P < 0.0001) but not with the remaining factors. Gelatin zymography detected proMMP‐9 in serum samples of healthy and COPD smoking groups. Our results suggest that associated serum levels of proMMP‐9, NGAL, proMMP‐9/NGAL and NE may reflect the state of systemic inflammation in COPD related to cigarette smoking.A growing body of evidence points towards smoking‐related phenotypic differences in chronic obstructive pulmonary disease (COPD). As COPD is associated with systemic inflammation, we determined whether smoking status is related to serum levels of matrix metalloproteinase‐9 (pro‐ and active MMP‐9), neutrophil gelatinase‐associated lipocalin (NGAL) and the proMMP‐9/NGAL complex in patients with COPD. Serum samples were collected in 100 stable‐phase COPD patients  and 28 healthy adults . Serum levels of studied factors were measured in ELISA. Our data provide the first evidence of simultaneously elevated serum levels of MMP‐9, NGAL and proMMP‐9/NGAL in COPD smokers. While the triad discriminated between smokers and non‐smokers in the COPD group, MMP‐9 and proMMP‐9/NGAL (but not NGAL) discriminated between smokers with and without COPD. Adjustment for age and smoking pack‐years did not alter the findings. Serum MMP‐9, NGAL and proMMP‐9/NGAL levels were not correlated with the GOLD stage or FEV1 decline. Furthermore, serum levels of neutrophil elastase (NE) and MMP‐3 (but not of IL‐6 and MMP‐12) were also higher in COPD smokers than in healthy smokers before and after adjustment for age and pack‐years. Among COPD smokers, levels of MMP‐9, NGAL and proMMP‐9/NGAL were positively correlated with NE ( COPD is characterized by chronic inflammation of the airways and the lung parenchyma, leading to progressive, partially reversible or irreversible airway constriction via the degradation of elastin and the modulation of inflammatory processes i) increased levels of serum MMP‐9 were not related to the decline in FEV1 ii) lower levels of serum MMP‐9 correlated with the disease severity Several proteinases are thought to be involved in the pathophysiology of COPD by destroying the extracellular matrix and by regulating inflammation via a covalent bond) to proMMP‐9 to form a 130‐kD disulphide‐linked heterodimer et al. et al. NGAL is a secreted 25‐kD protein that can bind  as a novel means of increasing treatment effectiveness in COPD n = 100) were enrolled at the Departments of Pulmonology and Physiology at Farhat Hached Hospital . Healthy adults  were recruited from the National Blood Transfusion Center . All participants lived on the Tunisian central coast. Airflow limitation in COPD is defined as a post‐bronchodilator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio below 70%, and FEV1 reversibility below 12% of the pre‐bronchodilator value after the inhalation of 400 μg of salbutamol. The COPD was staged in accordance with the GOLD guidelines; GOLD I (mild): FEV1 ≥80% predicted; GOLD II (moderate): FEV1 <80% and ≥50% predicted; GOLD III (severe): FEV1 <50% and ≥30% predicted; and GOLD IV (very severe): FEV1 <30% predicted. The COPD was considered to be stable if the patient had not experienced an exacerbation in the 8 weeks prior to the study. The included patients were only taking short‐ or long‐acting β2‐agonists, and they were requested to refrain from taking any medication in the 24 hrs before study measurements were taken. The main exclusion criteria  were as follows: neoplastic, metabolic or inflammatory disease, heart failure, current ischaemic symptoms, inhaled/oral corticosteroid treatment or lung disease (other than COPD for patients). The study was approved by the local independent ethics committee . All included persons provided their written, informed consent to participation.We defined COPD according to the GOLD criteria. COPD patients with mild, moderate, severe and very severe disease . All measurements complied with the American Thoracic Society's standards. Forced vital capacity and FEV1 were measured from a series of at least three forced expiratory curves. Spirograms were validated for analysis if they were free from artefacts (such as a cough or glottis closure) and if they had good initial sections with an extrapolated volume of less than 5% of the FVC. The exhaled breath manoeuvre lasted for at least 6 sec. After three acceptable manoeuvres, the two highest values for FVC and FEV1 had to be within 0.15 l of each other.Lung function was evaluated using whole‐body plethysmography  were isolated from the samples using Histopaque®‐1077 density gradient centrifugation. Cell pellets were frozen at −80°C until RNA extraction and analysis.Blood samples were collected within the same period from the patients with COPD and the healthy controls. Serum was immediately separated, aliquoted and frozen at −80°C pending further analyses. Peripheral blood mononuclear cells  and proMMP‐9/NGAL were analysed using 7.5% (w/v) SDS–polyacrylamide gels containing 0.1% gelatin (w/v), as described in RNA was extracted from PBMCs, and cDNA was synthesized as described in Genomic DNA was extracted from PBMCs in a salting‐out procedure, as previously described Levels of total (pro and active) MMP‐2, MMP‐3, MMP‐7 and MMP‐9, NGAL, proMMP‐9/NGAL (130 kD), IL‐6 and TNF‐α were determined using commercial ELISA kits . An ELISA for NE was purchased from Abcam , and an ELISA for (pro and active) MMP‐12 was obtained from Boster Biological Technology . The minimum detectable dose was 33 pg/ml for MMP‐2 and MMP‐12, 100 pg/ml for MMP‐9, 9–16 pg/ml for MMP‐3, MMP‐7, NGAL and proMMP‐9/NGAL, 1–2 pg/ml for IL‐6 and NE and 0.1 pg/ml for TNF‐α. The coefficients of variation of the intra‐ and interassay values were, respectively, 1.9–2.9% and 6.9–7.9% for MMP‐9, 3.6–7% and 6.5–7% for MMP‐2, 5.7–6.4% and 7–8.6% for MMP‐3, 3.4–5.1% and 4.1–4.6% for MMP‐7, 3.6–4.4% and 5.6–7.9% for NGAL, 2.3–4.1% and 5.1–7.6% for proMMP‐9/NGAL, 1.6–4.2% and 3.3–6.4% for IL‐6, 3.1–8.7% and 7.2–10.4% for TNF‐α, 4.8% and 5.6% for NE and 4.5–6% and 5.4–7.2% for MMP‐12. All assays were performed in accordance with the manufacturer's instructions. Wide variations in serum NGAL values exist within the healthy population  t‐test, the Mann–Whitney U‐test or an analysis of variance. Spearman's correlation coefficient was calculated as a guide to the relationships between MMP, NGAL, proMMP‐9/NGAL, NE and IL‐6 levels and respiratory parameters. An analysis of covariance was used to assess MMPs, proMMP‐9/NGAL, NGAL, NE and IL‐6 levels in healthy smokers  and COPD smokers (the COPD‐S group) as a function of age and pack‐years. All statistical analyses were performed using SPSS® software  and GraphPad Prism software . The threshold for statistical significance was set to P < 0.05.Data were expressed as the mean ± S.E.M. or the median . Groups were compared using Student's versus 17.39 ± 12.89, respectively; Table A total of 128 participants (28 controls and 100 patients with COPD) were included in the study. The participants’ demographic and clinical characteristics are summarized in Table P = 0.04 versus COPD‐S) and the COPD‐NS group  and the COPD‐NS group . There were no significant differences in either MMP‐9 or complex levels when comparing the healthy‐NS, healthy‐S and COPD‐NS groups . Likewise, serum NGAL levels were significantly higher in the COPD‐S group than in the COPD‐NS group . Moreover, there were no significant differences in the serum levels of MMP‐9, proMMP‐9/NGAL or NGAL between the two COPD‐S subgroups, .that is GOLD stage I/II and GOLD stage III/IV (Table P ≥ 0.33).The data on healthy controls and patients with COPD were categorized according to smoking status. All the serum assays of (pro and active) MMP‐9, NGAL and proMMP‐9/NGAL were performed at the same time‐point Fig. . Serum Mversus 46.89 ng/ml, respectively, P = 0.006; IL‐6: 3.13 versus 2.25 pg/ml, respectively; P = 0.001, both in a Mann–Whitney U‐test). However, there were no significant differences in NE or IL‐6 levels between the COPD‐S and COPD‐NS subgroups (P > 0.06). After adjustment for age and pack‐years, NE levels (but not IL‐6 levels) were still significantly higher in the COPD group than in the healthy controls . Serum levels of both NE and IL‐6 did not differ when comparing the two COPD‐S subgroups  but was not correlated with IL‐6 (P = 0.7).As serum NE and IL‐6 levels have been found to be associated with COPD r = 0.48, P = 0.03; Fig. r = 0.16, P = 0.48; Fig. r = 0.24, P = 0.28; Fig. r = 0.84, P < 0.0001; Fig. r = 0.56, P < 0.0001; Fig. r = 0.53, P < 0.0001; Fig. We first investigated correlations between serum levels of (pro and active) MMP‐9, NGAL and the proMMP‐9/NGAL complex in the COPD‐S and healthy‐S groups. In the healthy‐S subgroup, we observed a positive correlation between MMP‐9 and proMMP‐9/NGAL levels  but was not correlated with levels of the other MMPs (P ≥ 0.09). Furthermore, the correlations between the serum levels of MMP‐2, MMP‐3, MMP‐12 on one the hand and MMP‐9, NGAL, the complex and NE on the other were also evaluated in the COPD‐S group: we identified a single, negative correlation between MMP‐2 and NE .We examined the serum levels of (pro and active) MMP‐2/MMP‐3/MMP‐7 and MMP‐12 proteins in the healthy‐S and COPD‐S groups. The serum level of MMP‐2 was lower in the COPD‐S group than in the healthy‐S group  in the serum of healthy individuals , PBMCs from both groups expressed detectable levels of MMP‐9, NGAL, MMP‐12, MMP‐2 and IL‐6 transcripts . In contrast, FEV1% predicted was not correlated with levels of NGAL, MMP‐2, MMP‐12 or IL‐6 transcripts in the COPD‐S group (P ≥ 0.1).We next used a semiquantitative RT‐PCR method to profile the expression of MMP‐2/MMP‐9/MMP‐12, NGAL and IL‐6 transcripts in PBMCs isolated from blood samples of 19 COPD‐S patients and 12 healthy‐S participants . As shown in Figure pts Fig. A. The mepts Fig. B; in conpts Fig. C. The diversus smokers. The proportions of patients with the C‐1562T genotype in COPD‐NS and COPD‐S groups were within the same range , and the respective serum levels of MMP‐9 were similar .We previously reported that serum MMP‐9 levels were significantly higher in COPD patients with the CT genotype (regardless of smoking status) than in healthy controls n = 100) displayed higher serum MMP‐9 levels than the 28 healthy adults . In patients with COPD, MMP‐9 levels were significantly correlated  with the degree of airway obstruction. This observation emphasizes the bias caused by underestimating the impact of cigarette smoking on MMP‐9 levels Serum MMP‐9 and NGAL merit further investigation as putative, specific biomarkers of smoking status in COPD. To the best of our knowledge, the potential value of the proMMP‐9/NGAL complex in the pathogenesis of COPD has not previously been investigated. In the present study of a well‐characterized cohort of healthy and COPD smokers and non‐smokers, we observed that serum levels of MMP‐9, NGAL and proMMP‐9/NGAL were higher in COPD smokers than in COPD non‐smokers. Whereas levels of MMP‐9 and the proMMP‐9/NGAL complex discriminate between COPD smokers and healthy smokers, NGAL appears to be a marker of smoking status (irrespective of disease status). However, these relationships would need to be confirmed in a more extensive study of a larger cohort of healthy non‐smokers and smokers. In healthy adults, serum NGAL is correlated with age Our results highlighted the previously reported COPD‐related elevations in serum levels of NE and MMP‐3, irrespective of the patients’ smoking status The present study is the first to highlight the interrelationships between serum levels of MMP‐9, NGAL, the proMMP‐9/NGAL complex and NE in COPD smokers. There is growing evidence to suggest that the release of specific factors by blood monocytes and neutrophils contributes to chronic inflammation in COPD et al. Gene expression profiles in blood monocytes may serve as diagnostic markers in COPD Our study constitutes a step forward in the identification and validation of serum biomarkers for COPD in cohort trials. Serum MMP‐9, NGAL, proMMP‐9/NGAL and NE appear to be reliable, interlinked biomarkers of smoking status in COPD. It remains to be determined whether the association between these biomarkers reflects a causal relationship. In healthy adults and patients with COPD, serum MMP‐9 is mainly present as proMMP‐9. It is known that NE can activate proMMP‐9 S. Bchir collected clinical samples, designed the study, analysed and interpreted data and revised the manuscript for critical content. H. ben Nsar collected clinical samples. S. Bouchet provided critical technical support in experimental design and data analysis. M. Benzarti, A. Garrouch and Z. Tabka collected clinical samples and recorded the demographic and clinical characteristics of participants. S. Susin provided critical enhancement of data and revised the manuscript for critical content. K. Chahed contributed to the study design and revised the manuscript for critical content. B. Bauvois contributed to experimental design, analysed and interpreted data, performed a literature review and wrote up the main structure of the manuscript. All authors read and approved the submitted manuscript.The authors declare no conflict of interests.Table S1 P‐values of serum concentrations of MMPs, NGAL, proMMP‐9/NGAL, NE and IL‐6 between healthy smokers and COPD smokers, before and after adjustment for age and pack years.Click here for additional data file.Table S2 Mutual correlations among (pro and active) MMPs, proMMP‐9/NGAL, NGAL, NE and IL‐6 in serum from COPD smokers.Click here for additional data file.Table S3 Demographic and clinical characteristics of healthy and COPD smokers.Click here for additional data file.Figure S1 RT‐PCR analysis of MMP‐2/‐12 and IL‐6 transcripts in PBMCs from healthy smokers and COPD smokers.Click here for additional data file.


A 23-year-old East Indian woman with no significant medical history, except a depot-norethisterone enanthate injection taken 3 weeks prior to admission, presented with a gradually worsening headache for the past 5 days. She had no fever, vomiting, neck stiffness, focal weakness or rash, and examination was unremarkable with no focal neurological deficits. Vasculitic, thrombophilia and sepsis screens were normal. A brain CT scan showed a left parietal lobe venous infarct, secondary to a venous dural sinus thrombosis, with MRI and Magnetic Resonance Venogram (MRV) confirming a signal void. She was diagnosed to have multiple cerebral venous sinus thrombosis due to norethisterone enanthate. She made a complete recovery following treatment with mannitol, dexamethasone and anticoagulants. A follow-up brain MRI done at 6 months was normal. Thereafter, she sought emergency medical attention at a District Health Facility where she was treated with analgesia and discharged the same day. However, she had no significant relief in her headache. Five days after the initial onset of her symptoms, the headache worsened, and was associated with multiple episodes of vomiting and one episode of syncope lasting 2–3 min. She experienced no fever, blurred vision, photophobia, gait disturbance, seizure activity or focal sensory and motor deficit. She had no history of head trauma or neck stiffness. She had not taken any over-the-counter medication or prescription medicines such as antipsychotics or herbal medications, except norethisterone enanthate depot injections, which she received every 2 months for 2 years as a contraception following the birth of her last child. Her last dose was 3 weeks prior to the commencement of her symptoms. She was neither diabetic, hypertensive nor had hypercholesterolaemia. Additionally, she had no significant family history, did not smoke and only had alcohol occasionally.Examination on admission revealed a listless, exhausted patient with a Glasgow Coma Scale score of 15/15. She was oriented in time, place and person. Her blood pressure was 107/72 mm Hg, and pulse was 80 beats per minute and regular. Central nervous system examination revealed no abnormalities. Rest of the neurological examination, including cranial nerves, sensory and motor systems, deep tendon reflexes and planters were normal. Kernig’s and Brudzinski’s signs were negative.All routine blood investigations, including complete blood count, liver function tests, renal function tests, fasting lipids and electrolytes were all within normal limits. Furthermore, prothrombin time, partial thromboplastin time and international normalised ratio (INR) were 11 s, 26.2 s and 1.03, , respectively, as well as an estimated sedimentary rate of 23 mm/hour (0–15) and C reactive protein was 0.7 mg/dL (0–0.5). Antiphospholipid and thrombophilia screens were normal: Protein C 95.6% (70–140), Protein S 113% (63–135), Factor V Leiden 34.6 s (28–50), antithrombin III 117% (85–125) and anticardiolipin antibodies IgA 2.2 (<12 APL U/mL), IgG <2 (<12 GPL U/mL) and IgM 3.70 (<12 MPLU/mL). Urinalysis was normal. A brain CT scan  showed tA diagnosis of drug (norethisterone enanthate)-induced CVST was considered.The patient was treated with antioedema measures comprising mannitol 50 mL intravenously two times for 24 hours and dexamethasone 4 mg orally one time for 3 days. Anticoagulation was initiated with warfarin after bridging with low-molecular-weight heparin enoxaparin.The patient recovered completely within 1 week and was discharged. Her condition remained well throughout her follow-up visits. Anticoagulation was continued for 6 months as recommended, though recanalisation is expected after 3 months of anticoagulation therapy.A follow-up MRI brain with a venogram , performet al, analysed adult cerebral thromboses in 19 hospitals located in two Dutch provinces serving 3.1 million, (which is approximately three times the population of Trinidad), between 1 January 2008 and 31 December 2010. The study revealed an overall annual incidence of 1.32 per 100 000, a significantly higher incidence in women than men (1.86 vs 0.75), and a higher incidence among patients aged 31–50 years (1.71) with a median age of 41 years. Additionally, 52% of female patients used oral contraceptives, and 18% were pregnant or had recently given birth.7CVST is a rare and potentially fatal condition. This patient’s presentation with a severe headache is present in 90% of the cerebral venous thromboses cases; the list of differential diagnoses can be infectious, inflammatory, structural and even psychological disorders.Diagnosis of CVST is made using contrast-enhanced CT, MRI or MRV. Contrast-enhanced CT shows the classic empty delta sign, as was seen in this case . This is9et al analysed data from the International Study on Cerebral Vein and Dural sinus Thrombosis (ISCVT), a multicentre prospective observational study, and found that 465 of the 624 patients were women (75%), and a gender-specific risk factor  was present in 65% of the women. Women had a better prognosis than men (complete recovery 81% vs 71%). Congenital and acquired thrombophilia carried similar percentages for men and women . Of note, the incidence of infection and malignancy, as causes of CVST, were two times higher in men than in women .12Thrombosis of the cerebral veins causes local effects by venous obstruction, which results in oedema of the brain and venous infarction. Thrombosis of the major sinuses causes impaired absorption of cerebrospinal fluid (CSF) and intracranial hypertension.The patient’s blood and urine investigations were within normal limits. Dehydration was excluded in view of her moist mucous membranes, normal skin turgor and renal function tests. She had no predisposing risk factors associated with cerebral vein thrombosis, except for the use of the progestin-only contraceptive injection.Many observational studies have shown that combined oral contraceptives are associated with a twofold to sixfold increased risk of venous thrombosis.et al monitored 56 women using depot-norethisterone enanthate injections for 2 years and compared them to a control group of 48, and found there were no significant differences between the treatment and control groups with respect to factor VIIc and antithrombin. Factor Xc, however, was reduced in women who had taken the injections for over 2 years, but less than 5 years; while haemoglobin levels, red cell count and packed cell volume were higher in the treatment group as compared with those in the control group. Therefore, this study concluded that long-term use of norethisterone enanthate is not associated with any markedly deleterious effects on factors VIIc and Xc, antithrombin III or haemoglobin levels.18 20A study performed by McEwan The main priority in the treatment for CVST is stabilisation, prevention or reversal of cerebral oedema, and herniation with intravenous mannitol, (which was used in our patient) or decompressive hemicraniectomy, and/or removal of haemorrhagic infarct with surgical procedures.The prognosis of CVST is usually favourable, with more than 80% of patients, as in our case, having a good neurological outcome.24Cerebral venous sinus thrombosis (CVST) is a rare condition, and its presentation can mimic various benign conditions.Clinicians should have a high level of suspicion, identifying aetiology and predisposing conditions, to facilitate a prompt diagnosis.More research is needed to confirm or exclude a causal link between norethisterone enanthate and CVST.CVST management should be aggressive to ensure the best possible outcome for patients.Prognosis for CVST is usually favourable.


Among treatment modalities for lung cancer, the most promising therapy is the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs). Both erlotinib and gefitinib, the two first‐generation EGFR‐TKIs, exhibit significant clinical responses for patients with lung adenocarcinoma. However, few studies have compared the effects of these two drugs, and results have been inconclusive because of the small sample sizes in these studies. Therefore, this study was conducted to investigate this issue. This retrospective nationwide cohort study enrolled NSCLC patients who received EGFR‐TKIs after previous chemotherapy in Taiwan between 1996 and 2010 from the National Health Insurance Research Database. Clinical response and survival after receiving erlotinib and gefitinib were compared using logistic and Cox regression analyses, respectively. Inverse propensity score weighting and a sensitivity analysis in the EGFR‐TKI responder , adherent patients (receiving EGFR‐TKI on a daily basis), adenocarcinoma, and adenocarcinoma with second‐line TKIs subgroup were performed for bias adjustment. A total of 7222 patients, including 4592 (63.6%) who received gefitinib, were identified. In the survival analysis, erlotinib was associated with a decline in 1‐year progression‐free survival (PFS)  and overall survival (OS) (HR: 1.10 [1.03–1.18]). The effects of various TKIs were consistent in the 4939 EGFR‐TKI responders, adherent subgroup, adenocarcinoma subgroup, and adenocarcinoma with second‐line TKIs subgroup. In previously treated EGFT‐TKI‐naive NSCLC patients, those receiving gefitinib exhibited a longer PFS and OS than those receiving erlotinib. Additional large‐scale randomized controlled trials are warranted to confirm this finding. Lung cancer is the leading cause of cancer‐related deaths worldwide The practice of lung cancer treatment in Taiwan follows the National Comprehensive Cancer Network (NCCN) guideline. In 2009, the first‐line systemic therapy for advanced NSCLC is platinum‐based doublet chemotherapy and the second‐line therapy was single‐agent chemotherapy, erlotinib or gefitinib The NHI program in Taiwan has provided mandatory universal health insurance with comprehensive medical care coverage since 1996, and it currently covers more than 99% of residents in Taiwan The Institutional Review Board of National Taiwan University Hospital approved the study (NTUH REC: 201212001W) and waived the need for informed consent because of the retrospective design and use of an encrypted database.Lung cancer patients were selected using a compatible diagnosis  from the Registry of Catastrophic Illness Patients Database, a subset of the NHIRD. To apply to this registry, histological confirmation is obligatory. The index date was defined as the date that patients applied to this registry for lung cancer.The NHIRD was searched for key chemotherapy drugs for NSCLC according to the National Comprehensive Cancer Network Guidelines for NSCLC; the search included gemcitabine, vinorelbine, docetaxel, paclitaxel, etoposide, and pemetrexed The EGFR‐TKIs investigated in this study were gefitinib and erlotinib. Afatinib had not yet been approved by NHI during the study period. The prescription duration of individual EGFR‐TKIs was converted from the claims data according to the defined daily doses (DDDs) Patients who started EGFR‐TKIs earlier than the end date of first‐line chemotherapy were excluded. Patients who first received EGFR‐TKIs in 2010 or later were also excluded to ensure at least 1 year of follow‐up. The complete selection process is presented in Figure Comorbidities such as chronic obstructive pulmonary disease (COPD), diabetes mellitus, chronic kidney disease (CKD), liver cirrhosis, pneumoconiosis, autoimmune disease, organ transplantation, AIDS, and other malignancies were identified according to a previous study We used several surrogates between the index date and start date of EGFR‐TKI use to adjust for disease severity between gefitinib and erlotinib for possible selection bias by primary physicians. These surrogates, including cachexia t test or Mann–Whitney U test for continuous variables on the basis of their normality, and the chi‐squared test or Fisher's exact test was used for categorical variables, as appropriate. For each variable, 1‐year PFS and 1‐year OS (both from the start of EGFR‐TKI use) were generated using the Kaplan–Meier method and compared using the log‐rank test. Cox proportional hazards regression analysis was performed to identify the independent prognostic factors.For previously treated EGFT‐TKI‐naive NSCLC patients and the EGFR‐TKI responders among them, intergroup differences were compared using the We derived a propensity score, which is the logit (probability) for receiving erlotinib or gefitinib treatment from a multinomial logistic regression model by using crucial background covariates, including age, gender, operation, cachexia, IICP, PRBC transfusion, duration of hospitalization (days), COPD, diabetic mellitus, CKD, other malignancy, autoimmune disease, liver cirrhosis, transplantation, AIDS, and low income. Inverse propensity score weighting (IPSW) was used in the Cox model to adjust for potential confounders in selecting erlotinib and gefitinib P < 0.05. All analyses were conducted using SPSS version 20.0 , except the IPSW, which was performed using R version 3.3.1 .In the multivariate analysis, potential interactions between variables were checked, and all variables were included. Statistical significance was set at Sensitivity analysis was performed to evaluate the impact of erlotinib versus gefitinib in three subgroups: EGFR‐TKI adherent population, histological adenocarcinoma, and second‐line TKIs for adenocarcinoma.Adherence to EGFR‐TKI was assessed by calculating the total DDD of EGFR‐TKIs divided by the duration between the start and end dates of EGFR‐TKI use (medication possession ratio) For the 1996–2010 period, a total of 112,356 lung cancer patients were identified; 42,524 of them had previously received first‐line chemotherapy. Among these patients, 9156 patients were prescribed erlotinib or gefitinib after first‐line chemotherapy. Among them, 1934 patients received EGFR‐TKIs after 2009 and were excluded from the analysis. The final sample comprised 7222 patients; 4592 (63.6%) received gefitinib and 2630 (36.4%) received erlotinib  who were older  and had cachexia , IICP , a shorter duration of hospitalization , COPD , and higher drug adherence . The findings were similar in the EGFR‐TKI responders (Table P < 0.001) and had IICP , a shorter duration of hospitalization , COPD , and lower drug adherence .In the whole cohort, the erlotinib group mostly comprised men , older (OR: 1.01 [1.00–1.01] for per‐year increment in age), had cachexia (OR: 1.16 [1.05–1.28]), IICP (OR: 1.15 [1.04–1.28]), and were low‐income earners (OR: 1.57 [1.13–2.20]). By contrast, patients with longer duration of hospitalization (OR: 0.998 [0.997–1.000]) and autoimmune disease (OR: 0.48 [0.24–0.98]) were more likely to use gefitinib. All these factors were included in the propensity score calculation.In whole cohort, the Kaplan–Meier analysis revealed that the erlotinib group had a poorer 1‐year PFS than the gefitinib group    Three retrospective studies have compared erlotinib with gefitinib beyond first‐line therapy in NSCLC patients, all of which reported similar efficacy and outcomes between erlotinib and gefitinib, regardless of EGFR status Because a larger cohort was used, this study demonstrated a significantly higher 1‐year PFS and OS in patients receiving gefitinib compared with those receiving erlotinib. The results were consistent after adjusting for disease severity, comorbidities, and factors affecting the decision of selecting either erlotinib or gefitinib. Further analyses revealed that gefitinib use remained a strong predictor for longer PFS and OS in EGFR‐TKI responders, adherent patients, adenocarcinoma patients, and adenocarcinoma patients receiving EGFR‐TKIs as second‐line therapy. In contrast to previous studies that used smaller samples (242–716 patients) Several possible explanations can be offered for the superior therapeutic effect of gefitinib. First, the MTD was selected for erlotinib (150 mg/day) but not for gefitinib (250 mg/day) This study has some limitations. First, information on the initial staging of lung cancer was not available. Although we used pulmonary surgery as a surrogate for early‐stage lung cancer and the survival difference between erlotinib and gefitinib remained significant after adjusting for this factor, some bias may have remained. Second, results of molecular testing for EGFR gene mutation were not available in the cohort. Because the approval of EGFR‐TKI use for > 90 days in Taiwan requires a reaudit based on the therapeutic response, we used the prescription duration of TKI > 90 days as a marker for sensitive EGFR gene mutation. The advantage of gefitinib remained in the whole cohort, EGFR‐TKI responders, and the sensitivity analysis. Third, the performance status of each patient was unavailable. Therefore, the presence of cachexia, IICP, red blood cell transfusion, and longer duration of hospitalization were used as surrogates for disease severity. Nevertheless, bias may have still affected the results. Lastly, because the EGFR mutation rate is different between white and Asian populations The result of this study provides evidence that the efficacy of two first‐generation EFGR‐TKIs varies. Gefitinib appears to be more effective than erlotinib in previously treated NSCLC patients. Additional prospective, large‐scale, randomized control trials are necessary to confirm this finding.The authors have no conflicts of interests to declare.


Enterococcus strains isolated from traditional naturally fermented cream in China. Four Enterococcus isolates showed high cholesterol removal ability in media were identified as Enterococcus durans (KLDS 6.0930 and 6.0933) and Enterococcus faecalis (KLDS 6.0934 and 6.0935) by 16S rRNA and pheS gene sequences, respectively, and selected for further evaluation. In order to assess the probiotic potential and safety of these strains, the property of four Enterococcus strains were examined, including acid and bile tolerance, adherence to Caco‐2 cells and antibiotics susceptibility. All four strains showed potential cholesterol assimilation, de‐conjugation of bile salts and/or cholesterol degradation to remove cholesterol in vitro. In addition, the potential effect of E. durans KLDS 6.0930 on serum cholesterol levels was evaluated in Sprague‐Dawley rats. After 4 weeks administration, compared with rats fed a high‐cholesterol diet without lactic acid bacteria supplementation, there was a significant (P < 0.05) decrease in the total cholesterol and low‐density lipoprotein cholesterol levels in the serum of rats treated with KLDS 6.0930. Furthermore, total bile acid level in the feces was significantly (P < 0.05) increased after KLDS 6.0930 administration. These observations suggested that the strain E. durans KLDS 6.0930 may be used in the future as a good candidate for lowering human serum cholesterol levels.The purpose of this study was to evaluate the probiotic properties of  In general, these probiotic bacteria are also predominant organisms in the traditional fermented dairy products, such as Jiaoke, which is a homemade naturally fermented cream in Inner Mongolia of China  is a leading cause of death worldwide, and over 80% of CVD deaths take place in low and middle‐income countries WHO, . ElevateEnterococcus strains from the Jiaoke based on the cholesterol‐reducing activity, and to determine the cholesterol removal mechanisms of these strains from media, and then to evaluate their acid and bile tolerance, adhesion abilities to Caco‐2 cells and antibiotics susceptibility. A strain of Enterococcus showing desirable properties was further screened for assay of its cholesterol‐lowering effects in rats.The aims of the present study were to select probiotic Jiaoke. Four isolates were selected for further research based on the cholesterol removal ratio. Table In total, 23 strains of Gram‐positive, catalase‐negative, globular‐shaped isolates were obtained from 20 samples of pheS) gene sequences were created . These results showed that the KLDS 6.0930 and KLDS 6.0933 isolates were identified by 16S rRNA and pheS gene sequences as Enterococcus durans, while the KLDS 6.0934 and KLDS 6.0935 isolates were Enterococcus faecalis.The phylogenetic trees based on the 16S rRNA and phenylalanyl‐tRNA synthase alpha chain  after 2 h.The effect of an acidic pH  on the survival of the Enterococcus strains in de Man, Ragosa and Sharpe (MRS) broth without bile was used as control. The data exhibited that E. durans KLDS 6.0930 strain was better than other isolates growth in both MRS broth and MRS broth supplemented with bile. The times required to increase the A620 nm reading by 0.3 units were 3.9 h and 4.7 h when KLDS 6.0930 was grown in MRS broth and MRS broth plus 0.3% oxgall respectively. The significant differences (P < 0.05) were observed among the four strains in the tolerance to bile.The effect of bile on the growth of isolates was evaluated and shown in Table Enterococcus strains were examined for their ability to adhere to Caco‐2 cells. The results were shown in Fig. P < 0.05) stronger adhesion ability than other isolates, and the adhesion rate was 17.2%. The adhesion rate of strains KLDS 6.0930, KLDS 6.0933 and KLDS 6.0935 were 1.6%, 0.5% and 1.3% respectively.All the ‐1. Regarding the vancomycin, E. durans KLDS 6.0930 and KLDS 6.0933 were found to be susceptible, while E. faecalis KLDS 6.0934 and KLDS 6.0935 were not completely inhibited at 1024 μg ml‐1. Moreover, the two E. faecalis strains could be inhibited by chloramphenicol, while the two E. durans strains could be completely inhibited at 16 μg ml‐1. Subsequently, all antibiotic‐resistant strains were investigated for the presence of antibiotic‐resistance genes by polymerase chain reaction (PCR)‐based detection technology. From the results of PCR amplification, none of the tested antibiotic‐resistance gene was detected in all experimental strains.The resistance levels to antibiotic were detected for the four isolates and were shown in Table P > 0.05) was observed on body weight gain, food intake or food efficiency. This indicates that all rats grew in similar patterns.All the experimental rats were generally healthy throughout the feeding trial period, and their body weight gain, food intake and food efficiency were recorded and calculated for all the groups after 28 day gavage as indicated in Table P < 0.05) lower serum TC and LDL‐C levels compared with the high‐cholesterol diet control group. The reduction in TC and LDL‐C levels was 19.1% and 27.7% in the KLDS 6.0930 group respectively. However, no significant differences (P > 0.05) were observed in serum TG and HDL‐C levels between the KLDS 6.0930 group and high‐cholesterol diet control group.The effect of dietary treatments on serum lipid profile, including total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C) and high‐density lipoprotein cholesterol (HDL‐C), was shown in Fig. P < 0.05). The fecal total bile acid excretion in rats fed the KLDS 6.0930 diet was significantly higher than that of other groups. Moreover, the fecal bile acid content in rats fed on the normal diet was significantly lower than that of the high‐cholesterol diet control group (P < 0.05).As shown in Fig. Lactobacillus and Bifidobacterium, have exerted cholesterol‐lowering activity in vitro or in vivo, but few of Enterococcus strains was reported. For this reason, four Enterococcus strains isolated from Jiaoke were screened on the basis of the cholesterol removal ability in media, and identified as E. durans (KLDS 6.0930 and 6.0933) and E. faecalis (KLDS 6.0934 and 6.0935) by 16S rRNA and pheS gene sequences respectively. The cholesterol removal mechanisms of all four Enterococcus strains in media were evaluated by measuring the cholesterol concentration of the supernatant fluid, washing fluid and fragmentized‐cells solution respectively. A part of cholesterol detected in the washing fluid was due to de‐conjugation of bile salts by bile salt hydrolase (BSH) activity of bacteria  after 2 h, except for E. durans KLDS 6.0930, which was the most acid‐tolerant strain. In the small intestine, the most serious obstacle for probiotic survival is bile salts. 0.3% oxgall was used to examine the bacterial bile tolerance. All of the tested strains were grown better in MRS broth supplemented with oxgall. Moreover, the strain E. durans KLDS 6.0930 exhibited the highest tolerance to bile, because it could require a less time to increase by 0.3 units in absorbance at 620 nm than other strains exposed to oxgall. It is generally believed that the organism to live permanently in the host's intestine must be able to attach to intestinal mucosal cells , the respective resistance genes (vanA and vanB) were not found in these strains. Similarly, E. durans KLDS 6.0930 and KLDS 6.0933 were phenotypically resistant to chloramphenicol (MIC of 16 μg ml‐1), but the two strains did not contain the gene catpIP501. Moreover, all tested Enterococcus strains exhibited MICs ≥ 1024 μg ml‐1 to gentamycin, but no resistance gene [aac(6′)‐aph(2′)‐Ia] was observed. In this respect, the phenotypic resistance of Enterococcus strains to vancomycin or gentamycin might be attributed to other genes which were not detected in this paper  responsible for vancomycin resistance and several other genes  responsible for gentamycin resistance.It is necessary to evaluate the safety of natural isolates from traditional homemade products, although enterococci have important implications in dairy industry, particularly in variety products of cheese Giraffa, . The mosn Klein, . VariousEnterococcus, has been claimed to decrease the concentration of serum cholesterol in humans and/or animals  after 4 weeks of E. durans KLDS 6.0930 administration, but there was no significant impact on serum TG and HDL‐C levels (P > 0.05) compared with the high‐cholesterol diet control group. These findings were consistent with previously published papers  and two strains of E. faecalis (KLDS 6.0934 and 6.0935) were found to possess desirable probiotic properties in vitro. With regard to the strain E. durans KLDS 6.0930 showed cholesterol‐lowering effects in rats fed a cholesterol‐enriched diet for 4 weeks. This strain can be considered as a good candidate of potential cholesterol‐lowering agent.In conclusion, the results of this study showed that two strains of Enterococcus strains were isolated according to Guo and colleagues . The 16S rRNA gene was amplified by the universal primers, 27F and 1541R  according to Naser and colleagues , and KF776544, KJ818116, KJ818117 and KJ818118 (pheS gene).The isolates were identified by the analysis of 16S rRNA and lleagues . The ampoC) and washed twice with sterile saline buffer (0.85%), and then were re‐suspended in MRS broth adjusted by HCl to pH 2.0, pH 2.5 and pH 3.0, respectively, and incubated anaerobically at 37oC for 2 h. Viability was determined using the plate count method. One millilitre sample was taken under the sterile condition at 0 h, 1 h and 2 h, and 10‐fold serial dilutions were made using sterile saline buffer (0.85%). The dilutions were plated on MRS agar and incubated anaerobically at 37oC for 24 h before enumeration.The isolates grown in MRS broth were subcultured at least three times before the assay. Bacterial cells from overnight (18 h) cultures were harvested  at 620 nm at hourly intervals for 8 h. The absorbance values obtained were plotted against the incubation time, and the bile tolerance of each strain was based on the time required for the absorbance value to increase by 0.3 units. The isolates incubated in MRS broth without oxgall powder were taken as the control.Each strain was subcultured at least three times before the assay, and then the isolates were incubated in MRS broth added 0.3% (w/v) oxgall powder  at 37et al., ‐1) heat‐inactivated (56 oC for 30 min) fetal bovine serum, 100 U ml‐1 penicillin and 100 mg ml‐1 streptomycin. Cells were seeded in 6‐well tissue culture plates at a concentration of 105 cells well‐1 . The cell culture medium in the wells was replaced with fresh medium every other day. Cells were used for adhesion assays at late post‐confluence. The Caco‐2 cells were washed twice with PBS (pH 7.2) before bacterial cells were added  was added to each well, and then incubated 15 min at 37oC. One millilitre of DMEM supplemented with 10% bovine serum was added to each well to terminate the activity of trypsin. The serial 10‐fold dilutions of cell suspensions were plated on MRS agar to determine the number of adherent bacterial cells. The MRS plates were incubated at 37 oC for 24 h. The results of the adhesion assay were expressed as a percentage, i.e. the ratio between the number of bacterial cells remained and the total number of bacterial cells added initially to each well.The epithelial intestinal cell line Caco‐2 was employed for the adhesion assay of the isolates (Jacobsen ‐1) in MRS broth supplemented with different antibiotics at various final concentrations , including ampicillin, vancomycin, gentamicin, erythromycin, chloramphenicol and penicillin . The MICs of a given antibiotic was visually evaluated as the lowest concentration at which no growth was observed following a 24 h incubation period at 37oC. Interpretation for susceptibility status was based on the criteria adopted by European Food Safety Authority in the assessment of bacterial resistance to antibiotics ‐aph(2′)‐Ia], chloramphenicol (catpIP501) and vancomycin (vanA and vanB) was investigated for the four isolates by PCR assays. Primers and protocols were described by Maietti and colleagues : (i) a normal diet (ND) control group, regular chow diet + sterilized saline, (ii) a high‐cholesterol diet (HD) control group, high‐cholesterol diet + sterilized saline and (iii) a HD with KLDS 6.0930 group, high‐cholesterol diet + E. durans KLDS 6.0930. The strain E. durans KLDS 6.0930 was suspended in sterilized saline to a level of 2 × 109 cfu ml‐1 before administration. During the 4‐week study period, three groups intra‐gastrically received sterilized saline or E. durans KLDS 6.0930 suspensions at a dosage of 1 ml 100g‐1 body weight in each day. Food intake and body weight were recorded daily throughout the feeding trial.Twenty‐four male Sprague‐Dawley (SD) rats aged 6 weeks were obtained from the Animal Research Centre of Jilin University, Changchun, China. The rats were fed a regular chow diet. The high‐cholesterol diets were consisted of 1% cholesterol, 10% lard, 5% sucrose, 0.3% sodium cholate and 83.7% regular chow. All rats were housed in a controlled animal room at 20 oC to obtain serum. Serum was analysed for TC, TG, LDL‐C and HDL‐C using commercial kits .After 28 days of gavage, the rats were fasted for 12 h. Blood samples were collected and centrifuged immediately at 1500 × g for 15 min at 4 The faecal droppings of the experimental rats were collected over a 2‐day period (days 27 and 28). Then, the faecal samples were dried and ground to a fine powder for further analysis. Fecal bile acid was determined using a bile acid assay kit .spss 17.0 software . One‐way analysis of variance was employed to evaluate the experimental data. A P value < 0.05 was considered statistically significant.The results are expressed as mean ± standard deviation. Statistical analyses of the data were performed using None declared.Fig. S1. Neighbour‐joining tree showing the phylogenetic relationships of strain KLDS 6.0930, strain KLDS 6.0933, strain KLDS 6.0934, strain KLDS 6.0935 and related‐type strains based on the 16S rRNA gene sequences. Listeria monocytogenes was included as an outgroup.Fig. S2. Neighbour‐joining tree showing the phylogenetic relationships of strain KLDS 6.0930, strain KLDS 6.0933, strain KLDS 6.0934, strain KLDS 6.0935 and related‐type strains based on the pheS gene sequences. Ralstonia solanacearum was included as an outgroup.Click here for additional data file.


The survival of a child with severe volume depletion at the emergency department depends on the competency of the first responder to recognize and promptly treat hypovolemic shock. Although the basic principles on fluid and electrolytes therapy have been investigated for decades, the topic remains a challenge, as consensus on clinical management protocol is difficult to reach, and more adverse events are reported from fluid administration than for any other drug. While the old principles proposed by Holliday and Segar, and Finberg have stood the test of time, recent systematic reviews and meta-analyses have highlighted the risk of hyponatraemia, and hyponatraemic encephalopathy in some children treated with hypotonic fluids. In the midst of conflicting literature on fluid and electrolytes therapy, it would appear that isotonic fluids are best suitable for the correction of hypotonic, isonatraemic, and hypernatraemic dehydration. Although oral rehydration therapy is adequate to correct mild to moderate isonatraemic dehydration, parenteral fluid therapy is safer for the child with severe dehydration and those with changes in serum sodium. The article reviews the pathophysiology of water and sodium metabolism and, it uses the clinical case examples to illustrate the bed-side approach to the management of three different types of dehydration using a pre-mixed isotonic fluid solution . When 3% sodium chloride is unavailable to treat hyponatraemic encephalopathy, 0.9% sodium chloride becomes inevitable, albeit, a closer monitoring of serum sodium is required. The importance of a keen and regular clinical and laboratory monitoring of a child being rehydrated is emphasized. The article would be valuable to clinicians in less-developed countries, who must use pre-mixed fluids, and who often cannot get some suitable rehydrating solutions. The survival of a child with severe volume depletion at the emergency department depends on the competency of the first responder to recognize and promptly treat hypovolemic shock . Poor tiAlthough the basic principles on fluid and electrolytes therapy have been investigated for decades, the topic remains a challenge, as consensus on clinical management protocol is difficult to reach, and more adverse events are reported from fluid administration than for any other drug , 7.While the maintenance fluid therapy promoted by Holliday and Segar in 1957 has stood the test of time ; recent Apart from unavailability of some desired fluids , the clinicians in developing countries are also plagued with dearth of randomized clinical studies on fluids and electrolytes therapy, and confusion arising from conflicting literature on fluids and electrolytes therapy from developed countries, as new research findings continue to confound the old understandings –22.For example, the comprehensive treatise by K. Powers on management of isonatraemic, hypotonic, and hypernatraemic dehydration published in Pediatric Review in 2015  was soonFurthermore, Kiguli et al. in 2011 , followiAlthough the FEAST study excluded children with severe malnutrition and gastroenteritis, and their study population could only meet 2% of the WHO criteria for shock ; the perVolume depletion denotes reduction of effective circulating volume in the intravascular space, and since sodium constitutes the main extracellular solute, sick children may have isonatraemic, hyponatraemic and hypernatraemic dehydration depending on the differential loss of sodium and water , 28. DehIn this article, the terms dehydration and volume depletion will be used interchangeably, even when they are not necessarily the same .The choice of either oral rehydration therapy (ORT) or intravenous (IV) therapy in a child depends on accurate assessment of the degree of dehydration . While OSince pediatric dehydration is frequently the result of gastroenteritis, characterized by vomiting and diarrhea , this arClinical conditions relating to dehydration from burns, severe malaria, anemia, diabetes ketoacidosis, sickle cell disease, total parenteral nutrition (TPN), severe acute malnutrition, septic shock, acute kidney injury are outside the scope of this article.Although variations exist in the methods available for assessing dehydration, and in correcting for fluid and electrolytes deficits –20, the Diarrhea: WHO defines diarrhea as the “passage of loose or watery stools at least three times in a 24 h period” but emphasizes the importance of change in stool consistency rather than frequency, and the usefulness of parental insight in deciding whether children have diarrhea or not . The episode may begin either as watery diarrhea or as dysentery  in a dehydrated state  (Hypernatremia is when serum sodium is greater than 145 mmol/L. It represents lack of free water in the extracellular space (ar space .Fluid and electrolyte deficit: a deficit is the amount of water (and electrolytes) lost before rehydrating treatment is begun. For practical purposes, it is a one-time estimate  is equal to the sum of the osmolality of individual solutes in the intravascular space  (mmol/kg) .The blood tonicity : this denotes the concentration of solutes  that are impermeable to cell membranes which are therefore restricted to the extracellular compartment  and decreases to two-thirds of body weight (67%) after the neonatal period. This decreases further to 60% by the age of 12 months, which is the same value we have in adult male  .The TBW is distributed in various locations throughout the body, known as the fluid compartments. The intracellular fluid (ICF) compartment is about 40% of the TBW. The remaining 20% of the TBW constitutes the ECF compartment. The ECF comprises the interstitial fluid (15% of the TBW) and the intravascular plasma which makes up about 5% of the TBW  , the juxtaglomerular apparatus, the renin-angiotensin system and others , 39 see.Because sodium intake is generally not affected by ECF volume, it means that the sodium in the ECF is controlled by an increase or a decrease in renal sodium excretion . The bodA low ECF volume is detected by cardiopulmonary baroreceptors located in the atria, ventricles, and pulmonary interstitial tissue . A low EOther mechanisms involved in sodium metabolism include redistribution of intra-renal blood flow and renal prostaglandins . The expWater balance is achieved by ensuring that the amount of water consumed in food and drink and that endogenously generated by metabolism equals the amount of water excreted . The conUnder normal physiologic conditions, the kidneys control the volume of bodily fluids by the amount of water excreted in the urine. The kidneys conserve water  by producing concentrated urine, relative to plasma, or they can rid the body of excess water by producing diluted urine, relative to plasma.The direct control of water excretion is exercised by antidiuretic hormone  , 34. AVPThirst-induced water craving is an important pathologic response to hyper-osmolality or hypovolemia . Thirst,When the mechanisms of restoring the ECF volume are compromised, end-organ hypo-perfusion leads to poor oxygenation and nutrient delivery and ultimately tissue acidosis , 38.Table In the midst of these compensatory mechanisms, and in the face of ongoing losses, dehydration may ensue, which when accompanied by proportionate loss of sodium from extracellular space results in isonatraemic dehydration. Isonatraemic dehydration is the commonest (70–80%) type of dehydration and the type with the best prognosis .In this state, the normal tonicity of body fluids at 275–290 mOsm/kg is maintained, and the serum sodium concentration remains at normal ranges of 135 and 145 mmol/L , 38.The fluid deficit in isonatraemic dehydration is 100% from the extracellular space and when replacing the fluid deficit, the sodium concentration in the repletion fluid should be similar to that of the serum (averages 154 mmol/L) , 28, 40.The classical features of dehydration are commonly seen in isotonic dehydration. These include thirst, decreased skin turgor, tachycardia, dry mucous membranes, sunken eyes, lack of tears when crying, a sunken anterior fontanel in infants, and oliguria. The severe features of dehydration include anuria, hypotension, feeble and very rapid radial pulse, cool and moist extremities, and diminished consciousness.It is seen in 10–15% of cases of dehydration. It occurs more frequently with bacillary dysentery or cholera. Hyponatraemia may develop or worsen if there is a considerable oral ingestion of water, low-electrolyte or electrolyte-free fluids, or diluted formula during diarrhea. It may also follow iatrogenic intravenous administration of hypotonic fluids at the hospital.The serum sodium is less than 135 mmol/L. The Sosm is less than 275 mOsm/Kg because serum sodium accounts essentially for Sosm. Table Since solute loss (in vomiting or diarrhea) almost always occurs in an isosmotic fluid that has a sodium and potassium concentration less than that of plasma, loss of these fluids cannot directly lower the plasma sodium except there is increased water intake, or when excess water is retained . Thus, wNausea and malaise are typically seen when sodium level acutely falls below 125–130 mmol/L . HeadachIt is seen in 10–20% of patients with diarrhea. It can occur when too much salt is ingested or due to water deficit. Most frequently, it is due to water deficit from increased water losses in diarrheal stools, and also due to reduced water intake during the illness. In rare cases, it is due to an increase in total body sodium following ingestion of concentrated formula, incorrectly prepared highly concentrated oral electrolyte solution, and administration of high solute containing beverages to a child with diarrhea . The potDehydration state in which serum sodium is greater than 145 mmol/L, and Sosm higher than 290 mOsm/kg . Mild hyThere is a fluid shift from the intracellular to the extracellular space to maintain intravascular volume (intracellular dehydration), therefore, the vascular volume is usually maintained until the degree of dehydration is quite severe , 4, 14. Children with hypernatremia tend to have a fever, very dried tongue, doughy feeling skin, and warm extremities , 41. TheThe maintenance fluid requirement is the daily water needed for well individual to excrete iso-osmotic urine. The needs for maintenance fluid and electrolytes arose from the need to eliminate heat and solutes , which are the two by-products of the basal metabolism , 36. MajBecause metabolic rate per unit of body weight declines with increasing age, children generate less heat and solute from basal metabolism than do infants and, therefore, require less fluid and electrolytes per unit of body weight , 36. WhiThe Holliday–Segar system has gained wide acceptance and has stood the test of time , 36. It The Holliday–Segar formula estimates kilocalories that can be equated with milliliters of fluid. For each 100 kcal expended, approximately 100 ml of fluid is required. The 100 ml is a rounded estimate from (a) 50 mL of fluid required to provide for skin, respiratory tract, and basal stool losses, and (b) 55 to 65 mL of fluid required for the kidneys to excrete an ultra-filtrate of plasma at 300 mOsm/L (with a specific gravity of 1.010) without having to concentrate the urine .average child can then be based on body weight , acetate (Ringer’s acetate), and with acetate and gluconate , these isotonic fluids are said to be balanced or buffered as they now have electro-neutrality   Table 77.Because 0.9% normal saline  has been shown to cause dilutional coagulopathy , 46, hypHowever, Ringer’s lactate and Hartmann’s solutions, respectively, contain sodium concentrations of 130 and 131 mmol/L which are relatively lower than the serum sodium and their use should also be closely monitored as they could adversely lower the patient’s serum sodium . In addiWhile the addition of 20 mmol/L of potassium chloride to IV fluid is generally permissible , the amount of potassium chloride should be individualized to the patient needs and should be closely monitored , 42, 50.Therefore, a preferred fluid solution to be used for maintenance fluid and electrolytes is 5% dextrose in 0.9% saline with 20 mmol/L of KCL , 42.Unless hypokalemia is present, there is no pressing reason to administer more than this quantity of potassium , 41.Another consideration worthy of note in the acutely ill child is that reduction in the excretion of free water makes these children have a reduced urinary output and expectedly, the total fluid required to maintain a normal intravascular volume is reduced , 38, 51.Hence, while the maintenance volumes should be the starting point for these acutely ill dehydrated children, adjustment (between 50 and 80% reductions in maintenance volumes) can be made based on the clinical response to fluids in these children , 38.In contrast, some sick children will have increased fluid requirements . These children may need more than the standard maintenance fluid rate to maintain normal intravascular volume , 51. RefAbove all, prescribing maintenance fluid for ill children requires regular assessments, including weight assessment in order to ensure that adequate hydration is achieved without putting children to hyponatraemia and or over-hydration , 51.A deficit is the amount of water (and electrolytes) lost before treatment is begun . For praAlthough acute weight change (each gram of weight loss corresponds to 1 mL of water loss) is the most direct basis for determining the amount of deficit fluid, however , this muFrom the foregoing, it is admissible that assessing the extent of volume depletion can be difficult. This difficulty is also compounded by the fact that in most cases, the pre-illness weight of a child is unknown and the clinician is constrained to use clinical signs and symptoms as well as laboratory data to assess the degree of dehydration , 4, 36. Generally, regardless of what scoring method is used, the severity of dehydration is classified as mild (3–5% volume loss), moderate (6–10% volume loss), or severe (9–15% volume loss) . From thInfants and children with mild dehydration often have minimal or no clinical changes other than dry mucous membranes . Early hg = 10,000 ml) is clinically estimated to be mildly dehydrated at 5%, the volume of deficit to be given is 500 ml.In the replacement for fluid deficit, it is important to remember that each gram of weight loss equals I milliliter of fluid , therefoFor a simple bedside calculation, a formula is easily derivable to give this estimate as follows; % dehydration × 10 × body weight (in kg).Traditionally, intravenous fluids to replace existing fluid deficit are given over the first 24 h, while the patient continues to get his maintenance fluid over the same 24-h period .However, many clinicians quickly administered the fluid deficit either in whole (100%) in the first 8 h  or in part  as a combined deficit/maintenance approach , 55. In The appropriate fluid to correct fluid deficit is isotonic fluid with glucose and KCl if required, (once urine output is established). A good example is 0.9% normal saline with 5% glucose with 20 mmol/L of KCl added  , 20. ThiWhile Moritz and Ayus have argued strongly against the use of isotonic saline in treating hyponatraemic encephalopathy ; normal saline has been inevitably used when 3% NaCl is not available , 41. ThiThe clinician must remember that the clinical assessment of dehydration is only an estimate; therefore, the child must be continually re-evaluated during therapy to ensure that adequate replacement volumes are administered.On-going losses represent fluid and electrolytes that are being lost, and which causes the state of volume depletion in the first place (vomiting and diarrhea from gastroenteritis)  ThereforNon-cholera diarrhea fluid contains sodium of 56 mmol/L and chloride of 95 mmol/L, cholera stool contains a higher sodium of 101 mmol/L, and chloride of 92 mmol/L. Table , data inDiarrheal stool can also be replaced with 10 mL/kg of ORS per episode of diarrheal stool or the rate of replacement can occur cumulatively every 1–6 h , 51.Volume deficit/degree of dehydration. The clinician must first determine if hypovolaemic shock is present  and must be treated as an emergency. A careful history and further physical examination can point to the possible types of dehydration . DetermiDoes osmolar disturbance exist? While it is not important to do elaborate laboratory investigations for mild dehydration, it is important to obtain the serum sodium, Sosm, urinary osmolality, urinary sodium, fractional excretion of sodium, and the urinary specific gravity for moderate to severe forms of dehydration . Serum gIn patients with hypernatremia, the normal response is an increase in ADH release, resulting in an increase in urinary osmolality that can reach up to 500 to 1200 mOsm/kg. The presence of this increase in urinary osmolality suggests that the water loss responsible for the hypernatremia (in the absence of osmotic diuresis) is coming from extra-renal  sources. In comparison, hypernatremia with urinary osmolality below 300 mOsm/kg is indicative of renal concentration defect. This could be due to diabetes insipidus (ADH deficiency or non-response to ADH) or other renal concentration defects seen in the polyuric phase of acute tubular necrosis and diuresis that may follow a relief of urinary obstruction . The distinction between central (ADH deficiency) and nephrogenic (non-response to ADH) diabetes insipidus can be made with the administration of desmopressin acetate (DDAVP), an analog of ADH. If the urine osmolality rise by at least 50% in the first 2 h of DDAVP , this has proven a state of ADH deficiency  , 34.In hyponatraemia, clinical evaluation of the intravascular volume, Sosm, urine osmolality, and urinary sodium are helpful for the specific diagnosis of the hyponatraemia . See FigCheck for acid-base disturbance by determining the blood pH, the serum PCO2 and the serum bicarbonate , 55. TheCheck the serum potassium. Serum potassium may be low following the loss in diarrheal stool . It may Renal function test. The kidney may fail following tissue hypo-perfusion resulting from prolonged uncorrected hypovolemia . It is iThe management of a child with dehydration must seek to answer the following questions :Volume It is important to emphasize that oral rehydration can be safely and effectively accomplished in children with mild-to-moderate dehydration and in those with normal serum sodium values. Children with more severe dehydration or with abnormal serum sodium values should be treated with intravenous infusions , 41, 42.The following discussion focuses on how to treat the different types and severity of dehydration that may be seen in diarrheal disease, and it also emphasizes on the necessary intensive monitoring required in all types of dehydration:Oral rehydration therapy either by mouth or through the nasogastric tube can safely and effectively restore intravascular volume in children with mild-to-moderate isonatraemic dehydration, in as much as the child can tolerate it . The AmeOral rehydration therapy works in the most severe form of diarrhea. Even with on-going diarrhea, water can be absorbed across the intestinal lumen by the co-transport of sodium and glucose via the SGLT1 protein and by active transport via the sodium-potassium ATPase pump . OptimalThe glucose: sodium ratio of rehydration fluids should not exceed more than 2:1 for effective fluid repletion . While cBeverages like apple juice, tea, ginger ale, colas, sports drinks, and chicken broth are inappropriate to use for rehydration because they do not contain the correct sodium and glucose ratio to promote salt and water reabsorption , 14, 55.Oral rehydration therapy is unsuitable in the following conditions; (a) severe dehydration, (b) circulatory instability or hypovolemic shock, (c) altered mental status, (d) intractable vomiting, (e) bloody diarrhea, (f) paralytic ileus/abdominal distension, (g) abnormal serum sodium values, (h) glucose mal-absorption, (i) lack of caregiver to give close attention during ORT, and in (j) those averse to the taste of oral rehydration solution or those not tolerating because of stomatitis or pharyngitis , 14.The amount of fluid deficit is calculated based on the change in weight (if pre-illness weight is known) or based on clinical signs. Generally, mild to moderate dehydration is assumed at 5% (50 ml/kg body weight) and this is replaced over 2–4 h , 14. UsiReplace ongoing losses with ORS. When possible and measurable, ongoing losses should be replaced volume for volume using appropriate fluid, or with ORS. When it is impossible to have a measurement of the vomitus or stool, replacing 10 mL/kg body weight for each watery stool or 2 mL/kg body weight for each episode of emesis should suffice .Breastfeeding/formula or age-appropriate complementary feed should not be stopped during ORT as they serve as maintenance. Small frequent feeds decrease vomiting. However, carbonated drinks and drinks or food with high concentrations of simple carbohydrates should be avoided during therapy, and patient should be reassessed regularly , 14, 60.E. Coli 25%, Campylobacter jejuni 10–18%, Shigella spp, and Salmonella spp 5% each), 35% of viral (15–25% rotavirus) origin, and in many the cause is unidentified or mixed  and hospital admission, and it does not have the extrapyramidal effects of promethazine , 67. TheChallenges in the administration of ORT include the perception that IV therapy is superior to ORT; ORT is time-consuming for both parents and doctors; parents expect IV therapy once they are on admission at the hospital; and parents expect IV therapy since they may have tried ORT at home, even when they have used poor technique .Some key measures to prevent diarrhea include: access to safe drinking-water, improvement in environmental sanitation, exclusive breastfeeding for the first 6 months of life, good personal, and food hygiene (hand washing), health education about how infectious diarrhea is spread and administration of rotavirus and typhoid vaccines to susceptible children .ORT involves the following:Once it is determined that a patient is in shock, the general principles of hypovolemic shock management per pediatric advanced life support should be followed including obtaining rapid vascular access, which may be in the form of peripheral intravenous access or an intraosseous route if peripheral access is not successful , 71. Thi❖What type and degree of dehydration is AB?❖Outline the fluid prescription for AB?AB, a 11- month old child presented at emergency unit with 3 days history of vomiting and diarrhea, physical examination revealed that the child was lethargic, dried mouth, tearing, sunken eyeballs and anterior fontanelle, pulse was rapid and weak, BP was 45mmHg/inaudible diastolic capillary refills was in excess of 4 s. Child is making urine, but mother has no need to change the nappies as she usually does before the illness. The child weighs 8 kg. The laboratory results revealed Na 138 mmol/L, K 1.8 mmol/L, Cl 95 mmol/LAB has severe isonatraemic dehydration with hypokalemia. AB also presented in hypovolaemic shock, so rapidly expand the intravascular space with 0.9% Normal saline, i.e., 20 mL/kg = 160 mL, given over 10 min as initial fluid therapy.Calculate the deficit at 15% because AB is an infant, i.e., 15 × 10 × 8 = 1,200 ml; however, 160 mL has been given as a volume expander, you are left with 1,040 mL as a remaining deficit volume.Calculate the maintenance fluid volume, i.e., 100 × 8 = 800 mLMeasure ongoing loss by possible recording volume of stool or vomitus and record the volume to be replaced volume for volume with ORS. If measurement is impossible give 10 mL/kg = 80 mL of ORS/loose stool and 2 mL/kg = 20 mL of ORS/vomitus❖For combined deficit/maintenance approach:You can either use the combined deficit/maintenance approach OR sequential deficit-maintenance approachGive 1/2 remaining deficit  + 1/3 maintenance (1/3 × 800 = 267 mL) = 787 mL in the first 8 h❖For sequential deficit/maintenance approach:Then, follow with 1/2 remaining deficit  + 2/3 maintenance (2/3 × 800 = 533) = 1,053 ml over the remaining 16 hGive 1,040 mL (remaining deficit) over the first 8 hGive 800 maintenance fluids over the remaining 16 hChoice of fluid for both maintenance and deficit is Isotonic Saline (0.9%) with 5% dextrose20 mmol of KCl into each liter of fluid could have been adequate but could be increased to 40 mmol/L because of the hypokalemia (1.8 mmol/L). Once the serum K rises to 3.5  decrease KCL to 20 mmol/L.Regular monitoring is requiredHypovolaemic shock must be treated once recognized regardless of whether the child is having isonatraemia, hyponatraemia, or hypernatremia , 38, 42.Initial fluid therapy/resuscitative fluid . Remember that this is part of deficit replacement.Subsequent therapy: replace deficit  + maintenance fluid volume + on-going losses.Final therapy: when patients return to normal composition/establish oral feeds/correct potassium deficitMonitor therapy continuously.Stages involved , 36, 55:SR, an 8 week old infant weighing 4 kg presented with 1 week history of vomiting and passage of loose stool. Mother was advised to give water as frequently as the child could tolerate it. He was found with moderate dehydration on examination. Laboratory results revealed Na 130 mmol/L, Cl 94 mmol/L, K 1.9 mmol/L, and HCo3 8 mmol/L.Deficit fluid volume: 10 × 10 × 4 = 400 mLMaintenance fluid volume: 100 × 4 = 400 mL❖For combined deficit/maintenance approach:Measure ongoing loss by possible recording volume of stool or vomitus and record the volume to be replaced volume for volume with ORS. If measurement is impossible give 10 mL/kg = 40 ml of ORS/loose stool and 2 mL/kg = 8 ml of ORS/vomitusGive 1/2 deficit (200 mL) + 1/3 of maintenance (133 mL) in the first 8 h, then 1/2 of remaining deficit (200 mL) and 2/3 of the remaining maintenance (267 mL) in the next 16 h❖For sequential deficit/maintenance approach:Regular monitoring is requiredGive 400 mL of deficit volume in the first 8 h❖Choice of fluid for both maintenance and deficit is Isotonic (0.9%) normal saline with 5% dextroseGive 400 mL of maintenance fluid in the next 16 h20 mmol of KCl into each liter of fluid could have been adequate but this could be increased to 40 mmol/L because of the hypokalemia (1.9 mmol/L). Once the serum K rises to 3.5, i.e., hypokalemia corrected) decrease KCL to 20 mmol/LRegular monitoring is required.For the most part, the following discussion will focus more on the management of hyponatraemia in a child with volume depletion.Hyponatraemia is seldom symptomatic unless the serum Na is < 120 and if the hyponatraemia occurs quickly . So, theJK is a 5 month old child brought to the emergency unit with a 7 day history of vomiting and diarrhea. JK had stopped breastfeeding in the last 48 h which made JK’s mother to institute tea and water which JK took poorly. 15 min before presentation, JK was said to have convulsed, generalized tonic-clonic which lasted for 15 min. On examination, JK was found with dried tongue, sunken eyes and depressed anterior fontanel and tenting of the skin, weight was 5 kg, pulse rate was 160 beat/min, cold and pale extremities. The blood pressure was 45 mmHg/inaudible diastolic. Laboratory evaluation revealed serum Na of 105 mmol/L, CL 95 mmol/L, K 3.5 mmol/L, serum HCO3 8 mmol/L. Outline the management approach of JK.JK is having severe hyponatraemic dehydration with serum Na < 120 mmol/L, and metabolic acidosis.Since JK is in shock give 20 mL/5 kg = 100 mL of Normal Saline.Calculate JK fluid deficit at 15% deficit = 15 × 10 × 5 = 750 mLActual deficit left is (750–100) = 650 mLCalculate JK Na deficit = 120–105 × 0.6 × body weight = 15 × 0.6 × 5 = 45 mmol of NaThis is equal to 90 mL of 3%NaCl, since 0.5 mmol of Na = 1 ml of 3% NaCl which should be given over 30 min. This dose can be repeated until the serum sodium becomes 120–125 mmol/L..Calculate JK maintenance fluid volume = 100 × 5 kg = 500 mLGive the remaining deficit, 560 mL (650–90 mL) to go in the first 8 hGive the maintenance of 500 ml to go over the remaining 16 hIt only makes sense that only the sequential deficit/maintenance approach can be used if there is a need to correct symptomatic hyponatraemiaThe fluid choice for the deficit and maintenance volume is isotonic saline (0.9%) with 5% glucose and the rate of rise in serum sodium should be monitored hourly as the serum sodium should not rise more than 0.5 mmol/L every hour or 12 mmol/L over 24 h Once child is making urine, add 20 mmol/L of KCL into isotonic saline with 5% dextrose.Regular monitoring is required.The initial goal in treating hyponatraemia is the correction of intravascular volume depletion with isotonic normal saline. Urgent treatment of hyponatraemia is however required in all patients who exhibit neurological changes including seizure, change in sensorium and if the serum sodium level is < 120 mmol/L . Most frThe formula for the Na deficit mmol = (120–current Na) × 0.6 × body weight in kg .The 0.6 is 60%, which is the volume of distribution of sodium. The mmol of Na required should ideally be gotten from 3% NaCl as it contains 513 mmol of Na/L or 1 mL = 0.5 mmol of Na. A rule of thumb is that 4 mL/kg of 3% NaCl increases serum Na by 3 mmol/L , 41.Although isotonic 0.9% saline is inappropriate for the treatment of hyponatraemic encephalopathy because it is insufficiently hypertonic to result in a consistent increase in plasma sodium; it may still be given if a hypertonic saline solution is unavailable, 1 mL of 0.9% saline contains 0.154 mmol of Na , 41. ThiAcute rapid correction of hyponatraemia to stop seizures or address neurological changes followed by a slower correction (10–12 mmol/L/day) to normal serum levels is essential to prevent central pontine myelinolysis (CPM). CPM although rare in children, is characterized by neurologic symptoms including confusion, agitation, flaccid or spastic quadriparesis, and death. CPM is also commoner in patients treated for chronic hyponatraemia than in those treated for acute hyponatraemia.Hypernatremia (serum sodium > 145 mmol/L) usually arises because too much of free water is lost which should be replaced gradually. It is moderate hypernatremia when serum sodium is 150–169 mmol/L and severe hypernatremia when serum sodium is > 169 mmol/L.The gradual rehydration protocol suggested by Finberg in 1973 remains valid up till today .After the administration of resuscitative isotonic saline for hypovolemic shock , the volume of free water deficit should be calculated and given slowly over 48 h in moderate hypernatremia and over 72 h in severe hypernatremia .At both rates (48 or 72 h) of rehydration, the caution is not to reduce the serum sodium by more than 0.5 mmol/L per hour and/or by more than 12 mmol/L over 24 h , 52. CloIt is the free water deficit volume that is spread over 48–72 h as the child continues to get his daily maintenance fluid and fluid is continuously being replaced for ongoing losses , 38, 52.The deficit volume in hypernatraemic dehydration is the free water and the formula for free water deficit is , 41:FreIdeally, the best fluid to give is water as it contains 100% free water . 0.45% nTP is a 3 month old child who presented at emergency pediatric unit (EPU) with 3 weeks history of fever and occasional vomiting. TP mother also noticed that the child has not been suckling well as before and she also felt light in her breasts. TP mother complained to her neighbor who advised her to buy infant formula as the child “may not like her breast milk again” TP mother was adding little water to many scoops of the infant formula, contrary to the instruction on the tin. However, TP continues to get worse and she was rushed to the EPU by 3 am. The house officer could not understand why the mother was worried as examination revealed only a dried tongue and doughy feeling skin. The weight was 5 kg. The house officer treated TP for malaria fever and asked the mother to come back later in the day. He also requested for E/Urea because of the history of vomiting. The result came out 1 h later revealing malaria parasitaemia of 1 + , Na of 170 mEq/L, K 3.7 mEq/L, Cl 104 mEq/L. When the senior doctor examined the child later, TP was confirmed to be in hypovolemic shock.The child had severe hypernatraemic dehydration and also in hypovolemic shockSo 20 mL/kg of NS was given over 20 min = 100 mLCalculated free water deficit = (170/145−1) × 0.6 × 5 = 0.52 L = 517 mLThe remaining deficit = 517 – 100 = 417 mLThe calculated maintenance = 100 mL × 5 = 500 mLChild received (1/3 of 417 mL) 139 mL of deficit + 500 mL of maintenance = 639 mL in the first 24 h (+ongoing losses)Another (1/3 of 417) 139 mL of deficit + 500 mL of maintenance = 639 mL in the next 24 h (+ongoing losses)Remaining (1/3 of 417 mL) 139 mL of deficit + 500 mL of maintenance = 639 mL in the next 24 h (+ongoing losses)In other word, the free water deficit was spread over 72 h  from the time of treatment commencement, while the child continued to receive his daily maintenance and ongoing lossesThe fluid choice is isotonic saline (0.9% NaCl with 5% glucose)20 mmol/L of KCL was added|Regular monitoring is required.Regular monitoring:It is important to remember that the bed-side assessment for dehydration remains at best clinical estimates; therefore, close monitoring of patients on rehydration is the key. In as much as the kidney is functioning optimally, errors of under and over estimation in the calculation of fluid estimates are often corrected by the kidney. While the cause of the dehydration is being treated and regardless of the type of dehydration, the clinician should pay attention to the following , 41, 52;Regular monitoring of the vital signs  and having a good record of the fluid intake and output  and close watch on the physical examination . The best monitoring “tests” are the simple ones that all too frequently are overlooked, such as the resolution of signs of dehydration apparent on physical examination Children receiving deficit fluid should be weighed at least every 6 hA daily increase in weight of 5% or more indicates fluid overload, provided there is no third-spacing. Manage by stopping IV fluids and measure serum sodiumA daily decrease in weight of 5% or more indicates dehydration. Pay a closer attention to fluid rates, to ensure adequate rehydrationDaily assess for edema (eyelid and lower limb swelling) and stop IV fluid if edema is identifiedCheck serum electrolytes and glucose dailyCheck serum electrolytes and glucose every 4 h, if there is hypo/hypernatraemic dehydration, until serum values become normalRed flag if serum sodium is ≤ 130 mmol/L or has fallen by > 0.5 mmol/L per hour or >12 mmol/L per day OR serum sodium is ≥ 150 mmol/L or has risen by > 0.5 mmol/L per hour or >12 mmol/L per dayIf sodium is correctly too rapidly in hyponatraemic dehydration, cerebral  demyelination, and permanent brain injury may occurIf sodium is corrected too rapidly in hypernatraemic dehydration, cerebral edema may occurThe closure of rehydration therapy is suggested by normalization of vascular status, restoration of normal mental status, lack of clinical signs, and symptoms of fluid deficit, and adequate urinary output of >0.5 mL/kg/h (1 mL/kg/h for an infant).Other endpoints include normalization of laboratory results including blood urea, serum creatinine, Sosm, urine osmolality, and urinary electrolytes.Normalization is impossible if ongoing losses continue and this should be corrected as well.Again, it appears that isotonic 0.9% normal saline with 5% dextrose is an appropriate fluid, and it is safe as a starting fluid in cases of hypernatraemic dehydration , 42, 52.Even though the deficit in hypernatremia is predominantly water, it is safe to use isotonic saline (0.9% with 5% glucose) for both maintenance and deficit volumes as isotonic fluids are superior to hypotonic fluids for the prevention of hyponatraemia and are not associated with an increase in the incidence of hypernatremia or fluid overload , 14.However, the clinician must ever remain vigilant and adjust appropriately the rate (reduce by 20%) of rehydration with isotonic saline as the reduction in serum sodium should not be more than 0.5 mmol/L per hour , 41, 52.Management of hyponatraemia involves the following:Give bolus of 0.9% saline 20 mL/kg if child is in shock and as required. In the child with hypernatraemic dehydration, as in any child with dehydration, the first priority is restoration of intravascular volume with isotonic fluidSubtract the bolus given for hypovolaemic shock from calculated deficit = remaining deficitCalculate maintenance fluid based on weight of the childGive 1/2 of remaining deficit over the first 24 h + 24 h maintenance fluid + ongoing lossesGive 1/2 of remaining deficit over the second 24 h + 24 h maintenance fluid + ongoing lossesFor mild/moderate hypernatremia;Give 1/3 of remaining deficit over the first 24 h+ 24 h maintenance fluid + ongoing lossesGive 1/3 of remaining deficit over the second 24 h + 24 h maintenance fluid + ongoing lossesGive 1/3 of remaining deficit over the third 24 h + 24 h maintenance fluid + ongoing lossesFor severe hypernatremia;The fluid of choice for correcting hypernatraemic dehydration is 0.9% NaCl with 5% glucoseThe management of a child with dehydration requires a regular and close clinical and laboratory monitoring. In as much as the kidneys are functioning optimally, errors resulting from over-hydration can be corrected by the kidneys. Onus is on the attending physician to ensure that hypovolaemic shock is reversed, while ongoing losses are replaced to remove the child from a perpetual state of dehydration.A preferred fluid solution to be used for maintenance fluid and electrolytes is 5% dextrose in 0.9% saline with 20 mmol/L of potassium chloride added.The maintenance fluid volumes are the starting point for acutely ill dehydrated children, adjustment (between 50–80% reductions in maintenance volumes) can be made based on the clinical response to fluids in these children who tend to have a reduced free water excretion from high levels of ADH hormones. Some children may, however, require more than the usual maintenance fluid volumes.Maintenance fluid containing less than 75 mmol/L of sodium should never be used for maintenance hydration. 0.18% sodium chloride  contains only 30 mmol/L of sodium and is not appropriate for maintenance hydration.Oral rehydration is most suitable for mild to moderate isonatraemic dehydration.0.9% saline with 5% glucose with 20 mmol/L of potassium chloride  is suitable for most isonatraemic, hypernatraemic, and hyponatraemic dehydration.The correction of the deficit-free water volume in hypernatraemic dehydration is spread over 48–72 h, as the child continues to get his daily maintenance fluid, and fluid is continuously being replaced for ongoing losses.If sodium is corrected too rapidly in hypernatremia, cerebral edema, and permanent brain injury may occur.If sodium is corrected too rapidly in hyponatraemia, cerebral  demyelination, and permanent brain injury may occur.Regular clinical and laboratory (serum electrolytes and glucose) monitoring every 4 h is required in hyponatraemic and hypernatraemic dehydration until serum values become normal.The rate of change in serum sodium should not be more than 0.5 mmol/L per hour and/or 12 mmol/L per day in hyponatraemic and hypernatraemic dehydration.Responsible for the conceptualization, literature review, and critical review of the manuscript.While the information contained in this article is scientifically correct, the author hereby disclaims any and all liability to all persons arising out of, or related to the content of this article. Readers are advised to seek the services of an experienced, competent professional if expert assistance is required in childhood fluid and electrolytes therapy.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.