Trends in tolvaptan prescription and the association between hypernatremia and aging in tolvaptan-treated patients in Japan: Real-world data mining using Japanese databases.

OBJECTIVE: To identify the trends in tolvaptan prescription and the association between aging and tolvaptan-induced hypernatremia. MATERIALS AND METHODS: A health insurance claims database and a spontaneous adverse drug reaction database were used. RESULTS: Of all patients who had been prescribed tolvaptan, the proportion of patients aged 60 - 79 years and ≥ 80 years was consistent at ~ 40%. Moreover, the prescription frequency of tolvaptan increased over time for patients in the same age groups. The adjusted reporting odds ratio of tolvaptan-induced hypernatremia was 5.54 (95% confidence interval, 3.31 - 9.25) in patients aged ≥ 60 years from among all patients and 2.09 (95% confidence interval, 1.59 - 2.75) in those aged ≥ 80 years from among those aged ≥ 60 years. CONCLUSION: It may be necessary to be aware of hypernatremia in elderly patients who are expected to have increased prescriptions of tolvaptan.

COVID-19 and Headache Medicine: A Narrative Review of Non-Steroidal Anti-Inflammatory Drug (NSAID) and Corticosteroid Use.

OBJECTIVE: To summarize the current literature on non-steroidal anti-inflammatory drug and corticosteroid use during the coronavirus disease 2019 (COVID-19) pandemic, recognizing that these are commonly used treatments in the field of headache medicine. BACKGROUND: The use of non-steroidal anti-inflammatory drugs and corticosteroids in patients during the COVID-19 pandemic has been a controversial topic within the medical community and international and national health organizations. Lay press and social media outlets have circulated opinions on this topic despite the fact that the evidence for or against the use of these medications is sparse. In the field of headache medicine, these medications are used commonly and both patients and clinicians may have questions or hesitations pertaining to their use during the COVID-19 pandemic. METHODS: A detailed search of the scientific and popular literature was performed. RESULTS: There is limited literature pertaining to the safety of non-steroidal anti-inflammatory drugs and corticosteroids during the COVID-19 pandemic. To date, there are no clear scientific data that preclude the use of non-steroidal anti-inflammatory drugs in the general population who may acquire COVID-19 or in those acutely infected with the virus. Several health organizations have concluded that treatment with corticosteroids during active infection should be avoided due to concerns of prolonged viral shedding in the respiratory tract and the lack of survival benefit based on the data from past coronaviruses and influenza virus; specific exceptions exist including treatment for underlying asthma or chronic obstructive pulmonary disease, septic shock, and acute respiratory distress syndrome. CONCLUSION: Scientific information regarding the COVID-19 pandemic is constantly evolving, and limited or contradictory information can lead to confusion for both patients and clinicians. It is recommended that prior to prescribing non-steroidal anti-inflammatory drugs and steroids for the treatment of headache, clinicians have open discussions with their patients about the potential risks and benefits of using these medications during the COVID-19 pandemic. This manuscript summarizes the currently available evidence and understanding about these risks and benefits to help clinicians navigate such discussions.

Tolvaptan-induced hypernatremia related to low serum potassium level accompanying high blood pressure in patients with acute decompensated heart failure.

BACKGROUNDS: Tolvaptan significantly increases urine volume in acute decompensated heart failure (ADHF); serum sodium level increases due to aquaresis in almost all cases. We aimed to elucidate clinical factors associated with hypernatremia in ADHF patients treated with tolvaptan. METHODS: We enrolled 117 ADHF patients treated with tolvaptan in addition to standard therapy. We examined differences in clinical factors at baseline between patients with and without hypernatremia in the initial three days of hospitalization. RESULTS: Systolic (p = 0.045) and diastolic (p = 0.004) blood pressure, serum sodium level (p = 0.002), and negative water balance (p = 0.036) were significantly higher and serum potassium level (p = 0.026) was significantly lower on admission day in patients with hypernatremia (n = 22). In multivariate regression analysis, hypernatremia was associated with low serum potassium level (p = 0.034). Among patients with serum potassium level ≤ 3.8 mEq/L, the cutoff value obtained using receiver operating characteristic curve analysis, those with hypernatremia related to tolvaptan treatment showed significantly higher diastolic blood pressure on admission day (p = 0.004). CONCLUSION: In tolvaptan treatment combined with standard therapy in ADHF patients, serum potassium level ≤ 3.8 mEq/L may be a determinant factor for hypernatremia development. Among hypokalemic patients, those with higher diastolic blood pressure on admission may be carefully managed to prevent hypernatremia.

Short communication: Hypernatremia in diarrheic calves associated with oral electrolyte administration in water and milk replacer in absence of access to water.

A major goal in treatment of calves with diarrhea is to restore hydration and to correct metabolic acidosis. This can be achieved by the administration of oral electrolyte solutions (OES). However, the composition of OES products and the administration protocols in practice vary widely, which can potentially compromise the efficacy and safety of these treatments. In particular, administration of OES in milk replacer (MR) and the absence of water supply in young calves are not unusual and these conditions could compromise calf health. In this light, the objective of this study was to evaluate the efficacy and safety of OES administered in MR and in water without access to water. Forty-five male Holstein calves (16.6 ± 1.6 d of age and 45.4 ± 2.2 kg at arrival) were purchased from a collection center located in the Netherlands. After arrival, calves went through an adaptation period of 4 d. Calves that developed diarrhea within 6 d after the end of the adaptation period were enrolled in the study, and the remaining calves were sold after being weaned. Upon morning detection of abnormal fecal scores (d 1 starting point), calves were blocked based on initial BW. Within each block, calves were randomly assigned to 1 of 2 treatments, including a control consisting of a small dose of whey (CON; n = 12) and an OES treatment (OES; n = 14). Treatments were blinded to the farm staff by randomly assigning a letter to each treatment. Treatments were simultaneously administered for 4 d in MR (2.5 L at 0800 and 1730 h) and in water (3 L at 1300 and 2200 h). Calves had no supplemental access to plain water. Blood samples were taken at 0600 h for 4 d, and fecal scores (0 = normal; 1 = watery feces) were assessed daily at 0900 h for 15 consecutive days. Additionally, skin turgor and degree of enophthalmos were assessed at 1000 h from d 1 to 4 using a 3-level scoring system. Calves fed OES had a higher prevalence of diarrhea on d 3, 4, and 5 as well as higher prevalence of delayed skin turgor and increased degree of enophthalmos over the 4 monitoring days. Diarrhea duration was longer in calves receiving OES than in calves receiving CON (4.2 d vs. 2.1 d, respectively). The OES treatment resulted in hypernatremia (serum Na+ >145 mmol/L) within 48 h after the first OES administration. Hypernatremia was linked with higher serum Cl- and urea concentrations and thus higher serum osmolarity in OES calves compared with CON calves. Administered under these conditions, OES resulted in various degrees of hypernatremia and a delayed recovery from diarrhea, thus defeating the purpose of OES administration.

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial.

IMPORTANCE: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock. OBJECTIVE: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019. INTERVENTIONS: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). MAIN OUTCOMES AND MEASURES: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. RESULTS: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). CONCLUSIONS AND RELEVANCE: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03389555.

Effect of Environmental Temperature on Serum Sodium Level in Hospitalized Non-critically Ill Children.

BACKGROUND: Intravenous hypotonic fluid administered in children is associated with an increased risk of developing hyponatremia. This finding has been reported from temperate countries where climate is relatively cold. But whether this risk also occurs in tropical countries has not been elucidated. OBJECTIVE: The objective of this study was to determine the relationship between environmental temperature and serum sodium in non-critically ill children. METHODS: A retrospective study. RESULTS: A total of 1061 hospitalized children were enrolled. Incidences of hyponatremia were not different between patients who received isotonic and hypotonic fluids (29% vs. 31%). Subgroup analysis showed a trend of higher incidence of hyponatremia in patients who received hypotonic fluid than isotonic fluid only in patients admitted to the air-conditioned wards (29% vs. 21%, p = 0.08). CONCLUSION: Children admitted to the air-conditioned wards who received hypotonic fluid seemed to carry a higher risk of developing hyponatremia than those admitted to the non-air-conditioned ward.

Hyponatremia in Cirrhosis: Implications for Liver Transplantation.

Hyponatremia in cirrhosis is defined as a serum sodium level ≤130 mEq/L and occurs in approximately 22% of patients with cirrhosis. The appearance of hyponatremia in patients with cirrhosis portends a poor prognosis before liver transplantation (LT), independent of the Model for End-Stage Liver Disease (MELD) score. With the development of the MELD-sodium score, the management of hyponatremia has become more relevant than ever before. Overcorrection of hyponatremia before LT or perioperatively can lead to the devastating neurologic condition known as osmotic demyelination syndrome, which is often irreversible and fatal. Therefore, the most important tenet of hyponatremia is to avoid correcting the serum sodium by ≥8 mEq/L in a 24-hour period. Treatment of hyponatremia is highly challenging. The vast majority of patients with cirrhosis have chronic hypervolemic hyponatremia. Fluid restriction increases serum sodium levels, but tolerance and compliance are significant barriers. Diuretic withdrawal is helpful but contributes to worsening fluid overload. There are limited data to support use of intravenous concentrated albumin solutions. The use of the arginine vasopressin antagonists ("vaptans") is contentious; however, they may have a limited role. Risk factors for intraoperative overcorrection of serum sodium include increased utilization of packed red blood cell and fresh frozen plasma transfusions, which are often unavoidable. Intraoperative management is evolving, and more data are needed in regard to the use of sodium-reduced continuous venovenous hemofiltration and the use of trishydroxymethylaminomethane (Tris) to avoid excess sodium rebound. A thorough discussion of the current treatment options before and during LT is given in this review.

Novel Risk Score Efficiently Prevents Tolvaptan-Induced Hypernatremic Events in Patients With Heart Failure.

BACKGROUND: It has been 7 years since tolvaptan was approved in Japan for the indication of heart failure in patients with volume overload; the drug can be used in patients with normonatremia. Hypernatremia was identified as a significant adverse event to be prevented.Methods and Results:We compiled and analyzed data from 3,349 patients over 5 years to identify patients at high risk of hypernatremia with tolvaptan treatment. The incidence of hypernatremia, defined as serum sodium ≥150 mEq/L, was 3.65%. Baseline serum sodium concentrations, serum potassium concentrations, blood urea nitrogen : creatinine ratio, initial tolvaptan dose, and age were identified as risk factors for hypernatremia. A hypernatremia risk score was developed using the odds ratios for these factors. The high-risk population was defined as patients with a risk score ≥17.80. CONCLUSIONS: To prevent the occurrence of hypernatremic events in patients taking tolvaptan, we recommend a very low starting dose (i.e., 3.75 mg/day) in patients identified as being at high risk of hypernatremia using our new scoring process.

Salt, sweat, and unclear? Diaphoresis and hypernatremia in end-stage kidney disease: Questions.

This quiz will discuss two patients with end-stage kidney disease (ESKD) on dialysis presenting with diaphoresis and hypernatremia.

Comparison of the incidences of hyponatremia in adult postoperative critically ill patients receiving intravenous maintenance fluids with 140 mmol/L or 35 mmol/L of sodium: retrospective before/after observational study.

PURPOSE: The purpose of this study was to compare the incidences of hyponatremia in adult postoperative critically ill patients receiving isotonic and hypotonic maintenance fluids. METHODS: In this single-center retrospective before/after observational study, we included patients who had undergone an elective operation for esophageal cancer or for head and neck cancer and who received postoperative intensive care for >48 h from August 2014 to July 2016. In those patients, sodium-poor solution (35 mmol/L of sodium; Na35) had been administered as maintenance fluid until July 2015. From August 2015, the protocol for postoperative maintenance fluid was revised to the use of isotonic fluid (140 mmol/L of sodium; Na140). The primary outcome was the incidence of hyponatremia (<135 mmol/L) until the morning of postoperative day (POD) 2. RESULTS: We included 179 patients (Na35: 87 patients, Na140: 92 patients) in the current study. The mean volume of fluid received from ICU admission to POD 2 was not significantly different between the two groups (3291 vs 3337 mL, p = 0.84). The incidence of postoperative hyponatremia was 16.3% (15/92) in the Na140 cohort, which was significantly lower than that of 52.9% (46/87) in the Na35 group (odds ratio = 0.17, 95% confidence interval 0.09-0.35, p < 0.001]. The incidences of hypernatremia, defined as serum sodium concentration >145 mmol/L, were not significantly different between the two groups. CONCLUSION: In this study, the use of intravenous maintenance fluid with 35 mmol/L of sodium was significantly associated with an increased risk of hyponatremia compared to that with 140 mmol/L of sodium in adult postoperative critically ill patients.

[Hypernatremia caused by treatment with GHB obtained via a doctor's prescription]. / Hypernatriëmie door GHB op doktersrecept.

In the last few years, gamma hydroxybutyric acid (GHB) has been used increasingly as a party drug; this has led to a marked increase in the number of requests for professional help with the treatment of GHB addiction. Pharmaceutical GHB (sodium oxybate, the sodium-salt of GHB), registered for cataplexia in narcolepsy patients, is used off-label to treat the withdrawal symptoms associated with GHB addiction. Pharmaceutical GHB has a high sodium load. In this report we present the cases of two patients who developed symptomatic hypernatremia following treatment with pharmaceutical GHB and who thereafter needed intensive care for the severe withdrawal symptoms that they experienced.

Complications and management of hyponatremia.

PURPOSE OF REVIEW: Hyponatremia causes significant morbidity, mortality, and disability. This review considers the literature of the past 18 months to improve understanding of these complications and to identify therapeutic strategies to prevent them. RECENT FINDINGS: Acute hyponatremia causes serious brain swelling that can lead to permanent disability or death. A 4-6 mEq/l increase in serum sodium is sufficient to reverse impending herniation. Brain swelling is minimal in chronic hyponatremia, and to avoid osmotic demyelination, correction should not exceed 8 mEq/l/day. In high-risk patients, correction should not exceed 4-6 mEq/l/day. Inadvertent overcorrection of hyponatremia is common and preventable by controlling unwanted urinary water losses with desmopressin. Even mild chronic hyponatremia is associated with increased mortality, attention deficit, gait instability, osteoporosis, and fractures, but it is not known if the correction of mild hyponatremia improves outcomes. SUMMARY: Controlled trials are needed to identify affordable treatments for hyponatremia that reduce the need for hospitalization, decrease hospital length of stay, and decrease morbidity. Such trials could also help answer the question of whether hyponatremia causes excess mortality or whether it is simply a marker for severe, lethal, underlying disease.

Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment.

PURPOSE: The long-term efficacy of tolvaptan, a vasopressin V2 receptor antagonist, has been reported. However, the safety of long-term treatment remains to be fully elucidated. We assessed the safety profile of tolvaptan with respect to hypernatremia. METHODS: This retrospective study included 371 patients treated with tolvaptan. Risk factors for hypernatremia (serum sodium concentration ≥147 mEq/L) were determined. RESULTS: Hypernatremia occurred in 95 patients (25.6 %), of whom 71 (19.1 %) developed hypernatremia within 7 days of tolvaptan treatment (early onset). Stepwise logistic regression analysis demonstrated that baseline serum sodium ≥140 mEq/L, an initial tolvaptan dosage >7.5 mg, and a BUN/serum creatinine ratio ≥20 were independent risk factors for early onset of hypernatremia. Tolvaptan was prescribed for more than 7 days to 233 patients, of whom 123 were administrated tolvaptan for more than 1 month. Hypernatremia occurred in 24 of these patients (10.3 %) (late onset). Predictive factors for late onset of hypernatremia were an average daily dosage of tolvaptan >7.5 mg and age ≥75 years. CONCLUSIONS: A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia.

Does 2 L Polyethylene Glycol Plus Ascorbic Acid Increase the Risk of Renal Impairment Compared to 4 L Polyethylene Glycol?

BACKGROUND: The use of polyethylene glycol (PEG)-based solutions is the gold standard for bowel preparation. However, PEG use might be associated with the risk of acute kidney injury. AIMS: We aimed to compare the safety of 2 L PEG plus ascorbic acid (AA) versus 4 L PEG. METHODS: Health examinees that underwent colonoscopy and blood tests on the same day at our center were included in this retrospective study. All subjects were prescribed either 2 L PEG plus AA or 4 L PEG for the bowel preparation prior to the colonoscopy. The incidences of electrolyte imbalance and renal impairment after colonic preparation were investigated. Renal impairment was determined if the subject's estimated glomerular filtration rate was measured less than 60 mL/min/1.73 m2. RESULTS: Of the 29,789 cases, 14,790 received 2 L PEG plus AA (group A) and 14,999 received 4 L PEG (group B) for colonic preparation. Renal impairment occurred more commonly in group A (n = 467, 3.2 %) than in group B (n = 189, 1.3 %). Electrolyte changes such as hypernatremia and hyperkalemia were more common in group A than group B, whereas hyponatremia, hypokalemia, and hypophosphatemia were more common in group B than group A. Old age, male sex, and the use of 2 L PEG plus AA were independent risk factors for renal impairment. CONCLUSIONS: The evidence strongly suggests that acute kidney injury is more likely to occur when 2 L PEG plus AA is used for the bowel preparation than when 4 L PEG is used. CLINICAL TRIAL REGISTRATION NUMBER: KCT0001703.

Sodium polystyrene sulfonate for the treatment of acute hyperkalemia: a retrospective study.

BACKGROUND: Hyperkalemia is a common problem in hospitalized patients, especially those with underlying chronic kidney disease, but evidence-based guidelines for its treatment are lacking. Sodium polystyrene sulfonate (SPS), a cation exchange resin first approved by the FDA for the treatment of hyperkalemia in 1958, is frequently used alone or in conjunction with other medical therapies to lower serum potassium. Recently, the safety and efficacy of SPS have come into question based on multiple reported cases of bowel necrosis associated with SPS administration. OBJECTIVE: The primary objective of this study was to evaluate the use of SPS for the treatment of hyperkalemia, at a large tertiary community teaching hospital, to determine its effectiveness and the incidence of related adverse side effects. METHODS: A retrospective chart review was performed on all adult inpatients receiving single-dose SPS at a 466-bed tertiary community teaching hospital over a 3-year period. RESULTS: 501 patients received SPS for the treatment of hyperkalemia during their index hospital stay. Serum potassium levels decreased by 0.93 mEq/L on average at first recheck after SPS administration, with or without additional medical treatments. Our study identified 10 cases of hypernatremia (greater than 145 mEq/L), 31 cases of hypokalemia (less than 3.5 mEq/L), and 2 cases of bowel necrosis related to the administration of SPS. CONCLUSION: Our results suggest a serum potassium reduction of less than 1 mEq/L after administration of SPS for the treatment of acute hyperkalemia. Additionally, this study offers some evidence that the use of SPS may be associated with harm. We further note the need for standardized guidelines for the treatment of hyperkalemia at our institution.

Dexmedetomidine-related polyuria in a pediatric patient.

Polyuria related to pharmacologic α2-adrenoreceptor agonism has been well described in vitro and in animal models and is thought to be the result of functional antagonism of arginine vasopressin. Despite its widespread use as a sedative and anesthetic adjunct, very few reports of dexmedetomidine-related polyuria in humans exist in the literature. We present the first description of a pediatric patient manifesting polyuria and hypernatremia in association with dexmedetomidine infusion for posterior spinal fusion.

Intravenous solutions in the care of patients with volume depletion and electrolyte abnormalities.

Infusion fluids are often given to restore blood pressure (volume resuscitation), but may also be administered to replace ongoing losses, match insensible losses, correct electrolyte or acid-base disorders, or provide glucose. The development of new infusion fluids has provided clinicians with a wide range of products. Although the choice for a certain infusion fluid is often driven more by habit than by careful consideration, we believe it is useful to approach infusion fluids as drugs and consider their pharmacokinetic and pharmacodynamic characteristics. This approach not only explains why infusion fluids may cause electrolyte and acid-base disturbances, but also why they may compromise kidney function or coagulation. In this teaching case, we present a 19-year-old patient in whom severe hypernatremia developed as a result of normal saline solution infusion and explore the pharmacokinetic and pharmacodynamic effects of frequently used infusion fluids. We review clinical evidence to guide the selection of the optimal infusion fluid.