The PHARLAP Study
A Multi-centre RCT of An Open Lung Strategy including Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure in The PHARLAP Study Investigators for the ANZICS Clinical Trials Group
PHARLAP Study Aim To compare PHARLAP Open Lung Ventilation PH Permissive Hypercapnia AR Alveolar Recruitment (staircase RM) LAP Low Airway Pressures With Standard mechanical ventilation (ARDSnet)
PEEP + Recruitment Trials ALVEOLI LOVS EXPRESS Number 549 985 768 PEEP 8.3 13.2 9 14 7 14 Plateau press 24 27 24 28 21 28 Recruitment 35-40 for 30 (80 pt) 40 for 40 No RM Mortality 28% 25% 40% 36% 39% 36% P value not significant not significant not significant
Meta-analyses ALI/Hi'PEEP' Number' Hosp'Mortality' P'value! ALI!(all)! 2272! 35.2 32.9%! 0.25! ARDS! 992! 39.1 34.1%! 0.05! No!ARDS! 404! 19.2 27.2%! 0.07!!!! Briel JAMA 2010;303:865-83 Amato'2'unpublished'meta=analysis' Mortality'' P'value
Meta-analyses ' Amato'LOVS're=analysis' Mortality'' P'value ' ' ' RM,!Hi!PEEP,!Compl!!!!!<0.05!! RM,!Hi!PEEP,!Compl!!!!! ' ALI'Recruitment' P/F' Mortality
Research Program
PHARLAP Pilot Study
Pilot Study!PaO 2 /FIO 2!!(P=0.005)!Compliance!!!!(P<0.001) Hodgson C, Nichol A, Tuxen D, Davies A, Cooper J, et al.
Pilot Study PHARLAP Control P!value (10!pa>ents) (10!pa>ents) Hospital!mortality 3 2 0.61 ICU!LOS!(days) 9.9!(5.6814.8) 16.0!(8.1819.3) 0.19 Hospital!LOS!(days) 17.9!(13.7834.5) 24.7!(20.5839.8) 0.16 Dura>on!of!MV!(hrs) 180!(878298) 341!(1318351) 0.13 Rescue!Therapies 0 2 0.46 SOFA!(day!7) 8.6!±!0.3 8.4!±!0.6 0.27 Barotrauma 0 0 1.0 Hodgson C, Nichol A, Tuxen D, Davies A, Cooper J, et al.
Pilot Study PHARLAP Control P!value (10!pa>ents) (10!pa>ents) Hospital!mortality 3 2 0.61 ICU!LOS!(days) 9.9!(5.6814.8) 16.0!(8.1819.3) 0.19 Hospital!LOS!(days) 17.9!(13.7834.5) 24.7!(20.5839.8) 0.16 Dura>on!of!MV!(hrs) 180!(878298) 341!(1318351) 0.13 Rescue!Therapies 0 2 0.46 SOFA!(day!7) 8.6!±!0.3 8.4!±!0.6 0.27 Barotrauma 0 0 1.0 Hodgson C, Nichol A, Tuxen D, Davies A, Cooper J, et al.
'Research Question In ARDS patients, Does the Open Lung Strategy Increase ventilator free days (VFDs) at day 28 When compared with standard mechanical ventilation?
Methods Phase II RCT 340 patients ARDS < 48 hrs (but < 5 days of MV)
Sites Albury Wodonga Alfred Austin Bendigo Blacktown Box Hill Canberra Epworth Richmond Flinders Geelong Gold Coast John Hunter Lyell McEwin Nambour Northern Prince Charles Royal Darwin Sir Charles Gairdner St George St Vincent s Sydney Western Woolongong Christchurch CVICU Auckland DCCM Auckland Middlemore Wellington
Study Leadership Project Manager Victoria Bennett victoria.bennett@monash.edu Management Committee Andrew Davies (Co-Chair) Michael Bailey Jamie Cooper Lisa Higgins Shay McGuinness Rachael Parke Alistair Nichol (Co-Chair) Andrew Bersten John Fraser Carol Hodgson Lynne Murray David Tuxen
Outcome Measures Primary VFD at day 28 Secondary Physiological/inflammatory - Oxygenation, lung compliance - IL-6/IL-8 in blood/tracheal aspirates Clinical - Safety, LOS (ICU, hospital), mortality, - Use of rescue therapies - HRQoL 6mths Economic
Control Group Strategy Mechanical Ventilation: VCV assist control ventilation (or SIMV if required) Tidal volumes 6 mls/kg PBW Plateau pressures 30 cmh 2 O RR < 35 breaths/min Early spontaneous breathing using PSV allowed (careful tidal volumes) Neuromuscular blockers if required Oxygenation: Target oxygenation SpO 2 90-95% PaO 2 60-80 mmhg Oxygenation maintainenance using the PEEP/FiO 2 Chart FiO 2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18V24 Management of Acidosis and Hypercapnia: ph goal for control patients: ph 7.30-7.45
PHARLAP Group Strategy Combined Open Lung Procedure (up to 5 days): PCV Staircase recruitment manoeuvre PEEP titration manoeuvre Brief recruitment manoeuvre Ongoing PHARLAP mechanical ventilation: Tidal volume: 4-6 ml/kg PBW Total pressure (ie. inspiratory pressure + PEEP): 25-28 cmh 2 O Breath rate: 35 breaths/minute Leave PEEP on optimal setting unless weaning or a problem Target oxygenation SaO 2 90-95% (daily precise target) PaO 2 60-80 mmhg Brief recruitment manoeuvre if SaO 2 2% below the target Permissive hypercapnia: Breath rate aiming for a low ph in the range of 7.15-7.30 Tidal volume can be reduced Hypercapnia should be tolerated if ph 7.15
Severe Hypoxaemia Control Group: If PaO 2 < 60 mmhg or SaO 2 < 90% on 4 end columns PHARLAP Group: If PaO 2 < 60 mmhg or SaO 2 < 90% and brief recruit man done/contra-indicated Hypoxaemic rescue therapy: Inhaled NO Inhaled prostacyclin Prone positioning High frequency oscillation ECMO Choice depends on local practice, availability, feasibility No recruitment manoeuvres in control group unless no feasible alternative
Recruitment Manoeuvre Contra-indications MAP < 60 mmhg despite attempts to augment (vasopressor/fluid) Active air leak through intercostal catheter Pneumatoceles, subpleural cysts, pericardial/mediastinal emphysema on CXR Subcutaneous emphysema not related to trauma, surgery or ICU procedures SVT with MAP < 70 mmhg or Any VT
Fluid Management Day 1 fluid balance aim is what best suits patient s clinical state From Day 2 on, ignore Day 1 and aim to avoid cumulative positive fluid balance Correct unplanned positive fluid balance with fluid restriction +/- diuretics Monitor renal function carefully For hypotension during COLP, preference is vasopressors, then IV fluid
Directional tip for R or L lung samples Can be performed bedside in minutes Maintains PEEP Features a soft, cushioned tip
Two sizes of KimVent BAL Caths 13F is recommended for a size 7cm ETT and smaller 16F is recommended for a size 7.5cm ETT and larger
Preparation Pre-oxygenate: FiO 2 1.0 for 2 minutes Leave PEEP on current setting Draw up 60 ml of 0.9% saline (usually three 20 ml syringes) Prepare clean environment as per usual site practice for similar interventions Connect 0.9% saline syringe to upper port on 3 way tap and point off arrow to other port Ensure the blue locking device is open
Blue locking device
Introduce the BAL catheter by forwarding the catheter through connector B so that the catheter tip protrudes through the connector before connecting to the endotracheal tube Disconnect the in-line suction and ventilator and attach connector B to the endotracheal tube (Fig. 1) the catheter should be 2 cm into the endotracheal tube. Reconnect the ventilator tubing to connector B.
Advance catheter until the numbers on the catheter match the numbers on the endotracheal tube At this point the catheter is located exactly at the distal point of the endotracheal tube
Ensure the white oxygen port on the catheter is orientated to the right. This means that the internal catheter will be angled towards the right main bronchus. Forward the entire catheter another 5 cm and check that the white oxygen port remains orientated to the right side Flush the catheter with 5 ml 0.9% saline. Lock the blue locking device Gently advance the inner catheter until a spongy resistance is noted (ie. the catheter is appropriately wedged in a distal bronchus)
BAL Sample Collection Inject first syringe of 0.9% saline, followed by 5 ml air With same syringe, gently hand aspirate BAL, then do same with subsequent syringes via the 3 way port until a minimum volume of 10 ml is obtained Withdraw inner suction catheter until solid black mark outside connector to ETT Unlock blue locking device. Withdraw entire catheter Reconnect in-line suction catheter and original connectors
BAL Sample Collection Combine collected BAL fluid from each syringe into sterile container Label as BAL for PHARLAP study If patient in PHARLAP group, followed with combined open lung procedure or a brief recruitment manoeuvre as appropriate
Something to think about
PROSEVA Study 474 pts with severe and persistent ARDS 27 ICUs Prone (16 hrs/day) Vs Supine Guerin C, et al. ESICM 2012
PROSEVA Study 474 pts with severe and persistent ARDS 27 ICUs Prone (16 hrs/day) Vs Supine 50.0 37.5 25.0 12.5 Guerin C, et al. ESICM 2012 0 28 day mortality 90 day mortality Prone Supine