Hilliary Killer

Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR).

OBJECTIVES To determine the comparative effectiveness and cost-effectiveness of conventional ventilatory support versus extracorporeal membrane oxygenation (ECMO) for severe adult respiratory failure. DESIGN A multicentre, randomised controlled trial with two arms. SETTING The ECMO centre at Glenfield Hospital, Leicester, and approved conventional treatment centres and referring hospitals throughout the UK. PARTICIPANTS Patients aged 18-65 years with severe, but potentially reversible, respiratory failure, defined as a Murray lung injury score > or = 3.0, or uncompensated hypercapnoea with a pH < 7.20 despite optimal conventional treatment. INTERVENTIONS Participants were randomised to conventional management (CM) or to consideration of ECMO. MAIN OUTCOME MEASURES The primary outcome measure was death or severe disability at 6 months. Secondary outcomes included a range of hospital indices: duration of ventilation, use of high frequency/oscillation/jet ventilation, use of nitric oxide, prone positioning, use of steroids, length of intensive care unit stay, and length of hospital stay - and (for ECMO patients only) mode (venovenous/veno-arterial), duration of ECMO, blood flow and sweep flow. RESULTS A total of 180 patients (90 in each arm) were randomised from 68 centres. Three patients in the conventional arm did not give permission to be followed up. Of the 90 patients randomised to the ECMO arm, 68 received that treatment. ECMO was not given to three patients who died prior to transfer, two who died in transit, 16 who improved with conventional treatment given by the ECMO team and one who required amputation and could not therefore be heparinised. Ninety patients entered the CM (control) arm, three patients later withdrew and refused follow-up (meaning that they were alive), leaving 87 patients for whom primary outcome measures were available. CM consisted of any treatment deemed appropriate by the patients intensivist with the exception of extracorporeal gas exchange. No CM patients received ECMO, although one received a form of experimental extracorporeal arteriovenous carbon dioxide removal support (a clear protocol violation). Fewer patients in the ECMO arm than in the CM arm had died or were severely disabled 6 months after randomisation, [33/90 (36.7%) versus 46/87 (52.9%) respectively]. This equated to one extra survivor for every six patients treated. Only one patient (in the CM arm) was known to be severely disabled at 6 months. Patients allocated to ECMO incurred average total costs of 73,979 pounds compared with 33,435 pounds for those undergoing CM (UK prices, 2005). A lifetime model predicted the cost per quality-adjusted life-year (QALY) of ECMO to be 19,252 pounds (95% confidence interval 7622 pounds to 59,200 pounds) at a discount rate of 3.5%. Lifetime QALYs gained were 10.75 for the ECMO group compared with 7.31 for the conventional group. Costs to patients and their relatives, including out of pocket and time costs, were higher for patients allocated to ECMO. CONCLUSIONS Compared with CM, transferring adult patients with severe but potentially reversible respiratory failure to a single centre specialising in the treatment of severe respiratory failure for consideration of ECMO significantly increased survival without severe disability. Use of ECMO in this way is likely to be cost-effective when compared with other technologies currently competing for health resources. TRIAL REGISTRATION Current Controlled Trials ISRCTN47279827.

Poly-methyl pentene oxygenators have improved gas exchange capability and reduced transfusion requirements in adult extracorporeal membrane oxygenation

The performance of poly-methyl pentene (PMP) oxygenators (Medos Hilite 7000LT) was compared with that of silicone membrane (SM) oxygenators (Medtronic 1-4500-2A) for adult extracorporeal membrane oxygenation (ECMO). Forty consecutive patients were selected retrospectively pre- and post-introduction of PMP oxygenators. They were selected according to the dates they received ECMO and were separated into two equal groups with similar backgrounds. The flow path resistance, gas and heat exchange efficiency, consumption of coagulation factors and platelets, blood transfusion requirements, and incidence of clots for each oxygenator type was assessed. Adult PMP oxygenators showed lower blood path resistance than SM oxygenators. However, lower consumption of blood products in these oxygenators was a direct result of their smaller surface area and heparin coated design, reducing contact activation of coagulation factors. These oxygenators are noticeably smaller, require lower priming volumes, and have better gas exchange capability than SM oxygenators. They showed greater stability and preservation of coagulation factors and platelets compared with SM oxygenators. They also had the advantage of a functioning integrated heat exchanger. Using a single PMP oxygenator in the first instance may be adequate for the majority of patients and would significantly reduce red blood cell consumption during ECMO.

Performance of polymethyl pentene oxygenators for neonatal extracorporeal membrane oxygenation: a comparison with silicone membrane oxygenators

Objective: To review the performance of polymethyl pentene versus silicone oxygenators in terms of efficiency in priming and oxygenation, oxygenator resistance, requirements for coagulation proteins and consumption of blood products, for neonatal extracorporeal membrane oxygenation (ECMO) patients. Study design: Forty consecutive neonates were selected retrospectively pre- and post-introduction of the new polymethyl pentene (PMP) oxygenators. They formed two equal groups. After calculation of the sample size, data were collected from ELSO registry forms and patient records. Results were analysed using parametric and non-parametric tests. Results: Neonatal PMP (N-PMP) oxygenators were smaller, faster and easier to prime. They were less efficient than silicone oxygenators, especially in carbon dioxide elimination, and, therefore, required higher sweeps. The preservation of coagulation proteins was significantly better, but there was no reduction in the consumption of blood products, despite having less than half the surface area and significantly lower blood path resistance. Conclusion: Small PMP oxygenators (Medos Hilite 800 LT) provide adequate gas exchange and offer technical advantages in terms of more efficient priming, reduced haemodynamic resistance and better control and preservation of coagulation proteins than silicone oxygenators.

Effects of neonatal extracorporeal membrane oxygenation circuits on drug disposition

Abstract Background: It has been observed that neonatal patients receiving extracorporeal membrane oxygenation (ECMO) require larger doses of sedatives than do non-ECMO patients to achieve similar levels of sedation. Objective: The purpose of this study was to determine whether drug disposition of midazolam and morphine, 2 commonly used sedatives, are affected by the ECMO circuit. Methods: This was a 3-part study. First, a retrospective analysis of prescription charts for 10 ECMO neonates and 10 neonates who had undergone cardiac surgery was conducted to confirm that the former group required larger doses of sedatives. Second, uptake of midazolam and morphine by the polyvinylchloride (PVC) and silicone components of the neonatal ECMO circuits was evaluated in vitro. Third, known concentrations of midazolam were injected into a complete neonatal ECMO circuit and analyzed after the oxygenator to determine the effects of the circuit components on the bioavailability of midazolam. Results: Mean ± SD total dose of midazolam for the ECMO neonates was 21,283 ± 10,446 μg versus 9599 ± 5504 μg for the cardiac surgery group ( P = 0.008). Mean ± SD total dose of morphine for the ECMO neonates was 2364 ± 1280 μg versus 1158 ± 457 μg for the cardiac surgery group ( P = 0.017). There was significant uptake (68%) of midazolam by the PVC and silicone components of neonatal ECMO circuits, whereas morphine uptake of 16% was observed only during contact with the PVC component. After 40 minutes of running a new ECMO circuit, the concentration of midazolam leaving the circuit was Conclusions: There is significant interaction between the PVC and silicone components of an ECMO circuit and the sedative drugs that pass through them. These interactions may affect the bioavailability of these drugs and hence the doses required to induce a therapeutic effect.

Tubing failure during prolonged roller pump use: a laboratory study:

Little is known about the mechanical forces acting on extracorporeal circuit tubing with prolonged roller pump use during extracorporeal membrane oxygenation (ECMO). We examined the time to tubing rupture of three different materials during actual roller pump use, mean and standard deviation (SD) (SD shown in parentheses): Tygon® (control) 243.7 h (175.4); LVA 121 h (14.3); and SRT 6.6 h (2.1). Failure times for both LVA and SRT were significantly different from the control (paired t-test, p = 0.02 and p < 0.001, respectively). The minimum failure times for Tygon and LVA were 99 and 101 h, respectively. We then examined Tygon under conditions of pure compression, demonstrating that even after 3.67 million compression cycles at full occlusion crack formation did not occur. If the tubing was over-occluded, cracks appeared within 24 h. Scanning electron microscopy of Tygon, which has been used during clinical ECMO, and the failure pattern during destruction testing demonstrate that shear stress and compression coexist during clinical ECMO. Use of under-occlusive pump settings could improve tubing life.

How Does the Changing Profile of Infants Who Are Referred for Extracorporeal Membrane Oxygenation Affect Their Overall Respiratory Outcome

OBJECTIVE. Extracorporeal membrane oxygenation has been shown to be effective in term neonates with severe but reversible lung disease within the context of randomized, controlled trials. Extracorporeal membrane oxygenation now has been open to a wider population of infants in the United Kingdom, and other treatments have become available. The population referred for extracorporeal membrane oxygenation, therefore, has changed. The aims of this study were to (1) compare respiratory outcomes of infants who received extracorporeal membrane oxygenation in recent years with those from 10 years ago and (2) determine whether respiratory outcome varied with diagnostic group. METHODS. All infants who were referred to a single extracorporeal membrane oxygenation center and were <12 months old during a 7-year period were eligible. One year after extracorporeal membrane oxygenation, lung volume, airway conductance, maximum expiratory flow, and indices of tidal breathing were measured. RESULTS. A total of 106 infants (77% of those eligible) were tested, and results were compared with those of 51 infants referred for extracorporeal membrane oxygenation as part of the original United Kingdom extracorporeal membrane oxygenation trial. Lung volume was not different, but there was a strong trend for the infants who were seen in more recent years to have better forced expiratory flow and specific airway conductance. Restricting analysis to the major subgroup (meconium aspiration) confirmed these findings. When divided into diagnostic subgroups, infants who required extracorporeal membrane oxygenation for respiratory distress syndrome or who were >2 weeks old when extracorporeal membrane oxygenation was commenced had a poorer respiratory outcome than others. CONCLUSIONS. The respiratory outcome of infants who were treated beyond the tightly regulated criteria of the United Kingdom trial remains good and even shows a trend toward improvement. Certain subgroups require extracorporeal membrane oxygenation for longer and have poorer pulmonary function when followed up.

An in vitro method for comparing biocompatibility of materials for extracorporeal circulation

We measured the response of fresh heparinized human blood to recirculation through circuits made of LVA (Portex Industries, Hythe, Kent, UK), SRT (Rehau UK, Langley, Slough, UK) and Tygon® S-65-HL (Norton Performance Plastics, Corby, Northants, UK), as control. Circuit construction: 1/2 in. tubing, heat exchanger (Dideco D-720P), Stockert roller pump, just underoccluded, Cincinnati Sub Zero heater, circuit volume of 500 ml. Flow 3.45 l/min, 37°C. Samples: at 10 min, 1, 2, 4 and 6 h. n = 5 in each group; 2/5 SRT experiments were stopped at 45 and 60 min due to overpressurization. Results: Baseline activated clotting time (ACT) of 300 s, increasing in all groups as fibrinogen fell to zero with SRT and LVA. Minimum fibrinogen was 1 g/l for Tygon. Absolute thrombocytopenia occurred (SRT and LVA 60 min and Tygon 240 min). International normalized ratio (INR) in both the SRT and LVA circuits increased, but mean increase for Tygon (0.56) was smaller than the other two materials. Plasma free haemoglobin increased in all three materials; the increase was greater in the LVA circuits compared to the control. C5b9 levels increased equally in all groups. Lactoferrin levels rose equally in all groups to a maximum at 150 min. The neutrophil counts fell, mirroring the lactoferrin. The total white cell counts also fell in all groups; in the LVA circuits, the fall was significantly lower than in the control. Rapid disappearance of platelets and fibrinogen from the blood in the SRT and LVA circuits excludes them both from extracorporeal use. Paradoxically, SRT caused the least complement activation of the three materials. This method can be used to compare biocompatibility.