A national multi centre pre-hospital ECPR stepped wedge study; design and rationale of the ON-SCENE study.

BACKGROUND: The likelihood of return of spontaneous circulation with conventional advanced life support is known to have an exponential decline and therefore neurological outcome after 20 min in patients with a cardiac arrest is poor. Initiation of venoarterial ExtraCorporeal Membrane Oxygenation (ECMO) during resuscitation might improve outcomes if used in time and in a selected patient category. However, previous studies have failed to significantly reduce the time from cardiac arrest to ECMO flow to less than 60 min. We hypothesize that the initiation of Extracorporeal Cardiopulmonary Resuscitation (ECPR) by a Helicopter Emergency Medical Services System (HEMS) will reduce the low flow time and improve outcomes in refractory Out of Hospital Cardiac Arrest (OHCA) patients. METHODS: The ON-SCENE study will use a non-randomised stepped wedge design to implement ECPR in patients with witnessed OHCA between the ages of 18-50 years old, with an initial presentation of shockable rhythm or pulseless electrical activity with a high suspicion of pulmonary embolism, lasting more than 20, but less than 45 min. Patients will be treated by the ambulance crew and HEMS with prehospital ECPR capabilities and will be compared with treatment by ambulance crew and HEMS without prehospital ECPR capabilities. The primary outcome measure will be survival at hospital discharge. The secondary outcome measure will be good neurological outcome defined as a cerebral performance categories scale score of 1 or 2 at 6 and 12 months. DISCUSSION: The ON-SCENE study focuses on initiating ECPR at the scene of OHCA using HEMS. The current in-hospital ECPR for OHCA obstacles encompassing low survival rates in refractory arrests, extended low-flow durations during transportation, and the critical time sensitivity of initiating ECPR, which could potentially be addressed through the implementation of the HEMS system. When successful, implementing on-scene ECPR could significantly enhance survival rates and minimize neurological impairment. TRIAL REGISTRATION: Clinicaltyrials.gov under NCT04620070, registration date 3 November 2020.

Health-related quality of life, one-year costs and economic evaluation in extracorporeal membrane oxygenation in critically ill adults.

PURPOSE: This study reports on survival and health related quality of life (HRQOL) after extracorporeal membrane oxygenation (ECMO) treatment and the associated costs in the first year. MATERIALS AND METHODS: Prospective observational cohort study patients receiving ECMO in the intensive care unit during August 2017 and July 2019. We analyzed all healthcare costs in the first year after index admission. Follow-up included a HRQOL analysis using the EQ-5D-5L at 6 and 12 months. RESULTS: The study enrolled 428 patients with an ECMO run during their critical care admission. The one-year mortality was 50%. Follow up was available for 124 patients at 12 months. Survivors reported a favorable mean HRQOL (utility) of 0.71 (scale 0-1) at 12 months of 0.77. The overall health status (VAS, scale 0-100) was reported as 73.6 at 12 months. Mean total costs during the first year were $204,513 ± 211,590 with hospital costs as the major factor contributing to the total costs. Follow up costs were $53,752 ± 65,051 and costs of absenteeism were $7317 ± 17,036. CONCLUSIONS: At one year after hospital admission requiring ECMO the health-related quality of life is favorable with substantial costs but considering the survival might be acceptable. However, our results are limited by loss of follow up. So it may be possible that only the best-recovered patients returned their questionnaires. This potential bias might lead to higher costs and worse HRQOL in a real-life scenario.

Outcomes of Extracorporeal Membrane Oxygenation in COVID-19-Induced Acute Respiratory Distress Syndrome: An Inverse Probability Weighted Analysis.

Although venovenous extracorporeal membrane oxygenation (VV ECMO) has been used in case of COVID-19 induced acute respiratory distress syndrome (ARDS), outcomes and criteria for its application should be evaluated. OBJECTIVES: To describe patient characteristics and outcomes in patients receiving VV ECMO due to COVID-19-induced ARDS and to assess the possible impact of COVID-19 on mortality. DESIGN SETTING AND PARTICIPANTS: Multicenter retrospective study in 15 ICUs worldwide. All adult patients (> 18 yr) were included if they received VV ECMO with ARDS as main indication. Two groups were created: a COVID-19 cohort from March 2020 to December 2020 and a "control" non-COVID ARDS cohort from January 2018 to July 2019. MAIN OUTCOMES AND MEASURES: Collected data consisted of patient demographics, baseline variables, ECMO characteristics, and patient outcomes. The primary outcome was 60-day mortality. Secondary outcomes included patient characteristics, COVID-19-related therapies before and during ECMO and complication rate. To assess the influence of COVID-19 on mortality, inverse probability weighted (IPW) analyses were used to correct for predefined confounding variables. RESULTS: A total of 193 patients with COVID-19 received VV ECMO. The main indication for VV ECMO consisted of refractory hypoxemia, either isolated or combined with refractory hypercapnia. Complications with the highest occurrence rate included hemorrhage, an additional infectious event or acute kidney injury. Mortality was 35% and 45% at 28 and 60 days, respectively. Those mortality rates did not differ between the first and second waves of COVID-19 in 2020. Furthermore, 60-day mortality was equal between patients with COVID-19 and non-COVID-19-associated ARDS receiving VV ECMO (hazard ratio 60-d mortality, 1.27; 95% CI, 0.82-1.98; p = 0.30). CONCLUSIONS AND RELEVANCE: Mortality for patients with COVID-19 who received VV ECMO was similar to that reported in other COVID-19 cohorts, although no differences were found between the first and second waves regarding mortality. In addition, after IPW, mortality was independent of the etiology of ARDS.

Reduced anticoagulation targets in extracorporeal life support (RATE): study protocol for a randomized controlled trial.

BACKGROUND: Although life-saving in selected patients, ECMO treatment still has high mortality which for a large part is due to treatment-related complications. A feared complication is ischemic stroke for which heparin is routinely administered for which the dosage is usually guided by activated partial thromboplastin time (aPTT). However, there is no relation between aPTT and the rare occurrence of ischemic stroke (1.2%), but there is a relation with the much more frequent occurrence of bleeding complications (55%) and blood transfusion. Both are strongly related to outcome. METHODS: We will conduct a three-arm non-inferiority randomized controlled trial, in adult patients treated with ECMO. Participants will be randomized between heparin administration with a target of 2-2.5 times baseline aPTT, 1.5-2 times baseline aPTT, or low molecular weight heparin guided by weight and renal function. Apart from anticoagulation targets, treatment will be according to standard care. The primary outcome parameter is a combined endpoint consisting of major bleeding including hemorrhagic stroke, severe thromboembolic complications including ischemic stroke, and mortality at 6 months. DISCUSSION: We hypothesize that with lower anticoagulation targets or anticoagulation with LMWH during ECMO therapy, patients will have fewer hemorrhagic complications without an increase in thromboembolic complication or a negative effect on their outcome. If our hypothesis is confirmed, this study could lead to a change in anticoagulation protocols and a better outcome for patients treated with ECMO. TRIAL REGISTRATION: ClinicalTrials.gov NCT04536272 . Registered on 2 September 2020. Netherlands Trial Register NL7969.

Near-Infrared Spectroscopy-Derived Dynamic Cerebral Autoregulation in Experimental Human Endotoxemia-An Exploratory Study.

Cerebral perfusion may be altered in sepsis patients. However, there are conflicting findings on cerebral autoregulation (CA) in healthy participants undergoing the experimental endotoxemia protocol, a proxy for systemic inflammation in sepsis. In the current study, a newly developed near-infrared spectroscopy (NIRS)-based CA index is investigated in an endotoxemia study population, together with an index of focal cerebral oxygenation. Methods: Continuous-wave NIRS data were obtained from 11 healthy participants receiving a continuous infusion of bacterial endotoxin for 3 h (ClinicalTrials.gov NCT02922673) under extensive physiological monitoring. Oxygenated-deoxygenated hemoglobin phase differences in the (very)low frequency (VLF/LF) bands and the Tissue Saturation Index (TSI) were calculated at baseline, during systemic inflammation, and at the end of the experiment 7 h after the initiation of endotoxin administration. Results: The median (inter-quartile range) LF phase difference was 16.2° (3.0-52.6°) at baseline and decreased to 3.9° (2.0-8.8°) at systemic inflammation (p = 0.03). The LF phase difference increased from systemic inflammation to 27.6° (12.7-67.5°) at the end of the experiment (p = 0.005). No significant changes in VLF phase difference were observed. The TSI (mean ± SD) increased from 63.7 ± 3.4% at baseline to 66.5 ± 2.8% during systemic inflammation (p = 0.03) and remained higher at the end of the experiment (67.1 ± 4.2%, p = 0.04). Further analysis did not reveal a major influence of changes in several covariates such as blood pressure, heart rate, PaCO2, and temperature, although some degree of interaction could not be excluded. Discussion: A reversible decrease in NIRS-derived cerebral autoregulation phase difference was seen after endotoxin infusion, with a small, sustained increase in TSI. These findings suggest that endotoxin administration in healthy participants reversibly impairs CA, accompanied by sustained microvascular vasodilation.

Acetaminophen Use Concomitant with Long-Lasting Flucloxacillin Therapy: A Dangerous Combination.

Acetaminophen and flucloxacillin both interfere with the γ-glutamyl cycle. Long-lasting concomitant use of flucloxacillin and acetaminophen can lead to 5-oxoproline accumulation and severe high anion gap metabolic acidosis. Females and patients with sepsis, impaired kidney and/or liver function, malnutrition, advanced age, congenital 5-oxoprolinase deficiency and supratherapeutic acetaminophen and flucloxacillin dosage are associated with increased risk. Therefore, a critical attitude towards the prescription of acetaminophen concomitant with flucloxacillin in these patients is needed. We present the case of a 79-year-old woman with severe 5-oxoprolinaemia after long-lasting treatment with flucloxacillin and acetaminophen, explaining the toxicological mechanism and risk factors, and we make recommendations for acetaminophen use in patients with long-lasting flucloxacillin treatment. LEARNING POINTS: Although rare, long-lasting treatment with flucloxacillin concomitant with acetaminophen can lead to severe high anion gap metabolic acidosis.When prescribing long-lasting flucloxacillin therapy in combination with acetaminophen, regular blood gas analysis is needed to evaluate pH and the anion gap.In cases of 5-oxoproline-induced high anion gap metabolic acidosis in patients with long-lasting acetaminophen and flucloxacillin therapy, acetaminophen prescription should be stopped immediately. Replacing flucloxacillin with another antibiotic agent should be considered.

Emergency Department to ICU Time Is Associated With Hospital Mortality: A Registry Analysis of 14,788 Patients From Six University Hospitals in The Netherlands.

OBJECTIVES: Prolonged emergency department to ICU waiting time may delay intensive care treatment, which could negatively affect patient outcomes. The aim of this study was to investigate whether emergency department to ICU time is associated with hospital mortality. DESIGN, SETTING, AND PATIENTS: We conducted a retrospective observational cohort study using data from the Dutch quality registry National Intensive Care Evaluation. Adult patients admitted to the ICU directly from the emergency department in six university hospitals, between 2009 and 2016, were included. Using a logistic regression model, we investigated the crude and adjusted (for disease severity; Acute Physiology and Chronic Health Evaluation IV probability) odds ratios of emergency department to ICU time on mortality. In addition, we assessed whether the Acute Physiology and Chronic Health Evaluation IV probability modified the effect of emergency department to ICU time on mortality. Secondary outcomes were ICU, 30-day, and 90-day mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 14,788 patients were included. The median emergency department to ICU time was 2.0 hours (interquartile range, 1.3-3.3 hr). Emergency department to ICU time was correlated to adjusted hospital mortality (p < 0.002), in particular in patients with the highest Acute Physiology and Chronic Health Evaluation IV probability and long emergency department to ICU time quintiles: odds ratio, 1.29; 95% CI, 1.02-1.64 (2.4-3.7 hr) and odds ratio, 1.54; 95% CI, 1.11-2.14 (> 3.7 hr), both compared with the reference category (< 1.2 hr). For 30-day and 90-day mortality, we found similar results. However, emergency department to ICU time was not correlated to adjusted ICU mortality (p = 0.20). CONCLUSIONS: Prolonged emergency department to ICU time (> 2.4 hr) is associated with increased hospital mortality after ICU admission, mainly driven by patients who had a higher Acute Physiology and Chronic Health Evaluation IV probability. We hereby provide evidence that rapid admission of the most critically ill patients to the ICU might reduce hospital mortality.

Cost-effectiveness in extracorporeal life support in critically ill adults in the Netherlands.

BACKGROUND: Extracorporeal life support (ECLS) is used to support the cardiorespiratory function in case of severe cardiac and/or respiratory failure in critically ill patients. According to the ELSO guidelines ECLS should be considered when estimated mortality risk approximates 80%. ECLS seems an efficient therapy in terms of survival benefit, but no undisputed evidence is delivered yet. The aim of the study is to assess the health-related quality of life after ECLS treatment and its cost effectiveness. METHODS: We will perform a prospective observational cohort study. All adult patients who receive ECLS in the participating centers will be included. Exclusion criteria are patients in whom the ECLS is only used to bridge a procedure (like a high risk percutaneous coronary intervention or surgery) or the absence of informed consent. Data collection includes patient characteristics and data specific for ECLS treatment. Severity of illness and mortality risk is measured as precisely as possible using measurements for the appropriate age group and organ failure. For analyses on survival patients will act as their own control as we compare the actual survival with the estimated mortality on initiation of ECLS if conservative treatment would have been continued. Survivors are asked to complete validated questionnaires on health related quality of life (EQ5D-5 L) and on medical consumption and productivity losses (iMTA/iPCQ) at 6 and 12 months. Also the health related quality of life 1 month prior to ECLS initiation will be obtained by a questionnaire, if needed provided by relatives. With an estimated overall survival of 62% 210 patients need to be recruited to make a statement on cost effectiveness for all ECLS indications. DISCUSSION: If our hypothesis that ECLS treatment is cost-effective is confirmed by this prospective study this could lead to an even broader use of ECLS treatment. TRIAL REGISTRATION: The trial is registered at ( NCT02837419 ) registration date July 19, 2016 and with the Dutch trial register, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6599.

Vasopressors Do Not Influence Cerebral Critical Closing Pressure During Systemic Inflammation Evoked by Experimental Endotoxemia and Sepsis in Humans.

AIM: The aim of this study was to investigate the effects of different vasopressors on the cerebral vasculature during experimental human endotoxemia and sepsis. We used the critical closing pressure (CrCP) as a measure of cerebral vascular tone. METHODS: We performed a prospective pilot study, at the intensive care department (ICU) of a tertiary care university hospital in the Netherlands, in 40 healthy male subjects during experimental human endotoxemia (administration of bacterial lipopolysaccharide [LPS]) and in 10 patients with severe sepsis or septic shock.Subjects in the endotoxemia study were randomized to receive a 5 h infusion of either 0.05 µg/kg/min noradrenaline (n = 10, "LPS-nor"), 0.5 µg/kg/min phenylephrine (n = 10, "LPS-phenyl"), 0.04 IU/min vasopressin (n = 10, "LPS-AVP"), or saline (n = 10, "LPS-placebo") starting 1 h before intravenous administration of 2 ng/kg LPS. In patients with sepsis, fluid resuscitation and vasopressor use was at the discretion of the medical team, aiming at normovolemia and a mean arterial pressure (MAP) > 65 mm Hg, using noradrenaline.The mean flow velocity in the middle cerebral artery (MFVMCA) was measured by transcranial Doppler (TCD) with simultaneously recording of heart rate, arterial blood pressure, respiratory rate, and oxygen saturation. CrCP was estimated using the cerebrovascular impedance model. RESULTS: The CrCP decreased in the LPS-placebo group from 52.6 [46.6-55.5] mm Hg at baseline to 44.1 [41.2-51.3] mm Hg at 270 min post-LPS (P = 0.03). Infusion of phenylephrine increased the CrCP in the period before LPS administration from 46.9 [38.8-53.4] to 53.8 [52.9-60.2] mm Hg (P = 0.02), but after LPS administration, a similar decrease was observed compared with the LPS-placebo group. Noradrenaline or vasopressin prior to LPS did not affect the CrCP. The decrease in CrCP after LPS bolus was similar in all treatment groups. The CrCP in the sepsis patients equaled 35.7 [34.4-42.0] mm Hg, and was lower compared with that in the LPS-placebo subjects from baseline until 90 min after LPS (P < 0.01). CONCLUSIONS: Experimental human endotoxemia results in a decreased CrCP due to a loss of vascular resistance of the arterial bed. Vasopressors did not prevent this decrease in CrCP. Findings in patients with sepsis are comparable to those found in subjects after LPS administration.Patients with sepsis, despite treatment with vasopressors, have a risk for low cerebral blood flow and ischemia.

Middle cerebral artery flow, the critical closing pressure, and the optimal mean arterial pressure in comatose cardiac arrest survivors-An observational study.

AIM: This study estimated the critical closing pressure (CrCP) of the cerebrovascular circulation during the post-cardiac arrest syndrome and determined if CrCP differs between survivors and non-survivors. We also compared patients after cardiac arrest to normal controls. METHODS: A prospective observational study was performed at the ICU of a tertiary university hospital in Nijmegen, the Netherlands. We studied 11 comatose patients successfully resuscitated from a cardiac arrest and treated with mild therapeutic hypothermia and 10 normal control subjects. Mean flow velocity (MFV) in the middle cerebral artery was measured by transcranial Doppler at several time points after admission to the ICU. CrCP was determined by a cerebrovascular impedance model. RESULTS: MFV was similar in survivors and non-survivors upon admission to the ICU, but increased stronger in non-survivors compared to survivors throughout the observation period (P<0.001). MFV was significantly lower in survivors immediately after cardiac arrest compared to normal controls (P<0.001), with a gradual restoration toward normal values. CrCP decreased significantly from 61.4[51.0-77.1]mmHg to 41.7[39.9-51.0]mmHg in the first 48h, after which it remained stable (P<0.001). CrCP was significantly higher in survivors compared to non-survivors (P=0.002). CrCP immediately after cardiac arrest was significantly higher compared to the control group (P=0.02). CONCLUSIONS: CrCP is high after cardiac arrest with high cerebrovascular resistance and low MFV. This suggests that cerebral perfusion pressure should be maintained at a sufficient high level to avoid secondary brain injury. Failure to normalize the cerebrovascular profile may be a parameter of poor outcome.

An error in the CoaguChek S device results in prosthetic heart valve thrombosis.

The CoaguChek S device offers patients on oral anticoagulant treatment, a simple and fast method of direct monitoring of their international normalized ratio (INR). It is comparable with the glucose monitoring system, a fingerprick for a drop of capillary blood and some minutes to get the INR result for further anticoagulation monitoring. We present a case of tricuspid prosthetic valve thrombosis due to inadequate anticoagulation because of an error in the point-of-care device.

Risk of coronary surgery for hospital and early morbidity and mortality after initially successful percutaneous intervention.

This study examines the influence of a successful PCI upon preoperative patient profile, peroperative management and postoperative, including one-year follow-up, results. From January 1999 through December 2001, 1141 patients (91%) underwent coronary artery bypass grafting (CABG) as the primary intervention for myocardial revascularization (group A) and 113 patients (9%) underwent primary CABG after an initially successful PCI (group B). Patients undergoing CABG after a failed PCI were not included. Patients in group B were statistically significant younger (P=0.010), with more peripheral arterial vascular (P=0.015) and renal disease (P=0.036). Left main coronary artery stenosis was significantly lower in group B (P=0.004). The number of diseased vessels did not differ between the two groups. However, less distal anastomoses were performed in group B (P=0.001). Postoperatively there was no statistically significant differences, in the percentages of myocardial infarction, arrhythmias, reinterventions, neurological, renal and pulmonary complications, and hospital mortality. One-year follow-up did not show any statistically significant differences in cardiac related mortality (P=0.25) or recurrent ischemic events (P=0.27). Multivariate analysis did not identify a successful PCI as a risk factor for early and late adverse outcomes. Previous PCI does not seem to result in a higher postoperative mortality or morbidity after CABG.