https://orcid.org/0000-0002-5511-4668
Abstract
Out-of-hospital cardiac arrest is a leading cause of mortality. In the pre-hospital setting, bystander response with cardiopulmonary resuscitation and the use of publicly available automated external defibrillators have been associated with improved survival. Early in-hospital treatment still focuses on emergency coronary angiography for selected patients. For patients remaining comatose, temperature control to avoid fever is still recommended, but former hypothermic targets have been abandoned. For patients without spontaneous awakening, the use of a multimodal prognostication model is key. After discharge, follow-up with screening for cognitive and emotional disabilities is recommended. There has been an incredible evolution of research on cardiac arrest. Two decades ago, the largest trials include a few hundred patients. Today, undergoing studies are planning to include 10–20 times as many patients, with improved methodology. This article describes the evolution and perspectives for the future in post-cardiac arrest care.
Introduction
Out-of-hospital cardiac arrest (OHCA) is getting increasing attention worldwide. Around the year 2000, the 1-year survival rate of OHCA was 3–4% overall.1,2 This has in some countries increased three to four-fold to 10–15% in 2010–2019.2,3 Despite these improvements large variation in OHCA incidence, outcome, and treatment across Europe exists.4,5 Mortality remains high and OHCA is a major contributor to mortality and disability. Today, the annual incidence of OHCA in Europe is between 67 and 170 per 100 000 inhabitants.4,6
The Chain of Survival emphasize the time-sensitive interventions (as links) to maximize the chance of survival from OHCA.7 The message conveyed in each link has been embraced by The European Resuscitation Council (ERC) guidelines and summarizes the links needed for survival with the good neurological outcome: (1) Early recognition and call for help; (2) Early bystander cardiopulmonary resuscitation (CPR); (3) Early defibrillation; and (4) Early advanced life support (ALS) and standardized post-resuscitation care.8 Especially the first three links have improved in most European countries. In Denmark, the use of automated external defibrillators in public increased from 0% to 18%, while bystander CPR increased from a mere 20% to about 80%.2 These public initiatives are likely a major contributor to the improvement in outcomes.2,9
Today less than half of resuscitated OHCA patients who are admitted to the hospital in a coma will survive to discharge10 despite extensive and high-quality research into improving outcome during the last decades. Because these patients are circulatory unstable, require intensive care and the primary cause of death is an anoxic brain injury, interventions such as sedation, ventilation, haemodynamic management, the timing of coronary angiography, need for mechanical circulatory support, control of infection and inflammation as well as improving neurological outcomes, and neuroprognostication have all been studied intensely. The purpose of this review is to underline the evolution of post-resuscitation care and suggest areas of interest for improvement of care in the future.
Pre-hospital setting
In modern societies, cardiac arrest treatment starts even before the arrival of emergency medical services (EMS). Smartphone-activated volunteer responders can be utilized, guided over the phone, and assist with early basic life support including CPR and use of public automated external defibrillator (AEDs).11 Emergency telecommunicators can provide instant instructions with telecommunicator CPR (T-CPR) allowing high-quality bystander CPR to begin early even in situations where bystanders are not experienced in CPR. When EMS arrives, ALS algorithms are followed12 despite limited evidence on hard endpoints. Adrenaline (1 mg) improves survival to hospital admission and mid-term survival (3 months) but not good neurological outcome.13 Defibrillation is likely the most important medical intervention, however, few clinical studies have investigated this part of the- Chain of survival. In the cluster-randomized trial named ‘DOSE-ventricular fibrillation’, patients with refractory ventricular fibrillation were treated with either standard of care, double sequential external defibrillation (i.e. rapid sequential shocks from two defibrillators), vector-change defibrillation (i.e. switching defibrillation pads to an anterior–posterior position), survival to hospital discharge occurred more frequently among those who received vector-change or double sequential defibrillation compared to standard.14
After return of spontaneous circulation (ROSC) pre-hospital transportation to a cardiac arrest centre15 with advanced diagnostics and access to revascularization facilities is important.16 To facilitate transport and to improve the efficiency of chest compressions, devices for mechanical chest compressions have been developed. More than 10.000 patients have been randomized pre-hospital to mechanical chest compression or manual chest compressions17,18 without a signal for better survival with these devices, but they are still widely used.
When ROSC cannot be achieved with ALS, selected patients with refractory out-of-hospital cardiac arrest can be designated for early intra-arrest transport with mechanical chest compressions to extracorporeal cardiopulmonary resuscitation (eCPR). Two smaller trials (n < 300 each) with pre-hospital randomization did not find significantly improved survival or neurologically favourable outcome.19,20 The ARREST-trial (n = 30) randomized patients without ROSC upon arrival to the hospital did, however, find improved survival with eCPR.21 The trial was stopped prematurely by the data safety monitoring board based on an interim analysis suggesting the benefits of eCPR. The trial was planned to enrol 150 patients and a debate about stopping criteria for trials in acute settings is needed, to ensure patients safety while also not hampering clinical research.
Trials in this setting are notoriously difficult to carry out and larger adequately powered studies are needed, but eCPR may be used in highly selected patients followed by acute coronary angiography and revascularization at a cardiac arrest centre with proper training.
From mandatory acute coronary angiography to a more selective strategy
Modern EMS uses telemedicine to communicate the post-ROSC electrocaridogram (ECG) to a cardiologist or have a pre-hospital cardiologist present for diagnosis and pre-hospital activation of the catheterization laboratory-team.16 In case of a transmural myocardial infarction indicated by a pre-hospital ECG showing ST-elevation, it is recommended to triage the patient for immediate transport in addition to administering anti-thrombotic drugs as in st-elevaiton myocardial infarction (STEMI) without cardiac arrest.16 The overall goal is to revascularize transmural myocardial ischaemia as fast as possible. The post-ROSC ECG may, however, be difficult to interpretate,22 thus a new ECG upon arrival at the hospital of highly recommended.
Guidelines have recommended acute coronary angiography followed by revascularisation if needed for all OHCA-patients until recently.23 However, in patients without STEMI, other priorities may be more urgent than acute angiography. This dilemma has now been tested in several midsize randomized controlled trial (RCTs), where immediate coronary angiography did not reveal any benefit.24–26 However, these trials excluded patients developing severe haemodynamic or electrical instability. Thus, in such selected cases, acute angiography may still be indicated even in absence of ST-elevation in the ECG.
From therapeutic hypothermia to temperature control
When a cardiac arrest occurs, cerebral oxygen-delivery decreases within seconds. Lack of aerobic metabolism leads to dysfunction of energy-dependent ion channels, intracellular natrium-ion accumulation, anaerobic metabolism, and cerebral lactate accumulation.27 Brain function is compromised, and the patient becomes comatose. Ultimately, neurotransmitter-release and intracellular calcium-ion influx activates lytic enzymes resulting in irreversible brain damage or death. When perfusion is re-established, reperfusion injury further exacerbates organ damage. However, irreversible damage does not occur immediately. If cerebral oxygen-delivery is re-established the brain can recover. Despite, neurons being more susceptible to anoxic injury than other cells, research has shown that neurons may be more resilient than previously have been thought: Braincells from biopsies taking from deceased human brains several hours post-mortem have preserved the ability to grow and differentiate in the research laboratory.28 This suggests, that even in the case of long no-flow time and signs of brain dysfunction (coma), brain cells have the potential to recover for some time following cardiac arrest, if the right conditions are present.
Several initiatives have been undertaken to mitigate brain injury after OHCA. In the last century, it was hypothesized that hypothermia could be an effective treatment for anoxic brain injury. Before the year 2000, several case reports were published of resuscitated humans suffering an OHCA due to accidental hypothermia.29 Remarkably, hypothermia induced before or during cardiac arrest seemed to be neuroprotective. Experimental studies from the 1900s investigated interventions to lower body temperature during and after cardiac arrest, which seemed to mitigate brain injury and improve survival in dogs.30
The first two clinical studies of mild therapeutic hypothermia at 32–34°C were published in 2002 indicating a benefit of hypothermia after OHCA.31,32 In the ‘Hypothermia after cardiac arrest (HACA)-trial’, 273 resuscitated patients after OHCA with a primary shockable rhythm of ventricular fibrillation were randomized to therapeutic hypothermia for 24 h or standard intensive care without any temperature control. The trial was stopped prematurely due to lack of funding. After 6 months, mortality was 41% in the hypothermia group and 55% in the control group (risk ratio 0.74, 95% CI 0.58–0.95). The other trial by Bernard et al., was a smaller quasi-randomized trial of 77 patients, which found similar results as the HACA trial. The intervention was identical in terms of temperature-target, but the duration was shorter (12 h).
Therapeutic hypothermia gave hope and was rapidly introduced in international guidelines. Several trials investigated whether rapid initiation of hypothermia started in the pre-hospital setting after ROSC or even during active CPR, would improve outcomes.33–36 However, these trials of faster hypothermia did not show any beneficial effect on outcomes. In the following years, observational studies questioned the effect of mild therapeutic hypothermia post-arrest on survival and brain function,37 and methodological issues of the initial studies were discussed, namely poor randomization process in one and lack of blinding combined with early terminations of the other trial and perhaps less awareness in the control-groups. A large trial of OHCA-patients was undertaken to evaluate the effect of therapeutic hypothermia (at this time termed targeted temperature management, TTM). In this TTM-trial, 939 patients were randomly allocated to 33°C or 36°C for 24 h.31 Fever was treated actively for the first 72 h in both groups. The trial found no difference in mortality or neurological function after 6 months between the groups. In the following years, guidelines have allowed for a target temperature of 36°C for 24 h before gradual rewarming.6 A subsequent randomized trial of duration of TTM, the ‘Targeted Temperature Management for 48 vs. 24 Hours’-trial, showed no significant benefit of prolonged TTM.38 Various temperature targets as low as 31 C as well as intra-arrest cooling have been investigated without a signal of benefit.39,40
So far, all major trials investigating TTM have excluded patients with non-shockable primary rhythm. The HYPERION trial was published in 2019, including 584 comatose survivors of cardiac arrest [mix of in-hospital (IHCA) and OHCA] due to non-shockable rhythm (asystole or pulseless electrical activity).41 A significantly higher 90-day survival with good neurological outcome was found in the intervention group. Mortality at 90 days did, however, not differ significantly (81.3% and 83.2%). Limitations of this trial were the lack of blinding and telephone-based assessment of the primary outcome. The Fragility Index (i.e. the minimum number of patients whose status would have to change from a non-event to an event required to turn a statistically significant result to a non-significant result) of Hyperion was 1 and later analysis of the data showed that the benefit was confined to the IHCA.
In 2021 the largest clinical trial of temperature control in cardiac arrest patients so far was published: The TTM-2 trial, which reported no difference in survival with good neurological outcomes at 6 months among the 1850 comatose OHCA-patients included.42 Patients were included irrespective of initial rhythm. In this trial, the intervention dictated targeting a core temperature at 33°C for 24 h and subsequently, preventing fever for a total of 72 h. The control group was only treated if patients developed fever, defined as a body temperature >37.7°C. The updated guidelines for TTM (now called temperature control) for comatose patients after cardiac arrest by the ERC-European society of intensive care medicine,6 conclude that there is insufficient evidence to recommend for or against temperature control below 37°C, but do recommend monitoring of core temperature and actively preventing fever for at least 72 h. In a recent large trial of fever control after cardiac arrest, 789 comatose patients who had been resuscitated after OHCA of presumed cardiac cause were randomly assigned to feedback-controlled device-based fever control targeting 36°C for 24 h followed by targeting of 37°C for either 12 or 48 h (for total intervention times of 36 and 72 h, respectively) or until the patient regained consciousness.43 No difference was found at 90 days regarding the primary outcome of dead or neurological disability. Future studies are investigating if feedback-controlled devices for fever management are necessary at all (NCT05564754).
From hypoventilation and deep sedation to normoventilation and early awakening
Tracheal intubation with mechanical ventilation can be lifesaving for comatose patients unable to protect their airways. A comatose post-OHCA patient should preferably be intubated as soon as possible after it is evident that the patients remain comatose (Glasgow Coma Scale score <9).16 Besides securing the airway, tracheal intubation facilitates adequate post-resuscitation care including controlled oxygenation, ventilation, and sedation.10
The optimal partial pressure of oxygen (PaO2) has been much debated. Observational data suggest a U-shaped relationship between PaO2 levels with higher mortality at both very high and low levels of oxygen.44,45 In the EXACT-trial, 428 patients were randomized by paramedics to receive oxygen titration to achieve an oxygen saturation of either 90%–94% or 98%–100% until arrival in the intensive care unit.46 The trial stopped prematurely due to COVID and found a risk difference of −9.6% (95% CI, −18.9% to −0.2%), P = 0.05, favouring the higher oxygen-target.
In the BOX trial, which was a randomized clinical multicentre trial with a 2 × 2 factorial design allocating 789 comatose OHCA-patients to two target blood pressure targets and two oxygenation targets. Oxygenation was measured by arterial blood gas analysis and oxygenation was titrated with supplemental oxygen through the ventilator and by adjusting positive-end-expiratory pressure (PEEP). The restrictive oxygenation target was 9–10 kPa; vs. liberal 13–14 kPa.47 The intervention resulted in a similar incidence of death or severe disability or coma between the two groups at 90 days.
In patients undergoing mechanical ventilation after ROSC, a lung-protective ventilation strategy should be used aiming for a tidal volume of 6–8 mL/kg ideal body weight. Furthermore, ventilation should be adjusted to target a normal arterial partial pressure of carbon dioxide (PaCO2) i.e. 4.5–6.0 kPa or 35–45 mmHg.10 An analysis of the TTM2 trial-cohort showed that respiratory rate and driving pressure are independently associated with 6-month mortality.48 However, in the lack of randomized trials, the use of lung-protective ventilation and avoiding high airway pressure (Plateau pressure <27 cmH2O and driving pressure <15 cmH2O) is suggested. It has been proposed that increasing PaCO2 can improve brain perfusion and thus outcome after OHCA, since PaCO2 is a physiological regulator of cerebral blood flow.45 So far insufficient evidence exists to support his hypothesis, however, the TAME trial (ClinicalTrials.gov Identifier: NCT03114033) is a large trial recruiting 1700 patients comparing targeted PaCO2 of 50–55 mmHg vs. 35–45 mmHg for 24 h following randomization. The trial inclusion is complete, and the results are likely published this year. Until then normocapnia is suggested to avoid potential harmful effect on cerebral circulation.
Very little evidence regarding the type and duration of sedation exists. Usually, a combination of propofol and opioids (fentanyl, remifentanil, or morphine) is used. Midazolam has the advantage of less adverse haemodynamic effects compared to propofol, however, midazolam can take longer time to clear and has been associated with late awakening.10 Optimal duration of sedation is unknown, however, at least one trial is examining deep sedation for 36 h vs. shorter duration of sedation (ClinicalTrials.gov Identifier: NCT05564754).
Aggressive vasopressor-therapy and mechanical circulatory support perhaps loosening up
A major challenge in managing post-OHCA-patients is haemodynamic instability. Post-resuscitation myocardial dysfunction and low cardiac output may occur in most patients as part of post-cardiac arrest syndrome. Systemic ischaemia/reperfusion and inflammation cause vasodilation and vasoplegia, lowering blood pressure.49 Myocardial dysfunction and vasoplegia peak during the first 24–48 h, after which hemodynamics typically improve.50 Although low cardiac output may not be linked to poor outcomes, hypotension is associated with poor outcomes in most studies.51 To avoid severe hypotension, preload optimization, inotropes, and vasopressors are used.10 Three pilot-studies of higher mean arterial pressure (MAP)-targets did not show benefit on surrogate outcomes.52–54 In the larger, double-blinded ‘BOX’-trial, no benefit was found in targeting MAP above 65 mmHg,55 and the focus should likely be on avoiding hypoperfusion. ERC guidelines for 2021, define hypotension as a MAP < 65 mmHg and suggest targeting a MAP higher than this to achieve adequate urine output (>0.5 mL/kg/h) and normal or decreasing lactate.10
Mechanical circulatory support
OHCA may lead to oedema and dysfunction of the heart in hours to days.56 If conventional resuscitation with iv fluids, inotropes, and vasopressors is insufficient to maintain tissue perfusion, mechanical circulatory support [such as intra-aortic balloon pump (IABP), veno-arterial extracorporeal membrane oxygenation (VA-ECMO), IMPELLA, Abiomed USA] may be advised for selected patients.57 Retrospective data suggest that 15% of comatose OHCA-patients developing cardiogenic shock after OHCA may require mechanical circulatory support.58 Limited data support the use of mechanical circulatory support, and very few prospective trials have been undertaken in this patient population.
In a randomized, prospective, open-label, low-powered, multicentre trial, 48 patients (92% with OHCA) with severe cardiogenic shock due to acute myocardial infarction were assigned to Impella (n = 24) or IABP (n = 24). The primary endpoint was 30-day all-cause mortality, which was similar in the two groups. Post-resuscitation care ERC Guidelines10 include the recommendation that mechanical circulatory support including left-ventricular assist devices or VA-ECMO should be considered in haemodynamically unstable patients with persisting shock despite fluids, inotropes, and vasoactive drug administration. These devices should also be considered in patients with haemodynamic instability due to acute coronary syndromes (ACS) and recurrent ventricular arrhythmias despite optimal therapy.59
Antibiotic and anti-inflammatory treatment
The ischaemia/reperfusion injury with endothelial activation and systemic inflammation is a main part of the post-cardiac arrest syndrome. Global ischaemia during OHCA and the following reperfusion after resuscitation activate immunological and coagulatory responses, much like the systemic inflammatory response syndrome associated with severe sepsis.60 The haemodynamic consequences include impaired oxygen-extraction and -utilisation, intravascular volume depletion, and impaired vasoregulation. Clinical manifestations of this are low blood pressure due to low systemic vascular resistance and a relatively high central venous saturation, possibly due to shunting of arterial blood to the veins, and/or mitochondrial dysfunction.
In the TTM1-trial-cohort, interleukin-6 (IL-6) was measured at hospital arrival and the following days.61 High levels of IL-6 on days 2 and 3 were independently associated with the severity of post-cardiac arrest syndrome and mortality. Based on these observations, interventional trials to assess the effects of anti-inflammatory treatments to improve outcomes after OHCA have begun. In a small RCT of 80 patients, the inflammatory response after OHCA was modulated by blocking IL-6-mediated signalling with tocilizumab.62 Treatment with tocilizumab did result in lower levels of C-reactive protein, decreases of neutrophils and monocytes, lower level of biomarkers of cardiac injury, as well as reduced vasopressor and inotropy requirements.62 However, larger trials are needed to confirm the results in hard endpoints. In a trial of 158 OHCA-patients (ClinicalTrials.gov Identifier: NCT04624776), the use of methylprednisolone vs. placebo in the pre-hospital setting was assessed. The trial has finished inclusion, and publication of results is pending.
In 268 consecutive patients with in-hospital cardiac arrest receiving epinephrine, an intervention of combined vasopressin-epinephrine and methylprednisolone during CPR with stress-dose hydrocortisone in post-resuscitation shock resulted in improved survival to hospital discharge with favourable neurological status.63 In a larger confirmatory study, 501 patients with in-hospital cardiac arrest, vasopressin, and methylprednisolone, compared with placebo, increased ROSC with no certain positive effect on long-term survival.64
Infections and especially pneumonia after OHCA are problematic for several reasons. Many patients aspirate during cardiac arrest. Patients are intubated and mechanically ventilated. Diagnosis of pneumonia is hampered for several reasons including the inability to measure a fever due to therapeutic temperature control, and blood-born biomarkers of inflammation such as C-reactive protein are heavily elevated in almost all OHCA-patients even in absence of infection. Accordingly, one controversy regarding post-resuscitation care is whether patients should receive prophylactic antibiotics to prevent pneumonia and other infections. In the ANTHARTIC study,65 a multicentre, double-blind, placebo-controlled trial of patients resuscitated from shockable OHCA, patients were randomized to intravenous amoxicillin-clavulanate or placebo for two days. The primary endpoint was the incidence of ventilator-associated pneumonia within a week (as adjudicated by an independent, blinded committee). The intervention resulted in a lower incidence of early ventilator-associated pneumonia than a placebo. However, no significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28 making. Thus, the use of prophylactic antibiotics is still debatable.
Neuroprognostication
The high mortality rate of comatose OHCA-patients undergoing intensive care, is mainly related to neurological injury from anoxia. Withdrawal of life-sustaining therapy (WLST) should be undertaken when there is no hope for recovery due to severe irreversible brain injury. However, it is a challenge to distinguish this patient-group from patients with a potential for late recovery.16 Accurate prognostication is therefore extremely important to avoid prolongation of suffering for relatives in patients without the potential for recovery and to avoid inappropriate WLST.
Precise neuroprognostication has been extremely difficult. Mainly because, the requirements for a neuroprognostic test are high with a very low false positive rate usually set at only 1%. Furthermore, it is difficult to carry out high-quality neuroprognostication studies. Previous studies have been challenged by inherent limitations and biases with the risk of self-fulfilling prophecies; a new modality predicts poor outcome, thus WLST is done, leading to confirmation of the predictive value of the modality. Trials on blood-borne biomarkers have the advantage that these biomarkers are often only analysed in a core laboratorium at a later stage. Artificial intelligence could have potential for improving neuroprognostication in the future through the inclusion of the massive amount of data related to a cardiac arrest survivor.
Combing several modalities in a multimodal prognostication model is so far our best way of determining when a WLST decision is indicated.10 The ERC Guidelines on post-resuscitation care has proposed a model for the prediction of poor neurological outcome for comatose patients after cardiac arrest.10 The prognostication model includes a combination of tests including clinical/neurological examination, electrophysiology, blood-borne biomarkers, and imaging.
Clinical/neurological examination for motor response, absent pupillary and corneal reflexes, status myoclonus, and cranial nerve function, is important and a collaboration with a trained neurologist is preferred.66 One novel and easy-to-use modality is the automated pupillometry.67
Head computed tomography (CT) is used early to exclude potential intracranial haemorrhage as a cause of the OHCA or when the patients experience a fall or trauma related to a sudden arrest. CT upon arrival, however, should not be used for neuroprognostication. For neuroprognostication, a cerebral CT performed at a later stage, the reduction of grey matter/white matter ratio within 72 h after ROSC is a marker of cerebral oedema and thereby poor outcome.10 Magnetic resonance imaging has higher spatial resolution for detecting early anoxic brain injury, however, the little evidence exist68 in this area, and logistical challenges exist, since this imaging-modality requires more time and no use of magnetic utensils.56
Electroencephalography (EEG) is used widely to assess the extent of brain injury after OHCA and for diagnosing convulsive and non-convulsive seizures in comatose patients with brain injury. The background activity, superimposed discharges, and reactivity are the primary indices of prognoses. During post-resuscitation care, the EEG is repressed in most OHCA-patients, but in patients without severe anoxic brain injury, recordings return to normal within the first 24 h.10 Another electrophysiology test is somatosensory evoked potentials (SSEPs), which are brain and spinal cord responses elicited by sensory stimuli. Bilaterally absent SSEP waves are highly specific for a poor outcome,10 but have limited sensitivity.
Blood-born biomarkers have been studied more than any other neuroprognostic modality, due to their ease of use. Furthermore, it is more feasible to blind treating personal from study results, since blood-borne biomarkers are often analysed at a later stage in a core lab. In contrast to imaging and electrophysiologic studies, this role out the possibility of a self-fulfilling prophecy. The goal is to have an easily obtainable blood test, which can predict severe brain injury. So far, the most utilized test is neuron-specific enolase (NSE), where higher values indicate more brain injury. Neurofilament light chain has even more specificity compared to NSE but is so far used less.
Organ donation
In European healthcare systems, solid organ donations are vital for modern health care where demand for solid organs exceeds supply.69 If brain death occurs or a withdrawal of life-sustaining therapy (WLST) decision is made, international guidelines for post-resuscitation care support organ donation,10 and selected OHCA-patients who based on a multimodal neuroprognostication model are deemed without potential for recovery, should be evaluated for organ donation.
Follow-up and rehabilitation
OHCA-survivors, who are discharged alive from intensive care and hospital, have varying degrees of neurological, cognitive, and emotional impairments. Most impairments are mild to moderate and some patients recover cognitively during the first 3 months after the cardiac arrest.70 However, almost half of OHCA-survivors show signs of cognitive impairments after 3 months.70 Anxiety, depression, post-traumatic stress, and fatigue are other frequent symptoms with consequences for the patients’ quality of life.71 An assessment of physical and non-physical impairments before hospital discharge can help identify rehabilitation needs.10 Cognitive impairments are dynamic, and systematic follow-up for 3 months after hospital discharge gives a better view of the steady-state impairments. This follow-up can include screening for cognitive problems, screening for emotional problems, and fatigue.10 Cognitive screening using acknowledged tests should be used since patients are not always conscious of their cognitive impairments. The Montreal Cognitive Assessment (MoCA) tool takes around 10 min to complete. For emotional problems, short questionnaires, such as the hospital anxiety and depression scale (HADS), can be used. If signs of cognitive or emotional impairment are present, referral to more extensive neuropsychological assessment can be considered. For OHCA-survivors in work before the event, between 27% and 75% of pre-event working persons are reported to have returned to work at follow-up 180 days post-OHCA. Furthermore, many return to work part-time with a different workload as compared to before the arrest.72 This should be a focus in future rehabilitation-studies.73,74 One clinical study has indicated that early intervention for cardiac arrest survivors may have a positive impact on quality of life.75 Clearly more randomized clinical studies are needed here.
Perspectives for future research needs
Table 1 summarizes the moderate and largest randomized clinical trials of various interventions for cardiac arrest. Since 2002, with the publication of the first two therapeutic hypothermia trials in humans resuscitated from OHCA,31,32 research in this area has intensified. Even though, contemporary large-scale trials have questioned the effects of mild hypothermia, the mindset of how to treat and care for comatose, resuscitated OHCA-patients has changed. Before 2002, there were no specific treatment options for anoxic brain injury, thus post-resuscitation care was based on general intensive care of other patient categories.
Summarized data for moderate and large (above 100 participants) randomized clinical trials
| Author | Year | Trial design | Patients | Intervention | Control | No. Randomized | Primary outcome | Effect |
|---|---|---|---|---|---|---|---|---|
| Pre-hospital interventions | ||||||||
| Perkins et al.13 | 2018 | Randomized, double-blind | Pre-hospital cardiac arrest | Parenteral epinephrine | saline placebo | 8014 | The rate of survival at 30 days | Favors intervention |
| Cheskes et al.14 | 2022 | Cluster-randomized trial with crossover | Pre-hospital cardiac arrest with refractory ventricular fibrillation during out-of-hospital cardiac arrest | Double sequential external defibrillation and vector change | Standard defibrillation | 405 | Survival to hospital discharge. | Favors intervention |
| Perkins et al.17 | 2015 | Cluster-randomized controlled trial | Pre-hospital cardiac arrest | Mechanical compression device | Manual chest compression | 4471 | The rate of survival at 30 days | Neutral |
| Belohlavek et al.19 | 2022 | Single centre, randomized clinical trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Intra-arrest transport, extracorporeal cardiopulmonary resuscitation | Regular advanced cardiac life support was continued on-site | 256 | Survival with a good neurologic outcome (defined as cerebral performance category 1–2) | Neutral |
| Suverein et al.20 | 2023 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Extracorporeal CPR | standard advanced cardiac life support | 160 | Survival with a favorable neurologic outcome, defined as a cerebral performance category score of 1 or 2 | Neutral |
| Angiography | ||||||||
| Desch et al.24 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 530 | Death from any cause in 30 days | Neutral |
| Lemkes et al.25 | 2019 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 552 | Survival at 90 days | Neutral |
| Caroline Hauw-Berlemont et al.26 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 279 | 180-day survival rate with cerebral performance category of two or less | Neutral |
| Hypothermia | ||||||||
| Hypothermia after Cardiac Arrest Study Group | 2002 | Multicenter, randomized trial | Patients who had been resuscitated after cardiac arrest due to ventricular fibrillation | Therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the bladder) | Standard treatment with normothermia | 136 | Favorable neurologic outcome within 6 months | Favors intervention |
| Debaty et al.33 | 2014 | Multicenter, randomized, controlled trial | Pre-hospital intra-arrest | Infusion of cold saline and external cooling during cardiac arrest | Hypothermia started after hospital admission | 245 | Neuron-specific enolase serum concentrations at 24 h | Neutral |
| Kim et al.35 | 2014 | Randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation | Standard of care | 1359 | Survival to hospital discharge and neurological status at discharge. | Neutral |
| Nordberg et al.36 | 2019 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital trans-nasal evaporative intra-arrest cooling | Standard of care | 677 | Survival with good neurologic outcome, defined as cerebral performance category 1–2, at 90 days | Neutral |
| Nielsen et al.76 | 2013 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted temperature management at 36°C for 24 h | 939 | All-cause mortality through the end of the trial | Neutral |
| Kirkegaard et al.38 | 2017 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at either 33°C for 48 h | Targeted temperature management at 33°C for 24 h | 355 | Six-month neurologic outcome, with a cerebral performance categories score of one or two used to define favorable outcome | Neutral |
| May et al.40 | 2021 | Single-centre, double-blind, randomized, clinical superiority trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Moderate hypothermia (31°C) | Mild hypothermia (34°C) | 389 | All-cause mortality or poor neurologic outcome at 180 days | Neutral |
| Lascarrou et al.41 | 2019 | Open-label, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest with non-shockable rhythm and admitted comatose to the ICU | Moderate therapeutic hypothermia (33°C during the first 24 h) | Targeted normothermia (37°C) | 584 | Survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the cerebral performance category scale | Favoring intervention |
| Dankiewicz et al.42 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted normothermia with early treatment of fever (body temperature, ≥ 37.8°C) | 1850 | Death from any cause at 6 months | Neutral |
| Hassager et al.43 | 2023 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 48 h | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 12 h | 789 | Composite of death from any cause or hospital discharge with a cerebral performance category of three or four within 90 days after randomization | Neutral |
| Oxygenation and blood pressure | ||||||||
| Bernard et al.46 | 2022 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Oxygen titration to achieve an oxygen saturation of either 90% to 94% | Oxygen titration to achieve an oxygen saturation of either 98% to 100% | 428 | Survival to hospital discharge | Neutral |
| Schmidt et al.47 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Restrictive oxygen-target of partial pressure of arterial oxygen (Pao2) of 9–10 kPa (68–75 mm Hg) | Liberal oxygen-target of a PaO2 of 13–14 kPa (98–105 mm Hg) | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Kjaergaard et al.55 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Mean arterial blood-pressure target of 77 mm Hg | Mean arterial blood-pressure target of 63 mm Hg | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Jakkula et al.52 | 2018 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Low-normal mean arterial blood-pressure target (65–75 mmHg) | High-normal mean arterial blood-pressure target (80–100 mmHg) | 120 | Serum concentration of neuron-specific enolase at 48 h after cardiac arrest | Neutral |
| Ameloot et al.54 | 2019 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Early goal directed haemodynamic optimization strategy (mean arterial pressure 85–100 mmHg, SVO2 65–75%) | Standard of care | 112 | Extent of anoxic brain damage as quantified by the percentage of voxels below an apparent diffusion coefficient score of 650.10–6 mm2/s on diffusion-weighted magnetic resonance imaging (at day 5 ± 2 post-CA) | Neutral |
| Antibiotic and anti-inflammatory treatment | ||||||||
| Mentzelopoulos et al.63 | 2013 | Randomized, double-blind, placebo-controlled, parallel-group | Patients with in-hospital cardiac arrest requiring epinephrine according to resuscitation guidelines | Vasopressin (20 IU/CPR cycle) plus epinephrine (1 mg/CPR cycle | Saline placebo | 268 | Return of spontaneous circulation for 20 min or longer and survival to hospital discharge with a cerebral performance category score of 1 or 2. | Favors intervention |
| Andersen et al.64 | 2021 | Multicenter, randomized, double-blind, placebo-controlled trial | In-hospital cardiac arrest | Vasopressin and methylprednisolone | Saline placebo | 501 | Return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). | Favors intervention |
| François et al.65 | 2019 | Multicenter, double-blind, randomized, placebo-controlled | Resuscitated out-of-hospital cardiac arrest with shockable rhythm and admitted comatose to the ICU | Intravenous amoxicillin-clavulanate (at doses of 1 and 200 mg, respectively) | Placebo | 198 | Early ventilator-associated pneumonia (during the first 7 days of hospitalization). | Favors intervention |
| Rehabilitation | ||||||||
| Moulaert et al.75 | 2015 | Multicentre randomized controlled trial | Adult cardiac arrest survivors | Brief nursing intervention to detect cognitive and emotional problems, provide information and support, promote self-management, and refer them to specialized care if necessary | Standard of care | 185 | Societal participation and quality of life of the survivors at 1 year | Favors intervention |
| Author | Year | Trial design | Patients | Intervention | Control | No. Randomized | Primary outcome | Effect |
|---|---|---|---|---|---|---|---|---|
| Pre-hospital interventions | ||||||||
| Perkins et al.13 | 2018 | Randomized, double-blind | Pre-hospital cardiac arrest | Parenteral epinephrine | saline placebo | 8014 | The rate of survival at 30 days | Favors intervention |
| Cheskes et al.14 | 2022 | Cluster-randomized trial with crossover | Pre-hospital cardiac arrest with refractory ventricular fibrillation during out-of-hospital cardiac arrest | Double sequential external defibrillation and vector change | Standard defibrillation | 405 | Survival to hospital discharge. | Favors intervention |
| Perkins et al.17 | 2015 | Cluster-randomized controlled trial | Pre-hospital cardiac arrest | Mechanical compression device | Manual chest compression | 4471 | The rate of survival at 30 days | Neutral |
| Belohlavek et al.19 | 2022 | Single centre, randomized clinical trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Intra-arrest transport, extracorporeal cardiopulmonary resuscitation | Regular advanced cardiac life support was continued on-site | 256 | Survival with a good neurologic outcome (defined as cerebral performance category 1–2) | Neutral |
| Suverein et al.20 | 2023 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Extracorporeal CPR | standard advanced cardiac life support | 160 | Survival with a favorable neurologic outcome, defined as a cerebral performance category score of 1 or 2 | Neutral |
| Angiography | ||||||||
| Desch et al.24 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 530 | Death from any cause in 30 days | Neutral |
| Lemkes et al.25 | 2019 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 552 | Survival at 90 days | Neutral |
| Caroline Hauw-Berlemont et al.26 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 279 | 180-day survival rate with cerebral performance category of two or less | Neutral |
| Hypothermia | ||||||||
| Hypothermia after Cardiac Arrest Study Group | 2002 | Multicenter, randomized trial | Patients who had been resuscitated after cardiac arrest due to ventricular fibrillation | Therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the bladder) | Standard treatment with normothermia | 136 | Favorable neurologic outcome within 6 months | Favors intervention |
| Debaty et al.33 | 2014 | Multicenter, randomized, controlled trial | Pre-hospital intra-arrest | Infusion of cold saline and external cooling during cardiac arrest | Hypothermia started after hospital admission | 245 | Neuron-specific enolase serum concentrations at 24 h | Neutral |
| Kim et al.35 | 2014 | Randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation | Standard of care | 1359 | Survival to hospital discharge and neurological status at discharge. | Neutral |
| Nordberg et al.36 | 2019 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital trans-nasal evaporative intra-arrest cooling | Standard of care | 677 | Survival with good neurologic outcome, defined as cerebral performance category 1–2, at 90 days | Neutral |
| Nielsen et al.76 | 2013 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted temperature management at 36°C for 24 h | 939 | All-cause mortality through the end of the trial | Neutral |
| Kirkegaard et al.38 | 2017 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at either 33°C for 48 h | Targeted temperature management at 33°C for 24 h | 355 | Six-month neurologic outcome, with a cerebral performance categories score of one or two used to define favorable outcome | Neutral |
| May et al.40 | 2021 | Single-centre, double-blind, randomized, clinical superiority trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Moderate hypothermia (31°C) | Mild hypothermia (34°C) | 389 | All-cause mortality or poor neurologic outcome at 180 days | Neutral |
| Lascarrou et al.41 | 2019 | Open-label, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest with non-shockable rhythm and admitted comatose to the ICU | Moderate therapeutic hypothermia (33°C during the first 24 h) | Targeted normothermia (37°C) | 584 | Survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the cerebral performance category scale | Favoring intervention |
| Dankiewicz et al.42 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted normothermia with early treatment of fever (body temperature, ≥ 37.8°C) | 1850 | Death from any cause at 6 months | Neutral |
| Hassager et al.43 | 2023 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 48 h | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 12 h | 789 | Composite of death from any cause or hospital discharge with a cerebral performance category of three or four within 90 days after randomization | Neutral |
| Oxygenation and blood pressure | ||||||||
| Bernard et al.46 | 2022 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Oxygen titration to achieve an oxygen saturation of either 90% to 94% | Oxygen titration to achieve an oxygen saturation of either 98% to 100% | 428 | Survival to hospital discharge | Neutral |
| Schmidt et al.47 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Restrictive oxygen-target of partial pressure of arterial oxygen (Pao2) of 9–10 kPa (68–75 mm Hg) | Liberal oxygen-target of a PaO2 of 13–14 kPa (98–105 mm Hg) | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Kjaergaard et al.55 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Mean arterial blood-pressure target of 77 mm Hg | Mean arterial blood-pressure target of 63 mm Hg | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Jakkula et al.52 | 2018 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Low-normal mean arterial blood-pressure target (65–75 mmHg) | High-normal mean arterial blood-pressure target (80–100 mmHg) | 120 | Serum concentration of neuron-specific enolase at 48 h after cardiac arrest | Neutral |
| Ameloot et al.54 | 2019 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Early goal directed haemodynamic optimization strategy (mean arterial pressure 85–100 mmHg, SVO2 65–75%) | Standard of care | 112 | Extent of anoxic brain damage as quantified by the percentage of voxels below an apparent diffusion coefficient score of 650.10–6 mm2/s on diffusion-weighted magnetic resonance imaging (at day 5 ± 2 post-CA) | Neutral |
| Antibiotic and anti-inflammatory treatment | ||||||||
| Mentzelopoulos et al.63 | 2013 | Randomized, double-blind, placebo-controlled, parallel-group | Patients with in-hospital cardiac arrest requiring epinephrine according to resuscitation guidelines | Vasopressin (20 IU/CPR cycle) plus epinephrine (1 mg/CPR cycle | Saline placebo | 268 | Return of spontaneous circulation for 20 min or longer and survival to hospital discharge with a cerebral performance category score of 1 or 2. | Favors intervention |
| Andersen et al.64 | 2021 | Multicenter, randomized, double-blind, placebo-controlled trial | In-hospital cardiac arrest | Vasopressin and methylprednisolone | Saline placebo | 501 | Return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). | Favors intervention |
| François et al.65 | 2019 | Multicenter, double-blind, randomized, placebo-controlled | Resuscitated out-of-hospital cardiac arrest with shockable rhythm and admitted comatose to the ICU | Intravenous amoxicillin-clavulanate (at doses of 1 and 200 mg, respectively) | Placebo | 198 | Early ventilator-associated pneumonia (during the first 7 days of hospitalization). | Favors intervention |
| Rehabilitation | ||||||||
| Moulaert et al.75 | 2015 | Multicentre randomized controlled trial | Adult cardiac arrest survivors | Brief nursing intervention to detect cognitive and emotional problems, provide information and support, promote self-management, and refer them to specialized care if necessary | Standard of care | 185 | Societal participation and quality of life of the survivors at 1 year | Favors intervention |
ICU, intensive care unit; CA, cardiac arrest.
Summarized data for moderate and large (above 100 participants) randomized clinical trials
| Author | Year | Trial design | Patients | Intervention | Control | No. Randomized | Primary outcome | Effect |
|---|---|---|---|---|---|---|---|---|
| Pre-hospital interventions | ||||||||
| Perkins et al.13 | 2018 | Randomized, double-blind | Pre-hospital cardiac arrest | Parenteral epinephrine | saline placebo | 8014 | The rate of survival at 30 days | Favors intervention |
| Cheskes et al.14 | 2022 | Cluster-randomized trial with crossover | Pre-hospital cardiac arrest with refractory ventricular fibrillation during out-of-hospital cardiac arrest | Double sequential external defibrillation and vector change | Standard defibrillation | 405 | Survival to hospital discharge. | Favors intervention |
| Perkins et al.17 | 2015 | Cluster-randomized controlled trial | Pre-hospital cardiac arrest | Mechanical compression device | Manual chest compression | 4471 | The rate of survival at 30 days | Neutral |
| Belohlavek et al.19 | 2022 | Single centre, randomized clinical trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Intra-arrest transport, extracorporeal cardiopulmonary resuscitation | Regular advanced cardiac life support was continued on-site | 256 | Survival with a good neurologic outcome (defined as cerebral performance category 1–2) | Neutral |
| Suverein et al.20 | 2023 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Extracorporeal CPR | standard advanced cardiac life support | 160 | Survival with a favorable neurologic outcome, defined as a cerebral performance category score of 1 or 2 | Neutral |
| Angiography | ||||||||
| Desch et al.24 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 530 | Death from any cause in 30 days | Neutral |
| Lemkes et al.25 | 2019 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 552 | Survival at 90 days | Neutral |
| Caroline Hauw-Berlemont et al.26 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 279 | 180-day survival rate with cerebral performance category of two or less | Neutral |
| Hypothermia | ||||||||
| Hypothermia after Cardiac Arrest Study Group | 2002 | Multicenter, randomized trial | Patients who had been resuscitated after cardiac arrest due to ventricular fibrillation | Therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the bladder) | Standard treatment with normothermia | 136 | Favorable neurologic outcome within 6 months | Favors intervention |
| Debaty et al.33 | 2014 | Multicenter, randomized, controlled trial | Pre-hospital intra-arrest | Infusion of cold saline and external cooling during cardiac arrest | Hypothermia started after hospital admission | 245 | Neuron-specific enolase serum concentrations at 24 h | Neutral |
| Kim et al.35 | 2014 | Randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation | Standard of care | 1359 | Survival to hospital discharge and neurological status at discharge. | Neutral |
| Nordberg et al.36 | 2019 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital trans-nasal evaporative intra-arrest cooling | Standard of care | 677 | Survival with good neurologic outcome, defined as cerebral performance category 1–2, at 90 days | Neutral |
| Nielsen et al.76 | 2013 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted temperature management at 36°C for 24 h | 939 | All-cause mortality through the end of the trial | Neutral |
| Kirkegaard et al.38 | 2017 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at either 33°C for 48 h | Targeted temperature management at 33°C for 24 h | 355 | Six-month neurologic outcome, with a cerebral performance categories score of one or two used to define favorable outcome | Neutral |
| May et al.40 | 2021 | Single-centre, double-blind, randomized, clinical superiority trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Moderate hypothermia (31°C) | Mild hypothermia (34°C) | 389 | All-cause mortality or poor neurologic outcome at 180 days | Neutral |
| Lascarrou et al.41 | 2019 | Open-label, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest with non-shockable rhythm and admitted comatose to the ICU | Moderate therapeutic hypothermia (33°C during the first 24 h) | Targeted normothermia (37°C) | 584 | Survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the cerebral performance category scale | Favoring intervention |
| Dankiewicz et al.42 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted normothermia with early treatment of fever (body temperature, ≥ 37.8°C) | 1850 | Death from any cause at 6 months | Neutral |
| Hassager et al.43 | 2023 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 48 h | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 12 h | 789 | Composite of death from any cause or hospital discharge with a cerebral performance category of three or four within 90 days after randomization | Neutral |
| Oxygenation and blood pressure | ||||||||
| Bernard et al.46 | 2022 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Oxygen titration to achieve an oxygen saturation of either 90% to 94% | Oxygen titration to achieve an oxygen saturation of either 98% to 100% | 428 | Survival to hospital discharge | Neutral |
| Schmidt et al.47 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Restrictive oxygen-target of partial pressure of arterial oxygen (Pao2) of 9–10 kPa (68–75 mm Hg) | Liberal oxygen-target of a PaO2 of 13–14 kPa (98–105 mm Hg) | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Kjaergaard et al.55 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Mean arterial blood-pressure target of 77 mm Hg | Mean arterial blood-pressure target of 63 mm Hg | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Jakkula et al.52 | 2018 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Low-normal mean arterial blood-pressure target (65–75 mmHg) | High-normal mean arterial blood-pressure target (80–100 mmHg) | 120 | Serum concentration of neuron-specific enolase at 48 h after cardiac arrest | Neutral |
| Ameloot et al.54 | 2019 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Early goal directed haemodynamic optimization strategy (mean arterial pressure 85–100 mmHg, SVO2 65–75%) | Standard of care | 112 | Extent of anoxic brain damage as quantified by the percentage of voxels below an apparent diffusion coefficient score of 650.10–6 mm2/s on diffusion-weighted magnetic resonance imaging (at day 5 ± 2 post-CA) | Neutral |
| Antibiotic and anti-inflammatory treatment | ||||||||
| Mentzelopoulos et al.63 | 2013 | Randomized, double-blind, placebo-controlled, parallel-group | Patients with in-hospital cardiac arrest requiring epinephrine according to resuscitation guidelines | Vasopressin (20 IU/CPR cycle) plus epinephrine (1 mg/CPR cycle | Saline placebo | 268 | Return of spontaneous circulation for 20 min or longer and survival to hospital discharge with a cerebral performance category score of 1 or 2. | Favors intervention |
| Andersen et al.64 | 2021 | Multicenter, randomized, double-blind, placebo-controlled trial | In-hospital cardiac arrest | Vasopressin and methylprednisolone | Saline placebo | 501 | Return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). | Favors intervention |
| François et al.65 | 2019 | Multicenter, double-blind, randomized, placebo-controlled | Resuscitated out-of-hospital cardiac arrest with shockable rhythm and admitted comatose to the ICU | Intravenous amoxicillin-clavulanate (at doses of 1 and 200 mg, respectively) | Placebo | 198 | Early ventilator-associated pneumonia (during the first 7 days of hospitalization). | Favors intervention |
| Rehabilitation | ||||||||
| Moulaert et al.75 | 2015 | Multicentre randomized controlled trial | Adult cardiac arrest survivors | Brief nursing intervention to detect cognitive and emotional problems, provide information and support, promote self-management, and refer them to specialized care if necessary | Standard of care | 185 | Societal participation and quality of life of the survivors at 1 year | Favors intervention |
| Author | Year | Trial design | Patients | Intervention | Control | No. Randomized | Primary outcome | Effect |
|---|---|---|---|---|---|---|---|---|
| Pre-hospital interventions | ||||||||
| Perkins et al.13 | 2018 | Randomized, double-blind | Pre-hospital cardiac arrest | Parenteral epinephrine | saline placebo | 8014 | The rate of survival at 30 days | Favors intervention |
| Cheskes et al.14 | 2022 | Cluster-randomized trial with crossover | Pre-hospital cardiac arrest with refractory ventricular fibrillation during out-of-hospital cardiac arrest | Double sequential external defibrillation and vector change | Standard defibrillation | 405 | Survival to hospital discharge. | Favors intervention |
| Perkins et al.17 | 2015 | Cluster-randomized controlled trial | Pre-hospital cardiac arrest | Mechanical compression device | Manual chest compression | 4471 | The rate of survival at 30 days | Neutral |
| Belohlavek et al.19 | 2022 | Single centre, randomized clinical trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Intra-arrest transport, extracorporeal cardiopulmonary resuscitation | Regular advanced cardiac life support was continued on-site | 256 | Survival with a good neurologic outcome (defined as cerebral performance category 1–2) | Neutral |
| Suverein et al.20 | 2023 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest with refractory cardiac arrest | Extracorporeal CPR | standard advanced cardiac life support | 160 | Survival with a favorable neurologic outcome, defined as a cerebral performance category score of 1 or 2 | Neutral |
| Angiography | ||||||||
| Desch et al.24 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 530 | Death from any cause in 30 days | Neutral |
| Lemkes et al.25 | 2019 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 552 | Survival at 90 days | Neutral |
| Caroline Hauw-Berlemont et al.26 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest | Immediate coronary angiography | Initial intensive care assessment with delayed or selective angiography | 279 | 180-day survival rate with cerebral performance category of two or less | Neutral |
| Hypothermia | ||||||||
| Hypothermia after Cardiac Arrest Study Group | 2002 | Multicenter, randomized trial | Patients who had been resuscitated after cardiac arrest due to ventricular fibrillation | Therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the bladder) | Standard treatment with normothermia | 136 | Favorable neurologic outcome within 6 months | Favors intervention |
| Debaty et al.33 | 2014 | Multicenter, randomized, controlled trial | Pre-hospital intra-arrest | Infusion of cold saline and external cooling during cardiac arrest | Hypothermia started after hospital admission | 245 | Neuron-specific enolase serum concentrations at 24 h | Neutral |
| Kim et al.35 | 2014 | Randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation | Standard of care | 1359 | Survival to hospital discharge and neurological status at discharge. | Neutral |
| Nordberg et al.36 | 2019 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Pre-hospital trans-nasal evaporative intra-arrest cooling | Standard of care | 677 | Survival with good neurologic outcome, defined as cerebral performance category 1–2, at 90 days | Neutral |
| Nielsen et al.76 | 2013 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted temperature management at 36°C for 24 h | 939 | All-cause mortality through the end of the trial | Neutral |
| Kirkegaard et al.38 | 2017 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at either 33°C for 48 h | Targeted temperature management at 33°C for 24 h | 355 | Six-month neurologic outcome, with a cerebral performance categories score of one or two used to define favorable outcome | Neutral |
| May et al.40 | 2021 | Single-centre, double-blind, randomized, clinical superiority trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Moderate hypothermia (31°C) | Mild hypothermia (34°C) | 389 | All-cause mortality or poor neurologic outcome at 180 days | Neutral |
| Lascarrou et al.41 | 2019 | Open-label, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest with non-shockable rhythm and admitted comatose to the ICU | Moderate therapeutic hypothermia (33°C during the first 24 h) | Targeted normothermia (37°C) | 584 | Survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the cerebral performance category scale | Favoring intervention |
| Dankiewicz et al.42 | 2021 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Targeted temperature management at 33°C for 24 h | Targeted normothermia with early treatment of fever (body temperature, ≥ 37.8°C) | 1850 | Death from any cause at 6 months | Neutral |
| Hassager et al.43 | 2023 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 48 h | Device-based temperature control targeting 36°C for 24 h followed by targeting 37°C for 12 h | 789 | Composite of death from any cause or hospital discharge with a cerebral performance category of three or four within 90 days after randomization | Neutral |
| Oxygenation and blood pressure | ||||||||
| Bernard et al.46 | 2022 | Multicenter, randomized, controlled trial | Pre-hospital cardiac arrest | Oxygen titration to achieve an oxygen saturation of either 90% to 94% | Oxygen titration to achieve an oxygen saturation of either 98% to 100% | 428 | Survival to hospital discharge | Neutral |
| Schmidt et al.47 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Restrictive oxygen-target of partial pressure of arterial oxygen (Pao2) of 9–10 kPa (68–75 mm Hg) | Liberal oxygen-target of a PaO2 of 13–14 kPa (98–105 mm Hg) | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Kjaergaard et al.55 | 2022 | Multicenter, randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Mean arterial blood-pressure target of 77 mm Hg | Mean arterial blood-pressure target of 63 mm Hg | 789 | Composite of death from any cause or hospital discharge with a Cerebral Performance Category of three or four within 90 days after randomization | Neutral |
| Jakkula et al.52 | 2018 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Low-normal mean arterial blood-pressure target (65–75 mmHg) | High-normal mean arterial blood-pressure target (80–100 mmHg) | 120 | Serum concentration of neuron-specific enolase at 48 h after cardiac arrest | Neutral |
| Ameloot et al.54 | 2019 | Randomized, controlled trial | Resuscitated out-of-hospital cardiac arrest and admitted comatose to the ICU | Early goal directed haemodynamic optimization strategy (mean arterial pressure 85–100 mmHg, SVO2 65–75%) | Standard of care | 112 | Extent of anoxic brain damage as quantified by the percentage of voxels below an apparent diffusion coefficient score of 650.10–6 mm2/s on diffusion-weighted magnetic resonance imaging (at day 5 ± 2 post-CA) | Neutral |
| Antibiotic and anti-inflammatory treatment | ||||||||
| Mentzelopoulos et al.63 | 2013 | Randomized, double-blind, placebo-controlled, parallel-group | Patients with in-hospital cardiac arrest requiring epinephrine according to resuscitation guidelines | Vasopressin (20 IU/CPR cycle) plus epinephrine (1 mg/CPR cycle | Saline placebo | 268 | Return of spontaneous circulation for 20 min or longer and survival to hospital discharge with a cerebral performance category score of 1 or 2. | Favors intervention |
| Andersen et al.64 | 2021 | Multicenter, randomized, double-blind, placebo-controlled trial | In-hospital cardiac arrest | Vasopressin and methylprednisolone | Saline placebo | 501 | Return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). | Favors intervention |
| François et al.65 | 2019 | Multicenter, double-blind, randomized, placebo-controlled | Resuscitated out-of-hospital cardiac arrest with shockable rhythm and admitted comatose to the ICU | Intravenous amoxicillin-clavulanate (at doses of 1 and 200 mg, respectively) | Placebo | 198 | Early ventilator-associated pneumonia (during the first 7 days of hospitalization). | Favors intervention |
| Rehabilitation | ||||||||
| Moulaert et al.75 | 2015 | Multicentre randomized controlled trial | Adult cardiac arrest survivors | Brief nursing intervention to detect cognitive and emotional problems, provide information and support, promote self-management, and refer them to specialized care if necessary | Standard of care | 185 | Societal participation and quality of life of the survivors at 1 year | Favors intervention |
ICU, intensive care unit; CA, cardiac arrest.
After therapeutic hypothermia was introduced, patients were admitted with a specific goal. Doctors and cardiac ICUs specialized in post-resuscitation care, cardiac arrest centres have been implemented and neuroprognostication modalities became more important. Today WLST is withheld until multimodal prognostication algorithms have been applied. Coronary catheterization for STEMI is now standard practise and this is vital for the large group of OHCA-patients, who have a transmural myocardial infarction as the precipitating cause of the arrest. Volunteers are activated so bystander CPR and AEDs are used more swiftly. EMS has systems ensuring use of ALS pre-hospital and with the possibility for quick transport to catheterization laboratories for coronary revascularization and/or eCPR in selected cases. Also, focus on rehabilitation can help improve quality of life for patients suffering cognitive and neurological sequalae.
Just two decades ago, the largest trials within the field of post-resuscitation care included 273 and 77 patients, respectively,31,32 with unblinded interventions, and quasi-randomized trial designs. Today, trials are published using complex double-blinded interventions,55 including large sample sizes of around and above 1000 patients. Trials are now preregistered on open platforms such as clinicaltrials.gov and plans for methodology and statistical analysis are published before data-analyses, reducing risks of publication bias, cherry picking of analyses, and ‘P-hacking’. Ongoing trials are expanding the scope of post-resuscitation care to the pre-hospital setting, where time-sensitive interventions can be applied closer to the arrest. Planned pragmatic trials, have multiple interventions in the same trial thus testing multiple hypotheses and better utilized research resources. Furthermore, modern trials plan to include several thousand patients thus a factor 10–15 larger than the trials from 2002.
Previous trials have investigated neuroprotective strategies without major breakthroughs yet.77 In critically ill patients, numerous trials have shown neutral results for OHCA-survivors and other critically ill groups. A systematic review of interventions in this area, found no conclusive evidence of any pharmacologic intervention that has consistently reduced mortality in critically ill patients.77 Future research should also focus on improving and optimizing small parts of everyday post-resuscitation care. Over time, these small steps forwards, such as improving methods of temperature control and finding optimal targets for oxygen and vasopressor therapies, may significantly improve care. A large proportion of comatose OHCA-patients receive sedation and vasopressor therapy. However, the different types of vasopressors and types of sedation have not been investigated. Finding redundant interventions, which do not improve patient-outcome is just as important as finding new therapies. In this way, unnecessary interventions can be removed from practise, thus reducing costs and side-effects for patients and reserves time and effort of the clinical staff to focus on interventions with confirmed positive effects on clinical outcomes. The pre-hospital phase may be especially important, since duration of low- and no-flow is likely the most important factor, which can be affected by the medical system. Pre-hospital medical interventions are being tested and EMS-systems are improving, while also including lay-people volunteers via smart-phone applications.
On a road paved with neutral studies, overall post-cardiac arrest care has gone through a remarkable evolution and the future of post-cardiac arrest care is bright.
Funding
None declared.
References
Author notes
Conflict of interest: None declared.
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