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Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An in vivo multiphoton microscopy evaluation.

ABSTRACT: Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using in vivo multiphoton microscopy and laser speckle flowmetry, respectively, and on brain tissue oxygenation (PbO₂), behavioral outcomes, and neuropathology in 16-18-day-old rats. Epinephrine-treated rats had a more rapid return of spontaneous circulation and brisk immediate cortical reperfusion during 1-3 min post-CA vs. placebo. However, at the microvascular level, epinephrine-treated rats had penetrating arteriole constriction and increases in both capillary stalling (no-reflow) and cortical capillary transit time 30-60 min post-CA vs. placebo. Placebo-treated rats had increased capillary diameters post-CA. The cortex was hypoxic post-CA in both groups. Epinephrine treatment worsened reference memory performance vs. shams. Hippocampal neuron counts did not differ between groups. Resuscitation with epinephrine enhanced immediate reperfusion but produced microvascular alterations during the first hour post-resuscitation, characterized by vasoconstriction, capillary stasis, prolonged cortical transit time, and absence of compensatory cortical vasodilation. Targeted therapies mitigating the deleterious microvascular effects of epinephrine are needed.

SUBMITTER: Oghifobibi OA

PROVIDER: S-EPMC9670003 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An <i>in vivo</i> multiphoton microscopy evaluation.

Oghifobibi Onome A OA Toader Andrew E AE Nicholas Melissa A MA Nelson Brittany P BP Alindogan Nicole G NG Wolf Michael S MS Kline Anthony E AE Nouraie Seyed M SM Bondi Corina O CO Iordanova Bistra B Clark Robert Sb RS Bayır Hülya H Loughran Patricia A PA Watkins Simon C SC St Croix Claudette M CM Kochanek Patrick M PM Vazquez Alberto L AL Manole Mioara D MD

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20220719 12

Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using <i>in vivo</i> multiphoton microscopy and laser s ...[more]

PMID: 35854408

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Project description:BackgroundHalf of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness.MethodsPrespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status.ResultsOf 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001).ConclusionsIn this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

Project description:ImportanceDelay in administration of the first epinephrine dose is associated with decreased survival among adults after in-hospital, nonshockable cardiac arrest. Whether this association is true in the pediatric in-hospital cardiac arrest population remains unknown.ObjectiveTo determine whether time to first epinephrine dose is associated with outcomes in pediatric in-hospital cardiac arrest.Design, setting and participantsWe performed an analysis of data from the Get With the Guidelines-Resuscitation registry. We included US pediatric patients (age <18 years) with an in-hospital cardiac arrest and an initial nonshockable rhythm who received at least 1 dose of epinephrine. A total of 1558 patients (median age, 9 months [interquartile range [IQR], 13 days-5 years]) were included in the final cohort.ExposureTime to epinephrine, defined as time in minutes from recognition of loss of pulse to the first dose of epinephrine.Main outcomes and measuresThe primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC), survival at 24 hours, and neurological outcome. A favorable neurological outcome was defined as a score of 1 to 2 on the Pediatric Cerebral Performance Category scale.ResultsAmong the 1558 patients, 487 (31.3%) survived to hospital discharge. The median time to first epinephrine dose was 1 minute (IQR, 0-4; range, 0-20; mean [SD], 2.6 [3.4] minutes). Longer time to epinephrine administration was associated with lower risk of survival to discharge in multivariable analysis (multivariable-adjusted risk ratio [RR] per minute delay, 0.95 [95% CI, 0.93-0.98]). Longer time to epinephrine administration was also associated with decreased risk of ROSC (multivariable-adjusted RR per minute delay, 0.97 [95% CI, 0.96-0.99]), decreased risk of survival at 24 hours (multivariable-adjusted RR per minute delay, 0.97 [95% CI, 0.95-0.99]), and decreased risk of survival with favorable neurological outcome (multivariable-adjusted RR per minute delay, 0.95 [95% CI, 0.91-0.99]). Patients with time to epinephrine administration of longer than 5 minutes (233/1558) compared with those with time to epinephrine of 5 minutes or less (1325/1558) had lower risk of in-hospital survival to discharge (21.0% [49/233] vs 33.1% [438/1325]; multivariable-adjusted RR, 0.75 [95% CI, 0.60-0.93]; P = .01).Conclusions and relevanceAmong children with in-hospital cardiac arrest with an initial nonshockable rhythm who received epinephrine, delay in administration of epinephrine was associated with decreased chance of survival to hospital discharge, ROSC, 24-hour survival, and survival to hospital discharge with a favorable neurological outcome.

Project description:The goal of this study was to investigate the association between total epinephrine dosage during resuscitation and acute kidney injury after return of spontaneous circulation in patients with cardiac arrest. We performed a secondary analysis of previously published data on the resuscitation of cardiac arrest patients. Bivariate, multivariate logistic regression, and subgroup analyses were conducted to investigate the association between total epinephrine dosage during resuscitation and acute kidney injury after return of spontaneous circulation. A total of 312 eligible patients were included. The mean age of the patients was 60.8 ± 15.2 years. More than half of the patients were male (73.4%) and had an out-of-hospital cardiac arrest (61.9%). During resuscitation, 125, 81, and 106 patients received ≤2, 3 - 4, and ≥5 mg epinephrine, respectively. After return of spontaneous circulation, there were 165 patients (52.9%) and 147 patients (47.1%) with and without acute kidney injury, respectively. Both bivariate and multivariate analysis showed a statistically significant association between total epinephrine dosage and acute kidney injury. The subgroup analysis showed that the strength of the association between epinephrine dosage and acute kidney injury varied by location of cardiac arrest. Further multivariate regression analysis found that the association between epinephrine dosage and acute kidney injury was only observed in patients with in-hospital cardiac arrest after adjusting for multiple confounding factors. Compared with in-hospital cardiac arrest patients who received ≤2 mg of epinephrine, patients with 3-4 mg of epinephrine or ≥5 mg of epinephrine had adjusted odds ratios of 4.2 (95% confidence interval 1.0-18.4) and 11.3 (95% confidence interval 2.0-63.0), respectively, to develop acute kidney injury. Therefore, we concluded that a higher epinephrine dosage during resuscitation was associated with an increased incidence of acute kidney injury after return of spontaneous circulation in adult patients with in-hospital cardiac arrest.

Project description:Rationale: Cerebral cavernous malformation (CCM) is prone to recurring microhemorrhage, which can lead to drug-resistant epilepsy. Surgical resection is the first choice to control seizures for CCM-associated epilepsy. At present, removal of resection-related tissue only depends on cautious visual identification of CCM lesions and perilesional yellowish hemosiderin rim by the neurosurgeon. Inspired by the resection requirements, we proposed quantitative multiphoton microscopy (qMPM) for a histopathology-level diagnostic paradigm to assist clinicians in precisely complete resection. Methods: A total of 35 sections specimens collected from 12 patients with the CCM-related epilepsy were included in this study. First, qMPM utilized a label-free multi-channel selective detection to image the histopathological features based on the spectral characteristics of CCM tissues. Then, qMPM developed three customized algorithms to provide quantitative information, a vascular patterns classifier based on linear support vector machine, visualization of microhemorrhage regions based on hemosiderin-related parameters, and the CCM-oriented virtual staining generative adversarial network (CCM-stainGAN) was constructed to generate two types of virtual staining. Results: Focused on CCM lesion and perilesional regions, qMPM imaged malformed vascular patterns and micron-scale hemosiderin-related products. Four vascular patterns were automatically identified by the classifier with an area under the receiver operating characteristic curve of 0.97. Moreover, qMPM mapped different degrees of hemorrhage regions onto fresh tissue while providing three quantitative hemosiderin-related indicators. Besides, qMPM realized virtual staining by the CCM-stainGAN with 98.8% diagnostic accuracy of CCM histopathological features in blind analysis. Finally, we provided pathologists and surgeons with the qMPM-based CCM histopathological diagnostic guidelines for a more definitive intraoperative or postoperative diagnosis. Conclusions: qMPM can provide decision-making supports for histopathological diagnosis, and resection guidance of CCM from the perspectives of high-resolution precision detection and automated quantitative assessment. Our work will promote the development of MPM diagnostic instruments and enable more optical diagnostic applications for epilepsy.

Dataset Information

Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An in vivo multiphoton microscopy evaluation.

Publications

Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An <i>in vivo</i> multiphoton microscopy evaluation.

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