DTIC ADA629414: High-Frequency Percussive Ventilation and Low Tidal Volume Ventilation in Burns: A Randomized Controlled Trial

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by  Defense Technical Information Center

High-frequency percussive ventilation and low tidal volume
ventilation in burns: A randomized controlled trial*
Kevin K. Chung, MD; Steven E. Wolf, MD; Evan M. Renz, MD; Patrick F. Allan, MD; James K. Aden, PhD;
Gerald A. Merrill, PhD; Mehdi C. Shelhamer, DO; Booker T. King, MD; Christopher E. White, MD;
David G. Bell, MD; Martin G. Schwacha, PhD; Sandra M. Wanek, MD; Charles E. Wade, PhD;
John B. Holcomb, MD; Lorne H. Blackbourne, MD; Leopoldo C. Cancio, MD
Objectives:Inselectburnintensivecareunits,high-frequency ventilationgrouphadsimilardemographicstoincludemedianage
percussiveventilationispreferentiallyusedtoprovidemechanical (interquartile range) (28 yrs [23–45] vs. 33 yrs [24–46], p (cid:1)
ventilation in support of patients with acute lung injury, acute nonsignificant), percentage of total body surface area burn (34
respiratorydistresssyndrome,andinhalationinjury.However,we [20–52]vs.34[23–50],p(cid:1)nonsignificant),andclinicaldiagno-
found an absence of prospective studies comparing high-fre- sis of inhalation injury (39% vs. 35%, p (cid:1) nonsignificant). The
quency percussive ventilation with contemporary low-tidal vol- primary outcome was ventilator-free days in the first 28 days
ume ventilation strategies. The purpose of this study was to after randomization. Intent-to-treat analysis revealed no signifi-
prospectively compare the two ventilator modalities in a burn cant difference between the high-frequency percussive ventila-
intensive care unit setting. tion and the low-tidal volume ventilation groups in mean ((cid:2) SD)
Design: Single-center, prospective, randomized, controlled ventilator-free days (12 (cid:2) 9 vs. 11 (cid:2) 9, p (cid:1) nonsignificant). No
clinical trial, comparing high-frequency percussive ventilation significantdifferencewasdetectedbetweengroupsforanyofthe
withlow-tidalvolumeventilationinpatientsadmittedtoourburn secondary outcome measures to include mortality except the
intensive care unit with respiratory failure. need for “rescue” mode application (p (cid:1) .02). Nine (29%) in
Setting:A16-bedburnintensivecareunitatatertiarymilitary thelow-tidalvolumeventilationarmdidnotmeetpredetermined
teaching hospital. oxygenation or ventilation goals and required transition to a
Patients: Adult patients >18 yrs of age requiring prolonged rescue mode. By contrast, two in the high-frequency percussive
(>24 hrs) mechanical ventilation were admitted to the burn ventilation arm (6%) required rescue.
intensive care unit. The study was conducted over a 3-yr period Conclusions: A high-frequency percussive ventilation-based
betweenApril2006andMay2009.Thistrialwasregisteredwith strategy resulted in similar clinical outcomes when compared
ClinicalTrials.gov as NCT00351741. with a low-tidal volume ventilation-based strategy in burn pa-
Interventions: Subjects were randomly assigned to receive tients with respiratory failure. However, the low-tidal volume
mechanicalventilationthroughahigh-frequencypercussiveven- ventilation strategy failed to achieve ventilation and oxygenation
tilation-basedstrategy(n(cid:1)31)oralow-tidalvolumeventilation- goals in a higher percentage necessitating rescue ventilation.
based strategy (n (cid:1) 31). (Crit Care Med 2010; 38:1970–1977)
Measurements and Main Results: At baseline, both the high- KEYWORDS:burns;highfrequency;percussiveventilation;low-
frequency percussive ventilation group and the low-tidal volume tidal volume ventilation; inhalation injury
R
espiratory failure in the set- the products of combustion imparts air- mucosal edema, sloughing, and hemor-
ting of concomitant severe way and lung parenchymal damage rhage and carries a substantially in-
burn presents a variety of known as inhalation injury, a condition creasedattributableriskofpulmonaryin-
challenges that call for inno- that affects up to 15% of burn patients. fectionandpatientmortality(1–3).Even
vative therapeutic options. Inhalation of The injury results in tracheobronchial in the absence of inhalation injury, de-
creasedchestwallcomplianceearlyfrom
full-thickness burns or resuscitation-
related edema, and later from scar and
*Seealsop.2069. Supplementaldigitalcontentisavailableforthisar-
contracture formation, may make it dif-
FromtheU.S.ArmyInstituteofSurgicalResearch ticle.DirectURLcitationsappearintheprintedtextand
(KKC,SEW,EMR,JKA,BTK,CEW,CEW,LHB,LCC),Fort areprovidedintheHTMLandPDFversionsofthisarticle ficult to achieve clinically adequate gas
SamHouston,TX;theUniversityofTexasHealthSci- onthejournal’sWebsite(www.ccmjournal.com). exchange.
ence Center at San Antonio (KKC, SEW, EMR, CEW, Theauthorshavenotdisclosedanypotentialcon-
High-frequencypercussiveventilation
MGS,CEW,LCC),SanAntonio,TX;LandstuhlRegional flictsofinterest.
MedicalCenter(PFA,SMW),Landstuhl,Germany;San For information regarding this article, E-mail: (HFPV) is a pneumatically driven, pres-
AntonioMilitaryMedicalCenter(GAM,MCS,DGB),Fort [email protected] sure-limited, time-cycled mode of venti-
SamHouston,TX;theUniversityofTexasHealthSci- Copyright©2010bytheSocietyofCriticalCare lationthatdelivershigh-frequency((cid:1)300
enceCenteratHouston(JBH),Houston,TX;andUni- MedicineandLippincottWilliams&Wilkins
subtidal breaths/minute or 5 Hz) bursts
formed Services University of the Health Sciences
DOI:10.1097/CCM.0b013e3181eb9d0b
(EMR),Bethesda,MD. of gas superimposed on a biphasic in-
1970 CritCareMed2010Vol.38,No.10
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1. REPORT DATE 2. REPORT TYPE 3. DATES COVERED
01 OCT 2010 N/A -
4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER
High-frequency percussive ventilation and low tidal volume ventilation in
5b. GRANT NUMBER
burns: a randomized controlled trial
5c. PROGRAM ELEMENT NUMBER
6. AUTHOR(S) 5d. PROJECT NUMBER
Chung K. K., Wolf S. E., Renz E. M., Allan P. F., Aden J. K., Merrill G.
A., Shelhamer M. C., King B. T., White C. E., Bell D. G., Schwacha M. 5e. TASK NUMBER
G., Wanek S. M., Wade C. E., Holcomb J. B., Blackbourne L. H., Cancio
L. C., 5f. WORK UNIT NUMBER
7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION
United States Army Institute of Surgical Research, JBSA Fort Sam REPORT NUMBER
Houston, TX
9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S)
11. SPONSOR/MONITOR’S REPORT
NUMBER(S)
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Approved for public release, distribution unlimited
13. SUPPLEMENTARY NOTES
14. ABSTRACT
15. SUBJECT TERMS
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a REPORT b ABSTRACT c THIS PAGE UU 8
unclassified unclassified unclassified
Standard Form 298 (Rev. 8-98)
Prescribed by ANSI Std Z39-18
spiratory and expiratory pressure cycle Reasonsforexclusionwerepregnancy,noex- tionusingtheEVITAXL(Dra¨gerMedicalInc,
set at 10–15 cycles per minutes (4–6). pectationofsurvivalof(cid:1)24hrs,prisonersta- Telford, PA) were considered for “rescue”
Afterinhalationinjury,thepercussiveair tus, and traumatic brain injury requiring in- basedonclinicianpreference(seeSupplemen-
flow delivered by HFPV is believed to fa- tracranialpressuremonitoring. talFigs.3and4fortheairwaypressurerelease
Patientswhometinclusionandexclusion ventilationalgorithmandmethodofweaning
cilitate evacuation of debris originating
criteria were identified and surrogate deci- [Supplemental Digital Content 2, http://
from epithelial sloughing, hemorrhage,
sionmakers contacted for written informed links.lww.com/CCM/A159]). Criteria for
and inflammation. A number of case–
consent.Onceconsentwasobtained,subjects changing modes were as follows: severe hy-
control studies demonstrated a decrease were randomized by paired grouping by age poxemia with arterial partial pressure of oxy-
in the incidence of ventilator-associated ((cid:1)65or(cid:2)65yrs)andbyclinicaldiagnosisof gen (PaO2) (cid:2)60 mm Hg despite a positive
pneumonia (VAP) in patients with inha- inhalation injury. A random drawing of a end-expiratory pressure (cid:1)20 cm H2O on the
lation injury when supported with HFPV sealed envelope revealed the study arm and LTVmodeorapeakinspiratorypressure(cid:1)50
compared with conventional modes of subsequentsubjectsenrolledwithinthatsame cmH2OontheHFPVmodeatanFIO2of100%
ventilation (1, 7, 8). Thus, this mode is groupwereplacedintheoppositestudyarm. for (cid:1)1 hr; severe hypercapnia with arterial
favored in some burn centers for the After each complete pair, a new drawing was partialpressureofcarbondioxide(PaCO2)(cid:1)70
mmHgalongwithanarterialpH(cid:2)7.2despite
management of inhalation injury. When performed.
optimization of minute ventilation; or devel-
compared with conventional ventilation, Each patient underwent fiberoptic bron-
opment of ventilator-associated tracheobron-
HFPV has been shown to improve gas choscopy within the first 24 hrs of burn in-
chitis (VATB) (16). Use of other adjuncts be-
exchangeatlowerpeakandmeanairway tensive care unit admission for diagnosis of fore rescue such as induction of chemical
pressures in various patient populations inhalation injury. Diagnostic findings on paralysis,recruitmentmaneuvers,proneposi-
(4, 9–11). To date, only one prospective bronchoscopy included carbonaceous debris tioning, or initiation of inhaled nitric oxide
randomizedcontrolledtrialhasbeenper- below the vocal cords, mucosal erythema, wasdeterminedbytheattendingphysicianon
formed in adult burn patients involving and/or ulceration. Other standard practices acase-by-casebasis.
duringthestudyperiodincludedresuscitation Ventilator Weaning. Ventilator liberation,
35subjectswithinhalationinjury,which
of all patients with (cid:1)20% total body surface definedasextubationorthedisconnectionofa
demonstrated improved oxygenation
areaburnsusingthemodifiedBrookeformula patient’stracheostomytubefrommechanical
early but no difference in pulmonary in-
(15) to determine the initial fluid rate with ventilatorsupportfor48consecutivehrs,was
fection or mortality (12).
subsequent titration of intravenous fluids to standardized in both arms using a mode-
In the last decade, lung-protective sustain a 30 to 50 mL/hr urine output. All specific weaning protocol (see Supplemental
low-tidal volume conventional ventila- subjectswithfull-thicknessburnwoundsun- Figs. 5 and 6 [see Supplemental Digital Con-
tion (LTV) has led to an improvement in derwent early excision ((cid:2)7 days after burn) tent 1, http://links.lww.com/CCM/A158]). The
clinical outcomes among patients with and skin grafting, application of topical anti- liberation protocol included daily sedation
acute lung injury/acute respiratory dis- microbials, and implementation of standard- holidaysandrespiratorytherapy-guidedliber-
tress syndrome (ALI/ARDS) (13). This ized infection control protocols. Ventilator ationprotocolssupplementedbyspontaneous
strategy has been widely extrapolated to modebeforestudyenrollmentwasdetermined breathingtrials(seeSupplementalFig.7[see
Supplemental Digital Content 3, http://
patients without ALI/ARDS (14). How- bytheadmittingsurgeon.
links.lww.com/CCM/A160]).
ever,thebenchmarkstudiesthatdefined Ventilator Procedures. Subjects were
Compliance with specific algorithms was
the LTV approach largely excluded placedonthestudyventilationmodewithin1
monitored on a daily basis by the principal
burned patients from enrollment. In ad- hrofrandomization.Thoserandomizedtothe
investigator (KKC) along with the research
dition, the earlier studies of HFPV vs. HFPVarmwereplacedontheVDR-4(Percus-
sionaire, Sandpoint, ID) and managed using staff. Incidents of protocol noncompliance
conventional ventilation were conducted
an algorithm, which continued until libera- wererecordedasprotocoldeviationsorviola-
during the era before LTV. It is unclear
tion from the ventilator, rescue mode inter- tionsandreportedtotheInstitutionalReview
whether the LTV strategy can be effec-
vention, at least 28 days for persistent venti- Board.
tively applied in patients with severe
latorsupport,ordeath(seeSupplementalFig. DataCollection.Patientdemographicdata
burns with or without inhalation injury. 1 [Supplemental Digital Content 1, http:// as well as total body surface area, percent
We therefore conducted a prospective links.lww.com/CCM/A158]). Those random- full-thicknessburn,diagnosisofinhalationin-
randomizedcontrolledtrialtodetermine ized to the LTV arm were placed on volume- jury, Injury Severity Score, diagnosis of ALI/
whether HFPV would improve clinical limitedassist-controlventilationusingalow- ARDSusingthestandardcriteria(17),andthe
outcomes in comparison to LTV. tidal volume algorithm adapted and modified number of ventilator days before randomiza-
fromtheARDSnetstudy(13)(seeSupplemen- tion were recorded within 24 hrs of random-
MATERIALS AND METHODS tal Fig. 2 [Supplemental Digital Content 1, ization.Exceptwherestatedotherwise,allpa-
http://links.lww.com/CCM/A158]). The tidal tientandventilatorparameterswererecorded
Patients.Afterobtainingapprovalfromthe volume was set at 6 mL/kg of predicted body dailyuntil28daysafterrandomization.
local Institutional Review Board, we con- weight and reduced further by 1 mL/kg, if End Points. The primary end point was
ductedaprospective,randomizedclinicaltrial necessary, to maintain a plateau pressure of ventilator-freedaysinthefirst28days,defined
ina16-bedburnintensivecareunitlocatedin (cid:2)30 cm H O. Subjects in this arm were also as the number of days after randomization
2
atertiarymilitaryteachinghospital.Alladult continueduntilliberationfromtheventilator, from day 0 to day 28 alive without ventilator
patients(cid:1)18yrsofageadmittedtoourburn rescue mode intervention, at least 28 days of assistanceforatleast48consecutivehrs.Sec-
intensive care unit who were intubated and persistentventilatorsupport,ordeath. ondary end points were identified as follows:
placedonmechanicalventilationwereeligible Ventilator Rescue. Subjects who did not 28-day mortality; days free from nonpulmo-
forenrollmentiftheyhadananticipatedneed meetpredeterminedoxygenationandventila- naryorganfailureasadaptedfromtheARDS-
of (cid:1)24 hrs of continued ventilatory support. tiongoalsonthestudymodedespiteventila- netstudy(13);VAPasdefinedbytheAmerican
Patientswhowerenotintubatedatthetimeof tor-specific optimization were switched to a Thoracic Society and the Infectious Disease
admission but later intubated during their rescuemodeofventilation.EitherHFPVusing Society of America (18); barotrauma as de-
hospitalizationwerealsoeligibleforthestudy. theVDR-4orairwaypressurereleaseventila- fined as a new pneumothorax, pneumomedi-
CritCareMed2010Vol.38,No.10 1971
astinum, subcutaneous emphysema, intersti-
tial emphysema, or pneumatocele (cid:1)2 cm in
diameter not associated with a vascular pro-
cedure,lungbiopsy,orthoracentesis;VATBas
definedascarinalormainstemairwayfriabil-
ity and sloughing with associated bleeding;
need for rescue mode; and death before 28
days after randomization. Notably, VATB was
only diagnosed after the patient had spent at
least 7 days on the assigned ventilator mode
and had not been diagnosed with inhalation
injury on admission (16). Additional second-
ary outcome measures included the ratio of
PaO2toFIO2andtheoxygenationindexinthe
first7daysafterrandomization.Oxygenation
indexwasdefinedastheproductoftheFIO2in
percentandmeanairwaypressureincmH O
2
dividedbythePaO2.
PlasmaCytokineConcentrations.Foreach
Figure1. CONSORTdiagram.
subject, immunoassays for interleukin (IL)-
1(cid:3), IL-6, IL-8, granulocyte-macrophage colo-
ny-stimulatingfactor,andtumornecrosisfac-
tor-(cid:4) were performed using a human alyzed with SAS version 9.1 (SAS Institute, Table1.Baselinecharacteristicsofstudysubjects
inflammatoryfive-plexassaykit(BiosourceIn- Cary,NC).
HFPV LTV
ternational, Inc, Camarillo, CA) and analyzed
(n(cid:6)31) (n(cid:6)31) p
onaLuminex100luminescentanalyzer(Lu- RESULTS
minex Corp, Austin, TX) on days 0, 3, and 7.
Each sample was measured in duplicate and After 3 yrs of enrollment, interim Agea 28(23–45) 32(24–45) NS
Sex 87%males 84%males NS
averaged.Greaterthan90%ofvaluesresulted analysis revealed a significant number of
Combat-injured, 14(45) 14(45) NS
for IL-1(cid:3), granulocyte-macrophage colony- subjectsintheLTVarmrequiredrescue,
no.(%)
stimulating factor, and tumor necrosis fac- which served as the trigger to close the PercentTBSAa 34(21–51) 35(24–50) NS
tor-(cid:4)fellbelowthelowerlimitofquantitation study to further enrollment. Between PercentFTa 14(4–26) 16(8–31) NS
andthuswerenotfurtheranalyzed. April 2006 and May 2009, 387 patients Inhalation, 12(39) 11(35) NS
Statistical Analysis. In 2004, institutional no.(%)
werescreenedforeligibility.Ofthese,155
performance improvement data revealed that ISS 25(16–34) 25(16–34) NS
patients met criteria of which 62 were
ALI/ARDS, 12(39) 14(45) NS
the average ventilator days per patient stay
was 13 (cid:5) 7 in our burn intensive care unit. randomized,31totheHFPVarmand31 no.(%)
totheLTVarm(Fig.1).Subjectsinboth Priorventilator 2(1–3) 2(1–3) NS
Based on these data, sample size of 170 sub-
groups received mechanical ventilator days
jects(85ineacharm)wascalculatedtodetect
support a median of 2 (1–3) days before
anabsolutedifferenceof2ventilatordaysbe-
HFPV,high-frequencypercussiveventilation;
tween the two groups to achieve 80% power randomizationintothestudy.Therewere
LTV, low-tidal volume ventilation; TBSA, total
andtwo-sided(cid:4)(cid:6)0.05.Oneinterimanalysis no statistically significant differences in
body surface area burned; FT, full thickness
wasplannedaftereither50%enrollmentwas demographics, total body surface area
burned; ISS, Injury Severity Score; ALI/ARDS,
achievedorafter3yrshadpassedsincebegin- burned,percentfullthicknessburned,or
acutelunginjury/acuterespiratorydistresssyn-
ning enrollment. It was predetermined that diagnosisofinhalationinjuryatthetime drome;NS,nonsignificant.
enrollment would be stopped if significance of enrollment (Table 1). aMedian(interquartilerange,1–3).
wasachievedintheprimaryendpoint.Itwas A detailed description of ventilator
also predetermined, for safety reasons, that
characteristicsduringthefirstweekafter
enrollment would be stopped if 30% of sub-
randomization is provided in Table 2. 3). Of the secondary end points, the
jectsinonearmneededtoswitchtoarescue
Peak inspiratory pressures were signifi- number of patients requiring rescue
mode.
cantlylowerintheHFPVarmwhencom- (two [6%] vs. nine [29%], p (cid:6) .02) and
Forcontinuousvariables,alldataarepre-
sented as mean (cid:5) SD or median with inter- pdaaryesdawftietrhrtahnedLoTmVizaartmiondu.rTinhgertehewfiasrstno5 t(hzeeronu[0m%b]ervsw.hfooudre[v1e3l%op]e,dpb(cid:6)ar.0o4tr)awuemrea
quartilerange.Continuousdatawereanalyzed
significant difference in the daily mean significantly different between HFPV
using two-tailed Student’s t test or Mann-
airwaypressuresoverthefirstweeknoted and LTV. There was a trend toward
WhitneyUtestwhenappropriate.Categorical
between the two arms. Over the 28-day those in the HFPV arm having less VAP
datawereanalyzedwithchi-squareorFisher’s
study period, 90% of all recorded tidal than the LTV arm (10 [32%] vs. 16
exacttestswhenappropriate.Statisticalsignif-
icancewassetatp(cid:2).05.Whereappropriate, volumes were (cid:2)8 mL/kg as dictated by [52%], p (cid:6) .12).
repeated-measures analysis of variance was the LTV algorithm, whereas 87% of all Afterrandomization,ninemetcriteria
performed to assess for differences over time recordedplateaupressureswere(cid:2)30cm for rescue and switched to either airway
within the same group as well as differences H2O. pressure release ventilation or HFPV for
between groups over time. Comparisons of Overall, ventilator-free days in the profound hypoxemia (n (cid:6) 5) or for pro-
primaryandsecondaryendpointsbetweenthe first 28 days were no different between found hypercapnia (n (cid:6) 4). Three sub-
two groups were performed according to the theHFPVarmandtheLTVarm(12(cid:5)9 jects in the LTV arm were switched to
intention-to-treatprinciple.Alldatawerean- vs. 11 (cid:5) 9, p (cid:6) nonsignificant) (Table airway pressure release ventilation with-
1972 CritCareMed2010Vol.38,No.10
Table2.Ventilatorcharacteristicsforeacharm0,3,and7daysafterrandomization
Day0 Day3 Day7
HFPV LTV HFPV LTV HFPV LTV
Tidalvolume,mL/kg(no.) — 6.2(cid:5)1.0(24) — 6.5(cid:5)1.2(21) — 6.4(cid:5)1.3(7)
PIP,cmHO(no.) 26(cid:5)4(27) 32(cid:5)10(24)a 28(cid:5)8(24) 40(cid:5)11(22)a 27(cid:5)10(10) 33(cid:5)13(6)
2
Pulsefrequency, 562(cid:5)33(26) — 572(cid:5)74(19) — 580(cid:5)94(15) —
subtidalbreaths/min(no.)
Plateaupressure,cm — 23(cid:5)9(16) — 29(cid:5)8(15) — 31(cid:5)14(5)
HO(no.)
2
TotalCPAP(cid:7)/PEEP,cm 10(cid:5)1(20) 7(cid:5)3(29)a 11(cid:5)2(20) 10(cid:5)5(25) 11(cid:5)2(19) 10(cid:5)7(10)
H O(no.)
2
Meanairwaypressure,cm 18(cid:5)6(20) 16(cid:5)9(27) 20(cid:5)10(18) 21(cid:5)8(22) 20(cid:5)10(9) 16(cid:5)5(7)
HO(no.)
2
Respiratoryrate(no.) 22(cid:5)8(27) 22(cid:5)8(29) 28(cid:5)10(20) 29(cid:5)7(25) 21(cid:5)6(10) 25(cid:5)9(10)
Minuteventilation, — 10(cid:5)4(23) — 12(cid:5)6(20) — 14(cid:5)7(9)
L/min(no.)
pH(no.) 7.34(cid:5)0.05(30) 7.30(cid:5)0.11(28) 7.34(cid:5)0.11(22) 7.33(cid:5)0.10(27) 7.36(cid:5)0.08(17) 7.37(cid:5)0.07(15)
PaCO2,mmHg(no.) 44(cid:5)7(30) 52(cid:5)10(28)a 51(cid:5)12(22) 54(cid:5)14(27) 49(cid:5)16(17) 45(cid:5)9(15)
PaO2,mmHg(no.) 135(cid:5)77(30) 93(cid:5)36(28)a 94(cid:5)81(22) 85(cid:5)25(27)a 92(cid:5)23(17) 95(cid:5)29(15)
FiO2,%no. 46(cid:5)23(30) 54(cid:5)20(28)a 56(cid:5)29(22) 53(cid:5)20(27) 51(cid:5)28(17) 49(cid:5)21(15)
PFR(no.) 368(cid:5)128(30) 258(cid:5)117(28)a 285(cid:5)109(22) 213(cid:5)95(27)a 268(cid:5)131(17) 255(cid:5)103(15)
OI(no.) 9(cid:5)16(20) 10(cid:5)9(27) 7(cid:5)5(18) 12(cid:5)7(22)a 6(cid:5)4(9) 11(cid:5)7(7)
HFPV, high-frequency percussive ventilation; LTV, low-tidal volume ventilation; PIP, peak inspiratory pressure; CPAP, continuous positive airway
pressure;PEEP,positiveend-expiratorypressure;PFR,PaO2/FiO2ratio;OI,oxygenationindex.
ap(cid:2).05whencomparedwithHFPV.ForsubjectsontheHFPV,totalCPAPisasumoftheoscillatoryPEEPandthedemandPEEP.
Table3.Mainoutcomevariables Table4.Comparisonofsubgroupofpatientswith The ratio of PaO2 to FIO2 was signifi-
inhalationinjury cantlybetterintheHFPVarmondays0,
HFPV LTV
1,2,and3whencomparedwiththeLTV
(n(cid:6)31) (n(cid:6)31) p HFPV LTV
arm(Fig.2).Thisdifferencewasnotsus-
(n(cid:6)12) (n(cid:6)11) p
Ventilator-freedaysa 12(cid:5)9 11(cid:5)9 NS tained after 4 days. Furthermore, when
Daysfreefrom 15(cid:5)11 15(cid:5)10 NS Ventilator-freedaysa 9(cid:5)7 9(cid:5)10 NS comparing oxygenation index, there was
nonpulmonary Daysfreefrom 11(cid:5)11 13(cid:5)10 NS no difference detected between the two
organfailurea nonpulmonary groups or over time.
Death,no.(%) 6(19) 6(19) NS organfailurea Sedation requirements trended lower
Rescue,no.(%) 2(6) 9(29) .02 Death,no.(%) 3(25) 3(27) NS
intheHFPVarmcomparedwiththeLTV
VAP,no.(%) 10(32) 16(52) NS Rescue,no.(%) 0(0) 7(64) .001
VATB,no.(%) 2(6) 0 NS VAP,no.(%) 6(50) 7(64) NS arm with both the median (interquartile
Barotrauma,no.(%) 0(0) 4(13) .04 Barotrauma,no.(%) 0(0) 2(18) NS range)totaldoseoflorazepaminthefirst
7days(29[21–56]mgvs.55[31–76]mg)
HFPV,high-frequencypercussiveventilation; HFPV,high-frequencypercussiveventilation; or28days(54[27–96]mgvs.80[41–135]
LTV, low-tidal volume ventilation; VAP, ventila- LTV, low-tidal volume ventilation; VAP, ventila- mg).However,thesecomparisonsdidnot
tor-associated pneumonia; VATB, ventilator- tor-associatedpneumonia;NS,nonsignificant. reachstatisticalsignificance(p(cid:6).11and
associatedtracheobronchitis;NS,nonsignificant. aMean(cid:5)SD. .18, respectively).
aMean(cid:5)SD.
Mean plasma interleukin-6 and inter-
PaCO2 of 80 (cid:5) 14 mm Hg before rescue. lweeurkeinn-8oldevifeflesre(pngt/movLe)rattidmaeysw0i,t3h,inantdh7e
out meeting predetermined rescue crite- Six of nine rescues occurred within 7
same group or between the two groups
ria and were not counted as a true “res- daysafterrandomizationtotheLTVarm.
on repeated-measures analysis of vari-
cue.” Two subjects in the HFPV were Two patients died despite rescue, one
ance (Fig. 3).
switched to airway pressure release ven- withinthefirst7daysandanotheratday
tilation after meeting the criteria for 20,bothsecondarytomultipleorganfail-
DISCUSSION
VATB.AmongthefivesubjectsintheLTV ure. In an a priori subgroup analysis of
requiring rescue for profound hypox- patients with inhalation injury (n (cid:6) 23), To the best of our knowledge, this is
emia, the mean ratio of PaO2 to FIO2 was 64%ofsubjectsintheLTVarmrequired the first study to compare, in a random-
58 (cid:5) 6 with a mean positive end- rescue,whereasnoneoftheHFPVneeded ized controlled fashion, HFPV to a low-
expiratory pressure of 22 (cid:5) 2 cm H O rescue (p (cid:6) .001) (Table 4). Table 5 lists tidal volume strategy in severely burned
2
beforerescue.Twoofthesepatientswere ventilator and arterial blood gas charac- adult patients. By the intent-to-treat
paralyzed, received inhaled nitric oxide, teristicsofallrescuesubjects.Bothofthe principle, there was no detectible differ-
and were placed in the prone position subjectsintheHFPVarmwhodeveloped enceintheprimaryendpointofventila-
before rescue. Among the four subjects VATBdemonstratednormalizationofthe tor-freedaysinthefirst28daysbetween
requiring rescue for hypercapnia, the mucosa after 24 hrs on the alternate a HFPV group and a LTV group. Even if
mean pH was 7.18 (cid:5) 0.04 with a mean mode. the study had continued until target en-
CritCareMed2010Vol.38,No.10 1973
Table5.Ventilatorandarterialbloodgascharacteristicsofsubjectsrequiringrescue
Study Rescue
No. Mode Mode Criteria Daya TV RR PEEP Pl FiO2 pH PaCO2 PaO2 Outcome
1 LTV APRV Hypoxemia 4 5.3 34 24 36 100 7.21 65 57 Lived
2 LTV APRV Hypoxemia 5 4.5 30 20 32 100 7.35 54 50 Diedonday20
3 LTV APRV Hypoxemia 11 7.2 38 20 33 100 7.18 55 63 Lived
4 LTV APRV Hypoxemia 12 5.5 36 24 34 100 7.28 67 54 Lived
5 LTV APRV Hypoxemia 4 6.5 30 20 37 100 7.05 83 64 Lived
6 LTV HFPV Hypercapnia 13 6.2 40 5 28 80 7.16 61 105 Lived
7 LTV APRV Hypercapnia 3 7.1 36 10 37 60 7.23 76 145 Lived
8 LTV HFPV Hypercapnia 5 7.1 30 10 37 100 7.15 92 78 Lived
9 LTV HFPV Hypercapnia 5 7.5 30 8 38 40 7.18 89 90 Diedonday7
Study Rescue
No. Mode Mode Criteria Daya PF PIP RR CPAPt FiO2 pH Paco2 PaO2 Outcome
1 HFPV APRV VATB 5 800 30 20 10 50 7.29 47 75 Diedonday15
2 HFPV APRV VATB 4 700 22 15 10 30 7.33 58 74 Lived
TV,tidalvolumeinmillilitersperkilogram;RR,respiratoryrateperminute;PEEP,positiveend-expiratorypressure(cmH O);Pl,plateaupressure(cm
2
HO); LTV, low-tidal volume ventilation; APRV, airway pressure release ventilation; HFPV, high-frequency percussive ventilation; PF, pulse frequency
2
(subtidalbreath/minute);PIP,peakinspiratorypressure(cmHO);VATB,ventilator-associatedtracheobronchitis;CPAPt,totalcontinuouspositiveairway
2
pressure(cmHO).
2
aNumberofdaysafterrandomization.Allvaluesrepresentedarethoseobtainednomorethan1hrbeforerescue.
beenextrapolatedtopatientswithoutALI
(14, 26). Determann et al (27), in a pre-
ventive randomized trial, recently dem-
onstrated that mechanical ventilation
withtidalvolumesof6mL/kgincritically
illpatientswithoutALI/ARDSwasassoci-
ated with a decrease in the incidence of
lung injury (2.6% vs. 13.5%) when com-
pared with 10 mL/kg tidal volumes.
Highertidalvolumeswerealsoassociated
with sustained cytokine production as
measured in plasma in the form of IL-6
levels.
Basedonourfindings,itappearsstrict
applicationofaLTVstrategymaybesub-
optimal in the burn population, particu-
larly in those with inhalation injury.
Meeting oxygenation and ventilation
goalsinpatientswithsevereburnscanbe
challenging.Thepresenceofnoncompli-
antthoracicandabdominalescharbefore
excisionandgraftingandsubsequentcir-
Figure 2. Comparison of the ratio of the partial pressure of arterial oxygen (PaO2) to fraction of cumferential extrathoracic placement of
inspiratoryoxygen(FIO2).Datapointsaredepictedasmean(cid:5)SEM*p(cid:2).05. wound dressings make it difficult to in-
terpretplateaupressurestoguidealung-
rollment, it is unlikely that a significant on interim analysis, the decision was protectivestrategy.Theconsiderablevol-
difference would have been detected. madetostopthetrialforsafetyconcerns. ume of fluids needed to resuscitate
Among our secondary end points, need Overthelastdecade,applicationofthe patients with large burns has been well
forrescuewassignificantlyhigherinthe “first do no harm” principle in the form described previously (28–30). A recent
LTVarmwith29%ofthesubjectsunable of a lower tidal volume strategy in the report by our group demonstrated a re-
tomeetoxygenationandventilationgoals management of ALI/ARDS has been one quirement of up to a mean of 25(cid:5) 11 L
despite optimization of the study mode. oftheimportantadvancesincriticalcare in the first 24 hrs alone for an average
Inasubgroupofpatientswithinhalation (3, 13). Abundant experimental and clin- burn size of 50% total body surface area
injury, 64% (seven of 11 subjects) in the icalstudieshavedemonstratedthebene- (29). Edema secondary to massive burn
LTV arm required rescue. Thus, the ma- ficial effects of an LTV strategy on vo- resuscitation compounds the extrapul-
jority of rescue patients were those with lutraumaandbarotrauma(13,19–25).In monary impediment to lung excursion.
inhalationinjury.Basedonthesefindings clinical practice, the LTV strategy has Thepresenceofinhalationinjuryfurther
1974 CritCareMed2010Vol.38,No.10
Figure3. Comparisonofimmunoassaysforinterleukin(IL)-6andIL-8over7daysafterrandomization.
complicates ventilator management. In initiallybasedonoxygenationparameters study published to date in adult burns
animalmodels,ithasbeendemonstrated (13).Regardless,gasexchangegoalswere had neither the power nor an adequate
that the major insult after inhalation in- met in all subjects in the HFPV arm, follow-upperiodtodetectadifferencein
jury is the obstruction and collapse of whereastheywerenotinnearlyonethird the incidence of pneumonia (12). Based
smallairwaysleadingtodistalatelectasis of the LTV arm. Perhaps an alternate onourresults,setting(cid:4)(cid:6)0.05,asample
andsubsequentpneumonia(31).Inaddi- strategy is necessary to optimize LTV. It size of 110 patients in each arm would
tion, severe inhalation injury can result iswellrecognizedthatplateaupressureis havebeenrequiredtodetectadifference
inanalveolarfillingprocessthatischar- not the best measure of estimating inVAPwith80%power.Amulticentered
acterizedbydiffusealveolardamagecon- transalveolarpressureinthispatientpop- study would be necessary to attain these
sistent with ALI/ARDS (32). ulationwhenconsideringthevariousex- numbers in this population.
Although ventilation was similar in trapulmonary contributors. A strategy Despitethelackofapositivefindingin
both arms (Table 2), oxygenation, in the guidedbyesophagealpressuresmaybea many of our clinical outcome variables,
form of the ratio of PaO2 to FIO2, was more effective approach when dealing we have demonstrated that an HFPV-
significantlybetterintheHFPVarmover withsuchapopulation.Talmoretal(36) basedstrategyisatleastnomoreharmful
the first week after randomization (Fig. demonstrated that a ventilator strategy than an LTV-based strategy. From an in-
2). Carman et al (33) reported similar using esophageal pressures to estimate flammatory standpoint, it appears that
findingsin64childrenwithsevereburns transpulmonary pressure significantly HFPV does not promote more cytokine
and respiratory failure randomized to ei- improved oxygenation by allowing the release than a low-tidal volume strategy
ther HFPV or pressure-control ventila- use of higher levels of positive end- as evidenced by IL-6 and IL-8 levels over
tion (target tidal volume 6–8 mL/kg) by expiratory pressure. the first 7 days (Fig. 3). In fact, our re-
demonstrating improved oxygenation at Still,basedonintenttotreat,ourpri- sults indicate that HFPV may even be
lower peak airway pressures with HFPV. mary outcome of ventilator-free days in more “lung-protective” than LTV when
ThefactthattheratioofPaO2toFIO2was thefirst28dayswasnodifferenteitherby considering the 13% incidence of baro-
higher despite equivalent mean airway primaryanalysisorbylog-ranktest(Fig. trauma over 28 days compared with 0%
pressure and positive end-expiratory 4). Neither were other clinically impor- intheHFPVarm(Table3).However,this
pressuresettingsandlowerpeakinspira- tantoutcomessuchasmortalityandVAP finding should be counterbalanced by
torypressuresintheHFPVarm(Table2) (Table 3). In our study, there was only a the occurrence of VATB in 6% of the
suggeststhatHFPVusesalternatemech- trendtowardalowerincidenceofVAPin HFPV group. Supplemental Figure 8
anisms that augment gas exchange. the HFPV arm when compared with the depicts this condition in one of the
Thesemechanisms,toincludelongitudi- LTV arm (32% vs. 53%, p (cid:6) .12). The study subjects see Supplemental Fig. 8
naldispersion,pendelluft,andmolecular percussive effect generated by the flow- [see Supplemental Digital Content 4,
diffusion,havebeenpreviouslydescribed interrupted subtidal breaths in HFPV is http://links.lww.com/CCM/A161]). VATB
(9, 34, 35). It is important to note that thought to facilitate the evacuation of has been described previously as a condi-
early improvement in oxygenation may airwaydebrisandmucousoftenabundant tion that is likely to be secondary to inad-
not be relevant or may be countered by afterinhalationinjury(6).Assuch,HFPV equate humidification delivery (16). Allan
long-termharmasevidencedbytheARD- haslongbeenadvocatedasanimportant et al (38) demonstrated that HFPV’s dis-
Snettrialinwhichthelargetidalvolume mode of ventilation in patients with in- tinctgas-flowmechanismcanimpairheat-
group appeared to have favorable results halation (7, 37). The only prospective ing and humidification in the trachea.
CritCareMed2010Vol.38,No.10 1975
Figure4. Kaplan-Meiercurvedepictingtheprobabilityofsubjectsremainingonmechanicalventilationoverthe28-daystudyperiod.
Thus,testingandoptimizingthehumidifi- this purpose to date, perhaps highlight- tokine analyses. We also especially thank
cationsystemisvitalwhenusingthismode ing the difficultly faced by many investi- JohnJones,MS,forhisstatisticalanalysis
ofventilation. gators attempting clinical trials in niche during the planning stages of this trial;
There is an important trend toward populations.Therecentestablishmentof Denise Jimenez, CRT, for contributing
HFPV subjects requiring less sedation a multicenter trials group among burn her time for data entry and verification;
thanLTVpatients.Thismaybetheresult centersinNorthAmericamayhelpassist andOtiliaSanchez,forproofingthefinal
ofthe“inspiratoryfail-safe”featureinthe in future collaborative studies to over- manuscript. Finally, we are indebted to
HFPV that permits spontaneous ventila- come these types of limitations (41, 42). the burn intensive care unit nurses and
tion in both the inspiratory and expira- Anyfuturemulticenterstudieswouldhave respiratorytherapistswithoutwhomthis
tory phases (39). On the other hand, it totakeintoaccountthesepreliminaryfind- work would not be possible.
may be that LTV is not well tolerated in ingsandaddressthepotentialsafetyissues
thispopulation,perhapssecondarytoin- surrounding a low-tidal volume-based
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