Abstract

BACKGROUND Despite appropriate antibiotic therapy, the risk of mortality in neonatal sepsis still remains high. We conducted a systematic review to comprehensively evaluate different adjuvant therapies in neonatal sepsis in a network meta-analysis. METHODS We included randomized controlled trials (RCTs) and quasi-RCTs that evaluated adjuvant therapies in neonatal sepsis. Neonates of all gestational and postnatal ages, who were diagnosed with sepsis based on blood culture or sepsis screen were included. We searched MEDLINE, CENTRAL, EMBASE and CINAHL until 12th April 2021 and reference lists. Data extraction and risk of bias assessment were performed in duplicate. A network meta-analysis with bayesian random-effects model was used for data synthesis. Certainty of evidence (CoE) was assessed using GRADE. RESULTS We included 45 studies involving 6,566 neonates. Moderate CoE showed IVIG [Relative Risk (RR); 95% Credible Interval (CrI): 1.00; (0.67-1.53)] as an adjunctive therapy probably does not reduce all-cause mortality before discharge, compared to standard care. Melatonin [0.12 (0-0.08)] and granulocyte transfusion [0.39 (0.19-0.76)] may reduce mortality before discharge, but CoE is very low. The evidence is also very uncertain regarding other adjunctive therapies to reduce mortality before discharge. Pentoxifylline may decrease the duration of hospital stay [Mean difference; 95% CrI: -7.48 days (-14.50-0.37)], but CoE is very low. CONCLUSION Given the biological plausibility for possible efficacy of these adjuvant therapies and that the CoE from the available trials is very low to low except for IVIG, we need large adequately powered RCTs to evaluate these therapies in sepsis in neonates.

Abstract

BACKGROUND Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION The trial did not show that prehospital PRBC-LyoPlas resuscitation was superior to 0·9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders. FUNDING National Institute for Health Research Efficacy and Mechanism Evaluation.

Abstract

OBJECTIVES This systematic review and meta-analysis compared the use of saline to balanced crystalloid for fluid resuscitation in patients with diabetic ketoacidosis (DKA). DATA SOURCES We searched databases including Medline, Embase, and the Cochrane registry. STUDY SELECTION We included randomized controlled trials (RCTs) that compared saline to balanced crystalloid in patients with DKA. DATA EXTRACTION We pooled estimates of effect using relative risk for dichotomous outcomes and mean differences (MDs) for continuous outcomes, both with 95% CIs. We assessed risk of bias for included RCTs using the modified Cochrane tool and certainty of evidence using Grading of Recommendations, Assessment, Development, and Evaluation methodology. DATA SYNTHESIS We included eight RCTs (n = 482 patients). Both time to DKA resolution (MD, 3.51 hr longer; 95% CI, 0.90 longer to 6.12 longer; moderate certainty) and length of hospital stay (MD, 0.89 d longer in saline group; 95% CI, 0.34 longer to 1.43 d longer; moderate certainty) are probably longer in the saline group compared with the balanced crystalloid group, although for the latter, the absolute difference (under 1 d) is small. Post-resuscitation serum chloride level may be higher (MD, 1.62 mmol/L higher; 95% CI, 0.40 lower to 3.64 higher; low certainty), and post-resuscitation serum bicarbonate is probably lower (MD, 1.50 mmol/L; 95% CI, 2.33 lower to 0.67 lower; moderate certainty) in those receiving saline. CONCLUSIONS In patients with DKA, the use of saline may be associated with longer time to DKA resolution, higher post-resuscitation serum chloride levels, lower post-resuscitation serum bicarbonate levels, and longer hospital stay compared with balanced crystalloids. Pending further data, low to moderate certainty data support using balanced crystalloid over saline for fluid resuscitation in patients with DKA.

Abstract

Background: Hemorrhage is a leading cause of preventable mortality from trauma, necessitating resuscitation through blood product transfusions. Early and accurate identification of patients requiring transfusions in the prehospital setting may reduce delays in time to transfusion upon arrival to hospital, reducing mortality. The purpose of this study is to characterize existing literature on predictors of transfusion and analyze their utility in the prehospital context.Objectives: The objectives of this study are to characterize the existing quantity and quality of literature regarding predictor scores for transfusion in injured patients, and to analyse the utility of predictor scores for massive transfusions in the prehospital setting and identify prehospital predictor scores for future research.Methods: A search strategy was developed in consultation with information specialists. A literature search of OVID MEDLINE from 1946 to present was conducted for primary studies evaluating the predictive ability of scoring systems or single variables in predicting transfusion in all trauma settings.Results: Of the 5824 studies were identified, 5784 studies underwent title and abstract screening, 94 studies underwent full text review, and 72 studies were included in the final review. We identified 16 single variables and 52 scoring systems for predicting transfusion. Amongst single predictor variables, fluids administered and systolic blood pressure had the highest reported sensitivity (100%) and specificity (89%) for massive transfusion protocol (MTP) activation respectively. Amongst scoring systems for transfusion, the Shock Index and Modified Shock Index had the highest reported sensitivity (96%), while the Pre-arrival Model had the highest reported specificity (95%) for MTP activation. Overall, 20 scores were identified as being applicable to the prehospital setting, 25 scores were identified as being potentially applicable, and seven scores were identified as being not applicable.Conclusions: We identified an extensive list of predictive single variables, validated scoring systems, and derived models for massive transfusion, presented their properties, and identified those with potential utility in the prehospital setting. By further validating applicable scoring tools in the prehospital setting, we may begin to administer more timely transfusions in the trauma population.

Abstract

BACKGROUND AND AIM The choice of resuscitation fluid in cirrhosis patients with sepsis-induced hypotension (SIH) is unclear. 5% albumin has been superior to normal saline in the FRISC study. We compared the efficacy and safety of 20% albumin, which has greater oncotic properties with plasmalyte in reversing SIH. METHODS Critically-ill cirrhosis(CIC) patients underwent open-label randomization to receive either 20% albumin [0.5-1.0gm/kg over 3 hours; n=50] or plasmalyte (30ml/kg over 3 hours, n=50). The primary end-point of the study was the attainment of mean arterial pressure (MAP) above 65 mmHg at three hours. RESULTS Baseline characteristics were comparable in albumin and plasmalyte groups; arterial lactate(mmol/L) [6.16±3.18 vs. 6.38±4.77; p=0.78), MAP (mmHg) [51.4±6.52 vs. 49.9±4.45; p=0.17] and SOFA score [10.8±2.96 vs. 11.1±4.2; p=0.68] respectively. Most patients were alcoholics (39%) and had pneumonia (40%). In the intention-to-treat (ITT) analysis, albumin was superior to plasmalyte in achieving the primary end-point (62% vs. 22%; p<0.001). A rapid decline in arterial lactate (P=0.03), a lesser proportion of dialysis [48% vs. 62%; p=0.16], and a higher time to initiation of dialysis (in hours) [68.13±47.79 vs. 99.7± 63.4; p=0.06] was seen with albumin. However, the 28-day mortality was not different (58% vs. 62%, p=0.57). Patients in the albumin group required discontinuation of therapy in 11 (22%) patients due to adverse effects compared to none in plasmalyte group. CONCLUSION In patients with cirrhosis and SIH, 20% albumin transiently improves the hemodynamics with early lactate clearance than plasmalyte but needs monitoring as it is more often attended with pulmonary complications. Both fluids provide comparable 28 days survival. NCT02721238 LAY SUMMARY The current randomized controlled trial performed in critically ill patients with cirrhosis and sepsis-induced hypotension highlights that 20% albumin restores hemodynamics but causes more pulmonary complications than plasmalyte. The impact on renal functions was also modest. These effects did not result in improvement in deaths at 28-days. Plasmalyte is safer and well-tolerated and can be considered for volume resuscitation in patients with cirrhosis and sepsis-induced hypotension.

Abstract

BACKGROUND Haemorrhage and subsequent hypovolemia from traumatic injury is a potentially reversible cause of cardiac arrest, as interventions can be made to increase circulatory volume and organ perfusion. Traditionally, intravenous (IV) fluid therapy is recommended for all patients who have experienced a haemorrhagic emergency. There has been some argument, however, that this may not be the most effective treatment as isotonic fluids can dilute coagulation factors and further stimulate bleeding. Permissive hypotension, also known as hypotensive resuscitation within the context of damage control resuscitation, is a method of managing haemorrhagic trauma patients by restricting IV fluid administration to allow for a reduced blood pressure. It is important to evaluate and compare current research literature on the effects of both permissive hypotension and fluid therapy on patients suffering from traumatic haemorrhage. METHODS A rapid review was conducted by systematically searching and identifying literature to narratively compare permissive hypotension and fluid therapy. Searches were carried out across two databases to find relevant primary research containing quantitative data that provide contextual and statistical evidence to achieve the aim of this review. Papers were narratively synthesised to produce key themes for discussion. RESULTS The database searches identified 125 records, 78 from PubMed and 47 from ScienceDirect. Eleven duplicates were removed, and 114 titles screened. Ninety-four records were initially excluded and nine more after abstract review. Eleven papers were critiqued using Benton and Cormack's framework, with eight articles included in the final review. CONCLUSION Permissive hypotension may have a positive impact on 30-day mortality, when compared with fluid resuscitation methods, however there is evidence to suggest that hypotensive resuscitation may be more effective for blunt force injuries. Some studies even suggest a reduction in the treatment cost when reducing fluid volumes. Penetrating injuries are usually more likely to be a compressible source of haemorrhage within which haemorrhage control can be gained much more easily. There are recommendations for the use of permissive hypotension in both compressible and non-compressible injuries. It is difficult at this time to draw definitive conclusions for the treatment of every case related to traumatic haemorrhage given the variability and unpredictability of trauma.

Abstract

IMPORTANCE Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited. OBJECTIVE To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH. DATA SOURCES PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022. STUDY SELECTION The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded. DATA EXTRACTION AND SYNTHESIS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model. MAIN OUTCOMES AND MEASURES The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent. RESULTS A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events. CONCLUSIONS AND RELEVANCE In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.

Abstract

BACKGROUND While clinical guidelines provide a framework for hospital management of spontaneous intracerebral hemorrhage (ICH), variation in the resource utilization and costs of these services exist. OBJECTIVES Perform a systematic literature review to assess the evidence on hospital resource utilization and costs associated with management of adult ICH patients, as well as identify factors that impact variation in such hospital resource utilization and costs, regarding clinical characteristics and delivery of services. METHODS A systematic literature review was performed using PubMed, Cochrane Central Register of Controlled Trials, and Ovid MEDLINE(R) 1946 to Present. Articles were assessed against inclusion and exclusion criteria. Study design, ICH sample size, population, setting, objective, hospital characteristics, hospital resource utilization and cost data, and main study findings were abstracted. RESULTS 43 studies met the inclusion criteria. Pertinent clinical characteristics that increased hospital resource use included presence of comorbidities and baseline ICH severity. Aspects of service delivery that greatly impacted hospital resource consumption included ICU length of stay and performance of surgical procedures and intensive care procedures. CONCLUSION Hospital resource utilization and costs for ICH patients were high and differed widely across studies. Making concrete conclusions on hospital resources and costs for ICH care was constrained given methodological and patient variation in the studies. Future research should evaluate the long-term cost-effectiveness of ICH treatment interventions and use specific economic evaluation guidelines and common data elements to mitigate study variation.

Abstract

Objective: The "Stop the Bleed" campaign was created to educate laypeople about bleeding control and make bleeding control kits available in public locations. Unfortunately, previous research has indicated that up to half of all laypeople cannot effectively apply a tourniquet. The purpose of this study was to determine if laypeople could apply tourniquets more effectively with just-in-time training using combined audio-written instructions versus written-only instructions.Methods: We conducted a prospective randomized study comparing the application of a tourniquet using a simulated bleeding arm. Participants were laypeople 18 years and older and excluded those with any previous tourniquet experience or training. Participants were randomized to just-in-time training using either audio-written or written-only instructions. Time in seconds to tourniquet application and the effectiveness of the tourniquet application was recorded. Effective application was defined as stopping the flow or significantly slowing the flow to a slow drip. Ineffective tourniquet placement was defined as not significantly changing the flow. Statistical analysis was performed using Fisher's exact, t-test, and linear regression.Results: Eighty-two participants were included; 40 were in the audio-written instructions group, and 58.5% were male. The audio-written group's effective application rate was 92.5% and that of the written-only group was 76.2%. A significantly higher rate of ineffective tourniquet application was noted for the written-only group, (23.8%), versus the audio-written group (7.5%), p=.04. Regardless of the type of instructions used, time to effective application of the tourniquet decreased as participant age increased (p = 0.02, 95%CI (-1.24, -0.13). There was no relationship between age and effective tourniquet application (p = 0.06). Time for tourniquet placement was not different between the audio-written (mean 100.4 seconds) and written-only (mean 106.1 seconds) groups (p = 0.58).Conclusion: This study suggests that combined audio-written instructions decrease the rate of ineffective tourniquet application by laypeople compared with written-only instructions. Further studies are needed to assess if audio instructions and just-in-time training can further maximize effective tourniquet application.

Abstract

BACKGROUND The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.