The additional value of first pass myocardial perfusion imaging during peak dose of dobutamine stress cardiac MRI for the detection of myocardial ischemia Purpose of this study was to assess the additional value of first pass myocardial perfusion imaging during peak dose of dobutamine stress Cardiac-MR -LRB- CMR -RRB- . Dobutamine Stress CMR was performed in 115 patients with an inconclusive diagnosis of myocardial ischemia on a 1.5 T system -LRB- Magnetom Avanto , Siemens Medical Systems -RRB- . Three short-axis cine and grid series were acquired during rest and at increasing doses of dobutamine -LRB- maximum 40 μg/kg/min -RRB- . On peak dose dobutamine followed immediately by a first pass myocardial perfusion imaging sequence . Images were graded according to the sixteen-segment model , on a four point scale . Ninety-seven patients showed no New -LRB- Induced -RRB- Wall Motion Abnormalities -LRB- NWMA -RRB- . Perfusion imaging showed absence of perfusion deficits in 67 of these patients -LRB- 69 % -RRB- . Perfusion deficits attributable to known previous myocardial infarction were found in 30 patients -LRB- 31 % -RRB- . Eighteen patients had NWMA , indicative for myocardial ischemia , of which 14 -LRB- 78 % -RRB- could be confirmed by a corresponding perfusion deficit . Four patients -LRB- 22 % -RRB- with NWMA did not have perfusion deficits . In these four patients NWMA were caused by a Left Bundle Branch Block -LRB- LBBB -RRB- . They were free from cardiac events during the follow-up period -LRB- median 13.5 months ; range 6 -- 20 -RRB- . Addition of first-pass myocardial perfusion imaging during peak-dose dobutamine stress CMR can help to decide whether a NWMA is caused by myocardial ischemia or is due to an -LRB- inducible -RRB- LBBB , hereby preventing a false positive wall motion interpretation . Introduction Dobutamine stress Cardiac MRI -LRB- CMR -RRB- is used to detect myocardial ischemia of the left ventricle by means of wall motion analysis during the infusion of high-dose dobutamine -LSB- 1 -- 4 -RSB- . Previous studies have reported a broad range of sensitivity -LRB- 83 -- 91 % -RRB- and specificity -LRB- 80 -- 86 % -RRB- of dobutamine stress CMR for the detection of myocardial ischemia -LSB- 1 -- 3 , 5 -RSB- . It has been proven to be more accurate than dobutamine stress echocardiography -LSB- 2 -RSB- . The addition of myocardial tagging even further increased the sensitivity -LRB- 96 % -RRB- of dobutamine stress CMR -LSB- 4 -RSB- . False positive dobutamine stress CMR 's were described for left bundle branch block -LRB- LBBB -RRB- or an incidental low interpretability -LSB- 4 -RSB- . Means to overcome for these false-positive dobutamine stress CMR 's could increase specificity even further . Assessment of myocardial perfusion is used to provide information on the hemodynamic significance of a coronary artery stenosis . Segments with New Wall Motion Abnormalities -LRB- NWMA -RRB- detected with dobutamine stress CMR should also show perfusion deficits , since perfusion abnormalities precede wall motion abnormalities in the ischemic cascade -LSB- 6 -RSB- . Normal stress perfusion SPECT-results predict a less than 1 % annual risk of cardiac death or myocardial infarction , thereby yielding a high negative predictive value -LSB- 7 -- 10 -RSB- . High negative predictive values are also reported for MR perfusion imaging combined with MRI cine-angiography -LRB- 100 % -RRB- in a small study of 15 patients -LSB- 11 -RSB- . The addition of a perfusion sequence on peak-dose dobutamine may further enhance the interpretation of dobutamine stress CMR , by ruling out false positive findings , through the combined strength of both methods . The purpose of this study is to assess whether the addition of perfusion imaging to dobutamine stress CMR at peak-dose dobutamine reduces the number of false-positive dobutamine stress CMR examinations . Materials and methods Patient population Between September 2004 and April 2006 , 124 consecutive patients were referred from the department of Cardiology for a dobutamine stress CMR . The study was approved by the local ethical committee . Informed consent was obtained prior to the study , after the nature of the procedure had been explained . All patients had chest pain and an inconclusive diagnosis of coronary artery disease by means of history , ECG recordings at rest and , if performed , during a bicycle exercise test . Patients with an acute coronary syndrome , atrial fibrillation , severe arterial hypertension -LRB- > 220/120 -RRB- , CMR-incompatible metallic implants or known claustrophobia were not eligible . Protocol for dobutamine stress CMR with myocardial perfusion on peak-dose dobutamine To ensure cardiac response to dobutamine , all anti-anginal medication was stopped 4 days before the dobutamine stress CMR examination . After the patient was positioned on the scanning table , intravenous access was established via an anticubital vein . ECG monitoring leads , a phased-array surface coil covering the heart , and a brachial blood pressure cuff were applied . A single lead ECG was continuously monitored on the MRI-console . Systolic and diastolic blood pressures were recorded using an automatic device -LRB- Welch-Allyn , Emro-medical -RRB- at baseline and every 3 min throughout the procedure . Blood pressure and heart rate were recorded . The imaging methodology of dobutamine stress CMR has been described in detail previously -LSB- 4 -RSB- . Dobutamine stress CMR was performed on a 1.5 T system -LRB- Magnetom Avanto , Siemens Medical Systems , Erlangen , Germany -RRB- . Three short-axis cine breath-hold CMR images of the left ventricle , with and without myocardial tagging , were acquired at rest and during incremental dosage of dobutamine up to 40 μg/kg/min . An ECG-triggered segmental gradient-echo pulse sequence was used : TrueFisp : TR 57.64 , ms ; TE , 1.1 ms ; α , 59 ° ; FOV , 284 × 350 mm ; slice-thickness 6 mm ; and matrix 125 × 192 ; iPAT 2 . Tagging was performed with a standard FLASH grid-sequence : TR , 46 ms ; TE , 3.8 ms ; α , 14 ° ; FOV , 284 × 350 mm ; slice-thickness 6 mm and matrix 141 × 256 . The basal plane was taken 1.5 cm below the mitral valves . The midventricular and apical short-axis views were divided equally over the remaining part of the left ventricle . When a wall motion abnormality -LRB- WMA -RRB- was detected at baseline , infusion was started at 5 μg/kg/min , after which the dose of dobutamine was increased to 10 , 20 , 30 and 40 μg/kg/min . Starting dose of dobutamine was 10 μg/kg/min when no WMA was detected at baseline . Imaging started 6 min after each dose increase and required 3 min per dose increase . Termination criteria for dobutamine stress CMR were the development of new wall motion abnormalities -LRB- NWMA -RRB- or worsening WMA , a fall of systolic blood pressure of more than 40 mmHg , marked hypertension above 240/120 mmHg , severe chest pain , ventricular arrhythmias and intolerable side effects . NWMA are indicative of myocardial ischemia . On peak-dose dobutamine a bolus injection of 0.1 mmol/kg gadolinium-DTPA -LRB- Omniscan ® -RRB- was given and a perfusion sequence was started : TrueFisp : TR , 150.5 or 163.1 ms ; TE 1.03 ms ; TI 100/103 ms ; α 45/50 ° ; FOV 300 × 300 ; slice-thickness 6 mm ; matrix 76 × 128 ; iPAT 2 . The same three slices as the cine and tagging series were acquired . During the examination a radiologist present in the MR suite to monitor the condition of the patient and to visually evaluate the images . When NWMA 's with a corresponding perfusion deficit were seen , a coronary angiography -LRB- CAG -RRB- was performed within 3 weeks . Patients with NWMA 's and a normal first pass perfusion on peak stress entered follow-up . Image analysis Wall motion was scored on six segments of the basal plane , six on the midventricular plane and four on the apical plane . Segmental wall motion was qualitatively graded as 1 = normal or hyperkinesis ; 2 = hypokinesis ; 3 = akinesis ; and , 4 = dyskinesis . Myocardial ischemia was defined as a new -LRB- induced -RRB- or worsening WMA in at least two segments at consecutive planes of the left ventricle during infusion of dobutamine . Analysis was performed using both cine and tagging images as described in detail previously -LSB- 4 -RSB- . Wall Motion Score Index -LRB- WMSI -RRB- was derived as the mean score of all segments of all short-axis images . WMSI data from the combined analysis of the cine and tagging images were determined from baseline and peak stress images . The first pass perfusion images on peak-dose dobutamine were visually analyzed by an experienced radiologist and cardiologist in a consensus reading after the wall motion analysis by the same physicians . A perfusion abnormality , corresponding to the coronary artery distribution areas , in at least two segments at consecutive short-axis slices or one segment of the most apical slice of the left ventricle was defined as myocardial ischemia . Follow-up Follow-up data were obtained in September 2006 . The present status of the patient was determined by review of the hospital records or contacting the patient 's general physician . The date of the last review was used to calculate follow-up time . Evaluated end points were non-fatal myocardial infarction -LRB- angina of > 30 min duration and either 2 mm ST segment elevation in two consecutive ECG leads or a rise in creatine kinase level and its myoglobine fraction two times the upper limit of normal -RRB- , cardiac death -LRB- death in the presence of acute myocardial infarction , significant cardiac arrhythmias or refractory congestive heart failure -RRB- and coronary revascularization . Results Patient population From the 124 consecutively included patients , in nine patients the examination could not be completed due to : intolerable side effects -LRB- nausea , vomiting -RRB- in four patients , claustrophobia in three patients . Two patients were excluded due to insufficient image quality , one of whom had an irregular rhythm with triggering difficulties , and the other patient was unable to sustain breath holds . Therefore , 115 patients all with good image quality were analysed -LRB- 93 % -RRB- with a mean age 61 ± 11 years , 20 women -LRB- 30 % -RRB- . Demographic and hemodynamic data are listed in Table 1 . Table 1Demographic and hemodynamic dataVariableMean or % Age , years61 ± 11Female , % 29.6 Previous myocardial infarction , % 38.0 Revascularization , % 31.0 Rest wall motion abnormalities -LRB- RWMA -RRB- , % 40.9 Body weight , kg78 ± 12Resting diastolic blood pressure , mmHg87 ± 11Peak diastolic blood pressure , mmHg78 ± 12Resting systolic blood pressure , mmHg152 ± 26Peak systolic blood pressure , mmHg151 ± 31Resting heart rate , bpm79 ± 15Peak heart rate , bpm119 ± 21Rate-pressure producta at rest12 ,030 ± 3,545Rate-pressure product at peak stress17 ,935 ± 4,807 Wall Motion Score Index -LRB- WMSI -RRB- at baseline1 .18 ± 0,32 Wall Motion Score Index -LRB- WMSI -RRB- at peak dose1 .21 ± 0.34 Values are expressed as mean ± SD or percentageaRate-pressure product = -LRB- heart rate -RRB- × -LRB- systolic blood pressure -RRB- RWMA = Rest Wall Motion Abnormality ; WMSI = Wall Motion Score Index Dobutamine stress CMR with myocardial perfusion on peak-dose dobutamine Eighteen of the 115 patients -LRB- 16 % -RRB- had NWMA of whom 14 -LRB- 78 % -RRB- showed perfusion deficits on peak-dose dobutamine in the corresponding segments . Four patients -LRB- 22 % -RRB- with NWMA did not have a perfusion deficit . In these four patients , NWMA were attributable to a LBBB as could be confirmed with an independent -LRB- stress -RRB- ECG . Two of these were inducible LBBB , not known prior to the examination . CAG was positive for the corresponding segments in the 14 patients -LRB- 100 % -RRB- with NWMA and a corresponding perfusion deficit . Ninety-seven patients -LRB- 84 % -RRB- had no NWMA . The perfusion images on peak-dose dobutamine showed absence of perfusion deficits in 67 of these 97 patients -LRB- 69 % -RRB- and perfusion deficts in 30 -LRB- 31 % -RRB- . Of these patients 29 -LRB- 97 % -RRB- were attributable to a known previous myocardial infarction in the patients history combined with the presence of RWMA . One patient -LRB- 3 % -RRB- had a small perfusion deficit inferior which could not be assigned to a known previous event in the patients history . Figure 1 illustrates the course and outcome of the study . In Fig. 2 the additional value of cine or grid tagging images combined with stress first-pass perfusion images is illustrated . Fig. 1Flow chart illustrating course of the study and outcome NWMA = New Wall Motion Abnormality ; LBBB = Left Bundle Branch Block ; CAG = Coronary AngiogramFig . 2Short axis views at peak-dose dobutamine . Cine image illustrating a NWMA inferior . -LRB- A -RRB- Perfusion abnormality in the corresponding segment . -LRB- B -RRB- Dyskinetic septal wall in another patient . -LRB- C -RRB- No perfusion abnormalities in the corresponding segment . -LRB- D -RRB- Dyskinetic septal wall in C was due to a LBBB , this differentiation could be made by a perfusion sequence on peak-dose dobutamine . Arrows indicate the wall motion abnormality or perfusion abnormality NWMA = New Wall Motion Abnormality ; LBBB = Left Bundle Branch Block Follow-up results -LRB- median 13.5 months , range 6 -- 20 months -RRB- were obtained from all patients with NWMA 's and a normal first-pass perfusion . None of these patients had cardiac events or revascularizations at follow-up . Discussion This study demonstrates that adding first-pass myocardial perfusion imaging during peak-dose dobutamine has direct clinical relevance for the interpretation of dobutamine stress CMR examinations , by increasing the interpretation of possible wall motion abnormalities -LRB- NWMA -RRB- of the left ventricle . The addition of first pass perfusion relies on the conceptual use of the ischemic cascade . Ischemic wall motion abnormalities are preceded by perfusion abnormalities , therefore visualized NWMA due to myocardial ischemia should also show perfusion abnormalities . A normal perfusion study is used to identify wall motion abnormalities not due to myocardial ischemia , and an abnormal corresponding perfusion deficit is used to confirm NWMA , indicative for myocardial ischemia . This is the first study to assess the additional value of a first pass myocardial perfusion imaging sequence on peak-dose dobutamine during a dobutamine stress CMR . Previous studies have reported a broad range of sensitivity and specificity for dobutamine stress CMR in the detection of myocardial ischemia -LSB- 4 -RSB- . In this protocol we have chosen for a prolonged infusion time of dobutamine from 3 to 6 min without atropine and the use of the target heart rate rule , as described before -LSB- 4 , 12 -- 17 -RSB- . The use of the target heart rate rule from a physical exercise based concept can not be generalized to a pharmacological stress setting and has been questioned in several reports -LSB- 12 -- 14 , 18 -RSB- . It has also been shown that the target heart rate rule can not be extrapolated to a pharmacological stress examination -LSB- 19 -RSB- . In a recent overview of published dobutamine stress CMR examinations by Strach et al. -LSB- 20 -RSB- , the approach we used -LSB- 4 -RSB- showed to provide the highest diagnostic accuracy for significant coronary artery disease defined by a > 50 % luminal stenosis on a coronary angiogram . Specificity , although already high , was lowered , according to our opinion , in part due to LBBB . This could be overcome with a perfusion sequence , taking into account the high negative predictive value of normal myocardial perfusion imaging . The additional value of myocardial perfusion MRI could be used for this purpose and may add significant diagnostic information . In this study we added a perfusion sequence on peak-dose dobutamine in all patients . The results show a good agreement between the absence of NWMA and myocardial perfusion . The main purpose of this study was to assess the additional value of first-pass perfusion imaging in the presence of NWMA . Our recommendation for future clinical use is to add a first pass perfusion sequence on indication , namely if there is doubt on whether a NWMA is due to myocardial ischemia . In this way , the specificity of dobutamine stress CMR can be even further increased . By combining dobutamine stress CMR with myocardial perfusion , one still has the opportunity to examine for viability , which seems even superior to scar quantification -LSB- 21 -RSB- . Absolute specificity values can not be given with this study , because a CAG was not performed in case of a negative dobutamine stress examination . The outcome of the dobutamine stress CMR and myocardial perfusion on peak-dose dobutamine was used as a direct arbiter for subsequent clinical follow-up . In this respect follow-up was considered the reference standard . None of the patients with NWMA 's and a normal myocardial perfusion had an adverse outcome at follow-up . Therefore , it is reasonable to state that adding first pass myocardial perfusion imaging on peak-dose dobutamine increases the specificity of dobutamine stress CMR in this patient group . Our data could have been influenced by a referral bias , but in light of previous results , we found it not justifiable to perform a CAG in case of a negative examination -LSB- 12 -RSB- . Furthermore , the high negative predictive value of dobutamine stress CMR examination without perfusion imaging has been proven before -LSB- 12 , 22 -RSB- . Mahrholdt et al. -LSB- 23 -RSB- . examined 139 patients with a LBBB . All 139 patients had fixed perfusion defects with SPECT , 19 could not be confirmed with CAG . Rest wall motion analysis and myocardial perfusion -LRB- between 5 and 30 min after contrast administration -RRB- was performed on these 19 patients using MRI . All 19 patients showed septal wall motion abnormalities , but none showed subendocardial or transmural contrast enhancement . This also indicates that contrast enhanced imaging can help differentiate between WMA on the basis of coronary artery disease or a LBBB . Long term follow-up will provide information about the case in which a small perfusion abnormality was seen inferior without NWMA . Whether this abnormality is a `` true '' abnormality or an artefact is unclear . This patient did not have any adverse cardiac event at 14 months follow-up . Another limitation of our study is the fact that images were analysed semi-quantitatively . Quantitative wall motion analysis could possibly provide additional information , but due to the time-consuming nature this is not yet feasible in clinical practice . Furthermore , no decisions can be made during the examination , which we believe is crucial , since overstressing may lead to serious complications -LSB- 13 -RSB- . Visual analysis of wall motion and perfusion images was performed in a consensus reading by an experienced radiologist and cardiologist . This can be regarded as a limitation since the observers are not blinded for the previous wall motion images . However , this does represent routine clinical practice and is fundamental to the underlying concept of using first-pass perfusion imaging in the presence of NWMA . In recent studies the inter-observer agreement of dobutamine stress CMR was investigated and good agreement was found -LSB- 24 , 25 -RSB- . In a clinical post-infarct setting , delayed contrast enhancement imaging may provide valuable diagnostic information . To our opinion , this would in our study not have provided additional information regarding the fact whether a NWMA was caused by myocardial ischemia or a non-ischemic cause , and guide the necessity for an invasive coronary angiogram . Cine and grid tagging images were acquired at rest to look for rest wall motion abnormalities . New wall motion abnormalities in this setting would represent myocardial ischemia -LRB- whether or not in the presence of a previous myocardial infarction -RRB- . Delayed contrast enhancement imaging was therefore not performed in this protocol . In this protocol we only acquired stress first-pass perfusion images . Perfusion imaging at rest may be very useful in stress-rest perfusion imaging studies , but the main focus in this protocol is on a normal perfusion in case of NWMA . A rest perfusion exam would in this context not provide additional information -LRB- the rest perfusion exam will also be normal -RRB- . In this way the protocol is not unnecessarily prolonged and a second bolus injection of gadolinium-DTPA can be omitted . Conclusion Good agreement exists between the absence of NWMA and a normal myocardial perfusion . Furthermore , a perfusion sequence on peak-dose dobutamine can help decide whether a NWMA is caused by ischemia or is due to a LBBB . First pass myocardial perfusion during peak-dose dobutamine can be used as an additional tool to reduce the number of false-positive NWMA 's , to improve the detection of myocardial ischemia .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O


Impact

of

transanal

endoscopic

microsurgery

on

functional

outcome

and

quality

of

life

Introduction

Transanal

endoscopic

microsurgery

-LRB-

TEM

-RRB-

is

a

minimal

invasive

technique

for

local

excision

of

rectal

tumours

The

procedure

is

performed

via

a

rectoscope

with

a

diametre

of

cm

The

aim

of

this

prospective

study

was

to

assess

both

functional

outcome

and

quality

of

life

after

TEM

Introduction

Local

excision

of

benign

rectal

tumours

is

safer

compared

to

radical

surgery

and

considered

treatment

of

choice

-LSB-

-RSB-

Several

techniques

have

been

developed

for

local

excision

with

the

transanal

technique

according

to

Parks

as

the

most

frequently

used

-LSB-

-RSB-

Other

techniques

used

are

the

dorsal

transcoccygeal

approach

-LRB-

Kraske

-RRB-

and

the

dorsal

transsphincteric

approach

-LRB-

York

Mason

-RRB-

-LSB-

-RSB-

Each

procedure

has

its

own

-LRB-

dis

-RRB-

advantages

and

of

the

procedures

mentioned

is

able

to

achieve

local

excision

of

tumours

throughout

the

entire

rectum

Transanal

endoscopic

microsurgery

-LRB-

TEM

-RRB-

demonstrated

to

be

a

safe

procedure

capable

of

overcoming

this

shortcoming

In

early

publications

even

distal

sigmoid

tumours

could

be

locally

excised

with

excellent

results

Moreover

recurrence

rates

are

minimal

compared

to

other

local

techniques

As

a

result

the

indication

for

local

excision

of

rectal

tumours

has

expanded

dramatically

-LSB-

-RSB-

Few

studies

have

addressed

functional

outcome

following

TEM

and

with

the

operation

rectoscope

with

a

length

of

or

cm

and

a

diametre

of

mm

scepticism

towards

post-operative

faecal

continence

remains

In

manometric

studies

after

TEM

there

seems

to

be

a

detrimental

temporary

impact

on

internal

sphincter

functioning

although

without

clinical

significance

-LSB-

-RSB-

Cataldo

et

al.

-LSB-

-RSB-

recently

performed

a

prospective

study

on

faecal

continence

and

incontinence-specific

quality

of

life

after

TEM

using

standardised

surveys

They

stated

TEM

does

not

result

in

significant

alterations

These

results

are

promising

especially

with

a

relative

short

duration

of

follow-up

of

weeks

in

this

study

As

known

from

other

types

of

rectal

surgery

incidence

of

faecal

incontinence

diminishes

with

time

-LSB-

-RSB-

This

could

imply

results

after

TEM

may

even

improve

with

longer

follow-up

Quality

of

life

is

increasingly

recognised

as

the

ultimate

endpoint

when

assessing

clinical

outcomes

after

different

surgical

interventions

because

it

measures

the

patient

's

perspective

The

precise

impact

of

the

TEM

procedure

on

quality

of

life

has

not

been

well

studied

This

prospective

study

was

set

out

to

provide

a

comprehensive

insight

into

the

impact

of

TEM

on

functional

outcome

and

quality

of

life

Patients

and

methods

Between

January

and

January

a

consecutive

series

of

patients

were

referred

for

a

TEM

procedure

All

patients

were

evaluated

pre-operatively

according

to

a

standard

protocol

including

rigid

rectoscopy

tumour

biopsy

and

endorectal

ultrasound

If

TEM

was

considered

feasible

patients

were

eligible

for

this

study

Informed

consent

had

to

be

given

before

inclusion

Local

medical

ethical

committees

approved

this

study

A

full-thickness

excision

was

always

performed

The

portion

of

the

tumour

located

within

the

sphincter

musculature

was

excised

in

partial

thickness

Before

and

at

least

months

after

the

TEM

procedure

patients

were

asked

to

fill

out

a

questionnaire

to

assess

anorectal

functioning

and

quality

of

life

All

data

were

collected

by

an

independent

research

coordinator

not

previously

involved

in

the

patients

care

We

recorded

the

demographics

operative

details

post-operative

length

of

stay

post-operative

complications

and

functional

outcome

for

each

participant

We

evaluated

functional

outcome

by

means

of

a

detailed

questionnaire

based

on

the

Faecal

Incontinence

Severity

Index

-LRB-

FISI

-RRB-

-LSB-

-RSB-

This

system

developed

by

Rockwood

uses

two

basic

components

the

type

of

incontinence

and

its

frequency

FISI

scores

range

from

-LRB-

total

continence

-RRB-

to

-LRB-

complete

incontinence

to

solid

stool

on

a

daily

basis

-RRB-

We

used

the

validated

weighting

scores

that

are

based

on

patients

input

Quality

of

life

was

evaluated

using

both

the

EuroQol

and

the

Faecal

Incontinence

Quality

of

Life

-LRB-

FIQL

-RRB-

score

The

EuroQol

consists

of

a

so-called

index

score

representing

the

societal

value

of

the

health

state

and

has

a

scale

ranging

from

-LRB-

no

quality

of

life

-RRB-

to

-LRB-

optimal

quality

of

life

-RRB-

The

EuroQol

also

uses

a

visual

analogue

scale

the

EQ-VAS

representing

the

patient

perspective

This

scale

ranges

from

-LRB-

no

quality

of

life

-RRB-

to

-LRB-

optimal

quality

of

life

-RRB-

The

EuroQoL

scores

were

compared

with

a

sex

and

age-matched

community-based

sample

of

healthy

persons

without

co-morbidity

-LSB-

-RSB-

The

FIQL

score

as

described

by

Rockwood

et

al.

-LSB-

-RSB-

measures

specific

quality

of

life

issues

expected

to

affect

patients

with

faecal

incontinence

This

instrument

is

composed

of

questions

within

four

domains

lifestyle

issues

coping

behaviour

depression

and

self-perception

and

embarrassment

The

scores

in

the

FIQL

range

from

a

minimum

score

of

to

a

maximum

of

for

all

of

the

scales

-LRB-

quality

of

life

alteration

present

most

of

the

time

of

the

time

-RRB-

Data

are

presented

as

medians

and

standard

deviations

Changes

within

groups

were

evaluated

using

the

nonparametric

one-sample

Wilcoxon

's

signed-rank

test

Comparison

of

these

changes

between

groups

was

conducted

using

the

Mann

Witney

U

test

The

Spearman

's

correlation

coefficient

was

used

for

correlation

between

the

different

findings

A

P-value

of

was

considered

statistically

significant

Results

Fifty

patients

were

eligible

and

informed

consent

was

obtained

Three

patients

were

excluded

In

two

patients

TEM

could

not

be

performed

because

of

bulky

tumour

or

technical

problems

An

additional

patient

underwent

low-anterior

resection

for

locally

recurrent

disease

within

months

of

the

TEM

The

remaining

patients

completed

both

questionnaires

and

were

included

for

analysis

All

of

these

patients

were

alive

without

evidence

of

recurrent

disease

The

group

consisted

of

males

and

females

Median

age

was

years

-LRB-

range

-RRB-

Pre-operative

diagnosis

was

villous

adenoma

in

all

patients

Median

distance

from

the

distal

tumour

margin

to

the

dentate

line

was

cm

-LRB-

range

cm

-RRB-

and

median

tumour

size

was

-LRB-

range

-RRB-

The

median

rate

of

captured

circumference

of

the

rectal

wall

was

-LRB-

range

Table

-RRB-

Median

operative

time

defined

as

beginning

when

the

rectoscope

was

inserted

and

ending

when

it

was

removed

was

min

-LRB-

range

-RRB-

Complications

developed

in

of

-LRB-

-RRB-

patients

Two

patients

had

urinary

retention

one

patient

a

urinary

tract

infection

and

one

suffered

from

a

low

hemoglobin

rate

requiring

blood

transfusion

No

reoperations

were

necessary

and

mortality

rate

was

zero

Median

length

of

stay

was

days

-LRB-

range

days

Table

-RRB-

Definite

histopathological

examination

of

the

resected

specimens

revealed

an

adenoma

in

patients

and

an

invasive

carcinoma

in

three

patients

-LRB-

in

two

patients

and

in

one

patient

-RRB-

These

three

patients

were

reluctant

to

undergo

major

surgery

and

were

observed

with

rectoscopy

and

endorectal

ultrasound

every

months

without

signs

of

recurrence

at

months

after

TEM

In

three

adenomas

excisional

margin

was

considered

microscopic

irradical

resulting

in

of

tumours

being

radically

excised

Table

and

tumour

characteristicsCharacteristicsNumberMale/female

-LRB-

N

-RRB-

age

in

years

-LRB-

range

-RRB-

-LRB-

-RRB-

Median

distance

from

dentate

line

in

centimetres

-LRB-

range

-RRB-

-LRB-

-RRB-

Median

tumour

size

in

square

centimetres

-LRB-

range

-RRB-

-LRB-

-RRB-

Median

capture

of

circumference

of

rectal

wall

in

per

cent

-LRB-

range

-RRB-

-LRB-

-RRB-

Table

characteristicsCharacteristicsNumberMedian

duration

of

operation

in

minutes

-LRB-

range

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Urinary

tract

of

hospital

stay

in

days

-LRB-

range

-RRB-

-LRB-

-RRB-

Six

months

after

surgery

mean

FISI

scores

were

found

to

be

decreased

-LRB-

pre-operative

post-operative

-LRB-

p

-RRB-

-RRB-

depicting

an

improvement

in

faecal

continence

-LRB-

Fig.

-RRB-

Overall

when

pre-operative

and

post-operative

FISI

scores

were

compared

patients

improved

patients

were

unchanged

and

seven

deteriorated

Operation

time

or

tumour

size

did

not

influence

the

change

in

FISI

score

There

was

a

significant

correlation

between

the

decrease

in

FISI

score

and

tumour

height

-LRB-

p

-RRB-

Reduction

of

FISI

was

significantly

greater

in

patients

with

a

tumour

location

within

cm

from

the

dentate

line

-LRB-

p

Table

-RRB-

Mean

scores

and

ranges

of

the

EuroQol

are

presented

in

Table

Mean

general

quality

of

life

score

from

the

patients

perspective

-LRB-

EQ-VAS

-RRB-

was

found

to

be

significantly

higher

months

after

TEM

-LRB-

p

-RRB-

The

observed

changes

in

EQ-VAS

showed

no

correlation

with

the

post-operative

alterations

in

FISI

scores

or

tumour

characteristics

Mean

pre-operative

EQ-VAS

score

in

our

group

was

lower

compared

to

the

mean

EQ-VAS

score

of

the

sex

and

age-matched

general

population

-LRB-

p

-RRB-

Post-operative

EQ-VAS

score

was

comparable

with

the

general

population

Mean

index

score

-LRB-

social

perspective

-RRB-

remained

the

same

-LRB-

p

-RRB-

Both

pre

and

post-operative

index

scores

were

similar

to

those

of

the

sex

age-matched

general

population

Comparing

the

change

from

baseline

in

FIQL

scores

a

statistically

significant

improvement

was

observed

in

two

of

the

four

domains

-LRB-

embarrassment

p

and

lifestyle

p

-RRB-

The

domains

of

lifestyle

coping

and

behaviour

and

embarrassment

were

correlated

with

the

FISI

-LRB-

all

p

Table

-RRB-

Overall

and

FIQL

scores

were

not

affected

by

age

and

gender

of

the

patients

Surgical

aspects

and

tumour

characteristics

did

not

influence

the

outcome

Fig.

Faecal

Incontinence

Severity

Index

-LRB-

FISI

-RRB-

scores

-LRB-

SEM

-RRB-

before

and

after

Transanal

Endoscopic

Microsurgery

-LRB-

TEM

-RRB-

Table

FISI

scores

numbers

in

parentheses

are

standard

deviationsFISI

scorePre-operativePost-operativeStatistical

-LRB-

-RRB-

-LRB-

-RRB-

p

Duration

of

operation

min

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

Duration

of

operation

min

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

Tumours

cm

from

dentate

line

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

Tumours

cm

from

dentate

line

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

Median

tumour

size

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

Median

tumour

size

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

Lower

values

indicate

better

anorectal

functioningTable

EuroQoL

scores

numbers

in

parentheses

are

standard

deviations

Control

groupPre-operativePost-operativeStatistical

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

Index

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

represents

the

patients

perspective

on

quality

of

life

index

score

represents

the

societal

value

on

quality

of

life

Higher

scores

indicate

higher

quality

of

life

Both

scores

are

compared

with

a

healthy

sex

and

age-matched

control

group.Table

FIQL

scores

numbers

in

parentheses

are

standard

deviationsFIQLSPre-operativePost-operativeStatistical

-LRB-

-RRB-

-LRB-

-RRB-

p

-LRB-

-RRB-

-LRB-

-RRB-

p

-LRB-

-RRB-

-LRB-

-RRB-

p

-LRB-

-RRB-

-LRB-

-RRB-

p

Higher

scores

indicate

higher

quality

of

life

Discussion

In

rectal

adenomas

TEM

has

emerged

as

the

procedure

of

choice

because

of

its

safety

and

low

local

recurrence

rates

Especially

compared

to

radical

surgery

TEM

has

proven

its

safety

-LSB-

-RSB-

However

possible

adverse

effects

of

TEM

have

to

be

addressed

The

use

of

a

rectoscope

with

a

diametre

introduced

transanally

has

lead

to

substantial

scepticism

regarding

impact

on

anorectal

functioning

In

earlier

studies

we

already

showed

TEM

to

be

superior

to

total

mesorectal

excision

regarding

post-operative

defecation

disorders

although

this

did

not

result

in

improved

quality

of

life

-LSB-

-RSB-

In

the

present

study

TEM

resulted

in

improved

faecal

continence

as

measured

by

the

FISI

This

apparent

paradox

may

be

attributed

to

pre-operative

tumour

symptoms

such

as

mucinous

or

bloody

discharge

prolapse

tenesmi

and/or

urge

giving

rise

to

incontinence-like

symptoms

Post-operative

improvement

of

continence

was

most

significant

in

tumours

within

cm

from

the

dentate

line

but

disappeared

in

our

study

in

tumours

above

cm

from

the

dentate

line

Kreis

et

al.

-LSB-

-RSB-

performed

manometric

studies

after

TEM

and

found

a

significant

reduction

in

anal

resting

pressure

year

post-operative

and

a

temporary

reduction

in

anal

squeezing

pressure

resulting

in

a

temporary

rise

in

urge

incontinence

Kennedy

et

al.

-LSB-

-RSB-

found

a

significant

reduction

in

anal

resting

pressure

weeks

after

TEM

This

reduction

was

significantly

correlated

with

duration

of

the

procedure

but

mean

continence

score

was

not

changed

after

TEM

Both

of

the

above

studies

however

did

not

use

validated

questionnaires

on

faecal

continence

and

therefore

comparison

with

our

study

is

difficult

Cataldo

et

al.

-LSB-

-RSB-

reported

on

the

impact

of

TEM

on

functional

outcome

and

incontinence-specific

quality

of

life

using

the

same

questionnaires

No

significant

alteration

was

found

in

faecal

continence

after

TEM

The

discrepancy

between

both

studies

may

be

explained

by

the

relative

short

interval

between

the

TEM

procedure

and

post-operative

questioning

of

weeks

in

the

Cataldo

series

Also

in

his

study

indications

for

TEM

were

heterogeneous

which

may

have

influenced

results

The

positive

effect

of

TEM

on

faecal

continence

in

our

series

may

be

explained

by

the

differences

in

pre-operative

FISI

score

between

both

studies

-LRB-

versus

-RRB-

depicting

more

continence

problems

among

the

patients

in

our

series

Another

explanation

may

be

the

differences

in

tumour

distance

from

the

dentate

line

-LRB-

present

series

median

cm

Cataldo

series

cm

-RRB-

Also

in

our

series

tumours

were

larger

-LRB-

median

versus

-RRB-

Because

tumours

were

larger

in

our

series

more

extensive

resections

were

performed

often

in

tumours

located

within

the

sphincter

apparatus

These

latter

resections

were

already

shown

to

influence

rectoinhibitory

reflex

reflex

sphincter

contraction

rectal

sensitivity

and

compliance

-LSB-

-RSB-

Further

analysis

within

our

series

upon

this

issue

showed

only

tumour

distance

from

the

dentate

line

of

less

than

cm

to

be

a

significant

contributing

factor

These

results

however

are

based

upon

low

number

of

patients

and

therefore

solid

conclusions

can

not

be

drawn

Although

in

our

study

TEM

resulted

in

a

significant

improvement

in

continence

the

post-operative

FISI

was

still

worse

compared

to

the

Cataldo

series

-LRB-

versus

-RRB-

Regarding

quality

of

life

Cataldo

found

TEM

was

of

no

significant

influence

In

our

series

mean

general

quality

of

life

score

from

the

patients

perspective

EQ-VAS

was

significantly

higher

after

TEM

This

improvement

could

not

be

explained

by

improved

FISI

scores

but

probably

by

lower

pre-operative

EQ-VAS

scores

as

compared

to

healthy

controls

Another

explanation

may

be

the

rejoice

phenomena

that

is

patients

are

relieved

the

tumour

has

been

excised

and

in

most

cases

an

adenoma

was

found

-LSB-

-RSB-

However

because

of

the

low

number

of

invasive

carcinomas

in

our

series

this

is

purely

theoretical

The

societal

value

of

general

quality

of

life

remained

unchanged

Measuring

quality

of

life

using

the

FIQL

questionnaires

resulted

in

a

significant

improvement

in

two

of

the

four

FIQL

domains

-LRB-

embarrassment

and

lifestyle

-RRB-

Moreover

the

domains

of

lifestyle

coping

and

behaviour

and

embarrassment

were

all

significantly

correlated

with

the

FISI

In

conclusion

how

are

these

results

to

be

interpreted

This

study

supports

the

hypothesis

that

rectal

tumours

give

rise

to

incontinence-like

symptoms

especially

in

low-lying

rectal

tumours

After

the

tumour

is

excised

using

the

TEM

technique

faecal

continence

improves

TEM

itself

does

not

improve

continence

but

also

does

not

deteriorate

faecal

continence

Mean

quality

of

life

from

the

patients

perspective

following

TEM

is

improved

Based

on

as

we

know

the

only

two

studies

addressing

anorectal

functioning

and

quality

of

life

after

TEM

in

one

study

it

can

be

concluded

that

TEM

does

not

impair

faecal

continence

Also

quality

of

life

is

not

negatively

influenced

by

the

TEM

procedure

itself

and

therefore

TEM

is

the

procedure

of

choice

in

all

rectal

adenomas

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B O O O O O B O O O O O O O O O O

tem
local excision
quality of life
functional outcome


Meta-regression

analysis

of

high-frequency

ventilation

vs

conventional

ventilation

in

infant

respiratory

distress

syndrome

Objective

There

is

considerable

heterogeneity

among

randomized

trials

comparing

high-frequency

ventilation

-LRB-

HFV

-RRB-

with

conventional

mechanical

ventilation

-LRB-

CMV

-RRB-

in

premature

neonates

with

respiratory

distress

syndrome

We

investigated

what

factors

explained

differences

in

outcome

among

these

trials

Introduction

High-frequency

ventilation

-LRB-

HFV

-RRB-

has

been

compared

with

conventional

mechanical

ventilation

-LRB-

CMV

-RRB-

since

the

In

HFV

patients

are

ventilated

with

small

tidal

volumes

even

smaller

than

the

dead

space

of

their

airways

at

high

frequencies

normally

between

and

Hz

Because

HFV

combines

high

mean

airway

pressures

with

small

tidal

volumes

this

technique

of

ventilation

has

been

regarded

by

some

to

be

the

most

optimal

form

in

patients

with

infant

respiratory

distress

syndrome

-LRB-

IRDS

-RRB-

adult

respiratory

distress

syndrome

-LRB-

ARDS

-RRB-

and

other

forms

of

severe

lung

disease

-LSB-

-RSB-

The

HFV

has

been

extensively

investigated

in

premature

neonates

with

IRDS

a

population

specifically

at

risk

for

chronic

lung

disease

-LRB-

CLD

-RRB-

Unfortunately

the

results

of

these

studies

were

equivocal

-LSB-

-RSB-

thus

the

question

remains

whether

or

not

HFV

better

prevents

CLD

than

conventional

mechanical

ventilation

-LRB-

CMV

-RRB-

in

patients

with

severe

lung

disease

A

significant

number

of

meta-analyses

have

been

performed

to

answer

this

question

-LSB-

-RSB-

Pooled

estimates

of

pulmonary

outcomes

failed

to

show

clinically

relevant

differences

among

HFV

and

CMV

-LSB-

-RSB-

however

significant

heterogeneity

existed

between

studies

included

in

these

meta-analyses

In

a

recent

cumulative

meta-analysis

we

identified

improvements

of

the

conventional

treatment

of

IRDS

and

ventilation

strategies

applied

in

both

HFV

and

CMV

as

important

sources

of

heterogeneity

-LSB-

-RSB-

These

associations

could

be

confounded

by

other

explanatory

variables

Although

a

meta-analysis

may

pool

results

from

randomized

trials

differences

among

trials

will

not

be

randomly

or

independently

distributed

A

meta-analysis

constitutes

an

observational

study

of

trials

subjected

to

bias

inherent

to

observational

research

In

a

meta-regression

analysis

it

is

possible

to

adjust

for

confounding

covariates

A

number

of

alternative

hypotheses

have

been

formulated

to

explain

heterogeneity

between

trials

The

observed

regression

of

the

cumulative

relative

risks

to

the

level

of

unity

was

due

to

publication

bias.Use

of

the

Sensormedics

ventilator

resulted

in

better

results

in

HFV

treated

patients.A

prolonged

ventilation

on

CMV

before

initiating

HFV

treatment

could

reduce

the

benefits

of

HFV.In

subgroups

of

more

premature

neonates

with

lower

birth

weight

with

a

higher

susceptibility

for

CLD

HFV

could

result

in

better

pulmonary

outcome.With

outcome

rates

increasingly

representing

more

severe

disease

HFV

could

have

an

increasing

advantage

over

CMV

-LSB-

-RSB-

therefore

we

used

meta-regression

analysis

to

better

estimate

relative

treatment

effects

through

adjustments

for

factors

that

could

explain

trial

heterogeneity

Methods

Trials

were

included

based

on

a

previous

meta-analysis

that

we

had

conducted

-LSB-

-RSB-

The

same

search

strategy

as

well

as

the

same

inclusion

and

exclusion

criteria

as

in

our

previous

meta-analysis

were

used

for

an

update

yielding

two

more

studies

that

could

be

included

for

this

meta-regression

analysis

Validity

of

studies

was

assessed

by

criteria

published

by

Jadad

et

al.

-LSB-

-RSB-

The

validity

was

generally

deemed

as

high

with

adequate

allocation

concealment

in

all

trials

Blinding

of

treatment

was

not

possible

due

to

the

nature

of

the

interventions

Data

extraction

was

performed

as

has

been

reported

in

our

previous

meta-analysis

The

following

outcome

measures

were

used

mortality

chronic

lung

disease

-LRB-

CLD

-RRB-

as

defined

by

supplemental

oxygen

need

or

ventilator

dependency

at

the

age

of

weeks

post-menstrual

A

number

of

explanatory

variables

were

extracted

as

well

year

of

publication

type

of

ventilator

used

for

HFV

-LRB-

Sensormedics

ventilator

versus

other

-RRB-

ventilation

strategies

applied

in

the

HFV

and

CMV

treatment

groups

were

obtained

as

previously

described

-LSB-

-RSB-

time

on

CMV

before

study

initiation

gestational

age

and

birth

weight

and

outcome

rates

in

the

control

population

were

taken

as

proxy

for

baseline

disease

severity

in

the

source

population

The

Sensormedics

ventilator

was

singled

out

because

previous

research

suggested

better

performance

compared

with

other

oscillator

ventilators

-LSB-

-RSB-

Statistical

analysis

All

data

were

extracted

according

to

the

intention-to-treat

principle

The

number

of

patients

surviving

without

chronic

lung

disease

was

subtracted

from

the

total

number

of

randomized

patients

in

each

treatment

arm

to

calculate

the

composite

outcome

of

death

or

CLD

To

calculate

the

risk

of

CLD

the

number

of

surviving

patients

was

put

in

the

denominator

Publication

bias

was

assessed

by

visual

appraisal

of

symmetry

of

funnel

plots

and

performing

rank

tests

Smaller

studies

could

show

different

results

than

larger

studies

which

could

suggest

publication

bias

but

in

fact

was

caused

by

systematic

differences

among

studies

therefore

an

analysis

of

publication

bias

stratified

for

ventilation

strategies

was

performed

to

determine

whether

the

observed

association

between

the

inverse

of

the

standard

error

with

the

risk

ratio

was

confounded

by

ventilation

strategies

Meta-regression

analysis

was

used

to

evaluate

other

hypotheses

The

dependent

variables

RR

of

CLD

and

RR

of

CLD

or

death

were

natural

log

transformed

to

linearize

the

regression

models

Individual

studies

were

weighted

by

inverse

variances

of

relative

risks

of

outcomes

of

interest

so

that

the

more

precise

studies

had

more

influence

in

the

analysis

Firstly

linear

regression

analyses

were

applied

to

explanatory

variables

Secondly

linear

regression

analyses

with

continuous

covariates

were

conducted

stratified

by

HLVS

LPVS

and

use

of

surfactant

Finally

multivariable

linear

regression

analyses

were

performed

to

calculate

adjusted

contributions

of

different

explanatory

variables

of

rivalling

hypotheses

to

changes

in

RR

The

relative

effects

of

covariates

were

evaluated

by

relative

risk

ratios

-LRB-

RRR

-RRB-

A

relative

risk

ratio

quantifies

the

relative

change

in

RR

that

is

associated

with

a

specified

change

of

a

covariate

For

continuous

variables

the

RRR

was

calculated

for

the

ranges

of

minimum

and

maximum

values

of

covariates

that

were

reported

in

trials

For

example

the

RRR

for

year

of

publication

was

calculated

by

using

the

range

between

the

publication

year

of

the

first

year

and

the

publication

year

of

the

last

included

trial

The

RRR

for

year

of

publication

thus

estimates

the

relative

change

in

RR

due

to

the

difference

in

years

of

publication

between

the

first

and

last

trials

All

analyses

were

conducted

using

SPSS

for

Windows

software

-LRB-

SPSS

Chicago

Ill.

-RRB-

and

Excel

-LRB-

Microsoft

Redmond

Wash.

-RRB-

Results

For

the

analyses

studies

were

available

that

specified

either

CLD

in

survivors

or

death

or

CLD

as

outcome

measures

-LSB-

-RSB-

In

trials

a

high

frequency

oscillatory

ventilator

was

used

-LSB-

-RSB-

in

of

these

trials

this

was

the

SensorMedics

ventilator

-LSB-

-RSB-

Two

studies

used

a

high-frequency

jet

ventilator

-LSB-

-RSB-

and

in

two

studies

a

high-frequency

flow

interrupter

ventilator

was

used

-LSB-

-RSB-

In

the

HFV

group

a

total

of

patients

were

included

for

the

outcome

of

CLD

with

events

and

a

total

of

patients

with

events

for

the

outcome

death

or

CLD

In

the

CMV

group

a

total

patients

were

reported

for

the

outcome

of

CLD

with

events

and

a

total

of

patients

with

events

for

the

outcome

death

or

CLD

A

forest

plot

of

these

trials

can

be

found

in

the

Electronic

Supplement

Table

summarizes

the

main

characteristics

of

the

studies

The

outcome

of

CLD

was

available

in

all

studies

but

one

-LSB-

-RSB-

Time

on

CMV

to

start

of

the

study

was

not

reported

by

Plavka

et

al.

-LSB-

-RSB-

and

Craft

et

al.

-LSB-

-RSB-

In

only

one

study

was

surfactant

not

used

as

concomitant

treatment

-LSB-

-RSB-

A

high

lung

volume

strategy

-LRB-

HLVS

-RRB-

was

used

in

all

but

two

studies

-LSB-

-RSB-

A

ventilation

strategy

in

the

CMV-treated

patients

that

could

qualify

as

lung

protective

-LRB-

LPVS

-RRB-

was

reported

in

the

most

recent

studies

-LSB-

-RSB-

Studies

were

published

over

a

range

of

years

Other

reported

ranges

of

covariates

were

h

average

time

on

CMV

before

start

of

study

weeks

average

gestational

age

and

kg

average

birth

weight

These

ranges

were

used

to

calculate

RRRs

Two

studies

dominated

the

analyses

by

virtue

of

the

weight

they

received

in

the

analyses

Johnson

et

al.

-LSB-

-RSB-

and

Courtney

et

al.

-LSB-

-RSB-

-LRB-

together

for

CLD

and

for

death

or

CLD

as

outcome

-RRB-

Table

characteristicsReferenceYearTime

on

CMVAgeBirth

weightSensorMHLVSLPVSSurfCLD

lnRRWeightDeath

or

CLD

lnRRWeight

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

NNNY

-LSB-

-RSB-

-LSB-

-RSB-

NNNY

-LSB-

-RSB-

-LSB-

-RSB-

NYYY

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

YYYY

-LSB-

-RSB-

-LSB-

-RSB-

NYYY

-LSB-

-RSB-

Year

year

of

publication

Time

CMV

Mean

time

on

CMV

before

start

of

the

study

in

hours

Age

Mean

gestational

age

-LRB-

weeks

-RRB-

Birth

weight

mean

birth

weight

-LRB-

kg

-RRB-

HLVS

high

lung

volume

strategy

in

the

HFV

group

LPVS

lung

protective

ventilation

strategy

in

the

CMV

group

Surf

use

of

surfactant

in

the

study

CLD

chronic

lung

disease

defined

as

on

oxygen

at

weeks

postmenstrual

age

LnRR

natural

log

of

the

relative

risk

A

funnel

plot

of

the

inverse

of

the

standard

error

against

the

natural

logarithm

of

the

RR

for

CLD

was

indicative

of

publication

bias

because

of

asymmetry

round

the

line

of

the

pooled

effect

-LRB-

Fig

-RRB-

A

rank

test

showed

a

p-value

of

A

stratified

analysis

of

publication

bias

is

indicated

by

different

colors

in

Fig

To

visually

evaluate

publication

bias

within

subgroups

of

ventilation

strategy

the

distribution

of

trials

round

the

corresponding

colored

lines

-LRB-

mean

effect

size

within

subgroup

-RRB-

was

assessed

Stratification

by

ventilation

strategy

-LRB-

HLVS

and

LPVS

vs

either

no

HLVS

and/or

no

LPVS

-RRB-

showed

p-values

of

and

respectively

indicating

less

evidence

of

publication

bias

The

distribution

of

stratified

studies

round

the

lines

of

pooled

estimates

showed

less

asymmetry

-LRB-

Fig

-RRB-

Publication

bias

for

the

composite

outcome

of

death

or

CLD

was

less

likely

with

a

p-value

of

Stratified

analysis

showed

p-values

of

and

Fig.

plot

Selection

bias

in

reporting

RR

of

chronic

lung

disease

-LRB-

CLD

-RRB-

as

suggested

by

asymmetry

of

the

distribution

of

studies

x-axis

inverse

of

the

standard

error

of

the

RR

y-axis

natural

logarithm

of

the

RR

Blue

diamonds

studies

with

either

no

high

lung

volume

strategy

-LRB-

HLVS

-RRB-

or

no

lung

protective

volume

strategy

-LRB-

LPVS

-RRB-

pink

diamonds

studies

with

both

HLVS

and

LPVS

dotted

line

estimated

pooled

RR

including

all

studies

dashed

colored

lines

pooled

RR

of

subgroups

of

studies

Publication

bias

was

visually

appraised

by

assessing

symmetry

of

distribution

of

studies

around

the

lines

of

pooled

estimates

CMV

conventional

mechanical

ventilation

Figures

show

the

results

of

the

linear

meta-regression

analyses

for

continuous

explanatory

variables

with

relative

risk

of

CLD

as

dependent

variable

Two

studies

dominate

these

figures

designated

by

the

weight

they

received

in

the

analyses

-LSB-

-RSB-

Over

the

years

the

reported

benefit

of

HFV

over

CMV

seemed

to

diminish

-LRB-

Fig

-RRB-

A

longer

time

on

CMV

prior

to

study

initiation

and

a

higher

gestational

age

and

increase

of

birth

weight

-LRB-

data

not

shown

-RRB-

seemed

to

be

positively

associated

with

a

relatively

better

outcome

in

HFV

-LRB-

Figs

-RRB-

Table

shows

the

results

of

linear

meta-regression

analyses

showing

significant

associations

with

year

of

publication

-LRB-

times

higher

RR

with

change

of

publication

year

from

to

-RRB-

and

whether

or

not

a

protective

ventilation

strategy

was

applied

-LRB-

times

higher

RR

with

change

of

protective

ventilation

from

no

to

yes

Table

-RRB-

In

the

linear

regression

analyses

with

death

or

CLD

as

composite

outcome

no

significant

associations

were

detected

Whether

or

not

a

Sensormedics

high-frequency

oscillatory

ventilator

was

used

and

baseline

incidence

in

CMV

-LRB-

vs

-RRB-

treated

patients

displayed

the

smallest

effects

on

trial

outcome

-LRB-

RRR

and

for

CLD

and

RRR

and

for

death

or

CLD

respectively

-RRB-

Fig.

regression

analyses

Crude

and

subgroup

linear

regression

analyses

of

the

effect

of

year

of

publication

prior

time

on

CMV

and

gestational

age

with

natural

logarithm

of

RR

of

CLD

as

dependent

variable

y-axis

natural

logarithm

of

the

RR

x-axis

explanatory

variables

Blue

diamonds

studies

with

either

no

HLVS

or

no

LPVS

pink

diamonds

studies

with

both

HLVS

and

LPVS

The

size

of

the

diamonds

reflects

the

weights

the

individual

trials

contribute

to

the

analyses

Thin

blue

line

regression

line

including

all

studies

thick

pink

line

regression

line

including

only

studies

with

both

HLVS

and

LPVS

CMV

conventional

mechanical

ventilationFig

as

Fig.

as

Fig.

linear

regression

confidence

confidence

intervalCrude

BSig.LowerUpperRRRLowerUpperboundaryboundaryboundaryboundaryAll

studiesCLD

Year

-LRB-

no

to

yes

-RRB-

LPVS

Surf

Death

or

CLD

Year

LPVS

Surf

Studies

with

surfactant

HLVS

and

LPVSCLD

Year

Age

Weight

Death

or

CLD

Year

TimeCMV

Age

Weight

Simple

linear

regression

analyses

were

calculated

for

chronic

lung

disease

-LRB-

CLD

-RRB-

defined

as

on

oxygen

at

weeks

postgestational

age

and

death

or

CLD

The

following

co-variates

were

evaluated

Year

Number

of

years

after

the

first

included

study

SensorM

Whether

or

not

a

Sensormedics

type

of

HFV

was

used

TimeCMV

Mean

time

on

CMV

before

start

of

the

study

in

hours

Age

Mean

gestational

age

-LRB-

weeks

-RRB-

Weight

mean

birth

weight

-LRB-

kg

-RRB-

HLVS

high

lung

volume

strategy

in

the

HFV

group

LPVS

lung

protective

ventilation

strategy

in

the

CMV

group

Surf

use

of

surfactant

in

the

study

B

was

the

estimated

crude

coefficient

RRR

relative

risk

ratio

RRcovariate

for

binary

variables

-LRB-

SensorM

HLVS

and

LPVS

-RRB-

for

continues

variables

the

extreme

values

reported

in

the

studies

were

used

to

calculate

the

ranges

for

years

for

Time

on

CMV

for

Age

for

Weight

and

for

CMV

-LRB-

RRRyears

RRyear

RRRtime

on

CMV

RRtime

h/RRtime

h

RRRage

RRage

weeks/RRyear

weeks

RRRweight

RRweight

kg/RRyear

kg

RRRincidence

of

CLD

in

CMV

RRincidence

-RRB-

Figure

shows

how

the

incidence

of

CLD

in

the

CMV

treated

patients

was

related

to

the

incidence

in

HFV

treated

patients

for

each

of

the

studies

The

diagonal

line

represents

the

line

of

no

effect

in

this

figure

A

trend

line

was

fitted

by

weighted

linear

regression

showing

a

small

effect

of

change

in

incidence

in

CMV

on

incidence

in

HFV-treated

patients

Fig.

regression

analysis

of

incidence

of

CLD

in

CMV

on

incidence

of

CLD

in

HFV

y-axis

incidence

of

CLD

in

HFV

x-axis

incidence

of

CLD

in

CMV

Thin

pink

line

regression

line

including

all

studies

Year

of

publication

was

not

related

to

change

in

relative

risk

of

CLD

in

the

subgroup

of

studies

with

HLVS

LPVS

and

concomitant

use

of

surfactant

-LRB-

RRR

-RRB-

There

was

only

a

small

increase

in

relative

risk

for

death

or

CLD

-LRB-

RRR

Fig

Table

-RRB-

Opposite

effects

of

gestational

age

-LRB-

RRR

for

CLD

and

for

death

or

CLD

vs

RRR

for

CLD

and

for

death

or

CLD

respectively

-RRB-

and

birth

weight

were

detected

in

the

subgroup

analysis

-LRB-

Fig

Table

-RRB-

Prior

time

on

CMV

exerted

less

effect

on

outcome

compared

with

the

crude

analysis

RRR

for

CLD

and

for

death

or

CLD

and

RRR

for

CLD

and

for

death

or

CLD

in

the

adjusted

and

crude

analyses

respectively

-LRB-

Fig

Table

-RRB-

Multivariable

linear

regression

analyses

were

conducted

to

assess

the

independent

contributions

to

change

in

RR

by

explanatory

variables

-LRB-

Table

-RRB-

The

RRRs

in

Table

have

the

same

meaning

as

in

Table

only

they

represented

adjusted

RRRs

Year

of

publication

was

not

considered

as

an

independent

explanatory

variable

but

rather

as

proxy

for

changes

in

treatment

and

patient

population

Gestational

age

and

birth

weight

were

collinearly

related

by

nature

only

gestational

age

was

fitted

in

the

model

One

study

contributed

to

the

fact

that

surfactant

was

not

used

therefore

surfactant

was

not

used

in

the

multiple

linear

regression

analyses

Two

models

were

fitted

Model

A

used

Sensormedics

time

on

CMV

gestational

age

HLVS

and

LPVS

as

covariates

The

largest

estimated

effects

were

caused

by

ventilation

strategies

HLVS

and

LPVS

adjusted

for

use

of

Sensormedics

ventilator

prior

time

on

CMV

and

gestational

age

These

estimations

were

consistent

for

the

outcomes

CLD

-LRB-

RRR

and

RRR

for

HLVS

and

LPVS

respectively

-RRB-

and

death

or

CLD

-LRB-

RRR

and

RRR

fro

HLVS

and

LPVS

respectively

-RRB-

Use

of

a

Sensormedics

ventilator

seemed

to

have

a

much

smaller

effect

on

RR

for

outcome

The

RRR

of

gestational

age

comparing

weeks

with

weeks

for

CLD

and

death

or

CLD

were

larger

-LRB-

RRR

and

RRR

-RRB-

The

effect

of

a

difference

in

prior

time

on

CMV

of

h

on

CLD

vs

death

or

CLD

was

not

consistent

-LRB-

RRR

and

RRR

respectively

-RRB-

Table

linear

regression

confidence

confidence

intervalBSig.Lower

boundaryUpper

boundaryRRRLower

boundaryUpper

boundaryModel

ACLD

-LRB-

Constant

-RRB-

Age

LPVS

Death

or

CLD

-LRB-

Constant

-RRB-

TimeCMV

Age

LPVS

Model

BCLD

-LRB-

Constant

-RRB-

LPVS

Death

or

CLD

-LRB-

Constant

-RRB-

LPVS

Multiple

linear

regression

analyses

were

calculated

for

chronic

lung

disease

-LRB-

CLD

-RRB-

defined

as

on

oxygen

at

weeks

postgestational

age

and

death

or

CLD

The

following

co-variates

were

evaluated

SensorM

whether

or

not

a

Sensormedics

type

of

HFV

was

used

TimeCMV

mean

time

on

CMV

before

start

of

the

study

-LRB-

in

hours

-RRB-

HLVS

high

lung

volume

strategy

in

the

HFV

group

LPVS

lung

protective

ventilation

strategy

in

the

CMV

group

B

was

the

adjusted

estimated

coefficient

RRR

relative

risk

ratio

RRcovariate

for

binary

variables

-LRB-

SensorM

HLVS

and

LPVS

-RRB-

for

continues

variables

the

extreme

values

reported

in

the

studies

were

used

for

Time

on

CMV

-LRB-

RRRage

RRage

weeks/RRyear

weeks

-RRB-

A

sensitivity

analysis

was

conducted

by

fitting

a

second

model

-LRB-

model

B

-RRB-

with

the

most

important

variables

HLVS

and

LPVS

combined

with

whether

or

not

a

Sensormedics

ventilator

was

used

The

reported

RRRs

were

comparable

to

those

in

the

first

model

Type

of

ventilator

did

not

have

a

large

effect

compared

with

ventilation

strategies

-LRB-

RRR

and

RRR

-RRB-

The

HLVS

was

associated

with

a

decrease

of

the

RRs

comparing

HFV

with

CMV

-LRB-

RRR

and

RRR

-RRB-

while

LPVS

increased

the

RRs

to

the

line

of

no

effect

-LRB-

RRR

and

RRR

-RRB-

Discussion

Our

meta-regression

analysis

showed

a

clear

trend

of

decreasing

differences

in

pulmonary

outcome

between

HFV

and

CMV

in

randomized

trials

conducted

in

premature

neonates

with

IRDS

over

the

years

The

most

likely

hypothesis

for

this

trend

was

the

application

of

a

LPVS

in

the

most

recent

studies

Use

of

surfactant

could

also

have

a

significant

contribution

but

only

one

study

did

not

use

surfactant

-LSB-

-RSB-

In

previous

meta-analyses

subgroup

analyses

or

cumulative

methods

were

used

to

explore

heterogeneity

-LSB-

-RSB-

Subgroup

analysis

is

equivalent

to

meta-regression

with

a

categorical

trial-level

covariate

Considering

subgroup

analysis

formally

as

a

meta-regression

has

advantages

since

it

focuses

on

differences

between

subgroups

as

is

appropriate

rather

than

the

effects

in

each

subgroup

separately

Furthermore

it

is

appropriate

to

use

meta-regression

to

explore

sources

of

heterogeneity

even

if

an

initial

overall

test

for

heterogeneity

is

non-significant

This

test

often

has

low

power

and

therefore

a

non-significant

result

does

not

reliably

identify

lack

of

heterogeneity

-LSB-

-RSB-

In

this

meta-regression

analysis

we

evaluated

in

a

quantitative

way

a

number

of

hypotheses

that

were

raised

to

account

for

different

results

between

randomized

trials

A

relatively

large

proportion

of

well-conducted

trials

were

available

for

the

analyses

For

most

explanatory

variables

there

were

important

differences

among

trials

The

effects

of

the

two

most

important

covariates

HLVS

and

LPVS

were

consistent

in

the

different

models

and

were

even

increased

in

effect

size

by

adjusting

for

other

covariates

of

the

competing

hypotheses

were

more

likely

to

influence

results

as

shown

by

calculating

the

RRRs

Common

pitfalls

in

meta-regression

analysis

can

occur

such

as

multiple

or

post-hoc

analyses

and

lead

to

data

dredging

and

a

high

probability

of

false-positive

conclusions

-LSB-

-RSB-

We

therefore

restricted

our

analyses

to

a

limited

number

of

pre-specified

explanatory

covariates

Publication

bias

was

considered

unlikely

as

an

explanation

of

the

apparent

diminishing

relative

effect

of

HFV

Publication

bias

is

selection

bias

If

trials

are

selectively

published

either

because

of

their

size

or

because

of

significant

results

this

would

result

in

an

association

between

trial

size

and/or

precision

and

the

trial

outcome

Strictly

speaking

funnel

plots

probe

whether

studies

with

little

precision

-LRB-

small

studies

-RRB-

give

different

results

from

studies

with

greater

precision

-LRB-

larger

studies

-RRB-

Asymmetry

in

the

funnel

plot

may

therefore

result

not

from

a

systematic

under-reporting

of

negative

trials

but

from

an

essential

difference

between

smaller

and

larger

studies

that

arises

from

inherent

between-study

heterogeneity

-LSB-

-RSB-

thus

if

larger

studies

were

also

associated

with

changes

in

ventilation

strategies

and

these

strategies

resulted

in

changes

in

reported

RRs

the

assumed

publication

bias

would

be

in

fact

a

real

association

between

ventilation

strategy

and

study

outcome

therefore

we

conditioned

the

association

between

precision

and

effect

size

presumably

caused

by

publication

bias

on

ventilation

strategies

This

resulted

in

a

lower

p-value

for

publication

bias

and

more

symmetrical

distribution

of

studies

in

subgroups

in

the

funnel

plots

therefore

what

appeared

to

be

publication

bias

could

also

be

explained

by

differences

in

ventilation

strategies

related

to

both

study

size

and

observed

relative

risks

However

it

should

be

pointed

out

that

the

strength

of

this

evidence

is

difficult

to

assess

because

fewer

studies

in

the

subgroups

automatically

resulted

in

less

power

to

detect

publication

bias

Other

alternative

hypotheses

that

have

been

formulated

to

explain

differences

among

studies

were

also

less

compatible

with

the

evidence

-LSB-

-RSB-

The

type

of

ventilator

Sensormedics

vs

other

types

of

high-frequency

ventilators

displayed

RRR

close

to

one

In

the

crude

analyses

prior

time

on

CMV

before

study

initiation

showed

contradictory

effects

to

what

was

hypothesized

-LSB-

-RSB-

The

adjusted

analyses

showed

conflicting

results

depending

on

the

outcome

Gestational

age

and

birth

weight

could

also

influence

the

magnitude

of

the

effect

of

HFV

compared

with

CMV

In

the

adjusted

analysis

gestational

age

did

not

change

the

RR

for

CLD

but

showed

an

increase

of

the

RR

for

less

premature

neonates

Finally

an

increased

risk

of

CLD

was

not

accompanied

by

a

greater

relative

benefit

of

HFV

as

compared

with

CMV

The

observed

effects

of

continuous

variables

such

as

time

on

CMV

or

gestational

age

could

be

exaggerated

by

small

studies

with

outlying

results

For

the

covariate

time

on

CMV

the

two

largest

studies

showed

results

that

were

compatible

with

the

hypothesis

that

this

had

no

important

impact

on

the

results

of

these

trials

-LSB-

-RSB-

The

same

fact

applied

to

the

effect

of

baseline

incidence

of

CLD

or

death

or

CLD

Gestational

age

and

weight

were

comparable

between

the

two

largest

trials

which

made

it

more

difficult

to

ascertain

the

relevance

of

the

hypothesis

that

in

smaller

and

more

premature

infants

HFV

performed

better

than

CMV

treatment

The

observed

direction

of

the

effect

of

gestational

age

and

birth

weight

however

was

opposite

to

what

the

hypothesis

predicted

If

gestational

age

was

to

be

interpreted

as

a

higher

risk

of

acquiring

CLD

one

would

expect

that

an

increase

in

the

incidence

of

CLD

was

associated

with

a

relatively

lower

incidence

of

CLD

in

HFV

treated

patients

however

linear

regression

analysis

showed

perfectly

equal

increase

in

both

treatment

groups

Still

the

possibility

remains

that

the

relationship

with

patient

averages

such

as

gestational

age

and

birth

weight

across

trials

was

not

the

same

as

the

relationship

for

patients

within

trials

and

therefore

an

effect

of

these

patient

characteristics

can

not

be

excluded

but

only

considered

in

relation

to

other

covariates

-LSB-

-RSB-

Similar

findings

of

the

effects

of

ventilation

strategies

have

been

reported

by

us

and

other

authors

as

well

-LSB-

-RSB-

however

meta-analyses

are

subject

to

bias

when

differences

among

trials

are

used

to

explain

differences

in

reported

RRs

In

this

meta-regression

analysis

we

were

able

to

estimate

adjusted

association

measures

thereby

diminishing

the

effects

of

possible

confounders/effect-modifiers

By

calculating

less

biased

estimates

of

the

effects

of

ventilation

strategies

and

the

effect

of

using

a

Sensormedics

ventilator

instead

of

other

ventilators

on

the

outcome

in

the

different

HFV

trials

we

were

able

to

reinforce

the

hypothesis

that

ventilation

strategies

are

more

important

than

type

of

ventilator

to

prevent

CLD

The

results

of

this

meta-analysis

stresses

the

importance

of

using

appropriate

ventilation

strategies

to

prevent

ventilator-induced

lung

damage

in

a

highly

vulnerable

group

of

patients

therefore

in

clinical

practice

the

question

of

how

to

use

the

ventilator

is

more

important

than

the

question

of

which

ventilator

should

be

used

The

major

theoretical

advantage

of

HFV

to

CMV

is

delivery

of

smaller

tidal

volumes

to

an

optimally

recruited

lung

As

this

meta-regression

analysis

did

not

confirm

that

subgroups

of

more

premature

neonates

avoidance

of

CMV

prior

to

initiating

HFV

or

neonates

with

higher

risk

of

CLD

were

more

likely

to

benefit

form

elective

HFV

in

IRDS

future

research

should

be

directed

at

identifying

patients

in

whom

HFV

does

have

a

benefit

over

CMV

To

improve

the

robustness

of

these

conclusions

and

to

avoid

the

limitations

of

meta-analysis

of

trials

an

individual-patient-data-based

meta-regression

analysis

should

be

conducted

Conclusion

In

conclusion

confining

randomized

trails

to

smaller

or

more

premature

children

with

IRDS

did

not

seem

to

result

in

better

pulmonary

outcomes

of

HFV

compared

with

CMV

A

generally

held

opinion

that

a

prolonged

ventilation

time

on

CMV

prior

to

initiating

HFV

diminished

the

benefits

of

HFV

was

not

in

agreement

with

the

current

evidence

The

most

important

effects

resulting

in

differences

among

trials

were

probably

caused

by

ventilation

strategies

applied

in

HFV

and

CMV-treated

patients

Electronic

supplementary

material

Electronic

Supplementary

Material

-LRB-

DOC

-RRB-

O O O O O O O O O B B I I O O O O O O O O O O O O O O O B I I O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B I I O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

conventional mechanical ventilation
respiratory distress syndrome
infant

high-frequency ventilation
meta-regression analysis