Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial.

Importance: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial. Objective: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023. Interventions: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days. Results: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital. Conclusion and Relevance: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg. Trial Registration: ClinicalTrials.gov Identifier: NCT04425031.

Mild induced hypothermia and coagulation and platelet function in patients with septic shock: Secondary outcome of a randomized trial.

Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial. Adult patients with septic shock who required mechanical ventilation from eight intensive care units in Denmark were randomly assigned to mild induced hypothermia for 24 h or routine thermal management. Viscoelastography and platelet aggregation were assessed at trial inclusion, after 12 h of thermal management, and 24 h after inclusion. A total of 326 patients were randomized to mild induced hypothermia (n = 163) or routine thermal management (n = 163). Mild induced hypothermia slightly prolonged activated partial thromboplastin time and thrombus initiation time (R time 8.0 min [interquartile range, IQR 6.6-11.1] vs. 7.2 min [IQR 5.8-9.2]; p = .004) and marginally inhibited thrombus propagation (angle 68° [IQR 59-73] vs. 71° [IQR 63-75]; p = .014). The effect was also present after 24 h. Clot strength remained unaffected (MA 71 mm [IQR 66-76] with mild induced hypothermia vs. 72 mm (65-77) with routine thermal management, p = .9). The proportion of patients with hyperfibrinolysis was not affected (0.7% vs. 3.3%; p = .19), but the proportion of patients with no fibrinolysis was high in the mild hypothermia group (8.8% vs. 40.4%; p < .001). The mild induced hypothermia group had lower platelet aggregation: ASPI 85U (IQR 50-113) versus 109U (IQR 74-148, p < .001), ADP 61U (IQR 40-83) versus 79 U (IQR 54-101, p < .001), TRAP 108 (IQR 83-154) versus 119 (IQR 94-146, p = .042) and COL 50U (IQR 34-66) versus 67U (IQR 46-92, p < .001). In patients with septic shock, mild induced hypothermia slightly impaired clot initiation, but did not change clot strength. Platelet aggregation was slightly impaired. The effect of mild induced hypothermia on viscoelastography and platelet aggregation was however not in a range that would have clinical implications. We did observe a substantial reduction in fibrinolysis.

The Nordic perioperative and intensive care registries-Collaboration and research possibilities.

BACKGROUND: The Nordic perioperative and intensive care registries have been built up during the last 25 years to improve quality in intensive and perioperative care. We aimed to describe the Nordic perioperative and intensive care registries and to highlight possibilities and challenges in future research collaboration between these registries. MATERIAL AND METHOD: We present an overview of the following Nordic registries: Swedish Perioperative Registry (SPOR), the Danish Anesthesia Database (DAD), the Finnish Perioperative Database (FIN-AN), the Icelandic Anesthesia Database (IS-AN), the Danish Intensive Care Database (DID), the Swedish Intensive Care Registry (SIR), the Finnish Intensive Care Consortium, the Norwegian Intensive Care and Pandemic Registry (NIPaR), and the Icelandic Intensive Care Registry (IS-ICU). RESULTS: Health care systems and patient populations are similar in the Nordic countries. Despite certain differences in data structure and clinical variables, the perioperative and intensive care registries have enough in common to enable research collaboration. In the future, even a common Nordic registry could be possible. CONCLUSION: Collaboration between the Nordic perioperative and intensive care registries is both possible and likely to produce research of high quality. Research collaboration between registries may have several add-on effects and stimulate international standardization regarding definitions, scoring systems, and benchmarks, thereby improving overall quality of care.

Goal directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload: A trial protocol for a randomised, blinded trial (GODIF trial).

BACKGROUND: Fluid overload is a risk factor for mortality in intensive care unit (ICU) patients. Administration of loop diuretics is the predominant treatment of fluid overload, but evidence for its benefit is very uncertain when assessed in a systematic review of randomised clinical trials. The GODIF trial will assess the benefits and harms of goal directed fluid removal with furosemide versus placebo in ICU patients with fluid overload. METHODS: An investigator-initiated, international, randomised, stratified, blinded, parallel-group trial allocating 1000 adult ICU patients with fluid overload to infusion of furosemide versus placebo. The goal is to achieve a neutral fluid balance. The primary outcome is days alive and out of hospital 90 days after randomisation. Secondary outcomes are all-cause mortality at day 90 and 1-year after randomisation; days alive at day 90 without life support; number of participants with one or more serious adverse events or reactions; health-related quality of life and cognitive function at 1-year follow-up. A sample size of 1000 participants is required to detect an improvement of 8% in days alive and out of hospital 90 days after randomisation with a power of 90% and a risk of type 1 error of 5%. The conclusion of the trial will be based on the point estimate and 95% confidence interval; dichotomisation will not be used. CLINICALTRIALS: gov identifier: NCT04180397. PERSPECTIVE: The GODIF trial will provide important evidence of possible benefits and harms of fluid removal with furosemide in adult ICU patients with fluid overload.

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

BACKGROUND: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. METHODS: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONS: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).

Preferences for the measurement and supplementation of magnesium, phosphate and zinc in ICUs: The international WhyTrace survey.

BACKGROUND: Patients admitted to the Intensive Care Unit (ICU) often have low magnesium, phosphate and zinc levels. Monitoring of serum concentrations and supplementation may be important, but there is no consensus on optimal practice. The objective of the WhyTrace survey was to describe current practice regarding the measurement and supplementation of magnesium, phosphate and zinc in ICUs. METHODS: A 54-item electronic questionnaire was developed in accordance with SURGE, SUrvey Reporting GuidelinE, to address international clinical practice in the ICU. National investigators recruited ICUs in ten countries with one physician responding per ICU using a unique e-mail distributed survey-link. RESULTS: The questionnaire was sent to clinicians in 336 ICUs of whom 283 (84%) responded. In 62% of the ICUs, a standard procedure was in place regarding the measurement of serum magnesium levels, in 58% for phosphate and in 9% for zinc. Zinc was never or rarely measured in 64% of ICUs. The frequency of requesting serum levels varied from twice daily to once weekly. Regarding supplementation, 66% of ICUs had a standard procedure for magnesium, 63% for phosphate and 15% for zinc. Most procedures recommended supplementation when serum levels were below the lower reference level, but some used the upper reference levels as the threshold for supplementation and others decided on a case-by-case basis. CONCLUSION: The practice of measuring and supplementing magnesium, phosphate and zinc differed substantially between ICUs. Our findings indicate that there is a need for high-quality prospective data on frequencies of measurements, treatment goals and effects of supplementation on patient-important outcomes.

Nationwide Incidence and Outcomes of Patients With Coronavirus Disease 2019 Requiring Intensive Care in Iceland.

OBJECTIVES: To determine the nationwide demographics and hospital mortality of patients with severe acute respiratory syndrome coronavirus 2 infection requiring admission to the ICU for coronavirus disease 2019 in Iceland. DESIGN: Prospective observational study. SETTING: All ICUs in Iceland (Landspitali University Hospital and Akureyri Regional Hospital). PATIENTS: All patients admitted to the ICU for management of coronavirus disease 2019 between March 14, 2020, and April 13, 2020, with follow-up through May 5, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 27 patients were admitted to the ICU for coronavirus disease 2019 out of 1,788 severe acute respiratory syndrome coronavirus 2 positive cases, rendering an overall admission ratio of 1.5% (95% CI, 1.0-2.2%). The population rate of ICU admission for coronavirus disease 2019 was 7.4 (95% CI, 4.9-10.8) admissions per 100,000 individuals. The hospital mortality of patients admitted to the ICU was 15% (95% CI, 4-34%), and the mortality of patients receiving mechanical ventilation was 19% (95% CI, 4-46%). CONCLUSIONS: We report a lower overall ratio of ICU admissions for coronavirus disease 2019 among severe acute respiratory syndrome coronavirus 2 positive patients and a lower hospital mortality for patients treated in the ICU for coronavirus disease 2019 compared with initial reports from Italy and China. Our results could be explained by the early adoption of widespread testing and a successful national response to the pandemic.

[First case of COVID-19 treated with tocilizumab in Iceland]. / Fyrsta meðferð með tocilizumab við COVID-19 hérlendis - sjúkratilfelli

A gentleman in his early fifties became ill with flu-like symptoms after vacationing abroad and was diagnosed with COVID-19 after returning to Iceland. A few days later he was admitted to the University Hospital, Landspitali, due to worsening respiratory symptoms and severe fatigue. A computed tomography scan of lthe lungs showed diffuse bilateral consolidations and ground glass changes. He developed respiratory failure and was transferred to the intensive care unit where he received further treatment, including tocilizumab (IL-6 receptor inhibitor). He subsequently showed clinical improvement and did not require endotracheal intubation.

The handling oxygenation targets in the intensive care unit (HOT-ICU) trial: Detailed statistical analysis plan.

BACKGROUND: No solid evidence exists on optimal oxygenation targets in intensive care patients. The handling oxygenation targets in the intensive care unit (HOT-ICU) trial assesses the effects of a targeted arterial oxygen tension of 8 vs 12 kPa on 90-day mortality in acutely admitted adult patients with hypoxaemic respiratory failure. This article describes the detailed statistical analysis plan for the predefined outcomes and supplementary analyses in the HOT-ICU trial. METHODS: The trial will include 2928 patients to be able to detect or reject a true 20% relative risk reduction in the primary outcome of 90-day all-cause mortality with an α of 5% and a ß of 10%. Analyses of the primary and secondary outcomes will be conducted according to the intention-to-treat principle and adjusted for stratification variables. The primary outcome and dichotomous secondary outcomes will be analysed using a generalised linear model with a log-link and binomial error distribution. For the primary outcome, a 95% confidence interval (CI) not including 1.00 for the risk ratio will be considered statistically significant. Continuous secondary outcomes will be analysed using a generalised linear model or nonparametric test. CIs adjusted for the multiple secondary outcomes not including the null effect will be considered statistically significant. One planned interim analysis has been conducted. CONCLUSIONS: The HOT-ICU trial and the pre-planned statistical analyses are designed to minimise bias and produce high quality data on the effects of a lower vs a higher oxygenation target throughout ICU admission in acutely admitted adult patients with hypoxaemic respiratory failure. REGISTRATION: ClinicalTrials.gov identifier: NCT03174002, date of registration: June 2, 2017. European clinical trials database, EudraCT number 2017-000632-34.

Biomarker-assisted identification of sepsis-related acute liver impairment: a frequent and deadly condition in critically ill patients.

Background The prognostic impact of mild/moderate liver impairment among critically ill patients is not known. We aimed to determine whether acute liver impairment, as measured by several biomarkers, (i) is frequent, (ii) influences prognosis and (iii) to determine whether such an effect is specific for infected critically ill patients. Methods A biomarker and clinical cohort study based on a randomized controlled trial. All-cause mortality was the primary endpoint. Biomarkers hyaluronic acid (HA), bilirubin, albumin, alkaline phosphatase and the international normalized ratio (INR) were determined. Multivariable statistics were applied to estimate risk increase according to liver biomarker increase at baseline and the model was adjusted for age, APACHE II, severe sepsis/septic shock vs. milder infection, chronic alcohol abuse Charlson's co-morbidity index, cancer disease, surgical or medical patient, body mass index, sex, estimated glomerular filtration rate, mechanical ventilation and the other biomarkers. Time-to-event graphs were used. The patients were critically ill patients (n = 1096) from nine mixed medical/surgical intensive care units without known hepatobiliary disease. Results HA levels differed between infected patients (median 210.8 ng/mL [IQR: 93.2-556.6]) vs. the non-infected (median 56.8 ng/mL [IQR: 31.9-116.8], p < 0.001). Serum HA quartiles 2, 3 and 4 were independent predictors of 90-day all-cause mortality for the entire population (infected and non-infected). However, the signal was driven by the infected patients (positive interaction test, no signal in non-infected patients). Among infected patients, HA quartiles corresponded directly to the 90-day risk of dying: 1st quartile: 57/192 = 29.7%, 2nd quartile: 84/194 = 43.3%, 3rd quartile: 90/193 = 46.6%, 4th quartile: 101/192 = 52.3 %, p for trend: <0.0001. This finding was confirmed in adjusted analyses: hazard ratio vs. 1st quartile: 2nd quartile: 1.3 [0.9-1.8], p = 0.14, 3rd quartile: 1.5 [1.1-2.2], p = 0.02, 4th quartile: 1.9 [1.3-2.6], p < 0.0001). High bilirubin was also an independent predictor of mortality. Conclusions Among infected critically ill patients, subtle liver impairment, (elevated HA and bilirubin), was associated with a progressive and highly increased risk of death for the patient; this was robust to adjustment for other predictors of mortality. HA can identify patients at high risk.

Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU)-Protocol for a randomised clinical trial comparing a lower vs a higher oxygenation target in adults with acute hypoxaemic respiratory failure.

BACKGROUND: Acutely ill adults with hypoxaemic respiratory failure are at risk of life-threatening hypoxia, and thus oxygen is often administered liberally. Excessive oxygen use may, however, increase the number of serious adverse events, including death. Establishing the optimal oxygenation level is important as existing evidence is of low quality. We hypothesise that targeting an arterial partial pressure of oxygen (PaO2 ) of 8 kPa is superior to targeting a PaO2 of 12 kPa in adult intensive care unit (ICU) patients with acute hypoxaemic respiratory failure. METHODS: The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is an outcome assessment blinded, multicentre, randomised, parallel-group trial targeting PaO2 in acutely ill adults with hypoxaemic respiratory failure within 12 hours after ICU admission. Patients are randomised 1:1 to one of the two PaO2 targets throughout ICU stay until a maximum of 90 days. The primary outcome is 90-day mortality. Secondary outcomes are serious adverse events in the ICU, days alive without organ support and days alive out of hospital in the 90-day period; mortality, health-related quality-of-life at 1-year follow-up as well as 1-year cognitive and pulmonary function in a subgroup; and an overall health economic analysis. To detect or reject a 20% relative risk reduction, we aim to include 2928 patients. An interim analysis is planned after 90-day follow-up of 1464 patients. CONCLUSION: The HOT-ICU trial will test the hypothesis that a lower oxygenation target reduces 90-day mortality compared with a higher oxygenation target in adult ICU patients with acute hypoxaemic respiratory failure.

Low Incidence of Biphasic Allergic Reactions in Patients Admitted to Intensive Care after Anaphylaxis.

BACKGROUND: Biphasic allergic reactions-recurrence of allergy symptoms after a symptom-free period-are reported to occur in 1 to 23% of allergic reactions. Patients admitted to an intensive care unit after anaphylaxis potentially have more severe reactions and a higher risk of biphasic allergic reactions. The purpose of this study was to examine incidence, triggers, symptoms, and treatment of biphasic allergic reactions, in patients admitted to an intensive care unit. METHODS: Records of patients admitted to intensive care units with anaphylaxis from 2011 to 2014 were reviewed. Only patients with a reaction fulfilling internationally accepted criteria for anaphylaxis were included. Potential biphasic allergic reactions, defined as renewed allergy symptoms 1 to 72 h after initial symptoms had resolved, without further exposure to the trigger, were identified. RESULTS: A total of 83 cases of anaphylaxis were identified, and the most frequent triggers were medications (58 of 83 [70%]). Skin symptoms occurred in 69 (83%) cases, and circulatory and respiratory symptoms in 48 (58%) and 45 (54%) cases, respectively. In total, 82 (99%), 80 (96%), and 66 (80%) were treated with antihistamines, corticosteroids, and epinephrine, respectively. Only 10 patients presented with one or more relevant symptoms after the initial allergic reaction. Of these, three were possible, and one was a probable biphasic allergic reaction, giving a total incidence of 4 of 83 (4.8% [95% CI, 1.6 to 12.5]) or 1 of 83 (1.2% [95% CI, 0.1 to 7.46]), respectively. All cases were mild, presenting with skin symptoms only, occurring on average 14 h after initial reactions. CONCLUSIONS: The authors observed a low incidence of biphasic reactions in patients admitted to an intensive care unit after anaphylaxis, at a rate equivalent to that reported in other patient groups.

Predicting recovery from acute kidney injury in critically ill patients: development and validation of a prediction model.

OBJECTIVE: Intensive care unit (ICU) patients with acute kidney injury (AKI) who recover kidney function within 28 days experience less severe chronic kidney impairment and have increased long term survival. The aims of this study were to develop and validate a risk prediction model to identify these patients. DESIGN: Observational study with development and validation of a risk prediction model. SETTING: Nine academic ICUs in Denmark. PARTICIPANTS: Development cohort of critically ill patients with AKI at ICU admission from the Procalcitonin and Survival Study cohort (n = 568), validation cohort of adult patients with AKI admitted to two university hospitals in Denmark in 2012-13 (n = 766). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Recovery of kidney function was defined as living for 5 consecutive days with no renal replacement therapy and with creatinine plasma levels below 1.5-fold the levels determined before ICU admission. RESULTS: A total of 266 patients (46.8%) recovered prior kidney function in the development cohort, and 453 patients (59.1%) in the validation cohort. The prediction model included elevation in creatinine, urinary output, sex and age. In the validation cohort, 69 patients (9.0%) had a predicted chance of recovery < 25%, and their observed rate of recovery was 21.5%. This observed rate of recovery was 81.7% among the 325 patients who had a predicted chance > 75%. The area under the receiver operations curves for predicting recovery in the validation cohort was 73.1%. CONCLUSION: We constructed and validated a simple model that can predict the chance of recovery from AKI in critically ill patients.

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock. METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116. FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]). INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock. FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

Endothelial Damage Signals Refractory Acute Kidney Injury in Critically Ill Patients.

Critically ill patients with acute kidney injury (AKI) are heterogeneous on pathophysiology and prognosis. The role of endothelial damage in the pathogenesis of refractory AKI has not been clarified. The aim was to determine if biomarkers of endothelial damage, independently of the inflammatory insult on the kidney, can predict recovery of acute kidney injury. METHODS: From the "Procalcitonin And Survival Study" multicenter intensive care unit cohort, followed for 28 days after admission, we included patients without chronic kidney disease, who survived >24 h after admission and with plasma samples at admission available for biomarker analysis. We defined AKI by the "Kidney Disease: Improving Global Outcomes" guidelines and recovery of prior kidney function as alive for five consecutive days after admission with no need for renal replacement therapy and creatinine levels consistently below ×1.5 the level before admission. We adjusted models for age, gender, vasopressor treatment, mechanical ventilation and levels of creatinine, procalcitonin, platelets, and bilirubin at admission. RESULTS: Of a total 213 with AKI at admission, 99 recovered prior kidney function during follow-up. Endothelial damage on admission, measured by Soluble Thrombomodulin (sTM), was the strongest predictor of a reduced chance of recovery of prior kidney function (sTM in the highest vs. three lower quartiles hazard ratio 0.39; 95% confidence interval 0.21-0.73, P = 0.003). In contrast, the degree of the initial inflammatory insult on the kidney, measured by neutrophil gelatinase-associated lipocalin (NGAL), failed to predict this outcome (NGAL in highest vs. three lower quartiles hazard ratio = 1.20; 95% CI 0.72-2.00; P = 0.48). Procalcitonin, a specific marker of bacterial infection, was also associated with the rate of recovery (PCT in highest vs. three lower quartiles hazard ratio = 0.59; 95% CI 0.36-0.98; P = 0.04). CONCLUSION: AKI patients with high levels of sTM had a reduced chance of recovering prior renal function. Our findings support disintegration of the endothelium as a critical point in the pathogenesis of AKI that is refractory to treatment.

Prediction of non-recovery from ventilator-demanding acute respiratory failure, ARDS and death using lung damage biomarkers: data from a 1200-patient critical care randomized trial.

BACKGROUND: It is unclear whether biomarkers of alveolar damage (surfactant protein D, SPD) or conductive airway damage (club cell secretory protein 16, CC16) measured early after intensive care admittance are associated with one-month clinical respiratory prognosis. If patients who do not recover respiratory function within one month can be identified early, future experimental lung interventions can be aimed toward this high-risk group. We aimed to determine, in a heterogenous critically ill population, whether baseline profound alveolar damage or conductive airway damage has clinical respiratory impact one month after intensive care admittance. METHODS: Biobank study of biomarkers of alveolar and conductive airway damage in intensive care patients was conducted. This was a sub-study of 758 intubated patients from a 1200-patient randomized trial. We split the cohort into a "learning cohort" and "validating cohort" based on geographical criteria: northern sites (learning) and southern sites (validating). RESULTS: Baseline SPD above the 85th percentile in the "learning cohort" predicted low chance of successful weaning from ventilator within 28 days (adjusted hazard ratio 0.6 [95% CI 0.4-0.9], p = 0.005); this was confirmed in the validating cohort. CC16 did not predict the endpoint. The absolute risk of not being successfully weaned within the first month was 48/106 (45.3%) vs. 175/652 (26.8%), p < 0.0001 (high SPD vs. low SPD). The chance of being "alive and without ventilator ≥20 days within the first month" was lower among patients with high SPD (adjusted OR 0.2 [95% CI 0.2-0.4], p < 0.0001), confirmed in the validating cohort, and the risk of ARDS was higher among patients with high SPD (adjusted OR 3.4 [95% CI 1.0-11.4], p = 0.04)-also confirmed in the validating cohort. CONCLUSION: Early profound alveolar damage in intubated patients can be identified by SPD blood measurement at intensive care admission, and high SPD level is a strong independent predictor that the patient suffers from ARDS and will not recover independent respiratory function within one month. This knowledge can be used to improve diagnostic and prognostic models and to identify the patients who most likely will benefit from experimental interventions aiming to preserve alveolar tissue and therefore respiratory function. Trial registration This is a sub-study to the Procalcitonin And Survival Study (PASS), Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.

[Limited evidence for monitoring and treatment of hypophosphataemia in critically ill patients]. / Begrænset evidens for monitorering og behandling af fosfatmangel hos kritisk syge patienter

Hypophosphataemia is a potentially hazardous metabolic disturbance which is common in critically ill patients. The condition is reported to be associated with severe complications and increased mortality. It is unknown, whether hypophosphataemia has a causal effect or reflects the severity of illness. There are no randomized clinical trials to support treatment of hypophosphataemia with intravenous phosphate substitution, which has resulted in large variations in monitoring and treatment of hypophosphataemia in the intensive care unit.

Profound endothelial damage predicts impending organ failure and death in sepsis.

Endothelial damage contributes to organ failure and mortality in sepsis, but the extent of the contribution remains poorly quantified. Here, we examine the association between biomarkers of superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin [sTM], respectively), organ failure, and death in sepsis. The data from a clinical trial, including critically ill patients predominantly suffering sepsis (Clinicaltrials.gov: NCT00271752) were studied. Syndecan-1 and sTM levels at the time of study enrollment were determined. The predictive ability of biomarker levels on death and organ failures during follow-up were assessed in Cox models adjusted for potential confounders including key organ dysfunction measures assessed at enrollment. Of the 1,103 included patients, 418 died. sTM levels at the time of enrollment independently predicted risk of death in adjusted models (hazard ratio [HR] [highest quartile > 14 ng/mL vs. lowest quartile < 7 ng/mL] 2.2 [95% confidence interval [CI]: 1.2-4.0], p = 0.02, respectively). Conversely, syndecan-1 levels failed to predict death (adjusted HR [> 240 vs. < 70 ng/mL] 1.0 [95% CI: 0.6-1.5], p = 0.67). sTM but not syndecan-1 levels at enrollment predicted risk of multiple organ failure during follow-up (HR [> 14 ng/mL vs. < 7 ng/mL] 3.5 [95% CI: 1.5-8.3], p = 0.005 and 2.0 [95% CI: 0.8-5.0], p = 0.1321, respectively). Profound damage to the endothelium independently predicts risk of multiple organ failure and death in septic patients. Our findings also suggest that the detrimental effect of profound endothelial damage on risk of death operates via mechanisms other than causing organ failures per se. Therefore, damage to the endothelium appears centrally involved in the pathogenesis of death in sepsis and could be a target for intervention.

Mild induced hypothermia: effects on sepsis-related coagulopathy--results from a randomized controlled trial.

INTRODUCTION: Coagulopathy associates with poor outcome in sepsis. Mild induced hypothermia has been proposed as treatment in sepsis but it is not known whether this intervention worsens functional coagulopathy. MATERIALS AND METHODS: Interim analysis data from an ongoing randomized controlled trial; The Cooling And Surviving Septic shock (CASS) study. Patients suffering severe sepsis/septic shock are allocated to either mild induced hypothermia (cooling to 32-34°C for 24hours) or control (uncontrolled temperature). TRIAL REGISTRATION: NCT01455116. Thrombelastography (TEG) is performed three times during the first day after study enrollment in all patients. Reaction time (R), maximum amplitude (MA) and patients' characteristics are here reported. RESULTS: One hundred patients (control n=50 and intervention n=50; male n=59; median age 68years) with complete TEG during follow-up were included. At enrollment, 3%, 38%, and 59% had a hypocoagulable, normocoagulable, and hypercoagulable TEG clot strength (MA), respectively. In the hypothermia group, functional coagulopathy improved during the hypothermia phase, measured by R and MA, in patients with hypercoagulation as well as in patients with hypocoagulation (correlation between ΔR and initial R: rho=-0.60, p<0.0001 and correlation between ΔMA and initial MA: rho=-0.50, p=0.0002). Similar results were not observed in the control group neither for R (rho=-0.03, p=0.8247) nor MA (rho=-0.15, p=0.3115). CONCLUSION: Mild induced hypothermia did seem to improve functional coagulopathy in septic patients. This improvement of functional coagulopathy parameters during the hypothermia intervention persisted after rewarming. Randomized trials are warranted to determine whether the positive effect on sepsis-related coagulopathy can be transformed to improved survival.