Hyponatremia As A Predictor Of Adverse Outcome In Children With Severe Lower Respiratory Tract Infection In Tribhuvan University Teaching Hospital (Tuth), Nepal

Background Lower respiratory tract infection (LRTI) is one of the major causes of mortality in children with estimated 1 million deaths every year. Hyponatremia is the most common electrolyte abnormality seen in LRTI. Methods 16 of age breathing and chest indrawing or PICU of TUTH screened and among them, children having pediatric respiratory severity score of 4-5 were enrolled in the study. Serum sodium was sent during admission and collected within 2 hours. Daily follow up was done to nd need of respiratory support, duration to resolve hypoxia, total duration in hospital and nal outcome of patient. Statistical test applied were Chi-square test and Fisher exact test. Results 47.5% of study population had hyponatremia, of whom 65.79% had mild hyponatremia 26.31% had moderate and 7.89%had severe hyponatremia. Association of hyponatremia with need of non rebreathing face mask (p=0.001), ventilatio r (p=0.009), duration of hospital stay (p=0.047) were signicant. The study also found the association of severity of hyponatremia with need of non rebreathing facemask (p=0.001),ventilator (p=0.01), outcome (p=0.001), duration of stay (0.002). Mean time to resolve hypoxia in children with hyponatremia (4.5 days) was longer compared to normal sodium (2.58 days). Four patients died during the study period and all of them had hyponatremia. Single-center cohort in Children’s USA comprising children age 1month to 2 years admitted to the PICU January 2009 and 2011. Study done to characterize the relationship between hyponatremia and clinical outcome in bronchiolitis. One hundred and two children with bronchiolitis were enrolled. Twenty-three patients (22%) were diagnosed with hyponatremia. Mortality (13% vs 0%; P = .011), ventilator time (8.41 ± 2 days vs 4.11 ± 2 days; P = .001), duration of stay in the PICU (10.63 ± 2.5 days vs 5.82 ± 2.09 days; P = .007), and noninvasive ventilator support (65% vs 24%; P = .007) were signicantly different between subjects with Hyponatremia than those without (18). association of severity of hyponatremia with duration of hospital stay.


Abstract
Background Lower respiratory tract infection (LRTI) is one of the major causes of mortality in children with estimated 1 million deaths every year. Hyponatremia is the most common electrolyte abnormality seen in LRTI.
Objective To nd association of hyponatremia (serum sodium<135meq/l) with severe LRTI.
Design Prospective cross sectional study Settings Pediatric Emergency, Ward and Pediatric Intensive Care Unit of Tribhuvan University Teaching Hospital(TUTH) Subjects Children between 2 months to 16 years presenting with cough for less than 3 weeks, fast breathing and chest indrawing.
Methods Children between 2 month to 16 years of age having cough, fast breathing and chest indrawing admitted in emergency, ward or PICU of TUTH were screened and among them, children having pediatric respiratory severity score of 4-5 were enrolled in the study. Serum sodium was sent during admission and collected within 2 hours. Daily follow up was done to nd need of respiratory support, duration to resolve hypoxia, total duration in hospital and nal outcome of patient. Statistical test applied were Chi-square test and Fisher exact test.
Results 47.5% of study population had hyponatremia, of whom 65.79% had mild hyponatremia 26.31% had moderate and 7.89%had severe hyponatremia. Association of hyponatremia with need of non rebreathing face mask (p=0.001), ventilatio r (p=0.009), duration of hospital stay (p=0.047) were signi cant. The study also found the association of severity of hyponatremia with need of non rebreathing facemask (p=0.001),ventilator (p=0.01), outcome (p=0.001), duration of stay (0.002). Mean time to resolve hypoxia in children with hyponatremia (4.5 days) was longer compared to normal sodium (2.58 days). Four patients died during the study period and all of them had hyponatremia.

Background
Lower respiratory tract infection (LRTI) is infection below the level of the larynx and it includes bronchiolitis, pneumonia and empyema. It is in ammation of the airways/pulmonary tissue, commonly due to viral, bacterial or fungal infection (1).
ARIs are the major cause of mortality among children aged less than 5 years especially in developing countries. Worldwide, 1 million (16%) mortality among children aged less than 5 years is attributed to respiratory tract infections predominantly pneumonia associated. Southeast Asia stands rst in number for ARI incidence accounting for more than 80% of all incidences together with sub-Saharan African countries (2,3). Children with ARI account for 30% to 50% of the children attending outpatient clinics and 20% to 40% of admissions into hospitals (4).
LRTI comprises bronchiolitis, pneumonia and empyema. Bronchiolitis is one of the common childhood illness and Respiratory syncytial virus is the most common etiologic agent. Hospitalization due to bronchiolitis is required in approximately 1% of affected children, primarily because of associated dehydration, inadequate oral intake, or respiratory insu ciency. Among those admitted, 10-15% requires intensive care due to impending respiratory failure(6).
Pneumonia is a form of acute respiratory infection that affects the lungs Pneumonia is usually preceded by upper respiratory tract infection, which promote invasion of lower respiratory tract by virus, bacteria or other pathogens that trigger an immune response. (7).
Empyema is de ned as collection of pus in pleural cavity. Common pathogens are Streptococcus pneumonia , Staphylococcus aureus and Streptococcus pyogenes. Empyema starts as moderate to large exudative parapneumonic effusion, which can progress to being loculated with further development of a brinous peel. This can be associated with fever, fast breathing and respiratory distress(8).
Fluids and electrolytes are the main pillars in the maintenance of body homeostasis. Most important among electrolytes is sodium which is the abundant cation of the extracellular uid. Hyponatremia is the most common electrolyte abnormality seen in the intensive care unit (ICU), with an incidence as high as 30% in some reports (11,12).
Hyponatremia is de ned as serum sodium (Na) concentration of less than 135mEq/L (9-10).A major consequence of hyponatremia is in ux of water into the intracellular space, resulting in cellular swelling that can lead to cerebral edema and encephalopathy. The clinical manifestations of hyponatremia are primarily neurologic and related to cerebral edema caused by hypo-osmolality(13).
Hyponatremia associated with pediatric pneumonia is most commonly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This syndrome is characterized by hyponatremia and hypo-osmolality. It results from the inappropriate and continued secretion and/or action of antidiuretic hormone despite normal or increased plasma volume (14,15).
Hyponatremia associated with bronchiolitis is due to hyperin ation of lungs. Hyperin ation reduces blood ow to the right atrium and stimulates the release of vasopressin(AVP)from the posterior pituitary causing accumulation of intravascular uid leading to dilutional hyponatremia(16,).
In a study done by Shingi S et.al to determine the frequency of electrolyte disturbance in pneumonia in 264 hospitalized children in chandigrah, India found hyponatremia in 71(27%) children with pneumonia. It was associated with two fold increase in complications and 3.5 times higher mortality (17).
Single-center retrospective cohort study was done in Children's Hospital Colorado, USA comprising children age 1month to 2 years admitted to the PICU between January 2009 and April 2011. Study was done to characterize the relationship between hyponatremia and clinical outcome in bronchiolitis. One hundred and two children with bronchiolitis were enrolled. Twenty-three patients (22%) were diagnosed with hyponatremia. Mortality (13% vs 0%; P = .011), ventilator time (8.41 ± 2 days vs 4.11 ± 2 days; P = .001), duration of stay in the PICU (10.63 ± 2.5 days vs 5.82 ± 2.09 days; P = .007), and noninvasive ventilator support (65% vs 24%; P = .007) were signi cantly different between subjects with Hyponatremia than those without (18).
Acute respiratory tract infection is one of the serious health problems leading to hospitalization and mortality. In developing countries, 7 out of 10 deaths happen due to ARI in under 5-year age group (19).
Acute respiratory infection is classi ed by World Health Organization (WHO) as no pneumonia(child presenting as cough and cold), pneumonia(child with cough an fast breathing and or chest indrawing) and severe pneumonia or very severe disease( child with cough, fast breathing, chest indrawing and danger signs like unable to drink, convulsions, stridor) (20).
In Nepal, according to the most recent Annual Health Report by Department of Health Services (DOHS), in scal year 2073/74, a total of 1,810,722 ARI cases were registered, out of which 10.5% were categorized as pneumonia cases and 0.29% were severe pneumonia cases. The incidence of pneumonia at national level was 66 per 1000 under ve children(21).

Pneumonia
Pneumonia is a form of acute respiratory infection that affects the lungs. (7). The physiological intrapulmonary shunting of de-oxygenated blood and ventilation perfusion mismatch following these pathological changes results in hypoxemia (22). Bronchiolitis is a common cause of illness and is the leading cause of hospitalization in infants and young children. RSV infection is common in children older than two years (25).

Causes of pneumonia in children are
Hypoxia, co-morbid condition such as diarrhea, age below 1 year, inability to feed, presence of loose stools and severe malnutrition are known factors for adverse outcome in children with lower respiratory tract infection. These factors increases duration of stay at hospital and if not managed properly can lead to death (26, 27). Hyponatremia is de ned as serum sodium (Na) concentration of less than 135 mEq/L. The effect of ADH on plasma osmolality depends on intact kidney function, which is required for appropriate retention or excretion of free water. (28).

Hyponatremia
SIADH syndrome is characterized by hyponatremia and hypoosmolality and results from the inappropriate and continued secretion and/or action of antidiuretic hormone despite normal or increased plasma volume presumably due to in ammatory cytokines, such as interleukin-6 (29), stress, and hypoxemia (30,31). Hyperin ation of the lungs, a hallmark of the bronchiolitis, wheezing, reduces blood ow to the right atrium and stimulates the release of vasopressin(AVP)from the posterior pituitary causing accumulation of intravascular uid leading to dilutional hyponatremia (32).

Pediatric Respiratory Severity Score (PRESS score)
This score was devised for a study done in National Hospital Organization Yokohama Medical center, an urban emergency hospital in Japan, in 2010-2011 to establish and examine the utility for assessing severity in children with respiratory symptoms (33).
The World Health Organization has suggested that children suspected of having infective illnesses and presenting not only with drowsiness, feeding di culties, vomiting, convulsion but respiratory complains as dyspnoea should be hospitalized quickly (34). For calculating the score, objective signs such as respiratory rate, wheezing, retraction (accessory respiratory muscle use), SpO2, and feeding di culties are assessed with each component given a score of 0 or 1, and total scores classi ed as mild (0-1), moderate (2-3), or severe (4)(5). Using PRESS score, hospitalization rate was higher in moderate to severe cases and duration of oxygen therapy was signi cantly longer in severe cases compared with mild and moderate cases. Data were entered in Microsoft Excel and converted into SPSS 20 version for statistical analysis. The descriptive data were expressed in frequency, percentage, mean, standard deviation, median etc. along with graphical and tabular presentation.Descriptive statistics was used to analyse data like mean, median and mode and standard deviation (SD).
Inferential statistics i.e. Chi square test, Fisher exact test were used at 95% con dence interval where p value<0.05 was considered statistically signi cant to assess association of hyponatremia with selected outcome variables and to assess association of socio-demographic variables.

Results
The study was conducted over a period of 12 month from September 1 st 2017 to September 1 st 2018. Total 90 cases were screened, 10 cases were excluded. Among the excluded case 5 cases were of congenital heart disease, two patients came after receiving IV uids , 2 cases had cough for more than 3 weeks and 1 patient had PRESS score of less than 4.Total 80 children were enrolled. Thirty eight patients had hyponatremia at presentation. Patients were admitted in pediatrics ward or pediatric ICU. Serum sodium was sent during IV cannulation after stabilizing the patients, patients were followed till discharge or mortality. Outcome evaluated were need of non invasive and invasive respiratory support, time taken for hypoxia to resolve, discharge of the patient or mortality    Above table 3 depicts sociodemographic variable of study population, about one third of father had university level education followed by 28.8% in secondary level. Among mothers about one third that is 33.8% mothers had education upto secondary level followed by 26.3% university level. Occupation of most of the fathers was technical/ profession and sales/service each 32.5% and 77.5% of the mothers were housewife.       The above table 9 shows association between hyponatremia and outcome. Among the study population, 4 patients with hyponatremia had mortality and none of the patient with normal sodium expired.
Association of hyponatremia with outcome was statistically signi cant (p=0.047). *Chi square test was used to nd association of hyponatremia with duration of stay Above table 10 shows association of hyponatremia with duration of stay. Duration of stay was divided into more than and less than 7 days. Among eighty patient 59(73.75%) patient had duration of stay less than 7 days and21 (26.25%) had stay more than 7 days. Sixteen patients with hyponatremia had stay more than 7 days and 5 patients with normal sodium had stay more than 7 days. Association of hyponatremia with duration of stay was statistically signi cant (p value= 0.002).

Discussion
Lower respiratory tract infection is associated with electrolyte abnormalities like hyponatremia, hypernatremia, hypokalemia, hyperkalemia. Among them hyponatremia is the most common electrolyte imbalance (17).
This study was conducted to nd association between hyponatremia and adverse outcome of severe lower respiratory tract infection in children between 2 month to 16 year admitted in Emergency, ward and PICU of Tribhuvan University Teaching Hospital. The study was conducted over 12 months duration from September 1 st 2017 to September 1 st 2018. Total 80 cases were enrolled.
In current study, 47.5% of the study population presenting with severe lower respiratory tract infection at admission were found to have hyponatremia. Most of them (65.78%) had mild hyponatremia.
Association between hyponatremia and need of non-rebreathing facemask (p=0.001), need of ventilator (p=0.009) and clinical outcome (mortality or improvement) (p=0.047) was statistically signi cant (P<0.05). During the course of hospital stay, the mean time required for resolution of hypoxia was found higher in children with hyponatremia (4.5 days) as compared to the children with normal sodium (2.58 days). Association of hyponatremia with oxygen saturation at presentation was not signi cant. Children with hyponatremia had prolonged hospital stay compared to children with normal sodium and the association was statistically signi cant (p=0.047).
Age and gender of study population In this research mean age of study population was (2.3± 1.4) years and 66.25% of study population were boys.
In a study conducted by Chaitra et al had similar results. The study was conducted in 91 patients suffering from LRTI admitted in PICU of Kempegowda Institute of Medical Sciences, Banglore in children age 2 months to 16 years. The mean age of study population was 2 years and 59% of the children were boys(1).
In the cross sectional study done to see prevalence of hyponatremia in children admitted at Kenyatta national hospital with pneumonia in 135 children aged between 2 month to 12 years, the mean age was 1.8 + 2.3 years and 54.8% of the study population were boys (35).
Prevalence of hyponatremia hyponatremia. The result is higher compared to current nding. This may be because most of the children studied in Kenyatta national hospital presented late in hospital and they were critically ill and most of them also had associated complications (35).
Outcome -Need of respiratory support During this study, 38.75% patients were hypoxic at presentation. All patients were provided either noninvasive or invasive oxygen support. Noninvasive supports were nasal prongs, simple facemask and non-rebreathing facemask. Invasive respiratory support included bubble continuous positive air pressure (CPAP) and mechanical ventilation. Oxygen was provided via nasal prongs in 87.5% patients and via simple facemask in 76.25% during their hospital stay. Non re-breathing facemask was required 20% patient, CPAP in 8.75% patient. Total 6 (7.5%) patients were mechanically ventilated. Funding: The authors received no any speci c grant from any funding agency in public, commercial or nonpro t sectors.
Availability of data: data sheet was prepared by researcher by entering the respondents informations including outcomes of treatment obtained during data collection on excel for analysis of results. It is attached in section of additional le.

Ethical approval and consent to participants
The ethical clearance was taken from the Institutional Review Board of Institute of Medicine, Maharajgunj Medical Campus. Initial stabilization of patient was done immediately after presentation. The parents/ guardians of children ful lling the inclusion criteria explained about this study and approached for consent. After informed consent was obtained, the child was enrolled in the study. Participation was voluntarily taken. Informed (verbal and written) consent was taken from each participant's parents/guardians. Con dentiality and anonymity was maintained by writing code number instead of name of participants.

Figure 1
Flow chart of screened and enrolled cases in the study Figure 2