Furosemide versus placebo for fluid overload in intensive care patients-The randomised GODIF trial second version: Statistical analysis plan.

BACKGROUND: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. METHODS: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. CONCLUSION: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. TRIAL REGISTRATIONS: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU).

PURPOSE: Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. METHODS: We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. RESULTS: We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4-46.1) had thrombocytopenia; 23.4% (20-26) had thrombocytopenia at ICU admission, and 19.8% (17.6-22.2) developed thrombocytopenia during their ICU stay. Absence of acquired immune deficiency syndrome (AIDS), non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19-2.42). CONCLUSION: Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

BACKGROUND: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. METHODS: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. RESULTS: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. CONCLUSIONS: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

Reduction in omission events after implementing a Rapid Response System: a mortality review in a department of gastrointestinal surgery.

BACKGROUND: Hospitals worldwide have implemented Rapid Response Systems (RRS) to facilitate early recognition and prompt response by trained personnel to deteriorating patients. A key concept of this system is that it should prevent 'events of omission', including failure to monitor patients' vital signs, delayed detection, and treatment of deterioration and delayed transfer to an intensive care unit. Time matters when a patient deteriorates, and several in-hospital challenges may prevent the RRS from functioning adequately. Therefore, we must understand and address barriers for timely and adequate responses in cases of patient deterioration. Thus, this study aimed to investigate whether implementing (2012) and developing (2016) an RRS was associated with an overall temporal improvement and to identify needs for further improvement by studying; patient monitoring, omission event occurrences, documentation of limitation of medical treatment, unexpected death, and in-hospital- and 30-day mortality rates. METHODS: We performed an interprofessional mortality review to study the trajectory of the last hospital stay of patients dying in the study wards in three time periods (P1, P2, P3) from 2010 to 2019. We used non-parametric tests to test for differences between the periods. We also studied overall temporal trends in in-hospital- and 30-day mortality rates. RESULTS: Fewer patients experienced omission events (P1: 40%, P2: 20%, P3: 11%, P = 0.01). The number of documented complete vital sign sets, median (Q1,Q3) P1: 0 (0,0), P2: 2 (1,2), P3: 4 (3,5), P = 0.01) and intensive care consultations in the wards ( P1: 12%, P2: 30%, P3: 33%, P = 0.007) increased. Limitations of medical treatment were documented earlier (median days from admission were P1: 8, P2: 8, P3: 3, P = 0.01). In-hospital and 30-day mortality rates decreased during this decade (rate ratios 0.95 (95% CI: 0.92-0.98) and 0.97 (95% CI: 0.95-0.99)). CONCLUSION: The RRS implementation and development during the last decade was associated with reduced omission events, earlier documentation of limitation of medical treatments, and a temporal reduction in the in-hospital- and 30-day mortality rates in the study wards. The mortality review is a suitable method to evaluate an RRS and provide a foundation for further improvement. TRIAL REGISTRATION: Retrospectively registered.

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.

Kinetics of 2 different high-sensitive troponins during targeted temperature management in out-of-hospital cardiac arrest patients with acute myocardial infarction: a post hoc sub-study of a randomised clinical trial.

INTRODUCTION: Short term hypothermia has been suggested to have cardio protective properties in acute myocardial infarction (AMI) by reducing infarct size as assessed by troponins. There are limited data on the kinetics of these biomarkers in comatose out-of-hospital cardiac arrest (OHCA) patients, with and without AMI, undergoing targeted temperature management (TTM) in the ICU. PURPOSE: The aim of this post hoc analyses was to evaluate and compare the kinetics of two high-sensitivity cardiac troponins in OHCA survivors, with and without acute myocardial infarction (AMI), during TTM of different durations [24 h (standard) vs. 48 h (prolonged)]. METHODS: In a sub-cohort (n = 114) of the international, multicentre, randomized controlled study "TTH48" we measured high-sensitive troponin T (hs-cTnT), high-sensitive troponin I (hs-cTnI) and CK-MB at the following time points: Arrival, 24 h, 48 h and 72 h from reaching the target temperature range of 33 ± 1 °C. All patients diagnosed with an AMI at the immediate coronary angiogram (CAG)-18 in the 24-h group and 25 in the 48-h group-underwent PCI with stent implantation. There were no stent thromboses. RESULTS: Both the hs-cTnT and hs-cTnI changes over time were highly influenced by the cause of OHCA (AMI vs. non-AMI). In contrast to non-AMI patients, both troponins remained elevated at 72 h in AMI patients. There was no difference between the two time-differentiated TTM groups in the kinetics for the two troponins. CONCLUSION: In comatose OHCA survivors with an aetiology of AMI levels of both hs-cTnI and hs-cTnT remained elevated for 72 h, which is in contrast to the well-described kinetic profile of troponins in normotherm AMI patients. There was no difference in kinetic profile between the two high sensitive assays. Different duration of TTM did not influence the kinetics of the troponins. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01689077, 20/09/2012.

Quantitative pupillometry in comatose out-of-hospital cardiac arrest patients: A post-hoc analysis of the TTH48 trial.

BACKGROUND: Quantitative pupillometry is an objective method to examine pupil reaction and subsequently grade the response on a neurological pupil index (NPi) scale from 0 to 5. The aim of the present sub-study was to explore the long-term prognostic value of NPi in comatose out-of-hospital cardiac arrest patients undergoing targeted temperature management (TTM). METHODS: This planned sub-study of the "Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest: A randomized clinical trial." NPi was assessed from admission and throughout day 3 and linked to the Cerebral Performance Categories score at 6 months. We compared the prognostic performance of NPi in 65 patients randomized to a target temperature of 33 ± 1°C for 24 or 48 h. RESULTS: The NPi values were not different between TTM groups (p > .05). When data were pooled, NPi was strongly associated with neurological outcome at day 1 with a mean NPi of 3.6 (95% CI 3.4-3.8) versus NPi 3.9 (3.6-4.1) in the poor versus good outcome group, respectively (p < .01). At day 2, NPi values were 3.6 (3.1-4.0) and 4.1 (3.9-4.2) (p = .01) and at day 3, the values were 3.3 (2.6-4.0) and 4.3 (4.1-4.6), respectively (p < .01). The prognostic ability of NPi, defined by area under the receiver operating characteristic curve was best at day three. CONCLUSION: Quantitative pupillometry measured by NPi was not different in the two TTM groups, but overall, significantly associated with good and poor neurological outcomes at 6 months. NPI has a promising diagnostic accuracy, but larger studies are warranted.

MR-proANP and NT-proBNP During Targeted Temperature Management Following Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the TTH48 Trial.

We aimed to evaluate the effect of prolonged targeted temperature management (TTM) in patients with out-of-hospital cardiac arrest (OHCA) on the levels of midregional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) and assess their potential as prognostic biomarkers. A preplanned post hoc analysis of "Targeted temperature management for 48 h vs 24 h and neurologic outcome after out-of-hospital cardiac arrest: A randomized clinical trial (TTH48 trial)," where patients were randomized to TTM at 33°C ± 1°C of standard duration (24 hours) versus prolonged (48 hours). Blood samples were drawn from patients with OHCA at two Scandinavian university hospitals at admission to the ICU and at 24, 48, and 72 hours after reaching the target temperature. Primary outcome was levels of MR-proANP and NT-proBNP. Secondary outcome was cerebral performance category (CPC 1-5) at 6 months. Samples from 114 patients were analyzed. Prolonged TTM significantly decreased the levels of MR-proANP and NT-proBNP at 48 hours compared with standard 24 hours-TTM (p < 0.01). However, there were no significant differences at other time points. Patients with poor outcome (CPC 3-5) had a statistically significantly increased MR-proANP level at 24 hours (p < 0.01) and 72 hours (p < 0.01) compared with the good outcome group (CPC 1-2). Prognostic performance was best at 24 hours for both MR-proANP and NT-proBNP; with an AUC of 0.73 (confidence interval [95% CI]: 0.63-0.83) and 0.72 (95 % CI: 0.59-0.85), respectively. Prolonged TTM lowered the levels of both MR-proANP and NT-proBNP at 48 hours. MR-proANP may add prognostic information in postcardiac arrest patients. ClinicalTrials.gov ID: NCT01689077.

Characteristics, management and survival of ICU patients with coronavirus disease-19 in Norway, March-June 2020. A prospective observational study.

BACKGROUND: Norwegian hospitals have operated within capacity during the COVID-19 pandemic. We present patient and management characteristics, and outcomes for the entire cohort of adult (>18 years) COVID-19 patients admitted to Norwegian intensive care units (ICU) from 10 March to 19 June 2020. METHODS: Data were collected from The Norwegian intensive care and pandemic registry (NIPaR). Demographics, co-morbidities, management characteristics and outcomes are described. ICU length of stay (LOS) was analysed with linear regression, and associations between risk factors and mortality were quantified using Cox regression. RESULTS: In total, 217 patients were included. The male to female ratio was 3:1 and the median age was 63 years. A majority (70%) had one or more co-morbidities, most frequently cardiovascular disease (39%), chronic lung disease (22%), diabetes mellitus (20%), and obesity (17%). Most patients were admitted for acute hypoxaemic respiratory failure (AHRF) (91%) and invasive mechanical ventilation (MV) was used in 86%, prone ventilation in 38% and 25% of patients received a tracheostomy. Vasoactive drugs were used in 79% and renal replacement therapy in 15%. Median ICU LOS and time of MV was 14.0 and 12.0 days. At end of follow-up 45 patients (21%) were dead. Age, co-morbidities and severity of illness at admission were predictive of death. Severity of AHRF and male gender were associated with LOS. CONCLUSIONS: In this national cohort of COVID-19 patients, mortality was low and attributable to known risk factors. Importantly, prolonged length-of-stay must be taken into account when planning for resource allocation for any next surge.

The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: A post hoc analysis of the TTH48 trial.

BACKGROUND: Acute kidney injury (AKI) is common after cardiac arrest and targeted temperature management (TTM). The impact of different lengths of cooling on the development of AKI has not been well studied. In this study of patients included in a randomised controlled trial of TTM at 33 °C for 24 versus 48 h after cardiac arrest (TTH48 trial), we examined the influence of prolonged TTM on AKI and the incidence and factors associated with the development of AKI. We also examined the impact of AKI on survival. METHODS: This study was a sub-study of the TTH48 trial, which included patients cooled to 33 ±â€¯1 °C after out-of-hospital cardiac arrest for 24 versus 48 h. AKI was classified according to the KDIGO AKI criteria based on serum creatinine and urine output collected until ICU discharge for a maximum of seven days. Survival was followed for up to six months. The association of admission factors on AKI was analysed with multivariate analysis and the association of AKI on mortality was analysed with Cox regression using the time to AKI as a time-dependent covariate. RESULTS: Of the 349 patients included in the study, 159 (45.5%) developed AKI. There was no significant difference in the incidence, severity or time to AKI between the 24- and 48-h groups. Serum creatinine values had significantly different trajectories for the two groups with a sharp rise occurring during rewarming. Age, time to return of spontaneous circulation, serum creatinine at admission and body mass index were independent predictors of AKI. Patients with AKI had a higher mortality than patients without AKI (hospital mortality 36.5% vs 12.5%, p < 0.001), but only AKI stages 2 and 3 were independently associated with mortality. CONCLUSIONS: We did not find any association between prolonged TTM at 33 °C and the risk of AKI during the first seven days in the ICU. AKI is prevalent after cardiac arrest and TTM and occurs in almost half of all ICU admitted patients and more commonly in the elderly, with an increasing BMI and longer arrest duration. AKI after cardiac arrest is an independent predictor of time to death.

Combined Interscalene Brachial Plexus and Superficial Cervical Plexus Nerve Block for Midshaft Clavicle Surgery: A Case Series.

Clavicle fractures are common, and there has been a recent increase in surgical fixation of displaced fractures. General anesthesia is traditionally preferred for these operations because regional anesthesia can be challenging. This is partly due to a complex nerve innervation in this region, which makes the correct choice of nerve block difficult. The objective of this study was to evaluate the efficacy of a combined interscalene brachial plexus block and superficial cervical plexus peripheral nerve block as anesthesia for clavicle surgical procedures. Ten midshaft clavicle fractures were surgically repaired using a combination of an ultrasound-guided interscalene brachial plexus block and a superficial cervical plexus block as the primary anesthetic. All patients underwent surgery successfully using regional anesthesia with light sedation, without the need for rescue opioids or rescue local anesthesia. No adverse events were recorded. This case series describes a successful peripheral nerve block combination that can be used for clavicle surgery.

Long-Term Outcomes After ICU Admission Triage in Octogenarians.

OBJECTIVE: To describe ICU admission triage and outcomes in octogenarians. DESIGN: Multicenter prospective observational study. SETTING: Three nonuniversity hospitals and three university hospitals in Norway. PATIENTS: Patients 80 years old or older who were referred for ICU admission from November 2013 to October 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 355 included patients, 105 (29.6%) were refused ICU treatment. Risk factors for ICU refusal in patients considered "too ill/old" were advanced age and low functional status. Risk factors for ICU refusal in patients considered "too well" were advanced age, male sex, university hospital admission, comorbidity, and low Simplified Acute Physiology Score 3. Overall ICU survival was 71.6%. Hospital and 1-year survival were 56.0% and 40.0% in the ICU-admitted, 65.2% and 50.0% in the nonadmitted patients considered too well, and 32.7% and 11.5% in patients considered too ill/old, respectively. The adjusted Kaplan-Meier curves showed significantly lower survival for nonadmitted patients considered too ill/old than for ICU-admitted patients and nonadmitted patients considered too well. At follow-up, triage patients had lower health-related quality of life than an age- and sex-matched control group in the domains of self-care, usual care, and anxiety and depression, and a lower EuroQol visual analog scale scores. CONCLUSIONS: Overall, 29.6% of the patients were refused ICU treatment. The adjusted survival analyses showed a significantly higher survival for ICU-admitted octogenarians than for nonadmitted patients who were considered too ill/old, indicating a benefit of ICU admission. Overall, the follow-up of triage patients showed lower health-related quality of life than an age- and sex-matched control population.

Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial.

BACKGROUND: Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients. METHODS/DESIGN: The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year.The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P ≤0.001 is present at this point. DISCUSSION: The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated.

Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.

BACKGROUND: Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis. METHODS: In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.).