To the Editor:

We read with interest the recent meta-analysis of Maitra et al.,1  which included our randomized clinical study of intermittent recruitment with combined high-frequency oscillation (HFO) and tracheal gas insufflations (TGIs) in severe acute respiratory distress syndrome.2  As clearly mentioned/described in the Abstract and Results sections of our article,2  and pages 7 and 8 of the Supplement2  (eMethods section), our study was conducted in two periods (first period, n = 54; second period, n = 71; total participants, n = 125), primarily for reasons of feasibility; the study protocol can be accessed through the webpage of our hospital’s scientific society.3  As also (again) clearly stated in the Acknowledgments section of our article,2  the results of our study’s first period were partly presented in international congresses and published in abstract form and also summarized in the preceding HFO meta-analysis of Sud et al.4 

In the main analysis with respect to mortality presented in figure 3, Maitra et al.1  included the results of the first period (n = 54; control, n = 27) as reported in the meta-analysis of Sud et al.4  in addition to the results of the whole study (corresponding to both study periods, n = 125; control, n = 64).2  This inevitably resulted in a duplicate inclusion of the results of the first period. Furthermore, first period results do not correspond to reference 25 of the article by Maitra et al.1  The cited article reports the results of our prior physiological study that compared the short-term gas exchange and hemodynamic effects of HFO-TGI, standard HFO, and lung-protective conventional mechanical ventilation.5  This study included 14 patients as also correctly reported in table 2 of the article by Maitra et al.,1  thereby contrasting the wrong number of 54 patients reported in figure 3.

An additional, potential source of inaccuracy pertains to the inclusion of the study of Demory et al.1,6  This study had physiological endpoints and reported solely on intensive care unit (ICU) mortality, which does not necessarily coincide with either 30-day or in-hospital mortality.2  Consequently, the actual primary outcome of the meta-analysis was “30-day, or ICU, or in-hospital mortality” and not “30-day, or in-hospital mortality.” Lastly, another point requiring correction was that the 30-day mortality rate of the HFO arm of the study of Young et al.7  was 166 of 398 and not 165 of 398 as reported in figure 3 in the article by Maitra et al.1 

A corrected forest plot of 30-day, or ICU, or in-hospital mortality is presented in figure 1. Notably, the pooled risk ratio is quite close to that reported by Maitra et al.1  However, the 95% CI and the I2 value differ, and additional data corrections, including the elimination of the above-mentioned first period2  data duplication, are required in figures 4, 6, and 7.1  In addition, the refractory hypoxemia rates reported by Maitra et al. in figure 8 are again inaccurate with respect to our study.2  Indeed, refractory hypoxemia (as defined in the first paragraph of page 7 of the Supplement2 ) occurred in one patient of the HFO-TGI group (third paragraph of page 13 and eTable 11 of the Supplement2 ) and four patients of the control group (subsection Rescue Oxygenation Therapies of page 14 and eTable 11 of the Supplement2 ).

Fig. 1.

Corrected forest plot of the risk ratio of 30-day, or intensive care unit, or in-hospital mortality in the studies included in the meta-analysis of Maitra et al.1  Numbers in parentheses correspond to current article references. CMV = conventional mechanical ventilation (corresponding to standard treatment); HFO = high-frequency oscillation (corresponding to experimental treatment); M-H = Mantel–Haenszel.

Fig. 1.

Corrected forest plot of the risk ratio of 30-day, or intensive care unit, or in-hospital mortality in the studies included in the meta-analysis of Maitra et al.1  Numbers in parentheses correspond to current article references. CMV = conventional mechanical ventilation (corresponding to standard treatment); HFO = high-frequency oscillation (corresponding to experimental treatment); M-H = Mantel–Haenszel.

An additional, controversial issue pertains to the inclusion of our study.1,2  This contrasts the study selections of the authors of another two, very recently published, meta-analyses of HFO in acute respiratory distress syndrome.8,9  The HFO treatment we used had substantial differences from the HFO treatments of other clinical studies.7,10–13  These studies used continuous, standard HFO, without a mandatory cuff leak or TGI, as a lung-protective ventilatory strategy.7,10–13  In contrast, we applied intermittent, low-frequency HFO with short-lasting (i.e., approximately 40 s) recruitment maneuvers, a tracheal tube cuff leak, and superimposed TGI as a lung recruitment protocol that was repeated daily for an average of 11.2 h. HFO-TGI was used according to prespecified oxygenation criteria for a median (interquartile range) of 4 days (2 to 5 days) during the first 10 days postrandomization.2  The HFO-TGI recruitment strategy was aimed at reducing the ventilation pressures of the subsequent conventional mechanical ventilation and thus render it less traumatic to the lungs.2,14  The potential advantages of the HFO-TGI strategy relative to other HFO strategies, especially with respect to carbon dioxide elimination and hemodynamics, are shown and discussed in detail elsewhere.10,14 

A major advantage of meta-analyses is the reliable comparison of treatment effects, achieved mainly through a large, pooled sample size. This leads to improved external validity relative to included, independent studies, and generalizable results. Although it is perfectly understandable that errors can occur, the pooled results of meta-analyses must be accurate, and this can only be ensured through their repeated checking and verification before publication. Also, studies with methodologies exhibiting unique characteristics and clinical targets2  should be considered for inclusion mainly in sensitivity rather than in primary analyses to prevent potentially excessive increases in the heterogeneity of the pooled results (fig. 1).

Competing Interests

The authors declare no competing interests.

References

1.
Maitra
S
,
Bhattacharjee
S
,
Khanna
P
,
Baidya
DK
:
High-frequency ventilation does not provide mortality benefit in comparison with conventional lung-protective ventilation in acute respiratory distress syndrome: A meta-analysis of the randomized controlled trials.
Anesthesiology
2014
;
122
:
841
51
2.
Mentzelopoulos
SD
,
Malachias
S
,
Zintzaras
E
,
Kokkoris
S
,
Zakynthinos
E
,
Makris
D
,
Magira
E
,
Markaki
V
,
Roussos
C
,
Zakynthinos
SG
:
Intermittent recruitment with high-frequency oscillation/tracheal gas insufflation in acute respiratory distress syndrome.
Eur Respir J
2012
;
39
:
635
47
3.
HFO-TGI Study Protocol Access
:
Homepage of the Scientific Society of Evaggelismos Hospital (scroll down to the end of the webpage).
4.
Sud
S
,
Sud
M
,
Friedrich
JO
,
Meade
MO
,
Ferguson
ND
,
Wunsch
H
,
Adhikari
NK
:
High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): Systematic review and meta-analysis.
BMJ
2010
;
340
:
c2327
5.
Mentzelopoulos
SD
,
Roussos
C
,
Koutsoukou
A
,
Sourlas
S
,
Malachias
S
,
Lachana
A
,
Zakynthinos
SG
:
Acute effects of combined high-frequency oscillation and tracheal gas insufflation in severe acute respiratory distress syndrome.
Crit Care Med
2007
;
35
:
1500
8
6.
Demory
D
,
Michelet
P
,
Arnal
JM
,
Donati
S
,
Forel
JM
,
Gainnier
M
,
Brégeon
F
,
Papazian
L
:
High-frequency oscillatory ventilation following prone positioning prevents a further impairment in oxygenation.
Crit Care Med
2007
;
35
:
106
11
7.
Young
D
,
Lamb
SE
,
Shah
S
,
MacKenzie
I
,
Tunnicliffe
W
,
Lall
R
,
Rowan
K
,
Cuthbertson
BH
;
OSCAR Study Group
:
High-frequency oscillation for acute respiratory distress syndrome.
N Engl J Med
2013
;
368
:
806
13
8.
Huang
CT
,
Lin
HH
,
Ruan
SY
,
Lee
MS
,
Tsai
YJ
,
Yu
CJ
:
Efficacy and adverse events of high-frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome: A meta-analysis.
Crit Care
2014
;
18
:
R102
9.
Gu
XL
,
Wu
GN
,
Yao
YW
,
Shi
DH
,
Song
Y
:
Is high-frequency oscillatory ventilation more effective and safer than conventional protective ventilation in adult acute respiratory distress syndrome patients? A meta-analysis of randomized controlled trials.
Crit Care
2014
;
18
:
R111
10.
Vrettou
CS
,
Zakynthinos
SG
,
Malachias
S
,
Mentzelopoulos
SD
:
The effect of high-frequency oscillatory ventilation combined with tracheal gas insufflation on extravascular lung water in patients with acute respiratory distress syndrome: A randomized, crossover, physiologic study.
J Crit Care
2014
;
29
:
568
73
11.
Ferguson
ND
,
Cook
DJ
,
Guyatt
GH
,
Mehta
S
,
Hand
L
,
Austin
P
,
Zhou
Q
,
Matte
A
,
Walter
SD
,
Lamontagne
F
,
Granton
JT
,
Arabi
YM
,
Arroliga
AC
,
Stewart
TE
,
Slutsky
AS
,
Meade
MO
;
OSCILLATE Trial Investigators; Canadian Critical Care Trials Group
:
High-frequency oscillation in early acute respiratory distress syndrome.
N Engl J Med
2013
;
368
:
795
805
12.
Bollen
CW
,
van Well
GT
,
Sherry
T
,
Beale
RJ
,
Shah
S
,
Findlay
G
,
Monchi
M
,
Chiche
JD
,
Weiler
N
,
Uiterwaal
CS
,
van Vught
AJ
:
High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: A randomized controlled trial [ISRCTN24242669].
Crit Care
2005
;
9
:
R430
9
13.
Derdak
S
,
Mehta
S
,
Stewart
TE
,
Smith
T
,
Rogers
M
,
Buchman
TG
,
Carlin
B
,
Lowson
S
,
Granton
J
;
Multicenter Oscillatory Ventilation For Acute Respiratory Distress Syndrome Trial (MOAT) Study Investigators
:
High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: A randomized, controlled trial.
Am J Respir Crit Care Med
2002
;
166
:
801
8
14.
Vrettou
CS
,
Zakynthinos
SG
,
Malachias
S
,
Mentzelopoulos
SD
:
High-frequency oscillation and tracheal gas insufflation in patients with severe acute respiratory distress syndrome and traumatic brain injury: An interventional physiological study.
Crit Care
2013
;
17
:
R136