ECMO u EXTRA CORPOREAL MEMBRANE OXGENATION u PROVIDES PROLONGED RESPIRATORY AND CARDIAC SUPPORT u DOES NOT TREAT UNDERLYING PATHOLOGY u ALLOWS SUPPORT WHILST DISEASE RESOLVES OR REVERSES u ONLY APPROPRIATE IF UNDERLYING PATHOLOGY IS POTENTIALLY REVERSIBLE

PATHOLOGIES POTENTIALLY TREATABLE BY ECMO u Aspiration pneumonia u ARDS trauma u ARDS sepsis u ARDS obstetric u Pneumonia –viral –bacterial –atypical u Pancreatitis u Drowning u Burns - smoke inhalation u Pulmonary embolus u Tricyclic Antidepressant OD u Viral myocarditis u Post CPB failure to wean

NORMAL LUNG

CONSOLIDATED LUNG

ARDS Effects on the Lung u Capillary leak u Hyaline membranes u Surfactant depletion u Collapse/consolidation u VQ mismatch u Reduced compliance u Neutrophil infiltration and cytokine release

HISTORY OF ECMO -1 u MACLEAN - HEPARIN (JH) u JOHN GIBBON - FIRST INVESTIGATION INTO ECLS u KOLFF AND BERK - BLOOD OXYGENATION IN CELLOPHANE CHAMBERS OF ARTIFICIAL KIDNEY u EARLY DEVELOPEMENTS OF CPB u CLOWES - INVENTED MENBRANE OXGENATOR u KAMMERMEYER - INVENTED SILICONE - MEMBRANE LUNG

Dr & Mrs Gibbon with their CPB machine

HISTORY OF ECMO - 2 u EXPERIMENTS INTO PROLONGED CPB u HILL - FIRST ADULT ECMO - AORTIC RUPTURE u BARTLETT - FIRST SUCCESSFUL NEONATAL ECMO u USA 18 CENTRES ECMO u GATTINONI - 50% SURVIVAL IN ADULT ECCO 2 R u ELSO REGISTRY u CENTRES WORLD WIDE

ECMO in Leicester UK u Neonatal ~ 40 cases per year u Paediatric ~ 20 cases per year u Adult ~ 40 cases per year u Cardiac (v.small number)

The Circuit

DIFFERENCES WITH CPB –NO RESERVOIR; BLADDER SERVOREGULATOR –NO CENTRIFUGAL PUMP (haemolysis) –NO MICROPROUS OXYGENATOR –VENO-VENOUS PREFERRED WITH ADEQUATE CARDIAC FUNCTION –NORMOTHERMIA –HEPARIN ACT NOT 500+ –NO ARTERIAL FILTER –NOT HAEMODILUTED HB 40 –NO AUTOTRANSFUSION

TECHNICAL ASPECTS

Cannulation u Veno-venous (v=28Fr ; a= 21 to 28Fr) u Veno-arterial u Percutaneous u Open u Semi-Seldinger u Double lumen u Single lumen

VVAdvantages & Disadvantages u Pulmonary vasodilation (corr. Of hypoxia and acidosis u Myocardial oxygenation u Maintained pulmonary blood flow u Minimally invasive u Not affected by PDA u More difficult u Slower stabilisation u No circulatory support u Re-circulation

VA Advantages & Disadvantages u Easy to use u Circulatory support u Instant stabilisation u Huge experience u Right heart offloaded and rested u Carotid ligation u Jugular ligation u Raised LV afterload u Reduced pulmonary blood flow u Hypoxic coronary perfusion u Stun- high LV afterload u Duct

PT MANAGEMENT ON ECMO 1 LUNG REST u FIO u PEEP 10cm H20 u PEAK INSPIRATORY PRESSURE 20cm H2O u RATE 5- 10/min u THEREFORE REDUCE: –BAROTRAUMA –VOLUTRAUMA –OXYGEN TOXICITY –MYOCARDIAL DEPRESSION

PATIENT MANAGMENT ON ECMO 2 FLUID BALANCE u MULTIPLE TRANSFUSION u HYPOALBUMINAEMIC - SEPSIS, DILUTION u CAPILLARY LEAK SYDROME u RENAL FAILURE - SEPSIS u FLUID OVERLOAD FROM CIRCUIT PRIME u DIURESIS TO ‘DRY’ WEIGHT v DOPAMINE v FRUSEMIDE INFUSION v AMINOPHYLLINE v 40% CVVHF

PATIENT MANAGEMENT ON ECMO -3 u Percutaneous Veno-venous Cannulation. u Low range heparinisation; ACT u Lung Rest (20/10, RR10, FIO 2 30%). u Normothermia. u Diuresis to dry weight. u Hb ~ 14g/dl.

DOES ECMO WORK

RCTs of ECLS in Adults u NIH Adult ECMO Trial Zapol et al JAMA 242: ,1979 u PCIRV vs ECCO2R Morris et al, Am J Respir Crit Care Med 1994;149:

Early Adult ECMO/ECCO 2 R Trials u Zapol, : (NIH Trial) (VA ECMO +ventilation and ventilation only) Severe ARF. A Randomized Prospective Study. JAMA 1979:242:2193-6) u 90 patients, 9 US centres, u Survival < 10% in both arms u Criticism: –1. VA ECMO used (prone to microthrombi in lungs) –2. High anticoagulation and bleeding complications –3. High pressure ventilation used even DURING ECMO –4. Mean duration of ventilation prior to ECMO was 9 days u Little experience, varying technique in different centres

Early Adult ECMO/ECCO 2 R Trials u Morris, et.al: Randomized Trial of PCIRV and ECCO 2 R in ARDS. AJRCCM,1994;149: u 40 patients, severe ARDS (paO2/FiO2 63 mmHg) in one US centre u 33% survival in 21 patients ECCO2R + LFPPV u 42% survival in 19 patients PCIRV u P = 0.8, no significant difference u Little previous experience in centre with technique in humans u High pressure ventilation before and DURING ECCO2R (PEEP > 20, Peak cmH2) u Frequent severe bleeding complications (leading to discontinuation of ECCO2R in 7/19 cases)

BOTH TRIALS HAVE LITTLE RELEVANCE TO CURRENT ECMO REGIMENS

OBSERVATIONAL STUDIES

Cohort studies of ECMO- Leicester Cohort studies of ECMO- Leicester PaO 2 /FIO 2 65mmhg Murray Score=3.4

Cohort Studies of ECLS - Other u LFPPV with ECCO2R in severe acute respiratory failure, Gattinoni L et al, JAMA ;7:881-6 (50% survival) u ECLS for 100 adult patients with severe respiratory failure.PaO 2 /FiO 2 = 55mmHg Kolla S et al, Ann Surg 1997;226: (survival 54%)

OUTCOME IN ADULTS WHEN ECMO IS UNAVAILABLE

Results u Conventional patients 8/28 Survived (28.5%) u ECMO patients 39/57 Survived (68.4%) u p=0.001

However, time has passed and things have changed since... u Some centres in the US and Europe have been quite successful at providing ECMO for severe adult respiratory failure (Ann Arbor, Michigan, Berlin, Marburg, Munich, Glenfield Hospital, Leicester etc.) u ECMO has become ‘standard’ treatment for severe Neonatal Respiratory Failure and Persistent Pulmonary Hypertension of the Newborn

Survival for ARDS with ECMO u Michigan- 66% u Leicester- 80% u Berlin-77% u Vienna-80%

The Sceptics’ Perspective

ADVANCED CONVENTIONAL ITU TREATMENTS u HF JET VENTILATION - Romand 1995 u HF OSCILLATING - Moller 1995 u INHALED NITIC OXIDE - Gerlach 1993 u NEBULISED PROSTACYCLIN - Zwissler 1996 u PCIRV - Morris 1994 u PERMISSIVE HYPERCAPNOEA - Gentilello 1995 (91%n=11, survival in trauma pts ) u PRONE VENTILATION - Stoller 1990; Pappert 1994 u LIQUID VENTILATION - still experimental

Improved survival in severe ARDS with protective ventilatory strategies: u Hickling, Walsh, Henderson, Jackson: Low mortality rate in adult respiratory distress syndrome using low-volume, pressure limited ventilation with permissive hypercapnia: A prospective study.Crit Care Med1994,22: u 74 % survival (= 40 of 53 patients with severe ARDS, ie. Murray Lung Injury score > 2.5, paO2/FiO2 < 150 mmHg), , one centre u Mean Murray score 3.1 survivors, 3.2 non-survivors (3.4 first 50 adult VV ECMO Glenfield) u Mean PaO2/FiO2: 91+/-29 survivors, 81+/- 46 non- survivors (65 first 50 adult VV ECMO Glenfield)

Recent improved survival in severe ARDS u Abel, Finney, Brett, Keogh, Morgan, Evans: Reduced mortality in association with ARDS. Thorax 1998; 53: u 66% survival in moderate to severe ARDS 78 patients at Brompton Hospital (vs 34% survival in 41 patients ) u mean Murray score 2.8, mean PaO2/FiO2 90 mmHg u mean Murray score 2.8, mean PaO2/FiO2 90 mmHg/12 kPa (First 50 adult VV ECMO patients Glenfield Hospital, Leicester, : Murray lung injury score 3.4, PaO2/FiO2 65 mmHg, ( 66% survival)

Improved survival in severe ARDS with protective ventilatory strategies: u Amato, Barbas, Medeiros et al : Effect of a Protective-Ventilation Strategy on Mortality in ARDS. NEJM;1998;338: u 53 patients, two ICU’s in Brazil, , early ARDS extrapulmonary organ failures u 62% 28 day survival with protective ventilation (n = 29, mean PaO2/FiO2 112, mean LIS 3.4) mean PEEP 16 >> 13, Vt < 6 ml/kg ( ml), pressure limited ventilation with peak pressure < 30 cmH2O, permissive hypercapnoea u vs 29% survival and more deaths from progressive respiratory failure in low PEEP high Vt (12 ml/kg) group

Improved survival in severe ARDS with protective ventilatory strategies: u The ARDS Network: Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and ARDS. NEJM 4 May 2000;342: u 861 patients in 10 US university centres ALI/ARDS, ie. paO2/FiO2 < 300 mmHg, 80% < 200, mean 136 u 69% survival and less ventilator days with 6ml/kg tidal volume (mean paO2/FiO2 u 60% survival with 12 ml/kg Vt u 22% mortality difference, P = u No data on subgroup with paO2/FiO2 < 100)

Estimated mortality of most severe ARDS (paO2/FiO2 < 100 mmHg): u US: NIH ARDSnet database: 70 % u UK: u Intensive Care National Audit & Research Centre (ICNARC): 62% (1506 patients with paO2/FiO2 < 100 mmHg) u Phone survey Glenfield/Heartlink ECMO centre: ~ 72% mortality in patients referred for but not receiving ECMO (no bed/staff)

VASILYEV (1995) Chest 1995;107: u International multicentre prospecttive study of hospital survival in acute respiratory failure defn /Fio2 0.5 for >24hrs u 1426 patients from 25 centres (USA11; Europe 14) u Overall survival 55% u Survival only 33% in hypoxic and hypercarbic pts ie more like ECMO pts

We need another ECMO trial !

CRITERIA FOR ACCEPTANCE u Age <65 years u Reasonable long term outlook u No contraindication to anticoagulation u IPPV < 7 days u Reversible pathology u Optimum conventional treatment tried

Inclusion Criteria  Potentially reversible respiratory failure  Murray score > 3.0  hypercapnoea pH <7.20  aged years

Inclusion Criteria  duration of high pressure and high FIO 2 ventilation < 7 days  no contra-indication to limited heparinisation  no contra-indication to continuation of active treatment

Sample Size  Assuming a 10% risk of severe disability among survivors in both trial arms   = 0.05 (2 sided test)   = 0.2  Sample size of 120 patients in each group would be required to detect a reduction in the rate of primary outcome from 73% to 55%

CESAR Trial: Conventional Treatment u “.. Any treatment which relies on the patient’s lungs to provide gas exchange…” u Can include any treatment modality thought appropriate by patient’s intensivist, eg prone, NO, HFOV u Low (6ml/kg) tidal volume strategy (as in ARDSnet trial) and PIP < 40 cmH2O recommended, but not mandatory u Not standardized (no consensus) u (Analogous to UK Neonatal ECMO trial)

CESAR Trial: Outcome measures u Primary: death or severe disability at six months u Secondary: - Nature and duration of ventilation and other organ system support - Length of ICU and hospital stay - Blood product use - Cost/cost effectiveness to health and social services, patients and their families (by methods adopted from neonatal ECMO trial)

CESAR TRIAL: Potential Referring/conventional treatment hospitals - so far: 28 u Bristol Royal Infirmary u St James Leeds u Royal Liverpool University Hospitals (3) u University of WalesCardiff u South Manchester u Royal Infirmary, Edinburgh u Morriston, Swansea u North Devon District u Gloucester Royal u Walsgrave u Queen Elizabeth, Gateshead u Royal Chesterfield u Derby Royal Infirmary u Derby City u Milton Keynes General u Crosshouse, Kilmarnock u Pilgrim, Boston u Cheltenham u Queen’s, Burton-on Trent u Llandough, Penarth u Macclesfield u North Staffordshire, Stoke-on- Trent u Wrexham Maelor u West Suffolk u Chase Farm, Enfield

CONCLUSIONS. u ECMO with lung rest is a rational treatment. u Survival with conventional treatment remains poor in most centres. u Only an RCT can determine the best treatment.

Ventilation with lower tidal volumes for acute lung injury and the acute respiratory distress syndrome The Acute Respiratory Distress Syndrome Network N Engl J Med 2000;342: u 6ml/Kg (PIP<30) vs. 12ml/Kg (PIP<50) u 861 patients u Age vs u PaO 2 /FIO vs

RESULTS u TV vs ml/kg u PIP vs cm/H 2 O u Mortality 31.0% vs. 39.8% (p=0.007) u Days without organ failure also lower (p=0.006) Ventilation with lower tidal volumes for acute lung injury and the acute respiratory distress syndrome The Acute Respiratory Distress Syndrome Network N Engl J Med 2000;342:1301-8

Adult ECMO, PATIENT STATUS AT REFERRAL. u PaO 2 /FIO 2 65mmhg u Murray Score=3.4 u Time Vent=76.5 hrs u Time on 100% O 2 = 14 hrs. u PAP = 39.6 cmH 2 O. u PEEP = 10 cmH 2 O. u MV = 12.6 L/min. u MAP = 82 mmHg. u MPAP = 29 mmHg. u CVP = 12 mmHg. u PAWP = 12 mmHg. u CO = 127 ml/kg/min. u UO = 1.4 ml/kg/hr. u Age = 30.1 yrs. u Wt = 71.9 Kg. u Hb = 10.8 Kg.

COST IMPLICATIONS OF ECMO u Median length of stay of adult ECMO pts is 14 days (range 0-41days). ELSO recommend 2:1 specialist to patient ratio u Daily cost for conventional care for severe respiratory failure is £1500 -£2300 (Sheffield Health care costing system) u Total cost per case £ £63000

ECMO FOR CARDIAC SUPPORT

Cardiac ECLS at Glenfield u 40 pediatric cardiac u 10 adult cardiac

Adult Cardiac ECLS DIAGNOSES u Post op MVR u Pulmonary Emboli (2) u Loefflers syndrome u CABG (2) u Viral Myocarditis u Pericardectomy u septic shock post removal of infected pacing wire / vegative mass u Post infarct VSD

Cardiac ECLS at Glenfield u Between July 1991 and Sept 1998 u 505 patients received ECMO u 152 adult respiratory u 182 neonatal respiratory u 121 pediatric respiratory

Adult Cardiac ECLS u 10 patients, 5 survived u age 39.6 (19) u Run time 188 (220) hours u PaO2/FIO2 = 81 (20) mmHg

CESAR