Objective To assess the efficacy and safety of pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of baseline hypoalbuminaemia) in critically unwell adults with sepsis of any severity.Design Systematic review and meta-analysis of randomised clinical trials, with trial sequential analysis, subgroup, and meta-regression analyses. Eligibility criteria Prospective randomised clinical trials of adults with sepsis of any severity (with or without baseline hypoalbuminaemia) in critical or intensive care who received pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of hypoalbuminaemia) compared with those who received control fluids (crystalloid or colloid), were included if all-cause mortality outcome data were available. No restriction of language, date, publication status, or primary study endpoint was applied. Data sourcesData extraction Two reviewers independently assessed articles for inclusion, extracted data to assess risk of bias, trial methods, patients, interventions, comparisons, and outcome. The relative risk of all-cause mortality was calculated using a random effects model accounting for clinical heterogeneity.Primary outcome measure All-cause mortality at final follow-up.Results Eighteen articles reporting on 16 primary clinical trials that included 4190 adults in critical or intensive care with sepsis, severe sepsis, or septic shock. A median of 70.0 g daily of pooled human albumin was received over a median of 3 days by adults with a median age of 60.8 years as part of fluid volume expansion and resuscitation, with or without correction of hypoalbuminaemia. The relative risk of death was similar between albumin groups (that received a median of 175 g in total) and control fluid groups (relative risk 0.94; 95% confidence interval 0.87 to 1.01; P=0.11; I 2 =0%). Trial sequential analysis corrected the 95% confidence interval for random error (0.85 to 1.02; D 2 =0%). Eighty eight per cent of the required information size (meta-analysis sample size) of 4894 patients was achieved, and the cumulative effect size measure (z score) entered the futility area, supporting the notion of no relative benefit of albumin (GRADE quality of evidence was moderate). Evidence of no difference was also found when albumin was compared with crystalloid fluid (relative risk 0.93; 0.86 to 1.01; P=0.07; I 2 =0%) in 3878 patents (GRADE quality of evidence was high; 79.9% of required information size) or colloid fluids in 299 patients (relative risk 1.04; 0.79 to 1.38; P=0.76; I 2 =0%) (GRADE quality of evidence was very low; 5.8% of required information size). When studies at high risk of bias were excluded in a predefined subgroup analysis, the finding of no mortality benefit remained, and the cumulative z score was just outside the boundary of futility. Overall, the meta-analysis was robust to sensitivity, subgroup, meta-regression, and trial sequential analyses. ConclusionsIn this analysis, human ...

Mannose-binding lectin (MBL) genetic polymorphisms result in deficiency of the encoded protein and increased susceptibility to infection, especially in children and the immunocompromised. The objective of this study was to investigate the relationship between MBL-2 exon 1 and promoter -221 polymorphisms, plasma levels of the encoded protein, and the incidence and outcome of severe sepsis and septic shock. One hundred seventy-four white adult patients with severe sepsis or septic shock were recruited in a prospective multicenter study across eight intensive care units in the South of England, UK. Genotype and haplotype frequencies were compared between normal population controls and patients, and between survivors and nonsurvivors. Plasma levels of encoded protein were related to genotype and outcome. The exon 1 polymorphisms (A/O or O/O) were significantly more common in the patients with severe sepsis and septic shock than in normal healthy adults (54.6% vs. 39.7%, P = 0.001), and there was a significant difference in haplotype frequency between controls and septic patients (P < 0.0001). There was no significant difference in MBL-2 genotype or haplotype frequency between survivors and nonsurvivors. There was a strong relationship between MBL-2 haplotype and plasma MBL concentration (P < 0.001). Individual plasma levels were variable and increased between days 1 and 7. The mortality rate was higher in those with MBL levels <1000 microg/L than in those patients with levels >1000 microg/L (47.2 vs. 22.2%, P = 0.05). We conclude that genetic polymorphisms resulting in mannose-binding lectin deficiency are associated with increased susceptibility to sepsis. The close relationship between polymorphic variants and plasma MBL concentration persists during sepsis but individual levels vary widely. Lower circulating MBL levels are associated with a poor outcome.

PurposeTo assess the impact of 6% tetrastarch (hydroxyethyl starch (HES) 130/0.4 and 130/0.42) in severe sepsis patients. The primary outcome measure was 90-day mortality. MethodsA structured literature search to identify prospective randomized controlled trials (RCT) in adult patients with severe sepsis receiving 6% tetrastarch (potato or waxy maize origin), as part of fluid resuscitation in comparison to other non-HES fluids after randomisation, in the critical care setting was undertaken. A systematic review and meta-analysis was performed. ResultsSix RCTs were included (n = 3033): three from 2012 (n = 2913) had a low risk of bias. Median tetrastarch exposure was 37.4 ml/kg (range 30 to 43). Ninety-day mortality was associated with tetrastarch exposure (relative risk (RR) 1.13; 95% confidence interval (CI) 1.02 to 1.25; p = 0.02) compared to crystalloid. The number needed to harm (NNH) was 28.8 (95% CI 14.6 to 942.5). Publication bias and statistical heterogeneity (I 2 = 0%) were not present. Tetrastarch exposure was also associated with renal replacement therapy (p = 0.01; NNH 15.7) and allogeneic transfusion support (p = 0.001; NNH 9.9). No difference between groups was observed for 28-day mortality, comparison with colloid as control, and for waxy maize derived tetrastarch, but power was lacking. Overall mortality was associated with tetrastarch exposure (RR 1.13; 95% CI 1.02 to 1.25; p = 0.02). ConclusionsIn our analysis, 6% tetrastarch as part of initial fluid resuscitation for severe sepsis was associated with harm, and as alternatives exist, in our view should be avoided.

Summary Renal impairment is common in patients who are critically ill with coronavirus disease‐19 (COVID‐19). We examined the association between acute and chronic kidney disease with clinical outcomes in 372 patients with coronavirus disease‐19 admitted to four regional intensive care units between 10 March 2020 and 31 July 2020. A total of 216 (58%) patients presented with COVID‐19 and renal impairment. Acute kidney injury and/or chronic kidney disease was associated with greater in‐hospital mortality compared with patients with preserved renal function (107/216 patients (50%) (95%CI 44–57) vs. 32/156 (21%) (95%CI 15–28), respectively; p < 0.001, relative risk 2.4 (95%CI 1.7–3.4)). Mortality was greatest in patients with renal transplants (6/7 patients (86%) (95%CI 47–100)). Mortality rates increased in patients with worsening renal injury according to the Kidney Disease: Improving Global Outcomes classification: stage 0 mortality 33/157 patients (21%) (95%CI 15–28) vs. stages 1–3 mortality 91/186 patients (49%) (95%CI 42–56); p < 0.001, relative risk 2.3 (95%CI 1.7–3.3). Survivors were less likely to require renal replacement therapy compared with non‐survivors (57/233 patients (24%) vs. 64/139 patients (46%), respectively; p < 0.001, relative risk 1.9 (95%CI 1.4–2.5)). One‐fifth of survivors who required renal replacement therapy acutely in intensive care continued to require renal support following discharge. Our data demonstrate that renal impairment in patients admitted to intensive care with COVID‐19 is common and is associated with a high mortality and requirement for on‐going renal support after discharge from critical care. Our findings have important implications for future pandemic planning in this patient cohort.