Safety and effectiveness of propranolol in severely burned patients: systematic review and meta-analysis

Background The objective of this systematic review was to determine the effectiveness and safety of propranolol compared to placebo or usual care for improving clinical relevant outcomes in severely burned patients (TBSA \u3e20%). Methods Relevant articles from randomized controlled trials were identified by a literature search in MEDLINE, EMBASE, and CENTRAL. We included trials involving patients with a severe burn (\u3e20% of total body surface area affected). Trials were eligible if they evaluated propranolol and compared to usual care or placebo. Two investigators independently assessed articles for inclusion and exclusion criteria and selected studies for the final analysis. We conducted a meta-analysis using a random-effects model. Results We included ten studies in our systematic review. These studies randomized a total of 1236 participants. There were no significant differences between propranolol and placebo with respect to mortality (RD −0.02 [95% CI −0.06 to 0.02]), sepsis (RD −0.03 [95% CI −0.09 to 0.04]), and the overall hospital stay (MD −0.37 [−4.52 to 3.78]). Propranolol-treated adults had a decrease in requirements of blood transfusions (MD −185.64 [95% CI −331.06 to −40.43]) and a decreased heart rate (MD −26.85 [95% CI −39.95 to −13.75]). Conclusions Our analysis indicates that there were no differences in mortality or sepsis in severely burned patients treated with propranolol compared with those who had usual care or placebo. However, the use of propranolol in these patients resulted in lower requirements of blood transfusion and lower values of heart rate. The evidence synthesized in this systematic review is limited to conclude that propranolol reduces the length of hospital stay among severely burned patients. Future trials should assess the impact of propranolol on clinically relevant outcomes such as mortality and adverse events

Unlocking the potential of TIPS placement as a bridge to elective and emergency surgery in cirrhotic patients: a meta-analysis and future directions for endovascular resuscitation in acute care surgery

Abdominal surgery; Liver cirrhosis; Portal hypertensionCirugía abdominal; Cirrosis hepática; Hipertensión portalCirurgia abdominal; Cirrosi hepàtica; Hipertensió portalBackground In this systematic review and meta-analysis, we examined the evidence on transjugular intrahepatic portosystemic shunt (TIPS) as a bridge to elective and emergency surgery in cirrhotic patients. We aimed to assess the perioperative characteristics, management approaches, and outcomes of this intervention, which is used to achieve portal decompression and enable the safe performance of elective and emergent surgery. Methods MEDLINE and Scopus were searched for studies reporting the outcomes of cirrhotic patients undergoing elective and emergency surgery with preoperative TIPS. The risk of bias was evaluated using the methodological index for non-randomized studies of interventions, and the JBI critical appraisal tool for case reports. The outcomes of interest were: 1. Surgery after TIPS; 2. Mortality; 3. Perioperative transfusions; and 4. Postoperative liver-related events. A DerSimonian and Laird (random-effects) model was used to perform the meta-analyses in which the overall (combined) effect estimate was presented in the form of an odds ratio (summary statistic). Results Of 426 patients (from 27 articles), 256 (60.1%) underwent preoperative TIPS. Random effects MA showed significantly lower odds of postoperative ascites with preoperative TIPS (OR = 0.40, 95% CI 0.22–0.72; I2 = 0%). There were no significant differences in 90-day mortality (3 studies: OR = 0.76, 95% CI 0.33–1.77; I2 = 18.2%), perioperative transfusion requirement (3 studies: OR = 0.89, 95% CI 0.28–2,84; I2 = 70.1%), postoperative hepatic encephalopathy (2 studies: OR = 0.97, 95% CI 0.35–2.69; I2 = 0%), and postoperative ACLF (3 studies: OR = 1.02, 95% CI 0.15–6.8, I2 = 78.9%). Conclusions Preoperative TIPS appears safe in cirrhotic patients who undergo elective and emergency surgery and may have a potential role in postoperative ascites control. Future randomized clinical trials should test these preliminary results

A meta-analysis of resuscitative endovascular balloon occlusion of the aorta (REBOA) or open aortic cross-clamping by resuscitative thoracotomy in non-compressible torso hemorrhage patients

Background The objective of this systematic review and meta-analysis was to determine the effect of REBOA, compared to resuscitative thoracotomy, on mortality and among non-compressible torso hemorrhage trauma patients. Methods Relevant articles were identified by a literature search in MEDLINE and EMBASE. We included studies involving trauma patients suffering non-compressible torso hemorrhage. Studies were eligible if they evaluated REBOA and compared it to resuscitative thoracotomy. Two investigators independently assessed articles for inclusion and exclusion criteria and selected studies for final analysis. We conducted meta-analysis using random effect models. Results We included three studies in our systematic review. These studies included a total of 1276 patients. An initial analysis found that although lower in REBOA-treated patients, the odds of mortality did not differ between the compared groups (OR 0.42; 95% CI 0.17–1.03). Sensitivity analysis showed that the risk of mortality was significantly lower among patients who underwent REBOA, compared to those who underwent resuscitative thoracotomy (RT) (RR 0.81; 95% CI 0.68–0.97). Conclusion Our meta-analysis, mainly from observational data, suggests a positive effect of REBOA on mortality among non-compressible torso hemorrhage patients. However, these results deserve further investigation

Non-Alcoholic Fatty Liver Disease in Patients with Polycystic Ovary Syndrome : A Systematic Review, Meta-Analysis, and Meta-Regression

Background: The metabolic effects of polycystic ovary syndrome (PCOS) may increase the risk of non-alcoholic fatty liver disease (NAFLD). However, the burden of NAFLD in PCOS has not been unequivocally defined. This systematic review (SR), meta-analysis (MA) assessed NAFLD's prevalence, and risk factors in patients with PCOS. Methods: A literature search was performed in MEDLINE, Scopus, and Scielo. First, we performed a MA of proportions to estimate the prevalence of NAFLD in PCOS. Second, we performed meta-analyses of precalculated adjusted odds ratios to examine NAFLD risk factors. Finally, we performed a meta-regression to model how the estimated prevalence changed with changes in prespecified variables. Results: We identified 817 articles from the database searches. Thirty-six were included. MA of proportions found a pooled NAFLD prevalence of 43% (95% CI, 35-52%) with high heterogeneity (I 2 = 97.2%). BMI, waist circumference, ALT values, HOMA-IR values, free androgen index levels, hyperandrogenism, and triglycerides were associated with significantly higher risk-adjusted odds of NAFLD among patients with PCOS. Meta-regression showed that rises in NAFLD prevalence were mediated through increases in metabolic syndrome prevalence and higher levels of HOMA-IR, free androgen index, and total testosterone. Conclusion: The prevalence of NAFLD (43%) among PCOS patients is high despite their average young age, with several metabolic and PCOS-specific factors influencing its occurrence. Screening programs may aid in detecting metabolic-associated fatty liver disease and prevent its consequences. Further work is required to establish the burden of liver-related outcomes once NAFLD has progressed in the PCOS population

Review article: The need for more efficient and patient-oriented drug development pathways in NASH—setting the scene for platform trials

Drug development; Non-alcoholic steatohepatitis; Study designsDesenvolupament de fàrmacs; Esteatohepatitis no alcohòlica; Dissenys d'estudiDesarrollo de fármacos; Esteatohepatitis no alcohólica; Diseños de estudioBackground and Aims Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. Methods Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. Results Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. Conclusions PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, ‘proof-of-platform’ at a smaller scale needs to be provided.JMP reports having received consulting fees from Boehringer-Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. NAdP works for Janssen. QMA is Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. He reports research Grant Funding: Allergan/Tobira, AstraZeneca, Boehringer-Ingelheim, Glaxo SmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd. Consultancy: 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer-Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics. Speaker: Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape. Royalties: Elsevier Ltd. PM works for Novartis. MSK is an employee of and a shareholder in Novo Nordisk A/S. JG has received consulting fees from Boehringer-Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. JRE has received speaking fees from Gilead. FT lab’ work has been supported by the German Research Foundation (DFG, CRC/TR 362) and research grants from Gilead, Allergan, Bristol-Myers Squibb and Inventiva. VR consults for and Intercept, Novo Nordisk, Galmed, Poxel, NGM, Madrigal, Enyo, Sagimet, 89 Bio, Prosciento, Terns, and Theratechnologies, and received grants from Intercept and Gilead

Diastolic shock index and clinical outcomes in patients with septic shock

Background: Loss of vascular tone is a key pathophysiological feature of septic shock. Combination of gradual diastolic hypotension and tachycardia could reflect more serious vasodilatory conditions. We sought to evaluate the relationships between heart rate (HR) to diastolic arterial pressure (DAP) ratios and clinical outcomes during early phases of septic shock. Methods: Diastolic shock index (DSI) was defined as the ratio between HR and DAP. DSI calculated just before starting vasopressors (Pre-VPs/DSI) in a preliminary cohort of 337 patients with septic shock (January 2015 to February 2017) and at vasopressor start (VPs/DSI) in 424 patients with septic shock included in a recent randomized controlled trial (ANDROMEDA-SHOCK; March 2017 to April 2018) was partitioned into five quantiles to estimate the relative risks (RR) of death with respect to the mean risk of each population (assumed to be 1). Matched HR and DAP subsamples were created to evaluate the effect of the individual components of the DSI on RRs. In addition, time-course of DSI and interaction between DSI and vasopressor dose (DSI*NE.dose) were compared between survivors and non-survivors from both populations, while ROC curves were used to identify variables predicting mortality. Finally, as exploratory observation, effect of early start of vasopressors was evaluated at each Pre-VPs/DSI quintile from the preliminary cohort. Results: Risk of death progressively increased at gradual increments of Pre-VPs/DSI or VPs/DSI (One-way ANOVA, p < 0.001). Progressive DAP decrease or HR increase was associated with higher mortality risks only when DSI concomitantly increased. Areas under the ROC curve for Pre-VPs/DSI, SOFA and initial lactate were similar, while mean arterial pressure and systolic shock index showed poor performances to predict mortality. Time-course of DSI and DSI*NE.dose was significantly higher in non-survivors from both populations (repeated-measures ANOVA, p < 0.001). Very early start of vasopressors exhibited an apparent benefit at higher Pre-VPs/DSI quintile. Conclusions: DSI at pre-vasopressor and vasopressor start points might represent a very early identifier of patients at high risk of death. Isolated DAP or HR values do not clearly identify such risk. Usefulness of DSI to trigger or to direct therapeutic interventions in early resuscitation of septic shock need to be addressed in future studies

Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis

BACKGROUND: Optimal timing for the start of vasopressors (VP) in septic shock has not been widely studied since it is assumed that fluids must be administered in advance. We sought to evaluate whether a very early start of VP, even without completing the initial fluid loading, might impact clinical outcomes in septic shock. METHODS: A total of 337 patients with sepsis requiring VP support for at least 6 h were initially selected from a prospectively collected database in a 90-bed mixed-ICU during a 24-month period. They were classified into very-early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or not within/before the next hour of the first resuscitative fluid load. Then, VE-VPs (n = 93) patients were 1:1 propensity matched to D-VPs (n = 93) based on age; source of admission (emergency room, general wards, intensive care unit); chronic and acute comorbidities; and lactate, heart rate, systolic, and diastolic pressure at vasopressor start. A risk-adjusted Cox proportional hazard model was fitted to assess the association between VE-VPs and day 28 mortality. Finally, a sensitivity analysis was performed also including those patients requiring VP support for less than 6 h. RESULTS: Patients subjected to VE-VPs received significantly less resuscitation fluids at vasopressor starting (0[0-510] vs. 1500[650-2300] mL, p < 0.001) and during the first 8 h of resuscitation (1100[500-1900] vs. 2600[1600-3800] mL, p < 0.001), with no significant increase in acute renal failure and/or renal replacement therapy requirements. VE-VPs was related with significant lower net fluid balances 8 and 24 h after VPs. VE-VPs was also associated with a significant reduction in the risk of death compared to D-VPs (HR 0.31, CI95% 0.17-0.57, p < 0.001) at day 28. Such association was maintained after including patients receiving vasopressors for < 6 h. CONCLUSION: A very early start of vasopressor support seems to be safe, might limit the amount of fluids to resuscitate septic shock, and could lead to better clinical outcomes

Incidence, Risk Factors, and Outcomes of Intra-Abdominal Hypertension in Critically Ill Patients-A Prospective Multicenter Study (IROI Study)

To identify the prevalence, risk factors, and outcomes of intra-abdominal hypertension in a mixed multicenter ICU population. Prospective observational study. Fifteen ICUs worldwide. Consecutive adult ICU patients with a bladder catheter. None. Four hundred ninety-one patients were included. Intra-abdominal pressure was measured a minimum of every 8 hours. Subjects with a mean intra-abdominal pressure equal to or greater than 12 mm Hg were defined as having intra-abdominal hypertension. Intra-abdominal hypertension was present in 34.0% of the patients on the day of ICU admission (159/467) and in 48.9% of the patients (240/491) during the observation period. The severity of intra-abdominal hypertension was as follows: grade I, 47.5%; grade II, 36.6%; grade III, 11.7%; and grade IV, 4.2%. The severity of intra-abdominal hypertension during the first 2 weeks of the ICU stay was identified as an independent predictor of 28-and 90-day mortality, whereas the presence of intra-abdominal hypertension on the day of ICU admission did not predict mortality. Body mass index, Acute Physiology and Chronic Health Evaluation II score greater than or equal to 18, presence of abdominal distension, absence of bowel sounds, and positive end-expiratory pressure greater than or equal to 7 cm H2O were independently associated with the development of intra-abdominal hypertension at any time during the observation period. In subjects without intra-abdominal hypertension on day 1, body mass index combined with daily positive fluid balance and positive end-expiratory pressure greater than or equal to 7 cm H2O (as documented on the day before intra-abdominal hypertension occurred) were-associated with the development of intraabdominal hypertension during the first week in the ICU. In our mixed ICU patient cohort, intra-abdominal hypertension occurred in almost half of all subjects and was twice as prevalent in mechanically ventilated patients as in spontaneously breathing patients. Presence and severity of intra-abdominal hypertension during the observation period significantly and independently increased 28-and 90-day mortality. Five admission day variables were independently associated with the presence or development of intra-abdominal hypertension. Positive fluid balance was associated with the development of intra-abdominal hypertension after day 1474535542NIGMS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [U54 GM104940

Acute intestinal failure: international multicenter point-of-prevalence study

Background & aims: Intestinal failure (IF) is defined from a requirement or intravenous supplementation due to failing capacity to absorb nutrients and fluids. Acute IF is an acute, potentially reversible form of IF. We aimed to identify the prevalence, underlying causes and outcomes of acute IF. Methods: This point-of-prevalence study included all adult patients hospitalized in acute care hospitals and receiving parenteral nutrition (PN) on a study day. The reason for PN and the mechanism of IF (if present) were documented by local investigators and reviewed by an expert panel. Results: Twenty-three hospitals (19 university, 4 regional) with a total capacity of 16,356 acute care beds and 1237 intensive care unit (ICU) beds participated in this study. On the study day, 338 patients received PN (21 patients/1000 acute care beds) and 206 (13/1000) were categorized as acute IF. The categorization of reason for PN was revised in 64 cases (18.9% of total) in consensus between the expert panel and investigators. Hospital mortality of all study patients was 21.5%; the median hospital stay was 36 days. Patients with acute IF had a hospital mortality of 20.5% and median hospital stay of 38 days (P > 0.05 for both outcomes). Disordered gut motility (e.g. ileus) was the most common mechanism of acute IF, and 71.5% of patients with acute IF had undergone abdominal surgery. Duration of PN of ≥42 days was identified as being the best cut-off predicting hospital mortality within 90 days. PN ≥ 42 days, age, sepsis and ICU admission were independently associated with 90-day hospital mortality. Conclusions: Around 2% of adult patients in acute care hospitals received PN, 60% of them due to acute IF. High 90-day hospital mortality and long hospital stay were observed in patients receiving PN, whereas presence of acute IF did not additionally influence these outcomes. Duration of PN was associated with increased 90-day hospital mortality