Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial.

PURPOSE: Critically ill patients are vulnerable to penicillin allergy labels that may be incorrect. The validity of skin testing in intensive care units (ICUs) is uncertain. Many penicillin allergy labels are low risk, and validated tools exist to identify those amenable to direct oral challenge. This pilot randomised controlled trial explored the feasibility, safety, and validity of direct enteral challenge for low-risk penicillin allergy labels in critical illness. METHODS: Consenting patients with a low-risk penicillin allergy label (PAL) (PEN-FAST risk assessment score < 3) in four ICUs (Melbourne, Australia) were randomised 1:1 to penicillin (250 mg amoxicillin or implicated penicillin) direct enteral challenge versus routine care (2-h post-randomisation observation for each arm). Repeat challenge was performed post -ICU in the intervention arm. Patients were reviewed at 24 h and 5 days after each challenge/observation. RESULTS: We screened 533 patients. 130 (24.4%) were eligible and 80/130 (61.5%) enrolled (age median 64.5 years (interquartile range, IQR 53.5, 74), PEN-FAST median 1 (IQR 0,1)), with 40 (50%) randomised to direct enteral challenge. A positive challenge rate of 2.5% was identified. No antibiotic-associated serious adverse events were identified. 32/40 (80%) received a repeat challenge (zero positive). Post-randomisation, 13 (32%) of the intervention arm and 4 (10%) of the control arm received penicillin (odds ratio, OR 4.33 [1.27, 14.78] p = 0.019). CONCLUSION: These findings support the safety, validity, and feasibility of direct enteral challenge for critically ill patients with PEN-FAST assessed low-risk penicillin allergy. The absence of false negative results was confirmed by subsequent negative repeat challenges. A relatively low recruitment to screened ratio suggests that more inclusive eligibility criteria and integration of allergy assessment into routine ICU processes are needed to optimise allergy delabelling in critical illness.

The effect of age on clinical dose equivalency of fentanyl and morphine analgosedation in mechanically ventilated patients: Findings from the ANALGESIC trial.

BACKGROUND: The dose equivalency of fentanyl vs. morphine is widely considered to be approximately 1:100. However, little is known about the effect of age on this ratio when these agents are used as infusions for analgosedation. OBJECTIVES: To assess the impact of age on the clinical dose equivalency of fentanyl and morphine when used as infusions for analgosedation in mechanically ventilated intensive care unit patients. METHODS: We performed a post hoc analysis of the Assessment of Opioid Administration to Lead to Analgesic Effects and Sedation in Intensive Care (ANALGESIC) cluster randomised crossover trial of fentanyl and morphine infusions for analgosedation. Dose and analgosedative clinical equivalency of fentanyl and morphine were assessed by age and by using different body-size descriptors. RESULTS: We studied 663 patients (338 fentanyl, 325 morphine). Median (interquartile range) hourly dose of fentanyl and morphine were 58.1 (40.0-89.2) mcg and 3400 (2200-5000) mcg, respectively. The ratio of total dose of fentanyl:morphine was 1:93 in the 18- to 29-year-old group and 1:25 in the ≥80-year-old group (p = 0.015), respectively, with fentanyl becoming relatively less clinically effective as age increased. This effect was also seen when comparing dosing by different body-size descriptors with the strongest age-related change when using body surface area as body-size descriptor (p = 0.009). CONCLUSION: The analgosedative clinical dose equivalency of fentanyl vs. morphine is heterogeneous when used as infusions for analgosedation, with fentanyl becoming relatively less clinically effective as age increases. This information can help guide prescription of these agents during transition from one agent to the other in critically ill patients.

Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial.

BACKGROUND: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. METHODS: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score. RESULTS: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes. CONCLUSION: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.

Changes in SedLine-derived processed electroencephalographic parameters during hypothermia in patients undergoing cardiac surgery with cardiopulmonary bypass.

Objective: Processed electroencephalography (pEEG) is used to monitor depth-of-anesthesia during cardiopulmonary bypass (CPB). The SedLine device has been recently introduced for pEEG monitoring. However, the effect of hypothermia on its parameters during CPB is unknown. Accordingly, we aimed to investigate temperature-induced changes in SedLine-derived pEEG parameters during CPB. Design: Prospective observational study. Setting: Cardiac surgery operating theatre. Participants: 28 patients undergoing elective cardiac surgery with CPB. Interventions: We continuously measured patient state index (PSI), suppression ratio (SR), bilateral spectral edge frequency (SEF) and temperature. We used linear mixed modelling with fixed and random effects to study the interactions between pEEG parameters and core temperature. Measurements and main results: During CPB maintenance, the median temperature was 32.1°C [interquartile range (IQR): 29.8-33.6] at the end of cooling and 32.8°C (IQR: 30.1-34.0) at rewarming initiation. For each degree Celsius change in temperature during cooling and rewarming the PSI either decreased by 0.8 points [95% confidence interval (CI): 0.7-1.0; p < 0.001] or increased by 0.7 points (95% CI: 0.6-0.8; p < 0.001). The SR increased by 2.9 (95% CI: 2.3-3.4); p < 0.001) during cooling and decreased by 2.2 (95% CI: 1.7-2.7; p < 0.001) during rewarming. Changes in the SEF were not related to changes in temperature. Conclusions: During hypothermic CPB, temperature changes led to concordant changes in the PSI. The SR increased during cooling and decreased during rewarming. Clinicians using SedLine for depth-of-anesthesia monitoring should be aware of these effects when interpreting the PSI and SR values.

Delirium in ventilated patients receiving fentanyl and morphine for Analgosedation: Findings from the ANALGESIC trial.

PURPOSE: The differential effect of fentanyl vs. morphine analgosedation on the development of hospital inpatient delirium in patients receiving mechanical ventilation is unknown. We aimed to compare the incidence of coding for delirium and antipsychotic medication use in patients treated with fentanyl vs. morphine in the ANALGESIC trial. MATERIALS AND METHODS: We obtained data from a cluster randomized, cluster crossover trial of fentanyl vs. morphine for analgosedation on antipsychotic use and coding diagnosis of delirium and compared these outcomes according to treatment allocation. We assessed the relationship between opioid choice and dose, hospital inpatient delirium, and outcomes. RESULTS: Among 681 patients enrolled in the ANALGESIC trial, 160/344 (46.5%) in the fentanyl group vs. 132/337 (39.1%) in the morphine group (absolute difference 7.34% [95% CI -0.9 to 14.78]; RR: 1.19 [95%CI 1.00 to 1.41]; p = 0.053) developed hospital inpatient delirium. Antipsychotic use was linearly related to opioid dose. Antipsychotic use was not associated with increased mortality. CONCLUSIONS: Fentanyl is associated with a higher incidence of hospital inpatient delirium when used for analgosedation compared with morphine, and the dose of opioid is linearly related to the need for antipsychotic medication administration. The role of analgosedation in promoting delirium requires further investigation.

Evaluation of ferritin and the ferritin index as prognostic biomarkers in septic shock.

BACKGROUND: Ferritin, an acute phase reactant, and the ferritin index (FI = observed ferritin level/upper limit of normal level for age and sex) may be prognostic biomarkers in septic shock and cardiac surgery patients. OBJECTIVE: The purpose of this exploratory study is to assess the outcome associations of ferritin and FI levels in septic shock compared to post-cardiac surgery patients. DESIGN: This was a prospective, double-centre, observational study. SETTING: The study setting involved two adult intensive care units (ICUs) in Victoria, Australia. PARTICIPANTS: Sixty-one septic shock and 30 post-cardiac surgery patients participated in this study. MAIN OUTCOME MEASURES: We measured ferritin and FI on ICU admission (T1) and 24 h later (T2) to assess its correlation with mortality, illness severity, and hospital length of stay (LOS). RESULTS: The baseline characteristics of patients in the septic shock group and cardiac surgery group were similar apart from illness severity scores (APACHE III and modified SOFA score). Septic shock patients had more physiological derangements as well as greater use and higher doses of norepinephrine at both T1 and T2. Septic shock patients had significantly higher median ferritin levels (372 µg/L versus 198 µg/L; p < 0.001 at T1, 457 µg/L versus 264 µg/L; p = 0.001 at T2) than post-cardiac surgery patients. Ferritin levels, however, did not have a linear correlation with illness severity or hospital mortality. Instead, there was an association between high ferritin levels at T2 and longer ICU (p = 0.017) and hospital LOS (p = 0.013). Females with septic shock had significantly higher FI (p < 0.001 at T1, p = 0.004 at T2) than males. CONCLUSION: In septic shock patients, ferritin levels and FI were twice the level compared to post-cardiac surgery patients. Both had no association with mortality, but levels above the median at 24 h were associated with longer ICU and hospital LOS.

Effects of changes in inspired oxygen fraction on urinary oxygen tension measurements.

BACKGROUND: Continuous measurement of urinary PO2 (PuO2) is being applied to indirectly monitor renal medullary PO2. However, when applied to critically ill patients with shock, its measurement may be affected by changes in FiO2 and PaO2 and potential associated O2 diffusion between urine and ureteric or bladder tissue. We aimed to investigate PuO2 measurements in septic shock patients with a fiberoptic luminescence optode inserted into the urinary catheter lumen in relation to episodes of FiO2 change. We also evaluated medullary and urinary oxygen tension values in Merino ewes at two different FiO2 levels. RESULTS: In 10 human patients, there were 32 FiO2 decreases and 31 increases in FiO2. Median pre-decrease FiO2 was 0.36 [0.30, 0.39] and median post-decrease FiO2 was 0.30 [0.23, 0.30], p = 0.006. PaO2 levels decreased from 83 mmHg [77, 94] to 72 [62, 80] mmHg, p = 0.009. However, PuO2 was 23.2 mmHg [20.5, 29.0] before and 24.2 mmHg [20.6, 26.3] after the intervention (p = 0.56). The median pre-increase FiO2 was 0.30 [0.21, 0.30] and median post-increase FiO2 was 0.35 [0.30, 0.40], p = 0.008. PaO2 levels increased from 64 mmHg [58, 72 mmHg] to 71 mmHg [70, 100], p = 0.04. However, PuO2 was 25.0 mmHg [IQR: 20.7, 26.8] before and 24.3 mmHg [IQR: 20.7, 26.3] after the intervention (p = 0.65). A mixed linear regression model showed a weak correlation between the variation in PaO2 and the variation in PuO2 values. In 9 Merino ewes, when comparing oxygen tension levels between FiO2 of 0.21 and 0.40, medullary values did not differ (25.1 ± 13.4 mmHg vs. 27.9 ± 15.4 mmHg, respectively, p = 0.6766) and this was similar to urinary oxygen values (27.1 ± 6.17 mmHg vs. 29.7 ± 4.41 mmHg, respectively, p = 0.3192). CONCLUSIONS: Changes in FiO2 and PaO2 within the context of usual care did not affect PuO2. Our findings were supported by experimental data and suggest that PuO2 can be used as biomarker of medullary oxygenation irrespective of FiO2.

Improving the quality of family meeting documentation in the ICU at the end of life.

Objective: Improve documentation quality of end-of-life family meetings in a tertiary intensive care unit (ICU). Design: Before-and-after interventional quality improvement project between October 2018 and February 2020 utilising an electronic pro-forma record. Setting: Australian, University affiliated, mixed medical-surgical 22 bed adult ICU. Participants: Patients who were admitted to the ICU for active management and subsequently died during that ICU admission. We enrolled 50 patients who died before and 50 patients after the introduction of the electronic family meeting pro-forma record. Intervention: Through collaboration with ICU medical and nursing staff, End-of-life Special Interest Group and Clinical Documentation Committee we developed the ICU Family Meeting Discussion Note as an electronic pro-forma record with multiple key fields of entry. Main outcome measures: Patient records were examined for the presence of documented details around patient's admission, family meetings and specific elements surrounding the patient's death. Results: The introduction of a pro-forma record markedly improved the quality of documentation of end-of-life care related family meetings. Documentation increased in recording hospital admission date/time (6% vs 84%), meeting location (14% vs 70%), the reason patients were absent from the meeting (34% vs 72%), the Medical Treatment Decision Maker (MTDM) (10% vs 44%), the patient's resuscitation status (22% vs 54%), and treatment options discussed (78% vs 94%) (p ⩽ 0.005 for all). Conclusion: Introducing an electronic pro-forma record to facilitate family meeting documentation increased the frequency of important recorded information. Further studies are required to assess whether documentation quality improvements are sustainable and whether they affect patient- or relative-centred outcomes.

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators.

Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Small, short-term, point-of-care creatinine changes as predictors of acute kidney injury in critically ill patients.

PURPOSE: To assess short-term creatinine changes as predictors of acute kidney injury (AKI) when used alone and in combination with AKI risk factors. METHODS: In this prospective cohort study, we identified all creatinine measurements from frequent point-of-care arterial blood gas measurements from ICU admission until AKI. We evaluated the predictive value of small changes between these creatinine measurements for AKI development, alone and with AKI risk factors. RESULTS: Of 377 patients with 3235 creatinine measurements, generating 15,075 creatinine change episodes, 215 (57%) patients developed AKI, and 68 (18%) developed stage 2 or 3 AKI. In isolation, a creatinine increase over 4.1-7.3 h had a 0.65 area under the curve for predicting stage 2 or 3 AKI within 3-37.7 h. Combining creatinine increases of ≥1 µmol/L/h (≥0.0113 mg/dL/h) over 4-5.8 h with three AKI risk factors (cardiac surgery, use of vasopressors, chronic liver disease) had 83% sensitivity, 79% specificity and 0.87 area under the curve for stage 2 or 3 AKI occurring 8.7-25.6 h later. CONCLUSION: In combination with key risk factors, frequent point-of-care creatinine assessment on arterial blood gases to detect small, short-term creatinine changes provides a robust, novel, low-cost, and rapid method for predicting AKI in critically ill patients.

COMBED: Rapid non-invasive Cardiac Output Monitoring Baseline assessment in adult Emergency Department patients with haemodynamic instability.

OBJECTIVE: The application of rapid, non-operator-dependent, non-invasive cardiac output monitoring (COM) may provide early physiological information in ED patients with haemodynamic instability (HI). Our primary objective was to assess the feasibility of measuring pre-intervention (baseline) cardiac index (CI) and associated haemodynamic parameters. METHODS: We performed a prospective observational study of adults shortly after presentation to the ED of a large university hospital with tachycardia or hypotension or both. We applied non-invasive COM for 5 min and recorded CI, mean arterial pressure (MAP), stroke volume index (SVI) and systemic vascular resistance index (SVRI). We assessed for differences between those presenting with hypotension or hypotension and tachycardia with tachycardia alone and between those with or without suspected infection. RESULTS: We obtained haemodynamic parameters in 46 of 49 patients. In patients with hypotension or hypotension and tachycardia (n = 15) rather than tachycardia alone (n = 31), we observed a lower MAP (60.8 vs 87.7, P < 0.0001), CI (2.8 vs 3.9, P = 0.0167) and heart rate (85.5 vs 115.4, P < 0.0001). There was no difference in SVI (33.7 vs 33.4, P = 0.93) or SVRI (1970 vs 2088, P = 0.67). Patients with suspected infection had similar haemodynamic values except for a lower SVRI (1706 vs 2237, P = 0.011). CONCLUSIONS: Rapid, non-operator-dependent, non-invasive COM was possible in >90% of ED patients presenting with HI. Compared with tachycardia alone, patients with hypotension had lower CI, MAP and heart rate, while those with suspected infection had a lower SVRI. This technology provides novel insights into the early state of the circulation in ED patients with HI.

A pilot study of the pharmacokinetics of continuous magnesium infusion in critically ill patients.

Objective: The pharmacokinetics and haemodynamic effect of continuous magnesium infusion in non-cardiac intensive care unit (ICU) patients are poorly understood. We aimed to measure serum and urine magnesium levels during bolus and continuous infusion in critically ill adults, compare serum levels with those of a control population, and assess its haemodynamic effect. Design: Pharmacokinetic study Setting: A single tertiary adult ICU. Participants: Mechanically ventilated adults requiring vasopressor support. Intervention: A 10 mmol bolus of magnesium sulfate followed by 1.5-3 mmol/h infusion for 24 hours. Main outcome measures: The primary outcome was the change in total serum magnesium concentration. The main secondary outcome was mean arterial pressure (MAP)- adjusted vasopressor dose. Results: We matched 31 treated patients with 93 controls. Serum total magnesium concentration increased from a median 0.94 mmol/L (interquartile range [IQR], 0.83-1.10 mmol/L) to 1.38 mmol/L (IQR, 1.25-1.69 mmol/L; P < 0.001) and stabilised between a median 1.64 mmol/L (IQR, 1.38-1.88 mmol/L) at 7 hours and 1.77 mmol/L (IQR, 1.53-1.85 mmol/L) at 25 hours. This was significantly greater than in the control group (P < 0.001). The MAP-adjusted vasopressor dose decreased during magnesium infusion (P < 0.001). Conclusion: In critically ill patients, a magnesium sulfate bolus followed by continuous infusion achieved moderately elevated levels of total serum magnesium with a decrease in MAP-adjusted vasopressor dose. Trial registration number: ACTRN12619000925145.

The hemodynamic effects of warm versus room-temperature crystalloid fluid bolus therapy in post-cardiac surgery patients.

INTRODUCTION: The contribution of fluid temperature to the effect of crystalloid fluid bolus therapy (FBT) in post-cardiac surgery patients is unknown. We evaluated the hemodynamic effects of FBT with fluid warmed to 40°C (warm FBT) versus room-temperature fluid. METHODS: In this single centre prospective before-and-after study, we evaluated the effects of 500 ml of warm versus room-temperature compound sodium lactate administered over <30 minutes, in 50 cardiac surgery patients admitted to ICU. We recorded hemodynamics continuous before and for 30 minutes after the first FBT. We defined CI responsiveness (CI-R) as an CI increase >15% of baseline immediately after FBT and effect dissipation if the CI returned to <5% of baseline and MAP responsiveness as >10% increase and dissipation as return to <3 mmHg of baseline. RESULTS: Hypotension (56%) and low CI (40%) typically triggered FBT. Temperature decreased >0.3°C in 13 (52%) patients after room-temperature FBT versus 0 (0%) after warm FBT (p < 0.01). CI and MAP responsiveness was similar (16 [64%] versus 11 [44%], p = 0.15 and 15 [60%] versus 17 [68%], p = 0.77, respectively). Among CI responders, CI increased more with room-temperature FBT (+0.6 [IQR, 0.5-1.1] versus +0.5 [IQR, 0.4-0.6] L/min/m2, p = 0.01). However, dissipation was more common after room-temperature versus warm FBT (9/16 [56%] versus 1/11 [9%], p = 0.02). CONCLUSION: In postoperative cardiac surgery patients, warm FBT preserved core temperature and induced smaller but more sustained CI increases among responders. Fluid temperature appears to impact both core temperature and the duration of CI response.

Registrar triage, communication and moral distress during end-of-life care rapid response team calls in a teaching hospital.

BACKGROUND: Approximately one-third of rapid response teams (RRT) involve end-of-life care (EOLC) issues. Intensive care unit (ICU) registrar experience in such calls is underinvestigated. AIMS: To evaluate the proportion of RRT calls triaged as relating to EOLC issues, issues around communication regarding prognostication, registrar self-reported moral distress and associations between RRT EOLC classification and patient outcomes. METHODS: Prospective observational study of RRT calls in a tertiary referrals hospital between December 2016 and January 2017 using a standardised case report form and data from an electronic RRT database. RESULTS: There were 401 RRT calls in the study period, and data were available for 270 (67%) calls, of which 72%, 10% and 18% were triaged as 'obviously not EOLC call', 'obvious EOLC call' and 'uncertain EOLC call' respectively. Most discussions regarding prognostication occurred between registrars, and more than half (55%) were with a covering doctor. Consensus on prognostication was achieved in 93% cases. Registrars reported distress in 19% of calls that obviously related to EOLC and 22% of calls that were uncertain, compared with <1% of calls that were obviously not relating to EOLC. Inhospital mortality was 6%, 67% and 39% for obviously not EOLC, obvious EOLC and uncertain EOLC calls respectively. CONCLUSIONS: EOLC issues occur commonly in RRT calls and are often associated with moral distress to ICU registrars. Although consensus on prognostication is usually achieved, conversations often involve covering doctors. These issues impact on the ICU registrar experience of RRT calls and require further exploration.

Long-Term Functional Outcome and Quality of Life Following In-Hospital Cardiac Arrest-A Longitudinal Cohort Study.

OBJECTIVES: To evaluate the functional outcome and health-related quality of life of in-hospital cardiac arrest survivors at 6 and 12 months. DESIGN: A longitudinal cohort study. SETTING: Seven metropolitan hospitals in Australia. PATIENTS: Data were collected for hospitalized adults (≥ 18 yr) who experienced in-hospital cardiac arrest, defined as "a period of unresponsiveness, with no observed respiratory effort and the commencement of external cardiac compressions." INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Prior to hospital discharge, patients were approached for consent to participate in 6-month and 12-month telephone interviews. Outcomes included the modified Rankin Scale, Barthel Index, Euro-Quality of Life 5 Dimension 5 Level, return to work and hospital readmissions. Forty-eight patients (80%) consented to follow-up interviews. The mean age of participants was 67.2 (± 15.3) years, and 33 of 48 (68.8%) were male. Good functional outcome (modified Rankin Scale score ≤ 3) was reported by 31 of 37 participants (83.8%) at 6 months and 30 of 33 (90.9%) at 12 months. The median Euro-Quality of Life-5D index value was 0.73 (0.33-0.84) at 6 months and 0.76 (0.47-0.88) at 12 months. The median Euro-Quality of Life-Visual Analogue Scale score at 6 months was 70 (55-80) and 75 (50-87.5) at 12 months. Problems in all Euro-Quality of Life-5D-5 L dimension were reported frequently at both time points. Hospital readmission was reported by 23 of 37 patients (62.2%) at 6 months and 16 of 33 (48.5%) at 12 months. Less than half of previously working participants had returned to work by 12 months. CONCLUSIONS: The majority of in-hospital cardiac arrest survivors had a good functional outcome and health-related quality of life at 6 months, and this was largely unchanged at 12 months. Despite this, many reported problems with mobility, self-care, usual activities, pain, and anxiety/depression. Return to work rates was low, and hospital readmissions were common.

Hypothermic versus Normothermic Temperature Control after Cardiac Arrest.

BACKGROUND: The evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics. METHODS: An individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence). RESULTS: The primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups. CONCLUSIONS: Hypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)

A Phase II Cluster-Crossover Randomized Trial of Fentanyl versus Morphine for Analgosedation in Mechanically Ventilated Patients.

Rationale: The continuous infusion of fentanyl or morphine is often prescribed to assist with analgesia and sedation (analgosedation) during mechanical ventilation. Objectives: To compare the effect of fentanyl versus morphine on patient-centered outcomes in ventilated patients. Methods: We conducted a cluster-randomized, cluster-crossover trial between July 2019 and August 2020 in two adult ICUs. We compared two continuous infusion regimens (fentanyl versus morphine). One ICU was randomized to the fentanyl-morphine sequence and the other to the morphine-fentanyl sequence. The primary outcome was the number of ventilator-free days at Day 28. Secondary outcomes included, among others, duration of mechanical ventilation in survivors and ICU-free days at Day 28. Measurements and Main Results: Via cluster allocation, we randomized 737 patients. Of these, 56 were excluded because of the opt-out consent process, leaving 681 (344 to fentanyl and 337 to morphine) for primary analysis (median [interquartile range] age, 59 [44-69] years). Median ventilator-free days at Day 28 were 26.1 (20.7-27.3) in the fentanyl versus 25.3 (19.1-27.2) in the morphine group (median difference, 0.79 [95% confidence interval, 0.31 to 1.28], P = 0.001). ICU-free days were greater (P < 0.001) and length of stay in the ICU for survivors shorter (P < 0.001) in the fentanyl group. All other secondary outcomes were not statistically different by treatment group. Conclusions: Among adult patients requiring mechanical ventilation, compared with morphine, fentanyl infusion significantly increased the median number of ventilator-free days at Day 28. The choice of opioid infusion agent may affect clinical outcomes and requires further investigation.

A comparison of the hemodynamic effects of fluid bolus therapy with crystalloids vs. 4% albumin and vs. 20% albumin in patients after cardiac surgery.

BACKGROUND: Crystalloids, 4% albumin and 20% albumin are used for fluid bolus therapy (FBT) in patients after cardiac surgery. However, their detailed early (30 min) hemodynamic effects remain unstudied. METHODS: In a comparative prospective observational trial of 120 ventilated, we studied post cardiac surgery patients who received crystalloid 500 ml FBT, 4% albumin 500 ml FBT or 20% albumin 100 ml FBT (40 per group). We recorded second-by-second hemodynamic parameters and 15-minutely cardiac index (CI) data before and for 30 min after FBT. We compared the crystalloid group (reference) vs. the 4% albumin group, and vs. the 20% albumin group. RESULTS: Immediately after FBT, the mean (standard deviation) CI increase was 0.4 (0.4) L/min/m2 with crystalloids, 0.4 (0.5) L/min/m2 with 4% albumin and 0.3 (0.4) L/min/m2 with 20% albumin, despite the much smaller FBT volume with 20% albumin. Mean arterial pressure (MAP) increase was 11 (10), 12 (9) and 9 (6) mm Hg, respectively. There was no group effect or interaction for changes in CI. However, there were time-group interactions for MAP changes such that crystalloid FBT had faster MAP reduction than 4% (p<0.001) or 20% albumin (p < 0.001). Moreover, patients treated with crystalloid FBT showed a faster decline in central venous pressure, perfusion pressure than the two groups. Finally, 20% albumin attenuated the fall in temperature induced by FBT. CONCLUSION: In postoperative cardiac surgery patients, after a similar initial CI and MAP response, the MAP effect of crystalloid FBT dissipates faster than that of 4% or 20% albumin FBT. These findings can be used to inform clinical practice.

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).