The Role of Melatonin as an Adjuvant Therapy in Childhood Pneumonia

OPERATIONAL DEFINITION:

Pneumonia: defined as patient having fast breathing;

• 50 breaths/min in a child aged 2-11 months
• 40 breaths/min in a child aged 1-5 years Chest in-drawing

Severe Pneumonia: defined as patient having cough or difficulty in breathing with:

Oxygen saturation < 90% or central cyanosis Severe respiratory distress (e.g. grunting, very severe chest in-drawing) Signs of pneumonia with a general danger sign (inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions) Length of Hospital Stay: measured in days from the day of admission to the day of discharge for both groups.

Discharge Criteria: Discharge criteria for children who have been admitted to the hospital include:

Improvement of vital signs Ability to maintain adequate fluid and nutrition orally Ability to maintain oxygen saturation ≥90 percent in room air Overall clinical improvement including level of activity, appetite, and decreased fever

OPERATIONAL DEFINTION:

Pneumonia: defined as patient having fast breathing;

• 50 breaths/min in a child aged 2-11 months
• 40 breaths/min in a child aged 1-5 years Chest in-drawing

Severe Pneumonia: defined as patient having cough or difficulty in breathing with:

Oxygen saturation < 90% or central cyanosis Severe respiratory distress (e.g. grunting, very severe chest in-drawing) Signs of pneumonia with a general danger sign (inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions) Length of Hospital Stay: measured in days from the day of admission to the day of discharge for both groups.

Discharge Criteria: Discharge criteria for children who have been admitted to the hospital include:

Improvement of vital signs Ability to maintain adequate fluid and nutrition orally Ability to maintain oxygen saturation ≥90 percent in room air Overall clinical improvement including level of activity, appetite, and decreased fever

RESEARCH METHODOLOGY:

Study design: Randomized Controlled Clinical Trial (RCT) Setting: It will be conducted at Children Hospital, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan.

Study duration: Approx. 6 months after approval of synopsis. Sample size: Sample size is calculated based on a previous study on the same topic by using WHO sample size calculator; 60 in total having 30 in each group with level of significance 5%, power of test 80%. The median hospital discharge time was 15 days (range: 13-17) for the melatonin group and 21 days (range: 14-24) for the control group (9).

Sampling technique: Consecutive sampling

DATA COLLECTION PROCEDURE:

Prior to the study, healthcare professionals working in emergency departments/outpatient clinics will receive training on their respective roles, responsibilities and study protocols. The clinician will identify eligible patients and provide them with written and verbal information about the study. The parent/legal guardian of the patient will provide informed consent while the patient will provide informed assent if appropriate. After obtaining consent, the patients will be randomized. The control group will receive standard treatment (antibiotic such as ampicillin at a dose of 150mg/kg/day divided every 8 hours), while the intervention group will receive standard treatment plus melatonin for 14 days at the dose of 1 mg/dose in infants and 2.5 to 3mg/dose in children three times a day for 14 days. The patients who will not take more than 10% of the medication will be excluded from the study. The follow-up period will be 2 weeks for all patients.

DATA ANALYSIS PROCEDURE:

Once data collection is complete, the questionnaires will be checked for completeness and consistency by the data collectors. The normality distribution of variables will be evaluated using the Kolmogorov-Smirnov test. Qualitative variables (Gender, socioeconomic status and symptoms (fever, cough, breathing difficulty, decreased oral intake, fits, level of consciousness and persistent vomiting, pneumonia and severe pneumonia)) will be presented as frequencies and percentages (%). Quantitative variables (Age, weight, heart rate, respiratory rate, blood pressure, temperature, oxygen saturation, laboratory parameters (total leukocyte count, hemoglobin, neutrophils, lymphocytes, platelets, C-reactive protein, pH, PCO, P02, HCO3) and length of hospital stay) will be presented as mean ± standard deviation (SD). Both groups (melatonin and non-melatonin) will be compared for length of hospital stay by using independent sample t-test. Effect modifiers like age, gender, socioeconomic status, weight, and pneumonia/ severe pneumonia will be stratified using post stratified independent sample t-test. Statistical analyses will be conducted using SPSS software version 25.0, with a significance level of p-value <0.05.

Inclusion criteria

• 1 month to 12 years
• Both genders
• Patient diagnosed as having pneumonia or severe pneumonia according to WHO definition

Exclusion criteria

• Hospitalized within 14 days prior to the study
• Known TB exposure
• Active varicella or herpes simplex infection
• Allergy to the study medication
• Currently taking melatonin
• Any non pneumonia acute medical illness which requires antibiotic treatment as per local standard of care
• Galactose intolerance, the lapp-lactase deficiency or glucose-galactose malabsorption
• Significant co-morbid disease: lung, cardiac, immune, liver, endocrine, neurological or psychiatric