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rescue therapy such as prone-position ventilation, high-frequency ventilation, or inhaled nitric oxide.

Thus, despite four large, well-designed, randomized prospective studies, we still do not know what defines an optimal PEEP setting or whether higher PEEP provides any substantial survival benefits. It is important to recognize that the conflicting observations of the aforementioned studies may be related to inaccuracy of diagnosis of ALI and ARDS between study subjects due to the somewhat arbitrary consensus criteria of PaO2/FiO2 ratios and chest radiographic changes. Also, heterogeneity within the study populations in the type of ARDS (e.g. “sticky” non-recruitable vs. “loose” recruitable) that was present may have accounted for the variable responses to higher and lower PEEP settings [32, 40, 47].

At present, the recommendations of Gattinoni, et al. [37] to set PEEP at the highest level possible to maintain a plateau pressure between 28 to 30 cmH2O on a tidal volume of 6 mL/kg PBW have the most practical benefit to patients [47]. Again, in the unique case of burn patients with compromised thoracoabdominal compliance, higher pressure limits may be necessary. For example, transpulmonary end-ex- piratory pressure as estimated by an esophageal balloon catheter has been found to be substantially less than the set PEEP at the airway opening in some critically ill patients [48].

Lung recruitment maneuvers

A recruitment maneuver is an attempt to open atelectatic alveoli by deliberately applying an elevated transpulmonary pressure to these alveoli for a short duration. This may be achieved by application of transient continuous positive airway pressure (40 cmH2O for twenty to forty seconds). In ALI and ARDS the challenge is to apply enough pressure during a lung recruitment maneuver to open atelectatic alveoli but not too much pressure that would overstretch and damage alveoli that are already fully open [40]. The amount of pressure needed to re-open an alveolus is greater than the amount of pressure needed to keep it open and prevent re-collapse. Thus, it is usually necessary to apply lung recruitment maneuvers transiently and intermittently and to maintain (or more usually) increase PEEP be-

tween the recruitment maneuver so as not to lose recruited alveoli [40]. The best pressure duration and frequency of recruitment maneuvers is unknown at this time, however. Also, the safety of this intervention has not been rigorously assessed and potential complications include transient hypotension, oxygen desaturation, and barotrauma.

Unconventional mechanical ventilation strategies

High-frequency percussive ventilation (HFPV)

Conventional mechanical ventilation does not address many of the pathophysiologic derangements that follow a smoke inhalation injury. These include

(1) plugging of the small airways with sloughed mucosa and fibrin cast which causes progressive CO2 retention, impaired oxygenation, and ventilation perfusion mismatch, (2) potentially injurious elevation of airway pressures due to the combined effects of bronchospasm and diminished lung and chest wall compliance and (3) small airway obstruction leading to atelectasis and then pneumonia.

High-frequency percussive ventilation (HFPV), which utilizes intra-pulmonary percussion and high-frequency sub-tidal volume breaths, appears to be ideally suited for mechanical ventilation of burn patients with significant smoke inhalation injuries. Indeed, early animal studies using a primate model of smoke inhalation injury found that HFPV was beneficial both in terms of oxygenation as well as minimization of VILI [49]. HFPV is delivered using the Volume Diffusive Respirator (VDR). This is a pneumatically-driven, time-cycled and pressurelimited ventilator which utilizes a sliding Venturi valve which stacks breaths to achieve a desired inspiratory pressure, and then releases them for passive exhalation. The high-frequency breaths have a sub-dead space tidal volume and are delivered at frequencies (the pulse frequency or percussive rate) between 60 and 900 breaths per minute (1–15 Hz). The high-frequency breaths are stacked in a stepwise pattern and then are periodically interrupted to allow airway pressure to return to a set baseline continuous positive airway pressure (baseline or demand CPAP). This creates what is analogous to a

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conventional mechanical breath such that the high frequency breaths are superimposed on a conventional respiratory rate (the phasic rate) which is generally initially set at one half to one third of a conventional ventilation frequency (Fig. 3a).The duration of the percussive phase and the baseline phase are manipulated to affect oxygenation and CO2 removal. Peak airway pressure can also be adjusted to help control CO2 removal. The I:E ratio of the high frequency breaths can be adjusted to produce a more diffusive flow (low I:E ratio), or a more predominately percussive flow wave (high I:E ratio). The amplitude of the sub-tidal breath can also be adjusted to affect peak airway pressure.

The percussive nature of this mode of ventilation is its most important feature as it promotes loosening and mobilization of secretion and airway debris. This mucokinetic effect is optimized by the fact that the endotracheal tube balloon cuff is left deflated to allow mobilization of secretions. This, in addition to HFPV’s potential to improve oxygenation at lower airway pressure than CMW makes it useful for burn patients with significant smoke inhalation injury. However, while HFPV is well established in the armamentarium of ventilation strategies for smoke inhalation injury, the existing studies on HFPV do not provide a clear answer as to whether these potential benefits of HFPV have been uniformly achieved.

The early studies of HFPV conducted in the late 1980s and 1990s were retrospective with either no control groups [50–51] or used contemporaneous or historical controls [52–55]. The largest of these, by Cioffi et al. [52] assessed 54 adults admitted within 48 hours of injury with either bronchoscopy or xenon lung-scan confirmed inhalation injury who were placed on HFPV within one hour of burn centre admission. The incidence of pneumonia was 26% which was significantly lower than the rate in a historical cohort (46%). Similarly, mortality was significantly lower than that which would have been estimated from predictive model using a historical cohort. The other studies from this era generally found that HFPV resulted in improved oxygenation, lower peak airway pressures, less barotrauma, and a reduced incidence of pneumonia [51, 53–55]. However, these studies should be interpreted with caution because of their retrospective nature and differing indications for institution of HFPV and entry of

patients with differing degrees of respiratory failure. Also, comparisons were made with control patients ventilated with CMV strategies that allowed high tidal volumes and high inflation pressures which probably would not be acceptable by today’s standards.

Two randomized prospective studies have compared HFPV to CMV as acute ventilation strategies for patients which smoke inhalation (Table 5)[56, 57]. The first, in children [56], found that HFPV produced significantly better oxygenation at lower peak airway pressures than conventional pressure-controlled ventilation. However, both groups had P2O2/FiO2 ratios above 500 suggesting that neither group was experiencing severe or even moderate respiratory insufficiency. The second study, in adults with smoke inhalation [57] also found that HFPV produced significantly better oxygenation during the first three days of use than conventional volume-controlled ventilation but oxygenation was then equivalent between the groups on days four and five post-burn. Of note was that the CMV strategy which used tidal volumes of 10 mL/kg would now be considered an aggressive and potentially lung injurious strategy and may have been the reason that HFPV produced superior oxygenation. Neither study was able to demonstrate any significant differences in the incidence of pneumonia or in the mortality rate.

The most recent (and the largest) study of HFPV was a retrospective review of 92 adults (62 with bronchoscopy confirmed inhalation injury) ventilated with HFPV, compared to 130 contemporary controls (49 with bronchoscopy-confirmed inhalation injury) placed on CMV [58]. There was a change in CMV strategy during the study in which tidal volumes of 10 mL/kg were reduced to 6 ml/Kg and plateau pressures were limited to less than 35 cmH2O in keeping with ARDS Net guidelines. Also, patients in the HFPV group received nebulized Heparin-NAC whereas those on CMV did not. No significant differences were found between CMV and HFPV in ventilator days, length of stay, or incidence of ventilator associated pneumonia but there was significantly higher mortality in the CMV group.

In summary, a large amount of retrospective data suggests the use of HFPV in inhalation injury is associated with improved oxygenation at lower airway pressures, less occurrence of pneumonia and improved survival. However, the reliability of these

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Table 5. Randomized prospective studies which have compared conventional mechanical ventilation (CMV) with High Frequency Percussive Ventilation (HFPV) using the Volume Diffusive Respirator (VDR) for acute burns and smoke inhalation

Study	Design	N	Patient selection	Interventions	Outcomes
Carmen	Prospective	64	Pediatric	CMV with PCV at 6–8 mL/	mean PaO2/FiO2 ratio/peak
et al.	Randomized		Mean burn size 56% TBSA	kg, PEEP 4–6 cmH20	airway pressure was 507/40
[56]			86% with I I	VDR with frequency	on CMV Vs. 563/31 on VDR
				200–360/min, oscillatory	(p > 0.05)
				CPAP/PEEP 5–10 cm H20,	no differences between
				and demand CPAP/PEEP	groups in duration of MV,
				8–10 cm H20	barotraumas, pneumonia,
					or survival
Reper	Prospective	35	Adults	CMV was VCV using tidal	Significantly higher PaO2/
et al.	Randomized		burns > 20% TBSA	volume 10 mL/kg	FiO2 ratio over 1st 3 days in
[57]			requiring acute	HFPV using frequency of	HFPV Vs CMV.
			ventilator support	600–800/min	No differences in pulmonary
			15/17 bronchoscope-con-		infections or survival
			firmed I I in CMV group;		between groups.
			16/18 in HFPV group

I I: inhalation injury, PCV: pressure controlled ventilation, VCV: volume controlled ventilation, CPAP: continuous positive airway pressure, PEEP: positive end expiratory pressure, MV: mechanical ventilation

findings is limited by biases inherent in retrospective analyses, variations in indications for initiation for HFPV, varying severity of respiratory dysfunction in the study subjects, and variations in the CMV strategies utilized. The existing randomized prospective studies found only that HFPV resulted in better oxygenation than the accepted CMV modes of the day. A current randomized prospective study comparing HFPV to the best lung protective CMV strategies currently available (which would feature low tidal volume and pressure limited strategies with an open lung approach) is needed.

High-frequency oscillatory ventilation

High-frequency oscillatory ventilation (HFOV) is an unconventional form of mechanical ventilation which has been used for the past two decades in the neo-natal intensive care unit for respiratory distress syndrome. Recognition of HFOVs lung-protective properties combined with sound physiologic evidence with its ability to open and recruit the lung, have lead to translation of HFOV to the adult ICU, for patients with acute respiratory distress syndrome.

HFOV uses extremely small tidal volumes (1–2 mL/kg) at high frequencies (3–15 Hz), com-

bined with application of a relatively high sustained mean airway pressure (30–40 cmH2O). The key difference between CMV and HFOV is demonstrated in Fig. 3(b) Primarily, oxygenation is achieved by using the elevated and sustained mean airway pressure to achieve highly effective recruitment of the available lung (i. e. increased total lung volume) [59–62]. Alveolar ventilation is mainly related to the frequency of ventilation which is inversely related to the tidal volume (i. e. higher frequency = lower tidal volume, lower frequency = larger tidal volume) and is relatively independent of total lung volume [59, 60]. Hence, oxygenation and ventilation are essentially uncoupled and can each be controlled independent of the other [59, 60]. HFOV is currently delivered using the SensorMedics 3100B High Frequency Oscillatory Ventilator (the “adult oscillator”).

Numerous animal studies have found HFOV to produce less VILI than CMV [63–67]. HFOV ventilates the lung in a relatively restricted “safe window” avoiding excursion both into the zone of alveolar over distention (volutrauma) at high tidal volume and high inflation pressures as well as the zone of alveolar de-recruitment (atelectrauma) at insufficient pressures [68]. The very small tidal volumes during HFOV limit alveolar stretch even at higher airway pressures because the incremental expansion of the

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alveolus with each inspiration is still quite small. The use of such small tidal volumes then allows application of a higher sustained mean airway pressure which opens and recruits the lung to prevent atelectrauma in many groups of alveoli that would otherwise be subject to repetitive collapse and re-opening. The lung recruitment directly improves oxygenation allowing use of a lower FiO2 thus limiting oxygen toxicity.

HFOV has been widely reported as a rescue strategy for oxygenation crisis in adults with ARDS arising from critical illness and trauma [70 –74]. The main combined findings from these studies were that HFOV is safe with relatively low rates of barotraumas, and that it produces rapid and sustained correction of oxygenation failure when used as a rescue strategy. The improved oxygenation is usually achieved at a lower mean airway pressure “cost”. The improved oxygenation is not related to improved survival and no conclusions on HFOV is effect on mortality can be reached from these studies. Two randomized controlled trials [75, 76] have compared HFOV with CMV in adults with ARDS. Neither of these studies raised any important safety concerns but, importantly, neither showed any definite advantage of HFOV over CMV. HFOV may not have been optimally applied in these studies (lung recruitment maneuvers were not used, frequency may have been set too low and conversion to CMV may have been premature). Also, the control arms CMV strategy may not have been optimally lung protective. In summary, the existing randomized controlled trials of adult HFOV are inconclusive. The need for a larger randomized controlled trial of optimum HFOV against the best protective CMV strategy of the day is being addressed by the multi-centre OSCILLATE trial (Ferguson and Mead) which is currently in progress. A small body of research has reviewed the use of HFOV in burn patients with ARDS [77–79]. The main conclusions were as follows:

HFOV produced rapid and sustained improve-

ments in the PaO2/FiO2 ratio and oxygenation index for patients in extreme oxygenation crisis. As such, it is particularly useful as a rescue strategy for severe oxygenation failure. HFOV could be used as an intra-operative ventilation technique to allow sustained use of this ventilation strategy

and simultaneously satisfy the priority of serial burn wound excision and closure. Patients with ARDS who had sustained a smoke inhalation injury had a delayed and blunted oxygenation improvement compared to patients with no smoke inhalation injury. This was attributed to the classic small airway obstruction and gas-trapping characteristic of smoke inhalation injury which prevented alveolar recruitment through HFOV’s sustained mean airway pressure. Therefore, HFOV may not be an optimal rescue strategy for oxygenation crisis if there is a prior smoke inhalation injury.

HFOV potentially interferes with other important adjunctive therapies for smoke inhalation such as secretion clearance by suctioning and bronchoscopy and delivery of nebulized agents such as Heparin and NAC.

Airway pressure release ventilation (APRV)

APRV is a relatively new mode of ventilation which is being increasingly used as a ventilation strategy for patients with ALI and ARDS. Patients breathe spontaneously during this pressure-regulated and timecycled mode of ventilation. A high continuous air-

way pressure (the Phigh) is set by the clinician, and then pressure is periodically released to a lower set

continuous airway pressure (the Plow). The patient

breathes spontaneously at both Phigh and at Plow throughout this repetitive cycling of continuous air-

way pressure. The Phigh represents and inspiratory phase, and the Plow represents a release phase. The

level and duration of Phigh is used to affect oxygenation. Lung recruitment is achieved by using longer

and more frequent periods at Phigh. Clearance of CO2 is exchanged during the release phase [80–82]

(Fig. 3c).

The most important benefit of APRV is that it allows spontaneous breathing by the patient. The advantages of spontaneous breathing include the reduction in need for sedation, avoidance of paralytic agents, improved recruitment of atelectatic lung, improved venous return and cardiac output, and better diaphragmatic movement [80–82]. At the present time there are no prospective studies on APRV for burn /smoke inhalation patients or patients with ARDS. Some limited data in burn patients with

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