Hyponatremia Management: A Breakthrough Solution

Hyponatremia Management: A Breakthrough Solution

Date: 16 Jul 2021 (Friday)

Time: 1-2pm (GMT +8)

Hosted by: Otsuka, Farrer Park Hospital

Chairperson: Dr Matthew Tan

Speakers

• Prof Cheuk-Chun Szeto
• Dr Irem Bilgetekin

Introduction & Overview of Hyponatremia in Singapore, by Dr Matthew Tan

Definition of hyponatremia: low serum Na, generally regarded as below 135 mmol/L. Very common, especially in inpatient. A primarily disorder of water balance disorder. Usually associated with disturbance of ADH

Classifications of hypoNa

Usually due to hypotonic hypoNa (majority of the low sodium cases). Various aetiologies, some include SIADH (euvolemic). Usually just based on history taking and management. But sometimes diagnosis is not so clear, and need to think about the diagnostics flow, referring to various international and national guidelines.

Inherently it is usually multifactorial, so physicians may not follow the algorithm most of the times. Even when we look at severe hypoNa, the quality level is usually very low in the international guidelines (mainly expert consensus).

Hyponatremia Management: What would you do?, by Prof. Szeto

Principle: hypoNa is a problem of water balance (too much water as compared to the salt content). The underlying cause can be divided by volume status.

If no clinical features of hypovolemia and oedema, then it is usually classified as euvolemic. Single most common cause is due to SIADH. Classical differential diagnosis is hypothyroid and Addison’s disease. Management will follow the clinical assessment.

SIADH

In addition to low serum Na, diagnosis need to be clinical euvolemia, and inappropriate urine concentration. We do not require urine osmolarity to be higher than serum osmolarity.

Causes: tumours, lung diseases, neurologic diseases, some medications. Important point is that patients taking thiazides can give rise to identical pattern. Patients may mistakenly be classified as euvolemic form of hypoNa (although pathologically is not due to ADH).

Treatment of hypoNa

Directly depending on the volume status. Treat underlying cause (i.e. heart failure, liver failure). Presence of HypoNa usually means the prognosis is poor and the disease is already very severe.

If SIADH and euvolemic entities: need to clarify cause. Use PO NaCl and correct Na levels

How quick to correct?

Acute or chronic? if >48hours, then is considered as chronic. Myelin sheaths usually take 48 hours to adapt to new osmotic environment. If chronic, and not life-threatening, we do not want to rock the boat too much and correct slowly. If have neurological disturbances like seizures, then need to correct quickly.

If you are not sure, it is chronic. Unless there is a documentation of a previous serum Na levels, take it that the hypoNa is chronic.

Hypertonic saline infusion

Indications: acute hypoNa, neurological disturbances (seizures etc.)

Aim: increase Na by 4-6 mEq/L, but not more than 8-10 mmol/L in a day.

Regimen: Sodium deficit not use: the amount of Na does not depend on initial plasma Na

Rapid correction and demyelination

• If too fast, then will develop complications: breathing difficulties. Osmotic demyelination syndrome. No case reported if the Na rise is <8 mmol/L in 24 hours

Risk of chronic mild hypoNa (asymptomatic) –> far more common. For community based management. Majority of the patients are usually euvolemic or slightly hypervolemic. Rule of thumb is to restrict fluid. Also also dependent on how much Na and K the patient is excreting. If excreting a lot, then need to use pharmacological options:

• Loop diuretics
• Urea
• Vaptans

Would frusemide improve hypoNa?

Need to know MOA of frusemide. and where it acts. Only give frusemide to balance urine osmolarity to make it same as plasma osmolarity. Only give when urine osmolarity is higher than plasma

Drug-induced diabetes insipidus: no longer using Lithium and de… due to the toxicity.

Urea for hypoNa?

Use mostly in SIADH. Lower risk of inducing osmotic demyelination than hypertonic saline. Good to improve plasma osmolarity and increase plasma sodium levels. But PO Urea has poor taste and availability.

Most important pharmacological in this option

Non-peptide vasopressin antagonist (e.g. vaptans)

Tolvaptan: most evidence

• Evidence for use of tolvaptan for hypoNa: TACTICS-HF trial (HF with hypoNa)
  • 3 doses of tolvaptan: substantial improvement in body weight
  • Induce diuresis fairly quickly.
• EVEREST trial (tolvaptan vs placebo) for nearly 2 months
  • No difference in mortality!
  • But improvement in body weight etc.
• Meta-analysis of 14 trials
  • Improvement in SOB, serum Na, body weight
  • But no imrpovement in mortality and hoispitalisation (hard outcomes)

Tolvaptan for SIADH (euvolemic)

• These patients are not volume overloaded: risk of losing too much water and increasing plasma Na too much. Many experts would consider 15mg then encourage water intake to offset the resulting water loss (contrary to usual management of SIADH)

Summary: treatment of acute SIADH

• If acute: give hypertonic saline
• Reduce body weight by giving tolvaptan
• Fluid intake should be restricted to less than urine output (unless they are given tolvaptan)

Summary: treatment of chronic asymptomatic SIADH

• Fluid restriction
• Increase urinary water excretion, using tolvaptan and possibly fludrocortisone

Summary: treatment of other entities

• Euvolemic hyponatremia caused by protracted nausea and vomiting or isolated glucocorticoid deficiency. This can be quickly treated by giving antiemetic or stress doses of hydrocortisone
• Hypervolemic hyponatremia caused by CCF: V2 antagonists also effective, although use is limited to 30 days. Longer periods may lead to deranged liver function tests

Hyponatremia in cancer patients: evidence and clinical practice, by Dr Irem

• HypoNa is one of the most common fluid and electrolyte disorder, and also due to the treatment options.
• HypoNa affect performance status, and make patients unable to take chemotherapy
• SIADH is common seen in patients with small cell lung cancer. Usually has poor prognosis.

Statistics

• Small cell lung cancer: 11-15%
• Head and neck cancers: 3%

Causes of SIADH

• Tumours
• Lung diseases
• CNS
• Drug therapies
• Cerebral salt wasting
• Nausea, vomiting, diarrhoea
• CCF, liver cirrhosis

Tolvaptan treatment in hypoNa in cancer patients

• Study: Tolvaptan treatment in hyponatremia due to SIADH: effects on survival in patients with cancer
• Results: LOS was shorter, hypoNa symptoms less frequent, hospital complications less frequent
• No difference with overall survival

Case report

• 45yo male, presented with cough and weakness
• PMHx: smoker, CAD, anxiety, COPD
• On Sertraline (for anxiety) –> can cause SIADH also
• Familial hx: lung cancer in aunt, colon cancer uncle, larynx cancer father

Upon presentation:

• BP normal, PR 84, RR 22, Temp normal
• Chest X-ray: paramedisnal mass
• Chest CT-scan: paramediastinal mass lesion
• LVEF: 60%
• Biopsy: small cell lung cancer

Treatment: 6 cycles of chemotherapy, with radiotherapy given concurrently on 2nd and 3rd cycle

• Follow-up PET/CT (2013): no pathological involvement
• 2014: recurrence with mass lesion in R upp lobe –> administered 9 cycles of chemotherapy –> stable disease after 9 cycles
• 2018: local recurrence –> carboplatin-etoposide chemotherapy 3 cycles, then patient stopped going –> stable disease and clinical follow-up
• Apr 2018: hospitalised for hypoNa (mild nausea, vomiting) –> used tolvaptan 15mg (with fluid restrcition and NaCl 3%) –> 6th hour Na at 123mEq/L
• Follow-up Na value: by 4th day Na is at 131 mEq/L
• 3 weeks later: readmitted due to hypoNa (121), with nausea, vomiting, malaise. –> started on tolvaptan 15mg
• Follow-up Na value: by 4th day Na is at 133 mEq/L
• May 2018: size increase, progressive disease, started on topotecan chemotherapy
• July 2018: hospitalised with hypoNa (122)
• Follow-up Na value: by 4th day Na is at 135 mEq/L
• Aug 2018: 6 cycles topotecan administered, with progression in size of lesions in lung and liver
• Aug 2018: Hospitalised with hypoNa with Na 121, 15mg tolvaptan, increased to 131 during follow-up period
• Oct 2018: cranial MRI done, with metastatic lesion, started on RT, and weekly paclitaxel chemotherapy
• Jan 2019: passed away due to progression and pneumonia

Summary of case

• 6 years of survival time
• Recurrrent hypoNa, total of 10 times hospitalisation

Symptoms of hypoNa

• Headache
• Weakness
• Nausea, vomiting
• Muscle cramps
• Neurological findings
• Could also be asymptomatic

More about tolvaptan

MOA of tolvaptan: inhibits the opening of aquaporins by binding to V2 receptors instead of vasopressin –> inhibits water reabsorption –> free water that cannot be absorbed is excreted from the body via the urine

PK of tolvaptan: PO, T1/2 about 6 to 8 hours, metabolised by CYP3A4, excreted mainly via feces. Starting dose 15mg, maximum dose 60mg

Studies of tolvaptan

• SALT-1/ SALT-2/ SALTWATER
• Fluid restriction was less in tolvaptan group than placebo group
• Cisplatin is nephrogenic: need to give fluids, cannot be fluid restricted, hence tolvaptan is good option

Side effects of tolvaptan

• Thirst
• Dry mouth
• Polyuria
• Pollakiuria
• Asthenia
• Constipation
• Hyperglycemia
• Fever
• Anorexia

Considerations in tolvaptan therapy

• Rapid improvement in Na can cause dysarthria, dysphagia, lethargy, spastic quadriparesis, osmotic demyelination with coma and death
• Initiate at 15mg/day, increased after 24 hours. Max dose 60mg/day. Dose can be increased after at least 24 hours
• Renal adjustments: CrCl > 10 ml/min, no need adjust. If <10ml/min, not recommended for use
• Contraindicated in anuric patients
• Caution for liver damage
• Not recommended to continue therapy after 30 days

Summary

Treatment of hypoNa request multidisciplinary approach, positive effect on disease. increase QOL of patients, affect prognosis of primary disease, LOS and complications can be reduced.

Q&A

Q1: I have patients who have nausea with sodium levels just below the lower limit of normal 133mmol/L. is this abnormal. Should I be looking for another problem? Other electrolytes are normal, normotensive. Not taking any drugs

Prof Szeto: I think there is no need for further investigation. Nausea is actually a very strong inducer of hyponatremia. Just need to find out what makes the patient nauseate!

Q2: What are the most specific objective clinical signs of hyper, normo and hypovolemia?

Prof Stezko: Peripheral oedema (ankle or sacral) for hypervolemic form; postural hypotension and decreased skin turgor for hypovolemia. If neither is present, the patient could be classified as euvolemic clinically.

Q3: What is the incidence of SIADH as a cause of hyponatremia in an adult general medical ward in Hong Kong?

Prof Szeto: I am not aware of any formal study in Hong Kong. For my hospital that covers 600,000 population, around 20 patients are admitted to ICU for severe hyponatremia each year. Thiazide is the more common cause (probably 70% of these cases); the other 30% SIADH. For milder cases, I have no data.

Q4: What should we do when we can’t check urine osmolarity in our hospital? Is there other way for us to calculate the nearer score of urine osmolarity?

Prof Szeto: No easy answer. Some ward setting can do urine specific gravity at bedside, but I find it not very reliable. My advise is not to give frusemide in that case unless the patient has fluid retention clinically.

Q5: How can post surgery cause hyponatremia?

Prof Szeto: Pain, nausea, and many medicines used by anesthetists can cause hyponatremia.

Q6: I notice hyponatremia in diabetics, especially poorly controlled diabetes. Do I have to investigate and treat that too, or just treating the diabetes would suffice?

Prof Szeto: If the serum osmolality is normal (i.e. “compensated” by hyperglycemia), there is no need to investigate.

Q7: What if the person is on last stage of kidney disease and already going through haemodialysis 2 times a week and does not have urine anymore but on hyponatremia state and hypervolemic, is it fine if we use frusemide?

Prof Szeto: If the patient is anuric, frusemide will not work. We treat these patients with extra fluid removal with dialysis, sometimes covered with a small bolus of hypertonic saline (the one we used for treating muscle cramps during dialysis)

Q8: We get patients with CCF and Na of 120. Naturally, we give frusemide. However, with this, the Na may drop down to 116. My question is: 1) Do I have to worry about this? If so, what can I do. 2) Is there anything I can measure to ensure that more water than sodium is coming out of the kidney?

Prof Szeto: As I mentioned, check urine osmolality before frusemide. If the pre-treatment urine osmolality is higher than plasma, plasma sodium should come up with frusemide. If that does not work out, options are tolvaptan or frusemide plus sodium bicarbonate (less oedema and fluid retention as compared to NaCl).

Q9: How much to give hypertonic saline bolus? Is there any sign and symptom that occur during haemodialysis that make us have to give hypertonic saline bolus to patient?

Prof Szeto: We only give it when patient has cramp or an episode of hypotension. Our in-house regimen is 23.4% NaCl 5 ml. (Note that it is not the 3% NaCl preparation in ICU.)

Q10: For sodium monitoring, is it really necessary to monitor everyday?

Prof Szeto: It depends on the severity of hyponatremia. During the use of hypertonic saline, one should monitor it every 4 to 8 hours (but that would not last for anything more than 2 days, and is usually in the ICU setting). For asymptomatic hyponatremia, there is no need for very intensive (i.e. daily) monitoring.

Q11: Does increase in salt intake in the food help in correction of hyponatremia in euvolumic hyponatraemic patients partially at least?

Prof Szeto: Yes. In fact increase in potassium or protein intake is also effective.

Q12: How much water does a normal healthy person need to drink per day to get a good balance of sodium in the blood system?

Prof Szeto: It depends on the daily osmolyte intake – a very complicated subject.

Q13: How do you know that the headache presentation is not due to cancer and is due to hypoNa?

Dr Irem: important to use laboratory values as well. Mental status also. If the disease is stable, other things can cause the conditions. So need to think about the other abnormalities for your patient. For my patient, there was no other symptoms, only the presenting mild symptoms, hence laboratory values is very important for us.

Q14: How do we compute for urine osmolality of direct measurement is not available? will the urine specific gravity suffice?

Prof Szeto: You can estimate by [Na] x2 + [K] x2 + [urea]. Not absolutely reliable; but better than urine specific gravity.

Dr Matthew Tan: especially in a primary care setting, where urine osmolarity tests is not available.

Prof Szeto: The formula is reasonable. However, if your lab can calculate these, should be likely to measure urine osmolarity. Urine specific gravity may be available in some hospitals as bedside test (especially in paediatric wards). However it is very difficult to interpret as many factors affect it (e.g. proteins, infections).

Q15: Reset Osmostat: Type 2 SIADH

Prof Szeto: less frequently occurring, mostly in pregnancy. No known easily test. Usually this is diagnosed by clinical context. Treatment is not to treat, patients have likely adjust to the current status. Usually no problems if patient is not treated. No definitive data, but my impression is tolvaptan is used mainly for Type 1