Electrolyte-free Water Clearance Research Articles

Multiparametric renal function assessment in cirrhotic patients shows high prevalence of medically actionable changes in multiple modules.

Renal dysfunction is a common complication of cirrhosis, occurring either as part of multiorgan involvement in acute illness or secondary to advanced liver disease. To date, no study has comprehensively assessed multiple renal function parameters in hospitalized patients with cirrhosis through a multiparametric analysis of renal biochemistry markers. We conducted a retrospective, observational study including all consecutive patients hospitalized with cirrhosis who underwent a 43-multiparametric renal function assessment between January 1, 2021, and June 30, 2023. All patients showed at least one of the following renal abnormalities: Kidney Disease: Improving Global Outcomes stage G2 or higher, sodium and/or chloride excretion fraction <1%, electrolyte-free water clearance <0.4mL/min, or tubular maximum phosphate reabsorption capacity <0.8mmol/L. The estimated glomerular filtration rate equations significantly overestimated the measured creatinine clearance with median differences of +14mL/min/1.73m2 (95% CI 6-29) and +9mL/min/1.73m2 (95% CI 2-15) for European Kidney Function Consortium equations, respectively. Notably, 54% and 39% of patients demonstrated estimated glomerular filtration rates exceeding 30% of the measured creatinine clearance when the Chronic Kidney Disease - Epidemiology Collaboration and European Kidney Function Consortium formulas were employed, respectively. Substantial discrepancies in Kidney Disease: Improving Global Outcomes stage assignments were observed between the estimated glomerular filtration rate- and measured creatinine clearance-based assessments. This study underscores the value of a multiparametric renal function assessment as a routine tool for evaluating renal function in patients with cirrhosis. A high prevalence of medically actionable renal abnormalities spanning multiple renal function modules, including alterations in glomerular function, salt and solute-free water excretion, and proximal tubule phosphate reabsorption, has been demonstrated in hospitalized patients with cirrhosis.

Copeptin adaptive response to SGLT2 inhibitors in patients with type 2 diabetes mellitus: The GliRACo study.

In type 2 diabetes mellitus (T2DM), the antidiuretic system participates in the adaptation to osmotic diuresis further increasing urinary osmolality by reducing the electrolyte-free water clearance. Sodium glucose co-transporter type 2 inhibitors (SGLT2i) emphasize this mechanism, promoting persistent glycosuria and natriuresis, but also induce a greater reduction of interstitial fluids than traditional diuretics. The preservation of osmotic homeostasis is the main task of the antidiuretic system and, in turn, intracellular dehydration the main drive to vasopressin (AVP) secretion. Copeptin is a stable fragment of the AVP precursor co-secreted with AVP in an equimolar amount. To investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients. The GliRACo study was a prospective, multicenter, observational research. Twenty-six consecutive adult patients with T2DM were recruited and randomly assigned to empagliflozin or dapagliflozin treatment. Copeptin, plasma renin activity, aldosterone and natriuretic peptides were evaluated at baseline (T0) and then 30 (T30) and 90 days (T90) after SGLT2i starting. Bioelectrical impedance vector analysis (BIVA) and ambulatory blood pressure monitoring were performed at T0 and T90. Among endocrine biomarkers, only copeptin increased at T30, showing subsequent stability (7.5 pmol/L at T0, 9.8 pmol/L at T30, 9.5 pmol/L at T90; p = 0.001). BIVA recorded an overall tendency to dehydration at T90 with a stable proportion between extra- and intracellular fluid volumes. Twelve patients (46.1%) had a BIVA overhydration pattern at baseline and 7 of them (58.3%) resolved this condition at T90. Total body water content, extra and intracellular fluid changes were significantly affected by the underlying overhydration condition (p < 0.001), while copeptin did not. In patients with T2DM, SGLT2i promote the release of AVP, thus compensating for persistent osmotic diuresis. This mainly occurs because of a proportional dehydration process between intra and extracellular fluid (i.e., intracellular dehydration rather than extracellular dehydration). The extent of fluid reduction, but not the copeptin response, is affected by the patient's baseline volume conditions. Clinicaltrials.gov, identifier NCT03917758.

Perioperative water and electrolyte balance and water homeostasis regulation in children with acute surgery

BackgroundHospital-acquired hyponatremia remains a feared event in patients receiving hypotonic fluid therapy. Our objectives were to assess post-operative plasma-sodium concentration and to provide a physiological explanation for plasma-sodium levels over time in children with acute appendicitis.MethodsThirteen normonatremic (plasma-sodium ≥135 mmol/L) children (8 males), median age 12.3 (IQR 11.5–13.5) years participated in this prospective observational study (ACTRN12621000587808). Urine was collected and analyzed. Blood tests, including renin, aldosterone, arginine-vasopressin, and circulating nitric oxide substrates were determined on admission, at induction of anesthesia, and at the end of surgery.ResultsOn admission, participants were assumed to be mildly dehydrated and were prescribed 50 mL/kg of Ringer’s acetate intravenously followed by half-isotonic saline as maintenance fluid therapy. Blood tests, urinary indices, plasma levels of aldosterone, arginine-vasopressin, and net water-electrolyte balance indicated that participants were dehydrated on admission. Although nearly 50% of participants still had arginine-vasopressin levels that would have been expected to produce maximum antidiuresis at the end of surgery, electrolyte-free water clearance indicated that almost all participants were able to excrete net free water. No participant became hyponatremic.ConclusionsThe use of moderately hypotonic fluid therapy after correction of extracellular fluid deficit is not necessarily associated with post-operative hyponatremia.ImpactOur observations show that in acutely ill normonatremic children not only the composition but also the amount of volume infused influence on the risk of hyponatremia.Our observations also suggest that perioperative administration of hypotonic fluid therapy is followed by a tendency towards hyponatremia if extracellular fluid depletion is left untreated.After correcting extracellular deficit almost all patients were able to excrete net free water. This occurred despite nearly 50% of the cohort having high circulating plasma levels of arginine-vasopressin at the end of surgery, suggesting a phenomenon of renal escape from arginine-vasopressin-induced antidiuresis.

PS-B05-6: FABRY DISEASE MOUSE IS RESISTANT TO HIGH-SALT DIET-INDUCED HYPERTENSION PROBABLY VIA DYSFUNCTIONAL SODIUM TRANSPORTS AND AQUAPORIN 2

Background: Fabry disease is a rare X-linked lysosomal storage disorder resulting from an error in glycosphingolipid metabolism caused by the GLA gene mutation. Patients with Fabry disease often have near normal or even low systemic blood pressure although the mechanism underlying such observed finding remains unexplained. This study examined whether a high salt intake could affect transport of sodium and water and induce hypertension in mice with Fabry disease. Methods: Fabry disease model mice (B6;129-Glatm1Kul/J) and wild-type (WT) mice received 8% or normal NaCl salt diet for 2 weeks. Results: A high-salt diet for 2 weeks generated higher blood pressure in WT mice but not in Fabry disease mice. Free water clearance (FWC) and electrolyte free water clearance (EFWC) in groups fed with a high salt diet were lower than those in groups fed with a normal salt diet. Both high salt-fed WT and Fabry disease mice had decreased gamma-subunit of epithelial Na channel (ENaC) compared with normal salt-fed groups. In Fabry disease mice fed a high-salt diet, there was an decrease in renal expressions of Na+/H+ exchanger isoform 3 (NHE3) and Na+-Cl- cotransporter (NCC) compared with WT mice fed a high-salt diet. Although renal expression of vasopressin V2 receptor (V2R) was upregulated in Fabry mice fed with a high salt diet, renal aquaporin 2 (AQP2) level failed to increase up to the level in WT mice fed with a high salt diet. Conclusion: These findings suggest that the decreased expression of NHE3 and NCC and impaired response of AQP2 in kidneys of Fabry disease to a salt load could be one of mechanisms by which Fabry disease could have resistance to the development of hypertension.

Evaluation and management of hypernatremia in adults: clinical perspectives.

Hypernatremia is an occasionally encountered electrolyte disorder, which may lead to fatal consequences under improper management. Hypernatremia is a disorder of the homeostatic status regarding body water and sodium contents. This imbalance is the basis for the diagnostic approach to hypernatremia. We summarize the eight diagnostic steps of the traditional approach and introduce new biomarkers: exclude pseudohypernatremia, confirm glucose-corrected sodium concentrations, determine the extracellular volume status, measure urine sodium levels, measure urine volume and osmolality, check ongoing urinary electrolyte free water clearance, determine arginine vasopressin/copeptin levels, and assess other electrolyte disorders. Moreover, we suggest six steps to manage hypernatremia by replacing water deficits, ongoing water losses, and insensible water losses: identify underlying causes, distinguish between acute and chronic hypernatremia, determine the amount and rate of water administration, select the type of replacement solution, adjust the treatment schedule, and consider additional therapy for diabetes insipidus. Physicians may apply some of these steps to all patients with hypernatremia, and can also adapt the regimens for specific causes or situations.

Exploring the mechanisms of action of gliflozines in heart failure and possible implications in pulmonary hypertension

Although results from two major trials trials have shown a clear benefit of gliflozines in the management of heart failure (HF) irrespective of diabetes status, the mechanism of cardiac benefits remains incompletely understood. Gliflozines have an osmotic diuretic effect that differs from that of other diuretic classes, resulting in greater electrolyte-free water clearance, and clinical studies have shown that intravascular volume depletion is rare and occurs at similar frequency in the gliflozines and placebo groups. As a consequence of the negligible effects on the blood volume and body's fluid balance compared to diuretics, gliflozines may limit the reflex neurohumoral stimulation and activation of renin-angiotensin-aldosterone system (RAAS). Since neurohormonal and RAAS activation in patients with HF reduced or ejection fraction (HFrEF and HFpEF) also leads to systemic and pulmonary arterial stiffening, pulmonary hypertension (PH) and PH-related right ventricular failure, gliflozines may lead to a mitigation of systemic and pulmonary arterial stiffening, which in turn can reduce the degree of PH associated with HFrEF or HFpEF, can improve the ventricular arterial coupling and can reduce the overload of the left and right ventricle, improving their function. The current review discusses the latest findings regarding the effects of SGLT2 inhibitors on heart failure with focus also on pulmonary hypertension, discussing the molecular mechanisms involved.

The renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure (RECEDE-CHF) trial

Abstract Introduction The SGLT2 inhibitors have been shown to reduce heart failure (HF) hospitalisations in patients with Type 2 diabetes (T2D), and to improve outcomes in those with HF irrespective of T2D status. Given this, it is likely that they will be co-prescribed with a loop diuretic. The combined diuretic effect of SGLT2 inhibitors and loop diuretic has not been well defined. Purpose The aim of this study was to assess the diuretic and natriuretic effect of empagliflozin in patients with T2D and chronic HF in combination with loop diuretics. Methods and analysis RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in patients with T2D and Chronic HF) was a randomised, double-blind, placebo-controlled, cross-over trial. Patients were randomised to empagliflozin 25 mg once a day or placebo for 6 weeks with study assessments at day 3 and week 6. Following a 2 week washout period, patients then entered the second treatment arm. The primary outcome was change in 24-hour urinary volume, when compared to placebo at day 3 and week 6. Results 23 participants mean age 69.8 years, (male 73.9%) with T2D and chronic HF (all ejection fraction &amp;lt;50%) on a mean furosemide dose of 49.6 mg/day were recruited. In comparison to placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both time points (day 3, mean difference of 549.3 ml, 95% confidence interval 151.4 to 947.2, p=0.004 and week 6, mean difference of 542.8 ml, 95% CI 134.9 to 950.7, p=0.005), adjusted for treatment order and baseline 24-hour urine volume. Empagliflozin did not cause a significant increase in the 24-hour urinary sodium as measured in mmol/L at both time points (day 3, mean difference compared to placebo −2.96 mmol/L, 95% CI: −21.55 to 15.64, p=1.00, week 6 mean difference compared to placebo −8.41 mmol/L, 95% CI: −27.00 to 10.18, p=0.81). Empagliflozin caused a significant increase in electrolyte-free water clearance (cH20e) at day 3 (mean difference compared to placebo 287.36 ml/min, (95% CI 31.79 to 542.93, p=0.022) and at week 6 (mean difference when compared to placebo 255.69 ml/min (95% CI: −284.12 to 220.76, p=0.048) when corrected for furosemide dose. 21.7% (n=5) participants had to have their furosemide dose reduced by 50% whilst on the active treatment arm of empagliflozin by day 3. On discontinuation of the active treatment arm with empagliflozin, two participants experienced hospital admissions with decompensated cardiac congestion. Conclusions Empagliflozin caused a significant increase in 24-hour urine volume when used in combination with loop diuretic when compared to placebo. There was no increase in 24-hour urinary sodium excretion. The greater electrolyte-free water clearance induced by empagliflozin observed in this study may support a proposed hypothesis that this could result in a greater fluid clearance from the interstitial space than from the circulating volume. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation (BHF)

Influence of electrolyte balance on the prognosis of long-term cardiovascular events after acute coronary syndrome

Aim. To assess the effect of electrolyte changes on the prognosis of long-term cardiovascular events after acute coronary syndrome (ACS).Material and methods. The study included 105 patients with ACS who underwent coronary angiography (CA) with coronary stenting. At the study inclusion (before CA with coronary stenting), we collected data on traditional risk factors, analyzed levels of urinary sodium and potassium, kaliuresis and natriuresis. Free water clearance (FWC) and electrolyte free water clearance (EFWC), as well as fluid balance using bioelectrical impedance analysis were determined. Study endpoints (fatal and nonfatal cardiovascular events) were determined 6,2±0,2 months after CA with coronary stenting.Results. It was found that a decrease in urinary sodium (χ2=5,64, p=0,02, Constanta B0 =-0,62, Estimate =-16,5) and natriuresis (χ2=4,1, р=0,044, Constanta B0 =-1,38, Estimate =-5,2) increase the death risk. Urinary sodium of 0,2 mol/L and natriuresis of 0,5 mol are threshold levels of increased risk of death. Urinary potassium decrease was associated with an increase in death risk (threshold level — 0,5 mol/L, χ2=4,99, р=0,025, Constanta B0 =-0,63, Estimate =-70,4) and acute myocardial infarction (threshold level — 0,06 mol/L, χ2=3,93, р=0,04, Constanta B0 =-0,99, Estimate =-58,0) in the long-term period. Increase in EFWC increased the likelihood of long-term transient ischemic attack after ACS (χ2=4,61, р=0,03, Constanta B0 =-2,95, Estimate =-1,0). There were no significant relationships in the matter of FWC (p&gt;0,05). However, with a decrease in intracellular fluid volume compared to normal values and a decrease in FWC or an increase in EFWC, the likelihood of longterm composite endpoints after ACS increases.Conclusion. As a result of the study, risk markers for long-term fatal and non-fatal cardiovascular events after ACS were established: decrease in urinary sodium &lt;0,2 mol/l and potassium &lt;0,5 mol/l; decrease in FWC and increase in EFWC with or without cellular dehydration. The established markers can complement the current cardiovascular risk score methods in patients with ACS.

Empagliflozin Contributes to Polyuria via Regulation of Sodium Transporters and Water Channels in Diabetic Rat Kidneys.

Besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, have been known to provide cardiovascular and renal protection due to effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse. This study was performed to assess the renal effects of a 12-week treatment with empagliflozin (3 mg/kg) in diabetic OLETF rats by comparing it with other antihyperglycemic agents including lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. At 12 weeks of treatment, empagliflozin-treated diabetic rats produced still high urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide or voglibose-treated diabetic rats without significant change of serum sodium level and fractional excretion of sodium. In empagliflozin-treated rats, renal expression of Na+-Cl- cotransporter was unaltered, and expressions of Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, and epithelial Na+ channel were decreased compared with control diabetic rats. Empagliflozin increased an expression of aquaporin (AQP)7 but did not affect AQP3 and AQP1 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in empagliflozin-treated diabetic kidneys were significantly decreased compared to control diabetic kidneys. In addition, empagliflozin resulted in the increased phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. These results suggest that empagliflozin may contribute in part to polyuria via its regulation of sodium channels and AQP2 in diabetic kidneys.

Recurrent Polyuria

Recurrent Polyuria

Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.

Treatment of Cirrhosis-Associated Hyponatremia with Midodrine and Octreotide.

Hyponatremia in the setting of cirrhosis is a common electrolyte disorder with few therapeutic options. The free water retention is due to non-osmotic vasopressin secretion resulting from the cirrhosis-associated splanchnic vasodilatation. Therefore, vasoconstrictive therapy may correct this electrolyte abnormality. The aim of this study was to assess the efficacy of midodrine and octreotide as a therapeutic approach to increasing urinary electrolyte-free water clearance (EFWC) in the correction of cirrhosis-associated hyponatremia. This observational study consisted of 10 patients with cirrhosis-associated hyponatremia. Hypovolemia was ruled out as the cause of the hyponatremia with a 48-h albumin challenge (25 g IV q6 h). Patients whose hyponatremia failed to improve with albumin challenge were started on midodrine and octreotide at 10 mg po tid and 100 μg sq tid, respectively, with rapid up-titration as tolerated to respective maximal doses of 15 mg tid and 200 μg tid within the first 24 h. We assessed urinary EFWC and serum sodium concentration before and 72 h after treatment. Pretreatment serum sodium levels ranged from 119 to 133 mmol/L. The mean pretreatment serum sodium concentration ± SEM was 124 mmol/L ± 1.6 vs 130 mmol/L ± 1.5 posttreatment (p = 0.00001). The mean pretreatment urinary EFWC ± SEM was 0.33 L ± 0.07 vs 0.82 L ± 0.11 posttreatment (p = 0.0003). Our data show a statistically significant increase in serum sodium concentration and urinary EFWC with the use of midodrine and octreotide in the treatment of cirrhosis-associated hyponatremia.

Assessment of Electrolyte Free Water Clearance in Renal Transplant Recipients

Background: Few studies have been done on free water excretion capacity in renal transplant recipients. Objectives: This study was designed to compare electrolyte free water clearance (E-CH2O) in renal transplant recipients with healthy control group. Methods: A cross-sectional study was conducted to determine three-hour creatinine clearance (CCl), E-CH2O, and percent urine output in 3 hours after administering 20 mL/Kg oral water loading following 12-hour fasting, in 22 renal transplant recipients with good graft function (creatinine 0.05), the E-CH2O (1.83 ± 1.22 vs. 2.94 ± 2.02) and 3-hour urine output percent (55.93 ± 22.86 vs74.11 ± 30.38) in kidney recipients was significantly lower than healthy controls (P < 0.05). There wasn’t any significant correlation between E-CH2O and 3h-CCl in renal transplant recipients. Donor source and gender did not affect 3h-CCl and E-CH2O in renal transplant patients. Conclusions: This study demonstrated that E-CH2O has been decreased in renal transplant patients in comparison with control group when there was not any difference between3h- CCl in two groups. This indicates that E-CH2O may be decreased earlier than 3h-CCl in transplant patients.

The utility and accuracy of four equations in predicting sodium levels in dysnatremic patients.

BackgroundImproper correction of hyponatremia can cause severe complications, including osmotic demyelination syndrome (ODS). The Adrogué–Madias equation (AM), the Barsoum–Levine (BL) equation, the Electrolyte Free Water Clearance (EFWC) equation and the Nguyen–Kurtz (NK) equation are four derived equations based on the empirically derived Edelman equation for predicting sodium at a later time (Na2) from a known starting sodium (Na1), fluid/electrolyte composition and input and output volumes.MethodsOur retrospective study included 43 data points from 31 mostly hyponatremic patients. We calculated Na2 based on five sets of rules that were progressively more precisely calculated. Sets A–D included all 31 patients and 43 data points and set E was based on 15 patients and 27 data points.ResultsThe root mean square error was calculated and found to be between 4.79 and 6.37 mmol/L (mEq/L) for all sets. Bland–Altman analysis showed high variability and discrepancies between the predicted and actual Na2.ConclusionsLike similar studies in hypernatremic patients, the data suggest that hyponatremic modeling equations are not reliably accurate in predicting Na2 from Na1 and available clinical data regarding sodium, potassium and fluid balance over longer time frames (12–30 h). Our study was retrospective and was done in an inpatient setting and thus was subject to limitations and laboratory measurement variability, but showed that all four equations are not able to reliably predict Na2 from Na1 and inputs across a 12–30 h period.

Maintenance Intravenous Fluids in Acutely Ill Patients.

To the Editor: The recommendation by Moritz and Ayus (Oct. 1 issue)1 of 0.9% normal saline as default maintenance fluid in acutely ill patients fails to consider the increased risk of hypernatremia and volume expansion that may occur. Both complications may be potentially as damaging as the hyponatremia that the authors seek to avoid.2,3 Hypernatremia accompanies ongoing hypotonic losses, including from sweat and the urea-induced diuresis associated with nutritional supplementation, and the hypertonic gain of 0.9% saline with added potassium. By definition, maintenance represents an amount and content of fluid needed to maintain a steady state. The emergence of iatrogenic hyponatremia or hypernatremia with any one-size-fits-all prescription indicates a miscalculation of maintenance fluids for a given patient. It is necessary to first define and achieve the steady state desired, to measure or estimate all input and output volumes and electrolyte content, and to recalculate at regular intervals. Urinary sodium excretion, potassium excretion, and flow rate allow for simple calculations of a positive or negative electrolyte-free water clearance and isotonic loss. The best guideline to prevent severe complications would be an algorithm for constructing a therapeutic plan for an individual patient.

Prevention of hospital-acquired hyponatraemia: individualised fluid therapy.

Large amounts of fluids are daily prescribed to hospitalised patients across different medical specialities. Unfortunately, inappropriate fluid administration commonly causes iatrogenic hyponatraemia with associated increase in morbidity and mortality. Fundamental for prevention of hospital-acquired hyponatraemia is an understanding of what determines plasma sodium concentration (P-[Na(+) ]) in the individual patient. P-[Na(+) ] is determined by balances of water and cations according to Edelman. This paper discusses the mechanisms influencing water and cation balances. In the hospitalised patient, non-osmotic antidiuretic hormone secretion is frequent and results in a reduced renal electrolyte-free water clearance (EFWC). This condition puts the patient at risk of hyponatraemia upon infusion of fluids that are hypotonic such as 5% glucose, Darrow-glucose, NaKglucose and 0.45% NaCl in 5% glucose. It is suggested that individualised fluid therapy includes the following: Firstly, bolus therapy with Ringer-acetate/Ringer-lactate/0.9% NaCl in the hypovolaemic patient to minimise the risk of fluid under-/overload. Secondly, P-[Na(+) ] should be monitored together with the balances influencing P-[Na(+) ]. This may include EFWC in patients at additional risk of hyponatraemia. In patients with potentially reduced intracranial compliance (e.g. meningitis, intracranial bleeding, cerebral contusion and brain oedema), even a small decrease in P-[Na(+) ] induced by slightly hypotonic fluids like Ringer-acetate/Ringer-lactate can increase the intracranial pressure dramatically. Consequently, 0.9 % NaCl is recommended as first-line fluid for such patients. The occurrence of hospital-acquired hyponatraemia may be reduced by prescribing fluids, type and amount, with the same dedication as shown for other drugs.

Thiazide-induced hyponatraemia is associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin-2

Hyponatraemia is a common, potentially life-threatening, complication of thiazide diuretics. The mechanism of thiazide-induced hyponatraemia is incompletely understood. Previous experiments have suggested a direct effect of thiazide diuretics on the plasma membrane expression of aquaporin (AQP)2. We examined the effects of a single re-exposure to hydrochlorothiazide (HCTZ) 50 mg on water balance, renal sodium handling and osmoregulation in 15 elderly hypertensive patients with a history of thiazide-induced hyponatraemia and 15 matched hypertensive controls using thiazide diuretics without previous hyponatraemia. Patients with thiazide-induced hyponatraemia had significantly lower body weight and lower plasma sodium and osmolality at baseline. After HCTZ administration, plasma sodium and osmolality significantly decreased and remained lower in patients compared with controls (P < 0.001). Plasma antidiuretic hormone (ADH) and urine AQP2 were low or suppressed in patients, whereas solute and electrolyte-free water clearance was significantly increased compared with controls. Ad libitum water intake was significantly higher in patients (2543 ± 925 ml) than in controls (1828 ± 624 ml, P < 0.05), whereas urinary sodium excretion did not differ. In contrast, urea excretion remained significantly lower in patients (263 ± 69 mmol per 24 h) compared with controls (333 ± 97 mmol per 24 h, P < 0.05) and predicted the decrease in plasma sodium following HCTZ administration. Thiazide diuretics are associated with markedly impaired free water excretion at low ADH and AQP2 in elderly patients. The higher water intake and lower urea excretion in patients points to an important role for polydipsia and urea-mediated water excretion in the pathogenesis of thiazide-induced hyponatraemia.

Body salt and water balances in cardiothoracic surgery patients with intensive care unit–acquired hyponatremia

PurposeHyponatremia is frequently observed in intensive care unit (ICU) patients, but there is still lack information on the physiological mechanisms of development. Materials and MethodsIn this retrospective analysis we performed tonicity balances in 54 patients with ICU acquired hyponatremia. We calculated fluid and solute in and outputs during 24 hours in 106 patient days with decreasing serum-sodium levels. ResultsWe could observe a positive fluid balance as a single reason for hyponatremia in 25% of patients and a negative solute balance in 57%. In 18% both factors contributed to the decrease in serum-sodium. Hyponatremic patients had renal water retention, measured by electrolyte free water clearance calculation in 79% and positive input of free water in 67% as reasons for decline of serum-sodium. The theoretical change of serum sodium during 24 hours according to the calculations of measured balances correlated well with the real change of serum sodium (r = 0.78, P < .01). ConclusionsBalance studies showed that renal water retention together with renal sodium loss and high electrolyte free water input are the major contributors to the development of hyponatremia. Control of renal water and sodium handling by urine analysis may contribute to a better fluid management in the ICU population.

Osmotic diuresis-induced hypernatremia: better explained by solute-free water clearance or electrolyte-free water clearance?

Hypernatremia may result from inadequate water intake, excessive water loss or a combination of the two. Osmotic diuresis leads to losses of both solute and water. The relationship between solute and water losses determines the resulting changes in serum osmolality and sodium concentration. Total solute loss is routinely higher than loss of water in osmotic diuresis. Theoretically, then, decreases in serum osmolality (and serum sodium concentration) should follow. In clinical situations of osmotic diuresis, however, reduction in osmolality can take place, but not reduction in serum sodium concentration. It is of note that serum sodium concentration changes are related to urinary losses of sodium and potassium but not to the loss of total solute. In osmotic diuresis, the combined loss of sodium and potassium per liter of urine is lower than the concurrent serum sodium level. Consequently, hypernatremia can ensue. A patient who presented with osmotic diuresis and hypernatremia is described here. In this patient, we have shown that electrolyte-free water clearance is a better index of the effect of osmotic diuresis on serum sodium concentration than the classic solute-free water clearance.

Electrolyte-free water clearance: a clinical utility in managing osmotic urea diuresis-associated polyuria in tube feeding syndrome

Hypernatremia is a common problem in critically ill patients. Part of the reason for the inadequate treatment of hypernatremia may be that we tend to replace only the free water deficit (FWD) and neglect replacing ongoing losses of free water. In most cases, ongoing losses of free water occur in the urine, the quantity of which can be easily calculated using the electrolyte free water clearance (EFWC). We report a case of man presenting with tube feeding syndrome (TFS) and hyperglycemic hyperosmolar nonketotic syndrome (HHNS). He developed life-threatening hypernatremia from an osmotic urea diuresis that was appropriately treated by replacing both the FWD as well as ongoing free water losses calculated from the EFWC. A 37 year-old man in a persistent vegetative state from a left thalamic hemorrhage status post ventriculostomy and PEG tube placement was admitted with sepsis and HHNS. He was receiving large amounts of Jevity 1.2. He had acute kidney injury due to severe volume depletion from an osmotic urea diuresis. BUN was 200 mg/dL, sodium was 165 mEq/L, glucose was 635 mg/dL, and serum osmolality was 449 mOsm/kg. To prevent the development of cerebral edema from overly rapid correction of hyperosmolality, he was started on an insulin drip and hypernatremia was allowed to persist until the hyperglycemia was fully normalized. This was followed by correcting the hypernatremia over 3 days. He was urinating up to about 4 L/day of mostly electrolyte free water. Using the FWD to arrive at the rate of free water administration, he would only have received 2 L of free water per day and hypernatremia would have persisted. Instead, he required about 4.5 L/day of free water as calculated by the FWD and EFWC together, and his hypernatremia resolved as expected. Our patient presented with a triad of TFS including hypernatremia, dehydration, and azotemia. Rapidly increased fluid loss from sepsis and HHNS initially caused severe hypernatremia. Only by using the combination of FWD and EFWC calculations could we have arrived at the appropriate rate of free water administration.