ARDS and acute lung injury (ALI) syndromes are forms of type I or acute hypoxemic respiratory failure. This form of lung dysfunction arises from diseases causing the collapse and/or filling of alveoli, with the result that a substantial fraction of mixed venous blood traverses nonventilated airspaces, effecting a right-to-left intrapulmonary shunt. In addition to the adverse consequences on gas exchange, interstitial and alveolar fluid accumulation result in an increase in lung stiffness, imposing a mechanical load with a resulting increase in the work of breathing. When intrapulmonary shunting of blood is significant, the response of arterial hypoxemia to supplemental oxygen therapy is poor, and this failure of the patient to respond to oxygen is both a clinical sign of this syndrome and a reason that additional measures will need to be undertaken to achieve alveolar recruitment before the patient progresses to abject respiratory failure, tissue hypoxia, and death.
Acute lung injury has numerous consequences including
  1. Impairment of gas exchange. It is primarily due to ventilation-perfusion mismatching: physiologic shunting causes hypoxemia, while increased physiologic dead space impairs carbon dioxide elimination 
  2. Decreased lung compliance, due to stiff lungs
  3. Increased pulmonary arterial pressure. Pulmonary hypertension (PH) occurs in up to 25 percent of patients with ARDS who undergo mechanical ventilation. Causes include hypoxic vasoconstriction, vascular compression by positive airway pressure, parenchymal destruction, airway collapse, hypercarbia, and pulmonary vasoconstrictors
Sepsis, aspiration, pneumonia, severe trauma, surface burns, multiple blood transfusions, leukoagglutin reactions, TRALI (Transfusion of even one unit of a plasma-containing blood product sometimes causes ARDS) , pancreatitis, drug overdose, alcohol, near drowning, smoke inhalation, cardiopulmonary bypass, pulmonary contusion, multiple fractures, following upper airway obstruction, bone marrow transplantation, drug reaction, venous air embolism and amniotic fluid embolism
Pathogenesis: Patients with ARDS tend to progress through three relatively discrete pathologic stages. 
  • Exudative stage, characterized by diffuse alveolar damage. It lasts for 7-10 days.
  • Proliferative stage, characterized by resolution of pulmonary edema, proliferation of type II alveolar cells, squamous metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen.
  • Fibrotic stage, characterized by obliteration of normal lung architecture, diffuse fibrosis, and cyst formation
During tidal ventilation, 3 distinct lung zones are produced, associated with different types of ventilator-induced lung injury (VILI):
  1. Dependent: collapsed throughout tidal ventilation despite high levels of PEEP, causes chronic collapse injury
  2. Intermediate: cyclic collapse and re-expansion with each breath, causes shear induced injury (atelectrauma)
  3. Least dependent: regions that remain inflated throughout tidal ventilation and can be over inflated by TV of > 6mL/kg and plateau pressures exceeding > 30-35cmH2O, causes volutrauma and barotrauma
Clinical features:
Patients typically present with dyspnea, cyanosis (i.e. hypoxemia), diffuse crackles, tachypnea, tachycardia, diaphoresis, and use of accessory muscles of respiration. Arterial blood gases reveal hypoxemia, which is often accompanied by acute respiratory alkalosis and an elevated alveolar-arterial oxygen gradient.
The initial chest radiograph typically has bilateral alveolar infiltrates without blunting of costo-phrenic angle. CT chest usually reveals widespread patchy or coalescent airspace opacities that are usually more apparent in the dependent lung zones. The infiltrates do not have to be diffuse or severe, as bilateral infiltrates of any severity are sufficient.
The first several days of ARDS are characterized by hypoxemia requiring a moderate to high concentration of inspired oxygen. The bilateral alveolar infiltrates and diffuse crackles are persistent during this period and most patients who survive this initial course begin to exhibit better oxygenation and decreasing alveolar infiltrates over the next several days. The fibro proliferative phase of ARDS is characterized radiographically by progression from airspace opacification to a more coarsely reticular pattern of lung infiltration. These changes within the lung parenchyma are often accompanied by persistent hypoxemia, low lung compliance, high dead space, and sometimes by progressive pulmonary hypertension. The lungs of patients who survive the fibroproliferative phase enter into an extended subsequent phase of resolution and repair. Hypoxemia and pulmonary infiltrates gradually improve over weeks to months. Cardiopulmonary function often returns to near baseline levels by 6 months or longer after the initial lung injury. However, many survivors of severe ARDS are left with persistent cognitive impairment, emotional disturbances, and residual muscle weakness resulting in substantially reduced quality of life.
Patients with ARDS are predisposed to pulmonary barotrauma due to the physical stress of positive pressure mechanical ventilation on acutely damaged alveolar membranes. Nosocomial pneumonia is an important cause of morbidity and mortality in patients who have ARDS.
ARDS can be diagnosed once cardiogenic pulmonary edema and alternative causes of acute hypoxemic respiratory failure and bilateral infiltrates have been excluded. The Berlin Definition of ARDS requires that all of the following criteria be present to diagnose ARDS.
  • Bilateral opacities consistent with pulmonary edema must be present on a chest radiograph or computed tomographic (CT) scan. These opacities must not be fully explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules.
  • The patient’s respiratory failure must not be fully explained by cardiac failure or fluid overload.
  • PCWP <18 mm Hg or no clinical evidence of left atrial hypertension
  • A moderate to severe impairment of oxygenation must be present, as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2). The severity of the hypoxemia defines the severity of the ARDS:
    1. Mild ARDS – The PaO2/FiO2 is >200 mmHg, but ≤300 mmHg, on ventilator settings that include positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥5 cm H2O.
    2. Moderate ARDS – The PaO2/FiO2 is >100 mmHg, but ≤200 mmHg, on ventilator settings that include PEEP ≥5 cm H2O.
    3. Severe ARDS – The PaO2/FiO2 is ≤100 mmHg on ventilators setting that include PEEP ≥5 cm H2O.
Note: Berlin definition was with PEEP of 5 or above
  • Acute pulmonary edema is usually due to left ventricular systolic or diastolic dysfunction, fluid overload, uncontrolled hypertension, CKD or renal artery stenosis. Cardiogenic pulmonary edema is nearly identical to ARDS, except there may be evidence of cardiac dysfunction (eg, an S3 or S4 gallop, new or changed murmur), elevated right-sided filling pressures (eg, elevated jugular venous pressure), or related radiographic abnormalities (eg, pulmonary venous congestion, Kerley B lines, cardiomegaly, and pleural effusions). Distinguishing cardiogenic pulmonary edema from ARDS can be aided by measurement of a brain natriuretic peptide (BNP) level, echocardiography, and, less often, right heart catheterization.
  • An acute exacerbation of idiopathic pulmonary fibrosis or other chronic interstitial lung diseases can closely resemble ARDS in both clinical presentation and chest radiographic abnormalities showing diffuse interstitial markings. The diagnosis is suggested by careful review of previous chest radiographic images and absence of any alveolar edema.
  • Diffuse alveolar hemorrhage may be associated with an unexplained drop in the hemoglobin concentration and hematocrit. Hemoptysis may be present. Bronchoscopy often reveals frothy bloody secretions throughout the airways and there will be an increasing amount of red blood cells in serial bronchoalveolar lavage specimens. The recovery of hemosiderin-laden macrophages from bronchoalveolar lavage fluid is strongly suggestive of diffuse alveolar hemorrhage.
  • Cryptogenic organizing pneumonia (COP)/ BOOP often mimics community-acquired pneumonia with an flu-like intial symptoms with fever, malaise, fatigue, and cough. The most common features at presentation are a persistent nonproductive cough, dyspnea with exertion, and weight loss. Bronchoalveolar lavage usually contains a smaller proportion of macrophages and higher proportions of lymphocytes, neutrophils, and eosinophils than healthy patients. This "mixed pattern" of increased cellularity is thought to be characteristic of COP. The diagnosis is made by ruling out infectious causes of pneumonia and noticing typical pathologic changes in tissue obtained by open lung biopsy. It is treated with steroids for 6 months.
  • Acute interstitial pneumonia is a rare and fulminant form of diffuse lung injury that has a presentation similar to ARDS. The distinguishing characteristic is that ARDS is often associated with a known risk factor, whereas acute interstitial pneumonia is not.
  • Idiopathic acute eosinophilic pneumonia (IAEP) occurs in previously healthy individuals and is characterized by cough, fever and dyspnea. Bronchoalveolar lavage specimens always contain a large number of eosinophils, and peripheral eosinophilia may or may not be present.
  • Cancer can disseminate through the lungs so rapidly that the ensuing respiratory failure may be mistaken for ARDS. This is most often due to lymphoma or acute leukemia
Supportive Care :  Mortality rate is very high in patients due to ARDS and majority of them die of secondary complications such as sepsis or multiorgan system failure. Only a few of them due to acute respiratory failure. They require meticulous supportive care, including intelligent use of sedatives and neuromuscular blockade, proning, hemodynamic management, nutritional support, control of blood glucose levels, expeditious evaluation and treatment of nosocomial pneumonia, and DVT and GI prophylaxis.
  • Sedation and analgesia are useful in patients with ARDS because they decrease oxygen consumption and improve tolerance of mechanical ventilation. Since many patients with ARDS require sedation for several days or longer, long-acting agents such as lorazepam are a logical choice.
  • Nutritional support — Patients with ARDS are intensely catabolic and benefit from nutritional support
  • Prevention — Nosocomial pneumonia is difficult to prevent since patients with ARDS are frequently malnourished and immunosuppressed. HOB elevation in mechanically ventilated patients, particularly those receiving enteral feedings, has been associated with a significant decrease in the rate of ventilator-associated pneumonia
  1. Supplemental oxygen: Most patients require a high FiO2, especially early in ARDS when pulmonary edema is most severe. High flow nasal cannula can provide upto 90% oxygen noninvasively.  Patients whose oxygenation improves dramatically with supplemental oxygen generally have a small shunt and a larger component of ventilation-perfusion mismatch (or hypoventilation). When patients require lot of supplemental oxygen. it indicated larger shunt and may benefit from alveolar recruitment by non invasive or invasive positive pressure ventilation. At levels above 50% FiO2, the risk of oxygen toxicity is increased with a resultant oxygen free radical production and more lung damage. Hence, give only the amount of oxygen needed to keep SaO2 of 90% or greater. Hyperoxia also causes wash out of nitrogen in alveoli resulting in absorptive atelectasis. Hyperoxia also results in worsening of hypercarbia in patients with chronic respiratory acidosis.
        Oxygen-ICU trial: Among critically ill patients with an ICU length of stay of 72 hours or longer, a conservative protocol for oxygen therapy vs conventional therapy resulted in lower ICU mortality. JAMA. 2016 Oct 18;316(15):1583-1589.
  1. Fluid management: Increased vascular permeability is the primary cause of pulmonary edema in early ARDS. A conservative strategy of fluid management is warranted in patients with ARDS, as long as hypotension and organ hypoperfusion can be avoided. It is reasonable to target a central venous pressure of <4 mmHg or a pulmonary artery occlusion pressure <8 mmHg. ( FACTT Trial)
  2. Prone positioning: Prone positioning improved oxygenation in the majority of patients with ARDS, and recent data showed mortality benefits. For those patients with P/F ratio <150 with FiO2<60%, prone positioning for 18 hours a day should be considered in the first 48 hours, after 12 hrs of optimal mechanical ventilation support. (PROSEVA study).  Crit Care. 2011;15(1):R6 ,  Intensive Care Med. 2014 Mar;40(3):332-41. 

In the prone position, CT scan densities redistribute from dorsal to ventral as the dorsal region tends to reexpand while the ventral zone tends to collapse. Although gravitational influence is similar in both positions, dorsal recruitment usually prevails over ventral derecruitment, because of the need for the lung and its confining chest wall to conform to the same volume. The final result of proning is that the overall lung inflation is more homogeneous from dorsal to ventral than in the supine position, with more homogeneously distributed stress and strain. As the distribution of perfusion remains nearly constant in both postures, proning usually improves oxygenation. Also, by proning, the chest wall expansion is minimized and hence, pleural pressures will not be as much negative. Hence, we can decrease the transpulmonary pressures as well. It acts by less lung deformation in prone position, improving V/Q matching, much uniform distribution of plateau pressure, increase in FRC, improved drainage of secretions, decreased transpleural pressure gradient between dependent and non-dependent lung in the prone position, decreased transpulmonary pressures and more uniform distribution of plateau pressure and thereby alveolar ventilation. 

Contraindications to proning include hemodynamic instability, high ICP, high intra abdominal pressure.

  1. Decrease oxygen consumption: In diseases with severe pulmonary shunting, increasing the saturation of mixed venous blood (SvO2) may increase the SaO2,. Therapies that decrease oxygen consumption may improve SvO2 (and SaO2 subsequently) by decreasing the amount of oxygen extracted from the blood. Common causes of increased oxygen consumption include fever, anxiety and pain, and use of respiratory muscles; therefore, arterial saturation may improve after treatment with anti-pyretics, sedatives, analgesics, or paralytics
  2. Decreasing shunt fraction: Measures like proning , PEEP optimization to open up the collapsed alveoli help tp reduce the shunt fraction and improve oxygenation. However, increasing PEEP in a non recruitable lung may cause overdistension of normal alveoli resulting in collapse of pulmonary arterioles and thereby increasing pulmonary vascular resistance. It may lead to drop in cardiac output and decreased oxygen delivery. 
  3. Increase oxygen delivery — Oxygen delivery is determined by the following formula:

 DO2 = 10 x CO x (1.34 x Hgb x SaO2 + 0.003 x PaO2)

Cardiac output may be augmented by raising filling pressures with iv fluids and by using inotropic agents in patients with systolic heart failure. However, there is no role for augmenting cardiac output to supraphysiological numbers.

Mechanical ventilation in ARDS
The goal is to avoid overstretch (volutrauma) and inadequate recruitment (atelectrauma). The mode of ventilation ( Volume control or pressure control ) is not as improtant as keeping the transalveolar pressure under 30. In pressure control mode, the peak pressure and the plateau pressure are the same. One of the most common wrong assumption is to put a patient under pressure regulated volume control ( PRVC or VC+) and assume that its a pure volume control mode because we set up some tidal volume target as well. Remember, PRVC is a volume guaranteed pressure control mode and hence, patient can have unlimited flow and tidal volumes may be extremely high if patient is putting lot of effort.
  • Low Tidal Volume ventilation:  Low tidal volume ventilation (LTVV) is also referred to as lung protective ventilation. Smaller tidal volumes are less likely to generate alveolar overdistension, thereby leading to less ventilator-associated lung injury. ( Study)
Hypercapnic respiratory acidosis was an expected and generally well tolerated consequence of LTVV. Permissive hypercapnea is allowed as long as PH is >7.15. ARDS protocol allows respiratory rate as high as 35 for worsening acidosis. The degree of hypercapnia can be minimized by using the highest respiratory rate that does not induce auto-PEEP and shortening the ventilator tubing to decrease dead space. In an overzelaous enthusiasm to implement low tidal volume ventilation, some physicians ignore even PH values less than 7 and it is dangerous, considering the risks of severe acidemia. In those situations, after changing the rate upto 35, it is acceptable to relax the tidal volumes to 7cc/kg to bring the PH to atleast 7.15.
When respiratory rates are high, Auto-PEEP may develop due to very small expiratory time.
Work of breathing and patient-ventilator asynchrony may increase when tidal volumes are <7 mL/kg of predicted body weight (PBW) and hence, patients may need to be sedated. Breath stacking is a manifestation of asynchrony that can occur despite deep sedation. It causes episodic delivery of higher tidal volumes, which may undermine the benefits of LTVV. Frequent breath stacking (more than three stacked  breaths/min) can be ameliorated by delivering slightly higher tidal volumes (7 to 8 mL/kg PBW), as long as the plateau airway pressure remains less than 30 cm H2O, or by administering additional sedation or paralytics.
The initial tidal volume is set to 8 mL/kg IBW and the initial respiratory rate is set to meet the patient's minute ventilation requirements. Over the next one to three hours, the tidal volume is reduced to 7 mL/kg IBW and then 6 mL/kg IBW. The PIW is calculated using the following equations:
Male = 50 + 2.3 [height (inches) – 60]
Female =     45.5 + 2.3 [height (inches) – 60
The biggest benefit is achieved when both tidal volumes and plateau pressure are low. The benefit is not as big when plateau pressure is less than 30 but tidal volumes are high. Subsequent tidal volume adjustments are made on the basis of the plateau airway pressure, as measured using a 0.5 second inspiratory breath hold. The plateau airway pressure is checked at least every four hours and after each change in PEEP or tidal volume. The goal plateau airway pressure is ≤30 cm H2O. When the plateau airway pressure is >30 cm H2O, the tidal volume is decreased in 1 mL/kg PBW increments to a minimum of 4 mL/kg PBW. Change both PEEP and FiO2 simultaneously, as the requirements go down. Attempt weaning by PS when FIO2/PEEP combination is, 0.4 mm Hg/8 mm Hg.
  • High PEEP :  The rationale for delivering a high PEEP is that it opens collapsed alveoli, which decreases alveolar overdistension because the volume of each subsequent tidal breath is shared by more open alveoli. If the alveoli remain open throughout the respiratory cycle, cyclic atelectasis is also reduced.
By recruiting additional alveoli, PEEP decrease intrapulmonary shunting and improves oxygenation. However, PEEP can also be detrimental because it could over distend compliant alveoli and worsen ventilation/perfusion matching or even create dead space.
  • Recruitment Maneuvers — A recruitment maneuver is the brief application of a high level of continuous positive airway pressure, such as 35 to 40 cm H2O for 40 seconds. However, much of the recruitment occurs in the first 10 secs and hence, CPAP of 40 for 10 seconds is acceptable. The purpose of recruitment maneuvers is to open alveoli that have collapsed.
Most studies of recruitment maneuvers have looked at physiologic outcomes, such as oxygenation. The impact of routine recruitment maneuvers on clinical outcomes is unclear. There is no consensus regarding the best level of continuous positive airway pressure or the optimal frequency or duration of the maneuvers. The arterial oxygen tension (PaO2) generally increases after a recruitment maneuver. Recruitment maneuvers may be particularly beneficial after a patient has been disconnected from the ventilator (eg, tubing changes, transport) because even a brief moment without PEEP can result in alveolar collapse. Routine recruitment maneuvers are not indicated except when patient has refractory hypoxemia.
  • Refractory hypoxemia — Refractory hypoxemia can occur even if the applied PEEP and FiO2 are optimized. In this situation, increasing the I: E ratio by prolonging inspiratory time may improve oxygenation. Adjust for I: E of 1.1:1.3. The inspiratory time can be directly set during pressure limited ventilation. It is indirectly prolonged during volume limited ventilation by decreasing the inspiratory flow rate, changing from a square wave to a decelerating wave (Decelerating wave form produces less peak airway pressures, increased mean airway pressures but prolonged I-time) , or providing an end inspiratory breath hold. Increasing the I: E ratio will increase the mean airway pressure and may improve oxygenation in some patients.
Prolonging the inspiratory time can be an effective means of improving oxygenation in some patients with ARDS because the parenchymal abnormalities are heterogeneous, with different areas of the lung requiring more time to open and participate in gas exchange i.e times constants are different for different areas of lung. When the inspiratory time is increased, there is an obligatory decrease in the expiratory time. This can lead to air trapping, auto-PEEP, barotrauma, hemodynamic instability, and decreased oxygen delivery. In addition, a prolonged inspiratory time may require significant sedation or neuromuscular blockade, particularly if the inspiratory time surpasses the expiratory time (inverse ratio ventilation).
  • Glucocorticoids — The role of glucocorticoids in the management of ARDS is a source of ongoing controversy. Systemic glucocorticoids clearly have a role in situations when ARDS has been precipitated by a steroid-responsive process (eg, acute eosinophilic pneumonia). There might be some role for steroids if given within 14 days. However, in ARDS due to H1N1, there was an increased mortality with steroids. There are clearly worse outcomes if given after 14 days in any ARDS patient. 
  • THAM: In patients with elevated PCO2 and respiratory acidosis, some people use bicarb drip to correct the acidemia and it is a very dangerous practice. First of all, Ph >7.15 is easily tolerated and doesn't need any correction. Also, bicarb combines with H+ and produce CO2+H2o, resulting in worsening of PCO2 and thereby respiratory acidosis. THAM is a amion alcohol that buffers H+ ions without generating CO2. Also, unlike sodium bicarb, THAM is not a sodium salt and doesn't add unnecessary sodium load to the body. 
  • Extracorporeal Gas Exchange ( ECMO): The use of extracorporeal gas exchange (i.e. extracorporeal membrane oxygenation or ECMO) to adequately oxygenate and ventilate the blood.
Rescue therapy for refractory hypoxemia:
  1. Neuromuscular blockers
  2. Inhaled Flolan : also reduce PA pressures resulting in increased cardiac out put and thereby increased oxygen delivery.
  3. NO: given in 20ppm to 80ppm but anything >40ppm doesn’t add much. iNO is a potent, selective pulmonary vasodilator of those area of the lung being ventilated. Thus, it decreases pulmonary vascular resistance and PA pressures. Check methemoglobin levels daily. Watch for rebound hypoxia on abrupt stopping. Side effects include hypotension, AKI, platelet inhibition and prolonged bleeding time. Its elimination t1/2 is 5 seconds. In a meta analysis of 9 studies, there was no mortality benefit. Crit Care Med. 2014 Feb;42(2):404-12
  4. Proning
  5. Recruitment maneuvers
  6. Inverse ration ventilation
  7. APRV
  8. Tracheal gas insufflation: decrease circuit deadspace with a resultant decrease in PCO2 and increase in PO2/SaO2.
  9. ECMO
PEEP Titration strategies in ARDS:
There are many strategies used to optimise the PEEP levels for a given patient. The goal of PEEP titration is to minimise the amount of oxygen used and maximise the recruitment.  In other words, PEEP should be set to maintain oxygenation while preventing lung injury from alveolar collapse (atelectrauma) or overdistension. Set PEEP to maintain a transpulmonary pressure of 0 to 10 cm H2O at end expiration and below 25cm H2O at end inspiration. All these methods are dynamic and PEEP needs to be adjusted periodically. PEEP goals are reassessed as clinical condition changes. Some of the methods are:
  1. ARDSnet table : Simply use the ARDS protocol to titrate the PEEP and FiO2. It is a very common mistake to use 100% FiO2 with a PEEP of 5. With a 100% FiO2, ARDSnet protocol allows a PEEP of 18-24.
  2. Compliance measurement: The purpose of increasing PEEP is to recruit more lung and if increased PEEP is successful in recruiting more lung, it leads to better compliance and lower plateau pressures. Keep increasing the PEEP as long as plateau pressures are coming down and when plateau pressure is stable or slowly rising, thats the ideal PEEP.
  3. Oxygenation : Keep the SaO2 around 90%. As you increase PEEP, if the lung is recruitable, it leads to better oxygenation and SaO2 should improve. Cut back on the FiO2 and repeat the same. When sats doesn't improve any further with increase in PEEP, thats the ideal PEEP.
  4. End tidal CO2: As recruitment increase with uptitration of PEEP, the alveolar dead space decrease and hence, EtCO2 will decrease.
  5. Inflection points on pressure volume curves
  1. ALVEOLI study by ARDSnet: patients were randomized to high PEEP vs. low PEEP using tables of predetermined combinations by ARDSnet. The average P/F ratio in both groups before randomization is around 150. After randomization, average PEEP in low group was 10 and in high group was 15. In higher PEEP, they used peep as high as 24. It was interesting to note that even in high PEEP group, the average plateau pressure was still less than 30. They kept O2 sats between 88-95. There was no difference in hospital mortality rates or number of ventilator free days or ICU length of stay. There was a better P/F ratio, better compliance and higher plateau pressures in high PEEP group.
  1. EXPRESS study: patients were randomized to low PEEP vs. high PEEP to achieve a plateau pressure of 28-30 to improve recruitment.  Average P/F ratio in both groups was around 150 and plateau pressure around 23. Also, average PEEP in high group was only 15.
There was no difference in mortality rates. But, higher PEEP group had better ventilator free days, better oxygenation, better compliance and better organ free days. There was also less use of rescue therapies in higher peep group. Incidence of pneumothorax was same in both groups.
In alveoli study, maybe we didn’t see the benefit of high PEEP because pts who don’t have recruitable lung are also getting high PEEP based on poor oxygenation alone. However, in this study, if pt doesn’t have recruitable lung, their plateau pressure will be above 30 and we won’t be adding unnecessary PEEP.
  1. LOV study: Patients were randomized to low PEEP vs. high PEEP with recruitment maneuvers but allowed plateau pressure to be as high as 40. However, the average plateau pressure in experimental group was 30.
Patients started with a recruitment maneuver, which included a 40-second breath hold at 40 cm H2O airway pressure, on an FIO2 of 1.0. After the initial recruitment maneuver, starting with PEEP at 20 cm H 2 O, both FIO 2 and PEEP were reduced as per table. In this approach, even on 50% oxygen, pts were allowed peep as high as 20. However, the average PEEP even in high group was only 15. There was no difference in mortality rates but improved secondary end points related to hypoxemia and rescue therapies. It is unclear why the same benefit was not obtained in ALVEOLI trial, even though they also used recruitment in the early stages of plan.
  1. In a meta analysis comparing all there above studies, there was some mortality benefit in high PEEP group in ARDS patients and some increased risk of high peep in non ards group.
  2. In summary, Use high PEEP in severe ARDS with P/F ratio <150 and lower PEEP in mild ARDS and non ARDS pts. LOV’s strategy provides low PEEP in mild ards and high PEEP in severe ARDS.
  3. Advantages of high PEEP are increased FRC (prevention of airway collapse), increase in oxygenation, improved distribution of inspired gas, recruitment of alveoli by preventing cyclic de-recruitment on expiration, decreased airway resistance, reduced V/Q mismatch, reduced work of breathing, reduction in LV afterload (due to increased LV transmural pressure) with decreased preload and work of breathing.
  4. Disadvantages of high PEEP are decreased RV preload, increased RV afterload, decreased LV compliance (due to intra-ventricular septum displacement), increased pulmonary vascular resistance (PVR) (in West’s zone I and II where increased alveolar pressure exceeds venous pressure), decreased flow in West’s zone I causing increased dead space (PA > Pa >Pv) and increased ICP.
Clinical Trials:
  1. Steroids in early ARDS within 72 hours (Meduri): A loading dose of 1 mg/kg was followed by an infusion of 1 mg/kg/d from day 1 to day 14, 0.5mg/kg/d from day 15 to day 21, 0.25 mg/kg/d from day 22 to day25, and 0.125 mg/kg/d from day 26 to day 28. Steroids were initiated within 72 hours and were given for a total of 4 weeks. If they are extubated, their dose was advanced to that of day 15. Patients had a baseline P/F ratio of around 120 and PEEP of 12.
Methylprednisolone-induced down-regulation of systemic inflammation was associated with significant improvement in pulmonary and extrapulmonary organ dysfunction and reduction in duration of mechanical ventilation and ICU length of stay as well as mortality.
There were higher number of catecholamine dependent shock in control group (23 vs. 46%). Is their worse mortality due to lack of steroids or septic shock? The infection rate is actually lower in steroid group (16% vs. 29%). Chest. 2007 Apr; 131(4):954-63.
  1. Continuous Solumedrol infusion in early ARDS within 7 days:  In early ARDS, administration of methylprednisolone was associated with improvement in important biomarkers of inflammation and coagulation and clinical outcomes at 7 days.  Methylprednisolone decreased interleukin-6 and increased protein C levels (thereby improving coagulation profile) compared with control subjects during the first 7 days after onset of ARDS. Patients had a baseline P/F ratio less than 150.
Methylprednisone was given as early continuous low-dose infusion (1 mg/kg/day for 14 days and then tapered over 2 wks). Steroids were given for a total of 4 weeks. Patients who received methylprednisolone had greater improvement in Lung Injury Score, shorter duration of mechanical ventilation, and lower intensive care unit mortality than the patients who received usual care (Crit Care Med 2012 Vol. 40, No. 2)
  1. Steroids in persistent (Late) ARDS (7-28 days) or Late Steroid Rescue Study (LaSRS): Patients were eligible for enrollment 7-28 days after onset of ARDS. It was done by national heart, lung and blood institute. A single dose of 2 mg of methylprednisolone/Kg was followed by a dose of 0.5 mg/kg every 6 hours for 14 days, a dose of 0.5 mg/kg every 12 hours for 7 days, and then tapering of the dose.
Methylprednisolone increased the number of ventilator-free and shock free days during the first 28 days in association with an improvement in oxygenation, compliance, and blood pressure with fewer days of vasopressor therapy. It did decrease mortality slightly in patients enrolled between 7-14 days (36 vs. 27%). But, Methylprednisolone was also associated with significantly increased 60-and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS. Rate of infections was the same in both groups. But, resumption of ventilator assistance as well as neuromyopathy was more in steroid group.
It does not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death.  N Engl J Med 2006; 354:1671-1684
  1. Steroids in ARDS (Meta analysis by Meduri): Prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcome variables, and has a distinct survival benefit when initiated before day 14 of ARDS. Intensive Care Med. 2008 Jan; 34(1):61-9.
  2. Steroids in ARDS (Meta analysis by Lamontagne):  Corticosteroids did not significantly reduce hospital mortality. In a subgroup analysis by dose of corticosteroid, trials using the equivalent of 2 mg/kg/day or less of  methylprednisolone found lower hospital mortality with corticosteroid therapy. We conclude that the current evidence does not support strong conclusions regarding the benefit of systemic corticosteroids for patients with ALI, ARDS, and pneumonia. Low-dose regimens initiated less than 14 days after disease onset and continued for 7 days or more seem promising.  Journal of Critical Care (2010) 25, 420–435
  3. Steroids in H1N1 ARDS: corticosteroids use in ARDS from H1N1 was associated with increased mortality. AJRCCM 2011; 183:1200-1206., AJRCCM2011; 183:1207-1214.
  4. NO in ARDS: Inhaled nitroc oxide may provide only marginal oxygenation benefit but no effect on mortality and very costly. Critical Care Medicine 2014; 42(2):404-412. Anesth Analg. 2011 Jun;112(6)
  5. Neuromuscular blockers in ARDS (ACURASYS Trial): In patients with severe ARDS, early administration of a neuromuscular blocking agent within first 48 hours for 48 hours improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. NEJM 363:12 pages 1107-1116
  6. ECMO in ARDS: randomly assigned 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients had severe (Murray score >3·0 or pH <7·20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H₂O of peak inspiratory pressure) or high FiO₂ (>0·8) ventilation for more than 7 days. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital.  
Conclusion: We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3·0 or who have a pH of less than 7·20 on optimum conventional management, to a center with an ECMO-based management protocol to significantly improve survival without severe disability. 
Murray score is derived from four variables : PaO2/FiO2 ratio, PEEP, lung compliance, and chest radiograph appearance and FiO2=1.  Much sicker patients with higher plateau pressures and prolonged mechanical ventilation were excluded. Also, mortality rates improved just by transfer of care to higher centers, even if the patients didn't get ECMO. Standard of care might be higher in academic centers leading to confounding bias.  Did the higher use of better low TV/low pressure strategy, proning and steroids lead to better outcomes in ECMO group? did the higher use of HFOV in control group lead to worse outcomes? CESAR Study
  1.  OSCAR Trial (HFOV vs. standard ventilation): Patients were randomized to HFOV vs. conventional ventilation.  Oxygenation improved with HFOV when compared with conventional ventilation. All cause mortality at 30 days was 41.7% in HFOV vs. 41.1% in control.  40% mortality in both groups is pretty high.
ConclusionsHFOV improved oxygenation but did not improve 30 day mortality when compared with conventional ventilation in patients with ARDS. Also, patients receiving HFOV required higher doses of sedatives and greater use of neuromuscular blocking agents. NEJM 2013; DOI: 10.1056/NEJMoa1215716 
  1. OSCILLATE Trial (HFOV vs. standard ventilation): Patients were randomized to HFOV vs. conventional ventilation. All patients assigned either to HFOV or conventional group had an intial recruitment maneuver by applying 40 cm of water pressure for 40 seconds to the airway opening in an effort to reopen closed lung units. Oxygenation improved better with HFOV when compared with conventional ventilation  but mortality was 47% in HFOV vs. 35% in control.  HFOV group received more neuromuscular blockers, vasoactive drugs and more sedation ( Note: 35-47% mortality in both groups is pretty high). 
Conclusions In adults with moderate-to-severe ARDS, early application of HFOV, as compared with a ventilation strategy of low tidal volume and high positive end-expiratory pressure, does not reduce, and may increase, in-hospital mortality. N Engl J Med 2013; 368:795-805.
  1.  Fluid restrictive vs. liberal strategies (FACTT Trial):  Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing non pulmonary-organ failures. (N Engl J Med 2006; 354:2564-2575)
  2. PROSEVA Study (Proning in ARDS): Patients with PaO2:FiO2 <150mmHg with FiO2 ≥0.6, PEEP ≥5, TV~6cc/kg, were proned for at least 16 consecutive hours, for 28 days, or until improvement to set standard. All cause mortality at 28 days was 16% in prone group vs. 33% in supine group. 
Conclusions: In moderate ARDS with P/F ratio <150 and with FiO2 of at least 0.6, PEEP at least 5 cm), and TV 6 ml/kg of IBW, Proning the patients for 16 hours a day for 28 days resulted in 50% reduction in mortality at 28 days and 90 days. The effect was not significant if P/F ratio is >150.    N Engl J Med. 2013 Jun 6;368(23):2159-68.
  1. Effects of PEEP and pressure support in ARDS on tidal volume distribution:  In patients with acute respiratory distress syndrome undergoing pressure support ventilation, higher PEEP and lower pressure support levels increase the fraction of tidal ventilation reaching dependent lung regions, yielding more homogeneous ventilation and, possibly, better  ventilation/ perfusion coupling.  This study was done in only mild to moderate ARDS and has only 10 patients in the study. (Crit Care Med 2013; 41:1664–1673)
  2.  PEEP selection based on esophageal pressure ( Thalmore Study):
Selecting PEEP to get an end expiratory transpulmonary pressure of 0-10 resulted in improved oxygenation without causing over or under distension. PEEP levels were set to achieve a transpulmonary pressure of 0 to 10 cm of water at end expiration, according to a sliding scale based on the partial pressure of arterial oxygen (PaO2) and the fraction of inspired oxygen (FiO2). We also limited tidal volume to keep transpulmonary pressure at less than 25 cm of water at end inspiration. In both groups, the goals of mechanical ventilation included a PaO2 of 55 to 120 mm Hg or a SaO2 of 88 to 98%, pH of 7.30 to 7.45, and a PaCO2 of 40 to 60 mm Hg.
At end expiration, PEEP tries to keep alveoli open and positive pleural pressure tries to close the alveoli. If PEEP is sub-optimal based on plateau pressures, it may lead to derecruitment. Plateau pressures may be falsely high, if pleural pressure is very high as in cases of morbid obesity or intraabdominal hypertension. In that case, we may have to increase PEEP to keep transpulmonary pressure between 0-10. 
In ARDS patients with high pleural pressures, raising PEEP to maintain a positive transpulmonary pressure might improve aeration and oxygenation without causing over distention. Similarly, in patients with low pleural pressure, maintaining low PEEP would keep transpulmonary pressure low, preventing overdistention and minimizing the adverse hemodynamic effects of high PEEP.
Oxygenation and respiratory-system compliance improved in the esophageal-pressure–guided group as compared with the control group. There was no significant difference between the groups in ventilator-free days at day 28 or length of stay in the ICU. The mortality rate at 28 days was lower among patients in the esophageal-pressure–guided group than among control patients, although the difference was not significant. Multivariable analysis showed that after adjustment for baseline APACHE II score, the esophageal-pressure protocol was associated with a significant reduction in 28-day mortality. (N Engl J Med 2008; 359:2095-2104)
  1. Beta agonists in ALI( ALTA Study, BALTI-1 and BALTI-2 study): In animal studies, beta agonists accelerated resolution of pulmonary edema in experimental models. Potential beneficial effects of this therapy include enhanced mucociliary clearance, improved lung mechanics and decreased work of breathing. However, when tested in human subjects with ALI, albuterol didn't significantly improve ventilator free days. Routine use of bronchodilators in mechanically ventilated patients with ARDS/ALI is not recommended. Am J Respir Crit Care Med Vol 184. pp 561–568, 2011. 
In another study, iv salbutamol also increased mortality in ARDS. The lancet. Vol 379 January 21, 2012
  • 6 cc tidal volume for 6 feet male is roughly 450cc and for female is 400cc.
  • Recruitability: With an increase in PEEP, the compliance increases, P/F ratio improves and dead space fraction decreases.
  • Recruitment: CPAP of 40 for 40 secs (Usually 10 secs is enough) and then switch to previous mode. But, increase the baseline PEEP after recruitment to prevent derecruitment. PEEP prevents derecruitment.
  • Other method of recruitment is to increase both driving pressure and PEEP, one to recruit and another to prevent derecruitment.
  • Post recruitment PEEP: gradually decrease PEEP until SaO2 drops. PEEP is decreased by 2cm every 4 mins. If sats drop, do recruitment maneuver again and go back to previous PEEP.
  • Low PEEP, high FiO2 strategy: High oxygen foster free radical generation and causes absorption atelectasis.
  • NIPPV is risky in severe ARDS as it is very difficult to avoid high tidal volumes and transpulmonary pressures are high.
  • Mean RR in all major ARDS trials is around 30.
  • Draw backs of HFOV are: they need very high doses of sedatives/paralytics to avoid spontaneous breathing. They also have higher mean airway pressures resulting in lower blood pressure, thereby leading to increased fluid boluses and volume overload. 
  • Excessive focus on SaO2 may drive excessive use of interventions which carry substantial risks (e.g. increased airway pressures may cause barotrauma and shock, elevated FiO2 may cause lung toxicity). Oxygen delivery and extraction ratio may be much better markers of oxygenation than SaO2. Oxygen extraction can be indirectly measured using ScVO2.
  • Oxygen extraction ratio >50% is typically quoted in the literature as correlating with hypoperfusion, lactic acidosis, and poor outcomes.
  • Bicarb drip is used by many people to counteract respiratory acidosis. However, bicarb is metabolized into Co2 and H2O resulting in worsening PCO2 levels and thereby worsening acidosis. Can use THAM ( Tromethamine Sulphate) which acts as a buffer for acidity without affecting CO2 levels. 

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