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Cardiology Journal 2021There is a beneficial effect of adrenaline during adult cardiopulmonary resuscitation (CPR) from cardiac arrest but there is also uncertainty about its safety and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There is a beneficial effect of adrenaline during adult cardiopulmonary resuscitation (CPR) from cardiac arrest but there is also uncertainty about its safety and effectiveness. The aim of this study was to evaluate the use of adrenaline versus non-adrenaline CPR.
METHODS
PubMed, ScienceDirect, Embase, CENTRAL (Cochrane Central Register of Controlled Trials) and Google Scholar databases were searched from their inception up to 1st July 2020. Two reviewers independently assessed eligibility and risk of bias, with conflicts resolved by a third reviewer. Risk ratio (RR) or mean difference of groups were calculated using fixed or random-effect models.
RESULTS
Nineteen trials were identified. The use of adrenaline during CPR was associated with a significantly higher percentage of return of spontaneous circulation (ROSC) compared to non-adrenaline treatment (20.9% vs. 5.9%; RR = 1.87; 95% confidence interval [CI] 1.37-2.55; p < 0.001). The use of adrenaline in CPR was associated with ROSC at 19.4% and for non-adrenaline treatment - 4.3% (RR = 3.23; 95% CI 1.89-5.53; p < 0.001). Survival to discharge (or 30-day survival) when using adrenaline was 6.8% compared to non-adrenaline treatment (5.5%; RR = 0.99; 95% CI 0.76-1.30; p = 0.97). However, the use of adrenaline was associated with a worse neurological outcome (1.6% vs. 2.2%; RR = 0.57; 95% CI 0.42-0.78; p < 0.001).
CONCLUSIONS
This review suggests that resuscitation with adrenaline is associated with the ROSC and survival to hospital discharge, but no higher effectiveness was observed at discharge with favorable neurological outcome. The analysis showed higher effectiveness of ROSC and survival to hospital discharge in non-shockable rhythms. But more multicenter randomized controlled trials are needed in the future.
Topics: Cardiopulmonary Resuscitation; Epinephrine; Humans; Multicenter Studies as Topic; Out-of-Hospital Cardiac Arrest; Patient Discharge; Return of Spontaneous Circulation
PubMed: 33140398
DOI: 10.5603/CJ.a2020.0133 -
Human Fertility (Cambridge, England) Jul 2022This paper reports a systematic review and meta-analysis of the effectiveness of hyoscine-N-butylbromide (HBB) administration in hysterosalpingography (HSG). Four... (Meta-Analysis)
Meta-Analysis
The effect of hyoscine-N-butylbromide on pain perception during and after hysterosalpingography in infertile women: a systematic review and meta-analysis of randomised controlled trials.
This paper reports a systematic review and meta-analysis of the effectiveness of hyoscine-N-butylbromide (HBB) administration in hysterosalpingography (HSG). Four electronic databases were searched for randomised controlled trials (RCTs) that compared HBB versus placebo or no intervention in infertile women undergoing HSG. Pain during and after HSG and different adverse events including nausea, vomiting, and dizziness were evaluated. Three RCTs with 335 patients were included. The analysis showed HBB was significantly effective in reducing pain during and after HSG (MD = -0.76 mm, 95% CI [-1.35, -0.17], = 0.01) and (MD = -0.81 mm, 95% CI [-1.07, -0.56], < 0.001), respectively. There were no significant differences in adverse events between HBB and control groups. The methodological evidence quality was high as evaluated by GRADEpro. In conclusion, this review provides good evidence that prior administration of HBB is effective in reducing induced pain during and after HSG with tolerable side effects.
Topics: Butylscopolammonium Bromide; Female; Humans; Hydrocarbons, Brominated; Hysterosalpingography; Infertility, Female; Pain; Pain Perception; Randomized Controlled Trials as Topic; Scopolamine
PubMed: 33140669
DOI: 10.1080/14647273.2020.1842915 -
The American Journal of Emergency... Mar 2024The preferred vasopressor in post-cardiac arrest shock has not been established with robust clinical outcomes data. Our goal was to perform a systematic review and... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The preferred vasopressor in post-cardiac arrest shock has not been established with robust clinical outcomes data. Our goal was to perform a systematic review and meta-analysis comparing rates of in-hospital mortality, refractory shock, and hemodynamic parameters in post-cardiac arrest patients who received either norepinephrine or epinephrine as primary vasopressor support.
METHODS
We conducted a search of PubMed, Cochrane Library, and CINAHL from 2000 to 2022. Included studies were prospective, retrospective, or published abstracts comparing norepinephrine and epinephrine in adults with post-cardiac arrest shock or with cardiogenic shock and extractable post-cardiac arrest data. The primary outcome of interest was in-hospital mortality. Other outcomes included incidence of arrhythmias or refractory shock.
RESULTS
The database search returned 2646 studies. Two studies involving 853 participants were included in the systematic review. The proposed meta-analysis was deferred due to low yield. Crude incidence of in-hospital mortality was numerically higher in the epinephrine group compared with norepinephrine in both studies, but only statistically significant in one. Risk of bias was moderate to severe for in-hospital mortality. Additional outcomes were reported differently between studies, minimizing direct comparison.
CONCLUSION
The vasopressor with the best mortality and hemodynamic outcomes in post-cardiac arrest shock remains unclear. Randomized studies are crucial to remedy this.
Topics: Adult; Humans; Norepinephrine; Shock, Cardiogenic; Prospective Studies; Retrospective Studies; Epinephrine; Vasoconstrictor Agents; Heart Arrest; Shock; Hemodynamics
PubMed: 38150986
DOI: 10.1016/j.ajem.2023.12.031 -
The Cochrane Database of Systematic... Aug 2019Amblyopia is defined as impaired visual acuity in one or both eyes without demonstrable abnormality of the visual pathway, and is not immediately resolved by wearing...
BACKGROUND
Amblyopia is defined as impaired visual acuity in one or both eyes without demonstrable abnormality of the visual pathway, and is not immediately resolved by wearing glasses.
OBJECTIVES
In performing this systematic review, we aimed to synthesize the best available evidence regarding the effectiveness and safety of conventional occlusion therapy compared to atropine penalization in treating amblyopia.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 8); Ovid MEDLINE; Ovid Embase; LILACS BIREME; ClinicalTrials.gov; ISRCTN; and the WHO ICTRP on 7 September 2018.
SELECTION CRITERIA
We included randomized/quasi-randomized controlled trials comparing conventional occlusion to atropine penalization for amblyopia.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened abstracts and full-text articles, abstracted data, and assessed risk of bias.
MAIN RESULTS
We included seven trials (five randomized controlled trials and two quasi-randomized controlled trials) conducted in six countries (China, India, Iran, Ireland, Spain, and the United States) with a total of 1177 amblyopic eyes. Three of these seven trials were from the original 2009 version of the review. We assessed two trials as having a low risk of bias across all domains, and the remaining five trials as having unclear or high risk of bias for some domains.As different occlusion modalities, atropine penalization regimens, and populations were used across the included trials, we did not conduct any meta-analysis due to clinical and statistical heterogeneity. Evidence from six trials (two at low risk of bias) suggests that atropine penalization is as effective as conventional occlusion in improving visual acuity. Similar improvement in visual acuity was reported at all time points at which it was assessed, ranging from five weeks (improvement of 1 line) to 10 years (improvement of greater than 3 lines). At six months, although most participants (363/522) come from a trial rated as at low risk of bias with a precise estimate (mean difference (MD) 0.03, 95% confidence interval (CI) 0.00 to 0.06), two other trials rated as at high risk of bias produced inconsistent estimates and wide confidence intervals (MD -0.02, 95% CI -0.11 to 0.07 and MD -0.14, 95% CI -0.23 to -0.05; moderate-certainty evidence). At 24 months, additional improvement was found in both groups, but there continued to be no meaningful difference between those receiving occlusion and those receiving atropine therapies (moderate-certainty evidence).We did not find any difference in ocular alignment, stereo acuity, or sound eye visual acuity between occlusion and atropine penalization groups (moderate-certainty evidence). Both treatments were well tolerated. Atropine was associated with better adherence (moderate-certainty evidence) and quality of life (moderate-certainty evidence), but also a higher reported risk of adverse events in terms of mild reduction in the visual acuity of the sound eye not requiring treatment and light sensitivity (high-certainty evidence). Skin, lid, or conjunctival irritation were more common among participants receiving patching than those receiving atropine (high-certainty evidence). Atropine penalization costs less than conventional occlusion.
AUTHORS' CONCLUSIONS
Both conventional occlusion and atropine penalization produce visual acuity improvement in the amblyopic eye. Atropine penalization appears to be as effective as conventional occlusion, although the magnitude of improvement differed among the trials we analyzed.
Topics: Amblyopia; Atropine; Child; Child, Preschool; Humans; Occlusive Dressings; Ophthalmic Solutions; Randomized Controlled Trials as Topic; Visual Acuity
PubMed: 31461545
DOI: 10.1002/14651858.CD006460.pub3 -
Canadian Journal of Ophthalmology.... Aug 2021Topical cycloplegic agents often are used in ophthalmology in the context of management of ocular inflammation. Preliminary searches of the literature provided little... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Topical cycloplegic agents often are used in ophthalmology in the context of management of ocular inflammation. Preliminary searches of the literature provided little evidence to support their use in relieving pain or reducing inflammation. The goal of this study was to evaluate the current literature for any evidence regarding the effectiveness of cycloplegics for treatment of pain or inflammation in patients with anterior segment injury or inflammation through a systematic review and meta-analysis.
METHODS
Using multiple keywords relating to cycloplegics and inflammatory and infectious eye conditions, a search was conducted on multiple scientific databases for relevant articles. A 2-level screening approach was used and articles that were relevant to the topic were included in the systematic review. Data from these articles, if applicable, were extracted for meta-analyses. Statistical assessments involved computation of Istatistics, Z-value, and χ statistics.
RESULTS
We screened 5753 articles for relevance. Seven were included in the systematic review and 5 were included in the meta-analysis. There was considerable heterogeneity between the included studies. Statistical analysis revealed significant reductions in pain using homatropine and cyclopentolate after 2 days. Nonsignificant changes in the anterior chamber cells and flare were seen using cyclopentolate and atropine at different follow-up times.
CONCLUSIONS
Little published evidence exists in the literature to guide the use of cycloplegics on relieving pain and treating inflammation. Therefore, higher-quality randomized controlled trials with longer follow-up times are needed to fully understand the role that cycloplegics play in reducing pain in inflammatory conditions.
Topics: Analgesics; Humans; Inflammation; Mydriatics
PubMed: 33548176
DOI: 10.1016/j.jcjo.2020.12.004 -
The Journal of Allergy and Clinical... Mar 2021Uterine contractions are recognized as a potential manifestation of anaphylaxis, but literature on their proper management is limited. It is widely recognized that...
BACKGROUND
Uterine contractions are recognized as a potential manifestation of anaphylaxis, but literature on their proper management is limited. It is widely recognized that anaphylactic reactions can cause uterine contractions, but little is known about their optimal management.
OBJECTIVE
Review potential treatments for painful uterine contractions associated with anaphylaxis or mast cell activation.
METHODS
This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. PubMed, Embase, and Cochrane were searched in English, French, and Spanish for reports of uterine anaphylaxis published up until July 2020. The search strategy used a combination of Boolean operators and included the following Medical Subject Heading terms and keywords: hypersensitivity; anaphylaxis; mastocytosis; uterus; uterine contraction; pelvic pain; labor, obstetric; labor, premature; and endometriosis.
RESULTS
This systematic review identified 19 studies reporting on 31 cases of painful uterine contractions occurring during anaphylaxis or other events associated with mast cell activation. Nine patients were pregnant. We present 2 additional cases in nonpregnant women, one associated with an oral food challenge and the other associated with oral food desensitization. The most frequent triggers were subcutaneous immunotherapy (14 cases), food (6 cases), and drugs (4 cases). Uterine cramps were associated with systemic symptoms in 24 cases and lasted on average for 2.4 hours. Pretreatment with antihistamines and montelukast generally failed to prevent recurrence, but nonsteroidal anti-inflammatory drugs were used successfully in some reports. Response to intramuscular epinephrine was inconsistent. Data from ex vivo models indicate that epinephrine may paradoxically contribute to uterine contractions through alpha-receptor activity. A small number of cases showed good response to beta-2 agonists.
CONCLUSIONS
There is a lack of quality data on painful uterine contractions occurring in the context of anaphylactic reactions and on their optimal management. In the absence of counterindication, use of a beta-2 agonist and premedication with nonsteroidal anti-inflammatory drugs could be the preferred options.
Topics: Allergens; Anaphylaxis; Desensitization, Immunologic; Epinephrine; Female; Humans; Pregnancy; Uterine Contraction
PubMed: 33181341
DOI: 10.1016/j.jaip.2020.10.047 -
Current Opinion in Allergy and Clinical... Aug 2022To identify patterns and key issues though a systematic review in order to support prevention strategies and reduce avoidable deaths related to drug-induced anaphylaxis...
PURPOSE OF REVIEW
To identify patterns and key issues though a systematic review in order to support prevention strategies and reduce avoidable deaths related to drug-induced anaphylaxis (DAF).
RECENT FINDINGS
DAF rate has been estimated by 0.13-0.53/106 population/year. General global trends of DAF are increasing over time, mostly occurring at healthcare settings (62%) with a similar gender distribution and an average age of 53 years. Antibiotics, anaesthetics, radio-contrast media and NSAIDs were the most frequently implicated agents. Main comorbidities were personal history of drug allergy, cardiovascular diseases and asthma. Main manifestations were cardiovascular and respiratory commitments. Use of adrenaline is mentioned in only 29% of the articles.
SUMMARY
DAF is increasing worldwide and most cases are iatrogenic. This first systematic review of DAF identified key gaps and served as a wake-up call to prevent avoidable deaths. Phenotype at risk for DAF was represented by patients aged more than 54 years, with personal history of drug allergy/hypersensitivity with no or incomplete allergological work-up, cardiovascular disease and/or asthma with need of hospitalization and/or frequent healthcare assistance. Additional risk for those who need frequent use of intravenous antibiotics and/or undergoing surgery or image investigation with radiocontrast media.
Topics: Anaphylaxis; Anti-Bacterial Agents; Asthma; Contrast Media; Drug Hypersensitivity; Epinephrine; Humans
PubMed: 35852895
DOI: 10.1097/ACI.0000000000000835 -
Sleep Medicine Dec 2022To compare the levels of different urinary catecholamines amongst paediatric patients with and without sleep-disordered breathing (SDB). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To compare the levels of different urinary catecholamines amongst paediatric patients with and without sleep-disordered breathing (SDB).
METHODS
Literature searches were conducted on PubMed and EMBASE until 25/06/2022. Inclusion criteria were original human studies, English language, paediatric subjects diagnosed with SDB/obstructive sleep apnoea (OSA). The quality of studies was assessed by the Newcastle-Ottawa Quality Assessment (NOSGEN). The registered number of this study on the International Prospective Register of Systematic Reviews (PROSPERO) is CRD42022332939. The main outcome measured was standardised mean difference (SMD) of urinary catecholamine between subjects with and without SDB, between those with and without OSA, and also between subjects with mild OSA and those with moderate/ severe OSA. Sensitivity analyses were performed to avoid bias.
RESULTS
9 studies (8 cross-sectional and 1 cohort study) with a total of 838 subjects, were included in the quantitative analysis. Urine level of noradrenaline was higher in patients with SDB, which included primary snoring (PS), when compared to controls: SMD = 0.86 (95%CI=0.32-1.41; I=85%, P=0.002). The levels of urinary noradrenaline and adrenaline were higher in children with OSA when compared to controls: SMD = 1.45 (95%CI=0.91-2.00; I=75%, P < 0.001); SMD = 1.84 (0.00-3.67; I=97%, P=0.05). Urine level of noradrenaline was higher in subjects with moderate/severe OSA compared to the mild OSA: SMD = 0.55 (95%CI=0.10-1.00; I=0%, P=0.02). Urinary dopamine was not associated with SDB regardless of severity.
CONCLUSIONS
Urinary noradrenaline was higher in all patients with SDB. Subjects with OSA, a more severe form of SDB, had higher urine levels of noradrenaline and adrenaline. Hence, noradrenaline and adrenaline may be markers of sympathetic overtone in patients with SDB and could potentially act as surrogate markers for SDB complications. Further studies are needed to assess this association.
Topics: Humans; Child; Catecholamines; Cross-Sectional Studies; Cohort Studies; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Biomarkers; Norepinephrine; Epinephrine
PubMed: 36327585
DOI: 10.1016/j.sleep.2022.10.008 -
The Cochrane Database of Systematic... Jun 2021Neonates born through meconium-stained amniotic fluid (MSAF) are at risk of developing meconium aspiration syndrome (MAS). Neonates who are non-vigorous due to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neonates born through meconium-stained amniotic fluid (MSAF) are at risk of developing meconium aspiration syndrome (MAS). Neonates who are non-vigorous due to intrapartum asphyxia are at higher risk of developing MAS. Clearance of meconium from the airways below the vocal cords by tracheal suction before initiating other steps of resuscitation may reduce the risk of development of MAS. However, conducting tracheal suction may not only be ineffective, it may also delay effective resuscitation, thus prolonging and worsening the hypoxic-ischaemic insult. OBJECTIVES: To evaluate the efficacy of tracheal suctioning at birth in preventing meconium aspiration syndrome and other complications among non-vigorous neonates born through meconium-stained amniotic fluid.
SEARCH METHODS
We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 11) in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) (1946 to 25 November 2020) for randomised controlled trials (RCTs) and quasi-randomised trials. We also searched clinical trials databases and the reference lists of retrieved articles for RCTs and quasi-randomised trials (up to November 2020).
SELECTION CRITERIA
We included studies enrolling non-vigorous neonates born through MSAF, if the intervention being tested included tracheal suction at the time of birth with an intent to clear the trachea of meconium before regular breathing efforts began. Tracheal suction could be performed with an endotracheal tube or a wide-gauge suction catheter. Neonates in the control group should have been resuscitated at birth with no effort made to clear the trachea of meconium.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial quality and extracted data, consulting with a third review author about any disagreements. We used standard Cochrane methodological procedures, including assessment of risk of bias for all studies. Our primary outcomes were: MAS; all-cause neonatal mortality; and incidence of hypoxic-ischaemic encephalopathy (HIE). Secondary outcomes included: need for mechanical ventilation; incidence of pulmonary air leaks; culture-positive sepsis; and persistent pulmonary hypertension. We used the GRADE approach to assess the certainty of evidence.
MAIN RESULTS
We included four studies (enrolling 581 neonates) in the review. All four studies were conducted in tertiary care hospitals in India. Three of the four studies included neonates born at and beyond term gestation, whereas one included neonates born at and beyond 34 weeks of gestation. Due to the nature of the intervention, it was not possible to blind the healthcare personnel conducting the intervention. Tracheal suction compared to no suction in non-vigorous neonates born through MSAF In non-vigorous infants, no differences were noted in the risks of MAS (RR 1.00, 95% CI 0.80 to 1.25; RD 0.00, 95% CI -0.07 to 0.08; 4 studies, 581 neonates) or all-cause neonatal mortality (RR 1.24, 95% CI 0.76 to 2.02; RD 0.02, 95% CI -0.03 to 0.07; 4 studies, 575 neonates) with or without tracheal suctioning. No differences were reported in the risk of any severity HIE (RR 1.05, 95% CI 0.68 to 1.63; 1 study, 175 neonates) or moderate to severe HIE (RR 0.68, 95% CI 0.43 to 1.09; 1 study, 152 neonates) among non-vigorous neonates born through MSAF. We are also uncertain as to the effect of tracheal suction on other outcomes such as incidence of mechanical ventilation (RR 0.99, 95% CI 0.68 to 1.44; RD 0.00, 95% CI -0.06 to 0.06; 4 studies, 581 neonates), pulmonary air leaks (RR 1.22, 95% CI 0.38 to 3.93; RD 0.00, 95% CI -0.02 to 0.03; 3 studies, 449 neonates), persistent pulmonary hypertension (RR 1.29, 95% CI 0.60 to 2.77; RD 0.02, 95% CI -0.03 to 0.06; 3 studies, 406 neonates) and culture-positive sepsis (RR 1.32, 95% CI 0.48 to 3.57; RD 0.01, 95% CI -0.03 to 0.05; 3 studies, 406 neonates). All reported outcomes were judged as providing very low certainty evidence.
AUTHORS' CONCLUSIONS
We are uncertain about the effect of tracheal suction on the incidence of MAS and its complications among non-vigorous neonates born through MSAF. One study awaits classification and could not be included in the review. More research from well-conducted large trials is needed to conclusively answer the review question.
Topics: Amniotic Fluid; Bias; Bronchodilator Agents; Cardiopulmonary Resuscitation; Cause of Death; Confidence Intervals; Epinephrine; Humans; Hypertension, Pulmonary; Hypoxia-Ischemia, Brain; Incidence; India; Infant; Infant Mortality; Infant, Newborn; Intubation, Intratracheal; Meconium Aspiration Syndrome; Randomized Controlled Trials as Topic; Respiration, Artificial; Sepsis; Suction; Trachea
PubMed: 34133025
DOI: 10.1002/14651858.CD012671.pub2 -
American Journal of Cardiovascular... Sep 2022Cardiac arrest is often fatal if not treated immediately by cardiopulmonary resuscitation to restore a normal heart rhythm and spontaneous circulation. We aim to... (Meta-Analysis)
Meta-Analysis
The Effect of Vasopressin and Methylprednisolone on Return of Spontaneous Circulation in Patients with In-Hospital Cardiac Arrest: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
INTRODUCTION
Cardiac arrest is often fatal if not treated immediately by cardiopulmonary resuscitation to restore a normal heart rhythm and spontaneous circulation. We aim to evaluate the clinical benefits of vasopressin and methylprednisolone versus placebo for patients with in-hospital cardiac arrest.
DATA SOURCES
We searched PubMed, EMBASE, Scopus, Web of Science, Cochrane Central, and Google Scholar from inception to October 17, 2021, by using search terms included "Vasopressin" AND "Methylprednisolone" AND "Cardiac arrest".
STUDY SELECTION AND DATA EXTRACTION
We included randomized controlled trials (RCTs) that compared vasopressin and methylprednisolone to placebo. The main outcomes were the return of spontaneous circulation (ROSC) and survival to hospital discharge.
DATA SYNTHESIS
A total of three RCTs, with a total of 869 patients, were included. The pooled risk ratios (RRs) were calculated along with their 95% confidence intervals (CIs). Our result showed an increase in ROSC in patients who received vasopressin and methylprednisolone (RR = 1.32; 95% CI = [1.18, 1.47], p < 0.00001) when compared with the placebo group. However, there was no difference between both groups regarding survival to hospital discharge (RR = 1.76; 95% CI = [0.68, 4.56], p= 0.25).
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
The current guidelines recommend epinephrine for patients with in-hospital cardiac arrest. Our meta-analysis updates clinicians about using vasopressin and methylprednisolone besides epinephrine, providing them with the best available evidence in managing patients with in-hospital cardiac arrest.
CONCLUSION
Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone besides epinephrine is associated with increased ROSC compared with placebo and epinephrine. However, high-quality RCTs are necessary before drawing a firm conclusion regarding the efficacy of vasopressin and methylprednisolone for patients with in-hospital cardiac arrest.
Topics: Epinephrine; Heart Arrest; Hospitals; Humans; Methylprednisolone; Randomized Controlled Trials as Topic; Return of Spontaneous Circulation
PubMed: 35314927
DOI: 10.1007/s40256-022-00522-z