Gail M. Annich

Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality: Analysis of the extracorporeal life support organization registry

RATIONALE Recent pediatric studies suggest a survival benefit exists for higher-volume extracorporeal membrane oxygenation (ECMO) centers. OBJECTIVES To determine if higher annual ECMO patient volume is associated with lower case-mix-adjusted hospital mortality rate. METHODS We retrospectively analyzed an international registry of ECMO support from 1989 to 2013. Patients were separated into three age groups: neonatal (0-28 d), pediatric (29 d to <18 yr), and adult (≥18 yr). The measure of hospital ECMO volume was age group-specific and adjusted for patient-level case-mix and hospital-level variance using multivariable hierarchical logistic regression modeling. The primary outcome was death before hospital discharge. A subgroup analysis was conducted for 2008-2013. MEASUREMENTS AND MAIN RESULTS From 1989 to 2013, a total of 290 centers provided ECMO support to 56,222 patients (30,909 neonates, 14,725 children, and 10,588 adults). Annual ECMO mortality rates varied widely across ECMO centers: the interquartile range was 18-50% for neonates, 25-66% for pediatrics, and 33-92% for adults. For 1989-2013, higher age group-specific ECMO volume was associated with lower odds of ECMO mortality for neonates and adults but not for pediatric cases. In 2008-2013, the volume-outcome association remained statistically significant only among adults. Patients receiving ECMO at hospitals with more than 30 adult annual ECMO cases had significantly lower odds of mortality (adjusted odds ratio, 0.61; 95% confidence interval, 0.46-0.80) compared with adults receiving ECMO at hospitals with less than six annual cases. CONCLUSIONS In this international, case-mix-adjusted analysis, higher annual hospital ECMO volume was associated with lower mortality in 1989-2013 for neonates and adults; the association among adults persisted in 2008-2013.

Nitric oxide releasing silicone rubbers with improved blood compatibility: preparation, characterization, and in vivo evaluation.

Nitric oxide (NO) releasing silicone rubbers (SR) are prepared via a three-step reaction scheme. A diamino triaminoalkyltrimethoxysilane crosslinker is used to vulcanize hydroxyl terminated polydimethylsiloxane (PDMS) in the presence of ambient moisture and a dibutyltin dilaurate catalyst so that the respective diamine triamine groups are covalently linked to the cured SR structure. These amine sites are then diazeniumdiolated, in situ, when the cured SR is reacted with NO at elevated pressure (80 psi). Although nitrite species are also formed during the NO addition reaction, in most cases the diazeniumdiolated polymer is the major product within the final SR matrix. Temperature appears to be the major driving force for the dissociation of the attached diazeniumdiolate moieties, whereas the presence of bulk water bathing the SR materials has only minimal effect on the observed NO release rate owing to the low water uptake of the SR matrices. The resulting SR films/coatings release NO at ambient or physiological temperature for up to 20 d with average fluxes of at least 4 x 10(10) mol x cm(-2) x min(-1) (coating thickness > or = 600 microm) over first 4 h, comparable to the NO fluxes observed from stimulated human endothelial cells. The NO loading and concomitant NO release flux of the SR material are readily adjustable by altering the diamine triamine loading and film/coating thickness. The new NO releasing SR materials are shown to exhibit improved thromboresistance in vivo, as demonstrated via reduced platelet activation on the surface of these polymers when used to coat the inner walls of SR tubings employed for extracorporeal circulation in a rabbit model.

Reduced platelet activation and thrombosis in extracorporeal circuits coated with nitric oxide release polymers

Objective: To determine whether the use of nitric oxide (NO)‐releasing polymers coated onto the inner surface of extracorporeal circuits can reduce platelet consumption and activation in the absence of systemic heparinization using a rabbit model of venovenous extracorporeal circulation. Design: Prospective, controlled trial Setting: Research laboratory at an academic medical institution. Subjects: New Zealand White Rabbits Interventions: Anesthetized, tracheotomized, and ventilated New Zealand White rabbits were injected with freshly prepared, 111In(oxine)3 labeled single donor platelets through the external jugular vein. After baseline measurements, these animals were placed on venovenous extracorporeal circulation through a 1‐m control circuit or NO test circuit for 4 hrs at a blood flow rate of 109‐118 mL/min via roller pump. Four groups were studied: systemically heparinized control circuits, systemically heparinized NO test circuits, nonheparinized control circuits, and nonheparinized NO test circuits. Platelet counts, fibrinogen levels, and plasma free indium levels were measured hourly. Circuits were rinsed and retained for gamma counting after the 4‐hr run or when the circuit clotted. Four animals, one from each group, did not receive radiolabeled platelets so that the circuits could be preserved for scanning electron microscopic examination after the 4‐hr study. Measurements and Main Results: Platelet consumption was significantly reduced in both the heparinized and nonheparinized NO test groups when compared with the controls (p < .0001 and p < .0004, respectively). Platelet adhesion to the extracorporeal circuits was significantly reduced in the nonheparinized test circuits when compared with the controls (p < .05). Scanning electron microscopic examination of the circuits revealed that in the absence of heparin and in the presence of a NO‐releasing surface, platelets retained their spherical nonactivated shape. Conclusions: The incorporation of NO into the surface of extracorporeal circuits reduces platelet consumption and eliminates the need for systemic heparinization in a rabbit model of extracorporeal circulation.

Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy.

Objective:In pediatric patients, fluid overload at continuous renal replacement therapy initiation is associated with increased mortality. The aim of this study was to characterize the association between fluid overload at continuous renal replacement therapy initiation, fluid removal during continuous renal replacement therapy, the kinetics of fluid removal and mortality in a large pediatric population receiving continuous renal replacement therapy while on extracorporeal membrane oxygenation. Design:Retrospective chart review. Setting:Tertiary children’s hospital. Patients:Extracorporeal membrane oxygenation patients requiring continuous renal replacement therapy from July 2006 to September 2010. Interventions:None. Measurements and Main Results:Overall intensive care unit survival was 34% for 53 patients that were initiated on continuous renal replacement therapy while on extracorporeal membrane oxygenation during the study period. Median fluid overload at continuous renal replacement therapy initiation was significantly lower in survivors compared to nonsurvivors (24.5% vs. 38%, p = .006). Median fluid overload at continuous renal replacement therapy discontinuation was significantly lower in survivors compared to nonsurvivors (7.1% vs. 17.5%, p = .035). After adjusting for percent fluid overload at continuous renal replacement therapy initiation, age, and severity of illness, the change in fluid overload at continuous renal replacement therapy discontinuation was not significantly associated with mortality (p = .212). Models investigating the rates of fluid removal in different periods, age, severity of illness, and fluid overload at continuous renal replacement therapy initiation found that fluid overload at continuous renal replacement therapy initiation was the most consistent predictor of survival. Conclusions:Our data demonstrate an association between fluid overload at continuous renal replacement therapy initiation and mortality in pediatric patients receiving extracorporeal membrane oxygenation. The degree of fluid overload at continuous renal replacement therapy discontinuation is also associated with mortality, but appears to reflect the effect of fluid overload at initiation. Furthermore, correction of fluid overload to ⩽10% was not associated with improved survival. These results suggest that intervening prior to the development of significant fluid overload may be more clinically effective than attempting fluid removal after significant fluid overload has developed. Our findings suggest a role for earlier initiation of continuous renal replacement therapy in this population, and warrant further clinical studies.

Extracorporeal life support

#### Summary points Extracorporeal life support (ECLS) is a variation of cardiopulmonary bypass. Whereas cardiopulmonary bypass facilitates open heart surgery for a number of hours, extracorporeal life support maintains tissue oxygenation for days to weeks in patients with life threatening respiratory or cardiac failure (or both). As technology advances, indications increase, and the numbers of specialist centres rise, more doctors are likely to find themselves assessing patients for early referral, discussing this support option with relatives, directly or indirectly managing patients on extracorporeal life support, and providing follow-up outpatient and community based care. During the recent H1N1 influenza A pandemic, one third of patients admitted to the intensive care unit with severe respiratory failure required extracorporeal life support.1 Evidence from case series, cohort studies, registry database analyses, and randomised controlled trials form the basis of this overview. #### Sources and selection criteria We searched PubMed, Embase, and the Cochrane Library for systematic reviews, randomised trials, large population based studies, case controlled studies, case series, scientific and clinical reviews, evidence based guidelines, and published consensus statements between 1996 and 2010. We used the search terms “extracorporeal membrane oxygenation”, “extracorporeal circulation”, and “extracorporeal life support”. We also consulted the registry database of the Extracorporeal Life Support Organization, personal databases, reference collections, and contemporary …

The attenuation of platelet and monocyte activation in a rabbit model of extracorporeal circulation by a nitric oxide releasing polymer

Nitric oxide (NO) has been shown to reduce thrombogenicity by decreasing platelet and monocyte activation by the surface glycoprotein, P-selectin and the integrin, CD11b, respectively. In order to prevent platelet and monocyte activation with exposure to an extracorporeal circulation (ECC), a nitric oxide releasing (NORel) polymeric coating composed of plasticized polyvinyl chloride (PVC) blended with a lipophilic N-diazeniumdiolate was evaluated in a 4 h rabbit thrombogenicity model using flow cytometry. The NORel polymer significantly reduced ECC thrombus formation compared to polymer control after 4 h blood exposure (2.8 +/- 0.7 NORel vs 6.7 +/- 0.4 pixels/cm(2) control). Platelet count (3.4 +/- 0.3 NORel vs 2.3 +/- 0.3 x 10(8)/ml control) and function as measured by aggregometry (71 +/- 3 NORel vs 17 +/- 6% control) were preserved after 4 h exposure in NORel versus control ECC. Plasma fibrinogen levels significantly decreased in both NORel and control groups. Platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry was attenuated after 4 h on ECC to ex vivo collagen stimulation (27 +/- 1 NORel vs 40 +/- 2 MFI control). Monocyte CD11b expression was reduced after 4 h on ECC with NORel polymer (87 +/- 14 NORel vs 162 +/- 30 MFI control). These results suggest that the NORel polymer coatings attenuate the increase in both platelet P-selectin and monocytic CD11b integrin expression in blood exposure to ECCs. These NO-mediated platelet and monocytic changes were shown to improve thromboresistance of these NORel-polymer-coated ECCs for biomedical devices.

Extracorporeal life support: experience with 2,000 patients.

This is a review of the University of Michigan experience with extracorporeal life support (ECLS) also known as extracorporeal membrane oxygenation (ECMO). Two thousand patients were managed with ECMO from 1973 to 2010. The first 1,000 patients were reported previously. Of the 2,000 patients, 74% were weaned from ECLS, and 64% survived to hospital discharge. In patients with respiratory failure, survival to hospital discharge was 84% in 799 neonates, 76% in 239 children, and 50% in 353 adults. Survival in patients with cardiac failure was 45% in 361 children and 38% in 119 adults. ECLS during extracorporeal cardiopulmonary resuscitation was performed in 129 patients, with 41% surviving to discharge. Survival decreased from 74 to 55% between the first and second 1,000 patients. The most common complication was bleeding at sites other than the head, with an incidence of 39%, and the least frequent complication was pump malfunction, with a 2% incidence. Intracranial bleeding or infarction occurred in 8% of patients, with a 43% survival rate. This is the largest series of ECLS at one institution reported in the world to date. Our experience has shown that ECLS saves lives of moribund patients with acute pulmonary and cardiac failure in all age groups.

Venovenous versus venoarterial extracorporeal life support for pediatric respiratory failure : Are there differences in survival and acute complications?

Objectives: To examine the Extracorporeal Life Support Organization (ELSO) registry database of infants and children with acute respiratory failure to compare outcome and complications of venovenous (VV) vs. venoarterial (VA) Extracorporeal Life Support (ECLS). Design: Retrospective cohort study. Setting: ELSO registry for pediatric pulmonary support. Patients: All nonneonatal pediatric pulmonary support ECLS cases treated at U.S. centers and reported to the ELSO registry as of July 1997. Patients were excluded if they had one or more of the following diagnoses: hematologic‐oncologic, cardiac, abdominal surgical, burn, metabolic, airway, or immunodeficiency disorder. Interventions: Venoarterial or venovenous extracorporeal life support for severe pulmonary failure. Measurements and Main Results: From 1986 to June of 1997, 763 pediatric patients met the inclusion criteria. Overall, 595 were initially managed with VA bypass, and 168 with VV bypass. The VA group was younger (mean ± SD, 26.1 ± 42.2 months for VA vs. 63.5 ± 68.7 months for VV) and smaller (11.8 ± 15.1 kg vs. 22.9 ± 23.8 kg) (p < .001). There were no differences between groups in number of days on mechanical ventilation before ECLS, number of hours on ECLS, or number of hours on mechanical ventilation post‐ECLS in survivors. Mean pH and PaCO2 values, positive end‐expiratory pressure, and mean airway pressure just before placing the patient on ECLS were also similar. VA‐treated patients had higher FIO2 requirements (p = .034), lower PaO2 (p = .047), and lower PaO2/FIO2 ratio (p = .014) just before cannulation. There was a trend of higher peak inspiratory pressure in VA‐treated patients (p = .053). Overall, survival rate was not different for the two groups (55.8% for VA vs. 60.1% for VV; p = .33). Central nervous system complications were not different between the two groups. Examination of the same variables was then conducted after dividing the patients into four subgroups. There were no significant differences in survival or complications during bypass between VV and VA modes of ECLS in any subgroup. Stepwise logistic regression modeling was performed to control for variables associated with the outcome survival for VV and VA‐treated groups, and variables measured before bypass were identified as being associated with improved survival. There was a trend of improved survival in the VV‐treated patients (p = .12). Conclusions: Overall survival of pediatric patients with acute respiratory failure supported by VA or VV ECLS was comparable. A randomized clinical trial may be useful in clarifying these observations.

Effect of varying nitric oxide release to prevent platelet consumption and preserve platelet function in an in vivo model of extracorporeal circulation.

The gold standard for anticoagulation during extracorporeal circulation (ECC) remains systemic heparinization and the concomitant risk of bleeding in an already critically ill patient could lead to death. Normal endothelium is a unique surface that prevents thrombosis by the release of antiplatelet and antithrombin agents. Nitric oxide (NO) is one of the most potent, reversible antiplatelet agents released from the endothelium. Nitric oxide released from within a polymer matrix has been proven effective for preventing platelet activation and adhesion onto extracorporeal circuits. However, the critical NO release (NO flux) threshold for thrombus prevention during ECC has not yet been determined.1 Using a 4-hour arteriovenous (AV) rabbit model of ECC,2 we sought to find this threshold value for ECC circuits, using an improved NO-releasing coating (Norel-b ). Four groups of animals were tested at variable NO flux levels. Hourly blood samples were obtained for measurement of arterial blood gases, platelet counts, fibrinogen levels and platelet function (via aggregometry). A custom-built AV circuit was constructed with 36 cm of poly(vinyl)chloride (PVC) tubing, a 14 gauge (GA) angiocatheter for arterial access and a modified 10 French (Fr) thoracic catheter for venous access. The Norel-b coating reduced platelet activation and thrombus formation, and preserved platelet function — in all circuits that exhibited an NO flux of 13.65 × 10— 10 mol·cm—2·min—1. These results were significant when compared with the controls. With the Norel-b coating, the NO flux from the extracorporeal circuit surface can be precisely controlled by the composition of the polymer coating used, and such coatings are shown to prevent platelet consumption and thrombus formation while preserving platelet function in the animal. Perfusion (2007) 22, 193—200.

Hepatopulmonary syndrome: Use of extracorporeal life support for life‐threatening hypoxia following liver transplantation

Hepatopulmonary syndrome is an uncommon complication of nonacute liver failure, and in rare cases, hypoxia may be the presenting sign of liver dysfunction. The condition, once thought to be a contraindication, is improved in most cases by transplantation. There is a significant risk of postoperative, hypoxia‐related morbidity and mortality in patients with hepatopulmonary syndrome. We present a case of life‐threatening hypoxia following liver transplantation for liver failure and associated hepatopulmonary syndrome, with successful management using extracorporeal membrane oxygenation. Liver Transpl 14:966–970, 2008.