Conference Lectures

ACUTE LUNG INJURY/ ACUTE RESPIRATORY DISTRESS SYNDROME
Dr Atul Sharma, Sr DMO, JRH (WR), MUMBAI

A syndrome of inflammation and increased permeability that is associated with clinical, radiologic, and physiologic abnormalities that cannot be explained, but may co-exist with left atrial or pulmonary hypertension.
It is a  diffuse inflammatory process that spares little/no lung leading to hypoxemia refractory to usual O2 therapy and almost always requires positive end-expiratory pressure >5 cmH2O to reverse hypoxemia.
European Society of Intensive Care Medicine (ESICM), American Thoracic Society & Society of critical care medicine & their experts had defined ARDS in June 2012 in Berlin & was published as follows.
1. Timing-  Within 1 week of a known clinical insult or new or worsening respiratory symptoms.
2. Chest imaging-- Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules.
3. Origin of edema--Respiratory failure not fully explained by cardiac failure of fluid overload need objective assessment (eg., echocardiography) to exclude hydrostatic edema if no risk factor present.
A. Mild --        Oxygenation --200<PaO2/FiO2 ≤ 300with PEEP or CPAP ≥5 cmH2O
B. Moderate – Oxygenation - 100<PaO2/FiO2 ≤ 200with PEEP or CPAP ≥5 cmH2O
C. Severe--     Oxygenation--           PaO2/FiO2 <100with PEEP or CPAP ≥5 cmH2O
ARDS causes

Pathological Stages of  ARDS
Exudative (acute) phase (0- 4 days)
Proliferative phase (4- 8 days)
Fibrotic phase ( >8 days)
Recovery
Immunologic mechanisms triggers ALI & it varies from cause-to-cause. However, some features are suggested in models of DAD (diffuse alveolar damage). In the classic model, an inflammatory trigger causes recruitment of neutrophils to the capillary membrane through elaboration of surface adhesion molecules. Once caught in membrane neutrophils degranulate causing direct injury of the capillary membrane. If injury of sufficient severity, inflammatory events increases microvascular permeability to salt, water and macro molecules that came out  into the interstitium, excessivel to flood alveoli. Proteins in the leaked fluid may coagulate appearing as the classic hyaline membranes (on pathologic specimens) of early DAD.Meanwhile a variety of inflammatory mediators may incite apoptosis of type II pneumocytes( producer of surfactant). Surfactant depletion promotes atelectasis that is most prominent in dependent lung regions, i.e. posteriorly in a supine patient.
In addition to classical view of pathogenesis of ARDS the role of renin –angiotensin system has been highlighted.ACE is found on the surface of lung epithelial & endothelial cells1.Angiotensin II is strong fibrinogenic factor & it induces apoptosis of lung epithelial & endothelial cell2.
If the trigger mechanism is addressed and additional pro-inflammatory events prevented, many patients will heal with minimal residual.
Clinical Diagnosis

• Rapid
• Within 12 to 48 hr of the predisposing event.
• Awake patients become anxious, agitated & dyspnoeic.
• Dyspnoea on exertion proceeding to severe when hypoxemia intervenes.
• Stiffening of lung leads to increase work of breathing, small tidal volumes, rapid respiratory rate
• Initially respiratory alkalosis 
• Respiratory failure

Investigations
a.Chest x-ray & CT thorax:

• Bilateral diffuse alveolar infiltrates more on the peripheral lung fields.
• R/O Cardiogenic edema if there iscardiomegaly, pulmonary artery dilatation, bat’s wing perihilar distribution responding to diuretics. D/d between cardiogenic oedema & ARDS is some times not easy. Pulmonary vascular permeability index(PVPI) of 2.6 -2.85 provided a definitive diagnosis of ALI/ARDS (specificity 0.90—0.95) & index value less than 1.7 ruled out an ALI/ARDS (specificity -0.95)3.PVPI is ratio of extravascular lung water & pulmonary blood volume assessed by transpulmonary thermodilution method by putting thermistor in femoral artery & cold saline bolus in sup. Venacava to calculate cardiac output ,mean transit time, exponential downslop time of trans pulmonary thermodilution curve.

b.Arterial blood gas analysis:

• PaO2  range 55 – 60 mm of Hg
• Initially respiratory alkalosis later mixed acidosis

c. Routine CBC, urea, creatinine, Na, K
d.Echocardiogram to R/O Cardiogenic cause.
e. PAWP < 18mm of Hg à ALI / ARDS
f. Bronchoscopy (CCF)
POOR PROGNOSIS FACTORS:
Advanced age, Male sex, Extra pulmonary organ dysfunction, Sepsis, HIV, Alcoholism, Active malignancy & Organ transplantation. The development of cor-plmonale in ARDS has been considered as poor prognostic factor & careful monitoring of acute Cor-Pulmonale is recommended in ARDS4.
Complications

Management
Identify and reverse the inflammatory cause as quickly as possible. The initial insult determines the severity and duration of ARDS. It is essential to eradicate infections rapidly, including interventional/surgical drainage of loculated foci that will not otherwise respond to antibiotics alone.
Iatrogenic stimuli, including transfusions, nosocomial infections, drugs & mechanically ventilated already injured lung causing barotrauma (termed ventilator-induced lung injury; VILI) can promote additional injury. This model---called the "multiple hit hypotheses”means ARDS may be initiated by one insult & often maintained by readily preventable pro-inflammatory insults. Therefore minimizing every factor that might promote ongoing inflammation helps most patients to recover, usually without developing fibro proliferative ARDS.
While cardiogenic pulmonary edema often responds rapidly to preload reduction (e.g. diuretics, nitrates, non-invasive positive pressure ventilation; NIV) and interventions to improve left heart function, non-cardiogenic pulmonary edema ( ARDS )does not improve. The early, exudative phase is marked by a high shunt fraction have poor response to high concentrations of inspired oxygen.
The mainstay of supportive management of ARDS is invasive positive pressure ventilation (PPV). It is a bridge to buy doctor’s time to reverse the inflammatory stimuli that initiated ARDS and time for the lung to heal. It does not treat flooding, but it does recruit atelectatic lung, thereby reducing the shunt fraction. Since exhalation is the lowest pressure during tidal breathing on PPV, the risk of derecruitment is greatest during exhalation. Derecruitment is also common during cough and dys-synchrony on PPV.
Lungs of patients with ARDS are"small lungs," i.e. large areas of gravitationally dependent atelectasis, a border zone of sometimes-open, sometimes-closed alveoli, and a gravitationally independent region of a well-ventilated lung. PEEP can be used to  open some of the border-zone areas. However, if one applies "normal" tidal volumes to the remaining good alveoli they  become over-distended and injured, so less tidal volume(6ml/kg of B.W.) is  required.Titrate tidal volume to a peak pressure (28-30 cmH2O) whenever possible & appropriate PEEP is a key component of a lung protective ventilatory strategy5.
For patients with extreme obesity, extreme PEEP requirements i.e. more than 15 cmH2 O or in other restrictive diatheses, higher plateaus are acceptable but only if absolutely necessary, and should rarely exceed 35 cm H 2 O (never ≥40 cm H 2 O). 
PEEP/FiO2 combination to maintain & achieve oxygenation goal (PaO2 goal: 55-80mmHg or SpO2 goal 88-95%) .If hypoxemia (O 2 sat<90%) persists despite 100% oxygen and PEEP = 5 cmH 2 O, increase PEEP in increments of 2-3 cm H 2 O and/or simply increase to 12-15 cmH 2 O all at once if ARDS is strongly suspected (this is the mean level of PEEP required by patients with ARDS). Titrate up PEEP 2-3 cmH 2 O every 3-5 min, as you titrate down FiO 2 to 60% (keeping O 2 sat≥90%). As PEEP is increased, tidal volume must be reduced to maintain the Peak pressure < 30 cm H 2 O to prevent barotraumas to healthy" lung segments with excessive distending pressure.  Patients with very severe ARDS may require high PEEP (as high as 25 cmH 2 O) and very low tidal volumes (as low as 200 ml).
In ARDS, synchrony with the ventilator is essential. Deep sedation and muscle relaxation may be required for synchrony and allow PEEP to work in the most severe cases of ARDS.Muscle relaxation should be used in the lowest doses and shortest durations to prevent catastrophic neuromyopathies /quadriparesis that can result with prolonged relaxation. While daily awakening promotes recovery, it must be performed very carefully in patients with severe ARDS (as excessive awakening and subsequent dys-synchrony can promote prolonged derecruitment and hypoxemia). Short term use of cisatracurium reduces hospital stay & barotrauma .It did not increase muscle relaxant induced acquired weakness6.Alpha-2 adrenergic agonist ,Dexmedetomedine could be used safely, as this drug preserve respiratory drive, lower O2 consumption & pulmonary hypertension & increases diuresis.
Sometimes tidal volumes are so low, even at respiratory rates of 30/min (beware of going much higher), alveolar ventilation is insufficient, CO 2 rises and pH decreases. It has been demonstrated that such "permissive hypercapnia" is reasonably safe and bicarbonate infusions are seldom needed even for pH as low as 7.1. 
 As the lung heals and FiO 2 required to maintain oxygen saturation above 90% reaches 50%, PEEP can be reduced 2 cm H 2 O every 2-4 h as tolerated. So as PEEP can come down---as the lung heals and more alveoli become available at lower PEEP---tidal volume will need to be titrated up (again, using plateau 25-30 cm H 2 O as the set-point).
Prone ventilation can be used to take advantage of gravitational gradient, in cases that are refractory (PaO 2 :FiO 2 <100 on high PEEP) to the ARDS net strategy. (e.g. PaO 2 <60 mmHg on FiO 2 >60% and PEEP>15 cmH 2 O). It often improves oxygenation of patients who have refractory hypoxemia requiring high PEEP and FiO 2 >60% in the recumbent position. Several studies suggests that prone position reduces the tanspulmonary pressure gradient, recruits collapsed alveoli, decreases its instability without increasing airway pressure or hyperinflation observed at high PEEP in ARDS patient. It is more effective in obese patients7.
High frequency oscillatory ventilation is effective when used in early stage of disease & change in PaO2/FiO2 during first three hours helps to identify patient that are more likely to survive8.
Conservative fluid management is highly recommended after hemodynamic stabilization of ARDS patient. Septic shock is the most common cause of ARDS and fluid restriction in cases of septic shock complicated by ARDS could increase mortality. Clinicians must be particularly careful in such patients, filling (but not overfilling) during initial resuscitation and limiting fluid once hemodynamic stability is achieved. Since many critically ill patients require large volumes to maintain organ perfusion in early phases of critical illness, great attention may be required to "retrieve" fluid as it rushes back to the intravascular space (and often into the lung) during recovery. In hemodynamic unstable patient dynamic monitoring of lung fluid balance needs to be implemented to guide the administration of fluids in ARDS patients9. When patient   become stable and no longer requires presser agent to maintain their circulation, clinicians should seek to retrieve fluids via diuresis.
In several studies there was beneficial role of bronchodilator (B-2 agonist) for resolution of alveolar edema but recent evidence indicates detrimental effect10.
Extra corporeal membrane oxygenation (ECMO) can be used in severe cases of ARDS. ECMOis instituted for the management of life threatening pulmonary & cardiac failure. It is used as temporary support, usually awaiting recovery of organs. Blood is removed from venous system (Femoral vein /Rt. Atrium) & after oxygenation & extraction of CO2 returned back to femoral artery/Ascending Aorta. Recent literature shows varying mortality & morbidity for the use of ECMO for ARDS.Further research is needed for standardization of ECMO to reduce mortality & morbidity.
There are several highly experimental studies as pretreatment or for prevention strategy of ARDS & found that-
1. Mesenchymal stem cells transplantation can improve the regeneration of lung tissue11.
2. Mesenchymal stem cells help by incorporation of these cells in damaged lung, their interaction with damaged lung & immunologic modulation12.
3. Mesenchymal stem cells can control oxidative stress, transfer functional mitochondria to damaged cells & control bacterial infection by secreting antibacterial peptides.
ARDS may be thought of as a multifactorial disease whose etiology may involve several mechanisms initially and whose pathogenesis may change with time. We should understand the pathogenesis and treat on evidence based and common sense-based approach simultaneously.

References:
1. Igic R, Behnia R: Properties and distribution of angiotensin I converting enzyme. Curr Pharm Des 2003, 9:697-706
2. Wang R, Alam G, Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, Oezatalay D, Uhal BD: Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo. J Cell Physiol 2000, 185:253-259
3. Kushimoto S, Taira Y, Kitazawa Y, Okuchi K, Sakamoto T, Ishikura H, Endo T, Yamanouchi S, Tagami T, Yamaguchi J, Yoshikawa K, Sugita M, Kase Y, Kanemura T, Takahashi H, Kuroki Y, Izumino H, Rinka H, Seo R, Takatori M, Kaneko T, Nakamura T, Irahara T, Saito N, Watanabe A, The PiCCO Pulmonary Edema Study: The clinical usefulness of extravascular lung water and pulmonary vascular permeability index to diagnose and characterize pulmonary edema: a prospective multicenter study on the quantitative differential diagnostic definition for acute lung injury/acute respiratory distress syndrome. Crit Care 2012, 16:R232
4.a. Boissier F, Katsahian S, Razazi K, Thille AW, Roche-Campo F, Leon R, Vivier E, Brochard L, Vieillard-Baron A, Brun-Buisson C, MekontsoDessap A: Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome. Intensive Care Med 2013, 39:1725-1733
b. Lheritier G, Legras A, Caille A, Lherm T, Mathonnet A, Frat JP, Courte A, Martin-Lefèvre L, Gouëllo JP, Amiel JB, Garot D, Vignon P: Prevalence and prognostic value of acute cor pulmonale and patent foramen ovale in ventilated patients with early acute respiratory distress syndrome: a multicenter study. Intensive Care Med 2013, 39:1734-1742.
c. Repesse X, Charron C, Vieillard-Baron A: Right ventricular failure in acute lung injury and acute respiratory distress syndrome. Minerva Anestesiol 2012, 78:941-948
5. 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
6. Alhazzani W, Alshahrani M, Jaeschke R, Forel JM, Papazian L, Sevransky J, O Meade M:Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care 2013, 17:R43
7. De Jong A, Molinari N, Sebbane M, Prades A, Futier E, Jung B, Chanques G, Jaber S:Feasibility and effectiveness of prone position in morbidly obese ARDS patients: a case–control clinical study. Chest 2013, 163:1554-1561. 
8. Camporota L, Sherry T, Smith J, Lei K, McLuckie A, Richard B: Physiological predictors of survival during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care 2013, 17:R40.
9. Huh JW, Koh Y: Ventilation parameters used to guide cardiopulmonary function during mechanical ventilation.
Curr Opin Crit Care 2013, 19:215-220.

10. Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE, BALTI-2 study investigators: Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012, 379:229-235
11. a.Curley GF, Hayes M, Ansari B, Shaw G, Ryan A, Barry F, O'Brien T, O'Toole D, Laffey JG:Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax 2012, 67:496-501
b.Chimenti L, Luque T, Bonsignore MR, Ramirez J, Navajas D, Farre R: Pre-treatment with mesenchymal stem cells reduces ventilator-induced lung injury. Eur Respir J 2012, 40:939-948.
12. Otts JE, Matthay MA: Mesenchymal stem cells and acute lung injury. Crit Care Clin 2011, 27:719-733