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Archives of Gynecology and Obstetrics Jun 2023To summarize available evidence comparing the transdermal and the oral administration routes of hormone replacement therapy (HRT) in postmenopausal women. (Review)
Review
PURPOSE
To summarize available evidence comparing the transdermal and the oral administration routes of hormone replacement therapy (HRT) in postmenopausal women.
METHODS
We performed a systematic review of the literature on multiple databases between January 1990 and December 2021. We included randomized controlled trials and observational studies comparing the transdermal and oral administration routes of estrogens for HRT in postmenopausal women regarding at least one of the outcomes of interest: cardiovascular risk, venous thromboembolism (VTE), lipid metabolism, carbohydrate metabolism, bone mineral density (BMD), and risk of pre-malignant and malignant endometrial lesions, or breast cancer.
RESULTS
The systematic literature search identified a total of 1369 manuscripts, of which 51 were included. Most studies were observational and of good quality, whereas the majority of randomized controlled trials presented a high or medium risk of bias. Oral and transdermal administration routes are similar regarding BMD, glucose metabolism, and lipid profile improvements, as well as do not appear different regarding breast cancer, endometrial disease, and cardiovascular risk. Identified literature provides clear evidence only for the VTE risk, which is higher with the oral administration route.
CONCLUSIONS
Available evidence comparing the transdermal and oral administration routes for HRT is limited and of low quality, recommending further investigations. VTE risk can be considered the clearest and strongest clinical difference between the two administration routes, supporting the transdermal HRT as safer than the oral administration route.
Topics: Female; Humans; Postmenopause; Estrogen Replacement Therapy; Venous Thromboembolism; Administration, Cutaneous; Estrogens; Hormone Replacement Therapy; Breast Neoplasms; Administration, Oral; Lipids
PubMed: 35713694
DOI: 10.1007/s00404-022-06647-5 -
World Journal of Emergency Surgery :... Mar 2023During medical emergencies, intraosseous (IO) access and intravenous (IV) access are methods of administering therapies and medications to patients. Treating patients in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
During medical emergencies, intraosseous (IO) access and intravenous (IV) access are methods of administering therapies and medications to patients. Treating patients in emergency medical situations is a highly time sensitive practice; however, research into the optimal access method is limited and existing systematic reviews have only considered out-of-hospital cardiac arrest (OHCA) patients. We focused on severe trauma patients and conducted a systematic review to evaluate the efficacy and efficiency of intraosseous (IO) access compared to intravenous (IV) access for trauma resuscitation in prehospital care.
MATERIALS AND METHOD
PubMed, Web of Science, Cochrane Library, EMBASE, ScienceDirect, banque de données en santé publique and CNKI databases were searched for articles published between January 1, 2000, and January 31, 2023. Adult trauma patients were included, regardless of race, nationality, and region. OHCA patients and other types of patients were excluded. The experimental and control groups received IO and IV access, respectively, in the pre-hospital and emergency departments for salvage. The primary outcome was success rate on first attempt, which was defined as secure needle position in the marrow cavity or a peripheral vein, with normal fluid flow. Secondary outcomes included mean time to resuscitation, mean procedure time, and complications.
RESULTS
Three reviewers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies; meta-analyses were then performed using Review Manager (Version 5.4; Cochrane, Oxford, UK). The success rate on first attempt was significant higher for IO access than for IV access (RR = 1.46, 95% CI [1.16, 1.85], P = 0.001). The mean procedure time was significantly reduced (MD = - 5.67, 95% CI [- 9.26, - 2.07], P = 0.002). There was no significant difference in mean time to resuscitation (MD = - 1.00, 95% CI [- 3.18, 1.17], P = 0.37) and complications (RR = 1.22, 95% CI [0.14, 10.62], P = 0.86) between the IO and IV groups.
CONCLUSION
The success rate on first attempt of IO access was much higher than that of IV access for trauma patients, and the mean procedure time of IO access was significantly less when compared to IV access. Therefore, IO access should be suggested as an urgent vascular access for hypotensive trauma patients, especially those who are under severe shock.
Topics: Adult; Humans; Emergency Medical Services; Emergency Service, Hospital; Resuscitation; Infusions, Intraosseous
PubMed: 36918947
DOI: 10.1186/s13017-023-00487-7 -
The Cochrane Database of Systematic... Oct 2016Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or no trauma. Bisphosphonates are used in an attempt to increase bone mineral density and reduce these fractures in people with osteogenesis imperfecta. This is an update of a previously published Cochrane Review.
OBJECTIVES
To assess the effectiveness and safety of bisphosphonates in increasing bone mineral density, reducing fractures and improving clinical function in people with osteogenesis imperfecta.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of journals and conference proceedings. We additionally searched PubMed and major conference proceedings.Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Register: 28 April 2016.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials comparing bisphosphonates to placebo, no treatment, or comparator interventions in all types of osteogenesis imperfecta.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data and assessed the risk of bias of the included trials.
MAIN RESULTS
Fourteen trials (819 participants) were included. Overall, the trials were mainly at a low risk of bias, although selective reporting was an issue in several of the trials. Data for oral bisphosphonates versus placebo could not be aggregated; a statistically significant difference favouring oral bisphosphonates in fracture risk reduction and number of fractures was noted in two trials. No differences were reported in the remaining three trials which commented on fracture incidence. Five trials reported data for spine bone mineral density; all found statistically significant increased lumbar spine density z scores for at least one time point studied. For intravenous bisphosphonates versus placebo, aggregated data from two trials showed no statistically significant difference for the number of participants with at least one fracture, risk ratio 0.56 (95% confidence interval 0.30 to 1.06). In the remaining trial no statistically significant difference was noted in fracture incidence. For spine bone mineral density, no statistically significant difference was noted in the aggregated data from two trials, mean difference 9.96 (95% confidence interval -2.51 to 22.43). In the remaining trial a statistically significant difference in mean per cent change in spine bone mineral density z score favoured intravenous bisphosphonates at six and 12 months. Data describing growth, bone pain, and functional outcomes after oral or intravenous bisphosphonate therapy, or both, as compared to placebo were incomplete among all studies, but do not show consistent improvements in these outcomes. Two studies compared different doses of bisphosphonates. No differences were found between doses when bone mineral density, fractures, and height or length z score were assessed. One trial compared oral versus intravenous bisphosphonates and found no differences in primary outcomes. Two studies compared the intravenous bisphosphonates zoledronic acid and pamidronate. There were no significant differences in primary outcome. However, the studies were at odds as to the relative benefit of zoledronic acid over pamidronate for lumbosacral bone mineral density at 12 months.
AUTHORS' CONCLUSIONS
Bisphophonates are commonly prescribed to individuals with osteogenesis imperfecta. Current evidence, albeit limited, demonstrates oral or intravenous bisphosphonates increase bone mineral density in children and adults with this condition. These were not shown to be different in their ability to increase bone mineral density. It is unclear whether oral or intravenous bisphosphonate treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate with treatment. The studies included here do not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta. Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation. In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators.
Topics: Administration, Oral; Bone Density; Bone Density Conservation Agents; Diphosphonates; Fractures, Bone; Humans; Injections, Intravenous; Osteogenesis Imperfecta; Randomized Controlled Trials as Topic
PubMed: 27760454
DOI: 10.1002/14651858.CD005088.pub4 -
PloS One 2020To synthesize the current evidence for subcutaneous hydration and medication infusions from systematic reviews and to assess their methodological quality.
OBJECTIVE
To synthesize the current evidence for subcutaneous hydration and medication infusions from systematic reviews and to assess their methodological quality.
INTRODUCTION
Peripheral intravascular cannula/catheter insertion is a common invasive procedure for administering fluids and medications. Venous depletion is a growing concern for several patient populations. Subcutaneous access for the administration of isotonic solutions and medications is an alternative; however, vascular access assessment and planning guidelines rarely consider this route.
METHODS
Systematic review of systematic reviews (PROSPERO CRD42018046504). We searched 6 databases published in English language from 1990 to June 2020, identifying subcutaneous infusions an alternate route for fluids or medication. Methodological quality was evaluated using AMSTAR 2 criteria and data for mechanisms of infusion and outcomes related to effectiveness, safety, efficiency and acceptability extracted. The Johanna Briggs Institute's grades of recommendation informed the strength of recommendation.
RESULTS
The search yielded 1042 potential systematic reviews; 922 were excluded through abstract and duplicate screen. Of the remaining articles, 94 were excluded, and 26 were included. Overall, evidence is strong for recommending subcutaneous hydration infusions for older adults, weak for pediatric patients and inconclusive for palliative patients. There is strong evidence for 10 medications; weak evidence supporting 28 medications; however, there are eight medications with inconclusive evidence to make a recommendation and four medications not appropriate for subcutaneous delivery.
CONCLUSION
Subcutaneous access should be considered alongside intravenous therapy for hydration in older adults, and several medications. There are additional benefits in terms of ease of use and cost-effectiveness of this mode. Inclusion of subcutaneous access in clinical guidelines may promote uptake of this route to help preserve vessel health of vulnerable patients. Further high-quality research is needed to inform subcutaneous infusion therapy in a variety of populations (including pediatrics and palliative care) and medications and clarifying the mechanism of delivery.
Topics: Dehydration; Fluid Therapy; Humans; Hypodermoclysis; Infusions, Subcutaneous
PubMed: 32833979
DOI: 10.1371/journal.pone.0237572 -
Archivos de La Sociedad Espanola de... Apr 2023The Purpose is to identify, through a systematic literature review, the current evidence regarding the effectiveness of topical insulin treatment in ocular surface... (Review)
Review
The Purpose is to identify, through a systematic literature review, the current evidence regarding the effectiveness of topical insulin treatment in ocular surface pathologies. A literature search was implemented in Medline (Pubmed), Embase and Web Of Science medical indexing databases by using keywords such as "insulin" AND "cornea" OR "corneal" OR "dry eye" in published papers in English or Spanish within the last eleven years (2011-2022). Nine papers were identified with 180 participants from the United States, Spain, Ireland, Canada, Portugal and Malaysia, with persistent refractory epithelial defects and secondary to vitrectomy, whose extension of the lesion was from 3,75mm to 65.47mm. The preparation was dissolved with artificial tears and the insulin concentration ranged from 1 IU/ml to 100 IU/ml. In all cases, the resolution of the clinical picture was complete with a healing time from 2.5 days to 60.9 days, the latter being a secondary case to a difficult-to-control caustic burn. Topical insulin has been effective for the treatment of persistent epithelial defects. The intermediate action and low concentrations showed a shorter resolution time in neurotrophic ulcers and induced during vitreoretinal surgery.
Topics: Humans; Insulin; Cornea; Wound Healing; Lubricant Eye Drops; Administration, Topical
PubMed: 36871851
DOI: 10.1016/j.oftale.2023.03.007 -
The Journal of Clinical Endocrinology... Feb 2022Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also...
CONTEXT
Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some discomfort. Recently, subcutaneous (SC) administration of testosterone esters has gained popularity, as self-administration is easier with this route. Available data, though limited, support the feasibility of this route. Here we review the pharmacokinetics and safety of SC testosterone therapy with both long- and ultralong-acting testosterone esters. In addition, we provide guidance for clinicians on how to counsel and manage their patients who opt for the SC route.
EVIDENCE ACQUISITION
Systematic review of available literature on SC testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after SC administration.
EVIDENCE SYNTHESIS
Available evidence, though limited, suggests that SC testosterone therapy in doses similar to those given via IM route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters SC with relative ease and less discomfort compared with the IM route.
CONCLUSION
Although studies directly comparing the safety of SC vs IM administration of testosterone esters are desirable, clinicians should consider discussing the SC route with their patients because it is easier to self-administer and has the potential to improve patient adherence.
Topics: Feasibility Studies; Female; Humans; Hypogonadism; Injections, Intramuscular; Injections, Subcutaneous; Male; Self Administration; Sex Reassignment Procedures; Testosterone; Transgender Persons
PubMed: 34698352
DOI: 10.1210/clinem/dgab772 -
The Lancet. Psychiatry May 2021Evidence of comparative benefits of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics for schizophrenia has been inconsistent across study designs.... (Comparative Study)
Comparative Study Meta-Analysis
Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies.
BACKGROUND
Evidence of comparative benefits of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics for schizophrenia has been inconsistent across study designs. The aim of this study was to evaluate the comparative benefits of LAIs versus oral antipsychotics in three study designs to inform clinical decision making.
METHODS
We did a comprehensive systematic review and meta-analysis comparing LAIs versus oral antipsychotics for schizophrenia covering three study designs: randomised controlled trials (RCTs), cohort studies, and pre-post studies. Our literature search was without language restrictions, in MEDLINE and PubMed, the Cochrane Library, Scopus, and Embase, for studies published from database inception up to a last search on March 13, 2020. We also searched for unpublished studies and ClinicalTrials.gov. We included studies lasting at least 6 months that targeted adults with schizophrenia and related disorders (>80% of participants). Studies on penfluridol (neither an LAI or daily oral antipsychotic), case reports, and case series with fewer than 20 patients were excluded. Two investigators independently extracted study-level data and resolved disagreement by consensus, or via a third investigator. Study authors were contacted to obtain additional information as needed. For our primary outcome we meta-analysed the risk ratio (RR) for hospitalisation or relapse with LAIs versus oral antipsychotics by a random-effects model, with hospitalisation used preferentially over relapse. As secondary analyses, we reversed the preferential order to relapse over hospitalisation, and assessed hospitalisation risk and relapse risk individually. Other secondary outcomes included all meta-analysable data, classed by relevance to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, and analysed by study design. Dichotomous outcomes were expressed as pooled RR and continuous outcomes as standardised mean difference (SMD). The protocol is registered with PROSPERO (CRD42019142094).
FINDINGS
We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria (32 RCTs [23·4%; 8577 patients], 65 cohort studies [47·4%; 377 447 patients], and 40 pre-post studies [29·2%; 11 295 patients]) and were analysed. The quality of studies in terms of risk of bias varied across study designs and within each study design from low to high. LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0·88 [95% CI 0·79-0·99], p=0·033; cohort studies: 44 studies, 106 136 patients, RR 0·92 [0·88-0·98], p=0·0044; pre-post studies: 28 studies, 17 876 patients, RR 0·44 [0·39-0·51], p<0·0001). This association was maintained across the study designs when we reversed the preferential order to risk of relapse over hospitalisation, and in individual analysis of hospitalisation risk. The association was maintained only in pre-post studies for relapse risk alone. In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18·3%) of 328 comparisons, not different in 252 (76·8%) comparisons, and less beneficial in 16 (4·9%) comparisons when analysed by study design. Significant heterogeneity was observed across all three study designs. Publication biases were apparent in cohort and pre-post studies, but effect sizes were similar after trim-and-fill analyses.
INTERPRETATION
Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre-post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia.
FUNDING
None.
TRANSLATIONS
For the Chinese, French, German, Italian, Japanese, Portugese and Spanish translations of the abstract see Supplementary Materials section.
Topics: Administration, Oral; Antipsychotic Agents; Cohort Studies; Delayed-Action Preparations; Humans; Injections; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome
PubMed: 33862018
DOI: 10.1016/S2215-0366(21)00039-0 -
The Cochrane Database of Systematic... Jul 2017Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their... (Review)
Review
BACKGROUND
Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Opioid (morphine-like) drugs are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. The most commonly-used opioid drugs are buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, tramadol, and tapentadol.
OBJECTIVES
To provide an overview of the analgesic efficacy of opioids in cancer pain, and to report on adverse events associated with their use.
METHODS
We identified systematic reviews examining any opioid for cancer pain published to 4 May 2017 in the Cochrane Database of Systematic Reviews in the Cochrane Library. The primary outcomes were no or mild pain within 14 days of starting treatment, withdrawals due to adverse events, and serious adverse events.
MAIN RESULTS
We included nine reviews with 152 included studies and 13,524 participants, but because some studies appeared in more than one review the number of unique studies and participants was smaller than this. Most participants had moderate or severe pain associated with a range of different types of cancer. Studies in the reviews typically compared one type of opioid or formulation with either a different formulation of the same opioid, or a different opioid; few included a placebo control. Typically the reviews titrated dose to effect, a balance between pain relief and adverse events. Various routes of administration of opioids were considered in the reviews; oral with most opioids, but transdermal administration with fentanyl, and buprenorphine. No review included studies of subcutaneous opioid administration. Pain outcomes reported were varied and inconsistent. The average size of included studies varied considerably between reviews: studies of older opioids, such as codeine, morphine, and methadone, had low average study sizes while those involving newer drugs tended to have larger study sizes.Six reviews reported a GRADE assessment (buprenorphine, codeine, hydromorphone, methadone, oxycodone, and tramadol), but not necessarily for all comparisons or outcomes. No comparative analyses were possible because there was no consistent placebo or active control. Cohort outcomes for opioids are therefore reported, as absolute numbers or percentages, or both.Reviews on buprenorphine, codeine with or without paracetamol, hydromorphone, methadone, tramadol with or without paracetamol, tapentadol, and oxycodone did not have information about the primary outcome of mild or no pain at 14 days, although that on oxycodone indicated that average pain scores were within that range. Two reviews, on oral morphine and transdermal fentanyl, reported that 96% of 850 participants achieved that goal.Adverse event withdrawal was reported by five reviews, at rates of between 6% and 19%. Participants with at least one adverse event were reported by three reviews, at rates of between 11% and 77%.Our GRADE assessment of evidence quality was very low for all outcomes, because many studies in the reviews were at high risk of bias from several sources, including small study size.
AUTHORS' CONCLUSIONS
The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low, although the evidence we have indicates that around 19 out of 20 people with moderate or severe pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days. This accords with the clinical experience in treating many people with cancer pain, but overstates to some extent the effectiveness found for the WHO pain ladder. Most people will experience adverse events, and help may be needed to manage the more common undesirable adverse effects such as constipation and nausea. Perhaps between 1 in 10 and 2 in 10 people treated with opioids will find these adverse events intolerable, leading to a change in treatment.
Topics: Acetaminophen; Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Buprenorphine; Cancer Pain; Codeine; Fentanyl; Humans; Hydromorphone; Methadone; Oxycodone; Phenols; Review Literature as Topic; Tapentadol; Tramadol
PubMed: 28683172
DOI: 10.1002/14651858.CD012592.pub2 -
Obstetrics and Gynecology Dec 2014To comprehensively review and critically assess the literature on vaginal estrogen and its alternatives for women with genitourinary syndrome of menopause and to provide... (Review)
Review
OBJECTIVE
To comprehensively review and critically assess the literature on vaginal estrogen and its alternatives for women with genitourinary syndrome of menopause and to provide clinical practice guidelines.
DATA SOURCES
MEDLINE and Cochrane databases were searched from inception to April 2013. We included randomized controlled trials and prospective comparative studies. Interventions and comparators included all commercially available vaginal estrogen products. Placebo, no treatment, systemic estrogen (all routes), and nonhormonal moisturizers and lubricants were included as comparators.
METHODS OF STUDY SELECTION
We double-screened 1,805 abstracts, identifying 44 eligible studies. Discrepancies were adjudicated by a third reviewer. Studies were individually and collectively assessed for methodologic quality and strength of evidence.
TABULATION, INTEGRATION, AND RESULTS
Studies were extracted for participant, intervention, comparator, and outcomes data, including patient-reported atrophy symptoms (eg, vaginal dryness, dyspareunia, dysuria, urgency, frequency, recurrent urinary tract infection (UTI), and urinary incontinence), objective signs of atrophy, urodynamic measures, endometrial effects, serum estradiol changes, and adverse events. Compared with placebo, vaginal estrogens improved dryness, dyspareunia, urinary urgency, frequency, and stress urinary incontinence (SUI) and urgency urinary incontinence (UUI). Urinary tract infection rates decreased. The various estrogen preparations had similar efficacy and safety; serum estradiol levels remained within postmenopausal norms for all except high-dose conjugated equine estrogen cream. Endometrial hyperplasia and adenocarcinoma were extremely rare among those receiving vaginal estrogen. Comparing vaginal estrogen with nonhormonal moisturizers, patients with two or more symptoms of vulvovaginal atrophy were substantially more improved using vaginal estrogens, but those with one or minor complaints had similar symptom resolution with either estrogen or nonhormonal moisturizer.
CONCLUSION
All commercially available vaginal estrogens effectively relieve common vulvovaginal atrophy-related complaints and have additional utility in patients with urinary urgency, frequency or nocturia, SUI and UUI, and recurrent UTIs. Nonhormonal moisturizers are a beneficial alternative for those with few or minor atrophy-related symptoms and in patients at risk for estrogen-related neoplasia.
CLINICAL TRIAL REGISTRATION
PROSPERO International prospective register of systematic reviews, http://www.crd.york.ac.uk/PROSPERO/, CRD42013006656.
Topics: Administration, Intravaginal; Atrophic Vaginitis; Estrogens; Female; Humans; Menopause; Urologic Diseases
PubMed: 25415166
DOI: 10.1097/AOG.0000000000000526 -
The Cochrane Database of Systematic... Jan 2018Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and require urgent and appropriate anticonvulsant treatment. International consensus is that an anticonvulsant drug should be administered for any tonic-clonic convulsion that has been continuing for at least five minutes. Benzodiazepines (diazepam, lorazepam, midazolam) are traditionally regarded as first-line drugs and phenobarbital, phenytoin and paraldehyde as second-line drugs. This is an update of a Cochrane Review first published in 2002 and updated in 2008.
OBJECTIVES
To evaluate the effectiveness and safety of anticonvulsant drugs used to treat any acute tonic-clonic convulsion of any duration, including established convulsive (tonic-clonic) status epilepticus in children who present to a hospital or emergency medical department.
SEARCH METHODS
For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (23 May 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 23 May 2017), MEDLINE (Ovid, 1946 to 23 May 2017), ClinicalTrials.gov (23 May 2017), and the WHO International Clinical Trials Registry Platform (ICTRP, 23 May 2017).
SELECTION CRITERIA
Randomised and quasi-randomised trials comparing any anticonvulsant drugs used for the treatment of an acute tonic-clonic convulsion including convulsive status epilepticus in children.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and extracted data. We contacted study authors for additional information.
MAIN RESULTS
The review includes 18 randomised trials involving 2199 participants, and a range of drug treatment options, doses and routes of administration (rectal, buccal, nasal, intramuscular and intravenous). The studies vary by design, setting and population, both in terms of their ages and also in their clinical situation. We have made many comparisons of drugs and of routes of administration of drugs in this review; our key findings are as follows:(1) This review provides only low- to very low-quality evidence comparing buccal midazolam with rectal diazepam for the treatment of acute tonic-clonic convulsions (risk ratio (RR) for seizure cessation 1.25, 95% confidence interval (CI) 1.13 to 1.38; 4 trials; 690 children). However, there is uncertainty about the effect and therefore insufficient evidence to support its use. There were no included studies which compare intranasal and buccal midazolam.(2) Buccal and intranasal anticonvulsants were shown to lead to similar rates of seizure cessation as intravenous anticonvulsants, e.g. intranasal lorazepam appears to be as effective as intravenous lorazepam (RR 0.96, 95% CI 0.82 to 1.13; 1 trial; 141 children; high-quality evidence) and intranasal midazolam was equivalent to intravenous diazepam (RR 0.98, 95% CI 0.91 to 1.06; 2 trials; 122 children; moderate-quality evidence).(3) Intramuscular midazolam also showed a similar rate of seizure cessation to intravenous diazepam (RR 0.97, 95% CI 0.87 to 1.09; 2 trials; 105 children; low-quality evidence).(4) For intravenous routes of administration, lorazepam appears to be as effective as diazepam in stopping acute tonic clonic convulsions: RR 1.04, 95% CI 0.94 to 1.16; 3 trials; 414 children; low-quality evidence. Furthermore, we found no statistically significant or clinically important differences between intravenous midazolam and diazepam (RR for seizure cessation 1.08, 95% CI 0.97 to 1.21; 1 trial; 80 children; moderate-quality evidence) or intravenous midazolam and lorazepam (RR for seizure cessation 0.98, 95% CI 0.91 to 1.04; 1 trial; 80 children; moderate-quality evidence). In general, intravenously-administered anticonvulsants led to more rapid seizure cessation but this was usually compromised by the time taken to establish intravenous access.(5) There is limited evidence from a single trial to suggest that intranasal lorazepam may be more effective than intramuscular paraldehyde in stopping acute tonic-clonic convulsions (RR 1.22, 95% CI 0.99 to 1.52; 160 children; moderate-quality evidence).(6) Adverse side effects were observed and reported very infrequently in the included studies. Respiratory depression was the most common and most clinically relevant side effect and, where reported, the frequency of this adverse event was observed in 0% to up to 18% of children. None of the studies individually demonstrated any difference in the rates of respiratory depression between the different anticonvulsants or their different routes of administration; but when pooled, three studies (439 children) provided moderate-quality evidence that lorazepam was significantly associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93).Much of the evidence provided in this review is of mostly moderate to high quality. However, the quality of the evidence provided for some important outcomes is low to very low, particularly for comparisons of non-intravenous routes of drug administration. Low- to very low-quality evidence was provided where limited data and imprecise results were available for analysis, methodological inadequacies were present in some studies which may have introduced bias into the results, study settings were not applicable to wider clinical practice, and where inconsistency was present in some pooled analyses.
AUTHORS' CONCLUSIONS
We have not identified any new high-quality evidence on the efficacy or safety of an anticonvulsant in stopping an acute tonic-clonic convulsion that would inform clinical practice. There appears to be a very low risk of adverse events, specifically respiratory depression. Intravenous lorazepam and diazepam appear to be associated with similar rates of seizure cessation and respiratory depression. Although intravenous lorazepam and intravenous diazepam lead to more rapid seizure cessation, the time taken to obtain intravenous access may undermine this effect. In the absence of intravenous access, buccal midazolam or rectal diazepam are therefore acceptable first-line anticonvulsants for the treatment of an acute tonic-clonic convulsion that has lasted at least five minutes. There is no evidence provided by this review to support the use of intranasal midazolam or lorazepam as alternatives to buccal midazolam or rectal diazepam.
Topics: Administration, Inhalation; Administration, Oral; Administration, Rectal; Anticonvulsants; Child; Diazepam; Epilepsy, Tonic-Clonic; Humans; Injections, Intramuscular; Injections, Intravenous; Lorazepam; Midazolam; Randomized Controlled Trials as Topic; Status Epilepticus
PubMed: 29320603
DOI: 10.1002/14651858.CD001905.pub3