of Children with Severe Pneumonia. A Randomized Double-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
Abstract Objective To compare the clinical outcome of children having severe pneumonia, with and without zinc supplementation 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 randomly divided into 2 groups (64 in each) that received either zinc sulfate (2 mg/kg/d, maximum 20 mg in 2 divided doses, for 5 days) or a placebo, along with the standard antimicrobial therapy. Primary outcome measurements included the time taken for clinical symptoms of severe pneumonia such as fever and respiratory distress symptoms to resolve, and the secondary outcome included the duration of hospital stay. Results The time taken for all the symptoms to resolve in the zinc-supplemented group was significantly lesser then that in the placebo group (42.26 [6.66] vs. 47.52 [7.15] h respectively, p<0.001). The zinc-treated group had a significantly shorter duration of fever (23.29 [6.67] vs. 26.6 [6.26] h, p=0.024), E. Valavi : M. Hakimzadeh : A. Shamsizadeh : M. Aminzadeh Department of Pediatrics, Jundishapour University of Medical Sciences, Ahvaz, Iran M. Aminzadeh Jundishapour University of Medical Sciences, Diabetes Research Center, Ahvaz, Iran A. Alghasi Faculty of Medicine, Jundishapour University of Medical Sciences, Ahvaz, Iran E. Valavi (*) Department of Pediatrics, Abuzar Childrens Hospital, Pasdaran Street, Ahvaz, Iran e-mail: [email protected]
respiratory distress (32.87 [7.85] vs. 37.37 [4.43] h, p=0.001),
required a shorter hospital stay (126.74 [12.8] vs. 137.74 [11.52] h, p<0.001) than did the controls. The zinc supplement was well tolerated by the children. Conclusions The results suggest that adjuvant treatment with zinc accelerates recovery from severe pneumonia in young children and significantly reduces the duration of hospital stay. Further studies are required to develop appropriate recommendations for the use of zinc in the treatment of severe pneumonia in other populations. Keywords Children . Pneumonia . Supplementation . Treatment . Zinc
Introduction Severe pneumonia is one of the important causes of death in children younger than 5 years, and two-thirds of these deaths occur during infancy, with >90% in developing countries [1]. Elimination of most of the environmental risk factors of pneumonia is very difficult, but some nutritional factors, including the replacement of vitamin A, need a simple intervention [2]. Zinc deficiency is common among children in developing countries because of inadequate food intake, particularly from animal sources; limited zinc bioavailability from the local diets; and losses of zinc during recurrent diarrheal illnesses [3, 4]. Zinc deficiency impairs the immune system and can increase the rate of serious infections such as pneumonia [58]. This study was designed to assess the beneficial effects of oral zinc supplementation on the outcome of severe pneumonia in hospitalized children, because there is no consensus among the previously published reports. To the authors knowledge, this is the first such study in Iran.
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Material and Methods
Study Setting A double-blind placebo controlled trial was conducted in children aged 360 months of either sex, who were admitted with a clinical diagnosis of severe pneumonia to the Abuzar Childrens Hospital from December 2008 through January 2009. An informed written consent was obtained from the parents of all eligible children before enrollment. This study was registered with the Iranian Registry of Clinical Trials (ID; IRCT138810303122N1). The Ethical Committee of Ahvaz Jundishapour University of Medical Sciences approved the study protocol and the research department sponsored it. Subject Eligibility Children between 3 and 60 months of age, admitted to the general ward of Abuzar Hospital were examined by the study physicians and considered eligible for enrollment in the trial if they fulfilled the criteria for the diagnosis of severe pneumonia. Severe pneumonia was defined as tachypnea (respiratory rate >50/min for children aged 3 12 months; >40/min for children aged >12 months), accompanied with fever (axillary temperature >38.2C), a short crackle noise during inspiration, a significant finding of pneumonia on chest radiograph (including focal or diffuse parenchymal involvement), and the presence of any of the danger signs, including lethargy, inability to feed, chest indrawing, or central cyanosis. In addition, the ability to take the zinc or the placebo syrup orally was required. Children were excluded from the study on the basis of the following criteria: lack of consent; any sign of malnutrition, which could be classified as marasmus, kwashiorkor, or marasmus-kwashiorkor requiring micronutrient (e.g., zinc) supplementation; any sign of nonrespiratory systemic disease, including sepsis, acute meningitis, hemodynamic instability, congenital heart disease or any gross congenital malformation; the presence of diarrhea defined as the passage of 3 watery stools in the past 24 h, or any bloody diarrhea; a known case of intolerance or sensitivity to zinc or zinc-containing materials; a wheeze identified during chest auscultation or a past history of asthma; a clinical diagnosis of bronchiolitis; and receipt of any drugs (including zinc) or antibiotics during 2 wks before admission. Sample Size In this study, 128 children were enrolled and divided into two treatment groups of 64 children each. The sample size
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was calculated according to the method described in
previous studies [9, 10], assuming 80% power and a 2sided type 1 error of 5%. Blinding Details Investigators, study staff, and the participants were blinded to the assigned treatment. All eligible children were randomly assigned to receive a syrup containing either a 2 mg/kg/d (maximum 20 mg) of zinc sulfate or a placebo (similar in packaging, taste, odor, and appearance) orally, in two divided doses throughout the duration of their hospitalization. The zinc syrup was obtained from Alhavi Pharmaceutical Company. The department of pharmacology re-bottled the zinc syrups and prepared similar packages for drug and placebo. The syrups were labeled with randomly selected numbers by a pharmacist not involved in the study, and all other investigators were unaware about this design and distribution. Intervention All the enrolled children were treated according to the standard protocol for treatment of infants and children with pneumonia. They received parenteral ampicillin. If the chest radiograph or clinical presentation was found to be consistent with staphylococcal pneumonia, the patient was treated with cefazolin. Patients, who failed to improve after 48 h on this regimen of first-line antimicrobial therapy, were switched to parenteral ceftriaxone or vancomycin. This treatment was continued throughout the duration of their hospitalization and followed by adequate oral therapy, if necessary. Information on current illness, anthropometric data, and baseline physical findings as well as the number on the drug package for each patient was recorded at the time of enrollment. During hospitalization, each childs condition was assessed at 8-h intervals by the clinical staff that was unaware of the treatment allocation, and the findings were recorded. Respiratory rate was measured for a full minute with the childs upper torso clothing removed. The count was done at a time when the child was not crying. Oxygen saturation was measured by pulse oximetry. In patients that required oxygen supplementation, oxygen was administered nasally or via a hood. Axillary temperature was measured using a standard mercury thermometer. The presence of cough, chest indrawing, cyanosis, inability to feed, or lethargy was also noted at 8-h intervals and recorded in the patients chart. Children were discharged when their clinical condition had resolved and it was determined that they did not require further hospital care, i.e., they were on oral feed, had a normal respiratory rate (resolution of respiratory distress),
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Fig. 1 Trial profile
137 assessed for eligibility
9 refused to participate
128 randomly assigned
64 allocated to placebo group
2 withdrawals
64 allocated to Zinc group
3 withdrawals
61 Analyzed
62 Analyzed
and had no fever or tachypnea. The efficacy of zinc
supplementation was evaluated by comparing the resolution time of specific indicators in children who received zinc and those who did not. Primary outcome measurement included the time period for resolution of clinical symptoms of severe pneumonia such as fever as well as respiratory distress symptoms, including tachypnea, chest indrawing, cyanosis, inability to feed, and lethargy, and the secondary outcome measurement included the duration of hospital stay.
(SPSS) version 13.0 (SPSS Inc., Chicago, IL, USA), and
p values <0.05 were regarded as statistically significant. KaplanMeier survival functions were used to measure the median duration of outcomes and to assess the effect of treatment on the study outcomes. The authors also analyzed the effect of zinc supplementation on outcomes in the different subgroups by age and gender, separately.
Statistical Analysis
From December 2008 through January 2009, 128
patients were enrolled in the study and randomly administered zinc or a placebo along with standard antibiotic therapy. Five patients were excluded from the
Analysis was based on the clinical outcomes. Data were
analyzed using Statistical Package for Social Sciences Table 1 The baseline parameters of enrolled patients
Results
Zinc group (61 patients)
Placebo group (62 patients)
Age(months)
15.41
15.89
Male(%) Duration of illness (days) Height (cm) Weight (kg) Feeding Exclusive breast-fed(%) Artificially fed Breast fed and family diet Vaccination(%) Fever(%) Tachypnea(%) Respiratory distress(%) Leukocytosis(%)
54.1 2.89 77.4 10.13
51.6 3.05 78.5 10.19
4.9 4.9 75.4 100 100 100 100 93.4
3.2 3.2 71 100 100 100 100 90.3
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Table 2 Clinical characteristics
of patients in treatment groups
Time for resolving all symptoms:
Time interval from enrollment to absence of all symptoms, fever, tachypnea, chest indrawing and inability to feed
Primary outcomes Respiratory distress resolving (h) Fever resolving (h) Time for resolving all symptoms(h) Secondary outcome Stay in hospital(h)
study, of which 4 (2 from each group) left the hospital
against medical advice, and 1 (from the zinc group) withdrew from the study. Thus, the data of 61 and 62 patients from the zinc and placebo groups, respectively were 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%) were boys. Ninety (73.2%) were breast fed plus received their normal family diet, and five patients were exclusively breast fed (4.1%). The median duration of respiratory symptoms 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 of patients in the zinc-supplemented group was significantly lesser than that in the placebo group (42.26 [6.66] vs. 47.52 [7.15] h respectively, p<0.001). The zinc-treated group had a significantly shorter duration of fever (23.29 [6.67] vs. 26.6 [6.26] h, p=0.024) as well as respiratory distress (32.87 [7.85] vs. 37.37 [4.43] h, p=0.001), than did the placebo group. In addition, children who received zinc supplementation required a shorter hospital stay (126.74 [12.8] vs. 137.74 [11.52], p<0.001), than did the controls (Table 2). The pattern of recovery from fever, respiratory distress, as well as the duration of hospital stay in patients from both the groups is illustrated in Figs. 2a, 2b, and 2c. The zinc-supplemented group had a significantly accelerated recovery. The authors subdivided the patients into two groups by age (<1, and >1 year). The youngest patient was approximately 3.5 months old, and 43.9% of the patients were younger than 1 year. The mean time for resolving fever and respiratory distress and the mean length of hospital stay in the subgroup older than 12 months was significantly different between the groups that received zinc and the controls (p = 0.034, p = 0.006, p < 0.001 respectively). However, in the <1-year-old subgroup, only the mean duration of stay in the hospital was significantly shorter in the zinc group (p = 0.011). These findings did not show any gender differences. The mean duration of zinc supplementation was approximately 5.25 days. It was safe and
Zinc Group (61 patients)
Placebo Group (62 patients)
32.87 23.29 42.26
37.37 26.6 47.52
0.001 0.024 <0.001
126.74
137.74
<0.001
well tolerated by the children, and all of them were
discharged without any drug complications.
Discussion The authors evaluated the influence of zinc supplementation on improvement of the outcome of severe pneumonia in a group of sick infants and young children who required hospital care. This study showed significant reductions in time required for recovery from symptoms of severe pneumonia and reduction in the overall duration of hospital stay in children who received zinc supplementation along with standard antimicrobial therapy. The strengths of this study include its randomized double-blind design and similarity of the patient characteristics at baseline. Thus, any differences in the study outcomes were likely to be attributable to the supplements administered. There are several reports on the impact of supplementation with nutrients such as zinc and vitamin A for the treatment of pneumonia. Zinc as a micronutrient plays a key role in the development and maintenance of host defenses against infectious diseases, and zinc deficiency seems to enhance airway inflammation and cellular damage in respiratory infections [1116]. The reduction in recovery time from symptoms of severe pneumonia as well as the duration of hospitalization in the present cases can be attributable to the function of zinc in the protection of the lungs in inflammatory states. Micronutrient deficiencies are common in children in developing countries, including Iran [1719]. In addition to the diet being deficient in zinc, its high phytate/zinc ratio reduces zinc bioavailability [20]. Significant decreases in diarrheal morbidity and mortality were observed in zincsupplemented children in several therapeutic trials [9, 21]. Similar to the present results, in a study in Kolkata, Mahalanabis et al. showed significantly higher serum zinc concentrations along with a faster recovery from severe illness and fever in infants and children with severe pneumonia who received zinc vs. a placebo [22]. A similar clinical trial in Bangladesh in 270 children aged 223 months showed that elemental zinc (20 mg/d) supplementation along with the standard antimicrobial
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Fig. 2ac Kaplan-Meier survival curves of the median duration of hospitalization and recovery from fever and respiratory distress in the zinc treatment group (solid line; n=61) and in the placebo group (dashed line; n=62) in suspected bacterial pneumonia cases
management, resulted in significant reductions in the
recovery time from symptoms of severe pneumonia (including duration of chest indrawing, tachypnea, and hypoxia), and the overall duration of hospital stay. The mean reduction was equivalent to 1 hospital day for both the outcomes [10]. In the present study, the mean reduction in the length of hospitalization was approximately half a hospital day (p<0.001). The mean duration for resolving fever and respiratory distress in patients who received zinc supplementation was also significantly shorter than in the controls (p=0.024 and p=0.001, respectively). In contrast to the main findings of the current study, results from other clinical trials did not show a significant benefit of zinc supplementation in children with severe pneumonia [9, 2325]. In a clinical trial conducted in Vellore, India, there were no significant differences in the duration of tachypnea, hypoxia, chest indrawing, inability to feed, lethargy, severe illness, or hospitalization. In fact, zinc supplementation was associated with a significantly longer duration of pneumonia in the hot season. However, the mean plasma zinc concentrations in the Vellore study subjects at enrollment (11.0 mol/L) were significantly higher than those in the subjects in Bangladesh (10.1 mol/L) and Kolkata (9.6 mol/L, p=0.001) [9]. A recent study by Bansal et al. in Chandigarh, India, that studied 120 children aged 224 months who randomly received zinc (20 mg/d) or placebo, did not find any statistical difference in the resolution time from respiratory distress, tachypnea, hypoxia, or the duration of hospital stay between the two groups [24]. However, in contrast to this previous study, the authors did not include malnourished children or patients who suffered from wheezing or bronchiolitis. All of present patients were febrile, with significant focal or diffuse parenchymal involvement, as determined by chest radiography. In another recent systematic review of 15 randomized controlled trials by Mathew, the author concluded that there was no therapeutic benefit of adding zinc to antibiotic therapy in community acquired pneumonia [25]. The authors also analyzed the gender-specific influence of the zinc treatment, and contrary to the findings of Mahalanabis [22], found no significant difference between the genders. A limitation of the present study was that the authors did not measure serum zinc levels in their study subjects. However, an increase in serum zinc levels after supple-
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mentation is predictable, as has been shown by previous
studies [10, 22]. According to the present findings and those of other randomized clinical trials, the benefit of zinc supplementation in acute pneumonia is debatable. However, although the present study shows statistically significant benefit with zinc, it does not enough to confirm clinical benefit of zinc supplementation, since there is only a few hours difference in resolution of symptoms and duration of hospitalization. It appears that the effect of zinc supplementation in each population varies because of multifactorial interrelationships. Additional basic studies could help elucidate the mechanisms for these varying effects. However, zinc supplementation in populations at a risk of zinc deficiency would be beneficial. Acknowledgments The authors are grateful to Dr. Zargar, Department of Pharmaceutics, Jundishapur University of Medical Sciences, for the preparation of the placebo syrup. This study was supported by the vice-chancellor of the research center at the Jundishapur University of Medical Sciences (No: u-88091). The authors would like to thank Mr. Cheraghian for his help in the statistical analysis of the results. Conflict of Interest None.
Role of Funding Source This study was sponsored by the research
Department of Jundishapour University of Medical Sciences.
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