Copyright European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

INVITED COMMENTARY
Randomised controlled trials
Are we looking at treatment effects or absence of good clinical
practice in control groups?
Stefan De Hert and Luc De Baerdemaker
European Journal of Anaesthesiology 2014, 31:450451
In this months issue of the European Journal of Anaes-
thesiology, Rubes et al.
1
describe how a very simple
routine measure can make an important difference in
patient outcome. They hypothesised that active man-
agement of the cuff pressure of the endotracheal tube
during deep hypothermic circulatory arrest would
reduce silent subglottic aspiration. To address this
question, they randomised 24 patients undergoing elec-
tive pulmonary endarterectomy under deep hypother-
mic circulatory arrest in two groups: one control group
in which the endotracheal cuff pressure was monitored
without any further action; and one intervention group
in which the endotracheal cuff pressure was monitored
and reinated to 25 cm H
2
O whenever pressure
dropped below 20 cm H
2
O. Quality of lung isolation
was checked by the presence of subglottic leakage of
methylene blue after its application in the hypophar-
ynx. According to the data presented, cuff pressures
were as expected signicantly lower in the control
group. Interestingly, cuff insufation seemed to be
associated with a spectacularly lower incidence of leak-
age of uid into the lungs (0/12 in the intervention
group vs. 8/12 in the control group; P0.0013), a lower
postoperative ventilation time and a lower incidence of
positive bacterial culture growth from tracheal aspirate
(0/12 in the intervention group vs. 4/12 in the control
group; P0.0932).
How should these results be interpreted? There are
two possible approaches. The rst is to consider these
results as a positive message proving that simple controls
and interventions can markedly improve perioperative
outcome. The second implies a more critical analysis
questioning some aspects of the methodology and the
clinical implications of the study.
In the rst approach, the authors need to be commended
for their experimental question. On the basis of a relevant
physiological question, a potentially important clinical
problem is addressed and the effects of a treatment
strategy are assessed. Indeed, according to the current
data, it would seem that a potentially dangerous compli-
cation occurs at an unexpectedly high frequency (67%)
and that a simple intervention results in a better outcome.
The question, however, is whether the presented results
do indeed unequivocally point to this positive answer?
This brings us to the second approach. There are a
number of issues that need to be taken into account
when interpreting results from randomised controlled
trials.
Clinical trials basically aim to nd out whether a certain
intervention is associated with a better outcome when
compared with a control group. This better outcome can
be the result of an obvious benecial effect in the study
group but may also be observed when the outcome in the
control group is unexpectedly bad. Unfortunately, this is
the case in some studies. Reported data then mainly show
a complication rate in the intervention group, which is in
line with what is generally accepted and reported in
literature as being a good clinical practice. Contrarily,
the complication rate in the so-called control group is far
higher than what is routinely accepted.
24
Eur J Anaesthesiol 2014; 31:450451
This Invited Commentary accompanies the follow-
ing original article:
Rubes D, Klein AA, Lips M, et al. The effect of
adjusting tracheal tube cuff pressure during deep
hypothermic circulatory arrest. A randomised trial.
Eur J Anaesthesiol 2014; 31:452456.
From the Department of Anaesthesiology, Ghent University Hospital, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Correspondence to Stefan De Hert, MD, PhD, Department of Anesthesiology, Ghent University Hospital, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium
Tel: +32 9 332 32 81; fax: +32 9 332 49 87; e-mail: stefan.dehert@ugent.be
0265-0215 2014 Copyright European Society of Anaesthesiology DOI:10.1097/EJA.0000000000000039
Copyright European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Is this the case in the present study? For the sample
calculation, Rubes et al.
1
assumed a 50% baseline inci-
dence of tracheal leakage. It is unclear where this
assumption of 50% incidence in regular practice comes
from. Intuitively, one would consider such an incidence
of tracheal leakage to be very high. The observation of a
67% incidence of aspiration in the control group is,
therefore, rather alarming. Taking a closer look at avail-
able literature, it is striking to note that little information
seems to be available on the incidence of silent aspiration
secondary to insufcient sealing related to cuff pressure
or other cuff properties. Nevertheless, a recent study
comparing the incidence of intraoperative aspiration
between the traditional cuff design with a tapered-
shaped polyvinylchloride cuff also reported dye leakage
in the trachea in 67% of patients in the control group.
5
This study, together with the study of Rubes et al.,
1
suggests that we may be dealing with a problemoccurring
more frequently than we would expect based on so-called
clinical experience.
Then the question arises whether patients in the control
group did indeed receive treatment according to good
clinical practice or instead treatment that was suboptimal
and control mainly meant that nothing was done. This
seems to have been the case in the present study. Cuff
pressures were measured in all patients, but no action was
undertaken to inate the cuff when pressures dropped in
the control group. Yet, for many years now, it has been
considered a good clinical practice to keep cuff pressures
between 20 and 30 cm H
2
O in order to prevent aspira-
tion.
6,7
Consequently, the present data only conrm that
the existing recommendation of regular cuff pressure
measurement with active intervention (insufations)
whenever pressure drops below 20 cm H
2
O results in
less tracheal leakage.
Rubes et al.
1
expected a 50% treatment effect of their
proposed intervention. It is unclear why exactly 50% was
considered to be clinically signicant. In the case of
avoidance of tracheal leakage, one would consider a
0% incidence as the only clinically acceptable target.
In their sample size of two groups of 12 patients, a 0%
incidence of tracheal leakage was observed in the inter-
vention group compared with a 67% incidence in the
control group. This means a number needed to harm of
about 1.5, which again supports the recommendation to
check cuff pressures and adjust them if necessary.
In view of standard clinical practice, the major question is
whether this apparently high incidence of tracheal leak-
age, observed in the absence of regular cuff pressure
adjustments, is truly associated with worse outcome.
Indeed, the effect of one particular intervention on a
specic risk factor may not necessarily translate into a
signicant effect on the patients outcome.
8
This
might also be the case when considering the issue of
endotracheal cuff pressures. In the study of Rubes et al.,
1
it is not clear whether the tracheal leakage was indeed
associated with worse outcome. The study does not
mention the protocol for weaning from articial venti-
lation. This makes the interpretation of the mean differ-
ences in ventilation times extremely hazardous. In
addition, in their study population, the number of
patients necessitating prolonged ventilation longer than
48 h (control group: n 6; study group: n 2; P0.193)
and the incidence of positive cultures from tracheal
aspirate (control group: n 4; study group: n 0;
P0.093) did not differ between the intervention and
control groups, and reported outcome data were similar
in both groups.
In conclusion, the data of Rubes et al.
1
clearly show that
nonadherence to rules of good clinical practice is associ-
ated with an increased risk of complications. The data
also underscore that when designing randomised con-
trolled trials, researchers should take care to apply the
basic rules of good clinical practice in the control group.
In the end, research participants, who are our patients,
deserve the best known treatment, irrespective of the
study arm they have been allocated to.
Acknowledgements relating to this article
Assistance with the commentary: none.
Financial support and sponsorship: none.
Conicts of interest: none.
Comment from the Editor: this Invited Commentary was checked
and accepted by the editors but was not sent for external peer
review.
References
1 Rubes D, Klein AA, Lips M, et al. The effect of adjusting tracheal tube cuff
pressure during deep hypothermic circulatory arrest. A randomised trial. Eur
J Anaesthesiol 2014; 31:452456.
2 Deans KJ, Minneci PC, Suffredini AF, et al. Randomization in clinical trials of
titrated therapies: unintended consequences of using xed pretreatment
protocols. Crit Care Med 2007; 35:15091516.
3 Graf J, Janssens U. Critical care services and trial methodology: even at a
turning tide. Crit Care Med 2007; 35:16201622.
4 Schlack WS, De Hert SG, Hollmann MW. Epidurals and outcome after
cardiac surgery: an example of wishful thinking? J Cardiothor Vasc Anesth
2011; 25:e17e19.
5 DHaese J, De Keukeleire T, Remory I, et al. Assessment of intraoperative
microaspiration: does a modied cuff shape improve sealing? Acta
Anaesthesiol Scand 2013; 57:873880.
6 Rello J, Sonora R, Jubert P, et al. Pneumonia in intubated patients:
role of respiratory airway care. Am J Respir Crit Care Med 1996; 154:
111115.
7 Lucangelo U, Zin WA, Antonaglia V, et al. Effect of positive expiratory
pressure and type of tracheal cuff on the incidence of aspiration in
mechanically ventilated patients in an intensive care unit. Crit Care Med
2008; 36:409413.
8 De Hert SG, Van der Linden PJ. Clinical trials: evidence based and clinically
relevant or not? Curr Opin Anaesthesiol 2009; 22:6870.
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