ARDS: The Old and the New (-ish)

© The Children's Mercy Hospital, 2014. 03/14

TARA BENTON, MD MSCIPediatric Intensivist

Children’s Mercy Hospitals and ClinicsJune 27, 2014

Pediatric ARDS: the old and the new(-ish)


Disclosures

• none


Objectives

• Review history of ARDS

• Define acute lung injury and acute respiratory distress syndrome

• Discuss the epidemiology of pediatric ARDS

• Review relevant pathophysiology

• Discuss ventilator induced lung injury in the context of ARDS

• Discuss available treatment modalities

– In the context of pathophysiology

– Overview of research


What I want you to get out of this talk…

• ARDS is a very heterogeneous disease which makes it difficult to study

• Many studies have been performed (mainly in adults) BUT

– ONLY LUNG PROTECTIVE VENTILATION HAS BEEN ACCEPTED AS STANDARD THERAPY AND HAD MORTALITY BENEFIT

• Reducing iatrogenic harm is important

• Children are not small adults

• If you want to do an RCT that people remember, you must have a cool acronym


The first description of ARDS?

• 1821 – Laennec (guy who invented the stethoscope) described idiopathic lung anasarca which is pulmonary edema without heart failure in his text ‘A Treatise on Diseases of the Chest’


History Lesson

• 1925 – Sir William Osler – considered cause and pathophysiology in his textbook

– ‘uncontrolled septicemia leads to frothy pulmonary edema that resembles serum, not the sanguinous transudative edema fluid seen in dropsy or congestive heart failure’

• 1967 – “Adult” RDS was initially described by Ashbaugh et al in a case series of 12 patients

– Pao2/FiO2 ratio of <300, diffuse bilateral disease, an identifiable insult within 7 days, Pcwp <18 mmHg

– “A” was changed to acute by a consensus conference in 1994


DefinitionsAcute lung injury and ARDS (acute respiratory

distress syndrome) are sydromes that represent spectrum of lung disease

Hallmarks of this disease – hypoxia, tachypnea, decreased compliance

Histology – diffuse alveolar damage


Definitions1994- American-European Consensus Conference

o ARDS – acute noncardiogenic pulmonary edema with bilateral pulmonary infiltrates on chest x-ray and a ratio of PaO2 to FiO2 of ≤ 200

o ALI – same as above except P/F ratio 200-300o Clinical parameters

Acute onset Severe arterial hypoxemia resistant to oxygen therapy

alone (P/F ratios above) Diffuse pulmonary inflammation No evidence of left atrial hypertension


The Berlin Definition 2011Used consensus data as well as empirical data create “new” ARDS criteria


Epidemiology• ARDS occurs in 1-4% of PICU admissions

– As many as 10% of ventilated pts in PICU meet diagnostic criteria for ARDS

• Mortality 20-75% depending on coexisting conditions and risk factors (immunocompromise, nonpulmonary organ failure)

– Seems to be decreasing since the standard practice of low tidal volume ventilation – have been studies with mortality as low as 11%

– General peds mortality 22-26%

– SCT were found to have mortality rate of >75%

• PEDALIEN: 2012 Spain epidemiology study

– Mortality based on P/F ratio >300 = 0%, 200-300= 11.8%, 101-200 = 20.7%, <100 = 38.5%


Epidemiology of ARDS in children

Pneumonia and sepsis most frequent etiologies identified


Pathophysiology

Etiologies:

• Direct injury – – pneumonia, aspiration

• Regional consolidation from destruction of the alveolar architecture

• Indirect injury – – sepsis, shock, cardiopulmonary bypass, transfusion

related acute lung injury (TRALI), pancreatitis

• Pulmonary vascular congestion, interstitial edema, and less severe alveolar involvement


Alveolar-capillary unit in ARDS

Injury →

Inflammatory response →

Proteinaceous fluid filled alveoli and breaks down the alveolar epithelial barrier →

Thick barrier between alveolus and capillary


PathophysiologyPhases of disease

Exudative (Acute) phase

Acute development of decreased pulmonary compliance and arterial hypoxemia tachypneaProinflammatory state

Fibroproliferative phase

Increased alveolar dead space and refractory pulmonary hypertension may develop as a result of chronic inflammation and scarring of alveolar-capillary unit

Recovery phase

Restoration of the alveolar epithelial barrier, gradual improvement in pulmonary compliance and resolution of arterial hypoxemia and eventual return to premorbid pulmonary function


Diagnosis

• Clinical symptoms

– Hypoxia

– Tachypnea

– Eventual respiratory failure

– Other symptoms depend on inciting injury

• Imaging

– CXR – diffuse alveolar infiltrates, air bronchograms

– CT chest- “ground glass opacities,” consolidation along gravitational axis

• Remember diagnostic criteria for ARDS/ALI


Imaging

CXR


Imaging

CT images


Targets of Therapy

• Decrease mortality and morbidity

• Hasten recovery• Optimize long-term

cognitive and respiratory function– Minimize profound

hypoxia that leads to cell death and damages developing brain

• MINIMIZE HARM


Therapy options• Supplemental O2

• NIPPV

– HFNC

– CPAP/BiPAP

• Invasive ventilation

– Conventional ventilation

– HFOV

• iNO

• Surfactant

• Steroids

• Prone positioning

• Fluid management

• ECMO


Summary of therapy recommendations


Positive Pressure Ventilation

• Optimize oxygenation while minimizing lung injury

– PEEP to maintain FRC above closing volumes throughout the ventilator cycle (atelectatrauma)

– Limit plateau pressure, Pplat (barotrauma)

– Avoid overdistention (volutrauma)

– Limit radical-related injury due to high concentrations of inspired O2

• Permissive hypercapnea

– Allow Pco2 to rise as long as pH >7.25 (?)


Ventilator Induced Lung Injury• Results from injury to

the blood-gas barrier caused by mechanical ventilation

• Overall suggestion of this study, limit tidal volume (<10ml/kg) in patients with or without ARDS

• Lower rates associated with less VILI

NEJM 2013 Ventilator-Induced Lung Injury

NEJM 2013 Ventilator-Induced Lung Injury


Permissive hypercapnea• Goal is to minimize

VILI

• General consensus is that hypercapnea is not harmful

• pH limit usually set somewhere around 7.25

• Acidosis helps unload oxygen from hemoglobin


Lung Protective Ventilation Strategy

ARDS Network of investigators

• the National Heart, Lung, and Blood Institute, National Institutes of Health, initiated a clinical network to carry out multi-center clinical trials of ARDS treatments

ARDS-Net Trial NEJM 2000

• Sentinel article for lung protective ventilation

• Multicenter RCT enrolled 861 patients with ARDS

– Randomized to low tidal volume (6ml/kg) and low Pplat (<30 cmH2o) vs standard of care (12ml/kg and Pplat 50cm)

• Primary outcome mortality: 31% vs 39.8% p=0007

• Stopped early due to clear benefit of low tidal volume


Lung Protective Strategy

• Meta-analysis of multiple RCTs looking at low vs high tidal volume – Cochrane review 2012


Lung Protective Strategy - meta-analysis


So what makes the difference, high PEEP or low PIP (or Pplat)?

ALVEOLI – ARDS Net NEJM 2004

• RCT 549 with ALI/ARDS

– Low (~8) vs high PEEP (~13)

• Constant tidal volume 6ml/kg and Pplat <30

– Primary outcome – mortality – no difference 24.9 vs 27.5


So what makes the difference, high PEEP or low PIP (or Pplat)?

EXPRESS - Mercat JAMA 2008

• Multicenter RCT 767 adults in France with ALI/ARDS P/F <300

– Minimal distention (PEEP and Pplat kept low) vs recruitment strategy (PEEP adjusted based on airway pressure, Pplat kept <30)

– Primary outcome of mortality was not different between the groups

– Secondary outcomes

• Ventilator free days (7 vs 3 p=0.04)

• Organ failure free days (6 vs 2 p= 0.04)

• Higher compliance, better oxygenation, less use of adjunctive therapies, larger fluid requirements


PEEP strategies

LOVS (lung open ventilation study investigators) JAMA 2008

• Compared established low-tidal-volume ventilation strategy vs experimental strategy which combined low tidal volume, lung recruitment, and high PEEP

– 983 adult patients met ARDS criteria

– Mortality 36.4% vs 40.4% ([RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19

– Lower rates of refractory hypoxemia, death with refractory hypoxemia, and previously defined eligible use of therapies


PEEP and mortality

• Oxygenation Response to PEEP Predicts Mortality in ARDS: A Secondary Analysis of the LOVS and ExPress Trials - Hot of the presses- June 11, 2014 in press from AJRCCM

– Evaluated the physiologic response to PEEP (P/F ratio) and mortality

– Decreased mortality noted for those patients with >25mm Hg increase in P/F ratio following increase in PEEP (OR 0.80, 95% CI 0.72-0.89)

• Stronger association with severe ARDS (P/F ratio <150)

– Findings were supported in data sets from 2 studies

• “We hypothesize that this association may be linked through the physiological causal pathway of increased lung recruitment (reflected by improved oxygenation), protecting against VILI, reducing pulmonary and systemic organ failure, and ultimately lowering mortality.”


History of ARDS research in children

• Why hasn’t a similar sentinel trial been performed in children?

– lack of clinical equipoise

• As in all pediatric research, traditional outcome measures (mortality) would require very large sample size for an adequate study

– Mortality 10-15% most recent trials

– To power a study to detect 25% decrease in mortality -> would need over 2,000 patients

• To detect smaller decrease -> more patients

– PALIVE study – feasibility

• 4 years, 60 PICUs to enroll 800 children to use mortality as endpoint

• Pediatric Acute Lung Injury and Sepsis Investigators (PALISI)

– Collaborative group working on directing multicenter efforts

• Most recent outcome measure in pediatric trials (PALISI) = ventilator free days


High Frequency Oscillatory Ventilation (HFOV)

• Ultimate open lung strategy of ventilation

– very low tidal volume (1-2ml/kg/cycle), high mean airway pressure (low PIP)

• Used frequently in pediatrics (adopted from NICU)

• Early data in adults indicated that HFOV might be beneficial (however this was compared to high tidal volume conventional ventilation)

• Only one crossover trial in pediatrics (Arnold, et al CCM 1994) comparing rescue HFOV with conventional ventilation

– HFOV associated with higher MAPs, improved oxygenation, reduced need for O2 at 30 days


HFOV vs conventional ventilation

• In adults, two recent RCTs of HFOV vs low tidal volume high PEEP published in the NEJM demonstrated no mortality benefit and in one of the trials may have shown harm (higher mortality)

– OSCILLATE – multicenter RCT – 39 ICUs in 5 countries

• Moderate to severe ARDS (P/F ratio <200, FiO2 >0.5)

• HFOV targeting lung recruitment vs conventional ventilation targeting lung recruitment (low tidal volume, high PEEP)

• Primary outcome in-hospital mortality: HFOV 47% vs 35% (RR of death 1.33 with HFOV CI 1.09 to 1.64; p=0.005)

• Stopped early

• Should we be reconsidering our “lung protection”


Open Lung Ventilation – adverse effects

• Important hemodynamic considerations

– Increases intrathoracic pressure

• Decrease venous return to right atrium (preload) – lead to low cardiac output

• Support this with fluid, inotropes might be necessary

– Depending on how high MAP, might need muscle relaxation


Prone positioning

Goal of prone positioning is to improve V/Q matching.


Prone positioning

• Curley, et al. JAMA 2005

– Multicenter RCT 102 pediatric patients with ALI/ARDS

– Randomized to prone for 20hrs vs supine

– Stopped early due to futility

– No improvement in other secondary outcomes

• In adults, studies suggested that in the sub-group of more severe ARDS, prone positioning might be beneficial


Prone positioning

Guerin, et al in NEJM May 2013 (France and Spain)

– Multicenter prospective RCT – 466 pts with severe ARDS (P/F <150, FiO2 >0.6, PEEP >5, tidal volume 6ml/kg, Pplat <30) , enrolled at <36hrs of ventilation

• Prone-positioning for at least 16 hours vs standard supine

• Primary outcome 28 day mortality

– Prone 16% vs supine 32.8% (p<0.001)

– HR for death with prone positioning 0.39 [95%CI 0.29-0.63]

• Unadjusted 90 day mortality = 23.6% prone vs 41% supine (p<0.001)


Guerin, et al – early prone position


Inhaled Nitric Oxide (iNO)

• Potent selective vasodilator

– Goal is to improve V/Q matching by directing blood toward the more open alveoli

• Meta-analysis of multiple studies (children and adults)

– Improves oxygenation without improving chosen outcomes


iNO – mortality


iNO – oxygenation


Surfactant

• Surfactant –produced by Type II alveolar cell

– Reduces surface tension at the air: fluid interface and varies surface tension during the respiratory cycle

– WOB minimized, atelectasis at end expiration prevented, distribution of ventilation is equal during inspiration

• Early studies showed promise


Surfactant

• PALISI study Calfactant in pediatric ARDS – PCCM 2013

– Multicenter RCT 110 pts with ARDS due to direct lung injury

– Randomized to calfactant vs air within 48 hours of intubation (up to 3 doses)

– Stopped early due to futility

– Overall mortality was 11%

– Not associated with improvement in oxygenation


Steroids

No studies in pediatricsAdult studies indicate no improvement with treating in the acute phase (and might be harmful if used for “prevention”)Outcomes contradictory in many other studies (including meta-analysis)

Preventive steroids Therapeutic steroids

Steroids – meta-analysis Cochrane review 2008


Restrictive Fluid Management

• ARDSNet FACTT trial

– Conservative approach to fluid management increase VFDs and improves oxygenation in adults with ALI/ARDS when compared to more liberal fluid protocol

• Albumin + lasix - might be helpful in adults

• Should only be used after adequate initial resuscitation from shock


Restrictive Fluid Management

• Calfactant Trial secondary analysis

• Guideline was for conservative fluid management based on modified FACTT trail

• Conclusion - In pediatrics we are still fairly liberal, those patients that died were more fluid overloaded


Sedation and Muscle Relaxation

• No studies about appropriate type of sedation

– RESTORE data hopefully coming soon?

• Muscle relaxation – associated with weakness and critical illness myopathy in adult patients with ALI

– If concurrent use with steroids -> increases this risk?

– Early might be ok, but not prolonged

– Only use if necessary for oxygenation or ventilation


ECMO• Has been used as a rescue therapy for many years

• Recent adult study (CESAR Trial) showed benefit for ECMO use in adults with ARDS

– Survival at 6 months in ECMO 63% vs Conventional group 47%

• Another trial (ECMO to Rescue Lung Injury in severe ARDS – EOLIA) ongoing and anticipated to be completed this year

• Strategy and thoughts are changing about ECMO use

– What is lung rest?

– Extubation?

– Early mobilization

– Limit sedation/muscle relaxation


Novel Therapies

• Statins in sepsis induced ARDS (NEJM May, 2014)

– Statins are typically used to reduce cholesterol levels, but have been found to reduce inflammation

– Animal models have suggested that statins can prevent ARDS

– Human studies have suggested that statins used in sepsis or other inflammatory conditions improves outcome

– RCT of rosuvastatin vs placebo in adults with sepsis-induced ARDS

• Stopped for futility with ~75% of enrollment (745 patients)

• No mortality difference

• Increased incidence of renal and hepatic dysfunciton with statins


Novel Therapies

• Mesenchymal Stem Cells in Mouse and Sheep ARDS models have improved oxygenation and decreased pulm edema

– Mesenchymal stem cells have been shown to modulate the inflammatory response, augment tissue repair, enhance pathogen clearance, and reduce severity of injury, pulmonary dysfunction, and death


How are we practicing as pediatric intensivists?

• PALIVE PCCM 2013

• Survey sent out to multiple centers across US and Europe

• 3 case scenarios asking pediatric intensivists parameters they would use to manage the patients

• Bottom line: most use adult guidelines


How do we practice?


How do we practice?

Optimal PaCO2 levels Adjunctive treatments considered


How do we practice?

• The same group gathered actual data from the institutions and there was a discrepancy between the survey results and actual practice

– 25% of patients were ventilated with Vt >10ml/kg

– 16% had PIPs greater than 35cm H2O

• The conclusion of the group – though pediatric physicians agree generally with the adult guidelines, it is difficult in practice to maintain those parameters

– Even with protocols in clinical studies the compliance is usually between 66-87%


Summary• Pediatric ARDS is less common than in adults, but still accounts for a

large portion of our ventilated patients

• Most common etiologies are pneumonia and sepsis

• Lung protective ventilation is the ONLY therapeutic strategy that has showed reproducible mortality benefit

– Low tidal volume, low Pplat, high PEEP

– Permissive hypercapnea

• Likely there are subgroups of patients (i.e. severe ARDS) that benefit from additional therapeutic strategies (prone positioning, HFOV, iNO, etc.)

• More pediatric research is needed but difficult to organize and perform


So what’s new?

• Trying to determine appropriate inclusion criteria for clinical trials and appropriate clinical outcomes

– Thought is that many of the therapies that have been studies likely have benefit if we can identify the right group of patients

• Think early about minimizing harm (lung protection)

• ECMO

– Using more protocolized lung protection to determine if this is a better strategy and improves outcomes.

• Continuing search for biomarkers for ARDS to potentially help with future studies

• Continuing search for novel therapies


References• ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA

2012;307:2526-33.

• Lopez-Fernandex Y, et al. PED-ALIEN Network. Pediatric Acute Lung Injury Epidemiology and Natural History Study: Incidence and outcome of the acute respiratory distress syndrome in children. Crit Care Med 2012:40 (12);3238-3245

• Smith LS, Zimmerman JJ. Mechanisms of Acute Respiratory Distress Syndrome in Children and Adults: A Review and Suggestions for Future Research. Ped Crit Care Med 2013: 14; 631-643

• Biehl M, Kashiouris MG, Gajic O. Ventilator-Induced Lung Injury: Minimizing its Impact in Patients With or at Risk for ARDS. Respir Care 2013;8(6): 927-934.

• Slutsky AS, Ranieri VM. Ventilatory-Induced Lung Injury. N Engl J Med 2013;369: 2126-2136

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

• Petrucci N, De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome (Review). The Cochrane Library 2013:2; 1-36

• Mercat A, Richard J, Vielle B, Jaber S. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:646–655.

• Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE, Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637–645.


References• Ferguson ND, et al. OSCILLATE Trial Investigators and the Canadian Critical Care Trials Group. High-Frequency Oscillation in Early

Acute Respiratory Distress Syndrome. N Engl J Med 2013

• Goligher, et al. Oxygenation Response to PEEP Predicts Mortality in ARDS: A Secondary Analysis of the LOVS and ExPress Trials. AJRCCM 2014 in press

• Guerin C, Reignier J, et al. PROSEVA Study Group. Prone Positioning in Severe Acute Respiratory Distress Syndrome. N Engl J Med 2013: 368(23); 2159-2168

• Willson DF, et al. PALISI Network. Pediatric Calfactant in Acute Respiratory Distress Syndrome Trial. Ped Crit Care Med 2013: 14(7); 658-665

• Peter V, et al. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome in adults: meta-analysis. BMJ 2008 1-10

• Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564–2575

• Willson DF, et al. PALISI Network. The relationship of fluid administration to outcome in the Pediatric Calfactant in Acute Respiratory Distress Syndrome Trial. Ped Crit Care Med 2013: 14(7); 666-672

• Rosuvastain for Sepsis-Associated Acute Respiratory Distress Syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2014;370:2191-2200

• Assmussen S, et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax 2014 Jun 2 in press

• Santschi M, Randolph A, et al. PALIVE, PALISI, and ESPNIC investigators. Mechanical Ventilation Strategies in Children with Acute Lung Injury: A Survey on Stated Practice Pattern. Pediatr Crit Care Med 2012; 14:e332–e337


Thank you!

Healthcare

ARDS: The Old and the New (-ish)