ACUTE RESPIRATORY DISTRESS SYNDROME Cynthia H. Tinsley, MD PICU Attending Loma Linda University Children’s Hospital OBJECTIVES • Will discuss the following: • 1. Definition of Acute Respiratory Distress Syndrome • 2. Clinical Criteria • 3. Epidemiology and Incidence • 4. Mortality • 5. Mechanical ventilation and protective lung strategies • 6. Management strategies

Case Presentation

• A 8 year old male was diagnosed with Leukemia. He competed a full course of treatment and went into remission. • After completion of leukemia therapy he returned to the hospital with a fever, hypoxia and was noted on x-ray to have infiltrates. • He was diagnosed with viral pneumonia and admitted to the wards • He was treated with antibiotics. Oxygen by nasal cannula. • He developed progressive hypoxia and advanced from nasal cannula oxygen, to HFNC. • He was transferred to the PICU for Bi-Pap and rapidly progressed to intubation and ventilation for hypoxic respiratory failure. Patient initial X-ray Introduction

• Acute respiratory failure (ARF) is a common clinical situation seen in the PICU. • As many as 67% of PICU admissions will be admitted with a diagnosis of respiratory failure * • These cases represent multiple pathologic processes with a common end point. • ARF is categorized as: • Hypoxemic • Hypercapnic • Mixed

*Arikan Pediatric Critical Care Clinic 2012: 13(3) :253 Etiologies of ARF

Location Examples Upper airway Infection-croup, epiglottis, bacterial tracheitis obstruction Laryngotracheomalacia, foreign body, Anaphylaxis Lower airway Asthma, Bronchiolitis obstruction Cystic fibrosis Restrictive Lung Acute respiratory distress Syndrome (ARDS) disease Pleural effusion, pneumonia, pulmonary edema , Abdominal compartment syndrome Central nervous Intracranial injury, (hemorrhage, ischemia) system disorders Medications (sedatives) Metabolic encephalopathy Peripheral nervous Guillian Barre’, Muscular dystrophy, scoliosis, spinal cord system disorders injury, botulism, intoxications Difference between Children and Adults • Children have a higher incidence of ARF compared to adults • Infants have more complaint chest walls than adults • Makes it harder to develop negative intrathoracic pressure needed to develop adequate tidal volumes especially when the patient has decreased lung compliance (ARDS, pneumonia ) • The Chest wall has less elastic recoil. • The pores of Kohn or Lambert are less developed • These lead to more susceptible alveolar collapse Case Update

• The patient was initially placed on conventional ventilator • He continued to have hypoxia for which he was eventually placed on HFOV • His chest x-ray showed worsening infiltrates consistent with a diagnosis of Pediatric Acute Respiratory Distress Syndrome (PARDS) Pediatrics Acute Respiratory Distress Syndrome (PARDS)

• Severe form of Acute Respiratory failure • The incidence is low in all the admission to the PICU • Accounts for 2.2 to 2.6 % of PICU admissions • The mortality ranges between 18 to 32.8 % • Most patients die from multiple organ failure Acute Respiratory Distress Syndrome

• First described in 1967 in 12 adults patients • Described as a clinical pattern including • Severe dyspnea • Tachypnea • Cyanosis refractory to oxygen • Loss of lung compliance • Diffuse alveolar infiltrates • The mortality rate was 58% ( 7died)

Etiology of ARDS Pathophysiology

• ARDS follows cascade of events after direct pulmonary or systemic insult • Result in disruption of alveolar capillary unit. • 3 distinct components • 1. nature of the stimulus • 2. host response to the stimulus • 3. the role of iatrogenic factors –barotrauma, oxygen toxicity Pathology of ARDS-immune complex induces lung injury • Local or systemic trigger immune response • Macrophages release cytokines Like TNFα, IL 1, IL8 • Damage to alveolar epithelial from Oxygen free radials, H202,NO • Edema protein reach fluid leaks in causing Hyaline formation • Diffuse of oxygen is effected

ARDS

• Represents a small percentage of total PICU admission but represents one of the most challenging patient populations to manage. • In the past there was little pediatric-specific definitive data to guide clinical management of these patients. • Often we have relied on adult studies to guide pediatric practice. • There was a lack of definition for pediatric ARDS • 2012 Berlin definition was developed in Europe • 2015 PALICC published pediatric-specific definition and management recommendation 2012 Berlin definition for ARDS from recommendations from a 2011 Consensus panel of experts

• Acute diffuse inflammatory lung injury ( onset less than 1 week) • Bilateral opacities with pulmonary edema • Due to increased pulmonary vascular permeability • Increased lung weight and loss of aerated lung tissue • PF ratio < 300 mmHg with a minimum of 5 cm PEEP ARDS Severity Pa02/Fi02 Mortality (P/F) mild 200-300 27% moderate 100-200 32% Severe <100 45%

Definition of ARDS by the 2014 Pediatric Acute Lung Injury Consensus Conference (PALICC)

Age Exclude patients with perinatal related lung disease timing Within 7days of known clinical insult Origin of Respiratory failure not fully explained by cardiac failure or fluid edema overload Chest x-ray Chest imaging findings of new infiltrates consistent with acute pulmonary parenchymal disease Oxygenation None invasive ventilation Invasive mechanical ventilation PARDS (no severity stratification mild moderate Severe ) Full face- mask bi-level 4≤ OI<8 8≤OI<18 OI≥16 ventilation 5≤ 7.5 OSI≥12.3 Or CPAP ≥ 5 cm OSI≤7.5 ≤OSI<12.3 PF ration ≤ 300 OI= oxygenationSF ration index ≤ OSI=oxygenation 264 saturation index, PF= Pa02/Fi02, SF=Sp02/Fi02 Oxygenation calculation

• Patient has Fi02 of 60%, Sp02 98 %, Pa02 is 85 Mean Airway pressure of 20. • Oxygenation index: • Fi02 X mean airway pressure X 100/ Pa02 • 0.6 X 20 x100/85= 14.11 • Oxygenation Saturation Index • 0.6 X 20 X 100/98= 12.24 • P/F ratio=85/0.6= 141.66

Treatment of ARDS

• Conventional Mechanical Ventilation • Inverse ratio ventilation and High Frequency Ventilation • Lung Protective Strategies • Permissive Hypercapnia • Prone Positioning • Fluid Management • Corticosteroids • Inhaled Nitric Oxide

HFOV - General Principles

• A CPAP system with piston displacement of gas

• Active exhalation

• Tidal volume less than anatomic dead space (1 to 3 ml/kg)

• Rates of 180 – 900 breaths per minute

• Lower peak inspiratory pressures for a given mean airway pressure as compared to CMV

• Decoupling of oxygenation & ventilation Indications for HFOV

• Inadequate oxygenation that cannot safely be treated without potentially toxic ventilator settings and, thus, increased risk of VALI (Ventilator Associated Lung Injury) • Objectively defined by:

• Peak inspiratory pressure (PIP) > 30-35 cm H2O

• FiO2 > 0.60 or the inability to wean

• Mean airway pressure (Paw) > 15 cm H2O

• Peak end expiratory pressure (PEEP) > 10 cm H2O • Oxygenation index > 13-15 (P • F O ) aw i 2 OI = • 100 PaO2

HFOV • Do studies support it’s use in ARDS?

• What Have we learned? High Frequency Oscillatory Ventilation Studies

• 2013 OSCAR and OSCILLATE trials of HFOV in adults with ARDS shows concern for using HFOV. • The OSCAR trial (OSCillation in ARDS) • Performed in England with 398 patients in each group. • Reported no difference between HFOV and conventional ventilation • The OSCILLATE trial was stopped due to increased mortality in the HFOV treatment group • Goal was 1200 patients but was stopped after 548 patient because HFOV group had 14% increased rate of death (45% verses 31%)

N Engl J Med 2013;368:806-813 and 795-805 Are these Adult Studies telling us to stop using HFOV?

• The increased death rate maybe due to the effects of HFOV • Patient required more inotropic agents • This Probably due to increased thoracic pressure from HFOV • That caused hemodynamic compromise • The patient on HFOV patients required more sedation and muscle relaxants which may have contributed to the poorer outcome in the HFOV group • There is very little data on pediatric patients. Comment on these studies

• Higher mortality associated with an increase of vasopressor requirement • Which may represent very high intra-thoracic pressures and right ventricular afterload. • Patient required more fluids • May have caused worse barotrauma • More capillary leak • HFOV patient also required more paralysis and sedation medications What do we know from pediatric HFOV studies ?

• Using the RESTORE study on sedation • They reviewed the patients managed on HFOV • The HFOV was started within 24 to 48 hours after intubation. • Compared them to the patients treated with conventional ventilation and those on late HFOV • The study included 181 patients on HFOV and 883 on conventional • Results: • The patients treated with HFOV early , compared to conventional or late HFOV • Were on the ventilator longer but mortality was not increased.

Virtual PICU Data (2009-2011)

• A case Review of 9177 from 98 hospital • 902 received HFOV, and 8275 conventional ventilation • HFOV was divided into early and late HFOV initiation • The patients were matched for severity of illness and type of illness • Evaluated for length of stay, length of mechanical ventilation, mortality • THE HFOV whether it was early or late onset did worse in all categories

JAMA Pediatrics, March 2014, Vol 168 Graph of results HFOV summary

• We can speculate that HFOV has a role in management of pediatric PARDS • Especially during the peak lung injury phase • It should follow with aggressive weaning as lung recovery occurs • Early transition back to conventional ventilation has been the traditional management style HFOV important questions remain

• Are the poor outcomes due to HFOV or the how it is used? • Low tidal volumes ventilation ( 4 to 6 ml/kg) that is now used during conventional ventilation maybe better than HFOV • Clinicians are more aggressive in weaning conventional ventilators as compared to HFOV because of concerns for de-recruitment • Endotracheal suctioning is performed less on HFOV • Patient on HFOV are more likely receive more sedation and neuro- blockade medications.

Case Update

• He developed progressively worsening oxygenation requiring increasing efforts to improve oxygenation • Fi02 reached 100% • The mean airway pressure on the HFOV was increased Amp 48, Mean airway pressure was 35 • He was placed on Nitric oxide • He was paralyzed withVecuronium • Multiple Ventilator Modes were attempted • 1. Airway pressure release ventilation • 2 Pressure support alone

Chest X-ray Complication of ARDS

• Our patient developed all the complications of ARDS • High levels of mean airway pressure which caused Barotrauma • Multiple pneumothoracies requiring multiple chest tubes • Pulmonary hypertension treated with Nitric oxide and IV sildenafil • Other complications included: • Nosocomial infections • VAP (reported to be 50% or greater) –more than other respiratory diseases requiring ventilation • Line sepsis • UTI • Sinusitis with NG feedings • Development of drug resistant infections

Complication continued

• Functional impairment that continued after discharge • Muscle weakness and muscle wasting • Corticosteroid treatment and use of neuromuscular blockade agents increase this risk • Difficulty weaning from the ventilator • Eventually required a tracheostomy and chronic ventilator management • Renal failure • Contributing factors include: sepsis, hypotension, nephrotoxic drugs • Ileus, stress gastritis, anemia • Feeding intolerance

Ventilator Associated Lung Injury (VALI)

All forms of positive pressure ventilation (PPV) can cause ventilator associated lung injury (VALI).

VALI is the result of a combination of the following processes: Barotrauma Volutrauma Atelectrauma

Capillary Leak  Electron microscopy demonstrates the disruption of the alveolar-capillary membrane secondary to mechanical ventilation with lung distention.  Note the leakage of RBCs and other material into the alveolar space.

Fu Z, JAP, 1992; 73:123 Volutrauma • Lung overdistension can cause diffuse alveolar damage at the pulmonary capillary membrane. • This may result in increased epithelial and microvascular permeability, thus, allowing fluid filtration into the alveoli (pulmonary edema). • Excessive end-inspiratory alveolar volumes are the major determinant of volutrauma. Atelectrauma

• Mechanical ventilation at low end-expiratory volumes may be inefficient to maintain the alveoli open.

• Repetitive alveolar collapse and reopening of the under-recruited alveoli result in atelectrauma.

• The quantitative and qualitative loss of surfactant may predispose to atelectrauma. Clinical Goals • Reasonable oxygenation to limit oxygen toxicity

• SaO2 86 to 92%

• PaO2 55 to 90 mm Hg • Permissive hypercapnea • Provide “just enough” ventilatory support to maintain normal cellular function. • Monitor cardiac function, perfusion, lactate, pH

• Allow PaCO2 to rise but keep arterial pH 7.25 to 7.30. (Derdak, CCM, 2003)

• This strategy helps to minimize VALI. (Hickling, CCM, 1998)

• ‘Normal’ pH, PaCO2, & PaO2 are indictors of OVER ventilation!! Lung Protective Strategies

• Utilizing HFOV in an open lung strategy provides a more effective means to recruit and protect acutely injured lungs. • The ability to recruit and maintain FRC with higher mean airway pressures may: • improve lung compliance • decrease pulmonary vascular resistance • improve gas exchange • With attenuation of ∆P, there is less trauma to the lungs and, therefore, less risk of VALI. • HFOV improves outcome by ↓ shear forces associated with the cyclic opening of collapsed alveoli. Arnold, PCCM, 2000

Nitric Oxide • In spite of the theoretic potential, several randomized clinical trials in adults with ARDS • They have failed to show improvement • The studies did show improved oxygenation for 4 days • But no improvement in: • Mortality • Duration of ventilation • Ventilator free days • 2014 adults studies with few or no children • Included 9 RCT and 1142 patients.

Adhikari, Crit Care Medicine (2014) 42; 404-412

Nitric Oxide

• In the lung, nitric oxide is produced by a variety of cells • Epithelial cells • Adventitial nerve endings • Macrophages when activated • Causes • vasodilation • Prevents platelet adhesion- prevents plaque formation • Causes smooth muscle relaxation and prevents vasoconstriction

Nitric Oxide (NO) improves V/Q iNO what we know in ARDS and PARDS

• Patients with ARDS are exposed to hypoxia • Endothelial damage results in decreased NO production • Causes vasoconstriction • Leads to pulmonary hypertension • Right ventricular hypertrophy • In spite of the theoretic potential benefit of iNO • In pediatric and adults studies it has not been shown to improve survival • It does show a short term improved oxygenation Bronicki , RA et al, J Pediatrics (2015) 166 (2):365-9

Theory Why iN0 may not lead to improvement

• 1. iN0 converts to peoxynitrite (N000)a toxic moiety to cellular respiration.

• 2. Additional adverse and potential toxic effects of iNO • Methemoglobinemia • Increased nitrogen dioxide • Platelet inhibition • Increased left ventricular filling pressure • Rebound hypoxemia and pulmonary hypertension upon discontinuation

• These side effects are seen seen with high concentrations and Adhikariprolonged, NK Effect usage of nitric and oxidewith on high oxygenation oxygen and mortality :BMJ 2007; 334( 7597) : 77 Sedation

• Sedation is necessary to ensure the safety and comfort of mechanically ventilated infants and children • However the adverse effects of sedation medications include: • Limiting spontaneous ventilation • Prolonging the course of mechanical ventilation • Inducing critical illness neuromyopathy • Increasing the risk for delirium • Causing the development of iatrogenic withdrawal symptoms RESTORE STUDY SEDATION MANAGEMENT FOR PEDIATRIC PATIENTS WITH ARF

• Multi-center randomized clinical trial that studied the effect a nurse-implements, goal-directed sedation management protocol • Included infants, children, and adolescents with acute respiratory failure 2449 subjects were enrolled • Protocolized sedation did not reduce the length of mechanical ventilation • Did find that fewer days of opioid administration • Fewer categories of sedatives were given • Fewer required Methadone at discharge. Curley, MA JAMA 2015; 313(4): 379-389

WHAT WE LEARNED FROM RESTORE

• The safety of bedside-driven sedation protocols work. Where nursing can make at the bedside decisions in real time • Also showed that mechanically ventilated pediatric subjects can safely be maintained in a more awake state • Withdrawals may be less. The treatment group had a lower need for methadone. • The RESTORE study did not include Dexmedtomidine (Percedex) • We need a similar large scale study using Percedex Permissive Hypercapnia

• With smaller tidal volume to prevent lung injury leads to decreased minute ventilation and increased C02. and lower pH. • Elevated C02 can: • Worsen pulmonary hypertension • Increase intracranial pressure • Cardiovascular dysfunction • Several studies show a protective role in ARDS

Bench to bedside review: permissive hypercapnia Crit Care. 2005:9(1):51-9 2015 Update in Pediatric ARDS (PARDS)

• Because the Pediatric ARDS is distinct from adult ARDS • A panel of 27 experts met from 2012 to 2014 • They made 132 recommendations • The Berlin definitions were used • They added noninvasive ventilation without division based on severity of illness.

Summary of Recommendations

• 1. Ventilator Support • No outcome data to support mode of conventional ventilation • 2. Tidal volume • Tidal volume of 3 to 6 ml/kg in patients with poor pulmonary compliance • Inspiratory plateau pressure less than 30 cm • 3. PEEP • Elevated PEEP of 10-15 cm • Titrate to oxygenation and hemodynamic stability Recommendation continued

• High frequency ventilation • In patient’s with a plateau pressure greater than 28 cm • Oxygen Saturations • With a PEEP of least 10 accept SpO2 88- 92% • Monitor Central SvO2 when saturations less than 92% • Hypercapnia • pH 715 to 7.30 • Bicarbonate supplementation is not routinely recommended

Recommendation

• Inhaled Nitric Oxide • Not routinely recommended • Only in proven pulmonary hypertension • Exogenous surfactant-not recommended • Prone Positioning-not recommended • Suctioning- • Isotonic saline for suctioning is not recommended routinely only use if thick secretions • Caution to prevent de-recruitment Recommendations

• Chest PT –not recommended as standard of care • Corticosteroids –not recommended • Sedation • Patients should receive minimal yet effective targeted sedation • Use sedation scales • Develop an individualized sedation weaning plan • Neuromuscular blockade • Use if sedation is not enough • Monitor train of four • Transfusion for Hg < 7

THANK YOU QUESTIONS? References

• Oxygenation Index Predicts Outcome in Children with Acute Hypoxemic Respiratory Failure. American Journal of Respiratory and Critical Care Medicine No 2 (2005) pg 206-211 • Pediatric Acute Respiratory Distress Syndrome Consensus Recommendations From the Pediatric Acute Lung Injury Consensus Conference; Pediatric Critical Care Medicine; 2015 Vol 16 Number XXX www.pccmjournal.org