High-dose Oral Ambroxol for Early Treatmentof Pulmonary Acute Respiratory DistressSyndrome an Exploratory Randomized

Controlled Pilot Trialby Arun K Baranwal1 Aparna S Murthy2 and Sunit C Singhi2

1All India Institute of Medical Sciences Patna-801507 India2Postgraduate Institute of Medical Education and Research Chandigarh-160012 India

Correspondence Arun K Baranwal Additional Professor amp Head Department of Pediatrics All India Institute of Medical Sciences Patna801507 India Tel thorn91-7766908325 E-mail ltbaranwal1970gmailcomgt

A B S T R A C T

Objective To evaluate efficacy of high-dose oral ambroxol in acute respiratory distress syndrome(ARDS) with respect to ventilator-free days (VFD)

Design Prospective randomized placebo-controlled blinded pilot trialPatients Sixty-six mechanically ventilated patients (1 month to 12 years) with ARDS who were

hand-ventilated for lt24 hr before pediatric intensive care unit admissionInterventions Patients randomized to oral ambroxol (40 mgkgday in four divided doses)

(nfrac14 32) or placebo (nfrac14 34) until 10 days extubation or death whichever is earlierMeasurements and Main Results Majority (91) had pneumonia and bronchiolitis Two study

groups were similar in baseline characteristics Mean partial pressure of arterial oxygenfraction ofinspired oxygen and oxygenation index were gt175 and lt10 respectively with no difference in thetwo study groups VFD were similar in the two study groups Overall mortality was 26 No adverseevents were noted with ambroxol

Conclusions Among ventilated pulmonary ARDS patients with oxygenation index of lt10mortality was 26 Ambroxol did not improve VFD Study with higher and more frequently admin-istered doses of ambroxol in larger sample is suggested after having generated relevant pharmacoki-netic data among critically ill children

K E Y W O R D S ambroxol acute respiratory distress syndrome children ventilator-free days in 14days

I N T R O D U C T I O NAcute respiratory distress syndrome (ARDS) in chil-dren is usually caused by ldquodirectrdquo pulmonary causes[1] more so in resource-poor economies [2 3]Release of cytokines and oxidants proteasendashantipro-tease imbalance surfactant deficiency and alveolarbiofluid overproduction are final common pathways

irrespective of cause Despite pathologic understand-ing of ARDS its management continues to be chal-lenging Though lung-protective ventilatory strategyimproved outcome [4] search for an effective drugcontinues [5] Majority of pharmacotherapeuticinterventions eg steroid [6] anti-oxidants [7 8]surfactant replacement [9] and b-agonists [10 11]

VC The Author [2015] Published by Oxford University Press All rights reserved For Permissions please email journalspermissionsoupcom

339

Journal of Tropical Pediatrics 2015 61 339ndash350doi 101093tropejfmv033Advance Access Publication Date 30 June 2015Original Paper

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

have targeted a single pathway of otherwise complexprocess and failed Drug acting on multiple patho-genetic pathways may succeed clinically [8]

Ambroxol has mucoactive [12] anti-inflamma-tory anti-oxidant and surfactant-promoting proper-ties [13] Moreover it gets concentrated selectivelyin lungs [14] Though clinical data are scanty[14ndash18] ambroxolmdasha safe and economical drugmdashmay be considered for treatment of ARDS for itspotential to improve gas exchange [19ndash21] Ifclinical efficacy could be established ambroxol wouldbe an attractive therapeutic option for its low costand toxicity Current exploratory randomizedblinded controlled pilot trial was designed to evalu-ate efficacy of high-dose oral ambroxol in children(age 1 month to 12 years) requiring ventilation forpulmonary ARDS (pARDS) with specific referenceto ventilator-free days in 14 days (VFD14) in re-source-constraint setting Improvement in ventila-tory and oxygenation parameters were secondaryobjectives

M A T E R I A L S A N D M E T H O D S

PatientsAll intubated ventilated patients in 12-bed pediatricintensive care unit (PICU) were screened for studyeligibility each day over 14-month period (August2007ndashSeptember 2008) Entry criteria included allconsecutive children (age 1 month to 12 years) withrespiratory failure owing to diffuse bilateral pulmon-ary infiltrates partial pressure of arterial oxygen(PaO2)fraction of inspired oxygen (FiO2) 300positive end expiratory pressure (PEEP) 5 cmH2O and ventilated for 12 hr [22] Patients withpersistent hypotension (defined as systolic bloodpressure lt5th centile [70 mmHg thorn2 age in years])despite resuscitation for initial 12 hr were excludedto avoid indirect lung injury and to concentrate onpARDS only considering higher biological plausibil-ity of ambroxol in the later Patients hand-ventilatedfor gt24 hr before mechanical ventilation wasexcluded to limit risk of significant barotraumaPatients with active bleeding requiring bloodfluidvolume replacement chronicrestrictive lung diseasereactiveupper airway disease neuromuscular re-spiratory failure raised intracranial pressure

congenital valvular or myocardial heart disease car-diogenic pulmonary edema andor post-operativepatients were excluded to limit confounders Patientswith acute renal failure were excluded as ambroxol isexcreted mainly from kidneys

Study drugOral ambroxol is used for treatment of pulmonarydiseases and reported to be safe [23] Higher intra-venous doses in adults (1000 mgday) [14 16] andpreterm newborns (30 mgkgday 7 days) [15 24]were also safe Orally administered ambroxol gets ab-sorbed rapidly with 73 bioavailability with time topeak plasma concentration being 2 hr in an adultstudy [25] Elimination t12 is biphasicmdashwith an at12 of 13 hr and b t12 of 88 hr [25] Thus 40mgkgday (in four divided doses) may be con-sidered to be an acceptable maximal safe oral dosefor children Though intestinal absorption in critic-ally ill patients is different from healthy person thisdose was considered as starting point for the pilotstudy

Study protocolTrial was designed and analyzed according toConsolidated Standards of Reporting Trials recom-mendations and checklist (Fig 1) [26] After in-formed consent from fatherlegal guardian eligiblepatients were randomized to intervention or placebousing computer-generated random number tablewithin 24 hr of PICU admission Study assignmentswere serially numbered in opaque and sealed enve-lopes Intervention group received oral ambroxol(40 mgkgday) in four divided doses for 10 days oruntil extubation whichever was earlier Identical-looking tablets of ambroxol (of 50 mg) and placebowere prepared and packs containing dosage for 20kg body-weight patient were dispensed Tablets werecrushed suspended in water and administeredthrough nasogastric tube Investigators doctorsnurses and data manger were blinded to treatmentassignment Institutional ethics committee approvedthe study protocol

At enrollment patientsrsquo demographics baselineassessment and Pediatric Risk of Mortality III(PRISM-III) were recorded Vitals oxygen saturationon pulse oximeter (SpO2) and central venous

340 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

pressure (if required) were monitored continuouslyand recorded 2 hourly Ventilator settings bloodgases end-tidal CO2 and chest radiograph data werecollected for initial 28 days or until extubationwhichever was earlier In addition pulmonary statusand respiratory support extubation readiness fluidbalance caloric and protein intake and pediatric

logistic organ dysfunction (PeLOD) score [27] re-corded Investigations were recorded if available andreflected the values obtained closest to 0800 am

Patients in both groups were managed accordingto prevalent unit protocol for ventilation sedationhemodynamics nutrition extubation readiness andgeneral nursing care Lung-protective ventilation was

Paents fulfilled inclusion criteria (n=89)

Randomized (n=67)

Allocated to Placebo (n=34)

Received allocated intervenon (n=34)

Did not receive allocated intervenon (n=0)

Allocated to Ambroxol (n=33)

Received allocated intervenon (n=32)

Did not receive allocated intervenon (n=0)

Lost to follow up (n=0)

Disconnued intervenon (n=0)

Lost to follow up (n=0)

Disconnued intervenon (n=1)

( for acute renal failure within 2 days)

Included in Analysis (n=34)

Excluded from Analysis (n=0)

Included in Analysis (n=32)

Excluded from Analysis (n=1)

22 Excluded 2 Parents refused to parcipate 4 Missed enrollment window 2 Chronic Lung Disease 2 Neuromuscular Weakness 3 Raised Intracranial Pressure 2 Postoperave Paents 3 Acute Renal Failure 4 Refractory Shock

Fig 1 Patient flowchart through clinical trial

High-dose Oral Ambroxol for pulmonary ARDS 341

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

employed and included pressure-control ventilationwith peak inflating pressure lt30 cm H2O PEEP5ndash10 cm H2O tidal volume 5ndash6 mlkg FiO2 lt06and permissive hypercapnea (PaCO2 gt80torr whilepH gt725) if required Aim was to achieve optimaloxygenation (PaO2 60ndash80 mmHg SpO2 88ndash92)while limiting barotrauma Sedation protocolinvolved continuous diazepam (midazolam in some)and morphine infusions to achieve and maintainRamsay Score of 3ndash4 [28] with morning sedationinterruption Intravenous fluid was initiated as 23maintenance and feed was introduced at the earliestOnce patients were on full feed volume was relaxedto full maintenance After achievement of spontan-eous breathing oxygenation index (OI) lt6 decreaseandor plateau in ventilator support over 12 hourspatients were tested for extubation readiness Patientstatus was verified at discharge from PICU If diedprimary and secondary causes of death were re-corded Adverse events were monitored and reportedto Institutional Ethics Committee

Study outcomesConsidering difficulty in achieving mortality benefitin current critical care scenario [29] and unclear con-tribution of ARDS to mortality [30] composite out-come measure like ventilator-free days (VFD)incorporating both mortality and ventilation dur-ation are being considered [31] Primary outcomewas VFD14 which is defined as number of daysfrom point of successful weaning to day 14 (D14) ofenrollment Death during first 14 days is consideredto be equivalent to unresolved respiratory failureand thus is equated to zero VFD14 Secondary out-come measures included all-cause mortality ventila-tor days among survivors number of patients aliveand ventilator-free on D14 time-to-recovery fromARDS (ie when patients met extubation readinesscriteria after randomization) changes in ventilationand oxygenation parameters

Statistical analysisSimple unrestricted randomization was used to allo-cate patients in two groups Nonparametric MannndashWhitney U test and X2 test (or Fisherrsquos exact test ifrequired) were used to compare groups with quanti-tative outcomes Survival analysis using KaplanMeier curves was performed for time-to-event data

eg ventilation duration time-to-recovery and PICUstay Repeated measures analysis of variancewas planned to assess trend in ventilation and oxy-genation parameters SPSS version 16 was used forstatistical analysis A plt 005 was consideredsignificant

R E S U L T SOut of 67 eligible patients 33 were randomized toambroxol while 34 to placebo (Fig 1) Per-protocolanalysis was performed after excluding one patient inambroxol group who developed acute renal failureon day 2 leading to discontinuation of drugManagement included unmonitored hand-ventilationwith self-inflating bag for initial few hours (usuallyupto 24 h) in emergency room (ER) or pediatricwards (PWs) before PICU admission as more oftenthan not ventilator was not available for immediateapplication Of 66 patients 42(64) had moderateto severe ARDS (PaO2FiO2 200) [22] at ran-domization Thirteen of the remaining 24 patientswho had mild ARDS (PaO2FiO2 201ndash300) at en-rollment progressed in severity subsequently Twogroups were comparable for demographic profile nu-tritional status severity of illness at randomizationdiagnoses metabolic profile cause of lung injury aswell as in baseline respiratory characteristics (Tables1 and 2) Bronchopneumonia and bronchiolitis werethe commonest (91) causes of pARDS Three pa-tients (45) had chemotherapy-induced febrile neu-tropenia Eight (12) (four in each group) patientshad positive blood culture at PICU admissionmdashStaphylococcus aureus (3) Burkholderia cepacia (2)Acinetobacter (1) E coli (1) and Candida (1)

VFD14 was similar in two groups (pfrac14 056) sowas time-to-recovery from ARDS and other clinicaloutcomes (Table 3 and Fig 2) PaO2FiO2 OIneed for PEEP tidal volume and PaCO2 were alsosimilar during first 14 days (Figs 3 and 4) Healthcare associated infections (HCAIs) were seen in25(38) patients more in placebo group (1634 vs932 pfrac14 011) Out of these 19(76) were culturepositive gram-negative bacilli (14) being the com-monest (Candia 4 Staphylococcus 3) Blood-stream infections (14) were commonest followed byurinary tract infections (11) All-cause mortality was258 (1766) with similar distribution of early

342 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

(lt3 days) or late (gt3 days) deaths in the twogroups ARDS was considered as primary cause ofdeath in 53 (917) patients three of them wereimmunocompromised Forty-one percent (717)

of deaths were ascribed to HCAIs while onesuccumbed to hyperkalemia-induced arrhythmiaAmong survivors median (interquartile range) venti-lation duration was 7 (6) and 8 (45) days inambroxol and placebo groups respectively Diarrheawas noted in 6 (19) patients receiving ambroxolOne patient developed renal failure on D2 ofambroxol Serial blood pressure and cardiac compo-nent of PeLOD score were comparable in the twogroups during first 14 days contrasting the experi-mental data [33]

Table 1 Baseline patientsrsquo characteristics atenrollment

Characteristics Placebo(nfrac14 34)

Ambroxol(nfrac14 32)

Age (year) median (IQR) 115 (322) 137 (342)Age Number ()lt 1 year 16 (47) 13 (40)1ndash5 years 11 (32) 14 (44)gt5 years 7 (21) 5 (16)

Sex ratio (MF) 2311 2210Nutritional status (reference NCHS median)a

Normal (gt80) 18 (56) 17 (50)PEM grade 1 (71ndash80) 5 (16) 4 (12)PEM grade 2 (61ndash70) 5 (16) 8 (24)PEM grade 3 (51ndash60) 3 (9) 5 (15)PEM grade 4 (50) 1 (3) 0 (0)Serum albumin at

admission median(IQR) gmdl

229 (088) 260 (100)

Number ofpatients withhypoalbuminemia()b

24 (706) 23 (719)

PRISM III scoremedian (IQR)

500 (700) 600 (775)

PeLOD scoremedian (IQR)c

550 (1000) 1000 (1000)

Cause of pARDSPneumonia 29 (85) 27 (84)Bronchiolitis 5 (15) 1 (3)Kerosene poisoning 0 (0) 2 (6)Aspiration pneumonia 0 (0) 1 (3)Pulmonary hemorrhage 0 (0) 1 (3)

Blood culture positive 4 (12) 4 (13)Febrile Neutropenia 2 (6) 1 (3)

IQRfrac14 interquartile range PEMfrac14 protein energy malnutritionpARDSfrac14 Pulmonary Acute Respiratory DistressaMalnutrition was graded based on the criteria defined by IndianAcademy of PediatricsbHypoalbuminemia was defined as an albumin level of lt34 gdl for pa-tients gt7 months and lt25 gdl for patients lt7 months [32]cPeLOD Pediatric Logistic Organ Dysfunction (non-pulmonary) Score

Table 2 Baseline respiratory characteristics atenrollment

Respiratory characteristics Placebo(nfrac14 34)

Ambroxol(nfrac14 32)

PaO2FiO2 ratioa

mean (SD)1771 (707) 1906 (816)

Severity of ARDSnumber ()Mild ARDS

(PF ratio 201ndash300)10 (29) 14 (44)

Moderate ARDS(PF ratio 101ndash200)

20 (59) 14 (44)

Severe ARDS(PF ratio 100)

4 (12) 4 (12)

PEEP mean (SD) 65 (25) 62 (16)Quantitative pulmonary involvement

(as per chest radiograph)1 quadrant 0 (0) 0 (0)2 quadrant 2 (6) 2 (6)3 quadrant 7 (21) 6 (19)4 quadrant 25 (73) 24 (75)MAP mean (SD) 123 (51) 117 (42)OI mean (SD) 95 (108) 76 (46)VT (mlkg) mean (SD) 57 (17) 54 (13)PIP mean (SD) 194 (69) 186 (42)

Murrayrsquos lung injury scoreMild to moderate

(01ndash25)26 (76) 22 (69)

Severe (gt25) 8 (24) 10 (31)

IQRfrac14 interquartile range SDfrac14 standard deviation PaO2frac14 partial pres-sure of arterial oxygen FiO2frac14 fraction of inspired oxygenPEEPfrac14 positive end expiratory pressure PIPfrac14 peak inflating pressureMAPfrac14mean airway pressure OIfrac14 oxygenation Index VTfrac14 tidalvolumeaArterial blood gases in both groups were assessed at 0800 hours daily

High-dose Oral Ambroxol for pulmonary ARDS 343

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

D I S C U S S I O NCurrent study add to scarcely available data on clin-ical characteristics and outcomes of ventilated pediat-ric ARDS patients from developing economies [2 334] Ours being a tertiary care hospital without refer-ral and transport system we usually receive patientsvery late Thus patients are likely to be the severestof lot Pneumonia and bronchiolitis were commonest(90) causes of ARDS making it a syndrome ofrelatively homogeneous etiology in our setting as

against 40ndash65 reported from industrialized econo-mies (Table 4) PRISM-III score calculated fromdata collected during first 24 h of PICU admissionwere comparable with that in other pediatric ARDSstudies [35 37] However as all of our patients wereresuscitated and received post-resuscitation support-ive care (including hand-ventilation) for significantperiod in ERPWs before being shifted to PICUmany vital signs might have improved by the timethey reached PICU Thus actual PRISM-III scoresat beginning of hand-ventilation in ERPWs is likelyto be higher than ones calculated at PICU admissionmaking them sicker than what got reflected inPRISM-III scores All-cause mortality (of 26) is sig-nificantly higher compared with industrializedeconomies (Table 4) after factoring in higher meanPaO2FiO2 (gt175) lower mean OI (lt10) andlesser number of patients with immunocompromisedstatus Poor referral advanced stage of illness at ad-mission and suboptimal post-resuscitation care inERPWs may be one set of possible causative fac-tors While in PICU suboptimal patientsndashnurseratio poorly trained critical care nurses and poor in-fection control practices may be another These arethe issues of concern and indicate potentials of im-provement in critical care in the study settings

Early treatment was planned to have potentialbeneficial effects of ambroxol early during acute phase

Table 3 Primary and secondary outcome variables

Outcome Placebo (nfrac14 34) Ambroxol (nfrac14 32) pa

Primary outcome variableVentilator-free days at D14 (VFD14)b 50 (70) 50 (97) 056Ventilator-free days at D14 (VFD14) (mean 6 SD) 44 (36) 50 (45) ndash

Secondary outcome variablesAlive and ventilator-free at D14c 24 (71) 21 (66) 045Ventilator days among survivorsb 80 (45)(nfrac14 25) 70 (60) (nfrac14 24) 055Number of days to recover from ARDSd among survivorsb 100 (50)(nfrac14 25) 85 (70)(nfrac14 24) 054PICU stay among survivors (day)b 1200 (500) 1150 (775) 042All-cause mortalityc 9 (26) 8 (25) 089Early deaths (3 days)c 3 (38) 4 (44) 077Late deaths (gt3 days)c 5 (62) 5 (56)

ap-values are based on MannndashWhitney U test for number of VFD14 ventilator days among survivors time-to-recovery from ARDS duration of PICUstay v2 test (or Fisher Exact Test) for number of patients alive and ventilator-free at day 14 all-cause mortalitybData expressed as median (interquartile range)cData expressed as number (percentage)dAmong survivors number of days from randomization to meeting extubation readiness criteria for 24 consecutive hours through day 14

Time to recovery (Days)6050403020100

Cum

ulat

ive

a

t giv

en ti

me

10

08

06

04

02

00

placebo-censoreddrug-censoredplacebodrug

Study Groups

Fig 2 KaplanndashMeier curves comparing time-to-recoveryfrom ARDS in the two groups (censored for in-PICUmortality Log-Rank test pfrac14 094)

344 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

(a)

(b)

(c)

0

10

20

30

40

50

60

70

0 2 4 6 8 10 12 14 16

Placebo

Ambroxol

Linear (Placebo)

Linear (Ambroxol)

Days of Mechanical Venlaon

OI

0

100

200

300

400

500

600

700

0 5 10 15

Placebo

Ambroxol

Linear (Placebo)

Linear (Ambroxol)

Days of Mechanical Venlaon

PF

0

2

4

6

8

10

12

14

16

18

0 5 10 15

Placebo

Ambroxol

Linear (Placebo)

Linear (Ambroxol)

Days of Mechanical Venlaon

PEEP

Fig 3 Dot plot showing trend of mean PaO2FiO2 ratio oxygenation Index and PEEP during first 14 days

High-dose Oral Ambroxol for pulmonary ARDS 345

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

of illness We demonstrated safety tolerance and roleof high-dose oral ambroxol (40 mgkgday in fourdivided doses) in ventilated pARDS patients for thefirst time Ambroxol failed to improve oxygenationventilation VFD time-to-recovery mortality and thusto suggest therapeutic potential in pARDS in thestudy setting owing to small sample size Two-thirdsof patients had hypoalbuminemia and thus gut edema

possibly affecting ambroxolrsquos bioavailability Dosagechosen was maximal safe dose based on availableclinical data Therapeutic efficacy and safety of fur-ther higher dose may be subject of future scrutinyHigher doses may also be helpful in eradicating patho-gens adhered to bronchiolaralveolar epithelium [39]Ambroxol selectively gets concentrated in lungswithin 3 min of intravenous administration but it falls

(a)

(a)

0

50

100

150

200

250

0 2 4 6 8 10 12 14 16

Placebo

Ambroxol

Linear (Placebo)

Linear (Ambroxol)

Days of Mechanical Venlaon

PaCO

2

0

2

4

6

8

10

12

14

0 2 4 6 8 10 12 14 16

Placebo

Ambroxol

Linear (Placebo)

Linear (Ambroxol)

Days of Mechanical Venlaon

TV

FIG 4 Dot plot showing trend of mean tidal volume and PaCO2 during first 14 days

346 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

of illness We demonstrated safety tolerance and roleof high-dose oral ambroxol (40 mgkgday in fourdivided doses) in ventilated pARDS patients for thefirst time Ambroxol failed to improve oxygenationventilation VFD time-to-recovery mortality and thusto suggest therapeutic potential in pARDS in thestudy setting owing to small sample size Two-thirdsof patients had hypoalbuminemia and thus gut edema

possibly affecting ambroxolrsquos bioavailability Dosagechosen was maximal safe dose based on availableclinical data Therapeutic efficacy and safety of fur-ther higher dose may be subject of future scrutinyHigher doses may also be helpful in eradicating patho-gens adhered to bronchiolaralveolar epithelium [39]Ambroxol selectively gets concentrated in lungswithin 3 min of intravenous administration but it falls

(a)

(a)

0

50

100

150

200

250

0 2 4 6 8 10 12 14 16

Placebo

Ambroxol

Linear (Placebo)

Linear (Ambroxol)

Days of Mechanical Venlaon

PaCO

2

0

2

4

6

8

10

12

14

0 2 4 6 8 10 12 14 16

Placebo

Ambroxol

Linear (Placebo)

Linear (Ambroxol)

Days of Mechanical Venlaon

TV

FIG 4 Dot plot showing trend of mean tidal volume and PaCO2 during first 14 days

346 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

Tab

le4

Com

pari

son

ofcl

inic

alch

arac

teri

stic

san

dou

tcom

eof

pedi

atri

cA

RD

Sin

vari

ous

stud

ies

Clin

ical

Pro

file

Dah

lem

etal

[35

]C

urle

yet

al[

36]

Flor

iet

al[

37]

Wils

onet

al[

9]A

NZ

ICS

[38]

Hu et

al[

3]Z

hu etal

[2]

Che

tan

etal

[34

]In

dex

stud

y

nfrac14

443

nfrac14

102

nfrac14

328

nfrac14

152

nfrac14

117

nfrac14

306

nfrac14

401

nfrac14

17nfrac14

66

Stud

ype

riod

1998

ndash200

020

01ndash2

004

1996

ndash200

020

00ndash2

003

2004

ndash200

520

06ndash2

007

2009

2003

ndash200

620

07ndash2

008

Cou

ntry

ofst

udy

Net

herl

ands

USA

USA

USA

Aus

tral

iaan

dN

ewZ

eala

ndC

hina

Chi

naIn

dia

Indi

a

Pne

umon

ia11

4

56

35

34

46

75

63

18

82

Bro

nchi

oliti

s15

9

14

ndash7

12

ndashndash

ndash9

Asp

irat

ion

ndash11

15

8

8ndash

ndash6

5Se

psis

341

15

13

36

17

15

34

30

3

Nea

rdr

owni

ngndash

ndash9

53

ndash2

6ndash

Car

diac

dise

ase

ndashndash

7ndash

ndashndash

9ndash

ndashP

aO2

FiO

2ra

tio21

15a

147

and

153a

b

128

and

126a

b

17

71

and

190

6ab

Oxy

gena

tion

Inde

xN

A15

0an

d18

0a

b

200

and

205

ab

95

and

76a

b

Imm

uno-

com

prom

ised

Stat

us9

1N

A

34

45

Oth

ers

91

421

11

9

ndash1

540

2

Mor

talit

y27

8

22

28

35

45

30

70

26

NAfrac14

Info

rmat

ion

not

avai

labl

efrac14

info

rmat

ion

coul

dno

tbe

retr

ieve

ddu

eto

non-

acce

ssib

ility

offu

llm

anus

crip

ts

a Mea

nbIn

the

two

arm

sof

the

stud

yco

hort

High-dose Oral Ambroxol for pulmonary ARDS 347

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

dramatically at 2 h [33] Thus for sustained clinicaleffect more frequent administration (4 hourly or even2 hourly) may be required As pARDS was mostlycaused by pneumonia and bronchiolitis and majority(92) of survivors required ventilation for 14 daysD14 may be an optimal reference for measure of VFDin the study setting This pilot trial is relied on a con-venience sample results (Table 3) from which indi-cates need of sample size of 388 patients in each armwith one-sided significance level (a error) of 005 and80 power to detect 20 improvement in theobserved median VFD14 of 5 days (ie reduction of1 day in VFD14) [40]

Strengths include randomized design and care-fully planned protocols to define ventilator manage-ment sedation and extubation readiness to minimizevariations in daily management of patients Thereare many limitations as well major one being the un-regulated unmonitored hand-ventilation beforePICU admission which may have caused baro-trauma Lack of specific information on its durationmay be a potential confounder Study cohort was re-stricted to pARDS only These issues are unavoid-able and need to be tolerated to develop clinicallyefficacious interventions in the prevalent settingsHowever these would affect generalizability of re-sults Study was underpowered to demonstrate dif-ference in VFD14 There is lack of data onpharmacokinetics of enterally administered ambroxolin critically ill children It needs to be addressed be-fore conducting similar study in future Further in-flammatory oxidative and anti-protease markersshould also be evaluated to assess its pharmacologicefficacy Stratification according to severity of ARDSmay identify a subgroup of responders

C O N C L U S I O N SStudy provides useful information on prevalent situ-ation in the resource-constraint economies informsabout limitations in conducting trials in these set-tings and questionable generalizability of their re-sults Pediatric pARDS is mostly caused bypneumonia and bronchiolitis After factoring inhigher PaO2FiO2 lower OI and lesser patientswith immunocompromised states mortality is highcompared with industrialized peers High-dose oralambroxol failed to improve VFD14 In the current

cost-conscious health care environment its potentialas adjuvant therapy should be explored after havingaddressed the aforementioned issues Large pro-spective study of appropriate power with higherdoses of oral ambroxol administered more frequentlyis desirable VFD14 as composite outcome measuresis suggested for ventilated pediatric pARDS patientshowever it needs further validation

A C K N O W L E D G E M E N T SThe drug (ambroxol hydrochloride) was provided by MsAristo Pharmaceuticals Pvt Ltd Mumbai (India) The tabletsof drug (ambroxol) and placebo (lactose) was prepared atUniversity Institute of Pharmaceutical Sciences PunjabUniversity Chandigarh (India)

Work done at Emergency and Critical Care DivisionAdvanced Pediatrics Center Postgraduate Institute ofMedical Education and Research Chandigarh-160012 India

Presented at the 20th ESPNIC Medical amp NursingAnnual Congress at Verona Italy June 15ndash17 2009rdquo

R E F E R E N C E S1 Ventre KM Arnold JH Acute lung injury and acute re-

spiratory didtress syndrome In Nichols DG (ed) RogerrsquosTextbook of Pediatric Intensive Care 4th ednPhiladelphia PA Lippincott Williams amp Wilkins 2008731ndash66

2 Zhu YF Xu F Lu XL et al Chinese Collaborative StudyGroup for Pediatric Hypoxemic Respiratory FailureMortality and morbidity of acute hypoxemic respiratoryfailure and acute respiratory distress syndrome in infantsand young children Chin Med J 20121252265ndash71

3 Hu X Qian S Xu F et al Chinese Collaborative StudyGroup for Pediatric Respiratory Failure Incidence man-agement and mortality of acute hypoxemic respiratory fail-ure and acute respiratory distress syndrome from aprospective study of Chinese paediatric intensive care net-work Acta Paediatr 201099715ndash21

4 Hanson JH Flori H Application of the acute respiratorydistress syndrome network low-tidal volume strategy topediatric acute lung injury Respir Care Clin N Am 200612349ndash57

5 De Luca D Piastra M Tosi F et al Pharmacological thera-pies for pediatric and neonatal ALIARDS an evidence-based review Curr Drug Targets 201213906ndash16

6 Brun-Buisson C Richard JC Mercat A et al REVA-SRLFAH1N1v 2009 Registry Group Early corticosteroids insevere influenza AH1N1 pneumonia and acute respiratorydistress syndrome Am J Respir Crit Care Med 20111831200ndash6

348 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

dramatically at 2 h [33] Thus for sustained clinicaleffect more frequent administration (4 hourly or even2 hourly) may be required As pARDS was mostlycaused by pneumonia and bronchiolitis and majority(92) of survivors required ventilation for 14 daysD14 may be an optimal reference for measure of VFDin the study setting This pilot trial is relied on a con-venience sample results (Table 3) from which indi-cates need of sample size of 388 patients in each armwith one-sided significance level (a error) of 005 and80 power to detect 20 improvement in theobserved median VFD14 of 5 days (ie reduction of1 day in VFD14) [40]

Strengths include randomized design and care-fully planned protocols to define ventilator manage-ment sedation and extubation readiness to minimizevariations in daily management of patients Thereare many limitations as well major one being the un-regulated unmonitored hand-ventilation beforePICU admission which may have caused baro-trauma Lack of specific information on its durationmay be a potential confounder Study cohort was re-stricted to pARDS only These issues are unavoid-able and need to be tolerated to develop clinicallyefficacious interventions in the prevalent settingsHowever these would affect generalizability of re-sults Study was underpowered to demonstrate dif-ference in VFD14 There is lack of data onpharmacokinetics of enterally administered ambroxolin critically ill children It needs to be addressed be-fore conducting similar study in future Further in-flammatory oxidative and anti-protease markersshould also be evaluated to assess its pharmacologicefficacy Stratification according to severity of ARDSmay identify a subgroup of responders

C O N C L U S I O N SStudy provides useful information on prevalent situ-ation in the resource-constraint economies informsabout limitations in conducting trials in these set-tings and questionable generalizability of their re-sults Pediatric pARDS is mostly caused bypneumonia and bronchiolitis After factoring inhigher PaO2FiO2 lower OI and lesser patientswith immunocompromised states mortality is highcompared with industrialized peers High-dose oralambroxol failed to improve VFD14 In the current

cost-conscious health care environment its potentialas adjuvant therapy should be explored after havingaddressed the aforementioned issues Large pro-spective study of appropriate power with higherdoses of oral ambroxol administered more frequentlyis desirable VFD14 as composite outcome measuresis suggested for ventilated pediatric pARDS patientshowever it needs further validation

A C K N O W L E D G E M E N T SThe drug (ambroxol hydrochloride) was provided by MsAristo Pharmaceuticals Pvt Ltd Mumbai (India) The tabletsof drug (ambroxol) and placebo (lactose) was prepared atUniversity Institute of Pharmaceutical Sciences PunjabUniversity Chandigarh (India)

Work done at Emergency and Critical Care DivisionAdvanced Pediatrics Center Postgraduate Institute ofMedical Education and Research Chandigarh-160012 India

Presented at the 20th ESPNIC Medical amp NursingAnnual Congress at Verona Italy June 15ndash17 2009rdquo

R E F E R E N C E S1 Ventre KM Arnold JH Acute lung injury and acute re-

spiratory didtress syndrome In Nichols DG (ed) RogerrsquosTextbook of Pediatric Intensive Care 4th ednPhiladelphia PA Lippincott Williams amp Wilkins 2008731ndash66

2 Zhu YF Xu F Lu XL et al Chinese Collaborative StudyGroup for Pediatric Hypoxemic Respiratory FailureMortality and morbidity of acute hypoxemic respiratoryfailure and acute respiratory distress syndrome in infantsand young children Chin Med J 20121252265ndash71

3 Hu X Qian S Xu F et al Chinese Collaborative StudyGroup for Pediatric Respiratory Failure Incidence man-agement and mortality of acute hypoxemic respiratory fail-ure and acute respiratory distress syndrome from aprospective study of Chinese paediatric intensive care net-work Acta Paediatr 201099715ndash21

4 Hanson JH Flori H Application of the acute respiratorydistress syndrome network low-tidal volume strategy topediatric acute lung injury Respir Care Clin N Am 200612349ndash57

5 De Luca D Piastra M Tosi F et al Pharmacological thera-pies for pediatric and neonatal ALIARDS an evidence-based review Curr Drug Targets 201213906ndash16

6 Brun-Buisson C Richard JC Mercat A et al REVA-SRLFAH1N1v 2009 Registry Group Early corticosteroids insevere influenza AH1N1 pneumonia and acute respiratorydistress syndrome Am J Respir Crit Care Med 20111831200ndash6

348 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

7 Singer P Shapiro H Enteral omega-3 in acute respiratorydistress syndrome Curr Opin Clin Nutr Metab Care200912123ndash8

8 Pacht ER DeMichele SJ Nelson JL et al Enteral nutri-tion with eicosapentaenoic acid gamma-linolenic acidand antioxidants reduces alveolar inflammatory mediatorsand protein influx in patients with acute respiratory dis-tress syndrome Crit Care Med 200331491ndash500

9 Wilson DF Thomas NJ Markowitz BP et al Effect ofexogenous surfactant (calfactant) in pediatric acutelung injury a randomized controlled trial JAMA 2005293470ndash6

10 Matthay MA Abraham E Beta-adrenergic agonist therapyas a potential treatment for acute lung injury Am J RespirCrit Care Med 2006173254ndash5

11 Perkins GD McAuley DF Thickett DR et al The szlig-Agonist Lung Injury Trial (BALTI) a randomizedplacebo-controlled clinical trial Am J Respir Crit CareMed 2006173281ndash7

12 Wunderer H Morgenroth K Weis G The cleaningsystem of the airways physiology pathophysiologyand effects of ambroxol Med Monatsschr Pharm20093242ndash7

13 Malerba M Ragnoli B Ambroxol in the 21st centurypharmacological and clinical update Expert Opin DrugMetab Toxicol 200841119ndash29

14 Li Q Yao G Zhu X High-dose ambroxol reduces pul-monary complications in patients with acute cervical spi-nal cord injury after surgery Neurocrit Care 201216267ndash72

15 Wauer RR Schmalisch G Bohme B et al Randomizeddouble blind trial of Ambroxol for the treatment of respira-tory distress syndrome Eur J Pediatr 1992151357ndash63

16 Refai M Brunelli A Xiume F et al Short-term periopera-tive treatment with ambroxol reduces pulmonarycomplications and hospital costs after pulmonary lobec-tomy a randomized trial Eur J Cardiothorac Surg 200935469ndash73

17 Xia DH Xi L Xv C et al The protective effects ofambroxol on radiation lung injury and influence on pro-duction of transforming growth factor beta(1) and tumornecrosis factor alpha Med Oncol 201027697ndash701

18 Ulas MM Hizarci M Kunt A et al Protective effect ofambroxol on pulmonary function after cardiopulmonarybypass J Cardiovasc Pharmacol 200852518ndash23

19 Wang Y Wang FY Pan Z et al Effects of ambroxolcombined with low-dose heparin on TNF-alpha andIL-1beta in rabbits with acute lung injury [Article inChinese] Zhongguo Ying Yong Sheng Li Xue Za Zhi201127231ndash5

20 Su X Wang L Song Y et al Inhibition of inflammatoryresponses by ambroxol a mucolytic agent in a murinemodel of acute lung injury induced by lipopolysaccharideIntensive Care Med 200430133ndash140

21 Ma YT Tian YP Shi HW et al Effects of high doseambroxol on lung injury induced by paraquat in ratsZhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi200725523ndash6

22 ARDS Definition Task Force Ranieri VM RubenfeldGD Thompson BT et al Acute respiratory distress syn-drome the Berlin Definition JAMA 20123072526ndash33

23 Schulz M Hammrlein A Hinkel U Safety and usage pat-tern of an over-the-counter ambroxol cough syrup a com-munity pharmacy based cohort study Int J ClinPharmacol Ther 200644409ndash21

24 Schmalisch G Wauer RR Bohme B Effect of earlyambroxol treatment on lung functions in mechanically ven-tilated preterm newborns who subsequently developed abronchopulmonary dysplasia Respir Med 200094378ndash84

25 Couet W Girault J Reigner BG Steady-state bioavailabil-ity and pharmacokinetics of ambroxol and clenbuterol ad-ministered alone and combined in a new oral formulationInt J Clin Pharmacol Ther Toxicol 198927467ndash72

26 Schulz KF Altman DG Moher D CONSORT GroupCONSORT 2010 Statement updated guidelines for re-porting parallel group randomised trials BMC Med 2010818

27 Leteurtre S Martinot A Duhamel A et al Validation ofthe paediatric logistic organ dysfunction (PeLOD) scoreprospective observational multicentre study Lancet2003362192ndash7

28 Ramsay MAE How to use the Ramsay Score to assess thelevel of ICU Sedation http5jsnaccuminacjpHow20to20use20the20Ramsay20Score20too20assess20the20level20of20ICU20Sedationhtm (1August 2014 date last accessed)

29 Rubenfeld GD Caldwell E Peabody E et al Incidenceand outcomes of acute lung injury N Engl J Med 20053531685ndash93

30 Demling RH Adult respiratory distress syndrome cur-rent concepts New Horiz 19931388ndash401

31 Schoenfeld DA Bernard GR Network ARDS Statisticalevaluation of ventilator-free days as an efficacy measure inclinical trials of treatments for acute respiratory distresssyndrome Crit Care Med 2002301772ndash7

32 Horowitz IN Tai K Hypoalbuminemia in critically ill chil-dren Arch Pediatr Adolesc Med 20071611048ndash1052

33 Wauer RR Schmalisch G Ambroxol for prevention andtreatment of Hyaline membrane disease Eur Resp J 1989257sndash65s

34 Chetan G Rathisharmila R Narayanan P et al Acute re-spiratory distress syndrome in pediatric intensive careunit Indian J Pediatr 2009761013ndash16

35 Dahlem P van Aalderen W Hamaker M et al Incidenceand short-term outcome of acute lung injury in mechanic-ally ventilated children Eur Respir J 200322980ndash5

36 Curley MAQ Hibberd PL Fineman LD et al Effect ofprone positioning on clinical outcomes in children with

High-dose Oral Ambroxol for pulmonary ARDS 349

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017

acute lung injury a randomized controlled trial JAMA2005294229ndash37

37 Flori HR Glidden DV Rutherford GW et al Pediatricacute lung injury prospective evaluation of risk factorsassociated with mortality Am J Respir Crit Care Med2005171995ndash1001

38 Erickson S Schibler A Numa A et al Paediatric StudyGroup Australian and New Zealand Intensive Care Society(ANZICS) Acute lung injury in pediatric intensive care in

Australia and New Zealand a prospective multicentre ob-servational study Pediatr Crit Care Med 20078317ndash23

39 Capsoni F Ongari AM Minonzio F Effect of ambroxolon human phagocytic cell function Boll Ist Sieroter Milan198564236ndash9

40 Sample Size Calculator Two Parallel Sample MeansHypothesis One-Sided Non-InferioritySuperiorityhttpwwwcctcuhkeduhkstatmeantsmp_suphtm(24 March 2015 date last accessed)

350 High-dose Oral Ambroxol for pulmonary ARDS

Downloaded from httpsacademicoupcomtropejarticle-abstract6153391647427High-dose-Oral-Ambroxol-for-Early-Treatment-ofby gueston 05 October 2017