Sequential meta-analysis to determine whether or not to start another trial: the high frequency versus conventional mechanical ventilation example

Transcription

1 . Sequental meta-analyss to determne whether or not to start another tral: the hgh frequency versus conventonal mechancal ventlaton example Sequental analyss shows value of new trals Casper W. Bollen, Cuno S.P.M. Uterwaal, Adranus J. van Vught, Ingeborg van der Tweel Submtted 79

2 ABSTRACT Background Clncal trals can be stopped early based on nterm analyses or sequental analyses. Sequental analyses could also be appled to decde f already enough evdence s gathered n prevous trals. In a number of clncal trals, hgh frequency ventlaton has been compared wth conventonal mechancal ventlaton n premature neonates wth dopathc respratory dstress syndrome. Sequental meta-analyss was used to determne whether more trals have to be performed. Methods Fve trals were selected that compared hgh frequency ventlaton applyng a hgh lung volume strategy wth conventonal mechancal ventlaton usng a lung protectve ventlaton strategy. Death or chronc lung dsease and chronc lung dsease n survvors were prmary clncal outcomes of nterest. Sequental meta-analyses were appled to these fve studes. Results After ncludng the frst study of the last fve trals n a sequental metaanalyss, the boundary of no clncally relevant effect was crossed for the outcome, death or chronc lung dsease. A senstvty analyss usng a reducton n the sze of assumed clncally relevant effect showed the same fndngs after two trals. The same result was found for reducton of chronc lung dsease n survvors as outcome. 80

3 Conclusons Sequental meta-analyses showed that already n the frst out of fve studes a lack of clncally relevant effect was establshed of hgh frequency oscllatory ventlaton compared wth conventonal mechancal ventlaton n premature neonates. Ths could have been an mportant argument n decsons to change the study desgn or even refran from performng the last four trals. 81

4 Introducton Whether or not to start a randomzed clncal tral (RCT) should depend on the expected ablty of the yelded evdence n such a tral to change current clncal opnon, takng nto account prevously obtaned evdence. It s a matter of good statstcal practce to make a pror estmate of the requred sze of a randomzed clncal tral, based on the expected clncally relevant dfference between treatments, the power 1- and the sgnfcance level. Stoppng randomzed clncal trals early, before the estmated fxed sze s reached, s readly accepted for ethcal or economcal reasons. One or more nterm analyses can be planned to determne whether enough evdence has been obtaned to dscontnue a tral prematurely. Interm analyses are performed on cumulatve data of patents successvely ncluded n a RCT. Sequental testng s a collectve noun for these nterm analyses. We speak of contnuous sequental testng, when cumulatve data are analyzed after every new patent response. Group sequental testng s a seres of nterm analyses after every new group of patent responses. A meta-analyss pools the results of a number of comparable RCTs n a systematc and quanttatve way 1. A cumulatve meta-analyss can be vewed as a number of nterm analyses on the aggregated data of successve, chronologcally ordered RCTs. A cumulatve meta-analyss s thus a group sequental test, but each group now represents patents from another tral 2. In the followng we wll ntroduce the sequental meta-analyss as a partcular form of a cumulatve meta-analyss wth adjustment for multple testng and a guaranteed power (see Dscusson for further comments). We appled a sequental metaanalyss to determne whether or not enough evdence was gathered already n a number of publshed RCTs. 82

5 Avodance of ventlator nduced lung damage s a major ssue n research of mechancal ventlaton. It s generally thought that preventon of repeated collapse of alveol and lmtng overdstenson of alveol protects the lung from the adverse effects of mechancal ventlaton 3. Therefore, lung protectve ventlaton strateges am at reducng tdal volumes and mantanng hgher mean arway pressures. A consderable number of randomzed clncal trals have been performed to determne whether hgh frequency oscllatory ventlaton mproves pulmonary outcome n premature neonates wth dopathc respratory dstress syndrome compared wth conventonal mechancal ventlaton Hgh frequency oscllatory ventlaton s a method of ventlaton n whch alveolar gas exchange s mantaned by pressure swngs ntatng small dsplacements of ventlatory gases, consderably smaller than conventonal tdal volumes, at frequences generally from 5-20 Hz supermposed on a contnuous postve pressure. Hgh frequency oscllatory ventlaton allows hgher endexpratory pressures wth lower tdal volumes and hgher mean arway pressures and s therefore proposed as currently the most optmal form of lung protectve ventlaton 17;18. Two recent large randomzed controlled trals faled to demonstrate a sgnfcant advantage of hgh frequency oscllatory ventlaton over conventonal mechancal ventlaton, or showed only a small beneft 14;15. A meta-analyss showed no reducton n mortalty. However, a small reducton was shown n the rsk of chronc lung dsease at weeks post-gestatonal age 19. Our study used sequental meta-analyss to determne at what pont n tme addtonal trals dd not contrbute anymore to avalable evdence. 83

6 Methods In a prevous report we dentfed 13 studes n whch hgh frequency ventlaton was compared wth conventonal mechancal ventlaton n the treatment of dopathc respratory dstress syndrome n premature neonates 20. The last fve studes were comparable wth respect to patent populaton, type of hgh frequency ventlaton (oscllator) and ventlaton strateges that were appled n both hgh frequency oscllatory ventlaton and conventonal mechancal ventlaton 11; These fve studes were ncluded chronologcally n our sequental meta-analyss. The followng data were extracted: gestatonal age or brth weght; tme of ncluson; type of hgh frequency ventlator; ventlaton strateges appled n both treatment arms; prmary outcome measurements; power and estmated effect sze upon whch power analyss was based. The followng outcome measures were dentfed: chronc lung dsease, defned as oxygen dependency at the postconceptonal age of 36 weeks; mortalty to 36 weeks of age; ntraventrcular hemorrhage grade III and IV; and perventrcular leukomalaca. A hgh lung volume strategy wth hgh frequency ventlaton was assumed f two or more of the followng tems were explctly stated n the methods: ntal use of a hgher mean arway pressure than on conventonal mechancal ventlaton; ntal lowerng of nspred oxygen before reducng mean arway pressure; and/or use of alveolar recrutment maneuvers. A lung protectve strategy n the conventonal mechancal ventlaton group was based on specfyng the PaCO2 goal, allowng permssve hypercapna, and a hgh ntal ventlatory rate and/or explct avodance of hgh peak nspratory pressures, targeted at reducng tdal volumes. 84

7 Statstcal analyss An a pror estmate of the expected effect sze of the prmary outcome was deduced from reported expected clncally relevant dfferences n power analyses of ncluded studes. A probablty of 0.05 for a type I error and a power of 0.80 were specfed n our sequental meta-analyses Senstvty analyses were performed dmnshng the expected dfferences n effect estmates and excludng studes by Thome et al 11 and Morette et al 13 from the analyses. Those last studes were excluded n senstvty analyss because of methodologcal reasons. Thome et al 11 used a dfferent type of HFV ventlator and the HFV used by Morette et al 13 was wthdrawn from market. Reducng the sze of clncally nterestng effect would ordnarly requre a larger sample sze for that dfference to be detected. Senstvty analyss thus was conducted to rule out the need for more trals to establsh smaller clncally relevant dfferences. All data were extracted accordng to the ntenton-to-treat prncple. For the outcome chronc lung dsease or death, the total number of randomzed patents was put n the denomnator wth patents that ded or wth chronc lung dsease n the numerator. To calculate the rsk of chronc lung dsease, the denomnator was equal to the number of patents that survved and the numerator was equal to the number of patents wth CLD.. Intraventrcular hemorrhage grade III and IV and perventrcular leukomalaca were determned wth the number of randomzed patents n the denomnator. Statstcal heterogenety between trals was nvestgated by calculatng the test statstc I 2 (I 2 = 100% (Q df)/q, where Q s Cochran s heterogenety statstc and df the degrees of freedom) 21. Sequental meta-analyss The th of the chronologcally appeared RCTs contrbutes two quanttes V and Z to the cumulatve amount of nformaton. V s a measure for the amount of nformaton n that RCT,.e. V s approxmately proportonal to the number of patents ncluded n that RCT. Z s a measure for the effect 85

8 sze n that RCT. After every new RCT the total amount of nformaton s cumulated n V = V and Z = Z. Z and V are thus the pooled results from dfferent trals and the sequental meta-analyss can be vewed as a stratfed analyss (see Appendx). Every new RCT thus results n a new (Z,V)-pont, depcted n a graph wth V on the horzontal and Z on the vertcal axs. Four boundares are plotted n the graph. These boundares depend on the two-sded type I error, the power 1- and the expected effect sze (n terms of the logarthm of the odds rato (OR)) as stated under the alternatve hypothess. If the successve (Z,V)-ponts cross the upper or lower boundary, the sequental meta-analyss can be stopped: the null hypothess of treatment equvalence s rejected n favour of the alternatve hypothess,.e. sgnfcant evdence s gathered for the expected effect sze. If the successve (Z,V)-ponts cross one of the nner, wedge-shaped boundares, the sequental meta-analyss can be stopped for futlty : the null hypothess s accepted,.e. t s very unlkely that the treatments wll be concluded dfferent n the amount as stated under the alternatve hypothess. If the successve (Z,V)-ponts reman wthn the trangular boundares, results of a new RCT are added to the analyss. The outer straght-lne boundares represent the theoretcal lmts for decsonmakng. The nner, curved boundares represent a contnuty correcton, because the unt of analyss s the tral (a group of patents) and not the ndvdual patent. (For llustraton see Fgures 1 and 2). Specfcally, when one of the nner boundares s crossed one can stop the analyss. For further detals on the constructon of the boundares and on sequental analyss see ref. 1, 22 and 23 1;22;23. Results Fve hgh frequency ventlaton studes were evaluated wth a total number of 2152 patents randomzed. Those fve trals used both a hgh frequency 86

9 oscllatory ventlator wth a hgh lung volume strategy n the hgh frequency oscllatory ventlaton group, and a lung protectve ventlaton strategy n the conventonal mechancal ventlaton group. In Table 1 the exact numbers of the outcomes of nterest are tabulated. The cumulatve evdence of those fve studes comparng hgh frequency oscllatory ventlaton wth conventonal mechancal ventlaton showed an OR of 0.92 (95% CI ) for death or chronc lung dsease, an OR of 0.98 (95% CI ) for chronc lung dsease n survvors, an OR of 1.01 (95% CI ) for ntraventrcular hemorrhage grade III and IV and an OR of 0.90 (95% CI ) for perventrcular leukomalaca. Table 1. Randomzed Clncal Trals comparng hgh frequency ventlaton wth conventonal mechancal ventlaton. Author Year HLVS LPVS Death or CLD at 36 weeks or dscharge CLD 36 weeks n survvors HFOV CMV HFOV CMV 1 Thome 1999 Y Y 43/140 (31%) 44/144 (31%) 32/126 (25%) 30/129 (23%) 2 Morette 2001 Y Y 55/148 (37%) 57/144 (40%) 24/105 (23%) 30/107 (28%) 3 Courtney 2002 Y Y 103/244 (42%) 133/254 (52%) 70/201 (35%) 93/210 (44%) 4 Johnson 2002 Y Y 265/400 (66%) 268/397 (68%) 165/300 (55%) 163/292 (56%) 5 Reempts 2003 Y Y 49/147 (33%) 39/153 (25%) 24/122 (20%) 19/133 (14%) Author Year HLVS LPVS IVH PVL HFOV CMV HFOV CMV 1 Thome 1999 Y Y 19/140 (14%) 18/144 (13%) 3/140 (2%) 0/144 (0%) 2 Morette 2001 Y Y 34/148 (23%) 19/144 (13%) 14/148 (9%) 18/144 (13%) 3 Courtney 2002 Y Y 45/244 (18%) 45/254 (18%) 18/244 (7%) 26/254 (10%) 4 Johnson 2002 Y Y 38/400 (10%) 55/397 (14%) 8/400 (2%) 8/397 (2%) 5 Reempts 2003 Y Y 14/147 (10%) 13/153 (8%) 11/147 (7%) 8/153 (5%) Table 1. HLVS: hgh lung volume strategy n hgh frequency ventlaton. LPVS: lung protectve ventlatons strategy n conventonal mechancal ventlaton. CLD: chronc lung dsease at 36 weeks postconceptonal age. HFOV: hgh frequency oscllatory ventlaton. CMV: conventonal mechancal ventlaton. 87

10 Table 2. Study desgn of the last fve trals. Author Year Patents Outcome Power analyss Age or Weght Thome and <30 wks Tme (hours) Prmary Effect alpha power 6 treatment falures dfference of % Morette and 29 wks 6 death or chronc lung dsease at 28 days Courtney to 1200 g 4 death or chronc lung dsease at 36 weeks Johnson to 28 wks + 1 death or chronc lung 6 d dsease at 36 weeks mprovement from 45% to 65% mprovement from 50% to 65% dfference of 9-11% Reempts 2003 <32 wks 6 death or chronc lung reducton of dsease at 36 weeks 60% Table 2. Study desgn of the last fve trals. Tme: Age at randomzaton n hours. In Table 2 the patent groups, prmary outcomes and sample sze specfcatons are mentoned. All studes ncluded very low brth weght patents. Tme pror to randomzaton was no more than 6 hours. Thome et al and Morette et al used varants of the defnton for the prmary outcome upon whch a power analyss was based 11;13. However, n both studes death and chronc lung dsease were part of the prmary outcome. Overall, a reducton n death or chronc lung dsease of 15% was expected (correspondng to an OR of 0.54). All trals specfed a value of 0.05 for the type I error. Power for detectng a dfference was 0.80 or Treatment wth hgh frequency oscllatory ventlaton was comparable between trals (Table 3). Two trals used the SensorMedcs ventlator, n two studes the Infant Star was used and Morette et al used an OHF 1 Dufour ventlator 13. Mean arway pressure was 2 cmh2o above MAP measured on conventonal mechancal ventlaton n 2 trals and vared from 6 to 16 cmh2o dependng on gestatonal age of the patent or on FO2 that was needed. In all but one tral, MAP was decreased only f FO2 88

11 was less than The ventlaton strategy n the conventonal mechancal ventlaton groups dd not dffer much ether between trals. Frequency was set at breaths/mn and a PEEP of at least 3 cmh2o was appled. Peak nspratory pressures were explctly lmted n three studes and n all trals a certan amount of hypercapna was accepted up to mmhg. Inconsstency n prmary outcome assessed by I 2 was 7.5%, ndcatng a low percentage of total varaton across studes due to heterogenety. Sequental meta-analyss showed that one tral already provded enough evdence for no reducton n death or chronc lung dsease of 15% (Fgure 1). In a senstvty analyss decreasng the effect to be a reducton of 10% t took only two trals before the boundary for no such reducton was crossed (OR=0.97 wth 95% CI( )). Senstvty analyss excludng the studes by Thome et al and Morette et al resulted n an OR of 0.98 (95% CI (0.68 ; 1.39) (data not shown). The same result was found wth chronc lung dsease as outcome wth an estmated effect of 15% reducton (Fgure 2). After one tral, by Thome et al, the boundary for no such reducton was crossed (OR=0.89 wth 95% CI( )) 11. Sequental analyses were also appled wth ntraventrcular hemorrhage grade III and IV and perventrcular leukomalaca as outcome measures. For both outcomes there was not enough evdence to draw a defntve concluson yet (data not shown). Dscusson To be of value, a new RCT must add to current knowledge. Assessng whether clncal equpose was present at the start of a new RCT should be general research practce 24. Scence s meant to be cumulatve, but many scentsts are not cumulatng scentfcally. (Chalmers n hs Comment 89

12 Fgure 1. CLD or death: 50% (CMV) versus 35% (HFOV) Fgure 2. CLD: 50% (CMV) versus 35% (HFOV) Legend of Fgures 1 and 2. CLD: Chronc Lung Dsease. CMV: Conventonal Mechancal Ventlaton. HFOV: Hgh Frequency Oscllatory Ventlaton. The horzontal axs denotes the cumulatve amount of nformaton (V) (.e. a functon of the number of patents ncluded). The vertcal axs denotes a measure for the cumulatve effect sze (Z). When one of the upper or lower lnes s crossed, the null hypothess of treatment equvalence s rejected. When one of the nner, wedge-shaped boundaress crossed, the null hypothess s accepted. The x-symbol reflects the contrbuton of the one decsve study. The dashed lnes wthn the straghtlne boundares represent a contnuty correcton. (see text and Appendx for further explanaton.) 90

13 on Fergusson et al. (2005)) 25. Cumulatve meta-analyss s recognzed as a systematc revew technque. Varous authors performed cumulatve metaanalyses of RCTs on dfferent research questons (amongst others, Lau et al. (1992); Fergusson et al. (2005)) 24;26. The general approach used s to perform an analyss of the currently avalable studes and to test the null hypothess that the two treatments are equally effectve. If the test result s not sgnfcant, a new tral s added (when ts results become avalable) and the analyss and testng procedure s repeated. Ths approach contnues untl a statstcally sgnfcant result s found,.e. the null hypothess s rejected. Berkey et al. (1996) notced that ths general approach does not adjust for the multple testng and lacks a formal stoppng rule and a quantfcaton of the power of the concluson 27. We performed a sequental meta-analyss accordng to the approach as descrbed by A. Whtehead (1997) 28. Usng ths approach the overall sgnfcance level (the type I error) s preserved, thus preventng the ncrease of the cumulatve by multple testng. Moreover, a prespecfed power to detect a clncally relevant treatment dfference s guaranteed. Furthermore, ths approach permts stoppng when enough evdence s gathered ether to reject the null hypothess of treatment equvalence or to accept t. Ths s a second report that dscusses the relevance of new trals usng sequental meta-analyss. In trals wth hgh frequency oscllatory ventlaton versus conventonal mechancal ventlaton as an electve treatment of dopathc respratory dstress syndrome n premature neonates, a reducton n the composte outcome of death or chronc lung dsease at 36 weeks of 10% to 15% was expected. However, after one tral sequental meta-analyss showed no evdence for such reducton. Yet, four more studes were performed, powered to show the same amount of effect

14 To compare trals, equalty of treatment between trals s an mportant requrement. In a recent artcle we showed that ventlaton strateges n hgh frequency oscllatory ventlaton and conventonal mechancal ventlaton have changed n recent years 20. In a cumulatve meta-analyss ventlaton strateges were an mportant source of heterogenety between trals. In the last fve trals, however, ventlaton strateges were comparable and results were homogeneous between trals. A more formal approach showed that only a small amount of varaton between trals was due to heterogenety. The most mportant dfferences between trals conssted of two major advancements n the therapy of dopathc respratory dstress syndrome: the use of surfactant therapy and the applcaton of a lung protectve strategy n patents on conventonal mechancal ventlaton 20;29. Both modaltes have been appled n the last fve trals. In the only tral that showed a reducton n chronc lung dsease, the conventonal mechancal ventlaton therapy was most rgdly controlled 14. Therefore, t seems unlkely that n daly practce the same dfference between hgh frequency oscllatory ventlaton and conventonal mechancal ventlaton wll occur 30. Varous hgh frequency oscllatory ventlaton devces have been appled n dfferent trals. However, we showed that these dfferences dd not explan heterogenety between trals 20. Senstvty analyses excludng studes by Thome et al 11 for use of a flow nterrupter type of HFOV and Morette et al 13 for use of a ventlator that was subsequently wthdrawn from the market showed the robustness of our analyses. Furthermore, t has been demonstrated that when applyng the same ventlatory objectves, dfferences between devces are rrelevant because settngs are adjusted to acheve the desred effect resultng n comparable hgh frequency oscllatory ventlaton treatment 31;32. 92

15 Table 3. Ventlaton strateges of the last fve trals. Author Year HFOV strategy Ventlator Frequency Mean Arway Pressure FO2 Chest X-ray Thome 1999 Infant Star 10 Hz 1-2 cmh2o above MAP on CMV; cmh2o when prmary HFOV MAP ncreased untl FO2<0.3 nnth par of rbs Morette 2001 OHF1 Not stated 14 cmh2o f FO2 < 0.4; 16 MAP ncreased Not stated cmh2o f FO2>0.4 untl FO2<0.4 2 cmh2o above MAP on CMV Not stated expanson to 8 to 9.5 rbs Courtney 2002 SensorMedcs 3100A 10 to 15 Hz Johnson 2002 Dräger Babylog 8000; SensorMedcs 3100A; SLE 2000HFO 10 Hz 6-8 cmh2o MAP ncreased untl FO2<0.3 Reempts 2003 Infant Star Not stated 8 cm H2O f <29 weeks; 10 cm H2O f /7 weeks nnth par of rbs Not stated nnth par of rbs Author Year CMV strategy Frequency PEEP PIP Tdal Volume pco2 Thome /mn 3 cmh2o Morette 2001 Not stated 4-5 cmh2o Courtney /mn 4-6 cmh2o PIP as low as possble Not stated mm Hg; to 70 mm Hg after the 7th day PIP as low as possble Not stated mm Hg Not stated 4-7 ml/kg mm Hg; 45 to 65 mm Hg f CLD Johnson /mn Not stated Not stated Not stated mm Hg Reempts /mn 4-8 cmh2o cmh ml/kg mmhg durng the acute phase; up to 70 mmhg later

16 All trals were powered to show a relatve reducton of chronc lung dsease n survvors usng hgh frequency oscllatory ventlaton wth a hgh lung volume strategy compared wth conventonal mechancal ventlaton applyng a lung protectve strategy. In only one of these trals an mprovement n pulmonary outcome was demonstrated that was statstcally sgnfcant 14. The nablty of the last four trals to change the evdence that there was no mprovement to pulmonary outcome was robust to smaller dfferences n effect sze n a senstvty analyss. Wth respect to other mportant clncal outcomes, ntraventrcular hemorrhage grade III and IV and perventrcular leukomalaca, the last fve trals dd not result n enough evdence to draw defntve conclusons yet. Uncertanty remaned as to whether hgh frequency oscllatory ventlaton resulted n more ntraventrcular hemorrhage grade III and IV and/or perventrcular leukomalaca. In general, a clncal tral s undertaken to test relevant clncal treatment effects. The sze of a tral s estmated by a power analyss that s based on an expected effect sze and chosen probabltes for type I and II errors. However, ths does not answer the queston whether ths new tral wll be able to adjust the avalable cumulatve evdence suffcently to conclude that a clncally relevant effect can be refuted or accepted. By performng a sequental analyss,.e. a sequental meta-analyss of earler comparable trals t can be decded whether enough cumulatve evdence has been gathered already to render another tral unnformatve. Sequental analyss s already an accepted procedure wthn a tral. In ths report we demonstrated that performng a sequental meta-analyss before startng three randomzed trals comparng hgh frequency oscllatory ventlaton wth conventonal mechancal ventlaton could have resulted n a dfferent study desgn amed at nvestgatng other more promsng hypotheses (e.g. acceptng smaller dfferences n prmary outcome n the power analyss or choosng other prmary outcome varables). 94

17 We thnk that, n addton to a power analyss, sequental meta-analyss of earler comparable studes should be an ntegral part n the plannng and desgn of new randomzed trals. As we have shown n ths report, the results of sequental meta-analyses can have major consequences for study desgn or even result n the decson to refran from startng another tral. Summarzng, before expandng exstng expermental evdence by startng a new randomzed clncal tral, t s useful to perform a sequental metaanalyss, to determne whether a treatment effect has already been convncngly establshed by cumulatve evdence of prevous trals. Sequental meta-analyss may result n decsons to change study desgn or even refran from performng addtonal randomzed trals desgned to show the same objectves. 95

18 APPENDIX Suppose k RCTs are avalable for a sequental meta-analyss. All RCTs compare the same expermental treatment E wth a control treatment C and all have the same dchotomous outcome (event or no event). Results from the th RCT (I=1,,k) can be summarzed n a two-by-two table (Table X). Table X. th RCT E(xpermental) C(ontrol) overall event S E S C S no event F E F C F total N E N C N The proportons of events wth the expermental and wth the control treatment are P E = S E / N E and P C = S C / N C, respectvely. The logarthm of the odds rato, as a measure for assocaton between treatment and outcome, s defned as P log P (1 P (1 P ) ) E C. C E The test statstc Z s expressed as the dfference between the observed number of events wth E n the th RCT (S E ) and the expected number under the null hypothess of treatment equvalence. Z SE NES / N. The statstc V, the varance of Z, s defned as N V N E 2 N C (N S F 1 ) 96

19 The pooled estmate for the overall s equal to ˆ w ˆ w Z V, wth Z ˆ V as the estmated log(or) for the th RCT and the weghtng factor w = V. An approxmate 95% confdence nterval for can be estmated by ˆ. w (For further detals see References 1, 22 and 23.) Reference Lst 1. Whtehead A,.Whtehead J. A general parametrc approach to the metaanalyss of randomzed clncal trals. Stat.Med. 1991;10: Young C,.Horton R. Puttng clncal trals nto context. Lancet 2005;366: MacIntyre NR. Current ssues n mechancal ventlaton for respratory falure. Chest 2005;128:561S-7S. 4. Froese AB, Butler PO, Fletcher WA, Byford LJ. Hgh-frequency oscllatory ventlaton n premature nfants wth respratory falure: a prelmnary report. Anesth.Analg. 1987;66: Hgh-frequency oscllatory ventlaton compared wth conventonal mechancal ventlaton n the treatment of respratory falure n preterm nfants. The HIFI Study Group. N.Engl.J.Med. 1989;320: Carlo WA, Sner B, Chatburn RL, Robertson S, Martn RJ. Early randomzed nterventon wth hgh-frequency jet ventlaton n respratory dstress syndrome [see comments]. J.Pedatr. 1990;117: Ogawa Y, Myasaka K, Kawano T, Imura S, Inuka K, Okuyama K et al. A multcenter randomzed tral of hgh frequency oscllatory ventlaton as 97

20 compared wth conventonal mechancal ventlaton n preterm nfants wth respratory falure. Early Hum.Dev. 1993;32: Wswell TE, Grazan LJ, Kornhauser MS, Cullen J, Merton DA, McKee L et al. Hgh-frequency jet ventlaton n the early management of respratory dstress syndrome s assocated wth a greater rsk for adverse outcomes. Pedatrcs 1996;98: Keszler M, Modanlou HD, Brudno DS, Clark FI, Cohen RS, Ryan RM et al. Multcenter controlled clncal tral of hgh-frequency jet ventlaton n preterm nfants wth uncomplcated respratory dstress syndrome [see comments]. Pedatrcs 1997;100: Rettwtz-Volk W, Veldman A, Roth B, Verzg A, Kachel W, Varnholt V et al. A prospectve, randomzed, multcenter tral of hgh-frequency oscllatory ventlaton compared wth conventonal ventlaton n preterm nfants wth respratory dstress syndrome recevng surfactant [see comments]. J.Pedatr. 1998;132: Thome U, Kossel H, Lpowsky G, Porz F, Furste HO, Genzel-Borovczeny O et al. Randomzed comparson of hgh-frequency ventlaton wth hghrate ntermttent postve pressure ventlaton n preterm nfants wth respratory falure [see comments]. J.Pedatr. 1999;135: Plavka R, Kopecky P, Sebron V, Svhovec P, Zlatohlavkova B, Janus V. A prospectve randomzed comparson of conventonal mechancal ventlaton and very early hgh frequency oscllatory ventlaton n extremely premature newborns wth respratory dstress syndrome. Intensve.Care Med. 1999;25: Morette G, Pars-Llado J, Walt H, Escande B, Magny JF, Cambone G et al. Prospectve randomzed multcenter comparson of hgh-frequency oscllatory ventlaton and conventonal ventlaton n preterm nfants of less than 30 weeks wth respratory dstress syndrome. Pedatrcs 2001;107: Courtney SE, Durand DJ, Asseln JM, Hudak ML, Aschner JL, Shoemaker CT. Hgh-frequency oscllatory ventlaton versus conventonal mechancal ventlaton for very-low-brth-weght nfants. N.Engl.J.Med. 2002;347: Johnson AH, Peacock JL, Greenough A, Marlow N, Lmb ES, Marston L et al. Hgh-frequency oscllatory ventlaton for the preventon of chronc lung dsease of prematurty. N.Engl.J.Med. 2002;347: Van Reempts P, Borstlap C, Laroche S, Van der Auwera JC. Early use of hgh frequency ventlaton n the premature neonate. Eur.J.Pedatr. 2003;162:

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