Acute Respiratory Distress Syndrome

Allan Wardhaugh

Definition Aetiology Pathophysiology and CT work Molecular pathophysiologyConventional ventilation strategies Advanced treatments HFOV Surfactant iNOProne postioningSteroids

Definition (2012)Acute onset of respiratory symptoms (within 7days of trigger illness)CXR or CT chest with bilateral infiltratesnot fully explained by cardiac failure or fluid overload PaO2/FiO2:

200-300 mmHg mild100-200 mmHg moderate<100 mmHg severe

Acute Respiratory Distress SyndromeThe Berlin DefinitionThe ARDS Definition Task Force*JAMA. 2012;307(23):2526-2533. doi:10.1001/jama.2012.5669.

Aetiology Pulmonary

Infective pneumonia Aspiration pneumonia

Extra-pulmonary Trauma Sepsis Burns Other causes of SIRS

CT studies Demonstrate dependent oedema Shows heterogeneity of lung appearances Proportion of recruitable lung small

Gattinoni et al. Am J Respir Crit Care Med 2001; 164:1701-1711¡�

CT scan through the carina 5 d after severe trauma shows diffuse groundglass opacification, right greater than left. There is a nondependent to dependent gradient. Incidentally noted is pneumomediastinum and achest tube draining a pneumothorax

Seven days later, there is partialclearing of both the diffuse ground glass opacification and the gravity-dependent atelectasis. The pneumomediastinum is almost completely resolved.

Five days later, ground glass opacificationhas a more reticular pattern. There is now a pneumatocele in the left midlung and increasing atelectasis adjacent to it.

Fluid distribution

Molecular pathophysiology

Ventilation causes inflammation

Rat lungs (removed from body) ventilated for 2 hours at one of : -

Vt 7ml/kg, PEEP3Vt 15ml/kg, PEEP 10Vt 15ml/kg, PEEP 0Vt 40ml/kg PEEP 0

BAL fluid analysed for TNF α, IL 1β, IL 10.Inflammatory cytokines higher in lungs with no PEEP and highest in high tidal volume

Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J ClinInvest 1997; 99: 944-952

Ventilation strategies

PEEP Low tidal volume Permissive hypercapnia

Inflation pressures Volume

Optimum PEEP

Inflection point

Pressure

PEEP good, overdistension bad PIP 14 PIP 30 PIP 45

PEEP 0No lung damage

Perivascularoedema

Severe alveoalaroedema,

death by 1 hour

PEEP 10 Perivascular

oedema

Perivascularoedema, but no alveolar oedema -survived

Webb HH, Tierney DF. Am Rev Respir Dis 1974; 110: 556-565

Tidal volume vs pressure Rat model ventilated with 5 strategies: -

Low Volume, low pressure (controls) Low volume, high pressure (chest and abdomen strapped) High pressure (45cm), High volume (40ml/kg) High pressure with PEEP 10cm, volume 25ml/kg High volume, low pressure (iron lung).

Ventilation at high volume, irrespective of pressure produces pulmonary oedema and alveolar cell damage. Pressure on its own does not cause damage

Low tidal volume improves outcome?

Tidal volumes 5ml/kg, PIP < 40, permissive hypercapnia

Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 1990; 16: 372-377

Yes, low tidal volume improves outcome

Vt 6ml/kg vs 12ml/kg, PIP < 30, Sats 88% -95%. pH 7.3-7.45 Relative improvement in mortality 22%. Number needed to treat 11.4.

The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308¡

Ultra-low tidal volumes - HFOV Vt 1-3ml/kg Minimal pressure swings

HFOV improves outcome in children….

Prospective MCRCT . N=58. HFOV vs CMV (cross-over allowed). 12 dropouts. Patients were > 1month, <35kg, OI> 13. 30 day outcomes. FDA have used the results of this trial to allow HFOV in children with OI > 13 for over 6 hours.

HFOV only 83% survive without severe lung diseaseCMV only 30% ″ ″ ″CMV→HFOV 21% ″ ″ ″HFOV→CMV 0% ″ ″ ″

Arnold JH. Hanson JH. Toro-Figuero LO. Gutierrez J. Berens RJ. Anglin DL. Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. Critical Care Medicine. 22(10):1530-9, 1994

…and adults…

Sud S, Sud M, Friedrich JO et al. High frequency oscillation in patients with acute lung injury and acute respiratorydistress syndrome (ARDS): systematic review and meta-analysis. BMJ 2010;340:c2327

…or does it?OSCILLATE

Ferguson N, Cook DJ, Guyatt GH et al. High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome. N Engl J Med 2013. DOI: 10.1056/NEJMoa1215554

OSCARYoung D, Lamb S, Shah S et al. High Frequency Oscillation for Acute Respiratory Distress Syndrome. N Engl J Med 2013. DOI: 10.1056/NEJMoa1215716

HFOV - OSCILLATE

HFOV - OSCILLATE

HFOV-OSCILLATE

HFOV-OSCAR

HFOV-OSCAR

HFOV-OSCAR

Steroids improve outcome? Randomised double blinded controlled trial Memphis. N = 24. Patients ventilated >7 days with ARDS Methylpred 2mg/kg load IV, then 2mg/kg/day in 6 hourly doses from day 1-extubation or day 14; 1mg/kg 15-21; 0.5mg/kg 22-28; 0.25mg/kg 29-30; 0.125mg/kg 31-32 Trial stopped after interim analysis

Results

Mpred Placebo pICU Mortality 0% 63%

63%

0%

0.02

Hospital mortality 13% 0.03

Extubated by day 10

46% 0.05

Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomised controlled trial. JAMA 1998; 280(8): 159 – 65

ARDS network 2006

180 adult patientsARDS > 7daysRandomised placebo or methylprednisilonePrimary endpoint 60 day mortality

Results

Methylpred Placebo60 day mortality

29.2 % (20.8 to 39.4)

28.6% (20.3 to 38.6)

P = 1.0

180 day mortality

31.5% (22.8 to 41.7)

31.9% (23.2 to 42.0) P = 1.0

Starting methylprednisolone therapy more than two weeks after the onset of ARDS may increased risk of death

The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome. N Engl J Med 2006; 354:1671-1684

NMJ blockade

Papazian L, Forel JM, Gacouin A et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 doi: 10.1056/NEJMoa1005372.

NMJ blockade

iNOOne RCT including children Only briefly increases oxygenation but does not improve outcomes*. Cochrane - 5 RCTs, n = 535. No effect on mortality or ventilator free days. One study showed transient improvement in oxygenation in first 72 hours

Sokol J, Jacobs SE, Bohn D Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults (Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software.

*Macrae D et al. Inhaled nitric oxide therapy in neonates and children: reaching a European consensus. Intensive Care Medicine 2004; 30:372-380

iNO - mode of ventilation may be important

Dobyns EL, Anas NG, Fortenberry JD, Deshpande J, Cornfield DN, Tasker RC, Liu P, EellsPL, Griebel J, Kinsella JP, Abman SH. Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics. Crit Care Med. 2002;30: 2425-9.

Surfactant ARDS causes abnormalities in surfactant production and recycling Initial studies showed poor effect aerosolised surfactant used.Pilot study adults

bovine surfactantRCT (non-blinded) 50mg/kg 4 doses; 100mg/kg 4 doses; 100mg/kg 8 doses N = 59 100mg/kg 4 doses showed sustaine dimprovement oxygenation 120 hours Mortality 18.8% (surf) vs. 43% (control) p=0.07

Gregory TJ. Steinberg KP. Spragg R. Gadek JE. Hyers TM. Longmore WJ. Moxley MA. Cai GZ. Hite RD. Smith RM. Hudson LD. Crim C. Newton P. Mitchell BR. Gold AJ. Bovine surfactant therapy for patients with acute respiratory distress syndrome. American Journal of Respiratory & Critical Care Medicine. 155(4):1309-15, 1997

Surfactant - Children RCT, n = 35. 44/40 - 14 yrs, ventilated 12 - 120 hours 100mg/kg bovine surfactant PaO2: FiO2 improved at 48hours if patients had extra-pulmonary ARDS and initial PaO2: FiO2 >65 Study stopped because of recruitment difficulties

Moller JC. Schaible T. Roll C. Schiffmann JH. Bindl L. Schrod L. Reiss I. Kohl M. Demirakca S. Hentschel R. Paul T. Vierzig A. Groneck P. von Seefeld H. Schumacher H. Gortner L. Surfactant ARDS Study Group. Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study. Intensive Care Medicine. 29(3):437-46, 2003

Prone positioning improves oxygenation….

…but not survival (adults)

Gattinoni L., Tognoni G., Pesenti A., Taccone P., Mascheroni D., Labarta V., MalacridaR., Di Giulio P., Fumagalli R., Pelosi P., Brazzi L., Latini R., the Prone–Supine Study Group. Effect of Prone Positioning on the Survival of Patients with Acute Respiratory Failure. N Engl J Med 2001; 345:568-573, Aug 23, 2001

Prone positioning - childrenUncontrolled pilot study 25 paediatric patients 2 months - 17years with ALI/ARDS. Early and repeated prone positioning for median 4 days. 21/25 decreased OI by >10% and improved PaO2/ FiO2 ratios 20mmHg No serious adverse events, but 25% had pressure sores from prone positioning.

Curley MA. Thompson JE. Arnold JH. The effects of early and repeated prone positioning in pediatric patients with acute lung injury. Chest. 2000; 118:156-63

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yARDS prognosis (adults)

J. A. Milberg, D. R. Davis, K. P. Steinberg, and L. D. Hudson. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993 JAMA, Jan 1995; 273: 306 – 309.

ARDS prognosis (adults)ARDS Severity PaO2/FiO2 Mortality

Mild 200 – 300 27%

Moderate 100 – 200 32%

Severe <100 45%

ARDS prognosis - children

Peters MJ, Tasker RC, Kiff KM, Yates R, Hatch DJ. Acute hypoxaemic respiratory failure in children: case mix and the utility of respiratory severity indices. Intensive Care Med 1998; 24: 699 – 705

SummaryARDS is a dynamic process

Ventilation at low tidal volumes improves outcomes in adults

Some evidence that HFOV improves outcomes in children

Steroids don’t improve mortality in prolonged ARDS in adults

Other strategies improve physiological end points but do not improve survival

Prognosis has improved in adults

Prognosis in children closely related to underlying cause and presence of multi-organ failure