aDivision of Pediatric Critical Care, Department of Pediatrics, University of Campinas, Campinas, São Paulo, Brazil; and bDepartment of Pediatrics, School of Medicine, São Leopoldo Mandic, Campinas, São Paulo, Brazil

Dr de Souza conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript; Drs de Souza and Nadal designed the data collection instruments, collected data, conducted the initial analyses, and reviewed and revised the manuscript; Drs Brandão and Nogueira coordinated and

To cite: de Souza TH, Brandão MB, Nadal JAH, et al. Ultrasound Guidance for Pediatric Central Venous Catheterization: A Meta-analysis. Pediatrics. 2018;142(5):e20181719

CONTEXT: Central venous catheterization is routinely required in patients who are critically ill, and it carries an associated morbidity. In pediatric patients, the procedures can be difficult and challenging, predominantly because of their anatomic characteristics.OBJECTIVE: To determine whether ultrasound-guided techniques are associated with a reduced incidence of failures and complications when compared with the anatomic landmark technique.DATA SOURCES: We conducted a systematic search of PubMed and Embase.STUDY SELECTION: We included randomized controlled trials and nonrandomized studies in which researchers compare ultrasound guidance with the anatomic landmark technique in children who underwent central venous catheterization.DATA EXTRACTION: Study characteristics, sample sizes, participant characteristics, settings, descriptions of the ultrasound technique, puncture sites, and outcomes were analyzed. Pooled analyses were performed by using random-effects models.RESULTS: A total of 23 studies (3995 procedures) were included. Meta-analysis revealed that ultrasound guidance significantly reduced the risk of cannulation failure (odds ratio = 0.27; 95% confidence interval: 0.17–0.43), with significant heterogeneity seen among the studies. Ultrasound guidance also significantly reduced the incidence of arterial punctures (odds ratio = 0.34; 95% confidence interval: 0.21–0.55), without significant heterogeneity seen among the studies. Similar results were observed for femoral and internal jugular veins.LIMITATIONS: Potential publication bias for cannulation failure and arterial puncture was detected among the studies. However, no publication bias was observed when analyzing only the subgroup of randomized clinical trials.CONCLUSIONS: Ultrasound-guided techniques are associated with a reduced incidence of failures and inadvertent arterial punctures in pediatric central venous catheterization when compared with the anatomic landmark technique.

Ultrasound Guidance for Pediatric Central Venous Catheterization: A Meta-analysisTiago Henrique de Souza, MD, a Marcelo Barciela Brandão, MD, PhD, a José Antonio Hersan Nadal, MD, a Roberto José Negrão Nogueira, MD, PhDa, b

abstract

PEDIATRICS Volume 142, number 5, November 2018:e20181719 REVIEW ARTICLE

A central venous catheter (CVC) is a device that is frequently used in pediatric patients for hemodynamic monitoring, fluid infusion, the administration of medications and blood products, blood sampling, hemodialysis, and parenteral nutrition. In pediatric patients, the deep venous puncture can be technically challenging and carries a risk of several complications, such as arterial punctures, hematomas, thrombosis, pneumothorax, hemothorax, and nervous system injury.1 The traditional puncture technique based on palpation and the identification of anatomic landmarks is still widely used for CVC placement.2 However, the success of this method relies on the normal positioning of the vessels and the absence of thrombosis. Unfortunately, deep veins show significant anatomic variation: up to 18% for the internal jugular vein in children3 and 24% for femoral veins in infants.4

The ultrasound guidance technique emerged in the early 1990s as an alternative to overcome the limitations of the landmark technique.3 The image offered by using 2-dimensional ultrasonography allows the operator to predict variant anatomy and to assess the patency of a target vein. Moreover, when used in real time, it allows for a direct visualization of the relative position of the needle, vein, and surrounding structures. Current evidence reveals that ultrasound guidance is an effective and safe technique for central venous catheterization in adults and children.5, 6 However, this evidence should be interpreted cautiously owing to the participant characteristics (patients and operators), risk of bias, and heterogeneity among the studies. Although ultrasound guidance was associated with a reduced incidence of cannulation failures, a previous meta-analysis did not reveal a reduction in complication

rates.6 Furthermore, statistical tests were not performed to evaluate publication bias. The analysis of publication bias is critical in meta-analyses because it may compromise the validity of the presented results.7

We systematically searched the literature to investigate the effects of ultrasound guidance on clinical outcomes in pediatric patients undergoing central venous catheterization. Our main objective in this meta-analysis was to determine whether ultrasound-guided techniques are associated with a reduced occurrence of failures and complications when compared with the landmark technique. Additionally, we have carefully analyzed the characteristics of the studies to understand whether the results of this meta-analysis are universally true.

METHODS

This review was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement8, 9 and the Cochrane Handbook.10 In March 2018, the study protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews database (registration number CRD42018091333).

Search Strategy

Searched literature databases included PubMed and Embase. Keywords used included combinations of “ultrasound, ” “ultrasonography, ” “central venous catheterization, ” “internal jugular vein, ” “femoral vein, ” “subclavian vein, ” “brachiocephalic vein, ” “neonate, ” “neonates, ” “infant, ” “infants, ” “child, ” “children, ” “pediatric, ” and “pediatrics.” The complete search strategy is presented in the Supplemental Information. No language or publication date restrictions were applied. No

attempts were made to contact the study authors to identify missing and confusing data. A manual search of the references found in the selected articles, reviews, and meta-analyses was also performed. The search was conducted in April 2018.

Study Selection

Two authors (T.H.d.S. and J.A.H.N.) screened the titles and abstracts independently and in duplicate for potential eligibility. They subsequently read the full texts to determine final eligibility. Discrepancies were resolved through discussion and consensus, and if necessary, the assistance of a third author (M.B.B.) was sought.

Eligible studies fulfilled the following criteria: (1) included a population that was limited to patients <18 years old; (2) included original data from interventional (randomized controlled trials [RCTs] or non-RCTs), cohort, or case-control studies; (3) included a comparison of the use of ultrasound guidance with anatomic landmark guidance for deep venous punctures; and (4) contained at least 1 outcome of interest. Studies were excluded if they met at least 1 of the following characteristics: (1) included patients ≥18 years old; (2) were case reports, case series, review articles, or observational studies without a control or comparator; or (3) included an evaluation of Doppler guidance or open cut-down techniques.

Outcomes Measures

The primary outcome for the current analysis was cannulation failure. Secondary outcomes included mean attempts to success, mean time to success, and incidence of complications, such as arterial puncture, hematoma, pneumothorax, hemothorax, or procedure-related infections. The definition of each outcome mentioned above was the same as that used in each study.

DE SOUZA et al2

Data Extraction

A structured data-extraction form was piloted and then used to extract data from the reports of all included studies in duplicate and independently by 2 authors (T.H.d.S. and J.A.H.N.). Discrepancies in the extracted data were resolved through discussion. The following data were extracted, when available, from each selected article: first author, publication year, study design, sample size, participants’ characteristics, settings, description of ultrasound technique, operators’ profiles (medical specialty and experience), puncture sites, success rates, procedure times, number of attempts, and rates of complications (hematomas, arterial punctures, pneumothorax, hemothorax, procedure-related infections, or other). No simplifications or assumptions were made.

Quality Assessment of Studies

The risk of bias assessment was independently assessed by 2 authors (T.H.d.S. and M.B.B.) using the Cochrane Risk of Bias Tool.11 This tool contains 7 items: (1) randomization sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessors; (5) incomplete outcome data; (6) selective reporting; and (7) other sources of bias. One of the following 3 responses was assigned to each item: low risk of bias, high risk of bias, or unclear risk of bias according to the Cochrane Handbook.10 The evaluation was plotted in Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

Discrepancies were addressed by rereading the study, in discussions between the 2 authors, and (if necessary) with the assistance of a third author (R.J.N.N.).

Data Synthesis and Analysis

Meta-analyses of the pooled data were performed by using Review Manager. When using the inverse variance method, fixed-effects and random-effects models generated similar findings. However, because of the heterogeneity detected among the studies, a random-effects model was used to estimate the odds ratio (OR) of dichotomous outcomes and associated 95% confidence intervals (CIs). To assess the heterogeneity among the studies, both Cochran’s Q statistic and the I2 statistic were used. Heterogeneity was considered to be statistically significant when P < .05 or I2 > 50.10 Potential publication bias was assessed by visually inspecting the Begg and Mazumdar12 funnel plots in which the log relative risks were plotted against their SEs. Publication bias was also assessed by using Begg and Mazumdar’s12 adjusted rank correlation test and Egger et al’s13 regression asymmetry test. Sensitivity analyses were conducted to determine the influence of a single study on the overall OR estimates by omitting 1 study in each turn.

We conducted a series of subgroup analyses stratified by ultrasound technique (real-time or prelocation), the type of study (randomized or nonrandomized), and the puncture site to explore the impacts of these variables on the outcomes.

RESULTS

Study Selection and Characteristics

Of 2631 potentially relevant articles identified by using the search strategy, 23 met the inclusion criteria.3, 14 – 34 A total of 3995 CVC placements were included in the meta-analysis (1852 ultrasound-guided procedures and 2143 landmark-guided procedures). In the flow diagram (Supplemental Fig 5), we summarize the steps followed

to identify the studies meeting the inclusion criteria.

Nineteen studies (9 RCTs14, 25, 28 – 34 and 10 nonrandomized studies17 – 24, 26, 27) investigated the real-time ultrasound (RTUS) guidance technique, 3 RCTs investigated the ultrasound-assisted prelocation technique, 3, 15, 16 and 1 nonrandomized study evaluated both techniques.35 With the exception of 2 multicenter studies, 19, 35 all others were unicentric studies. Of the 23 included studies, 9 were conducted in the United States, * 3 were in Japan, 15, 23, 26 2 were in Brazil, 14, 25 1 was in China, 16 1 was in Colombia, 17 1 was in Egypt, 29 1 was in Lebanon, 30 1 was in Russia, 31 1 was in Spain, 35 1 was in Turkey, 20 1 was in Tunisia, 18 and 1 was in the United Kingdom.32

Fifteen studies examined procedures performed exclusively in the operating room.† Three studies analyzed procedures performed exclusively in the PICU.14, 24, 35 Three studies evaluated procedures performed in multiples settings.17, 22, 25 One study was conducted in the emergency department, 21 and researchers in 1 study did not describe the study settings.31 Anesthesiologists were operators in 9 studies, 15, 17, 22, 23, 27, 30, 32 – 34 surgeons were operators in 5, 17, 19, 22, 25, 28 intensivists were operators in 4, 14, 22, 24, 35 and pediatricians were operators in 3.17, 21, 29 Attending physicians were involved in 11 studies, 15, 17, 19, 21 – 25, 28, 32, 35 fellows were involved in 6 studies, 22, 24, 28, 29, 33, 34 and residents were involved in 6 studies.14, 21, 24, 27, 30, 35 Researchers in 5 studies did not specify the medical specialty of the operators, 3, 16, 18, 26, 31 and researchers in 4 studies did not specify their graduation (resident, fellow, or attending physician).3, 16, 26, 31

Regarding the puncture sites, researchers in most RCTs evaluated internal jugular vein catheterizations3, 14 – 16, 25, 31 – 34;

* Refs 3, 19, 21, 22, 24, 27, 28, 33, and 34.† Refs 3, 15, 16, 18– 20, 23, 26– 30, and 32–34.

PEDIATRICS Volume 142, number 5, November 2018 3

researchers in 2 evaluated femoral vein punctures, 29, 30 and researchers in 1 compared the RTUS guidance technique for internal jugular vein catheterization with the landmark technique for subclavian vein catheterization.28 Of the nonrandomized studies, 2 evaluated only internal jugular vein procedures23, 27; 2 evaluated only femoral vein procedures, 22, 26 and 6 evaluated >1 puncture site.17 – 19, 21, 24, 35 The sample size calculation was described only in 4 RCTs.14, 15, 28, 30

The main characteristics of the 23 studies are presented in Table 1.

Risk of Bias

The details for risk of bias are shown in Supplemental Figs 6 and 7.

Most RCTs had adequate random sequence generation; researchers in only 3 studies did not specify the used method of randomization.3, 15, 29 In addition to the methods described in the Cochrane Handbook, 10 we considered that allocation concealment was appropriate when randomization occurred immediately before the procedure. Thus, 6 RCTs had adequate allocation concealment, 14, 25, 28 – 30, 32 whereas researchers in the other 6 studies did not describe this process.3, 16, 31, 33, 34 Because blinding participants and personnel was impossible, all studies of this meta-analysis were considered to be at high risk for performance bias. The blinding of outcome assessment was also impossible, but we believe that the outcome measurement is not likely to be influenced by the lack of blinding. Therefore, all studies were considered to have a low risk of detection bias. Six RCTs were considered to have an unclear risk of attrition bias because the researchers did not state the number of patients who were randomly assigned or provide sufficient information on follow-up.3, 15, 16, 29, 31, 34 Because of a significant loss of participants in

the intervention group, 1 RCT was classified as having a high risk of attrition bias.32

Once the outcomes depend on the operators’ skills, we considered that studies in which researchers did not describe the number of operators nor the operators’ experience in the evaluated techniques were at an unclear risk of other bias.15, 16, 20, 22, 23, 26 – 34 Studies were considered to be at a high risk for other biases if they were performed with only 1 operator3, 25; researchers jointly analyzed the procedures performed by operators with heterogeneous experience17, 19; or researchers jointly analyzed procedures performed at different sites of puncture.17, 18, 21, 24, 28, 35

Primary Outcome: Cannulation Failure

Of the 23 selected studies, researchers in 22 reported the primary outcome, and these were used to calculate the pooled estimate for assessing cannulation failure.3, 14 – 16, 18 – 35 Pooled overall ORs for the primary outcome are shown in Fig 1. Overall, the rates of cannulation failure in the ultrasound group and control group were 9.1% and 19.2%, respectively. The analysis revealed that ultrasounds significantly reduced the risk of cannulation failure (OR = 0.27; 95% CI: 0.17–0.43; P < .00001), with significant heterogeneity seen among the studies (I2 = 66%; P < .00001).

A subgroup analysis of the 9 RCTs that compared RTUS versus landmark techniques14, 25, 28 – 34 revealed a significant reduction of failure (5.3% vs 25%; OR = 0.16 [95% CI: 0.04–0.56]; P = .004), with significant heterogeneity seen among the studies (I2 = 76%; P < .0001). In the analysis of the ultrasound-assisted vein prelocation technique, significantly lower rates of cannulation failure were observed (1% vs 27%; OR = 0.06 [95% CI: 0.01–0.28];

P = .0003), without heterogeneity seen among the 3 studies3, 15, 16 (I2 = 0%; P = .97). Finally, the analysis of nonrandomized studies also revealed a significant reduction of cannulation failure in RTUS guidance over the landmark technique (10.1% vs 16.9%; OR = 0.44 [95% CI: 0.29–0.66]; P < .0001), with moderate heterogeneity seen among the studies (I2 = 50%; P = .03).18 – 24, 26, 27, 35

Analyses of the studies in which procedures were performed exclusively in the internal jugular veins revealed a significant reduction of cannulation failure in the ultrasound group (6.4% vs 27.3%; OR = 0.15 [95% CI: 0.06–0.39]; P < .0001; Fig 2), with significant heterogeneity seen among the studies (I2 = 71%; P = .0001).3, 14 –16, 23, 25, 27, 31 – 34

A reduction in cannulation failure with the ultrasound guidance technique was also observed in studies in which researchers evaluated procedures performed exclusively on the femoral vein (10.4% vs 21.8%; OR = 0.41 [95% CI: 0.17–0.99]; P = .05; Fig 3), without significant heterogeneity seen among the studies (I2 = 23%; P = .27).22, 26, 29, 30

Secondary Outcome: Arterial Puncture

The secondary outcome of arterial puncture was addressed in 22 studies.3, 14 – 16, 18 – 22, 24 – 35 Pooled overall ORs for the secondary outcome are shown in Fig 4. Ultrasound guidance significantly reduced the incidence of arterial punctures compared with the landmark technique (5.4% vs 8.4%; OR = 0.34 [95% CI: 0.21–0.55]; P < .0001). Moderate heterogeneity was observed among the studies (I2 = 46%; P = .01).

The highest heterogeneity was observed in the subgroup of RCTs that compared RTUS guidance with the landmark technique (I2 = 65%; P = .004). In this subgroup, the pooled OR was 0.26 (95% CI: 0.08–0.84; P = .02). Nonrandomized studies had a pooled OR of 0.42 (95%

DE SOUZA et al4

PEDIATRICS Volume 142, number 5, November 2018 5

TABL

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in tr

ansv

erse

app

roac

h, w

ith

need

le g

uide

ass

ista

nce

IJV

5.8

± 2

.0

vs 6

.0 ±

2.

3

100

vs 7

6.9

(P <

.0

01)

1.3

± 0

.6 v

s 3.

3 ±

2.8

(P

< .0

01)

4.2’

± 2

.8 v

s 14

.0’ ±

15.

1 (P

< .0

01)

0 vs

25

(P <

.0

01)

Hem

atom

as,

0 vs

7.6

; he

mot

hora

x,

0 vs

2;

pneu

mot

hora

x,

0 vs

2 (

P NM

)

RCTs

: ultr

asou

nd-a

ssis

ted

vein

pre

loca

tion

vers

us

anat

omic

land

mar

k

Shim

e et

al15

30 v

s 34Op

erat

ing

room

Two

anes

thes

iolo

gist

s w

ith a

t le

ast 3

y o

f exp

erie

nce;

ther

e w

as n

o de

scri

ptio

n of

pre

viou

s ex

peri

ence

or

trai

ning

in th

e ul

tras

ound

gui

danc

e te

chni

que.

IJV

7.7

(2.2

–14)

vs

7.4

(2

.7–1

9)

97 v

s 62

(P

< .0

01)

NMNM

NMTo

tal:

0 vs

0 (

NS)

Ch

uan

et a

l1632

vs 30

Oper

atin

g ro

omNo

spe

cifie

d No

. ope

rato

rs,

profi

le, p

revi

ous

expe

rien

ce,

or tr

aini

ng in

any

of t

he

tech

niqu

es

IJV

8.9

± 2

.09

vs 8

.8 ±

1.

97

100

vs 8

0 (P

<

.05)

1.57

± 1

.04

vs

2.55

± 1

.76

(P =

.007

)

NM3.

1 vs

26.

7 (P

<

.025

)NM

TABL

E 1

Cont

inue

d

PEDIATRICS Volume 142, number 5, November 2018 7

Stud

yna

Sett

ing

Oper

ator

s’ P

rofil

e an

d Ul

tras

ound

Gu

idan

ce A

ppro

ach

Site

Wt (

kg)a,

bSu

cces

s Ra

te,

%a

Atte

mpt

a, c

Proc

edur

es

Tim

ea, d

Arte

rial

Pu

nctu

re (

%)

Othe

r Co

mpl

icat

ions

, %a

Al

ders

on e

t al3

20 v

s 20Op

erat

ing

room

One

expe

rien

ced

card

iac

anes

thet

ist;

ther

e w

as n

o de

scri

ptio

n of

pre

viou

s ex

peri

ence

or

trai

ning

in th

e ul

tras

ound

gui

danc

e te

chni

que.

IJV

6.6

± 2

.5

vs 6

.8 ±

2.

5

100

vs 8

0 (N

S)1.

35 ±

0.7

vs

2.0

± 1

.0 (

P <

.05)

23.0

± 2

7.4

vs

56.4

± 4

8.9

(P <

.05)

5 vs

10

(NS)

Inab

ility

to p

ass

guid

ewir

e: 1

5 vs

40

(P <

.05)

Nonr

ando

miz

ed s

tudi

es: R

TUS

guid

ance

ver

sus

anat

omic

la

ndm

ark

Ri

vera

-Toc

anci

pá e

t al17

(r

etro

spec

tive)

58 v

s 14

3Op

erat

ing

room

, PI

CU, E

D

No s

peci

fied

No. o

pera

tors

, pr

evio

us e

xper

ienc

e, o

r tr

aini

ng

in a

ny o

f the

tech

niqu

es;

pedi

atri

cs, s

urge

ons

and

anes

thes

iolo

gist

s; n

o de

scri

ptio

n of

the

ultr

asou

nd

appr

oach

IJV,

EJV

, FV

, SC

V

19.8

(15

.4–

24.2

) vs

14.

4 (1

2.7–

16.2

)

NMNM

NM0

vs 3

.5 (

P NM

)He

mat

omas

, 1.7

vs

2; i

nabi

lity

to p

ass

guid

ewir

e, 5

.2

vs 5

.6 (

NS)

Ou

lego

-Err

oz e

t al

35 (

pros

pect

ive

mul

ticen

ter)

323

vs

177

PICU

No. o

pera

tors

not

spe

cifie

d;

oper

ator

s w

ere

pedi

atri

c in

tens

ive

care

res

iden

ts o

r at

tend

ing

phys

icia

ns w

ith

vary

ing

degr

ees

of e

xper

ienc

e.

The

ultr

asou

nd-g

uide

d te

chni

que

was

defi

ned

as

the

use

of u

ltras

ound

for

eith

er r

eal-t

ime

guid

ance

or

prel

ocat

ion

of th

e ve

ssel

.

FV, I

JV,

SCV

9 (4

.9–

17.9

) vs

9.8

(4

.4–

18.7

)

80.8

vs

72.9

(N

S)2

[1–3

] vs

2

[1–4

] (P

<

.01)

60 (

30–2

42)

vs

90 (

32–3

00)

(NS)

5.9

vs 1

0.7

(NS)

Pneu

mot

hora

x,

0.7

vs 2

(NS

); he

mat

omas

, 9.

3 vs

14.

7 (N

S)

Fe

rhi e

t al18

(pr

ospe

ctiv

e)30

vs 15

PICU

No s

peci

fied

No. o

pera

tors

, pr

ofile

, pre

viou

s ex

peri

ence

, or

trai

ning

in a

ny o

f the

te

chni

ques

IJV,

FV

NM96

.6 v

s 80

(P

NM)

1.1

vs 3

(P

NM)

3’ v

s 7’

(P

NM)

0 vs

20

(P N

M)

—

Gu

rien

et a

l19 (r

etro

spec

tive

mul

ticen

ter)

360

vs

774

Oper

atin

g ro

omNo

spe

cifie

d No

. ope

rato

rs,

prev

ious

exp

erie

nce,

or

trai

ning

in a

ny o

f the

te

chni

ques

; ped

iatr

ic s

urge

ry

resi

dent

s, p

edia

tric

sur

gery

fe

llow

s, a

nd p

edia

tric

su

rgeo

ns; n

o de

scri

ptio

n of

the

ultr

asou

nd a

ppro

ach

IJV,

SCV

19 [

11–4

1]

vs 2

0 [1

1–42

]

Succ

ess

on

first

site

: 88

.9 v

s 93

(P

= .0

3)

NM42

’ vs

43’ (

NS)

Arte

rial

pu

nctu

re o

n fir

st s

ite: 1

.2

vs 2

.2 (

NS)

Pneu

mot

hora

x,

1.1

vs 2

.3 (

NS);

hem

otho

rax,

0.

2 vs

1.5

(P

= .0

2)

Ç

elik

et a

l20 (

pros

pect

ive)

36 v

s 36Op

erat

ing

room

No. o

pera

tors

not

spe

cifie

d;

inex

peri

ence

d op

erat

ors

unde

r ex

peri

ence

d at

tend

ing

supe

rvis

ion;

ultr

asou

nd-g

uide

d pu

nctu

res

perf

orm

ed in

rea

l tim

e

SCV

8.86

± 5

.9

vs 7

.7 ±

7.

7

91.7

vs

94.7

(P

= .6

3)NM

179.

7 ±

68.

1 vs

15

3.6

± 8

2.6

(P =

.1)

0 vs

9 (

P =

.07)

Pneu

mot

hora

x.

2.8

vs 0

(P

= .3

1);

hem

atom

as, 0

vs

0 (

P NM

)

TABL

E 1

Cont

inue

d

DE SOUZA et al8

Stud

yna

Sett

ing

Oper

ator

s’ P

rofil

e an

d Ul

tras

ound

Gu

idan

ce A

ppro

ach

Site

Wt (

kg)a,

bSu

cces

s Ra

te,

%a

Atte

mpt

a, c

Proc

edur

es

Tim

ea, d

Arte

rial

Pu

nctu

re (

%)

Othe

r Co

mpl

icat

ions

, %a

Ga

llagh

er e

t al21

(r

etro

spec

tive)

98 v

s 70ED

No. o

pera

tors

not

spe

cifie

d;

pedi

atri

c em

erge

ncy

phys

icia

n at

tend

ing

or r

esid

ent w

ith

atte

ndin

g su

perv

isio

n; th

e op

erat

ors

wer

e su

bmitt

ed to

a

form

al tr

aini

ng p

rogr

am

on u

ltras

ound

gui

danc

e. T

he

oper

ator

s’ e

xper

ienc

e w

as

sign

ifica

ntly

hig

her

in th

e ul

tras

ound

gro

up.

FV, I

JV40

(20

–57)

vs

22

(11–

45.9

)

98 v

s 79

NMNM

5.1

vs 8

.6 (

P NM

)He

mat

omas

: 2 v

s 0

(P N

M)

Al

ten

et a

l22 (

retr

ospe

ctiv

e)76

vs 39

PICU

, op

erat

ing

room

In th

e ul

tras

ound

gro

up, t

he

oper

ator

s w

ere

2 in

tens

ivis

ts

expe

rien

ced

in th

e te

chni

que

(4–6

y o

f exp

erie

nce)

or

fello

ws

unde

r di

rect

sup

ervi

sion

(n

= 9)

. In

the

cont

rol g

roup

, the

op

erat

ors

wer

e 4

pedi

atri

c an

esth

etis

ts o

r 1

surg

eon,

eac

h w

ith a

t lea

st 1

0 y

of e

xper

ienc

e.

Ultr

asou

nd-g

uide

d pu

nctu

res

wer

e pe

rfor

med

in r

eal t

ime

in

a lo

ngitu

dina

l app

roac

h.

FV3.

07 ±

0.4

7 vs

3.0

8 ±

0.2

9

94.7

vs

79.5

(P

= .0

2)1.

6 ±

1.5

vs

3.3

± 2

.7 (

P <

.001

)

NM4

(5.3

) vs

9

(23.

1) (

P =

.01)

Cent

ral l

ine–

asso

ciat

ed B

SI:

9.2

vs 7

.6 (

NS)

Yo

shid

a et

al23

(r

etro

spec

tive)

101

vs

55Op

erat

ing

room

No s

peci

fied

No. o

pera

tors

, pr

evio

us e

xper

ienc

e, o

r tr

aini

ng

in a

ny o

f the

tech

niqu

es;

the

oper

ator

s in

all

case

s w

ere

anes

thes

iolo

gist

s. N

o de

scri

ptio

n of

the

ultr

asou

nd

appr

oach

was

giv

en.

IJV

8.7

± 5

.0

vs 1

0.4

± 6

.1

90 v

s 76

(P

< .0

5)NM

35.0

± 1

6.6

vs

26.7

± 1

1.2

(P <

.01)

NMNM

Fr

oehl

ich

et a

l24

(pro

spec

tive)

119

vs

93PI

CUNo

spe

cifie

d No

. ope

rato

rs,

prev

ious

exp

erie

nce,

or

trai

ning

in a

ny o

f the

te

chni

ques

; res

iden

ts, c

ritic

al

care

fello

ws,

att

endi

ng

phys

icia

ns, a

nd a

nur

se

prac

titio

ner;

ultr

asou

nd-g

uide

d pu

nctu

res

perf

orm

ed in

rea

l tim

e in

tran

sver

se a

ppro

ach

IJV,

FV,

SC

V18

[9–

41]

vs 1

3.6

[5.4

–30]

90.8

vs

88.2

(P

= .5

4)NM

150”

[76.

5–43

5]

vs 2

69”

[75–

900]

(N

S)

8.5

vs 1

9.4

(P

= .0

3)NM

TABL

E 1

Cont

inue

d

CI: 0.26–0.67 [P = .0003]; I2 = 26% [P = .20]), and RCTs that analyzed ultrasound-assisted vein prelocation technique had a pooled OR of 0.18 (95% CI: 0.04–0.92 [P = .04]; I2 = 0% [P = .32]).

A meta-analysis on data from other secondary outcomes was not conducted because of a small number of reports and a wide range of definitions between studies.

Sensitivity Analyses

Significant heterogeneity was observed among the included studies in the subgroup “RTUS versus landmark (RCTs)” for the primary and secondary outcomes (I2 = 76% and 65%, respectively). As shown in Fig 1, the study conducted by Grebenik et al32 revealed a higher failure rate with RTUS guidance than with the anatomic landmark technique, and this probably contributed to the heterogeneity. After excluding this study, the results suggested that compared with controls, RTUS cannulation was associated with increased success (OR = 0.10; 95% CI: 0.05–0.20; P < .00001). Insignificant heterogeneity was observed among the remaining studies (I2 = 1%; P = .42). The same was true for the secondary outcome (OR = 0.18 [95% CI: 0.06–0.56 (P = .003)]; I2 = 49% [P = .06]).

Sensitivity analyses revealed that the overall ORs estimated in the subgroup RTUS versus landmark (RCTs) were substantially modified by the inclusion of 2 studies, 31, 32 with a range of ORs from 0.10 to 0.21 (95% CI: 0.06–0.74; P = .02) for cannulation failure and from 0.18 to 0.38 (95% CI: 0.13–1.13; P = .08) for the incidence of arterial punctures.

The other 2 subgroups did not show significant heterogeneity; therefore, no sensitivity analysis was performed.

PEDIATRICS Volume 142, number 5, November 2018 9

Stud

yna

Sett

ing

Oper

ator

s’ P

rofil

e an

d Ul

tras

ound

Gu

idan

ce A

ppro

ach

Site

Wt (

kg)a,

bSu

cces

s Ra

te,

%a

Atte

mpt

a, c

Proc

edur

es

Tim

ea, d

Arte

rial

Pu

nctu

re (

%)

Othe

r Co

mpl

icat

ions

, %a

Iw

ashi

ma

et a

l26

(pro

spec

tive)

43 v

s 44Op

erat

ing

room

Each

ultr

asou

nd-g

uide

d pr

oced

ure

was

per

form

ed

by 2

ope

rato

rs (

assi

stan

t m

aint

aine

d th

e tr

ansd

ucer

). Pr

evio

us e

xper

ienc

e or

trai

ning

in

any

of t

he te

chni

ques

wer

e no

t des

crib

ed. U

ltras

ound

-gu

ided

pun

ctur

es w

ere

perf

orm

ed in

a tr

ansv

erse

ap

proa

ch.

FV10

.5 (

2.9–

84.2

) vs

8.6

(2

.9–

55.6

)

67.4

vs

59.1

(N

S)NM

NM7

vs 3

1.8

(P <

.0

1)NM

Le

yvi e

t al27

(pr

ospe

ctiv

e)47

vs

102

Oper

atin

g ro

omNo

spe

cifie

d No

. ope

rato

rs,

prev

ious

exp

erie

nce,

or

trai

ning

in

any

of t

he te

chni

ques

; an

esth

esia

res

iden

ts w

ith

facu

lty a

nest

hesi

olog

ists

pr

ovid

ing

dire

ctio

n; u

ltras

ound

-gu

ided

pun

ctur

es p

erfo

rmed

in

tran

sver

se a

ppro

ach

IJV

15.7

± 9

.1

vs 1

8.5

± 1

5.6

91.5

vs

72.5

(P

= .0

1)NM

NM4.

3 vs

2.9

(NS

)He

mat

omas

: 2.1

vs

2 (

NS)

BSI,

bloo

d st

ream

infe

ctio

n; E

D, e

mer

genc

y de

part

men

t; EJ

V, e

xter

nal j

ugul

ar v

ein;

FV,

fem

oral

vei

n; IJ

V, in

tern

al ju

gula

r ve

in; N

M, n

ot m

entio

ned;

NS,

not

sig

nific

ant;

SCV,

sub

clav

ian

vein

.a

Pres

ente

d as

inte

rven

tion

(ultr

asou

nd)

vers

us c

ontr

ol (

land

mar

k).

b Va

lues

are

sho

wn

as m

ean

± S

D, 3,

17 – 22

, 24, 28

, 30,

31, 34

med

ian

[int

erqu

artil

e ra

nge]

, 14, 15

, 27,

29, 32

, 35 m

ean

(ran

ge), 16

, 25 a

nd m

edia

n (r

ange

).23, 33

c Val

ues

are

show

n as

mea

n ±

SD,

3, 19

, 22, 24

, 30 m

edia

n [i

nter

quar

tile

rang

e], 14

, 15, 35

med

ian

(ran

ge), 17

, 18 a

nd m

edia

n.21

, 26

d Va

lues

are

sho

wn

as m

ean

± S

D, 3,

19, 21

, 22, 2

8, 31

med

ian

[int

erqu

artil

e ra

nge]

, 14, 15

, 32, 3

5 med

ian

(ran

ge), 17

, 18 m

ean

(ran

ge), 16

, 20 a

nd m

edia

n.26

, 27

TABL

E 1

Cont

inue

d

Other Outcomes

The time to success was reported in 17 studies.3, 14, 18 –20, 23 – 26, 28 – 35 Although the definition varied among articles, 8 revealed a significant reduction in time to success in the ultrasound groups, 3, 14, 23, 25, 30, 31, 34 8 studies revealed no difference between the techniques, 18, 19, 24, 26, 28, 32, 33, 35 and 1 revealed a shorter time to success in the landmark group.23 All 9 studies that assessed the attempts required

for success revealed a reduction with ultrasound assistance.‡

Regarding the complications, 3 studies revealed a significant reduction of hematomas in the ultrasound group, 14, 25, 29 whereas in 8 studies, no difference between the groups was observed.17, 20, 21, 27, 28, 30, 34, 35 In 1 study, a significant reduction in the occurrence of hemothorax was detected, 19 whereas another 2 studies

‡ Refs 3, 14, 16, 22, 25, 30, 31, 33, and 34.

revealed no difference between the groups.28, 34 None of the 6 studies that reported the occurrence of pneumothorax revealed a difference between the groups.14, 19, 20, 28, 34, 35 Moreover, no difference was found between the groups in the 2 studies in which researchers reported procedure-related infections.14, 22

Publication Bias

The assessment of publication bias performed by using the Egger et al13

DE SOUZA et al10

FIGURE 1Meta-analysis of the risk of cannulation failure between ultrasound-assistance versus anatomic landmark techniques. A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); df, degrees of freedom; E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias; IV, inverse variance.

test revealed a potential publication bias for cannulation failure among the 22 included studies (Egger’s test, P = .002; Begg’s test, P = .080). However, no publication bias was observed when analyzing only the subgroup RTUS versus landmark (RCTs) (Egger’s test, P = .113; Begg’s test, P = .761). The funnel plots for cannulation failure are shown in Supplemental Figs 8 and 9.

Neither the Begg and Mazumdar12 nor the Egger et al13 tests yielded evidence of significant publication bias for arterial puncture in the subgroup RTUS versus landmark (RCTs) (Egger’s test, P = .103; Begg’s test, P = .259). Nevertheless, a potential publication bias was observed when including all studies evaluating arterial punctures (Egger’s test, P = .038; Begg’s test,

P = .176). The funnel plot for arterial puncture is shown in Supplemental Figs 10 and 11.

DISCUSSION

This meta-analysis revealed that pediatric patients who require central venous catheterization can obtain significant benefits from ultrasound guidance techniques, whether that be RTUS guidance or ultrasound-assisted vein prelocation. In addition to updating evidence on the superiority of ultrasound guidance over the landmark technique, the overall pooled results of this meta-analysis revealed, for the first time, a statistically significant reduction of the incidence of arterial puncture in the ultrasound-guided

procedures. In fact, arterial puncture can be associated with several complications, such as major stroke, false aneurysm, and massive bleeding, that are serious events; when these complications occur, an endovascular approach may be required.36

However, some important considerations should be made regarding the results presented here. Similar to the authors of a previously published meta-analysis, 6 we decided to include nonrandomized studies in addition to RCTs. This decision was made to increase the amount of data for analysis because the number of published studies on this issue in pediatrics is low. The objective was achieved but not without cost.

PEDIATRICS Volume 142, number 5, November 2018 11

FIGURE 2Meta-analysis of the risk of failure of internal jugular vein cannulation between ultrasound assistance versus anatomic landmark techniques. A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); df, degrees of freedom; E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias; IV, inverse variance.

This meta-analysis has the largest amount of data analyzed on the issue in pediatric patients; however, we included more studies with a high risk of bias. Therefore, the data from RCTs and nonrandomized studies were carefully analyzed in different subgroups.

Even among RCTs, serious problems were observed regarding the risk of bias. These include the lack of detail in the number and profile of the operators evaluated. These are important considerations because we cannot extrapolate the conclusions associated with studies that involved experienced operators to those that involved resident physicians and vice versa. In addition, even operators with similar experience may have different skill levels. Thus, studies in which researchers do not describe the number of operators or those involving a single operator should be interpreted with caution. Meta-analyses such as this are important owing to the gathering of data from multiple operators; however, it would be of great value to stratify

the analysis by operator experience or training. Moreover, similar to conclusions not being extrapolatable to different operators, the same holds true for different patient profiles. Only 2 randomized studies evaluated children who were critically ill and admitted to the PICU.14, 25 Finally, it is essential to emphasize that the puncture technique is not identical for all sites. Nevertheless, researchers in some nonrandomized studies presented results obtained from punctures performed at different sites, whereas Bruzoni et al28 evaluated different sites in each group in their RCT. It might be more appropriate to analyze the data obtained from the punctures of the jugular, femoral, and subclavian veins separately.

Despite the limitations on the evidence cited above, many professional organizations and governmental agencies have long supported the systematic use of ultrasound in deep vein punctures. The Agency for Healthcare Research and Quality in the United States

was the first to announce its recommendation in 2001, 37 followed in 2002 by the National Institute for Health and Care Excellence in the United Kingdom.38 The same was done in 2010 by the American College of Surgeons.39 These efforts seem successful. A survey conducted in the United Kingdom in 2006 revealed that 85% of pediatric anesthetists had access to ultrasound, but only 27% used it routinely.40 This study also revealed that 62% of respondents believed that ultrasound was unnecessary. Almost 10 years later, similar research in Nordic countries revealed that 80% of pediatric anesthetists used ultrasound regularly for central venous cannulation.41 However, even in developed countries, the use of the ultrasound guidance technique has had low adherence rates. In 2015, only 23% of the pediatric surgeons in the United States admitted to using ultrasound regardless of the puncture site.2

After all, why is the ultrasound guidance technique not completely

DE SOUZA et al12

FIGURE 3Meta-analysis of the risk of failure of femoral vein cannulation between ultrasound assistance versus anatomic landmark techniques. A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); df, degrees of freedom; E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias; IV, inverse variance.

diffused among all practitioners? It is reasonable to consider that the limitations in the evidence cited above may contribute to this fact and may be used to explain why 38% of the interviewed members of the American Pediatric Surgical Association were convinced that the use of ultrasound is unnecessary for deep vein punctures.2 However, this is probably not the greatest barrier to the diffusion of the ultrasound guidance technique. The lack of formal training in ultrasonography

and the unavailability of the device were indicated as the primary causes for not using the ultrasound for CVC in children.2, 41 It is surprising that only 19% of the pediatric anesthetists and 24% of the pediatric surgeons interviewed received formal ultrasound training.2, 41 These problems can be even more serious in low-income countries, especially with regard to the availability of ultrasound machines. However, a cost-effectiveness analysis revealed favorable results on the ultrasound

guidance technique in the central venous catheterization of adults.42

CONCLUSIONS

The current meta-analysis reveals that ultrasound-guided techniques are associated with a reduced incidence of failure and inadvertent arterial puncture in pediatric central venous cannulation when compared with the anatomic landmark technique. However, results should be interpreted

PEDIATRICS Volume 142, number 5, November 2018 13

FIGURE 4Meta-analysis of the risk of arterial punctures between ultrasound assistance versus anatomic landmark techniques. A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); df, degrees of freedom; E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias; IV, inverse variance.

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well-designed RCTs are needed to support the use of ultrasound for central venous cannulation in all pediatric patients.

ACKNOWLEDGMENT

Thank you to Carolina Grotta Ramos Télio for her review of the article.

DE SOUZA et al14

supervised data collection and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This trial has been registered with the PROSPERO Register (identifier CRD42018091333).

DOI: https:// doi. org/ 10. 1542/ peds. 2018- 1719

Accepted for publication Aug 1, 2018

Address correspondence to Tiago Henrique de Souza, MD, Division of Pediatric Critical Care, Department of Pediatrics, 126 Tessália Vieira de Camargo St, Campinas, São Paulo 13083-887, Brazil. E-mail: tiago.souza@hc.unicamp.br

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

ABBREVIATIONS

CI:  confidence intervalCVC:  central venous catheterOR:  odds ratioRCT:  randomized controlled

trialRTUS:  real-time ultrasound

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