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Background: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19.Methods: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement.Discussion: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome.Trial Registration: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Objective: Tight blood glucose control (TGC) in critically ill patients is difficult and labor intensive, resulting in poor efficacy of glycemic control and increased hypoglycemia rate. The LOGIC-Insulin computerized algorithm has been developed to assist nurses in titrating insulin to maintain blood glucose levels at 80-110 mg/dL (normoglycemia) and to avoid severe hypoglycemia (<40 mg/dL). The objective was to validate clinically LOGIC-Insulin relative to TGC by experienced nurses.Research Design and Methods: The investigator-initiated LOGIC-1 study was a prospective, parallel-group, randomized, controlled clinical trial in a single tertiary referral center. A heterogeneous mix of 300 critically ill patients were randomized, by concealed computer allocation, to either nurse-directed glycemic control (Nurse-C) or algorithm-guided glycemic control (LOGIC-C). Glycemic penalty index (GPI), a measure that penalizes both hypoglycemic and hyperglycemic deviations from normoglycemia, was the efficacy outcome measure, and incidence of severe hypoglycemia (<40 mg/dL) was the safety outcome measure.Results: Baseline characteristics of 151 Nurse-C patients and 149 LOGIC-C patients and study times did not differ. The GPI decreased from 12.4 (interquartile range 8.2-18.5) in Nurse-C to 9.8 (6.0-14.5) in LOGIC-C (P < 0.0001). The proportion of study time in target range was 68.6 ± 16.7% for LOGIC-C patients versus 60.1 ± 18.8% for Nurse-C patients (P = 0.00016). The proportion of severe hypoglycemic events was decreased in the LOGIC-C group (Nurse-C 0.13%, LOGIC-C 0%; P = 0.015) but not when considered as a proportion of patients (Nurse-C 3.3%, LOGIC-C 0%; P = 0.060). Sampling interval was 2.2 ± 0.4 h in the LOGIC-C group versus 2.5 ± 0.5 h in the Nurse-C group (P < 0.0001).Conclusions: Compared with expert nurses, LOGIC-Insulin improved efficacy of TGC without increasing rate of hypoglycemia. [ABSTRACT FROM AUTHOR]

Rationale: Early parenteral nutrition to supplement insufficient enteral feeding during intensive care (early PN) delays recovery as compared with withholding parenteral nutrition for 1 week (late PN). Objectives: To assess whether deleterious effects of early PN relate to severity of illness or to the dose or type of macronutrients. Methods: Secondary analyses of a randomized controlled trial (EPaNIC; n = 4,640) performed in seven intensive care units from three departments in two Belgian hospitals. In part 1, all patients were included to assess the effect of the randomized allocation to early PN or late PN in subgroups of patients with increasing-on-admission severity of illness. In part 2, observationally, the association of the amount and type of macronutrients with recovery was documented in those patient cohorts still present in intensive care on Days 3, 5, 7, 10, and 14. Measurements and Main Results: The primary end point was time to live discharge from the intensive care unit. For part 1, a secondary end point, acquisition of new infections, was also analyzed. All statistical analyses were performed by univariable and adjusted multivariable methods. In none of the subgroups defined by type or severity of illness was a beneficial effect of early PN observed. The lowest dose of macronutrients was associated with the fastest recovery and any higher dose, administered parenterally or enterally, was associated with progressively more delayed recovery. The amount of proteins/amino acids rather than of glucose appeared to explain delayed recovery with early feeding. Conclusions: Early combined parenteral/enteral nutrition delayed recovery irrespective of severity of critical illness. No dose or type of macronutrient was found to be associated with improved outcome. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122). [ABSTRACT FROM AUTHOR]

Context: A large randomized controlled trial revealed that tight glucose control (TGC) to age-adjusted normoglycemia (50-80 mg/dL at age <1 year and 70-100 mg/dL at age 1-16 years) reduced intensive care morbidity and mortality compared with usual care (UC), but increased hypoglycemia (≤40 mg/dL) (25% vs 1%).Objective: As both hyperglycemia and hypoglycemia may adversely affect the developing brain, long-term follow-up was required to exclude harm and validate short-term benefits of TGC.Design, Setting, and Patients: A prospective, randomized controlled trial of 700 patients aged 16 years or younger who were admitted to the pediatric intensive care unit (ICU) of the University Hospitals in Leuven, Belgium, between October 2004 and December 2007. Follow-up was scheduled after 3 years with infants assessed at 4 years old between August 2008 and January 2012. Assessment was performed blinded for treatment allocation, in-hospital (83%) or at home/school (17%). For comparison, 216 healthy siblings and unrelated children were tested.Main Outcome Measures: Intelligence (full-scale intelligence quotient [IQ]), as assessed with age-adjusted tests (Wechsler IQ scales). Further neurodevelopmental testing encompassed tests for visual-motor integration (Beery-Buktenica Developmental Test of Visual-Motor Integration); attention, motor coordination, and executive functions (Amsterdam Neuropsychological Tasks); memory (Children's Memory Scale); and behavior (Child Behavior Checklist).Results: Sixteen percent of patients declined participation or could not be reached (n = 113), resulting in 569 patients being alive and testable at follow-up. At a median (interquartile range [IQR]) of 3.9 (3.8-4.1) years after randomization, TGC in the ICU did not affect full-scale IQ score (median [IQR], 88.0 [74.0-100.0] vs 88.5 [74.3-99.0] for UC; P = .73) and had not increased incidence of poor outcomes (death or severe disability precluding neurocognitive testing: 19% [68/349] vs 18% [63/351] with UC; risk-adjusted odds ratio, 0.93; 95% CI, 0.60-1.46; P = .72). Other scores for intelligence, visual-motor integration, and memory also did not differ between groups. Tight glucose control improved motor coordination (9% [95% CI, 0%-18%] to 20% [95% CI, 5%-35%] better, all P ≤ .03) and cognitive flexibility (19% [95% CI, 5%-33%] better, P = .02). Brief hypoglycemia evoked by TGC was not associated with worse neurocognitive outcome.Conclusion: At follow-up, children who had been treated with TGC during an ICU admission did not have a worse measure of intelligence than those who had received UC.Trial Registration: clinicaltrials.gov Identifier NCT00214916. [ABSTRACT FROM AUTHOR]

Background Critical illness results in activation of the hypothalamic–pituitary–adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRα, of which two splice variants involving the hormone-binding domain exist, GRβ and GR-P. Objective To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. Design and methods We assessed mRNA expression of the GRα, GRβ and GR-P variants in liver ( n = 58) and muscle ( n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. Results GRα and GR-P mRNA constituted 87 ± 8% and 13 ± 2%, respectively, of total GR mRNA in liver. GRβ mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (α = 96 ± 11%, P = 3·9 ± 0·4%, β = 0·010 ± 0·002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle ( P < 0·001 for all). Serum cortisol levels were negatively associated with liver GRα and muscle GR-P expression ( P < 0·05). mRNA expression of both liver GRα and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids ( P < 0·01). Conclusion We demonstrate the presence of GRα and GR-P mRNA in liver and of GRα, GRβ and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids. [ABSTRACT FROM AUTHOR]

The nutrition dose truly absorbed by a patient is crucial information in the management or the investigation of nutrition during critical illness. In the present issue of Critical Care, assessment of nutritional losses in stools was studied. These losses together with enteral nutrition lost in gastric fluids and enteral nutrition prescribed but never infused make up the difference between the dose supposedly given to a patient and the amount effectively taken up. Additionally, the optimal dosing and timing of nutrition during critical illness are still debated. When enteral nutrition is insufficient, the options are limited. [ABSTRACT FROM AUTHOR]