Pediatric Respiratory Failure – Acute Hypoxemic Respiratory Failure – ARDS

1. Description of the problem

What every clinician needs to know

Clinical ARDS is characterized by hypoxemic respiratory failure that is refractory and life-threatening. Once thought to be primarily an adult condition, it is now recognized as a syndrome in all age groups. ARDS closely resembles, but should not be confused with Infant Respiratory Distress Syndrome, a condition due to surfactant deficiency in premature infants.

Profound hypoxia is the hallmark and the severity at presentation is a predictor of mortality in children. It can be caused by direct injury to the lungs such as a pneumonic infection or inhalation injury, or indirectly from a systemic inflammatory condition such as septic shock or trauma.

The most common trigger is infection, notably of the lower respiratory tract. Management is primarily supportive care, mechanical ventilation and treatment of the underlying cause. A low tidal volume ventilator strategy with pressure limited ventilation (6 ml/kg of predicted body weight, aiming for a plateau pressure of <30 cm of water) is the only ventilation strategy shown to improve outcomes to date.

High PEEP, lung recruitment maneuvers and prone positioning have been shown to improve oxygenation but not long-term survival. High Frequency Ventilation (HFOV) can be safely employed when a patient is failing conventional ventilation but there is no data to show that it independently improves outcomes.

Improvements in ventilator strategy, monitoring devices, fluid and nutritional support, sepsis management and nosocomial preventive measures may have contributed to the recent decline in the pediatric ARDS mortality rate which is now reported as low as 29%.

Clinical features

ARDS is a rapidly progressive condition characterized by the acute onset of tachypnea, dyspnea, and hypoxia within 24 to 72 hours of an inciting event. The physical exam typically reveals tachycardia, tachypnea, cyanosis and diffuse rales.

The condition rapidly progresses to profound hypoxemia with bilateral pulmonary infiltrates on CXR and almost invariably requires mechanical ventilation. Usually these patients reflect the clinical findings of the inciting illness such as septic shock or trauma. As a consequence, these children will have varying degrees of multi-organ dysfunction or failure including DIC, liver failure, and renal insufficiency. It is not uncommon to need continuous venovenous hemofiltration or dialysis.

Patients with ARDS tend to progress through three distinct stages with different clinical, radiographic, and histopathological manifestations. The initial acute or exudative phase occurs during the first week and is characterized by a rapid onset of respiratory failure requiring aggressive mechanical ventilation.

During this phase the patients are at risk for ventilator induced lung injury from high inspiratory pressures, high tidal volume, or oxygen toxicity. Ongoing alveolar damage combined with ventilatory pressures and tidal volumes can result in air leak into the chest and mediastinum.

The subacute or proliferative phase usually begins after the first week of therapy and is manifested by persistent hypoxemia, progressive hypercarbia due to an increase in alveolar dead space, and further decrease in pulmonary compliance with progression of lung restriction. Secretions become problematic, and air leak and ventilator associated pneumonia are potential complications.

The recovery phase follows approximately 2 or more weeks out from onset of the illness and is characterized by the gradual resolution of hypoxemia and radiographic abnormalities, and improved lung compliance. Patients are at risk for complications of prolonged illness and bed rest such as musculoskeletal weakness, nosocomial infections, deep venous thrombosis, and decubitus injury. Gastrointestinal bleeding from stress ulcers also occurs in this phase.

Key management points

Management remains essentially supportive and is aimed at decreasing mortality and morbidity, hastening recovery, and optimizing long-term respiratory and cognitive function. Identification and treatment of the underlying cause is essential to optimize clinical outcome. Early antibiotic therapy is justified because sepsis is often the trigger. Infections should be treated with antibiotics guided by cultures and sensitivities. Removal of any identifiable source of infection is paramount.

Prevention or early treatment of nosocomial infections is critical. A “fluid conservative” approach is recommended once the patient is adequately resuscitated and adequate nutrition through the use of enteral feeding is preferred. The prevention of gastrointestinal bleeding and venous thromboembolism is also important.

2. Emergency Management

Emergency management steps

Patients almost invariably require high levels of oxygen, intubation, and mechanical ventilation. Noninvasive ventilatory support can be tried in some instances but should be abandoned quickly for invasive support if there is no improvement. Central venous and arterial access is warranted early in patients at risk and is often times necessary to manage the underlying cause. Central venous and arterial monitoring can be used to monitor hemodynamics and optimize fluid and oxygen delivery.

Ventilation management and adjunctive therapies should be directed at correcting hypoxia to minimize brain and other vital organ injury. A volume and pressure limited lung protective ventilator strategy should be used to minimize ventilator induced lung injury.

The gold standard for assessment of adequate oxygen delivery and cardiac function remains the pulmonary artery catheter. However, as this technique is rarely utilized due to concerns of the risk/benefit ratio in children and reports in adults of no difference in outcome with care guided by its information, less invasive devices are more frequently applied.

Venous saturation monitoring, near infrared spectroscopy and other devices to assess cardiac output and lung water are used in some patients. The impact of these on overall survival has yet to be confirmed. End-tidal CO2 monitoring and information from ventilator assessment of compliance such as pressure-volume loops can guide optimal management.

It is important to wean FiO2 as soon as the patient allows. A volume and pressure limited “open-lung” ventilator strategy should be instituted with a tidal volume of 6 mL/kg of predicted body weight, PEEP determined by pressure-volume loops, and limitation of plateau pressures of < 30 cm of water.

Ventilated patients will require sedation and some may require the intermittent use of paralytics to facilitate the initial ventilator management. Frequent assessments to minimize the use for paralytics are important to prevent prolonged mental status depression, persistent paralysis and prolonged muscle weakness.

Newer modes of ventilator support may provide more patient synchrony and optimize spontaneous breathing. Neurally assisted ventilation interprets the patients respiratory effort to initiate ventilation. Other modes such as airway-pressure release, are also available in various semantic forms, but none of these new and improved modes have been shown to improve outcome.

Of note, however, pressure control ventilation, long thought to be the optimal mode in severe lung injury, has never been proven superior to other modes in randomized trials.

Assessment of lung injury is often followed by the PaO2/FiO2 ratio, although this parameter provides no information on the degree of ventilator support being applied. The oxygenation index (OI) is another commonly used tool that incorporates the level of ventilator support and is calculated by: (mean airway pressure x FiO2) / PaO2.

While no single measurement has been correlated with death, following serial OI levels do give some guide as to the severity of lung injury over time. Historically, OI’s ranging between 20-30 indicate moderately severe disease and levels consistently over 40 have been noted in patients with high mortality. Thus OI levels > 20 often is a point where adjunct therapy such as high frequency ventilation is introduced.

Prone positioning is also often applied to select patients. Inhaled nitric oxide can be trialed, especially in patients with any evidence of pulmonary hypertension. While improved oxygenation may occur, neither prone positioning or inhaled nitric oxide have been shown to improve survival in randomized trials. Given the cost of nitric oxide therapy, this treatment should be quickly abandoned if no beneficial effects are noted within a short period.

In patients refractory to the “conventional” therapies above, extracorporeal life support (ECLS) provides another adjunct therapy. Veno-venous cannulation is preferred over veno-arterial unless the patient has significant myocardial dysfunction.

New miniaturized extracorporeal oxygenators and devices may open up a new paradigm for respiratory failure management and are actually replacing mechanical ventilation in some patients such as those with chronic obstructive pulmonary disease or bridging to lung transplant. Whether they will impact the treatment of ARDS remains to be seen.

Drugs and dosages

Figure 1

Figure 1.

Recommendations below are suggestions during initial ventilation managements:

Start with 100% oxygen.

Cuffed ET tubes can be used safely in children and may be necessary to ensure optimal PEEP and TV in patients with poor lung compliance.

Target pH 7.25-7.40. Higher PaCO2 levels can be tolerated.

Target SaO2 > 87% if the patient is difficult to oxygenate. Lower levels can be tolerated if organ oxygenation appears adequate.

Maintain the Hgb >10 gm/dl for patients with severe hypoxemia. The exact level for hemoglobin maintenance between 7-10 gm/dL remains controversial.

Keep HOB elevated at least 30 degrees to minimize risk of ventilator acquired pneumonia (VAP).

Follow the Oxygenation Index and/or PaO2/FiO2 ratio to monitor progress and adjust therapies.

Oxygenation Index = Mean Airway Pressure x FiO2 / PaO2

20-30 = consider HFOV

30-40 without improvement may indicate need for alternative therapies (ECLS)

PaO2 / FiO2 ratio

<300 = ALI

<200 = ARDS

Start broad spectrum antibiotics consistent with the patient’s immune status and community patterns.

Initiate aggressive work up to determine the cause of the patient’s ARDS.

3. Diagnosis

Diagnostic criteria and tests

The American European Consensus Conference Committee defines ARDS as an acute condition with bilateral radiographic infiltrates, a pulmonary-artery wedge pressure less than 18 or the absence of clinical evidence of left atrial hypertension, and a PaO2 / FiO2 ratio less than 200.

A CXR, arterial blood gas and in some cases, an echocardiogram are necessary to make this diagnosis.

Normal lab values

Figure 2

Figure 2.

Initial labs should be guided by the history and potential etiologies. A complete blood count and routine bacterial and respiratory viral cultures should be obtained when indicated, to rule out infectious etiologies. An arterial blood gas is necessary to calculate the oxygenation index and PaO2:FiO2 ratio.

While some clinicians now advocate less invasive monitoring of oxygenation by arterial saturation:FiO₂ ratio, this approach is not traditional. Use of invasive arterial lines also provides hemodynamic information.

Analysis usually reveals an acute respiratory alkalosis with an elevated alveolar-arterial oxygen gradient and severe hypoxemia. Laboratory findings are otherwise nonspecific and depend on the potential etiology, and may include evidence of DIC and lactic acidosis. The chest radiograph may demonstrate focal changes early on in patients with direct pulmonary insult such as an aspiration or may be nonspecific with indirect insults such as sepsis.

As the disease progresses, the chest radiograph typically shows diffuse bilateral alveolar infiltrates with prominent air bronchograms. In some cases, mediastinal and intrathoracic air may be visible from air leak caused by barotrauma and lung friability. Thereafter, the characteristic bilateral diffuse alveolar and reticular opacities become evident and may progress to linear opacities and cysts in the presence of evolving fibrosis.

Typically the radiographic abnormalities resolve completely over time though in more severe cases, chronic interstitial changes may persist.

Additional studies depend on the patient’s history and inciting event.

A complete blood count, coagulation studies, and arterial blood gas is likely to reveal a leukocytosis and thrombocytopenia, coagulopathy, and lactic acidosis with sepsis.

A serum BNP, echocardiography and pulmonary artery placement or cardiac catheterization may be necessary to exclude heart failure.

Pulmonary artery catheter or echocardiogram data may also be useful to assess volume status, ventricular function, cardiac output, and presence and degree of pulmonary hypertension.

A serum lipase can be useful to exclude pancreatitis.

A spiral chest CT with a CT angiogram may be necessary to exclude pulmonary embolic disease. Consider bronchoscopy if the cause cannot be determined otherwise.

Hemosiderin-laden macrophages from bronchoalveolar lavage, in a patient with hypoxia and unexplained drop in hemoglobin is suggestive of diffuse alveolar hemorrhage.

An elevated percentage of lipid laden macrophages suggest chronic aspiration. Idiopathic acute eosinophilic pneumonia is distinguished from ARDS by the large number of eosinophils in bronchoalveolar lavage specimens.

Establishing the diagnosis

If the patient meets the above AECC diagnostic criteria, the patient has ARDS. The underlying trigger will also have a diagnosis.

Differential diagnosis

Viral or Bacterial Pneumonia

Pulmonary contusion

Congestive Heart Failure

Diffuse Alveolar Hemorrhage

Acute Interstitial Pneumonia

Idiopathic Acute Eosinophilic Pneumonia

Leukemic Infiltrates

Miliary tuberculosis

Aspiration pneumonia

Opportunistic infection in an immunocompromised child

Alveolar Capillary Dysplasia

Neurogenic Edema

Flash pulmonary edema following relief of chronic, severe upper airway obstruction

4. Specific Treatment

First-line therapy

Aggressive treatment of the underlying disease and meticulous supportive care are the mainstays of therapy. Many studies have been published in the past 20 years to determine the best management strategies to minimize lung injury, ventilator and ICU days, and mortality. None have proven to be definitive in children.

Despite the few excellent collaborative pediatric studies, much of our approach is driven by the findings in adult studies. To date, low tidal volume (<6 ml/kg) pressure limited ventilation is the only method of mechanical ventilation that has been shown to improve survival in ARDS.

A recent meta-analysis of over 2,000 individual adult patient data concluded that higher levels of PEEP were associated with improved survival in a subgroup of patients with severe ARDS, but there is no determined level to universally recommend.

Inverse I:E ratio ventilation and HFOV both improve oxygenation and intuitively seem more gentle than conventional ventilation but neither strategy has been shown to improve outcomes over conventional support.

HFOV has been shown to be safe and unlikely to cause harm and may be associated with a decrease in mortality. HFOV is commonly recommended in patients whose hypoxemia appears to be refractory to conventional ventilation. The major disadvantage of HFOV is the high levels of sedation that is required to tolerate the technique in children outside the newborn period.

Prone positioning can be used safely in children and improve oxygenation in patients with severe ARDS, but have not been shown to improve ventilator free days in children. Caregivers should use a preventative strategy to decrease the risk of decubitus if the prone position is applied. Recruitment maneuvers with brief periods of high levels of pressure or PEEP have also been trialed with variable results – some studies find oxygenation benefit and others increased air leak and complications.

Inhaled nitric oxide is a potent pulmonary vasodilator that can improve oxygenation. Outcomes though, were not favorable in a recent meta-analysis of adults and children.

Corticosteroids come in and out of favor in ARDS. Studies are variable in terms of benefit or risk. Currently, many clinicians advocate low to moderate doses started during the second week of ARDS for a prolonged duration.

Surfactant has also been evaluated in pediatric respiratory failure, but no study has found consistent improvement with this therapy.

Initially, fluid therapy may need to be aggressive to resuscitate the patient in shock but subsequently fluid restriction should be initiated based on the recent findings from the NHLBI adult trial that showed a restrictive fluid management protocol to reduce ventilator days when compared to a more liberal protocol.

When exactly “resuscitation” ends and fluid restriction begins is controversial. Many advocate that by the third day of acute illness, fluid balance should be maintained. Use of diuretics or hemofiltration, in patients with renal insufficiency, is frequent.

Currently there is no proof that transfusing hemoglobin levels to super normal levels benefits ARDS patients. Maintaining adequate oxygen carrying capacity is the goal. Targets of a Hgb level >10 g/dL in unstable children are often used. Evidence supports dropping the hemoglobin transfusion threshold to 7 g/dL once profound hypoxia and shock have resolved. A comparison study of hemoglobin targets in children is currently in the planning stage.

Nutritional support is vital. Enteral feeds are the preferred method over parenteral nutrition. Nutrient supplementation with immune modulating formulas has not been shown to be effective in improving outcomes. Overfeeding must be avoided, and caloric intake of 50 kcal/kg or even less may be sufficient in the acute phase of illness. Use of metabolic cart analysis of carbon dioxide production and oxygen consumption would be beneficial but these devices have not proven reliable in intubated children.

Sedation is unfortunately a standard part of routine care. There is no data to support any specific regime currently. Paralytics should be avoided to prevent long-term muscle weakness. Surprisingly, one recent adult trial showed an increased survival, increased ventilator free days, and less barotrauma and air leak in patients given muscle relaxants in the first 48 hours of care.

Tight glucose control in critically ill patients has been advocated. However, more recent evaluation has found a significantly higher risk of hypoglycemia. Hyperglycemia is to be avoided.

The use of protocols established to prevent ventilator acquired pneumonia and catheter related blood stream infections should be implemented and meticulously followed. Use of a standardized ventilator management and weaning protocol is recommended to potentially minimize ventilator induced injury and decrease the number of ventilator days.

Newer ventilator “support modes” combined with the use of Neuronal Activation Ventilatory Assist (NAVA) allows a variable breathing pattern and has been shown to improve patient-ventilator synchrony, optimize respiratory muscle unloading, and improve patient comfort.

CMV guidelines for ALI/ARDS as adapted from NHLBI ARDS Network

Set mode to volume assist-control, pressure regulated volume control or similar modes.

Set initial tidal volume to 6-8 mL/kg ideal body weight.

Set the rate to approximate patients rate but not to exceed 35/min.

Optimally, PEEP should be adjusted to a level above the lower inflection point of the patients inspiratory pressure volume curve.

Reduce tidal volume by 1 mL/kg every two hours or less until a tidal volume of 4-6 mL/kg is reached and pH and plateau pressure goals are reached.

Goal plateau pressure 30 cm water or less.

The plateau pressure (PP) is the pressure applied to small airways and alveoli. It is measured during an inspiratory pause on the ventilator.

Without lung disease, the peak inspiratory pressure (PIP) is only slightly above the plateau pressure. Increasing peak pressure with no change in plateau pressure is seen with increased airway resistance or high inspiratory gas flow rates. Increased peak and plateau pressure is indicative of a decrease in lung compliance.

Check plateau pressure every 4 hours and after every adjustment of PEEP and oxygen.

If the plateau pressure is greater than 30, the tidal volume is decreased by 1 mL/kg to a tidal volume of 4 mL/kg or a plateau pressure of less than 30 is reached.

In some patients, a tidal volume of 6 cc/kg will still result in over-inflation of normal areas of the lung. Reduction of minute ventilation to decrease lung injury may result in respiratory acidosis from hypercarbia which may not be well tolerated. Permissive hypercapnia has been shown to be well tolerated in many patients even with pH <7.25.

Bicarbonate can be used for buffering if needed, especially if the arterial pH is < 7.0 keeping in mind that bicarbonate will result in additional carbon dioxide to be eliminated. Permissive hypercapnia should be used with caution in patients with head injury to avoid excessive cerebral blood flow and in patients who are at high risk for cardiac dysrhythmias if acidosis is severe.

Goal oxygen saturation is usually greater than 88% or a PaO2 greater than 50 mmHg, although permissive hypoxemia with lower levels of saturation and paO2 can be safe in many patients if organ perfusion is maintained and delivery adequate.

FiO2 less than 0.60 is desired to prevent additional lung toxicity.

HFOV guidelines for ALI/ARDS

Patients with an oxygenation index of 15-20, mean airway pressure of >20 cm H2O or center-specific criteria should be considered.

Contraindicated in patients with intracranial hypertension and severe airflow obstruction.

Optimization of intravascular volume prior to or during initiation of HFOV to counteract the decrease in venous return from the higher intrathoracic pressure is an important management therapy.

Frequent adjustment of ventilator and oxygen settings to optimize oxygen delivery and maintain adequate ventilation may be required initially.

Subsequent changes often are limited to weaning oxygen to non-toxic levels until improved compliance allows weaning of mean airway pressure and frequency.

Chest radiograph is useful to assess endotracheal tube placement, lung inflation and areas of worsened consolidation. Serial evaluations to assess lung inflation, tube and line positions, and identify air leak are performed.

High frequency ventilation

Initial amplitude should cause wiggle to hips / upper thighs. One simple rule is to begin amplitude at twice the mean airway pressure and adjust for oxygenation as needed. Maximal levels of amplitude are determined by the amount of bias flow the ventilator can provide. Newer adult oscillator models allow peak amplitudes of 90 cm of water

Frequency should be 10-12 Hz for infants, 8-10 Hz for children, and 5-8 for adults. An important factor in the presumed “lung protective” aspect of HFOV is using the highest level of frequency that provides adequate ventilation. Lower frequencies result in larger tidal volume breaths which in turn may exceed dead space ventilation and contribute to lung injury.

Initial IT% should be 33.

Adjustments for ventilation with a target pH 7.25-7.35.

Follow-up arterial blood gas within 30 minutes.

Increase frequency by 1-2 Hz to maximum of 15 Hz.

Should pH fall for a given frequency, increase amplitude 5 cm of water to maximum of 90 cm of water.

Adjustments for ventilation with a pH greater than 7.35.

Follow-up arterial blood gas within 30 minutes.

Increase frequency by 1-2 Hz to maximum of 15 Hz, then decrease amplitude by 5 cm of water to a minimum of 20 cm H₂O.

Adjustments for ventilation with a pH less than 7.25

Follow-up arterial blood gas within 30 minutes.

Treat metabolic acidosis, relieve pneumothorax or obstructed tube, and recruit.

Increase amplitude by 5 cm of water to a maximum of 90 cm of water, then deflate cuff and increase IT to 50

Decrease frequency by 1 Hz to a minimum of 3 Hz.

Oxygenation

– GOAL – PaO₂ 44-80 mmHg or SaO₂ 88-95%

Initial FiO₂ should be 100%

Initial mean airway pressure should be the mean airway pressure CMV + 5 cm H2O maximum of 35 cm H2O

Consider recruitment to 35-45 cm H2O for 40-60 seconds (HFO on pause)

If oxygenation is less than target, increase mean airway pressure by 5 cm H2O to a maximum of 35 cm H2O

Optimize intravascular volume and consider packed red blood cells for a Hgb < 10 g/dL

Consider recruitment as needed, then

Prone position and consider inhaled nitric oxide, then

Increase mean airway pressure by 5 cm H2O to maximum of 45 cm H2O, then

Consider ECMO

If oxygenation is greater than target, decrease FiO2 by 5% to 60%, then

Decrease mean airway pressure by 2 cm H2O to a minimum of 20 cm H2O

When patient is improving, and you are weaning, do not forget to

• Return IT to 33%

• Reinflate cuff

• Increase frequency as tolerated (pH>7.25)

• Wean amplitude to about 20 before transitioning back to CMV

Other therapies

Inhaled nitric oxide cannot be recommended as standard therapy for ARDS, but it may be useful as a rescue therapy in a subgroup of patients with refractory hypoxemia and presumed pulmonary hypertension. Treatment with several other less selective vasodilators has also not been shown to be beneficial.

Inhaled nitric oxide protocol

Obtain arterial blood gas prior to initiation

Start iNO at 20 ppm

Follow-up arterial blood gas in 30 minutes

Discontinue iNO therapy if patient is unresponsive

Positive response indicators

• Increase in the PaO₂ above 20 mmHg or greater than 20% from baseline, with goal PaO₂ greater than 60 mmHg

• Increase in the oxygen saturation by 10% (if unable to obtain arterial PaO2)

• Decrease in the pulmonary artery pressure of 20% or more from baseline (ECHO or PA line)

If patient is responsive to iNO therapy

Begin weaning FiO₂ by 2-5% every 30 minutes for saturations >92%, PaO₂ >60 mmHg, to a goal FiO₂ of 60% or less.

Weaning protocol

Decrease iNO to 10 ppm and monitor for 30 minutes

If saturation decrease is greater than 5%, then return to 20 ppm

If saturation decrease is les than 5%, then decrease to 5 ppm and monitor for 30 minutes

If saturation decrease is greater than 5%, then return to 10 ppm

If saturation decrease is less than 5%, then decrease by 1 ppm every hour to off for a saturation decrease less than 5%

If patient falls below the success criteria, return to previous settings and try again in 4 hours if no lability

If there are no successful weans in 12 hours, hold weaning for 12-24 hours

Consider use of sildenafil to wean off of iNO

Though there is no benefit to prophylactic steroid therapy several adult studies have demonstrated a possible benefit from low-dose steroid therapy when initiated during the second week before day 14 and continued for a prolonged period. The protocol by Meduri and colleagues presents an attractive therapeutic option, but steroids cannot be recommended as standard therapy at this time. It may, however, be beneficial in the subacute or fibroproliferative phase of the disease.

Proponents of the prolonged low-to-moderate-dose corticosteroids emphasize that abrupt withdrawal of therapy should be avoided.

Glucocorticoid therapy

Methylprednisolone as IV push every 6 hours and changed to PO dose when oral intake is restored.

Loading dose of 2 mg/kg

Followed by:

2 mg/kg per day from day 1 to day 14

1 mg/kg per day from day 15 to day 21

0.5 mg/kg per day from day 22 to day 28

0.25 mg/kg per day on day 29 and 30

0.125 mg/kg per day on days 31 and 32

Prophylactic antibiotics have no role in the management of ARDS. No advantage has yet been demonstrated with the use of immune modulators. There may be a role for surfactant therapy, but several unanswered questions remain including the dose and frequency.

Refractory cases

Prone positioning can be used safely and results in improved oxygenation in most patients with ARDS.

HFOV should be considered in patients with severe ARDS who have failed conventional mechanical ventilation, typically with an FiO2 greater than 60% on >15 cm of water PEEP, a plateau pressure greater than 30 cm of water, and respiratory acidosis.

More simply, it should be considered when the OI is >15 and worsening. ECMO may have a role in combination with other modalities mentioned earlier and should be considered early in the course of disease in patients who require sustained high pressure ventilation.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Most patients follow a fairly stereotypical course, characterized by severe hypoxemia followed by a prolonged need for mechanical ventilation, but the course of each phase and the overall disease progression is variable.

The acute or exudative phase is manifested by the rapid onset of respiratory failure with hypoxemia refractory to treatment with supplemental oxygen. This lasts from several hours to about a week and is followed by the subacute or proliferative phase characterized by persistent hypoxemia and development of hypercarbia. Some patients progress to a fibrotic phase with a clinical course complicated by barotrauma, nosocomial infection, or the development of MOSF.

The recovery phase is characterized by the gradual resolution of hypoxemia and improved lung compliance. Approximately one third of patients with ARDS die from the disease. Long-term survivors may show mild abnormalities in pulmonary function and are often asymptomatic unless they progress to the fibrotic phase.

Incorrect diagnosis

ARDS is a diagnosis of exclusion. Every effort should be made to rule other causes of acute hypoxemic respiratory failure before giving the patient the diagnosis of ARDS.

Follow-up

Pulmonary function studies, neurodevelopmental evaluation of muscle weakness and Global Health Assessment at three, six, and twelve months following discharge form the hospital.

Pathophysiology

Figure 3

Figure 3.

ARDS is characterized by an initial insult that triggers a release of a variety of mediators leading to endothelial injury, increased vascular permeability, and neutrophil recruitment. The histological hallmarks of ARDS are hyaline membranes, flooded alveoli with proteinaceous edema, and infiltrates of polymorphonuclear neutrophils, macrophages and erythrocytes.

Proinflammatory mediators are released from alveolar and endothelial cells that perpetuate this cascade and inactivate surfactant. This leads to reduced lung compliance and ventilation perfusion mismatch. In addition, activation of pro-coagulative factors and inhibition of fibrinolysis leads to the development of small vessel thrombosis in the lung which increases dead space ventilation.

The combination of the decreased compliance, increased dead space and hypoxemia leads to an increased work of breathing. Eventually the oxygen demands exceed the ability of the lung to oxygenate the blood and hypoxemic respiratory failure takes place.

Figure 4

Figure 4.

The degree and duration of injury is dependent on the balance between pro- and anti-inflammatory mediators. For overall resolution to occur, the dynamic balance interaction between capillary leak, coagulation and cell function must rebalance and surfactant production restarted. Apoptosis must normalize and pulmonary edema and transcapillary water must be cleared.

This begins the second phase of the illness called the subacute or proliferative stage. It is characterized by resolution of pulmonary edema and by proliferation of type II alveolar cells, squamous metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen.

Unfortunately in some patients, resolution is hampered and they progress to a fibrotic stage characterized by obliteration of normal lung architecture, diffuse fibrosis, and cyst formation. These patients develop permanent abnormalities in respiratory function with a reduced health-related quality of life.

Recently, a polymorphism in the gene encoding angiotensin-converting enzyme (ACE) was linked to the susceptibility and outcome of ARDS. ACE cleaves angiotensin I to form angiotensin II which in turn activates pro-inflammatory mediators and plays an important role in alveolar epithelial cell apoptosis.

Epidemiology

The incidence, natural history and outcomes have been hampered by the lack of a standardized definition. In 1994 the American European Consensus Committee on ARDS standardized the definition and renamed it acute rather than adult respiratory distress syndrome because it occurs in all age groups.

The consensus definition introduced the term acute lung injury (ALI) to differentiate patients with less severe hypoxemia. ALI is defined by a PaO2/FiO2 ratio of < 300 mmHg, and ARDS by a ratio of < 200 mmHg. While the exact occurrence in children remains controversial, it is thought to represent 3-4% of all PICU admissions.

Based on population estimates, each year 2500-9000 children in the United States will have acute lung injury contributing to 500-2000 deaths.

Reported mortality ranges from 29-50%; however, the trials with a higher percentage included children who had received bone marrow transplants. Excluding these patients would likely result in an overall lower mortality in children. Encouraging recent reports have found improved survival in the current era with mortality rates < 30%.

Prognosis

Prognosis depends on underlying medical condition, presence of multisystem organ failure, and severity of illness. The majority of deaths are attributable to sepsis and multi-organ dysfunction rather than primary respiratory causes. The overall mortality ranges from 26 to 50%.

The ELSO Registry shows that survival on ECMO varies from 40% to 59% depending on the underlying illness that triggered the ARDS. Younger age, survival beyond the first two weeks, and trauma etiology predict a more favorable outcome. Risk factors predictive of increased mortality include chronic liver disease, immune compromised state, and advanced age.

Multivariate logistical regression analysis shows that the initial severity of hypoxia (PaO2/FiO2), the ratio of dead space to tidal volume (Vd/Vt) as assessed by end-tidal CO2 levels, multi-organ dysfunction, and CNS injury were associated with mortality and prolonged ventilation. Failure of pulmonary function to improve during the first week of treatment is a negative prognostic factor.

The persistence of neutrophils in bronchoalveolar lavage fluid correlates with death particularly in patients with sepsis induced ARDS. Continued expression of proinflammatory cytokines is also associated with poor outcome. In general, survivors have good recovery with return of nearly normal pulmonary function within 6 to 12 months.

Residual impairment of pulmonary mechanics may include mild to moderate obstruction, diffusion and restrictive abnormalities. Quality of life appears to be reduced for at least one year secondary to persistent functional disabilities. Muscle weakness and fatigue largely contribute to these findings.

Etiologic factors may relate to: steroid myopathy, critical illness neuropathy, disuse, and weight loss. Neuropsychologic testing may reveal significant deficits in patients who had more severe and protracted hypoxemia.

Special considerations for nursing and allied health professionals.

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What's the evidence?

Ware, LB, Matthay, MA. “Medical Progress: The Acute Respiratory Distress Syndrome”. NEJM. vol. 18. 2000. pp. 1334-1349. (The authors are authorities in the field and serve as investigators from Moffitt Hospital, an affiliate of the University of San Francisco and an ARDS Network Center. This article is the most comprehensive article. It provides a good historical prospective with excellent figures depicting the phases of ARDS. The approach to treatment presented still guides us today.)

“Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome”. N Engl J Med. vol. 342. 2000. pp. 1301-1308. (In this article, the NIH ARDS Network compared a traditional tidal volume (12mL/kg of predicted body weight) with a lower tidal volume (6 mL/kg of predicted body weight). There are many reviews and opinions on this paper, but it is the only big trial that has shown such an impressive reduction in mortality from such a simple ventilator intervention. There had been negative trials before, but this was the biggest and probably the only adequately powered one. The obvious flaw is the traditional group getting a tidal volume of 12 mL/kg, which by anyone's standards is huge.)

“Comparison of Two Fluid-Management Strategies in Acute Lung Injury (FACTT)”. N Engl J Med. vol. 354. 2006. pp. 2564-2575. (The NIH ARDS Network compared restrictive with liberal fluid management based on monitoring hemodynamics with either a pulmonary artery catheter or a central venous catheter to evaluate effects on mortality and morbidity.
In this multicenter, randomized, prospective clinical comparison of the two strategies, the patients in the "conservative-strategy" group experienced faster improvement in lung function and spent significantly fewer days on the ventilator and in the ICU. It also demonstrated that routine use of pulmonary artery catheters is not indicated.)

Randolph, A. “Management of acute lung injury and acute respiratory distress syndrome in children”. Crit Care Med. vol. 37. 2009. pp. 2448-2454. (Randolph is an authority in the field and serves on the Board of Directors for the ARDS Foundation. In this review, he provides the clinician with a summary of the literature on the epidemiology, diagnosis, prognosis, and management of ALI/ARDS in children. This is a comprehensive and up-to-date review.)

Froese, A, Kinsella, J. “High frequency oscillatory ventilation: Lessons from the neonatal/pediatric experience”. Crit Care Med. vol. 33. 2005. pp. s115(A nice summary of the key physiologic principles for managing children on high frequency ventilation that have been learned from the cumulative pediatric and neonatal experience. A good review of the open lung concept and the history of the research that brings us to current management recommendations. The article finishes with a unique introspective section that identifies the lessons learned through the past three decades that saw this form of ventilation progress from the lab to the bedside.)

Alsaghir, A. “Effect of prone positioning in patients with acute respiratory distress syndrome: A meta-analysis”. Crit Care Med. vol. 36. 2008. pp. 603(A systematic review and meta-analysis of five adult RCTs that compared prone position to supine. The review did not find an overall improvement in survival but the analysis did show beneficial effects in oxygenation without any major side effects. Post hoc analysis of a subgroup of severe ARDS patients (saps II > 50) did show a significant improvement in mortality.)
Being a relatively simple and inexpensive intervention, it was recommended to be considered early in the management of patients with severe ARDS.)

Duffett, M. “Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis”. Crit Care. vol. 11. 2007. (A pediatric meta-analysis of six RCTs that prospectively compared a surfactant preparation to air placebo or no control. Three studies evaluated bronchiolitis patients with zero mortality and three studies looked at ALI/ARDS patients.
The primary outcome was mortality which was improved in the three ALI/ARDS trials. In addition, the analysis of all six trials showed an increase in ventilator free days and a reduction in the duration of ventilation without significant adverse effects. Questions remain regarding the optimal dose and timing of treatment and which patients are most likely to derive benefit.)

Zabrocki, L. “Extracorporeal membrane for pediatric respiratory failure: Survival and predictors of mortality”. CCM. vol. 39. 2011. pp. 364-370. (This retrospective case series is an excellent review of the ELSO data banked over 15 years from over 115 centers worldwide. 3213 pediatric patients met criteria of which there were 1824 survivors and 1389 non-survivors. Of this group, 411 were ARDS patients. ARDS survival varied from 40% (sepsis) to 59% (trauma). Mortality was much lower in patients with other causes for respiratory failure.
As our experience and familiarity with ECMO broadens, we are now putting more medically complex patients on with pre-ECMO ventilation runs of longer durations. It appears that mortality on ECMO increases with ventilator runs greater than 2 weeks.)

Boriosi, J. “Efficacy and safety of lung recruitment in pediatric patients with acute lung injury”. PCCM. vol. 12. 2010. pp. 1-6. (This is a prospective cohort study using a repeated-measures design that evaluates a recruitment maneuver using an incremental positive end-expiratory pressure called the Open Lung Tool. This is software used on the Servo-I ventilator that allows the physician to determine dynamic compliance to help find optimal peep and optimal recruitment. In a selected group of pediatric ARDS patients, it demonstrated recruitment maneuvers improved oxygenation and was safe and well tolerated.)

Tang, B. “Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis”. CCM. vol. 37. 2009. pp. 1594-1603. (The role of corticosteroids in unresolving ARDS remains controversial. Tang and colleagues meta-analyses that broadened the time frame of initiation of prolonged low-to-moderate dose corticosteroids to 1-14 days after ARDS onset indicated mortality benefit and other benefits, without more adverse effects, including myoneuropathy. Nevertheless, the number of patients enrolled in the studies has been quite small.)
More research is needed to clarify the role of methylprednisolone in all stages of ARDS.)

Asbaugh, DG, Bigelow, DB, Petty, TL, Levine, BE. “Acute Respiratory Distress in Adults”. Lancet. vol. 2. 1967. pp. 319-23.

Murray, JF, Matthay, MA, Luce, JM, Flick, MR. “An Expanded Definition of the Adult Respiratory Distress Syndrome”. Am Rev Respir Dis. vol. 138. 1988. pp. 720-723.

Bernarg, GR, Artigas, A, Brigham, KL. “The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination”. Am J Respir Crit Care Med. vol. 148. 1994. pp. 818-824.

Anzueto. “Exosurf ARDS Sepsis Study”. N Engl J Med. vol. 334. 1996. pp. 1417-21.

Wheeler, A, Gordon, B. “ALI and ARDS: A Clinical Review”. Lancet. vol. 369. 2007. pp. 1553

Herridge, MS, Cheung, AM, Tansey, CM. “One-Year Outcomes in Survivors of The Acute Respiratory Distress Syndrome”. N Engl J Med. vol. 348. 2003. pp. 683-693.

Dillinger, RP. “iNO Study Group”. Crit Care Med. vol. 26. 1998. pp. 15-23.

N Engl J Med. vol. 354. 2006.

Gattinoni, L, Caironi, P, Cressoni, M. “Lung Recruitment in Patients with Acute Respiratory Distress Syndrome”. N Engl J Med. vol. 354. 2006.

Amato, M, Barbas, C, Medeiros, D. “Effect of a Protective-Ventilation Strategy on Mortality in The Acute Respiratory Distress Syndrome”. N Eng J Med. vol. 338. 1998. pp. 347-54.

Gattinoni, L, Tognongi, G, Pesenti, A. “Effect of Prone Positioning on Survival of Patients with Acute Respiratory Failure”. N Engl J Med. vol. 345. 2001. pp. 568-73.

Meduri, G, Tolley, E, Chrousos, G. “Prolonged Methylprednisolone Treatment Suppresses Systemic Inflammation in Patients with Unresolving Acute Respiratory Distress syndrome: Evidence for Inadequate Endogenous Glucocorticoid Secretion and Inflammation-Induced Immune Cell Resistance to Glucocorticoids”. Am J Respir Crit Care Med. vol. 165. 2002. pp. 983-91.

Flori, R. “Pediatric Acute Lung Injury”. AJRCCM. vol. 171. 2005. pp. 995

Girard, T, Bernard, G. “Mechanical Ventilation in ARDS: A state of the art review”. Chest. vol. 131. 2007. pp. 191-929.

Raoof, S. “Severe Hypoxemic Respiratory Failure part 2 – nonventilator strategies”. Chest. vol. 137. 2010. pp. 1437-1448.

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