An Overview of Salvage Therapies for Acute Respiratory Distress Syndrome Caused By H1N1 Infection

Andrew M. Luks, MD
University of Washington

Introduction

While most novel influenza patients develop mild, self-limited illness, some patients progress to respiratory failure requiring mechanical ventilation and, in some cases, develop the acute respiratory distress syndrome (ARDS). As with other causes of ARDS, oxygenation can be supported in most of these patients using increased inspired oxygen concentrations (F_IO₂) or higher levels of positive end-expiratory pressure (PEEP). Occasionally, however, as increasing reports from institutions around the world indicate, some of these patients are developing “critical hypoxemia” whereby arterial oxygen tensions cannot be maintained at adequate levels with basic techniques and alternative strategies become necessary. Given the expected burden of novel influenza in the coming months, it is highly likely that critical care physicians will face situations such as this and, as a result, it is necessary to develop familiarity with the various alternative or “salvage” strategies, including the data supporting their use and other nuts and bolts of their application at the bedside.

What Are the Salvage Therapies?

Several “salvage” techniques can be used in patients with critical hypoxemia. Brief descriptions of these modalities are provided below, while more detailed information about the various techniques follows this introduction.

Prone ventilation: Mechanical ventilation in the prone position is thought to benefit patients by causing favorable changes in regional ventilation and perfusion as well as potentially aiding in secretion clearance and redistribution of extravascular lung water.

Inhaled pulmonary vasodilators: Administration of nitric oxide or prostacyclin by the inhalational route causes localized pulmonary vasodilation in areas that receive adequate ventilation, thereby improving ventilation-perfusion matching and, as a result, arterial oxygenation.

Recruitment maneuvers: Increased transpulmonary pressure is applied to the airways for short periods of time using one of several different techniques in an effort to decrease atelectasis, improve gas exchange and limit ventilator-induced lung injury.

Alternative modes of mechanical ventilation: consideration can be given to using less commonly used modes of mechanical ventilation including pressure control-inverse ratio ventilation (PC-IRV), airway pressure release ventilation (APRV) and high frequency oscillatory or jet ventilation (HFOV and HFJV).

Neuromuscular blocking agents: Patients can be paralyzed in an effort to eliminate muscle activity, patient-ventilator dysynchrony or patient triggered breaths that could be contributing to increased oxygen demand or inadequate ventilation. 

Extracorporeal Membrane Oxygenation:  More commonly used in neonatology and pediatrics, this strategy utilizes a technique similar to that used in cardiopulmonary bypass surgery and handles gas exchange in an extracorporeal manner (i.e. outside the lungs).

When Are Salvage Strategies Warranted?

An important issue to consider in the management of patients with severe ARDS is exactly when clinicians should move away from standard lung protective ventilation in ARDS patients and consider the salvage therapies mentioned above and described in greater detail below. Unfortunately, the literature does not adequately define “critical” or “refractory” hypoxemia and there are no formally established thresholds for using these non-standard measures. ARDS is deemed to be present when the P_aO₂/F_IO₂ ratio is below 200 but clearly not everyone who meets this criterion requires non-standard therapies. It also seems difficult to apply consistent thresholds across all patients because the ability to tolerate a low P_aO₂ may vary between patients. A 20 year-old man with ARDS following trauma might tolerate P_aO₂ values in the 50 mm Hg range, for example, while the same value might be quite problematic in a 70 year-old with underlying severe coronary artery disease. In fact, a recent study documenting arterial blood gases in climbers at 8,400 m on Mount Everest provides a useful reminder that certain individuals can tolerate remarkable degrees of hypoxemia, including P_aO₂ values as low as 20 mm Hg. (1)

In general, rigid P_aO₂ thresholds are not warranted and the decision to initiate non-standard therapies should be tailored to the individual patient. These strategies should only be considered when there is impaired oxygenation and concurrent evidence of clinical instability or untoward effects of hypoxemia (eg. myocardial ischemia, multi-organ dysfunction). Clinical trends can also be used to guide decision-making. If a patient’s P_aO₂ falls to the 50-60 mm Hg range, for example, but remains stable over time, salvage therapies are likely not necessary but should those values instead follow a steady downward trend, more aggressive measures would be warranted. A particularly challenging situation is the patient in whom P_aO₂ generally remains in an adequate range but drops precipitously with any movement. If such drops are accompanied by signs of clinical instability (eg. bradycardia and hypotension) or fail to resolve within just a few minutes, salvage therapies might be warranted.

What else can be done besides the salvage therapies?

Before initiating non-standard therapies, which might be associated with high cost and potential risk to the patient, other interventions warrant consideration.  Although maintenance of an adequate P_aO₂ is an important objective, the more important goal is ensuring adequate oxygen delivery. Oxygen delivery is a function of cardiac output, hemoglobin concentration and arterial saturation, with only a minor contribution from the P_aO₂. Table 1 illustrates the impact on oxygen delivery from manipulating each of these variables in a hypothetical patient with baseline poor cardiac output, anemia and impaired oxygenation. This hypothetical data demonstrates that for a similar 33% increase in each of the variables, there is a greater gain in oxygen delivery from manipulating cardiac output and hemoglobin concentration than there would be from increasing the P_aO₂. This suggests that in very severe cases, consideration should be given to red blood cell transfusion if the patient is anemic – even if their hematocrit is above the now accepted transfusion threshold of 21% -- and to assessment and possible support of cardiac function.

In addition to focusing on the supply side of the oxygen equation, efforts should also be directed towards minimizing oxygen demand. Treatment of fever and elimination of shivering are warranted, as are efforts to minimize patient triggering on the ventilator. Breath-stacking, for example, can be minimized with aggressive use of sedation and manipulation of ventilator settings such as the inspiratory flow rate. In rare instances, neuromuscular blocking agents can be considered although there is no data demonstrating a mortality benefit from this practice and these agents increase the risk of critical care polyneuropathy. In the event paralytics are used, the duration of use should be minimized and train-of-four monitoring should be employed to ensure an appropriate degree of paralysis.

Which Salvage Therapy is Best for My Patient

As will be evident from the detailed discussion of the various salvage therapies that follows, the data supporting improvements in patient outcomes from these therapies are limited. Oxygenation can be improved but we still have no evidence these therapies improve mortality or other important outcomes. As a result, there remains no clear sense of the order in which these various therapies should be attempted or which is best for particular patients. Instead, clinicians will need to rely on other factors to guide their decisions as to which therapy to apply in a given situation. Perhaps the most important factor will be clinicians’ familiarity with a particular modality and emphasis should be placed on only employing options with which they have adequate experience and comfort.  High frequency oscillatory ventilation, for example, is a unique mode of mechanical ventilation that operates according to fundamentally different principles than assist control ventilation. Successful application requires prior experience with the modality whereas application by inexperienced providers can lead to severe adverse consequences for the patient. In addition, even if the physicians have experience with this modality, respiratory therapy staff may not be sufficiently comfortable with the technique to make necessary adjustments in the physician’s absence. Application of alternative strategies in such situations might be more prudent.

Another factor will be the relative availability of the various modalities. Prone positioning, for example, is easier to implement using specialty beds such as the RotoProne® system, but the number of beds at a particular hospital or in a given region may be limited, necessitating prone positioning in standard beds. This increases the risk of problems such as endotracheal tube dislodgement or decubitus ulcers and, until an institution has adequately trained its staff to prone patients in standard beds, it might be better for that institution to rely on other therapies such as inhaled pulmonary vasodilators or recruitment maneuvers.

Salvage Therapies for Patients with Critical Hypoxemia

Having considered some preliminary issues pertinent to the management of patients with critical hypoxemia, we will now consider the various salvage therapies in greater detail.

Many patients with ARDS develop significant dependent atelectasis that contributes to gas exchange abnormalities. Prone ventilation is thought to benefit such patients by eliminating this atelectasis and, as a result, improving ventilation-perfusion matching. Other purported benefits include improvements in respiratory mechanics and secretion clearance, increased end-expiratory volume and decreased mechanical compression of the lungs by the heart. Multiple studies have shown that the technique does improve oxygenation in ARDS patients, although the observed changes vary in magnitude between individuals, often take several hours to occur and may wane over time. Variable responses have also been observed when patients are returned to the supine position, with some patients returning to basal supine oxygenation and others showing sustained improvements. (2)

Despite the improvements in oxygenation, there are still no data demonstrating improvements in mortality. Earlier randomized controlled trials, (3, 4) which failed to show a mortality benefit, were criticized due to the short duration of proning and high tidal volumes employed in the studies. A more recent trial, (5) in which patients were proned for an average of 17 hours per day, showed a trend toward decreased mortality but this result was not statistically significant and the mortality rate in the proned group (43%) was still higher than those reported for low tidal-volume ventilation in the ARDSnet trial (30%). In considering the utility of proning as salvage therapy in patients with critical hypoxemia, it is important to note that the trials mentioned above examined ARDS patients across a broad range of severity and did not focus solely on those patients with critical hypoxemia. As a result, we still lack information about the benefits of the technique in patients requiring salvage therapies due to very severe ARDS.

In considering whether to prone patients with critical hypoxemia, several important logistical issues must be considered. The technique is time and labor intensive and may be particularly difficult to implement in obese individuals, one of the groups noted to develop critical hypoxemia in the current novel influenza outbreak. In addition, access to the patient is impaired and patients are at increased risk for pressure sores, aspiration events and accidental discontinuation of lines and tubes. Of particular note is the fact that cardiopulmonary resuscitation is difficult, if not impossible, to perform with the patient in the prone position, a fact which will limit application of the technique to those patients who are hemodynamically stable and not at risk for imminent cardiac arrest. Patients with elevated intracranial pressure have generally been excluded from most of the trials on prone positioning due to concerns that the prone position will worsen intracranial hypertension, although a recent non-randomized pilot study of 11 patients with traumatic brain injury or intracerebral hemorrhage demonstrated improvements in arterial oxygenation without significant change in intracranial or cerebral perfusion pressure during a 3 hour period of prone positioning. (6)

Many of the logistical issues can be addressed using specialized beds, such as the RotoProne® system, which obviate the need for staff help in turning the patient and include devices to secure lines and tubes as well as a mechanism by which the patient can be rapidly moved to the supine position in the event of a cardiac arrest or hemodynamic instability. The beds are very large and bulky, however, and access to the patient through all of the padding and support mechanisms is still challenging, particularly for procedures such as central line placement or cardiopulmonary resuscitation. Because these beds are also costly to rent and are in limited supply in certain regions, less expensive alternative systems, such as the Vollman Proner® are available for purchase that allow the patient to remain in their original bed, contain pads to support the head, chest and pelvis while allowing free suspension of the abdomen, and providing access to lines and tubes. These systems do still require staff assistance to rotate the patient and, in some cases, can only support patients weighing < 300 lbs, (136 kg) which may limit their utility in very obese patients.

Recruitment maneuvers involve intentional, short-term use of high transpulmonary pressures in an effort to open atelectactic lung units and increase end-expiratory lung volume. The goals of these maneuvers are to improve gas exchange and limit ventilator-induced lung injury by preventing the repetitive opening and closing of alveoli in these atelectactic regions. The available data demonstrate that these various techniques do, on average, improve oxygenation. However, no studies have demonstrated improvements in mortality and, of particular note, the benefits are not sustained over time; oxygenation declines anywhere from minutes to hours following completion of the maneuver and increased levels of PEEP may be necessary to sustain the observed improvements.

Because of the lack of clear, sustained benefits, these maneuvers should not be used in all patients with severe hypoxemia and, instead, should be used on a more selective basis in patients with evidence of significant dependent atelectasis on chest imaging. In those cases where recruitment maneuvers are thought to be of possible benefit, there are a variety of different techniques that can be used for this purpose. In some of the studies, for example, patients underwent sustained inflation at increased pressure (eg. 30-45 cm H₂O) for periods of 20-30 seconds, (7, 8) while in others patients were treated with transient high levels of pressure-control ventilation, (9) intermittent sighs at high distending pressures (10) or incremental increases in PEEP over a period of several minutes. (11) The specific protocols are described in greater depth in each of the studies. Unfortunately, it is difficult to determine which of these possible strategies is best for the patient with critical hypoxemia; no studies have compared the different recruitment maneuvers with each other and, as a result, we lack information about their relative effects on oxygenation or the sustainability of any observed improvements.

For those clinicians who do opt to use recruitment maneuvers, a key concern is whether the use of high transpulmonary pressures might predispose patients to complications such as barotrauma and hypotension. The available data suggest, however, that the protocols are, in fact, safe to implement. A recent systematic review of trials using the various techniques (12) revealed that transient hypotension and desaturation are the most common complications, occurring in 12% and 8% of cases, respectively, while more serious adverse events, such as barotrauma and arrhythmia, were uncommon, each occurring in only 1% of patients undergoing the various techniques.

Table 1.
Changes in Oxygen Delivery with Manipulation of Different Parameters

The values in this table are for a hypothetical patient with impaired cardiac output, anemia and hypoxemia at baseline. A 33% increase in either cardiac output or hemoglobin concentration increases oxygen delivery more than a corresponding 33% increase in the P_aO₂.

References

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2. Gattinoni, L., F. Valenza, P. Pelosi, and D. Mascheroni. 2006. Prone positionining in acute respiratory failure. In M. J. Tobin, editor. Principles and Practice of Mechanical Ventilation, 2nd ed. McGraw-Hill, New York. 1081-1092.
3. Guerin, C., S. Gaillard, S. Lemasson, L. Ayzac, R. Girard, P. Beuret, B. Palmier, Q. V. Le, M. Sirodot, S. Rosselli, V. Cadiergue, J. M. Sainty, P. Barbe, E. Combourieu, D. Debatty, J. Rouffineau, E. Ezingeard, O. Millet, D. Guelon, L. Rodriguez, O. Martin, A. Renault, J. P. Sibille, and M. Kaidomar. 2004. Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial. Jama 292(19):2379-87.
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6. Thelandersson, A., A. Cider, and B. Nellgard. 2006. Prone position in mechanically ventilated patients with reduced intracranial compliance. Acta Anaesthesiol Scand 50(8):937-41.
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8. Brower, R. G., A. Morris, N. MacIntyre, M. A. Matthay, D. Hayden, T. Thompson, T. Clemmer, P. N. Lanken, and D. Schoenfeld. 2003. Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure. Crit Care Med 31(11):2592-7.
9. Gattinoni, L., P. Caironi, M. Cressoni, D. Chiumello, V. M. Ranieri, M. Quintel, S. Russo, N. Patroniti, R. Cornejo, and G. Bugedo. 2006. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 354(17):1775-86.
10. Pelosi, P., P. Cadringher, N. Bottino, M. Panigada, F. Carrieri, E. Riva, A. Lissoni, and L. Gattinoni. 1999. Sigh in acute respiratory distress syndrome. Am J Respir Crit Care Med 159(3):872-80.
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The ATS is providing this information about salvage therapies that are available as a resource for those interested in this information, but it is important to note that none of these therapies have been shown to improve survival for patients with ALI/ARDS and that the ATS is not recommending the use of these therapies.