Richard K. Firmin

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

BACKGROUND Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support. METHODS In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18-65 years and had severe (Murray score >3.0 or pH <7.20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H(2)O of peak inspiratory pressure) or high FiO(2) (>0.8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827. FINDINGS 766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0.69; 95% CI 0.05-0.97, p=0.03). Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected]. A lifetime model predicted the cost per QALY of ECMO to be pound19 252 (95% CI 7622-59 200) at a discount rate of 3.5%. INTERPRETATION We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK. FUNDING UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.

Referral to an Extracorporeal Membrane Oxygenation Center and Mortality Among Patients With Severe 2009 Influenza A(H1N1)

CONTEXT Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients with severe acute respiratory distress syndrome (ARDS), but its role has remained controversial. ECMO was used to treat patients with ARDS during the 2009 influenza A(H1N1) pandemic. OBJECTIVE To compare the hospital mortality of patients with H1N1-related ARDS referred, accepted, and transferred for ECMO with matched patients who were not referred for ECMO. DESIGN, SETTING, AND PATIENTS A cohort study in which ECMO-referred patients were defined as all patients with H1N1-related ARDS who were referred, accepted, and transferred to 1 of the 4 adult ECMO centers in the United Kingdom during the H1N1 pandemic in winter 2009-2010. The ECMO-referred patients and the non-ECMO-referred patients were matched using data from a concurrent, longitudinal cohort study (Swine Flu Triage study) of critically ill patients with suspected or confirmed H1N1. Detailed demographic, physiological, and comorbidity data were used in 3 different matching techniques (individual matching, propensity score matching, and GenMatch matching). MAIN OUTCOME MEASURE Survival to hospital discharge analyzed according to the intention-to-treat principle. RESULTS Of 80 ECMO-referred patients, 69 received ECMO (86.3%) and 22 died (27.5%) prior to discharge from the hospital. From a pool of 1756 patients, there were 59 matched pairs of ECMO-referred patients and non-ECMO-referred patients identified using individual matching, 75 matched pairs identified using propensity score matching, and 75 matched pairs identified using GenMatch matching. The hospital mortality rate was 23.7% for ECMO-referred patients vs 52.5% for non-ECMO-referred patients (relative risk [RR], 0.45 [95% CI, 0.26-0.79]; P = .006) when individual matching was used; 24.0% vs 46.7%, respectively (RR, 0.51 [95% CI, 0.31-0.81]; P = .008) when propensity score matching was used; and 24.0% vs 50.7%, respectively (RR, 0.47 [95% CI, 0.31-0.72]; P = .001) when GenMatch matching was used. The results were robust to sensitivity analyses, including amending the inclusion criteria and restricting the location where the non-ECMO-referred patients were treated. CONCLUSION For patients with H1N1-related ARDS, referral and transfer to an ECMO center was associated with lower hospital mortality compared with matched non-ECMO-referred patients.

Directly measured tissue oxygen tension and arterial oxygen tension assess tissue perfusion

Mean subcutaneous tissue PO2 (PsqO2) measurements were obtained in dogs with an unheated electrode placed in an implanted Silastic tonometer, while PaO2 was increased in increments from 40 to 600 torr during normal, increased, and reduced blood volume. These changes reflect that the mean PsqO2 is approximately 10 torr below the PO2 of venous blood draining that tissue. Since PaO2 was already known, the oxygen content of arterial and venous blood entering and leaving this tissue could be determined by reference to blood-oxygen dissociation curves. Therefore, relative changes in blood flow could be calculated using the Fick principle. After a 20% blood loss, the PsqO2 measured during breathing of room air fell to 20% of baseline, corresponding to an 80% fall in sc blood flow; it remained low until the shed blood was returned despite compensatory changes in cardiac output. Rapid infusion of electrolyte solutions in normovolemic animals produced a temporary increase in local blood flow. Subcutaneous oximetry seems capable of quantifying peripheral perfusion and may be clinically useful.

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.

Early experience with a polymethyl pentene oxygenator for adult extracorporeal life support

Silicone oxygenators are the standard devices used for Extracorporeal Life Support (ECLS), but they have some limitations. Microporous polypropylene hollow fiber oxygenators overcome many of these problems but, unfortunately, develop plasma leak. Polymethyl-pentene (PMP) is a novel oxygenator material. We report our initial experience with the Medos Hilite 7000LT, a PMP hollow fiber oxygenator, in six adult respiratory ECLS patients with these characteristics: age, mean 32.2 (±13) years; weight, mean 81.2 (±17) kg; PaO2/FIO2, mean 62.8 [±33] mm Hg; Murray Score, mean 3.4 [±0.3]; and sepsis related organ failure assessment score, mean 9.6 [±2.3]. One patient was cannulated within 10 hours of multiple trauma and 1 hour after thoracolaparotomy; another patient was cannulated 12 hours after a thoracotomy. All six patients survived. Heparin was infused (7.8–32.5 u/kg/hr) to maintain activated clotting time at 162 to 238 seconds; international normalized ratio was 0.9 to 3.4. Two of the six patients required transfusions of fresh frozen plasma, receiving one and five units, respectively. Fibrinogen was 1.4 to 6 g/dl; no cryoprecipitate was needed. Platelet counts were between 65 and 306, and very little platelet transfusion (mean 2.33; ±3.03 units per patient) was required to maintain these levels. Two patients did not require any platelet transfusion. Maximum blood flow was 5.3 L/min, sweep was 3 to 10 L/min, and resistance was 11 to 43 Paul Wood Units. There were no oxygenator failures. Mean duration of ECLS was 151.7 hours (±75.6). Our initial experience with PMP oxygenators in adults was satisfactory, and platelet consumption and resistance to blood flow seem to be greatly reduced with PMP.

Parenteral ivermectin in Strongyloides hyperinfection

Strongyloides hyperinfection, unresponsive to oral ivermectin and oral albendazole, was controlled by subcutaneous administration of a veterinary preparation of ivermectin.

Risk factors for intestinal ischaemia in cardiac surgical patients.

OBJECTIVE Mesenteric ischaemia is an uncommon (<1%) but serious complication of cardiac surgery associated with a mortality >50%. Predictors of this complication are not well defined, and diagnosis can be difficult and prompt surgical intervention can be lifesaving. METHODS AND RESULTS In a retrospective case-note analysis from May 1994 through to May 2000, we identified mesenteric ischaemia in 39 of 5349 consecutive patients (0.07%) undergoing cardiac surgery with cardiopulmonary bypass. By logistic multivariate analysis, we have identified six possible predictors of intestinal ischaemia: duration of cross-clamp, use of significant inotropic support, intra-aortic balloon counterpulsation for low cardiac output, need for blood transfusions, triple vessel disease and peripheral vascular disease. In all patients a combination of four predictors were present. Patients who survived this complication had surgical intervention earlier (6.4+/-3.8 h) than those who did not (16.9+/-10 h). CONCLUSIONS The diagnosis and prompt treatment of mesenteric ischaemia post cardiac surgery requires a high degree of awareness. These predictors may be useful in alerting medical staff to the possibility of gastro-intestinal ischaemic complications after cardiac surgery particularly that early surgical intervention reduces mortality.

Extracorporeal membrane oxygenation and the treatment of critical pulmonary hypertension in congenital heart disease.

Certain forms of congenital heart disease (CHD) confer a high risk for the development of severe pulmonary hypertension before and after corrective cardiac surgery. Extracorporeal membrane oxygenation (ECMO) has theoretical benefits in the treatment of this complication in that it assures oxygenation, corrects acid-base balance and provides haemodynamic support at the same time as allowing lung rest from ventilation. We examined our experience of the 117 children and neonates supported with ECMO between November 1989 and July 1993. Of these, five received support for critical pulmonary hypertension associated with congenital heart disease. They comprised three who had undergone surgical repair of CHD, one whose total anomalous pulmonary venous drainage was diagnosed and corrected whilst on ECMO and one neonate with functional pulmonary atresia. Pulmonary artery pressure (PAP) was estimated by Doppler echocardiography in all patients and confirmed invasively in two. The median systolic PAP was 46 (range 42-65) mmHg prior to ECMO. The median ratio of pulmonary to systemic arterial pressure (PAP/SAP) was 0.75 (0.70-0.92). Following ECMO of 16-120 h duration, the median systolic PAP was 34 (30-49) mmHg with PAP/SAP 0.50 (0.35-0.60). All patients survived and there were no complications related to ECMO. Extracorporeal membrane oxygenation is an effective treatment in critical pulmonary hypertension and should be considered in all patients in whom this is refractory to conventional measures.

Pharmacokinetics of Midazolam in Neonates Undergoing Extracorporeal Membrane Oxygenation

Background Although the pharmacokinetics of midazolam in critically ill children has been described, there are no such reports in extracorporeal membrane oxygenation. Methods The pharmacokinetics of midazolam and 1-hydroxy midazolam after continuous infusion (50–250 &mgr;g · kg−1 · h−1) were determined in 20 neonates undergoing extracorporeal membrane oxygenation. Patients were randomized into two groups: group 1 (n = 10) received midazolam extracorporeally (into the circuit), and group 2 received drug via central or peripheral access. Blood samples for determination of plasma concentrations were taken at baseline, 2, 4, 6, 12, 18, and 24 h, then every 12 h. Population pharmacokinetic analysis and model building was conducted using WinNonMix (Pharsight Corporation, Mountain View, CA). The 1-hydroxy midazolam/midazolam metabolic ratio was determined as a surrogate marker of cytochrome P450 3A activity. Results The parameter estimates (n = 19) were based on a one-compartment model with time-dependent change in volume of distribution. Volume (mean ± standard error) expanded monoexponentially from the onset of extracorporeal membrane oxygenation to a maximum value, 0.8 l ± 0.5 and 4.1 ± 0.5 l/kg, respectively. Consequently, plasma half-life was substantially prolonged (median [range]) from onset to steady-state: 6.8 (2.2–39.8) and 33.3 (7.4–178) h, respectively. Total body clearance was determined as (mean ± standard error) 1.4 ± 0.15 ml · kg−1 · min−1. The median metabolic ratio was 0.17 (0.03–0.9). No significant differences were observed between the two groups with respect to parameter estimates. Simulations of plasma concentration profiles revealed excess levels at conventional doses. Conclusions These results reveal significantly increased volume of distribution and plasma half-life in neonates receiving extracorporeal membrane oxygenation. Altered kinetics may reflect sequestration of midazolam by components of the extracorporeal membrane oxygenation circuit.