[Extracorporeal cardiopulmonary resuscitation in out-of-hospital resuscitation]. / Extracorporale cardiopulmonale resuscitatie bij reanimatie buiten het ziekenhuis.

If an out-of-hospital cardiac arrest (OHCA) takes longer than 15 minutes, the chances of survival are greatly reduced. With a shockable rhythm (VF/VT), there is often a treatable underlying cause, which most often can only be treated in a hospital. The patient can be transported, and circulation can be restored in the hospital, using extracorporeal cardiopulmonary resuscitation (ECPR) to gain time to treat the underlying problem. There are observational studies and one single-centre study that support the use of ECPR in refractory OHCA. However, two recent larger trials could not establish a significant benefit for ECPR. As many of these patients in refractory cardiac arrest will ultimately not survive, we will need solid cost-benefit analyses to evaluate the value of ECPR. We also need to explore the possibility of starting ECPR on scene, to reduce low-flow time even more, and hopefully improve the outcome of out-of-hospital cardiac arrest patients.

Self-reported limitations in physical function are common 6 months after out-of-hospital cardiac arrest.

Title: Self-reported limitations in physical function are common 6 months after out-of-hospital cardiac arrest. Background: Out-of-hospital cardiac arrest (OHCA) survivors generally report good health-related quality of life, but physical aspects of health seem more affected than other domains. Limitations in physical function after surviving OHCA have received little attention. Aims: To describe physical function 6 months after OHCA and compare it with a group of ST elevation myocardial infarction (STEMI) controls, matched for country, age, sex and time of the cardiac event. A second aim was to explore variables potentially associated with self-reported limitations in physical function in OHCA survivors. Methods: A cross-sectional sub-study of the Targeted Temperature Management at 33 °C versus 36 °C (TTM) trial with a follow-up 6 months post-event. Physical function was the main outcome assessed with the self-reported Physical Functioning-10 items scale (PF-10). PF-10 is presented as T-scores (0-100), where 50 represents the norm mean. Scores <47 at a group level, or <45 at an individual level indicate limitations in physical function. Results: 287 OHCA survivors and 119 STEMI controls participated. Self-reported physical function by PF-10 was significantly lower for OHCA survivors compared to STEMI controls (mean 46.0, SD 11.2 vs. 48.8, SD 9.0, p = 0.025). 38% of OHCA survivors compared to 26% of STEMI controls reported limitations in physical function at an individual level (p = 0.022). The most predictive variables for self-reported limitations in physical function in OHCA survivors were older age, female sex, cognitive impairment, and symptoms of anxiety and depression after 6 months. Conclusion: Self-reported limitations in physical function are more common in OHCA survivors compared to STEMI controls. Trial registration: ClinicalTrials.gov Identifier: NCT01946932.

Brain death/death by neurologic criteria determination: an update.

PURPOSE OF REVIEW: Brain death, also known as death by neurologic criteria (DNC), is a well-established concept. In this article, we present a short history of the concept and give an overview of recent changes and a practical update on diagnosis and definitions of brain death/DNC. Unresolved issues will be discussed. RECENT FINDINGS: There is variability in brain death/DNC determination worldwide. In recent years, successful attempts have been made to harmonize these criteria and, consequently, to improve public trust in the process and diagnosis. An international multidisciplinary collaboration has been created and it has published minimum criteria, provided guidance for professionals and encouragement to revise or develop guidelines on brain death/DNC worldwide. SUMMARY: There are two sets of criteria for declaration of death. First, if there is neither cardiac output nor respiratory effort, then cardiopulmonary criteria are used. Second, if both the cerebrum and brainstem have completely and permanently lost all functions, and there is a persistent coma, absent brainstem reflexes and no spontaneous respiratory effort, death can be declared on the basis of brain death/DNC. Although attempts to formulate uniform criteria are ongoing, consensus has been reached on the minimum criteria. Some inconsistencies and questions remain.

Data-driven platform for identifying variants of interest in COVID-19 virus.

New SARS-CoV-2 variants emerge as part of the virus' adaptation to the human host. The Health Organizations are monitoring newly emerging variants with suspected impact on disease or vaccination efficacy as Variants Being Monitored (VBM), like Delta and Omicron. Genetic changes (SNVs) compared to the Wuhan variant characterize VBMs with current emphasis on the spike protein and lineage markers. However, monitoring VBMs in such a way might miss SNVs with functional effect on disease. Here we introduce a lineage-agnostic genome-wide approach to identify SNVs associated with disease. We curated a case-control dataset of 10,520 samples and identified 117 SNVs significantly associated with adverse patient outcome. While 40% (47) SNV are already monitored and 36% (43) are in the spike protein, we also identified 70 new SNVs that are associated with disease outcome. 31 of these are disease-worsening and predominantly located in the 3'-5' exonuclease (NSP14) with structural modelling revealing a concise cluster in the Zn binding domain that has known host-immune modulating function. Furthermore, we generate clade-independent VBM groupings by identifying interacting SNVs (epistasis). We find 37 sets of higher-order epistatic interactions joining 5 genomic regions (nsp3, nsp14, Spike S1, ORF3a, N). Structural modelling of these regions provides insights into potential mechanistic pathways of increased virulence as well as orthogonal methods of validation. Clade-independent monitoring of functionally interacting (epistasis, co-evolution) SNVs detected emerging VBM a week before they were flagged by Health Organizations and in conjunction with structural modelling provides faster, mechanistic insight into emerging strains to guide public health interventions.

At Least Three Doses of Leading Vaccines Essential for Neutralisation of SARS-CoV-2 Omicron Variant.

Plasma samples taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8-fold reduction in 50% neutralizing antibody titres (NT50) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose; followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most samples having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca samples derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These findings indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.

Association Between EEG Patterns and Serum Neurofilament Light After Cardiac Arrest: A Post Hoc Analysis of the TTM Trial.

BACKGROUND AND OBJECTIVES: EEG is widely used for prediction of neurologic outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explored the association between EEG and neurofilament light (NfL) as a marker of neuroaxonal injury, evaluated whether highly malignant EEG patterns are reflected by high NfL levels, and explored the association of EEG backgrounds and EEG discharges with NfL. METHODS: We performed a post hoc analysis of the Target Temperature Management After Out-of-Hospital Cardiac Arrest trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours postarrest. Patients who awoke or died prior to 36 hours postarrest were excluded. EEG experts blinded to clinical information classified EEG background, amount of discharges, and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NfL after trial completion. The highest available concentration at 48 or 72 hours postarrest was used. RESULTS: A total of 262/939 patients with EEG and NfL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NfL levels than patients with malignant patterns and NfL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI 1.4-6.1 and 6.5-26.2, respectively; effect size 0.47; p < 0.001). Both background and the amount of discharges were independently strongly associated with NfL levels (p < 0.001). The EEG background had a stronger association with NfL levels than EEG discharges (R2 = 0.30 and R2 = 0.10, respectively). NfL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression, and suppression, respectively: 2.26-18.06, 3.91-41.71, and 5.74-41.74; effect size 0.30; p < 0.001 for all). NfL levels did not differ between suppression and burst suppression. Superimposed discharges were only associated with higher NfL levels if the EEG background was continuous. DISCUSSION: Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NfL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NfL may be useful to better identify patients misclassified by single methods. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT01020916.

Highly Thermotolerant SARS-CoV-2 Vaccine Elicits Neutralising Antibodies against Delta and Omicron in Mice.

As existing vaccines fail to completely prevent COVID-19 infections or community transmission, there is an unmet need for vaccines that can better combat SARS-CoV-2 variants of concern (VOC). We previously developed highly thermo-tolerant monomeric and trimeric receptor-binding domain derivatives that can withstand 100 °C for 90 min and 37 °C for four weeks and help eliminate cold-chain requirements. We show that mice immunised with these vaccine formulations elicit high titres of antibodies that neutralise SARS-CoV-2 variants VIC31 (with Spike: D614G mutation), Delta and Omicron (BA.1.1) VOC. Compared to VIC31, there was an average 14.4-fold reduction in neutralisation against BA.1.1 for the three monomeric antigen-adjuvant combinations and a 16.5-fold reduction for the three trimeric antigen-adjuvant combinations; the corresponding values against Delta were 2.5 and 3.0. Our findings suggest that monomeric formulations are suitable for upcoming Phase I human clinical trials and that there is potential for increasing the efficacy with vaccine matching to improve the responses against emerging variants. These findings are consistent with in silico modelling and AlphaFold predictions, which show that, while oligomeric presentation can be generally beneficial, it can make important epitopes inaccessible and also carries the risk of eliciting unwanted antibodies against the oligomerisation domain.

Inhibition of N-type calcium ion channels by tricyclic antidepressants - experimental and theoretical justification for their use for neuropathic pain.

A number of tricyclic antidepressants (TCAs) are commonly prescribed off-label for the treatment of neuropathic pain. The blockade of neuronal calcium ion channels is often invoked to partially explain the analgesic activity of TCAs, but there has been very limited experimental or theoretical evidence reported to support this assertion. The N-type calcium ion channel (CaV2.2) is a well-established target for the treatment of neuropathic pain and in this study a series of eleven TCAs and two closely related drugs were shown to be moderately effective inhibitors of this channel when endogenously expressed in the SH-SY5Y neuroblastoma cell line. A homology model of the channel, which matches closely a recently reported Cryo-EM structure, was used to investigate via docking and molecular dynamics experiments the possible mode of inhibition of CaV2.2 channels by TCAs. Two closely related binding modes, that occur in the channel cavity that exists between the selectivity filter and the internal gate, were identified. The TCAs are predicted to position themselves such that their ammonium side chains interfere with the selectivity filter, with some, such as amitriptyline, also appearing to hinder the channel's ability to open. This study provides the most comprehensive evidence to date that supports the notion that the blockade of neuronal calcium ion channels by TCAs is at least partially responsible for their analgesic effect.

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.)

Caregiver burden and health-related quality of life amongst caregivers of out-of-hospital cardiac arrest survivors.

AIMS: To describe burden and health-related quality of life amongst caregivers of out-of-hospital cardiac arrest survivors and explore the potential association with cognitive function of the survivors. Caregivers of patients with ST-elevation myocardial infarction were used as controls. METHODS: Data were collected from the cognitive substudy of the Targeted Temperature Management-trial. Caregiver burden was assessed with the 22-item Zarit Burden Interview, with scores ≤20 considered as no burden. Health-related quality of life was assessed with the SF-36v2®, with T-scores 47-53 representing the norm. Cardiac arrest survivors were categorized based on the results from cognitive assessments as having "no cognitive impairment" or "cognitive impairment". RESULTS: Follow-up 6 months post event was performed for caregivers of 272 cardiac arrest survivors and 108 matched myocardial infarction controls, included at an intended ratio of 2:1. In general, caregivers of cardiac arrest survivors and controls reported similar caregiver burden. The overall scores for quality of life were within normative levels and similar for caregivers of cardiac arrest survivors and control patients. Compared to those with no cognitive impairment, caregivers of cognitively impaired cardiac arrest survivors (n = 126) reported higher levels of burden (median 18 versus 8, p < 0.001) and worse quality of life in five of eight domains, particularly "Role-Emotional" (mean 45.7 versus 49.5, p = 0.002). CONCLUSIONS: In general, caregivers of cardiac arrest survivors and myocardial infarction controls reported similar levels of burden and quality of life. Cognitive outcome and functional dependency of the cardiac arrest survivor impact burden and quality of life of the caregiver.

Live Virus Neutralisation of the 501Y.V1 and 501Y.V2 SARS-CoV-2 Variants following INO-4800 Vaccination of Ferrets.

The ongoing COVID-19 pandemic has resulted in significant global morbidity and mortality on a scale similar to the influenza pandemic of 1918. Over the course of the last few months, a number of SARS-CoV-2 variants have been identified against which vaccine-induced immune responses may be less effective. These "variants-of-concern" have garnered significant attention in the media, with discussion around their impact on the future of the pandemic and the ability of leading COVID-19 vaccines to protect against them effectively. To address concerns about emerging SARS-CoV-2 variants affecting vaccine-induced immunity, we investigated the neutralisation of representative 'G614', '501Y.V1' and '501Y.V2' virus isolates using sera from ferrets that had received prime-boost doses of the DNA vaccine, INO-4800. Neutralisation titres against G614 and 501Y.V1 were comparable, but titres against the 501Y.V2 variant were approximately 4-fold lower, similar to results reported with other nucleic acid vaccines and supported by in silico biomolecular modelling. The results confirm that the vaccine-induced neutralising antibodies generated by INO-4800 remain effective against current variants-of-concern, albeit with lower neutralisation titres against 501Y.V2 similar to other leading nucleic acid-based vaccines.

The Impact of Nursing Delirium Preventive Interventions in the ICU: A Multicenter Cluster-randomized Controlled Clinical Trial.

Rationale: Delirium is common in critically ill patients and is associated with deleterious outcomes. Nonpharmacological interventions are recommended in current delirium guidelines, but their effects have not been unequivocally established. Objectives: To determine the effects of a multicomponent nursing intervention program on delirium in the ICU. Methods: A stepped-wedge cluster-randomized controlled trial was conducted in ICUs of 10 centers. Adult critically ill surgical, medical, or trauma patients at high risk of developing delirium were included. A multicomponent nursing intervention program focusing on modifiable risk factors was implemented as standard of care. The primary outcome was the number of delirium-free and coma-free days alive in 28 days after ICU admission. Measurements and Main Results: A total of 1,749 patients were included. Time spent on interventions per 8-hour shift was median (interquartile range) 38 (14-116) minutes in the intervention period and median 32 (13-73) minutes in the control period (P = 0.44). Patients in the intervention period had a median of 23 (4-27) delirium-free and coma-free days alive compared with a median of 23 (5-27) days for patients in the control group (mean difference, -1.21 days; 95% confidence interval, -2.84 to 0.42 d; P = 0.15). In addition, the number of delirium days was similar: median 2 (1-4) days (ratio of medians, 0.90; 95% confidence interval, 0.75 to 1.09; P = 0.27). Conclusions: In this large randomized controlled trial in adult ICU patients, a limited increase in the use of nursing interventions was achieved, and no change in the number of delirium-free and coma-free days alive in 28 days could be determined. Clinical trial registered with www.clinicaltrials.gov (NCT03002701).

"But Mouse, You Are Not Alone": On Some Severe Acute Respiratory Syndrome Coronavirus 2 Variants Infecting Mice.

In silico predictions combined with in vitro, in vivo, and in situ observations collectively suggest that mouse adaptation of the severe acute respiratory syndrome 2 virus requires an aromatic substitution in position 501 or position 498 (but not both) of the spike protein's receptor binding domain. This effect could be enhanced by mutations in positions 417, 484, and 493 (especially K417N, E484K, Q493K, and Q493R), and to a lesser extent by mutations in positions 486 and 499 (such as F486L and P499T). Such enhancements, due to more favorable binding interactions with residues on the complementary angiotensin-converting enzyme 2 interface, are, however, unlikely to sustain mouse infectivity on their own based on theoretical and experimental evidence to date. Our current understanding thus points to the Alpha, Beta, Gamma, and Omicron variants of concern infecting mice, whereas Delta and "Delta Plus" lack a similar biomolecular basis to do so. This paper identifies 11 countries (Brazil, Chile, Djibouti, Haiti, Malawi, Mozambique, Reunion, Suriname, Trinidad and Tobago, Uruguay, and Venezuela) where targeted local field surveillance of mice is encouraged because they may have come in contact with humans who had the virus with adaptive mutation(s). It also provides a systematic methodology to analyze the potential for other animal reservoirs and their likely locations.

Experimental and in silico evidence suggests vaccines are unlikely to be affected by D614G mutation in SARS-CoV-2 spike protein.

The 'D614G' mutation (Aspartate-to-Glycine change at position 614) of the SARS-CoV-2 spike protein has been speculated to adversely affect the efficacy of most vaccines and countermeasures that target this glycoprotein, necessitating frequent vaccine matching. Virus neutralisation assays were performed using sera from ferrets which received two doses of the INO-4800 COVID-19 vaccine, and Australian virus isolates (VIC01, SA01 and VIC31) which either possess or lack this mutation but are otherwise comparable. Through this approach, supported by biomolecular modelling of this mutation and the commonly-associated P314L mutation in the RNA-dependent RNA polymerase, we have shown that there is no experimental evidence to support this speculation. We additionally demonstrate that the putative elastase cleavage site introduced by the D614G mutation is unlikely to be accessible to proteases.

Circulating Levels of Brain-Enriched MicroRNAs Correlate with Neuron Specific Enolase after Cardiac Arrest-A Substudy of the Target Temperature Management Trial.

Outcome prognostication after cardiac arrest (CA) is challenging. Current multimodal prediction approaches would benefit from new biomarkers. MicroRNAs constitute a novel class of disease markers and circulating levels of brain-enriched ones have been associated with outcome after CA. To determine whether these levels reflect the extent of brain damage in CA patients, we assessed their correlation with neuron-specific enolase (NSE), a marker of brain damage. Blood samples taken 48 h after return of spontaneous circulation from two groups of patients from the Targeted Temperature Management trial were used. Patients were grouped depending on their neurological outcome at six months. Circulating levels of microRNAs were assessed by sequencing. NSE was measured at the same time-point. Among the 673 microRNAs detected, brain-enriched miR9-3p, miR124-3p and miR129-5p positively correlated with NSE levels (all p < 0.001). Interestingly, these correlations were absent when only the good outcome group was analyzed (p > 0.5). Moreover, these correlations were unaffected by demographic and clinical characteristics. All three microRNAs predicted neurological outcome at 6 months. Circulating levels of brain-enriched microRNAs are correlated with NSE levels and hence can reflect the extent of brain injury in patients after CA. This observation strengthens the potential of brain-enriched microRNAs to aid in outcome prognostication after CA.

Serum GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients.

OBJECTIVE: Neurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischaemic injury may aid in outcome prediction. The only serum biomarker presently recommended in the European Resuscitation Council prognostication guidelines is neuron-specific enolase (NSE), but NSE has limitations. In this study, we therefore analyzed the outcome predictive accuracy of the serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients after cardiac arrest. METHODS: Serum GFAP and UCH-L1 were collected at 24, 48 and 72 h after cardiac arrest. The primary outcome was neurological function at 6-month follow-up assessed by the cerebral performance category scale (CPC), dichotomized into good (CPC1-2) and poor (CPC3-5). Prognostic accuracies were tested with receiver-operating characteristics by calculating the area under the receiver-operating curve (AUROC) and compared to the AUROC of NSE. RESULTS: 717 patients were included in the study. GFAP and UCH-L1 discriminated between good and poor neurological outcome at all time-points when used alone (AUROC GFAP 0.88-0.89; UCH-L1 0.85-0.87) or in combination (AUROC 0.90-0.91). The combined model was superior to GFAP and UCH-L1 separately and NSE (AUROC 0.75-0.85) at all time-points. At specificities ≥95%, the combined model predicted poor outcome with a higher sensitivity than NSE at 24 h and with similar sensitivities at 48 and 72 h. CONCLUSION: GFAP and UCH-L1 predicted poor neurological outcome with high accuracy. Their combination may be of special interest for early prognostication after cardiac arrest where it performed significantly better than the currently recommended biomarker NSE.

Copeptin as a marker of outcome after cardiac arrest: a sub-study of the TTM trial.

BACKGROUND: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest. METHODS: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score. RESULTS: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06-1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01-1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02-1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12-0.27], p < 0.001. CONCLUSION: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure. TRIAL REGISTRATION: Clinical Trials, NCT01020916. Registered November 26, 2009.

[How does a doctor declare death?] / Hoe stelt een arts de dood vast?

Ward doctors in regular medical departments have to be competent in declaring the death of a patient. The majority of literature on confirmation of death focuses on special circumstances, including intensive care patients and cases involving organ donation. There is no consensus regarding the procedure and criteria for declaration of death in a 'normal' patient on a medical ward. In this article we describe the death criteria, changes that occur in the body following death, and how death can be declared in in a 'normal' patient on a medical ward and in special circumstances.

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.