Ventilatory strategies and adjunctive therapy in ARDS
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《美国医学杂志》
Clinical Fellow, PICU, St. Mary's Hospital, London, United Kingdom
Abstract
Acute respiratory distress syndrome, a diagnosis based on physiologic and radiological criteria, occurs commonly in critical care setting. A major challenge in evaluating therapies that may improve survival in ARDS is that it is not a single disease entity but, rather, numerous different diseases that result in endothelial injury, where the most obvious manifestation is within the lung resulting in pulmonary oedema. It has been shown that poor ventilatory technique that is injurious to the lungs can propagate systemic inflammatory response and adversely affect the mortality. The current data suggest that high tidal volumes with high plateau pressures are deleterious and a strategy of ventilation with lower tidal volumes and lower plateau pressure is associated with lower mortality. There may be a role for recruitment manoeuvres as well. Other forms of respiratory support still require further research. The present understanding of optimal ventilatory management and other adjunctive therapies are reviewed.
Keywords: Acute respiratory distress syndrome; Systemic inflammatory response; Low tidal volume; Permissive hypercapnia; Adjunctive therapy
Acute respiratory distress syndrome (ARDS) was first described by Ashbaugh et al in 1967, in a group of adult patients with profound respiratory failure and bilateral infiltrates on chest radiograph.[1] According to the American-European Consensus Conference, ARDS represents a subset of Acute Lung Injury (ALI). Both require the following characteristics: (a) acute onset of respiratory symptoms, (b) frontal Chest X-ray (CXR) with bilateral infiltrates, and (c) no clinical evidence of left atrial hypertension. ARDS, requires more severe respiratory failure: PaO2/FiO2 <200 mmHg (regardless of PEEP level).
The incidence of ARDS in Pediatric Intensive Care Units (PICU) varies between 8.5 - 27 cases per 1000 PICU admissions. [2],[3],[4],[5],[6] In a case series of ARDS patients published from All India Institute of Medical Sciences (AIIMS) by Lodha R et al, the incidence of ARDS was found to be 20.1 per 1000 PICU admissions.[7] ARDS can be a result of either direct lung injury ("Pulmonary" ARDS) or indirect lung injury ("Extrapulmonary" ARDS).[8] Shock, sepsis and drowning are the most common causes of ARDS in children. The etiological factors are different in developed and developing nations with infections like malaria, dengue hemorrhagic fever being the dominant etiological factors in developing nations as shown by Khilnani et al . [9] The overall mortality in ARDS is approximately 35-50%, and death is usually due to multi-organ system failure rather than pulmonary failure per se.[10] Risk factors predictive of increased mortality in ARDS/ ALI as reviewed by Vasudevan A et al include liver dysfunction, age, sepsis, HIV infection, oxygenation index, length of mechanical ventilation prior to ARDS, mechanism of lung injury, right ventricular dysfunction and PaO2/FiO2 ratio less than 100. [11],[12],[13],[14],[15]
Ventilator-Associated Lung Injury
It is now clear that the manner in which mechanical ventilatory support is applied has the potential to exacerbate pre-existing lung injury further. Such ventilator-associated lung injury is attributable in part to the application of physiological tidal volumes to the reduced area of non-consolidated alveoli: the so-called "baby lung" concept. Ventilator-Associated Lung Injury (VALI) is a complex process initiated by the repetitive application of excessive stress or strains on the lung's fibroskeleton, microvasculature, terminal airways, and juxta-alveolar tissues. Delivering standard tidal volumes of 10-12 ml/Kg inevitably causes overdistension of alveoli. Increased inflammation ensues, in that plasma and BAL levels of interleukin (IL)-6, IL-8, tumor necrosis factor, IL-1 increase. The cytokines generated during high tidal volume ventilation may spill into systemic circulation, causing multi-organ system failure, the most common cause of death in ARDS.
Conventional Mechanical Ventilation
Fraction of Inspired Oxygen [FiO2] and Permissive Hypoxemia
Major problems of using very high concentrations of inspired oxygen include absorption atelectasis, lung toxicity and possibly, systemic toxicity. Various animal studies have shown that exposure to an FiO2 1.0 leads to reduction in functional residual capacity. Proliferation of type 2 epithelial cells and interstitial fibrosis has been demonstrated after 2 weeks of exposure to an FiO2 of 0.6 and this damage continued after the cessation of oxygen administration.[16]
There is no clinical evidence to support the use of specific FiO 2 thresholds but the standard practice is to titrate the FiO 2 (with the objective of reducing FiO 2 to less than 0.6) to a partial oxygen tension of 8.0 kPa [approximately 60 mmHg] or, more importantly for oxygen delivery, an arterial oxygen saturation of 90%.[17] Oxygen saturation values of around 90% are commonly accepted but oxygen delivery decreases quickly below 85-88% considering the steep descent in the oxyhemoglobin dissociation curve. If higher oxygen saturation can only be obtained by increasing airway pressure to levels that result in hemodynamic compromise, lower oxygen saturation may have to be accepted. However, it is vital to note that no child should be allowed to die because of hypoxemia and in such cases 100% oxygen should be administered.
Inspiratory Time and Inverse Ratio Ventilation[18],[19],[20],[21],[22]
Heterogeneously damaged lungs have regions of differing compliance and airway resistance. Prolongation of inspiratory time allows regions with long time constants (the product of airway resistance and compliance) to fill, by interfiling from areas of different time constants. Also, mean airway pressure (Paw), a reflection of mean alveolar pressure, is considered a major determinant of arterial oxygenation in acute respiratory distress syndrome.
On the other hand, there is the potential of developing dynamic hyperinflation and auto-PEEP (which may be undesirable) during inverse ratio ventilation (IRV), which is an extreme form of lengthening the Ti. The I:E ratio is a balance between oxygen demands and ventilatory requirements. In a case report, Tripathi et al suggested that patients with low dynamic lung compliance (less than 20 ml/cmH 2 O) in the setting of high PIP (more than 50 cmH 2 O) and normal I:E ratio (1:2) might benefit from PC-IRV.
Positive End-Expiratory Pressure (PEEP)
ARDS causes redistribution of pulmonary blood flow away from dependent lung regions that exhibit increased pulmonary vascular resistance (PVR) because of pulmonary edema. PEEP may lower the PVR hence improving V/Q matching by shifting pulmonary blood flow from non-dependant lung regions to dependant regions. The PEEP is effective in early ARDS, because it acts as a counterforce, preventing the compression atelectasis secondary to severe pulmonary edema whereas the fibro-proliferative processes may explain the lack of effects of PEEP in the late stage of ARDS.[23]
Through stepwise increases in PEEP (increments of 2-3), a level should be sought that maintains approximately 90% arterial oxygen saturation at 50-60% FiO 2 . Application of PEEP beyond 15-20 cm H 2 O may result in decreased venous return (hence ensure normal volume prior to starting PEEP), in turn reducing the cardiac output. If volume loading is insufficient, the next step to restore cardiac output would be to add inotropes. If cardiac output still remains depressed, PEEP needs to be decreased stepwise until cardiac output is restored.
PEEP optimization may lead to lung protection via mechanisms other than alveolar recruitment -for example, by avoiding surfactant depletion and disruption occurring at low end-expiratory lung volumes.[24] Gattinoni and co-workers showed that PEEP improves lung mechanics and induces significant alveolar recruitment in patients with extrapulmonary ARDS, whereas it results in lung overinflation and worsening of lung mechanics in patients with pulmonary ARDS.[25],[26]
In the ARDS Network clinical trial, it was concluded that in patients with acute lung injury and ARDS who received mechanical ventilation with lower tidal volumes and inspiratory pressures (all patients received a tidal-volume goal of 6 ml per kilogram of predicted body weight and an inspiratory plateau pressure of 30 cm of water or less), raising PEEP to levels that exceeded those used in their lower-PEEP strategy (8.3±3.2 cm of water in the lower-PEEP group and 13.2±3.5 cm of water in the higher-PEEP group) did not achieve statistically significant survival benefit.[27]
Inflection Points and Alveolar Recruitment
The earlier concept was that the lower inflection point (LIP) on the Pressure-Volume (P-V) curve reflects the average critical pressure needed to re-open those regions of the lung that close during expiration.[28] However, there is a poor relationship between the level of LIP and the amount of the alveolar recruitment determined by application of PEEP. Also, the absence of a LIP on the P-V curve does not preclude the possibility of recruitment with PEEP.[29] Many factors (reflex bronchoconstriction, pneumoconstriction due to a release of inflammatory mediators, and peribronchial edema)[30] explain poor correlation between LIP and recruitment. Chest wall mechanics rather that lung mechanics could affect LIP on P-V curve. [31], [32]
Tidal Volume and Permissive Hypercapnia
The most revolutionary change in the management of children with ARDS has been the adoption of techniques in which lower tidal volumes are used to prevent ventilator-induced lung injury, while at the same time optimising oxygen delivery. Permissive hypercapnia is an inherent element of accepted protective lung ventilatory strategies. Mechanotrauma, which results from repetitive over-stretching and damage of lung tissue and cyclic recruitment-derecruitment of collapsed areas of lung, plays a pivotal role.[33] Minute ventilation can be reduced with lower tidal volumes as long as partial pressure of carbon dioxide (PaCO 2 ) is balanced by serum bicarbonate levels such that pH is acceptable, usually more than 7.15-7.20. Low volume/pressure strategy of the National Institute of Health ARDS Network Trial has shown that ventilation with a tidal volume of 6 ml/kg compared with 12 ml/kg resulted in a significant decrease in mortality table1. The study randomised patients with ARDS or ALI to either traditional ventilation using tidal volumes (VT) of 12 ml/kg and peak pressure (PIP) of < 50 cm H2O, or a lung-protective strategy using tidal volumes < 6ml/kg and peak pressure <30 cm H2O. The primary outcome was mortality, and the secondary outcome was ventilator-free days. This trial was terminated after randomising 861 patients because of significantly lower mortality in patients randomised to the lung- protective strategy. The greatest reduction in mortality was seen in patients with worse compliance at randomisation.[34] However, doubts were raised if the results meant low tidal volumes were beneficial or if it simply meant unconventionally high peak pressures were harmful and 2 ongoing studies by ARDS Net group were put to hold.
It is likely that acidosis may constitute a protective adaptation in the context of cellular stress, and may in fact constitute beneficial effects in the setting of acute organ injury.[35] It is hypothesized that hypercapneic acidosis may down-regulate inflammatory cell activity, and may inhibit xanthine oxidase, thus reducing oxidant stress. There are insufficient clinical data to suggest that hypercapnia should be independently induced, nor do out-come data exist to support the practice of buffering hypercapnic acidosis using sodium bicarbonate.
Airway Pressure Release Ventilation (APRV)
Airway pressure release ventilation (APRV) has been described as continuous positive airway pressure [CPAP] with regular, brief, intermittent releases in airway pressure.[39] APRV, unlike CPAP, facilitates both oxygenation and CO 2 clearance.[40] The CPAP level drives oxygenation, while the timed releases aid in CO 2 clearance (ventilation). Spontaneous breathing is advantageous because it decreases intrapulmonary shunting and improves venous return. The ability to avoid neuromuscular blockade and decreased use of sedation results in fewer complications.[41]
High Frequency Ventilation (HFV)
All modes of HFV eliminate CO 2 by cycling a below normal tidal volume at supraphysiologic rate. Lung volume is usually inferred by CXR, aiming for at least 9 ribs of lung expansion.[42]A multicenter randomized controlled trial showed HFOV was as safe and effective as conventional mechanical ventilation (CMV). There was no significant difference in mortality, however there was a trend in the HFV group towards decreasing mortality: 37% vs 52% at 30 days (p=0.098) and 47% vs 59% at 6 months. In this study, the time on CMV prior to the enrolment was predictive of mortality, suggesting that early intervention may be helpful.[43]
In a prospective trial of 24 patients with severe ARDS, patients who failed CMV (requiring FiO 2 > 0.6 or inspiratory plateau pressures of >35 cm H 2 O) were treated with HFOV. Patients had higher Paw, improved oxygenation and ventilation than baseline. Early intervention with HFOV may be beneficial, perhaps due to the prevention of further VALI. [44]
Arnold et al recently conducted a survey of 10 pediatric intensive care units across the United States to study the role of HFOV in respiratory failure.[45] A total of 290 patients were identified who were treated with HFOV over a period of 18 months. Patients were further subdivided as to whether they had pre-existing lung disease and their acute response to HFOV. Patients with or without HFOV had improvement in oxygenation index. The variables associated with increased risk of mortality included immunocompromised state, sepsis syndrome, oxygenation index prior to initiation of HFOV, oxygenation index at 12 and 24 hours after initiation of HFOV, duration of conventional ventilation before HFV.
A recent Cochrane review compared the effect of HFV with conventional ventilation for ALI or ARDS and found a statistically significant reduction in the risk of requiring supplemental oxygen amongst survivors at 30 days in the paediatric study. There was not enough evidence to conclude whether HFV reduced mortality or long-term morbidity in these patients.[46]
Adjunctive therapy
Important achievements have been made in the arena of adjunctive therapy especially agents with specific physiological goals.
Recruitment Manoeuvres
Habashi et al describe three 'compartments' in ARDS-affected lungs: (a) aerated normal lung susceptible to barotrauma induced by inappropriate ventilation, (b) air spaces that are filled with exudate and not recruitable, and (c) areas that are collapsed due to interstitial infiltration and are potentially recruitable. Recruitment is a strategy aimed at re-expanding collapsed lung tissue, and then maintaining high PEEP to prevent subsequent 'de-recruitment'. In order to recruit collapsed lung tissue, sufficient pressure must be imposed to exceed the critical opening pressure of the affected lung. In dependent areas of the lung, the pressures required may exceed 50cm H 2 O.[47]
The clinicians need more information about many aspects of these manoeuvres; namely, the optimal time to perform RMs, how often they should be used, their duration and the recommended ventilatory mode (CPAP, sighs, pressure controlled ventilation, short duration high PEEP level). Moreover, the long-lasting effects of RMs on arterial blood gases are contradictory.[48],[49]
Various types of RMs have been described: application of sigh during lung protective strategy,[50] three consecutive sighs per minute at 45 cm H 2 O of plateau pressure for 1 hour in patients ventilated with a protective strategy,[50] sustained lung inflations with continuous positive airway pressure (CPAP, of 30-45 cmH 2 O for 20 s) etc.
The ARDS Clinical Trials Network study concluded that in ALI/ARDS patients receiving mechanical ventilation with low tidal volumes and high PEEP, short-term effects of RMs were variable. The beneficial effects on gas exchange in those who responded appeared to be of brief duration.[51]
Prone Position
Bryan in 1974 first advocated the use of prone positioning for patients with ARDS.[52] Prone positioning is known to rapidly improve oxygenation in 70% of patients with ARDS, an effect that persists in 50% after returning to the supine position.[53]
The exact mechanism responsible for improved oxygenation seen in patients of ARDS placed in prone position is still debatable. It is postulated that ARDS patients have inhomogeneous distribution of alveolar collapse and that patients in the prone position appear to have more recruitment of atelectatic dorsal lung regions. Other explanations include decrease in abdominal compression of the thorax and /or mobilisation and removal of secretions.
The transpulmonary pressure in a homogeneous lung, is shared equally by each fibre of the lung's fibrous skeleton. In a non-homogeneous lung, the collapsed or consolidated regions do not strain, whereas the neighbouring fibres experience excessive strain leading to biological activation of macrophages (releasing cytokines) and/or mechanical rupture. The prone position may attenuate ventilator-induced lung injury by increasing homogenecity of transpulmonary pressure distribution.[54] Improved secretion drainage and altered diaphragmatic mechanics may also contribute to clinical improvement. Prone positioning can be discontinued when it no longer makes an impressive difference to oxygenation and plateau pressure can be kept in safe range when supine.[55]
A randomized, prospective study was carried out to compare prone positioning and continuous rotation of patients with ARDS. The conclusion was that, in severe lung injury, continuous rotational therapy seemed to exert effects comparable to prone positioning and could serve, as an alternative when prone positioning seems inadvisable.[56]
Inhaled Nitric Oxide
Inhaled nitric Oxide [iNO] is a selective pulmonary capillary vasodilator. It has been shown that inhaled nitric oxide may attenuate increases in capillary permeability and may also decrease the overproduction of cytokines in patients with severe ARDS. The short-term effect of iNO on PaO2 has been confirmed by others who found a response to iNO in about 80% of patients with ARDS. Although the dosage range for iNO is 0-80 ppm, increasing the dose beyond 20 ppm has little value. In a prospective study evaluating the acute effects of 3 concentrations of iNO (1 ppm, 10 ppm and 20 ppm) on gas exchange and hemodynamics in children with ARDS Tong et al showed that low concentration (1 ppm) was as effective as high concentrations (10 ppm and 20 ppm) of inhaled nitric oxide.[57] In contrast, recent studies found no significant long-term effects of iNO on mortality and arterial oxygenation. In a randomised controlled clinical trial, Michael et al compared PaO 2 in two groups of patients with ARDS randomised to either iNO or conventional therapy. Giving 5-20 ppm of iNO increased PaO 2 which reached statistical significance during the first 24 hours of study. However, beyond 24 hours, there was no difference in arterial oxygenation between the two groups.[58] These results do not support the routine use of nitric oxide in patients with hypoxemia due to acute lung injury. However, in children with severe hypoxic respiratory failure, iNO reduced the requirement for extra-corporeal membrane oxygenation (ECMO) from 54% in-group without NO treatment to 39% when NO was used. Like ECMO, iNO may be useful as a rescue therapy in patients dying from intractable hypoxemia.[59] Methemoglobinemia, decreased platelet aggregation and rebound deterioration in arterial oxygenation and elevation of pulmonary arterial pressure are significant possible side effects. Formation of peroxynitrite, hydroxyl radicals and nitrogen dioxide can inactivate already decreased defective surfactant, damage type II alveolar cells thereby accentuating the already existing acute lung injury.
Sildenafil
Up to 60% of septic patients with ARDS show no or only minimal response to inhaled NO. Nitric oxide induces relaxation of smooth muscle cells via the second messenger 3', 5'-cyclic monophosphate (cGMP) which is metabolized by phosphodiesterase (PDE) type 5. Sildenafil inhibits PDE type 5 and stabilises cGMP (unlike prostacyclins, which act through an increase in cAMP). At present, there is no evidence to support the use of sildenafil in patients with ARDS. It is hypothesized that in sepsis induced ARDS, decreased responsiveness to inhaled nitric oxide is at least in part attributable to increased pulmonary PDE type 5 activity. In such patients, sildenafil could be useful in improving the responsiveness to iNO.[60]
Corticosteroids
Meduri et al reported mortalities of 17% in 29 patients who improved lung function on methylprednisolone therapy (responders) and 100% in 5 patients (non-responders) with ARDS. The open lung biopsy specimens obtained prior to the methylprednisolone treatment showed myxoid cellular fibrosis and preserved alveolar architecture in responders but dense acellular fibrosis in non-responders. These findings suggested that the efficacy of prolonged methylprednisolone therapy might be lost once end-stage fibrosis had begun. They concluded that, if administered before end-stage fibrosis develops, methylprednisolone therapy could be effective in improving lung function and outcome in patients with unresolving ARDS.[61] A blinded, randomized, controlled trial involving adult patients showed marked differences in Intensive care unit and hospital outcome between 8 patients receiving placebo and 16 patients treated with methylprednisolone starting at 2 mg/kg daily at an early stage (after at least 7 days of mechanical ventilation), continuing up to 32 days. Outcome appeared to be significantly improved in the treatment group, with no significant increase in infection.[62] However, similar data in pediatric patients is not available. In fact, it has been hypothesized that fibrosis may represent an early response to lung injury, progressing "in parallel" with exudative and proliferative changes rather than in "succession".[63]
Surfactant
Samples of bronchoalveolar-lavage fluid from patients with ARDS have lower concentrations of phosphatidyl choline, phosphatidyl glycerol, and surfactant proteins than samples from healthy persons. The inflammatory alveolar environment may damage and inactivate surfactant, and the alveolar exudates may compete with surfactant for incorporation into the air-fluid interface. Surfactant-replacement therapy in ARDS is therefore both a biologically plausible hypothesis and a therapeutic possibility, as demonstrated by successful trials in premature infants.
Willson et al in 1999 published the use of surfactant for pediatric hypoxic respiratory failure.[64] The authors concluded that surfactant therapy appears to improve oxygenation acutely and lead to more rapid weaning from mechanical ventilation. However, the study population contained both ARDS and non-ARDS causes of respiratory failure. Also, no difference in mortality could be demonstrated. Preferential deposition in healthy lung units, inactivation in damaged alveoli, and variable delivery systems may all contribute to failure in these trials.[65]
Partial Liquid Ventilation
ARDS is associated with loss of surfactant, rise of surface tension and alveolar collapse. Filling the lung with liquid removes the air-liquid interface and supports alveoli thus preventing their collapse. In partial liquid ventilation (PLV), the lung is filled to its functional residual capacity with a perfluorocarbon (PFC), and gaseous mechanical ventilation is performed simultaneously. PFCs are dense volatile liquids with low biological reactivity, which ultimately evaporate from the lung with minimal systemic absorption. They have low surface tension and an unusually high solubility for oxygen and carbon dioxide. They effectively splint alveoli open, and circumvent the unstable air-liquid interface. PLV is associated with increased incidence of pneumothorax, mucus plugging and disruption of normal surfactant system. In a recent Cochrane review, it was concluded that there was no evidence from randomized controlled trials to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory syndrome.[66]
Extra-Corporeal Membrane Oxygenation (ECMO)
Many anecdotal reports suggest that ECMO may be beneficial in children with severe ARDS unresponsive to maximal conventional therapy. However, it is difficult to define maximal "conventional" therapy. While on ECMO, patient's lungs are allowed to rest on low ventilator settings. Most studies have shown the survival increases with "early" (7 days or less of mechanical ventilation) institution of ECMO therapy, presumably when the disease remains reversible and before ventilator induced lung injury occurs. Ventilator duration for more than 10 days prior to commencing ECMO is a relative contraindication.
The most common index used to assess refractory hypoxemia is the oxygenation index (OI). An OI greater than 40-55% is thought to predict an 80% predicted mortality.[67] In a recent review, Robert Bartlett from Michigan concluded that " ECMO is a safe and effective means to keep patients alive during severe respiratory failure that would otherwise be fatal."[68]
Summary
ARDS is a relatively common cause of admission to the PICU. Profound changes in lung compliance and ventilation-perfusion mismatch lead to hypoxemia. Respiratory management and pharmacological manipulation form two main strategies for treating patients with ARDS. The respiratory management should aim at prevention of development of ventilator associated lung injury and progression to multi-organ dysfunction syndrome. The use of low tidal volumes, titration of PEEP for lung recruitment, early consideration of HFOV appear to be a sound, scientifically based approach to the care of these challenging patients. As yet, there is no definite evidence to support the routine use of pharmacological adjuncts. The inhaled nitric oxide and ECMO remain as rescue therapies. Inspite of innumerable advances in the care of ARDS patients, the mortality still remains as high as 36-50%. Though all pediatric intensive care units in developing nations may not be able to provide therapies such as iNO or ECMO, lung protective ventilation strategies combined with good supportive care will help to limit the mortality rate which is already on a declining trend.
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53. Albert RK. Prone position in ARDS: what do we know, and what do we need to know Crit Care Med 1999; 27 : 2574-2575.
54. Gattinoni L, Carlesso E, Cadringher P, Valenza F, Vagginelli F. and Chiumello D. Physical and biological triggers of ventilator-induced lung injury and its prevention. Eur Respir J 2003; 22 : 15S-25S.
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59. Payen D. Is nitric oxide inhalation a "cosmetic" therapy in acute respiratory distress syndrome American Journal of Respiratory and Critical Care Medicine 1998; 157 : 1361-1362.
60. ED Moloney and TW Evans. Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome. Eur Respir J 2003; 21 : 720-727.
61. Meduri GU, Chinn AJ, Leeper KV, et al. Corticosteroid rescue treatment of progressive fibroproliferation in late ARDS: patterns of response and predictors of outcome. Chest 1994; 105 : 1516-1527.
62. Meduri GU, Headley AS, Golden E et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. JAMA 1998, 280: 159-165.
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65. Robertson B, Halliday HL. Principles of surfactant replacement. Biochim Biophys Acta 1998; 1408 : 346-361.
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Abstract
Acute respiratory distress syndrome, a diagnosis based on physiologic and radiological criteria, occurs commonly in critical care setting. A major challenge in evaluating therapies that may improve survival in ARDS is that it is not a single disease entity but, rather, numerous different diseases that result in endothelial injury, where the most obvious manifestation is within the lung resulting in pulmonary oedema. It has been shown that poor ventilatory technique that is injurious to the lungs can propagate systemic inflammatory response and adversely affect the mortality. The current data suggest that high tidal volumes with high plateau pressures are deleterious and a strategy of ventilation with lower tidal volumes and lower plateau pressure is associated with lower mortality. There may be a role for recruitment manoeuvres as well. Other forms of respiratory support still require further research. The present understanding of optimal ventilatory management and other adjunctive therapies are reviewed.
Keywords: Acute respiratory distress syndrome; Systemic inflammatory response; Low tidal volume; Permissive hypercapnia; Adjunctive therapy
Acute respiratory distress syndrome (ARDS) was first described by Ashbaugh et al in 1967, in a group of adult patients with profound respiratory failure and bilateral infiltrates on chest radiograph.[1] According to the American-European Consensus Conference, ARDS represents a subset of Acute Lung Injury (ALI). Both require the following characteristics: (a) acute onset of respiratory symptoms, (b) frontal Chest X-ray (CXR) with bilateral infiltrates, and (c) no clinical evidence of left atrial hypertension. ARDS, requires more severe respiratory failure: PaO2/FiO2 <200 mmHg (regardless of PEEP level).
The incidence of ARDS in Pediatric Intensive Care Units (PICU) varies between 8.5 - 27 cases per 1000 PICU admissions. [2],[3],[4],[5],[6] In a case series of ARDS patients published from All India Institute of Medical Sciences (AIIMS) by Lodha R et al, the incidence of ARDS was found to be 20.1 per 1000 PICU admissions.[7] ARDS can be a result of either direct lung injury ("Pulmonary" ARDS) or indirect lung injury ("Extrapulmonary" ARDS).[8] Shock, sepsis and drowning are the most common causes of ARDS in children. The etiological factors are different in developed and developing nations with infections like malaria, dengue hemorrhagic fever being the dominant etiological factors in developing nations as shown by Khilnani et al . [9] The overall mortality in ARDS is approximately 35-50%, and death is usually due to multi-organ system failure rather than pulmonary failure per se.[10] Risk factors predictive of increased mortality in ARDS/ ALI as reviewed by Vasudevan A et al include liver dysfunction, age, sepsis, HIV infection, oxygenation index, length of mechanical ventilation prior to ARDS, mechanism of lung injury, right ventricular dysfunction and PaO2/FiO2 ratio less than 100. [11],[12],[13],[14],[15]
Ventilator-Associated Lung Injury
It is now clear that the manner in which mechanical ventilatory support is applied has the potential to exacerbate pre-existing lung injury further. Such ventilator-associated lung injury is attributable in part to the application of physiological tidal volumes to the reduced area of non-consolidated alveoli: the so-called "baby lung" concept. Ventilator-Associated Lung Injury (VALI) is a complex process initiated by the repetitive application of excessive stress or strains on the lung's fibroskeleton, microvasculature, terminal airways, and juxta-alveolar tissues. Delivering standard tidal volumes of 10-12 ml/Kg inevitably causes overdistension of alveoli. Increased inflammation ensues, in that plasma and BAL levels of interleukin (IL)-6, IL-8, tumor necrosis factor, IL-1 increase. The cytokines generated during high tidal volume ventilation may spill into systemic circulation, causing multi-organ system failure, the most common cause of death in ARDS.
Conventional Mechanical Ventilation
Fraction of Inspired Oxygen [FiO2] and Permissive Hypoxemia
Major problems of using very high concentrations of inspired oxygen include absorption atelectasis, lung toxicity and possibly, systemic toxicity. Various animal studies have shown that exposure to an FiO2 1.0 leads to reduction in functional residual capacity. Proliferation of type 2 epithelial cells and interstitial fibrosis has been demonstrated after 2 weeks of exposure to an FiO2 of 0.6 and this damage continued after the cessation of oxygen administration.[16]
There is no clinical evidence to support the use of specific FiO 2 thresholds but the standard practice is to titrate the FiO 2 (with the objective of reducing FiO 2 to less than 0.6) to a partial oxygen tension of 8.0 kPa [approximately 60 mmHg] or, more importantly for oxygen delivery, an arterial oxygen saturation of 90%.[17] Oxygen saturation values of around 90% are commonly accepted but oxygen delivery decreases quickly below 85-88% considering the steep descent in the oxyhemoglobin dissociation curve. If higher oxygen saturation can only be obtained by increasing airway pressure to levels that result in hemodynamic compromise, lower oxygen saturation may have to be accepted. However, it is vital to note that no child should be allowed to die because of hypoxemia and in such cases 100% oxygen should be administered.
Inspiratory Time and Inverse Ratio Ventilation[18],[19],[20],[21],[22]
Heterogeneously damaged lungs have regions of differing compliance and airway resistance. Prolongation of inspiratory time allows regions with long time constants (the product of airway resistance and compliance) to fill, by interfiling from areas of different time constants. Also, mean airway pressure (Paw), a reflection of mean alveolar pressure, is considered a major determinant of arterial oxygenation in acute respiratory distress syndrome.
On the other hand, there is the potential of developing dynamic hyperinflation and auto-PEEP (which may be undesirable) during inverse ratio ventilation (IRV), which is an extreme form of lengthening the Ti. The I:E ratio is a balance between oxygen demands and ventilatory requirements. In a case report, Tripathi et al suggested that patients with low dynamic lung compliance (less than 20 ml/cmH 2 O) in the setting of high PIP (more than 50 cmH 2 O) and normal I:E ratio (1:2) might benefit from PC-IRV.
Positive End-Expiratory Pressure (PEEP)
ARDS causes redistribution of pulmonary blood flow away from dependent lung regions that exhibit increased pulmonary vascular resistance (PVR) because of pulmonary edema. PEEP may lower the PVR hence improving V/Q matching by shifting pulmonary blood flow from non-dependant lung regions to dependant regions. The PEEP is effective in early ARDS, because it acts as a counterforce, preventing the compression atelectasis secondary to severe pulmonary edema whereas the fibro-proliferative processes may explain the lack of effects of PEEP in the late stage of ARDS.[23]
Through stepwise increases in PEEP (increments of 2-3), a level should be sought that maintains approximately 90% arterial oxygen saturation at 50-60% FiO 2 . Application of PEEP beyond 15-20 cm H 2 O may result in decreased venous return (hence ensure normal volume prior to starting PEEP), in turn reducing the cardiac output. If volume loading is insufficient, the next step to restore cardiac output would be to add inotropes. If cardiac output still remains depressed, PEEP needs to be decreased stepwise until cardiac output is restored.
PEEP optimization may lead to lung protection via mechanisms other than alveolar recruitment -for example, by avoiding surfactant depletion and disruption occurring at low end-expiratory lung volumes.[24] Gattinoni and co-workers showed that PEEP improves lung mechanics and induces significant alveolar recruitment in patients with extrapulmonary ARDS, whereas it results in lung overinflation and worsening of lung mechanics in patients with pulmonary ARDS.[25],[26]
In the ARDS Network clinical trial, it was concluded that in patients with acute lung injury and ARDS who received mechanical ventilation with lower tidal volumes and inspiratory pressures (all patients received a tidal-volume goal of 6 ml per kilogram of predicted body weight and an inspiratory plateau pressure of 30 cm of water or less), raising PEEP to levels that exceeded those used in their lower-PEEP strategy (8.3±3.2 cm of water in the lower-PEEP group and 13.2±3.5 cm of water in the higher-PEEP group) did not achieve statistically significant survival benefit.[27]
Inflection Points and Alveolar Recruitment
The earlier concept was that the lower inflection point (LIP) on the Pressure-Volume (P-V) curve reflects the average critical pressure needed to re-open those regions of the lung that close during expiration.[28] However, there is a poor relationship between the level of LIP and the amount of the alveolar recruitment determined by application of PEEP. Also, the absence of a LIP on the P-V curve does not preclude the possibility of recruitment with PEEP.[29] Many factors (reflex bronchoconstriction, pneumoconstriction due to a release of inflammatory mediators, and peribronchial edema)[30] explain poor correlation between LIP and recruitment. Chest wall mechanics rather that lung mechanics could affect LIP on P-V curve. [31], [32]
Tidal Volume and Permissive Hypercapnia
The most revolutionary change in the management of children with ARDS has been the adoption of techniques in which lower tidal volumes are used to prevent ventilator-induced lung injury, while at the same time optimising oxygen delivery. Permissive hypercapnia is an inherent element of accepted protective lung ventilatory strategies. Mechanotrauma, which results from repetitive over-stretching and damage of lung tissue and cyclic recruitment-derecruitment of collapsed areas of lung, plays a pivotal role.[33] Minute ventilation can be reduced with lower tidal volumes as long as partial pressure of carbon dioxide (PaCO 2 ) is balanced by serum bicarbonate levels such that pH is acceptable, usually more than 7.15-7.20. Low volume/pressure strategy of the National Institute of Health ARDS Network Trial has shown that ventilation with a tidal volume of 6 ml/kg compared with 12 ml/kg resulted in a significant decrease in mortality table1. The study randomised patients with ARDS or ALI to either traditional ventilation using tidal volumes (VT) of 12 ml/kg and peak pressure (PIP) of < 50 cm H2O, or a lung-protective strategy using tidal volumes < 6ml/kg and peak pressure <30 cm H2O. The primary outcome was mortality, and the secondary outcome was ventilator-free days. This trial was terminated after randomising 861 patients because of significantly lower mortality in patients randomised to the lung- protective strategy. The greatest reduction in mortality was seen in patients with worse compliance at randomisation.[34] However, doubts were raised if the results meant low tidal volumes were beneficial or if it simply meant unconventionally high peak pressures were harmful and 2 ongoing studies by ARDS Net group were put to hold.
It is likely that acidosis may constitute a protective adaptation in the context of cellular stress, and may in fact constitute beneficial effects in the setting of acute organ injury.[35] It is hypothesized that hypercapneic acidosis may down-regulate inflammatory cell activity, and may inhibit xanthine oxidase, thus reducing oxidant stress. There are insufficient clinical data to suggest that hypercapnia should be independently induced, nor do out-come data exist to support the practice of buffering hypercapnic acidosis using sodium bicarbonate.
Airway Pressure Release Ventilation (APRV)
Airway pressure release ventilation (APRV) has been described as continuous positive airway pressure [CPAP] with regular, brief, intermittent releases in airway pressure.[39] APRV, unlike CPAP, facilitates both oxygenation and CO 2 clearance.[40] The CPAP level drives oxygenation, while the timed releases aid in CO 2 clearance (ventilation). Spontaneous breathing is advantageous because it decreases intrapulmonary shunting and improves venous return. The ability to avoid neuromuscular blockade and decreased use of sedation results in fewer complications.[41]
High Frequency Ventilation (HFV)
All modes of HFV eliminate CO 2 by cycling a below normal tidal volume at supraphysiologic rate. Lung volume is usually inferred by CXR, aiming for at least 9 ribs of lung expansion.[42]A multicenter randomized controlled trial showed HFOV was as safe and effective as conventional mechanical ventilation (CMV). There was no significant difference in mortality, however there was a trend in the HFV group towards decreasing mortality: 37% vs 52% at 30 days (p=0.098) and 47% vs 59% at 6 months. In this study, the time on CMV prior to the enrolment was predictive of mortality, suggesting that early intervention may be helpful.[43]
In a prospective trial of 24 patients with severe ARDS, patients who failed CMV (requiring FiO 2 > 0.6 or inspiratory plateau pressures of >35 cm H 2 O) were treated with HFOV. Patients had higher Paw, improved oxygenation and ventilation than baseline. Early intervention with HFOV may be beneficial, perhaps due to the prevention of further VALI. [44]
Arnold et al recently conducted a survey of 10 pediatric intensive care units across the United States to study the role of HFOV in respiratory failure.[45] A total of 290 patients were identified who were treated with HFOV over a period of 18 months. Patients were further subdivided as to whether they had pre-existing lung disease and their acute response to HFOV. Patients with or without HFOV had improvement in oxygenation index. The variables associated with increased risk of mortality included immunocompromised state, sepsis syndrome, oxygenation index prior to initiation of HFOV, oxygenation index at 12 and 24 hours after initiation of HFOV, duration of conventional ventilation before HFV.
A recent Cochrane review compared the effect of HFV with conventional ventilation for ALI or ARDS and found a statistically significant reduction in the risk of requiring supplemental oxygen amongst survivors at 30 days in the paediatric study. There was not enough evidence to conclude whether HFV reduced mortality or long-term morbidity in these patients.[46]
Adjunctive therapy
Important achievements have been made in the arena of adjunctive therapy especially agents with specific physiological goals.
Recruitment Manoeuvres
Habashi et al describe three 'compartments' in ARDS-affected lungs: (a) aerated normal lung susceptible to barotrauma induced by inappropriate ventilation, (b) air spaces that are filled with exudate and not recruitable, and (c) areas that are collapsed due to interstitial infiltration and are potentially recruitable. Recruitment is a strategy aimed at re-expanding collapsed lung tissue, and then maintaining high PEEP to prevent subsequent 'de-recruitment'. In order to recruit collapsed lung tissue, sufficient pressure must be imposed to exceed the critical opening pressure of the affected lung. In dependent areas of the lung, the pressures required may exceed 50cm H 2 O.[47]
The clinicians need more information about many aspects of these manoeuvres; namely, the optimal time to perform RMs, how often they should be used, their duration and the recommended ventilatory mode (CPAP, sighs, pressure controlled ventilation, short duration high PEEP level). Moreover, the long-lasting effects of RMs on arterial blood gases are contradictory.[48],[49]
Various types of RMs have been described: application of sigh during lung protective strategy,[50] three consecutive sighs per minute at 45 cm H 2 O of plateau pressure for 1 hour in patients ventilated with a protective strategy,[50] sustained lung inflations with continuous positive airway pressure (CPAP, of 30-45 cmH 2 O for 20 s) etc.
The ARDS Clinical Trials Network study concluded that in ALI/ARDS patients receiving mechanical ventilation with low tidal volumes and high PEEP, short-term effects of RMs were variable. The beneficial effects on gas exchange in those who responded appeared to be of brief duration.[51]
Prone Position
Bryan in 1974 first advocated the use of prone positioning for patients with ARDS.[52] Prone positioning is known to rapidly improve oxygenation in 70% of patients with ARDS, an effect that persists in 50% after returning to the supine position.[53]
The exact mechanism responsible for improved oxygenation seen in patients of ARDS placed in prone position is still debatable. It is postulated that ARDS patients have inhomogeneous distribution of alveolar collapse and that patients in the prone position appear to have more recruitment of atelectatic dorsal lung regions. Other explanations include decrease in abdominal compression of the thorax and /or mobilisation and removal of secretions.
The transpulmonary pressure in a homogeneous lung, is shared equally by each fibre of the lung's fibrous skeleton. In a non-homogeneous lung, the collapsed or consolidated regions do not strain, whereas the neighbouring fibres experience excessive strain leading to biological activation of macrophages (releasing cytokines) and/or mechanical rupture. The prone position may attenuate ventilator-induced lung injury by increasing homogenecity of transpulmonary pressure distribution.[54] Improved secretion drainage and altered diaphragmatic mechanics may also contribute to clinical improvement. Prone positioning can be discontinued when it no longer makes an impressive difference to oxygenation and plateau pressure can be kept in safe range when supine.[55]
A randomized, prospective study was carried out to compare prone positioning and continuous rotation of patients with ARDS. The conclusion was that, in severe lung injury, continuous rotational therapy seemed to exert effects comparable to prone positioning and could serve, as an alternative when prone positioning seems inadvisable.[56]
Inhaled Nitric Oxide
Inhaled nitric Oxide [iNO] is a selective pulmonary capillary vasodilator. It has been shown that inhaled nitric oxide may attenuate increases in capillary permeability and may also decrease the overproduction of cytokines in patients with severe ARDS. The short-term effect of iNO on PaO2 has been confirmed by others who found a response to iNO in about 80% of patients with ARDS. Although the dosage range for iNO is 0-80 ppm, increasing the dose beyond 20 ppm has little value. In a prospective study evaluating the acute effects of 3 concentrations of iNO (1 ppm, 10 ppm and 20 ppm) on gas exchange and hemodynamics in children with ARDS Tong et al showed that low concentration (1 ppm) was as effective as high concentrations (10 ppm and 20 ppm) of inhaled nitric oxide.[57] In contrast, recent studies found no significant long-term effects of iNO on mortality and arterial oxygenation. In a randomised controlled clinical trial, Michael et al compared PaO 2 in two groups of patients with ARDS randomised to either iNO or conventional therapy. Giving 5-20 ppm of iNO increased PaO 2 which reached statistical significance during the first 24 hours of study. However, beyond 24 hours, there was no difference in arterial oxygenation between the two groups.[58] These results do not support the routine use of nitric oxide in patients with hypoxemia due to acute lung injury. However, in children with severe hypoxic respiratory failure, iNO reduced the requirement for extra-corporeal membrane oxygenation (ECMO) from 54% in-group without NO treatment to 39% when NO was used. Like ECMO, iNO may be useful as a rescue therapy in patients dying from intractable hypoxemia.[59] Methemoglobinemia, decreased platelet aggregation and rebound deterioration in arterial oxygenation and elevation of pulmonary arterial pressure are significant possible side effects. Formation of peroxynitrite, hydroxyl radicals and nitrogen dioxide can inactivate already decreased defective surfactant, damage type II alveolar cells thereby accentuating the already existing acute lung injury.
Sildenafil
Up to 60% of septic patients with ARDS show no or only minimal response to inhaled NO. Nitric oxide induces relaxation of smooth muscle cells via the second messenger 3', 5'-cyclic monophosphate (cGMP) which is metabolized by phosphodiesterase (PDE) type 5. Sildenafil inhibits PDE type 5 and stabilises cGMP (unlike prostacyclins, which act through an increase in cAMP). At present, there is no evidence to support the use of sildenafil in patients with ARDS. It is hypothesized that in sepsis induced ARDS, decreased responsiveness to inhaled nitric oxide is at least in part attributable to increased pulmonary PDE type 5 activity. In such patients, sildenafil could be useful in improving the responsiveness to iNO.[60]
Corticosteroids
Meduri et al reported mortalities of 17% in 29 patients who improved lung function on methylprednisolone therapy (responders) and 100% in 5 patients (non-responders) with ARDS. The open lung biopsy specimens obtained prior to the methylprednisolone treatment showed myxoid cellular fibrosis and preserved alveolar architecture in responders but dense acellular fibrosis in non-responders. These findings suggested that the efficacy of prolonged methylprednisolone therapy might be lost once end-stage fibrosis had begun. They concluded that, if administered before end-stage fibrosis develops, methylprednisolone therapy could be effective in improving lung function and outcome in patients with unresolving ARDS.[61] A blinded, randomized, controlled trial involving adult patients showed marked differences in Intensive care unit and hospital outcome between 8 patients receiving placebo and 16 patients treated with methylprednisolone starting at 2 mg/kg daily at an early stage (after at least 7 days of mechanical ventilation), continuing up to 32 days. Outcome appeared to be significantly improved in the treatment group, with no significant increase in infection.[62] However, similar data in pediatric patients is not available. In fact, it has been hypothesized that fibrosis may represent an early response to lung injury, progressing "in parallel" with exudative and proliferative changes rather than in "succession".[63]
Surfactant
Samples of bronchoalveolar-lavage fluid from patients with ARDS have lower concentrations of phosphatidyl choline, phosphatidyl glycerol, and surfactant proteins than samples from healthy persons. The inflammatory alveolar environment may damage and inactivate surfactant, and the alveolar exudates may compete with surfactant for incorporation into the air-fluid interface. Surfactant-replacement therapy in ARDS is therefore both a biologically plausible hypothesis and a therapeutic possibility, as demonstrated by successful trials in premature infants.
Willson et al in 1999 published the use of surfactant for pediatric hypoxic respiratory failure.[64] The authors concluded that surfactant therapy appears to improve oxygenation acutely and lead to more rapid weaning from mechanical ventilation. However, the study population contained both ARDS and non-ARDS causes of respiratory failure. Also, no difference in mortality could be demonstrated. Preferential deposition in healthy lung units, inactivation in damaged alveoli, and variable delivery systems may all contribute to failure in these trials.[65]
Partial Liquid Ventilation
ARDS is associated with loss of surfactant, rise of surface tension and alveolar collapse. Filling the lung with liquid removes the air-liquid interface and supports alveoli thus preventing their collapse. In partial liquid ventilation (PLV), the lung is filled to its functional residual capacity with a perfluorocarbon (PFC), and gaseous mechanical ventilation is performed simultaneously. PFCs are dense volatile liquids with low biological reactivity, which ultimately evaporate from the lung with minimal systemic absorption. They have low surface tension and an unusually high solubility for oxygen and carbon dioxide. They effectively splint alveoli open, and circumvent the unstable air-liquid interface. PLV is associated with increased incidence of pneumothorax, mucus plugging and disruption of normal surfactant system. In a recent Cochrane review, it was concluded that there was no evidence from randomized controlled trials to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory syndrome.[66]
Extra-Corporeal Membrane Oxygenation (ECMO)
Many anecdotal reports suggest that ECMO may be beneficial in children with severe ARDS unresponsive to maximal conventional therapy. However, it is difficult to define maximal "conventional" therapy. While on ECMO, patient's lungs are allowed to rest on low ventilator settings. Most studies have shown the survival increases with "early" (7 days or less of mechanical ventilation) institution of ECMO therapy, presumably when the disease remains reversible and before ventilator induced lung injury occurs. Ventilator duration for more than 10 days prior to commencing ECMO is a relative contraindication.
The most common index used to assess refractory hypoxemia is the oxygenation index (OI). An OI greater than 40-55% is thought to predict an 80% predicted mortality.[67] In a recent review, Robert Bartlett from Michigan concluded that " ECMO is a safe and effective means to keep patients alive during severe respiratory failure that would otherwise be fatal."[68]
Summary
ARDS is a relatively common cause of admission to the PICU. Profound changes in lung compliance and ventilation-perfusion mismatch lead to hypoxemia. Respiratory management and pharmacological manipulation form two main strategies for treating patients with ARDS. The respiratory management should aim at prevention of development of ventilator associated lung injury and progression to multi-organ dysfunction syndrome. The use of low tidal volumes, titration of PEEP for lung recruitment, early consideration of HFOV appear to be a sound, scientifically based approach to the care of these challenging patients. As yet, there is no definite evidence to support the routine use of pharmacological adjuncts. The inhaled nitric oxide and ECMO remain as rescue therapies. Inspite of innumerable advances in the care of ARDS patients, the mortality still remains as high as 36-50%. Though all pediatric intensive care units in developing nations may not be able to provide therapies such as iNO or ECMO, lung protective ventilation strategies combined with good supportive care will help to limit the mortality rate which is already on a declining trend.
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