences in lung function (0.02 (95% CI: -0.10 to 0.14)), health-related quality of life (-1.12 (95% CI: -3.83 to 1.59)) or other adverse events (1.02 (95% CI: 0.96 to 1.08)) were found. Most of the observational evidence trended in the same direction as pooled RCT data.
CONCLUSION
Further evidence, especially pragmatic trials, are needed to fully understand the characteristics of patient subgroups who may benefit from triple therapy and for those whom the extra risk of adverse events, such as pneumonia, may outweigh any benefits.
PROSPERO REGISTRATION NUMBER
CRD42018088013.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory Therapy
PubMed: 32994234
DOI: 10.1136/bmjopen-2019-036455 -
Drugs & Aging Nov 2020Cumulative exposure to one or more anticholinergic medications ("anticholinergic burden") is associated with an increased risk of adverse outcomes, particularly among...
BACKGROUND
Cumulative exposure to one or more anticholinergic medications ("anticholinergic burden") is associated with an increased risk of adverse outcomes, particularly among older individuals. Mirabegron, an oral selective β3-adrenergic receptor agonist, has demonstrated efficacy in managing the symptoms of overactive bladder without contributing to anticholinergic burden. However, it is not known whether the favorable safety profile of mirabegron relative to antimuscarinics varies with increasing age among a patient population who may have a high anticholinergic burden.
OBJECTIVE
The primary objective of this study was to indirectly compare the safety and efficacy profile of mirabegron relative to antimuscarinics in older adults with overactive bladder.
METHODS
A systematic literature review was conducted to identify randomized controlled trials that reported safety and efficacy endpoints among patients aged ≥ 65 years. Identified randomized controlled trials were subsequently synthesized via a network meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines in designing, performing, and reporting the literature review were followed. In line with current best practices, the network meta-analysis was conducted using a Bayesian approach and according to the overall general guidance for evidence synthesis developed by the National Institute for Health and Care Excellence decision support unit. Estimates of relative safety were assessed via the odds ratio and estimates of relative efficacy were assessed via means and credible intervals.
RESULTS
A total of 3078 abstracts, 300 of which underwent full-text screening, were identified using the search criteria. Twenty articles reporting on 21 randomized controlled trials were eligible for data extraction and synthesis. Following review, five safety and five efficacy endpoints were considered for inclusion in the network meta-analysis. Regarding findings typical of anticholinergic exposure in older adults, mirabegron was not associated with an increased odds of dry mouth (odds ratio 95% credible interval 0.76 [0.26-2.37]) or constipation (1.08 [0.39-3.02]) relative to placebo, whereas antimuscarinics were strongly associated with these events (odds ratio range 3.78-7.85 and 2.12-4.66, respectively). In this older population, mirabegron was associated with a similar odds of experiencing adverse event-related treatment discontinuations relative to placebo (0.99 [0.57-1.70]), while the odds of experiencing an adverse event-related treatment discontinuation for antimuscarinics had a range of 1.14-3.03 (in most cases, the association was mild). No increased odds of experiencing overall treatment-emergent adverse events was observed for mirabegron or antimuscarinics (odds ratio range 1.25-1.55), apart from fesoterodine (2.23 [1.37-3.37]). Finally, a similar treatment effect was observed across all efficacy endpoints between mirabegron and antimuscarinics in this older population.
CONCLUSIONS
This study indicates that the safety and efficacy profile of mirabegron remains favorable compared with antimuscarinics among older adults. This includes safety outcomes typically associated with anticholinergic burden, which were less frequently observed in patients treated with mirabegron.
Topics: Acetanilides; Aged; Benzhydryl Compounds; Constipation; Female; Humans; Male; Muscarinic Antagonists; Network Meta-Analysis; Odds Ratio; Randomized Controlled Trials as Topic; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive
PubMed: 32960422
DOI: 10.1007/s40266-020-00792-9 -
Indian Journal of Anaesthesia Aug 2020Evaluations of adverse heart rate (HR)-responses and HR-variations during anaesthesia in beach-chair-position (BCP) for shoulder surgeries have not been done earlier. We...
Adverse heart rate responses during beach-chair position for shoulder surgeries - A systematic review and meta-analysis of their incidence, interpretations and associations.
BACKGROUND AND AIMS
Evaluations of adverse heart rate (HR)-responses and HR-variations during anaesthesia in beach-chair-position (BCP) for shoulder surgeries have not been done earlier. We analysed the incidence, associations, and interpretations of adverse HR-responses in this clinical setting.
METHODS
We performed a meta-analysis of trials that reported HR-related data in anaesthetised subjects undergoing elective shoulder surgeries in BCP. Studies included prospective, randomised, quasi-randomised and non-randomised, controlled clinical trials as well as observational cohorts. Literature search was conducted in MEDLINE, EMBASE, CINHAL and the Cochrane Central Register of Controlled Trials of the 21 century. In the first analysis, we studied the incidence and associations of bradycardia/hypotension-bradycardia episodes (HBE) with respect to the type of anaesthesia and different pharmacological agents. In the second, we evaluated anaesthetic influences, associations and inter-relationships between monitored parameters with respect to HR-behaviours.
RESULTS
Among the trials designed with bradycardia/HBE as a primary end point, the observed incidence of bradycardia was 9.1% and that of HBE, 14.9% and 22.7% [(for Interscalene block (ISB) ± sedation) subjects and general anaesthesia (GA) + ISB, respectively]. There was evidence of higher observed risk of developing adverse HR-responses for GA subjects over ISB (Risk Difference, < 0.05). Concomitant use of β-agonists did not increase risk of HBEs ( = 0.29, = 11.4%) or with fentanyl ( = 0.45, = 0%) for ISB subjects (subgroup analysis). Fentanyl significantly influenced the HR-drop over time [meta-regression, estimates (standard error), 14.9 (5.4), 9.8 (4.3) and 17 (2.6); = 0.007, 0.024 and <0.001; for early, mid and delayed periods, respectively] in GA subjects. With respect to number of subjects experiencing cerebral desaturation events (CDEs), total intravenous anaesthesia (TIVA)- propofol had higher risk over inhalational anaesthesia ( = 0.006, = 86.7%). Meta-correlation analysis showed relationships between the HR and rSO(regional cerebral oxygen saturation) or SjvO(jugular venous oxygen saturation) values (r = 0.608, 95%CI, 0.439 to 0.735, < 0.001, = 77.4% and r = 0.397, 95%CI, 0.151 to 0.597, < 0.001, = 64.3%, respectively).
CONCLUSIONS
There is not enough evidence to claim the associations of adverse HR-responses with any specific factor. HR-fall is maximal with fentanyl and its variability is associated with changes in rSO. Fall in rSO could be the common link triggering adverse HR-responses in BCP.
PubMed: 32934399
DOI: 10.4103/ija.IJA_228_20 -
The Cochrane Database of Systematic... Sep 2020Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA).
OBJECTIVES
To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.
SELECTION CRITERIA
We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device.
MAIN RESULTS
Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion.
AUTHORS' CONCLUSIONS
There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.
Topics: Acebutolol; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Bias; Blood Pressure; Circadian Rhythm; Controlled Clinical Trials as Topic; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Pindolol; Time Factors
PubMed: 32888198
DOI: 10.1002/14651858.CD010054.pub2 -
Respiratory Medicine 2020Pressurised metered dose inhalers (pMDIs) are effective drug delivery devices prescribed in obstructive airway diseases due to their convenience, portability, ease of... (Comparative Study)
Comparative Study
INTRODUCTION
Pressurised metered dose inhalers (pMDIs) are effective drug delivery devices prescribed in obstructive airway diseases due to their convenience, portability, ease of enabling multiple doses in a single formulation, and storage in any orientation. For the management of asthma, the fixed-dose combination of a long-acting β-agonist (LABA) and an inhaled corticosteroid (ICS) has been recommended by Global Initiative for Asthma guideline as a preferred treatment option for patients who are uncontrolled with only ICS doses. One of the available LABA/ICS combinations is the formoterol/budesonide (FB).
AREAS COVERED
This article systematically reviews the efficacy and safety of the FB pMDI compared with the FB dry powder inhaler (DPI), individual mono-components (formoterol and budesonide) or salmeterol/fluticasone (SF) combination in the treatment of asthma among paediatric and adult patients. PubMed was searched with the string: ''((Budesonide) AND Formoterol) AND ((((pMDI) OR MDI) OR Pressurised Metered-dose inhaler) OR Metered-dose inhaler)'', in ALL fields. Screening of all the articles was done till February 2020. We have included 24 articles from the total of 142 hits received.
CONCLUSIONS
The FB pMDI is efficacious for the long-term management of asthma in patients 6 years of age and above. It has been shown to improve lung function and asthma control, and to reduce daytime and night-time symptoms, the number of rescue medication doses and asthma exacerbations. It also showed rapid onset of bronchodilatory effect with a dose-response relationship that allows patients to utilise it as a Single Maintenance And Reliever Therapy (SMART) regimen.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Age Factors; Anti-Asthmatic Agents; Asthma; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Child; Dose-Response Relationship, Drug; Drug Combinations; Female; Formoterol Fumarate; Humans; Maintenance; Male; Metered Dose Inhalers; Practice Guidelines as Topic; Treatment Outcome
PubMed: 32843176
DOI: 10.1016/j.rmed.2020.106055 -
British Journal of Anaesthesia Jan 2021The aim of this systematic review was to summarise the results of randomised controlled trials (RCTs) that have evaluated pharmacological interventions for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The aim of this systematic review was to summarise the results of randomised controlled trials (RCTs) that have evaluated pharmacological interventions for renoprotection in people undergoing surgery.
METHODS
Searches were conducted to update a previous review using the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE to August 23, 2019. RCTs evaluating the use of pharmacological interventions for renal protection in the perioperative period were included. The co-primary outcome measures were 30-day mortality and acute kidney injury (AKI). Pooled effect estimates were expressed as risk ratios (RRs) (95% confidence intervals).
RESULTS
We included 228 trials enrolling 56 047 patients. Twenty-three trials were considered to be at low risk of bias across all domains. Atrial natriuretic peptides (14 trials; n=2207) reduced 30-day mortality (RR: 0.63 [0.41, 0.97]) and AKI events (RR: 0.43 [0.33, 0.56]) without heterogeneity. These effects were consistent across cardiac surgery and vascular surgery subgroups, and in sensitivity analyses restricted to studies at low risk of bias. Inodilators (13 trials; n=2941) reduced mortality (RR: 0.71 [0.53, 0.94]) and AKI events (RR: 0.65 [0.50, 0.85]) in the primary analysis and in cardiac surgery cohorts. Vasopressors (4 trials; n=1047) reduced AKI (RR: 0.56 [0.36, 0.86]). Nitric oxide donors, alpha-2-agonists, and calcium channel blockers reduced AKI in primary analyses, but not after exclusion of studies at risk of bias. Overall, assessment of the certainty of the effect estimates was low.
CONCLUSIONS
There are multiple effective pharmacological renoprotective interventions for people undergoing surgery.
Topics: Acute Kidney Injury; Adrenergic alpha-2 Receptor Agonists; Atrial Natriuretic Factor; Calcium Channel Blockers; Humans; Nitric Oxide Donors; Postoperative Complications; Randomized Controlled Trials as Topic; Surgical Procedures, Operative; Vasoconstrictor Agents
PubMed: 32828488
DOI: 10.1016/j.bja.2020.06.064 -
Cells Aug 2020As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor...
As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.e., they are greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, they may differ between parts of a tissue, for instance, atria vs. ventricles of the heart, and within a cell type, between cellular responses. The basal tone of endogenously expressed receptors is often low, leading to less consistent detection and a lesser extent of observed inverse agonism. Extent inverse agonism depends on specific molecular properties of a compound, but inverse agonism appears to be more common in certain chemical classes. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of the extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.
Topics: Drug Development; Drug Inverse Agonism; Humans; Receptors, Adrenergic, beta-2
PubMed: 32825009
DOI: 10.3390/cells9091923 -
The Cochrane Database of Systematic... Aug 2020Asthma is an illness that commonly affects adults and children, and it serves as a common reason for children to attend emergency departments. An asthma exacerbation is...
BACKGROUND
Asthma is an illness that commonly affects adults and children, and it serves as a common reason for children to attend emergency departments. An asthma exacerbation is characterised by acute or subacute worsening of shortness of breath, cough, wheezing, and chest tightness and may be triggered by viral respiratory infection, poor compliance with usual medication, a change in the weather, or exposure to allergens or irritants. Most children with asthma have mild or moderate exacerbations and respond well to first-line therapy (inhaled short-acting beta-agonists and systemic corticosteroids). However, the best treatment for the small proportion of seriously ill children who do not respond to first-line therapy is not well understood. Currently, a large number of treatment options are available and there is wide variation in management.
OBJECTIVES
Main objective - To summarise Cochrane Reviews with or without meta-analyses of randomised controlled trials on the efficacy and safety of second-line treatment for children with acute exacerbations of asthma (i.e. after first-line treatments, titrated oxygen delivery, and administration of intermittent inhaled short-acting beta-agonists and oral corticosteroids have been tried and have failed) Secondary objectives - To identify gaps in the current evidence base that will inform recommendations for future research and subsequent Cochrane Reviews - To categorise information on reported outcome measures used in trials of escalation of treatment for acute exacerbations of asthma in children, and to make recommendations for development and reporting of standard outcomes in future trials and reviews - To identify relevant randomised controlled trials that have been published since the date of publication of each included review METHODS: We included Cochrane Reviews assessing interventions for children with acute exacerbations of asthma. We searched the Cochrane Database of Systematic Reviews. The search is current to 28 December 2019. We also identified trials that were potentially eligible for, but were not currently included in, published reviews. We assessed the quality of included reviews using the ROBIS criteria (tool used to assess risk of bias in systematic reviews). We presented an evidence synthesis of data from reviews alongside an evidence map of clinical trials. Primary outcomes were length of stay, hospital admission, intensive care unit admission, and adverse effects. We summarised all findings in the text and reported data for each outcome in 'Additional tables'.
MAIN RESULTS
We identified 17 potentially eligible Cochrane Reviews but extracted data from, and rated the quality of, 13 reviews that reported results for children alone. We excluded four reviews as one did not include any randomised controlled trials (RCTs), one did not provide subgroup data for children, and the last two had been updated and replaced by subsequent reviews. The 13 reviews included 67 trials; the number of trials in each review ranged from a single trial up to 27 trials. The vast majority of comparisons included between one and three trials, involving fewer than 100 participants. The total number of participants included in reviews ranged from 40 to 2630. All studies included children; 16 (24%) included children younger than two years of age. Most of the reviews reported search dates older than four years. We have summarised the published evidence as outlined in Cochrane Reviews. Key findings, in terms of our primary outcomes, are that (1) intravenous magnesium sulfate was the only intervention shown to reduce hospital length of stay (high-certainty evidence); (2) no evidence suggested that any intervention reduced the risk of intensive care admission (low- to very low-certainty evidence); (3) the risk of hospital admission was reduced by the addition of inhaled anticholinergic agents to inhaled beta-agonists (moderate-certainty evidence), the use of intravenous magnesium sulfate (high-certainty evidence), and the use of inhaled heliox (low-certainty evidence); (4) the addition of inhaled magnesium sulfate to usual bronchodilator therapy appears to reduce serious adverse events during hospital admission (moderate-certainty evidence); (5) aminophylline increased vomiting compared to placebo (moderate-certainty evidence) and increased nausea and nausea/vomiting compared to intravenous beta-agonists (low-certainty evidence); and (6) the addition of anticholinergic therapy to short-acting beta-agonists appeared to reduce the risk of nausea (high-certainty evidence) and tremor (moderate-certainty evidence) but not vomiting (low-certainty evidence). We considered 4 of the 13 reviews to be at high risk of bias based on the ROBIS framework. In all cases, this was due to concerns regarding identification and selection of studies. The certainty of evidence varied widely (by review and also by outcome) and ranged from very low to high.
AUTHORS' CONCLUSIONS
This overview provides the most up-to-date evidence on interventions for escalation of therapy for acute exacerbations of asthma in children from Cochrane Reviews of randomised controlled trials. A vast majority of comparisons involved between one and three trials and fewer than 100 participants, making it difficult to assess the balance between benefits and potential harms. Due to the lack of comparative studies between various treatment options, we are unable to make firm practice recommendations. Intravenous magnesium sulfate appears to reduce both hospital length of stay and the risk of hospital admission. Hospital admission is also reduced with the addition of inhaled anticholinergic agents to inhaled beta-agonists. However, further research is required to determine which patients are most likely to benefit from these therapies. Due to the relatively rare incidence of acute severe paediatric asthma, multi-centre research will be required to generate high-quality evidence. A number of existing Cochrane Reviews should be updated, and we recommend that a new review be conducted on the use of high-flow nasal oxygen therapy. Important priorities include development of an internationally agreed core outcome set for future trials in acute severe asthma exacerbations and determination of clinically important differences in these outcomes, which can then inform adequately powered future trials.
Topics: Acute Disease; Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aminophylline; Anti-Asthmatic Agents; Anti-Bacterial Agents; Asthma; Bias; Bronchodilator Agents; Child; Child, Preschool; Cholinergic Antagonists; Disease Progression; Helium; Humans; Infant; Length of Stay; Leukotriene Antagonists; Magnesium Sulfate; Nausea; Oxygen; Positive-Pressure Respiration; Randomized Controlled Trials as Topic; Systematic Reviews as Topic; Vomiting; Work of Breathing
PubMed: 32767571
DOI: 10.1002/14651858.CD012977.pub2 -
Critical Care (London, England) Aug 2020The effect of the timing of norepinephrine initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The effect of the timing of norepinephrine initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early and late start of norepinephrine support on clinical outcomes in patients with septic shock.
METHODS
We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of March 2020. We included studies involving adult patients (> 18 years) with septic shock. All authors reported our primary outcome of short-term mortality and clearly comparing early versus late norepinephrine initiation with clinically relevant secondary outcomes (ICU length of stay, time to achieved target mean arterial pressure (≥ 65 mmHg), and volume of intravenous fluids within 6 h). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI).
RESULTS
Five studies including 929 patients were included. The primary outcome of this meta-analysis showed that the short-term mortality of the early group was lower than that of the late group (odds ratio [OR] = 0.45; 95% CI, 0.34 to 0.61; P < 0.00001; χ = 3.74; I = 0%). Secondary outcomes demonstrated that the time to achieved target MAP of the early group was shorter than that of the late group (mean difference = - 1.39; 95% CI, - 1.81 to - 0.96; P < 0.00001; χ = 1.03; I = 0%). The volume of intravenous fluids within 6 h of the early group was less than that of the late group (mean difference = - 0.50; 95% CI, - 0.68 to - 0.32; P < 0.00001; χ = 33.76; I = 94%). There was no statistically significant difference in the ICU length of stay between the two groups (mean difference = - 0.11; 95% CI, - 1.27 to 1.05; P = 0.86; χ = 0.85; I = 0%).
CONCLUSIONS
Early initiation of norepinephrine in patients with septic shock was associated with decreased short-term mortality, shorter time to achieved target MAP, and less volume of intravenous fluids within 6 h. There was no significant difference in ICU length of stay between early and late groups. Further large-scale RCTs are still required to confirm these results.
Topics: Adrenergic alpha-Agonists; Cohort Studies; Humans; Norepinephrine; Randomized Controlled Trials as Topic; Shock, Septic; Time Factors; Treatment Outcome
PubMed: 32762765
DOI: 10.1186/s13054-020-03204-x -
Journal of the National Medical... Feb 2021Outcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This... (Review)
Review
PURPOSE
Outcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This review assessed systematic variation in β agonist treatment outcomes among Blacks compared to other groups.
METHODS
We conducted a systematic review of studies reporting differential response to β agonists among Blacks, including studies identifying pharmacogenetic variants.
RESULTS
Of 3158 papers, 20 compared safety or efficacy of β agonists among Blacks as compared with other subgroups. Six papers evaluating efficacy of short-acting β agonists (SABA) found similar or improved results among Blacks compared with other groups, while one small study found reduced response to SABA therapy among Blacks. Reports of safety and efficacy of long-acting β agonists (LABA) indicated similar results among Blacks in four papers, while four reports found reduced safety among Blacks, as compared with other groups. Four papers assessed genomic variation and relative treatment response in Blacks, with two finding significant effects of the p.Arg16Gly variant in ADRB2 on β agonist response and one finding significant gene-gene IL6/IL6R interaction effects on albuterol response.
CONCLUSIONS
Evidence suggests the potential for differences in β agonist outcomes among Blacks compared with other groups. This literature, however, remains small and significantly underpowered for substantive conclusions. There are notable opportunities for adequately-powered investigations exploring safety and efficacy of β agonists among Blacks, including pharmacogenomic modifiers of response.
Topics: Administration, Inhalation; Adrenergic Agonists; Black or African American; Asthma; Drug Therapy, Combination; Humans
PubMed: 32732018
DOI: 10.1016/j.jnma.2020.07.001