New ventilatory modes, ventilator types, pharmacological agents, and protective lung strategies are available to help promote more positive outcomes when managing ARDS

A patient is ventilated on a high-frequency percussive ventilator.

In adults, lung injury may complicate a wide range of serious medical and surgical conditions, only some of which involve a direct pulmonary insult. The most extreme form of acute lung injury, adult respiratory distress syndrome (ARDS), was first described formally 35 years ago by Ashbaugh et al.¹ The overall incidence of ARDS remains unclear, but many studies² suggest a rate of two to eight cases per 100,000 people per year. The American-European Consensus Conference³ members agreed that the diagnostic criteria for ARDS should include acute onset, bilateral infiltrates visible in chest radiographs, a pulmonary-artery–occlusion pressure of less than 18 mm Hg or a lack of evidence of left ventricular failure, and impaired oxygenation.

Recent data⁴ have demonstrated that ARDS is clearly a heterogeneous lung injury marked by consolidation, normal lung tissue, and markedly overdistended lung units. CT scans have shown infiltration that is generally more dense in the dependent regions of the lung, along with signs of atelectasis caused by the hydrostatic effect of edema fluid interspersed with normal-appearing lung tissue. The pathological picture of ARDS is characterized by diffuse alveolar damage, marked by the replacement of alveolar type I cells by proliferating alveolar type II cells. Gattinoni et al⁵ have referred to the lungs of patients with ARDS as baby lungs to emphasize that there is a considerable loss of lung units; approaches to ventilatory management should focus on this fact.

The severe hypoxemia that is both a hallmark and a diagnostic criterion for ARDS is caused by the presence of intrapulmonary shunting or areas having very low ratios of ventilation to perfusion. The shunting is presumably due to edema and atelectasis. Normocapnia (or even hypocapnia) is common during the early stages of ARDS. Later, carbon dioxide retention is caused by an increase in dead space that results from the formation of bullae, fibrosis, and vascular obliteration.

Recently, experiments⁶ and clinical evidence have suggested that ARDS may represent an inflammatory response in the lung that may also be present in other organs, accounting for their dysfunction or failure. Considerable attention has focused on neutrophils and their aggregation by complement. A recent study⁷ using bronchoalveolar lavage has shown increased amounts of concretions of neutrophils in patients with ARDS, along with the presence of inflammatory cytokines.

Management of patients with ARDS should be aimed at revealing the underlying diseases associated with the condition and preventing iatrogenic lung injuries associated with supportive care. Ventilator-induced lung trauma, pneumonia, and impaired cardiac output decrease the likelihood of a positive outcome. Until recently, the fatality rate for ARDS was considered to be around 50%.⁸ Mortality is higher in patients aged 60 or more years and in those with marked sepsis, but new ventilatory strategies and innovations are aimed at reducing that percentage and preventing ventilator-induced trauma.

High-Frequency Ventilation
High-frequency ventilation (HFV) is defined as mechanical ventilatory support using respiratory rates that are higher than normal. Usually, the respiratory rate for HFV is set at more than 300 breaths per minute. When high frequencies are used, tidal volume (Vt) is usually smaller than normal and airway-pressure swings are consequently smaller.

An example of airway–pressure-release ventilation mode.

There are two main reasons for considering HFV in ARDS. First, the smaller pressure swings, coupled with appropriate baseline pressure elevations, create an ideal lung-protective strategy. The combination of applied and intrinsic positive end-expiratory pressure (PEEP) promotes alveolar recruitment and the smaller pressure swings prevent overdistention. Ventilation occurs between the upper and lower inflection points, maintaining alveolar inflation and preventing lung injury due to overinflation. Second, in addition to better alveolar recruitment, the rapid flow pattern may enhance gas mixing and improve ventilation-perfusion matching.

Delivery of HFV can employ either a high-frequency oscillator (HFO) or a high-frequency percussive ventilator (HFPV). HFOs operate using a to-and-fro application of pressure to the airway opening by either pistons or microprocessor gas controllers. Fresh gas is supplied within the ventilator circuit as a bias flow, and mean airway pressure is adjusted according to the relationship between fresh gas inflow and any positive or negative pressure placed on the gas outflow from the bias flow circuit. The clinician has the ability to set oscillator frequency, oscillator displacement (volume), inspiratory-to-expiratory ratio, and bias flow.

Several mechanisms of gas transport are involved in oscillatory ventilation. Bulk flow from subtidal volume delivery, coaxial flow, Taylor dispersion, molecular diffusion, and pendelluft all contribute to ventilation and oxygenation during oscillatory ventilation.⁹ Currently, trials are being conducted comparing oscillatory ventilation with conventional ventilatory management.

In an attempt to combine the beneficial effects of HFV and conventional ventilation, an HFPV ventilator delivers a small Vt and percussion, along with a bulk distribution of gas similar to that of a pressure-limited conventional breath. This allows for gas stacking and provides alveolar recruitment at lower peak inspiratory and mean airway pressures. In contrast to the exhalation seen in HFO support, exhalation is passive. Several small studies^10,11 and case scenarios have demonstrated positive outcomes in ARDS patients. In addition, HFPV may have a role in the care of head-injury patients who develop ARDS. By providing internal mucokinesis, head-injured patients are not subject to elevated intercerebral pressures often associated with conventional secretion-removal procedures.

Airway–Pressure-Release Ventilation
Airway–pressure-release ventilation (APRV) can be described as consisting of two levels of PEEP that are applied for set periods of time, allowing spontaneous breathing to occur at both levels. Alveolar recruitment is maintained by the baseline pressure application, while ventilatory support is provided through two mechanisms. First, periodic, brief deflations lasting less than 1 second provide some level of bulk gas distribution. Second, spontaneous ventilation is provided through use of a dynamic or floating exhalation valve. APRV is often referred to as inverse-pressure ventilation with spontaneous ventilation or as invasive bilevel positive airway pressure.

The advantage of APRV is that the prolonged baseline pressure (which lasts more than 4 seconds) maintains alveolar recruitment without imposing additional peak inspiratory pressures that could lead to barotrauma. Clinical studies¹² have shown that oxygenation and ventilation can be maintained at lower pressures with APRV than with conventional ventilatory management. Because the patient is allowed to breathe spontaneously, there are fewer cardiac side effects, and the negative consequences of paralytic drugs are avoided.¹³ Typical ventilatory settings would be a high PEEP of 25 to 30 cm H2O with an inspiratory time of 4 to 5 seconds and a low PEEP of 0 to 3 cm H2O for 0.5 to 1 second. As the high PEEP is lowered, the inspiratory time is increased in order to maintain a high mean airway pressure. Several newer ventilators have this mode available.

Low-Vt Ventilation and Recruitment
Recently, the ARDS network founded by the National Heart, Lung, and Blood Institute published a study¹⁴ indicating 22% lower mortality among ARDS patients for whom a low-Vt strategy was used. The network’s protocol reduces Vt to 4 to 6 mL/kg to limit plateau pressures to less than 30 cm H2O. During the acute phase, patients are managed using volume-targeted assist-control mechanical ventilation. The continuous mechanical ventilation portion of the protocol contains five interdependent algorithm components that control Vt, plateau pressure, arterial pH, oxygenation, and respiratory rate. The goal of the protocol is to provide adequate oxygenation with the minimal amount of alveolar distending pressure. Weaning is based on daily spontaneous breathing trials. Several major medical centers are currently using this ventilatory strategy.

Monotonous Vt can lead to lung collapse. It has been postulated that periodic hyperinflation can prevent the alveolar derecruitment associated with edema. Evidence of alveolar inflation can be seen as variation in inflection points along the pressure-volume curve. Selected intervals that increase PEEP to more than 35 cm H2O have been studied in animals¹⁵ and have shown alveolar recruitment. Typically, a high level of PEEP is maintained for 2-minute intervals and the best PEEP is determined after lung units have been reinflated and the pressure-volume curve has been reexamined for evidence of reinflation. Currently, clinical trials are under way to examine the effectiveness of these maneuvers in ARDS patients.

Liquid Ventilation
Liquid ventilation uses fluorinated organic liquids (perfluorocarbons) as respiratory media. Perfluorocarbons are an attractive choice, both for the high solubility of respiratory gases in them and for their low surface tensions.¹⁶ Partial liquid ventilation uses a conventional ventilator to supply a gas Vt to lungs filled partially with a perfluorocarbon. The liquid is allowed to trickle in slowly or is administered using a buretrol-regulating setup that uses the side port of an endotracheal connector. Filling the functional residual capacity (FRC) requires approximately 20 mL/kg of the perfluorocarbon; filling is confirmed through the observation of a fluid meniscus in the endotracheal tube when the patient is receiving no PEEP. Up to 5 days of redosing may be performed to maintain a liquid-filled FRC. A ventilator-management algorithm is used to reduce the chance of ventilator-induced trauma. The perfluorocarbon acts as a liquid form of PEEP, holding open previously collapsed lung units and reducing edema and exudative debris.¹⁷ Perfluorocarbon use can reexpand closed lung units, increase lung volume, improve oxygenation in a dose-dependent manner, improve lung compliance, and prevent or reduce the lung impairment that might otherwise occur due to the high airway pressures that characterize conventional mechanical ventilation.¹⁸ The low miscibility of perfluorocarbons makes them very effective at washing unwanted debris from the lungs in a form of alveolar lavage. Exudative debris and aspirated materials tend to float on top of the perfluorocarbon all the way to the airways, where they can be removed using suction.

In clinical and animal studies,¹⁹ liquid ventilation has improved oxygenation and shown a possible lung-protective mechanism. A reduction in neutrophils was observed during lung lavage following the administration of liquid ventilation.²⁰ Currently, the results of a large, multicenter randomized trial are being examined to determine the impact of liquid ventilation on ventilator-free days and mortality.

Sivelestat Use
ARDS is often characterized by neutrophilic inflammation and increased permeability of the pulmonary vasculature.²¹ Neutrophil elastase is a mediator released by the neutrophil that is responsible for endothelial injury and increased vascular leakage into the lung. It has also been shown to induce mucus hypersecretion, to reduce ciliary beating frequency, to induce respiratory metaplasia, and to induce pulmonary endothelial-cell detachment.²² In a clinical study,6 neutrophils have been found to be the predominant inflammatory cell in the bronchoalveolar fluid of subjects with ARDS. Furthermore, both neutrophil counts and concentrations of total neutrophil elastase have been found to correlate with the severity of lung injury in ARDS patients.

Sivelestat is a therapeutic agent that is a potent, low–molecular-weight inhibitor of human elastase. It is administered as a continuous intravenous infusion. The duration of infusion depends on the length of mechanical ventilation; sivelestat can be administered for a maximum of 14 days. A phase II clinical study is now under way to determine the effectiveness of sivelestat in reducing ventilator days and mortality in patients with ARDS.

Despite the technological innovations of the past 30 years, ARDS still has a significant mortality rate. Ventilator strategy has shifted from curative to lung protective. Today’s clinicians have a great arsenal from which to select in managing ARDS. New ventilatory modes, ventilator types, pharmacological agents, and protective lung strategies are available to help promote more positive outcomes. The quest for more and better weapons in this fight continues to be the goal of clinicians who manage ARDS patients.

Kenneth Miller, RRT, is a clinical educator, Lehigh Valley Hospital, Allentown, Pa.

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