Hooray for Hypoxia?

The mortality of critically ill patients rises steadily as the partial pressure of arterial oxygen falls below about 11 kPa (80 mm Hg). A new animal study in the May 2005 issue of PLoS Biology showing a potential benefit for hypoxia is thus a challenge to current thinking

Notes on the Afrotropical hover fly genus Meromacroides Curran (Syrphidae, Eristalinae)

The African endemic hover fly Meromacroides meromacriformis (Bezzi, 1915) (Syrphidae, Eristalinae) was described more than a century ago and its monotypic status established in 1927, but subsequent collections and publications are rare. Only the male has been described and nothing is known about its biology. We re-describe the male, including geographic variation, describe the female for the first time and provide the first DNA barcodes for the species. Despite the large range and observed variations, there is insufficient evidence to describe additional taxa in the genus. Biological observations are presented, which may shed some insight into this rare and enigmatic hover fly, whose known distribution now spans the Afrotropical Region

A multicentre, randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of early nutritional support via the parenteral versus the enteral route in critically ill patients (CALORIES)

BACKGROUND: Malnutrition is a common problem in critically ill patients in UK NHS critical care units. Early nutritional support is therefore recommended to address deficiencies in nutritional state and related disorders in metabolism. However, evidence is conflicting regarding the optimum route (parenteral or enteral) of delivery. OBJECTIVES: To estimate the effect of early nutritional support via the parenteral route compared with the enteral route on mortality at 30 days and on incremental cost-effectiveness at 1 year. Secondary objectives were to compare the route of early nutritional support on duration of organ support; infectious and non-infectious complications; critical care unit and acute hospital length of stay; all-cause mortality at critical care unit and acute hospital discharge, at 90 days and 1 year; survival to 90 days and 1 year; nutritional and health-related quality of life, resource use and costs at 90 days and 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Adult general critical care units in 33 NHS hospitals in England. PARTICIPANTS: 2400 eligible patients. INTERVENTIONS: Five days of early nutritional support delivered via the parenteral (n = 1200) and enteral (n = 1200) route. MAIN OUTCOME MEASURES: All-cause mortality at 30 days after randomisation and incremental net benefit (INB) (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: By 30 days, 393 of 1188 (33.1%) patients assigned to receive early nutritional support via the parenteral route and 409 of 1195 (34.2%) assigned to the enteral route had died [p = 0.57; absolute risk reduction 1.15%, 95% confidence interval (CI) -2.65 to 4.94; relative risk 0.97 (0.86 to 1.08)]. At 1 year, INB for the parenteral route compared with the enteral route was negative at -£1320 (95% CI -£3709 to £1069). The probability that early nutritional support via the parenteral route is more cost-effective - given the data - is < 20%. The proportion of patients in the parenteral group who experienced episodes of hypoglycaemia (p = 0.006) and of vomiting (p < 0.001) was significantly lower than in the enteral group. There were no significant differences in the 15 other secondary outcomes and no significant interactions with pre-specified subgroups. LIMITATIONS: Blinding of nutritional support was deemed to be impractical and, although the primary outcome was objective, some secondary outcomes, although defined and objectively assessed, may have been more vulnerable to observer bias. CONCLUSIONS: There was no significant difference in all-cause mortality at 30 days for early nutritional support via the parenteral route compared with the enteral route among adults admitted to critical care units in England. On average, costs were higher for the parenteral route, which, combined with similar survival and quality of life, resulted in negative INBs at 1 year. FUTURE WORK: Nutritional support is a complex combination of timing, dose, duration, delivery and type, all of which may affect outcomes and costs. Conflicting evidence remains regarding optimum provision to critically ill patients. There is a need to utilise rigorous consensus methods to establish future priorities for basic and clinical research in this area. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17386141. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 28. See the NIHR Journals Library website for further project information

A cohort study of 30 day mortality after NON-EMERGENCY surgery in a COVID-19 cold site

BACKGROUND: Two million non-emergency surgeries are being cancelled globally every week due to the COVID-19 pandemic, which will have a major impact on patients and healthcare systems. METHODS: During the peak of the pandemic in the United Kingdom, we set up a multicentre cancer network amongst 14 National Health Service institutions, performing urological, thoracic, gynaecological and general surgical urgent and cancer operations at a central COVID-19 cold site. This is a cohort study of 500 consecutive patients undergoing surgery in this network. The primary outcome was 30-day mortality from COVID-19. Secondary outcomes included all-cause mortality and post-operative complications at 30-days. RESULTS: 500 patients underwent surgery with median age 62.5 (IQR 51-71). 65% were male, 60% had a known diagnosis of cancer and 61% of surgeries were considered complex or major. No patient died from COVID-19 at 30-days. 30-day all-cause mortality was 3/500 (1%). 10 (2%) patients were diagnosed with COVID-19, 4 (1%) with confirmed laboratory diagnosis and 6 (1%) with probable COVID-19. 33/500 (7%) of patients developed Clavien-Dindo grade 3 or higher complications, with 1/33 (3%) occurring in a patient with COVID-19. CONCLUSION: It is safe to continue cancer and urgent surgery during the COVID-19 pandemic with appropriate service reconfiguration

Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191

Effectiveness of emergency surgery for five common acute conditions: an instrumental variable analysis of a national routine database.

The effectiveness of emergency surgery vs. non-emergency surgery strategies for emergency admissions with acute appendicitis, gallstone disease, diverticular disease, abdominal wall hernia or intestinal obstruction is unknown. Data on emergency admissions for adult patients from 2010 to 2019 at 175 acute National Health Service hospitals in England were extracted from the Hospital Episode Statistics database. Cohort sizes were: 268,144 (appendicitis); 240,977 (gallstone disease); 138,869 (diverticular disease); 106,432 (hernia); and 133,073 (intestinal obstruction). The primary outcome was number of days alive and out of hospital at 90 days. The effectiveness of emergency surgery vs. non-emergency surgery strategies was estimated using an instrumental variable design and is reported for the cohort and pre-specified sub-groups (age, sex, number of comorbidities and frailty level). Average days alive and out of hospital at 90 days for all five cohorts were similar, with the following mean differences (95%CI) for emergency surgery minus non-emergency surgery after adjusting for confounding: -0.73 days (-2.10-0.64) for appendicitis; 0.60 (-0.10-1.30) for gallstone disease; -2.66 (-15.7-10.4) for diverticular disease; -0.07 (-2.40-2.25) for hernia; and 3.32 (-3.13-9.76) for intestinal obstruction. For patients with 'severe frailty', mean differences (95%CI) in days alive and out of hospital for emergency surgery were lower than for non-emergency surgery strategies: -21.0 (-27.4 to -14.6) for appendicitis; -5.72 (-11.3 to -0.2) for gallstone disease, -38.9 (-63.3 to -14.6) for diverticular disease; -19.5 (-26.6 to -12.3) for hernia; and - 34.5 (-46.7 to -22.4) for intestinal obstruction. For patients without frailty, the mean differences (95%CI) in days alive and out of hospital were: -0.18 (-1.56-1.20) for appendicitis; 0.93 (0.48-1.39) for gallstone disease; 5.35 (-2.56-13.28) for diverticular disease; 2.26 (0.37-4.15) for hernia; and 18.2 (14.8-22.47) for intestinal obstruction. Emergency surgery and non-emergency surgery strategies led to similar average days alive and out of hospital at 90 days for five acute conditions. The comparative effectiveness of emergency surgery and non-emergency surgery strategies for these conditions may be modified by patient factors

Decision making in interhospital transport of critically ill patients: national questionnaire survey among critical care physicians

Objective: This study assessed the relative importance of clinical and transport-related factors in physicians' decision-making regarding the interhospital transport of critically ill patients. Methods: The medical heads of all 95 ICUs in The Netherlands were surveyed with a questionnaire using 16 case vignettes to evaluate preferences for transportability; 78 physicians (82%) participated. The vignettes varied in eight factors with regard to severity of illness and transport conditions. Their relative weights were calculated for each level of the factors by conjoint analysis and expressed in beta. The reference value (beta = 0) was defined as the optimal conditions for critical care transport; a negative beta indicated preference against transportability. Results: The type of escorting personnel (paramedic only: beta = 3.1) and transport facilities (standard ambulance beta = 1.21) had the greatest negative effect on preference for transportability. Determinants reflecting severity of illness were of relative minor importance (dose of noradrenaline beta = 0.6, arterial oxygenation beta = 0.8, level of peep beta = 0.6). Age, cardiac arrhythmia, and the indication for transport had no significant effect. Conclusions: Escorting personnel and transport facilities in interhospital transport were considered as most important by intensive care physicians in determining transportability. When these factors are optimal, even severely critically ill patients are considered able to undergo transport. Further clinical research should tailor transport conditions to optimize the use of expensive resources in those inevitable road trip

A conceptual cellular interaction model of left ventricular remodelling post-MI: dynamic network with exit-entry competition strategy

Abstract Background Progressive remodelling of the left ventricle (LV) following myocardial infarction (MI) is an outcome of spatial-temporal cellular interactions among different cell types that leads to heart failure for a significant number of patients. Cellular populations demonstrate temporal profiles of flux post-MI. However, little is known about the relationship between cell populations and the interaction strength among cells post-MI. The objective of this study was to establish a conceptual cellular interaction model based on a recently established graph network to describe the interaction between two types of cells. Results We performed stability analysis to investigate the effects of the interaction strengths, the initial status, and the number of links between cells on the cellular population in the dynamic network. Our analysis generated a set of conditions on interaction strength, structure of the network, and initial status of the network to predict the evolutionary profiles of the network. Computer simulations of our conceptual model verified our analysis. Conclusions Our study introduces a dynamic network to model cellular interactions between two different cell types which can be used to model the cellular population changes post-MI. The results on stability analysis can be used as a tool to predict the responses of particular cell populations

Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial.

PURPOSE: Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS). METHODS: This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers. RESULTS: No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO2/FiO2 < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365. CONCLUSIONS: Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population.National Institutes of Health, Innovate UK, and Athersys, In