Acute Lung Injury after Cardiopulmonary Resuscitation: A Narrative Review.

Although cardiopulmonary resuscitation (CPR) includes lifesaving maneuvers, it might be associated with a wide spectrum of iatrogenic injuries. Among these, acute lung injury (ALI) is frequent and yields significant challenges to post-cardiac arrest recovery. Understanding the relationship between CPR and ALI is determinant for refining resuscitation techniques and improving patient outcomes. This review aims to analyze the existing literature on ALI following CPR, emphasizing prevalence, clinical implications, and contributing factors. The review seeks to elucidate the pathogenesis of ALI in the context of CPR, assess the efficacy of CPR techniques and ventilation strategies, and explore their impact on post-cardiac arrest outcomes. CPR-related injuries, ranging from skeletal fractures to severe internal organ damage, underscore the complexity of managing post-cardiac arrest patients. Chest compression, particularly when prolonged and vigorous, i.e., mechanical compression, appears to be a crucial factor contributing to ALI, with the concept of cardiopulmonary resuscitation-associated lung edema (CRALE) gaining prominence. Ventilation strategies during CPR and post-cardiac arrest syndrome also play pivotal roles in ALI development. The recognition of CPR-related lung injuries, especially CRALE and ALI, highlights the need for research on optimizing CPR techniques and tailoring ventilation strategies during and after resuscitation.

Incidence, characteristics, and outcome of out-of-hospital cardiac arrest in Italy: A systematic review and meta-analysis.

Introduction: Data on out-of-hospital cardiac arrest (OHCA) is limited in Italy, and there has never been a comprehensive systematic appraisal of the available evidence. Therefore, this review aims to explore the incidence, characteristics, and outcome of OHCA in Italy. Methods: We systematically searched PubMed, Embase, Google Scholar, ResearchGate, and conference proceedings up to September 23, 2022. Studies investigating OHCA in Italy and reporting at least one outcome related to cardiac arrest were considered eligible. The primary outcome was survival at the longest follow-up available. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool. A random-effects model proportion meta-analysis was performed to calculate the pooled outcomes with 95% confidence interval (CI). Results: We included 42 studies (43,042 patients) from 13 of the 20 Italian regions published between 1995 and 2022. Only five studies were deemed to be at low risk of bias. The overall average incidences of OHCA attended by emergency medical services and with resuscitation attempted were 86 (range: 10-190) and 55 (range: 6-108) per 100,000 populations per year, respectively. Survival at the longest follow-up available was 9.0% (95% CI, 6.7-12%; 30 studies and 15,195 patients) in the overall population, 25% (95% CI, 21-30%; 16 studies and 2,863 patients) among patients with shockable rhythms, 28% (95% CI, 20-37%; 8 studies and 1,292 patients) among the Utstein comparator group. Favourable neurological outcome was 5.0% (95% CI, 3.6-6.6%; 16 studies and 9,675 patients). Return of spontaneous circulation was achieved in 19% (95% CI, 16-23%; 40 studies and 30,875 patients) of cases. Bystanders initiated cardiopulmonary resuscitation in 26% (95% CI, 21-32%; 33 studies and 23,491 patients) of cases but only in 3.2% (95% CI, 1.9-4.9%; 9 studies and 8,508 patients) with an automated external defibrillator. The mean response time was 10.2 (95% CI, 8.9-11.4; 25 studies and 23,997 patients) minutes. Conclusions: Survival after OHCA in Italy occurred in one of every ten patients. Bystanders initiated cardiopulmonary resuscitation in only one-third of cases, rarely with a defibrillator. Different areas of the country collected data, but an essential part of the population was not included. There was high heterogeneity and large variation in outcomes results and reporting, limiting the confidence in the estimates of incidence and outcome. Creating and maintaining a nationwide registry is a priority.

Central venous pressure swing outperforms diaphragm ultrasound as a measure of inspiratory effort during pressure support ventilation in COVID-19 patients.

PURPOSE: The COVID-19-related shortage of ICU beds magnified the need of tools to properly titrate the ventilator assistance. We investigated whether bedside-available indices such as the ultrasonographic changes in diaphragm thickening ratio (TR) and the tidal swing in central venous pressure (ΔCVP) are reliable estimates of inspiratory effort, assessed as the tidal swing in esophageal pressure (ΔPes). METHODS: Prospective, observational clinical investigation in the intensive care unit of a tertiary care Hospital. Fourteen critically-ill patients were enrolled (age 64 ± 7 years, BMI 29 ± 4 kg/m2), after 6 [3; 9] days from onset of assisted ventilation. A three-level pressure support trial was performed, at 10 (PS10), 5 (PS5) and 0 cmH2O (PS0). In each step, the esophageal and central venous pressure tidal swing were recorded, as well as diaphragm ultrasound. RESULTS: The reduction of pressure support was associated with an increased respiratory rate and a reduced tidal volume, while minute ventilation was unchanged. ΔPes significantly increased with reducing support (5 [3; 8] vs. 8 [14; 13] vs. 12 [6; 16] cmH2O, p < 0.0001), as did the diaphragm TR (9.2 ± 6.1 vs. 17.6 ± 7.2 vs. 28.0 ± 10.0%, p < 0.0001) and the ΔCVP (4 [3; 7] vs. 8 [5; 9] vs. 10 [7; 11] cmH2O, p < 0.0001). ΔCVP was significantly associated with ΔPes (R2 = 0.810, p < 0.001), as was diaphragm TR, albeit with a lower coefficient of determination (R2 = 0.399, p < 0.001). CONCLUSIONS: In patients with COVID-19-associated respiratory failure undergoing assisted mechanical ventilation, ΔCVP is a better estimate of inspiratory effort than diaphragm ultrasound.

Esmolol during cardiopulmonary resuscitation reduces neurological injury in a porcine model of cardiac arrest.

Primary vasopressor efficacy of epinephrine during cardiopulmonary resuscitation (CPR) is due to its α-adrenergic effects. However, epinephrine plays ß1-adrenergic actions, which increasing myocardial oxygen consumption may lead to refractory ventricular fibrillation (VF) and poor outcome. Effects of a single dose of esmolol in addition to epinephrine during CPR were investigated in a porcine model of VF with an underlying acute myocardial infarction. VF was ischemically induced in 16 pigs and left untreated for 12 min. During CPR, animals were randomized to receive epinephrine (30 µg/kg) with either esmolol (0.5 mg/kg) or saline (control). Pigs were then observed up to 96 h. Coronary perfusion pressure increased during CPR in the esmolol group compared to control (47 ± 21 vs. 24 ± 10 mmHg at min 5, p < 0.05). In both groups, 7 animals were successfully resuscitated and 4 survived up to 96 h. No significant differences were observed between groups in the total number of defibrillations delivered prior to final resuscitation. Brain histology demonstrated reductions in cortical neuronal degeneration/necrosis (score 0.3 ± 0.5 vs. 1.3 ± 0.5, p < 0.05) and hippocampal microglial activation (6 ± 3 vs. 22 ± 4%, p < 0.01) in the esmolol group compared to control. Lower circulating levels of neuron specific enolase were measured in esmolol animals compared to controls (2[1-3] vs. 21[16-52] ng/mL, p < 0.01). In this preclinical model, ß1-blockade during CPR did not facilitate VF termination but provided neuroprotection.

Ventilation With Argon Improves Survival With Good Neurological Recovery After Prolonged Untreated Cardiac Arrest in Pigs.

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4-hour post-resuscitation ventilation with: 70% nitrogen-30% oxygen (control); 50% Ar-20% nitrogen-30% oxygen (Ar 50%); and 70% Ar-30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety-six-hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group (P<0.0001). Histology showed less neuronal degeneration in the cortex (P<0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus (P=0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation (P<0.05), were present in Ar-treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release (P<0.01). Conclusions Post-resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no-flow duration. Benefits are greater after Ar 70% than Ar 50%.

A Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation.

OBJECTIVES: Supplementation of antithrombin might decrease the amount of heparin needed to achieve a given anticoagulation target during extracorporeal membrane oxygenation. However, exogenous antithrombin itself may increase the risk of bleeding. We conceived a study to evaluate the effect of antithrombin supplementation in adult patients requiring venovenous extracorporeal membrane oxygenation for respiratory failure on heparin dose, adequacy of anticoagulation, and safety. DESIGN: Prospective randomized controlled trial. SETTING: ICUs of two Italian referral extracorporeal membrane oxygenation centers. PATIENTS: Adult patients requiring venovenous extracorporeal membrane oxygenation for severe respiratory failure and unfractionated heparin for systemic anticoagulation. INTERVENTIONS: Before extracorporeal membrane oxygenation start, patients were randomized to either receive antithrombin concentrate to maintain a plasmatic level 80-120% (treatment) or not (control) during the extracorporeal membrane oxygenation course. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the total amount of heparin required to maintain activated partial thromboplastin time ratio 1.5-2. Secondary outcomes were anti-factor Xa, the incidence of hemorrhagic and thrombotic events, and the amount of blood products transfused. Twenty-four patients in the treatment group and 24 in the control group were included in the intention-to-treat analysis. Antithrombin was 109.5% (93.0-123.0%) in the treatment group and 84.0% (68.5-98.0%) in the control group (p = 0.001). Supplementation of antithrombin did not decrease heparin dose (13.5 international units/kg/hr [9.6-17.9 international units/kg/hr] vs 15.1 international units/kg/hr [10.7-18.3 international units/kg/hr] in the treatment and control group, respectively; p = 0.33) and anti-Factor Xa levels (0.4 international units/mL [0.3-0.5 international units/mL] vs 0.3 international units/mL [0.2-0.5 international units/mL] in the treatment group and control group respectively; p = 0.65). Bleeding, blood product transfusions, and thrombosis were not different in the two groups. CONCLUSIONS: Antithrombin supplementation may not decrease heparin requirement nor diminish the incidence of bleeding and/or thrombosis in adult patients on venovenous extracorporeal membrane oxygenation.

Antithrombin supplementation during extracorporeal membrane oxygenation: study protocol for a pilot randomized clinical trial.

BACKGROUND: Normal levels of plasma antithrombin (AT) activity might decrease heparin requirements to achieve an adequate level of anticoagulation during treatment with extracorporeal membrane oxygenation (ECMO). Acquired AT deficiency during ECMO is common, but formal recommendations on target, timing, and rate of AT supplementation are lacking. Thus, we conceived a pilot trial to evaluate the feasibility and safety of prolonged AT supplementation in patients requiring veno-venous ECMO for respiratory failure. METHODS: Grifols Antithrombin Research Awards (GATRA) is a prospective, randomized, single blinded, multicenter, controlled two-arm trial. Patients undergoing veno-venous ECMO will be randomized to either receive AT supplementation to maintain a functional AT level between 80 and 120% (AT supplementation group) or not (control group) for the entire ECMO course. In both study groups, anticoagulation will be provided with unfractionated heparin following a standardized protocol. The primary endpoint will be the dose of heparin required to maintain the ratio of activated partial thromboplastin time between 1.5 and 2. Secondary endpoints will be the adequacy of anticoagulation and the incidence of hemorrhagic and thrombotic complications. DISCUSSION: GATRA is a pilot trial that will test the efficacy of a protocol of AT supplementation in decreasing the heparin dose and improving anticoagulation adequacy during ECMO. If positive, it might provide the basis for a future larger trial aimed at verifying the impact of AT supplementation on a composite outcome endpoint including hemorrhagic events, transfusion requirements, and mortality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03208270 . Registered on 5 July 2017.

LUCAS Versus Manual Chest Compression During Ambulance Transport: A Hemodynamic Study in a Porcine Model of Cardiac Arrest.

Background Mechanical chest compression (CC) is currently suggested to deliver sustained high-quality CC in a moving ambulance. This study compared the hemodynamic support provided by a mechanical piston device or manual CC during ambulance transport in a porcine model of cardiopulmonary resuscitation. Methods and Results In a simulated urban ambulance transport, 16 pigs in cardiac arrest were randomized to 18 minutes of mechanical CC with the LUCAS (n=8) or manual CC (n=8). ECG, arterial and right atrial pressure, together with end-tidal CO2 and transthoracic impedance curve were continuously recorded. Arterial lactate was assessed during cardiopulmonary resuscitation and after resuscitation. During the initial 3 minutes of cardiopulmonary resuscitation, the ambulance was stationary, while then proceeded along a predefined itinerary. When the ambulance was stationary, CC-generated hemodynamics were equivalent in the 2 groups. However, during ambulance transport, arterial and coronary perfusion pressure, and end-tidal CO2 were significantly higher with mechanical CC compared with manual CC (coronary perfusion pressure: 43±4 versus 18±4 mmHg; end-tidal CO2: 31±2 versus 19±2 mmHg, P<0.01 at 18 minutes). During cardiopulmonary resuscitation, arterial lactate was lower with mechanical CC compared with manual CC (6.6±0.4 versus 8.2±0.5 mmol/L, P<0.01). During transport, mechanical CC showed greater constancy compared with the manual CC, as represented by a higher CC fraction and a lower transthoracic impedance curve variability ( P<0.01). All animals in the mechanical CC group and 6 (75%) in the manual one were successfully resuscitated. Conclusions This model adds evidence in favor of the use of mechanical devices to provide ongoing high-quality CC and tissue perfusion during ambulance transport.

Heterogeneity of large cell carcinoma of the lung: an immunophenotypic and miRNA-based analysis.

Large cell carcinomas (LCCs) of the lung are heterogeneous and may be of different cell lineages. We analyzed 56 surgically resected lung tumors classified as LCC on the basis of pure morphologic grounds, using a panel of immunophenotypic markers (adenocarcinoma [ADC]-specific, thyroid transcription factor-1, cytokeratin 7, and napsin A; squamous cell carcinoma [SQCC]-specific, p63, cytokeratin 5, desmocollin 3, and Δnp63) and the quantitative analysis of microRNA-205 (microRNA sample score [mRSS]). Based on immunoprofiles 19 (34%) of the cases were reclassified as ADC and 14 (25%) as SQCC; 23 (41%) of the cases were unclassifiable. Of these 23 cases, 18 were classified as ADC and 5 as SQCC according to the mRSS. Our data show that an extended panel of immunohistochemical markers can reclassify around 60% of LCCs as ADC or SQCC. However, a relevant percentage of LCCs may escape convincing immunohistochemical classification, and mRSS could be used for further typing, but its clinical relevance needs further confirmation.

miR-205 Expression levels in nonsmall cell lung cancer do not always distinguish adenocarcinomas from squamous cell carcinomas.

Accurate classification of nonsmall cell lung cancers is of paramount clinical relevance, as novel chemotherapeutic agents show different efficacy in adenocarcinomas (ADCs) compared with squamous cell carcinomas (SQCCs). Cyto and histomorphology may sometimes be insufficient for this distinction and immunohistochemistry may improve diagnostic accuracy. The measurement of miR-205 may be another tool for the distinction between ADC and SQCC. The aim of our study was to compare morphologic and immunohistochemical classification with the relative quantification of miR-205 and miR-21 insurgically resected and well-characterized lung tumors (25 ADCs, 24 SQCCs, 1 adenosquamous). The miR-21 relative levels were similar in SQCC and ADC, whereas the miR-205 relative levels were lower in ADC (P<0.0001). The miR-205 sample score value, determined according to Lebanony et al, was higher in ADC (range, 2.8 to 9.08) compared with SQCC (range, -4.17 to 2.445) (P<0.0001). Accordingly, 22 tumors were classified as ADC and 28 tumors as SQCC, although 8 cases (2 SQCCs and 6 ADCs) were in the range of "near cutoff values." Four cases classified as SQCC (according to the sample score method) corresponded to cases classified as ADC on the basis of morphoimmunohistochemical evaluation. In conclusion, the relative quantification of miR-205 and miR-21 seems to be a promising diagnostic tool. However, the molecular approach is still not completely satisfactory as it may misclassify a non-negligible percentage of cases. Therefore, it cannot be used as a substitute of accurate morphologic and immunophenotypical characterization of tumors, but could be used as an adjunctive diagnostic criterion in selected cases.