Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT
Health technology assessment (Winchester, England). 2021;25(26):1-76
BACKGROUND Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. OBJECTIVE To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. DESIGN Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. SETTING 175 hospitals in 29 countries. PARTICIPANTS Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. INTERVENTION Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. MAIN OUTCOME MEASURES Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. RESULTS Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). CONCLUSION Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. FUTURE WORK Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. LIMITATIONS Time to treatment may have been underestimated. TRIAL REGISTRATION Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. FUNDING The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.
Adults with traumatic brain injury enrolled in the CRASH-3 trial (n=9127).
Tranexamic acid (TXA), (n= 4613).
Matching placebo (n= 4514).
The risk of head injury death was 18.5% in the TXA group versus 19.8% in the placebo group. In a pre-specified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the TXA group versus 14.0% in the placebo group. There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury, but in those with severe head injury there was no apparent reduction. Early treatment was more effective in mild and moderate head injury, but there was no obvious impact of time to treatment in cases of severe head injury. The risk of disability, vascular occlusive events and seizures was similar in both groups.
The risks associated with tourniquet use in lower limb trauma surgery: a systematic review and meta-analysis
European journal of orthopaedic surgery & traumatology : orthopedie traumatologie. 2021
PURPOSE Tourniquet use in lower limb fracture surgery may reduce intra-operative bleeding, improve surgical field of view and reduce length of procedure. However, tourniquets may result in pain and the production of harmful metabolites cause complications or affect functional outcomes. This systematic review aimed to compare outcomes following lower limb fracture surgery performed with or without tourniquet. METHODS We searched databases for RCTs comparing lower limb fracture surgery performed with versus without tourniquet reporting on outcomes pain, physical function, health-related quality of life, complications, cognitive function, blood loss, length of stay, length of procedure, swelling, time to union, surgical field of view, volume of anaesthetic agent, biochemical markers of inflammation and injury, and electrolyte and acid-base balance. Random-effects meta-analysis was performed. PROSPERO ID CRD42020209310. RESULTS Six RCTs enabled inclusion of 552 procedures. Pooled analysis demonstrated that tourniquet use reduced length of procedure by 6 minutes (95% CI -10.12 to -1.87; p < 0.010). We were unable to exclude increased harms from tourniquet use. Pooled analysis showed post-operative pain score was higher in tourniquet group by 12.88 on 100-point scale (95% CI -1.25-27.02; p = 0.070). Risk differences for wound infection, deep venous thrombosis and re-operation were 0.06 (95% CI -0.00-0.12; p = 0.070), 0.05 (95% CI -0.02-0.11; p = 0.150) and 0.03 (95% CI -0.03-0.09; p = 0.340). CONCLUSION Tourniquet use was associated with a reduced length of procedure. It is possible that tourniquets also increase incidence of important complications, but the data are too sparse to draw firm conclusions. Methodological weaknesses of the included RCTs prevent any solid conclusions being drawn for outcomes investigated. Further studies are required to address these limitations.
Comparison of Hematocrit Change in Preterm Neonates with Birth Weight Based Versus Formula Based Packed Red Blood Cell Transfusion: A Randomized Control Trial
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2021;:1-7
Conventionally the packed red blood cell (PRBC) transfusion volume given to neonates is 10 ml/kg to 20 ml/kg. The weight-based formulae underestimate the volume of PRBC required to achieve a target hematocrit (Hct) in preterm neonates. The study was done to compare the rise in Hct after transfusing PRBC volume calculated either based on body weight or using formula considering Hct of blood bag and Hct of preterm neonates. This prospective study included a total of 68 preterm neonates requiring transfusion for the first time having ≤ 34 weeks of gestational age. Neonates were randomized using block randomization, to receive 15 ml/kg of PRBC transfusion (group A) or transfusion based on the formula (group B). The primary outcome of interest was post-transfusion rise in hematocrit. The secondary outcome was the effect of transfusion on neonatal morbidities in terms of retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and death. Baseline variables (birth weight, gestation age, APGAR score and score of neonatal acute physiology) pre-transfusion hemodynamics and hematocrit of the bag were comparable in both groups. The mean volume of PRBC in group A was 18.8 ± 4.9 ml, whereas in group B it was 29.6 ± 7.3 ml, p = 0.0001. Group B transfusions had a statistically significant change in 24 h post-transfusion hematocrit. Secondary outcomes were comparable in two groups. Post transfusion rise in Hct of the patient in group B was significant as compared to group A. The study needed huge sample size to establish a difference in the number of re-transfusions required across two groups. The trial was registered under the clinical trial registry of India (CTRI/2018/01/011,063). SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s12288-021-01420-1.
Intravenous versus oral omeprazole on patients with high risk bleeding peptic ulcers: A prospective randomized clinical trial protocol
BACKGROUND Proton pump inhibitors (PPIs) decrease the rate of rebleeding following endoscopic hemostatic therapy in patients with bleeding peptic ulcers. This study compares the efficacy of oral omeprazole vs intravenous omeprazole in decrease of rebleeding of peptic ulcer patients. METHOD The present study was authorized by the local research ethics committee of Jiangjin District Central Hospital (2020120987) and informed consent was obtained from all patients. All adult patients who were admitted to medical emergency rooms of Jiangjin District Central Hospital due to upper gastrointestinal bleeding (as evidenced by hematemesis, melena or hematochezia) were considered for inclusion in the study. Endoscopy was performed within 24 hours after admission. Patients older than 18 years with successful endoscopic therapy of high risk ulcers [defined as active bleeding (Forrest IA, IB), non-bleeding visible vessel (NBVV, Forrest IIA) or adherent clots (Forrest IIB)] were enrolled. Patients with low risk ulcers (clean base, ulcers with a simple washable clot), suspicious malignant ulcer, bleeding tendency, uremia, liver cirrhosis, Mallory Weiss tear or already on PPI as an outpatient were excluded from study. All were managed endoscopically by injecting 5-30 ml of epinephrine (diluted 1:10000) around the ulcer crater. Cavitations or flattening of bleeding vessel and disappearance of NBVV was considered as established homeostasis. A biopsy was taken from antrum for evaluating Helicobacter pylori infection. Patient with unsuccessful endoscopic therapy were not enrolled and were referred to general surgeon. Information on demography, history of previous upper gastrointestinal bleeding, NSAID or ASA ingestion, ulcer location, bleeding stigmata and blood transfusion volume at entry were recorded in all patients. In the oral omeprazole group, the patients received 40 mg omeprazole orally twice daily for 72 hours. In intravenous omeprazole group, they received omeprazole 80 mg bolus and then 8 mg/hour infusion for 48-72 hours. Then, all patients received omeprazole 20 mg orally for 30 days. On the day of discharge Helicobacter pylori infected patients received standard regimens. RESULTS Figure 1 showed the primary and secondary end points. DISCUSSION Intravenous administration of PPIs has limitations. They are expensive, require a dedicated intravenous line, need nursing supervision and hospital admission. So, it would be reasonable to prescribe oral PPIs to patients with high risk bleeding ulcers provided that it is as effective as its intravenous counterpart. Oral PPIs have a high bioavailability. Its effect initiates one hour after ingestion and the maximal plasma concentration is achieved after 2-3 hours. However, there are few studies comparing oral and intravenous PPI in decreasing risk of rebleeding in peptic ulcer patients. More high quality randomized controlled trials are still necessary. REGISTRATION NUMBER researchregistry 6588.
Clinical protocols for oral anticoagulant reversal during high risk of bleeding for emergency surgical and nonsurgical settings: a narrative review
Brazilian journal of anesthesiology (Elsevier). 2021
BACKGROUND AND OBJECTIVES Oral anticoagulants prevent thromboembolic events but expose patients to a significant risk of bleeding due to the treatment itself, after trauma or during surgery. Any physician working in the emergency department or involved in the perioperative care of a patient should be aware of the best reversal approach according to the type of drug and the patient's clinical condition. This paper presents a concise review and proposes clinical protocols for the reversal of oral anticoagulants in emergency settings, such as bleeding or surgery. CONTENTS The authors searched for relevant studies in PubMed, LILACS, and the Cochrane Library database and identified 82 articles published up to September 2020 to generate a review and algorithms as clinical protocols for practical use. Hemodynamic status and the implementation of general supportive measures should be the first approach under emergency conditions. The drug type, dose, time of last intake, and laboratory evaluations of anticoagulant activity and renal function provide an estimation of drug clearance and should be taken into consideration. The reversal agents for vitamin K antagonists are 4-factor prothrombin complex concentrate and vitamin K, followed by fresh frozen plasma as a second-line treatment. Direct oral anticoagulants have specific reversal agents, such as andexanet alfa and idarucizumab, but are not widely available. Another possibility in this situation, but with less evidence, is prothrombin complex concentrates. CONCLUSION The present algorithms propose a tool to help health care providers in the best decision making for patients under emergency conditions.
Risk factors for transfusion-related acute lung injury
Respiratory care. 2021
Background: Until now, transfusion-related acute lung injury (TRALI) has been considered to be the leading cause of blood transfusion-related diseases and death. And there is no clinically effective treatment plan for TRALI. The aim of this study was to systematically summarize the literature on risk factors for TRALI in critical patients.Methods: Electronic searches (up to March 2020) were performed in the Cochrane Library, Web of Knowledge, Embase, and PubMed databases. We included studies reporting on the risk factors of TRALI for critical patients and extracted the risk factors. Finally, thirteen studies met the inclusion criteria.Results: We summarized and analyzed the potential risk factors of TRALI for critical patients in 13 existing studies. The host-related factors were age (odds ratio (OR) [95% confidence interval] = 1.16 [1.08-1.24]), female sex (OR = 1.26 [1.16-1.38]), tobacco use status (OR = 3.82 [1.91-7.65]), chronic alcohol abuse (OR = 3.82 [2.97-26.83]), positive fluid balance (OR = 1.24 [1.08-1.42]), shock before transfusion (OR = 4.41 [2.38-8.20]), and ASA score of the recipients (OR = 2.72 [1.43-5.16]). The transfusion-related factors were the number of transfusions (OR = 1.40 [1.14-1.72]) and fresh frozen plasma (FFP) units (OR = 1.21 [1.01-1.46]). The device-related factor was mechanical ventilation (OR = 4.13 [2.20-7.76]).Conclusions: The risk factors for TRALI in this study included Number of transfusions and FFP units were positively correlated with TRALI. Age, female sex, tobacco use, chronic alcohol abuse, positive fluid balance, shock before transfusion, ASA score and mechanical ventilation may be potential risk factors for TRALI. Our study suggests that host-related risk factors may play a more important role in the occurrence and development of TRALI than blood transfusion-related risk factors.
Critical care patients (13 studies).
Systematic review on the risk factors for transfusion-related acute lung injury (TRALI).
The host-related factors were age, female sex, tobacco use status, chronic alcohol abuse, positive fluid balance, shock before transfusion, and ASA score of the recipients. The transfusion-related factors were the number of transfusions and fresh frozen plasma units. The device-related factor was mechanical ventilation.
Mortality benefit of crystalloids administered in 1-6 hours in septic adults in the ED systematic review with narrative synthesis
Emergency medicine journal : EMJ. 2021
BACKGROUND Based on the 2018 update of the Surviving Sepsis Campaign, the Committee for Quality Improvement of the NHSs of England recommended the instigation of the elements of the 'Sepsis-6 bundle' within 1 hour to adult patients screened positive for sepsis. This bundle includes a bolus infusion of 30 mL/kg crystalloids in the ED. Besides the UK, both in the USA and Australia, compliance with similar 1-hour targets became an important quality indicator. However, the supporting evidence may neither be contemporaneous nor necessarily valid for emergency medicine settings. METHOD A systematic review was designed and registered at PROSPERO to assess available emergency medicine/prehospital evidence published between 2012 and 2020, investigating the clinical benefits associated with a bolus infusion of a minimum 30 mL/kg crystalloids within 1 hour to adult patients screened positive for sepsis. Due to the small number of papers that addressed this volume of fluids in 1 hour, we expanded the search to include studies looking at 1-6 hours. RESULTS Seven full-text articles were identified, which investigated various aspects of the fluid resuscitation in adult sepsis. However, none answered completely to the original research question aimed to determine either the effect of time-to-crystalloids or the optimal fluid volume of resuscitation. Our findings demonstrated that in the USA/UK/Australia/Canada, adult ED septic patients receive 23-43 mL/kg of crystalloids during the first 6 hours of resuscitation without significant differences either in mortality or in adverse effects. CONCLUSION This systematic review did not find high-quality evidence supporting the administration of 30 mL/kg crystalloid bolus to adult septic patients within 1 hour of presentation in the ED. Future research must investigate both the benefits and the potential harms of the recommended intervention.
The 'swirl sign' as a marker for haematoma expansion and outcome in intra-cranial haemorrhage: A meta-analysis
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2021;87:103-111
The 'swirl sign' is a CT imaging finding associated with haematoma expansion and poor prognosis. We performed a systematic review and meta-analysis to determine its prognostic value. PubMed/MEDLINE and EMBASE were searched until 16/12/2020 for related articles. Articles detailing the relationship between the swirl sign and any of haematoma expansion (HE), neurological outcome in the form of Glasgow Outcome Score (GOS) or mortality were included. A meta-analysis was performed and the pooled sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were calculated for each of HE, GOS and mortality. 15 papers were assessed. Nine papers related to HE, for which the pooled sensitivity was 50% (95% CI 30-71), specificity was 77% (95%CI 67-85) and PLR was 2.16 (95%CI 1.89-2.42). There was significant heterogeneity (I(2) = 70%, Q = 26.9). Three papers related to GOS, for which the pooled sensitivity was 45% (95%CI 20-74), specificity was 78.3% (95%CI 40-95.2) and PLR was 1.77 (95%CI 1.04-2.62). Three papers related to mortality, for which the pooled sensitivity was 65% (95% CI 32-88), specificity was 75% (95%CI 42-92) and pooled PLR was 2.64 (95%CI 1.60-4.13). Our findings indicated that the swirl sign is a useful prognostic marker in the radiological evaluation of intracranial haemorrhage. However, more research is needed to assess its independence from other risk factors for haematoma expansion.
Impact of red blood cell transfusion on oxygen transport and metabolism in patients with sepsis and septic shock: a systematic review and meta-analysis
Revista Brasileira de terapia intensiva. 2021;33(1):154-166
Red blood cell transfusion is thought to improve cell respiration during septic shock. Nevertheless, its acute impact on oxygen transport and metabolism in this condition remains highly debatable. The objective of this study was to evaluate the impact of red blood cell transfusion on microcirculation and oxygen metabolism in patients with sepsis and septic shock. We conducted a search in the MEDLINE®, Elsevier and Scopus databases. We included studies conducted in adult humans with sepsis and septic shock. A systematic review and meta-analysis were performed using the DerSimonian and Laird random-effects model. A p value < 0.05 was considered significant. Nineteen manuscripts with 428 patients were included in the analysis. Red blood cell transfusions were associated with an increase in the pooled mean venous oxygen saturation of 3.7% (p < 0.001), a decrease in oxygen extraction ratio of -6.98 (p < 0.001) and had no significant effect on the cardiac index (0.02L/minute; p = 0,96). Similar results were obtained in studies including simultaneous measurements of venous oxygen saturation, oxygen extraction ratio, and cardiac index. Red blood cell transfusions led to a significant increase in the proportion of perfused small vessels (2.85%; p = 0.553), while tissue oxygenation parameters revealed a significant increase in the tissue hemoglobin index (1.66; p = 0.018). Individual studies reported significant improvements in tissue oxygenation and sublingual microcirculatory parameters in patients with deranged microcirculation at baseline. Red blood cell transfusions seemed to improve systemic oxygen metabolism with apparent independence from cardiac index variations. Some beneficial effects have been observed for tissue oxygenation and microcirculation parameters, particularly in patients with more severe alterations at baseline. More studies are necessary to evaluate their clinical impact and to individualize transfusion decisions.
Randomized Controlled Trial of Ultrasound-guided Fluid Resuscitation of Sepsis-Induced Hypoperfusion and Septic Shock
The western journal of emergency medicine. 2021;22(2):369-378
INTRODUCTION The ultrasound measurement of inferior vena cava (IVC) diameter change during respiratory phase to guide fluid resuscitation in shock patients is widely performed, but the benefit on reducing the mortality of sepsis patients is questionable. The study objective was to evaluate the 30-day mortality rate of patients with sepsis-induced tissue hypoperfusion (SITH) and septic shock (SS) treated with ultrasound-guided fluid management (UGFM) using ultrasonographic change of the IVC diameter during respiration compared with those treated with the usual-care strategy. METHODS This was a randomized controlled trial conducted in an urban, university-affiliated tertiary-care hospital. Adult patients with SITH/SS were randomized to receive treatment with UGFM using respiratory change of the IVC (UGFM strategy) or with the usual-care strategy during the first six hours after emergency department (ED) arrival. We compared the 30-day mortality rate and other clinical outcomes between the two groups. RESULTS A total of 202 patients were enrolled, 101 in each group (UGFM vs usual-care strategy) for intention-to-treat analysis. There was no significant difference in 30-day overall mortality between the two groups (18.8% and 19.8% in the usual-care and UGFM strategy, respectively; p > 0.05 by log rank test). Neither was there a difference in six-hour lactate clearance, a change in the sequential organ failure assessment score, or length of hospital stay. However, the cumulative fluid amount given in 24 hours was significantly lower in the UGFM arm. CONCLUSION In our ED setting, the use of respiratory change of IVC diameter determined by point-of-care ultrasound to guide initial fluid resuscitation in SITH/SS ED patients did not improve the 30-day survival probability or other clinical parameters compared to the usual-care strategy. However, the IVC ultrasound-guided resuscitation was associated with less amount of fluid used.