Appendix 2|Review Questions – PICOM Format Chapter 1. In patients with hypotonic hyponatraemia, how sensitive and or specific are various 'diagnostic strategies' in comparison with a gold reference standard of sodium challenge in differentiating hypovolemic from euvolaemic hyponatraemia? Patients In people with hypotonic hyponatraemia Children, adults, aged adults Intervention Clinical signs and symptoms of hypovolaemia Orthostatic hypotension Tachycardia Dry mouth Decreased skin turgor Prolonged capillary refill Flat jugular central venous pressure Urine sodium concentration Fractional sodium excretion Serum urea concentration Fractional urea excretion Serum uric acid concentration Fractional uric acid excretion Urine osmolality Serum urea/creatinine ratio Comparator Sodium challenge (2L saline/24h) Outcome Differentiating hypovolemic from euvolaemic hyponatraemia Methodology Systematic review Diagnostic test accuracy study

Chapter 1. In patients with hypotonic hyponatraemia, how sensitive and or specific are various 'diagnostic strategies' in comparison with a gold reference standard of expert panel diagnosis in differentiating hypovolemic from euvolaemic hyponatraemia? Patients In people with hyponatraemia Children, adults, aged adults Intervention Urine sodium concentration Urine osmolality Fractional sodium excretion Fractional uric acid excretion Serum urea concentration Serum uric acid concentration serum urea/creatinine ratio / copeptin Plus Clinical signs and symptoms of hypovolaemia Orthostatic hypotension Tachycardia Dry mouth Decreased skin turgor Prolonged capillary refill Flat jugular central venous pressure Comparator Expert panel clinical diagnosis of 'type' of hyponatraemia Outcome Differentiating hypovolemic from euvolaemic hyponatraemia Methodology Systematic review Diagnostic test accuracy study

Chapter 2. In patients with hypotonic hyponatraemia, which treatments are effective in improving outcomes? Patients In people with hyponatraemia Children, adults, aged adults Acute or chronic hyponatraemia Symptomatic or asymptomatic hyponatraemia Intervention Saline, NaCl, Sodium Chloride (normal, hypertonic, isotonic) Urea Mannitol Loop diuretics, furosemide, bumetanide, ethacrinic acid, torasemide , DDAVP Phenytoin , lixivaptan, , , Fludrocortisone, hydrocortisone, mineralocorticoids, glucocorticoids Fluid restriction, water restriction Comparator No treatment Placebo Outcome Survival Sodium increase Fall Bone fracture CNS Status Myelinolysis Osmotic demyelination syndrome (ODS) Respiratory arrest Coma Seizures, epilepsy Brain oedema, brain damage Length of hospital stay Quality of life Cost Methodology Systematic review RCT Cohort study Case‐control study Case reports No letters, editorials or letters Other information Head to head comparisons of all interventions Note: initially combined search, if yield too high (>600) separate search for interventions versus no treatment separately, all 'strategies' versus fluid restriction, all except fluid restriction head to head.

Chapter 2. In patients with hypotonic hyponatraemia, does the rate of sodium correction influence the outcome? Patients In people with hyponatraemia Children, adults, aged adults Acute or chronic hyponatraemia Symptomatic or asymptomatic hyponatraemia Intervention 'Slow' "Correction rate" "Daily increase" "Daily increase" "Rate of increase" *per hour, per day, per 24 h, per 48 h, per 72 h Comparator 'Fast' correction Outcome Survival Sodium increase Fall Bone fracture CNS Status Myelinolysis Osmotic demyelination syndrome (ODS) Respiratory arrest Coma Seizures, epilepsy Brain edema, brain damage Length of hospital stay Quality of life Cost Methodology Systematic review RCT Cohort study Case‐control study Case reports No letters, editorials or letters Other information Head to head comparisons of all interventions