Typically, the presentation of acute respiratory failure is a reflection of the underlying etiology. Depending upon the underlying pathology and the associated finding of hypoxemia or hypercapnia, the clinical presentation can vary. Hypercapnia causes asterixis and tachycardia, while hypoxemia causes cyanosis and neurologic impairment including restlessness, confusion, convulsions, and coma. Cyanosis is the bluish discoloration of the skin and mucous membranes caused by hypoxemia. Cyanosis becomes obvious if the concentration of deoxygenation hemoglobin in the tissues is or above 5g/dl.

• Fatigue

  She first presented with dizziness, general fatigue, and nausea 2 months before admission. She was hospitalized for intense general fatigue, nausea, and occipitalgia. [ncbi.nlm.nih.gov]

  This usually occurs when the respiratory loads are increased to the point where the respiratory muscles begin to fatigue and fail. [mcgill.ca]

  For example, a patient with severe pneumonia, in general, initially presents hypoxemic ARF that may progress to respiratory muscle fatigue and secondary failure of the ventilatory “pump” and hypercapnia. [xlung.net]

  Lung diseases may result in muscle fatigue and ventilatory failure through an imbalance between demands and supplies. [physio-pedia.com]

• Unconsciousness

  Eventually, the brain and heart malfunction, resulting in drowsiness (sometimes to the point of becoming unconscious) and abnormal heart rhythms (arrhythmias), both of which can lead to death. [merckmanuals.com]

  Upon arrival to the ER, the patient was unconscious and unresponsive. [medbullets.com]

  At this point, patients will be unconscious or about to become unconscious.[3] Symptoms of respiratory compromise can differ with each patient. [en.wikipedia.org]

  CASE We present case of one-year-old boy, who had chief complaint of seizure and unconscious. [msic.org.my]

• Euthyroid

  Euthyroid multinodular goiters may lead to acute respiratory failure caused by airway obstruction or laryngotracheal compression. [ncbi.nlm.nih.gov]

• Tachypnea

  Also Be Sure to Checkout our YouTube Channel 4 Main Causes of Acute Respiratory Failure: Increased Work of Breathing: Look for the triad of Tachypnea(short shallow tidal volumes), Tachycardia and Diaphoresis (↑Catecholamine surge) Refractory Hypoxemia [rebelem.com]

  Direct Links to chapters: 1:59-Chapter 2: Transient Tachypnea of the Newborn 3:32-Chapter 3: Neonatal Pneumonia 5:11-Chapter 4: Respiratory Distress Syndrome 6:41-Chapter 5: Meconium Aspiration Syndrome 8:19-Chapter 6: Case Study Please visit: www.openpediatrics.org [youtube.com]

  Clinical signs include respiratory distress characterized by tachypnea and dyspnea, and affected cattle may be found dead if clinical signs are unobserved. [merckvetmanual.com]

  Findings include dyspnea and tachypnea. Diagnosis is by ABGs and chest x-ray. Treatment usually requires mechanical ventilation. [msdmanuals.com]

• Pulmonary Disorder

  August 2001 Vol. 101, No. 8 Free Case Report | August 2001 Osteopathic philosophy and emergent treatment in acute respiratory failure Article Information Pulmonary Disorders / Being a DO Case Report | August 2001 Osteopathic philosophy and emergent treatment [jaoa.org]

  Guides you through the anatomy, physiology, and pathophysiology relevant to major pulmonary disorders, and then focuses on the clinical aspects and treatment of specific diseases. [books.google.com]

  English Pulmonary disorders There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS) in patients receiving [mymemory.translated.net]

  Additional types of acute respiratory failure are described elsewhere in this book: disorders that result from neuromuscular disease in Chap. 19 and pulmonary disorders of the circulation, including pulmonary thromboembolism, in Chap. 27. [link.springer.com]

  By this selection process, studies with inhome use of noninvasive ventilation for chronic pulmonary disorders, CPAP or NIV during intrahospital transport, expert opinions, editorials, reports, and case series were excluded. [doi.org]

• Cyanosis

  Cyanosis is the bluish discoloration of the skin and mucous membranes caused by hypoxemia. Cyanosis becomes obvious if the concentration of deoxygenation hemoglobin in the tissues is or above 5g/dl. [symptoma.com]

  It manifests with dyspnea and cyanosis and may lead to cardiovascular shock Respiratory function fails to maintain adequate oxygen supply and carbon dioxide removal 518.81 Excludes ICD-9-CM Volume 2 Index entries containing back-references to 518.81 : [icd9data.com]

  For those with hypoxemia, symptoms usually include difficulty breathing, blueish or pale skin, known as cyanosis, anxiety and restlessness. Symptoms for hypercapnia usually include rapid breathing and confusion. [study.com]

  Their study was based on a case series of 12 patients with acute respiratory distress, cyanosis refractory to oxygen therapy, decreased lung compliance and diffuse infiltrates evident on the chest radiograph. [ncbi.nlm.nih.gov]

  Low oxygen levels in the blood cause shortness of breath and result in a bluish coloration to the skin (cyanosis). Low oxygen levels, high carbon dioxide levels, and increasing acidity of the blood cause confusion and sleepiness. [merckmanuals.com]

Once acute respiratory failure is suspected, arterial blood gas analysis should be done to confirm the diagnosis. Complete blood count may be necessary to reveal common findings such as anemia.

Further investigations are necessary to detect the underlying cause of the acute respiratory failure including chest radiographs or CT scans and pulmonary function tests to check for pulmonary pathology. If cardiac pathology is suspected as the cause of the disease, an echocardiogram may be recommended. Blood electrolytes are also analysed to assess renal function.

• Hypercapnia

  Evaluation of Hypercapnia: The physiologic reasons for hypercapnia can be determined at the bedside. Minute Ventilation, RR, Vt, Assessment of patient's work of breathing - accessory respiratory muscle use, indrawing, retractions, abdominal paradox. [mcgill.ca]

  Results from acute or chronic impairment of gas exchange between the lungs and the blood causing hypoxia with or without hypercapnia. [bestpractice.bmj.com]

  Type 1 represents respiratory failure with hypoxemia without hypercapnia. Type 2 is noted if both hypoxemia and hypercapnia are present. [study.com]

  V/Q dysfunction mechanisms in the pulmonary parenchyma may cause hypoxemia and/or hypercapnia. [xlung.net]

  Convert to ICD-10-CM : 518.81 converts approximately to: 2015/16 ICD-10-CM J96.00 Acute respiratory failure, unspecified whether with hypoxia or hypercapnia Or: 2015/16 ICD-10-CM J96.90 Respiratory failure, unspecified, unspecified whether with hypoxia [icd9data.com]

The management of acute respiratory failure begins with emergency resuscitation which aims to restore ventilation and oxygenation. After the acute management has been achieved, further treatment involves determining the diagnosis and controlling the underlying disease. 

Oxygenation is achieved with administration of supplemental oxygen and all patients should have their oxygen saturation monitored with a pulse oximeter. Oxygen saturation should generally be maintained at over 90%. Adequate oxygenation is usually successful with supplemental oxygen because the rate of oxygen diffusion into the alveolar capillaries is directly proportional to the PaO2.

There are various oxygen-delivery devices which differ in their rate of oxygen delivery and therefore, their effectiveness also varies. These devices may be open or closed systems. These oxygen-delivery devices include:

1. Nasal cannula: This is an open device with low flow rate and low oxygen-delivery rate at 0.5 to 6L/min. Nasal prongs are usually used for stable patients with little or no demand for a high fraction of inspired oxygen (FIO2).
2. Venturi masks: These are open devices with low to moderate flow rate, and low to moderate oxygen concentration. Oxygen delivery can be controlled with these devices because of the jet-mixing apparatus through which 100% oxygen is delivered. These devices are, therefore, used in patients who require precise oxygen concentration delivery to the airways such as patients with COPD.
3. Reservoir face masks: These are open devices with high flow rates and high oxygen concentration. The masks are affixed to a bag filled with 100% oxygen. These devices minimize room air entry.
4. Resuscitation bag-mask-valve unit: These are devices with high flow rate and high oxygen concentration. The oxygen flow rate may be as high as 15L/min. The design of the device minimizes room air entry.
5. Non-invasive positive pressure ventilation: This employs a tight-fitting face mask to deliver oxygen from the ventilator. It is ideal for patients in whom intubation is contraindicated. 

Patients with acute respiratory failure are treated with supportive care which includes mechanical ventilation and prophylactic treatment of thromboembolism, stress ulcers, and pressure sores. Oxygenation has been shown to be better in both positions, prone and upright, with the prone position being preferred in patients with ARDS. Robak et al in a report noted short-term benefits of combined prone and upright positions [15]. However, in ARDS patients, prone position is preferred with the upright position being regarded as an effective alternative [16] [17]. It has also been reported that both positions cause a reduction in pneumonia associated with ventilator [18] [19] [20].

Mortality from acute respiratory failure varies depending on the etiology. ARDS is associated with a mortality rate of 40-45% which has remained high for a long period of time [12] [13]. COPD contributes to a rate of 10% mortality, whereas, an acute exacerbation of COPD causes death in 30% of patients. Generally, mortality rates are highest among the elderly and over two-thirds of survivors may develop pulmonary sequela within a year of treatment.

Hypercapnic respiratory failure is associated with a relatively higher mortality rate, possibly attributable to the chronicity of the underlying disease, notable systemic comorbidities, and poor nutritional status.

As noted in a study by Noveanu et al, administration of beta-blockers before and during admission is associated with significant reduction in mortality rates within a year of treatment [14].

Acute respiratory failure causes various pulmonary and extrapulmonary complications including the underlisted:

• Pulmonary complications: Pulmonary embolism, pulmonary fibrosis, nosocomial pneumonia, and barotrauma are common complications of acute respiratory failure. Routine radiographic chest evaluation is therefore part of the management of acute respiratory failure.
• Cardiac complications: Acute respiratory failure commonly results in hypotension, arrhythmias, acute myocardial infarction, and heart failure. These could occur as a result of the underlying pathology, mechanical ventilation, or the pulmonary artery catheterization.
• Gastrointestinal complications: These include ileus, pleuroperitoneum, stress ulcers, and diarrhea. Stress ulcers can be prevented by concomitant administration of anti-secretory or mucus protecting medications.
• Renal complications: Acute renal failure is a poor prognostic factor in acute respiratory failure. It usually occurs as a result of renal hypoperfusion and nephrotoxic medications used.
• Nosocomial infections: In addition to pneumonia, other nosocomial infections which may infect critically-ill cases with acute respiratory failure are urinary tract infections and catheters-associated sepsis. Nosocomial pneumonia is very common in patients having acute respiratory failure and is a poor prognostic factor.
• Nutritional complications: These include malnutrition and the complications of enteral or parenteral administrtion such as diarrhea and bloating from nasogastric tubes. Parenteral nutrition may also cause metabolic imbalances and infections at the site of insertion of the intravenous line.

Acute respiratory failure is classified into four main groups largely based on the etiopathogenesis. These include:

Type 1 (Hypoxemic type). This type is characterized by hypoxemia (PO2 <50 mmHg) and is generally the result of diseases which impair alveolar exchange by damaging the alveolar structures. These diseases include acute respiratory distress syndrome (ARDS), pulmonary embolism, bronchiectasis, pneumoconiosis, pulmonary edema, asthma, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). 

Extrapulmonary diseases which cause hypoxemic respiratory failure include kyhoscoliosis, cyanotic congenital heart disease, and obesity. Hypoxemic respiratory failure is the commonest type of acute respiratory failure.

Type 2 (Hypercapnic) respiratory failure is also called ventilatory respiratory failure and is caused by ventilatory problems. These diseases can be grouped into four types for descriptive purposes.

1. Diseases which inhibit the respiratory centers in the brain stem: These include brain stem tumors, head injury, metabolic disorders, narcotic or sedative toxicity, and myxedema coma.
2. Diseases which impair chest wall movement during respiration: These include kyphoscoliosis, myasthenia gravis, and muscular dystrophy.
3. Diseases which cause inhibition of neural signals to the respiratory muscles including Guillain-Barre syndrome, polyneuropathy, and poliomyelitis.
4. Diseases which cause obstruction of air flow through the airways. These include COPD, chronic asthma, acute epiglottitis, airway malignancies, and cystic fibrosis.

Hypercapnic respiratory failure is marked by a PCO2 of over 50mmHg and may be associated with hypoxemia.

Type 3 respiratory failure occurs preoperatively while type 4 occurs secondary to shock.

The number of inpatient cases diagnosed with acute respiratory failure between 2001 to 2009 increased from 1,007,549 to 1,917,910 according to the Nationwide inpatient sample based on the international classification of diseases (ICD). The total hospital costs rose from $30.1 billion in 2001 to $54.3 billion in 2009; the change in the mean hospital cost per case was insignificant. The mortality from respiratory failure in the inpatients during this period dropped from 27.6% to 20.6% [5]. 

It's not fully settled whether there is a racial predisposition to acute respiratory failure. More so, as reported by Khan et al in a study, there were no racial differences in mortality rates of acute respiratory failure among Asians and the native patients [6]. However, some studies have pointed significant differences in mortality rates between African Americans and whites [7].

Severe acute respiratory syndrome (SARS), an infectious pulmonary disease, causes acute respiratory failure. SARS is most prevalent in Asia, Europe and North America. It was recorded that at least 8,000 people contracted SARS between November, 2002 and August, 2003 with countries worst hit were Singapore, Taiwan, Vietnam, Canada, and China [8].

SARS is associated with significant morbidity and mortality; 32% of cases of SARS are associated with significant mortality while mortality is present in up to 80% of severe cases [9] [10] [11].

In the physiologic state of the body, the ventilatory capacity always exceeds the ventilatory demand. In acute respiratory failure, however, the reverse happens such that either the ventilatory capacity becomes inadequate to meet the body's ventilatory demands or there is increased ventilatory demand.

The functional unit of the respiratory system is the alveolus, in which gas exchange takes place. During alveolar capillary gas exchange, oxygen diffuses into the blood while carbon dioxide diffuses out. Oxygen in the blood reversibly binds to hemoglobin such that 1.36 ml of oxygen is bound to 1g of hemoglobin. However, what amount of oxygen binds to hemoglobin depends on Pa O2, the partial pressure of oxygen in the blood. This relationship is represented by oxygen-hemoglobin dissociation curve.

In physiologic respiration, there are occurrences of ventilation-perfusion mismatch whereby ventilation doesn't match the perfusion provided in terms of the oxygen tension (PO2) thereby creating a gradient. Therefore, this creates a physiologic scenario in which some alveoli are over-ventilated while others are underventilated for a given alveolar perfusion and creating a spectrum of hypoperfused and hyper-perfused alveoli for a given ventilation. The over-ventilated alveoli with poor or no perfusion are termed high Ventilation/Perfusion (V/Q) units while the alveoli which are poorly ventilated but highly perfused are termed low V/Q units. The former category of alveoli is regarded as dead space because of the poor perfusion for gas exchange while the later group of alveoli is described as shunt.

Carbon dioxide is transported in the blood in three main forms: as a simple solution, as bicarbonate, and bound to hemoglobin. Normally, the rate of tissue production of carbon dioxide is equal to its rate of pulmonary elimination. This is represented by the equation below:

VA = K x VCO2/ Pa CO2. 

(K is a constant with a value of 0.863; VA, alveolar ventilation; VCO2, carbon dioxide ventilation). 

V/Q mismatch and shunting are the main processes which cause hypoxemic respiratory failure by causing a large alveolar-arterial PO2 gradient. Although, these two processes may occur simultaneously, V/Q mismatch is the commonest cause of hypoxaemia. The low V/Q units are particularly responsible for causing hypoxemia while the high V/Q units do not cause significant respiratory complication unless the underlying disease becomes severe. The low V/Q match may occur as a result of either under-ventilation or hyperperfusion. Under-ventilation may be caused by the diseases listed above which inhibit respiratory drive or impair chest wall movement while over-perfusion may be seen in pulmonary embolism.

Shunt is referred to as an unresolved hypoxaemia despite administration of 100% oxygen. This is a result of several hyperperfused alveolar units with minimal ventilation. This causes a reduced arterial blood content. Shunt is seen in pneumonia, severe pulmonary edema, and atelectasis. Hypoxaemia secondary to shunt is relatively more difficult to treat by oxygen supplementation. Hypercapnia may result if shunt is severe.

Hypercapnic respiratory failure basically results from reduction in alveolar ventilation. In these settings, both hypoxemia and hypercapnia may occur, however, alveolar-arterial PO2 gradient remains normal.  Hyperventilation rarely causes respiratory failure and it commonly results from drug toxicity. 

Primary prevention of acute respiratory failure includes strategies to prevent the underlying causes of acute respiratory failure. It has been suggested that influenza and pneumococcal vaccinations may reduce the risk of acute respiratory failure in high risk patients such as those with COPD. Quitting smoking also reduces the incidence of acute respiratory failure in patients with lung disease.

Secondary prevention of acute respiratory failure involves constant management of chronic pulmonary diseases to prevent progression to respiratory failure.

Acute respiratory failure refers to the inability of pulmonary system to meet oxygen demand for blood oxygenation and /or CO2 elimination. The causes of acute respiratory failure are grouped into four types on the basis of the etiopathogenesis.

Type 1 (hypoxemic type) is the commonest acute respiratory failure. Type 2 is marked by hypercapnia and is caused by diseases which impair minute ventilation either by inhibiting respiratory drive or impairing respiratory muscles or neuromuscular activity. Type 1 respiratory failure is generally caused by diseases which damage the alveoli such as pneumoconiosis, pulmonary embolism, and acute respiratory distress syndrome.

Types 3 and 4 occur preoperatively and as a result of shock, respectively. Respiratory infections especially bronchiolitis and pneumonia are the most common indications for mechanical ventilation in children [1]. Inadequate production or abnormal functioning of surfactant is implicated in the etiology of acute respiratory failure in children due to secondary acute lung injury, acute respiratory distress syndrome [2], and bronchiolitis [3] [4].

The signs and symptoms of acute respiratory failure are those of the underlying disease and the features of hypoxemia and hypercapnia.

Diagnosis of acute respiratory failure depends on a high index of suspicion which is confirmed by arterial blood gas analysis with pulse oximetry. This is followed by laboratory and imaging studies to determine the underlying disease cause.

Management of acute respiratory failure involves urgent administration of supplemental oxygen which is followed by diagnosis and management of the underlying cause.

Acute respiratory failure is a medical emergency in which oxygen and carbon dioxide can no longer be adequately exchanged in the lungs. Normally, the oxygen we inhale gets exchanged with carbon dioxide in small structures within the lungs called alveoli; the carbon dioxide is then expired while oxygen diffuses into the blood for use by every cell in the body. In acute respiratory failure, this exchange is compromised, therefore, the body is short of oxygen to provide for the body.

Several diseases can cause acute respiratory failure. Some of these diseases destroy the alveoli while others impair breathing. Diseases which destroy the alveoli include acute respiratory distress syndrome, pneumonia, pulmonary fibrosis, and asthma. Diseases which reduce deep breathing include brain damage, drug toxicity, disorders of the chest wall muscles, spinal cord injury, brain tumors and airway tumors. All of these conditions significantly reduce the amount of oxygen made available to the body either by destroying the alveoli or by reducing the amount of oxygen which is made available for diffusion. 

Although, death from acute respiratory failure depends on the cause, the respiratory failure is fatal, if it is not treated urgently. Survivors may still be left with some damage done to the lungs. Furthermore, in the absence of early treatment, acute respiratory failure may cause significant complications in many tissues of the body, such as heart attack, heart failure, low blood pressure, stomach ulcers, diarrhea, kidney failure, and lung infections.

Symptoms of acute respiratory failure are difficulty in breathing, fast heart rate, confusion, restlessness, convulsions and even coma. A very typical finding in this condition is the bluish discoloration of the lips, skin, and other body linings. This is called cyanosis and is due to very low oxygen content of the blood.

First, once this condition is suspected, doctors would perform a test called arterial blood gas analysis to see if the oxygen is low or the carbon dioxide is high. If this is confirmed, doctors would perform several tests to determine the cause of the respiratory failure. These tests would include chest x-ray, chest CT scan, and electrocardiogram (ECG).

The mainstay of treatment of acute respiratory failure is providing an artificial source of oxygen via mechanical ventilation. Here, oxygen is delivered through the patient's nose via face mask, tubes passed down the throats, or via small tubes passed into the nostrils. Once the delivery of adequate oxygen is achieved, the doctors would proceed to treating the underlying cause and prevent the development of complications.

1. Randolph AG, Meert KL, O'Neil ME, et al. The feasibility of conducting clinical trials in infants and children with acute respiratory failure. Am J Respir Crit Care Med. 2003; 167:1334-1340.
2. Royall JA, Levin DL: Adult respiratory distress syndrome in pediatric patients. I. Clinical aspects, pathophysiology, pathology, and mechanisms of lung injury. J Pediatr. 1988; 112:169-180.
3. Skelton R, Holland P, Darowski M, Chetcuti PA, Morgan LW, Harwood JL: Abnormal surfactant composition and activity in severe bronchiolitis. Acta Paediatr. 1999; 88:942-946. 
4. Dargaville PA, South M, McDougall PN. Surfactant abnormalities in infants with severe viral bronchiolitis. Arch Dis Child. 1996; 75:133-136.
5. Stefan MS, Shieh MS, Pekow PS et al. Epidemiology and outcomes of acute respiratory failure in the United States, 2001 to 2009: a national survey. 2013; 8(2):76-82.
6. World Health Organization. Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July, 2003. http://www.who.int/csr/SARS/country/table2003_09_23/en/. Revised 26 September 2003. Accessed December 4, 2015. 
7. World Health Organization. Consensus Document on the Epidemiology of Severe Acute Respiratory Syndrome. http://www.who.int/csr/SARS/en/WHOconsensus.pdf. Accessed December 4, 2015.
8. Khan NA, Palepu A, Norena M, et al. Differences in hospital mortality among critically ill patients of Asian, Native Indian, and European descent. Chest. 2008; 134 (6):1217-22. 
9. Booth C, Matukas L, Tomlinson G, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:2801-2809. 
10. Fowler RA, Lapinsky SE, Hallett D, et al. Critically ill patients with severe acute respiratory syndrome. JAMA. 2003;290:367–373. 
11. Lew TWK, Kwek TK, Tai D, et al. Acute respiratory distress syndrome in critically Ill patients with severe acute respiratory distress syndrome. JAMA. 2003;290:374-380.
12. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000; 342(18):1301-8. 
13. Phua J, Badia JR, Adhikari NK, et al. Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review. Am J Respir Crit Care Med. 2009;179(3):220-7. 
14. Noveanu M, Breidthardt T, Reichlin T, et al. Effect of oral beta-blocker on short and long-term mortality in patients with acute respiratory failure: results from the BASEL-II-ICU study. Crit Care. 2010;14(6): R198.
15. Robak O, Schellongowski P, Bojic A, Laczika K, Locker GJ, Staudinger T: Short-term effects of combining upright and prone positions in patients with ARDS: a prospective randomized study. Crit Care. 2011;15: R230. 
16. Hoste EA, Roosens CD, Bracke S, et al. Acute effects of upright position on gas exchange in patients with acute respiratory distress syndrome. J Intensive Care Med. 2005; 20:43-49.
17. Richard JC, Maggiore SM, Mancebo J, Lemaire F, Jonson B, Brochard L: Effects of vertical positioning on gas exchange and lung volumes in acute respiratory distress syndrome. Intensive Care Med. 2006; 32:1623-1626.
18. Sud S, Friedrich JO, Taccone P, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med. 2010; 36:585-599.
19. Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogue S, Ferrer M: Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999; 354:1851-1858.
20. Alexiou VG, Ierodiakonou V, Dimopoulos G, Falagas ME: Impact of patient position on the incidence of ventilator-associated pneumonia: a metaanalysis of randomized controlled trials. J Crit Care. 2009; 24:515-522.