IN VIVO GENERATION OF C4d, Bb, iC3b, AND SC5b-9 AFTER OKT3 ADMINISTRATION: CORRELATION BETWEEN COMPLEMENT ACTIVATION AND PULMONARY HEMODYNAMIC CHANGES
Heather VallhonratManuel PascualW. W. WilliamsNina Tolkoff‐RubinS L WeeS BoskovićLeo C. GinnsJohn WainFrederic I. PrefferA. Benedict Cosimi
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155 Background: OKT3 monoclonal antibody therapy results in an acute clinical syndrome (ACS) associated with the release of cytokines such as tumor necrosis factor (TNF) and sequestration of neutrophils in the lungs. We have previously shown that inhibition of TNF does not eliminate OKT3-ACS, suggesting that other factors also contribute to the ACS. We analyzed the mechanisms of complement (C) activation in vivo, during the first hour following OKT3 administration. Methods: Renal transplant (Tx) recipients (n=4) with steroid-resistant rejection and lung Tx recipients (n=4) received OKT3 as treatment for rejection and induction therapy, respectively. Blood samples were obtained in Nafamostat-EDTA tubes. C activation products C4d (classical pathway), Bb (alternative pathway), iC3b (C3 cleavage product) and SC5b-9 (terminal pathway) were measured using ELISA kits (QUIDEL Corporation, San Diego, CA). Hemodynamic parameters were monitored using a Swan-Ganz catheter in lung Tx recipients in the ICU. Neutrophil CD11a, CD11b, and CD18 were monitored in two patients by flow cytometry. Controls included patients receiving 500mg i.v. methylprenisolone (MP) pulses for rejection, adults with acute respiratory distress syndrome who received extracorporeal membrane oxygenation (ECMO) in the ICU and normal individuals. Data were analyzed using the student's t-test and correlated by regression analysis. Results: An increase in the levels of C4d, Bb, iC3b, and SC5b-9 was observed in 7/8 OKT3-treated patients. No significant differences in C activation were found between lung and Table kidney Tx recipients. Total WBC and neutrophil counts at 60 minutes were 65% and 70% of their pre-OKT3 values. A marked increase in the expression of CD11b and CD18 and a decrease of CD11a on neutrophils in parallel with C activation was observed. In lung Tx recipients C4d and iC3b production correlated with increases in central venous pressure (p = 0.023, p = 0.003) and iC3b production correlated with increases in mean pulmonary arterial pressure (p = 0.024). As compared to ECMO (silicone membrane), OKT3 induced activation of C occurred predominantly by the classical pathway, whereas ECMO activated C by the alternative pathway and MP pulses did not activate C.TableConclusions: C activation is an early event after OKT3 administration and is associated with activation of neutrophils and pulmonary hemodynamic changes. In addition to cytokine production, C activation should be studied to delineate potential side-effects of new monoclonal antibodies used in organ transplantation.Oxygenation index
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We reviewed all patients who were supported with extracorporeal membrane oxygenation and/or ventricular assist device at our institution in order to describe diagnostic characteristics and assess mortality.A retrospective cohort study was performed including all patients supported with extracorporeal membrane oxygenation and/or ventricular assist device from our first case (8 October, 1998) through 25 July, 2016. The primary outcome of interest was mortality, which was modelled by the Kaplan-Meier method.A total of 223 patients underwent 241 extracorporeal membrane oxygenation runs. Median support time was 4.0 days, ranging from 0.04 to 55.8 days, with a mean of 6.4±7.0 days. Mean (±SD) age at initiation was 727.4 days (±146.9 days). Indications for extracorporeal membrane oxygenation were stratified by primary indication: cardiac extracorporeal membrane oxygenation (n=175; 72.6%) or respiratory extracorporeal membrane oxygenation (n=66; 27.4%). The most frequent diagnosis for cardiac extracorporeal membrane oxygenation patients was hypoplastic left heart syndrome or hypoplastic left heart syndrome-related malformation (n=55 patients with HLHS who underwent 64 extracorporeal membrane oxygenation runs). For respiratory extracorporeal membrane oxygenation, the most frequent diagnosis was congenital diaphragmatic hernia (n=22). A total of 24 patients underwent 26 ventricular assist device runs. Median support time was 7 days, ranging from 0 to 75 days, with a mean of 15.3±18.8 days. Mean age at initiation of ventricular assist device was 2530.8±660.2 days (6.93±1.81 years). Cardiomyopathy/myocarditis was the most frequent indication for ventricular assist device placement (n=14; 53.8%). Survival to discharge was 42.2% for extracorporeal membrane oxygenation patients and 54.2% for ventricular assist device patients. Kaplan-Meier 1-year survival was as follows: all patients, 41.0%; extracorporeal membrane oxygenation patients, 41.0%; and ventricular assist device patients, 43.2%. Kaplan-Meier 5-year survival was as follows: all patients, 39.7%; extracorporeal membrane oxygenation patients, 39.7%; and ventricular assist device patients, 43.2%.This single-institutional 18-year review documents the differential probability of survival for various sub-groups of patients who require support with extracorporeal membrane oxygenation or ventricular assist device. The indication for mechanical circulatory support, underlying diagnosis, age, and setting in which cannulation occurs may affect survival after extracorporeal membrane oxygenation and ventricular assist device. The Kaplan-Meier analyses in this study demonstrate that patients who survive to hospital discharge have an excellent chance of longer-term survival.
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Remarkable outcomes have been reported after prolonged mechanical circulatory support in the pediatric population, but there is yet no clear delineation of the duration beyond which supporting a child becomes futile. The likelihood of survival in patients supported on extracorporeal membrane oxygenation for respiratory failure decreases with the length of support. However, extracorporeal membrane oxygenation can be successfully used in these patients for long periods (weeks to months) provided adequate support is maintained without complications. This is not the case with cardiac failure and mechanical circulatory support. Extracorporeal membrane oxygenation is usually the initial form of mechanical circulatory support used in patients with primary refractory myocardial dysfunction. There is evidence and consensus that if the patient shows no signs of recovery after a maximum duration of 2 weeks, he or she should be transitioned to a ventricular assist device, which allows prolonged support. In post-cardiac surgery patients, survival is only anecdotal beyond 12 days of extracorporeal membrane oxygenation support, and myocardial recovery is exceptionally rare after this time period unless new diagnoses and management strategies are formulated. Repeat extracorporeal membrane oxygenation should generally not be offered to patients unless it is established that support was withdrawn prematurely or a new intervention is planned. Repeat extracorporeal membrane oxygenation may achieve some improvement in early survival, but the long-term outcomes of survivors are so poor that these attempts cannot be generally recommended unless organ transplantation is an option.
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Abstract Background Veno-arterial extracorporeal membrane oxygenation is frequently used in patients with cardiac disease. We evaluated short-term outcomes and identified factors associated with hospital mortality in cardiac patients supported with veno-arterial extracorporeal membrane oxygenation. Methods A retrospective review of patients supported with veno-arterial extracorporeal membrane oxygenation at a university-affiliated children’s hospital was performed. Results A total of 253 patients with cardiac disease managed with extracorporeal membrane oxygenation were identified; survival to discharge was 48%, which significantly improved from 39% in an earlier era (1995–2001) (p=0.01). Patients were categorised into surgical versus non-surgical groups on the basis of whether they had undergone cardiac surgery before or not, respectively. The most common indication for extracorporeal membrane oxygenation was extracorporeal cardiopulmonary resuscitation: 96 (51%) in the surgical group and 45 (68%) in the non-surgical group. In a multiple covariate analysis, single-ventricle physiology (p=0.01), duration of extracorporeal membrane oxygenation (p<0.01), and length of hospital stay (p=0.03) were associated with hospital mortality. Weekend or night shift cannulation was associated with mortality in non-surgical patients (p=0.05). Conclusion We report improvement in survival compared with an earlier era in cardiac patients supported with extracorporeal membrane oxygenation. Single-ventricle physiology continues to negatively impact survival, along with evidence of organ dysfunction during extracorporeal membrane oxygenation, duration of extracorporeal membrane oxygenation, and length of stay.
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Central MessageExtracorporeal membrane oxygenation is associated with persistent limitations on functional status years after treatment.See Article page XXX. Extracorporeal membrane oxygenation is associated with persistent limitations on functional status years after treatment. See Article page XXX. Rossong and colleagues1Rossong H. Debrueil S. Yan W. Heibert B. Singal R. Arora R. et al.Long-term survival and quality of life after extracorporeal membrane oxygenation.J Thorac Cardiovasc Surg. 2022; (XXX:XXX)Google Scholar analyzed institutional data to track long-term outcomes following treatment with extracorporeal membrane oxygenation (ECMO). In doing so, they have attempted to answer the question faced by countless intensivists, surgeons, nurses, ECMO specialists, physical therapists, and others: Now that my patient is off ECMO, what is going to happen to her when she leaves the intensive care unit? Most research on ECMO understandably focuses on survival to decannulation and to discharge from an intensive care unit or from the hospital because the conditions requiring ECMO are still associated with very high mortality rates. Growing recognition of the long-term morbidity following critical illness has prompted investigations into long-term functional outcomes. Rossong and colleagues1Rossong H. Debrueil S. Yan W. Heibert B. Singal R. Arora R. et al.Long-term survival and quality of life after extracorporeal membrane oxygenation.J Thorac Cardiovasc Surg. 2022; (XXX:XXX)Google Scholar followed patients for a substantial duration after ECMO (median contact time from ECMO was 5.7 years for venovenous [VV] ECMO and 4.2 years for venoarterial [VA] ECMO). They found high conditional 5-year survival following discharge among both their VV ECMO and VA ECMO populations (73% and 71%, respectively). They found a lower reported quality of life and poorer functional status after VV ECMO as opposed to VA ECMO, which seems counterintuitive given the well-known complications associated with arterial ECMO cannulation.2Pillai A.K. Bhatti Z. Bosserman A.J. Mathew M.C. Vaidehi K. Kalva S.P. Management of vascular complications of extra-corporeal membrane oxygenation.Cardiovasc Diagn Ther. 2018; 8: 372-377Crossref PubMed Scopus (20) Google Scholar Less than one-third of patients treated with VA ECMO reported difficulty with activities of daily life, whereas two-thirds did following VV ECMO. A surprising 83% of patients in the VV ECMO cohort reported problems with mobility, compared with 52% of patients treated with VA ECMO. Obviously, an institutional study has inherent limitations. The other main caveat here is patient heterogeneity: Although the authors have assiduously separated outcomes between VV and VA ECMO, they are still very different in their underlying conditions. Certainly ischemic cardiomyopathy requiring ECMO as a bridge to durable left ventricular assist device will have far different implications for long-term survival than, say, severe influenza requiring VV ECMO in an otherwise healthy person. Still, identifying a common set of long-term functional limitations among patients treated with ECMO would help guide post-ECMO treatment. These questions are more relevant than ever as larger numbers of patients are being treated with ECMO for COVID-19, and for a longer average duration than described in this article.3Barbaro R.P. MacLaren G. Boonstra P.S. Combes A. Agerstrand C. Annich G. et al.Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the International Extracorporeal Life Support Organization Registry.Lancet. 2021; 398: 1230-1238Abstract Full Text Full Text PDF Scopus (65) Google Scholar There will be a far larger population of ECMO survivors, and a substantially larger number of otherwise healthy adults treated with ECMO aged in their 20s and 30s with potential for several decades of life ahead of them. The objective and subjective aspects of their long-term recovery must be followed and measured carefully. Subsequent research will certainly include trying to identify what factors are associated with more functional impairment. For example, does renal failure during ECMO therapy portend worse long-term functional status even if it resolves? Or, is there an inflection point along the duration of ECMO therapy after which point long-term functional status is noticeably worse? The narrator of Bob Dylan's song “Mississippi” blames his troubles on the fact that he “stayed…a day too long.”4Dylan B. “Mississippi.” Love and Theft. Columbia Records, 2001Google Scholar He laments: “You can always come back, but you can't come back all the way.”4Dylan B. “Mississippi.” Love and Theft. Columbia Records, 2001Google Scholar Is there a number of days of ECMO treatment that is one day too long for good functional recovery to come back all the way? Answers that specific are unlikely, but the overall functional outcomes after ECMO can likely be better anticipated. Rossong and colleagues1Rossong H. Debrueil S. Yan W. Heibert B. Singal R. Arora R. et al.Long-term survival and quality of life after extracorporeal membrane oxygenation.J Thorac Cardiovasc Surg. 2022; (XXX:XXX)Google Scholar have provided a solid foundation for this future work.
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The first successful neonatal extracorporeal membrane oxygenation case (1975) is important in the development of extracorporeal life support, but the case report was never published. This is the report of that case with commentary on the evolution of extracorporeal membrane oxygenation since 1975.
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