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INVITED COMMENTARY

Randomised controlled trialsAre 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 ofthe 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 reinflated to 25cm H2O whenever pressure

dropped below 20cm H2O. 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 significantly lower in the control

group. Interestingly, cuff insufflation seemed to be

associated with a spectacularly lower incidence of leak-

age of fluid 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 aretwo possible approaches. The first 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 first 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 find 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 beneficial effect in the studygroup 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.2 4

Eur J Anaesthesiol2014; 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 Anaesthesiol2014; 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, BelgiumTel: +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

http://-/?-http://dx.doi.org/10.1097/EJA.0000000000000039http://dx.doi.org/10.1097/EJA.0000000000000039http://-/?-

8/11/2019 Randomised_controlled_trials__Are_we_looking_at.2.pdf

2/2of 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 insufficient 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 problem occurring

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 inflate 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 30cm H2O in order to prevent aspira-

tion.6,7 Consequently, the present data only confirm that

the existing recommendation of regular cuff pressuremeasurement with active intervention (insufflations)

whenever pressure drops below 20 cm H2O 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 significant. 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 ofabout 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

specific risk factor may not necessarily translate into a

significant effect on the patients outcome.8 This

might also be the case when considering the issue of

endotracheal cuff pressures. In the study of Rubeset 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 artificial 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:n6; study group:n2; P0.193)

and the incidence of positive cultures from tracheal

aspirate (control group: n4; study group: n0;

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 articleAssistance with the commentary: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Comment from the Editor: this Invited Commentary was checkedand accepted by the editors but was not sent for external peer

review.

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J Anaesthesiol2014; 31:452456.

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