Frequency and severity of hyponatremia in healthy children with acute illnesses

Frequency and severity of hyponatremia in healthy children with acute illnesses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Frequency and severity of hyponatremia in healthy children with acute illnesses Shoichiro Shirane, Riku Hamada, Yoshihiko Morikawa, Ryoko Harada, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4224559/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Oct, 2024 Read the published version in Pediatric Nephrology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Hyponatremia can occur in the acute phase of any illness through various mechanisms. However, the frequency and severity of hyponatremia are not well known across a broad range of illnesses including medical and surgical diseases and trauma. Methods The present, retrospective chart review was conducted at Tokyo Metropolitan Children’s Medical Center from 2018 to 2019. Included were healthy children aged < 16 years with an acute illness who were urgently admitted and had their serum sodium level measured on admission. Results In total, 2,717 patients were urgently admitted and had their serum sodium level measured. Of these, 1,890 were included. Hyponatremia occurred in 260 patients (13.8%). The most common hyponatremic disease was type 1 diabetes mellitus (69%) followed by acute encephalopathy (60%), pyogenic arthritis (60%), and Kawasaki disease (51%). Kawasaki disease, seizure, urinary tract infection, acute appendicitis, lower respiratory tract infection, and acute gastroenteritis were associated with a significantly lower serum sodium value than cases of fracture comprising a control group. Conversely, acute bronchial asthma exacerbation (3%), anaphylaxis (0%), intussusception (0%), acute scrotal disease (0%), head injury (1%), and fracture (0%) were very infrequently associated with hyponatremia. Conclusion The present study determined the frequency and severity of hyponatremia in various, acute, pediatric illnesses, including medical and surgical diseases and trauma. Despite reports of respiratory distress and pain inducing vasopressin secretion, hyponatremia was rarely observed on admission in cases of acute bronchial asthma exacerbation, anaphylaxis, intussusception, acute scrotal diseases, head injury, and fracture. Hyponatremia acute illness medical disease surgical disease trauma syndrome of inappropriate secretion of antidiuresis Figures Figure 1 Figure 2 Introduction Hyponatremia occurs in the acute phase of illnesses through various mechanisms, such as low effective arterial blood volume, syndrome of inappropriate secretion of antidiuresis (SIAD), loss of sodium in the renal tubules, high effective plasma osmolality, and excess free water intake [1]. Low effective arterial blood volume induces hyponatremia via impaired urinary dilution in the renal tubules caused by decreased glomerular filtration and vasopressin secretion [1]. SIAD is one of the major causes of hyponatremia in the acute phase of diseases; central nervous system diseases, pulmonary diseases (respiratory distress), fever, inflammatory cytokines, such as Interluekin-6, and stress, including vomiting and pain, stimulate abnormal vasopressin secretion independently of osmotic and non-osmotic control, thereby inducing hyponatremia [1–4]. In exceptional cases, when the effective plasma osmolality is abnormally high, increased vasopressin secretion and water movement along the osmotic gradient from the intracellular to the extracellular space can induce hyponatremia [1]. These conditions, combined with a relative excess of free water intake, can further conduce to hyponatremia. While some reports have discussed hyponatremia associated with a few medical diseases [5, 6], no reports have as of yet compared the frequency and severity of hyponatremia in multiple, acute illnesses, including medical and surgical diseases and trauma. Knowing which diseases are likely to cause hyponatremia is essential to prevent its progression and complications. The present study investigated the frequency and severity of hyponatremia in a variety of acute, pediatric illnesses, including medical and surgical diseases and trauma. Materials and methods Study design and population The present, monocentric, retrospective, observational study was conducted at Tokyo Metropolitan Children’s Medical Center, a tertiary pediatric medical center, from 1 March 2018 to 30 June 2019 and enrolled children aged < 16 years who were urgently admitted to the study center and had their serum sodium level measured on admission. The exclusion criteria were any of the underlying diseases or conditions described below; transfer from another hospital; lack of pre-intervention blood test data; admission to the Department of Psychiatry, Psychosomatic Medicine or Neonatology; chromosomal abnormalities or multiple, morphological abnormalities; congenital heart disease (except after radical operation); neurological disease with fixed symptoms (such as cerebral palsy, congenital central nervous system diseases, chronic phase of cerebral hemorrhage, infarction, and encephalitis); endocrine and metabolic disorders (except first-episode of type 1 diabetes); renal or urinary tract diseases (except first-episode of idiopathic nephrotic syndrome and acute nephritis syndrome); hematological and oncological diseases receiving treatment; gastrointestinal diseases receiving treatment; diuretics or antihypertensive medication; and diseases deemed ineligible for the study or whose diagnosis was unknown. In short, pediatric inpatients with an acute medical or surgical disease or trauma with no underlying disease were included. Data collection Patients who were urgently admitted to the study center during the designated period and had their serum sodium level measured on admission were extracted from a medical database. Electronic medical records were then reviewed to identify patients meeting the exclusion criteria. Age, sex, diagnosis, serum sodium at admission, and the presence or absence of hyponatremia symptoms were noted. Definitions Hyponatremia was defined as serum sodium (Na) < 135 mEq/L. Severity was defined as follows in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0: Na 130–134 mEq/L for mild disease, Na 125–129 mEq/L and asymptomaticity for moderate disease, Na 125–129 mEq/L and symptomaticity or Na 120–124 mEq/L for severe disease, and Na < 120 mEq/L for very severe disease. Ethics This study adheres to the ethical principles outlined in the Helsinki Declaration, the Ethical Guidelines for Medical and Biological Research Involving Human Subjects jointly issued by the Ministry of Health, Labour and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Economy, Trade and Industry of Japan, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Ethical approval was obtained from the Institutional Research Ethics Board of Tokyo Metropolitan Children’s Medical Center (2023b-116). Written informed consent was waived. Consent to participate was implied in an opt-out clause on the center’s website. Statistical analysis Continuous variables were expressed as the mean and 95% confidence interval (95% CI) and the median and interquartile range (IQR) because normally distributed and non-normally distributed data were mixed. Categorical variables were summarized using a frequency (n) and percentage (%). Dunnett’s test was performed for diseases with more than 30 cases, assuming a normal distribution based on the central limit theorem. Among diseases with more than 30 cases, the disease with a mean serum sodium level closest to 140 mEq/L was selected as the control. To investigate the impact of age on the serum sodium value, correlation analysis was conducted using Pearson’s correlation coefficient for diseases with more than 30 cases. Two-sided P < 0.05 was considered to indicate statistical significance. The data were analyzed using EZR version 1.41 [7]. Results In total, 2,717 patients were urgently admitted and had their serum sodium measured during the study period. Of these, 827 were excluded, leaving 1,890 for analysis (Fig. 1). Table 1 shows their clinical characteristics. Hyponatremia occurred in 260 patients (13.8%); of these, 237 (12.5%), 20 (1.1%), one (0.1%), and two (0.1%) had mild, moderate, severe, and very severe disease, respectively. Table 2 shows the frequency and severity of hyponatremia and the median and IQR of the serum sodium level for each major illness. The most common hyponatremic disease (>50% of the sample) was type 1 diabetes mellitus followed by acute encephalopathy, pyogenic arthritis, and Kawasaki disease. The two, very severe cases of hyponatremia consisted of the first episode of idiopathic nephrotic syndrome (Na 107 mEq/L) in a 5-year-old, male patient and respiratory syncytial virus bronchiolitis (Na 119 mEq/L) in a 1-month-old, female patient. Severe hyponatremia occurred in a 1-year-old, male patient with Shiga toxin-producing Escherichia coli -associated hemolytic uremia syndrome (Na 121 mEq/L). The only patient with apparent symptoms of hyponatremia was the 5-year-old, male patient mentioned above, who also presented with impaired consciousness (Na 107 mEq/L). Among the diseases with more than 30 cases, fractures had a mean serum sodium level closest to 140 mEq/L, with none of the patients exhibiting hyponatremia. Hence, fractures were used as a control for Dunnett’s test. Compared with the control group consisting of fracture cases, the serum sodium value was significantly lower in Kawasaki disease, seizure, urinary tract infection, acute appendicitis, lower respiratory tract infection, acute gastroenteritis (all P < 0.001), and acute bronchial asthma exacerbation ( P < 0.05) (Fig. 2). Conversely, acute bronchial asthma exacerbation (3%), anaphylaxis (0%), intussusception (0%), acute scrotal disease (0%), head injury (1%), and fracture (0%) were very infrequently associated with hyponatremia. Correlation analysis was conducted to investigate the impact of age on serum sodium in diseases with more than 30 cases. Supplementary Fig. 1 shows the scatter plots, correlation coefficients (95% CI), and P -values. No strong correlation was observed between age and serum sodium in any of the diseases, nor did the sign of the coefficient align across diseases. Discussion The present study determined the frequency and severity of hyponatremia in various, acute, pediatric illnesses, including medical and surgical diseases and trauma. It also found specific trends in the frequency and severity of hyponatremia and illness characteristics. Among diseases with more than 30 cases, Kawasaki disease, seizure, urinary tract infection, acute appendicitis, and acute gastroenteritis had a significantly lower mean serum sodium value than fractures (the control) and a higher frequency of hyponatremia than all the other diseases. Kawasaki disease was associated with a relatively high rate of moderate hyponatremia. Although the number of cases was inadequate, type 1 diabetes mellitus, pyogenic arthritis, and acute encephalopathy were associated with a low median serum sodium value and high frequency of hyponatremia, suggesting a potent, hyponatremic tendency. On the other hand, acute bronchial asthma exacerbation, anaphylaxis, intussusception, acute scrotal disease, head injury, and fracture were very weakly associated with hyponatremia on admission. In the present study, certain diseases, such as Kawasaki disease, urinary tract infection, and acute appendicitis, had a strong tendency toward hyponatremia, presumably due to the coexistence of multiple factors [1–4], especially fever and elevated inflammatory cytokines. On the other hand, for diseases with a low frequency of hyponatremia, such as acute bronchial asthma exacerbation, intussusception, acute scrotal disease, and fracture, symptoms capable of stimulating vasopressin secretion, such as respiratory distress and pain, were likely to be present but were unlikely to cause fever or inflammation. Thus, fever and inflammatory cytokines may be more potent than respiratory distress or pain in their ability to trigger hyponatremia via stimulation of vasopressin secretion. In the United States, the United Kingdom, and other nations, the risk of hospital-acquired hyponatremia is considered to be of utmost importance, and isotonic fluids are strongly recommended as maintenance infusion during the acute phase except in certain patients [8–10]. In diseases with a strong tendency to hyponatremia, administering hypotonic fluids should be avoided until the acute phase is past. Conversely, complications, such as hypernatremia, extracellular fluid overload, and hypokalemia, can occur with the administration of isotonic solutions [11]. Ideally, acute infusions should be personalized using patient background, disease, and pathophysiology. The findings of the present study, which demonstrated variations in the risk and severity of hyponatremia by disease, will hopefully contribute to the personalization of treatment strategies. However, as this study did not examine changes in the post-hospitalization serum sodium level, further research is needed in this direction. Of all the included patients, those with hyponatremia were significantly younger. Therefore, to investigate the impact of age on serum sodium, multiple regression analysis using age and disease as explanatory variables was considered as a possibility. However, due to substantial age differences across the diseases, the potential for extrapolation bias in models integrating multiple diseases caused concern. Hence, correlation analysis was conducted separately for each disease using age as the explanatory variable. In all the diseases examined, the correlation coefficient was modest irrespective of the P -value, suggesting that young age may have little or no involvement in hyponatremia onset. Patients with hyponatremia were younger mainly because diseases affecting young patients tend to result in hyponatremia. In other words, the diseases themselves were the confounding factor. One of the principal strengths of this study was its inclusion only of patients with no underlying disease. Moreover, it was the first study to investigate a wide range of diseases, including medical and surgical diseases and trauma, and was conducted at a tertiary pediatric institution with a North American-style emergency room, which enabled patients with diverse diseases of varying severity to be included. The limitations were the relatively small number of cases of rare diseases and the inability to investigate the pathomechanism in each instance of hyponatremia. In conclusion, the present study determined the frequency and severity of hyponatremia in a variety of acute pediatric illnesses, including medical and surgical diseases and trauma. Although respiratory distress and pain induce vasopressin secretion, hyponatremia was rarely observed on admission in cases of acute bronchial asthma exacerbation, anaphylaxis, intussusception, acute scrotal diseases, head injury, and fracture. Declarations Acknowledgement The authors would like to thank James Robert Valera for his editorial assistance. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Funding No funding was received for conducting this study. Data availability The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Author contributions Shoichiro Shirane: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. Riku Hamada: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing – review & editing. Yoshihiko Morikawa: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Validation, Writing – review & editing. Ryoko Harada: Methodology, Writing – review & editing. Yuko Hamasaki: Methodology, Writing – review & editing. Kenji Ishikura: Methodology, Writing – review & editing. Masataka Honda: Methodology, Supervision, Writing – review & editing. Hiroshi Hataya: Supervision, Writing – review & editing. Ethics approval and consent to participate Ethics approval was granted by the Institutional Research Ethics Board of Tokyo Metropolitan Children’s Medical Center (2023b-116). Written informed consent of the patients and caregivers was waived. Consent to participate was implied in the opt-out clause on institutional website. References Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D et al (2014) Clinical Practice Guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 170:G1–47. https://doi.org/10.1530/EJE-13-1020y Moritz ML (2019) Syndrome of Inappropriate Antidiuresis. Pediatr Clin North Am 66:209–226. https://doi.org/10.1016/j.pcl.2018.09.005 Sharif-Naeini R, Ciura S, Bourque CW (2008) TRPV1 gene required for thermosensory transduction and anticipatory secretion from vasopressin neurons during hyperthermia. Neuron 58:179–185. https://doi.org/10.1016/j.neuron.2008.02.013 Swart RM, Hoorn EJ, Betjes MG, Zietse R (2011) Hyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation. Nephron Physiol 118:45–51. https://doi.org/10.1159/000322238 Lehtiranta S, Honkila M, Anttila S, Huhtamäki H, Pokka T, Tapiainen T (2022) The incidence, hospitalisations and deaths in acutely ill children with dysnatraemias. Acta Paediatrica 111:1630–1637. https://doi.org/10.1111/apa.16348 Matsumura H, Ashida A, Shirasu A, Okasora K, Nakakura H, Hattori M (2022) Serum sodium level is inversely correlated with body temperature in children. Pediatr Int 64:e14841. https://doi.org/10.1111/ped.14841 Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48:452–458. https://doi.org/10.1038/bmt.2012.244 Feld LG, Neuspiel DR, Foster BA, Leu MG, Garber MD, Austin K et al (2018) Clinical Practice Guideline: Maintenance Intravenous Fluids in Children. Pediatrics 142:e20183083. https://doi.org/10.1542/peds.2018-3083 National Institute for Health and Care Excellence (2020) Intravenous fluid therapy in children and young people in hospital. National Institute for Health and Care Excellence (NICE): Guidelines 2020 Friedman JN; Canadian Paediatric Society, Acute Care Committee (2013) Risk of acute hyponatremia in hospitalized children and youth receiving maintenance intravenous fluids. Paediatr Child Health 18:102–104. Lehtiranta S, Honkila M, Kallio M, Paalanne N, Peltoniemi O, Pokka T, Renko M, Tapiainen T (2021) Risk of Electrolyte Disorders in Acutely Ill Children Receiving Commercially Available Plasmalike Isotonic Fluids: A Randomized Clinical Trial. JAMA Pediatr 175:28–35. https://doi.org/10.1001/jamapediatrics.2020.3383 Tables Table 1. Sex, age, and frequency and severity of hyponatremia in the study population Total Hyponatremia Non-hyponatremia P- value n 1,890 260 1,630 Male sex 1,125 (59.5%) 157 (60.4%) 968 (59.4%) 0.81* Age (years), median (IQR) 3 (1–7) 2 (1–4) 3 (1–8) 0.004** Hyponatremia 260 Mild: Na 130–134 237 (12.5%) Moderate: Na 125–129 and asymptomatic 20 (1.1%) Severe: Na 125–129 and symptomatic or Na 120–124 1 (0.1%) Very severe: Na < 120 2 (0.1%) *Pearson’s chi-square test, **Mann-Whitney U test IQR, interquartile range; Na, serum sodium. Table 2. Frequency and severity of hyponatremia and the median and IQR of serum sodium for each major illness by sample size Diagnosis Age (years), median (IQR) n Hyponatremia Serum sodium (mEq/L), median (IQR), mean (95% CI) Total Mild Moderate Severe Very severe Medical and surgical diseases Lower respiratory tract infection 1 (0–2) 338 34 (10%) 32 (9%) 1 (0.3%) 1 (0.3%) 138 (136–139), 138 (137–138) Seizure 2 (1–3) 178 58 (33%) 58 (33%) 136 (134–137), 136 (135–136) Kawasaki disease 2 (1–3) 126 64 (51%) 59 (47%) 5 (4%) 134 (133–136), 134 (134–135) Acute bronchial asthma exacerbation 4 (2–5) 115 4 (3%) 4 (3%) 139 (137–143), 139 (138–139) Acute appendicitis 10 (7–12) 95 15 (16%) 15 (16%) 137 (136–139), 137 (137–138) Anaphylaxis 4 (2–7) 71 0 (0%) 139 (138–140), 139 (139–140) Febrile urinary tract infection 0 (0–0) 42 11 (26%) 10 (24%) 1 (2%) 136 (134–138), 136 (135–137) Acute gastroenteritis 4 (1–8) 42 8 (19%) 7 (17%) 1 (2%) 138 (136–140), 138 (137–139) Intussusception 1 (0–3) 42 0 (0%) 139 (138–140), 139 (138–139) Cellulitis 3 (1–5) 19 5 (26%) 5 (26%) 137 (134–138), 137 (135–138) Acute scrotal diseases 13 (12–14) 17 0 (0%) 0 (0%) 140 (139–141), 140 (139–141) Type 1 diabetes mellitus 10 (3–12) 16 11 (69%) 7 (44%) 4 (25%) 133 (130–135), 133 (130–135) Viral sepsis 0 (0–2) 15 6 (40%) 6 (40%) 135 (132–137), 135 (133–136) Lymphadenitis 3 (1–4) 15 4 (27%) 4 (27%) 136 (134–137), 136 (134–137) Idiopathic nephrotic syndrome 3 (3–5) 14 4 (29%) 3 (21%) 1 (7%) 137 (133–139), 135 (130–139) Meningitis 0 (0–1) 11 3 (27%) 3 (27%) 136 (134–139), 136 (134–137) Acute encephalopathy 4 (1–7) 5 3 (60%) 3 (60%) 134 (132–136), 135 (131–140) Pyogenic arthritis 4 (2–10) 5 3 (60%) 1 (20%) 2 (40%) 131 (129–135), 132 (129–135) Trauma Fracture 8 (6–11) 239 0 (0%) 139 (138–140), 139 (139–140) Head injury 5 (0–8) 70 1 (1%) 1 (1%) 139 (138–141), 139 (139–140) Burn 1 (1–1) 11 1 (9%) 1 (9%) 136 (136–138), 136 (135–138) IQR, interquartile range; CI, confidence interval Supplementary Files Hyponatremiasupplfigure1.docx Cite Share Download PDF Status: Published Journal Publication published 09 Oct, 2024 Read the published version in Pediatric Nephrology → Version 1 posted Editorial decision: Major Revisions Needed 29 Apr, 2024 Reviewers agreed at journal 05 Apr, 2024 Reviewers invited by journal 05 Apr, 2024 Editor assigned by journal 05 Apr, 2024 First submitted to journal 05 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4224559","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":288093612,"identity":"2f96a069-cd85-43b6-9860-715ae9ae92a7","order_by":0,"name":"Shoichiro Shirane","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYDACCSBmbACRDIwPgAQPHylamA1AWtiI1AJmsoE1EtQiP7v5AOPPHRb5/LObj1V+zbGTYWNgfvjoBh4tBneOJTDznpGwnHHnWNpt2W3JQIexGRvn4NMikWPAzNgmYcBwI8fstuQ2ZqAWHjZpfFrkZ+QYMP4EapG/kf+tWHJbPWEtQMMNGHiBWgxu5LAxftx2mLAWgxtpCYdBWgxvpBlLM247zsPGTMAv8jOSDz782VZnIHcj+eHHn9uq7fnZmx8+xuswIDgAYzDzgEkCylEA4w9SVI+CUTAKRsGIAQDvkEJq69S1lAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4948-4902","institution":"Tokyo Metropolitan Children's Medical Center: Tokyo Toritsu Shoni Sogo Iryo Center","correspondingAuthor":true,"prefix":"","firstName":"Shoichiro","middleName":"","lastName":"Shirane","suffix":""},{"id":288093613,"identity":"1cdb69e6-d6ce-4f0d-b2e1-3eee61112cd8","order_by":1,"name":"Riku Hamada","email":"","orcid":"https://orcid.org/0000-0002-7151-459X","institution":"Tokyo Metropolitan Children's Medical Center: Tokyo Toritsu Shoni Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Riku","middleName":"","lastName":"Hamada","suffix":""},{"id":288093614,"identity":"233d61b6-adbc-42c7-877a-cea1120e2c1b","order_by":2,"name":"Yoshihiko Morikawa","email":"","orcid":"","institution":"Tokyo Metropolitan Children's Medical Center: Tokyo Toritsu Shoni Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Yoshihiko","middleName":"","lastName":"Morikawa","suffix":""},{"id":288093615,"identity":"c197608a-7c65-4ab3-a96b-a6465b499303","order_by":3,"name":"Ryoko Harada","email":"","orcid":"","institution":"Tokyo Metropolitan Children's Medical Center: Tokyo Toritsu Shoni Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Ryoko","middleName":"","lastName":"Harada","suffix":""},{"id":288093616,"identity":"d9ebe6a4-7301-45bc-8418-5d3f7379623c","order_by":4,"name":"Yuko Hamasaki","email":"","orcid":"","institution":"Toho University: Toho Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Hamasaki","suffix":""},{"id":288093617,"identity":"1ddf0367-29ad-455c-a75a-699e1ec52be3","order_by":5,"name":"Kenji Ishikura","email":"","orcid":"","institution":"Kitasato University School of Medicine: Kitasato Daigaku Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Ishikura","suffix":""},{"id":288093618,"identity":"b968c3ce-b8b3-4860-a22b-99fc1a8a7092","order_by":6,"name":"Masataka Honda","email":"","orcid":"","institution":"Tokyo Metropolitan Children's Medical Center: Tokyo Toritsu Shoni Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Masataka","middleName":"","lastName":"Honda","suffix":""},{"id":288093619,"identity":"d69009ee-c617-412e-9624-c0972bd32495","order_by":7,"name":"Hiroshi Hataya","email":"","orcid":"","institution":"Tokyo Metropolitan Children's Medical Center: Tokyo Toritsu Shoni Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Hataya","suffix":""}],"badges":[],"createdAt":"2024-04-05 19:08:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4224559/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4224559/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-024-06550-y","type":"published","date":"2024-10-09T15:57:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":54449983,"identity":"1e3d7f17-a468-4977-ae1d-c1f103603fe0","added_by":"auto","created_at":"2024-04-10 17:41:33","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":993314,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of exclusion and inclusion\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4224559/v1/625d74bb7f64ea9fefbdcd09.jpeg"},{"id":54450814,"identity":"ef7c4ffe-154d-4a9c-91d8-5b98c955e32e","added_by":"auto","created_at":"2024-04-10 17:49:33","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":605024,"visible":true,"origin":"","legend":"\u003cp\u003eDunnett’s test for sodium level in illnesses with more than 30 cases and fracture cases as the control group. Two-sided \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 was considered to indicate statistical significance. I bars indicate the 95% confidence interval. Na, serum sodium\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4224559/v1/06bcd4e693f930cd7e766e98.jpeg"},{"id":66597066,"identity":"c65a2540-ef2f-43aa-9987-01965886631c","added_by":"auto","created_at":"2024-10-14 16:06:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1979098,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4224559/v1/6d91edd9-ab83-461b-852c-414406bbebbf.pdf"},{"id":54449982,"identity":"204fe774-8f13-47f4-96ec-28b34f95eb05","added_by":"auto","created_at":"2024-04-10 17:41:33","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":961255,"visible":true,"origin":"","legend":"","description":"","filename":"Hyponatremiasupplfigure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4224559/v1/698339535923d3c654bcc980.docx"}],"financialInterests":"","formattedTitle":"Frequency and severity of hyponatremia in healthy children with acute illnesses","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHyponatremia occurs in the acute phase of illnesses through various mechanisms, such as low effective arterial blood volume, syndrome of inappropriate secretion of antidiuresis (SIAD), loss of sodium in the renal tubules, high effective plasma osmolality, and excess free water intake [1]. Low effective arterial blood volume induces hyponatremia via impaired urinary dilution in the renal tubules caused by decreased glomerular filtration and vasopressin secretion [1]. SIAD is one of the major causes of hyponatremia in the acute phase of diseases; central nervous system diseases, pulmonary diseases (respiratory distress), fever, inflammatory cytokines, such as Interluekin-6, and stress, including vomiting and pain, stimulate abnormal vasopressin secretion independently of osmotic and non-osmotic control, thereby inducing hyponatremia [1\u0026ndash;4]. In exceptional cases, when the effective plasma osmolality is abnormally high, increased vasopressin secretion and water movement along the osmotic gradient from the intracellular to the extracellular space can induce hyponatremia [1]. These conditions, combined with a relative excess of free water intake, can further conduce to hyponatremia.\u003c/p\u003e\n\u003cp\u003eWhile some reports have discussed hyponatremia associated with a few medical diseases [5, 6], no reports have as of yet compared the frequency and severity of hyponatremia in multiple, acute illnesses, including medical and surgical diseases and trauma. Knowing which diseases are likely to cause hyponatremia is essential to prevent its progression and complications.\u003c/p\u003e\n\u003cp\u003eThe present study investigated the frequency and severity of hyponatremia in a variety of acute, pediatric illnesses, including medical and surgical diseases and trauma.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cem\u003eStudy design and population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe present, monocentric, retrospective, observational study was conducted at Tokyo Metropolitan Children’s Medical Center, a tertiary pediatric medical center, from 1 March 2018 to 30 June 2019 and enrolled children aged \u0026lt; 16 years who were urgently admitted to the study center and had their serum sodium level measured on admission. The exclusion criteria were any of the underlying diseases or conditions described below; transfer from another hospital; lack of pre-intervention blood test data; admission to the Department of Psychiatry, Psychosomatic Medicine or Neonatology; chromosomal abnormalities or multiple, morphological abnormalities; congenital heart disease (except after radical operation); neurological disease with fixed symptoms (such as cerebral palsy, congenital central nervous system diseases, chronic phase of cerebral hemorrhage, infarction, and encephalitis); endocrine and metabolic disorders (except first-episode of type 1 diabetes); renal or urinary tract diseases (except first-episode of idiopathic nephrotic syndrome and acute nephritis syndrome); hematological and oncological diseases receiving treatment; gastrointestinal diseases receiving treatment; diuretics or antihypertensive medication; and diseases deemed ineligible for the study or whose diagnosis was unknown. In short, pediatric inpatients with an acute medical or surgical disease or trauma with no underlying disease were included.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData collection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients who were urgently admitted to the study center during the designated period and had their serum sodium level measured on admission were extracted from a medical database. Electronic medical records were then reviewed to identify patients meeting the exclusion criteria. Age, sex, diagnosis, serum sodium at admission, and the presence or absence of hyponatremia symptoms were noted.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDefinitions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eHyponatremia was defined as serum sodium (Na) \u0026lt; 135 mEq/L. Severity was defined as follows in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0: Na 130–134 mEq/L for mild disease, Na 125–129 mEq/L and asymptomaticity for moderate disease, Na 125–129 mEq/L and symptomaticity or Na 120–124 mEq/L for severe disease, and Na \u0026lt; 120 mEq/L for very severe disease.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study adheres to the ethical principles outlined in the Helsinki Declaration, the Ethical Guidelines for Medical and Biological Research Involving Human Subjects jointly issued by the Ministry of Health, Labour and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Economy, Trade and Industry of Japan, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Ethical approval was obtained from the Institutional Research Ethics Board of Tokyo Metropolitan Children’s Medical Center (2023b-116). Written informed consent was waived. Consent to participate was implied in an opt-out clause on the center’s website.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were expressed as the mean and 95% confidence interval (95% CI) and the median and interquartile range (IQR) because normally distributed and non-normally distributed data were mixed. Categorical variables were summarized using a frequency (n) and percentage (%). Dunnett’s test was performed for diseases with more than 30 cases, assuming a normal distribution based on the central limit theorem. Among diseases with more than 30 cases, the disease with a mean serum sodium level closest to 140 mEq/L was selected as the control. To investigate the impact of age on the serum sodium value, correlation analysis was conducted using Pearson’s correlation coefficient for diseases with more than 30 cases. Two-sided \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 was considered to indicate statistical significance. The data were analyzed using EZR version 1.41 [7].\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn total, 2,717 patients were urgently admitted and had their serum sodium measured during the study period. Of these, 827 were excluded, leaving 1,890 for analysis (Fig. 1). Table 1 shows their clinical characteristics. Hyponatremia occurred in 260 patients (13.8%); of these, 237 (12.5%), 20 (1.1%), one (0.1%), and two (0.1%) had mild, moderate, severe, and very severe disease, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 shows the frequency and severity of hyponatremia and the median and IQR of the serum sodium level for each major illness. The most common hyponatremic disease (\u0026gt;50% of the sample) was type 1 diabetes mellitus followed by acute encephalopathy, pyogenic arthritis, and Kawasaki disease. The two, very severe cases of hyponatremia consisted of the first episode of idiopathic nephrotic syndrome (Na 107 mEq/L) in a 5-year-old, male patient and respiratory syncytial virus bronchiolitis (Na 119 mEq/L) in a 1-month-old, female patient. Severe hyponatremia occurred in a 1-year-old, male patient with Shiga toxin-producing \u003cem\u003eEscherichia coli\u003c/em\u003e-associated hemolytic uremia syndrome (Na 121 mEq/L). The only patient with apparent symptoms of hyponatremia was the 5-year-old, male patient mentioned above, who also presented with impaired consciousness (Na 107 mEq/L).\u003c/p\u003e\n\u003cp\u003eAmong the diseases with more than 30 cases, fractures had a mean serum sodium level closest to 140 mEq/L, with none of the patients exhibiting hyponatremia. Hence, fractures were used as a control for Dunnett\u0026rsquo;s test. Compared with the control group consisting of fracture cases, the serum sodium value was significantly lower in Kawasaki disease, seizure, urinary tract infection, acute appendicitis, lower respiratory tract infection, acute gastroenteritis (all \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), and acute bronchial asthma exacerbation (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) (Fig. 2).\u003c/p\u003e\n\u003cp\u003eConversely, acute bronchial asthma exacerbation (3%), anaphylaxis (0%), intussusception (0%), acute scrotal disease (0%), head injury (1%), and fracture (0%) were very infrequently associated with hyponatremia.\u003c/p\u003e\n\u003cp\u003eCorrelation analysis was conducted to investigate the impact of age on serum sodium in diseases with more than 30 cases. Supplementary Fig. 1 shows the scatter plots, correlation coefficients (95% CI), and \u003cem\u003eP\u003c/em\u003e-values. No strong correlation was observed between age and serum sodium in any of the diseases, nor did the sign of the coefficient align across diseases.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study determined the frequency and severity of hyponatremia in various, acute, pediatric illnesses, including medical and surgical diseases and trauma. It also found specific trends in the frequency and severity of hyponatremia and illness characteristics. Among diseases with more than 30 cases, Kawasaki disease, seizure, urinary tract infection, acute appendicitis, and acute gastroenteritis had a significantly lower mean serum sodium value than fractures (the control) and a higher frequency of hyponatremia than all the other diseases. Kawasaki disease was associated with a relatively high rate of moderate hyponatremia. Although the number of cases was inadequate, type 1 diabetes mellitus, pyogenic arthritis, and acute encephalopathy were associated with a low median serum sodium value and high frequency of hyponatremia, suggesting a potent, hyponatremic tendency. On the other hand, acute bronchial asthma exacerbation, anaphylaxis, intussusception, acute scrotal disease, head injury, and fracture were very weakly associated with hyponatremia on admission.\u003c/p\u003e\n\u003cp\u003eIn the present study, certain diseases, such as Kawasaki disease, urinary tract infection, and acute appendicitis, had a strong tendency toward hyponatremia, presumably due to the coexistence of multiple factors [1\u0026ndash;4], especially fever and elevated inflammatory cytokines. On the other hand, for diseases with a low frequency of hyponatremia, such as acute bronchial asthma exacerbation, intussusception, acute scrotal disease, and fracture, symptoms capable of stimulating vasopressin secretion, such as respiratory distress and pain, were likely to be present but were unlikely to cause fever or inflammation. Thus, fever and inflammatory cytokines may be more potent than respiratory distress or pain in their ability to trigger hyponatremia via stimulation of vasopressin secretion.\u003c/p\u003e\n\u003cp\u003eIn the United States, the United Kingdom, and other nations, the risk of hospital-acquired hyponatremia is considered to be of utmost importance, and isotonic fluids are strongly recommended as maintenance infusion during the acute phase except in certain patients [8\u0026ndash;10]. In diseases with a strong tendency to hyponatremia, administering hypotonic fluids should be avoided until the acute phase is past. Conversely, complications, such as hypernatremia, extracellular fluid overload, and hypokalemia, can occur with the administration of isotonic solutions [11]. Ideally, acute infusions should be personalized using patient background, disease, and pathophysiology. The findings of the present study, which demonstrated variations in the risk and severity of hyponatremia by disease, will hopefully contribute to the personalization of treatment strategies. However, as this study did not examine changes in the post-hospitalization serum sodium level, further research is needed in this direction.\u003c/p\u003e\n\u003cp\u003eOf all the included patients, those with hyponatremia were significantly younger. Therefore, to investigate the impact of age on serum sodium, multiple regression analysis using age and disease as explanatory variables was considered as a possibility. However, due to substantial age differences across the diseases, the potential for extrapolation bias in models integrating multiple diseases caused concern. Hence, correlation analysis was conducted separately for each disease using age as the explanatory variable. In all the diseases examined, the correlation coefficient was modest irrespective of the \u003cem\u003eP\u003c/em\u003e-value, suggesting that young age may have little or no involvement in hyponatremia onset. Patients with hyponatremia were younger mainly because diseases affecting young patients tend to result in hyponatremia. In other words, the diseases themselves were the confounding factor.\u003c/p\u003e\n\u003cp\u003eOne of the principal strengths of this study was its inclusion only of patients with no underlying disease. Moreover, it was the first study to investigate a wide range of diseases, including medical and surgical diseases and trauma, and was conducted at a tertiary pediatric institution with a North American-style emergency room, which enabled patients with diverse diseases of varying severity to be included. The limitations were the relatively small number of cases of rare diseases and the inability to investigate the pathomechanism in each instance of hyponatremia.\u003c/p\u003e\n\u003cp\u003eIn conclusion, the present study determined the frequency and severity of hyponatremia in a variety of acute pediatric illnesses, including medical and surgical diseases and trauma. Although respiratory distress and pain induce vasopressin secretion, hyponatremia was rarely observed on admission in cases of acute bronchial asthma exacerbation, anaphylaxis, intussusception, acute scrotal diseases, head injury, and fracture.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank James Robert Valera for his editorial assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShoichiro Shirane: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing. Riku Hamada: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing \u0026ndash; review \u0026amp; editing. Yoshihiko Morikawa: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Validation, Writing \u0026ndash; review \u0026amp; editing. Ryoko Harada: Methodology, Writing \u0026ndash; review \u0026amp; editing. Yuko Hamasaki: Methodology, Writing \u0026ndash; review \u0026amp; editing. Kenji Ishikura: Methodology, Writing \u0026ndash; review \u0026amp; editing. Masataka Honda: Methodology, Supervision, Writing \u0026ndash; review \u0026amp; editing. Hiroshi Hataya: Supervision, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was granted by the Institutional Research Ethics Board of Tokyo Metropolitan Children\u0026rsquo;s Medical Center (2023b-116). Written informed consent of the patients and caregivers was waived. Consent to participate was implied in the opt-out clause on institutional website.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSpasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D et al (2014) Clinical Practice Guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 170:G1\u0026ndash;47. https://doi.org/10.1530/EJE-13-1020y\u003c/li\u003e\n\u003cli\u003eMoritz ML (2019) Syndrome of Inappropriate Antidiuresis. Pediatr Clin North Am 66:209\u0026ndash;226. https://doi.org/10.1016/j.pcl.2018.09.005\u003c/li\u003e\n\u003cli\u003eSharif-Naeini R, Ciura S, Bourque CW (2008) TRPV1 gene required for thermosensory transduction and anticipatory secretion from vasopressin neurons during hyperthermia. Neuron 58:179\u0026ndash;185. https://doi.org/10.1016/j.neuron.2008.02.013\u003c/li\u003e\n\u003cli\u003eSwart RM, Hoorn EJ, Betjes MG, Zietse R (2011) Hyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation. Nephron Physiol 118:45\u0026ndash;51. https://doi.org/10.1159/000322238\u003c/li\u003e\n\u003cli\u003eLehtiranta S, Honkila M, Anttila S, Huhtam\u0026auml;ki H, Pokka T, Tapiainen T (2022) The incidence, hospitalisations and deaths in acutely ill children with dysnatraemias. Acta Paediatrica 111:1630\u0026ndash;1637. https://doi.org/10.1111/apa.16348\u003c/li\u003e\n\u003cli\u003eMatsumura H, Ashida A, Shirasu A, Okasora K, Nakakura H, Hattori M (2022) Serum sodium level is inversely correlated with body temperature in children. Pediatr Int 64:e14841. https://doi.org/10.1111/ped.14841\u003c/li\u003e\n\u003cli\u003eKanda Y (2013) Investigation of the freely available easy-to-use software \u0026lsquo;EZR\u0026rsquo; for medical statistics. Bone Marrow Transplant 48:452\u0026ndash;458. https://doi.org/10.1038/bmt.2012.244\u003c/li\u003e\n\u003cli\u003eFeld LG, Neuspiel DR, Foster BA, Leu MG, Garber MD, Austin K et al (2018) Clinical Practice Guideline: Maintenance Intravenous Fluids in Children. Pediatrics 142:e20183083. https://doi.org/10.1542/peds.2018-3083\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence (2020) Intravenous fluid therapy in children and young people in hospital. National Institute for Health and Care Excellence (NICE): Guidelines 2020\u003c/li\u003e\n\u003cli\u003eFriedman JN; Canadian Paediatric Society, Acute Care Committee (2013) Risk of acute hyponatremia in hospitalized children and youth receiving maintenance intravenous fluids. Paediatr Child Health 18:102\u0026ndash;104.\u003c/li\u003e\n\u003cli\u003eLehtiranta S, Honkila M, Kallio M, Paalanne N, Peltoniemi O, Pokka T, Renko M, Tapiainen T (2021) Risk of Electrolyte Disorders in Acutely Ill Children Receiving Commercially Available Plasmalike Isotonic Fluids: A Randomized Clinical Trial. JAMA Pediatr 175:28\u0026ndash;35. https://doi.org/10.1001/jamapediatrics.2020.3383\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Sex, age, and frequency and severity of hyponatremia in the study population\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\n \u003cp\u003eNon-hyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e1,890\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\n \u003cp\u003e260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\n \u003cp\u003e1,630\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e1,125 (59.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\n \u003cp\u003e157 (60.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\n \u003cp\u003e968 (59.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.81*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003eAge (years), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e3 (1\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\n \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\n \u003cp\u003e3 (1\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.004**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003e Mild: Na 130\u0026ndash;134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e237 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003e Moderate: Na 125\u0026ndash;129 and asymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e20 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003e Severe: Na 125\u0026ndash;129 and symptomatic\u003cbr\u003e\u0026nbsp; \u0026nbsp; or Na 120\u0026ndash;124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e1 (0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.795918367346935%\" valign=\"bottom\"\u003e\n \u003cp\u003e Very\u0026nbsp;severe: Na \u0026lt; 120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.306122448979592%\" valign=\"bottom\"\u003e\n \u003cp\u003e2 (0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"bottom\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"bottom\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"bottom\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Pearson\u0026rsquo;s chi-square test, **Mann-Whitney U test\u003c/p\u003e\n\u003cp\u003eIQR, interquartile range; Na, serum sodium.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Frequency and severity of hyponatremia and the median and IQR of serum sodium for each major illness by sample size\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36%\" colspan=\"2\" rowspan=\"2\" style=\"width: 26.9495%;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" rowspan=\"2\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003eAge (years),\u003cbr\u003e\u0026nbsp;median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" rowspan=\"2\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.61538461538461%\" colspan=\"5\" style=\"width: 45.2982%;\"\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" rowspan=\"2\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003eSerum sodium (mEq/L),\u003cbr\u003e\u0026nbsp;median (IQR), mean (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.94273127753304%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.94273127753304%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.502202643171806%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.977973568281937%\" style=\"width: 5.1606%;\"\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.026431718061673%\" style=\"width: 5.1606%;\"\u003e\n \u003cp\u003eVery severe\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\n \u003cp\u003eMedical and surgical diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eLower respiratory tract infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e1 (0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e338\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e34 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e32 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003e1 (0.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\n \u003cp\u003e1 (0.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e138 (136\u0026ndash;139), 138 (137\u0026ndash;138)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eSeizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e58 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e58 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e136 (134\u0026ndash;137), 136 (135\u0026ndash;136)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eKawasaki disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e64 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e59 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003e5 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e134 (133\u0026ndash;136), 134 (134\u0026ndash;135)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eAcute bronchial asthma exacerbation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e4 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e4 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e139 (137\u0026ndash;143), 139 (138\u0026ndash;139)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eAcute appendicitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e10 (7\u0026ndash;12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e15 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e15 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e137 (136\u0026ndash;139), 137 (137\u0026ndash;138)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eAnaphylaxis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e4 (2\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e139 (138\u0026ndash;140), 139 (139\u0026ndash;140)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eFebrile urinary tract infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e11 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e10 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e136 (134\u0026ndash;138), 136 (135\u0026ndash;137)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eAcute gastroenteritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e4 (1\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e8 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e7 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e138 (136\u0026ndash;140), 138 (137\u0026ndash;139)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eIntussusception\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e139 (138\u0026ndash;140), 139 (138\u0026ndash;139)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eCellulitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e3 (1\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e5 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e5 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e137 (134\u0026ndash;138), 137 (135\u0026ndash;138)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eAcute scrotal diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e13 (12\u0026ndash;14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e140 (139\u0026ndash;141), 140 (139\u0026ndash;141)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eType 1 diabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e10 (3\u0026ndash;12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e11 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e7 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e133 (130\u0026ndash;135), 133 (130\u0026ndash;135)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eViral sepsis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e0 (0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e135 (132\u0026ndash;137), 135 (133\u0026ndash;136)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eLymphadenitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e3 (1\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e136 (134\u0026ndash;137), 136 (134\u0026ndash;137)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eIdiopathic nephrotic syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e3 (3\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e4 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e3 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e137 (133\u0026ndash;139), 135 (130\u0026ndash;139)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eMeningitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e0 (0\u0026ndash;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e3 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e3 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e136 (134\u0026ndash;139), 136 (134\u0026ndash;137)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eAcute encephalopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e4 (1\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e3 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e3 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e134 (132\u0026ndash;136), 135 (131\u0026ndash;140)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003ePyogenic arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e4 (2\u0026ndash;10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e3 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e1 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003e2 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e131 (129\u0026ndash;135), 132 (129\u0026ndash;135)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\n \u003cp\u003eTrauma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eFracture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e8 (6\u0026ndash;11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e139 (138\u0026ndash;140), 139 (139\u0026ndash;140)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eHead injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e5 (0\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e139 (138\u0026ndash;141), 139 (139\u0026ndash;140)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.846153846153847%\" style=\"width: 11.2385%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20.153846153846153%\" style=\"width: 15.8257%;\"\u003e\n \u003cp\u003eBurn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\" style=\"width: 7.1101%;\"\u003e\n \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4%\" style=\"width: 3.3257%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e1 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.615384615384615%\" style=\"width: 12.3853%;\"\u003e\n \u003cp\u003e1 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.461538461538462%\" style=\"width: 10.3211%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.230769230769231%\" style=\"width: 5.1606%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6923076923076925%\" style=\"width: 5.1606%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.46153846153846%\" style=\"width: 6.8807%;\"\u003e\n \u003cp\u003e136 (136\u0026ndash;138), 136 (135\u0026ndash;138)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIQR, interquartile range; CI, confidence interval\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Hyponatremia, acute illness, medical disease, surgical disease, trauma, syndrome of inappropriate secretion of antidiuresis","lastPublishedDoi":"10.21203/rs.3.rs-4224559/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4224559/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHyponatremia can occur in the acute phase of any illness through various mechanisms. However, the frequency and severity of hyponatremia are not well known across a broad range of illnesses including medical and surgical diseases and trauma.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e The present, retrospective chart review was conducted at Tokyo Metropolitan Children\u0026rsquo;s Medical Center from 2018 to 2019. Included were healthy children aged\u0026thinsp;\u0026lt;\u0026thinsp;16 years with an acute illness who were urgently admitted and had their serum sodium level measured on admission.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 2,717 patients were urgently admitted and had their serum sodium level measured. Of these, 1,890 were included. Hyponatremia occurred in 260 patients (13.8%). The most common hyponatremic disease was type 1 diabetes mellitus (69%) followed by acute encephalopathy (60%), pyogenic arthritis (60%), and Kawasaki disease (51%). Kawasaki disease, seizure, urinary tract infection, acute appendicitis, lower respiratory tract infection, and acute gastroenteritis were associated with a significantly lower serum sodium value than cases of fracture comprising a control group. Conversely, acute bronchial asthma exacerbation (3%), anaphylaxis (0%), intussusception (0%), acute scrotal disease (0%), head injury (1%), and fracture (0%) were very infrequently associated with hyponatremia.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe present study determined the frequency and severity of hyponatremia in various, acute, pediatric illnesses, including medical and surgical diseases and trauma. Despite reports of respiratory distress and pain inducing vasopressin secretion, hyponatremia was rarely observed on admission in cases of acute bronchial asthma exacerbation, anaphylaxis, intussusception, acute scrotal diseases, head injury, and fracture.\u003c/p\u003e","manuscriptTitle":"Frequency and severity of hyponatremia in healthy children with acute illnesses","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-10 17:41:28","doi":"10.21203/rs.3.rs-4224559/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2024-04-29T13:20:01+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-04-05T22:56:28+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-05T22:44:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-05T22:07:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2024-04-05T15:08:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"17e9c52e-1418-4321-a8ed-ff4c46322108","owner":[],"postedDate":"April 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T15:59:34+00:00","versionOfRecord":{"articleIdentity":"rs-4224559","link":"https://doi.org/10.1007/s00467-024-06550-y","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2024-10-09 15:57:07","publishedOnDateReadable":"October 9th, 2024"},"versionCreatedAt":"2024-04-10 17:41:28","video":"","vorDoi":"10.1007/s00467-024-06550-y","vorDoiUrl":"https://doi.org/10.1007/s00467-024-06550-y","workflowStages":[]},"version":"v1","identity":"rs-4224559","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4224559","identity":"rs-4224559","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}