Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Urea for hyponatremia?

Once the standard of care for cerebral edema, urea can also be used to treat hyponatremia. The 2014 European Clinical Practice Guidelines recommend urea for the treatment of the syndrome of inappropriate antidiuretic hormone, while discouraging use of vasopressin antagonists. Although there is evidence that urea can diminish hypertonic injury to brain cells caused by rapid correction of hyponatremia, clinical trials are needed that include patients at high risk to develop complications from overcorrection.

Safe and effective use of chronic transdermal estradiol for life-threatening uremic bleeding in a patient with coronary artery disease.

Uremic platelet dysfunction rarely causes significant bleeding in adequately dialyzed patients. When encountered, the management is complicated by a lack of well-supported treatment modalities. Estrogen use in uremic platelet dysfunction has been described, but enthusiasm for the treatment has been dampened by the risk of thrombotic events in vasculopathic dialysis patients. We present a patient on long-term peritoneal dialysis with coronary disease who developed recurrent life-threatening bleeding episodes secondary to uremia, where treatment with transdermal estrogen was used safely and effectively for a 24-month period.

Managing combined critical hypothermia, diabetic ketoacidosis and cocaine intoxication noninvasively.

Severe hypothermia with a core temperature below 28°C is critical especially in patients with diabetic ketoacidosis (DKA) and carries a high risk of mortality. Our case of a 52-year-old woman presenting with DKA, pH of 6.9, potassium of 7.6 mEq/L, and body temperature of 26°C demonstrates that conservative management can be safe and successful. We used an established cardiac arrest rewarming phase protocol modified to active warming with the Meditherm 3 Machine and the facility-used rigorous DKA protocol to successfully and safely achieve rewarming without hemodialysis or extracorporeal maneuvers. Our patient arrived even more hypothermic than all previously described cases and regained normothermia and an equalized acid-base and electrolyte balance within 12 hours after admission. Eventually, no new neurologic deficit was present on discharge.

Management of hyponatremia in the ICU.

Hyponatremia is common in critical care units. Avoidance of neurologic injury requires a clear understanding of why the serum sodium (Na) concentration falls and why it rises, how the brain responds to a changing serum Na concentration, and what the goals of therapy should be. A 4 to 6 mEq/L increase in serum Na concentration is sufficient to treat life-threatening cerebral edema caused by acute hyponatremia. In chronic (> 48 h), severe (< 120 mEq/L) hyponatremia, correction by > 8 to 10 mEq/L/d risks iatrogenic osmotic demyelination syndrome (ODS); therefore, a 4 to 6 mEq/L daily increase in serum Na concentration should be the goal in most patients. With the possible exception of hyponatremia caused by heart failure or hepatic cirrhosis, a rapid initial increase in serum Na for severe symptoms and avoidance of overcorrection are best achieved with 3% saline given in either a peripheral or central vein. Inadvertent overcorrection can be avoided in high-risk patients with chronic hyponatremia by administration of desmopressin to prevent excessive urinary water losses. In patients with hyponatremia with oliguric kidney failure, controlled correction can be achieved with modified hemodialysis or continuous renal replacement therapies. ODS is potentially reversible, even in severely affected patients who are quadriplegic, unresponsive, and ventilator dependent. Supportive care should be offered several weeks before concluding that the condition is hopeless.

Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia.

BACKGROUND: Prompt correction of severe hyponatremia is important, but correction also must be limited to avoid iatrogenic osmotic demyelination. Expert opinion recommends that serum sodium level not be increased by more than 10-12 mEq/L in any 24-hour period and/or 18 mEq/L in any 48-hour period. However, inadvertent overcorrection is common, usually caused by the unexpected emergence of a water diuresis. STUDY DESIGN: Quality improvement report. SETTING & PARTICIPANTS: All 25 patients admitted to a community teaching hospital between October 1, 2008, and September 30, 2011, who were treated for serum sodium level <120 mEq/L with concurrently administered desmopressin and hypertonic saline solution. QUALITY IMPROVEMENT PLAN: Concurrently administered desmopressin (1-2 µg parenterally every 6-8 hours) and hypertonic saline with weight-based doses adjusted to increase the serum sodium concentration by 6 mEq/L, avoiding inadvertent overcorrection of severe hyponatremia. OUTCOMES: Rate of correction of hyponatremia, predictability of response to the combination, adverse events related to therapy. MEASUREMENTS: Rate of correction of hyponatremia at 4, 24, and 48 hours; administered dose of 3% saline solution, salt tablets, and potassium; predicted increase in serum sodium level. RESULTS: Mean changes in serum sodium levels during the first and second 24 hours of therapy were 5.8 ± 2.8 (SD) and 4.5 ± 2.2 mEq/L, respectively, without correction by >12 mEq/L in 24 hours or >18 mEq/L in 48 hours and without a decrease during therapy. There was no significant difference between actual and predicted increases during the first 24 hours. There was no adverse effect associated with therapy. LIMITATIONS: Without concurrent controls, we cannot be certain that outcomes are improved. Balance studies were not performed. CONCLUSIONS: Combined 3% saline solution and desmopressin appears to be a valid strategy for correcting severe hyponatremia, but studies comparing the regimen with other therapeutic strategies are needed.

Diuretic-associated hyponatremia.

Soon after their introduction in 1957, thiazide diuretics became a recognized cause of hyponatremia. Thiazides may be the sole cause and they may exacerbate hyponatremia in patients with disorders that cause the syndrome of inappropriate antidiuretic hormone secretion. Although thiazides do not inhibit the ability to concentrate the urine, they impair diluting ability in several ways: inhibition of sodium and chloride transport at cortical diluting sites; stimulation of vasopressin release; reduction of glomerular filtration and enhanced proximal water reabsorption, which reduce delivery to the distal diluting sites; and, possibly, a direct effect on water flow in the collecting duct. Water retention caused by impaired water excretion combined with cation depletion may result in severe hyponatremia. Thiazides should be avoided in frail elderly patients with chronically high water intake or in others who depend on the excretion of maximally dilute urine to maintain fluid balance, such as patients with psychogenic polydipsia or heavy beer drinking. Inadvertent rapid correction of hyponatremia is common in thiazide-induced hyponatremia because the ability to dilute the urine is restored when the diuretic is discontinued and volume deficits are repaired. Hypokalemia, which often is present, increases the susceptibility to osmotic demyelination syndrome and replacement of potassium deficits contributes to the increase in serum sodium concentration.

Treating profound hyponatremia: a strategy for controlled correction.

An alcoholic patient presented with profound hyponatremia (serum sodium concentration, 96 mEq/L) caused by the combined effects of a thiazide diuretic, serotonin reuptake inhibitor, beer potomania, and hypovolemia. A computed tomographic scan of the brain was indistinguishable from one obtained 3 weeks earlier when he was normonatremic. Concurrent administration of 3% saline solution and desmopressin controlled the rate of correction to an average of 6 mEq/L daily and resulted in full neurologic recovery without evidence of osmotic demyelination. This case illustrates the value of controlled correction of profound hyponatremia.

Treatment of hyponatremia.

PURPOSE OF REVIEW: We review literature from the past 18 months on the treatment of hyponatremia. Therapy must address both the consequences of the untreated electrolyte disturbance (including fatal cerebral edema due to acute water intoxication) and the complications of excessive therapy (the osmotic demyelination syndrome). RECENT FINDINGS: Correction of hyponatremia by 4-6 mEq/l within 6 h, with bolus infusions of 3% saline if necessary, is sufficient to manage the most severe manifestations of hyponatremia. Planning therapy to achieve a 6 mEq/l daily increase in the serum sodium concentration can avoid iatrogenic brain damage by staying well clear of correction rates that are harmful. Conservative correction goals are wise because inadvertent overcorrection is common. Administration of desmopressin to halt a water diuresis can help prevent overcorrection; if overcorrection occurs, therapeutic relowering of the serum sodium concentration is supported by data in experimental animals and was found to be safe in a small observational clinical trial. Even mild and apparently asymptomatic hyponatremia may lead to falls because of impaired gait, and an increased likelihood of fracture because of hyponatremia-induced osteoporosis, a newly described entity. Recently approved vasopressin antagonists now make it possible to normalize the serum sodium concentration on a chronic basis, but practical considerations have limited their use.

Atrial natriuretic peptide for preventing and treating acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalised patients and is associated with significant morbidity and mortality. Despite recent advances, outcomes have not substantially changed in the last four decades. Atrial natriuretic peptide (ANP) has shown promise in animal studies, however randomised controlled trials (RCTs) have shown inconsistent clinical benefits. OBJECTIVES: To assess the benefits and harms of ANP for preventing and treating AKI. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE and reference lists of retrieved articles. SELECTION CRITERIA: RCTs that investigated all forms of ANP versus any other treatment in adult hospitalised patients with or "at risk" of AKI. DATA COLLECTION AND ANALYSIS: Results were expressed as risk ratios (RR) with 95% confidence intervals (CI) or mean difference (MD). Outcomes were analysed separately for low and high dose ANP for preventing or treating AKI. MAIN RESULTS: Nineteen studies (11 prevention, 8 treatment; 1,861 participants) were included. There was no difference in mortality between ANP and control in either the low or high dose prevention studies. Low (but not high) dose ANP was associated with a reduced need for RRT in the prevention studies (RR 0.32, 95% CI 0.14 to 0.71). Length of hospital and ICU stay were significantly shorter in the low dose ANP group. For established AKI, there was no difference in mortality with either low or high dose ANP. Low (but not high) dose ANP was associated with a reduction in the need for RRT (RR 0.54, 95% CI 0.30 to 0.98). High dose ANP was associated with more adverse events (hypotension, arrhythmias). After major surgery there was a significant reduction in RRT requirement with ANP in the prevention studies (RR 0.56, 95% CI 0.32 to 0.99), but not in the treatment studies. There was no difference in mortality between ANP and control in either the prevention or treatment studies. There was a reduced need for RRT with low dose ANP in patients undergoing cardiovascular surgery (RR 0.35, 95% CI 0.18 to 0.70). ANP was not associated with outcome improvement in either radiocontrast nephropathy or oliguric AKI. AUTHORS' CONCLUSIONS: ANP may be associated with improved outcomes when used in low doses for preventing AKI and in managing postsurgery AKI and should be further explored in these two settings. There were no significant adverse events in the prevention studies, however in the high dose ANP treatment studies there were significant increases hypotension and arrhythmias.

Overcorrection of hyponatremia is a medical emergency.

Overcorrection of hyponatremia is a medical emergency. Excessive correction usually results from the unexpected emergence of a water diuresis after resolution of the cause of water retention. The concurrent administration of desmopressin and 5% dextrose in water can be given to cautiously re-lower the serum sodium concentration when therapeutic limits have been exceeded. Nephrologists should be equally aggressive in correcting hyponatremia and in un-correcting it when their patients get too much of a good thing.

The treatment of hyponatremia.

Virtually all investigators now agree that self-induced water intoxication, symptomatic hospital-acquired hyponatremia, and hyponatremia associated with intracranial pathology are true emergencies that demand prompt and definitive intervention with hypertonic saline. A 4- to 6-mmol/L increase in serum sodium concentration is adequate in the most seriously ill patients and this is best achieved with bolus infusions of 3% saline. Virtually all investigators now agree that overcorrection of hyponatremia (which we define as 10 mmol/L in 24 hours, 18 mmol/L in 48 hours, and 20 mmol/L in 72 hours) risks iatrogenic brain damage. Appropriate therapy should keep the patient safe from serious complications of hyponatremia while staying well clear of correction rates that risk iatrogenic injury. Accordingly, we suggest therapeutic goals of 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours. Inadvertent overcorrection owing to a water diuresis may complicate any form of therapy, including the newly available vasopressin antagonists. Frequent monitoring of the serum sodium concentration and urine output are mandatory. Administration of desmopressin to terminate an unwanted water diuresis is an effective strategy to avoid or reverse overcorrection.

Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized and observational studies.

BACKGROUND: Acute kidney injury (AKI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Controversy exists regarding whether an off-pump technique can reduce post-CABG renal injury. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adult patients undergoing CABG. SELECTION CRITERIA FOR STUDIES: MEDLINE, EMBASE, Cochrane Renal Library, and Google Scholar were searched in May 2008 for randomized controlled trials (RCTs) and observational studies comparing off-pump CABG (OPCAB) with conventional CABG (CAB) for renal outcomes. Studies involving patients on long-term renal replacement therapy (RRT) were excluded. INTERVENTION: OPCAB. OUTCOMES: Primary outcomes were overall AKI and AKI requiring RRT. RESULTS: 22 studies (6 RCTs and 16 observational studies) comprising 27,806 patients met the inclusion criteria. The pooled effect from both study cohorts showed a significant reduction in overall AKI (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.43 to 0.76; P for effect < 0.001; I(2) = 67%; P for heterogeneity < 0.001) and AKI requiring RRT (OR, 0.55; 95% CI, 0.43 to 0.71; P for effect < 0.001; I(2) = 0%; P for heterogeneity = 0.5) in the OPCAB group compared with the CAB group. In RCTs, overall AKI was significantly reduced in the OPCAB group (OR, 0.27; 95% CI, 0.13 to 0.54); however, no statistically significant difference was noted in AKI requiring RRT (OR, 0.31; 95% CI, 0.06 to 1.59). In the observational cohort, both overall AKI (OR, 0.61; 95% CI, 0.45 to 0.81) and AKI requiring RRT (OR, 0.54; 95% CI, 0.40 to 0.73) were significantly less in the OPCAB group. RCTs were noted to be underpowered and biased toward recruiting low-risk patients. Sensitivity analysis restricted to good-quality studies showed a significant reduction in AKI. LIMITATIONS: Lack of uniform AKI definition in the included studies, heterogeneity for overall AKI outcome. CONCLUSIONS: Analysis of the current evidence suggests a reduction in AKI using the OPCAB technique; however, studies lack consistency in defining AKI. Available RCTs are underpowered to detect a difference in AKI requiring RRT; evidence from observational studies suggests a reduction in RRT requirement. Future studies should apply a standard definition of AKI and target a high-risk population.

The role of natriuretic peptide administration in cardiovascular surgery-associated renal dysfunction: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Randomized controlled trials involving natriuretic peptide administration in the perioperative cardiovascular setting have shown inconsistent effects for renal and other clinical endpoints. The authors aimed to systematically review these trials to ascertain the role of natriuretic peptide administration in the management of cardiovascular surgery-associated renal dysfunction. DESIGN: A systematic review and meta-analysis. SETTING: A hospital. PARTICIPANTS: A total of 934 adult patients from 13 randomized controlled trials. INTERVENTIONS: Natriuretic peptides. MEASUREMENTS AND MAIN RESULTS: MEDLINE, EMBASE, Cochrane Renal Health Library, and Google scholar were searched independently by 2 reviewers for randomized controlled studies comparing natriuretic peptides with placebo in patients undergoing cardiovascular surgeries. Studies reporting data on renal outcomes were included. Two reviewers independently assessed the studies for eligibility and extracted the relevant data. The pooled estimate showed that natriuretic peptide administration was associated with a reduction in acute renal failure requiring dialysis (odds ratio = 0.32 [0.15-0.66]) and a statistically nonsignificant trend toward a reduction in 30-day or in-hospital mortality (odds ratio = 0.59 [0.31-1.12]). Other benefits were a reduction in postsurgery peak serum creatinine levels, an increase in postsurgery urine output, a reduction in postsurgery serum aldosterone levels, and reductions in mechanical ventilation duration and intensive care unit stay length. Most of the included studies addressing this topic were small and lacked adequate power to reach statistical significance on their own. CONCLUSIONS: Current literature analyzing studies evaluating the administration of natriuretic peptides in cardiovascular surgery may be associated with significant improvements in clinical outcomes. Given the limitations of meta-analysis, these observations need to be confirmed in a larger, adequately powered, prospective multicenter study.

Atrial natriuretic peptide for management of acute kidney injury: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Randomized controlled trials (RCTs) with atrial natriuretic peptide (ANP) have shown inconsistent effects for renal end-points. The authors aimed to systematically review these trials to ascertain the benefit of ANP in prevention and treatment of acute kidney injury (AKI). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The authors searched MEDLINE, EMBASE, and Cochrane Renal Health Library that investigated ANP in adult patients considered with or at risk for AKI. Outcomes were analyzed separately for prevention and treatment of AKI. RESULTS: Nineteen RCTs (11 prevention, 8 treatment) involving 1861 participants were included. Pooled analysis of prevention trials showed a trend toward reduction in renal replacement therapy in the ANP group (OR = 0.45, 95% CI, 0.21 to 0.99) and good safety profile, but no improvement in mortality. For the treatment of established AKI, ANP, particularly in high doses, was associated with a trend toward increased mortality and more adverse events. Subgroup analysis of AKI after a major surgery (14 RCTs, 817 participants) showed a significant reduction in renal replacement therapy requirement in the ANP group (OR = 0.49, 95% CI, 0.27 to 0.88). Included RCTs were mostly low- or moderate-quality, underpowered studies. CONCLUSIONS: There are an insufficient number of high-quality studies to make any definite statement about the role of ANP in AKI. Analysis of the existing literature suggests ANP might be associated with beneficial clinical effects when administered in patients undergoing major surgery such as cardiovascular surgery. Its use, in low doses, should be explored further in this setting.

Calciphylaxis from nonuremic causes: a systematic review.

BACKGROUND AND OBJECTIVES: Calciphylaxis, or calcific uremic arteriolopathy, is a well-described entity in end-stage kidney disease and renal transplant patients; however, little systematic information is available on calciphylaxis from nonuremic causes. This systematic review was designed to characterize etiologies, clinical features, laboratory abnormalities, and prognosis of nonuremic calciphylaxis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic review of literature for case reports and case series of nonuremic calciphylaxis was performed. Cases included met the operational definition of nonuremic calciphylaxis-histopathologic diagnosis of calciphylaxis in the absence of end-stage kidney disease, renal transplantation, or acute kidney injury requiring renal replacement therapy. RESULTS: We found 36 cases (75% women, 63% Caucasian, aged 15 to 82 yr) of nonuremic calciphylaxis. Primary hyperparathyroidism, malignancy, alcoholic liver disease, and connective tissue disease were the most common reported causes. Preceding corticosteroid use was reported for 61% patients. Protein C and S deficiencies were seen in 11% of patients. Skin lesions were morphologically similar to calcific uremic arteriolopathy. Mortality rate was 52%, with sepsis being the leading cause of death. CONCLUSION: Calciphylaxis should be considered while evaluating skin lesions in patients with predisposing conditions even in the absence of end-stage kidney disease and renal transplantation. Nonuremic calciphylaxis is reported most often in white women. Mineral abnormalities that are invoked as potential causes in calcific uremic arteriolopathy are often absent, suggesting that heterogeneous mechanisms may contribute to its pathogenesis. Nonuremic calciphylaxis is associated with high mortality, and there is no known effective treatment.