Autophagy is a catabolic process by which cells can dispose of damaged content and intracellular microorganisms. Recent evidence implicates autophagy as a crucial repair process necessary to recover ...from critical illness-induced organ failure. Withholding parenteral nutrition in the acute phase of critical illness activates autophagy and enhances recovery. Several registered drugs have autophagy-stimulating properties, but all lack specificity and none has been investigated in critically ill patients for this purpose.
Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have ...developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.
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•A postmortem bedside surgical procedure was developed for COVID-19 and control patients•Ciliated cells are the main target cell type for SARS-CoV-2 in the respiratory mucosa•Sustentacular cells (non-neuronal) are the main target cell type in the olfactory mucosa•No evidence for infection of olfactory sensory neurons or olfactory bulb parenchyma
Postmortem samples of respiratory and olfactory mucosa and whole olfactory bulbs are harvested immediately after the death of COVID-19 patients revealing ciliated cells and sustentacular cells but not olfactory sensory neurons as the main target cell types for SARS-CoV-2 infection and replication.
Purpose
To assess the independent association between ICU-acquired neuromuscular complications and 5-year mortality and morbidity. To explore the optimal threshold of the Medical Research Council ...(MRC) sum score, assessing weakness, for the prediction of 5-year outcomes.
Methods
Sub-analyses of a prospective, 5-year follow-up study including 883 EPaNIC patients (Early versus Late Parenteral Nutrition in Intensive Care) (Clinicaltrials.gov:NCT00512122), systematically screened in ICU for neuromuscular complications with MRC sum score (‘MRC-cohort’,
N
= 600), electrophysiology on day 8 ± 1 to quantify compound muscle action potential (‘CMAP-cohort’,
N
= 689), or both (‘MRC&CMAP-cohort’,
N
= 415). Associations between ICU-acquired neuromuscular complications and 5-year mortality, hand-grip strength (HGF, %predicted), 6-min-walk distance (6-MWD, %predicted) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36) at 5-years were assessed with Cox regression and linear regression, adjusted for confounders. The optimal threshold for MRC at ICU discharge to predict 5-year outcomes was determined by martingale residual plots (survival) and scatterplots (morbidity).
Results
Both lower MRC sum score at ICU discharge, indicating less strength HR, per-point-increase: 0.946 (95% CI 0.928–0.968),
p
= 0.001, and abnormal CMAP, indicating nerve/muscle dysfunction HR: 1.568 (95% CI 1.165–2.186),
p
= 0.004, independently associated with increased 5-year mortality. In the MRC&CMAP-cohort, MRC HR: 0.956 (95% CI 0.934–0.980),
p
= 0.001 but not CMAP HR: 1.478 (95% CI 0.875–2.838),
p
= 0.088 independently associated with 5-year mortality. Among 205 survivors, low MRC independently associated with low HGF 0.866 (95% CI 0.237–1.527),
p
= 0.004, low 6-MWD 105.1 (95% CI 12.1–212.9),
p
= 0.043 and low PF-SF-36 − 0.119 (95% CI − 0.186 to − 0.057),
p
= 0.002, whereas abnormal CMAP did not correlate with these morbidity endpoints. Exploratory analyses suggested that MRC ≤ 55 best predicted poor long-term morbidity and mortality. Both MRC ≤ 55 and abnormal CMAP independently associated with 5-year mortality.
Conclusions
ICU-acquired neuromuscular complications may impact 5-year morbidity and mortality. MRC sum score, even if slightly reduced, may affect long-term mortality, strength, functional capacity and physical function, whereas abnormal CMAP only related to long-term mortality.
Purpose
To provide a practical overview of the management of the potential organ donor in the intensive care unit.
Methods
Seven areas of donor management were considered for this review: hemodynamic ...management; fluids and electrolytes; respiratory management; endocrine management; temperature management; anaemia and coagulation; infection management. For each subchapter, a narrative review was conducted.
Results and conclusions
Most elements in the current recommendations and guidelines are based on pathophysiological reasoning, epidemiological observations, or extrapolations from general ICU management strategies, and not on evidence from randomized controlled trials. The cardiorespiratory management of brain-dead donors is very similar to the management of critically ill patients, and the same applies to the management of anaemia and coagulation. Central diabetes insipidus is of particular concern, and should be diagnosed based on clinical criteria. Depending on the degree of vasopressor dependency, it can be treated with intermittent desmopressin or continuous vasopressin, intravenously. Temperature management of the donor is an area of uncertainty, but it appears reasonable to strive for a core temperature of > 35 °C. The indications and controversies regarding endocrine therapies, in particular thyroid hormone replacement therapy, and corticosteroid therapy, are discussed. The potential donor should be assessed clinically for infections, and screening tests for specific infections are an essential part of donor management. Although the rate of infection transmission from donor to receptor is low, certain infections are still a formal contraindication to organ donation. However, new antiviral drugs and strategies now allow organ donation from certain infected donors to be done safely.
Although numerous observational studies associated underfeeding with poor outcome, recent randomized controlled trials (RCTs) have shown that early full nutritional support does not benefit ...critically ill patients and may induce dose-dependent harm. Some researchers have suggested that the absence of benefit in RCTs may be attributed to overrepresentation of patients deemed at low nutritional risk, or to a too low amino acid versus non-protein energy dose in the nutritional formula. However, these hypotheses have not been confirmed by strong evidence. RCTs have not revealed any subgroup benefiting from early full nutritional support, nor benefit from increased amino acid doses or from indirect calorimetry-based energy dosing targeted at 100% of energy expenditure. Mechanistic studies attributed the absence of benefit of early feeding to anabolic resistance and futile catabolism of extra provided amino acids, and to feeding-induced suppression of recovery-enhancing pathways such as autophagy and ketogenesis, which opened perspectives for fasting-mimicking diets and ketone supplementation. Yet, the presence or absence of an anabolic response to feeding cannot be predicted or monitored and likely differs over time and among patients. In the absence of such monitor, the value of indirect calorimetry seems obscure, especially in the acute phase of illness. Until now, large feeding RCTs have focused on interventions that were initiated in the first week of critical illness. There are no large RCTs that investigated the impact of different feeding strategies initiated after the acute phase and continued after discharge from the intensive care unit in patients recovering from critical illness.
Glucose management in intensive care unit (ICU) patients has been a matter of debate for almost two decades. Compared to intermittent monitoring systems, continuous glucose monitoring (CGM) can offer ...benefit in the prevention of severe hyperglycemia and hypoglycemia by enabling insulin infusions to be adjusted more rapidly and potentially more accurately because trends in glucose concentrations can be more readily identified. Increasingly, it is apparent that a single glucose target/range may not be optimal for all patients at all times and, as with many other aspects of critical care patient management, a personalized approach to glucose control may be more appropriate. Here we consider some of the evidence supporting different glucose targets in various groups of patients, focusing on those with and without diabetes and neurological ICU patients. We also discuss some of the reasons why, despite evidence of benefit, CGM devices are still not widely employed in the ICU and propose areas of research needed to help move CGM from the research arena to routine clinical use.
Purpose
Early diagnosis of acute kidney injury (AKI) remains a major challenge. We developed and validated AKI prediction models in adult ICU patients and made these models available via an online ...prognostic calculator. We compared predictive performance against serum neutrophil gelatinase-associated lipocalin (NGAL) levels at ICU admission.
Methods
Analysis of the large multicenter EPaNIC database. Model development (
n
= 2123) and validation (
n
= 2367) were based on clinical information available (1) before and (2) upon ICU admission, (3) after 1 day in ICU and (4) including additional monitoring data from the first 24 h. The primary outcome was a comparison of the predictive performance between models and NGAL for the development of any AKI (AKI-123) and AKI stages 2 or 3 (AKI-23) during the first week of ICU stay.
Results
Validation cohort prevalence was 29% for AKI-123 and 15% for AKI-23. The AKI-123 model before ICU admission included age, baseline serum creatinine, diabetes and type of admission (medical/surgical, emergency/planned) and had an AUC of 0.75 (95% CI 0.75–0.75). The AKI-23 model additionally included height and weight (AUC 0.77 (95% CI 0.77–0.77)). Performance consistently improved with progressive data availability to AUCs of 0.82 (95% CI 0.82–0.82) for AKI-123 and 0.84 (95% CI 0.83–0.84) for AKI-23 after 24 h. NGAL was less discriminant with AUCs of 0.74 (95% CI 0.74–0.74) for AKI-123 and 0.79 (95% CI 0.79–0.79) for AKI-23.
Conclusions
AKI can be predicted early with models that only use routinely collected clinical information and outperform NGAL measured at ICU admission. The AKI-123 models are available at
http://akipredictor.com/
.
Trial registration
Clinical Trials.gov NCT00512122
Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral ...Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition PN) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres.
In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate.
With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically ill patients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition.
Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness.
UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.
SEE PDF We first performed a time course analysis in a propensity-score-matched subset of 110 patients (Table 1), to study whether late-PN enhanced ketogenesis and to identify the day of maximal ...effect (if any) (Fig. 1b). ...we studied a potential mediator role of this 3HB effect on time to live ICU discharge, live ICU discharge within 8 days, and incidence of new infection through multivariable Cox, respectively logistic regression analysis, adjusted for baseline risk factors (age, BMI, malignancy, APACHEII score, NRS score, diagnostic group). ...withholding early parenteral nutrition enhanced ketogenesis in critically ill adults, but in contrast to children, increased ketones did not explain the improved outcome. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
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