unilateral vocal fold paralysis after congenital...

Unilateral Vocal Fold Paralysis After CongenitalCardiothoracic Surgery: A Meta-analysis

abstractBACKGROUND AND OBJECTIVE: There is variation in the literature inregard to the occurrence of unilateral vocal fold paralysis (UVFP) aftercongenital cardiothoracic surgery. The objective of this study was toidentify and appraise the evidence for the occurrence of UVFP aftercongenital cardiothoracic surgery in a meta-analysis.

METHOD: A comprehensive search strategy in Medline, Embase, andthe Cochrane Library was conducted, limited to English publications.Two independent reviewers screened studies for eligibility criteria. Ofthe 162 identified studies, 32 (20%) met the inclusion criteria. Using theOxford Centre for Evidence-Based Medicine guidelines, 2 reviewersappraised the level of evidence, extracted data, and resolveddiscrepancies by consensus. Weighted pooled proportion and 95%confidence intervals (CIs) are reported.

RESULTS: Thirty-two studies (n = 5625 patients) were included. Levelsof evidence varied from level 3 to 4. Among all studies, the weightedpooled proportion of UVFP was 9.3% (95% CI, 6.6% to 12.5%), andamong 11 studies (n = 584 patients) that postoperatively evaluatedpatients with flexible nasopharyngolaryngoscopy to documentpresence of UVFP, the weighted pooled proportion of UVFP was29.8% (95% CI, 18.5% to 42.5%). Twenty-one studies (n = 2748patients) evaluated patients undergoing patent ductus arteriosusligation surgery, and the weighted pooled proportion of UVFP was8.7% (95% CI, 5.4% to 12.6%). Six of these (n = 274 patients) assessedall patients postoperatively, and the weighted pooled proportion ofUVFP was 39% (95% CI, 18% to 63%). Pooled analyses of risk factorsand comorbidities are reported. Heterogeneity and publication biaswere detected.

CONCLUSIONS: UVFP is a demonstrated risk of congenital cardiotho-racic surgery. Routine postoperative nasopharyngolaryngoscopy forvocal fold assessment by an otolaryngologist is suggested. Pediatrics2014;133:e1708–e1723

AUTHORS: Julie E. Strychowsky, MD,a Gavin Rukholm, MD,FRCSC,a,b Michael K. Gupta, MD, MSc, FRCSC,a and DianeReid, MD, FRCSCa

aDepartment of Surgery, Division of Otolaryngology–Head andNeck Surgery, McMaster University, Hamilton, Ontario, Canada;and bPeterborough Regional Health Centre, Peterborough,Ontario, Canada

KEY WORDSunilateral vocal fold paralysis, cardiothoracic surgery, patentductus arteriosus

ABBREVIATIONSCI—confidence intervalG-tube—gastrostomy tubeOCEBM—Oxford Centre for Evidence-Based MedicinePDA—patent ductus arteriosusUVFP—unilateral vocal fold paralysis

Dr Strychowsky conceptualized and designed the study,designed the data collection instruments, performed theliterature search and data extraction, appraised the levels ofevidence, carried out the initial analyses and interpretation ofdata, and drafted the initial manuscript; Dr Rukholmconceptualized and designed the study, performed the literaturesearch and data extraction, appraised the levels of evidence,interpreted the data, and critically reviewed and revised themanuscript; Dr Gupta conceptualized and designed the study,carried out the statistical analysis, interpreted the data, andcritically reviewed and revised the manuscript; Dr Reidconceptualized and designed the study, interpreted the data,and critically reviewed and revised the manuscript; and allauthors approved the final manuscript as submitted.

This article was presented as a podium presentation at theAnnual Meeting of the American Society of PediatricOtolaryngology in Arlington, Virginia, on April 26, 2013.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-3939

doi:10.1542/peds.2013-3939

Accepted for publication Mar 4, 2014

Address correspondence to Julie E. Strychowsky, MD, Departmentof Surgery, Division of Otolaryngology–Head and Neck Surgery,McMaster University, 1200 Main St West, Hamilton, Ontario,Canada, L8N 3Z5. E-mail: [email protected]

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

Copyright © 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

FUNDING: No external funding.

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

e1708 STRYCHOWSKY et al

by guest on May 25, 2018http://pediatrics.aappublications.org/Downloaded from

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Unilateral vocal fold paralysis (UVFP)secondary to left recurrent laryngealnerve injury during cardiothoracic sur-gery is a known risk.1 The path of thenerve, which loops around the arch ofthe aorta, makes it susceptible to injury.This is especially true in patent ductusarteriosus (PDA) ligation surgery, giventhe nerve’s proximity to the PDA.2 Se-quelae of UVFP may include stridor, ab-sent or weak cry, aspiration, or feedingand swallowing difficulties.3 Therefore,adequate and timely diagnosis can helpguide appropriatemanagement. Althoughsome patients are asymptomatic, thisdoes not preclude proper assessment.Flexible nasopharyngolaryngoscopy isa short and well-tolerated procedureperformed without sedation by otolar-yngologists that allows direct visualiza-tion of the larynx and subsequentdiagnosis of UVFP.

There is variation in the literature inregard to the occurrence of UVFP aftercongenital cardiothoracic surgery. Thismay result from the lack of routinepostoperative vocal fold function as-sessment. To date, there has been nosystematic review of the evidence forthe occurrence of UVFP after cardio-thoracic surgery in infants and chil-dren.

The primary objective of this study wasto identify and appraise the evidence forthe occurrence of UVFP after congenitalcardiothoracic surgery (all types ofsurgeryandPDA ligationsurgeryonly) ininfants and young children. We alsosought to determine the occurrence ofUVFP in patients who underwent post-operative assessment by flexible naso-pharyngolaryngoscopy. Other outcomesinvestigated included UVFP-associatedrisk factors and comorbidities.

METHODS

This review was conducted in accor-dance with the Preferred ReportingItems for Systematic Reviews andMeta-Analyses guideline.4

Literature Search Strategy

The literature was searched using OvidMedline (1946 to October 2012), Embase(1980to2012Week41),andtheCochraneLibrary (Cochrane Database of Sys-tematic Reviews, 2012, Issue 3). Theelectronic database search combinedintervention-specific terms (cardiotho-racic surgery, cardiac surgery, heartsurgery, cardiopulmonary bypass, pat-ent ductus arteriosus, PDA ligation, li-gation, closure) and outcome-specificterms (vocal fold, vocal cord, recurrentlaryngeal nerve, immobility, mobility,paralysis, paresis, injury). To ensure thatall relevant published articles werecaptured, the search was not limited bypublication date or study design. Rele-vant articles and abstracts were se-lected and reviewed. Reference listsfrom these sources and recent reviewarticles were searched for additionalpublications.

Study Selection Criteria

Articles were assessed for eligibilityindependently by2 reviewauthors (J.E.S.and G.R.) and were included if theywere prospective or retrospective fullypublished studies that reported oc-currence of UVFP after congenitalcardiothoracic surgery in infants andyoung children. Secondary outcomesincluded type of surgery (PDA ligationor other), postoperative assessmentof vocal cord function by flexiblenasopharyngolaryngoscopy, patient de-mographics, respiratory and swallow-ing outcomes, and comorbidities. Non-English publications were excluded.

Assessment of Quality

Methodological quality of identifiedstudieswas appraised using the OxfordCentre for Evidence-Based Medicine(OCEBM) 2011 Levels of Evidence5:

� Level 1: Systematic review of ran-domized trials, systematic reviewof nested case–control studies,n-of-1 trials

� Level 2: Individual randomized tri-als or (exceptionally) observa-tional studies with dramatic effect

� Level 3: Nonrandomized controlledcohort/follow-up studies providedthere are sufficient numbers torule out a common harm

� Level 4: Case series, case–control,or historically controlled studies

� Level 5: Mechanism-based reason-ing

Data Analysis

Relevant data were extracted from fullypublished reports by 2 independentreview authors (J.E.S. and G.R.) follow-ing prescribed tables developed a pri-ori. Disagreement was resolved byconsensus.

Descriptive statistics were extractedor calculated for occurrence of UVFP.Cases of bilateral vocal fold paralysiswere excluded. A qualitative synthesisof results was performed when appli-cable. Meta-analysis was performed bycalculating pooled proportion of theweighted occurrence for UVFP usingDerSimonian–Laird weights for therandom effects model. Subgroup anal-yses developed a priori for post-operative assessment for UVFP and PDAligation surgery only were conducted.Inverse variance measuring mean dif-ference for the random effects modelwas used for the analysis of continuousvariables. Heterogeneity between stud-ies was tested using the Q statistic withthe I2 approach. Publication bias was an-alyzed by visual inspection of the funnelplot and Egger’s test. StatsDirect software1.7.8 (StatsDirect Limited, Cheshire, UK)and Review Manager 5.1.7 (The NordicCochrane Centre, The Cochrane Collabo-ration, Oxford, UK) were used.

RESULTS

One hundred sixty-two studies wereidentified through the literaturesearch.Titles and abstracts of these studies

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PEDIATRICS Volume 133, Number 6, June 2014 e1709



were screened for the inclusion andexclusion criteria. The search strategydid not include a limit for study design;therefore, many of the studies excludedwere comments, editorials, or reviews.A resultant 50 full-text articles werefurther screened. Thirty-two studiesthatsatisfiedthe inclusioncriteriawereincluded in the analysis (Fig 1).6–37

OCEBM levels of evidence varied fromlevel 3 (9 studies)9–11,14–16,20,23,26 to level4 (23 studies)6–8,12,13,17–19,21,22,24,25,27–37

(Table 1). Occurrence of UVFP, type ofsurgery, patient demographics, andvocal fold assessment are reported inTable 1.

Analysis by Type of Surgery

Thirty-two studies involving 5625 pa-tients reported the occurrence ofUVFP after any type of cardiothoracic

surgery.6–37 The weighted pooled pro-portion for UVFP was 9.3% (95% CI,6.6% to 12.5%) (Fig 2). Heterogeneityanalysis measured an I2 (incon-sistency) of 91.4% (95% CI, 89.3% to92.9%). This is the percentage of vari-ation across studies that is due toheterogeneity rather than chance.Funnel plot analysis revealed a possi-ble publication bias; Egger’s testshowed the presence of bias (bias =2.5; 95% CI, 1.8 to 3.2; P , .0001).

Twenty-onestudies involving2748patientsreported the occurrence of UVFP afterPDA ligation only.7,8,10–15,17,20,21,24,27–31,34–37

The weighted pooled proportion was8.7% (95% CI, 5.4% to 12.6%) (Fig 3).Heterogeneity analysis measured anI2 of 81.6% (95% CI, 65.0% to 88.4%).Funnel plot analysis and Egger’s testshowed the presence of publication

bias (bias = 3.3; 95% CI, 2.2 to 4.4; P,.0001).

Analysis for PostoperativeAssessment of Vocal Fold Function

Only 10% of patients underwentpostoperative vocal fold functionassessment. Among patients un-dergoing any type of cardiothoracicsurgery procedure, 11 studies in-volving 584 patients postoperativelyevaluated every patient with flexiblenasopharyngolaryngoscopy.6,9–11,14–17,20,22,23

The weighted pooled proportion forUVFP was 29.8% (95% CI, 18.5% to42.5%) (Fig 4). Heterogeneity analysismeasured an I2 of 90.4% (95% CI, 85.2%to 93.1%). Both funnel plot and Egger’stest analyses showed publication biasamong the studies (bias = 7.0; 95% CI,2.3 to 11.7; P = .0079).

FIGURE 1Flow diagram of study selection.




TABLE1

Outcom

es

Author,YearR

ef(Country),YearsofStudy

Type

ofSurgery

Patient

Demographics

Occurrence

ofUVFP

(Cases/Total)

(%)

Assessmentfor

VocalCordFunction

Levelof

Evidence

Dewan

etal,20126

(USA),May

2007–May

2008

Allcardiothoracicsurgery

+VCP:

15/76(19.7%

)FlexibleNPLafterextubation,sw

allowing

evaluation

4SA

8.86

65.99

dSW

2.99

60.54

kg2VCP:

SA10.366

6.73

dSW

3.11

60.50

kgHeuchanetal,20127

(UK),2001–2007

PDAligation

GA26

wk(25–27)

6/125(4.8%)

NR4

BW840g(730–1035)

SA31

d(25–41)

Rukholmetal,20128

(Canada),Jul2003–Jul

2010

PDAligation

+VCP:

19/111

(17.1%

)27.9%NPLpostoperative

4GA

25.4wk(24.8–26.0)

0.9%

NPLpreoperative

BW743.8g(665.4–822.1)

SA28.9wk(28.0–30.0)

SW845.8g(766.5–925.2)

2VCP:

GA26.7wk(26.0–27.5)

BW990.0g(858.4–1121.5)

SA34.0wk(29.5–38.5)

SW1404

g(966.3–1843.3)

Carpes

etal,20119

(Canada),Nov

2008–Aug

2009


+VCP:

8/100(8%)

FlexibleNPLimmediatelypreoperatively

andwithin72

hofextubation

3SA

0.7m(0.1–14.2)

SW3.7kg

(3.2–9.2)

2VCP:

SA7.8m(4.1–36.7)

SW7.5kg

(4.9–15.7)

Benjam

in,20101

0(USA),Jan2004–Dec2006

PDAligation

Extrem

elylowBW

22/55(40%

)FlexibleNPLifsuspectedVCP

3+VCP:

22/25(88%

)scoped

GA24.56

1.1wk

BW7226

122g

SA17

68.7d

SW7226

140g

2VCP:

GA24.86

1.3wk

BW7286

132g

SA22

614.5d

SW7986

219g

Roksund,2010

11(Norway),1982–1985

(surgery),

2008–2009

(study)

PDAligation

GA,28

wkor

BW,1000

g7/11

(64%

)FlexibleNPLandcontinuous

laryngoscopy

during

maximal

treadm

illexercise

3SA

12d(4–29)

+VCP:

GA27.16

1.5wk

BW8746

138g

2VCP:

GA27.06

2.9wk

BW9286

283g

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TABLE1

Continued

Author,YearR


Type

ofSurgery

Patient

Demographics

Occurrence

ofUVFP

(Cases/Total)

(%)

Assessmentfor

VocalCordFunction

Levelof

Evidence

Sørensen,20101

2(Denmark),1998–2007

PDAligation

GA,37

wk

3/46

(7%)

NR4

GA26

66.5wk(236

3to34)

BW943.5g(535–1793)

SA29

64.7wk(256

6to40

64)

SW1104

g(525–2520)

Mandhan,20091

3(New

Zealand),Jan

1987–Dec

2005

PDAligation

GA25.56

2.3wk

1/145(0.7%)

NR4

BW837.76

277.2g

SA14.16

1.8d

SW881.36

338.1g

Smith,20091

4(USA),Apr2004–Oct2007

PDAligation

Prem

atureinfants:

14/86(16%

)PostextubationflexibleNPL

3GA

26.66

2.5wk

BW1000

6394g

SA17

612

dSpanos,20091

5(USA),1995–2005

PDAligation(sutureligatureor

clip)

SW,1kg

13/68(19%

)FlexibleNPLafterextubation

3Suture

ligature:

GA25

62.0wk

BW7406

288g

SW1054

6626g

Clip:

GA24.76

1.3wk

BW6516

169g

SW7626

210g

Srinivasan,20091

6(USA)

Norw

oodprocedure

Group1:

4/40

(10%

)FlexibleNPLallpatientsinGroup2

3SA

10d(3–218)

18/40(45%

)(allscoped)

Group1,2001–2004

SW3.2kg

(2.0–5.7)

Group2,2005–2007

(standardized

managem

ent)

Group2:

SA6d(2–64)

SW3.3kg

(2.3–4.3)

Clem

ent,2008

17(Canada),Oct2003–May

2004

PDAligation

+VCP:

12/23(52%

)FlexibleNPL,20

pts

4GA

24.8wk(24–26)

Videofluoroscopicsw

allowstudy

BW725g(580–887)

SA14.5d(6–31)

2VCP:

GA27.0wk(25–31)

BW1040

g(700–1540)

SA13.8d(4–53)

Davis,2008

18(USA)

Hypoplastic

leftheartsyndrom

e;TGA

BW3.19

60.69

kg5/27

(18.5%

)NR

4

SA6.16

3.8d

0/26

(0%)

BW3.35

60.65

kgSA

9.26

10.0d




TABLE1

Continued

Author,YearR


Type

ofSurgery

Patient

Demographics

Occurrence

ofUVFP

(Cases/Total)

(%)

Assessmentfor

VocalCordFunction

Levelof

Evidence

Sachdeva,20071

9(USA),Jan2000–Jan2006


SA13.5d(1–1604)

38/2255(1.7%)

NRifallscoped

4SW

3.45

kg(0.9–14.5)

Pereira,2006

20(USA),Mar

2001–Feb2004

PDAligation

GA25

wk

7/61

(11.5%

)FlexibleNPLpostextubation

3BW

740g

SA23

dSW

914g

Villa,20062

1(France),Sep

1991–Feb2004

PDAligation

LowBW

infants,24

pts

LowBW

infants:

NR4

LowBW

infants:2.16

0.4kg

2/24

(8.3%)transient

1/24

(4.2%)persistent

Children:

15/676

(2.2%)transient

2/676(0.3%)persistent

Khariwala,2005

22(USA),4-yperiod


Pediatric

11/48(23%

)UVFP

3/48

(6%)BilateralVCP

Inpatient

ORLconsultation

4

Skinner,2005

23(USA),Apr2003–Dec2004

Norw

oodprocedure

SA6d(2–19)

3/33

(9%)

FlexibleNPL(m

edian10

dpostoperative)

3Aorticarch

reconstruction

SW3.1kg

(1.9–4.2)

4/16

(25%

)Modified

barium

swallow

SA9d(4–33)

SW3.1(2.0–3.7)

Vida,20042

4(Italy),Jun

1994–Dec2002

PDAligation

SA45

m(3–161)

1/150(0.7%)

NR4

SW18

kg(4.2–73)

Einarson,20032

5(Canada),Jan

1998–Dec1999


Neonates

,28

d:8/101(8%)

ORLassessmentnotspecified

4SA

7.86

5.6d(1–25)

SW3.22

60.62

kg(1.5–4.8)

Kohr,20032

6(USA),Mar

1999–Sep1999


SA4.86

5.2y(1

d–16.7y)

4/50

(8%)

ORLifrecommendedby

speech–language

pathologist

3SW

19.66

17.8kg

(3.1–72.6)

Prem

atureinfantsexcluded

Liang,2003

27(Taiwan),Mar

1998–May

2001

PDAligation

Subgroup

,1y

3/18

(16.7%

)Bronchoscopy

ifhoarseness,

inspiratorystridor,or

weakcry

4+VCP:

SW9.0kg

(8.9–9.1)

2VCP:

SW10.3kg

(6.2–11.5)

Niinikoski,20012

8(Finland),1988–1998

PDAligation

Very

lowBW

infants,1500

g:1/101(1%)

NR4

GA27.2wk

BW9636

239g

SA12

68d

SW9696

231g

LeBlanc,2000

29(Canada),Jan

1985–Dec1998

PDAligation

Nonprematureinfants

3/261(1.1%)

NR4

Russell,1998

30(Canada),Jan

1985–Dec1997

PDAligation

Prem

atureinfants:

3/176(1.7%)

NR4

GA26

wk(23–36)

BW847.5g(400–2300)

SA21

d(4–60)

SW982.5(475–2740)

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TABLE1

Continued

Author,YearR


Type

ofSurgery

Patient

Demographics

Occurrence

ofUVFP

(Cases/Total)

(%)

Assessmentfor

VocalCordFunction

Levelof

Evidence

Hawkins,19963

1(USA),Jul1994–Mar

1996

PDAligation(coilocclusion

orsurgicalclosure)

Coilocclusion:

0/20

(0%)

NR4

SA4.16

4.9y(6

m–15

y)1/20

(5%)

SW18

616

kgSurgicalclosure:

SA36

3.9y(4

m–10

y)SW

126

7kg

Lavoie,19963

2(USA),DatesNR

VATS

forvariousprocedures

SA2.65

y(1

d–14.1y)

1/45

(2.2%)

NR4

SW11.78kg

(580

g–45.9kg)

Rajasinghe,19963

3(USA),Jul1992–Jan1995

Aorticcoarctation

andtubularhypoplasiarepair

SA13

d(3–34)and

69d(61–78)

1/23

(4.3%)

NR4

SW2.9kg

(1.3–5)

Zbar,19963

4(USA),Jan1991–Jan1994

PDAligation

,12

m6/68

(8.8%)

ORLassessmentonlyifsymptom

atic

4+VCP:

22.7%forextrem

elylowBW

(,1kg)

GA26.3wk

BW0.9kg

SA31.9d

SW1.1kg

2VCP:

GA33.8wk

BW2.3kg

SA88.4d

SW3.4kg

Laborde,1995

35(USA),Sep1991–Mar

1995

PDAligation

,6m,70pts(30%

)6/230(2.6%)

Postoperativelaryngoscopy

46–48

m,123

pts(54%

)5transient

.48

m,37pts(16%

)1persistent

SW12.6kg

(1.2–65)

Fan,1989

36(USA),DatesNR

PDAligation

,1500

g7/167(4.2%)

Fiberopticlaryngoscopy

4Davis,1988

37(USA),Jun1980–Jul1987

PDAligation

Prem

atureinfants

3/106(2.8%)

NR4

BW,birthweight;GA,gestationalage;NPL,nasopharyngolaryngoscopy;NR

,notreported;ORL,otorhinolaryngology;pts,patients;SA,age

atsurgery;SW

,weightatsurgery;TGA,transpositionofthegreatarteries;VATS,video-assistedthoracoscopicsurgery;

VCP,vocalcordparalysis.




Six studies involving 274 patientspostoperatively evaluated every patientwith flexible nasopharyngolaryngo-

scopyafterPDA ligation.10,11,14,15,17,20 Theweighted pooled proportion for UVFPwas 39% (95% CI, 18% to 63%) (Fig 5).

Heterogeneity analysis measured an I2

of 93.2% (95% CI, 88.5% to 95.4%).Analysis of the funnel plot by visual

FIGURE 2UVFP after all types of cardiothoracic surgery (32 studies). Weighted pooled proportion for UVFP was 9.3% (95% CI, 6.6% to 12.5%).

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inspection did not suggest publicationbias; Egger’s test confirmed its absence(bias = 7.6; 95% CI,23.4 to 18.5; P = .13).

Analysis for Demographics

Five studies involving 354 patients re-ported birthweights for patientswith andwithout UVFP after surgery.8,10,11,14,17,34 Forpatients with and without UVFP, birthweights ranged from 725 to 900 g and 728to 2300 g, respectively. The weightedpooled mean difference between patientswith and without UVFP was2201 g (95%CI, 2372 g to 230 g) (P = .02) (Fig 6);patients with UVFP were 201 g smaller

than those without. Heterogeneity analy-sis measured an I2 of 79%.

Weight at the time of surgery wasreported among 6 studies (373patients) as a comparison for patientswith and without UVFP.6,8,9,27,34 Surgicalweight ranged from 846 g to 9000 gamong patients with UVFP and 1404 gto 10 300 g for those without. Theweighted pooled mean difference was2820 g (95% CI,21564 g to276 g) (P =.03), showing patients with UVFP tohave significantly smaller weights atthe time of surgery (Fig 7). Heteroge-neity analysis measured an I2 of 71%.

Gestational age of patients with andwithout UVFP was reported among 6studiesinvolving399patients.8,10,11,14,17,34

Among patients with and without UVFP,gestational ages ranged from 24.5 to27.1 weeks and 24.8 to 33.8 weeks, re-spectively. The weighted pooled meandifferencewas21.1weeks (95%CI,21.7to 20.46 weeks, P = .0007), statisticallysignificantly correlating younger gesta-tional ages with a higher incidence ofUVFP (Fig 8). There was low heteroge-neity among the studies (I2 = 28%).

Five studies involving 378 patientsreported age at the time of surgery for

FIGURE 3UVFP after PDA ligation only (21 studies). Weighted pooled proportion of UVFP was 8.7% (95% CI, 5.4% to 12.6%).




FIGURE 4UVFP after all cardiothoracic surgery in patients who underwent postoperative vocal fold assessment (11 studies). Weighted pooled proportion for UVFP was29.8% (95% CI, 18.5% to 42.5%).

FIGURE 5UVFP after PDA ligation only and postoperative vocal fold assessment (6 studies). Weighted pooled proportion for UVFP was 39% (95% CI, 18% to 63%).

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patients with and without UVFP.6,8,9,17,34

Surgical ages ranged from 8.9 to 31.9days and 10.4 to 237 days, respectively.The weighted pooled mean differencebetween patients with and withoutUVFP was217.8 days (95% CI,241.8 to6.3 days, P = .15) and not statisticallysignificant (Fig 9). Heterogeneity anal-ysis measured an I2 of 62%.

Analysis for Duration of Ventilation

Five studies, comprising 226 patients,reported a comparison of duration ofventilation forpatientswithandwithoutUVFP.6,10,11,17,20 The weighted pooledmean difference was not statistically

significant (6.88 days; 95% CI, 22.1 to15.9 days; P = .13) (Fig 10). I2 was 51%.

Analysis for Gastrostomy Tube Use

A comparison of gastrostomy tube(G-tube) use in patientswithandwithoutUVFP was reported among 283 patientsin 5 studies.8,10,17,20,23 The pooled oddsratio was 7.3 (95% CI, 1.6 to 32.8, P =.010), suggesting a correlation of G-tubeuse among patients without UVFP(Fig 11). I2 was 49%.

Other Analyses

Additional pooling of data were notpossible because of the nonuniform

reporting of data among studies in-cluded or too few studies that reportedthe same outcome. Length of stay inhospital was reported in 2 studies.6,17

Mean length of stay was statisticallysignificantly longer among patientswith UVFP in both studies. Dewan et al6

reported on patients who underwentmedian sternotomy for cardiac sur-gery (34.9 6 29.5 days vs 22.9 6 14.6days, P = .02), and Clement et al17 in-vestigated extremely low birth weightinfants undergoing PDA ligation (148.2vs 96.8 days, P , .001).

Two studies did not report any recoveryof vocal fold function at follow-up points

FIGURE 6Birth weight (6 studies). Weighted pooled mean difference between patients with and without UVFP was 2201 g (95% CI, 2372 g to 230 g) (P = .02).

FIGURE 7Weight at time of surgery (5 studies). Weighted pooled mean difference was 2820 g (95% CI, 21564 g to 276g) (P = .03).

FIGURE 8Gestational age (6 studies). Weighted pooled mean difference was 21.1 weeks (95% CI, 21.7 to 20.46 weeks) (P = .0007).




of 6 and 5 to 19 months, respectively.34,36

Khariwala et al22 reported a recovery 9 of11 patients (82%). Carpes et al9 reportedrecovery of vocal fold movement in 3 of 7patients at 3 months’ follow-up. Fur-thermore, Spanos et al15 reported long-term follow-up (range 1–18 months) for6 patientswith UVFP. Only 2 patientswerefound to have full recovery. Sachdevaet al19 reported follow-up in 9 patientswith UVFP and found full recovery offunction in 3 patients, partial recovery in4 patients, and no signs of recovery in 2patients; however, no time frame forfollow-up was reported.

DISCUSSION

To our knowledge, this is the first sys-tematic review and meta-analysis to re-port the pooled occurrence of UVFP aftercardiothoracic surgery in infants andchildren. Among 32 studies, involving5625 patients, the weighted pooledproportion of UVFPwas 9.3%. For thoseundergoing only PDA ligation, the pooledproportion was 8.7%. However, it is im-portant to consider the occurrence ofUVFP in the population of patients whounderwent routine postoperative vocalcord function assessment by flexible

nasopharyngolaryngoscopy. Only 10% ofpatients after any type of cardiothoracicsurgeryorPDAligationsurgeryunderwentpostoperative vocal fold function assess-ment. The weighted pooled proportion ofpatients with UVFP in this population was30% for patients undergoing all types ofcardiothoracic surgeryand39% for thoseundergoing PDA ligation.

These data suggest that the occurrence ofUVFP among patients who were post-operatively assessed for vocal fold func-tion is significant. Ninety percent ofpatients included in our analysis of 32

FIGURE 9Age at time of surgery (5 studies). Weighted pooled mean difference between patients with and without UVFP was 217.8 days (95% CI, 241.8 to 6.3 days)(P = .15).

FIGURE 10Duration of ventilation (5 studies). Weighted pooled mean difference was 6.88 days (95% CI, 22.1 to 15.9 days), P = .13.

FIGURE 11G-tube use (5 studies). Pooled odds ratio was 7.3 (95% CI, 1.6 to 32.8) (P = .010).

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studies did not undergo routine post-operative assessment. Among thesepatients, stridor, absent or weak cry, as-piration, or feeding or swallowing diffi-culties most often prompt additionalinvestigation of vocal fold function. Chil-dren who are asymptomatic initially maynot be diagnosed until early childhood,when they presentwith an inability to singor a weak voice. Smith et al14 reporteda rate of delayed diagnosis of 14%. Timelydiagnosis would ensure that appropriatetreatment options such as use of thick-ened foods, voice therapy, or surgical in-tervention be made available to them.38

Methods of Vocal Fold Assessment

Methods of vocal fold assessment gen-erally included assessment with flexiblenasopharyngolaryngoscopy, a well-tolerated bedside examination thatdoes not require sedation. Ten studiesperformed the assessment after extu-bation.6,9–11,14–17,20,23 One study did notspecify whether patients underwentflexible nasopharyngolaryngoscopy;however, an otorhinolaryngologist as-sessed all the patients, and thereforewe assumed that those needing addi-tional assessment would have un-dergone the diagnostic laryngoscopy.22

Carpes et al9 also performed the as-sessment immediately preoperatively.Roksund et al11 assessed patients ap-proximately 25 years after PDA ligationby performing flexible nasopharyn-golaryngoscopy and continuous laryn-goscopy during maximal treadmillexercise. Three studies also includedswallowing assessments.6,7,23

Preoperative assessment of vocal foldfunction merits discussion. The inherentbenefit is the avoidance of attributing theoccurrence of UVFP to iatrogenic injury ifit is noted preoperatively. However,patients may have associated heart fail-ure, pulmonary failure, and poor re-spiratory reserve secondary to theircardiac anomaly, which may precludeadequate preoperative evaluation. Pre-

operative assessment of vocal fold func-tion was reported only in the study fromBC Children’s Hospital.9 The authors per-formed flexible laryngoscopy immedi-ately before surgery in the operatingroom and within 72 hours after extuba-tion. Twenty-four (15%) patients could notundergo preoperative assessment be-cause of endotracheal intubation, and 4(2.5%) were found to have UVFP pre-operatively andwere excluded from theirstudy. Additional techniques for vocal foldfunction assessment may include extu-bation followed by direct laryngoscopyand rigid bronchoscopy, laryngeal elec-tromyography, or laryngeal ultrasound.Maturo et al39 prospectively showed thatlaryngeal electromyography could pre-dict recurrent laryngeal nerve functionreturnwhen comparedwith diagnosis byflexible fiberoptic laryngeal examination.The authors reported this technique tobe a safe, operator-friendly method fordetermining the likelihood of functionreturn in a variety of patients, includingthose who had undergone PDA ligation.The mean patient age was 21.4 months.Wang et al40 reported the usefulness oflaryngeal ultrasound for vocal fold as-sessment. They showedmaximum glotticangle and vocal fold–arytenoid angle tobe quantitative ultrasonographic indica-tors of vocal fold immobility among 45children of median age 4 years and 6months (range 9 months–13 years).However, the efficacy of laryngeal elec-tromyography or ultrasound has notbeen described in neonates or infants,nor has it been used in the intubatedpatient.

Risk Factors

UVFP was shown to be statistically sig-nificantly associated with younger ges-tational age, lower birth weight, andlower surgical weight among the limitednumber of studies that reported theseoutcomes. Age at time of surgerywas notasignificantrisk factor forUVFP.Lengthofmechanical ventilation was not signifi-

cantly different between groups. G-tubeuse was statistically significantly higheramong patients without UVFP. Theseanalyses are based on limited patientnumbers because of the small numberofstudies that reported these outcomes bypresence or absence of UVFP.

Patients who need congenital cardiacsurgeryoftenhavemultiplecomorbidities.Two studies8,11 reported associations be-tween bronchopulmonary dysplasia andUVFP after PDA ligation. Roksund et al11

reported outcomes for 11 patients;bronchopulmonary dysplasia was pres-ent in 86% of patients with UVFP and50% of those without UVFP (P , .001).Among 111 patients, Rukholm et al8

reported 74% of patients with UVFP tohave bronchopulmonary dysplasia, com-pared with 47% of those without UVFP(P = .043); however, given the Bonferronimethod of statistical analysis for multiplecomparisons, only P , .006 was consid-ered significant. This retrospective studyfrom our center at McMaster Universityshowed only gastroesophageal refluxdisease to be statistically significantlyassociated with UVFP after PDA ligation,and not G-tube feeding, sepsis, pneumo-nia, retinopathy of prematurity, or ane-mia of prematurity.8 Benjamin et al10

comparedneurodevelopmental outcomesbetween patients with and without UVFPafter PDA ligation and found no signif-icant difference between groups.

Surgical technique for PDA ligation andits correlation with occurrence of UVFPhas also been investigated. Spanoset al15 compared rates of paralysisbetween vascular clip and suture liga-tion procedures in a prospective studyand found similar incidence of UVFP inboth groups (19% vs 20%). All cases ofUVFP were in infants who weighed ,1kg at birth. Zbar et al34 showed iatro-genic UVFP to be associated only withthe use of surgical clips and not suture;however, the authors determined thatit was not possible to establish a plau-sible correlation because clips were




used in 91% of premature infants whoneeded PDA ligation. Carpes et al9

reported the use of cautery in 8 (100%)patients with UVFP, compared with 60(65%) patients without UVFP. Additionalinquiry in regard to surgical techniqueand perhaps operator learning curvemay be warranted.

Study Weaknesses

The inherentweaknessofourstudy isdueto the heterogeneity that is introducedwhen data are pooled from studies withnonuniform patient populations andmethods. Variability in the typeof surgery(PDA ligation versusothercardiothoracicsurgery), vocal fold assessment, andpatient demographics contributes to thisweakness. The random effects model forstatistical analysis and a priori subgroupanalyseswere undertaken to account forsome of these limitations.

Caseserieswerethemostcommontypeofstudy. This study type satisfied the criteriafor level 4 evidence according to theOCEBM; future studies should be aimedtoward higher levels of evidence. Signifi-cant publication bias was detected for allanalyses (type of surgery and post-operative vocal fold assessment) exceptfor thesubgroupof6studies that includedpatients who underwent PDA ligation onlyand routine postoperative assessment.

Recovery of Vocal Fold Function

Recovery of vocal fold function warrantsdiscussion. From the studies included inthis analysis, 2 studies reported no re-covery at follow-up points of 6 and 5 to 19months, respectively.34,36 The populationof patients with vocal fold paralysis inthese studies was 6 and 7 patients, re-spectively.34,36 Zbar et al34 hypothesizedthat their high rate of nonrecoveryresulted from the surgical clippingtechnique. Conversely, Khariwala et al22

reported a recovery rate of 82% (9 of 11patients) among their single-center ret-rospective review of patients undergoingsurgical repair of congenital cardiac

defects, attributing the rate of recoveryto stretching of the recurrent laryngealnerve and subsequent return of fullfunction. The time frame for this re-covery ranged from 8 weeks to 10months.22 Carpes et al9 also reportedrecovery of vocal fold movement in 3 of 7patients at 3 months’ follow-up. Spanoset al15 reported long-term follow-up of 6patients with UVFP. Follow-up rangedfrom 1 to 18 months, and of the 6patients, only 2 were found to have fullrecovery. Sachdeva et al19 reportedfollow-up in 9 patients with UVFP andfound recovery of function in 3 patients,partial recovery in 4 patients, and nosigns of recovery in 2 patients. Althoughexcluded from our current analysis be-cause their study population includedonly patients with UVFP, Truong et al41

reported a retrospective case series todetermine the rate of recovery of pedi-atric vocal fold paralysis after cardiacsurgery. They reported that 28 (35%)patients recovered function, with a me-dian time from diagnosis to recovery of6.6 months, and that 52 (65%) of patientshad persistent paralysis, with a medianfollow-up time of 16.4 months. Further-more, the authors reported that pre-mature patients were significantly lesslikely to recover vocal fold function. Giventhe wide variation of results, additionalinvestigation is needed to adequatelydetermine recovery of vocal fold functionafter cardiac surgery. However, it shouldbe noted that recovery of UVFP has beenreported as late as 11 years after theinitial surgery; therefore, the resultsshowing poor recovery may simply re-flect follow-up time that is too short.17

Surgical Management of UVFP

Early identification of UVFP would allowsubsequent surgical interventions suchas medialization laryngoplasty (injectionor surgical) or laryngeal reinnervation ifappropriate. Injection medialization lar-yngoplasty was reviewed in 13 patients(27 injections) with a variety of injectablematerials (Gelfoam, Radiesse Voice, or

Radiesse Voice Gel). Cohen et al42 dem-onstrated the procedure to be a safe andeffective treatment for carefully selectedpatients. Subjective or objective symptomimprovement was experienced in 24 of 27injections (89%). Zur43 reported her re-cent success with recurrent laryngealnerve reinnervation using the ansa cer-vicalis for unilateral vocal fold immobilityin children. Among10 children (9 ofwhomhad previous PDA ligation), 7 demon-strated physiologic frequency range im-provement at 6months’ follow-up.Mediantime from injury to repair was 64.5months. Paniello et al44 reported theresults of a multicenter randomized con-trolled trial comparing medialization lar-yngoplasty with laryngeal reinnervationand showed older patients to be bettersuited for laryngoplasty, whereas rein-nervation was better suited for youngerpatients. Given these possible surgicalinterventions, adequate postoperativeassessment of vocal fold function is war-ranted to identify patients who may ben-efit from these procedures. However,conservative management includingvoice therapy should always be con-sidered before surgical intervention.

Future Studies

Future studies should focus on pro-spectivelyenrollingandfollowingpatientsundergoing congenital cardiothoracicsurgery, assessing vocal fold functionroutinelypostoperatively,anddeterminingrisk factors, comorbidities, and long-termrespiratory function, swallowing, voiceoutcomes, and recovery rates.

CONCLUSIONS

UVFP is a demonstrated risk of cardio-thoracic surgery among infants andchildren. Pooled analysis suggests that itmay be associated with a younger ges-tational age and lower birth weight andweight at time of surgery. Routine post-operativenasopharyngolaryngoscopyforvocal cord assessment by an otolaryn-gologist is suggested.

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DOI: 10.1542/peds.2013-3939 originally published online May 19, 2014; 2014;133;e1708Pediatrics

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DOI: 10.1542/peds.2013-3939 originally published online May 19, 2014; 2014;133;e1708Pediatrics

Julie E. Strychowsky, Gavin Rukholm, Michael K. Gupta and Diane ReidMeta-analysis

Unilateral Vocal Fold Paralysis After Congenital Cardiothoracic Surgery: A

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