Acute Respiratory Failure

Allah Haafiz, M.D. and Niranjan Kissoon, M.D.
Allah Haafiz, M.D. is with the Family Medical & Dental Center, Palatka, Florida.
Niranjan Kissoon, M.D. is Professor and Chief, Critical Care Medicine at the
University of Florida Health Science Center/Jacksonville & Nemours Children's Clinic.

Respiratory Failure

Acute respiratory failure remains a major cause of morbidity and mortality in both pediatric and adult populations. The annual incidence in the United States may be as high as 150,000 cases, with mortality rates generally ranging between 50% and 70%.1 Recent studies of acute respiratory distress syndrome in children report a 60% to 75% mortality rate.2-4 Sepsis and multiple organ system dysfunction contribute the most to the high mortality and morbidity seen in both adults and children with acute respiratory distress syndrome (ARDS). Although acute respiratory compromise may be a manifestation of ventilatory failure, most commonly it results from an acute lung injury (ALI). ALI is defined as a syndrome of inflammation and increased permeability that is associated with a constellation of clinical, radiologic, and physiologic abnormalities that cannot be explained by, but may coexist with, left atrial or pulmonary capillary hypertension.1

On the spectrum of pulmonary insult, ARDS represents the most severe form of ALI. A variety of conditions can cause ALI including sepsis, primary pneumonia, aspiration, smoke inhalation, drowning, and multiple trauma. Less common associations include pulmonary contusion, cardiopulmonary bypass, multiple transfusions, fat embolism and pancreatitis. Sepsis is not only the most common cause of ARDS, but patients with ARDS may be as much as six times more susceptible to infection than patients without ARDS. Furthermore, sepsis-induced ARDS has higher mortality than ARDS secondary to other etiologies. Despite the diverse etiologies, hypoxemia is the major pathophysiologic consequence of ALI. The severity of hypoxemia, reflected by paO2/FiO2 varies with the magnitude of alveolar injury rather than the inciting disease. The predominant pathological findings associated with ALI include diffuse alveolar damage, alveolar wall edema and inflammatory infiltrates.5 An optimum approach to this clinical syndrome remains a dilemma. Much of this deficiency results from lack of a satisfactory definition and standardization of diagnostic and therapeutic interventions in the past. Therefore notwithstanding the significant inroads in supportive care, a significant improvement in outcome has yet to occur. Nonetheless, the development of the Lung Injury Score6, and standardization of terminology and diagnostic criteria by the American-European consensus conference1 will help collect and compare the uniform epidemiological data as well as evaluate the efficacy of various treatment modalities. This review will entail the prevailing wisdom and the emerging horizons in the management of acute, severe ALI.

Conventional Therapy

There are no specific interventions to reverse or significantly limit the degree of altered vascular permeability. Although there are a number of pharmacologic interventions that are being investigated for use in patients with ARDS, their role remains controversial and limited. Therefore, the management of ARDS at present is largely supportive in nature. Ventilation and optimization of oxygenation is the quintessential element of this support. Although noninvasive positive pressure ventilation may suffice for relatively less severe forms of ALI, most patients ultimately need invasive positive pressure ventilatory support. Although readily available in most pediatric intensive care units, this approach is frequently associated with complications like barotrauma, oxygen toxicity, compromised cardiac output, and nosocomial infections. A review of studies of ARDS in children2-3,7-8 by Holbrook and colleagues, reveal the application of volume-controlled ventilation with tidal volumes of approximately 10 to 12 cc/kg.9 This strategy is fraught with high peak pressures and large tidal pressure amplitudes. As the volume of lung participating in gas exchange is significantly reduced in ARDS,10 tidal volumes in this range (10 to 12 cc/kg) may grossly overdistend and damage the ventilated portion of the lung. Mechanical ventilation using large tidal volumes and high peak inspiratory pressures, especially with limited use of positive end-expiratory pressure leads to progressive ventilator-induced injury that can be indistinguishable from that of ARDS.11-14 In addition to ventilation induced lung injury, the high concentrations of inspired oxygen required to maintain adequate oxygenation in this strategy adds to the lung injury. Indeed both animal and human studies have demonstrated pathologic changes in lung parenchyma on exposure to high concentrations of oxygen.15-16 To minimize these complications the alternative ventilatory methods such as high frequency ventilation and extracorporial membrane oxygenation (ECMO) were developed during last two decades. However, these modalities are expensive, require extremely sophisticated monitoring and invoke their own complication. Moreover, these modalities fail to target the pathophysiologic mechanisms and therefore did not change the overall outcome. Therefore a stern shift from conventional wisdom is essential to improve the outcome in a cost-effective fashion. The following modalities are at various stages of evaluation for their role in the treatment of severe ALI.

  1. Pressure-controlled ventilation with permissive hypercapnia;
  2. High-frequency modes of ventilation;
  3. ECMO and ECCO2-R;
  4. Per fluorocarbon liquid ventilation;
  5. Inhaled nitric oxide (INO); and
  6. Exogenous surfactant replacement.

A brief account of the evolution and future prospect of the individual approaches is given below.

Pressure-controlled ventilation with permissive hypercapnia

The evolution and widespread application of this technique reflects the fundamental change in our understanding of ventilation induced lung injury. Contrary to historic belief the ventilation induced lung injury results more from high tidal volume (volutrauma) than inspiratory pressure during conventional ventilation. Indeed the VT that can be tolerated in severe ALI may be too small to target eucapnia as a therapeutic endpoint during conventional ventilation.17-19 Therefore hypercapnia is accepted (permissive hypercapnia) for the pathophysiologic advantage of limited yet critical end-expiratory distension of alveoli to preserve alveolar recruitment.17-18, 20-21 This strategy is usually tolerated by most patients and may improve the outcome.18 In general, pH is maintained greater than or equal to 7.25 by using sodium bicarbonate, acetate, or tromethamine. Most institutions take the approach of minimizing secondary lung injury due to mechanical ventilation in patients with ARDS by accepting oxygen saturation of 88% or better and by keeping FiO2 less than or equal to 0.6. Because the oxygen content of blood is dependent on the amount of hemoglobin (Hb) and the percent saturation of Hb rather than the amount of oxygen in plasma, patients may frequently need to be transfused with packed red blood cells in order to be able to accept a relatively lower oxygen saturation. This modality of ventilation is contraindicated in clinical situations of raised intracranial pressure and pulmonary hypertension.

High-frequency modes of ventilation

Since Sjostrand's initial description22 of high-frequency positive-pressure ventilation in 1967, both high-frequency jet ventilation23 and high-frequency oscillation24 have shown promising results in children with ARDS. HFV is unique in that despite the use of small VT (1 to 3 mL/kg) and large ventilatory rates (300 to 2400 breaths/minute), gas exchange is achieved without significant air trapping. HFV is essentially a high volume strategy (high PEEP with I/E ratio of 1:1) without using high PIP, tidal pressure amplitude, or tidal volume. Using pressure and high frequency in this manner maintains the airways throughout the ventilator cycle while avoiding the tidal opening and closing of gas exchange units, which otherwise may cause shearing forces several magnitudes greater than the delivered PIP. 25 Theories that explain gas transport during HFV include bulk axial flow, transit time profiles, interregional gas mixing, augmented dispersion (Taylor dispersion), asymmetric velocity profiles, and molecular diffusion. Despite impressive theoretical grounds, the exact role of HFV needs to be defined.

Based on studies in adults, it was recently suggested that HFV did not offer any significant advantage over conventional
mechanical ventilation.26-27 However, HFV may have a role in the management of pediatric patients with ARDS. In children with ARDS, HFV has been used with more success. In 1994, Arnold and colleagues28 reported the results of a multi-center, randomized, clinical trial comparing HFV and conventional mechanical ventilation in pediatric patients with ARDS. They concluded that using HFV resulted in improved survival, less barotrauma, and less oxygen requirement at 30 days. Currently, many pediatric intensive care units consider using high frequency oscillation relatively early in patients with worsening lung disease, rather than escalating the parameters on the conventional ventilation.

ECMO and ECCO2-R

Studies using these two techniques in adult patients with ARDS have not shown any significant improvement in outcome. A National Heart, Lung, and Blood Institute sponsored randomized trial to compare ECMO and conventional mechanical ventilation in 90 adult patients with ARDS did not demonstrate any difference in survival between the two groups.29 ECMO, however, may be useful for patients awaiting lung transplantation. Although there are a few pediatric studies evaluating the use of ECMO, they include relatively small numbers of patients. In 1993, Moler and colleagues30 reported that the use of ECMO after 1988 was associated with better survival as compared with before 1988 in pediatric patients with respiratory failure.30 In general, it appears that centers where ECMO is more frequently used in managing pediatric patients with ARDS have better outcomes as compared with centers with less experience in this technique. ECCO2 -R techniques have been more popular in Europe and have been shown to improve survival using historical controls. LFPPV-ECCO2-R technique utilizes the native lung that is perfusion dependent to be used for oxygenation. CO2 removal, on the other hand, requires bulk flow and large minute volume and is achieved extracorporeally utilizing a membrane lung exposed to more than 30-L minute ventilation. A National Heart, Lung, and Blood Institute-sponsored randomized trial to compare ECCO2 -R and conventional mechanical ventilation in 40 adult patients with ARDS did not demonstrate any significant difference in survival.31 Additionally, the new therapy was more expensive and associated with more bleeding complications. There is currently little experience in treating children with this technique.

Per fluorocarbon liquid ventilation

Per fluorocarbons are unique colorless inert fluids with 16 times the oxygen solubility, and three times the CO2 solubility of water. These compounds are eliminated by evaporation without any significant absorption through the lungs. The concept of liquid ventilation has been there since the 1920s, when researchers attempting to ameliorate the effects of war gas poisoning found that the lungs could tolerate lavage with large quantities of saline solution.32 In the 1960s, Kylstra and colleagues,33,34 reported adequate oxygen exchange in dogs mechanically ventilated with hyperbarically oxygenated saline. In 1966, Clark and Gollan35 demonstrated the ability of spontaneously breathing mice to support themselves immersed in perfluorocarbon and survive indefinitely following return to gas breathing. In recent decades, multiple investigators have evaluated the ability of perfluorochemicals to enhance gas exchange and improve pulmonary function in the setting of acute lung injury.36-42

Earlier studies in this regards were performed in premature, surfactant-deficient animals.43-47 Recent studies have concentrated on large-animal models of the acute respiratory distress syndrome (ARDS) and have demonstrated the ability of liquid breathing with perfluorocarbons to improve gas exchange.48-52

Liquid ventilation with perfluorocarbon can be accomplished by one of two techniques:

  1. Full liquid ventilation: In this technique the lungs are completely filled with perfluorocarbon and ventilated using a liquid ventilator with tidal volumes consisting entirely of the liquid. A liquid ventilator appropriate for clinical use is not yet available and much of the existing laboratory research has concentrated on the partial liquid ventilation.
  2. Partial liquid ventilation. This technique requires only partial filling of the lungs with perfluorocarbon and ventilation with gas tidal volumes using a conventional gas mechanical ventilator.53-55 The initial clinical experience with partial liquid ventilation appears to be a significant leap forward in the evolution of this technology, with modest improvements in gas exchange.56 The technique has developed sufficiently to warrant clinical application and investigation in patients at high risk of mortality due to respiratory failure. Previous human trials have been limited to moribund premature newborns.57 In 1996, Gauger and colleagues58 reported the safety and improvement in gas exchange and pulmonary compliance in a study involving six pediatric patients on extracorporeal membrane life support. The mechanisms of improved gas exchange during partial liquid ventilation in the setting of ARDS have been investigated. Cross-sectional computed tomography imaging of the lungs in patients with ARDS has demonstrated that the atelectasis and consolidation occurs predominantly in the dependent zones, while ventilation is most preserved in the nondependent regions.59 The high density and low surface tension of perfluorocarbon are ideal qualities to counteract this pathophysiology and studies60 Hirschl and colleagues61 suggest that recruitment of dependent atelectatic alveolar units does occur. Evidence also suggests that pulmonary blood flow, predominantly distributed to the dependent and diseased portions of the lungs, may be redistributed to the nondependent, better-ventilated lung regions due to the physical mass of the perfluorocarbon in the dependent lung regions.62

Finally, there is a lavage effect of liquid breathing that mobilizes alveolar and bronchiolar exudate and fluid to the central airways, where they can be removed by suctioning. Currently, many investigators are exploring the possibility that perfluorocarbons may have a direct anti-inflammatory effect and may ameliorate transalveolar exudation.63 Despite the encouraging animal model and limited clinical studies, the indications, limitations and complications of partial liquid ventilation have yet to be defined.

Inhaled Nitric Oxide (INO)

Of all the novel therapies, inhaled nitric oxide has received much attention during last seven years. The success of INO as selective pulmonary arterial vasodilator makes it an ideal therapeutic agent for pulmonary arterial hypertension (PAH) and V/Q mismatch which contributes significantly to the hypoxemia encountered in ALI.64 Inhalation of nitric oxide by patients with severe adult respiratory distress syndrome reduces the pulmonary-artery pressure and increases arterial oxygenation by improving the matching of ventilation with perfusion, without producing systemic vasodilatation.65

In 1993 Gerlach and colleagues,66 reported the effectiveness of inhaled nitric oxide in 12 adult patients with ARDS. Almost two thirds of these patients were also supported with ECMO. Their data suggested that there was an improvement in Pa O2 after 1 to 2 minutes of therapy with nitric oxide in concentrations of 0.01 to 100 ppm administered for 15-minute intervals. No additional improvements in oxygenation were observed at nitric oxide concentrations exceeding 10 ppm, and in fact a decrease in oxygenation was noted in some patients. In 1996, Demirakça and colleagues67 reported the use of inhaled nitric oxide in 17 pediatric patients with ARDS and demonstrated improvement in pulmonary gas exchange with concomitant hemodynamic stabilization. They observed that the optimal dose of nitric oxide was 20 ppm in neonates and 10 ppm in pediatric patients. They also noted that prolonged inhalation (4 to 21 days) was associated with continued improvement in oxygenation. Despite several animal studies evaluating the efficacy of nitric oxide and some studies in human subjects, the role of nitric oxide needs to be evaluated in greater detail in larger numbers of patients. However, the current evidence does appear to suggest that inhaled nitric oxide may have a role in the therapy of ARDS particularly in younger patients with a significant component of reversible pulmonary vasoconstriction. Randomized, prospective, placebo-controlled trials are currently underway in adult patients with ARDS.

Surfactant Replacement

Although exogenous surfactant has an established primary role in treatment of hyaline membrane disease, its role in acute parenchymal lung injury beyond the neonatal period is not well studied. The pulmonary dysfunction and histopathologic derangements of severe ALI (ARDS) and hyaline membrane are similar. However, the mechanism of injury to alveolar-capillary interface in ALI is complex and multi-factorial.

Several poorly understood factors implicated in the pathogenesis of ALI include local complement and leukocyte activation, oxygen free radicals, interleukin-1, interleukin-8, and tumor necrosis factor. The efficacy of exogenous surfactant and the factors which may influence its efficacy as a treatment modality is the focus of current laboratory and clinical investigations. These factors include delivery method (instillation vs. aerosolization), the timing of surfactant treatment over the course of injury, the specific preparation used, and the dose of surfactant administered. Each of these factors, alone or in combination, may influence the interaction of the exogenous surfactant with the host's alveolar environment. A recent multi-center, randomized, placebo-controlled study of using aerosolized surfactant involving 725 adult patients with sepsis-induced ARDS, however, did not show any significant benefit with respect to improvements in 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function.68 Although there are small studies that have investigated the role of surfactant, there are limited large published studies evaluating surfactant use in pediatric patients with ARDS.69 Therefore, surfactant is currently not recommended for use in children or adults with ARDS. The combination of INO and surfactant has sound physiologic grounds that need to be tapped in clinical trials.

Pharmacologic Agents

A number of pharmacologic agents have been used as adjunct to conventional therapies for a putative primary role in ARDS. None of these drugs could sustain favor for subsequent clinical use. Some of the pharmacologic agents that have been suggested as adjuncts in the management of patients with ARDS include antioxidants (acetylcysteine), prostaglandin inhibitors (indomethacin); vasodilators (sodium nitroprusside) phosphodiesterase inhibitors (pentoxifylline), and thromboxane synthesis inhibitors (ketoconazole).70-79

Conclusions

Severe acute lung injury (ALI) is a common problem in adults and children and is associated with significant morbidity and mortality. Although the clinical syndrome of ARDS has been studied by many investigators, its definition has only recently been clarified. The inconsistency in definitions has resulted in the inability to compare studies reliably. ARDS is a clinical entity with varied etiologies and heterogeneous pathology. Currently, there are no proven treatment options that decrease the extent of lung injury. Therefore, management of adults and children with ARDS is largely supportive in nature. The goals of mechanical ventilation are to provide adequate oxygenation and ventilation without causing ventilation induced lung injury. The role of novel therapeutic modalities like inhaled nitric oxide, liquid ventilation and surfactant replacement is under investigation. Future research should target pathophysiologic mechanism to develop a unified approach to various etiologies that produce similar clinical and pathologic derangements.

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September, 1998/ Jacksonville Medicine

 

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