Acute Respiratory Distress Syndrome (ARDS)

ARDS Symptoms, Causes & Risk Factors

ARDS may initially be diagnosed as pneumonia or pulmonary edema (fluid in the lungs from heart disease). However, your doctor may suspect ARDS if you are not getting better and have one of the known causes of ARDS.

What Are Symptoms of ARDS?
Patients with ARDS have shortness of breath, often severe. They also have a cough and many have fever. Those with ARDS also have fast heart rates and rapid breathing. Occasionally, they experience chest pain, especially during inhalation. Some patients who have very low oxygen levels may have bluish coloring of nails and lips from the severely decreased oxygen levels in the blood.

What Causes ARDS?
The causes of ARDS are divided into two categories: direct or indirect injuries to the lung.

Some of the direct injuries to the lung include pneumonia, breathing stomach contents into the lung (also known as aspiration), near drowning, lung bruising from trauma (such as a car accident) and smoke inhalation from a house fire.

The indirect injuries to the lung include inflammation of the pancreas, severe infection (also known as sepsis), blood transfusions, burns, and medication reactions.
Fortunately, most patients with the above problems will not develop ARDS. It is not known why some will.

What Are Risk Factors?
While it is not clear who will develop ARDS, there are a few factors that may increase the risk for ARDS. These factors include:
•A history of cigarette smoking
•Oxygen use for a pre-existing lung condition
•Recent high-risk surgery
•Obesity
•Low protein in the blood
•Alcohol abuse
•Recent chemotherapy

When to See Your Doctor?
Most patients who develop ARDS will already be in the hospital, but some may not be hospitalized. Call your doctor or 911 if you experience severe shortness of breath, or if you have a new cough or fever.

Diagnosing and Treating ARDS

How Is ARDS Diagnosed?
The diagnosis is based on your symptoms, vital signs, and a chest X-ray. There is no single test to confirm the diagnosis of ARDS. Patients with ARDS will have rapid onset of shortness of breath and very low oxygen levels in the blood. The chest X-ray will show fluid present in both lungs (often described as "infiltrates" by doctors reading chest X-rays). Since ARDS and some heart problems have similar symptoms, your doctor might perform certain tests to rule out a heart problem.

How Is ARDS Treated?
Because there is no direct cure for ARDS, treatment focuses on supporting the patient while the lung heals. ARDS will often worsen in the first few days following the diagnosis before the lung begins to heal. The goal of this supportive care is to keep enough oxygen in the blood to prevent further damage to your body and to treat whatever caused ARDS in the first place. Another important part of the care for ARDS is to prevent and manage complications related to being in an intensive care unit.

Ventilator support
All patients with ARDS will require oxygen therapy. Oxygen alone is usually not enough, and you will likely need to be supported by a ventilator. A ventilator is a machine that delivers breaths and oxygen therapy through a tube inserted into the trachea or windpipe.

Prone positioning
Hospitalized patients are typically in bed on their backs. However, lying face down (prone) may help improve oxygen levels in the blood and increase survival in patients with ARDS. This can be a very complicated task that takes an entire team to accomplish, and some patients may be too sick for this treatment. There are specialized beds designed to help position patients in the intensive care unit face down and, although they are convenient, they are not absolutely necessary for this therapy.

Sedation and medications to prevent movement
It is uncomfortable and painful to be supported by a ventilator. This often leads to restlessness and agitation, which can cause even more problems for the lungs. In order to keep comfortable and prevent this, the patient may need sedation to remain calm. There are medications called paralytics that can temporarily prevent patients from moving. Because the side effects related to these medications are significant, the risks and benefits need to be closely considered.

Fluid management
Sometimes doctors will give patients with ARDS a medication called a diuretic to help increase urination. This removes fluid from the body and can help prevent fluid from building up in the lungs. This must be done carefully, because too much fluid removal can lead to low blood pressure or kidney problems.

ECMO
ECMO stands for extracorporeal membrane oxygenation. This is a very complicated treatment that takes blood outside of your body and pumps it through a membrane that adds oxygen and removes carbon dioxide and then returns the blood to your body. This is a high-risk therapy with many complications. It is not suitable for every patient.

ARDS-Symptoms and causes

Overview

Acute respiratory distress syndrome (ARDS) occurs when fluid builds up in the tiny, elastic air sacs (alveoli) in your lungs. The fluid keeps your lungs from filling with enough air, which means less oxygen reaches your bloodstream. This deprives your organs of the oxygen they need to function.

ARDS typically occurs in people who are already critically ill or who have significant injuries. Severe shortness of breath — the main symptom of ARDS — usually develops within a few hours to a few days after the precipitating injury or infection.

Many people who develop ARDS don't survive. The risk of death increases with age and severity of illness. Of the people who do survive ARDS, some recover completely while others experience lasting damage to their lungs.

Symptoms

The signs and symptoms of ARDS can vary in intensity, depending on its cause and severity, as well as the presence of underlying heart or lung disease. They include:
•Severe shortness of breath
•Labored and unusually rapid breathing
•Low blood pressure
•Confusion and extreme tiredness

When to see a doctor

ARDS usually follows a major illness or injury, and most people who are affected are already hospitalized.

Causes

The mechanical cause of ARDS is fluid leaked from the smallest blood vessels in the lungs into the tiny air sacs where blood is oxygenated. Normally, a protective membrane keeps this fluid in the vessels. Severe illness or injury, however, can cause damage to the membrane, leading to the fluid leakage of ARDS.

The most common underlying causes of ARDS include:
•Sepsis. The most common cause of ARDS is sepsis, a serious and widespread infection of the bloodstream.
•Inhalation of harmful substances. Breathing high concentrations of smoke or chemical fumes can result in ARDS, as can inhaling (aspirating) vomit or near-drowning episodes.
•Severe pneumonia. Severe cases of pneumonia usually affect all five lobes of the lungs.
•Head, chest or other major injury. Accidents, such as falls or car crashes, can directly damage the lungs or the portion of the brain that controls breathing.
•Others. Pancreatitis (inflammation of the pancreas), massive blood transfusions and burns.

Risk factors

Most people who develop ARDS are already hospitalized for another condition, and many are critically ill. You're especially at risk if you have a widespread infection in your bloodstream (sepsis).

People who have a history of chronic alcoholism are at higher risk of developing ARDS. They're also more likely to die of ARDS.

Complications

If you have ARDS, you can develop other medical problems while in the hospital. The most common problems are:
•Blood clots. Lying still in the hospital while you're on a ventilator can increase your risk of developing blood clots, particularly in the deep veins in your legs. If a clot forms in your leg, a portion of it can break off and travel to one or both of your lungs (pulmonary embolism) — where it blocks blood flow.
•Collapsed lung (pneumothorax). In most ARDS cases, a breathing machine called a ventilator is used to increase oxygen in the body and force fluid out of the lungs. However, the pressure and air volume of the ventilator can force gas to go through a small hole in the very outside of a lung and cause that lung to collapse.
•Infections. Because the ventilator is attached directly to a tube inserted in your windpipe, this makes it much easier for germs to infect and further injure your lungs.
•Scarring (pulmonary fibrosis). Scarring and thickening of the tissue between the air sacs can occur within a few weeks of the onset of ARDS. This stiffens your lungs, making it even more difficult for oxygen to flow from the air sacs into your bloodstream.

Thanks to improved treatments, more people are surviving ARDS. However, many survivors end up with potentially serious and sometimes lasting effects:
•Breathing problems. Many people with ARDS recover most of their lung function within several months to two years, but others may have breathing problems for the rest of their lives. Even people who do well usually have shortness of breath and fatigue and may need supplemental oxygen at home for a few months.
•Depression. Most ARDS survivors also report going through a period of depression, which is treatable.
•Problems with memory and thinking clearly. Sedatives and low levels of oxygen in the blood can lead to memory loss and cognitive problems after ARDS. In some cases, the effects may lessen over time, but in others, the damage may be permanent.
•Tiredness and muscle weakness. Being in the hospital and on a ventilator can cause your muscles to weaken. You also may feel very tired following treatment.

ARDS-Diagnosis and Treatment

Diagnosis

There's no specific test to identify ARDS. The diagnosis is based on the physical exam, chest X-ray and oxygen levels. It's also important to rule out other diseases and conditions — for example, certain heart problems — that can produce similar symptoms.

Imaging
•Chest X-ray. A chest X-ray can reveal which parts of your lungs and how much of the lungs have fluid in them and whether your heart is enlarged.
•Computerized tomography (CT). A CT scan combines X-ray images taken from many different directions into cross-sectional views of internal organs. CT scans can provide detailed information about the structures within the heart and lungs.

Lab tests
A test using blood from an artery in your wrist can measure your oxygen level. Other types of blood tests can check for signs of infection or anemia. If your doctor suspects that you have a lung infection, secretions from your airway may be tested to determine the cause of the infection.

Heart tests
Because the signs and symptoms of ARDS are similar to those of certain heart problems, your doctor may recommend heart tests such as:
•Electrocardiogram. This painless test tracks the electrical activity in your heart. It involves attaching several wired sensors to your body.
•Echocardiogram. A sonogram of the heart, this test can reveal problems with the structures and the function of your heart.

Treatment

The first goal in treating ARDS is to improve the levels of oxygen in your blood. Without oxygen, your organs can't function properly.

Oxygen
To get more oxygen into your bloodstream, your doctor will likely use:
•Supplemental oxygen. For milder symptoms or as a temporary measure, oxygen may be delivered through a mask that fits tightly over your nose and mouth.
•Mechanical ventilation. Most people with ARDS will need the help of a machine to breathe. A mechanical ventilator pushes air into your lungs and forces some of the fluid out of the air sacs.

Fluids
Carefully managing the amount of intravenous fluids is crucial. Too much fluid can increase fluid buildup in the lungs. Too little fluid can put a strain on your heart and other organs and lead to shock.

Medication
People with ARDS usually are given medication to:
•Prevent and treat infections
•Relieve pain and discomfort
•Prevent blood clots in the legs and lungs
•Minimize gastric reflux
•Sedate

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Lifestyle and home remedies

If you're recovering from ARDS, the following suggestions can help protect your lungs:
•Quit smoking. If you smoke, seek help to quit, and avoid secondhand smoke whenever possible.
•Get vaccinated. The yearly flu (influenza) shot, as well as the pneumonia vaccine every five years, can reduce your risk of lung infections.

Coping and support

Recovery from ARDS can be a long road, and you'll need plenty of support. Although everyone's recovery is different, being aware of common challenges encountered by others with the disorder can help. Consider these tips:
•Ask for help. Particularly after you're released from the hospital, be sure you have help with everyday tasks until you know what you can manage on your own.
•Attend pulmonary rehabilitation. Many medical centers now offer pulmonary rehabilitation programs, which incorporate exercise training, education and counseling to help you learn how to return to your normal activities and achieve your ideal weight.
•Join a support group. There are support groups for people with chronic lung problems. Discover what's available in your community or online and consider joining others with similar experiences.
•Seek professional help. If you have symptoms of depression, such as hopelessness and loss of interest in your usual activities, tell your doctor or contact a mental health professional. Depression is common in people who have had ARDS, and treatment can help.

Acute Respiratory Distress Syndrome: The Berlin Definition

ABSTRACT:
The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged.
Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance.
A draft definition proposed
3 mutually exclusive categories of ARDS based on degree of hypoxemia:
    mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg),
    moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and
    severe (PaO2/FIO2 ≤ 100 mm Hg) and
4 ancillary variables for severe ARDS:
    radiographic severity,
    respiratory system compliance (≤40 mL/cm H2O),
    positive end-expiratory pressure (≥10 cm H2O), and
    corrected expired volume per minute (≥10 L/min).

The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information.
The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition.
Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001).
Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001).
This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition.
The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.
(JAMA. 2012;307(23):2526-2533)

Note:
PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure to fractional inspired oxygen.
Fraction of inspired oxygen (FiO2) is the fraction of oxygen in the volume being measured. Medical patients experiencing difficulty breathing are provided with oxygen-enriched air, which means a higher-than-atmospheric FiO2. Natural air includes 21% oxygen, which is equivalent to FiO2 of 0.21. Oxygen-enriched air has a higher FiO2 than 0.21; up to 1.00 which means 100% oxygen. FiO2 is typically maintained below 0.5 even with mechanical ventilation, to avoid oxygen toxicity.

Acute Respiratory Distress Syndrome: Definition

Clinical review: Acute respiratory distress syndrome - clinical ventilator management and adjunct therapy

Berlin Definition of acute respiratory distress syndrome
• Timing - Within 1 week of a known clinical insult or new/worsening respiratory symptoms
• Chest imaging - Bilateral opacities - not fully explained by effusions, lobar/lung collapse, or nodules
• Origin of oedema - Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (for example, echocardiography) to exclude hydrostatic oedema if no risk factor present
• Oxygenation^b -
    Mild: PaO2/FiO2 ≤ 300, with PEEP or CPAP ≥ 5 cm H2O
    Moderate: PaO2/FiO2 ≤ 200, with PEEP ≥ 5 cm H2O
    Severe: PaO2/FiO2 ≤ 100, with PEEP ≥ 5 cm H2O

^bIf altitude higher >1,000 m, correction factor should be made as follows: PaO2/FiO2×(barometric pressure / 760).

Clinical ventilator management

Goals of mechanical ventilation
The goals of mechanical ventilation for ARDS are to minimise iatrogenic lung injury while providing acceptable oxygenation and carbon dioxide clearance.

While the contribution of ventilator-induced lung injury (VILI) to ARDS has not been fully elucidated, it is clear from animal models that mechanical ventilation can cause pathologic changes consistent with ARDS in the absence of other insults. Mechanisms of VILI include alveolar overdistension (volutrauma), repetitive alveolar opening and closure (atelectrauma), oxygen toxicity, and biotrauma, the pulmonary and systemic response to alveolar overdistension that may exacerbate lung inflammation and contribute to multiple organ dysfunction. Efforts to minimise VILI are focused on the use of low tidal volume ventilation to prevent volutrauma, the use of positive end-expiratory pressure (PEEP) to reduce alveolar collapse, and minimisation of exposure to potentially harmful oxygen concentrations. Specific therapies targeted at the immune response remain experimental to date.

Acceptable parameters for the partial pressure of arterial oxygen (PaO2) and the partial pressure of arterial carbon dioxide are difficult to define. Although PaO2 of 55 to 80 mmHg is considered the target range in many studies, more profound hypoxaemia may be well tolerated, as evidenced by the relatively rare occurrence of death due to refractory hypoxaemia in ARDS, the occurrence of well-tolerated profound hypoxaemia (average of 24.6 mmHg or 3.28 kPa) in climbers on Everest, and the reported survival of patients with ARDS and PaO2 <30 mmHg (4 kPa). However, caution should be exercised in view of the reported correlation between cognitive defects in survivors of ARDS and duration of arterial oxygen saturation <90%.

Inhalation of high concentrations of oxygen (fraction of inspired oxygen (FiO2) ≥ 0.8) is associated with progressive alveolar damage and death in animal studies. In healthy human volunteers exposed to high concentrations of oxygen, tracheobronchitis develops after several hours and prolonged exposure is associated with decreased vital capacity, increased dead space, increased production of reactive oxygen species, and biochemical markers of alveolar-capillary leak. In a small series of patients with ARDS, ventilation with 100% oxygen was associated with increased intrapulmonary shunt, attributed to nitrogen reabsorption and atelectasis. Compared with other aspects of VILI, however, relatively little work has been done on oxygen toxicity in adults with ARDS, and the threshold for toxicity, particularly in the setting of an open lung strategy and low tidal volume ventilation, is unknown. Based on the limited available data, our practice is to aim for FiO2 ≤ 0.6 and to consider adjunctive therapies where this cannot be achieved by recruitment manoeuvres and higher PEEP alone.

Since low tidal volumes are protective despite resulting in higher partial pressure of arterial carbon dioxide levels, there has been increasing acceptance of hypercapnia as being harmless or even potentially beneficial by virtue of rightward shift of the oxyhaemoglobin dissociation curve, systemic and microcirculatory vasodilatation, and inhibitory effects on neutrophils and other inflammatory cells. The optimal partial pressure of arterial carbon dioxide level for patients with ARDS is not clear, but mean levels of 66.5 mmHg (8.87 kPa) and pH 7.23 appear safe in the absence of a clear contraindication to hypercapnia, such as raised intracranial pressure.

Ventilation
Following numerous animal and observational human studies, the landmark ARDS Network study provided clear evidence of large mortality benefit when patients with ARDS were ventilated with a lung-protective strategy aimed at avoidance of alveolar overdistension using tidal volumes of 6 ml/kg predicted body weight (Box 1) with plateau pressures ≤30 cmH2O. Adjustment of the ventilator rate was used to target a normal pH, with a mean respiratory rate of 30 breaths/minute in the low tidal volume arm. Tidal volumes in patients with ARDS should therefore be in the order of 6 ml/kg predicted body weight with plateau pressures <30 cmH2O, accepting pH as low as 7.15 to achieve these targets.

Many ventilation modes have been employed in ARDS. To add to the confusion, manufacturers often use different names for similar modes. One must choose between spontaneous breathing modes with partial ventilatory support, or controlled modes; either a pressure-controlled mode in which tidal volume is the dependent variable, or a volume-controlled mode in which peak pressure may vary.

Spontaneous breathing with partial ventilatory support has been postulated to allow for better patient-ventilator synchrony, lower sedation requirements, and better preservation of diaphragmatic function with earlier liberation from mechanical ventilation. Data supporting this hypothesis, however, are currently very limited. A recent systematic review identified only two small randomised controlled trials (RCTs) addressing this question, both of which used airway pressure release ventilation as the spontaneous breathing mode. One of these trials suggested improved oxygenation and increased number of ventilator-free days, but concerns exist that these may have been driven largely by decrements in the control group; meanwhile, the other trial showed no effect on clinical outcomes. The main disadvantage of spontaneous breathing is the potential for the patient to generate high transpulmonary pressures and tidal volumes; suppression of this often requires the use of high doses of sedation with or without muscle relaxants. Balancing the risks between increasing sedation in order to provide lung protection and allowing spontaneous ventilation in a more awake patient is often a difficult clinical problem with limited applicable evidence. Our practice is to aim for spontaneous breathing with partial ventilatory support, frequently using pressure support ventilation in patients with mild to moderate ARDS, while in moderate to severe ARDS patients we use sedation and muscle relaxants as necessary to achieve lung-protective ventilation.

Proponents of pressure-controlled ventilation argue that this allows for better patient-ventilator synchrony, that the decelerating flow pattern allows better distribution of inspired gases, and that high transpulmonary pressures are more easily avoided. Conversely, volume-controlled ventilation allows safe tidal volumes to be delivered in a consistent pattern, thus avoiding alveolar overdistension. Pressure-regulated volume control ventilation aims to combine the advantages of both approaches, but may be problematic when patients are making variable or intermittent inspiratory efforts. There is no evidence of benefit for any one mode, the important point being to ensure both safe tidal volumes (6 ml/kg predicted body weight) and plateau pressures (≤30 cmH2O) regardless of the mode used.

Various less conventional modes (for example, proportional assist ventilation, neurally adjusted ventilatory assist, and so forth) have so far not been demonstrated to offer significant benefits over conventional modes of ventilation in ARDS.

Alveolar recruitment and positive end-expiratory pressure
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Conclusion

Understanding mechanical ventilation as a potentially harmful yet life-saving intervention has led to the development of an approach that aims to minimise harm while providing acceptable gas exchange. Ventilation in ARDS should include the use of low tidal volumes, the avoidance of high plateau pressures, titration of PEEP to provide acceptable oxygenation, and avoidance of high inspired oxygen concentrations. Individualised targets for oxygenation and carbon dioxide clearance should be set, recognising the lack of harm associated with hypercapnia and the risk of harm associated with high inspired oxygen concentrations.

Useful rescue strategies when lung-protective ventilation fails to provide acceptable gas exchange include recruitment manoeuvres and optimisation of PEEP, neuromuscular blockade, and prone positioning. Fluid overload must be avoided, and diuretics or ultrafiltration should be used to achieve a negative fluid balance in stable patients. Failure of these measures should lead to consideration of nonconventional modes of ventilation or the use of extracorporeal therapies in selected patients with reversible disease. In spite of all these measures, however, ARDS remains a difficult clinical problem and carries a high mortality - we still have work to do.

Box 1.
Calculation of predicted body weight
50 + 0.91(cm of height - 152.4) for males
45.5 + 0.91(cm of height -152.4) for females

Pharmacological adjuncts

Pulmonary vasodilators
Inhaled nitric oxide is a potent but extremely short-acting pulmonary vasodilator that selectively improves perfusion to well-ventilated alveoli, reducing intrapulmonary shunt and improving oxygenation. Despite improvements in oxygenation, the use of inhaled nitric oxide is not associated with any mortality benefit, is expensive, and requires a specialist delivery system. A recent systematic review found a suggestion of increased renal failure in association with its use, although biologically plausible explanations for this remain speculative [53]. Our practice is to use inhaled nitric oxide in ARDS as rescue therapy for reversible, life-threatening hypoxaemia, usually as a starting dose of 5 ppm and titrating to a maximum of 20 ppm, with discontinuation if no significant improvement in oxygenation is apparent after a short trial.

Inhaled prostacyclin has similar theoretical benefits to nitric oxide in terms of selective pulmonary vasodilatation, but has been less extensively studied in the context of ARDS. Small physiological studies suggest an equivalent effect on pulmonary artery pressures and oxygenation to inhaled nitric oxide, although none have been powered to compare clinically important endpoints. Evidence for prostacyclin use is confined to these small studies and case reports. The clinical relevance of theoretical side effects such as systemic vasodilatation and platelet dysfunction is unknown. Prostacyclin is considerably less expensive and does not require the same commercial delivery system as nitric oxide, but the nebuliser requires continual observation during prostacyclin delivery, and the technique remains an unproven rescue therapy for life-threatening hypoxaemia.

Fluid balance
The three factors involved in oedema formation are hydrostatic pressure, colloid osmotic pressure, and the capillary filtration coefficient. In the absence of effective methods to reduce pulmonary capillary leak (that is, the filtration coefficient), efforts to reduce extravascular lung water in ARDS are centred on minimising hydrostatic pressure by avoiding fluid overload, and potentially the use of albumin solutions to increase colloid osmotic pressure.

An association between positive fluid balance and worse outcome in patients with ARDS has been demonstrated in a number of studies. Data from the ARDS Network Fluids and Catheter Therapy Trial support the use of a conservative fluid management strategy in ARDS, with the use of diuretics in haemodynamically stable patients to achieve an even fluid balance associated with improved oxygenation and faster liberation from mechanical ventilation. While a dry approach to patients with sepsis and particularly ARDS has traditionally been assumed to benefit lungs at the expense of renal and other organ perfusion, a growing body of evidence exists to the contrary. In ARDS patients enrolled in the Fluids and Catheter Therapy Trial, for instance, conservative fluid management was associated with lower rates of acute kidney injury in ARDS patients once correction for changes in the volume of distribution of creatinine was used. These findings of acute improvements from the Fluids and Catheter Therapy Trial need to be interpreted in light of a recent report showing potential for worse long-term cognitive function in a subset of the trial survivors.

In general, unnecessary fluid administration should be minimised using small-volume fluid boluses titrated to resolution of hypoperfusion states. Diuretics or ultrafiltration should be employed to restore euvolaemia in haemodynamically stable patients who have received fluid loading in the resuscitation phase of their illness. However, in some patients, particularly those with severe ARDS requiring high mean airway pressures for oxygenation, hypovolaemia may exacerbate hypoxaemia by virtue of increased intrapulmonary shunt, and clinical benefit may result from the careful administration of fluid boluses.

Neuromuscular blockade
Neuromuscular blockers are used in ARDS to improve patient-ventilator synchrony, to facilitate lung-protective ventilation, and to improve chest wall compliance. These blockers also reduce oxygen consumption by respiratory (and other skeletal) muscles, leading to an improved mixed venous saturation and in turn to an improved partial pressure of arterial oxygen, all other things being equal in most ARDS patients. In a recent large RCT, cisatracurium infusion for a 48-hour period early in the course of moderate-severe ARDS (PaO2/FiO2 ratio <150 mmHg) resulted in a reduction in the duration of mechanical ventilation and mortality. Concerns regarding the use of neuromuscular blockers relate primarily to the risk of critical illness myopathy, a concern that was not borne out in this study and which may have been overemphasised. Aminosteroid muscle relaxants such as rocuronium may present a higher risk than benzylquinolinium compounds such as cisatracurium in this regard. In this group of severe ARDS patients, almost all of whom will require heavy sedation to facilitate lung-protective ventilation and patient-ventilator synchrony, some benefit of neuromuscular blockers may derive from a sedative-sparing effect. Our current approach is to consider neuromuscular blockade for patients with severe ARDS in whom patient-ventilator asynchrony is thought to contribute to difficulty in gas exchange or in achieving lung-protective ventilation.

Other pharmacological adjuncts
Based on the observation that hypoproteinaemia is a strong risk factor for ARDS, the use of albumin along with furosemide has been studied in two small phase II trials. Albumin use was associated with improved oxygenation, diuresis and haemodynamics, and represents an approach in need of further evaluation.

Corticosteroids have been investigated extensively in ARDS. High-dose steroids used in the early stages of ARDS have no benefit and may increase the rate of infectious complications. One small randomised study suggested a survival benefit in the late (fibroproliferative) phase of ARDS, but a larger study failed to replicate this benefit despite showing improvements in physiological parameters. Most recently, a trial of early, low-dose steroids in ARDS showed improvements in gas exchange without improvements in clinically significant endpoints. Overall, the data are unclear and thus steroids have yet to find their place in the routine management of ARDS.

Other agents with a biological rationale but that have recently failed to demonstrate clinical utility in randomised trials include β-agonists (both nebulised and intravenous) and omega-3 fatty acid supplements.

Nonpharmacological adjuncts
Prone positioning has a sound pathophysiologic basis and has been used for many years in the management of ARDS. Recruitment of dorsal lung regions where greater lung mass is located, displacement of the cardiac mass away from lung tissue, and more homogeneous distribution of ventilation in the prone position are among the mechanisms postulated for the improved oxygenation that is consistently observed in studies of prone positioning in ARDS. Unfortunately, several large trials have demonstrated that although oxygenation generally improves with prone positioning, this does not appear to result in a survival benefit when all patients with ARDS are considered. Two recent meta-analyses did, however, demonstrate an improvement in ICU mortality in patients with severe ARDS [84]. The benefit appears to be greater when the prone position is maintained for longer (that is, 17 or 18 hours), and although significant complications can develop (skin necrosis, dislodgement of catheters and tubes) these are not significantly more frequent when prone positioning is used. Prone positioning should be considered as an option to improve oxygenation for patients in whom conventional measures have failed and for patients with severe ARDS (PaO2/FiO2 <100).

The injurious effects and limitations of conventional ventilation have led to the development of a number of alternative modes of ventilation. Airway pressure release ventilation is a spontaneous breathing mode in which a high baseline pressure is released to a low level intermittently (6 to 12 times/minute) to allow ventilation, with spontaneous breaths permitted throughout the cycle. This technique may result in improvements in lung recruitment, oxygenation, and patient-ventilator synchrony, although with the potential cost of alveolar overdistension. Although some early studies have been promising, no definite outcome benefit has been demonstrated to date for this mode of ventilation.

Neurally adjusted ventilatory assist utilises an oesophageal electrode to measure diaphragmatic electrical activity, delivering positive pressure proportionately. While potentially useful in patients who are difficult to manage with conventional ventilation due to asynchrony, no prospective outcome studies have been carried out in ARDS patients.

High-frequency oscillatory ventilation utilises rapidly cycling positive and negative pressure oscillations around a high mean airway pressure to deliver very small tidal volumes at high frequencies (5 to 15 Hz or 300 to 900 per minute). The mechanisms of gas flow and ventilation involved are complex, but high-frequency oscillatory ventilation appears to result in maintenance of lung recruitment as well as improvements in oxygenation and ventilation in ARDS patients refractory to conventional ventilation and is potentially less injurious to the lung. At the current time, high-frequency oscillatory ventilation appears safe and appropriate as rescue therapy for patients with refractory hypoxemia. Results are expected in the near future from at least two large clinical trials comparing high-frequency oscillatory ventilation with conventional ventilation in moderate-severe ARDS patients.

The role of extracorporeal lung support in ARDS is controversial and availability is currently limited to specialist centres. The most extensively studied form used in ARDS patients is venovenous extracorporeal membrane oxygenation (ECMO). A recent RCT of transfer to an ECMO centre found a mortality benefit when compared with conventional therapy. However, this study has been criticised for conflating ECMO treatment and regionalisation effects, and for a lack of well-documented protective ventilation in the control group. Even more recently the H1N1 influenza epidemic has highlighted the potential benefits of extracorporeal lung support. Potential drawbacks of extracorporeal lung support include lack of widespread availability and the need for systemic anticoagulation. Transfer to an ECMO centre should be considered in patients with reversible disease in whom lung-protective ventilation cannot provide acceptable gas exchange when other rescue measures have failed, and should be utilised early in the course of disease, before irreversible lung injury has occurred.

Review: Acute respiratory distress syndrome and acute lung injury

Acute respiratory distress syndrome (ARDS) is a life threatening respiratory failure due to lung injury from a variety of precipitants. Pathologically ARDS is characterised by diffuse alveolar damage, alveolar capillary leakage, and protein rich pulmonary oedema leading to the clinical manifestation of poor lung compliance, severe hypoxaemia, and bilateral infiltrates on chest radiograph. Several aetiological factors associated with the development of ARDS are identified with sepsis, pneumonia, and trauma with multiple transfusions accounting for most cases.

Optimal treatment involves judicious fluid management, protective lung ventilation with low tidal volumes and moderate positive end expiratory pressure, multi-organ support, and treatment where possible of the underlying cause.
Moreover, advances in general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thromboembolism and gastrointestinal ulceration are likely contributory reasons for the improved outcomes.
Although therapies such as corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants have shown promising clinical effects in animal models, these have failed to translate positively in human studies. Most recently, clinical trials with b2 agonists aiding alveolar fluid clearance and immunonutrition with omega-3 fatty acids have also provided disappointing results.
Despite these negative studies, mortality seems to be in decline due to advances in overall patient care.
Future directions of research are likely to concentrate on identifying potential biomarkers or genetic markers to facilitate diagnosis, with phenotyping of patients to predict outcome and treatment response. Pharmacotherapies remain experimental and recent advances in the modulation of inflammation and novel cellular based therapies, such as mesenchymal stem cells, may reduce lung injury and facilitate repair.

Causes of ARDS

Differential diagnosis of acute respiratory distress syndrome
 Acute cardiogenic pulmonary oedema
 Other causes of flash pulmonary oedema:
    – Renal artery stenosis
    – High altitude
    – Drugs (eg, naloxone)
    – Head injury
 Lymphangitis carcinomatosa
 Pulmonary veno-occlusive diseases
 Pulmonary vasculitis
 Acute presentation of idiopathic interstitial lung diseases
 Acute hypersensitivity pneumonitis
 Acute eosinophilic pneumonia

Treatment

The treatment of ARDS involves general supportive measures necessary for all critically ill patients (eg, infection control, early enteral nutrition, stress ulcer prophylaxis, and thromboprophylaxis) combined with focused ventilatory strategies and appropriate treatment of the underlying conditions. There are no effective pharmacological therapies for ARDS. The following section is a review of key therapies that have been trialled in patients with ARDS and ALI. Table 3 illustrates the adopted treatment strategies for patients with ARDS/ALI in current clinical practice.

The treatment of ARDS involves general supportive measures necessary for all critically ill patients (eg, infection control, early enteral nutrition, stress ulcer prophylaxis, and thromboprophylaxis) combined with focused ventilatory strategies and appropriate treatment of the underlying conditions. There are no effective pharmacological therapies for ARDS. The following section is a review of key therapies that have been trialled in patients with ARDS and ALI. Table 3 illustrates the adopted treatment strategies for patients with ARDS/ALI in current clinical practice.

Ventilation

Low tidal volume ventilation/protective ventilation
The main supportive therapy for ARDS is positive pressure mechanical ventilation which helps to ensure adequate oxygenation. Early ventilation strategies involved volume controlled ventilation with tidal volume (Vt) of 10–15 ml/kg to achieve ‘normal’ arterial blood gases. However, ventilation itself can cause lung injury. A landmark trial conducted in the late 1990s by the ARDS Network compared conventional Vt of 12 ml/kg with low Vt of 6 ml/kg and permissive hypercapnia. A 9% absolute mortality reduction was found in the low Vt ventilation group along with reduced pulmonary and circulating inflammatory cytokines. In this study, Vt was calculated based on ideal body weight (IBW) with targeted plateau pressures of <30 cm H2O and permissive hypercapnia. This study produced a significant impact in our current ventilatory practices and has been confirmed by a subsequent study in which patients who were ventilated with higher Vt and lower PEEP had increased ICU and hospital mortality. A recent trial in patients with respiratory failure without ALI also demonstrated low Vt ventilation to be protective, preventing ALI and associated with a reduction in the release of inflammatory cytokines. This study was stopped early due to an increased incidence of lung injury in patients ventilated with higher Vt. Taken together, these studies demonstrate the importance of using lower Vt to ventilate the injured lung as opposed to aiming to normalise blood gases variables.

Earlier concerns of a possible need for increased sedation and haemodynamic compromise, requiring increased cardiovascular support in patients ventilated with low Vt, prevented many physicians from practising this strategy. However, studies addressing these concerns have shown that low TV ventilation is a safe strategy and should be adopted in the management of patients with ARDS/ALI.

The level of PEEP
The optimal level of PEEP in ventilated patients with ARDS/ALI remains controversial. PEEP helps to recruit alveolar units and reduces alveoli collapse due to alveolar flooding and thereby reduces ventilation perfusion mismatch. The level of PEEP needed to achieve optimal recruitment without causing alveolar over-distension and damage is not established. Three large clinical trials conducted to determine ‘best PEEP’ in patients with ALI showed clinical improvement but no mortality benefit when using high PEEP in comparison with low PEEP (14 cm H2O vs approximately 8 cm H2O). A meta-analysis of these trials confirmed this finding of no mortality benefit, but when patients with ARDS were analysed separately (Pao2/Fio2 <200 mm Hg) there was a statistically significant improvement in survival in the higher PEEP group.

The percentage of potentially recruitable lung is variable among patients and in the absence of recruitable lung, application of higher levels of PEEP may be harmful. This may partly explain the results of these clinical trials. Methods that have been utilised to assess recruitability and the response to PEEP include CT of the thorax, determination of oesophageal pressure, and thoracic ultrasound. Due to the heterogeneous nature of this disease, the response to PEEP should be individually assessed when applying higher PEEP, and the utility of various methods as predictors of recruitability in day-to-day practice needs to be established. The ARDS Network has developed a grid of applicable PEEP according to oxygenation which is a valuable guide for estimation of PEEP required.

Recruitment manoeuvres
While low tidal volume ventilation is lung protective, it may exacerbate lung atelectasis and worsen hypoxia. Various alveolar recruitment manoeuvres have been used to open or recruit collapsed alveoli. These involve either a steady or rapid increase in PEEP or inspiratory holds to increase transpulmonary pressures. A systematic review of 1185 patients suggested significant improvement in oxygenation after a recruitment manoeuvre. This effect, however, was transient and frequent complications were observed including hypotension and associated desaturation. Although recruitment manoeuvres can improve oxygenation without causing cardiovascular compromise or barotraumas, they need to be individualised, and the lack of standardisation remains a major issue in assessing this treatment modality.

High frequency oscillatory ventilation
High frequency oscillatory ventilation (HFOV) is an unconventional way of ventilation whereby a piston pump oscillates at a frequency of 3–10 Hz, generating pressure swings leading to small Vt with a high respiratory rate. The mean airway pressure is slightly higher than in conventional ventilation, but the pressure differences throughout the respiratory cycle are smaller. The small Vt generated, coupled with higher mean airway pressures, provide continued alveolar recruitment. HFOV is therefore an intuitively attractive method of ventilating ARDS patients. However, to date there are few studies involving small numbers of patients comparing HFOV to conventional ventilation. A recent meta-analysis suggested a trend towards mortality benefit and more ventilator free days. The results of this analysis need to be interpreted cautiously as the main study contributing to the meta-analysis used high Vt in the control group rather than current lung protection ventilation techniques. A large multicentred clinical study (OSCAR) is currently underway, which may indicate whether there is a definitive role of HFOV in patients with ARDS. In the meantime, HFOV remains as a rescue mode of ventilation for patients with severe hypoxaemic ARDS.

Partial liquid ventilation
Partial liquid ventilation (PLV) is a unique method of ventilation where the lungs are partially filled with an inert liquid called perflourocarbon which has a superior oxygen dissolving capacity to blood and facilitates gaseous exchange. Patients are mechanically ventilated in the usual way. Although there is improvement in gaseous exchange and reduced lung injury in animal models with PLV, a randomised controlled trial failed to show any mortality benefit in ARDS patients. This is not a recommended ventilation strategy for ALI/ARDS patients.

Extracorporeal membrane oxygenation
In the UK extracorporeal membrane oxygenation (ECMO) is only performed by specialised centres. ECMO involves oxygenation of the patient's blood outside the body via a membrane oxygenator which acts as an artificial lung, allowing adequate gaseous exchange without vigorous mechanical ventilation. An earlier study conducted in the 1970s showed no survival benefit, with overall mortality exceeding >90%. A UK clinical trial (CESAR) randomised eligible patients with ARDS to ‘conventional’ treatment in the referring centre or transfer to the specialist centre for ECMO. This study showed a survival advantage in the ECMO group (63% for ECMO vs 47% for controls). However, the study was criticised for not having a standardised protocol management for the control group and because some patients in the treatment arm did not receive ECMO. The major risks associated with ECMO are the risks of transfer of seriously ill patients, complications of large bore vascular access, and bleeding due to anticoagulation. Currently ECMO remains an option as a rescue therapy for patients with refractory hypoxaemia. Its use is likely to be limited to specialised centres.

Prone positioning

Prone positioning results in a consistent improvement in oxygenation in patients with hypoxic respiratory failure. The possible mechanisms for improved oxygenation are: recruitment of dependent lung units, redistribution of blood flow to the more unaffected lung regions, reducing ventilation perfusion mismatch, minimising compression of lung from anterior mediastinal structures, and facilitation of respiratory secretion clearance. Four large randomised controlled trials have consistently shown improvements in oxygenation without survival benefit or reduction in duration of ventilation. A recent meta-analysis performed by Gattinoni et al suggests survival benefit in a subgroup of patients with severe ARDS (Pao2/Fio2 <100 mm Hg). They concluded that prone positioning should be considered for patients with severe hypoxaemia including ARDS. The common adverse effects of prone positioning are pressure sores and tube displacement. Prone positioning may be considered in patients with severe ARDS to improve oxygenation in centres with capable nursing expertise.

Pharmacological therapies

Pharmacotherapies have a very limited role in the management of ARDS. So far there is no effective medical treatment that improves survival for adult patients with ARDS, although exogenous surfactant is beneficial in the paediatric population.

Neuromuscular agents
Neuromuscular agents (NMA) can be used to improve patient–ventilator synchrony and assist mechanical ventilation in patients with severe hypoxaemia. There is evidence that using NMA in patients with severe ARDS (Pao2/Fio2 <150 mm Hg) improves oxygenation and reduces inflammatory cytokines. A phase IV randomised controlled trail comparing cis-atracurium with placebo for 48 h in patients with severe ARDS (Pao2/Fio2 <150 mm Hg) showed improved adjusted 90 day survival rate and increased ventilator fee days in the cis-atracurium group without significant increase in muscle weakness. It is not clear whether the observed benefit was due to neuromuscular paralysis alone, possible additional anti-inflammatory effects, or a possible reduction in oxygen consumption. Paralysing patients with NMA can be associated with critical care neuromyopathy, longer weaning times, longer ICU stays, and a higher mortality and they therefore need to be used cautiously. From this evidence, it is not possible to recommend routine use of NMA beyond the usual indications. Further studies are necessary to evaluate the routine use of NMA in ARDS/ALI.

Vasodilators
Inhaled nitric oxide
Inhaled nitric oxide (NO) is an endogenous vasodilator. When inhaled it reduces V/Q mismatch and improves oxygenation by selective pulmonary vasodilatation in alveolar units that are ventilated. It has been used in clinical trials in patients with hypoxic ventilatory failure, ALI, and ARDS. Inhaled NO also reduces elevated pulmonary vascular resistance in patients with ARDS. Adverse effects of inhaled NO are methaemoglobinaemia, cytotoxic nitrogen products (nitrogen dioxide), and renal failure. A Canadian survey in 2004 reported that up to 30% of critical care physicians were using inhaled NO in selected patients with ARDS, suggesting widespread usage as rescue therapy despite the lack of evidence. A Cochrane review of 14 clinical trials with 1303 patients (which included three paediatric and one combined adult and paediatric study) showed only a transient improvement in oxygenation with no survival benefit or increase in ventilator free days. Furthermore, no improvement was seen in secondary outcomes such as length of ICU or hospital stay, and increased renal impairment was noted in the inhaled NO treated group. Current use is declining due to the poor outcome data and escalating costs of using inhaled NO. Its use is not recommended as routine therapy but may be considered for improvement of oxygenation in patients with refractory hypoxaemia.

Prostanoids
Prostacyclins are arachidonic acid derivatives that cause pulmonary vasodilatation and are used to treat patients with primary pulmonary hypertension. They have additional immunomodulatory effects such as reducing neutrophil adhesion, and inhibition of neutrophil, macrophage and platelet activation. Nebulised prostacyclin (PGI2) has comparable effects in improving oxygenation, pulmonary vasodilatation and shunt reduction when compared with inhaled NO. Improved oxygenation has been seen in a paediatric study, but this has not yet been demonstrated in adult patients with ARDS.

Intravenous prostaglandin (PGE1) has been evaluated in a Cochrane systematic review which identified seven studies including a total of 697 patients. These studies were difficult to compare due to protocol and drug formulation differences, but no mortality benefit was seen and more hypotension, arrhythmias and hypoxia occurred in the study group. Clinically prostanoids are rarely used and not recommended for routine practice.

Anti-inflammatory agents
Steroids
ARDS is characterised by a profound inflammatory process followed by fibro-proliferative changes; using steroids to reduce this inflammation or to moderate the fibrotic recovery is an obvious approach that has been tried in several clinical studies. The dose of corticosteroids, duration of treatment, and the timing of initiation in both prevention and treatment of ARDS has been evaluated. Studies of ARDS prevention for at risk patients suggest that there is no preventative effect conferred by the use of high dose short duration courses of steroids. High dose short duration steroids also have no mortality benefit in early ARDS. In a phase III study, the ARDS Network investigators assessed the effect of steroids in the late stage fibrotic phase of ARDS (after 7 days of onset) and again showed no mortality benefit in the treatment group, with a higher mortality in patients treated 14 days after onset. A study by Meduri et al showed improved ICU mortality, LIS, lower infection rate, and shorter duration of mechanical ventilation and ICU stay when low dose corticosteroids were commenced in the early stages of ARDS. However, this study was limited by small numbers and methodological issues, including a 2:1 randomisation allocation ratio and frequent crossovers. Moreover, an increased number of patients with catecholamine dependent shock in the treatment group may have biased the mortality outcome in this group.

Further larger randomised controlled trials are needed to assess the effect of low dose corticosteroids in patients with early ARDS. From the available evidence, corticosteroids are not indicated for prevention, but low dose steroids (1–2 mg/kg methylprednisolone) may be considered in patients with severe early (<72 h) ARDS. The dose titration and the duration of treatment remains a contentious issue. While prolonged use of corticosteroids may moderate fibrotic recovery, this should be balanced against the deleterious effects of steroids. It is not recommended to initiate corticosteroids beyond 14 days after the onset of ARDS.

Ketoconazole
Ketoconazole is an imidazole based antifungal medication which inhibits the synthesis of thromboxane A2, a potent vasoconstrictor involved in platelet aggregation and neutrophil recruitment. It is also known to reduce alveolar macrophage inflammatory mediator and was therefore assessed for its role as an anti-inflammatory agent in ARDS. Although early preventive studies suggested benefit, a phase III study conducted in 2000 by the ARDS Network showed no improvement in mortality or secondary outcome measures. Ketoconazole is not recommended for the treatment of ARDS/ALI.

Lysofylline and pentoxifylline
Pentoxifylline is a phosphodiesterase inhibitor and lisofylline is a pentoxifylline derivative with anti-inflammatory properties. Lisofylline reduces elevated circulating oxidised free fatty acids levels, seen in patients with ARDS, and inhibits neutrophil accumulation as well as reducing pro-inflammatory cytokines (TNFα, IL1, and IL6). While animal studies showed promising results, a phase II/III study conducted by the ARDS Network showed no treatment benefit and a trend towards increased mortality in patients treated with lisofylline. This is not recommended as treatment for ARDS/ALI.

Sivelestat (neutrophil elastase inhibitor)
Neutrophil elastase secreted by activated neutrophils is thought to play an important role in endothelial damage and changes in vascular permeability during ALI. Sivelestat is an inhibitor of neutrophil elastase and was studied in a phase II/III randomised controlled trial (STRIVE). Mortality was increased in the treatment arm and the study was stopped prematurely. Depelestat is another neutrophil elastase inhibitor currently being assessed in ARDS patients in a phase II study, the results of which are expected soon. Neutrophil elastase inhibitors remain an experimental therapy while further results are awaited.

Antioxidants
Oxygen free radicals produced by activated neutrophils and macrophages are thought to play an important role in the inflammatory pathways that lead to cell damage in patients with ARDS. Glutathione is an antioxidant which is produced in the liver, the levels of which are reduced in alveolar fluid in patients with ARDS. Glutathionine levels can be replenished by supplementation with its precursor N-acetylcysteine. Several small studies have demonstrated no mortality benefit with the use of N-acetylcysteine in ALI and ARDS patients.

Fluid management and alveolar fluid clearance
Optimal fluid management is an essential step in the resuscitation of critically ill patients. While it is important to maintain an adequate intravascular pressure to perfuse major organs, raised capillary hydrostatic pressure from excess fluid therapy can lead to worsening of pulmonary oedema in patients with ARDS. Positive fluid balance is associated with worse clinical outcomes in patients with ARDS. A phase III study conducted by the ARDS Network compared liberal versus conservative fluid strategy in patients with ALI. Despite showing no difference in mortality between the groups, the conservative group had improved oxygenation, LIS, and shortened duration of mechanical ventilation without any increase in other organ failures. We recommend a conservative fluid management approach, once resuscitation is complete, with the aim being to achieve cumulative neutral balance without compromising cardiovascular and renal variables. Some patients accumulate a significant positive fluid balance during the resuscitation phase, and use of diuretics (after resolution of haemodynamic instability) to achieve a sustained negative balance may be valuable. Careful monitoring of renal function and other indices of perfusion is important if this strategy is adopted.

The resolution of ARDS depends on the adequate clearance of the alveolar oedema. Defective alveolar fluid clearance is associated with decreased survival in ARDS patients. The role of β2 agonists in assisting alveolar fluid clearance has been investigated using salbutamol in ARDS patients. A small study demonstrated reduced extravascular lung water and a trend towards survival benefit. The effect of β2 agonists in ARDS/ALI has been further investigated in phase II/III multicentre studies in the USA with aerolised albuterol (ALTA) and in the UK with intravenous salbutamol (BALTI-2). Both studies were stopped prematurely. Preliminary data suggest that β2 agonists provide no survival benefit in ARDS/ALI and in fact may be associated with increased mortality. β2 agonists are not recommended as part of therapy for patients with ARDS/ALI.

Immunonutrition

Nutritional input has been increasingly valued in critically ill patients and early enteral nutrition is generally advised. Manipulation of nutrition with supplementation of fish oil based omega-3 fatty acids, eicosapentanoic acid (EPA), docosahexaenoic acid (DHA), and gamma-linolenic acid (GLA) in borage oil are thought to reduce arachidonic acid availability for the generation of inflammatory pathways. Supplementation with EPA and GLA has resulted in alveolar neutrophil de-recruitment, improved gaseous exchange, and reduction in duration of mechanical ventilation. A recent systematic review to assess immunonutrition in critically ill patients showed significant reduction in mortality, secondary infections and length of hospital stay with fish oil based immunonutrition in the ICU setting.

A recent phase III clinical trial conducted by the ARDS Network supplementing omega-3 fatty acids, GLA and antioxidants in patients with ALI (OMEGA) showed no mortality benefit. Further trials are currently underway to assess the effect fish oil in ARDS patients. This form of nutrition remains experimental and further studies are needed to elucidate the effects of various types of immunonutrition for inflammatory modulation in patients with ARDS/ALI.

Exogenous surfactants

Pulmonary surfactant is a complex mixture of phospholipids, proteins and neutral lipids produced by alveolar type II cells. Surfactant helps to maintain alveolar surface tension and is also involved in the host immune response. Bronchial lavage surfactants recovered from patients with ARDS show changes in phospholipids composition and decreased levels of surfactant proteins. A number of clinical trials have tested the hypothesis that administration of exogenous surfactant confers clinical benefit in adult patients with ARDS, but in contrast to the literature in newborns and children, no mortality benefit has been demonstrated. Limitations of these studies include insufficient surfactant delivery, lack of incorporation of hydrophilic surfactant proteins and, possibly most importantly, no targeting of populations who might be most likely to benefit (eg, where there is reduced production rather than inactivation or increased breakdown due to hydrolysis and/or oxidation). Novel techniques utilising stable isotope labelling of surfactant precursors, to assess surfactant synthesis and metabolism, open up the possibility of characterising and targeting patients with reduced synthesis who may most likely benefit from exogenous surfactant. However, at present exogenous surfactant has no added value in the management of adult patients with ARDS.

Mesenchymal stem cells

Mesenchymal stem cells (MSC) are bone marrow derived stem cells with a capacity to differentiate into many cell types. Their therapeutic importance is under investigation in many diseases including lung injury. In animal models with lung injury, intravenous MSC lead to favourable outcome with reduction in inflammation, pro-inflammatory cytokines and lung oedema. In ex vivo human lung models of endotoxin induced lung injury, administration of MSC resulted in improved alveolar fluid clearance with quantitative increase in keratinocyte growth factor (KGF). KGF is a cytokine and a potent mitogen which specifically acts on epithelial cells, and in lung injury models it is protective and induces type II cell proliferation and oedema clearance.112 Human studies with MSC are still awaited. A single centre phase II study is underway to assess the effect of intravenous KGF in ALI patients.

Management of ARDS

3 cornerstones:
1. Recognizing patients with acute lung injury and ruling out other causes of acute hypoxemia
2. Identifying and treating the underlying disease
3. Mechanical ventilation to secure oxygenation and ventilation whilst protecting the lung from ventilation-induced lung injury

Approach To Clinical Diagnosis

1. Chest x ray

 Early stages - interstitial edema
 Established cases - full blown pulmonary edema
• Progression to diffuse, bilateral alveolar infiltrates within 4 24 hours after the first abnormal radiographic signs appear
• Diagnostic confusion: cardiac failure, pneumonia, pulmonary embolism

Radiographic criteria differentiating ARDS from cardiogenic edema

• Homogenous infiltrates & absence of pleural effusion – more characteristic of ARDS
• As alveolar filling continues Ground glass appearance or white-out of all lung fields →→
• CXR’s are influenced by the effects of therapy -
  ▫ IV Fluids can increase alveolar content
  ▫ Diuretic agents may decrease total content
  ▫ PEEP increases lung inflation thereby reducing regional lung density

2. CT Scan

3. Laboratory studies

 Arterial Blood Gases -
  • Initial stages - hypoxemia with hypocapnia, respiratory alkalosis
  • Later stages - hypoxia, hypercapnia, respiratory and metabolic acidosis
 Leukocytosis/Leucopenia/anemia are common
 Renal function / liver function abnormalities
 Von willebrand’s factor or complement in serum may be high
 Acute phase reactants like ceruloplasmin or cytokine (TNF,IL-1,IL-6,IL-8) may be high.

4. Echocardiography

Echocardiography – method to detect cardiac causes of respiratory failure

5. Invasive hemodynamic monitoring

 Insertion of a Swan Ganz catheternot essential
 Pulmonary edema with pulmonary wedge pressure <18 mm Hg in presence of normal colloid oncotic pressure

6. Pulmonary compliance

 <30ml/ cm H2O
 Easily measured in mechanically ventilated patients

7. Full bacteriological screen

 Blood , urine and tracheal aspirate cultures
 Culture of other body secretions and discharges
 Culture of bronchoalveolar lavage fluid.

8. Bronchoalveolar Lavage

 Very reliable & underutilized
 In normal subjects, less than 5% of cells are neutrophils. In patients with ARDS, upto 80% cells are neutrophils.
 Lavage fluid is rich in protein in patients of ARDS as the inflammatory exudates are rich in protein.
Hydrostatic edema: Lavage protein/ Plasma protein < 0.5
ARDS: Lavage protein/ Plasma protein > 0.7
 Presence of a marker of pulmonary fibrosis called procollagen peptide III (PCPIII) correlates with mortality.

Ventilatory management in ARDS

• In the early stages of ARDS, the hypoxia may be corrected by 40 to 60% inspired oxygen with CPAP.
• If the patient is well oxygenated on ≤ 60 % inspired oxygen and apparently stable, then close ward monitoring , continuous oximetry and regular blood gas estimation is required.

Indications of ventilatory support

 Inadequate Oxygenation(PaO2 < 60mm Hg on FiO2 >= 0.6)
 Rising or elevated PaCO2(>= 45 mmHg)
 Clinical signs of incipient respiratory failure

Conventional mechanical ventilation

• Tidal volumes are 12-15ml/kg
• In ARDS, the functional portion of the lungs is greatly reduced
• High inflation volumes results in overdistension and rupture of the distal airspaces.
• Ventilator associated lung injury:
   High inflation pressure Barotrauma
   Over distension Volutrauma
   Repetitive opening & closing of alveoli Atelectrauma
   SIRS & cytokines release Biotrauma

Mechanical Ventilation

Lung protective ventilation

• Tidal volumes – 6 ml/kg
• Limits risk of volutrauma and biotrauma
• Uses positive end expiratory pressure to limit the risk of atelectrauma.
• Currently, the only therapy that has been proven to be effective at reducing mortality in ALI/ARDS in a large, randomized, multi-center , controlled trial is a protective ventilatory strategy.

Tidal Volume Strategies in ARDS

ARDS conducted trials -
• Low tidal volume ventilation 6ml/kg predicted body wt., limited end inspiratory pressure (pplat) 30cm H2O in one group and 12ml/kg tidal volume in the other group.
• Results suggested decreased mortality from 40% to 31%

Ventilator setup and adjustment

Oxygenation Goal

Plateau Pressure Goal

pH Goal

Weaning

A. Conduct a spontaneous breathing trial daily when:
1. FiO2 ≤ 0.40 and PEEP ≤ 8
2. PEEP and FiO2 ≤ values of previous day
3. Patient has acceptable spontaneous breathing efforts. (May decrease ventilation rate by 50% for 5 minutes to detect effort.)
4. Systolic BP ≥ 90 mmHg without vasopressor support.
5. No neuromuscular blocking agents or blockad.

B. Spontaneous breathing trial (SBT):
If all above criteria are met for at least 12 hours, initiate a trial of upto 120minutes of spontaneous breathing with FiO2 < 0.5 and PEEP < 5:
1. Place on T-piece, trach collar, or CPAP ≤ 5 cm H2O with PS < 5
2. Assess for tolerance as below for up to two hours
    a. SpO2 ≥ 90: and/or PaO2 ≥ 60 mmHg
    b. Spontaneous VT ≥ 4 ml/kg PBW
    c. RR ≤ 35/min
    d. pH ≥ 7.3
    e. No respiratory distress (distress= 2 or more)
        1. HR > 120% of baseline
        2. Marked accessory muscle use
        3. Abdominal paradox
        4. Diaphoresis
        5. Marked dyspnoea
3. If tolerated for at least 30 minutes, consider extubation
4. If not tolerated resume pre-weaning settings.

Consequences of low tidal volume ventilation:

 Reduction in CO2 elimination via lungs – hypercapnia, respiratory acidosis, increased cardiac output.
 Increased cerebral blood flow, cerebral edema, intracranial hemorrhage
 Leads to brainstem stimulation-hyperventilaton

Contraindications of low tidal volume ventilation:

 Increased intracranial pressure
 Stroke
 Acute or chronic myocardial ischemia
 Severe pulmonary hypertension
 Right ventricular failure
 Severe metabolic acidosis
 Sickle cell anemia
 TCA (Tricyclic Antidepressant) overdose
 Beta blockers
 Pregnancy

Adjunsts to protective lung ventilation

• Permissive hypercapnia
• Fluid and hemodynamic management
• Inhaled nitric oxide
• Prone position ventilation
• Tracheal gas insufflation
• Steroids
• Nutritional support
• Other drug therapies

1. Permissive hypercapnia

• Low tidal volume ventilation results in hypercapnia.
• Clinicians have allowed hypercapnia to persist in patients of ARDS as long as there is no evidence of harm.
• Clinical trials have shown that arterial pCO2 level of 60-70 mmHg and arterial pH of 7.2-7.25 are safe for most of the patients

2. Fluid management

• NIH/ARDS Network Fluid Management Trial (The FACTT Study) – FACTT (Fluid and Catheter Therapy Trial; 2005-6) -
fluid restriction results in improved outcome (may reduce pulmonary edemadue to increased pulmonary vascular permeability).

• FACTT – fluid management protocol based on –
1. Mean arterial pressure >60mmHg
2. Urine output >0.5ml/kg
3. Effectiveness of circulation CI >2.5l/min/m2
4. Intravascular pressure –CVP <4mmHg

• Result – improved lung function, improved central nervous system function, less sedation, mechanical ventilation , less complications
• Avoiding a positive fluid balance in ARDS patients reduces the time on mechanical ventilation and also mortality.

3. Hemodynamic management

ARDSNet FACTT compared hemodynamic management guided -
CVP/PAC SUPPORT – use of PAC (Pulmonary Artery Catheter) increases mortality
   PAC allows measurement of central venous and pulmonary arterial pressure, pulmonary artery occlusion pressure, mixed venous blood gases, cardiac output.
   no added benefit, increasing complications
   CVP (Central Venous Catheter) better indicator of measurement than PAC

Inotropes
   Dobutamine is preferred because vasodilators increase intrapulmonary shunt
   Dopamine – constricts pulmonary veins, rise in pulmonary capillary hydrostatic pressure

4. Prone ventilation

• Routine use of prone positioning in all patients with ALI / ARDS cannot be currently recommended due to a lack of clinical data support.
• Indications:
  – as an adjunctive therapy to improve oxygenation in established ALI and ARDS
  – considered in patients who require PEEP >12 cmH2O and a FiO2 >0.60
• should better be used early within 36 hours of the onset of ARDS
• optimum duration unknown

Prone position
• Atelectasis and ventilation perfusion mismatch appear to be dependent on gravity - improves oxygenation

• Mechanism -
   Increased FRC
   Change in regional diaphragmatic motion
   Perfusion redistribution – better oxygenation
   Improved clearance of secretions

• Limitations:
   Need extra care prevent pressure necrosis
   Secure ET
   Dislodgement of line or chest tube
   Hemodynamic instability

GATTINONI AND COLLEAGUES – multicentre prospective randomized trial (2001) - No survival advantage, salvage therapy

Prone position
Absolute Contraindications
• Burns or open wounds on the face or ventral body surface
• Spinal instability
• Pelvic fractures
• Life-threatening circulatory shock
• Increased intracranial pressure

Complications
• Facial and periorbital edema
• Pressure sores
• Accidental displacement of the endotracheal tube, thoracic or abdominal drains, and central venous catheters
• Airway obstruction
• Hypotension
• Arrythmias
• Vomiting

5. Inhaled nitric oxide

• Selectively dilates pulmonary capillaries
• Decreases pulmonary capillary pressure
• Selectively vasodilates ventilated areas of lung
• Inhibit neutrophils activation
• Used as a salvage therapy to improve oxygenation
• Adverse effects - methemoglobinemia, renal dysfunction.

6. Tracheal gas insufflation

 Delivering fresh gas through modified ET just above carina
• Removes CO2 rich gas from trachea, small airways
• Reduces anatomic dead space

Risks -
• Tracheal erosion
• Oxygen toxicity due to increased Fio2
• Hemodynamic compromise
• Barotraumas

 Salvage therapy

7. Steroids

• Steroid therapy is currently recommended only for early severe and unresolving ARDS:
• Early severe ARDS (PaO2/FiO2<200 mmHg, PEEP=10 cm H2O):
 Methylprednisolone IV loading dose of 1 mg/kg over 30 min, followed by 1 mg/kg/day for 14 days, then taper over next 14 days and then discontinue.

Unresolving ARDS
• In cases where ARDS has not started to resolve after 7 days, high dose steroid therapy should be started (but it should not begin after 14 days of onset)

 Methylprednisolone IV loading dose of 2 mg/kg over 30 min, followed by 2 mg/kg/day for 14 days, then 1 mg/kg/day for next 7 days. Gradually taper the dose and discontinue therapy at 2 weeks after extubation.
 5 days after the patient is able to ingest oral medications, oral prednisone or prednisolone can be started as a single daily dose.

8. Nutrition

• Goals -
  ▫ Provision of adequate nutrition
  ▫ Prevention and treatment of deficiencies

Enteral nutrition superior because
   Prevents bacterial translocation
   Lowers levels of TNF, arterial glucagon & epinephrine
   Lesser febrile responses
   Lower incidence of infection
   Less costlyH owever parenteral maybe needed in some patients

9. Other drug therapies

 Prostaglandin E1 - pulmonary vasodilatation , antiinflammatory effects on neutrophils and macrophages
 Aerosolized prostacyclin – selective pulmonary vasodilatation of ventilated lung areas
 Almitrine – selective pulmonary vasoconstrictor of non ventilated areas of lung
 Surfactant – prevents collapse, protects against inflammation and infection
 N-acetylcysteine, procysteine, lisofylline
 Anti oxidants – protect against oxidant damage
 Partial liquid ventilation - PFC, liquid PEEP
 Anti inflammatory drugs – ibuprofen
 Antifungalketoconazole
 Recombinant activated protein C
 ECMO/ ECCOR
  All used as salvage modalities , no benefit seen.

Clinical course outcome

• Most ARDS related deaths occur within first 2 wks, one third occurring by day 7 and two third by 14 day.
• Most common cause of deaths - sepsis, associated multiorgan failure
• Long term sequelae - impaired pulmonary, neurologic, musculoskeletal, cognitive, and psychosocial functions.
• Pulmonary sequelae - impaired diffusion capacity, restrictive or obstructive abnormalities. Restoration of normal lung function occurs in a substantial proportion.
• Physical and neuromuscular sequelaelow exercise capacity, weakness, decreased muscle mass.
• Cognitive andpsychological sequelae - impaired memory, reduced attention, decreased concentration, depression and anxiety.

RVF in acute lung injury

• ARDS involves not only alveoli but also capillaries → constant pulmonary HTN → acute cor pulmonale in 20-25% of patients
• Diagnosis - Echocardiography
• Considering the poor prognosis of patients suffering from such acute right ventricular (RV) dysfunction, RV protection by appropriate ventilatory settings -
  ▫ including strict limitation of Pplat,
  ▫ diminution of positive end-expiratory pressure (PEEP),
  ▫ control of hypercapnia,
  ▫ prone positioning

Conlusion

• The managment strategies for ARDS patients should focus on -
 Lung protective ventilation strategy
    • Low tidal volume (6 ml/kg)
    • Optimal peep and Pplat
    • Oxygenation goal PaO2 -55-80 mmHg /Spo2 – 88-95%
 Conservative fluid management
 Treat the underlying cause.

Acute Respiratory Distress Syndrome: Diagnosis and Management

Acute respiratory distress syndrome manifests as rapidly progressive dyspnea, tachypnea, and hypoxemia. Diagnostic criteria include acute onset, profound hypoxemia, bilateral pulmonary infiltrates, and the absence of left atrial hypertension. Acute respiratory distress syndrome is believed to occur when a pulmonary or extrapulmonary insult causes the release of inflammatory mediators, promoting neutrophil accumulation in the microcirculation of the lung. Neutrophils damage the vascular endothelium and alveolar epithelium, leading to pulmonary edema, hyaline membrane formation, decreased lung compliance, and difficult air exchange.

Acute respiratory distress syndrome (ARDS) is a rapidly progressive disorder that initially manifests as dyspnea, tachypnea, and hypoxemia, then quickly evolves into respiratory failure. The American-European Consensus Conference (AECC) has published diagnostic criteria for ARDS: acute onset; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) of 200 or less, regardless of positive end-expiratory pressure; bilateral infiltrates seen on frontal chest radiograph; and pulmonary artery wedge pressure of 18 mm Hg or less when measured, or no clinical evidence of left atrial hypertension.

Acute respiratory distress syndrome often has to be differentiated from congestive heart failure, which usually has signs of fluid overload, and from pneumonia. Treatment of acute respiratory distress syndrome is supportive and includes mechanical ventilation, prophylaxis for stress ulcers and venous thromboembolism, nutritional support, and treatment of the underlying injury. Low tidal volume, high positive end-expiratory pressure, and conservative fluid therapy may improve outcomes. A spontaneous breathing trial is indicated as the patient improves and the underlying illness resolves. Patients who survive acute respiratory distress syndrome are at risk of diminished functional capacity, mental illness, and decreased quality of life; ongoing care by a primary care physician is beneficial for these patients.

KEY RECOMMENDATIONS FOR PRACTICE

When mechanical ventilation is required, patients with ARDS should be started at lower tidal volumes (6 mL per kg) instead of at traditional volumes (10 to 15 mL per kg). (Evidence rating: A)

Higher positive end-expiratory pressure values (12 to 18 or more cm H2O) should be considered for initial mechanical ventilation in patients with ARDS. (Evidence rating: B)

Conservative fluid therapy (targeting lower central pressures) in patients with ARDS may be associated with decreased days on a ventilator and increased days outside the intensive care unit. (Evidence rating: B)

Pulmonary artery catheters should not be used for the routine management of ARDS. (Evidence rating: A)

Surfactant therapy does not improve mortality in adults with ARDS. (Evidence rating: A)

A = consistent, good-quality patient-oriented evidence;
B = inconsistent or limited-quality patient-oriented evidence;
C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series.
For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.xml.

Pathophysiology

The pathophysiology of ARDS is not completely understood. Initially, a direct pulmonary or indirect extrapulmonary insult is believed to cause a proliferation of inflammatory mediators that promote neutrophil accumulation in the microcirculation of the lung. These neutrophils activate and migrate in large numbers across the vascular endothelial and alveolar epithelial surfaces, releasing proteases, cytokines, and reactive oxygen species. This migration and mediator release lead to pathologic vascular permeability, gaps in the alveolar epithelial barrier, and necrosis of type I and II alveolar cells. This, in turn, leads to the pulmonary edema, hyaline membrane formation, and loss of surfactant that decrease pulmonary compliance and make air exchange difficult. Subsequent infiltration of fibroblasts can lead to collagen deposition, fibrosis, and worsening disease.

In recovery, multiple actions occur simultaneously. Anti-inflammatory cytokines deactivate inciting neutrophils, which then undergo apoptosis and phagocytosis. Type II alveolar cells proliferate and differentiate into type I cells, reestablishing the integrity of the epithelial lining and creating an osmotic gradient that draws fluid out of the alveoli and into the pulmonary microcirculation and lung lymphatics. Simultaneously, alveolar cells and macrophages remove protein compounds from the alveoli, allowing the lungs to recover.

Management of Acute Respiratory Distress Syndrome

General measures
Nutritional support
Prophylaxis: Stress ulcer, Venous thromboembolism
Ventilator settings
Choose any mode, such as volume assist
Inspiratory to expiratory ratio of 1:1 to 1:3
PEEP and FiO2 set in accordance with ARDSNet protocol*
Respiratory rate ≤ 35 breaths per minute
Tidal volume of 6 mL per kg
Monitoring parameters
Arterial pH of 7.30 to 7.45
Oxygen saturation of 88 to 95 percent
PaO2 of 55 to 80 mm Hg
Plateau pressure ≤ 30 cm H2O
Adjunctive measures
Conservative fluid therapy

MECHANICAL VENTILATION
Most patients with ARDS need sedation, intubation, and ventilation while the underlying injury is treated. Any ventilator mode may be used, according to the Surviving Sepsis Clinical Practice Guideline and the National Heart, Lung, and Blood Institute's ARDS Network (ARDSNet).20,21 Respiratory rate, expiratory time, positive end-expiratory pressure, and FiO2 are set in accordance with ARDSNet protocols. Settings are adjusted to maintain an oxygen saturation of 88 to 95 percent and a plateau pressure of 30 cm H2O or less to avoid barotrauma. Clinical practice guidelines recommend maintaining an arterial pH of 7.30 to 7.45, although patients in some research trials have tolerated permissive hypercapnia and a pH as low as 7.15.

Evidence has shown that starting with low tidal volumes of 6 mL per kg is superior to starting with traditional tidal volumes of 10 to 15 mL per kg (number needed to treat = 11.4).21,22 Similarly, higher positive end-expiratory pressure values (12 cm H2O or more) are associated with decreased mortality compared with lower values of 5 to 12 cm H2O (number needed to treat = 20).23 Conservative fluid therapy (titrated to lower central pressures) has been associated with decreased days on a ventilator and increased days outside the ICU.24 Because of the potential complications of pulmonary artery and central venous catheters, they are not used routinely and should be administered only by those with training and experience.

PHARMACOLOGIC THERAPIES

Pharmacologic options for the treatment of ARDS are limited. Although surfactant therapy may be helpful in children with ARDS, a Cochrane review did not find it to be beneficial in adults.

The use of corticosteroids is controversial. Randomized controlled trials and cohort studies tend to support early use of corticosteroids (with dosages of methylprednisolone [Solu-Medrol] ranging from 1 to 120 mg per kg per day) for decreasing the number of days on a ventilator; however, no consistent mortality benefit has been shown with this therapy.

In addition to ventilatory measures, patients with ARDS should receive
low-molecular-weight heparin (40 mg of enoxaparin [Lovenox] or 5,000 units of dalteparin [Fragmin] subcutaneously per day) or low-dose, unfractionated heparin (5,000 units subcutaneously twice daily) to prevent venous thromboembolism, unless contraindicated.

Patients should also be on stress ulcer prophylaxis with an agent such as
sucralfate (Carafate; 1 g orally or via nasogastric tube four times daily),
ranitidine (Zantac; 150 mg orally or via nasogastric tube twice daily, 50 mg intravenously every six to eight hours, or a 6.25-mg-per-hour continuous intravenous infusion), or
omeprazole (Prilosec; 40 mg orally, intravenously, or via nasogastric tube daily).
Finally, patients should receive nutritional support, preferably enteral, within 24 to 48 hours of admission to the ICU.