Shock Resuscitation Research Articles

Drug therapy versus placebo or usual care for comatose survivors of cardiac arrest; a systematic review with meta-analysis.

In Europe, approximately 291,000 cardiac arrests occur annually. Despite critical care therapy, hospital mortality remains high. This systematic review assessed whether, in comatose survivors of cardiac arrest, any drug therapy, compared to placebo or usual care, improves outcomes. We searched Medline, EMBASE, the Cochrane Central Register of Controlled Trials, and The International Clinical Trials Registry Platform for randomized controlled trials of drug therapy in comatose survivors of cardiac arrest (last searched 20th October 2024). The primary outcome was mortality at 30 days / hospital discharge. Other outcomes reflected those of the Core Outcome Set for Cardiac Arrest. Risk of bias was assessed using Cochrane Risk-Of-Bias Version 1. Studies of steroids, coenzyme Q10 and thiamine were meta-analysed. From 2,562 records, 207 full texts were screened and 45 studies (5,800 patients) investigating 30 therapies were included. Studies were grouped thematically as supportive drug therapies (n = 10), neuroprotective agents (n = 19), and anti-inflammatory / antioxidants (n = 16). Four studies reported reduced mortality at 30 days / hospital discharge: one of the anticholinergic penehyclidine hydrochloride, two of intra-arrest vasopressin and methylprednisolone plus hydrocortisone for post resuscitation shock, and one of the traditional Chinese medicine, shenfu. Studies of steroids, coenzyme Q10 and thiamine were meta-analysed. We could not detect an effect on mortality with steroids (n = 739, risk ratio (RR), 0.93; 95 % CI 0.83-1.04, p = 0.21; I2 = 60 %, low certainty), coenzyme Q10 (n = 107, RR, 0.91; 95 % CI 0.61-1.37, p = 0.65; I2 = 0 %, low certainty), or thiamine (n = 149, RR, 1.11; 95 % CI 0.88-1.40, p = 0.39; I2 = 0 %, very low certainty). In comatose survivors of cardiac arrest, the majority of trials of drug therapy reported no effect on mortality. Meta-analyses of steroids, coenzyme Q10 and thiamine demonstrated no evidence of an effect on mortality. However, the low certainty of evidence warrants further research.

Understanding Hemodynamic Incoherence: Mechanisms, Phenotypes, and Implications for Treatment.

The reversal of microcirculation dysfunction is crucial for assessing the success of shock resuscitation and significantly influences patient prognosis. However hemodynamic incoherence is observed when microcirculatory dysfunction persists despite the restoration of macrocirculatory function post-resuscitation. Recent advancements in technology have enabled bedside assessment of microcirculation in shock patients, allowing for direct visualization of microcirculatory morphology and quantitative evaluation of its functional status. This article reviews the pathophysiological mechanisms that lead to hemodynamic incoherence. It also introduces the current understanding and classification framework for the different phenotypes of hemodynamic incoherence. Existing evidence indicates that the diverse mechanisms leading to microcirculatory disorders result in varied manifestations among patients experiencing hemodynamic incoherence, highlighting the heterogeneity of this population. Some classification frameworks have been proposed to enhance our understanding of these phenotypes. By integrating pathophysiological mechanisms, clinical symptoms, indicators of macrocirculation, microcirculation, tissue metabolism, and biomarkers, we can summarize certain clinical features of phenotypes in hemodynamic incoherence to form a conceptual framework. Additionally, strategies for creating targeted treatments based on different phenotypes require further validation.

Fire at Sea: A 70-year Review of Fire-Related Mass Casualty Events on U.S. Aircraft Carriers.

A major fire at sea is among the most devastating events that can occur while a U.S. Navy combatant vessel is underway. Since World War II, no attack on a large U.S. Navy capital ship has occurred during combat operations. However, increasing global tensions raise the threat of future peer adversary naval combat, and shipboard medical caregivers must be prepared for mass casualty events in the deployed maritime environment. To better prepare modern naval caregivers for this possibility, we reviewed mass casualty events from major fires aboard large U.S. Navy aircraft carriers from 1950 through 2020 to summarize available objective data and identify lessons learned. Underway fires from any cause aboard U.S. Navy aircraft carriers and large amphibious assault ships causing more than 10 casualties (injuries + deaths) were reviewed from 1950 through 2020 using available open access sources including literature review, the Naval Safety Command mishap database, and U.S. Navy Judge Advocate Manual reports. Of 246 fires identified, 27 met inclusion criteria resulting in 1,634 casualties with a combined crew mortality of 23% of those injured. In the 16 events with at least 1 death, 2.0% of the total crew was injured with a combined mortality of 28%. All mishaps occurred while underway during routine training or combat operations; none were caused by an enemy combatant attack. Those events affecting more than 5% of the crew were particularly devastating resulting in a mortality rate of 29% of 1,056 total casualties. Given that main medical spaces may be damaged or destroyed during major fires from any cause, identified lessons learned included the need for (1) distributed medical supplies, (2) flexible medical treatment locations throughout the ship, (3) specific training to prepare non-physician caregivers and non-medical first responders to provide burn and hemorrhagic shock resuscitation, airway management, and prolonged care at or near the point of injury, and (4) the prolonged holding capability of critically ill burned and injured patients if evacuation off the ships is unavailable. Shipboard fires underway pose a significant threat to crew safety with a mortality of nearly a quarter of those injured. These fire mass casualty events immediately overwhelm shipboard medical capabilities requiring a complex response from all hands beginning with non-medical first responders. Notably, all events occurred outside of direct enemy combat, potentially underestimating the impact and number of casualties of a shipboard fire during naval combat. Advances in peer weaponry and the threat of future conflict emphasize the need for pre-deployment burn care training for all shipboard medical caregivers as well as advanced airway and resuscitation training for non-physician caregivers. This review underscores the profound impact of shipboard fires on crew safety, highlighting the critical need for enhanced preparedness and response strategies to prepare for fire-related mishaps during routine operations and naval combat.

Heterogeneity in the Effect of Early Goal-Directed Therapy for Septic Shock: A Secondary Analysis of Two Multicenter International Trials.

The optimal approach for resuscitation in septic shock remains unclear despite multiple randomized controlled trials (RCTs). Our objective was to investigate whether previously uncharacterized variation across individuals in their response to resuscitation strategies may contribute to conflicting average treatment effects in prior RCTs. We randomly split study sites from the Australian Resuscitation of Sepsis Evaluation (ARISE) and Protocolized Care for Early Septic Shock (ProCESS) trials into derivation and validation cohorts. We trained machine learning models to predict individual absolute risk differences (iARDs) in 90-day mortality in derivation cohorts and tested for heterogeneity of treatment effect (HTE) in validation cohorts and swapped these cohorts in sensitivity analyses. We fit the best-performing model in a combined dataset to explore roles of patient characteristics and individual components of early goal-directed therapy (EGDT) to determine treatment responses. Eighty-one sites in Australia, New Zealand, Hong Kong, Finland, Republic of Ireland, and the United States. Adult patients presenting to the emergency department with severe sepsis or septic shock. EGDT vs. usual care. A local-linear random forest model performed best in predicting iARDs. In the validation cohort, HTE was confirmed, evidenced by an interaction between iARD prediction and treatment (p < 0.001). When patients were grouped based on predicted iARDs, treatment response increased from the lowest to the highest quintiles (absolute risk difference [95% CI], -8% [-19% to 4%] and relative risk reduction, 1.34 [0.89-2.01] in quintile 1 suggesting harm from EGDT, and 12% [1-23%] and 0.64 [0.42-0.96] in quintile 5 suggesting benefit). Sensitivity analyses showed similar findings. Pre-intervention albumin contributed the most to HTE. Analyses of individual EGDT components were inconclusive. Treatment response to EGDT varied across patients in two multicenter RCTs with large benefits for some patients while others were harmed. Patient characteristics, including albumin, were most important in identifying HTE.

Methylene Blue and Blood Transfusion in Hemorrhagic Shock Resuscitation: An Experimental Porcine Study.

Hemorrhagic shock requires immediate treatment to prevent mortality and organ dysfunction. This study evaluates the efficacy of methylene blue (MB) with blood transfusion (BT) as a potential rescue therapy in acute severe bleeding in pigs. Thirty animals were randomly assigned to one of six groups following the induction of fixed-pressure hemorrhagic shock, after reaching a mean arterial pressure (MAP) of 55 mmHg - Group 1 (60 BT: BT after 60 minutes), Group 2 (60 MB: MB infusion after 60 minutes), Group 3 (60 MB + BT: MB and BT after 60 minutes), Group 4 (15 MB + BT: MB and BT after 15 minutes), Group 5 (15 BT + 60 MB: BT after 15 minutes and MB infusion after 60 minutes), and Group 6 (15 MB + 60 BT: MB infusion after 15 minutes and BT after 60 minutes). Hemodynamic and blood gas parameters were meticulously recorded, reversal of the shock was considered when MAP reached 90% of the baseline MAP. Except for Group 2, all groups reverted from the shock. However, groups that received MB in combination with BT, specifically Groups 3 and 4, exhibited statistically significant higher ratios of maximum MAP to baseline MAP. Using MB concomitant with BT allowed the reversal of hemorrhagic shock with higher median arterial pressure levels compared to BT alone or applying MB separately from BT. This suggests that simultaneous application of MB and BT could be a more effective strategy for reversing the effects of severe acute bleeding.

The effect of using low dose norepinephrine before hypotensive resuscitation in hemorrhagic shock; a randomized controlled trial

Background &amp; Objectives: Hemorrhagic shock is not a very rare occurrence in big hospitals. It might be encountered in the emergency room (ER) or in the operating rooms (OR). A rapid response and systematic management will save the life of the victim. The objective of this research was to investigate the impact of a low dose of norepinephrine (NE) administered prior to the initiation of hypotensive resuscitation in patients with hemorrhagic shock. Methodology: This randomized controlled trial was conducted on 200 participants, at least 18 years old, classified as severely traumatized and had significant hemorrhage with mean arterial pressure ranging from 65 to 75 mmHg. We divided the patients into two equal groups. Group I received a low dose of NE (&lt; 0.3 µg/kg/min) concurrently with resuscitation fluids. Group II received resuscitative fluids only. If the resuscitative fluids failed to keep mean arterial pressure (MAP) &gt; 65 mmHg, the patient was progressively administered NE even with high doses (0.05 to more than 0.3 µg/kg/min). The primary outcome was 24-hour mortality. In-hospital mortality, incidence of acute kidney injury (AKI), and duration of hospital and intensive care unit (ICU) stay constituted the secondary outcomes. Results: Group I had lower 24-hour mortality compared to Group II (3% vs 13%; P &lt; 0.05). Compared to Group II, Group I needed reduced amount of fluid resuscitation within 24 h, had lower serum lactate levels at 6 and 12 h, and lower serum creatinine at 6, 12, and 18 h (P &lt; 0.001). Group I had a lower incidence of mechanical ventilation (13% vs 27%), hospital and ICU stays, and in-hospital mortality (9% vs 21%) (P &lt; 0.05). There was a lack of disparity seen in the incidence of AKI and duration of mechanical ventilation. Conclusion: Low-dose norepinephrine infusion during the early period of hypotensive resuscitation reduces resuscitative fluid requirement, improves tissue perfusion, preserves renal function, and lowers mortality in hemorrhagic shock patients. Abbreviations: AKI - acute kidney injury; APACHE III - Acute Physiology And Chronic Health Evaluation III; HS - hemorrhagic shock; ICU - intensive care unit; MAP - mean arterial pressure; NE - Norepinephrine Keywords: Hemorrhagic Shock; Hypotensive Resuscitation; Norepinephrine; Fluid Therapy; Renal Protection; Mortality; Low Dose Citation: Mohamed RM, Anwar AG, Eid AA. The effect of using low dose norepinephrine before hypotensive resuscitation in hemorrhagic shock; a randomized controlled trial. Anaesth. pain intensive care 2024;28(5):914−921; DOI: 10.35975/apic.v28i5.2560 Received: April 17, 2024; Reviewed: August 03, 2024; Accepted: September 04, 2024

The Impact of Point-of-Care Ultrasound-Guided Resuscitation on Clinical Outcomes in Patients With Shock: A Systematic Review and Meta-Analysis.

To determine the impact of point-of-care ultrasound (POCUS)-guided resuscitation on clinical outcomes in adult patients with shock. We searched MEDLINE, Embase, and unpublished sources from inception to December 2023. We included randomized controlled trials (RCTs) that examined the use of POCUS to guide resuscitation in patients with shock. We collected data regarding study and patient characteristics, POCUS protocol, control group interventions, and outcomes. We identified 18 eligible RCTs. POCUS slightly influences physicians' plans for IV fluid (IVF) and vasoactive medication prescription (moderate certainty), but results in little to no changes in the administration of IVF (low to high certainty) or inotropes (high certainty). POCUS may result in no change in the number of CT scans performed (low certainty) but probably reduces the number of diagnostic echocardiograms performed (moderate certainty). POCUS-guided resuscitation probably reduces 28-day mortality (relative risk [RR] 0.88; 95% CI, 0.78-0.99), the duration of vasoactive medication (mean difference -0.73 d; 95% CI, -1.16 to -0.30), and the need for renal replacement therapy (RRT) (RR 0.80; 95% CI, 0.63-1.02) (low to moderate certainty evidence), and lactate clearance (high certainty evidence). POCUS-guided resuscitation may results in little to no difference in ICU or hospital admissions, ICU and hospital length of stay, and the need for mechanical ventilation (MV) (low to moderate certainty evidence). There is an uncertain effect on the risk of acute kidney injury and the duration of MV or RRT (very low certainty evidence). POCUS-guided resuscitation in shock may yield important patient and health system benefits. Due to lack of sufficient evidence, we were unable to explore how the thresholds of operator competency, frequency, and timing of POCUS scans impact patient outcomes.

Fibrinolytic Dysfunction and Endotheliopathy After Major Thermal Injury: Considerations Needed for New Approaches to Burn Shock Resuscitation.

In recent years, it has become apparent that fibrinolytic dysfunction and endotheliopathy develop in up to 40% of patients during the first hours following thermal injury and are associated with poor outcomes and increased resuscitation requirements. Rapidly following burn injury, the fibrinolytic system is activated, with activation generally greater with increased severity of injury. Very high plasma concentrations of plasmin-antiplasmin complex (marker of activation), have been associated with mortality. Patients display hyperfibrinolytic, physiologic/normal or hypofibrinolytic/fibrinolytic shutdown phenotypes, as assessed by viscoelastic assay. Phenotypes change in over 50% of patients during the acute burn resuscitation period, with some patterns (maladaptive) associated with increased mortality risk and others (adaptive, trending toward the physiologic phenotype) associated with survival. Endotheliopathy, as reflected in elevated plasma concentrations of syndecan-1 has also been associated with increased mortality. Here we review the incidence and effects of these responses after burn injury and explore mechanisms and potential interactions with the early inflammatory response. Available data from burn and non-burn trauma suggest that the fibrinolytic, endothelial, and inflammatory systems interact extensively and that dysregulation in one may exacerbate dysregulation in the others. This raises the possibility that successful treatment of one may favorably impact the others.

Component Blood Transfusion with Restrictive Fluid Resuscitation in Ectopic Pregnancy Hemorrhage with Hemorrhagic Shock

Objective: To study the effect of using component blood transfusion with restrictive fluid resuscitation in ectopic pregnancy hemorrhage complicating hemorrhagic shock. Methods: 50 cases of ectopic pregnancy hemorrhage complicating hemorrhagic shock were selected for data study, and after grouping, 25 cases in each group were grouped, and the use of component blood transfusion with restrictive fluid resuscitation was used in the study group and restrictive fluid resuscitation was used in the control group, and the differences in the data were compared. Results: Compared with the control group, the study group had a significantly higher resuscitation success rate, significantly fewer complications, significantly higher hemodynamic indexes 2 h after treatment, significantly better coagulation function indexes, and significantly fewer various quantities in the therapeutic situation, P &lt; 0.05. Conclusion: The use of component blood transfusion with restrictive fluid resuscitation in ectopic pregnancy hemorrhage-complicating hemorrhagic shock has an ideal effect.

Evaluating Large Language Models in Dental Anesthesiology: A Comparative Analysis of ChatGPT-4, Claude 3 Opus, and Gemini 1.0 on the Japanese Dental Society of Anesthesiology Board Certification Exam.

Purpose Large language models (LLMs) are increasingly employed across various fields, including medicine and dentistry. In the field of dental anesthesiology, LLM is expected to enhance the efficiency of information gathering, patient outcomes, and education. This study evaluates the performance of different LLMs in answering questions from the Japanese Dental Society of Anesthesiology Board Certification Examination (JDSABCE) to determine their utility in dental anesthesiology. Methods The study assessed three LLMs, ChatGPT-4 (OpenAI, San Francisco, California, United States), Gemini 1.0 (Google, Mountain View, California, United States), and Claude 3 Opus (Anthropic, San Francisco, California, United States), using multiple-choice questions from the 2020 to 2022 JDSABCE exams. Each LLM answered these questions three times. The study excluded questions involving figures or deemed inappropriate. The primary outcome was the accuracy rate of each LLM, with secondary analysis focusing on six subgroups: (1) basic physiology necessary for general anesthesia, (2) local anesthesia, (3) sedation and general anesthesia, (4) diseases and patient management methods that pose challenges in systemic management, (5) pain management, and (6) shock and cardiopulmonary resuscitation. Statistical analysis was performed using one-way ANOVA with Dunnett's multiple comparisons, with a significance threshold of p<0.05. Results ChatGPT-4 achieved a correct answer rate of 51.2% (95% CI: 42.78-60.56, p=0.003) and Claude 3 Opus 47.4% (95% CI: 43.45-51.44, p<0.001), both significantly higher than Gemini 1.0, which had a rate of 30.3% (95% CI: 26.53-34.14). In subgroup analyses, ChatGPT-4 and Claude 3 Opus demonstrated superior performance in basic physiology, sedation and general anesthesia, and systemic management challenges compared to Gemini 1.0. Notably, ChatGPT-4 excelled in questions related to systemic management (62.5%) and Claude 3 Opus in pain management (61.53%). Conclusions ChatGPT-4 and Claude 3 Opus exhibit potential for use in dental anesthesiology, outperforming Gemini 1.0. However, their current accuracy rates are insufficient for reliable clinical use.These findings have significant implications for dental anesthesiology practice and education, including educational support, clinical decision support, and continuing education. To enhance LLM utility in dental anesthesiology, it is crucial to increase the availability of high-quality information online and refine prompt engineering to better guide LLM responses.

Age above all: The impact of storage duration in mice resuscitated with whole blood or packed red blood cells and plasma in a hemorrhagic shock model

BackgroundThe use of whole blood compared with a balanced ratio of components in trauma resuscitation remains an area of ongoing investigation. One factor that may affect outcomes is the age of the blood product transfused. We used a murine model of blood banking and hemorrhagic shock resuscitation to compare the effect of storage duration in whole blood and packed red blood cells on the recipient inflammatory response. MethodsMurine whole blood or packed red blood cells were evaluated for the red blood cells storage lesion up to 14 days. Mice underwent hemorrhagic shock followed by resuscitation with whole blood or packed red blood cells combined with equal volume of thawed plasma (1:1) stored for 1, 7, or 14 days. Serum and lung cytokine/chemokine levels were measured and leukocyte infiltration determined via immunohistochemistry. ResultsBoth whole blood and packed red blood cells develop a blood storage lesion. Four hours after resuscitation, mice resuscitated with either day 14 whole blood or 1:1 demonstrated increased inflammatory cytokines and chemokines with similar findings within lung tissue compared with mice resuscitated with whole blood and 1:1 products stored for 1 or 7 days. ConclusionsResuscitation with murine packed red blood cells or whole blood stored for 14 days produces a pronounced recipient inflammatory response compared with those units stored for lesser durations. Given the shorter storage duration of human whole blood to packed RBCs, resuscitation with whole blood within current storage limits may represent an advantageous resuscitation strategy compared with older packed red blood cells.

Response to Letter to the Editor Regarding "American Burn Association Clinical Practice Guidelines on Burn Shock Resuscitation" by Cartotto et al.

Response to Letter to the Editor Regarding "American Burn Association Clinical Practice Guidelines on Burn Shock Resuscitation" by Cartotto et al.

β-Adrenoceptor Agonists Attenuate Thrombin-Induced Impairment of Human Lung Endothelial Cell Barrier Function and Protect the Lung Vascular Barrier during Resuscitation from Hemorrhagic Shock.

β-adrenoceptor (β-AR) agonists are known to antagonize thrombin-induced impairment (TII) of bovine and ovine lung endothelial barrier function. The effects of adrenoceptor agonists and other vasoactive agents on human lung microvascular endothelial cell (HULEC-5a) barrier function upon thrombin exposure have not been studied. Furthermore, it is unknown whether the in vitro effects of adrenoceptor agonists translate to lung protective effects in vivo. We observed that epinephrine, norepinephrine, and phenylephrine enhanced normal and prevented TII of HULEC-5a barrier function. Arginine vasopressin and angiotensin II were ineffective. α1B-, α2A/B-, and β1/2-ARs were detectable in HULEC-5a by RT-PCR. Propranolol but not doxazosin blocked the effects of all adrenoceptor agonists. Phenylephrine stimulated β2-AR-mediated Gαs activation with 13-fold lower potency than epinephrine. The EC50 to inhibit TII of HULEC-5a barrier function was 1.8 ± 1.9 nM for epinephrine and >100 nM for phenylephrine. After hemorrhagic shock and fluid resuscitation in rats, Evans blue extravasation into the lung increased threefold (p < 0.01 vs. sham). Single low-dose (1.8 μg/kg) epinephrine administration at the beginning of resuscitation had no effects on blood pressure and reduced Evans blue extravasation by 60% (p < 0.05 vs. vehicle). Our findings confirm the effects of β-adrenoceptor agonists in HULEC-5a and suggest that low-dose β-adrenoceptor agonist treatment protects lung vascular barrier function after traumatic hemorrhagic shock.

Comparing the effects of various fluid resuscitative strategies on Glycocalyx damage in a canine hemorrhage model

Hemorrhagic shock and subsequent resuscitation can cause significant dysregulation of critical systems, including the vascular endothelium. Following hemorrhage, the endothelial lining (glycocalyx) can shed, causing release of glycocalyx components, endothelial activation, and systemic inflammation. A canine model of hemorrhagic shock was used to evaluate five resuscitation fluids, including Lactated Ringers+Hetastarch, Whole Blood (WB), Fresh Frozen Plasma+packed Red Blood Cells (FFP+pRBC), and two hemoglobin-based oxygen carrier (HBOC) fluids, for their impact on glycocalyx shedding. Under anesthesia, purpose-bred adult canines were instrumented and subjected to a controlled hemorrhage with blood being drawn until a mean arterial pressure of <50 mmHg was reached or 40 % of the estimated blood volume was removed. Canines were left in shock for 45 mins before being resuscitated with one of the resuscitation fluids over 30 mins. Following resuscitation, the dogs were monitored up to 2 weeks. Following an additional 3–4 weeks for washout, the canines repeated the protocol, undergoing each resuscitation fluid individually. Blood samples were collected during each round at various timepoints for serum isolation, which was used for detection of glycocalyx biomarker. Comparison of baseline and post-hemorrhage alone showed a significant reduction in serum protein (p<0.0001), heparan sulfate (p<0.001), and syndecan-1 (p<0.0001) concentrations, and a significant increase in hyaluronan (p<0.0001) concentration. Intercomparisons of resuscitation fluids indicated minimal differences in glycocalyx markers over time. Comparisons within each fluid showed dynamic responses in glycocalyx biomarkers over time. Relative to individual baselines, syndecan-1 was significantly reduced after resuscitation in most cases (p<0.0001), excluding WB and FFP+pRBC. In all cases, VE-cadherin was significantly elevated at 24 hr compared to baseline (p<0.001). Hyaluronan was significantly elevated by 3 hr in all cases (p<0.01), except for HBOC fluids. Total glycosaminoglycans were significantly reduced only at 3 hr (p<0.001) for non-HBOC fluids. Similarly, heparan sulfate was significantly reduced with all fluids between resuscitation and 24 hr (p<0.01), except WB. The temporal changes in canine glycocalyx biomarkers were atypical of hemorrhage response in other species. This suggests that the hemorrhage lacked severity and/or typical glycocalyx biomarkers do not reflect the canine endothelium compared to other species. Further research is needed to characterize the canine endothelium and the response to resuscitation fluids.

Letter to the Editor Regarding "American Burn Association Clinical Practice Guidelines on Burn Shock Resuscitation" by Cartotto et al.

Letter to the Editor Regarding "American Burn Association Clinical Practice Guidelines on Burn Shock Resuscitation" by Cartotto et al.

Analysis of hemodynamics and impedance using bioelectrical impedance analysis in hypovolemic shock-induced swine model

To treat hypovolemic shock, fluid infusion or blood transfusion is essential to address insufficient volume. Much controversy surrounds resuscitation in hypovolemic shock. We aimed to identify the ideal fluid combination for treating hypovolemic shock-induced swine model, analyzing bioelectrical impedance and hemodynamics. Fifteen female three-way crossbred pigs were divided into three different groups. The three resuscitation fluids were (1) balanced crystalloid, (2) balanced crystalloid + 5% dextrose water, and (3) balanced crystalloid + 20% albumin. The experiment was divided into three phases and conducted sequentially: (1) controlled hemorrhage (1 L bleeding, 60 min), (2) resuscitation phase 1 (1 L fluid infusion, 60 min), and (3) resuscitation phase 2 (1 L fluid infusion, 60 min). Bioelectrical impedance analysis was implemented with a segmental multifrequency bioelectrical impedance analyzer. A total of 61 impedance measurements were assessed for each pig at six different frequencies in five segments of the pig. Pulse rate (PR), mean arterial pressure (MAP), stroke volume (SV), and stroke volume variation (SVV) were measured using a minimally invasive hemodynamic monitoring device. The three-dimensional graph showed a curved pattern when infused with 1 L of balanced crystalloid + 1 L of 5% dextrose water and 1.6 L of balanced crystalloid + 400 ml of 20% albumin. The 1M impedance increased in all groups during the controlled hemorrhage, and continuously decreased from fluid infusion to the end of the experiment. Only balanced crystalloid + 20% albumin significantly restored MAP and SV to the same level as the start of the experiment after the end of fluid infusion. There were no significant differences in MAP and SV from the time of recovery to the initial value of 1M impedance to the end of fluid infusion in all groups. The change and the recovery of hemodynamic indices such as MAP and SV coincide with the change and the recovery of 1M impedance. Using balanced crystalloid mixed with 20% albumin in hypovolemic shock-induced swine model may be helpful in securing hemodynamic stability, compared with balanced crystalloid single administration.

The Sublingual Microcirculation in Critically Ill Children with Septic Shock Undergoing Hemoadsorption: A Pilot Study.

Background: The importance of perfusion-guided resuscitation in septic shock has recently emerged. We explored whether the use of hemoadsorption led to a potential beneficial role in microvascular alterations in this clinical setting. Methods: A pre-planned secondary analysis of a Phase-II interventional single-arm pilot study (NCT05658588) was carried out, where 17 consecutive septic shock children admitted into PICU were treated with continuous renal replacement therapy (CRRT) and CytoSorb. Thirteen patients were eligible to be investigated with sublingual microcirculation at baseline, 24, 48, 72 and 96 h from the onset of blood purification. Patients achieving a microvascular flow index (MFI) ≥ 2.5 and/or proportion of perfused vessels (PPV) exceeding 90% by 96 h were defined as responders. Results: In 10/13 (77%), there was a significant improvement in MFIs (p = 0.01) and PPVs% (p = 0.04) between baseline and 24 h from the end of treatment. Eight patients displayed a high heterogenicity index (HI > 0.5) during blood purification and among these, five showed an improvement by the end of treatment (HI < 0.5). Conclusions: In this pilot study, we have found a potential association between CytoSorb hemoadsorption and a microcirculation improvement in pediatric patients with septic shock, particularly when this observation has been associated with hemodynamic improvement.

Digital twin mathematical models suggest individualized hemorrhagic shock resuscitation strategies

BackgroundOptimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting.MethodsWe sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation.ResultsThe mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time.ConclusionsThis workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings.

How preclinical models help to improve outcome in cardiogenic shock.

Preclinical experimentation of cardiogenic shock resuscitation on large animal models represents a powerful tool to decipher its complexity and improve its poor outcome, when small animal models are lacking external validation, and clinical investigation are limited due to technical and ethical constraints. This review illustrates the currently available preclinical models addressing reliably the physiopathology and hemodynamic phenotype of cardiogenic shock, highlighting on the opposite questionable translation based on low severity acute myocardial infarction (AMI) models. Three types of preclinical models replicate reliably AMI-related cardiogenic shock, either with coronary microembolization, coronary deoxygenated blood perfusion or double critical coronary sub-occlusion. These models overcame the pitfall of frequent periprocedural cardiac arrest and offer, to different extents, robust opportunities to investigate pharmacological and/or mechanical circulatory support therapeutic strategies, cardioprotective approaches improving heart recovery and mitigation of the systemic inflammatory reaction. They all came with their respective strengths and weaknesses, allowing the researcher to select the right preclinical model for the right clinical question. AMI-related cardiogenic shock preclinical models are now well established and should replace low severity AMI models. Technical and ethical constraints are not trivial, but this translational research is a key asset to build up meaningful future clinical investigations.

Statistical analysis plan for the SQUEEZE trial: A trial to determine whether septic shock reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy vs. usual care (SQUEEZE)

BackgroundThe SQUEEZE trial is a multicentred randomized controlled trial which seeks to determine the optimal approach to fluid resuscitation in paediatric septic shock. SQUEEZE also includes a nested translational study, SQUEEZE-D, investigating the value of plasma cell-free DNA for prediction of clinical outcomes. ObjectiveTo present a pre-specified statistical analysis plan (SAP) for the SQUEEZE trial prior to finalizing the trial data set and prior to commencing data analysis. DesignSQUEEZE is a pragmatic, two-arm, open-label, prospective multicentre randomized controlled trial. SettingCanadian paediatric tertiary care centres. ParticipantsPaediatric patients with suspected sepsis and persistent signs of shock in need of ongoing resuscitation. Sample size target: 400 participants. InterventionsThe trial is designed to compare a fluid-sparing resuscitation strategy to usual care. Main outcome measuresThe primary outcome for the SQUEEZE trial is the time to shock reversal (in hours). The primary outcome analysis will assess the difference in time to shock reversal between the intervention and control groups, reported as point estimate with 95% confidence intervals. The statistical test for the primary analysis will be a two-sided t-test. Secondary outcome measures include clinical outcomes and adverse events including measures of organ dysfunction and mortality outcomes. ResultsThe SAP presented here is reflective of and where necessary clarifies in detail the analysis plan as presented in the trial protocol. The SAP includes a mock CONSORT diagram, figures and tables. Data collection methods are summarized, primary and secondary outcomes are defined, and outcome analyses are described. ConclusionsWe have developed a statistical analysis plan for the SQUEEZE Trial for transparency and to align with best practices. Analysis of SQUEEZE Trial data will adhere to the SAP to reduce the risk of bias. RegistrationClinicalTrials.gov identifiers: Definitive trial NCT03080038; Registered Feb 28, 2017. Pilot Trial NCT 01973907; Registered Oct 27, 2013.