Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed. RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

High Osmol Gap Hyponatremia Caused by Icodextrin: A Case Series Report.

Recently, hyperosmolar hyponatremia following excessive off-label use of two exchanges of 2 L icodextrin daily during peritoneal dialysis (PD) was reported. We encountered a cluster of 3 cases of PD patients who developed hyperosmolar hyponatremia during on-label use of icodextrin. This appeared to be due to absorption of icodextrin since after stopping icodextrin, the serum sodium level and osmol gap returned to normal, while a rechallenge again resulted in hyperosmolar hyponatremia. We excluded higher than usual concentrations of specific fractions of dextrins in fresh icodextrin dialysis fluid (lot numbers of used batches were checked by manufacturer). We speculate that in our patients, either an exaggerated degradation of polysaccharide chains by α-amylase activity in dialysate, lymph, and interstitium and/or rapid hydrolysis of the absorbed larger degradation products in the circulation may have contributed to the hyperosmolality observed, with the concentration of oligosaccharides exceeding the capacity of intracellular enzymes (in particular maltase) to metabolize these products to glucose. Both hyponatremia and hyperosmolality are risk factors for poor outcomes in PD patients. Less conventional PD prescriptions such as off-label use of two exchanges of 2 L icodextrin might raise the risk of this threatening side effect. This brief report is intended to create awareness of a rare complication of on-label icodextrin use in a subset of PD patients and/or PD prescriptions.

Beyond SEP-1 Compliance: Assessing the Impact of Antibiotic Overtreatment and Fluid Overload in Suspected Septic Patients.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) developed the Severe Sepsis and Septic Shock Performance Measure bundle (SEP-1) metric to improve sepsis care, but evidence supporting this bundle is limited and harms secondary to compliance have not been investigated. OBJECTIVE: This study investigates the effect of an emergency department (ED) sepsis quality-improvement (QI) effort to improve CMS SEP-1 compliance, looking specifically at antibiotic overtreatment and harm from fluid resuscitation. METHODS: This was a retrospective observational study conducted between March and July 2021 with patients for whom a sepsis order set was initiated. The primary outcomes included the number of patients treated with antibiotics who were ultimately deemed nonseptic and the number of patients who developed pulmonary edema, with or without need for positive pressure ventilation (PPV), within 48 h of receiving a 30 mL/kg fluid bolus. Data were collected via nonblinded chart reviews, with a free marginal κ-calculation indicating excellent interrater reliability. RESULTS: The study cohort included 273 patients, 170 (62.3%) who were ultimately determined to be septic and 103 (37.7%) who were nonseptic. Of the 103 nonseptic patients, 82 (79.6%) received antibiotics in the ED. Of the 121 patients (44.3%) who received a 30 mL/kg bolus, 5 patients (4.1%) developed pulmonary edema and 0 of 121 patients required PPV within 48 h. CONCLUSIONS: The QI effort led to moderate rates of antibiotic overtreatment and very few patients developed pulmonary edema due to a 30 mL/kg fluid bolus.

Efficacy of tolvaptan on advanced chronic kidney disease with heart failure: a randomized controlled trial.

BACKGROUND: Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective. However, it is not clear whether TLV addition is effective for advanced CKD patients with heart failure. METHODS: An open-label, parallel-group randomized trial was performed. The subjects were 33 patients with CKD stage G3-G5 who had fluid overload despite taking 20-100 mg/day FUR. They were divided into two groups: a group administered 15 mg/day TLV plus their original FUR dose for 7 days (TLV group), and a group administered 120-200 mg/day FUR (i.e., 100 mg/day over their previous dose) for 7 days (FUR group). RESULTS: The mean change in urine volume was significantly higher in the TLV group compared to the FUR group (637 ml vs 119 ml; p < 0.05). The difference was greater when the urine osmolality before treatment was high. Serum creatinine was increased only in the FUR group. The incidence of worsening renal function (WRF) was significantly lower in the TLV group (18.8% vs 58.8%; p < 0.05). Serum sodium decreased significantly in the FUR group, but did not change in the TLV group. CONCLUSIONS: In patients with advanced CKD with fluid overload, the addition of TLV achieved a significantly higher urine volume with less adverse effects on renal function compared with increasing the dose of FUR. The efficacy and safety of TLV were higher in patients who had higher urine osmolality and lower serum sodium before treatment. CLINICAL TRIAL REGISTRATION: UMIN000014763.

Comprehensive and Safe Decongestion in Acutely Decompensated Heart Failure.

PURPOSE OF THE REVIEW: Progressive intravascular, interstitial, and alveolar fluid overload underlies the transition from compensated to acutely decompensated heart failure and loop diuretics are the mainstay of treatment. Adverse effects and resistance to loop diuretics received much attention while the contribution of a depressed cardiac output to diuretic resistance was downplayed. RECENT FINDINGS: Analysis of experience with positive inotropic agents, especially dobutamine, indicates that enhancement of cardiac output is not consistently associated with increased renal blood flow. However, urinary output and renal sodium excretion increase likely due to dobutamine-mediated decrease in renal and systemic reduced activation of sympathetic nervous- and renin-angiotensin-aldosterone system. Mechanical circulatory support with left ventricular assist devices ascertained the contribution of low cardiac output to diuretic resistance and the pathogenesis and progression of kidney disease in acutely decompensated heart failure. Diuretic resistance commonly occurs in acutely decompensated heart failure. However, failure to resolve fluid overload despite high doses of loop diuretics should alert to the presence of a low cardiac output state.

Characterizing the impact of magnesium and potassium-supplemented hydration with cisplatin and the subsequent electrolyte replacement requirements.

BACKGROUND: Cisplatin-associated electrolyte dysregulation is a prevalent therapy-related adverse effect. There are numerous electrolyte-supplemented hydration regimens that have been evaluated, however these studies focused on the development of nephrotoxicity. The objective of this study was to characterize the impact of magnesium and potassium-supplemented hydration during cisplatin administration on subsequent magnesium and potassium imbalances. METHODS: A single-region retrospective study from central Texas at Baylor Scott & White Cancer Clinics who were treated with two or more cycles of cisplatin were included. Standard hydration for this study was defined as normal saline before and after cisplatin along with potassium chloride 10 mEq and magnesium sulfate 1 g added to the cisplatin bag. RESULTS: A total of 477 patients were included in the study with376 patients receiving the standard hydration. Overall, 17 percent of patients experienced a potassium level below 3.5 mEq/L, but no major depletion was observed. Thirty-three percent of the patients experienced a magnesium level below 1.8 mg/dL, and time to first rescue magnesium supplementation was 4 weeks. CONCLUSION: Our study demonstrated despite routine magnesium and potassium supplementation in hydration, magnesium imbalances were observed. Potassium levels post cisplatin administration were maintained with minimal routine supplementation in hydration.

Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status.

BACKGROUND: We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation. METHODS: We examined baseline total body water (TBW), Na+ space, HCO3- space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO3 infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na+ space that exceeds TBW uncovers nonosmotic sodium storage. RESULTS: Na+ space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na+ space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = -0.01x + 1.4, p= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked. CONCLUSIONS: This study demonstrates that hypobicarbonatemic animals have a Na+ space that exceeds TBW after an acute infusion of hypertonic NaHCO3 indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na+ space, these animals have a larger HCO3- space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO3- loading whenever initial [HCO3-]e is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium.

Impact of protocolized diuresis for de-resuscitation in the intensive care unit.

OBJECTIVE: Administration of diuretics has been shown to assist fluid management and improve clinical outcomes in the critically ill post-shock resolution. Current guidelines have not yet included standardization or guidance for diuretic-based de-resuscitation in critically ill patients. This study aimed to evaluate the impact of a multi-disciplinary protocol for diuresis-guided de-resuscitation in the critically ill. METHODS: This was a pre-post single-center pilot study within the medical intensive care unit (ICU) of a large academic medical center. Adult patients admitted to the Medical ICU receiving mechanical ventilation with either (1) clinical signs of volume overload via chest radiography or physical exam or (2) any cumulative fluid balance ≥ 0 mL since hospital admission were eligible for inclusion. Patients received diuresis per clinician discretion for a 2-year period (historical control) followed by a diuresis protocol for 1 year (intervention). Patients within the intervention group were matched in a 1:3 ratio with those from the historical cohort who met the study inclusion and exclusion criteria. RESULTS: A total of 364 patients were included, 91 in the protocol group and 273 receiving standard care. Protocolized diuresis was associated with a significant decrease in 72-h post-shock cumulative fluid balance [median, IQR - 2257 (- 5676-920) mL vs 265 (- 2283-3025) mL; p < 0.0001]. In-hospital mortality in the intervention group was lower compared to the historical group (5.5% vs 16.1%; p = 0.008) and higher ICU-free days (p = 0.03). However, no statistically significant difference was found in ventilator-free days, and increased rates of hypernatremia and hypokalemia were demonstrated. CONCLUSIONS: This study showed that a protocol for diuresis for de-resuscitation can significantly improve 72-h post-shock fluid balance with potential benefit on clinical outcomes.

Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome.

The genetic background of a mouse strain determines its susceptibility to disease. C57BL/6J and Balb/CJ are two widely used inbred mouse strains that we found react dramatically differently to angiotensin II and high-salt diet (ANG II + Salt). Balb/CJ show increased mortality associated with anuria and edema formation while C57BL/6J develop arterial hypertension but do not decompensate and die. Clinical symptoms of heart failure in Balb/CJ mice gave the hypothesis that ANG II + Salt impairs cardiac function and induces cardiac remodeling in male Balb/CJ but not in male C57BL/6J mice. To test this hypothesis, we measured cardiac function using echocardiography before treatment and every day for 7 days during treatment with ANG II + Salt. Interestingly, pulsed wave Doppler of pulmonary artery flow indicated increased pulmonary vascular resistance and right ventricle systolic pressure in Balb/CJ mice, already 24 h after ANG II + Salt treatment was started. In addition, Balb/CJ mice showed abnormal diastolic filling indicated by reduced early and late filling and increased isovolumic relaxation time. Furthermore, Balb/CJ exhibited lower cardiac output compared with C57BL/6J even though they retained more sodium and water, as assessed using metabolic cages. Left posterior wall thickness increased during ANG II + Salt treatment but did not differ between the strains. In conclusion, ANG II + Salt treatment causes early restriction of pulmonary flow and reduced left ventricular filling and cardiac output in Balb/CJ, which results in fluid retention and peripheral edema. This makes Balb/CJ a potential model to study the adaptive capacity of the heart for identifying new disease mechanisms and drug targets.

Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: A comparison study with furosemide and tolvaptan.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic properties. We recently reported that an SGLT2 inhibitor ameliorated extracellular fluid expansion with a transient increase in urinary Na+ excretion. However, the effects of SGLT2 inhibitors on fluid distribution in comparison to conventional diuretics remain unclear. METHODS: Forty chronic kidney disease patients with fluid retention (average estimated glomerular filtration rate 29.2 ± 3.2 mL/min per 1.73 m2 ) were divided into the SGLT2 inhibitor dapagliflozin (DAPA), loop diuretic furosemide (FR) and vasopressin V2 receptor antagonist tolvaptan (TLV). The body fluid volume was measured on days 0 and 7 using a bioimpedance analysis device. RESULTS: In all three groups, body weight was significantly and similarly decreased, and urine volume numerically increased for 7 days. Bioimpedance analysis showed that the changes in intracellular water were similar, but that there were significant changes in the extracellular water (ECW) (DAPA -8.4 ± 1.7, FR -12.5 ± 1.3, TLV -7.4 ± 1.5%, P = 0.048). As a result, the change in the ratio of ECW to total body water in the DAPA group was significantly smaller than that in the FR group, but numerically larger than that in the TLV group (DAPA -1.5 ± 0.5, FR -3.6 ± 0.5, TLV -0.5 ± 0.4%, P < 0.001). CONCLUSION: Sodium-glucose cotransporter 2 inhibitor DAPA predominantly decreased the ECW with a mild increase in urine volume, but the change in the ECW/total body water was smaller than that in patients treated with FR, and larger than that in patients treated with TLV, suggesting that the effects of SGLT2 inhibitors on fluid distribution may differ from those of conventional diuretics.

Diuretics prescribing in chronic kidney disease patients: physician assessment versus bioimpedence spectroscopy.

INTRODUCTION: The relationship between hypertension and fluid overload in pre-dialysis CKD patients need to be elucidated. Current study aimed to find relationship between fluid overload and hypertension along with prescribed diuretic therapy using bioimpedance spectroscopy (BIS). METHODOLOGY: A prospective observational study was conducted by inviting pre-dialysis CKD patients. Fluid overload was assessed by BIS. RESULTS: A total of 312 CKD patients with mean eGFR 24.5 ± 11.2 ml/min/1.73 m2 were enrolled. Based on OH value ≥7 %, 135 (43.3 %) patients were hypervolemic while euvolemia was observed in 177 (56.7 %) patients. Patients were categorized in different regions of hydration reference plot (HRP) generated by BIS i.e., 5.1 % in region-N (normal BP and fluid status), 20.5 % in region I (hypertensive with severe fluid overload), 29.5 % in region I-II (hypertensive with mild fluid overload), 22 % in region II (hypertensive with normohydration), 10.2 % in region III (underhydration with normal/low BP) and 12.5 % in region IV (normal BP with severe fluid overload). A total of 144 (46 %) patients received diuretics on basis of physician assessment of BP and edema. Maximum diuretics 100 (69.4 %) were prescribed in patients belonging to regions I and I-II of HRP. Interestingly, a similar number of diuretic prescriptions were observed in region II (13 %) and region IV (12 %). Surprisingly, 7 (4.9 %) of patients in region III who were neither hypervolemic nor hypertensive were also prescribed with diuretics. CONCLUSION: BIS can aid clinicians to categorize CKD patients on basis of their fluid status and provide individualized pharmacotherapy to manage hypertensive CKD patients.

The Role of Magnesium in Post-thyroidectomy Hypocalcemia.

BACKGROUND: The purpose of this study was to determine the prevalence of hypomagnesemia in patients undergoing thyroidectomy and evaluate the relationship of hypomagnesemia with transient and severe hypocalcemia. MATERIALS AND METHODS: This was a prospective observational study of 50 patients undergoing thyroidectomy. Blood samples were collected pre- and postoperatively for calcium, albumin, magnesium, phosphorous and parathormone (PTH). Signs, symptoms of hypocalcemia and volume of intravenous fluids used perioperatively were documented. The statistical analysis was performed using STATA I/C 10.1. RESULTS: Preoperatively, twelve patients (24 %) had hypomagnesemia and one (2 %) hypocalcemia. On the first postoperative day, hypomagnesemia was seen in 70 % and hypocalcemia in 30 %. A similar trend was observed in the fall and rise of postoperative calcium and magnesium values (p = 0.41). Severe hypocalcemia was present in three patients (6 %). All three patients had a very low postoperative PTH (<2 pg/ml). Among them, two patients (66 %) had hypomagnesemia and their hypocalcemia responded to intravenous magnesium correction. Significant risk factors for postoperative hypocalcemia include a higher volume of fluid used perioperatively and low postoperative PTH (<8 pg/ml) (p = 0.01 and 0.03, respectively). CONCLUSION: Preoperative hypomagnesemia (24 %) was prevalent in this cohort of patients. Postoperative hypomagnesemia is a common event (70 %) following total thyroidectomy, and magnesium levels tend to mimic the calcium levels postoperatively. The cause of hypocalcemia post-thyroidectomy in this study is mainly a factor of parathyroid function and fluid status. Severe hypocalcemia is a rare event, and hypomagnesemia is associated in the majority of these patients. The role of magnesium correction to alleviate severe hypocalcemia needs to be further studied.

Efficacy of Tolvaptan on Fluid Management After Cardiovascular Surgery Using Cardiopulmonary Bypass.

OBJECTIVE: To investigate the efficacy of the selective vasopressin V2-receptor antagonist tolvaptan in postoperative fluid management after cardiovascular surgery using cardiopulmonary bypass. DESIGN: A retrospective cohort study. SETTING: A tertiary care center. PARTICIPANTS: The study comprised 99 patients undergoing cardiovascular surgery using cardiopulmonary bypass. INTERVENTIONS: Oral tolvaptan was administered after surgery. MEASUREMENTS AND MAIN RESULTS: Fifty-one patients treated with tolvaptan were compared with 48 patients treated with intravenous diuretics. Urine volume, the time interval until the patients' body weight returned to the preoperative value, and the length of oxygen dependency after extubation were assessed as surrogate markers for resolution of fluid overload. Urine output on postoperative days 1 and 2 was significantly higher in the tolvaptan-treated patients (29.2 v 20.1 mL/kg/day, p = 0.001; 43.0 v 27.4 mL/kg/day, p<0.001, respectively). Postoperative body weight returned to baseline in 49 tolvaptan-treated patients compared with 33 patients treated with intravenous diuretics (96.1% v 68.8%, p<0.001). Among those with successful body weight reduction, the time interval was shorter in the tolvaptan-treated patients (5 v 7 days, p = 0.006). The length of oxygen dependency after extubation also was shorter in the tolvaptan-treated patients (2 v 3 days, p = 0.006). The urine osmolarity reduction rate before and 4 hours after the first dose of tolvaptan emerged as a significant predictor of its efficacy with a cutoff point of 33.7%, sensitivity of 0.73, and specificity of 0.67 (p = 0.030). CONCLUSION: Tolvaptan facilitated early improvement of postoperative fluid overload after cardiovascular surgery.

[MODERN APPROACHES TO CORRECTION OF HYPERNATREMIA IN NEUROSURGICAL PATIENTS].

The article presents the analysis of the intensive therapy through the correction of persistent hypernatremia in neurosurgical patients after removal of brain tumors. The aim of this work was to evaluate the effectiveness of Sterofundin in the framework of complex therapy of hypernatremia in neurosurgical patients after removal of brain tumors. We analyzed the dynamics of the concentrations of sodium, potassium, chorus of the plasma, anion gap and buffer bases in the postoperative period of these patients. For obtaining reliable results, the patients were divided into groups according to the nature of the treatment: Sterofundin and symptomatic correction of hypotonic solution of sodium chloride, saluretic and Verospiron respectively. In a comparison between the groups, a distinct difference in the speed of regression of hypernatremia and durability of the achieved effect was observed. In case of treatment with Sterofundin there was a significant decrease of hypernatremia by the end of the second day of the postoperative period without tendency to re-raise. The prevalence of hypotonic solutions of sodium chloride and potassium-sparing saluretics in intensive care allowed reducing the sodium concentration non-persistently to the fourth day on the background of significant fluctuations in its concentration. The use of Sterofundin in complex therapy of electrolyte disturbances, particularly of hypernatremia in neurosurgical patients after removal of brain tumors, is reflected in the form of significant regression of increased sodium concentration in plasma compared with the method of use "hypotonic" hemodilution, saluretics and potassium-sparing diuretics.

Advances in the pathophysiology and treatment of heart failure with preserved ejection fraction.

PURPOSE OF REVIEW: With the failure of multiple trials to identify a successful therapy for heart failure with preserved ejection fraction (HFpEF), attention has shifted to defining specific phenotypes within the HFpEF spectrum in an effort to develop a targeted approach to treatment. Here we summarize the most recent studies investigating the pathophysiology and clinical features of HFpEF, and discuss recent clinical trials in the context of developing treatments that look toward the underlying cause of this disorder. RECENT FINDINGS: Advances in basic science and clinical research have further characterized HFpEF, identifying multiple pathophysiological mechanisms that ultimately lead to exercise intolerance and volume overload. The success of small studies focused on specific subsets of the HFpEF population has promoted the concept that there may not be one treatment strategy that can universally be applied to HFpEF. SUMMARY: HFpEF is associated with significant morbidity and mortality and accounts for approximately half of patients with chronic heart failure. HFpEF is a complex disease, encompassing a diverse cohort of patients and marked by the presence of multiple etiological mechanisms. The failure to develop successful therapies for the management of HFpEF may be because of inadequate standardization of the HFpEF diagnosis, overly broad inclusion criteria and inadequate differentiation of disease subtypes. Given the heterogeneity among patients with HFpEF, much of the current research is focused on understanding of pathophysiology and identifying disease phenotypes that may respond to a targeted treatment approach. Several newer approaches, including neprilysin inhibition and device therapy, offer promise for a new era of HFpEF treatment.

Oral sodium and potassium binders in heart failure.

Significant improvements in the morbidity and mortality associated with chronic heart failure have been gained with the use ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics. However, the use of these agents is often limited by their propensity to precipitate worsening renal function and hyperkalemia, particularly in patients with chronic kidney disease. Several pharmacologic agents have been developed in recent years that utilize the gastrointestinal tract as an alternate route for drug absorption, electrolyte exchange, and drug and electrolyte elimination. The existing data establishing the safety and efficacy of these novel agents will be the focus of this review.

N-acetyl cysteine in prevention of amphotericin- induced electrolytes imbalances: a randomized, double-blinded, placebo-controlled, clinical trial.

PURPOSE: The aim of this study was to evaluate the effectiveness of oral n-acetyl cysteine, as a potential nephroprotective agent, in preventing and/or attenuating amphotericin B-induced electrolytes imbalances. METHODS: During a one year period, patients were to receive conventional amphotericin b for any indication for at least one week and were randomly allocated to receive either placebo or 600 mg oral n-acetyl cysteine twice daily during the treatment course of amphotericin b. Demographic and clinical data of the study population were gathered. Different aspects of amphotericin b nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, renal magnesium and potassium wasting were assessed. Each patient was monitored for any adverse reaction to n-acetyl cysteine. Sixteen and 14 patients in the n-acetyl cysteine and placebo groups completed the study, 3incidences of hypokalemia (75 % versus 70 %; P = 0.724) and hypomagnesemia (30 % versus 20 %; P = 0.468) did not differ significantly between placebo and NAC groups, respectively. Although the rate of AmB nephrotoxicity was higher in the placebo than in the NAC group (60 % versus 40 %), this difference was not statistically significant (P = 0.209) even after adjusting for probable associated factors of amphotericin b nephrotoxicity (P = 0.206). The incidence as well as time of onset of electrolyte abnormalities also did not differ significantly between placebo and n-acetyl cysteine groups. About 44 % of n-acetyl cysteine recipients experienced new onset nausea and a mild unpleasant taste during the study. CONCLUSION: Oral n-acetyl cysteine during the amphotericin B treatment course was not significantly effective in preventing or mitigating different features of its nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, and renal potassium as well as magnesium wasting.

Indications and management of mechanical fluid removal in critical illness.

BACKGROUND: The Acute Dialysis Quality Initiative (ADQI) dedicated its Twelfth Consensus Conference (2013) to all aspects of fluid therapy, including the management of fluid overload (FO). The aim of the working subgroup 'Mechanical fluid removal' was to review the indications, prescription, and management of mechanical fluid removal within the broad context of fluid management of critically ill patients. METHODS: The working group developed a list of preliminary questions and objectives and performed a modified Delphi analysis of the existing literature. Relevant studies were identified through a literature search using the MEDLINE database and bibliographies of relevant research and review articles. RESULTS: After review of the existing literature, the group agreed the following consensus statements: (i) in critically ill patients with FO and with failure of or inadequate response to pharmacological therapy, mechanical fluid removal should be considered as a therapy to optimize fluid balance. (ii) When using mechanical fluid removal or management, targets for rate of fluid removal and net fluid removal should be based upon the overall fluid balance of the patient and also physiological variables, individualized, and reassessed frequently. (iii) More research on the role and practice of mechanical fluid removal in critically ill patients not meeting fluid balance goals (including in children) is necessary. CONCLUSION: Mechanical fluid removal should be considered as a therapy for FO, but more research is necessary to determine its exact role and clinical application.

Pharmacological management of fluid overload.

BACKGROUND: Standard treatment practice for the hypotensive patient with poor tissue perfusion is rapid volume resuscitation; in some scenarios, such as septic shock, this is performed with targeted goal-directed endpoints within 6 h of presentation. As a result, patients often develop significant positive fluid accumulation, which has been associated with poor outcomes above certain thresholds. METHODS: The aim of the current paper is to provide guidance for active pharmacological fluid management in the patient with, or at risk for, clinically significant positive fluid balance from either resuscitation for hypovolaemic shock or acute decompensated heart failure. RESULTS: We develop rationale for pharmacological fluid management targets (prevention of worsening fluid accumulation, achievement of slow vs rapid net negative fluid balance) in the context of phases of critical illness provided in the earlier Acute Dialysis Quality Initiative 12 papers.

Dynamic regulation and dysregulation of the water channel aquaporin-2: a common cause of and promising therapeutic target for water balance disorders.

The human body is two-thirds water. The ability of ensuring the proper amount of water inside the body is essential for the survival of mammals. The key event for maintenance of body water balance is water reabsorption in the kidney collecting ducts, which is regulated by aquaporin-2 (AQP2). AQP2 is a channel that is exclusively selective for water molecules and never allows permeation of ions or other small molecules. Under normal conditions, AQP2 is restricted within the cytoplasm of the collecting duct cells. However, when the body is dehydrated and needs to retain water, AQP2 relocates to the apical membrane, allowing water reabsorption from the urinary tubule into the cell. Its impairments result in various water balance disorders including diabetes insipidus, which is a disease characterized by a massive loss of water through the kidney, leading to severe dehydration in the body. Dysregulation of AQP2 is also a common cause of water retention and hyponatremia that exacerbate the prognosis of congestive heart failure and hepatic cirrhosis. Many studies have uncovered the regulation mechanisms of AQP2 at the single-molecule level, the whole-body level, and the clinical level. In clinical practice, urinary AQP2 is a useful marker for body water balance (hydration status). Moreover, AQP2 is now attracting considerable attention as a potential therapeutic target for water balance disorders which commonly occur in many diseases.