DOI: 10.1542/peds.2009-3631; originally published online September 20, 2010; 2010;126;e807Pediatrics

Fazlul Haque, Mohammed A. Salam and Niklaus GyrHasan Ashraf, Rokhsana Mahmud, Nur H. Alam, Selina A. Jahan, Syed M. Kamal,

Pneumonia in BangladeshRandomized Controlled Trial of Day Care Versus Hospital Care of Severe

  

  http://pediatrics.aappublications.org/content/126/4/e807.full.html

located on the World Wide Web at: The online version of this article, along with updated information and services, is

 

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

Randomized Controlled Trial of Day Care VersusHospital Care of Severe Pneumonia in Bangladesh

WHAT’S KNOWN ON THIS SUBJECT: Severe and very severepneumonia in children without comorbidities can be successfullymanaged on a day care basis at established day care clinics, ifadequately trained and motivated staff members and logisticsupport can be made available.

WHAT THIS STUDY ADDS: Severe childhood pneumonia withoutassociated comorbidities, such as severe acute malnutrition, canbe managed safely and effectively on a day care basis atestablished day care clinics, except for children with hypoxemiawho require oxygen therapy for�6 hours.

abstractOBJECTIVE: A randomized controlled trial compared day care versushospital care management of pneumonia.

METHODS: Children 2 to 59 months of age with severe pneumoniareceived either day care, with antibiotic treatment, feeding, and sup-portive care from 8:00 AM to 5:00 PM, or hospital care, with similar24-hour treatment.

RESULTS: In 2006–2008, 360 children were assigned randomly to re-ceive either day care or hospital care; 189 (53%) had hypoxemia, with amean� SD oxygen saturation of 93� 4%, which increased to 99� 1%after oxygen therapy. The mean � SD durations of day care and hos-pital care were 7.1� 2.3 and 6.5� 2.8 days, respectively. Successfulmanagement was possible for 156 (87.7% [95% confidence interval[CI]: 80.9%–90.9%]) of 180 children in the day care group and 173(96.1% [95% CI: 92.2%–98.1%]) of 180 children in the hospital caregroup (P� .001). Twenty-three children in the day care group (12.8%[95% CI: 8.7%–18.4%] and 4 children in the hospital care group (2.2%[95% CI: 0.9%–5.6%] required referral to hospitals (P � .001). Duringthe follow-up period, 22 children in the day care group (14.1% [95% CI:9.5%–20.4%]) and 11 children in the hospital care group (6.4% [95% CI:3.6%–11%]) required readmission to hospitals (P � .01). The esti-mated costs per child treated successfully at the clinic and the hospitalwere US$114 and US$178, respectively.

CONCLUSION: Severe childhood pneumonia without severe malnutri-tion can be successfully managed at day care clinics, except for chil-dren with hypoxemia who require prolonged oxygen therapy.Pediatrics 2010;126:e807–e815

AUTHORS: Hasan Ashraf, MD,a Rokhsana Mahmud,MBBS,a Nur H. Alam, MD,a Selina A. Jahan, MBBS,a Syed M.Kamal, MBBS,b Fazlul Haque, FCPS,c Mohammed A. Salam,MBBS,a and Niklaus Gyr, MDd

aClinical Sciences Division, International Centre for DiarrhoealDisease Research, Bangladesh, Dhaka, Bangladesh; bRaddaMaternal and Child Health-Family Planning Centre, Dhaka,Bangladesh; cInpatient Department, Institute of Child Health andShishu Sasthya Foundation Hospital, Dhaka, Bangladesh; anddDepartment of Internal Medicine, University of Basel, Basel,Switzerland

KEY WORDSday care clinic, hospital care, severe pneumonia, children

ABBREVIATIONSICDDRB—International Centre for Diarrhoeal Disease Research,BangladeshICHSH—Institute of Child Health and Shishu Sasthya FoundationHospitalRCT—randomized controlled trialSAM—severe acute malnutritionCI—confidence interval

This trial has been registered at www.clinicaltrials.gov (identi-fier NCT00455468).

www.pediatrics.org/cgi/doi/10.1542/peds.2009-3631

doi:10.1542/peds.2009-3631

Accepted for publication Jun 18, 2010

Address correspondence to Hasan Ashraf, MD, InternationalCentre for Diarrhoeal Disease Research, Bangladesh, ClinicalSciences Division, 68 Shaheed Tajuddin Ahmed Sharani,Mohakhali, Dhaka 1212, Bangladesh. E-mail: ashrafh@icddrb.org

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

Copyright © 2010 by the American Academy of Pediatrics

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

ARTICLE

PEDIATRICS Volume 126, Number 4, October 2010 e807 at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

The fourth Millennium DevelopmentGoal has concentrated efforts on ad-dressing priority areas for improvingchild survival rates throughout theworld, with an aim of reducing nationalchild mortality rates by two-thirds in1990–2015.1 Improvements in man-agement strategies for major causesof child death, such as pneumonia andneonatal illnesses, should be a priorityfor improving child survival rates indeveloping countries.2–4 An estimated150 million episodes of pneumonia oc-cur throughout the world each year,and 11 to 20 million of those episodesrequire hospitalization in developingcountries.5,6 Acute lower respiratorytract infections, particularly pneumo-nia, currently are the greatest singlecause of deaths among �5-year-oldchildren in developing countries, beingresponsible for 19% of 9.7 milliondeaths per year.7,8 Acute lower respira-tory tract infections cause �2 milliondeaths per year throughout the world,mostly resulting from pneumonia, and90% to 95% of the deaths occur in de-veloping countries.9–13 In Bangladesh,acute lower respiratory tract infec-tions account for 25% of deaths among�5-year-old children and 40% ofdeaths among infants.14 Depending onclinical presentation, pneumonia canbe classified as very severe, severe, ornonsevere, according to the WorldHealth Organization,15–18 which recom-mends that diagnosis of pneumoniashould be based primarily on visibleclinical parameters.15,19,20 Severe child-hood pneumonia requires hospitaliza-tion for supportive treatment, such assuctioning, oxygen therapy, fluid andnutritional management, and closemonitoring.15–18 In Bangladesh, thereare not enough pediatric beds in hos-pitals for admission of all patients withsevere pneumonia. Therefore, it is im-portant to provide institutional carefor children who cannot be hospital-ized. Two prospective observationalstudies showed that day care facility-

based, modified primary caremanage-ment of severe acute malnutrition21

and severe pneumonia22 were suc-cessful and cost-effective as alterna-tives to hospitalization. On the basis ofthe findings of earlier studies indicat-ing both efficacy and safety of daycare-based management, we per-formed a randomized controlled trial(RCT) to compare day care manage-ment with hospital care managementof severe childhood pneumonia.

METHODS

Setting

This was a collaborative study involv-ing the International Centre for Diar-rhoeal Disease Research, Bangladesh(ICDDRB), the Radda Maternal andChild Health-Family Planning Centre,the Institute of Child Health and ShishuSaystha Foundation Hospital (ICHSH),and the University of Basel (Basel,Switzerland). The research and ethicalreview committees of the ICDDRB ap-proved the study. We conducted thestudy from September 2006 throughNovember 2008 at the Radda clinic andthe ICHSH. The Radda clinic is a nongov-ernmental organization that has pro-vided maternal and child health ser-vices since 1974 in Mirpur, Dhaka,from 8:00 AM to 4:00 PM every day exceptfor weekends and holidays. It providescare for common childhood illnesses,including pneumonia, on an outpatientbasis. We had a ward consisting of 5beds and a study team comprising 1physician, 2 nurses, and 4 health careworkers.22

The ICHSHwas the primary site for hos-pital care; it has provided health careto children through outpatient facili-ties, attended by �450 children perday, and 125-bed inpatient facilities forpediatric medicine, pediatric surgery,and neonatology since 1994. We had award consisting of 5 beds and a studyteam comprising 2 physicians, 4nurses, 1 research assistant, and 4

health care workers. Provisions for ox-ygen therapy and electric suction ther-apy, a pulse oximeter, a nebulizer, aglucometer, and aweighing scaleweremade available at both the clinic andthe hospital.

Sample Size

We estimated the sample size for se-vere pneumonia on the basis of thesuccess rate of 93% in our recentlypublished day care pneumonia study,22

with the assumption of a maximal ex-pected success rate of 99%with hospi-tal management. With 80% power and5% significance, the required samplesize was estimated to be 165 for eachof the 2 treatment groups. To allow10% rates of discontinuation for anyreason, 368 children (184 at each site)with severe pneumonia needed tobe studied at both the clinic and thehospital.

Eligibility Criteria

Children of either gender, 2 to 59months of age, with symptoms of se-vere pneumonia, defined as cough ordifficulty breathing with lower chestwall indrawing, according to WorldHealth Organization criteria,15–18 wereenrolled after parental consent wasobtained. Children with a history of re-ceiving injectable antibiotics for treat-ment of pneumonia during the illnessand those with associated comorbidi-ties, such as tuberculosis, congenitalheart disease, bronchiolitis, bronchialasthma, severe acute malnutrition(SAM) (weight-for-age z score of �3),sepsis, hypoglycemia, convulsions, ormeningitis, were not eligible. Childrenwere not screened for HIV exposurethrough history or laboratory investi-gation, because the prevalence ofHIV infection is very low (�1%) in oursetting.

Randomization

After the eligibility criteria were ful-filled and written informed consent

e808 ASHRAF et al at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

was obtained, children were assignedrandomly to receive either day care atthe clinic or hospital care at the ICHSH.We used block randomization and pro-duced computer-generated randomnumbers assigned to 1 of the 2 inter-ventions. The random numbers, corre-sponding to specific interventions,were sealed in sequentially numberedenvelopes. Until the envelopes wereopened, neither patients nor physi-cians were aware of the treatmentgroups. Treatment was assigned at en-rollment through opening of the se-quentially numbered envelopes, start-ing with the lowest number andmoving toward higher numbers. Onestatistician not involved in the studyprepared the randomization list.

Case Management

Parents brought their children to theclinic at 8:00 AM and took them home at5:00 PM each day. Oxygen saturationwas measured routinely, by usingpulse oximetry, for every child after en-rollment and before administration ofoxygen therapy. Because oxygen satu-ration measurements depend on pa-tients’ skin pigmentation and a highertarget value of 95% resulted in a satis-factory level of oxygenation for blackpatients, we used this cutoff value forour study.23,24 Routinemonitoring of hy-poxemic children was performed at in-tervals of 30 minutes to 2 hours, de-pending on the patient’s condition,until oxygen saturation remained sta-ble at�95%with room air. Oxygen sat-uration was checked again during oxy-gen therapy, as well as after removalof administered oxygen for 2 to 5 min-utes. Children who remained hypox-emic at 5:00 PM were referred to theICHSH or Dhaka Hospital of the ICDDRB.All children received once-daily injec-tions of ceftriaxone, in doses of 75 to100mg/kg, for�5 days. Cotrimoxazolewas not considered for the treatmentof pneumonia attributable to Pneumo-cystis jiroveci (previously known as

Pneumocystis carinii), because theprevalence of HIV infection is very lowin our setting. Feeding of children re-ceiving day care was described in ourrecent report.22

The management described abovecontinued on each day of the week un-til there was clinical improvement, de-fined as no fever, no fast breathing, nolower chest wall indrawing, no dangersigns, no rales on auscultation, and nohypoxemia. Children were consideredafebrile when the rectal temperaturebecame �38°C and remained so for�24 hours. No fast breathing was de-fined as age-specific respiratory ratesof�50 breaths per minute for infants2 to 12months of age and�40 breathsper minute for children 12 to 59months of age. No lower chest wall in-drawing was indicated if the lowerchest wall did not go in when child in-

haled. No danger signs referred to theabsence of all of the following dangersigns: not able to drink/feed, centralcyanosis, head nodding, stridor in acalm child, abnormal sleepiness, con-vulsion, and severe clinical malnutri-tion. Therewas no hypoxemiawhen theoxygen saturation was �95% withroom air, as recorded by the pulseoximeter. After successful treatment,children were discharged from theclinic with advice for follow-up care.Children were referred to the ICHSH orDhaka Hospital of the ICDDRB if theyfailed to experience improvement withthe day care management.

Children assigned randomly to receivehospital care remained at the ICHSHfor the entire duration of the illnessand received similar treatment, withonce-daily injections of ceftriaxone, indoses of 75 to 100 mg/kg, for�5 days

913 children screened for eligibility

553 children excluded from study • 326 did not meet inclusion

criteria• 176 did not consent to

participate • 51 had other reasons

1 discontinued treatment • 1 mother sick

23 referred to hospitals• 20 had severe hypoxaemia • 1 had pnuemothorax • 1 had lobar pneumonia with suspected

staphylococcal infection • 1 had difficult and rapid breathing

156 successfully managed at the day-care clinic

180 allocated to the day-care and received day-care management for severe pneumonia

3 discontinued treatment • 1 left Dhaka • 2 mothers had personal reasons

4 referred to other specialized hospitals • 1 had pulmonary tuberculosis • 1 had dehydrating diarrhoea • 1 had heart failure • 1 had heart failure with hospital

acquired infection

173 successfully managed at the hospital

180 allocated to hospital-care and received hospital-care management for severe pneumonia

360 enrolled in study

Randomized to either day-care, or hospital-care

180 children included in analysis 180 children included in analysis

FIGURE 1Trial profile.

ARTICLE

PEDIATRICS Volume 126, Number 4, October 2010 e809 at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

and supportive care such as suction-ing, oxygen therapy, and diet. Infantsand children �6 months of age re-ceived milk-suji (a mixture of milk andrice powder boiled together, with 281kJ and 1.4 g of protein per 100 mL) at10 mL/kg per feeding, every 2 hours.Breastfed children continued breast-feeding, and infant formula (286 kJand 1.5 g of protein per 100 mL) wasgiven to nonbreastfed infants 2 to 6months of age. The same treatmentcontinued for 24 hours every day (com-pared with 9 hours/day at the clinic)until improvement of the child’s condi-tion, as defined earlier, was observed.Parents were asked to bring their chil-dren to their primary sites of manage-ment (clinic or hospital) every 2 weeksfor a period of 3 months, for examina-tion by a physician, as described in ourrecent report.22

Data Analysis

The main outcome measures of thestudy were the success of day care/hospital care, defined as improvementin clinical condition without referral toanother hospital, full compliance withthe day care/hospital care manage-ment until recovery, without prema-ture discontinuation of the study forany reason, and not dying during thestudy. All data were collected on pre-tested case report forms, edited, en-tered into a personal computer, andanalyzed by using SPSS 11.5 (SPSS, Chi-cago, IL). The main outcome measureswere expressed as the proportions(with 95% confidence intervals [CIs])of successes and failures of day care/hospital care management. Other out-come measures were the proportions(with 95% CIs) of children who re-quired hospital referrals and who dis-continued the study prematurely with-out fulfilling the criteria for success.

Cost Analysis

The cost implications for treating se-vere childhood pneumonia were as-

sessed for an urban day care healthfacility. In addition to the assessmentof clinical effectiveness, analysis ofcost-effectiveness of the day careclinic-based approach would be usefulfor determining the real value of theseday care facilities for treating severechildhood pneumonia. The analysiswas performed from a societal per-spective, as recommended by currentstandards for cost-effectiveness anal-yses. The costs incurred at 2 alterna-

tive health care settings for treatmentof children with severe pneumoniawere recorded over a period of 1 year(January through December 2007).The components of provider or facilitycosts included costs related to person-nel, diagnostic tests, drugs, diet, foodpreparation, and supportive care, andthe average costs per patient were cal-culated. Estimates of treatment suc-cess were determined from the studyfor both health care facilities. The cost-

TABLE 1 Comparison of Baseline Characteristics of Study Children

Characteristics Total(N� 360)

Day Care(N� 180)

Hospital Care(N� 180)

Male, n (%) 220 (61) 102 (57) 118 (66)AgeMean� SD, mo 8� 7 8.7� 8.0 7.3� 6.82–11 mo, n (%) 291 (81) 137 (76) 154 (86)12–59 mo, n (%) 69 (19) 43 (24) 26 (14)Breastfed, n (%) 330 (92) 163 (91) 167 (93)History, n (%)Cough 359 (99.7) 180 (100) 179 (99)Fever 328 (91) 159 (88) 169 (94)Difficulty breathing 169 (47) 59 (33) 110 (61)Rapid breathing 129 (36) 84 (47) 45 (25)Lower chest wall indrawing 127 (35) 88 (49) 39 (22)Vomiting 8 (2.2) 3 (1.6) 5 (2.7)Diarrhea 19 (5) 10 (6) 9 (5)Weight, mean� SD, kg 6.4� 1.6 6.6� 1.7 6.4� 1.5Height, mean� SD, cm 64.7� 8.3 65� 8.3 64� 8.3Weight-for-age z score, mean� SD �1.41� 1.19 �1.42� 1.23 �1.4� 1.7Weight-for-height z score, mean� SD �0.74� 2.39 �0.63� 1.15 �0.87� 3.19Duration of cough before admission, dMean� SD 5.15� 3.39 5.37� 3.67 4.92� 3.07Median (interquartile range) 4.0 (3.0–7.0) 4.0 (3.0–7.0) 4.0 (3.0–6.0)Temperature, mean� SD, °C 38.0� 0.8 37.9� 0.9 38.0� 0.8Temperature of�38°C, n (%) 174 (48) 94 (52) 80 (44)Duration of fever before admission, dMean� SD 4.15� 3.35 4.55� 4.20 3.78� 2.20Median (interquartile range) 4.0 (2.0–5.0) 3.0 (2.0–6.0) 4.0 (2.0–5.0)Pulse rate, mean� SD, beats per min 153� 17 151� 18 155� 16Pulse rate of�160 beats per min, n (%) 99 (27) 47 (26) 52 (29)Respiratory rate, mean� SD, breaths per min 63� 12 62� 10 64� 13Respiratory rate of�40 breaths per min, n (%) 360 (100) 180 (100) 180 (100)Duration of rapid breathing before admission, dMean� SD 2.30� 2.10 2.32� 2.24 2.30� 1.97Median (interquartile range) 2.0 (1.0–3.0) 2.0 (1.0–3.0) 2.0 (1.0–3.0)Lower chest wall indrawing, n (%) 358 (99.4) 180 (100) 178 (99)Duration of lower chest wall indrawing beforeadmission, dMean� SD 2.24� 2.23 2.31� 2.50 2.16� 1.93Median (interquartile range) 2.0 (1.0–3.0) 2.0 (1.0–3.0) 2.0 (1.0–3.0)Vesicular breath sounds, n (%) 352 (98) 175 (97) 177 (98)Rales/crepitation on auscultation, n (%) 356 (99) 177 (98) 179 (99)Hepatomegaly (liver palpable for�2 cm), n (%) 106 (29) 92 (51) 14 (8)Hypoxemia at admission (oxygen saturation of

�95%), n (%)189 (53) 113 (63) 76 (42)

Oxygen saturation at admission, mean� SD, % 93� 4 93� 5 94� 4

e810 ASHRAF et al at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

effectiveness analysis involved calcu-lation of the average cost per patienttreated successfully; the estimation in-volved computing the total cost esti-mate and then dividing that by thenumber of patients who were treatedsuccessfully.

RESULTS

We screened 913 children from theRadda clinic and the ICHSH, 553 ofwhom were not enrolled in the studyfor various reasons (Fig 1). Three hun-dred sixty children with severe pneu-monia were enrolled either from theday care clinic (51%) or from the hos-pital (49%) and were equally (180 ineach) assigned randomly to day careor hospital care (Table 1). Tables 1 and2 show the comparison of baselinecharacteristics of the study children. Astatistically significant difference be-tween the 2 groups was observed fornone of the parameters except hypox-emia and hepatomegaly. On examina-tion, 189 (53%) of 360 children had hy-poxemia, with a mean � SD oxygensaturation of 91� 5% (Table 3), whichincreased to 99 � 1% with oxygentherapy (Table 4). The mean � SD du-ration of oxygen therapy for correctionof hypoxemia was 340 � 555 minutes(Table 2). Of 113 clinic children withhypoxemia, 20 (17.7% [95% CI: 11.8%–25.8%]) were referred to the hospitalbecause they remained hypoxemic forprolonged periods, even up to the endof the first day of enrollment (5:00 PM)(Fig 1). A significantly greater numberof children with hypoxemia weretreated at the clinic, compared withthe hospital (P� .001) (Table 1).

Successful management was possiblefor 156 (87.7% [95% CI: 80.9%–90.9%])of 180 children who received day careand 173 (96.1% [95% CI: 92.2%–98.1%])of 180 children who received hospitalcare (P � .001). Of the remaining 24children (13.3% [95% CI: 9.1%–19.1%])in the day care group, 23 (12.8% [95%

CI: 8.7%–18.4%]) were referred to thehospital and 1 (0.6% [95% CI:0.1%–3.1%]) discontinued treatment(Table 5). Of the remaining 7 children(3.9% [95% CI: 1.9%–7.8%]) in the hos-pital care group, 4 (2.2% [95% CI:0.9%–5.6%]) were referred to otherspecialized hospitals and 3 (1.7% [95%CI: 0.6%–4.8%]) discontinued treat-ment (Table 5). There were no deathsduring the day care and hospital carestudy period; however, 2 children(1.1% [95% CI: 0.2%–4%]) died duringthe 3-month follow-up period and 1child (0.6% [95% CI: 0.1%–3.1%]) diedafter the follow-up period, all 3 in thehospital care group, with none in theday care population (Tables 5 and 6).During the follow-up period, 22 chil-dren (14.1% [95% CI: 9.5%–20.4%]) inthe day care group and 11 children(6.4% [95% CI: 3.6%–11%]) in the hos-pital care group required hospital re-admission (P� .01) (Table 5).

The total annual costs incurred fortreatment at the clinic and the hospital

were US$9951 and US$17 516, respec-tively. The average cost per patient atthe ICHSH (US$175) was much higherthan that at the clinic (US$99.5). Theestimated costs per patient treatedsuccessfully at the clinic and the hos-pital were US$114 and US$178, respec-tively. For 87 patients who weretreated successfully at the clinic, a to-tal amount of US$6581 (difference incosts) was saved, compared with hos-pitalized children. If those 87 patientshad been treated at the ICHSH, then ad-ditional costs of US$6581 (the savings)would have been incurred.

DISCUSSION

The main purposes of this RCT were toassess whether it would be possible totreat severe childhood pneumoniasafely and effectively on a day care ba-sis andwhether thismodality would bemore cost-effective than hospital care.The results showed that children withsevere pneumonia could be treatedsafely and effectively on a day care ba-

TABLE 2 Comparison of Secondary Outcomes for Study Children

Characteristics Total(N� 360)

Day Care(N� 180)

HospitalCare

(N� 180)

P

Duration of cough, dMean� SD 6.6� 3.0 6.9� 2.7 6.2� 3.1 .02Median (interquartile range) 6.0 (5.0–8.0) 7.0 (6.0–8.0) 6.0 (5.0–8.0) .005Duration of fever, dMean� SD 1.15� 1.3 1.1� 1.2 1.2� 1.4 .43Median (interquartile range) 1.0 (0–2.0) 1.0 (0–2.0) 1.0 (0–2.0) .36

Duration of rapid breathing, dMean� SD 4.0� 2.9 4.6� 2.8 3.3� 2.8 �.001Median (interquartile range) 3.0 (2.0–6.0) 4.0 (3.0–6.0) 2.0 (1.0–5.0) �.001Duration of lower chest wall indrawing, dMean� SD 5.7� 3.0 6.7� 2.7 4.7� 3.1 �.001Median (interquartile range) 6.0 (3.0–7.0) 7.0 (5.0–8.0) 4.0 (3.0–6.0) �.001Oxygen saturation after oxygen therapy,mean� SD, %

99� 1 99� 1 99� 1 .77

Duration of oxygen therapyMean� SD, min 340� 555 330� 505 350� 630 .81Median (interquartile range), h 2.0 (0–7.05) 2.1 (0.2–6.35) 1.42 (0–8.48) .21Duration of ceftriaxone therapy, dMean� SD 7.0� 1.6 7.5� 1.6 6.5� 1.6 �.001Median (interquartile range) 7.0 (6.0–8.0) 7.0 (7.0–9.0) 7.0 (5.0–7.0) �.001Duration of stay, dMean� SD 6.8� 2.6 7.1� 2.3 6.5� 2.8 .04Median (interquartile range) 6.0 (5.0–8.0) 6.0 (6.0–8.0) 6.0 (5.0–7.0) �.001Duration of stay of�10 d, n (%) 24 (6.6) 16 (9) 8 (4) .09

ARTICLE

PEDIATRICS Volume 126, Number 4, October 2010 e811 at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

sis, as effectively as in the hospital.These results may have a great impacton the treatment of severe childhoodpneumonia, particularly in resource-poor countries where hospital bedsare scarce. The findings should be eas-ily replicated in most urban and ruraloutpatient clinics in developing coun-tries, provided proper training andmotivation of staff members and pro-vision of logistic support are guaran-teed. The additional funds neededwould be well invested, given the lower

costs of day care versus hospital care(US$114 vs US$178). However, policyand program changes would be neces-sary to add such components to outpa-tient clinics, and this would requireadditional human and financial re-sources, which would not be easy toobtain.

The reason for a significantly greaternumber of children in the day caregroup, compared with the hospitalcare group, requiring referral to a hos-

pital during the follow-up period wasthe greater number of children withsevere hypoxemia in the day caregroup. Twenty (17.7%) of 113 childrenin the day care group who presentedwith hypoxemia were referred to thehospital for prolonged oxygen therapy,and thus day care management was afailure. In addition, 20 (87%) of 23 chil-dren who experienced failure of daycare management had hypoxemia.Moreover, 12 children were readmit-ted to a hospital because of hypoxemia

TABLE 3 Comparison of Baseline Characteristics of Study Children With and Without Hypoxemia

Characteristics Total(N� 360)

WithHypoxemia(N� 189)

WithoutHypoxemia(N� 171)

P

Male, n (%) 220 (61) 102 (54) 118 (66) .003AgeMean� SD, mo 8� 7 8.7� 7.9 7.2� 6.9 .042–11 mo, n (%) 291 (81) 143 (76) 148 (87) .00812–59 mo, n (%) 69 (19) 46 (24) 23 (13) .008Breastfed, n (%) 330 (92) 174 (92) 156 (91) .77History, n (%)Cough 359 (99.7) 189 (100) 170 (99) .47Fever 328 (91) 175 (93) 153 (90) .30Difficulty breathing 157 (44) 62 (33) 95 (56) �.001Rapid breathing 129 (36) 81 (43) 48 (28) .003Lower chest wall indrawing 127 (35) 78 (41) 49 (29) .01Vomiting 8 (2.2) 5 (2.6) 3 (2.7) .41Diarrhea 19 (5) 9 (5) 10 (6) .64Weight, mean� SD, kg 6.4� 1.6 6.5� 1.7 6.4� 1.5 .40Height, mean� SD, cm 64.7� 8.3 65.5� 8.0 64.3� 7.2 .05Weight-for-age z score, mean� SD �1.41� 1.19 �1.5� 1.2 �1.3� 1.2 .09Weight-for-height z score, mean� SD �0.74� 2.39 �0.91� 3.1 �0.56� 1.22 .16Duration of cough before admission, dMean� SD 5.15� 3.39 5.0� 3.6 5.25� 3.0 .59Median (interquartile range) 4.0 (3.0–7.0) 4.0 (3.0–7.0) 5.0 (3.0–7.0) .15

Temperature, mean� SD, °C 38.0� 0.8 38.1� 0.8 37.9� 0.8 .008Temperature of�38°C, n (%) 174 (48) 100 (53) 74 (43) .06Duration of fever before admission, dMean� SD 4.15� 3.35 4.3� 4.0 3.9� 2.3 .30Median (interquartile range) 3.0 (2.0–5.0) 3.5 (2.0–5.0) 4.0 (2.0–5.0) .88

Pulse rate, mean� SD, beats per min 153� 17 156� 18 149� 16 �.001Pulse rate of�160 beats per min, n (%) 99 (27) 64 (34) 35 (20) .004Respiratory rate, mean� SD, breaths per min 63� 12 65� 11 60� 8 �.001Respiratory rate of�40 beats per min, n (%) 360 (100) 189 (100) 171 (100)Duration of rapid breathing before admission, dMean� SD 2.30� 2.10 2.3� 2.3 2.32� 1.80 .92Median (interquartile range) 2.0 (1.0–3.0) 2.0 (1.0–3.0) 2.0 (1.0–3.0) .38

Lower chest wall indrawing, n (%) 358 (99.4) 189 (100) 169 (99) .22Duration of lower chest wall indrawing before admission, dMean� SD 2.24� 2.23 2.25� 2.5 2.24� 1.79 .98Median (interquartile range) 2.0 (1.0–3.0) 2.0 (1.0–3.0) 2.0 (1.0–3.0) .28

Vesicular breath sounds, n (%) 352 (98) 184 (97) 168 (98) .42Rales/crepitation on auscultation, n (%) 356 (99) 188 (99) 168 (98) .27Hepatomegaly (liver palpable for�2 cm), n (%) 106 (29) 63 (33) 43 (25) .08Hypoxemia at admission (oxygen saturation of�95%), n (%) 189 (53) 189 (100) 0 (0) �.001Oxygen saturation at admission, mean� SD, % 94� 4 91� 5 97� 1 �.001

e812 ASHRAF et al at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

that developed during the follow-up pe-riod. All of these findings clearly indi-cate that hypoxemia is an important

risk factor for failure of day care man-agement, as well as the need forfollow-up admissions. Our results are

consistent with earlier reports that hy-poxemia in children with pneumonia isa predictor of severe disease and is arisk factor for death.25,26 There is nowevidence that ensuring ample suppliesof oxygen and promoting a routine,systematic approach to screening forhypoxemia by using pulse oximetry areassociated with improved quality ofcare and reduced mortality rates andthat the required technology is afford-able and sustainable in district-levelhospitals and outpatient clinics in de-veloping countries.25,27–31 However, asignificant proportion of the childrenin the current study had hypoxemia,which clearly indicates the importanceof accurate diagnosis of hypoxemia indetermining the safety of outpatienttreatment.32 Pulse oximetry would en-able accurate identification of hypox-emia and might increase the safetyand cost-effectiveness of this recom-mendation,33 and this diagnostic toolshould be included. This was demon-strated in our recent study that notedsuccessful day care management of

TABLE 4 Comparison of Secondary Outcomes for Study Children With and Without Hypoxemia

Characteristics Total(N� 360)

WithHypoxemia(N� 189)

WithoutHypoxemia(N� 171)

P

Duration of cough, dMean� SD 6.6� 3.0 7.1� 2.7 6.0� 3.2 �.001Median (interquartile range) 6.0 (5.0–8.0) 7.0 (6.0–8.0) 6.0 (5.0–7.0) �.001Duration of fever, dMean� SD 1.15� 1.3 1.3� 1.2 0.9� 1.4 .003Median (interquartile range) 1.0 (0–2.0) 1.0 (1.0–2.0) 1.0 (0–1.0) �.001Duration of rapid breathing, dMean� SD 4.0� 2.9 4.8� 2.8 3.1� 2.7 �.001Median (interquartile range) 3.0 (2.0–6.0) 5.0 (2.0–6.0) 2.0 (1.0–4.0) �.001Duration of lower chest wall indrawing, dMean� SD 5.7� 3.0 6.3� 2.9 5.0� 3.0 �.001Median (interquartile range) 6.0 (3.0–7.0) 6.0 (4.0–8.0) 5.0 (3.0–6.0) �.001Oxygen saturation after oxygen therapy,mean� SD, %

99� 1 99� 1 99� 1 .84

Duration of oxygen therapyMean� SD, min 340� 560 340� 560 0 .71Median (interquartile range), h 2.0 (0–7.05) 2.0 (0–7.15) 3.25 (1.40–5.10) .72Duration of ceftriaxone therapy, dMean� SD 7.0� 1.6 7.4� 1.7 6.6� 1.5 �.001Median (interquartile range) 7.0 (6.0–8.0) 7.0 (6.0–9.0) 7.0 (5.0–7.0) �.001Duration of stay, dMean� SD 6.8� 2.6 7.1� 2.3 6.5� 2.8 .01Median (interquartile range) 6.0 (5.0–8.0) 7.0 (6.0–8.0) 6.0 (5.0–7.0) �.001Duration of stay of�10 d, n (%) 24 (6.6) 16 (8.5) 8 (5) .15

TABLE 5 Primary Outcomes for Study Children

Characteristic n (% [95% CI]) Odds Ratio P

Day Care (N� 180) Hospital Care (N� 180) Total (N� 360)

Success 156 (87.7 [80.9–90.9]) 173 (96.1 [92.2–98.1]) 329 (91.4 [88–93.9]) 0.26 .001Failure 24 (13.3 [9.1–19.1]) 7 (3.9 [1.9–7.8]) 31 (8.6 [6.1–12]) 3.80 .001Referred to hospital 23 (12.8 [8.7–18.4]) 4 (2.2 [0.9–5.6]) 27 (7.5 [5.2–10.7]) 6.45 �.001Discontinued treatment 1 (0.6 [0.1–3.1]) 3 (1.7 [0.6–4.8]) 4 (1.1 [0.4–2.8]) 0.33 .31Death during 3-mo follow-up perioda 0 (0 [0–2.1]) 2 (1.1 [0.2–4]) 2 (0.6 [0.2–2]) 0 .25Referred/readmitted to hospital during3-mo follow-up periodb

22 (14.1 [9.5–20.4]) 11 (6.4 [3.6–11]) 33 (10 [7.2–13.8]) 2.42 .01

a No infants died during the day care/hospital care study period.b Of 329 successful cases.

TABLE 6 Primary Outcomes for Study Children With or Without Hypoxemia

Characteristic n (% [95% CI]) Odds Ratio P

With Hypoxemia (N� 189) Without Hypoxemia (N� 171) Total (N� 360)

Success 164 (86.8 [81.2–90.9]) 165 (96.5 [92.6–98.4]) 329 (91.4 [88–93.9]) 0.24 .001Failure 25 (13.2 [9.1–18.8]) 6 (3.5 [1.6–7.4]) 31 (8.6 [6.1–12]) 4.19 .001Referred to hospital 23 (12.2 [8.2–17.6]) 4 (2.3 [0.9–5.9]) 27 (7.5 [5.2–10.7]) 5.78 �.001Discontinued treatment 2 (1.1 [0.3–3.8]) 2 (1.2 [0.3–4.2]) 4 (1.1 [0.4–2.8]) 0.90 .91Death during 3-mo follow-up perioda 0 (0 [0–2.1]) 2 (1.1 [0.2–4]) 2 (0.6 [0.2–2]) 0 .22Referred/readmitted to hospital during3-mo follow-up periodb

25 (13.2 [9.1–18.8]) 8 (4.7 [2.4–9]) 33 (10 [7.2–13.8]) 3.11 .004

a No infants died during the day care/hospital care study period.b Of 329 successful cases.

ARTICLE

PEDIATRICS Volume 126, Number 4, October 2010 e813 at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

severe childhood pneumonia with theuse of pulse oximetry as an importantpart of the treatment algorithm.22,34

A reviewer identified the total durationof parenteral ceftriaxone therapy asthe reason for prolonged duration ofday care and hospital care, which wasattributable to the study design ofkeeping all children until full recoveryand completion of antibiotic therapy.We are now planning investigations ofa modified day care concept with re-duction of the total duration of the daycare stay, with proper arrangementfor administration of injections in dailyclinic visits after most of the endpoints are met. We also can considerthe possibility of prescribing suitableoral antibiotic therapy as home ther-apy after improvement, as shown in amulticenter study in which parenteralpenicillin therapy for 48 hours was re-placed by oral amoxicillin therapy af-ter improvement.35

The fact that none of the children whowere treated on either a day care orhospital care basis died is very reas-suring. However, this may be attribut-able to exclusion of children with asso-ciated comorbidities such as SAM,sepsis, hypoglycemia, convulsions,meningitis, congenital heart disease,and tuberculosis, according to proto-col guidelines. Children were treatedby adequately trained research staff

members who remained undergreater supervision than normal andthus were likely to have beenmoremo-tivated and to have worked withgreater devotion. A better staff mem-ber/patient ratio than normal, in acountry where the ratio is usually sub-optimal, also might have played a role.

A major strength of our study is thatthis was a RCT; therefore, the efficacyof day care management was com-pared directly with that of hospitalcare. This RCT also included a compo-nent for assessment of the cost-effectiveness of interventions, whichindicated that day care managementwas less expensive. This would be im-portant for selection of the interven-tion for wider implementation in na-tional programs.

A major limitation of our study was theexclusion of children with SAM, whichis a common underlying conditionamong children with pneumonia in de-veloping countries. We are now con-ducting another study comparing theeffectiveness and safety of day care-based management with those ofhospital-based management of severechildhood pneumonia with SAM, at theRadda clinic and the ICHSH.

CONCLUSIONS

The results of this RCT identified a wayto use scarce hospital beds in develop-

ing countries more efficiently, by se-lecting for day care treatment childrenwith severe pneumonia who, on the ba-sis of existing guidelines, would havebeen identified as requiring hospital-ization. This would be a practical ap-proach in developing countries. Asmaller investment in upgrading daycare facilities through development oftrained resources and procurement ofsupporting equipment could provide amuch greater return. Our results dem-onstrated that a select group of chil-dren with severe pneumonia, withoutassociated comorbidities such as SAM,could be treated safely and effectivelyon a day care basis, as effectively aswith hospital management, except forchildren with hypoxemia who requiredoxygen therapy for �6 hours. Identifi-cation of these children with hypox-emia is necessary, because they are atrisk of death and therefore need to behospitalized for support and care for alonger period. Such an ambulatorytreatment option also is less expensivethan hospital care.

ACKNOWLEDGMENTSThis study was funded by the EagleFoundation (Geneva, Switzerland)(grant GR-00485); the ICDDRB acknowl-edges with gratitude the commitmentof the Eagle Foundation to the re-search efforts of the ICDDRB.

REFERENCES

1. United Nations General Assembly. UnitedNations Millennium Declaration. New York,NY: United Nations; 2000. Available at: www.un.org/millennium/declaration/ares552e.pdf; Accessed March 2, 2009

2. Walley J, Lawn J, Tinker A, et al. Primaryhealth care: making Alma-Ata a reality. Lan-cet. 2008;372(9642):1001–1007

3. Duke T, Tamburlini G; Paediatric QualityCare Group. Improving the quality of paedi-atric care in peripheral hospitals in devel-oping countries. Arch Dis Child. 2003;88(7):563–565

4. World Health Organization. Life in the 21stCentury : A V is ion for A l l . Geneva ,

Switzerland: World Health Organization;1998:66

5. Rudan I, Tomaskovic L, Boschi-Pinto C, et al.Global estimate of the incidence of clinicalpneumonia among children under fiveyears of age. Bull World Health Organ. 2004;82(12):895–903

6. Rudan R, Boschi-Pinto C, Biloglav Z, Mulhol-land K, Campbell H. Epidemiology and etiol-ogy of childhood pneumonia. Bull WorldHealth Organ. 2008;86(5):408–416

7. Wardlaw TM, Johansson EW, Hodge M.Pneumonia: The Forgotten Killer of Chil-dren. Geneva, Switzerland: World HealthOrganization; 2006

8. Graham SM, English M, Hazir T, Enarson P,Duke T. Challenges to improving case man-agement of childhood pneumonia at healthfacilities in resource-limited settings. BullWorld Health Organ. 2008;86(5):349–355

9. Murray CJ, Lopez AD. Mortality by cause foreight regions of the world: Global Burden ofDisease Study. Lancet. 1997;349(9061):1269–1276

10. Garenne M, Ronsmans C, Campbell H. Themagnitude of mortality from acute respira-tory infections in children under 5 years indeveloping countries. World Health Stat Q.1992;45(2–3):180–191

11. Mulholland K. Magnitude of the problem of

e814 ASHRAF et al at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

childhood pneumonia. Lancet . 1999;354(9178):590–592

12. Williams BG, Gouws E, Boschi-Pinto C, BryceJ, Dye C. Estimates of world-wide distribu-tion of child deaths from acute respiratoryinfections. Lancet Infect Dis. 2002;2(1):25–32

13. Mulholland K. Global burden of acute respi-ratory infections in children: implicationsfor interventions. Pediatr Pulmonol. 2003;36(6):469–474

14. Baqui AH, Black RE, Arifeen SE, Hill K, MitraSN, al Sabir A. Causes of childhood deaths inBangladesh: results of a nationwide verbalautopsy study. Bull World Health Organ.1998;76(2):161–171

15. World Health Organization. Acute Respira-tory Infections in Children: Case Manage-ment in Small Hospitals in DevelopingCountries: A Manual for Doctors and OtherSen ior Hea l th Workers . Geneva ,Switzerland: World Health Organization;1990. Publication WHO/ARI/90.5

16. World Health Organization. A programmefor controlling acute respiratory infectionsin children: memorandum from a WHOmeeting. Bull World Health Organ. 1984;62(1):47–58

17. World Health Organization. Management ofthe Child With a Serious Infection or SevereMalnutrition: Guidelines for Care at theFirst-Referral Level in Developing Countries.Geneva, Switzer land: World HealthOrganization; 2000. Publication WHO/FCH/CAH/00.1

18. World Health Organization. Management ofthe Young Child With an Acute RespiratoryInfection: Programme for Control of AcuteResp i ra tory In fec t ions . Geneva ,

Switzerland: World Health Organization;1991

19. World Health Organization. Technical Basisfor the WHO Recommendations on the Man-agement of Pneumonia in Children at First-Level Health Facilities. Geneva, Switzerland:World Health Organization; 1991. Publica-tion WHO/ARI/91.20

20. Cashat-Cruz M, Morales-Aguirre JJ,Mendoza-Azpiri M. Respiratory tract infec-tions in children in developing countries.Semin Pediatr Infect Dis. 2005;16(2):84–92

21. Ashraf H, Ahmed T, Hossain MI, et al. Day-care management of children with severemalnutrition in an urban health clinic inDhaka, Bangladesh. J Trop Pediatr. 2007;53(3):171–178

22. Ashraf H, Jahan SA, Alam NH, et al. Day-caremanagement of severe and very severepneumonia, without associated co-morbidities such as severe malnutrition, inan urban health clinic in Dhaka, Bang-ladesh. Arch Dis Child. 2008;93(6):490–494

23. Jubran A. Pulse oximetry. Crit Care. 1999;3(2):R11–R17

24. Jubran A, TobinMJ. Reliability of pulse oxim-etry in titrating supplemental oxygen ther-apy in ventilator-dependent patients. Chest.1990;97(6):1420–1425

25. Duke T, Mgone J, Frank D. Hypoxaemia inchildren with severe pneumonia in PapuaNew Guinea. Int J Tuberc Lung Dis. 2001;5(6):511–519

26. Onyango FE, Steinhoff MC, Wafula EM,Wariua S, Musia J, Kitonyi J. Hypoxaemia inyoung Kenyan children with acute lower re-spiratory infection. BMJ. 1993;306(6878):612–615

27. Dobson M, Peel D, Khallaf N. Field trial ofoxygen concentrations in upper Egypt. Lan-cet. 1996;347(9015):1597–1599

28. Duke T, Wandi F, JonathanM, et al. Improvedoxygen systems for childhood pneumonia: amulti-hospital effectiveness study in PapuaNew Guinea. Lancet . 2008;372(9646):1328–1333

29. Dobson MB. Oxygen concentrators offercost savings for developing countries: astudy based on Papua New Guinea. Anaes-thesia. 1991;46(3):217–219

30. Steinhoff M, Black R. Childhood pneumonia:we must move forward. Lancet. 2007;369(9571):1409–1410

31. Matai S, Peel D, Wandi F, Jonathan M, SubhiR, Duke T. Implementing an oxygen pro-gramme in hospitals in Papua New Guinea.Ann Trop Paediatr. 2008;28(1):71–78

32. Hazir T, Fox LM, Nisar YB, et al. Ambulatoryshort-course high-dose oral amoxicillin fortreatment of severe pneumonia in children:a randomised equivalency trial. Lancet.2008;371(9606):49–56

33. Duke T, Campbell H, Graham S. Ambulatoryoral amoxicillin for severe pneumonia inchildren. Lancet. 2008;371(9621):

34. Subhi R, Adamson M, Campbell H, et al. Theprevalence of hypoxaemia among ill chil-dren in developing countries: a systematicreview. Lancet Infect Dis. 2009;9(4):219–227

35. Addo-Yobo E, Chisaka N, Hassan M, et al.Oral amoxicillin versus injectable penicillinfor severe pneumonia in children aged 3 to59 months: a randomised multicentreequivalency study. Lancet. 2004;364(9440):1141–1148

ARTICLE

PEDIATRICS Volume 126, Number 4, October 2010 e815 at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from

DOI: 10.1542/peds.2009-3631; originally published online September 20, 2010; 2010;126;e807Pediatrics

Fazlul Haque, Mohammed A. Salam and Niklaus GyrHasan Ashraf, Rokhsana Mahmud, Nur H. Alam, Selina A. Jahan, Syed M. Kamal,

Pneumonia in BangladeshRandomized Controlled Trial of Day Care Versus Hospital Care of Severe

  

ServicesUpdated Information &

tmlhttp://pediatrics.aappublications.org/content/126/4/e807.full.hincluding high resolution figures, can be found at:

References

tml#ref-list-1http://pediatrics.aappublications.org/content/126/4/e807.full.hat:This article cites 27 articles, 4 of which can be accessed free

Citations

tml#related-urlshttp://pediatrics.aappublications.org/content/126/4/e807.full.hThis article has been cited by 1 HighWire-hosted articles:

Subspecialty Collections

al_child_health_subhttp://pediatrics.aappublications.org/cgi/collection/internationInternational Child Healththe following collection(s):This article, along with others on similar topics, appears in

Permissions & Licensing

mlhttp://pediatrics.aappublications.org/site/misc/Permissions.xhttables) or in its entirety can be found online at: Information about reproducing this article in parts (figures,

Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml

Information about ordering reprints can be found online:

rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

at Indonesia:AAP Sponsored on October 23, 2014pediatrics.aappublications.orgDownloaded from