Special Feature
Update on Rescue Therapies for Hypoxemic Respiratory Failure
By David J. Pierson, MD, Editor, Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, is Editor for Critical Care Alert.
Critical hypoxemia in acute respiratory failure may be defined as a degree of impairment in tissue oxygenation that in and of itself, and separately from the primary cause of the respiratory failure threatens the life of the patient. How this conceptual definition translates to objective measurements has not been standardized. Several clinical trials of different ventilation strategies for managing patients with severe acute respiratory distress syndrome (ARDS) have included the option for the managing physician to employ "adjunct" or "rescue" therapies over and above the study interventions. The thresholds for such interventions generally have consisted of measures of arterial oxygenation, such as a PaO2/FIO2 ratio of less than 60-80 mm Hg on a specified amount of positive end-expiratory pressure (PEEP). What has emerged from all such studies is the fact that, whatever the study's designated threshold for considering rescue therapies, participating clinicians have employed such interventions substantially more often than the thresholds recommend. This has definitely been my observation in clinical practice. Thus, a pragmatic definition for critical hypoxemia is "that level of arterial oxygenation in a patient with acute respiratory failure that prompts the managing physician to do something different," such as a change in ventilator management or the addition of some additional intervention, over and above conventional lung-protective ventilation (LPV).
This newsletter published a concise review of rescue therapies for critical hypoxemia in 2008.1 In this essay, I provide an update on the topic, comparing the available interventions and summarizing their current status in the management of patients with hypoxemic acute respiratory failure. In the past year, several excellent, more comprehensive reviews have been published on this topic.2-6 In 2011, the standard of care for patients with ARDS the clinical setting in which rescue therapies for critical hypoxemia are most often considered is LPV. All patients should receive low-tidal-volume ventilation; delivered tidal volume should be set according to predicted (not actual) body weight, and be not more than 8 mL/kg, preferably 6 or less; and alveolar distending pressure (end-inspiratory plateau pressure in most instances) should be closely monitored and kept below 30 cm H2O. These things have been established by high-quality evidence: they save lives and are no longer optional at the discretion of the clinician. Beyond the components of conventional LPV, the evidence that other interventions improve patient outcomes in ARDS is much less convincing.
A clinical trial in which patients with early ARDS were heavily sedated for the initial 48 hours and given either the nondepolarizing muscle relaxant cisatracurium or placebo7 found improved survival and a shorter duration of mechanical ventilation in the experimental group. It has been proposed that cisatracurium has anti-inflammatory properties separate from its action as a muscle relaxant, which may alter the evolution of acute lung injury.8 This concept is consistent with the fact that the survival curves in the two groups did not begin to diverge until the second week after completion of the infusion. Because of the many negative aspects of the use of paralytic agents in patients with acute respiratory failure,9 changing practice on the basis of this intriguing study is inadvisable at this point. In any event, the investigators did not study cisatracurium as a rescue therapy, and its effects on arterial oxygenation, if any, are not reported.7
Aside from the study just mentioned, no clinical trial has demonstrated a survival benefit when any of the rescue therapies listed in the accompanying table9-18 has been compared or added to conventional LPV. However, as discussed in the most recent review of these modalities,6 subsequent subset analyses and meta-analyses of the findings in multiple trials have uncovered some significant differences. In a patient-level meta-analysis of three clinical trials, higher PEEP was associated with slightly improved survival among patients with ARDS as opposed to those with less severe hypoxemia,10 although the 95% confidence interval (CI) for the relative risk included 1.00. Another meta-analysis, of three clinical trials of prone positioning, found a significant survival benefit in the subset of patients with PaO2/FIO2 < 100 mm Hg (relative risk, 0.84; 95% CI, 0.74-0.96).19 Similarly, a meta-analysis of eight randomized trials of high-frequency oscillatory ventilation (none of which individually showed a survival benefit compared to conventional LPV) found a relative risk of death of 0.77, 95% CI, 0.61-0.98, with that ventilation modality.20 How clinicians should interpret these survival benefits derived from individually negative studies is uncertain.
| Table. Characteristics of Currently Available Rescue Therapies for Refractory Hypoxemia in ARDS Patients* | ||||
Intervention |
Rationale for Use |
Beneficial Effects |
Disadvantages; Potential for Harm |
Added Monetary Cost |
Use of higher PEEP10,11 |
Keep atelectatic or poorly inflated alveoli open throughout the respiratory cycle; prevent atelectrauma |
Increased PaO2 |
May decrease venous return and cardiac output, requiring more fluid and/or vasopressor administration and potentially increasing risk for barotrauma |
None (but may require more aggressive hemodynamic monitoring) |
Inverse I:E ratio ventilation (either volume- or pressure-controlled) |
Keep poorly inflated alveoli open for more of the respiratory cycle; increased mean airway pressure |
Increased PaO2, usually with increased auto-PEEP |
Decreased venous return and cardiac output; variable auto-PEEP in different lung regions; increased risk for pneumothorax and other barotrauma |
None (but requires more aggressive hemodynamic monitoring and heavy sedation) |
Esophageal pressure monitoring12 |
Determine actual trans-pulmonary pressure in face of high chest-wall pressure, and adjust PEEP accordingly |
Usually leads to use of higher PEEP, with corresponding increase in PaO2 |
Catheter may be difficult to place; data can be misleading when sensor not in proper position |
Requires special catheter and monitoring system |
Airway pressure release ventilation13 |
Higher mean airway pressure with lower peak pressure; permits spontaneous breathing |
As effective as conventional ventilation in supporting oxygenation and ventilation; may require less sedation |
Tidal volume may exceed LPV goals with spontaneous breathing |
None (but not available on all current critical care ventilators) |
Recruitment maneuvers14,15 |
Open atelectatic alveoli; maintain lung inflation at lower end-expiratory pressure |
Increased PaO2, although effect less with time requiring repeated maneuvers |
Hypoxia, hypotension, alveolar rupture (but generally safe); Increased risk for VAP if breaking ventilator circuit is involved |
None |
High-frequency oscillatory ventilation13 |
"Ultimate lung-protective ventilation"; mean airway pressure maintained with minimal increase during cycle |
Generally as effective as conventional ventilation in supporting oxygenation and ventilation |
Requires specific, very different ventilator, with unique requirements for monitoring and skills on part of staff |
Separate ventilator used only for this purpose; costs associated with staff training |
Neuromuscular blocking agents (therapeutic paralysis)9 |
Reduce oxygen consumption from skeletal muscle activity; eliminate breath-stacking; improve ventilation distribution |
Eliminates patient-ventilator asynchrony and breath-stacking; variably improves PaO2; no outcome data when used as rescue therapy |
Loss of neurologic exam; increased risk for pressure ulcers; increased duration of mechanical ventilation; increased risk for subsequent neuromuscular weakness and PTSD in survivors |
Cost of paralytic agent and train-of-4 monitoring |
Prone positioning16 |
Improve regional ventilation and perfusion; aid in redistribution of extravascular lung water; facilitate secretion clearance |
Usually improves PaO2 |
Cannot be used in patients with severe obesity, intracranial hypertension, open abdomen, multiple drains, etc; time- and labor-intensive; increased risk for pressure ulcers; oxygenation benefits tend to wane over time |
Added cost if commercial proning system used; vendor charges $1295 per day at my institution |
Inhaled nitric oxide17 |
Vasodilation in ventilated lung regions; improved ventilation-perfusion matching |
Increases PaO2 in most patients; relatively easy to administer and generally safe |
May increase risk for renal impairment; may be difficult to wean; use in this clinical setting is not FDA-approved |
Vendor charges hospital $119 per hour used ($2859/day) at my institution; this cost to hospital is not reimbursed |
Aerosolized prostacyclin18 |
Same as with nitric oxide |
Increased PaO2; same benefits as with nitric oxide at lower cost |
Clogs filters in ventilator circuits; requires close monitoring and frequent filter changes |
Costs of drug, administration system, and frequent circuit filter changes |
ECMO |
Maintain tissue oxygenation and CO2 removal while lung recovers |
Fully supports gas exchange |
Available only at specialized centers; many patients are not candidates because of comorbidities, etc. |
Equipment and personnel for specialized life-support system |
*Note: Improved survival and other patient-relevant outcome benefits are not included in the table, since none has been demonstrated for any of these interventions in appropriately rigorous clinical trials. |
||||
The table compares the main rescue therapies currently available for treating critical hypoxemia. These interventions vary a great deal in ease of application, invasiveness, cost, and local availability. The lack of convincing evidence from clinical trials that these interventions reduce mortality in all comers with ARDS should not be interpreted to mean that they may not be beneficial for certain patients, nor should it necessarily imply that they should never be used. However, it suggests that careful consideration of the potential advantages and disadvantages of each modality is appropriate, and that clinicians should not feel compelled to deviate from conventional LPV in managing their most severely ill patients.
Walkey and Wiener recently examined the utilization patterns and patient outcomes associated with the use of rescue therapies in six clinical trials conducted by the ARDS Network between 1996 and 2005.21 Such therapies were allowed according to the study protocols, at clinician discretion, and had been employed in 166 of the 2632 patients in the trials. The interventions used were prone positioning (97 patients, or 58% of those who received at least one rescue therapy), inhaled vasodilators (mainly nitric oxide, 47 patients, 28%), high-frequency ventilation (12 patients, 7%), and extracorporeal membrane oxygenation (ECMO, 10 patients, 6%). With multivariate analysis, predictors of the use of a rescue therapy were patient age (odds ratio per 10 years, 0.88; 95% CI, 0.78-0.99; P = 0.049), the amount of PEEP used (OR per 5-cm H2O increase, 1.33; 95% CI, 1.05-1.69; P = 0.019), and peak airway pressure (OR per 5-cm H2O increase, 1.11; 95% CI, 0.001-1.237; P = 0.047). Thus, clinicians managing the patients enrolled in the ARDS Network studies used rescue therapies more often in younger patients who had worse oxygenation defects and stiffer lungs. In their analysis, Walkey and Wiener found no evidence for a survival benefit among patients who received rescue therapies.21 Space does not allow a more in-depth discussion of the different aspects of using rescue therapies for critical hypoxemia. However, considering the above discussion, the information in the table, my own observations in the medical and surgical ICUs of a level-1 trauma center, and the literature available to date on this subject, I draw the following conclusions:
- There is great practice variation in the use of rescue therapies regionally, among different institutions, and among individual clinicians, as well as with respect to which patients are offered such therapies;
- Regardless of local practice guidelines or study threshold criteria, individual clinicians decide when to use rescue therapies, and they tend to use them in more patients than the guidelines or study protocols would indicate;
- Rescue therapies often improve arterial oxygenation, but few studies have been done in patients with critical hypoxemia, and no rescue therapy has been clearly shown to have a favorable impact on survival;
- Because of the power of anecdotal experience, this lack of evidence is unlikely to deter clinicians from using them;
- Clinicians should bear in mind that an increased PaO2/FIO2 ratio is no guarantee of an improved clinical outcome, and in fact that some interventions that improve oxygenation such as larger tidal volumes actually worsen outcomes;
- Which rescue therapies are used in a particular institution or ICU will be determined largely by local availability and practice culture;
- Because the available rescue therapies vary a great deal in invasiveness, discomfort, and costs, patients and families should be given the opportunity to help decide what interventions beyond conventional LPV should be used in a particular case.
References
- Luks AM. Managing critical hypoxemia in the ICU. Critical Care Alert 2008;15:85-88.
- Esan A, et al. Severe hypoxemic respiratory failure: Part 1 ventilatory strategies. Chest 2010;137:1203-1216.
- Raoof S, et al. Severe hypoxemic respiratory failure: Part 2 nonventilatory strategies. Chest 2010;137:1437-1448.
- Diaz JV, et al. Therapeutic strategies for severe acute lung injury. Crit Care Med 2010;38:1644-1650.
- Liu LL, et al. Rescue therapies for acute hypoxemic respiratory failure. Anesth Analg 2010;111:693-702.
- Pipeling MR, Fan E. Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA 2010;304:2521-2527.
- Papazian L, et al. ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-1116.
- Slutsky AS. Neuromuscular blocking agents in ARDS. N Engl J Med 2010;363:1176-1180.
- Bennett S, Hurford WE. When should sedation or neuromuscular blockade be used during mechanical ventilation? Respir Care 2011;56:168-180.
- Briel M, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: Systematic review and meta-analysis. JAMA 2010;303:865-873.
- Putensen C,et al. Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009;151:566-576.
- Talmor D, et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008;359:2095-2104.
- Siau C, Stewart TE. Current role of high frequency oscillatory ventilation and airway pressure release ventilation in acute lung injury and acute respiratory distress syndrome. Clin Chest Med 2008;29:265-275, vi.
- Hodgson C, et al. Recruitment manoeuvres for adults with acute lung injury receiving mechanical ventilation. Cochrane Database Syst Rev 2009;CD006667.
- Fan E, et al. Recruitment maneuvers for acute lung injury: A systematic review. Am J Respir Crit Care Med 2008;178:1156-1163.
- Fessler HE, Talmor DS. Should prone positioning be routinely used for lung protection during mechanical ventilation? Respir Care 2010;55:88-99.
- Afshari A, et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev 2010;CD002787.
- Afshari A, et al. Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Cochrane Database Syst Rev 2010; CD007733.
- Sud S, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: Systematic review and meta-analysis. Intensive Care Med 2010;36:585-599.
- Sud S, et al. High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): Systematic review and meta-analysis. BMJ 2010; 340:c2327.
- Walkey AJ, Wiener RS. Utilization patterns and patient outcomes associated with use of rescue therapies in acute lung injury. Crit Care Med 2011;39(6):[epub prior to print].
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