This study will address the following research questions:
What are the characteristics of circulatory failure in PCAS?
What are the characteristics of transitions between different clinical circulatory states during PCAS?
What is the inflammatory response measured by inflammatory and endothelial biomarkers in PCAS?
Which clinical characteristics and biomarkers predict changes in clinical circulatory states?
This study is a single-center, prospective, observational cohort study.
The study will take place at the intensive care unit (ICU) and the coronary care unit (CCU) at the St. Olav’s University Hospital, a tertiary referral university hospital in Trondheim, Norway, with a catchment population of 700,000.
All adult patients who are admitted to either the ICU or the CCU with obtained ROSC after OHCA will be considered for inclusion. Inclusion is performed immediately after arrival to the ICU or CCU.
Exclusion criteria are age <18 years, CA of septic or anaphylactic origin, sepsis within 24 hours before CA, pregnant women, transferred from other hospitals after OHCA, and decision to not initiate life-sustaining therapy after hospital arrival.
Patients are censored from further follow-up if the patient undergoes acute cardiothoracic surgery or intervention with extracorporeal membranous oxygenation support or a ventricular assist device, at the time of death, if life-prolonging therapy is withdrawn or withheld, or when the patient is transferred to a general ward or another hospital. The reason for censoring is recorded, and all data obtained until censoring will be included in the analysis.
This is an observational study, and the frequency of abnormal biomarkers, circulatory states, and endpoints are largely unknown; therefore, no formal sample size calculation has been performed [
The treatment of the patients is decided by the physician in charge and will not be changed due to the participation in the study. The routine treatment after OHCA at St. Olav’s University Hospital will be applied unless there are specific indications for alternative strategies. Routine care is briefly outlined below.
For OHCA suspected to be caused by disease in the coronary arteries, procedures for revascularization are routinely considered and performed if decided by the cardiologist. All use of medications for cardiac diseases and for anticoagulation is decided by the cardiologist in charge of treatment.
According to the current practice at St. Olav’s University Hospital, the target temperature is usually 36°C. Active temperature management is performed for 24 hours.
Sedation is initiated with either propofol or midazolam, and analgesia with either fentanyl or remifentanil. Sedation is titrated to Motor Activity Assessment Scale (MAAS) 0-1 during active temperature management and later titrated to the lowest dose achieving adequate patient comfort [
The primary treatment goal for circulatory support is to ensure adequate circulation, as evaluated by clinical examination (eg, tachycardia, pallor, cold skin, capillary refill), a mean arterial blood pressure (MAP) ≥65 mm Hg, and a urine output of ≥0.5 mL·kg−1·h−1. Generally, circulatory optimization is achieved through fluid and vasopressor administration after the following algorithm: in the presence of hypotension and/or tachycardia, the first step is to assess signs of tissue hypoperfusion (eg, cold, clammy skin and extremities, prolonged capillary refill time, diminished urine output, increasing lactate and decreasing base excess, decreasing central/mixed venous oxygenation, and if not sedated—deteriorating mental status). If the physician suspects tissue hypoperfusion, volume status is assessed through the presence of stroke volume variation >10% (pulsus paradoxus) and/or echocardiographic assessment of the heart and the inferior caval vein. If increased preload is indicated, repeated fluid boluses of 250 mL are given until cardiac output (CO) does not respond. If a fluid load is not indicated or does not improve the perfusion, vasoactive medication is administered. The standard vasoactive medications are norepinephrine and/or dobutamine, depending on whether vasoconstrictive and/or inotropic effects are indicated. If the vasoplegia is not improved by a high dose of norepinephrine (≥0.5 μg·kg−1·min−1), vasopressin (0.4 mU·kg−1·min−1) is considered.
Ventilation is administered by a SERVOi ventilator (Maquet Siemens, Germany). Ventilation is either pressure controlled or pressure supported for patients who have adequate spontaneous ventilation. The ventilator settings are adjusted to a positive end-expiratory pressure (PEEP) level, which give the best arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) ratio (usually PEEP is set at 8 cm H2 O at the start of ventilation), a plateau pressure to give a tidal volume of 6-8 mL/kg, a respiratory rate to give a PaCO2 within the normal range, and a FiO2 to give a O2 saturation above 95%. Tracheostomy is considered for patients who are difficult to wean from mechanical respiratory support, usually on days 8-10 of the ICU or CCU stay.
No nutrition is given on the day of arrival to the ICU or CCU. Enteral nutrition is given as soon as possible in increasing doses (from 500 kcal/day to 1000 kcal/day to 2000 kcal/day). If enteral nutrition is not feasible or nutrition targets cannot be reached within approximately 4 to 6 days, total parenteral nutrition is gradually introduced on the fourth day (25 kcal·kg−1·day−1). Before nutrition is started, the patients receive glucose 100 g/daily. Metabolic control of blood sugar is aimed at 5-10 mmol/L by a continuous infusion of insulin. Patients who use insulin on a regular basis will receive insulin at all times, and hypoglycemia is corrected with increased glucose or nutrition administration.
Antibiotics are not given routinely, but they are introduced if there is a clinical suspicion of an infection.
Assessment of hypoxic cerebral injury is primarily based on the combination of clinical signs, serum neuron-specific enolase concentrations, and neurophysiological examination of somatosensory evoked potentials. Other examinations, for example, magnetic resonance imaging, are performed when required. The evaluation of potential hypoxic cerebral injury is usually initiated on the third or fourth day after CA.
Airway suction is routinely performed once daily to secure patent airway and as needed if there are signs of excessive airway secretions. Airway suction is performed with a 10, 12, or 14 French scale catheter (depending on endotracheal tube size) through a closed suction system.
Shift of position is routinely performed every third hour.
Spontaneous breathing trials (SBTs) are considered in patients who have spontaneous respiration, airway patency, reversal of the cause of respiratory failure, no uncontrolled infection or metabolic disturbance, heart rate <120, systolic BP 90-180 mm Hg, oxygen saturation >90%, FiO2 <0.5, and positive end-expiratory pressure (PEEP) ≤8 cmH2 O. The SBT is performed using pressure-supported ventilation with inspiratory pressure support of approximately 8 cmH2 O and PEEP 6-8 cmH2 O for 10-30 min.
Patients will be screened for eligibility and recruited at the time they are admitted to the ICU or CCU for intensive care after OHCA (
Demographic and clinical data will be extracted from the patient’s medical records and documentation from emergency medical service (EMS) personnel involved in the treatment of CA. Registrations of clinical variables, as part of routine critical care from the time of ICU/CCU arrival until inclusion, will be used.
If there is no contraindication to insert a pulmonary artery catheter (PAC), the catheter is inserted as early as possible after inclusion.
At time of inclusion the following variables will be registered:
Patient characteristics: age, sex, ethnicity, weight, height, and premorbid cerebral performance category (CPC) [
Charlson Comorbidity Index [
Characteristics related to the CA (
Temperature at admission
Known pulmonary aspiration during CPR
Interventions
Clinical data are registered in the electronic ICU chart, Picis Critical Care Manager (Optum Inc, USA). After inclusion, the following variables will be recorded:
At the time of inclusion and every minute:
Basic vital measurements: heart rate and rhythm, invasive arterial blood pressure, pulmonary artery pressure, mixed venous oxygen saturation (SvO2, calibrated twice daily), central venous blood pressure, peripheral transcutaneous oxygen saturation, and temperature
Central hemodynamic measurements: CO and systemic vascular resistance (SVR), and corresponding indexed values (related to body-surface area)
Respiratory support: ventilator mode, respiratory rate, FiO2, minute ventilation, PEEP, and plateau pressure
At the time of inclusion and every following hour:
Fluid balance: fluid administrations, transfusions, and urine output
All medications
At the time of inclusion and every sixth hour:
Arterial blood gas analysis, including electrolytes
MAAS score
After 24 hours:
Simplified acute physiology score (SAPS) II [
At the time of inclusion and twice daily:
Pulmonary artery occlusion pressure
Central venous and mixed venous blood gas
At the time of inclusion and daily:
Standardized echocardiographic evaluation performed by a trained cardiologist
Intra-abdominal pressure
Clinical chemistry: white blood count, thrombocyte count, creatinine, blood urea nitrogen, C-reactive protein, troponin-T, probrain natriuretic peptide, bilirubin, albumin, and haptoglobin
Blood samples for inflammatory and endothelial biomarkers
Modified clinical pulmonary infection score (CPIS) [
Sequential organ failure assessment (SOFA) score [
Glasgow Coma Score [
Percutaneous coronary intervention, dialysis, and/or aorta balloon pump
Results from chest x-ray or other diagnostic imaging tools ordered during the hospital stay
Other events during the study period (eg, arrhythmias and seizures)
Flowchart summarizing patient enrollment and main study procedures. OHCA: out-of-hospital cardiac arrest; ROSC: return of spontaneous circulation; CCU: coronary care unit; ICU: intensive care unit; CA: cardiac arrest; PAC: pulmonary artery catheter; PAOP: pulmonary artery occlusion pressure; CPC: cerebral performance category.
As part of the study, we will establish a biobank for analysis of inflammatory and endothelial biomarkers. Blood samples will be taken at inclusion and every morning the 5 following days. After gentle mixing, the blood samples are placed vertical for 30 min in ambient temperature, and then centrifuged at 2200 g for 10 min. The supernatants are stored at −80°C within 1 hour from the time of sampling. During the study period, additional full blood will be drawn and stored at −80°C.
We will analyze the following biomarkers: interleukin (IL)-1β, IL-1 receptor antagonist (IL1-ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, basic fibroblast growth factor, granulocyte-colony stimulating factor, granulocyte macrophage colony stimulating factor, interferon γ, interferon-inducible protein 10, monocyte chemotactic protein 1, macrophage inflammatory protein 1α and 1β, platelet derived growth factor-BB, regulated upon activation T cell expressed and secreted, tumor necrosis factor, vascular endothelial growth factor, syndecan-1, sE-selectin, heparan sulfate, hyaluronic acid, soluble trombomodulin, and sVE-cadherin. Other biomarkers of interest, identified later, may be included in the final analysis.
Follow-up after discharge from the hospital will include the following:
ICU length of stay.
Hospital length of stay.
Survival status at hospital discharge and after 6 months.
CPC at hospital discharge and after 6 months.
Research on critically ill patients, who are sedated or comatose and, therefore, not able to provide consent, calls for special ethical considerations. For the study, it is vital that clinical information is obtained from the initial critical stage of the disease. This study will not increase the overall risk for the patients, and the study is justifiable according to the
Besides establishing and calibrating PAC (Swan-Ganz CCOmbo, Edward Lifescience, USA) and drawing blood for analysis of inflammatory biomarkers at a maximum of 5 time points, the study does not involve other interventions differing from routine care after OHCA. The insertion of PAC induces some benefits and some risks. One of the benefits is the potential of improved circulatory monitoring and support, including a more precise administration of fluids and vasoactive medications. However, complications related to the placement of PAC have also been reported. In a Cochrane report, PAC was neither found to increase mortality or length of stay in the ICU or the hospital (high-quality evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for both the findings). The Acute Decompensated Heart Failure Syndromes Registry compared 502 patients with decompensated heart failure and PAC with 502 controls [
Descriptive data are presented with either median or interquartile range, or mean with 95% CI, as appropriate. For missing observation of physiological variables (eg, blood pressure), a value corresponding to the mean of the observation before and after this time point will be applied. For biomarkers, the value 0 is attributed if a result is below the detection limits of the assay. Statistical analyses will be performed using Stata or R.
During critical illness, most patients go through different states of hemodynamic stability. We have categorized the circulatory state after CA in 3 different categories based on data obtained from routine care (
We will validate the appropriateness of the defined categories against the cardiac index.
Patients may go back and forth between the clinical states, defined in
Circulatory states.
| Variables | Circulation | ||
| Undisturbed | Disturbed | Severely disturbed | |
| Mean arterial pressure, mm Hg | ≥65 | 45-64 | <45 |
| Heart rate, bpm | 51-100 | <50, 101-130 | ≤40, >130 |
| Lactate, mmol/L | <2 | 2–4 | >4 |
| ScvO2, % | ≥65 | 50-64 | <50 |
| Fluid resuscitation, L/hours | <0.5 | 0.5-1.9 | ≥2 |
| Norepinephrine, μg·kg−1·min−1 | <0.1 | 0.1-0.29 | ≥0.3 |
| Dobutamine, μg·kg−1·min−1 | No | <10 | ≥10 |
| Vasopressin | No | No | Yes |
| Epinephrine | No | No | Yes |
| Levosimedan | No | No | Yes |
| Aorta balloon pump | No | No | Yes |
Possible transitions between circulatory states.
The Kaplan-Meier estimator accurately estimates the transition from one state to another, assuming that these 2 states describe all possible states. To be useful in a competing risk framework, the Kaplan-Meier estimator has been generalized into a matrix version, called the Aalen-Johansen estimator. To describe when, in time, most state transitions occur (ie, transition intensity), we will use the Nelson-Aalen estimator. The Nelson-Aalen estimator is a nonparametric estimator of the “cumulative hazard” of a given event, and it can be applied in a multi-state model.
We anticipate that not all patients will follow the same circulatory trajectory; during the study, some will deteriorate and some will improve in circulatory status, and during our observation, many will have several state transitions. We plan to analyze events before deteriorations to identify patterns of circulatory and inflammatory response measurements predictive of clinical state deteriorations. These patterns will be compared with those in patients who improve their circulatory status or remain unchanged.
To explore the predictive value of previous measurements to foresee a clinical deterioration, we will use 2 different approaches. The outcome variable will be dichotomized to deterioration versus no deterioration (status quo or improvement). First, we will test different timelags between measurements and deteriorations to see which is more informative (eg, 1 hour, 2 hours, 3 hours). For this analytic approach, we will use univariable and multivariable logistic regression. Second, we will use methods from survival analysis to assess continuous alterations in covariates on the outcome. For this analysis, we will use Aalen’s linear model, which is an intensity regression model. Variables from the 2 groups will also be explored in respect to its relation to mortality and CPC at discharge from hospital.
We will study the relationship between alterations in inflammatory and endothelial biomarkers and the changes in SVR, in CO, and the need for fluid replacement. As described above, patients with hypotension and low SVR will be treated with norepinephrine. Therefore, we will analyze potential independent biomarkers and other predictors of SVR adjusted for a dose of norepinephrine.
Vasoplegia might also occur as part of an infection, and CA patients are prone to aspiration and pneumonia after CPR. Therefore, we will calculate modified CPIS daily to describe how many patients develop clinical pneumonia.
Circulatory failure might also be due to structural heart defects (eg, mitral valve insufficiency). An experienced cardiologist will perform echocardiogram daily to assess the heart’s function.