Evaluation of Newly Integrated Bivalirudin Titration Protocol in Patients With Mechanical Circulatory Support.

BACKGROUND: Patients with cardiogenic shock or end-stage heart failure can be maintained on mechanical circulatory support (MCS) devices. Once a patient undergoes placement of a device, obtaining and maintaining therapeutic anticoagulation is vital. Guidelines recommend the use of institutional protocols to assist in dosing and titration of anticoagulants. OBJECTIVE: The purpose of this study was to characterize the use of bivalirudin before and after the implementation of a standardized titration protocol in patients with MCS. METHODS: A retrospective review of patients who received bivalirudin for MCS (VA ECMO [veno-arterial extracorporeal membrane oxygenation], Impella, or LVAD [left ventricular assist device]) before and after the implementation of the titration protocol into the electronic health record (EHR) was conducted. The primary outcome was to compare the proportion of therapeutic activated partial thromboplastin time (aPTT). Secondary outcomes included number of subtherapeutic and supratherapeutic aPTTs, incidence of bleeding and clotting events, bivalirudin titrations per day, and percentage of patients with therapeutic aPTT level. RESULTS: A total of 100 patients were included (precohort = 67; postcohort = 33). The proportion of therapeutic aPTTs was significantly higher in the postcohort than that in the precohort (62% vs 48%; P < 0.001). The postcohort had 0% of patients failing to achieve therapeutic aPTT levels. The number of titrations per day was significantly lower in the postcohort, with 1.20 titrations per day versus 1.93 in the precohort (P < 0.001). CONCLUSIONS: Implementation of the bivalirudin titration nomograms within the EHR significantly increased the number of therapeutic aPTTs, reduced the number of patients who never achieved a therapeutic aPTT, and reduced the required number of titrations per day.

Bivalirudin Versus Unfractionated Heparin in Patients With Cardiogenic Shock Requiring Venoarterial Extracorporeal Membrane Oxygenation.

This study evaluated differences in efficacy and safety outcomes with bivalirudin compared with unfractionated heparin (UFH) in patients with cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation (VA ECMO). We performed a retrospective study at an academic medical center that included patients greater than 18 years of age supported with VA ECMO due to cardiogenic shock from January 2009 to February 2021. The primary endpoint was ECMO-associated thrombotic events normalized to duration of ECMO support. Secondary safety endpoints included major bleeding (per ELSO criteria) and blood product administration. Overall, 143 patients were included in our analysis with 54 having received bivalirudin and 89 having received UFH. Median duration of ECMO support was 92 (interquartile range, 56-172) hours. ECMO-associated thrombotic events per ECMO day were significantly less among those that received bivalirudin ( P < 0.001). In adjusted regression, bivalirudin was independently associated with an increased time to thrombosis when compared with UFH (Exp[B] -3.8; 95% confidence interval, 1.7-8.8; P = 0.002). Patients receiving bivalirudin experienced less major bleeding events ( P = 0.02) with less total red blood cell and fresh frozen plasma administration ( P = 0.04 and P = 0.03, respectively). Bivalirudin is a safe and efficacious alternative to UFH in patients requiring VA ECMO for cardiogenic shock.

Trajectories of Host-Response Subphenotypes in Patients With COVID-19 Across the Spectrum of Respiratory Support.

BACKGROUND: Hospitalized patients with severe COVID-19 follow heterogeneous clinical trajectories, requiring different levels of respiratory support and experiencing diverse clinical outcomes. Differences in host immune responses to SARS-CoV-2 infection may account for the heterogeneous clinical course, but we have limited data on the dynamic evolution of systemic biomarkers and related subphenotypes. Improved understanding of the dynamic transitions of host subphenotypes in COVID-19 may allow for improved patient selection for targeted therapies. RESEARCH QUESTION: We examined the trajectories of host-response profiles in severe COVID-19 and evaluated their prognostic impact on clinical outcomes. STUDY DESIGN AND METHODS: In this prospective observational study, we enrolled 323 inpatients with COVID-19 receiving different levels of baseline respiratory support: (1) low-flow oxygen (37%), (2) noninvasive ventilation (NIV) or high-flow oxygen (HFO; 29%), (3) invasive mechanical ventilation (27%), and (4) extracorporeal membrane oxygenation (7%). We collected plasma samples on enrollment and at days 5 and 10 to measure host-response biomarkers. We classified patients by inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker, and subphenotype trajectories and outcomes during hospitalization. RESULTS: IL-6, procalcitonin, and angiopoietin 2 persistently were elevated in patients receiving higher levels of respiratory support, whereas soluble receptor of advanced glycation end products (sRAGE) levels displayed the inverse pattern. Patients receiving NIV or HFO at baseline showed the most dynamic clinical trajectory, with 24% eventually requiring intubation and exhibiting worse 60-day mortality than patients receiving invasive mechanical ventilation at baseline (67% vs 35%; P < .0001). sRAGE levels predicted NIV failure and worse 60-day mortality for patients receiving NIV or HFO, whereas IL-6 levels were predictive in all patients regardless of level of support (P < .01). Patients classified to a hyperinflammatory subphenotype at baseline (< 10%) showed worse 60-day survival (P < .0001) and 50% of them remained classified as hyperinflammatory at 5 days after enrollment. INTERPRETATION: Longitudinal study of the systemic host response in COVID-19 revealed substantial and predictive interindividual variability influenced by baseline levels of respiratory support.

Evolution of extracorporeal membrane oxygenation trigger criteria in COVID-19 acute respiratory distress syndrome.

OBJECTIVE: To understand the implications of a tiered extracorporeal membrane oxygenation (ECMO) criteria framework and the outcomes of patients with COVID-19 acute respiratory distress syndrome who we were consulted on for ECMO but ultimately declined. METHODS: All patients declined for ECMO support by a large regional health care system between March 2020 and July 2021 were included. Restrictive selection criteria were enacted midway through the study stratifying the cohort into 2 groups. Primary outcomes included 30-day mortality. Secondary outcomes included reasons for declining ECMO and survival stratified by phase. RESULTS: One hundred ninety-three patients with COVID-19 acute respiratory distress syndrome were declined for ECMO within the study period out of 260 ECMO consults. At the time of consult, 71.0% (n = 137) were mechanically ventilated and 38% (n = 74) were proned and chemically paralyzed. Thirty-day mortality was 66% (n = 117), which increased from 53% to 73% (P = .010) when restrictive criteria were enacted. Patients with multisystem organ failure, prolonged ventilator time, and advanced age had respectively an 11-fold (odds ratio, 10.6; 95% CI, 1.7-65.2), 4-fold (odds ratio, 3.5; 95% CI, 1.1-12.0), and 4-fold (odds ratio, 4.4; 95% CI, 1.9-10.2) increase in the odds of mortality. CONCLUSIONS: Patients with COVID-19 acute respiratory distress syndrome declined for ECMO represent a critically ill cohort. We observed an increase in the severity of disease and 30-day mortality in consults in the latter phase of our study period. These findings may reflect our use of tiered selection criteria coupled with ongoing education and communication with referring centers, sparing both patients likely to respond to medical therapy and those who were unsalvageable by ECMO.

Trajectories of host-response biomarkers and inflammatory subphenotypes in COVID-19 patients across the spectrum of respiratory support.

Purpose: Enhanced understanding of the dynamic changes in the dysregulated inflammatory response in COVID-19 may help improve patient selection and timing for immunomodulatory therapies. Methods: We enrolled 323 COVID-19 inpatients on different levels of baseline respiratory support: i) Low Flow Oxygen (37%), ii) Non-Invasive Ventilation or High Flow Oxygen (NIV_HFO, 29%), iii) Invasive Mechanical Ventilation (IMV, 27%), and iv) Extracorporeal Membrane Oxygenation (ECMO, 7%). We collected plasma samples upon enrollment and days 5 and 10 to measure host-response biomarkers. We classified subjects into inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker and subphenotype trajectories and outcomes during hospitalization. Results: IL-6, procalcitonin, and Angiopoietin-2 were persistently elevated in patients at higher levels of respiratory support, whereas sRAGE displayed the inverse pattern. Patients on NIV_HFO at baseline had the most dynamic clinical trajectory, with 26% eventually requiring intubation and exhibiting worse 60-day mortality than IMV patients at baseline (67% vs. 35%, p<0.0001). sRAGE levels predicted NIV failure and worse 60-day mortality for NIV_HFO patients, whereas IL-6 levels were predictive in IMV or ECMO patients. Hyper-inflammatory subjects at baseline (<10% by both models) had worse 60-day survival (p<0.0001) and 50% of them remained classified as hyper-inflammatory on follow-up sampling at 5 days post-enrollment. Receipt of combined immunomodulatory therapies (steroids and anti-IL6 agents) was associated with markedly increased IL-6 and lower Angiopoietin-2 levels (p<0.05). Conclusions: Longitudinal study of systemic host responses in COVID-19 revealed substantial and predictive inter-individual variability, influenced by baseline levels of respiratory support and concurrent immunomodulatory therapies.

The Use of Extracorporeal Support to Rescue Patients With Acute Respiratory Distress Syndrome Following Thoracic Surgery.

Postoperative acute respiratory distress syndrome (ARDS) following a general thoracic procedure is associated with high morbidity and mortality. Extracorporeal membrane oxygenation (ECMO) offers an alternate means of cardiopulmonary support in the setting of refractory respiratory failure. We report indications and outcomes patients who after complex general thoracic surgery developed ARDS requiring ECMO support. We performed a retrospective analysis of all patients requiring venovenous (VV) ECMO support in the postoperative period following a general thoracic surgical procedure from January 2011 to December 2019. Exclusion criteria include those who underwent a cardiac procedure, venoarterial (VA) ECMO, cardiothoracic transplantation, or required ECMO only for intraoperative support. Forty instances of postoperative VV ECMO were utilized in patients who underwent a surgery with the thoracic surgical service. Lung procedures were the most common index operations performed (45%) followed by esophageal procedures (40%). Mean time to ECMO initiation from the index operation was 5.45 days with a range of 0 days to 1.3 months. Median length of ECMO support was 9.41 days with a range of 12 hours to 33 days. Patients were cannulated in an elective (70%) or emergent (30%) fashion. ECMO-related complications included a major bleeding event in seven patients. Thirty day survival was 62.5% for the entire cohort and 52.5% of patients were discharged from the hospital and 80.95% of these patients were still alive 90 days after discharge. ECMO is a viable means of cardiopulmonary support that can provide a survival advantage for patients who experience severe refractory respiratory failure following a complex general thoracic surgery.

ECMO and Impella Support Strategies as a Bridge to Surgical Repair of Post-Infarction Ventricular Septal Rupture.

Background and Objectives: Post-infarct ventricular septal rupture (PIVSR) continues to have significant morbidity and mortality, despite decreased prevalence. Impella and venoarterial extracorporeal membranous oxygenation (VA-ECMO) have been proposed as strategies to correct hemodynamic derangements and bridge patients to delayed operative repair when success rates are higher. This review places VA-ECMO and Impella support strategies in the context of bridging patients to successful PIVSR repair, with an additional case report of successful bridging with the Impella device. Materials and Methods: We report a case of PIVSR repair utilizing 14 days of Impella support. We additionally conducted a systematic review of contemporary literature to describe the application of VA-ECMO and Impella devices in the pre-operative period prior to surgical PIVSR correction. Expert commentary on the advantages and disadvantages of each of these techniques is provided. Results: We identified 19 studies with 72 patients undergoing VA-ECMO as a bridge to PIVSR repair and 6 studies with 11 patients utilizing an Impella device as a bridge to PIVSR repair. Overall, outcomes in both groups were better than expected from patients who were historically managed with medicine and balloon pump therapy, however there was a significant heterogeneity between studies. Impella provided for excellent left ventricular unloading, but did result in some concerns for reversal of shunting. VA-ECMO resulted in improved end-organ perfusion, but carried increased risks of device-related complications and requirement for additional ventricular unloading. Conclusions: Patients presenting with PIVSR in cardiogenic shock requiring a MCS bridge to definitive surgical repair continue to pose a challenge to the multidisciplinary cardiovascular team as the diverse presentation and management issues require individualized care plans. Both VA-ECMO and the Impella family of devices play a role in the contemporary management of PIVSR and offer distinct advantages and disadvantages depending on the clinical scenario. The limited case numbers reported demonstrate feasibility, safety, and recommendations for optimal management.

Outcomes of systemic anticoagulation with bivalirudin for Impella 5.0.

Temporary mechanical circulatory support (tMCS) devices are used for the management of cardiogenic shock. The Impella 5.0 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation in IMP5. This single center, retrospective study included patients supported on IMP5 with BIV based AC. The efficacy and safety end points were recovery, bridge to left ventricular assist device (LVAD), cardiac transplant (HTX), or death as well as clinically significant bleeding, incidence of Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure. There were 31 patients included, and 26 (84%) received BIV purge solutions. The median duration of IMP5 was 6 (IQR 4-10) days. Most patients were bridged to LVAD (39%, 12); 16% (5) were bridged to HTX, 16% (5) recovered, and 29% (9) died. One patient (3%) suffered from ischemic stroke and 12% (4) patients developed clinically significant bleeding. tPA was administered to 8 (26%) patients. Logistic regression analysis demonstrated that duration of IMP5 was a significant predictor of tPA use (OR 1.28; 95% Confidence Interval 1.04-1.56). There were no cases of pump failure. Our experience highlights the feasibility of utilizing BIV for routine AC use in IMP5.

Comparison of Anticoagulation Strategies in Patients Requiring Venovenous Extracorporeal Membrane Oxygenation: Heparin Versus Bivalirudin.

OBJECTIVES: Extracorporeal membrane oxygenation is a life-sustaining therapy for severe respiratory failure. Extracorporeal membrane oxygenation circuits require systemic anticoagulation that creates a delicate balance between circuit-related thrombosis and bleeding-related complications. Although unfractionated heparin is most widely used anticoagulant, alternative agents such as bivalirudin have been used. We sought to compare extracorporeal membrane oxygenation circuit thrombosis and bleeding-related outcomes in respiratory failure patients receiving either unfractionated heparin or bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation support. DESIGN: Retrospective cohort study. SETTING: Single-center, cardiothoracic ICU. PATIENTS: Consecutive patients requiring venovenous extracorporeal membrane oxygenation who were maintained on anticoagulation between 2013 and 2020. INTERNVENTIONS: IV bivalirudin or IV unfractionated heparin. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were the presence of extracorporeal membrane oxygenation in-circuit-related thrombotic complications and volume of blood products administered during extracorporeal membrane oxygenation duration. One hundred sixty-two patients receiving unfractionated heparin were compared with 133 patients receiving bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation. In patients receiving bivalirudin, there was an overall decrease in the number of extracorporeal membrane oxygenation circuit thrombotic complications (p < 0.005) and a significant increase in time to circuit thrombosis (p = 0.007). Multivariable Cox regression found that heparin was associated with a significant increase in risk of clots (Exp[B] = 2.31, p = 0.001). Patients who received bivalirudin received significantly less volume of packed RBCs, fresh frozen plasma, and platelet transfusion (p < 0.001 for each). There was a significant decrease in the number major bleeding events in patients receiving bivalirudin, 40.7% versus 11.7%, p < 0.001. CONCLUSIONS: Patients receiving bivalirudin for systemic anticoagulation on venovenous extracorporeal membrane oxygenation experienced a decrease in the number of extracorporeal membrane oxygenation circuit-related thrombotic events as well as a significant decrease in volume of blood products administered.

Platelet transfusion is associated with 90-day and 1-year mortality for adult patients requiring veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Studies examining one-year mortality respecting component blood transfusion are sparse. We hypothesize that component blood product transfusions are negatively associated with 90-day and 1-year survival for all patients requiring veno-arterial (VA) or veno-venous (VV) ECMO. STUDY DESIGN AND METHODS: This was an IRB-approved retrospective cohort analysis of 676 consecutive patients requiring ECMO at the University of Pittsburgh between 2005 and 2016. Patients were analysed both as an entire cohort and as two subsets with respect to ECMO modality (VA vs. VV). Additional data collected and analysed included patient characteristics, laboratory values and blood product transfusion. RESULTS: Multivariable analysis revealed that platelet transfusion was associated with 90-day mortality (OR: 1·05, P = 0·037) and one-year mortality for the entire cohort (OR = 1·05, P = 0·046,). Platelet transfusion volume was also associated with mortality in the VA-ECMO subset of patients at both 90 days (OR = 1·08, P = 0·03) and one year (OR: 1·11, P = 0·014). Age, peak International Normalized Raton ECMO, nadir haemoglobin (on ECMO) and final haemoglobin (after ECMO) were significantly associated with mortality for patients requiring VA-ECMO. For VV-ECMO patients, age, INR and peak creatinine on ECMO were associated with mortality. No individual component blood product was associated with one-year mortality for patients requiring VV-ECMO. CONCLUSION: Platelet transfusion was associated with increased 90-day and 1-year mortality for patients requiring VA-ECMO.

Comparison of Hydromorphone versus Fentanyl-based Sedation in Extracorporeal Membrane Oxygenation: A Propensity-Matched Analysis.

INTRODUCTION: Data comparing sedatives in patients receiving extracorporeal membrane oxygenation (ECMO) are sparse. However, it is known that the ECMO circuit alters the pharmacokinetic properties of medications via drug sequestration of lipophilic agents and increased volume of distribution. OBJECTIVES: This study evaluated the difference in days alive without delirium or coma and the sedative requirements in patients receiving fentanyl versus hydromorphone in ECMO patients. METHODS: This single-center retrospective observational study evaluated adults receiving ECMO for more than 48 hours and continuous infusion of either fentanyl or hydromorphone for at least 6 hours. Of 148 patients evaluated, 88 received fentanyl and 60 received hydromorphone continuous infusion sedation. Outcomes included delirium-free and coma-free (DFCF) days, narcotic use, and sedative use. MAIN RESULTS: There was an increase in the number of DFCF days in the hydromorphone group at day 7 (p=0.07) and day 14 (p=0.08) and a significant reduction in daily fentanyl equivalent exposure. Propensity score matching yielded 54 matched pairs. An 11.1% increase was observed in the proportion of ECMO days alive without delirium or coma in the hydromorphone group at 7 days (53.2% vs 42.1%, p=0.006). Patients in the hydromorphone group received significantly fewer narcotics with a median of 555 µg (interquartile range [IQR] 287-905 µg) of fentanyl equivalents per day compared with 2291 µg (IQR 1053-4023 µg) in the fentanyl group (p<0.005). CONCLUSION: The use of hydromorphone-based sedation in ECMO patients resulted in more days alive without delirium or coma while significantly reducing narcotic requirements.

Hemodynamic Resuscitation Characteristics Associated with Improved Survival and Shock Resolution After Cardiac Arrest.

PURPOSE: To determine which strategy of early post-cardiac arrest hemodynamic resuscitation was associated with best clinical outcomes. We hypothesized that higher mean arterial pressure (MAP) achieved using IV fluids over vasopressors would yield better outcomes. METHODS: Retrospective cohort study of post-cardiac arrest patients between March 2011 and June 2012. Patients successfully resuscitated from cardiac arrest, admitted to an intensive care unit and surviving at least 24 h, were included. Patients missing data for >2 h after return of spontaneous circulation were excluded. The institutional standard for post-resuscitation MAP was ≥65 mm Hg with no guidelines on how MAP was supported. We examined the association between early (6 h) average MAP, vasopressor use summarized as cumulative vasopressor index and fluid intake with outcomes including survival to discharge, favorable neurologic outcome based on Cerebral Performance Category 1 or 2, and the surrogate outcome measure of lactate clearance using Pearson correlation and multivariable regression. RESULTS: Of 118 patients, 55 (46%) survived to hospital discharge, 21 (18%) with favorable neurologic outcome. Higher 6-h mean cumulative vasopressor index was independently associated with worsened survival (OR 0.67; 95% CI 0.53, 0.85; P = 0.001). Resuscitation subgroups receiving higher than median vasopressors had worsened survival to hospital discharge regardless of fluid intake. In addition, higher MAP-6h correlated with increased lactate clearance (r = 0.29; P = 0.011). CONCLUSIONS: Early post-return of spontaneous circulation hemodynamic resuscitation achieving higher MAP using fluid preferentially over vasopressors is associated with improved survival to hospital discharge as well as better lactate clearance.

Initial experience with single cannulation for venovenous extracorporeal oxygenation in adults.

PURPOSE: Historically, venovenous extracorporeal membrane oxygenation has required dual cannulation. A single-venous cannulation strategy may facilitate implantation and patient mobilization. Here we present our early experience with a single cannulation technique. DESCRIPTION: Review of venovenous extracorporeal membrane oxygenation support using internal jugular vein insertion of the Avalon elite bicaval dual lumen catheter (Avalon Laboratories, Rancho Dominguez, CA) in 11 consecutive patients with severe respiratory failure. EVALUATION: Adequate oxygenation was obtained in all patients: 115 mm Hg PaO(2) (median), 53 to 401 mm Hg (range). Median time of support was 78 hours (range, 3 to 267 hours). No mortality was directly related to the cannulation strategy. There were three nonfatal cannulation-related events. Two patients had proximal cannula displacement requiring repositioning. One patient suffered an acute thrombosis of the cannula. CONCLUSIONS: Our series supports single-venous cannulation in venovenous extracorporeal membrane oxygenation as a promising technique. It may be an excellent alternative to current cannulation strategies in patients requiring prolonged support and specifically for those considered for a bridge-to-lung transplantation.

Ethics roundtable debate: patients and surrogates want 'everything done'--what does 'everything' mean?

Highly complex and specialized care plans sometimes overwhelm the comprehension of patients and families. Many optimistic surrogates of critically ill patients err on the side of desiring that everything be done but with a nebulous idea of what 'everything' entails. Physicians must work closely to educate surrogates as to the benefits versus the risks of treatment. Our roundtable experts ponder the question of whether providers possess the authority to interpret unilaterally the nature of requests for everything.

Ethics roundtable debate: is a physician-patient confidentiality relationship subservient to a greater good?

Is a health care provider's most proximal obligation to individuals or society as a whole? Our International panel of critical care providers grapple over the issue of whether patient-physician confidentiality exists as an open ended ideal it should be subservient to a greater good.

The relationship of intraocular pressure to intracranial pressure.

STUDY OBJECTIVE: The early detection of intracranial hypertension can lead to timely medical and neurosurgical intervention, preventing brain herniation and death. In this investigation, we hypothesize that an increase in intracranial pressure can be detected by an increase in intraocular pressure using noninvasive existing technology, the handheld tonometer. METHODS: This was a prospective observational pilot study conducted at a community hospital. Admitted patients with an invasive intracranial pressure monitor were solicited for participation. Patients were excluded if they had known glaucoma or had sufficient ocular or facial trauma that precluded intraocular pressure determination. Simultaneous measurements of intracranial and intraocular pressure were recorded. RESULTS: Twenty-seven patients were enrolled, and 76 individual measurements were performed. All patients with an abnormal intracranial pressure had an abnormal intraocular pressure; similarly, all patients with a normal intracranial pressure had a normal intraocular pressure (sensitivity 1.00, 95% confidence interval 0.86 to 1.0; specificity 1.0, 95% confidence interval 0.93 to 1.0) CONCLUSION: Abnormal intraocular pressure as measured with the handheld tonometer is an excellent indicator of abnormal intracranial pressure in patients with known intracranial pathology.