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.).

Quality of life-related and non-quality of life-related issues in ICU survivors and non-ICU-treated controls: a multi-group exploratory factor analysis.

BACKGROUND: Quality of life (QoL) is a key outcome measure in healthcare. However, the heterogeneity in its definitions presents challenges in the objective evaluation of improvement. Universal questionnaires, tailored for a broad demographic group, inadequately represent the unique experiences of intensive care unit (ICU) survivors, including a lack of ability to discriminate issues related to QoL from issues that do not. METHODS: Using a 218-item, 13-domain provisional questionnaire, we assessed 395 adult ICU survivors, with a minimum 72-h stay at one of three Swedish university hospital ICUs, at 6 months to three years post-discharge. Their responses were compared to those of 195 controls, matched for age and sex and randomly recruited from the Swedish Population Registry. By multi-group exploratory factor analysis, we compared dimensionality in QoL perceptions between the two groups, emphasising patterns of correlation to 13 domain-specific QoL questions. Model fit was assessed using information criteria. Internal consistency reliability for each scale was determined using McDonald's omega or Cronbach's alpha. All analyses were conducted using Mplus, applying full information maximum likelihood to handle missing data. RESULTS: All domains except Cognition had a subset of questions correlating to the domain-specific QoL question in at least the ICU survivor group. The similarity between the two groups varied, with Physical health, Sexual health and Gastrointestinal (GI) functions mainly correlating the same issues to QoL in the two groups. In contrast, Fatigue, Pain, Mental health, activities of daily living, Sleep, Sensory functions and Work life showed considerable differences. In all, about one-fourth of the issues correlated to QoL in the ICU survivor group and about one-tenth of the issues in the control group. CONCLUSIONS: We found most issues experienced by ICU survivors to be unrelated to quality of life. Our findings indicate that the consequences of post-ICU issues may play a more significant role in affecting QoL than the issues themselves; issues restricting and affecting social life and work life were more related to QoL in ICU survivors than in non-ICU-treated controls. Caution is advised before associating all post-ICU problems with an effect on quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Ref# NCT02767180; Registered 28 April 2016.

Neuropsychological outcome after cardiac arrest: results from a sub-study of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial.

BACKGROUND: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA. METHODS: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes. RESULTS: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance. CONCLUSIONS: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.

Post-cardiac arrest intensive care in Sweden: A survey of current clinical practice.

BACKGROUND: European guidelines recommend targeted temperature management (TTM) in post-cardiac arrest care. A large multicentre clinical trial, however, showed no difference in mortality and neurological outcome when comparing hypothermia to normothermia with early treatment of fever. The study results were valid given a strict protocol for the assessment of prognosis using defined neurological examinations. With the current range of recommended TTM temperatures, and applicable neurological examinations, procedures may differ between hospitals and the variation of clinical practice in Sweden is not known. AIM: The aim of this study was to investigate current practice in post-resuscitation care after cardiac arrest as to temperature targets and assessment of neurological prognosis in Swedish intensive care units (ICUs). METHODS: A structured survey was conducted by telephone or e-mail in all Levels 2 and 3 (= 53) Swedish ICUs during the spring of 2022 with a secondary survey in April 2023. RESULTS: Five units were not providing post-cardiac arrest care and were excluded. The response rate was 43/48 (90%) of the eligible units. Among the responding ICUs, normothermia (36-37.7°C) was applied in all centres (2023). There was a detailed routine for the assessment of neurological prognosis in 38/43 (88%) ICUs. Neurological assessment was applied 72-96 h after return of spontaneous circulation in 32/38 (84%) units. Electroencephalogram and computed tomography and/or magnetic resonance imaging were the most common technical methods available. CONCLUSION: Swedish ICUs use normothermia including early treatment of fever in post-resuscitation care after cardiac arrest and almost all apply a detailed routine for the assessment of neurological prognosis. However, available methods for prognostic evaluation varies between hospitals.

Veno-arterial CO2 difference and lactate for prediction of early mortality after cardiac arrest.

Patients admitted to intensive care after cardiac arrest are at risk of circulatory shock and early mortality due to cardiovascular failure. The aim of this study was to evaluate the ability of the veno-arterial pCO2 difference (∆pCO2 ; central venous CO2 - arterial CO2 ) and lactate to predict early mortality in postcardiac arrest patients. This was a pre-planned prospective observational sub-study of the target temperature management 2 trial. The sub-study patients were included at five Swedish sites. Repeated measurements of ∆pCO2 and lactate were conducted at 4, 8, 12, 16, 24, 48, and 72 h after randomization. We assessed the association between each marker and 96-h mortality and their prognostic value for 96-h mortality. One hundred sixty-three patients were included in the analysis. Mortality at 96 h was 17%. During the initial 24 h, there was no difference in ∆pCO2 levels between 96-h survivors and non-survivors. ∆pCO2 measured at 4 h was associated with an increased risk of death within 96 h (adjusted odds ratio: 1.15; 95% confidence interval [CI]: 1.02-1.29; p = .018). Lactate levels were associated with poor outcome over multiple measurements. The area under the receiving operating curve to predict death within 96 h was 0.59 (95% CI: 0.48-0.74) and 0.82 (95% CI: 0.72-0.92) for ∆pCO2 and lactate, respectively. Our results do not support the use of ∆pCO2 to identify patients with early mortality in the postresuscitation phase. In contrast, non-survivors demonstrated higher lactate levels in the initial phase and lactate identified patients with early mortality with moderate accuracy.

The relationship between ICU survivorship, comorbidity and educational level in quality of life after intensive care.

BACKGROUND: ICU survivors have lower quality of life (QoL) compared to a non-ICU-treated population. The reason for this is not fully understood, but differences in baseline characteristics may be an important factor. This study evaluates the roles of comorbidity and educational level as possible explanatory factors for differences in QoL in ICU survivors compared to a non-ICU-treated population. METHODS: Using a provisional questionnaire with 218 questions in 13 domains on QoL after intensive care, we compared the responses from 395 adult ICU survivors and 195 non-ICU-treated controls. An initial bivariable linear correlation analysis compared the responses from the two groups. Two secondary multivariable regression analyses tested for effect modification by comorbidity and educational level, respectively, on the effect on QoL from belonging to the ICU survivor group compared to the control group. RESULTS: There was a significant difference in QoL between the two groups in 170 of 218 (78%) questions. In the multivariable analyses, associations between group belonging and QoL remained in 139 questions. In 59 of these, both belonging to the ICU survivor group and comorbidity was associated to QoL, in parallel to each other. Comorbidity moderated the association between group belonging and QoL in six questions, with the highest proportion of questions within the domains of cognition and urinary functions, and the lowest proportion within appetite and alcohol, physical health, and fatigue. In 26 questions, both belonging to the ICU survivor group and educational level were associated to QoL, in parallel to each other. Educational level moderated the association between group belonging and QoL in 34 questions, with the highest proportion of questions within the domains of urinary functions, ADL and physical health, and the lowest proportion within the domains of cognition, appetite and alcohol, pain, sensory functions, and fatigue. CONCLUSIONS: Lower QoL seen in ICU survivors compared to non-ICU-treated controls, as measured by our provisional questionnaire, cannot be explained only by a higher burden of comorbidity, and rarely by only educational level. In issues where comorbidity or educational level was associated to QoL, it often was so in parallel to an association from belonging to the ICU survivor group. Comparing QoL in ICU survivors to that of a non-ICU-treated population may be adequate despite differences in baseline characteristics.

Targeted temperature management evolving over time-A local process analysis.

BACKGROUND: Post-resuscitation care of comatose survivors from cardiac arrest includes target temperature management (TTM) to mitigate cerebral reperfusion injury. High-quality TTM requires protocols enhancing good precision. This study explored how the quality of TTM may have evolved with increasing experience from clinical trial protocols and standard operating procedures. We hypothesized that there would be a positive effect over time, detectable between trial periods and between trial periods and later everyday practice. METHODS: Three TTM quality parameters were defined: time to target, temperature variability, and fever incidence. Data from 181 patients treated during three different time periods in a tertiary center were analyzed; 45 from Period 1 (local trial cohort 2011-2013) targeting 33°C or 36°C; 76 from Period 2 (local trial cohort 2018-2020) targeting 33 or <37.5°C; 60 from Period 3 (current standard operating procedure 2020-2021) targeting 36°C. Groups of similar target temperatures from different time periods were compared using ordinary group statistics. RESULTS: TTM quality in all three parameters increased between trial periods. There were no differences in TTM quality as to temperature variability or fever incidence between the <37.5°C Period 2 and the 36°C Period 3 groups. A 33°C target temperature was associated with lower fever incidence than 36°C and <37.5°C target regimes. CONCLUSION: The observed increase in TTM quality in this single-center study may be a result of increased competence through learning and training in different strict TTM protocols. If so, the results of this study further support the protocolization of post-cardiac arrest intensive care.

Long-term health-related quality of life and burden of disease after intensive care: development of a patient-reported outcome measure.

BACKGROUND: ICU survivorship includes a diverse burden of disease. Current questionnaires used for collecting information about health-related problems and their relation to quality of life lack detailed questions in several areas relevant to ICU survivors. Our aim was to construct a provisional questionnaire on health-related issues based on interviews with ICU survivors and to test if this questionnaire was able to show differences between ICU survivors and a control group. METHODS: Thirty-two ICU survivors were identified at a post-ICU clinic and interviewed at least six months after ICU discharge. Using an established qualitative methodology from oncology, all dysfunctions and disabilities were extracted, rephrased as questions and compiled into a provisional questionnaire. In a second part, this questionnaire was tested on ICU survivors and controls. Inclusion criteria for the ICU survivors were ICU stay at least 72 h with ICU discharge six months to three years prior to the study. A non-ICU-treated control group was obtained from the Swedish Population Register, matched for age and sex. Eligible participants received an invitation letter and were contacted by phone. If willing to participate, they were sent the questionnaire. Descriptive statistics were applied. RESULTS: Analysis of the interviews yielded 238 questions in 13 domains: cognition, fatigue, physical health, pain, psychological health, activities of daily living, sleep, appetite and alcohol, sexual health, sensory functions, gastrointestinal functions, urinary functions and work life. In the second part, 395 of 518 ICU survivors and 197 of 231 controls returned a completed questionnaire, the response rates being 76.2% and 85.3%, respectively. The two groups differed significantly in 13 of 22 comorbidities. ICU survivors differed in a majority of questions (p ≤ 0.05) distributed over all 13 domains compared with controls. CONCLUSIONS: This study describes the development of a provisional questionnaire to identify health-related quality of life issues and long-term burden of disease after intensive care. The questionnaire was answered by 395 ICU survivors. The questionnaire could identify that they experience severe difficulties in a wide range of domains compared with a control group. Trial registry ClinicalTrials.gov Ref# NCT02767180.

Outcomes of catheter-directed interventions in high-risk pulmonary embolism-a retrospective analysis.

BACKGROUND: First-line treatment of high-risk pulmonary embolism with persistent hypotension and/or signs of shock is intravenous thrombolysis. However, if thrombolysis is contraindicated due to risk of serious bleeding, or if it yields insufficient effect, surgical thrombectomy or catheter-directed intervention (CDI) plus anticoagulation is recommended. The aim of this study was to assess the outcomes of the CDI modality introduced in a tertiary referral centre in 2013. METHODS: Retrospective comparison between patients treated with CDI plus anticoagulation (n = 22) and patients treated with anticoagulation only (n = 23) as used before the CDI technique was available. The main outcomes of interest were 90-day survival and reduction of right to left ventricle diameter (RV/LV) ratio, using the Fischer's exact test and a mixed model, respectively, for statistical analysis. RESULTS: Ninety-day survival was 59% after CDI and 61% after anticoagulation only; P = .903. The rate of RV/LV ratio reduction was 0.4 units higher per 24 hours in the CDI group (median 2.1 pre-treatment), than in the anticoagulation only group (median 1.3 pre-treatment); P = .007. CONCLUSION: In patients with high-risk pulmonary embolism, 90-day survival was similar after treatment with CDI plus anticoagulation compared to anticoagulation only. The mean reduction in RV/LV ratio was larger in the CDI group. Our results support the use of CDI in selected patients, respecting the limitations and potential side effects of each technical device used.

The capacity of neurological pupil index to predict absence of somatosensory evoked potentials after cardiac arrest-A study protocol.

BACKGROUND: Anoxic-ischemic brain injury is the most common cause of death after cardiac arrest (CA). Robust methods to detect severe injury with a low false positive rate (FPR) for poor neurological outcome include the pupillary light reflex (PLR) and somatosensory evoked potentials (SSEP). The PLR can be assessed manually or with automated pupillometry which provides the neurological pupil index (NPi). We aim to describe the interrelation between NPi values and the absence of SSEP cortical response and to evaluate the capacity of NPi to predict the absence of cortical SSEP response in comatose patients after CA. METHODS: A total of 50 patients will be included in an explorative, prospective, observational study of adult (>18 years) comatose survivors of CA admitted to intensive care in a university hospital. NPi assessed with a hand-held pupillometer will be compared to SSEP signals recorded >48 hours after CA. Primary outcomes are sensitivity, specificity, and odds ratio for NPi to predict bilateral absence of the SSEP N20 signal, with NPi values corresponding to <5% FPRs of SSEP absence. Secondary outcomes are the PLR and SSEP sensitivity, specificity, and odds ratio for poor neurological outcome at hospital discharge and death at 30 days. DISCUSSION: The PLR and SSEP may have a systematic interrelation, and a certain NPi threshold could potentially predict the absence of cortical SSEP response. If this can be concluded from the present study, SSEP testing could be excluded in certain patients to save resources in the multimodal prognostication after CA. Editorial comment The interrelation between loss of the pupillary light reflex (PLR) and the loss of cortical response to a somatosensory evoked potential (SSEP) in comatose cardiac arrest patients is not known. This exploratory prospective study is designed to evaluate whether a specific degree of attenuated PLR, as measured by semiautomated pupillometry, can predict the bilateral loss of cortical SSEP response in severe anoxic/ischemic brain injury. Such an interrelation between the two methods would enable the use of pupillometry rather than the more resource demanding SSEP for neurologic prognostication in post cardiac arrest patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04720482, Registered 21 January 2021, retrospectively registered.

Expiratory Resistances Prevent Expiratory Diaphragm Contraction, Flow Limitation, and Lung Collapse.

Rationale: Tidal expiratory flow limitation (tidal-EFL) is not completely avoidable by applying positive end-expiratory pressure and may cause respiratory and hemodynamic complications in ventilated patients with lungs prone to collapse. During spontaneous breathing, expiratory diaphragmatic contraction counteracts tidal-EFL. We hypothesized that during both spontaneous breathing and controlled mechanical ventilation, external expiratory resistances reduce tidal-EFL.Objectives: To assess whether external expiratory resistances 1) affect expiratory diaphragmatic contraction during spontaneous breathing, 2) reduce expiratory flow and make lung compartments more homogeneous with more similar expiratory time constants, and 3) reduce tidal atelectasis, preventing hyperinflation.Methods: Three positive end-expiratory pressure levels and four external expiratory resistances were tested in 10 pigs after lung lavage. We analyzed expiratory diaphragmatic electric activity and respiratory mechanics. On the basis of computed tomography scans, four lung compartments-not inflated (atelectasis), poorly inflated, normally inflated, and hyperinflated-were defined.Measurements and Main Results: Consequently to additional external expiratory resistances, and mainly in lungs prone to collapse (at low positive end-expiratory pressure), 1) the expiratory transdiaphragmatic pressure decreased during spontaneous breathing by >10%, 2) expiratory flow was reduced and the expiratory time constants became more homogeneous, and 3) the amount of atelectasis at end-expiration decreased from 24% to 16% during spontaneous breathing and from 32% to 18% during controlled mechanical ventilation, without increasing hyperinflation.Conclusions: The expiratory modulation induced by external expiratory resistances preserves the positive effects of the expiratory brake while minimizing expiratory diaphragmatic contraction. External expiratory resistances optimize lung mechanics and limit tidal-EFL and tidal atelectasis, without increasing hyperinflation.

Hidden sources of fluids, sodium and potassium in stabilised Swedish ICU patients: A multicentre retrospective observational study.

BACKGROUND: Fluid overload in ICU patients is associated with increased morbidity and mortality. Although studies report on optimisation of resuscitation fluids given to ICU patients, increasing evidence suggests that maintenance fluids and fluids used to administer drugs are important sources of fluid overload. OBJECTIVES: We aimed to evaluate the volume of maintenance fluids and electrolytes on overall fluid balance and their relation to mortality in stabilised ICU patients. DESIGN: Multicentre retrospective observational study. SETTING: Six mixed surgical and medical ICUs in Sweden. PATIENTS: A total of 241 adult patients who spent at least 7 days in the ICU during 2018. MAIN OUTCOME MEASURES: The primary endpoint was the volume of maintenance, resuscitation and drug diluent fluids administered on days 3 to 7 in the ICU. Secondary endpoints were to compare dispensed amounts of maintenance fluids and electrolytes with predicted requirements. We also investigated the effects of administered fluids and electrolytes on patient outcomes. RESULTS: During ICU days 3 to 7, 56.4% of the total fluids given were maintenance fluids, nutritional fluids or both, 25.4% were drug fluids and 18.1% were resuscitation fluids. Patients received fluids 1.29 (95% confidence interval 1.07 to 1.56) times their estimated fluid needs. Despite this, 93% of the cohort was treated with diuretics or renal replacement therapy. Patients were given 2.17 (1.57 to 2.96) times their theoretical sodium needs and 1.22 (0.75 to 1.77) times their potassium needs. The median [IQR] volume of fluid loss during the 5-day study period was 3742 [3156 to 4479] ml day-1, with urine output the main source of fluid loss. Death at 90 days was not associated with fluid or electrolyte balance in this cohort. CONCLUSION: Maintenance and drug fluids far exceeded resuscitative fluids in ICU patients beyond the resuscitative phase. This excess fluid intake, in conjunction with high urinary output and treatment for fluid offload in almost all patients, suggests that a large volume of the maintenance fluids given was unnecessary. TRIAL REGISTRATION: ClinicalTrials.org NCT03972475.

Simplified Postoperative Care After Spring-assisted Strip Craniotomy for Sagittal Synostosis: A Prospective Before-and-After Study.

ABSTRACT: Since the development of spring-assisted techniques for corrective craniofacial surgery, routine postoperative admission to intensive care units (ICUs) has been questioned. However, close monitoring is necessary if the continuous infusion of morphine is used as recommended for better pain relief. In this study, the authors evaluated a simplified postoperative protocol without continuous morphine infusion and no indwelling urinary catheter following spring-assisted surgery (SAS) for sagittal synostosis. Ten children were cared for according to a standard protocol with postoperative intravenous (i.v.) infusion of morphine and an indwelling urinary catheter, and 11 consecutive children were treated according to a simplified protocol with pain relief based on intermittent injections of morphine and clonidine [according to Face, Legs, Activity, Cry, Consolability (FLACC) scores >4] without the indwelling catheter. A Mann-Whitney U test was used for comparison of distributions between the two groups. The results revealed no differences between groups regarding the proportion of FLACC scores >4, total amount of administered i.v. morphine and clonidine, total volume of buffered glucose infused, time to first feeding on breast milk or substitute, or the length of stay. Despite the inherent limitations of our small observational study, the authors concluded that at our institution, it was possible to exclude a standard continuous i.v. infusion of morphine and an indwelling urinary catheter from our postoperative care protocol without decreasing the quality of pain relief in children submitted to SAS for sagittal synostosis. This finding supports downgrading the level of care from the ICU to a regular ward after limited immediate postoperative observation.

Neuropsychological outcome after cardiac arrest: a prospective case control sub-study of the Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest trial (TTM2).

BACKGROUND: This study is designed to provide detailed knowledge on cognitive impairment after out-of-hospital cardiac arrest (OHCA) and its relation to associated factors, and to validate the neurocognitive screening of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2-trial), assessing effectiveness of targeted temperature management after OHCA. METHODS: This longitudinal multi-center clinical study is a sub-study of the TTM2-trial, in which a comprehensive neuropsychological examination is performed in addition to the main TTM2-trial neurocognitive screening. Approximately 7 and 24 months after OHCA, survivors at selected study sites are invited to a standardized assessment, including performance-based tests of cognition and questionnaires of emotional problems, fatigue, executive function and insomnia. At 1:1 ratio, a matched control group from a cohort of acute myocardial infarction (MI) patients is recruited to perform the same assessment. We aim to include 100 patients per group. Potential differences between the OHCA patients and the MI controls at 7 and 24 months will be analyzed with a linear regression, using composite z-scores per cognitive domain (verbal, visual/constructive, working memory, episodic memory, processing speed, executive functions) as primary outcome measures. Results from OHCA survivors on the main TTM2-trial neurocognitive screening battery will be compared with neuropsychological test results at 7 months, using sensitivity and specificity analyses. DISCUSSION: In this study we collect detailed information on cognitive impairment after OHCA and compare this to a control group of patients with acute MI. The validation of the TTM2 neurocognitive screening battery could justify its inclusion in routine follow-up. Our results may have a potential to impact on the design of future follow-up strategies and interventions after OHCA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371 . Registered 1 June 2018.

Transpulmonary driving pressure during mechanical ventilation-validation of a non-invasive measurement method.

BACKGROUND: Transpulmonary driving pressure plays an important role in today's understanding of ventilator induced lung injury. We have previously validated a novel non-invasive method based on stepwise increments of PEEP to assess transpulmonary driving pressure in anaesthetised patients with healthy lungs. The aim of this study was to validate the method in patients who were mechanically ventilated for different diagnoses requiring intensive care. METHODS: We measured transpulmonary pressure (Ptp) and calculated transpulmonary driving pressure (ΔPtp) in 31 patients undergoing mechanical ventilation in an intensive care unit. Parallel triplicate measurements were performed with the PEEP step method (PtpPSM) and the conventional oesophageal balloon method (Ptpconv). Their agreement was compared using the intraclass correlation coefficient (ICC) and the Bland Altman plot. RESULT: The coefficient of variation for the repeated measurements was 4,3 for ΔPtpPSM and 9,2 for ΔPtpconv. The ICC of 0,864 and the Bland Altman plot indicate good agreement between the two methods. CONCLUSION: The non-invasive method can be applied in mechanically ventilated patients to measure transpulmonary driving pressure with good repeatability and accuracy comparable to the traditional oesophageal balloon method.

Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial-Rationale and design.

BACKGROUND: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. METHODS: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4-6) at 180 days after arrest. DISCUSSION: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest.

Historic review of long-term outcomes research.

PURPOSE OF REVIEW: This review summarizes the results from long-term intensive care outcome research over the past 50 years. Key findings from early studies are reflected in citations of contemporary research. RECENT FINDINGS: The postintensive care syndrome (PICS) is a multifaceted entity of residual disability and complications burdening survivors of critical illness. Some interventions applied early in the history of outcomes research have now been confirmed as effective in counteracting specific PICS components. SUMMARY: Interest in patient-centred outcomes has been present since the beginning of modern intensive care. Findings from early long-term studies remain valid even in the face of contemporary large registries that facilitate follow-up of larger cohorts. A further understanding of the mechanisms leading to experienced physical and psychological impairment of PICS will be essential to the design of future intervention trials.

Serum tau and neurological outcome in cardiac arrest.

OBJECTIVE: To test serum tau as a predictor of neurological outcome after cardiac arrest. METHODS: We measured the neuronal protein tau in serum at 24, 48, and 72 hours after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor neurological outcome, defined as Cerebral Performance Categories 3-5 at 6 months. RESULTS: Increased tau was associated with poor outcome at 6 months after cardiac arrest (median = 38.5, interquartile range [IQR] = 5.7-245ng/l in poor vs median = 1.5, IQR = 0.7-2.4ng/l in good outcome, for tau at 72 hours, p < 0.0001). Tau improved prediction of poor outcome compared to using clinical information (p < 0.0001). Tau cutoffs had low false-positive rates (FPRs) for good outcome while retaining high sensitivity for poor outcome. For example, tau at 72 hours had FPR = 2% (95% CI = 1-4%) with sensitivity = 66% (95% CI = 61-70%). Tau had higher accuracy than serum neuron-specific enolase (NSE; the area under the receiver operating characteristic curve was 0.91 for tau vs 0.86 for NSE at 72 hours, p = 0.00024). During follow-up (up to 956 days), tau was significantly associated with overall survival. The accuracy in predicting outcome by serum tau was equally high for patients randomized to 33 °C and 36 °C targeted temperature after cardiac arrest. INTERPRETATION: Serum tau is a promising novel biomarker for prediction of neurological outcome in patients with cardiac arrest. It may be significantly better than serum NSE, which is recommended in guidelines and currently used in clinical practice in several countries to predict outcome after cardiac arrest. Ann Neurol 2017;82:665-675.

Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome.

Shiga toxin (Stx)-producing Escherichia coli (STEC) cause hemolytic uremic syndrome (HUS). This study investigated whether Stx2 induces hemolysis and whether complement is involved in the hemolytic process. RBCs and/or RBC-derived microvesicles from patients with STEC-HUS (n = 25) were investigated for the presence of C3 and C9 by flow cytometry. Patients exhibited increased C3 deposition on RBCs compared with controls (p < 0.001), as well as high levels of C3- and C9-bearing RBC-derived microvesicles during the acute phase, which decreased after recovery. Stx2 bound to P1 (k) and P2 (k) phenotype RBCs, expressing high levels of the P(k) Ag (globotriaosylceramide), the known Stx receptor. Stx2 induced the release of hemoglobin and lactate dehydrogenase in whole blood, indicating hemolysis. Stx2-induced hemolysis was not demonstrated in the absence of plasma and was inhibited by heat inactivation, as well as by the terminal complement pathway Ab eculizumab, the purinergic P2 receptor antagonist suramin, and EDTA. In the presence of whole blood or plasma/serum, Stx2 induced the release of RBC-derived microvesicles coated with C5b-9, a process that was inhibited by EDTA, in the absence of factor B, and by purinergic P2 receptor antagonists. Thus, complement-coated RBC-derived microvesicles are elevated in HUS patients and induced in vitro by incubation of RBCs with Stx2, which also induced hemolysis. The role of complement in Stx2-mediated hemolysis was demonstrated by its occurrence only in the presence of plasma and its abrogation by heat inactivation, EDTA, and eculizumab. Complement activation on RBCs could play a role in the hemolytic process occurring during STEC-HUS.

Early predictors of poor outcome after out-of-hospital cardiac arrest.

BACKGROUND: Early identification of predictors for a poor long-term outcome in patients who survive the initial phase of out-of-hospital cardiac arrest (OHCA) may facilitate future clinical research, the process of care and information provided to relatives. The aim of this study was to determine the association between variables available from the patient's history and status at intensive care admission with outcome in unconscious survivors of OHCA. METHODS: Using the cohort of the Target Temperature Management trial, we performed a post hoc analysis of 933 unconscious patients with OHCA of presumed cardiac cause who had a complete 6-month follow-up. Outcomes were survival and neurological function as defined by the Cerebral Performance Category (CPC) scale at 6 months after OHCA. After multiple imputations to compensate for missing data, backward stepwise multivariable logistic regression was applied to identify factors independently predictive of a poor outcome (CPC 3-5). On the basis of these factors, a risk score for poor outcome was constructed. RESULTS: We identified ten independent predictors of a poor outcome: older age, cardiac arrest occurring at home, initial rhythm other than ventricular fibrillation/tachycardia, longer duration of no flow, longer duration of low flow, administration of adrenaline, bilateral absence of corneal and pupillary reflexes, Glasgow Coma Scale motor response 1, lower pH and a partial pressure of carbon dioxide in arterial blood value lower than 4.5 kPa at hospital admission. A risk score based on the impact of each of these variables in the model yielded a median (range) AUC of 0.842 (0.840-0.845) and good calibration. Internal validation of the score using bootstrapping yielded a median (range) AUC corrected for optimism of 0.818 (0.816-0.821). CONCLUSIONS: Among variables available at admission to intensive care, we identified ten independent predictors of a poor outcome at 6 months for initial survivors of OHCA. They reflected pre-hospital circumstances (six variables) and patient status on hospital admission (four variables). By using a simple and easy-to-use risk scoring system based on these variables, patients at high risk for a poor outcome after OHCA may be identified early.