Mechanical Ventilation

One of the most hotly debated aspect of inhalation injury is the “best” method of mechanicalventilation. Mechanical ventilation protocols differ between both physicians and burn centers,and multiple different strategies for mechanical ventilation are currently being used to supportthe burn patient with inhalation injury. These strategies range from applying recent advances inacute respiratory distress syndrome to conventional mechanical ventilation to the use of alterna-tive modes of ventilation such as the volumetric diffusive respirator. The articles in this sectiondescribe recent changes in philosophy with respect to mechanical ventilation, the various modesof ventilation being used to support the patient with inhalation injury, and the rationale behindeach strategy. (J Burn Care Res 2009;30:172-183)

Low-Tidal-Volume Ventilation as a Strategy toReduce Ventilator-Associated Injury in ALIand ARDS

Michael D. Peck, MD, ScD, Tammy Koppelman, MD

Smoke inhalation injury follows the breathing in oftoxic smoke from the incomplete combustion ofburning materials such as fabrics, plastics, synthetics,and building materials. Acute lung injury (ALI) de-scribes the acute onset of impaired oxygen exchangethat results from smoke inhalation, and is character-ized by an alveolar-arteriolar gradient of less than300. Severe cases of ALI are termed acute respiratorydistress syndrome (ARDS), defined by an alveolar-arteriolar gradient of less than 200.1 Radiographs ofthe chest show the presence of bilateral alveolar orinterstitial infiltrates; yet there is no evidence of leftheart failure to account for the presence of pulmonaryedema.

When the severity of oxygen exchange becomesmore impaired, the associated risk of mortality fromALI/ARDS rises, and has been reported as high as 40to 50%.2 Mortality from ALI/ARDS may be due di-

rectly to respiratory failure and inability to oxygenatesufficiently, or it may result from associated multisys-tem organ failure or ventilator-associated pneumo-nia. In addition, patients become ventilator depen-dent and length of stay in intensive care units isincreased.3 Reduced health care quality of life, in-creased disability, and cognitive impairment arenoted in long-term survivors.4

ALI and ARDS are characterized by diffuse alveolardamage caused by increased permeability of the peri-alveolar capillary endothelia. Protein-rich fluid leaksfrom the intravascular space into the extravascularspace, from which it diffuses into the alveoli. Similarto the accumulation of plasma-like fluid in the al-veoli that results from an elevation in hydrostaticpressure within the pulmonary veins with left heartfailure, this noncardiogenic pulmonary edema hasits origin in systemic diseases, such as sepsis, pan-creatitis, and drug toxicity, and in inflammatorystates secondary to trauma or aspiration. For exam-ple, the toxins adsorbed onto alveolar surfaces frominhaled smoke diffuse across the alveolar-arteriolarspace and result in widening of cell-to-cell contactin the vascular endothelium.

Cytokine release is also a feature of ALI/ARDS.Macrophages and neutrophils accumulate in thealveolar-arteriolar interstitium, and inflammatory cy-

From the Department of Surgery, Maricopa Integrated HealthSystem, Phoenix, Arizona.

This study was supported by Shriners Hospital for Children Grant#8431.

Address correspondence to Michael D. Peck, MD, ScD, ArizonaBurn Center, Phoenix, Arizona 85008.

Copyright © 2009 by the American Burn Association.1559-047X/2009

DOI: 10.1097/BCR.0b013e3181923c32

172

tokines are released, adding to the local damage doneby toxins in the smoke. As the cytokines pour intosystemic circulation, they can contribute to multisys-tem organ failure, seen commonly with ARDS.5,6 Ad-ditionally, hyaline membranes form in the alveoli, andsurface tension is altered because of damages in sur-factant production, leading to alveolar collapse.

Because of the severe impairment in gas exchange(primarily oxygen exchange, but also involving car-bon dioxide elimination eventually) and because ofloss of pulmonary compliance due to accumulation ofintra- and peri-alveolar fluid, endotracheal intubationand mechanical ventilation are necessary for survival.Twenty years ago, the goal of ventilatory support wasto normalize arterial blood gases, bringing pH asclose as possible to 7.4 and keeping oxyhemoglobinsaturation above 95%. This was accomplished usinghigh concentrations of inspired oxygen and highminute ventilations delivered by volume-controlledventilators. Tidal volumes of 10 to 15 ml/kg werenot unusual, rationalized by the need for increasedrecruitment of collapsed alveoli.

Treatment of Ventilator-Induced Lung InjuryWith Low Tidal VolumesUnfortunately, this approach may have violated theinjunctive, first do no harm (primum non nocere).Ventilator-induced lung injury (VLI) is associatedwith hyperinflation of normal regions of aerated lungbecause of high tidal volumes. Alveolar rupture andaccumulation of extra-alveolar air (barotraumas) re-sult from higher inflating pressures. Because compli-ance in poorly aerated regions of diseased lung is low,the rapid cyclic inflation–deflation of normal, inflatedalveoli in continuity to the collapsed alveoli createshigh shear forces. Additionally, the overexpansion ofnormal alveoli leads to high transpulmonary pressuresin the aerated regions, making them susceptible todirect physical damage, including disruption of alve-olar epithelia and capillary endothelia. The flood ofcytokines both locally and systemically may also beincreased as the inflammatory response is aggravated.

Data from animal studies led to the recommenda-tion of reduction in plateau pressures of 35 cm ofwater to lessen the contribution of VLI to the alteredphysiology of ALI and ARDS. This reduction in peaktranspulmonary pressures was accomplished by in-creasing positive end-expiratory pressure (PEEP) anddecreasing tidal volume. The consequent reduction inminute ventilation mandated acceptance of some de-gree of hypercapnia, popularized as permissive hyper-capnia.7 This recommendation led to a series of clinicaltrials in the search for evidence to support the claim ofbenefit of lung-protective ventilation strategy. How-

ever, severe hypercapnia and respiratory acidosis are notwithout risk. Adverse effects include increase inintracranial pressure, diminished myocardial con-tractility, pulmonary hypertension, and diminishedrenal blood flow. For certain critically ill patients,therefore, permissive hypercapnia may be relatively con-traindicated. Despite this, multiple studies have shownthat modest permissive hypercapnia is safe.8,9,10

Meta-analysis of these trials was conducted recentlyby the Cochrane Anesthesia Review Group.11 Theobjective of this review was to study the effect ofventilation with lower tidal volumes on morbidityand mortality of critically ill adults with either ALI orARDS. Only randomized, controlled trials with guar-antees of no selection bias were selected. Out of 10studies of potential relevance, six were included forthe final analysis.12–17 Mortality at day 28 in 1030patients in three studies12–14 showed a distinct pro-tective advantage of a ventilation strategy using tidalvolume less than 7 ml/kg of measured body weightand plateau pressure less than 31 cm water (Table 1).Duration of mechanical ventilation was also lower in288 patients studied in three studies.14,15,17

Reduction in mortality correlated directly with themagnitude of difference in tidal volume between thecontrol and treatment groups. Studies in which dif-ferences in mean tidal volume between the twogroups were in the range of 2.9 to 3.7 ml/kg14,15,17

showed less protection of low-tidal-volume ventila-tory strategy than did trials in which the differences

Table 1. Ventilator procedures according to ARDSNettrial13

Volume assist-control mode with volumes based on predictedweight*

Initial tidal volume 6 ml/kg of predicted weightReduced by 1 ml/kg until plateau pressure† �30 cm H2O;

minimum tidal volume � 4 ml/kgIf plateau pressure �25 cm H2O, increase tidal volume by

1 ml/kg until either plateau pressure �25 cm H2O ortidal volume � 6 ml/kg

Management of respiratory acidosisIf pH �7.30, increase respiratory rate to maximum 35

breaths per minuteIf pH �7.30 and respiratory rate 35 breaths per minute,

consider bicarbonate infusionIf pH �7.15, increase tidal volume even if plateau

pressures exceed 30 cm H2OSedation strategies should be used that are recommended for all

critically ill, mechanically ventilated patients

* Predicted weight of males � 50 � 0.91 (height in cm—152.4); predictedweight of females � 45.5 � 0.91 (height in cm—152.4).† Plateau pressure measured at 0.5 seconds after peak inspiration (inspiratorypause).

Journal of Burn Care & ResearchVolume 30, Number 1 Peck and Koppelman 173

between tidal volumes ranged from 4.9 to 5.6 ml/kg.12,16 Moreover, the two studies showing the high-est protective value of low-tidal-volume ventilationalso calculated delivered tidal volume based on pre-dicted, rather than measured, patient weight.12,13 Be-cause predicted weight is approximately 25% lower thanmeasured weight, the magnitude in difference betweencontrol and treatment group tidal volumes would beeven greater if expressed in ml per kg measured weight.

Adjunctive Tactics inLung-Protective StrategiesBecause many of these studies utilized increases in PEEPtoensuresatisfactoryoxygenationduringreduction intidalvolumes, subsequent studies focused on whether someof the protective benefit was from higher levels ofPEEP. The ARDS Network performed a multicenter,randomized, prospective clinical trial (ALVEOLI trial�assessment of low-tidal-volume and elevated end-expiratory pressure to obviate acute lung injury�).18

All patients with ALI or ARDS were treated with 6ml/kg predicted body weight tidal volumes, and ran-domized to either low (5 cm H2O up to 24) or high(12 cm H2O up to 24) PEEP. On day 1, the differ-ence in mean PEEP between the two groups was 5.8cm H2O (8.9 � 3.5 vs 14.7 � 3.5 cm H2O). Al-though elevated PEEP theoretically confers the ad-vantage of maintaining recruitment of alveoli duringend expiration of smaller tidal volumes, the ALVEOLItrial showed no effect of higher levels of PEEP onduration of mechanical ventilation, duration of non-pulmonary organ failure, and in-hospital mortality.Similarly, lack of beneficial effect of high PEEP waspreviously noted in smaller clinical studies.12,16

Additionally, prone positioning has been proposed tobe an adjunct in the treatment of hypoxemia associatedwith ARDS. Placement of the patient with ARDS in theprone position improves oxygenation via alveolar re-cruitment, redistribution of ventilation toward dorsalareas (improving ventilation/perfusion matching),and elimination of compression of the lungs by theheart.19–22 However, prospective, randomized stud-ies of prone positioning during mechanical ventila-tion in ARDS have shown consistently that althoughoxygenation is transiently improved, there is no re-duction in mortality.23–25 Nonetheless, prone posi-tioning may be valuable as rescue therapy in patientswith potentially injurious levels of inspired oxygencontent or plateau pressures.26 Prone positioningshould only be used with extreme caution because oflife-threatening complications such as endotrachealtube dislodgement or obstruction.

CONCLUSIONS

Significant advances in mechanical ventilation strategiesin ARDS have been developed in the past 2 decades, themajority of which are designed to decrease VLI. How-ever, how these advances should be applied to patientswith inhalation injury is less clear. The challenge for theburn professional is to determine when and how to ap-ply these strategies to the patient with smoke inhalationinjury.

REFERENCES

1. Bernard GR, Artigas A, Brigham KL, et al. Report of theAmerican-European Consensus conference on acute respi-ratory distress syndrome: definitions, mechanisms, rele-vant outcome, and clinical trial coordination. J Crit Care1994;9:72–81.

2. Lewandowski K. Epidemiological data challenge ARDS/ALI. Intensive Care Med 1999;25:884–6.

3. Davidson TA, Caldwell ES, Curtis JR, Hudson LD, Stein-berg KP. Reduced quality of life in survivors of acute respira-tory distress syndrome compared with critically ill controlpatients. JAMA 1999;281:354–60.

4. Dowdy DW, Eid MP, Dennison CR, et al. Quality of life afteracute respiratory distress syndrome: a meta-analysis. IntensiveCare Med 2006;32:1115–24.

5. Slutsky AS, Tremblay LN. Multiple system organ failure: ismechanical ventilation a contributing factor? Am J Respir CritCare Med 1998;157:1721–5.

6. Dreyfuss D, Saumon G. From ventilator-induced lung injuryto multiple organ dysfunction? Intensive Care Med 1998;24:102–4.

7. Slutsky AS. Mechanical ventilation: American College of ChestPhysicians’ Consensus Conference. Chest 1993;104:1833–59.

8. Hickling KG, Walsh J, Henderson S, Jackson R. Low mor-tality rate in acute respiratory distress syndrome using low-volume, pressure-limited ventilation with permissivehypercapnia: a prospective study. Crit Care Med 1994;22:1568–78.

9. Laffey JG, O’Croinin D, McLoughlin P, Kavanagh BP. Per-missive hypercapnia: role in protective lung ventilatory strat-egies. Intensive Care Med 2004;30:347–56.

10. Bidani A, Tzouanakis AE, Cardenas VJ, Zwischenberger JB.Permissive hypercapnia in acute respiratory failure. JAMA1994;272:957–62.

11. Petrucci N, Iacovelli W. Lung protective ventilation strategyfor the acute respiratory distress syndrome. Cochrane Library2007;3:CD003844.

12. Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of aprotective-ventilation strategy on mortality in the acute respira-tory distress syndrome. N Engl J Med 1998;338:347–54.

13. ARDS Network. Ventilation with lower tidal volumes ascompared with traditional tidal volumes for acute lung injuryand the acute respiratory distress syndrome. N Engl J Med2000;342:1301–8.

14. Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal vol-ume reduction for prevention of ventilator-induced lung in-jury in the acute respiratory distress syndrome. Am J RespirCrit Care Med 1998;158:1831–8.

15. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of aventilation strategy to prevent barotrauma in patients at highrisk for acute respiratory distress syndrome. Pressure- andVolume-Limited Ventilation Strategy Group. N Engl J Med1998;338:355–61.

16. Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. Ahigh positive end-expiratory pressure, low tidal volume ven-tilatory strategy improves outcome in persistent acute respi-

Journal of Burn Care & Research174 Peck and Koppelman January/February 2009

ratory distress syndrome: a randomized, controlled trial. CritCare Med 2006;34:1311–8.

17. Brower RG, Shanholtz CB, Fessler HE, et al. Prospectiverandomized, controlled clinical trial comparing traditional vs.reduced tidal volume ventilation in ARDS patients. Crit CareMed 1999;27:1492–8.

18. ARDS Network. Higher versus lower positive end-expiratorypressures in patients with the acute respiratory distress syn-drome. N Engl J Med 2004;351:327–36.

19. Guerin C, Badet M, Rosselli S, et al. Effects of prone positionon alveolar recruitment and oxygenation in acute lung injury.Intensive Care Med 1999;25:1222–30.

20. Mutoh T, Guest RJ, Lamm WJ, Albert RK. Prone positionalters the effect of volume overload on regional pleural pres-sures and improves hypoxemia in pigs in vivo. Am Rev RespirDis 1992;146:300–6.

21. Richard JC, Janier M, Lavenne F, et al. Effect of position,

nitric oxide, and almitrine on lung perfusion in a porcinemodel of acute lung injury. J Appl Physiol 2002;93:2181–91.

22. Albert RK, Hubmayr RD. The prone position eliminatescompression of the lungs by the heart. Am J Respir Crit CareMed 2000;161:1660–5.

23. Gattinoni L, Tognoni G, Pesenti A, et al. Effect of pronepositioning on the survival of patients with acute respiratoryfailure. N Engl J Med 2001;345:568–73.

24. Guerin C, Gaillard S, Lemasson S, et al. Effects of systematicprone positioning in hypoxemic acute respiratory failure: arandomized controlled trial. JAMA 2004;292:2379–87.

25. Mancebo J, Fernandez R, Blanch L, et al. A multicenter trialof prolonged prone ventilation in severe acute respiratorydistress syndrome. Am J Respir Crit Care Med 2006;173:1233–9.

26. Girard TD, Bernard GR. Mechanical ventilation in ARDS: astate-of-the-art review. Chest 2007;131:921–9.

Volumetric Diffusive VentilatorDavid Harrington, MD, FACS

Following an airway and parenchymal injury such asinhalation injury, an ideal ventilator would apply lowpeak airway pressures, facilitate clearance of soot,sloughed mucosa and secretions, and recruit col-lapsed airways. The Volume Diffusive Respirator(VDR), which has been utilized for the managementof burn patients with inhalation injury since the mid1980s, has these abilities. It is a pneumatically pow-ered, pressure limited ventilator that stacks oscillatorybreaths to a selected peak airway pressure by means ofa sliding venturi called a phasitron. After inspiration,exhalation is passive and ends at a selected level ofoscillatory CPAP. A retrospective analysis comparingthe VDR ventilator to conventional volume ventila-tion, in patients with similar distribution of age andburn sizes, revealed a decreased rate of pneumoniaand mortality in those patients ventilated with theVDR.1 The beneficial effects of this ventilator havebeen confirmed in other burn centers clinically and ina primate model of inhalation injury.2,3 The VDRventilator also reestablishes normal gas exchange inthat it returns gas exchange to a predominately diffu-

sive process. Standard ventilatory strategies such aspressure-control ventilation (PCV) and volume-control ventilation predominately employ convec-tive gas exchange. Reestablishing diffusive ventilationallows for the use of lower airway pressures to venti-late patients as shown in a recent prospective, ran-domized comparison of the VDR with PCV inburned children with inhalation injury.4 Similar find-ings of lower airway pressures and improved survivalwith the VDR in comparison to PCV were found in a7 day LD100 sheep model of smoke/burn injury.5

The adoption of VDR in many burn centers for thetreatment of inhalation injury preceded the strategyof low-pressure, low-volume ventilation for AcuteRespiratory Distress Syndrome that received widepublication in the New England Journal of Medicinein 1998 and 2000.6,7 The VDR was the original low-volume ventilatory strategy.

Despite good outcomes the VDR is not universallyadopted by burn centers. Several reasons may explainthis phenomenon. One is that the ventilator is quiteunlike other ventilators and it requires special trainingand attention by both respiratory therapists and sur-geons. Because of its unique phasitron delivery devicewhere entrained air and exhaled gas is mixed, it does notallow for a monitoring of tidal volumes and minute vol-umes and therefore electronic “low-volume” alarms arenot possible. Due to the high flow of gas in the airways,the ventilator needs both humidified air and nebulizedsaline to prevent airway dessication. Lastly, some burnsurgeons and intensivists feel that the VDR showed an

From the Warren Alpert Medical School of Brown University,Providence, Rhode Island.

This study was supported by a Grant 8431 from Shriners Hospitalsfor Children.

Address correspondence to David Harrington, MD, FACS, 593Eddy Street, APC 443, Rhode Island Hospital, Providence,Rhode Island 02818.

Copyright © 2009 by the American Burn Association.1559-047X/2009

DOI: 10.1097/BCR.0b013e3181923c44

Journal of Burn Care & ResearchVolume 30, Number 1 Harrington 175

improvement in survival when it was compared withhigh-pressure, high-volume ventilatory strategies, andthat this survival benefit would not be shown in today’sburn intensive care unit if the VDR was compared withlow-volume pressure-limited ventilation.

CONCLUSION

There are two major questions that should be exploredconcerning the VDR and they should be explored in asequential manner:

1. What are the optimal settings for the VDR venti-lator? Some papers use the VDR with the oscilla-tion set at 10 Hertz, other papers use significantlylower oscillation of 4 to 7 Hertz.

2. Does the VDR impart a survival benefit as com-pared with low-volume, pressure-limited venti-lation in patients with moderate size burn andsmoke inhalation injury?

The answers to these questions will only be deter-mined by employing well-designed multicenter clinicaltrials.

REFERENCES

1. Rue LW III, Cioffi WG, Mason AD, McManus WF, Pruitt BAJr. Improved survival of burned patients with inhalation in-jury. Arch Surg 1993;128:772–80.

2. Cioffi WG, DeLemos RA, Coalson JJ, Gerstmann DA, PruittBA Jr. Decreased pulmonary damage in primates with inha-lation injury treated with high-frequency ventilation. AnnSurg 1993;218:328–35; discussion 335–7.

3. Rodeberg DA, Housinger TA, Greenhalgh DG, MaschinotNE, Warden GD. Improved ventilatory function in burn pa-tients using volumetric diffusive respiration. J Am Coll Surg1994;179:518–22.

4. Carman B, Cahill T, Warden G, McCall J. A prospective, ran-domized comparison of the volume diffusive respirator vs con-ventional ventilation for ventilation of burned children. 2001ABA paper. J Burn Care Rehabil 2001;13:444–8.

5. Wang D, Zwischenberger JB, Savage C, et al. High-frequency percussive ventilation with systemic heparin im-proves short-term survival in a LD100 sheep model of acuterespiratory distress syndrome. J Burn Care Res 2006;27:463–71.

6. Ventilation with Lower Tidal Volumes as Compared withTraditional Tidal Volumes for Acute Lung Injury and theAcute Respiratory Distress Syndrome. The Acute RespiratoryDistress Syndrome Network. N Engl J Med 2000;342:1301–8.

7. Amato MB, Barbas CS, Medeiros DM, et al. Effect of aprotective-ventilation strategy on mortality in the acute re-spiratory distress syndrome. N Engl J Med 1998;339:198–9.

Airway Pressure Release VentilationRonald P. Mlcak, PhD, RRT, FAARC

Airway pressure release ventilation (APRV) is a rel-atively new approach to ventilation that was firstdescribed by Stock et al.1 APRV can be classified asa time-triggered, pressure-limited and time-cycledventilation mode. Basically, APRV provides two lev-els of airway pressure, Pressure high (P high) andPressure low (P low) during two time periods, Timehigh (T high) and Time low (T low). APRV usuallyinvolves a long T high (4–7) seconds and a short Tlow (0.5–0.8 seconds). Because of this APRV has

been referred to as a ventilation mode that basicallysets a continuous positive airway pressure that inter-mittently time-cycles to a lower airway pressure. Ad-ditionally, APRV uses an active exhalation valve thatallows spontaneous breathing during both T highand T low. APRV generates a higher mean airwaypressure with a lower tidal volume and lower end-expiratory pressure when compared with other ven-tilator strategies.2 The concept of APRV is based on amechanical ventilator approach designed to maxi-mize and maintain alveolar recruitment throughoutthe entire ventilatory cycle.3 This is accomplished bysetting the P high well above the closing pressure ofrecruitable alveoli. During the long inflation phasealveolar recruitment is maintained, and during theshort release phase, inherent recoil properties of thelung facilitate ventilation.4 Oxygenation is a functionof open surface area, therefore airway pressure andPaO2 are directly related. APRV improves oxygen-ation with prolonged increases in inspiratory pressureand long inspiratory times.

From the Respiratory Care Department, Shriners Hospital forChildren; and Department of Respiratory Care, The School ofAllied Health Science, The University Texas Medical Branch,Galveston.

This study was supported by a Grant 8431 from Shriners Hospitalfor Children.

Address correspondence to Ronald P. Mlcak, PhD, RRT, FAARC,Respiratory Care Department, Shriners Hospital for Children,Galveston Burns Unit, 815 Market Street, Galveston, Texas77550.

Copyright © 2009 by the American Burn Association.1559-047X/2009

DOI: 10.1097/BCR.0b013e3181923c58

Journal of Burn Care & Research176 Mlcak January/February 2009

The theoretical advantages of APRV includes:minimize ventilator induced lung injury, improvedhemodynamic parameters, provides benefits fromallowing spontaneous breathing, decreases the workof breathing and decreases the need for sedation/neuromuscular blocker.2,3 The proposed indicationsfor the use of APRV include: recruitable low lungcompliance disorders and inadequate oxygenation.The advantages to APRV include; lower peak inspira-tory pressures at similar mean airway pressure and itallows for spontaneous breathing which can lead toincreased patient comfort and synchrony.

A number of clinical crossover studies have lookedat physiological end points with APRV.5–10 Thesestudies suggest that APRV required less applied end-inflation pressures and less sedation. AdditionallyAPRV often produced better oxygenation than otherforms of mechanical ventilation. There have been tworandomized controlled trials (RCT) of APRV. OneRCT enrolled 30 mechanically ventilated traumapatients.11 In this study, APRV was compared withPressure Controlled Ventilation (PCV) with sedationand paralysis for 72 hours. After 72 hours the PCVgroup was crossed over to APRV. APRV was associ-ated with lower end inflation pressures, improvedoxygenation, decreased ventilator days, decreases inintubation days and intensive care unit stay. How-ever, there was no change in mortality and the PCVgroup required paralysis for the first 72 hours.

In the second RCT, Varpula et al12 compared 45patients on APRV to synchronized intermitted manda-tory ventilation and pressure support. Findings includeda lower end-inflation pressure, similar gas exchange, se-dation needs and ventilator free days. There was no dif-ference in mortality or intensive care unit stay.

A possible limitation of this mode of ventilation forpatients with inhalation injury include a high level ofintrinsic positive end expiratory pressure secondary toincreased airway resistance and short expiratory timeswhich may result in hyperinflation of the lungs.

CONCLUSIONS

APRV provides the clinician with an additional po-tential ventilatory modality for the use in inhalationinjury. However, its role in mechanical ventilation ofthe burn patient remains to be defined. Thus, furtherstudy of the effects of APRV in inhalation injury iswarranted to determine how this mode of ventilationshould be applied in inhalation injury.

REFERENCES

1. Stock MC, Downs JB, Frolicher DA. Airway pressure releaseventilation. Crit Care Med 1987;15:462–6.

2. Myers TR, MacIntyre NR. Does airway pressure support ven-tilation offer important new advantages in mechanical venti-lation support? Respir Care 2007;52:452–8.

3. Habashi NM. Other approaches to open lung ventilation:airway pressure release ventilation. Crit Care Med 2005;33(Suppl 3):S228–S240.

4. Haitsma JJ, Lachmann B. Lung protective ventilation in ARDS:the open lung maneuver. Minerva Anestesiol 2006;72:117–32.

5. Kaplan LJ, Bailey H, Formosa V. Airway pressure releaseventilation increases cardiac performance in patients withacute lung injury/adult respiratory distress syndrome. CritCare 2001;5:221–6.

6. Rasanen J, Cane RD, Downs JB, et al. Airway pressure releaseventilation during acute lung injury: a prospective multi-center trail. Crit Care Med 1991;19:1234–41.

7. Schuttz TR, Costarino AT Jr, Durning SM, et al. Airwaypressure release ventilation in pediatric. Pediatr Crit CareMed 2001;2:243–6.

8. Dart BW IV, Maxwell RA, Richart CM, et al. Preliminaryexperience with airway pressure release ventilation in a trauma/surgical intensive care unit. J Trauma 2005;59:71–6.

9. Sydow M, Burchardi H, Ephraim E, Zielmann S, Crozier TA.Long-term effects of two different ventilatory modes on oxy-genation in acute lung injury: comparison of airway pressurerelease ventilation and volume-controlled inverse ratio ventila-tion. Am J Respir Crit Care Med 1994;149:1550–6.

10. Cane RD, Peruzzi WT, Shapiro BA. Airway pressure releaseventilation in severe acute respiratory failure. Chest 1991;100:460–3.

11. Putensen C, Zech S, Wrigge H, et al. Long-term effects ofspontaneous breathing during ventilatory support in patientswith acute lung injury. Am J Respir Crit Care Med 2001;164:43–9.

12. Varpula T, Jousela I, Niemi R, Takkunen O, Pettiala V. Com-bined effects of prone positioning and airway pressure releaseventilation on gas exchange in patients with acute lung injury.Acta Anaesthesiol Scand 2003;47:516–24.

Journal of Burn Care & ResearchVolume 30, Number 1 Mlcak 177

Use of High Frequency Oscillatory Ventilation inInhalation Injury

Robert Cartotto, MD, FRCS(C)

High frequency oscillatory ventilation (HFOV) is anunconventional form of mechanical ventilation whichhas been used for the past two decades in the neonatalintensive care unit for respiratory distress syndrome.Recognition of HFOV’s lung protective propertiescombined with sound physiologic evidence of its abil-ity to open and recruit the lung, have led to transla-tion of HFOV to the adult ICU, for patients with theAcute Respiratory Distress Syndrome (ARDS). Ini-tially HFOV was employed as a rescue therapy forsevere ARDS cases with end-stage oxygenation fail-ure. More recently, however, HFOV has been suc-cessfully employed as a ventilation approach earlierand earlier in the course of ARDS among diversepatient populations including burn patients.

Currently, very little has been reported on the useof HFOV after inhalation injury, aside from one an-imal experiment,1 a pediatric case report,2 and data(unpublished) from 19 adult burn and inhalation in-jury patients treated with HFOV at our institution.3

Therefore, at the present time (and for the purposesof this discussion), HFOV must primarily be viewedwithin the context of its use as a rescue ventilationstrategy in ARDS, to which smoke inhalation injurypatients are obviously prone. Consideration of HFOVafter smoke inhalation outside the scenario of severeARDS, for example, as a mode of ventilation for earlyacute lung injury (ALI), or immediately after injury,may be somewhat premature. Nevertheless, there aredistinct and potentially fruitful research questionssurrounding HFOV and its role among thermally in-jured patients with smoke inhalation, which will beexplored in this section.

What is HFOV?HFOV uses extremely small Vt’s (1–2 ml/kg), athigh frequencies (3–15 Hz), combined with applicationof a relatively high sustained mean airway pressure(mPaw) (30–40 cm H2O). The key difference betweenCMV and HFOV is demonstrated in Figure 1.4

Primarily oxygenation is achieved by using the el-evated and sustained mPaw to achieve highly effec-tive recruitment of the available lung (ie, increasedtotal lung volume).4–7 Alveolar ventilation is mainly re-lated to the frequency of ventilation which is inverselyrelated to tidal volume, (ie, higher frequency � lowerVt, lower frequency � larger Vt), and is relatively inde-pendent of total lung volume.4,5 Hence, oxygenationand ventilation are essentially uncoupled and can eachbe controlled independent of the other.4,5 HFOV iscurrently delivered using the SensorMedics 3100B highfrequency oscillatory ventilator (the “adult oscillator”).

How is HFOV a Lung ProtectiveVentilation Strategy?Numerous animal studies have found HFOV to pro-duce less VILI than CMV.8–12 HFOV’s ability to limitVILI is best understood by examining Figure 2.13

HFOV ventilates the lung in a relatively restricted “safewindow,” avoiding excursion into the zone of alveolaroverdistention (volutrauma) at high Vt’s and high infla-tion pressures, and the zone of alveolar derecruitment(atelectrauma) at insufficient pressures.13 The very smallVt’s during HFOV limit alveolar stretch even at higherairway pressures because the incremental expansion of

From the Department of Surgery, The Ross Tilley Burn Centre atSunnybrook Health Sciences Centre, Toronto, Canada.

This study was supported by a Grant 8431 from Shriners Hospitalsfor Children.

Address correspondence to Robert Cartotto, MD, FRCS(C), TheRoss Tilley Burn Centre at the Sunnybrook Health SciencesCentre, Toronto, Ontario, Canada.

Copyright © 2009 by the American Burn Association.1559-047X/2009

DOI: 10.1097/BCR.0b013e3181923c6a

Figure 1. Airway pressure Vs. time during conventionalmechanical ventilation (CMV) and high frequency oscilla-tory ventilation (HFOV). Adapted from Ferguson et al.4

Journal of Burn Care & Research178 Cartotto January/February 2009

the alveolus with each inspiration is still quite small. Theuse of such small Vt’s then allows application of a highersustained mPaw which opens and recruits the lung toprevent atelectrauma in many groups of alveoli thatwould otherwise be subject to repetitive collapse andre-opening. The lung recruitment directly improves ox-ygenation, allowing use of a lower FiO2, thus limitingoxygen toxicity.

Experience With HFOV in Adult ARDSHFOV has now been widely reported as a rescuestrategy for oxygenation crisis in adults with ARDS,arising from critical illness,14–17 trauma,18,19 andburn injury.20 The main combined findings fromthese studies can be summarized as follows:

• HFOV appears to be safe with relatively lowrates of barotrauma.

• HFOV produces rapid and sustained correctionof oxygenation failure, when used as a rescuestrategy.

• The improved oxygenation is usually achieved ata lower mean airway pressure “cost,” as mea-sured by the oxygenation index (OI).

• Improved oxygenation is not related to improvedsurvival, and no conclusions on HFOV’s effect onmortality can be reached from these studies.

• Optimal application of HFOV likely requires useof periodic Lung Recruitment Maneuvers(LRM)21 (similar to that which has been previ-ously shown in animal models).22,23

RCTs of HFOV in Adult ARDSTwo Randomized Controlled Trials (RCT) (N � 14824

and N � 6125) have compared HFOV with CMV inadults with ARDS. Neither of these studies raised anyimportant safety concerns, but importantly neithershowed any definitive advantage of HFOV over CMV.However, interpretation of these findings must takeinto account certain limitations, specifically13,22:

a. HFOVmaynothavebeenoptimallyutilized (lackofLRMs, lower frequencies, premature weaning ofmean Paw, and too early conversion to CMV).

b. The control arms’ CMV strategy may not havebeen optimally lung protective (high or unlim-ited plateau pressures [PPLAT], absence of initialLRMs, relatively low PEEP).

In summary, the existing RCTs of adult HFOV are in-conclusive. The need for a larger RCT of optimumHFOV against the “best” protective CMV strategy ofthe day is being addressed by the multi-center OSCIL-LATE Trial (Ferguson and Meade) which is based inToronto and which is now entering patients into itspilot phase. This study will compare HFOV (utilizingLRMs, relatively higher frequencies, and less aggressiveweaning/conversion to CMV), with protective CMV(utilizing LRM’s, Vt 6–8 mL/kg, PPLAT �35 cmH2O, and relatively higher PEEP settings). This study isextremely important because it will likely set the best ac-ceptable standard forany subsequent trialswhereHFOVisstudied (eg, application of HFOV in specialized patientsubsets such as smoke inhalation injury).

Important Considerations for Research ofHFOV After Smoke InhalationAlthough smoke inhalation injury predisposes burnpatients to ALI and ARDS, it does not necessarilyfollow that HFOV may be a rational or effective ven-tilatory modality for smoke inhalation patients de-spite the promising early experience with HFOV inadult ALI and ARDS. This is due to the unique clin-ical and pathophysiologic features of smoke inhala-tion which may pose limitations to the application ofHFOV, including:

1. Small airway obstruction (edema, bronchospasm,sloughing mucosa and carbonaceous debris) maylimit the ability of HFOV to recruit alveoli distally.

2. Gas trapping and related hypercapnia in inhala-tion injury may be difficult to control duringHFOV. During HFOV measures to increaseCO2 removal are slow-working and potentiallycompromise HFOV’s protective effects.

3. Copious secretions after inhalation injury aredifficult to manage during HFOV.

Figure 2. A hypothetical pressure volume curve during con-ventional mechanical ventilation (CMV) showing excursion(grey shaded area) into zones of injury at high pressure andvolume and again at low end expiratory pressures during de-flation, compared to high frequency oscillatory ventilation(HFOV) which ventilates the lung in a “safe zone” (whitearea). Reprinted with permission from Froese AB. High-frequency oscillatory ventilation for adult respiratory syn-drome: let’s get it right this time. Crit Care Med 1997; 25:906–8. Copyright © 1997, Lippincott Williams & Wilkins.

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4. ARDS is recognized as a heterogeneous diseaseprocess whereby different etiologies can poten-tially produce important variations in pathology.For example, it is conceivable, (but unknown atpresent), whether ARDS after smoke inhalationmay feature a predominance of “sticky” non-re-cruitable alveoli, rather than “loose” more re-cruitable alveoli. This fundamental difference inpathology could affect HFOV’s ability to effec-tively open and recruit the lung.26,27

5. HFOV complicates delivery of adjunctive therapiesin inhalation injury (nebulized heparin, mucomyst,bronchodilators, therapeutic bronchoscopy).

Because of these considerations, research into HFOV’srole should follow a logical sequence which proceeds fromuse of HFOV as a rescue therapy in ARDS in smoke inha-lation patients, to earlier application as a protective strategyin ALI or early phase ARDS, and ultimately to consider itas an initial ventilatory strategy immediately after smokeinhalation injury.

Is HFOV Effective as Rescue Strategyin ARDS Among Burn Patients WithSmoke Inhalation?Among human adults with ARDS after smoke inhala-tion, our group has found that patients with burns andsmoke inhalation do not respond as vigorously toHFOV as those with a burn injury alone, when HFOVwas used as a rescue strategy for ARDS- related oxygen-ation failure. Those with inhalation injury failed toachieve significant improvement in PaO2/FiO2 ratio orOI compared with baseline on CMV before HFOV,until after 72 hours of HFOV therapy, and never ob-tained a significant reduction in OI. This contrastedsharply with non-inhalation cases where there was a sig-nificant improvement in oxygenation within 8 hours ofHFOV. There were no differences between those withinhalation injury and those without with respect to CO2levels, duration of ventilation, or mortality. However,this was a retrospective study that did not use a fixedHFOV strategy, and there were significant baseline dif-ferences between the groups in timing of HFOV initi-ation (earlier in inhalation group), and pre-HFOVPEEP level on CMV (lower in inhalation group).3 IsHFOV a beneficial (and protective) early interventionalstrategy in ALI or early ARDS after smoke inhalation?No studies to date have attempted to answer this ques-tion. Conceptually, the use of a protective ventilationstrategy earlier in the course of lung injury in an effort toprevent deterioration is appealing. One animal study1

found that HFOV actually produced more histologicevidence of lung injury than CMV or high frequencypercussive ventilation, in a primate model of smoke in-halation. However, cautious interpretation of these

findings is needed because of the small number of sub-jects studied (N � 3),and the absence of reported dataon the mean Paw in the HFOV treated cases, and thelikelihood that optimal HFOV, based on today’s stan-dards, was not employed.

A key question regarding HFOV is whether it issuitable as an immediate ventilation modality aftersmoke inhalation injury. Gas trapping, small airwayobstruction, and copious respiratory secretions areclassic features after smoke inhalation, and wouldlikely prove to be problematic during HFOV. Fur-thermore, HFPV has proven benefits as an immediateventilation strategy immediately after smoke inhala-tion.28–30 However, one important advantage ofHFOV might be the reduced nosocomial infectionrisks from respiratory droplet dissemination, com-pared with HFPV, which is an open system with adeflated endotracheal balloon cuff.

CONCLUSION

Although HFOV is a promising mode of ventilationfor ARDs, at present the data do not clearly indicatehow or whether it should be used following inhala-tion injury. Further investigation is needed to deter-mine the optimal use of HFOV as well as its efficacy incomparison with other modes of ventilation.

REFERENCES

1. Cioffi WG, deLemos RA, Coalson JJ, Gerstmann DA, PruittBA. Decreased pulmonary damage in primates with inhala-tion injury treated with high frequency ventilation. Ann Surg1993;218:328–37.

2. Jackson MP, Philip B, Murdoch LJ, Powell BWEM. Highfrequency oscillatory ventilation successfully used to treat asevere pediatric inhalation injury. Burns 2002;28:509–11.

3. Cartotto R, Walia G, Ellis S, Gomez M, Fowler R. HFOV forthe burn patient with ARDS: does inhalation injury affect theresponse? (abstract) J Burn Care Res 2007;28:S56.

4. Ferguson ND, Stewart TE. New therapies for adults withacute lung injury: high frequency oscillatory ventilation. CritCare Clin 2002;18:1–13.

5. Derdak S. High-frequency oscillatory ventilation for acuterespiratory distress syndrome in adult patients. Crit Care Med2003;31:S317–23.

6. Suzuki H, Papazoglou K, Bryan AC. Relationship betweenPaO2 and lung volume during high frequency oscillatory ven-tilation. Acta Paediatr Jpn 1992;34:494–500.

7. Kolton M, Cattran CB, Kent G, Volgyesi G, Froese AB,Bryan AC. Oxygenation during high-frequency ventilationcompared with conventional mechanical ventilation in twomodels of lung injury. Anesth Analg 1982;61:323–32.

8. Hamilton PP, Onayemi A, Smyth JA, et al. Comparison of con-ventional and high-frequency oscillatory ventilation: oxygen-ation and lung pathology. J Appl Physiol 1983;55:131–8.

9. McCulloch PR, Forkert PG, Froese AB. Lung volume main-tenance prevents lung injury during high frequency oscilla-tory ventilation in surfactant-deficient rabbits. Am Rev RespirDis 1988;137:1185–92.

10. Bond DM, Froese AB. Volume recruitment maneuvers areless deleterious than persistent low lung volumes in the

Journal of Burn Care & Research180 Cartotto January/February 2009

atelectasis-prone rabbit lung during high-frequency oscil-lation. Crit Care Med 1993;21:402–12.

11. Rotta AT, Gunnarsson B, Fuhrman BP, Hernan LJ, Stein-horn DM. Comparison of lung protective ventilation strate-gies in a rabbit model of acute lung injury. Crit Care Med2001;29:2176–84.

12. Imai Y, Nakagawa S, Ito Y, Kawano T, Slutsky AS, MiyasakaK. Comparison of lung protection strategies using conven-tional and high-frequency oscillatory ventilation. J ApplPhysiol 2001;91:1836–44.

13. Froese AB. High-frequency oscillatory ventilation for adultrespiratory distress syndrome: let’s get it right this time. CritCare Med 1997;25:906–8.

14. Fort P, Farmer C, Westerman J, et al. High-frequency oscil-latory ventilation for adult respiratory distress syndrome—apilot study. Crit Care Med 1997;25:937–47.

15. Mehta S, Lapinsky SE, Hallett DC, et al. A prospective trial ofhigh frequency oscillatory ventilation in adults with acuterespiratory distress syndrome. Crit Care Med 2001;29:1360–9.

16. Andersen FA, Guttormsen AB, Flaatten HK. High frequencyoscillatory ventilation in adult patients with acute respiratorydistress syndrome—a retrospective study. Acta AnaesthesiolScand 2002;46:1082–8.

17. Mehta S, Granton J, MacDonald RJ, et al. High-frequencyoscillatory ventilation in adults: the Toronto experience.Chest 2004;126:518–27.

18. Claridge JA, Hostetter RG, Lowson SM, Young JS. High-frequency oscillatory ventilation can be effective as rescuetherapy for refractory acute lung dysfunction. Am Surg 1999;65:1092–6.

19. David M, Weiler N, Heinrichs W, et al. High-frequency os-cillatory ventilation in adult acute respiratory distress syn-drome. Intensive Care Med 2003;29:1656–65.

20. Cartotto R, Ellis S, Gomez M, Cooper A, Smith T. High fre-quency oscillatory ventilation in burn patients with the acuterespiratory distress syndrome. Burns 2004;30:453–63.

21. Ferguson ND, Chiche JD, Kacmarek RM, et al. Combininghigh-frequency oscillatory ventilation and recruitment ma-neuvers in adults with early acute respiratory distresssyndrome: the Treatment with Oscillation and an Open LungStrategy (TOOLS) Trial pilot study. Crit Care Med 2005;33:479–86.

22. Froese AB. The incremental application of lung-protectivehigh-frequency oscillatory ventilation. Am J Respir Crit CareMed 2002;166:786–7.

23. Froese AB. Role of lung volume in lung injury: HFO in theatelectasis-prone lung. Acta Anaesthesiol Scand Suppl 1989;90:126–30.

24. Derdak S, Mehta S, Stewart TE, et al. High frequency oscil-latory ventilation for acute respiratory distress syndrome: arandomized controlled trial. Am J Respir Crit Care Med2002;166:801–8.

25. Bollen CW, van Well GT, Sherry T, et al. High frequencyoscillatory ventilation compared with conventional mechan-ical ventilation in adult respiratory distress syndrome: a ran-domized controlled trial. Crit Care 2005;9:R430–9.

26. Crotti S, Mascheroni D, Caironi P, et al. Recruitment andderecruitment during acute respiratory failure: a clinicalstudy. Am J Respir Crit Care Med 2001;164:131–40.

27. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitmentin patients with the acute respiratory distress syndrome.N Engl J Med 2006;354:1775–86.

28. Cioffi WG, Loring WR, Graves TA, McManus WF, MasonAD, Pruitt BA. Prophylactic use of high frequency percussiveventilation in patients with inhalation injury. Ann Surg 1991;213:575–82.

29. Reper P, Wibaux O, VanLaeka P, Vandeenan D, DuinslagerL, Vanderkelen A. High frequency percussive ventilation andconventional ventilation after smoke inhalation: a random-ized study. Burns 2002;28:503–8.

30. Hall JJ, Hunt JL, Arnoldo BD, Purdue GF. Use of highfrequency percussive ventilation in inhalation injuries. J BurnCare Res 2007;28:396–400.

Potential Studies of Mode of Ventilation inInhalation Injury

Michael D. Peck, MD,* David Harrington, MD,† Ronald P. Mlcak, PhD,‡Robert Cartotto, MD, FRCS(C)§

Future studies of modes of ventilation after inhalationinjury fall into two categories: 1) optimizing a specificventilator mode’s use in inhalation injury followed by 2)comparison of the different ventilator modes in inhala-

tion injury. The key to determining optimal ventilatorstrategies is the use of well-defined hypotheses in con-junction with meticulous study design. Studies assessingmodes of ventilation after smoke inhalation injuryshould include attention to several issues that arose dur-ing the trials of low tidal volume therapy. Ventilatorygoals need to be clarified, and protocols for ventilatoradjustments need to be developed. For example, duringpermissive hypercapnia, how low can the pH descendwithout needing treatment, and when respiratory aci-dosis does need treatment, should it be done with so-dium bicarbonate, increased ventilation rate, or largertidal volumes need to be clarified prior to study initia-tion. When tidal volumes are calculated should they be

From the *Arizona Burn Center, Phoenix; †Department ofSurgery, Brown University Medical School, Providence, RhodeIsland; ‡Shriners Hospital for Children, Galveston, Texas; and§The Ross Tilley Burn Centre at the Sunnybrook Health SciencesCentre, Toronto, Canada.

Address correspondence to Michael D. Peck, MD, 2601 EastRoosevelt Street, Phoenix, Arizona 85008.

Copyright © 2009 by the American Burn Association.1559-047X/2009

DOI: 10.1097/BCR.0b013e3181923c7a

Journal of Burn Care & ResearchVolume 30, Number 1 Peck et al 181

reported as related to predicted or measured bodyweight? Should the interventions be based on tidal vol-ume or plateau pressure? What levels of positive endexpiratory pressure should be used? Should chest wallcompliance and intraabdominal pressures be measured?Dependent variables should be expanded beyond mor-tality to include:

• Development of multisystem organ failure• Duration of mechanical ventilation• Length of intensive care unit and hospital stay• Long-term mortality• Long-term health-related quality of life• Long-term cognitive outcome• Costs/charges.

The first phase of the study of ventilator modes isthe determination of the “ideal” parameters afterinhalation injury. This could entail an initial retro-spective comparison of ventilator parameters andoutcomes followed by a prospective observationaldata collection of outcomes utilizing the goals andparameters developed in the retrospective cohort.An example of such a proposal appears below.

PHASE 1 PROPOSAL EXAMPLE:OPTIMIZATION OF VENTILATORMODE: THE VOLUMETRIC DIFFUSIVEVENTILATOR (VDR)

The settings on the VDR ventilator can be set inmany ways. The sinusoidal rate (essentially the re-spiratory rate on standard ventilation), inspiratorytime, ratio of inspiratory to expiratory time (i/eratio), oscillatory continuous positive airway pres-sure (CPAP), peak inspiratory pressure, oscillatoryrate and i/e ratio of the oscillatory component canall be titrated to desired effect. In the publishedliterature, there are two basic methods the VDR isused. The groups in Cincinnati and Galveston usedthe VDR with an oscillatory rate of 4 to 7 Hertz.This method improves the ventilatory componentof the ventilator at the expense of oxygenation. TheInstitute of Surgical Research in San Antonio uses astandard oscillatory rate of 10 Hertz. These set-tings will improve oxygenation at the expense ofventilation. Each group then uses the oscillatoryCPAP and FiO2 to attain a desired systemic oxygensaturation and titrates sinusoidal rate and positiveinspiratory pressure (PIP) to attain CO2 clearance.Both groups reported improved outcomes in theirexperience utilizing the VDR, though their studygroups where different with one group studyingthe pediatric population and the other an adultpopulation. An optimal method for using the VDRshould be found so that experience with the venti-

lator and improvements in outcome can be stan-dardized.

Study HypothesisOscillatory rates of 10 Hertz with a standard inspira-tory time of 2 seconds will attain better outcomesthan oscillatory rates of either 4 or 7 Hertz.

Methods and MaterialsPatients of all ages with bronchoscopic evidence of in-halation injury and burn size greater than 20% will berandomized to different standard settings on the VDRventilator. Group 1 will have an oscillatory rate of 10Hertz, an i/e ratio of 1 and an inspiratory time of 2seconds. Group 2 will have an oscillatory rate of 7 Hz,an i/e ratio of 1 and an inspiratory time of 2 seconds.Group 3 will have an oscillatory rate of 4 Hz, an i/eratio of 1 and an inspiratory time of 2 seconds. Eachgroup will titrate PIP, SR to a PaCO2 between 35 and45 and will titrate oscillatory CPAP, FiO2 to keep O2saturation �90%. The primary outcome measures willbe best double product (sinusoidal rate � PIP) on post-burn day 5, 10, and 15. The secondary outcome mea-sure will be best P/F ratio on postburn day 5, 10, and15. Performing a power analysis is difficult becausethe PIP from the Institute of Surgical Research werenot reported from the adult survival studies. Assum-ing a 5 cm H2O (30 cm H2O � 5 SD and 25 cmH2O � 5, 20 cm H2O � 5 SD) difference betweenthe groups and a power of 0.9, an @ error of 0.05, and2 planned, nonindependent, pairwise comparisons, 27patients will be needed for each group to detect a sta-tistically significant difference.

CommentsOptimizing and standardizing the use of any mode ofmechanical ventilation is a necessary first step beforeembarking on a multicenter trial comparing differentmodes of ventilation. The study cited above needs tobe applied to each of the newer modes of mechanicalventilation (airway pressure release ventilation [APRV],oscillatory ventilator, etc) prior to beginning phase 2,the comparison of different modes of ventilation. Phase1 will likely require multiple centers to establish pop-ulation generalizability. Due to its observational na-ture, it would be less likely to interfere with otherstudies in progress, but will be subject to vagaries inpatient treatment.

Phase 2 would involve a multicenter comparativetrial of different modes of ventilation on inhalationinjury and would ideally occur only after phase 1 hasbeen completed. This study will require a significantlylarger number of patients, multiple centers, and be ofmuch longer duration to have sufficient power to

Journal of Burn Care & Research182 Peck et al January/February 2009

detect a difference in groups. Comparing more thantwo modes of mechanical ventilation in a single studyis not likely to be feasible. This phase will need toprioritized with other studies of burn and inhalationinjury to maximize research productivity in burns. Anexample of such a trial is described below.

PHASE 2 PROPOSAL EXAMPLE:DETERMINING THE “BEST” MODE OFVENTILATION: APRV VS VDR

Proposed StudyWhether APRV ventilation will be of value to patientswith inhalation injury is yet to be determined. A ran-domized clinical trial for patients with inhalation in-jury is necessary to answer the question.

Hypothesis. This proposed project will test thecentral hypothesis that APRV ventilation will de-crease mortality, improve oxygenation, decrease ven-tilator days and length of intubation and decrease theincidence of pneumonia/atelectasis when comparedto High Frequency Percussive Ventilation in patientswith inhalation injury.

Endpoints. The primary endpoint will be survivaland the secondary endpoints will include: improvedoxygenation, decreased ventilator days, decreased in-tubation time, decreased incidence of pneumonia/atelectasis, decreased end-inflation pressures and im-proved pulmonary function studies.

Feasibility. Primary endpoint, survival, based onthe Varpula et al1 study, the number of patientsneeded to show a significant difference in mortality is

497 per group. Secondary endpoints based on pub-lished clinical trials of APRV, the number of patientsneeded to show a significant difference in secondaryendpoints is 30 to 40 patients per group.

Cost. To be determined based upon the followingmajor factors:

1. Finalizing endpoints.2. Total no. of patients required.3. Centers needing ventilators with the APRV

mode and high frequency percussive ventilation.4. Training of all centers to follow specific proto-

cols for initial set-up, ventilator usage and weaningpatients.

5. A point person for design, coordination and ex-ecution of study protocols.

Clinical Relevance of StudyReduced mortality.

Reduction in ventilator days and length of intuba-tion:

1. Reduce the incidence of ventilator-associatedpneumonia.

2. Reduce cost.Determination of the best mode of mechanical ven-tilation is likely to remain a challenge to clinicians fordecades to come.

REFERENCE

1. Varpula T, Jousela I, Niemi R, et al. Combined effects ofprone positioning and airway pressure release ventilation ongas exchange in patients with acute lung injury. Acta Anaes-thesiol 2003;47:516–524.

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