A Randomized Embedded Multifactorial Adaptive Platform for Extra Corporeal Membrane Oxygenation (REMAP ECMO) - Design and Rationale of the Left Ventricular Unloading trial domain.

BACKGROUND: The use of Extracorporeal Membrane Oxygenation (ECMO) remains associated with high rates of complications, weaning failure and mortality which can be partly explained by a knowledge gap on how to properly manage patients on ECMO support. To address relevant patient management issues, we designed a "Randomized Embedded Multifactorial Adaptive Platform (REMAP)" in the setting of ECMO (REMAP ECMO) and a first embedded randomized controlled trial (RCT) investigating the effects of routine early left ventricular (LV) unloading through intra-aortic balloon pumping (IABP). METHODS: REMAP ECMO describes a registry-based platform allowing for the embedding of multiple response adaptive RCTs (trial domains) which can perpetually address the effect of relevant patient management issues on ECMO weaning success. A first trial domain studies the effects of LV unloading by means of an IABP as an adjunct to veno-arterial (V-A) ECMO versus V-A ECMO alone on ECMO weaning success at 30 days in adult cardiogenic shock patients admitted to the Intensive Care Unit (ICU). The primary outcome of this trial is "successful weaning from ECMO" being defined as a composite of survival without the need for mechanical circulatory support, heart transplantation, or left ventricular assist device (LVAD) at 30 days after initiation of ECMO. Secondary outcomes include the need for interventional escalation of LV unloading strategy, mechanistic endpoints, survival characteristics until one year after ECMO initiation, and quality of life. Trial data will be analysed using a Bayesian statistical framework. The adaptive design allows for a high degree of flexibility, such as response adaptive randomization and early stopping of the trial for efficacy or futility. The REMAP ECMO LV unloading study is approved by the Medical Ethical Committee of the Erasmus Medical Center and is publicly registered. CONCLUSION: This REMAP ECMO trial platform enables the efficient roll-out of multiple RCTs on relevant patient management issues. A first embedded trial domain will compare routine LV unloading by means of an IABP as an adjunct to V-A ECMO versus V-A ECMO alone. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05913622.

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.

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.

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.

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.

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.

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.

A mini-fluid challenge of 150mL predicts fluid responsiveness using ModelflowR pulse contour cardiac output directly after cardiac surgery.

STUDY OBJECTIVE: The mini-fluid challenge may predict fluid responsiveness with minimum risk of fluid overloading. However, the amount of fluid as well as the best manner to evaluate the effect is unclear. In this prospective observational pilot study, the value of changes in pulse contour cardiac output (CO) measurements during mini-fluid challenges is investigated. DESIGN: Prospective observational study. SETTING: Intensive Care Unit of a university hospital. PATIENTS: Twenty-one patients directly after elective cardiac surgery on mechanical ventilation. INTERVENTIONS: The patients were subsequently given 10 intravenous boluses of 50mL of hydroxyethyl starch with a total of 500mL per patient while measuring pulse contour CO. MEASUREMENTS: We measured CO by minimal invasive ModelflowR (COm) and PulseCOR (COli), before and one minute after each fluid bolus. We analyzed the smallest volume that was predictive of fluid responsiveness. A positive fluid response was defined as an increase in CO of >10% after 500mL fluid infusion. MAIN RESULTS: Fifteen patients (71%) were COm responders and 13 patients (62%) COli responders. An increase in COm after 150mL of fluid >5.0% yielded a positive and negative predictive value (+PV and -PV) of 100% with an area under the curve (AUC) of 1.00 (P<0.001). An increase in COli >6.3% after 200mL was able to predict a fluid response in COli after 500mL with a +PV of 100% and -PV of 73%, with an AUC of 0.88 (P<0.001). CONCLUSION: The use of minimal invasive ModelflowR pulse contour CO measurements following a mini-fluid challenge of 150mL can predict fluid responsiveness and may help to improve fluid management.

Cardiac output response to norepinephrine in postoperative cardiac surgery patients: interpretation with venous return and cardiac function curves.

OBJECTIVE: We studied the variable effects of norepinephrine infusion on cardiac output in postoperative cardiac surgical patients in whom norepinephrine increased mean arterial pressure. We hypothesized that the directional change in cardiac output would be determined by baseline cardiac function, as quantified by stroke volume variation, and the subsequent changes in mean systemic filling pressure and vasomotor tone. DESIGN: Intervention study. SETTING: ICU of a university hospital. PATIENTS: Sixteen mechanically ventilated postoperative cardiac surgery patients. INTERVENTIONS: Inspiratory holds were performed at baseline-1, during increased norepinephrine infusion, and baseline-2 conditions. MEASUREMENTS AND MAIN RESULTS: We measured mean arterial pressure, heart rate, central venous pressure, cardiac output, stroke volume variation and, with use of inspiratory hold maneuvers, mean systemic filling pressure, then calculated resistance for venous return and systemic vascular resistance. Increasing norepinephrine by 0.04 ± 0.02 µg·kg·min increased mean arterial pressure 20 mm Hg in all patients. Cardiac output decreased in ten and increased in six patients. In all patients mean systemic filling pressure, systemic vascular resistance and resistance for venous return increased and stroke volume variation decreased. Resistance for venous return and systemic vascular resistance increased more (p = 0.019 and p = 0.002) in the patients with a cardiac output decrease. Heart rate decreased in the patients with a cardiac output decrease (p = 0.002) and was unchanged in the patients with a cardiac output increase. Baseline stroke volume variation was higher in those in whom cardiac output increased (14.4 ± 4.2% vs. 9.1 ± 2.4%, p = 0.012). Stroke volume variation >8.7% predicted the increase in cardiac output to norepinephrine (area under the receiver operating characteristic curve 0.900). CONCLUSIONS: The change in cardiac output induced by norepinephrine is determined by the balance of volume recruitment (increase in mean systemic filling pressure), change in resistance for venous return, and baseline heart function. Furthermore, the response of cardiac output on norepinephrine can be predicted by baseline stroke volume variation.

Bedside assessment of total systemic vascular compliance, stressed volume, and cardiac function curves in intensive care unit patients.

BACKGROUND: Mean systemic filling pressure (Pmsf) can be measured at the bedside with minimally invasive monitoring in ventilator-dependent patients using inspiratory hold maneuvers (Pmsf(hold)) as the zero flow intercept of cardiac output (CO) to central venous pressure (CVP) relation. We compared Pmsf(hold) with arm vascular equilibrium pressure during vascular occlusion (Pmsf(arm)) and their ability to assess systemic vascular compliance (Csys) and stressed volume by intravascular fluid administration. METHODS: In mechanically ventilated postoperative cardiac surgery patients, inspiratory holds at varying airway pressures and arm stop-flow maneuvers were performed during normovolemia and after each of 10 sequential 50-mL bolus colloid infusions. We measured CVP, Pmsf(arm), stroke volume, and CO during fluid administration steps to construct CVP to CO (cardiac function) curves and Δvolume/ΔPmsf (compliance) curves. Pmsf(hold) was measured before and after fluid administration. Stressed volume was determined by extrapolating the Pmsf-volume curve to zero pressure intercept. RESULTS: Fifteen patients were included. Pmsf(hold) and Pmsf(arm) were closely correlated. Csys was linear (64.3 ± 32.7 mL · mm Hg(-1), 0.97 ± 0.49 mL · mm Hg(-1) · kg(-1) predicted body weight). Stressed volume was estimated to be 1265 ± 541 mL (28.5% ± 15% predicted total blood volume). Cardiac function curves of patients with an increase of >12% to 500 mL volume extension (volume responsive) were steep, whereas the cardiac function curves of the remaining patients were flat. CONCLUSIONS: Csys, stressed volume, and cardiac function curves can be determined at the bedside and can be used to characterize patients' hemodynamic status.

Estimation of mean systemic filling pressure in postoperative cardiac surgery patients with three methods.

PURPOSE: To assess the level of agreement between different bedside estimates of effective circulating blood volume-mean systemic filling pressure (Pmsf), arm equilibrium pressure (Parm) and model analog (Pmsa)-in ICU patients. METHODS: Eleven mechanically ventilated postoperative cardiac surgery patients were studied. Sequential measures were made in the supine position, rotating the bed to a 30° head-up tilt and after fluid loading (500 ml colloid). During each condition four inspiratory hold maneuvers were done to determine Pmsf; arm stop-flow was created by inflating a cuff around the upper arm for 30 s to measure Parm, and Pmsa was estimated from a Guytonian model of the systemic circulation. RESULTS: Mean Pmsf, Parm and Pmsa across all three states were 20.9 ± 5.6, 19.8 ± 5.7 and 14.9 ± 4.0 mmHg, respectively. Bland-Altman analysis for the difference between Parm and Pmsf showed a non-significant bias of -1.0 ± 3.08 mmHg (p = 0.062), a coefficient of variation (COV) of 15 %, and limits of agreement (LOA) of -7.3 and 5.2 mmHg. For the difference between Pmsf and Pmsa we found a bias of -6.0 ± 3.1 mmHg (p < 0.001), COV 17 % and LOA -12.4 and 0.3 mmHg. Changes in Pmsf and Parm and in Pmsf and Pmsa were directionally concordant in response to head-up tilt and volume loading. CONCLUSIONS: Parm and Pmsf are interchangeable in mechanically ventilated postoperative cardiac surgery patients. Changes in effective circulatory volume are tracked well by changes in Parm and Pmsa.

Determination of vascular waterfall phenomenon by bedside measurement of mean systemic filling pressure and critical closing pressure in the intensive care unit.

BACKGROUND: Mean systemic filling pressure (Pmsf) can be determined at the bedside by measuring central venous pressure (Pcv) and cardiac output (CO) during inspiratory hold maneuvers. Critical closing pressure (Pcc) can be determined using the same method measuring arterial pressure (Pa) and CO. If Pcc > Pmsf, there is then a vascular waterfall. In this study, we assessed the existence of a waterfall and its implications for the calculation of vascular resistances by determining Pmsf and Pcc at the bedside. METHODS: In 10 mechanically ventilated postcardiac surgery patients, inspiratory hold maneuvers were performed, transiently increasing Pcv and decreasing Pa and CO to 4 different steady-state levels. For each patient, values of Pcv and CO were plotted in a venous return curve to determine Pmsf. Similarly, Pcc was determined with a ventricular output curve plotted for Pa and CO. Measurements were performed in each patient before and after volume expansion with 0.5 L colloid, and vascular resistances were calculated. RESULTS: For every patient, the relationship between the 4 measurements of Pcv and CO and of Pa and CO was linear. Baseline Pmsf was 18.7 ± 4.0 mm Hg (mean ± SD) and differed significantly from Pcc 45.5 ± 11.1 mm Hg (P < 0.0001). The difference of Pcc and Pmsf was 26.8 ± 10.7 mm Hg, indicating the presence of a systemic vascular waterfall. Volume expansion increased Pmsf (26.3 ± 3.2 mm Hg), Pcc (51.5 ± 9.0 mm Hg), and CO (5.5 ± 1.8 to 6.8 ± 1.8 L · min(-1)). Arterial (upstream of Pcc) and venous (downstream of Pmsf) vascular resistance were 8.27 ± 4.45 and 2.75 ± 1.23 mm Hg · min · L(-1); the sum of both (11.01 mm Hg · min · L(-1)) was significantly different from total systemic vascular resistance (16.56 ± 8.57 mm Hg · min · L(-1); P = 0.005). Arterial resistance was related to total resistance. CONCLUSIONS: Vascular pressure gradients in cardiac surgery patients suggest the presence of a vascular waterfall phenomenon, which is not affected by CO. Thus, measures of total systemic vascular resistance may become irrelevant in assessing systemic vasomotor tone.

Evaluation of mean systemic filling pressure from pulse contour cardiac output and central venous pressure.

OBJECTIVE: The volemic status of a patient can be determined by measuring mean systemic filling pressure (Pmsf). Pmsf is obtained from the venous return curve, i.e. the relationship between central venous pressure (Pcv) and blood flow. We evaluated the feasibility and precision of Pmsf measurement. METHODS: In ten piglets we constructed venous return curves using seven 12 s inspiratory holds transiently increasing Pcv to seven different steady state levels and monitored the resultant blood flow, by pulse contour (COpc) and by flow probes around the pulmonary artery (COr) and aorta (COl). Pmsf is obtained by extrapolation of the venous return curve to zero flow. Measurements were repeated to evaluate the precision of Pmsf. RESULTS: During the inspiratory holds, 133 paired data points were obtained for COr, COl, COpc and Pcv. Bland-Altman analysis showed no difference between COr and COl, but a small significant difference was present between COl and COpc. All Pcv versus flow (COl or COpc) relationships were linear. Mean Pmsf was 10.78 with COl and 10.37 mmHg with COpc. Bland-Altman analysis for Pmsf with COl and with COpc, showed a bias of 0.40  ±  0.48 mmHg. The averaged coefficient of variation for repeated measurement of Pmsf with COl was 6.2% and with COpc 6.1%. CONCLUSIONS: During an inspiratory hold pulmonary flow and aortic flow equilibrate. Cardiac output estimates by arterial pulse contour and by a flow probe around the aorta are interchangeable. Therefore, the venous return curve and Pmsf can be estimated accurately by pulse contour methods.

Partitioning the resistances along the vascular tree: effects of dobutamine and hypovolemia in piglets with an intact circulation.

OBJECTIVE: We present a new physiological model that discriminated between changes in the systemic arterial and venous circulation. To test our model, we studied the effects of dobutamine and hypovolemia in intact pentabarbital-anesthetized piglets. METHODS: Aorta pressure (Pao), central venous pressure (Pcv), mean systemic filling pressure (Pmsf) and cardiac output (CO), were measured in 10 piglets, before, during and after dobutamine infusion (6 µg kg⁻¹ min⁻¹), as well as during hypovolemia (-10 mL kg⁻¹), and after fluid resuscitation to normovolemia. Venous (Rv) and total systemic (Rsys) resistance were determined from Pao, Pcv, Pmsf and CO. The quotient of Rv/Rsys was used to determine the predominant location of vascular changes (i.e. vasoconstriction or dilatation on either venous or arterial side). RESULTS: Administration of dobutamine increased heart rate and CO, whereas it decreased Pmsf, Rsys, Rv and Rv/Rsys. The decrease in Rv was significantly greater than Rsys. Pao and Pcv did not change. Hypovolemia decreased CO, Pcv, Pmsf, Rv and Rv/Rsys, but kept Rsys constant and increased heart rate. CONCLUSIONS: Hypovolemia and dobutamine differentially alter Pmsf, Rsys, Rv and Rv/Rsys ratio. The increase in CO during dobutamine infusion was attributed to the combined increased cardiac function and decreased Rv. The decrease in CO with hypovolemia was due to a decreased Pmsf but was partly compensated for by a decrease in Rv tending to preserve venous return and thus CO.

Bedside assessment of mean systemic filling pressure.

PURPOSE OF REVIEW: The physiology of the venous part of the human circulation seems to be a forgotten component of the circulation in critical care medicine. One of the main reasons, probably, is that measures of right atrial pressure (Pra) do not seem to be directly linked to blood flow. This perception is primarily due to an inability to measure the pressure gradient for venous return. The upstream pressure for venous return is mean systemic filling pressure (Pmsf) and it does not lend itself easily to be measured. Recent clinical studies now demonstrate the basic principles underpinning the measure of Pmsf at the bedside. RECENT FINDINGS: Using routinely available minimally invasive monitoring of continuous cardiac output and Pra, one can accurately construct venous return curves by performing a series of end-inspiratory hold maneuvers, in ventilator-dependent patients. From these venous return curves, the clinician can now finally obtain at the bedside not only Pmsf but also the derived parameters: resistance to venous return, systemic compliance and stressed volume. SUMMARY: Measurement of Pmsf is essential to describe the control of vascular capacitance. It is the key to distinguish between passive and active mechanisms of blood volume redistribution and partitioning total blood volume in stressed and unstressed volume.

Tranexamic acid and aprotinin in low- and intermediate-risk cardiac surgery: a non-sponsored, double-blind, randomised, placebo-controlled trial.

OBJECTIVE: Tranexamic acid has been suggested to be as effective as aprotinin in reducing blood loss and transfusion requirements after cardiac surgery. Previous studies directly comparing both antifibrinolytics focus on high-risk cardiac surgery patients only or suffer from methodological problems. We wanted to compare the effectiveness of tranexamic acid versus aprotinin in reducing postoperative blood loss and transfusion requirements in the patient group representing the majority of cardiac surgery patients: low- and intermediate-risk patients. METHODS: We conducted a non-sponsored, double-blind, randomised, placebo-controlled trial in which 298 patients scheduled for low- or intermediate-risk (mean logistic EuroSCORE 4.1) first-time heart surgery with use of cardiopulmonary bypass were randomised to receive either tranexamic acid, high-dose aprotinin, or placebo. All patients had preoperative normal renal function. End points of the study were monitored from the time of surgery until patient discharge. This trial was executed between June 2004 and October 2006. RESULTS: Both antifibrinolytics significantly reduced blood loss and transfusion requirements when compared with placebo. Aprotinin was about twice as effective as tranexamic acid in reducing total postoperative blood loss (estimated median difference 155 ml, 95% confidence interval (CI) 60-260; p < 0.001). Accordingly, aprotinin reduced packed red blood cell transfusions more than tranexamic acid, although the difference did not reach statistical significance. Only aprotinin significantly reduced the proportion of transfused patients when compared with placebo (mean difference -20.9%, 95% CI 7.3-33.5; p = 0.013), and only aprotinin completely abolished bleeding-related re-explorations (mean difference 6.8%, 95% CI 1.6-13.4%; p = 0.004). Neither antifibrinolytic agent increased the incidence of mortality (mean difference tranexamic acid -0.4%, 95% CI -4.6 to 4.4; p = 0.79, mean difference aprotinin -1.3%, 95% CI -6.2 to 3.5; p = 0.62) or other serious adverse events when compared with placebo. CONCLUSION: Aprotinin has clinically significant advantages over tranexamic acid in patients with normal renal function scheduled for low- or intermediate-risk cardiac surgery.

Assessment of venous return curve and mean systemic filling pressure in postoperative cardiac surgery patients.

OBJECTIVE: To measure the relationship between blood flow and central venous pressure (Pcv) and to estimate mean systemic filling pressure (Pmsf), circulatory compliance, and stressed volume in patients in the intensive care unit. DESIGN: Intervention study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twelve mechanically ventilated postoperative cardiac surgery patients. INTERVENTIONS: Inspiratory holds were performed during normovolemia in supine position (baseline), relative hypovolemia by placing the patients in 30 degree head-up position (hypo), and relative hypervolemia by volume loading with 0.5 L colloid (hyper). MEASUREMENTS AND MAIN RESULTS: We measured the relationship between blood flow and Pcv using 12-second inspiratory-hold maneuvers transiently increasing Pcv to three different steady-state levels and monitored the resultant blood flow via the pulse contour method during the last 3 seconds. The Pcv to blood flow relation was linear for all measurements with a slope unaltered by relative volume status. Pmsf decreased with hypo and increased with hyper (18.8 +/- 4.5 mm Hg, to 14.5 +/- 3.0 mm Hg, to 29.1 +/- 5.2 mm Hg [baseline, hypo, hyper, respectively, p < 0.05]). Baseline total circulatory compliance was 0.98 mL x mm Hg x kg and stressed volume was 1677 mL. CONCLUSIONS: Pmsf can be determined in intensive care patients with an intact circulation with use of inspiratory pause procedures, making serial measures of circulatory compliance and circulatory stressed volume feasible.

Should amiodarone or lidocaine be given to patients who arrest after cardiac surgery and fail to cardiovert from ventricular fibrillation?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether the administration of amiodarone or lidocaine in patients with refractory VT/VF after cardiac surgery results in successful cardioversion. Altogether more than 434 papers were found using the reported search, from which 23 articles were used to answer the clinical question. No randomized trials have been found in which amiodarone was studied in patients with refractory VF/VT after cardiac surgery. Recommendations on the use of amiodarone in patients with refractory VF/VT in both European and American 2005 Guidelines on Resuscitation are mainly based on expert consensus and are supported by a few randomized trials in patients with out-of-hospital cardiac arrest. We would therefore recommend that amiodarone is the first line drug that should be used in patients with refractory ventricular arrhythmias after cardiac surgery that persist after three failed attempts at cardioversion. Lidocaine should only be used if amiodarone is not available or if its use is contraindicated. Amiodarone should be administered as an intravenous bolus of 300 mg after the third unsuccessful shock.