International Survey on Mechanical Ventilation During Extracorporeal Membrane Oxygenation.

The optimal ventilation strategy for patients on extracorporeal membrane oxygenation (ECMO) remains uncertain. This survey reports current mechanical ventilation strategies adopted by ECMO centers worldwide. An international, multicenter, cross-sectional survey was conducted anonymously through an internet-based tool. Participants from North America, Europe, Asia, and Oceania were recruited from the extracorporeal life support organization (ELSO) directory. Responses were received from 48 adult ECMO centers (response rate 10.6%). Half of these had dedicated ventilation protocols for ECMO support. Pressure-controlled ventilation was the preferred initial ventilation mode for both venovenous ECMO (VV-ECMO) (60%) and venoarterial ECMO (VA-ECMO) (34%). In VV-ECMO, the primary goal was lung rest (93%), with rescue therapies commonly employed, especially neuromuscular blockade (93%) and prone positioning (74%). Spontaneous ventilation was typically introduced after signs of pulmonary recovery, with few centers using it as the initial mode (7%). A quarter of centers stopped sedation within 3 days after ECMO initiation. Ventilation strategies during VA-ECMO focused less on lung-protective goals and transitioned to spontaneous ventilation earlier. Ventilation strategies during ECMO support differ considerably. Controlled ventilation is predominantly used initially to provide lung rest, often facilitated by sedation and neuromuscular blockade. Few centers apply "awake ECMO" early during ECMO support, some utilizing partial neuromuscular blockade.

Transfusion of red blood cells in venoarterial extracorporeal membrane oxygenation: A multicenter retrospective observational cohort study.

BACKGROUND: Evidence-based recommendations for transfusion in patients with venoarterial extracorporeal membrane oxygenation (VA ECMO) are scarce. The current literature is limited to single-center studies with small sample sizes, therefore complicating generalizability. This study aims to create an overview of red blood cell (RBC) transfusion in VA ECMO patients. METHODS: This international mixed-method study combined a survey with a retrospective observational study in 16 centers. The survey inventoried local transfusion guidelines. Additionally, retrospective data of all adult patients with a VA ECMO run >24 h (January 2018 until July 2019) was collected of patient, ECMO, outcome, and daily transfusion parameters. All patients that received VA ECMO for primary cardiac support were included, including surgical (i.e., post-cardiotomy) and non-surgical (i.e., myocardial infarction) indications. The primary outcome was the number of RBC transfusions per day and in total. Univariable logistic regressions and a generalized linear mixed model (GLMM) were performed to assess factors associated with RBC transfusion. RESULTS: Out of 419 patients, 374 (89%) received one or more RBC transfusions. During a median ECMO run of 5 days (1st-3rd quartile 3-8), patients received a median total of eight RBC units (1st-3rd quartile 3-17). A lower hemoglobin (Hb) prior to ECMO, longer ECMO-run duration, and hemorrhage were associated with RBC transfusion. After correcting for duration and hemorrhage using a GLMM, a different transfusion trend was found among the regimens. No unadjusted differences were found in overall survival between either transfusion status or the different regimens, which remained after adjustment for potential confounders. CONCLUSION: RBC transfusion in patients on VA ECMO is very common. The sum of RBC transfusions increases rapidly after ECMO initiation, and is dependent on the Hb threshold applied. This study supports the rationale for prospective studies focusing on indications and thresholds for RBC transfusion.

Plasma Transfusion and Procoagulant Product Administration in Extracorporeal Membrane Oxygenation: A Secondary Analysis of an International Observational Study on Current Practices.

OBJECTIVES: To achieve optimal hemostatic balance in patients on extracorporeal membrane oxygenation (ECMO), a liberal transfusion practice is currently applied despite clear evidence. We aimed to give an overview of the current use of plasma, fibrinogen concentrate, tranexamic acid (TXA), and prothrombin complex concentrate (PCC) in patients on ECMO. DESIGN: A prespecified subanalysis of a multicenter retrospective study. Venovenous (VV)-ECMO and venoarterial (VA)-ECMO are analyzed as separate populations, comparing patients with and without bleeding and with and without thrombotic complications. SETTING: Sixteen international ICUs. PATIENTS: Adult patients on VA-ECMO or VV-ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 420 VA-ECMO patients, 59% (n = 247) received plasma, 20% (n = 82) received fibrinogen concentrate, 17% (n = 70) received TXA, and 7% of patients (n = 28) received PCC. Fifty percent of patients (n = 208) suffered bleeding complications and 27% (n = 112) suffered thrombotic complications. More patients with bleeding complications than patients without bleeding complications received plasma (77% vs. 41%, p < 0.001), fibrinogen concentrate (28% vs 11%, p < 0.001), and TXA (23% vs 10%, p < 0.001). More patients with than without thrombotic complications received TXA (24% vs 14%, p = 0.02, odds ratio 1.75) in VA-ECMO, where no difference was seen in VV-ECMO. Of 205 VV-ECMO patients, 40% (n = 81) received plasma, 6% (n = 12) fibrinogen concentrate, 7% (n = 14) TXA, and 5% (n = 10) PCC. Thirty-nine percent (n = 80) of VV-ECMO patients suffered bleeding complications and 23% (n = 48) of patients suffered thrombotic complications. More patients with than without bleeding complications received plasma (58% vs 28%, p < 0.001), fibrinogen concentrate (13% vs 2%, p < 0.01), and TXA (11% vs 2%, p < 0.01). CONCLUSIONS: The majority of patients on ECMO receive transfusions of plasma, procoagulant products, or antifibrinolytics. In a significant part of the plasma transfused patients, this was in the absence of bleeding or prolonged international normalized ratio. This poses the question if these plasma transfusions were administered for another indication or could have been avoided.

The interaction of thrombocytopenia, hemorrhage, and platelet transfusion in venoarterial extracorporeal membrane oxygenation: a multicenter observational study.

BACKGROUND: Thrombocytopenia, hemorrhage and platelet transfusion are common in patients supported with venoarterial extracorporeal membrane oxygenation (VA ECMO). However, current literature is limited to small single-center experiences with high degrees of heterogeneity. Therefore, we aimed to ascertain in a multicenter study the course and occurrence rate of thrombocytopenia, and to assess the association between thrombocytopenia, hemorrhage and platelet transfusion during VA ECMO. METHODS: This was a sub-study of a multicenter (N = 16) study on transfusion practices in patients on VA ECMO, in which a retrospective cohort (Jan-2018-Jul-2019) focusing on platelets was selected. The primary outcome was thrombocytopenia during VA ECMO, defined as mild (100-150·109/L), moderate (50-100·109/L) and severe (< 50·109/L). Secondary outcomes included the occurrence rate of platelet transfusion, and the association between thrombocytopenia, hemorrhage and platelet transfusion, assessed through mixed-effect models. RESULTS: Of the 419 patients included, median platelet count at admission was 179·109/L. During VA ECMO, almost all (N = 398, 95%) patients developed a thrombocytopenia, of which a significant part severe (N = 179, 45%). One or more platelet transfusions were administered in 226 patients (54%), whereas 207 patients (49%) suffered a hemorrhagic event during VA ECMO. In non-bleeding patients, still one in three patients received a platelet transfusion. The strongest association to receive a platelet transfusion was found in the presence of severe thrombocytopenia (adjusted OR 31.8, 95% CI 17.9-56.5). After including an interaction term of hemorrhage and thrombocytopenia, this even increased up to an OR of 110 (95% CI 34-360). CONCLUSIONS: Thrombocytopenia has a higher occurrence than is currently recognized. Severe thrombocytopenia is strongly associated with platelet transfusion. Future studies should focus on the etiology of severe thrombocytopenia during ECMO, as well as identifying indications and platelet thresholds for transfusion in the absence of bleeding. TRIAL REGISTRATION: This study was registered at the Netherlands Trial Registry at February 26th, 2020 with number NL8413 and can currently be found at https://trialsearch.who.int/Trial2.aspx?TrialID=NL8413.

Risk factors for elective and emergency oxygenator exchanges during veno-venous extracorporeal membrane oxygenation.

BACKGROUND: Despite systemic anticoagulation and antithrombotic surface coating, oxygenator dysfunction remains one of most common technical complications of Extracorporeal membrane oxygenation (ECMO). Several parameters have been associated with an oxygenator exchange, but no guidelines for when to perform an exchange are published. An exchange, especially an emergency exchange, has a risk of complications. Therefore, a delicate balance between oxygenator dysfunction and the exchange of the oxygenator exists. This study aimed to identify risk factors and predictors for elective and emergency oxygenator exchanges. METHODS: This observational cohort study included all adult patients supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO). We compared patients' characteristics and laboratory values of patients with and without an oxygenator exchange and between an elective and emergency exchange, defined as an exchange outside office hours. Risk factors for an oxygenator exchange were identified with cox regression analyses, and risk factors for an emergency exchange were identified with logistic regression analyses. RESULTS: We included forty-five patients in the analyses. There were twenty-nine oxygenator exchanges in nineteen patients (42%). More than a third of the exchanges were emergency exchanges. Higher partial pressure of carbon dioxide (PaCO2), transmembrane pressure difference (ΔP), and hemoglobin (Hb) were associated with an oxygenator exchange. Lower lactate dehydrogenase (LDH) was the only risk factor for an emergency exchange. CONCLUSION: Oxygenator exchange is frequent during V-V ECMO support. PaCO2, ΔP and Hb were associated with an oxygenator exchange and lower LDH with the risk of an emergency exchange.

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.

Incidence and risk factors of deep vein thrombosis after extracorporeal life support.

BACKGROUND: Deep vein thrombosis (DVT) after decannulation of extracorporeal life support (ECLS) is not uncommon. Moreover, the impact of anticoagulation and potential risk factors is unclear. Furthermore, it is unclear if cannula-associated DVT is more common in ECLS patients compared to critically ill patients without ECLS. METHODS: All adult patients who were successfully weaned from ECLS and were screened for DVT following decannulation were included in this observational cohort study. The incidence of post-ECLS-DVT was assessed and the cannula-associated DVT rate was compared with that of patients without ECLS after central venous catheter (CVC) removal. The correlation between the level of anticoagulation, risk factors, and post-ECLS-DVT was determined. RESULTS: We included 30 ECLS patients and 53 non-ECLS patients. DVT was found in 15 patients (50%) of which 10 patients had a DVT in a cannulated vein. No correlation between the level of anticoagulation and DVT was found. V-V ECLS mode was the only independent risk factor for post-ECLS-DVT (OR 5.5; 95%CI 1.16-26.41). We found no difference between the ECLS and non-ECLS cohorts regarding cannula-associated DVT rate (33% vs. 32%). CONCLUSION: Post-ECLS-DVT is a common finding that occurs in half of all patients supported with ECLS. The incidence of cannula-associated DVT was equal to CVC-associated DVT in critically ill patients without ECLS. V-V ECLS was an independent risk factor for post-ECLS-DVT.

RBC Transfusion in Venovenous Extracorporeal Membrane Oxygenation: A Multicenter Cohort Study.

OBJECTIVES: In the general critical care patient population, restrictive transfusion regimen of RBCs has been shown to be safe and is yet implemented worldwide. However, in patients on venovenous extracorporeal membrane oxygenation, guidelines suggest liberal thresholds, and a clear overview of RBC transfusion practice is lacking. This study aims to create an overview of RBC transfusion in venovenous extracorporeal membrane oxygenation. DESIGN: Mixed method approach combining multicenter retrospective study and survey. SETTING: Sixteen ICUs worldwide. PATIENTS: Patients receiving venovenous extracorporeal membrane oxygenation between January 2018 and July 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion receiving RBC, the amount of RBC units given daily and in total. Furthermore, the course of hemoglobin over time during extracorporeal membrane oxygenation was assessed. Demographics, extracorporeal membrane oxygenation characteristics, and patient outcome were collected. Two-hundred eight patients received venovenous extracorporeal membrane oxygenation, 63% male, with an age of 55 years (45-62 yr), mainly for acute respiratory distress syndrome. Extracorporeal membrane oxygenation duration was 9 days (5-14 d). Prior to extracorporeal membrane oxygenation, hemoglobin was 10.8 g/dL (8.9-13.0 g/dL), decreasing to 8.7 g/dL (7.7-9.8 g/dL) during extracorporeal membrane oxygenation. Nadir hemoglobin was lower on days when a transfusion was administered (8.1 g/dL [7.4-9.3 g/dL]). A vast majority of 88% patients received greater than or equal to 1 RBC transfusion, consisting of 1.6 U (1.3-2.3 U) on transfusion days. This high transfusion occurrence rate was also found in nonbleeding patients (81%). Patients with a liberal transfusion threshold (hemoglobin > 9 g/dL) received more RBC in total per transfusion day and extracorporeal membrane oxygenation day. No differences in survival, hemorrhagic and thrombotic complication rates were found between different transfusion thresholds. Also, 28-day mortality was equal in transfused and nontransfused patients. CONCLUSIONS: Transfusion of RBC has a high occurrence rate in patients on venovenous extracorporeal membrane oxygenation, even in nonbleeding patients. There is a need for future studies to find optimal transfusion thresholds and triggers in patients on extracorporeal membrane oxygenation.

Hospital Costs of Extracorporeal Membrane Oxygenation in Adults: A Systematic Review.

BACKGROUND: Costs associated with extracorporeal membrane oxygenation (ECMO) are an important factor in establishing cost effectiveness. In this systematic review, we aimed to determine the total hospital costs of ECMO for adults. METHODS: The literature was retrieved from the PubMed/MEDLINE, EMBASE, and Web of Science databases from inception to 4 March 2020 using the search terms 'extracorporeal membrane oxygenation' combined with 'costs'; similar terms or phrases were then added to the search, i.e. 'Extracorporeal Life Support' or 'ECMO' or 'ECLS' combined with 'costs'. We included any type of study (e.g. randomized trial or observational cohort) evaluating hospital costs of ECMO in adults (age ≥18 years). RESULTS: A total of 1768 unique articles were retrieved during our search. We assessed 74 full-text articles for eligibility, of which 14 articles were selected for inclusion in this review; six papers were from the US, five were from Europe, and one each from Japan, Australia, and Taiwan. The sample sizes ranged from 16 to 18,684 patients. One paper exclusively used prospective cost data collection, while all other papers used retrospective data collection. Five papers reported charges instead of costs. There was large variation in hospital costs, ranging from US$22,305 to US$334,608 (2019 values), largely depending on the indication for ECMO support and location. The highest reported costs were for lung transplant recipients who were receiving ECMO support in the US, and the lowest reported costs were for extracorporeal cardiopulmonary resuscitation patients presenting with non-shockable rhythm in Japan. The additional costs of ECMO patients compared with non-ECMO patients varied between US$2518 and US$200,658. Personnel costs varied between 11 and 52% of the total amount. CONCLUSIONS: ECMO therapy is an advanced and expensive technology, although reported costs differ considerably depending on ECMO indication and whether charges or costs are measured. Combined with the ongoing gathering of outcome data, cost effectiveness per ECMO indication could be determined in the future.

Hemorrhagic complications during extracorporeal membrane oxygenation - The role of anticoagulation and platelets.

PURPOSE: Hemorrhagic complications during extracorporeal membrane oxygenation are frequent and have a negative impact on outcome. We studied the association between activated partial thromboplastin time or platelet count and the occurrence of hemorrhagic complications. The secondary objective was to determine risk factors for hemorrhagic complications. METHODS: Retrospective cohort study in a single-center Dutch university hospital. We included all adult patients on extracorporeal membrane oxygenation admitted to the intensive care unit between 2010 and 2017. RESULTS: We included 164 consecutive patients of which 73 (45%) had a hemorrhagic complication. The most prevalent hemorrhagic complications were surgical site (62%) and cannula site bleeding (18%). Survival to discharge was 67% in the patients without a hemorrhagic complication and 33% in the patients with hemorrhagic complications (p < .01). A higher activated partial thromboplastin time in the 24 h prior was associated with the occurrence of hemorrhagic complications (adjusted hazard ratio per 10 s increase 1.14; (95% CI 1.05-1.24). Venoarterial extracorporeal membrane oxygenation, duration of support, and higher activated partial thromboplastin time were risk factors for the occurrence of hemorrhagic complications. CONCLUSIONS: Higher activated partial thromboplastin time is associated with the occurrence of hemorrhagic complications.

Incidence of Massive Transfusion and Overall Transfusion Requirements During Lung Transplantation Over a 25-Year Period.

OBJECTIVE: To establish the incidence of massive transfusion and overall transfusion requirements during lung transplantation, changes over time, and association with outcome in relation to patient complexity. DESIGN: Retrospective cohort study. SETTING: University hospital. PARTICIPANTS: All 514 adult patients who underwent transplantation from 1990 until 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient records and transfusion data, divided into 5-year intervals, were analyzed. The incidence of massive transfusion (>10 units of red blood cells [RBCs] in 24 h) was 27% and did not change over time, whereas the median (interquartile range) transfusion requirement in the whole cohort decreased from 8 (5-12) to 3 (0-10) RBCs (p < 0.001). In patients transplanted from the intensive care unit, the incidence of massive transfusion increased over time from 25% to 54% (p = 0.04) and median transfusion requirements from 4.5 (3-8.5) units to 14.5 (5-26) units of RBCs (p = 0.03). Multivariable analysis showed that circulatory support, pulmonary hypertension, re-transplantation, cystic fibrosis, Eisenmenger syndrome, bilateral transplantation, and low body mass index were associated with massive transfusion. Patients with massive transfusion had more primary graft dysfunction grade III at 0, 24, 48, and 72 hours (p < 0.001), higher 30-day mortality (13% v 4%; p < 0.001), and lower 5-year survival (hazard ratio 3.67 [95% confidence interval 1.72-7.85]; p < 0.001). CONCLUSION: The incidence of massive transfusion did not change over time, whereas transfusion requirements in the whole cohort decreased. In patients transplanted from the intensive care unit, massive transfusion and transfusion requirements increased. Massive transfusion was associated with poor outcome.

Ganciclovir Therapeutic Drug Monitoring: A Case Series.

This article presents 3 cases of immunocompromised patients for whom therapeutic drug monitoring of ganciclovir in combination with cytomegalovirus viral load measurement was used to guide treatment. The first patient is diagnosed with thymoma A, the second is a heart transplant recipient, and the third is an HIV-positive patient. These patients were all diagnosed with cytomegalovirus and treated with ganciclovir. Our case studies illustrate how therapeutic drug monitoring-guided dosing can be helpful in the management of these complex cases.

Estimation of sodium and chloride storage in critically ill patients: a balance study.

BACKGROUND: Nonosmotic sodium storage has been reported in animals, healthy individuals and patients with hypertension, hyperaldosteronism and end-stage kidney disease. Sodium storage has not been studied in ICU patients, who frequently receive large amounts of sodium chloride-containing fluids. The objective of our study was to estimate sodium that cannot be accounted for by balance studies in critically ill patients. Chloride was also studied. We used multiple scenarios and assumptions for estimating sodium and chloride balances. METHODS: We retrospectively analyzed patients admitted to the ICU after cardiothoracic surgery with complete fluid, sodium and chloride balance data for the first 4 days of ICU treatment. Balances were obtained from meticulously recorded data on intake and output. Missing extracellular osmotically active sodium (MES) was calculated by subtracting the expected change in plasma sodium from the observed change in plasma sodium derived from balance data. The same method was used to calculate missing chloride (MEC). To address considerable uncertainties on the estimated extracellular volume (ECV) and perspiration rate, various scenarios were used in which the size of the ECV and perspiration were varied. RESULTS: A total of 38 patients with 152 consecutive ICU days were analyzed. In our default scenario, we could not account for 296 ± 35 mmol of MES in the first four ICU days. The range of observed MES in the five scenarios varied from 111 ± 27 to 566 ± 41 mmol (P < 0.001). A cumulative value of 243 ± 46 mmol was calculated for MEC in the default scenario. The range of cumulative MEC was between 62 ± 27 and 471 ± 56 mmol (P = 0.001 and P = 0.003). MES minus MEC varied from 1 ± 51 to 123 ± 33 mmol in the five scenarios. CONCLUSIONS: Our study suggests considerable disappearance of osmotically active sodium in critically ill patients and is the first to also suggest rather similar disappearance of chloride from the extracellular space. Various scenarios for insensible water loss and estimated size for the ECV resulted in considerable MES and MEC, although these estimates showed a large variation. The mechanisms and the tissue compartments responsible for this phenomenon require further investigation.

Donor Hypernatremia is Not Related with the Duration of Postoperative Mechanical Ventilation, Primary Graft Dysfunction, or Long-Term Outcome Following Lung Transplantation.

BACKGROUND Donor hypernatremia has been associated with reduced graft and recipient survival after heart, liver, kidney, and pancreas transplantation. However, it is unknown what effect donor hypernatremia has on graft and recipient outcomes after lung transplantation. The aim of this study was to investigate the relation of donor hypernatremia with the duration of postoperative mechanical ventilation, the incidence of severe primary graft dysfunction, and survival following lung transplantation. MATERIAL AND METHODS We analyzed all consecutive lung transplantations performed in adult patients at our center between 1995 and 2016. During the study period, donor hypernatremia was not considered a reason to reject lungs for transplantation. Donors were classified into 3 groups: normonatremia (sodium <145 mmol/L), moderate hypernatremia (sodium 145-154 mmol/L), or severe hypernatremia (sodium ≥155 mmol/L). Short-term outcome was defined by the duration of mechanical ventilation and incidence of primary graft dysfunction; long-term outcome was defined by 10-year mortality. RESULTS Donor hypernatremia was recorded in 275 (58%) of the 474 donors. There were no differences in baseline characteristics between the 3 study groups. The duration of mechanical ventilation was similar for all groups (8±25, 7±17, and 9±15 days respectively, P=0.204). Severe primary graft dysfunction was not different between the 3 groups (29%, 26%, 28%, P=0.724). Donor hypernatremia was not associated with (graft) survival, or after correction for potential confounders. CONCLUSIONS Donor hypernatremia was not associated with a worse outcome in lung transplant recipients. Thus, in contrast to solid organ transplantation, donor hypernatremia is not a contraindication for lung transplantation.

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.

Systematic comparison of routine laboratory measurements with in-hospital mortality: ICU-Labome, a large cohort study of critically ill patients.

BACKGROUND: In intensive care unit (ICU) patients, many laboratory measurements can be deranged when compared with the standard reference interval (RI). The assumption that larger derangements are associated with worse outcome may not always be correct. The ICU-Labome study systematically evaluated the univariate association of routine laboratory measurements with outcome. METHODS: We studied the 35 most frequent blood-based measurements in adults admitted ≥6 h to our ICU between 1992 and 2013. Measurements were from the first 14 ICU days and before ICU admission. Various metrics, including variability, were related with hospital survival. ICU- based RIs were derived from measurements obtained at ICU discharge in patients who were not readmitted to the ICU and survived for >1 year. RESULTS: In 49,464 patients (cardiothoracic surgery 43%), we assessed >20·106 measurements. ICU readmissions, in-hospital and 1-year mortality were 13%, 14% and 19%, respectively. On ICU admission, lactate had the strongest relation with hospital mortality. Variability was independently related with hospital mortality in 30 of 35 measurements, and 16 of 35 measurements displayed a U-shaped outcome-relation. Medians of 14 of 35 ICU-based ranges were outside the standard RI. Remarkably, γ-glutamyltransferase (GGT) had a paradoxical relation with hospital mortality in the second ICU week because more abnormal GGT-levels were observed in hospital survivors. CONCLUSIONS: ICU-based RIs for may be more useful than standard RIs in identifying ICU patients at risk. The association of variability with outcome for most of the measurements suggests this is a consequence and not a cause of a worse ICU outcome. Late elevation of GGT may confer protection to ICU patients.

Long-term changes in dysnatremia incidence in the ICU: a shift from hyponatremia to hypernatremia.

BACKGROUND: Dysnatremia is associated with adverse outcome in critically ill patients. Changes in patients or treatment strategies may have affected the incidence of dysnatremia over time. We investigated long-term changes in the incidence of dysnatremia and analyzed its association with mortality. METHODS: Over a 21-year period (1992-2012), all serum sodium measurements were analyzed retrospectively in two university hospital ICUs, up to day 28 of ICU admission for the presence of dysnatremia. The study period was divided into five periods. All serum sodium measurements were collected from the electronic databases of both ICUs. Serum sodium was measured at the clinical chemistry departments using standard methods. All sodium measurements were categorized in the following categories: <120, 120-124, 125-129, 130-134, 135-139, 140-145, 146-150, 151-155, 156-160, >160 mmol/L. Mortality was determined at 90 days after ICU admission. RESULTS: In 80,571 ICU patients, 913,272 serum sodium measurements were analyzed. A striking shift in the pattern of ICU-acquired dysnatremias was observed: The incidence of hyponatremia almost halved (47-25 %, p < 0.001), whereas the incidence of hypernatremia nearly doubled (13-24 %, p < 0.001). Most hypernatremias developed after ICU admission, and the incidence of severe hypernatremia (sodium > 155 mmol/L) increased dramatically over the years. On ICU day 10 this incidence was 0.7 % in the 1992-1996 period, compared to 6.3 % in the 2009-2012 period (p < 0.001). More severe dysnatremia was associated with significantly higher mortality throughout the 21-year study period (p < 0.001). CONCLUSIONS: In two large Dutch cohorts, we observed a marked shift in the incidence of dysnatremia from hyponatremia to hypernatremia over two decades. As hypernatremia was mostly ICU acquired, this strongly suggests changes in treatment as underlying causes. This shift may be related to the increased use of sodium-containing infusions, diuretics, and hydrocortisone. As ICU-acquired hypernatremia is largely iatrogenic, it should be-to an important extent-preventable, and its incidence may be considered as an indicator of quality of care. Strategies to prevent hypernatremia deserve more emphasis; therefore, we recommend that further study should be focused on interventions to prevent the occurrence of dysnatremias during ICU stay.