Published on April 21, 2014
PULMONARY AND CRITICAL CARE- NOON CONFERENCE HYPONATREMIA IN ICU PATIENTS Avaneesh Jakkoju, M.D.
What we are going to cover… Why serum sodium falls How the brain responds to a change in serum Na concentration. What the goals of therapy should be.
Why serum Sodium level rises and falls… • Serum Sodium is a function of exchangeable Sodium, Potassium and total body water. Total body (Nae+Ke) Serum Sodium = ----------------------------------- Total body water
Serum Sodium levels… • Extra renal losses do not cause fall in serum sodium levels. – For example GI losses such as vomiting and diarrhea leads to loss of Na and K along with free water loss and serum sodium level will be same. – Sweating. What causes hyponatremia in the above situations is replacing the lost fluid with regular water, that makes the Sodium levels to drop.
Why does hyponatremia develop… Renal loss of Sodium leads to hyponatremia. To put it simply, if the urine is more concentrated than plasma then there is net loss of Sodium leading to hyponatremia. ADH (vasopressin) plays a crucial role to this effect.
ADH in normal human beings.. Secreted by hypothalamus Vasopressin is released from posterior pituitary in response to dehydration and/or hyponatremia.
Abnormal secretion of ADH… • Pathologically ADH secretion is released in spite of normal or even low Na concentration in response to stimuli such as – Inadequate circulation – Stress – Hypoxia – Cortisol deficiency – Neurological diseases – Ectopic vasopressin release such as SCC of lung.
Cerebral Salt Wasting… In acute neurological conditions particularly in SAH, to maintain cerebral perfusion large volumes of isotonic fluids are commonly prescribed. Volume expansion suppresses aldosterone secretion and enhances natriuretic hormones that increase urine Na excretion leading to hyponatremia.
Hyponatremia in Kidney disease… Acute kidney injury or advanced chronic kidney disease results in a urine osmolality equal to that of plasma. Replacing fluid losses with electrolyte free water in kidney diseases leads to hyponatremia due to dilution.
Brain response to changing serum Na concentration… Na does not readily cross BBB. If the serum sodium falls rapidly then free water crosses blood brain barrier leading to increase in Intra cranial pressure some times with fatal outcomes. On the other hand if the serum Sodium concentration increases rapidly, water is drawn from brain.
Slow vs. fast serum Na changes… • Brain cells achieve osmotic equality with plasma by exchanging organic solutes as well as taking on water. • Loss of these organic osmolytes leads to decreased brain swelling. • This is an effective mechanism to prevent cerebral edema in response to hyponatremia, but unfortunately this is a slow process. • It takes 48 hours for the brain to adapt to hyponatremia, any fall in Na faster than this leads to fatal rise in ICP.
Slow vs. fast Na changes… • Rapid correction of chronic hyponatremia starts a cascade of adverse events leading to programmed death of myelin producing oligodendrocytes. • This is because of the delay in repletion of organic osmolytes within the brain cells. • This injury presents clinically as a progressive neurological disease- Osmotic demyelination syndrome (ODS).
Osmotic demyelination syndrome… • Classically associated with demyelination of the central pons- central pontine myelinolysis. • Extra pontine myelinolysis is also equally common. • Clinical symptoms start 2 to 6 days after the correction and include dysarthria, dysphagia, paraparesis or quadriparesis, behavioral disturbances, lethargy, confusion, disorientatio n, obtundation and coma. • Seizures although uncommon are seen. • Severe cases, patients are „locked in‟;
Predisposition to ODS… • ODS is seen not with hyponatremia but with rapid correction; can be prevented by lowering Na with Desmopressin after rapid correction. • Patients who has a very longstanding hyponatremia, with serum Na<105 mEq/L, hypokalemia, alcoholism, malnutrition and liver disease are prone to develop ODS. • On the other hand serum Na<120 mEq/L, with out above risk factors and whose hyponatremia is of very short duration are not prone to develop ODS, they can be treated with rapid Na correction.
Goals of Therapy… Serum Na concentration should be increased enough to prevent complications of untreated hyponatremia. Treatment should be at the optimal rate so as not to cause any iatrogenic brain injury.
Acute hyponatremia… Brain death from cerebral edema is the most feared complication of acute hyponatremia. This was observed in patients.. Who were given hypotonic IV fluids after surgery. Water intoxication associated with psychosis, marathon running or recreational drug use of „ecstasy‟. Intracranial pathology.
Acute hyponatremia-clinical picture… • Headache, nausea, vomiting, drowsiness and mild confusion can be seen. • These non specific symptoms rapidly progress to seizure, respiratory arrest and permanent or fatal brain injury. • Seizures are uncommon in chronic hyponatremia even with very low Sodium concentration and they usually reflect and underlying seizure pathology.
Acute hyponatremia- how to correct… • Serious neurological symptoms warrant aggressive treatment irrespective of any other factors. • Treatment with hypertonic saline to raise serum sodium concentration 4 to 6 mEq/L is suggested by several studies. • A 4 year, single center study of 63 patients treated for transtentorial herniation caused by a variety of neurosurgical conditions found that, an increase in plasma sodium concentration by 5 mEq/L promptly reversed clinical signs of herniation and reduced ICP by 50% with in 1 hour. • Seizures due to hyponatremia do not respond to anti epileptic drugs.
Severe chronic hyponatremia… Patients with chronic hyponatremia rarely are symptomatic. There is little evidence to suggest Sodium level to be brought to „safe‟ (>120 mEq/L or in some cases >130 mEq/L) levels for better outcome. In spite of lack of evidence correcting well compensated hyponatremia continues to be the standard of care.
Severe Chronic hyponatremia- rationale for treatment… • Typically patients with serum Na<110 mEq/L are admitted to the hospital. • These patients have a very good prognosis and there is no need for aggressive treatment or large increase in Sodium. • As serum sodium levels fall mortality rate rises, but below 120 mEq/L paradoxically mortality rate falls, and at 110 mEq/L mortality rate is same as that of normonatremic patients.
Severe Chronic Hyponatremia- clinical picture… • Although hyponatremia that developed over days rarely ever presents with life threatening symptoms such as seizures and coma, it still causes distressing symptoms. • Even mild chronic hyponatremia which is seemingly “asymptomatic” can cause gait disturbances and disturbed cognition. • It markedly increases the risk of falls and fractures.
Severe Chronic hyponatremia- treatment goals… • Goal of treating chronic hyponatremia should not be aimed at bringing the Sodium level to „normal‟ levels, but bringing it to a level where it provides symptom relief. • Rapid or over correction of Sodium is associated with adverse neurological outcomes that we have reviewed in the beginning. • A correction of 4 to 6 mEq/L/day is considered an ideal Sodium correction rate.
ODS- treatment goals… It takes about 1 week for the repletion of organic osmolytes in the brain. Several observational studies have shown, treatment of severe (defined as <120mEq/L) and chronic (>48 h) hyponatremia by >10 to 12 mEq/L/d or >18 mEq/L/2days has been shown to be associated with ODS. However these values do not represent the treatment guidelines for the correction of hyponatremia, therapeutic goals should be much lower than these values.
A Universal Therapeutic Goal: Rule of Sixes… Six a day makes sense for safety; so give six in six hours for severe Sx and stop.
Rule of Sixes- What does it mean? For all patients with severe symptoms of hyponatremia therapeutic range of correction should be <6 mEq/L/D. Give 6 mEq/L on the first day for 6 hours and stop. Can be resumed on day 2 with a goal of 4 to 6 mEq/L/D.
Rule of Sixes- Why? An increase of 4 to 6 mEq/L/D is enough to treat most symptoms of hyponatremia. This level allows enough room for error should correction inadvertently exceed the rate that was intended. As previously mentioned upper limit of correction 10 to 12 mEq/L/D or 18 mEq/L/2day reported by previous observational studies.
How to treat: General Measures… Unless urine is maximally dilute, patients should be fluid restricted. No unintended sources of electrolyte-free water such as tube feedings and IV meds administered in D5W. If it is unavoidable, give 300 ml of 3% saline (150 mEq of Na) for every liter of free water.
How to treat: Avoiding hyponatremia in patients with Intracranial disease… High risk for cerebral edema and resultant tentorial herniation. Fluid restriction will be ineffective in presence of concentrated urine and not suggested as it can compromise cerebral circulation. Most reliable way is to give sodium rich fluids based on this proposed sliding scale.
How to treat: Sliding Scale protocol to avoid Hypo-natremia in Neurosurgical patients with serum Sodium < 140 mEq/L… Serum Sodium Infusion Rate <130 mEq/L Increase by 20 ml/h to maximum of 80 ml/h 130 – 135 mEq/L Increase by 10 ml/h to maximum of 80 ml/h 136 – 140 mEq/L No change in infusion rate >140 mEq/L Hold infusion and resume when in therapeutic range. 3 gm of NaCl orally or NG tube Q6hr RTC and 3% IV NaCl given at an initial rate of 20 ml/hr and adjusting infusion rates Q6hrs based on serum sodium.
How to treat: Urgent intervention… Acute (<24 h) symptomatic hyponatremia, Severe neurological sx (seizures and/or coma) regardless of duration of hyponatremia and patients with coexistent intracranial pathology… Should be treated urgently with hypertonic saline. 100 ml bolus of 3% saline with two additional doses administered every 15 min till the patient improves.
How to avoid over correction in Chronic hyponatremia… • In many patients SIADH and/or concentrated urine resolves after initial management such as fluid repletion in hypovolemia, hormone replacement in adrenal insufficiency or discontinuation of thiazide diuretics etc. • In such circumstances, body starts to lose free water instead of making concentrated urine and Sodium level may start to rise more than anticipated. • Once the urine becomes maximally dilute the resulting water diuresis can increase serum Na level by >2mEq/L/h
How to avoid over correction in Chronic hyponatremia: Desmopressin.. • If urine sodium concentration is increasing too rapidly, urine water losses can be matched with D5W. OR • We can give desmopressin 2 to 4 mcg parenterally to halt water diuresis.
How to avoid over correction in Chronic hyponatremia: D5W or Desmopressin? If serum sodium level has already increased by >10 to 12 mEq/L over 24 hours Or by >8 mEq/L in high risk patients* Bring the sodium level down again. Bring to 8 mEq/L more than previous day. Do this by giving infusions of 3ml/kg D5W over 1 hour or 2 to 4 mcg of Desmopressin parenterally.
Correction of chronic hyponatremia: Desmopressin and 3% saline… • Rather than giving desmopressin to stop water diuresis after it has begun we can start giving desmopressin along with 3% saline to achieve a more controlled rate of correction. • Hypertonic saline is titrated to achieve the desired rate of correction, with an initial bolus if clinically indicated. • Combination therapy is continued until the serum Na concentration has been increased to >128 mEq/L.
Correction of chronic hyponatremia: When to avoid combination treatment? • We avoid desmopressin combination treatment when there is little likelihood of a reversible cause of water retention such as SIADH due to small cell lung cancer or brain tumor. • In hypotensive patients with hyponatremia who require large amounts of isotonic fluid for volume resuscitation we would still give desmopressin but avoid 3% saline, as each liter of NS increases serum Na by 1mEq.
Correction of chronic hyponatremia: Patients who are hypokalemic… • In patients who are hypokalemic, Potassium replacement will increase serum Na level too as it is a function of exchangeable K as well as Na. • In such patients dose of hypertonic saline must be reduced. • A recent report described a case of ODS following overcorrection primarily attributable to replacement of a large K deficit. • In such patients KCl infusion along with desmopressin achieved a controlled rate of correction of both Na and K levels.
Renal replacement therapy… • Hyponatremia is commonly seen in oliguric kidney failure. • Conventional hemodialysis has shown to increase serum Na concentration very rapidly. • Luckily ODS after dialysis is rare and uremia has been shown to be protective. • However large increases in the serum Na concentration during dialysis should be avoided if possible.
Hyponatremia in edematous conditions… Hyponatremia is associated with poor outcomes in heart failure and liver disease. Hypertonic saline is usually not advisable in volume overloaded patients, but it can be given combined with high doses of loop diuretics. Alternatively “aquaretics” can be used to treat hyponatremia in volume overloaded patients.
Samsca (tolvaptan) • Tolvaptan is an oral vasopressin V2 receptor antagonist. • Increases free water clearance and increases serum Sodim concentrations. • Indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia that is symptomatic and has resisted correction with fluid restriction. • Most commonly used in heart failure and SIADH.
Samsca (tolvaptan) Dosing… • Initial dose of 15 mg P.O. qD • Can be increased to 30 mg P.O qD after atleast 24 hours of beginning of the treatment. • Can be increased to a maximum of 60 mg P.O. qD titrating at 24 hours intervals to desired Sodium concentration. • Avoid fluid restriction for first 24 hours. • Can be used for a maximum duration of 30 days.
Samsca (tolvaptan) Contraindications… • As of April 2013, the U.S. Food and Drug Administration (FDA) determined that tolvaptan can not be used in patients with underlying liver disease including cirrhosis. • A double blinded, placebo controlled trial showed an increase in serum ALT and total bilirubin in 3 patients (n=1445) with ADPKD. • Other contraindications include acute hyponatremia with sever symptoms, anuria, patients who have altered mental status who cannot respond to thirst and anuria.
Samsca (tolvaptan) Adverse reactions… • GI: Nausea (21%), Xerostomia (7% to 13%), GI bleeding (10%, in cirrhosis patients), Constipation (7%), anorexia (4%), hepatotoxicity (<4%) • Renal: Polyuria (4% to 11%) • Endocrine and metabolic: hyperglycemia (6%), hypernatremia (<2%) • Musculoskeltal: Weakness (9%) • Misc: Thirst (12% to 16%), Fever (4%)
Thank you References: Stern RH, Hix JK, Silver SM; Management of hyponatremia in the ICU. Chest. 2013 Aug; 144 (2): 672-9 Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what difference? J Am Soc Nephrol. 2008;19(2):194-196. Lin SH, Chau T, Wu CC, Yang SS. Osmotic demyelination syndrome after correction of chronic hyponatremia with normal saline. Am J Med Sci. 2002;323(5):259-262. Laureno R. Central pontine myelinolysis following rapid correction of hyponatremia. Ann Neurol. 1983;13(3):232-242. Arieff AI, Llach F, Massry SG. Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine (Baltimore). 1976;55(2):121-129 Woo CH, Rao VA, Sheridan W, Flint AC. Performance characteristics of a sliding-scale hypertonic saline infusion protocol for the treatment of acute neurologic hyponatremia. Neurocrit Care. 2009;11(2):228-234 Gowrishankar M, Chen CB, Mallie JP, Halperin ML. What is the impact of potassium excretion on the intracellular fluid volume: importance of urine anions. Kidney Int. 1996;50(5):1490-1495. Wendland EM, Kaplan AA. A proposed approach to the dialysis prescription in severely hyponatremic patients with end-stage renal disease. Semin Dial. 2012;25(1):82-85. Cluitmans FH, Meinders AE. Management of severe hyponatremia: rapid or slow correction? Am J Med. 1990;88(2):161-166
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