-
Cureus Dec 2021Attention-deficit hyperactivity disorder (ADHD) affects multiple cognitive domains, including impaired attention, hyperactivity, and increased impulsivity. According to... (Review)
Review
Attention-deficit hyperactivity disorder (ADHD) affects multiple cognitive domains, including impaired attention, hyperactivity, and increased impulsivity. According to the CDC, 9.4% of children between 2 and 17 years old have been diagnosed with ADHD. Neurotransmitters such as noradrenaline and dopamine have been suggested as crucial players in the pathophysiology of ADHD and are often targets of modern medication. Adenosine receptors types A1 and A2a in the brain are inhibited by caffeine: a stimulant known to augment attention by increasing cholinergic and dopaminergic transmission. The cognitive function of attention is also enhanced by the amino acid: L-theanine. The mechanism of action is that it behaves like a glutamate reuptake inhibitor while also acting in the hippocampus as a competitive low-affinity glutamate receptor antagonist. It's also shown to have a neuroprotective effect by its action on the gamma aminobutyric acid (GABA)-A receptors. Our systematic review investigates the literature and clinical trials on the cognitive-enhancing effects of caffeine and L-theanine.
PubMed: 35111479
DOI: 10.7759/cureus.20828 -
Molecular Autism Mar 2022There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD.
METHODS
We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses.
RESULTS
We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles.
LIMITATIONS
Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms.
CONCLUSIONS
Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.
Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Child; Humans; Network Meta-Analysis; Oxytocin; Risperidone
PubMed: 35246237
DOI: 10.1186/s13229-022-00488-4 -
Molecular Psychiatry Feb 2022A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological... (Meta-Analysis)
Meta-Analysis
A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.
Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Bipolar Disorder; Carbamazepine; Female; Haloperidol; Humans; Lithium; Male; Mania; Network Meta-Analysis; Olanzapine; Paliperidone Palmitate; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Tamoxifen; Valproic Acid
PubMed: 34642461
DOI: 10.1038/s41380-021-01334-4 -
Acta Psychiatrica Scandinavica Oct 2022Rapid cycling is a common and disabling phenomenon in individuals with bipolar disorders. In the absence of a recent literature examination, this systematic review and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Rapid cycling is a common and disabling phenomenon in individuals with bipolar disorders. In the absence of a recent literature examination, this systematic review and meta-analysis aimed to synthesise the evidence of efficacy, acceptability and tolerability of treatments for individuals with rapid cycling bipolar disorder (RCBD).
METHOD
A systematic search was conducted to identify randomised controlled trials assigning participants with RCBD to pharmacological and/or non-pharmacological interventions. Study inclusion and data extraction were undertaken by two reviewers independently. The primary outcome was continuous within-subject RCBD illness severity before and after treatment. Pre-post random effects meta-analyses were conducted for each outcome/intervention arm studied, generating a standardised effect size (hedge's g) and 95% confidence interval (CI).
RESULTS
A total of 34 articles describing 30 studies were included. A total of 16 separate pharmacological treatments were examined in contrast to 1 psychological therapy study. Only quetiapine and lamotrigine were assessed in >5 studies. By assessing 95% CI overlap of within-subject efficacy effects compared to placebo, the only interventions suggesting significant depression benefits (placebo g = 0.60) were olanzapine (with/without fluoxetine; g = 1.01), citalopram (g = 1.10) and venlafaxine (g = 2.48). For mania, benefits were indicated for quetiapine (g = 1.01), olanzapine (g = 1.19) and aripiprazole (g = 1.09), versus placebo (g = 0.33). Most of these effect sizes were from only one trial per treatment. Heterogeneity between studies was variable, and 20% were rated to have a high risk of bias.
CONCLUSIONS
While many interventions appeared efficacious, there was a lack of robust evidence for most treatments. Given the limited and heterogeneous evidence base, the optimal treatment strategies for people with RCBD are yet to be established.
Topics: Aripiprazole; Bipolar Disorder; Citalopram; Fluoxetine; Humans; Lamotrigine; Olanzapine; Quetiapine Fumarate; Venlafaxine Hydrochloride
PubMed: 35778967
DOI: 10.1111/acps.13471 -
Gastroenterology Apr 2023Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of randomized controlled trials (RCTs).
METHODS
We searched the literature to September 7, 2022. We judged the efficacy of drugs based on global symptoms of gastroparesis; individual symptoms, including nausea, vomiting, abdominal pain, bloating, or fullness; and safety according to total adverse events and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of not improving with 95% confidence intervals (CIs), ranking drugs according to P-score.
RESULTS
We identified 29 RCTs (3772 patients). Based on global symptoms, clebopride ranked first for efficacy (RR, 0.30; 95% CI, 0.16-0.57; P-score = .99) followed by domperidone (RR, 0.68; 95% CI, 0.48-0.98; P-score = .76). No other drug was superior to placebo. Only 2 drug classes were efficacious: in rank order, oral dopamine antagonists (RR, 0.58; 95% CI, 0.44-0.77; P-score = .96) and tachykinin-1 antagonists (RR, 0.69; 95% CI, 0.52-0.93; P-score = .83). For individual symptoms, oral metoclopramide ranked first for nausea (RR 0.46; 95% CI, 0.21-1.00; P-score = .95), fullness (RR 0.67; 95% CI, 0.35-1.28; P-score = .86), and bloating (RR 0.53; 95% CI, 0.30-0.93; P-score = .97), based on only 1 small trial. Only prucalopride was more likely to be associated with adverse events than placebo.
CONCLUSIONS
In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo for gastroparesis, but confidence in the evidence was low to moderate for most comparisons. There is an unmet need for efficacious therapies for gastroparesis.
Topics: Humans; Gastroparesis; Network Meta-Analysis; Nausea; Dopamine Antagonists; Tachykinins
PubMed: 36581089
DOI: 10.1053/j.gastro.2022.12.014 -
Molecular Psychiatry Aug 2023Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic... (Meta-Analysis)
Meta-Analysis
Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D receptor (DR) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The DR occupancy curves showed that the risk increased substantially when DR occupancy exceeded 75-85%, except for DR partial agonists that had smaller ORs albeit high DR occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current DR therapeutic window for EPS.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Haloperidol; Clozapine; Receptors, Dopamine D2; Drug-Related Side Effects and Adverse Reactions
PubMed: 37537284
DOI: 10.1038/s41380-023-02203-y -
Antipsychotics for agitation and psychosis in people with Alzheimer's disease and vascular dementia.The Cochrane Database of Systematic... Dec 2021Typical and atypical antipsychotics are widely used to treat agitation and psychosis in dementia. However, whether or not they are beneficial is uncertain. Some trials... (Review)
Review
BACKGROUND
Typical and atypical antipsychotics are widely used to treat agitation and psychosis in dementia. However, whether or not they are beneficial is uncertain. Some trials have yielded negative results and effectiveness may be outweighed by harms.
OBJECTIVES
To assess the efficacy and safety of antipsychotics for the treatment of agitation and psychosis in people with Alzheimer's disease and vascular dementia.
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid Sp), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov and the World Health Organization's meta-register, and the International Clinical Trials Registry Portal on 7 January 2021. Two review authors independently screened the title and abstract of the hits, and two review authors assessed the full text of studies that got through this screening.
SELECTION CRITERIA
We included randomised, placebo-controlled, parallel-arm trials comparing the effects of antipsychotics and placebo for the treatment of agitation or psychosis in people with dementia due to Alzheimer's disease or vascular dementia, or both, irrespective of age, severity of cognitive impairment, and setting. (The majority of) participants had to have clinically significant agitation (including aggression) or psychosis or both at baseline. We excluded studies about antipsychotics that are no longer available in the USA or EU, or that are used for emergency short-term sedation. We also excluded head-to-head trials and antipsychotic withdrawal trials.
DATA COLLECTION AND ANALYSIS
The primary outcomes were (1) reduction in agitation or psychosis in participants with agitation or psychosis, respectively at baseline, and (2) the number of participants with adverse events: somnolence, extrapyramidal symptoms, any adverse event, any serious adverse event (SAE), and death. Two review authors independently extracted the necessary data and assessed risk of bias with the Cochrane risk of bias tool. We calculated the pooled effect on agitation and psychosis for typical and atypical antipsychotics separately, and the pooled risk of adverse effects independent of the target symptom (agitation or psychosis). We used RevMan Web for the analyses.
MAIN RESULTS
The search yielded 8233 separate hits. After assessing the full-text of 35 studies, we included 24 trials that met the eligibility criteria. Six trials tested a typical antipsychotic, four for agitation and two for psychosis. Twenty trials tested an atypical antipsychotic, eight for agitation and 12 for psychosis. Two trials tested both drug types. Seventeen of 26 comparisons were performed in patients with Alzheimer's disease specifically. The other nine comparisons also included patients with vascular dementia or mixed dementia. Together, the studies included 6090 participants (12 to 652 per study). The trials were performed in institutionalised, hospitalised and community-dwelling patients, or a combination of those. For typical antipsychotics (e.g. haloperidol, thiothixene), we are uncertain whether these drugs improve agitation compared with placebo (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.57 to -0.15, 4 studies, n = 361); very low-certainty evidence, but typical antipsychotics may improve psychosis slightly (SMD -0.29, 95% CI -0.55 to -0.03, 2studies, n= 240; low-certainty evidence) compared with placebo. These drugs probably increase the risk of somnolence (risk ratio (RR) 2.62, 95% CI 1.51 to 4.56, 3 studies, n = 466; moderate-certainty evidence) and increase extrapyramidal symptoms (RR 2.26, 95% CI 1.58 to 3.23, 3 studies, n = 467; high-certainty) evidence. There was no evidence regarding the risk of any adverse event. The risks of SAEs (RR 1.32, 95% CI 0.65 to 2.66, 1 study, n = 193) and death (RR 1.46, 95% CI 0.54 to 4.00, 6 studies, n = 578) may be increased slightly, but these estimates were very imprecise, and the certainty was low. The effect estimates for haloperidol from five trials were in line with those of the drug class. Atypical antipsychotics (e.g. risperidone, olanzapine, aripiprazole, quetiapine) probably reduce agitation slightly (SMD -0.21, 95% CI -0.30 to -0.12, 7 studies, n = 1971; moderate-certainty evidence), but probably have a negligible effect on psychosis (SMD -0.11, 95% CI -0.18 to -0.03, 12 studies, n = 3364; moderate-certainty evidence). These drugs increase the risk of somnolence (RR 1.93, 95% CI 1.57 to 2.39, 13 studies, n - 3878; high-certainty evidence) and are probably also associated with slightly increased risk of extrapyramidal symptoms (RR 1.39, 95% CI 1.14 to 1.68, 15 studies, n = 4180; moderate-certainty evidence), serious adverse events (RR 1.32, 95% CI 1.09 to 1.61, 15 studies, n= 4316; moderate-certainty evidence) and death (RR 1.36, 95% CI 0.90 to 2.05, 17 studies, n= 5032; moderate-certainty evidence), although the latter estimate was imprecise. The drugs probably have a negligible effect on the risk of any adverse event (RR 1.05, 95% CI 1.02 to 1.09, 11 studies, n = 2785; moderate-certainty evidence). The findings from seven trials for risperidone were in line with those for the drug class.
AUTHORS' CONCLUSIONS
There is some evidence that typical antipsychotics might decrease agitation and psychosis slightly in patients with dementia. Atypical antipsychotics reduce agitation in dementia slightly, but their effect on psychosis in dementia is negligible. The apparent effectiveness of the drugs seen in daily practice may be explained by a favourable natural course of the symptoms, as observed in the placebo groups. Both drug classes increase the risk of somnolence and other adverse events. If antipsychotics are considered for sedation in patients with severe and dangerous symptoms, this should be discussed openly with the patient and legal representative.
Topics: Alzheimer Disease; Antipsychotic Agents; Dementia, Vascular; Humans; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone
PubMed: 34918337
DOI: 10.1002/14651858.CD013304.pub2 -
Journal of Psychopharmacology (Oxford,... Mar 2023Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below).
METHODS
We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions.
RESULTS
In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low ( = 57) or moderate ( = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses.
CONCLUSIONS
Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.
Topics: Adult; Humans; Aripiprazole; Risperidone; Depression; Depressive Disorder, Major; Ketamine
PubMed: 35861202
DOI: 10.1177/02698811221104058 -
PloS One 2022Long acting injectable (LAI) antipsychotics are an alternative to oral antipsychotic (OAP) treatment and may be beneficial for patients in the early stages of... (Review)
Review
AIM
Long acting injectable (LAI) antipsychotics are an alternative to oral antipsychotic (OAP) treatment and may be beneficial for patients in the early stages of schizophrenia. This study aims to provide a comprehensive review on the efficacy of first-generation and second-generation LAI antipsychotics in recent-onset, first-episode, and early psychosis patients.
METHODS
MEDLINE, EMBASE, PsycINFO, and Web of Science Core databases were used to search for studies that used LAIs in early psychosis patients. Studies published up to 06 Jun 2019 were included with no language restrictions applied. Inclusion criteria were a diagnosis of schizophrenia or related disorder, where patients were in their first episode or had a duration of illness ≤5 years.
RESULTS
33 studies were included: 8 RCTs, 4 post-hoc analyses, 2 case reports, and 19 naturalistic studies. The majority of studies evaluated risperidone LAIs (N = 14) and paliperidone palmitate (N = 10), while the remainder investigated fluphenazine decanoate (N = 3), flupentixol decanoate (N = 2), and aripiprazole (N = 1). Two studies did not specify the LAI formulation used, and one cohort study compared the efficacy of multiple different LAI formulations.
CONCLUSIONS
While the majority of data is based on naturalistic studies investigating risperidone LAIs or paliperidone palmitate, LAIs may be an effective treatment for early psychosis patients in terms of adherence, relapse reduction, and symptom improvements. There is still a need to conduct more high quality RCTs that investigate the efficacy of different LAI formulations in early psychosis patients.
Topics: Antipsychotic Agents; Cohort Studies; Delayed-Action Preparations; Humans; Paliperidone Palmitate; Psychotic Disorders; Risperidone
PubMed: 35486616
DOI: 10.1371/journal.pone.0267808 -
The Cochrane Database of Systematic... Apr 2023Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Several non-pharmacological, pharmacological, and surgical... (Review)
Review
BACKGROUND
Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Several non-pharmacological, pharmacological, and surgical approaches have been explored to prevent or treat a PDA.
OBJECTIVES
To summarise Cochrane Neonatal evidence on interventions (pharmacological or surgical) for the prevention of PDA and related complications, and interventions for the management of asymptomatic and symptomatic PDA in preterm infants.
METHODS
We searched the Cochrane Database of Systematic Reviews on 20 October 2022 for ongoing and published Cochrane Reviews on the prevention and treatment of PDA in preterm (< 37 weeks' gestation) or low birthweight (< 2500 g) infants. We included all published Cochrane Reviews assessing the following categories of interventions: pharmacological therapy using prostaglandin inhibitor drugs (indomethacin, ibuprofen, and acetaminophen), adjunctive pharmacological interventions, invasive PDA closure procedures, and non-pharmacological interventions. Two overview authors independently checked the eligibility of the reviews retrieved by the search, and extracted data from the included reviews using a predefined data extraction form. Any disagreements were resolved by discussion with a third overview author. Two overview authors independently assessed the methodological quality of the included reviews using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) tool. We reported the GRADE certainty of evidence as assessed by the respective review authors using summary of findings tables.
MAIN RESULTS
We included 16 Cochrane Reviews, corresponding to 138 randomised clinical trials (RCT) and 11,856 preterm infants, on the prevention and treatment of PDA in preterm infants. One of the 16 reviews had no included studies, and therefore, did not contribute to the results. Six reviews reported on prophylactic interventions for the prevention of PDA and included pharmacological prophylaxis with prostaglandin inhibitor drugs, prophylactic surgical PDA ligation, and non-pharmacologic interventions (chest shielding during phototherapy and restriction of fluid intake); one review reported on the use of indomethacin for the management of asymptomatic PDA; nine reviews reported on interventions for the management of symptomatic PDA, and included pharmacotherapy with prostaglandin inhibitor drugs in various routes and dosages, surgical PDA ligation, and adjunct therapies (use of furosemide and dopamine in conjunction with indomethacin). The quality of reviews varied. Two reviews were assessed to be high quality, seven reviews were of moderate quality, five of low quality, while two reviews were deemed to be of critically low quality. For prevention of PDA, prophylactic indomethacin reduces severe intraventricular haemorrhage (IVH; relative risk (RR) 0.66, 95% confidence interval (CI) 0.53 to 0.82; 14 RCTs, 2588 infants), and the need for invasive PDA closure (RR 0.51, 95% CI 0.37 to 0.71; 8 RCTs, 1791 infants), but it does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability (RR 1.02, 95% CI 0.90 to 1.15; 3 RCTs, 1491 infants). Prophylactic ibuprofen probably marginally reduces severe IVH (RR 0.67, 95% CI 0.45 to 1.00; 7 RCTs, 925 infants; moderate-certainty evidence), and the need for invasive PDA closure (RR 0.46, 95% CI 0.22 to 0.96; 7 RCTs, 925 infants; moderate-certainty evidence). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (RR 1.09, 95% CI 0.07 to 16.39; 1 RCT, 48 infants). Necrotising enterocolitis (NEC) was lower with both prophylactic surgical ligation (RR 0.25, 95% CI 0.08 to 0.83; 1 RCT, 84 infants), and fluid restriction (RR 0.43, 95% CI 0.21 to 0.87; 4 RCTs, 526 infants). For treatment of asymptomatic PDA, indomethacin appears to reduce the development of symptomatic PDA post-treatment (RR 0.36, 95% CI 0.19 to 0.68; 3 RCTs, 97 infants; quality of source review: critically low). For treatment of symptomatic PDA, all available prostaglandin inhibitor drugs appear to be more effective in closing a PDA than placebo or no treatment (indomethacin: RR 0.30, 95% CI 0.23 to 0.38; 10 RCTs, 654 infants; high-certainty evidence; ibuprofen: RR 0.62, 95% CI 0.44 to 0.86; 2 RCTs, 206 infants; moderate-certainty evidence; early administration of acetaminophen: RR 0.35, 95% CI 0.23 to 0.53; 2 RCTs, 127 infants; low-certainty evidence). Oral ibuprofen appears to be more effective in PDA closure than intravenous (IV) ibuprofen (RR 0.38, 95% CI 0.26 to 0.56; 5 RCTs, 406 infants; moderate-certainty evidence). High-dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (RR 0.37, 95% CI 0.22 to 0.61; 3 RCTs, 190 infants; moderate-certainty evidence). With respect to adverse outcomes, compared to indomethacin administration, NEC appears to be lower with ibuprofen (any route; RR 0.68, 95% CI 0.49 to 0.94; 18 RCTs, 1292 infants; moderate-certainty evidence), oral ibuprofen (RR 0.41, 95% CI 0.23 to 0.73; 7 RCTs, 249 infants; low-certainty evidence), and with acetaminophen (RR 0.42, 95% CI 0.19 to 0.96; 4 RCTs, 384 infants; low-certainty evidence). However, NEC appears to be increased with a prolonged course of indomethacin versus a shorter course (RR 1.87, 95% CI 1.07 to 3.27; 4 RCTs, 310 infants).
AUTHORS' CONCLUSIONS
This overview summarised the evidence from 16 Cochrane Reviews of RCTs regarding the effects of interventions for the prevention and treatment of PDA in preterm infants. Prophylactic indomethacin reduces severe IVH, but does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability. Prophylactic ibuprofen probably marginally reduces severe IVH (moderate-certainty evidence), while the evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH. All available prostaglandin inhibitor drugs appear to be effective in symptomatic PDA closure compared to no treatment (high-certainty evidence for indomethacin; moderate-certainty evidence for ibuprofen; low-certainty evidence for early administration of acetaminophen). Oral ibuprofen appears to be more effective in PDA closure than IV ibuprofen (moderate-certainty evidence). High dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (moderate-certainty evidence). There are currently two ongoing reviews, one on fluid restriction for symptomatic PDA, and the other on invasive management of PDA in preterm infants.
Topics: Infant, Newborn; Humans; Ductus Arteriosus, Patent; Ibuprofen; Cyclooxygenase Inhibitors; Acetaminophen; Prostaglandin Antagonists; Systematic Reviews as Topic; Infant, Premature; Indomethacin
PubMed: 37039501
DOI: 10.1002/14651858.CD013588.pub2