The ARDSnet and Lung Protective Ventilation: Where Are We Today

The ARDSnet and Lung Protective Ventilation: Where Are We Today 4-16-12 RCSW Bob Kacmarek PhD, RRT Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

Conflict of Interest Disclosure Robert M Kacmarek I disclose the following financial relationships with commercial entities that produce healthcare-related products or services relevant to the content I am presenting: Company Relationship Content Area Newport Medical Consultant Mechanical Ventilation Bayer Consultant Aerosol Therapy KCI Consultant Patient Positioning Hamilton Honorarium/Lecturing Mechanical Ventilation Maquet Honorarium/Lecturing Mechanical Ventilation Hollester Research Grant Airway Care Covidien Research Grant Mechanical Ventilation

Hickling ICM 1990; 16:216 50 ARDS patients Mortality: actual 16%, predicted 40% SIMV, volume targeted P I P < 40 cmh 2 O V T as low as 5 ml/kg PaCO 2 averaged about 60 mmhg PEEP 9 + 6 cmh 2 O, F I O 2 < 0.60

Mechanical Ventilation Biochemical Injury Biophysical Injury Distal Organs Affected MSOF Slutsky, Tremblay AJRCCM 1998;157:1721

ARDSnet NEJM 2000;342:1301 A V T of 6 ml/kg PBW results in a lower mortality than a V T of 12 ml/kg PBW Mortality 31% vs. 39.8% p = 0.0054

Mortality vs Day 1 Plateau Pressure NIH Trial of 6 vs 12 ml/kg Tidal Volume

Gajic CCM 2004;32:1817

Main risk factor for ALI large V T (OR 1.3 for ea ml above 6 ml/kg PBW p < 0.001 Transfusion blood products (OR 3.0, p<0.001) Acidemic ph < 7.35 (OR 2.0 p=0.32) Gajic CCM 2004;32:1817

Plateau Pressure NOT V T End inspiratory over distension primary cause of VILI Transpulmonary pressure best indicator of over distension TPP = Pplat - Ppleural The best clinical indicator of TPP is plateau pressure not tidal volume

Impact of Plat/V T on Mortality in ARDS P PLAT < 30 cmh 2 O, mortality reduced Lower the P PLAT, better the outcome RR limit based on autopeep, up to 40 or greater? P PLAT > 30 cmh 2 O, V T 4-5 ml/kg P PLAT 25 to 30 cmh 2 O, V T 6 ml/kg P PLAT < 25 cmh 2 O V T 6-8; if patient has a strong ventilatory demand, better to allow a little larger V T then to heavily sedate and force a very low V T! Kacmarek (Editorial) RC 2005;50:1624-1616

Ranieri JAMA 1999;282:54 Impact of a LPVS on pulmonary and systemic inflammatory mediator response in ARDS Cont: V T 11.1+1.3 ml/kg, PEEP 6.5+1.7 cmh 2 0 P flex : V T 7.6+1.1 ml/kg, PEEP 14.8+2.7 cmh 2 0 Outcome: pulmonary and systemic inflammatory mediator response attenuated in the treatment group 28 day Mortality 38% P flex vs. 58% Control, NS

ALVEOLI: PaO 2 = 55-80 mmhg or SpO 2 = 88-95% Control PEEP 5 5 8 8 10 12 14 16-18 20-24 FiO 2.3.4.4.5.5-.7.7.7-.9.9 1.0 Higher PEEP PEEP 12 14 14 16 16 18 20 22 24 FiO 2.3.3.4.4.5.5.5-.8.8-.9 1.0

ALVEOLI - Mortality Before Hospital Discharge Unadjusted p=0.56 Adjusted p= 0.44 25.1 27.2 27.6 24.9 Low PEEP High PEEP Low PEEP High PEEP

Villar, Kacmarek et al CCM 2006;34:1311 RCT severe ARDS P/F < 200 mmhg : High PEEP, Low V T vs. Low PEEP, Moderate V T Control: V T 9-11 ml/kg PBW, PEEP > 5 cmh 2 O Treatment: PEEP P flex + 2 cmh 2 O, V T 5-8 ml/kg PBW Targets: PCO 2 35-50 mmhg, PO 2 70-100 mmhg PCO 2 managed by respiratory rate Treatment: decreased oxygenation - increase PEEP; increased oxygenation - decrease F I O 2

Villar, Kacmarek et al CCM 2006;34:1311 CONTROL TREATMENT n = 50 n= 53 Mortality 54% Mortality 30% As a result of a randomization problem in one center identified after termination of the study during manuscript revision data from that center had to be eliminated n =45 n = 50 Mortality 53.3% Mortality 32% p = 0.04 (0.017)

EXPRESS Mercat JAMA 2008 RCT High vs. Low PEEP, P/F < 300 mmhg regardless of PEEP or F I O 2 All 6 ml/kg PBW Min Alveolar distension PEEP 5 to 9 cm H 2 O Max PEEP V T set than PEEP to Pplat 28 to 30 Stopped early for futility: 382 vs. 385 pts PEEP 6.9 vs. 14.5 cmh 2 O, Pplat 21 vs. 28 cmh 2 O Mortality 28 days 31.2 vs. 27.8% P = NS Ventilator free days 9.5 + 9.4 vs. 8.1 + 9.1, p < 0.03 Prone or NO and organ failure free days, p < 0.01

LOV Meade JAMA 2008 RCT High (n=457) vs. Low PEEP (n=502), P/F < 250 mmhg regardless of PEEP and F I O 2 All 6 ml/kg PBW Control ARDSnet protocol PA/C, RM, PEEP/F I O 2 table PEEP 14.6+3.4 vs. 9.8+2.7 cmh 2 O Pplat 28 vs. 25 cmh 2 O Mortality 36.4 vs. 40.4% p =NS Need for rescuer therapy 7.8 vs. 12.0% p < 0.02

Why the Differences in Outcome in Studies Evaluating PEEP in ARDS? Difference in tidal volume between groups! Method of setting PEEP! Alveoli - use of a PEEP/F I O 2 table LOV - use of a PEEP/F I O 2 table EXPRESS PEEP to bring Pplat to 28 to 30 CWP Ranieri -P-V curve Amato - P-V curve Villar - P-V curve Patients enrolled into study ALI vs. ARDS

Villar, Kacmarek AJRCCM 2007;176:795 Overall mortality 34.1% (n = 58) 24 hrs PEEP > 10 cmh 2 O, F I O 2 > 0.05 ARDS n=99, P/F 155.8 +29.8 mmhg ICU mortality 45.5% (45) ALI n=55, P/F 246.5+25.6 mmhg ICU mortality 20% (11) ARF n=16, P/F 370+54 mmhg ICU mortality 6.3% (1) p=0.0001

Criteria for Study Entry ALVEOLI and LOV P/F < 300 mmhg, EXPRESS P/F < 250 mm Hg, no PEEP or F I O 2 criteria (AECC) Ranieri P/F < 200 mmhg, no PEEP F I O 2 or criteria Amato P/F < 200 mmhg P/F of enrolled patients 126+43, PEEP 9 cmh 2 O, F I O 2 > 0.5 Villar P/F < 200 mmhg, then standard ventilator setting : V T 10 ml/kg, PEEP > 5 cmh 2 O, F I O 2 > 0.5, 24 hr later on standard ventilator settings P/F still < 200 mmhg

Phoenix Anes 2009;110:1098

Phoenix Anes 2009;110:1098

The Unrecruited Lung Higher pressure to ventilate Higher F I O 2 to oxygenate Increased likelihood for infection Decreased surfactant function Increased inflammatory mediator response

RM in ARDS Amato NEJM 1998 ;338:347 Peloci AJRCCM 1999;159:872 Lapinski ICM 1999; 25:1297 Foti ICM 2000;26:501 Medoff CCM 2000;28:1210 Richard AJRCCM 2001;163:1609 Lim CCM 2001;29:1255 Crotti AJRCCM 2001;164:131 Brower AJRCCM 2001;163:A767 Richards J ICM 2001;16:193 Patronili Anes 2002;96:788 Grasso Anes 2002;96:795 Villagra AJRCCM 2002;165:165 Tugrul CCM 2003;31:738 Kamal Respir Care 2006 Borges AJRCCM 2006 Toth CCM 2007;35:787

Borges, Kacmarek, Amato et al AJRCCM 2006

Borges, Kacmarek, Amato et al AJRCCM 2006

Borges, Kacmarek, Amato et al AJRCCM 2006

Gattinoni NEJM 2006;354:1775 68 pts with ARDS /ALI in which recruitable lung was evaluated at 5, 15 and 45 cmh 2 O using CT scan Recruitment varied considerably, accounting for 13+11% of the lung weight. On average 24% of the lung could not be recruited. Pts with a higher % of recruitable lung (median > 9%) had higher lung wt (p=0.002), poorer oxygenation p < 0.001), poorer compliance (p = 0.002), higher levels of DS (p = 0.002) and a higher death rate (p = 0.02)

Gattinoni et al NEJM 2006;354:1775

Gattinoni NEJM 2006;354:1775 RM at PIP 45 cmh 2 O, PEEP 5 cmh 2 O, rate 10/min, I:E 1;1 for 2 min After RM patient randomized to 5 or 15 cmh 2 O PEEP. CT at 45 cmh 2 O during an end-inspiratory pause of 15 to 25 second thereafter at a PEEP of 5 and 15 cm H 2 O during a 15 to 25 sec end-expiratory pause Length of ventilation before study 5+6 days

Setting PEEP PEEP/F I O 2 algorithm either stated or unstated Increasing PEEP trial Oxygenation Lung Mechanics Cardiovascular Stability Pressure Volume Curve (P flex ) Decremental PEEP Trial

Suarez-Sipmann CCM 2007;35:214

Suarez-Sipmann CCM 2007;35:214

Tugrul CCM 2003;31:738 P/F (mmhg) Baseline 15 min 6 hr ARDS p 105+32 173+75 164+57 ARDS exp 121+27 210+12 236+93 PEEP (cmh 2 O) Before RM After RM ARDS p 9.6+3 15.6+2.5 ARDS exp 10.3+3.6 16.7+2.3 F I O 2 Baseline 15 min 6 hr ARDS p 0.80+0.2 0.74+0.2 0.62+0.15 ARDS exp 0.82+0.2 0.77+0.2 0.56+0.13

350 300 *# 250 200 P/F 150 * * * * 100 50 0 BL PRE RM POST RM PEEP 1 HR 4 HR F I O 2 0.54 1.00 1.00 0.375* 0.375* 0.375* PEEP 11.9 11.9 20 9.1 9.1 9.1 ±3.0 ±3.0 ±4.7 ±4.7 ±4.7 Kamal Respir Care 2006

Relative Contraindications Preexisting pulmonary cysts Preexisting bulbous lung disease Preexisting barotrauma Hemodynamic instability Unilateral/localized lung disease

Performance of RM Set F I O 2 at 1.0 Allow time for stabilization Insure appropriate sedation Insure hemodynamic stability

18 patients with ARDS RM 40/40 followed by a decremental PEEP trial form 26 cm H 2 O PEEP No change in EVLW CI decreased during RM but no change in HR, CVP, or MAP Toth CCM 2007;35 :787

Monitoring during RM Set guidelines for aborting the RM, for example: MAP < 60 mmhg or decreases by > 20 mmhg SpO 2 < 88% Heart rate >130 or < 60/ minute New arrhythmias

Performance of RM - PCV Pressure control ventilation, F I O 2 1.0: PEEP 20-30 cmh 2 O Peak Inspir Press 40-50 cmh 2 O Inspir Time: 1 to 3 sec Rate: 8 to 20/min Time 1 to 3 min Initial RM PEEP 20 to 25 cmh 2 O, PIP 40 cmh 2 O Set PEEP at 20, ventilate VC, V T 4 to 6 ml/kg PBW, increase rate, avoid auto-peep Measure dynamic compliance Decrease PEEP 2 cm H 2 O

Performance of RM - PCV Measure dynamic compliance Repeat until max compliance determined Optimal PEEP max comp PEEP+2 cm H 2 O Repeat recruitment maneuver and set PEEP at the identified settings, adjust ventilation After PEEP and ventilation set and stabilized, decrease F I O 2 until PO 2 in target range If response is poor, repeat RM, PEEP 25, Peak Pressure 45 If response is poor, repeat RM, PEEP 30, Peak Pressure 50

Stoker Chest 1997;111:1008

Sud ICM 2010;36:585

Chatte AJRCCM 1997;155:437 294 periods of prone positioning 2 apical atelectasis 1 IV catheter loss 1 IV catheter compression 1 extubation 1 transient supraventricular tachycardia

High Frequency Oscillation Arnold et al CCM 2000;22:1530 Derdak AJRCCM 2002;166:801 Shah ICM 2004;30:S84 Bollen Critical Care 2005;9:R430 Samransamruajkit Asian Pac J Allergy Immunol 2005;23:181 Mentzelopoulus ICM 2007;33:S142 All Negative RCT s CMV vs. HFO equivalent No data to indicate rescue use of HFO improves outcome!! If you prefer HFO use it immediately after intubation!

Derdak AJRCCM 2002;166:801 Summary of Ventilator Strategies CV(PCV) HFO VT ml/kg ABW 6-10 ------ RR per min or Hz Max 35 5(3-8) PEEP cmh2o 10-18 ------- mpaw cmh2o ------ CV+5 (max45) Delta P cmh2o ------ CW vibration % Inspir time 33-66% 33% HFO used cuff leak to improve ventilation HFO to CV when mpaw < 24cm H2O, FIO2 < 0.5

Primary Outcome: Status at 30 Days HFOV CV P value CI N 75 73 Alive no 27 (36%) 23 (31%) P=0.686-12 to 22% mechanical ventilation Alive on 20 (26%) 12 (16%) P=0.190-4 to 24% mechanical ventilation Dead 28 (37%) 38 (52%) P=0.102-32 to 2%

Bollen Crit Care 2005;9:R430 RCT HFO vs. CMV 61 patients stopped early for enrollment problems No significant difference for any outcome variablies Mortality HFO 33% vs. CMV 23% VT 8-9 ml/kg PBW and plateau pressure above 30 in many patients

Sud BMJ 2010;340:2327

The ARDSnet and Lung Protective Ventilation: Where Are We Today P PLAT < 30 cmh 2 O, mortality reduced Lower the P PLAT, better the outcome RR limit based on autopeep, up to 40 or greater? P PLAT > 30 cmh 2 O, V T 4-5 ml/kg P PLAT 25 to 30 cmh 2 O, V T 6 ml/kg P PLAT < 25 cmh 2 O V T 6-8 ml/kg Recruit the lung before setting final PEEP PEEP ALI 8 to 15; ARDS 12 to 20 cm H 2 O Prone positioning P/F < 100 mmhg HFO Still questionable benefit???

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