Hyponatremia

How Fast Should We Correct Severe Hyponatremia?

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Correcting serum sodium slowly was associated with longer length of stay and excess mortality.

Rapid overcorrection of hyponatremia has been associated with osmotic demyelination syndrome (ODS), but data also suggest that correcting sodium slowly might be associated with longer hospital length of stay and excess in-hospital mortality. To examine the relation between serum sodium correction rates and clinical outcomes, researchers performed a retrospective study of more than 3000 patients with severe hyponatremia (<120 mEq/L) who were admitted to two Massachusetts hospitals during a 25-year period.

The cohort was divided into three groups according to calculated correction rates: Slow (<6 mEq/L/24 hours), moderate (6 to 10 mEq/L/24 hours), and fast (>10 mEq/L/24 hours). About one third of the cohort fell into each group. The moderate-correction group was chosen as a reference, as that rate aligns with guideline recommendations.

In adjusted analyses, slow correction was associated with higher in-hospital mortality. Fast correction was associated with shorter hospital length of stay and lower mortality in a multivariable analysis, but with no difference in mortality in a propensity-weighted analysis. The overall incidence of ODS in the entire cohort was low (7 patients; 0.2%), and 5 of those cases occurred in patients with sodium correction rates of ≤8 mEq/L/24 hours.

Comment

The prevailing concern when treating patients with severe hyponatremiatraditionally has been to avoid rapid overcorrection of serum sodium levels. These data argue that repleting serum sodium too slowly might be the more important problem. ODS is an uncommon complication of correcting sodium levels and appears to occur because of patients’ clinical factors (e.g., alcohol-use disorder, other electrolyte derangements) rather than because of fast sodium correction.

Thiazide Diuretics May Promote Hyponatremia

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Adults who used thiazide diuretics for hypertension were more likely than were those who used nonthiazide agents to develop hyponatremia within 2 years of starting treatment, a new study of more than 180,000 people has found.

Although thiazide diuretics generally are well-tolerated in the routine treatment of uncomplicated hypertension, severe adverse effects are possible, and their frequency has not been examined, according to Niklas Worm Andersson, MD, of Statens Serum Institut, in Copenhagen, Denmark, and his colleagues.

“Thiazide diuretics are commonly used drugs for the treatment of uncomplicated hypertension, and hyponatremia is a known potential side effect to thiazide treatment, but the frequency of this adverse event is inconsistently reported across drug labels,” Andersson told Medscape Medical News. 

Product labels for thiazide diuretics list hyponatremia as a potential adverse event that can occur rarely (defined as a range from less than 1 in 10,000 to less than 1 in 100 individuals), but the extent of the burden is unclear given the wide range of symptoms of the condition, the researchers write. 

In a study published in Annals of Internal Medicine, Andersson and his colleagues reviewed data from population-based registries in Denmark of adults aged 40 years or older with uncomplicated hypertension, no recent prescriptions for antihypertensives, and no previous history of hyponatremia. They emulated two target trials. One trial compared the incidence of hyponatremia in new users of bendroflumethiazide (BFZ) vs a calcium-channel blocker (CCB). The other emulation compared the incidence of hyponatremia in new users of hydrochlorothiazide (HCTZ) plus a renin-angiotensin system (RAS) inhibitor vs a RAS inhibitor without HCTZ. 

The primary outcome was hyponatremia, defined as blood sodium < 130 mmol/L, within 2 years of starting treatment. 

The 2-year incidence of hyponatremia for the two thiazide diuretics was 3.83% for BFZ and 3.51% for HCTZ-RAS inhibitor. The risk difference in the incidence of hyponatremia was 1.35% for BFZ vs CCB and 1.38% for HCTZ-RAS inhibitor vs RAS inhibitor, the researchers reported. 

The study population included 37,786 new users of BFZ who were compared with 44,963 new users of CCBs as well as 11,943 new users of HCTZ-RAS inhibitors who were compared with 85,784 new users of RAS inhibitors only. 

Overall, older age and a greater number of comorbidities increased the cumulative hyponatremia in new users of thiazide-based hypertensives. The risk differences among individuals aged 80 years or older were 4.80% in the BFZ vs CCB study and 5.52% in the HCTZ-RAS inhibitor vs RAS inhibitor study. Among participants with three or more comorbidities, the risk differences in the two studies were 5.24% and 2.91%, respectively, Andersson’s group found.

The findings were limited by several factors, mainly the potential for confounding on the basis of the assumption that filled prescriptions equaled drug use, the researchers noted. Other limitations included the focus on new users and a Danish population only, which might limit generalizability, and a lack of data on blood pressure measures.

However, the results suggest a greater risk for hyponatremia with thiazide diuretics than what the drug labels indicate, especially early in treatment, the researchers concluded. 

Data Reinforce Need for Vigilance in the Clinic

“Our findings highlight the continued need for clinical awareness and monitoring of this adverse drug reaction; particularly during the first months of treatment, in persons who are older or who have comorbidities,” Andersson told Medscape Medical News. “Further mapping of potential subpopulations at risk in terms of specific comorbidities is important to improve the prevention of this adverse event.”

“The thiazide diuretics have been recommended as first-line therapy for hypertension, and it was important to evaluate the potential development of hyponatremia, especially in the older patients given the potentially serious health effects caused by hyponatremia,” said Noel Deep, MD, a general internist in private practice in Antigo, Wisc onsin. Deep, who was not involved in the study, also serves as chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo. 

The current study findings were not surprising, Deep added. “I have seen this occur in my patients, especially in the older female patients,” he said. “The results reinforce my practice of monitoring the electrolytes and renal function in 1-2 weeks after starting a thiazide diuretic, and then at regular intervals.”

In practice, clinicians should be aware of the potential development of hyponatremia and monitor and address the electrolyte abnormalities, Deep said. “While thiazide and thiazide-like diuretics are an important component of our treatment options for patients with hypertension and other conditions, we should also ensure that we are cognizant of and address the potential side effects or electrolyte imbalances caused by the medications.” 

Bruce Lee and Hyponatremia

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Bruce Lee was the most influential martial artist of the 20th century. In the 1970’s, his fame as a movie star and martial arts instructor sparked North American interest in Asian martial arts. He brought martial arts to North America by founding Jeet Kune Do, which is the basis for modern mixed martial arts. On July 20, 1973, at age 32, he died suddenly with massive swelling of his brain. The cause of his brain swelling was not proven by an autopsy, but was originally reported as possibly caused by sensitivity to aspirin. Now, almost 50 years after his death, a well-researched paper with solid journal references explains that he probably died from hyponatremia, drinking too much water (Clin Kidney J, Dec 2022;15(12):2169–2176).

• Hyponatremia occurs when drinking too much water dilutes the salt level in your bloodstream.
• However, the level of salt in your brain usually remains normal or high.
• Fluid moves from tissues that have low-salt levels to dilute those that have high-salt levels.
• Blood fluids move from the bloodstream into the brain, so the brain expands with extra fluid.
• The brain is in a tight box called the skull that cannot expand, so the enlarged brain is crushed inside the non-expanding skull.
• The person stops breathing and dies.

Early Years and Movie Career
Lee was born in Chinatown, San Francisco, the son of Lee Hoi-chuen, a leading Chinese opera and film actor and Grace Ho, daughter of extremely wealthy Hong Kong entrepreneurs and philanthropists. Lee’s family returned to Hong Kong when he was three months old and he was raised there. His father arranged for him to get minor parts in movies, and he had roles in 20 films by the time he was eighteen.

Lee became the leader of a street gang, and after he came home from school one day with wounds from a fight, his father began to teach him martial arts. All this did was encourage him to get into more street fights with rival gangs. When he was 18, he beat up the son of a prominent gang leader and word got out of a contract to kill him. Fearing for his life, his father sent him to the safety of the United States to live with his older sister, Agnes Lee, in San Francisco.

In March 1961, Lee enrolled at the University of Washington to major in drama. There he met Linda Emery, and they were married in August 1964. They had two children, Brandon and Shannon, both of whom became actors. Lee dropped out of college in the spring of 1964 and moved to Oakland to open a martial arts studio with James Yimm Lee. He then moved to Los Angeles where he taught martial arts and starred in a television series, “The Green Hornet,” in 1966 and 1967. However, he was not able to get movie jobs in Hollywood, so he left Los Angeles for Hong Kong in the summer of 1971. There he quickly became a major star in “Fists of Fury,” followed by an even more popular film, “The Chinese Connection.” In 1972, he founded a company to make his own film, “Return of the Dragon.”

Top 10 BRUCE LEE MOMENTS
YOUTUBE URL:https://www.youtube.com/embed/Se1y2R5QRKU

Fitness and Health Food Obsession
Bruce ran virtually every day, usually in the late afternoon, and did a lot of stretching. Whenever he watched television he would exercise and stretch. He had almost no fat in his body and was always in top shape. He also became good enough at table tennis to compete successfully with some of the best players in his area.

Several times a day he would drink special protein mixes or vegetable cocktails. His drinks contained commercial protein powders, powdered milk, eggs with their shells, vegetable oils, peanut flour and bananas. He juiced carrots, celery and apples regularly. He also took a lot of vitamin and mineral pills and drank water frequently throughout the day. No good research supports any of these “health food” habits, but they may have been responsible for the tremendous amount of excess fluids that he took in that caused his death.

Events That Led to His Death
On May 10, 1973, two months before his death, Lee had an attack of brain swelling. He suffered headaches followed by a seizure, and fell on the floor while working on the movie “Enter the Dragon”. He was rushed to Hong Kong Baptist Hospital where doctors diagnosed that he had massive swelling of his brain. A very competent physician saved his life by immediately giving him intravenous mannitol. This drug increases the concentration of sugar in the bloodstream to shrink the brain by drawing fluid from the brain into the bloodstream. The mannitol also acts on the kidneys to draw the extra fluid out of the body and into the urine.

On July 20, 1973, while reviewing a movie script at the home of Taiwanese actress Betty Ting Pei, Lee complained of a headache and took a painkiller called Equagesic, which contained aspirin and meprobamate, a muscle relaxant. He went to sleep and then could not be awakened. A doctor and ambulance were called, but he was dead before he reached the hospital.

An autopsy showed that his brain was massively swollen. The only drugs found in his body were aspirin, meprobamate and small amounts of marijuana. A reaction to aspirin can cause brain swelling, confusion and seizures, but now researchers believe that hyponatremia was a more likely cause (Clin Kidney J, Dec 2022;15(12):2169–2176).

Since low blood salt levels can cause massive brain swelling, and the brain is enclosed in the skull and has nowhere to go, it is squashed to cause headache, nausea, and blurred vision. As blood salt levels drop even lower, the person becomes confused, develops seizures and falls unconscious.

Risk Factors for Hyponatremia
Lee had multiple risk factors for hyponatremia:
• High chronic fluid intake. he preached a high intake of fluids as the healthiest way to live and drank water throughout the day.
• Marijuana (found at autopsy) increases thirst so you drink more.
• Acute kidney damage causes the body to retain fluids. His physician said that blood urea nitrogen (a measure of kidney damage) at Baptist Hospital was very high at 92 mg/dL, but was normal on May 25 when Lee was examined previously.
• Alcohol (Lee drank frequently), which can cause low blood salt levels.
• Low dietary salt and high fluid intake. His wife says that in her husband’s final months, he had stopped eating solid food and was existing primarily on fluids, mostly carrot juice and apple juice
• Recent weight loss. He looked emaciated and had lost 15 percent of his total body weight in the previous two months, and he had minimal body fat to start.
• Active exercise and inadequate food and fluid intake. He continued to exercise every day on his meager diet. Exercise can cause salt loss through sweating (Wilderness Environ Med 2020; 33: 50–62)
• Some evidence that he was taking diuretics, which can deplete the body of salt.
• Possible prescription and over-the-counter drugs. Various reports say that he took aspirin, diuretics, phenytoin and painkillers.
• Possible anabolic steroids, which can cause adrenal insufficiency that causes salt loss

Lessons From Bruce Lee’s Death
You need extra fluid when you exercise, particularly in hot weather, but how much fluid should you drink? You will not become thirsty during exercise until you have lost between two and four pints of fluid, so you can’t wait for thirst to encourage you to drink. Blood has a much higher concentration of salt than sweat, so when you sweat, you lose far more water than salt, so you will not become thirsty until you are significantly dehydrated. Dehydration makes you tired and it is unlikely that you could maintain your race pace after you become thirsty, because you will have to slow down while you drink enough fluid to replace what you have lost.

The American College of Sports Medicine recommends up to five cups of fluid per hour, but for a person who is not exercising near their maximum, this could be too much. People slowed down by fatigue, or those out of shape, should limit fluid intake, probably to less than two water bottles per hour. If you are exercising for more than an hour, you should also replace salt, either with salted sports drinks or salted foods. More on hyponatremia

Bruce Lee
Nov 27, 1940 – July 20, 1973

A Woman with Hyponatremia.

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What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?

Hyponatremia can occur in all forms of adrenal insufficiency, although it tends to occur most prominently in primary adrenal insufficiency (Addison’s disease). Primary adrenal insufficiency is caused by impairment of the adrenal glands, whereas secondary adrenal insufficiency is the result of corticotropin deficiency caused by either pituitary or hypothalamic disease. A Case Record of the Massachusetts General Hospital explains.

Clinical Pearl

  • What is the most common cause of primary adrenal insufficiency in high-income countries?

Primary adrenal insufficiency is a rare entity, and in high-income countries, autoimmune adrenalitis is the most common cause.

Clinical Pearl

  • Do patients with adrenal insufficiency have a normal life expectancy?

Patients with adrenal insufficiency have a mortality rate that is 2 or 3 times the normal rate, and they have an increased incidence of certain cancers. Morbidity is considerable. Patients often have absences from school or work, frequent hospitalizations, and alterations in work life, social life, family life, and physical activity.

Morning Report Questions

Q: What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?
A: The signs and symptoms are nonspecific and include fatigue, dizziness, gastrointestinal illness, salt craving, and hyperpigmentation. Hyperpigmentation is almost always present in chronic primary adrenal insufficiency. There are also some case reports of chronic primary adrenal insufficiency in which hyperpigmentation is absent, most likely because there are adequate resting levels of plasma cortisol, which would prevent increased corticotropin secretion and subsequent melanocyte stimulation. Among patients with adrenal insufficiency, hyperkalemia occurs only in those with the primary form, owing to the aldosterone deficiency. Hyperkalemia occurs in only 50 to 60% of patients with primary adrenal insufficiency, perhaps because of aldosterone-independent regulatory mechanisms in the distal nephron that maintain eukalemia. A fraction of patients with adrenal insufficiency have a peripheral eosinophilia.

Figure 1. Laboratory Abnormalities in Primary Adrenal Insufficiency.

 

Q: How sensitive is the 21-hydroxylase antibody test for autoimmune adrenal insufficiency?
A: A 21-hydroxylase antibody test is approximately 60 to 75% sensitive, so a positive test would indicate an autoimmune cause, but a negative test does not rule it out. Other antibodies have been identified in patients with autoimmune primary adrenal insufficiency, such as antibodies against the steroid 17α-hydroxylase and side-chain cleavage enzymes. These tests are not widely available and are not specific.

Source:nejm.org

Antidepressants Associated With Hyponatremia

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TAKE-HOME MESSAGE

  • A cohort of 638,352 people was evaluated from 1998 through 2012 to investigate the relationship between the use of antidepressants and the risk of hyponatremia. The incidence rate ratio for the association with hyponatremia after initiation of treatment was highest for citalopram (7.80) and lowest for mianserin (0.90). The incidence rate ratio for other agents were: clomipramine 4.93, duloxetine 2.05, venlafaxine 2.90, and mirtazapine 2.95.
  • Apart from mianserin, all antidepressant agents are associated with an increased risk of hyponatremia, with the highest risk seen with citalopram.

Antidepressants are associated with the development of several metabolic abnormalities. This study reports an association between antidepressants and the development of hyponatremia. With the wide use of antidepressants such as SSRIs and SNRIs, it is important to remember to monitor patients periodically on such medications for electrolyte disturbances, glucose intolerance, and lipid abnormalities. Elderly patients are especially at risk and may warrant closer monitoring as the use of other chronic medications and decreased renal clearance may further increase the risk for hyponatremia.

OBJECTIVE

To examine the association between classes of antidepressants and hyponatremia, and between specific antidepressants and hyponatremia.

DESIGN

Retrospective register-based cohort study using nationwide registers from 1998 to 2012.

SETTING

The North Denmark Region.

PARTICIPANTS

In total, 638 352 individuals were included.

PRIMARY AND SECONDARY OUTCOME MEASURES

Plasma sodium was obtained from the LABKA database. The primary outcome was hyponatremia defined as plasma sodium (p-sodium) below 135 mmol/L and secondary outcome was severe hyponatremia defined as p-sodium below 130 mmol/L. The association between use of specific antidepressants and hyponatremia was analysed using multivariable Poisson regression models.

RESULTS

An event of hyponatremia occurred in 72 509 individuals and 11.36% (n=6476) of these events happened during treatment with antidepressants. Incidence rate ratios and CIs for the association with hyponatremia in the first p-sodium measured after initiation of treatment were for citalopram 7.8 (CI 7.42 to 8.20); clomipramine 4.93 (CI 2.72 to 8.94); duloxetine 2.05 (CI 1.44 to 292); venlafaxine 2.90 (CI 2.43 to 3.46); mirtazapine 2.95 (CI 2.71 to 3.21); and mianserin 0.90 (CI 0.71 to 1.14).

CONCLUSIONS

All antidepressants except mianserin are associated with hyponatremia. The association is strongest with citalopram and lowest with duloxetine, venlafaxine and mirtazapine.

Hyponatremia Frequent After Surgery for Traumatic Hip Fracture

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Hyponatremia is common after surgery for traumatic hip fracture, according to a new retrospective review.

“This study provides evidence that an average post-operative drop in serum sodium concentration should be expected in this patient group,” Dr. James Edward Rudge and Dr. Daniel Kim of City Hospital, Sandwell and West Birmingham Hospitals NHS Trust write in their report, published online June 7 in Age and Ageing.

From 15% to 30% of hospital inpatients develop moderate hyponatremia (130-135 mmol/l), while the electrolyte disorder can also be a late complication of surgery, the researchers write. Hyponatremia is also common after orthopedic surgery, they add.
To examine the incidence of hyponatremia after hip fracture surgery as well as risk factors for the disorder, Dr. Rudge and Dr. Kim looked at 254 patients who underwent hip surgery after trauma in their unit in 2012. Mean serum sodium dropped by 1.8 mmol after surgery. Twenty-seven percent of patients developed moderate hyponatremia, while 9% developed severe hyponatremia (< 130 mmol/l).

Patients on selective serotonin reuptake inhibitors, those on proton pump inhibitors, and those on an increasing number of medications were all significantly more likely to develop hyponatremia, the researchers found. There was no association between gender, operative procedure, fracture type, ethnicity, or American Society of Anesthesiologists’ grade. Average hospital stay was 30 days for the hyponatremic patients, versus 21 days for the normonatremic patients.

The rate of postoperative hyponatremia in the current study was higher than seen in past studies, the researchers note; one study found a 6% risk in orthopedic surgery patients for the first six days after surgery, while another found 3% in the first three days after surgery. The second study, they note, also found most cases of hyponatremia occurred in hip fracture patients. “The current study provides evidence that this subset of orthopedic patients is at greater risk of post-operative hyponatremia,” the authors write.

“The operative process itself may be a risk factor and all patients should be considered at risk of developing the condition,” they conclude.

Nutritional Management of Patients with Cirrhosis and Hepatic Encephalopathy.

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Consensus recommendations are now available despite continued knowledge gaps in this area.
An expert panel commissioned by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism has recommended that all patients with cirrhosis and hepatic encephalopathy should receive nutritional management similar to that for patients with cirrhosis but without hepatic encephalopathy. Specific recommendations from their consensus document are described below.

Strongest recommendations:

  • All patients should undergo baseline nutritional assessment as a part of management. (The authors acknowledged that no clinically practical, well-validated tools to assess nutrition are currently available.)
  • Optimal daily energy intake should be 35 to 40 kcal/kg ideal body weight.
  • Optimal daily protein intake should be 1.2 to 1.5 g/kg ideal body weight.
  • Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrate are ideal.
  • Hyponatremia should always be corrected slowly.

Recommendations with less certainty, but with moderate evidence:

  • Encourage a diet rich in vegetable and daily protein.
  • Branched-chain amino acid supplementation might allow recommended nitrogen intake to be maintained in patients intolerant of dietary protein.
  • A 2-week course of a multivitamin could be justified in patients with decompensated cirrhosis.
  • Encourage a diet containing 25 to 45 g of fiber daily.
  • Avoid long-term treatment with manganese-containing nutritional formulations.

Source: NEJM

 

Use of Vaptans Is Not Recommended for Hyponatremia in Cirrhosis.

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These costly drugs did not reduce mortality in a meta-analysis of randomized, controlled trials.

In patients with cirrhosis, hemodynamic changes lead to increased secretion of arginine vasopressin, which results in water retention and dilutional hyponatremia. Vaptans (nonpeptide vasopressin receptor antagonists) promote increased free water clearance with hypotonic dieresis. Although vaptans are approved for use in hyponatremic patients, their efficacy and safety in patients with cirrhosis is debated.

Now, investigators have conducted a systematic review and meta-analysis of 12 industry-funded, randomized, controlled trials that evaluated the safety and efficacy of vaptans (tolvaptan, satavaptan, and lixivaptan) in patients with cirrhosis and hyponatremia or ascites. Of 2266 total participants, 1483 received vaptans, and 783 controls received no intervention, placebo treatment, or a different diuretic agent (furosemide or spironolactone). The primary outcome was mortality; secondary outcomes included complications of cirrhosis, renal failure, serum sodium levels, mobilization of ascites, and adverse events.

Mortality was similar in the vaptan and control groups, as were rates of complications of cirrhosis and renal failure. Compared with controls, use of vaptans increased serum sodium levels (weighted mean difference, 2.02 mmol/L), reduced body weight (weighted mean difference, –1.82 kg), increased the time to the first large-volume paracentesis, and increased the rate of nonserious adverse events such as thirst and excessive urine volume. Subgroup and sensitivity analysis did not alter these findings.

Comment: This well executed meta-analysis demonstrated no survival benefit from the use of vaptans in patients with cirrhosis and ascites or hyponatremia. Although no serious adverse events occurred with the use of vaptans, nonserious adverse events were common. Because this class of drugs is expensive and its benefits are questionable, it cannot be recommended for routine clinical use in patients with cirrhosis.

Source: Journal Watch Gastroenterology

 

Preoperative Hyponatremia May Heighten Mortality Risk .

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The presence of even mild hyponatremia before surgery is associated with increased perioperative mortality, according to a cohort study in the Archives of Internal Medicine.

Nearly 1 million U.S. adult patients in a surgical-quality registry had their sodium levels measured within 90 days before surgery. About 8% of patients had hyponatremia (defined as a serum sodium level under 135 mEq/L), with most of these being only mildly hyponatremic (values ranging from 130 to 134 mEq/L).

The study’s primary outcome, mortality within 30 days after surgery, was higher in those with hyponatremia than in those with normal sodium levels (5.2% vs. 1.3%); the difference remained significant even after adjustment for other risk factors such as smoking and functional health status.

Editorialists comment that the findings are not surprising, given the comorbidities associated with hyponatremia. They say it remains an open question whether elective surgery should be postponed in the face of mild hyponatremia, “but the diagnosis should contribute to the informed consent process.”

Source:Archives of Internal Medicine