ORIGINAL ARTICLE

The Efficacy of Zinc Supplementation on Outcomeof Children with Severe Pneumonia. A RandomizedDouble-blind Placebo-controlled Clinical Trial

Ehsan Valavi & Mehran Hakimzadeh &Ahmad Shamsizadeh & Majid Aminzadeh &Arash Alghasi

Received: 24 December 2010 /Accepted: 3 May 2011 /Published online: 10 June 2011# Dr. K C Chaudhuri Foundation 2011

AbstractObjective To compare the clinical outcome of childrenhaving severe pneumonia, with and without zinc supplemen-tation by a randomized double-blind placebo controlled trial.Methods In this study, 128 children (360 months old)admitted to the hospital with severe pneumonia were randomlydivided into 2 groups (64 in each) that received either zincsulfate (2 mg/kg/d, maximum 20 mg in 2 divided doses, for5 days) or a placebo, along with the standard antimicrobialtherapy. Primary outcome measurements included the timetaken for clinical symptoms of severe pneumonia such as feverand respiratory distress symptoms to resolve, and thesecondary outcome included the duration of hospital stay.Results The time taken for all the symptoms to resolve in thezinc-supplemented group was significantly lesser then that inthe placebo group (42.26 [6.66] vs. 47.52 [7.15] h respectively,p

Material and Methods

Study Setting

A double-blind placebo controlled trial was conducted inchildren aged 360 months of either sex, who wereadmitted with a clinical diagnosis of severe pneumonia tothe Abuzar Childrens Hospital from December 2008through January 2009. An informed written consent wasobtained from the parents of all eligible children beforeenrollment. This study was registered with the IranianRegistry of Clinical Trials (ID; IRCT138810303122N1).The Ethical Committee of Ahvaz Jundishapour Universityof Medical Sciences approved the study protocol and theresearch department sponsored it.

Subject Eligibility

Children between 3 and 60 months of age, admitted to thegeneral ward of Abuzar Hospital were examined by thestudy physicians and considered eligible for enrollment inthe trial if they fulfilled the criteria for the diagnosis ofsevere pneumonia. Severe pneumonia was defined astachypnea (respiratory rate >50/min for children aged 312 months; >40/min for children aged >12 months),accompanied with fever (axillary temperature >38.2C), ashort crackle noise during inspiration, a significant findingof pneumonia on chest radiograph (including focal ordiffuse parenchymal involvement), and the presence ofany of the danger signs, including lethargy, inability tofeed, chest indrawing, or central cyanosis. In addition, theability to take the zinc or the placebo syrup orally wasrequired.

Children were excluded from the study on the basis ofthe following criteria: lack of consent; any sign ofmalnutrition, which could be classified as marasmus,kwashiorkor, or marasmus-kwashiorkor requiring micro-nutrient (e.g., zinc) supplementation; any sign of non-respiratory systemic disease, including sepsis, acutemeningitis, hemodynamic instability, congenital heart diseaseor any gross congenital malformation; the presence ofdiarrhea defined as the passage of 3 watery stools in thepast 24 h, or any bloody diarrhea; a known case of intoleranceor sensitivity to zinc or zinc-containing materials; a wheezeidentified during chest auscultation or a past history ofasthma; a clinical diagnosis of bronchiolitis; and receipt ofany drugs (including zinc) or antibiotics during 2 wks beforeadmission.

Sample Size

In this study, 128 children were enrolled and divided intotwo treatment groups of 64 children each. The sample size

was calculated according to the method described inprevious studies [9, 10], assuming 80% power and a 2-sided type 1 error of 5%.

Blinding Details

Investigators, study staff, and the participants were blindedto the assigned treatment. All eligible children wererandomly assigned to receive a syrup containing either a2 mg/kg/d (maximum 20 mg) of zinc sulfate or a placebo(similar in packaging, taste, odor, and appearance) orally, intwo divided doses throughout the duration of theirhospitalization. The zinc syrup was obtained from AlhaviPharmaceutical Company. The department of pharmacologyre-bottled the zinc syrups and prepared similar packages fordrug and placebo. The syrups were labeled with randomlyselected numbers by a pharmacist not involved in the study,and all other investigators were unaware about this design anddistribution.

Intervention

All the enrolled children were treated according to thestandard protocol for treatment of infants and children withpneumonia. They received parenteral ampicillin. If thechest radiograph or clinical presentation was found to beconsistent with staphylococcal pneumonia, the patient wastreated with cefazolin. Patients, who failed to improve after48 h on this regimen of first-line antimicrobial therapy,were switched to parenteral ceftriaxone or vancomycin.This treatment was continued throughout the duration oftheir hospitalization and followed by adequate oral therapy,if necessary.

Information on current illness, anthropometric data, andbaseline physical findings as well as the number on thedrug package for each patient was recorded at the time ofenrollment. During hospitalization, each childs conditionwas assessed at 8-h intervals by the clinical staff that wasunaware of the treatment allocation, and the findings wererecorded. Respiratory rate was measured for a full minutewith the childs upper torso clothing removed. The countwas done at a time when the child was not crying. Oxygensaturation was measured by pulse oximetry. In patients thatrequired oxygen supplementation, oxygen was administerednasally or via a hood. Axillary temperature was measuredusing a standard mercury thermometer. The presence ofcough, chest indrawing, cyanosis, inability to feed, or lethargywas also noted at 8-h intervals and recorded in the patientschart.

Children were discharged when their clinical conditionhad resolved and it was determined that they did not requirefurther hospital care, i.e., they were on oral feed, had anormal respiratory rate (resolution of respiratory distress),

1080 Indian J Pediatr (September 2011) 78(9):10791084

and had no fever or tachypnea. The efficacy of zincsupplementation was evaluated by comparing the resolutiontime of specific indicators in children who received zincand those who did not. Primary outcome measurementincluded the time period for resolution of clinical symptomsof severe pneumonia such as fever as well as respiratorydistress symptoms, including tachypnea, chest indrawing,cyanosis, inability to feed, and lethargy, and the secondaryoutcome measurement included the duration of hospitalstay.

Statistical Analysis

Analysis was based on the clinical outcomes. Data wereanalyzed using Statistical Package for Social Sciences

(SPSS) version 13.0 (SPSS Inc., Chicago, IL, USA), andp values

study, of which 4 (2 from each group) left the hospitalagainst medical advice, and 1 (from the zinc group)withdrew from the study. Thus, the data of 61 and 62patients from the zinc and placebo groups, respectivelywere analyzed (Fig. 1).

The mean age was 15.65 (8.71) months, 54 patients(43.9%) were younger than 1 year, and 65 (52.8%) wereboys. Ninety (73.2%) were breast fed plus received theirnormal family diet, and five patients were exclusivelybreast fed (4.1%). The median duration of respiratorysymptoms before hospitalization in both groups was 3 days.All these variables were not different between the groups(Table 1).

The time taken for resolving all the symptoms ofpatients in the zinc-supplemented group was significantlylesser than that in the placebo group (42.26 [6.66] vs.47.52 [7.15] h respectively, p

management, resulted in significant reductions in therecovery time from symptoms of severe pneumonia(including duration of chest indrawing, tachypnea, andhypoxia), and the overall duration of hospital stay. Themean reduction was equivalent to 1 hospital day for boththe outcomes [10].

In the present study, the mean reduction in the lengthof hospitalization was approximately half a hospital day(p

mentation is predictable, as has been shown by previousstudies [10, 22].

According to the present findings and those of otherrandomized clinical trials, the benefit of zinc supplemen-tation in acute pneumonia is debatable. However,although the present study shows statistically significantbenefit with zinc, it does not enough to confirm clinicalbenefit of zinc supplementation, since there is only a fewhours difference in resolution of symptoms and durationof hospitalization.

It appears that the effect of zinc supplementation in eachpopulation varies because of multifactorial interrelation-ships. Additional basic studies could help elucidate themechanisms for these varying effects. However, zincsupplementation in populations at a risk of zinc deficiencywould be beneficial.

Acknowledgments The authors are grateful to Dr. Zargar, Depart-ment of Pharmaceutics, Jundishapur University of Medical Sciences,for the preparation of the placebo syrup. This study was supported bythe vice-chancellor of the research center at the JundishapurUniversity of Medical Sciences (No: u-88091). The authors wouldlike to thank Mr. Cheraghian for his help in the statistical analysis ofthe results.

Conflict of Interest None.

Role of Funding Source This study was sponsored by the researchDepartment of Jundishapour University of Medical Sciences.

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