Protocol for a systematic review of the impact of resuscitation fluids on the microcirculation after haemorrhagic shock in animal models

BACKGROUND: Modern resuscitation strategies following haemorrhagic shock are influenced by global haemodynamic parameters such as blood pressure and cardiac output. Microcirculatory dysfunction in this context may persist even after restoration of satisfactory global parameters. Additional monitoring of the microcirculatory function may therefore be warranted in order to facilitate goal-directed therapy at a tissue oxygenation level. Although such a phenomenon is recognised in the case of sepsis, clinical evidence regarding the behaviour of the microcirculation following the delivery of resuscitation fluids after haemorrhagic shock is sparse. A summation of the current state of pre-clinical evidence is justified in order to direct avenues for future clinical research. METHODS/DESIGN: Systematic review methodology will be utilised in order to identify relevant studies, assess for bias, and extract data for analysis. Medical databases will be searched to find pre-clinical studies that monitor the microcirculatory function following haemorrhagic shock and subsequent fluid resuscitation. Different fluid types (e.g. blood products, crystalloid, and colloid fluids) will be compared. The search strategy will combine terms for the animal model, resuscitation fluid, and microcirculatory parameters. Randomised and non-randomised experiments, as well as case series, will be eligible for inclusion. Specific quality assessment tools for pre-clinical research will be used depending on study design. A combination of narrative and meta-analysis techniques will be used for the synthesis of data. DISCUSSION: The choice of type, sequence, and quantity of resuscitation fluid following haemorrhagic shock is controversial, and the optimal strategy for restoration of microcirculatory function is yet unknown. A detailed examination of pre-clinical data regarding the microcirculation is timely and will enable a focussed approach to clinical research for the improvement of resuscitation following haemorrhagic shock. SYSTEMATIC REVIEW REGISTRATION: Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES) ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13643-015-0113-4) contains supplementary material, which is available to authorized users

Observational study of the effects of traumatic injury, haemorrhagic shock and resuscitation on the microcirculation: a protocol for the MICROSHOCK study

Introduction: The microcirculation is the physiological site of oxygen and substrate exchange. Its effectiveness during circulatory shock is vital for the perfusion of tissues, and has a bearing on subsequent organ function and prognosis. Microcirculatory dysfunction following traumatic haemorrhagic shock (THS) has been understudied compared with other pathologies such as sepsis. The aim of the MICROSHOCK study is to investigate changes seen in the microcirculation of patients following THS, and to assess its response to resuscitation. A greater understanding of the behaviour and mechanisms of microcirculatory dysfunction in this context may direct future avenues of goal-directed resuscitation for these patients. Methods and analysis: This multicentre prospective longitudinal observational study includes patients who present as an emergency with THS. Microcirculatory parameters are recorded using sublingual incident dark field microscopy alongside measurements of global flow (oesophageal Doppler and transthoracic echocardiography). Patients are enrolled into the study as soon as feasible after they arrive in hospital, and then at subsequent daily time points. Blood samples are taken for investigation into the mechanisms of microcirculatory dysfunction. Sequential Organ Failure Assessment scores will be analysed with microcirculatory parameters to determine whether they correlate with greater fidelity than more conventional, global circulatory parameters. Ethics and dissemination: Research Ethics Committee approval has been granted for this study (Reference: 14/YH/0078). Owing to the nature of THS, capacity for informed consent will be absent on patient enrolment. This will be addressed according to the Mental Health Capacity Act 2005. The physician in charge of the patient's care (nominated consultee) may consent on behalf of the patient. Consent will also be sought from a personal consultee (close relative or friend). After capacity is regained, the participant will be asked for their consent. Results will be submitted for publication in peer-reviewed journal format and presented at relevant academic meetings

Protocol for a systematic review of the clinical effectiveness of pre-hospital blood components compared to other resuscitative fluids in patients with major traumatic haemorrhage

BACKGROUND: There is growing interest in the use of blood components for pre-hospital resuscitation of patients with major traumatic haemorrhage. It has been speculated that early resuscitation with blood components may have benefits in terms of treating trauma-induced coagulopathy, which in turn may influence survival. The proposed systematic review will evaluate the evidence on the clinical effectiveness of pre-hospital blood components (red blood cells and/or plasma or whole blood), in both civilian and military settings, compared with other resuscitation strategies in patients with major traumatic haemorrhage. METHODS/DESIGN: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. General medical and specialist databases will be searched; the search strategy will combine terms for the population, intervention and setting. Studies will be selected for review if the population includes adult patients with major traumatic haemorrhage who receive blood components in a pre-hospital setting (civilian or military). Systematic reviews, randomised and non-randomised controlled trials and controlled observational studies will be included. Uncontrolled studies will be considered depending on the volume of controlled evidence. Quality assessment will be tailored to different study designs. Both patient related and surrogate outcomes will be considered. Synthesis is likely to be primarily narrative, but meta-analyses and subgroup analyses will be undertaken where clinical and methodological homogeneity exists. DISCUSSION: Given the increasing use by emergency services of blood components for pre-hospital resuscitation, this is a timely systematic review, which will attempt to clarify the evidence base for this practice. As far as the authors are aware, the proposed systematic review will be the first to address this topic. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD4201401379

Searching for the Optimal Fluid to Restore Microcirculatory Flow Dynamics After Haemorrhagic Shock:A Systematic Review of Preclinical Studies

BACKGROUND: Increased microcirculatory flow and perfusion has been reported to improve clinical outcomes following shock. The optimal resuscitation fluid to restore the flow dynamics of the microcirculation is unknown. This review summarises the preclinical literature in order to inform the direction and most important hypotheses for future clinical interventional studies.METHODS: Standard systematic review methodology was utilized, and registered with the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES). Medline and Embase (via OVID SP) and SCOPUS were searched for all preclinical studies of haemorrhagic shock that compared fluid resuscitation of any kind (e.g. blood products, crystalloids, colloids, or haemoglobin based oxygen carriers) to another fluid or haemorrhage only, and reported at least one microcirculatory physical endpoint (such as flow rate, velocity, vessel diameter, functional capillary density or glycocalyx thickness). Risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. Translatability was also assessed for each study based on the most common recommendations.RESULTS: There were 3103 potential studies of interest, of which 71 studies fulfilled all eligibility criteria. There were 62 rodent, 5 canine and 4 porcine studies. Flow rate, velocity, and vessel diameter were the most commonly reported endpoints. Studies reported the importance of the presence of haemoglobin, as well as osmotic potential and viscosity in providing optimal restoration of microcirculatory flow dynamics. Others reported the restoration of the endothelial glycocalyx and attenuation of inflammation as important properties for the choice of fluid. All studies were at potential risk of bias due to unclear randomization, concealment, and blinding. There were important threats to translatability for all studies.CONCLUSION: The ideal resuscitation fluid for restoration of the microcirculation following haemorrhagic shock is likely to contain a preparation of haemoglobin, favour higher oncotic potential and viscosity, protect and reconstitute the endothelium, and attenuate inflammation. These hypotheses that are derived from preclinical research warrant further exploration in the clinical context.</p

Intraoperative fluid irrigation for traumatic wounds (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of intraoperative fluid irrigation in preventing wound infection in traumatic wounds

Resuscitation with pre-hospital blood products in adults with trauma-related haemorrhagic shock:the RePHILL RCT

Background: The treatment of traumatic haemorrhagic shock has been transformed through better haemorrhage control, use of tranexamic acid and use of blood products. The improved survival seen from these strategies has stimulated an interest in pre-hospital transfusion.Objectives: To determine if the clinical effectiveness of resuscitation with red blood cells and lyophilised plasma was superior to 0.9% saline for improving tissue perfusion and reducing mortality in adults with haemorrhagic shock following major trauma.Design: A multi-centre, allocation concealed, open-label, parallel group, randomised controlled trial (with internal pilot).Setting: The trial was conducted in four civilian pre-hospital critical care services who operated within the National Health Service (NHS) England Major Trauma Networks.Participants: Adults (aged ≥16 years) who had sustained traumatic injuries, were attended by a pre-hospital emergency medical team and were hypotensive (systolic blood pressure &lt;90 mmHg or absence of radial pulse) as a consequence of traumatic haemorrhage were eligible for inclusion. The exclusion criteria were known or apparently &lt;16 years, blood administered on scene prior to the arrival of the RePHILL team, traumatic cardiac arrest where (1) the arrest occurred prior to arrival of the team and/or (2) the primary cause is not hypovolaemia, refusal of blood product administration, known Jehovah’s Witness, pregnancy, isolated head injury without evidence of external haemorrhage, prisoners in the custody of HM Prison and Probation Service.Interventions: Participants were randomised to receive up to either two units each of red blood cells and lyophilised plasma or up to 1 L 0.9% saline. Treatment was administered through the intravenous or intraosseous route.Main outcome measures: The primary outcome was a composite of episode mortality and/or impaired lactate clearance. The secondary outcomes included the individual components of the primary outcome.Results: From 6 December 2016 to 2 January 2021, pre-hospital medical teams randomised 432 participants to red blood cell/lyophilised plasma (n = 209) or 0.9% saline (n = 223) out of a target sample size of 490. Most participants were white (62%), males (82%), median age 38 (interquartile range 26 to 58), involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, interquartile range 25 to 50). Prior to randomisation participants had received on average 430 ml crystalloid fluids and tranexamic acid (90%). The primary outcome occurred in 128/199 (64.3%) of participants randomised to red blood cell/lyophilised plasma and 136/210 (64.8%) randomised to 0.9% saline [adjusted risk difference –0.025% (95% confidence interval –9.0% to 9.0%), p = 0.996]. The event rates for the individual components of the primary outcome, episode mortality and lactate clearance were not statistically different between groups [adjusted average differences −3% (−12% to 7%); p = 0.57 and −5% (−14% to 5%), p = 0.33, respectively].Limitations: Recruitment stopped prematurely due to disruption caused by the COVID-19 pandemic.Future work: Identify the characteristics of patients who may benefit from pre-hospital blood products and whether alternative transfusion regimens are superior to standard care.Conclusions: The trial did not demonstrate that pre-hospital red blood cell/lyophilised plasma resuscitation was superior to 0.9% saline for trauma-related haemorrhagic shock.Trial registration: This trial is registered as ISRCTN62326938.Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 14/152/14) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 2. See the NIHR Funding and Awards website for further award information.<br/

Mapping the Steroid Response to Major Trauma From Injury to Recovery : A Prospective Cohort Study

CONTEXT: Survival rates after severe injury are improving, but complication rates and outcomes are variable. OBJECTIVE: This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DESIGN: We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15). MAIN OUTCOME MEASURES: We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models. FINDINGS: We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. CONCLUSION: The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure