Metabolic Brain Disease

, Volume 25, Issue 1, pp 91–96

100 cc 3% sodium chloride bolus: a novel treatment for hyponatremic encephalopathy


    • Division of Nephrology, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMCThe University of Pittsburgh School of Medicine
  • Juan Carlos Ayus
    • Renal Consultants of Houston
Original Paper

DOI: 10.1007/s11011-010-9173-2

Cite this article as:
Moritz, M.L. & Ayus, J.C. Metab Brain Dis (2010) 25: 91. doi:10.1007/s11011-010-9173-2


Hyponatremic encephalopathy is a potentially lethal condition with numerous reports of death or permanent neurological injury. The optimal treatment for hyponatremic encephalopathy remains controversial. We have introduced a unified approach to the treatment of hyponatremic encephalopathy which uses 3% NaCl (513 mEq/L) bolus therapy. Any patient with suspected hyponatremic encephalopathy should receive a 2 cc/kg bolus of 3% NaCl with a maximum of 100 cc, which could be repeated 1–2 times if symptoms persist. The approach results in a controlled and immediate rise in serum sodium with little risk of inadvertent overcorrection.


HyponatremiaEncephalopathyFluid therapyMyelinolysisArginine vasopressin


Hyponatremic encephalopathy is a potentially lethal condition with numerous reports of death or permanent neurological injury in children and adults in both the inpatient and outpatient settings. The majority of neurological complications are related to failure to recognize hyponatremic encephalopathy and failure to institute prompt therapy with hypertonic saline (3% NaCl, 513 mEq/l). A significant barrier to the use of 3% NaCl is the fear of developing neurological complications from overcorrection of hyponatremia. (Ayus et al. 1992; Ayus et al. 2000; Moritz and Ayus 2005; Moritz and Ayus 2009) The treatment of hyponatremic encephalopathy is controversial, with no accepted standard for when and how to treat hyponatremic encephalopathy when it develops, and a variety of opinions on how to treat chronic versus acute symptomatic hyponatremia in patients with severe versus mild symptoms. We have introduced a unified approach to the use of 3% NaCl for the treatment of hyponatremic encephalopathy which uses a 100 cc 3% NaCl bolus. (Moritz and Ayus 2009) This approach facilitates early and aggressive therapy, can be used equally well in chronic or acute hyponatremia with either mild or advanced symptoms, and minimizes the risk of inadvertent overcorrection of hyponatremia. We have also set forth strategies to prevent overcorrection of severe hyponatremia, including the judicious use of 1-desamino-8d-arginine vasopressin (dDAVP). (Moritz and Ayus 2009)

Pathogenesis of hyponatremic encephalopathy

The primary symptoms of hyponatremia are those of cerebral edema. Hypoosmolality results in intracellular or cytotoxic cerebral edema caused by the influx of water into the intracellular space down a concentration gradient, resulting in parenchymal brain swelling. Cerebral edema results in increased intracranial pressure which can lead to brain ischemia, herniation and death. The brain’s primary mechanism in adapting to hyponatremia is the intra-cellular extrusion of electrolytes and organic osmolytes. Some of these organic osmolytes are excitatory amino acids, such as glutamate and aspartate, which can produce seizures in the absence of detectable cerebral edema. (Kimelberg 2004)

There are a variety of risk factors that place certain subgroups of patients at particularly high risk for the development of hyponatremic encephalopathy. These high-risk groups include children, menstruant females, post-operative patients, and patients with hypoxemia or underlying central nervous system disease. Children have a relatively larger brain-to-skull-size ratio than adults, which allows less room for brain expansion in the rigid skull. (Arieff et al. 1992; Arieff et al. 1995) The majority of deaths due to hyponatremic encephalopathy in adults have occurred in menstruant females. (Ayus et al.1992) Estrogens appear to impair brain-cell-volume regulation by reducing the sodium/ potassium/ adenosine triphosphate (Na+/K+/ATPase) pump activity, thereby inhibiting sodium extrusion from brain astrocytes. (Ayus et al. 2008) Postoperative patients are at particularly high risk for developing hyponatremic encephalopathy, and this may be explained in part by the high AVP levels associated with surgery. (Ayus et al. 1992) AVP is known to increase brain-water content in the absence of hyponatremia and to impair brain regulatory volume mechanisms. (Doczi et al. 1984; Vajda et al. 2001; Kozniewska et al. 2008) Hypoxia is a major risk factor for poor neurologic outcome when hyponatremic encephalopathy develops, as hypoxia impairs brain-cell-volume regulation and decreases cerebral perfusion. (Vexler et al. 1994; Ayus et al. 2006) Hyponatremia is poorly tolerated in patients with CNS disease. (Moritz and Ayus 2001; Moritz and Ayus 2009) CNS disease can result in increased intracranial pressure from space-occupying brain lesions, hydrocephalus, or cytotoxic or vasogenic cerebral edema. The additional water movement into the brain from even mild hyponatremia can prove lethal.

Hyponatremic encephalopathy can be difficult to recognize as the presenting symptoms are variable and can be nonspecific. The only universal presenting features of hyponatremic encephalopathy are headache, nausea, vomiting, and lethargy. These symptoms can easily be overlooked as they occur in a variety of conditions. There must be a high index of suspicion for diagnosing hyponatremic encephalopathy, as the progression from mild to advanced symptoms can be abrupt and does not follow a consistent progression. A cranial CT scan cannot consistently be used to rule out hyponatremic encephalopathy, as it is not sensitive enough to detect mild cerebral edema which could be detected by diffusion weighted imaging MRI. (Sundgren et al. 2002; Schoonman et al. 2008)

A common yet under-recognized feature of hyponatremic encephalopathy is non-cardiogenic pulmonary edema, also referred to as Ayus-Arieff syndrome. (Kalantar-Zadeh et al. 2006; Campbell and Rosner 2008) Cerebral edema leads to increased intracranial pressure, which can result in pulmonary edema via two mechanisms: (1) centrally mediated increase in pulmonary vascular permeability to proteins, leading to increased alveolar and interstitial fluid (McClellan et al. 1989), and (2) increased sympathetic neuronal activity with catecholamine release, resulting in pulmonary vasoconstriction with increased capillary hydrostatic pressure and capillary wall injury. (Smith and Matthay 1997; Moritz and Ayus 2008) This has primarily been reported in patients with post-operative hyponatremic encephalopathy and exercise-associated hyponatremia. (Ayus and Arieff 1995; Ayus et al. 2000) It is important to recognize this syndrome as it is rapidly reversible with hypertonic saline and is almost universally fatal if left untreated.

Treatment of hyponatremic encephalopathy

The definitive therapy for treating hyponatremic encephalopathy is the administration of hypertonic saline (3% NaCL, 513 mEq/L). The majority of the morbidity associated with hyponatremic encephalopathy has resulted from insufficient therapy rather than overcorrection. (Ayus et al. 1987; Ayus and Arieff 1999; Nzerue et al. 2002; Hoorn et al. 2006; Huda et al. 2006) Fluid restriction alone is inadequate therapy for symptomatic hyponatremia. 0.9% and 1.8% NaCl, and V2 receptor antagonists are also inappropriate for the treatment of hyponatremic encephalopathy. 0.9% and 1.8% NaCl are not sufficiently hypertonic to consistently induce the rapid rise in plasma osmolality necessary for the reduction in cerebral edema central to the management of this condition. Also, the use of V2-receptor antagonists alone is unlikely to cause either an increase in serum sodium sufficiently rapid or consistent for it to be effective in the treatment of symptomatic hyponatremia.

Current data indicate that V2-receptor antagonists do not exert an effect for 1 to 2 h, which would make it an inappropriate agent for symptomatic hyponatremia. (Decaux et al. 2008) The only consistent way of acutely increasing the plasma sodium is to administer 3% NaCl, which has a sodium concentration that exceeds the kidney’s ability to generate free water. 3% NaCl is the most effective therapy for the treatment of hyponatremic encephalopathy. Unfortunately, significant controversy exists about the indications and appropriate use of 3% NaCl for the treatment of this condition.

We have introduced a new approach: We have recommended that any patient with suspected hyponatremic encephalopathy, with either mild or advanced symptoms, children or adult, should receive a 2 cc/kg bolus of 3% NaCl with a maximum of 100 cc (Table 1). (Moritz and Carlos Ayus 2007; Moritz and Ayus 2008; Moritz and Ayus 2009) A single bolus would result in at most a 2 mEq/L acute rise in serum sodium, which would quickly reduce brain edema. The bolus could be repeated 1–2 times if symptoms persist. The advantage of this approach over a continuous infusion of 3% NaCl is that there is a controlled and immediate rise in serum sodium and there is also little or no risk of inadvertent overcorrection, as can occur with a 3% NaCl infusion running too long.
Table 1

Treatment of symptomatic hyponatremia

1. 2 cc/kg bolus of 3% NaCl over 10 min. Maximum 100 cc.

2. Repeat bolus 1–2 times as needed until symptoms improve.

Goal: 5–6 mEql/L increase in serum sodium in first 1–2 h.

3. Recheck serum sodium following second bolus or Q 2 hrs

4. Hyponatremic encephalopathy is unlikely if no clinical improvement following an acute rise in serum sodium of 5–6 mEq/L,

5. Stop further therapy with 3% NaCl boluses when patient is either:

 a. Symptom free: awake, alert, responding to commands, resolution of headache and nausea

 b. Acute rise in sodium of 10 mEq/L in if first 5 hrs

6. Correction in first 48 h should:

 a. Not exceed 15–20 mEq/L

 b. Avoid normo or hypernatremia

No harm could come from using this approach in a patient with suspected hyponatremic encephalopathy, even if the patient proves not to have hyponatremic encephalopathy. It is our opinion that treatment of suspected symptomatic hyponatremic encephalopathy should begin with a 3% NaCl bolus. This should precede radiologic investigations because a) neurologic deterioration could occur if there is a delay in therapy, and b) a CT scan cannot always rule out hyponatremic encephalopathy. This maneuver will stabilize the patient until further diagnostic studies can be done and serve as a bridge to instituting other therapies such as vasopressin 2 receptor antagonists.

At times the diagnosis of hyponatremic encephalopathy can be difficult to establish, such as in patients with either: a) hepatic encephalopathy, b) CNS infections, tumors, or trauma, or c) post-operative nausea and vomiting with associated hyponatremia. Bolus therapy with 3% NaCl can serve as a diagnostic maneuver, as a patient who does not show some clinical improvement after 2–3 boluses of 3% NaCl most likely is not suffering from hyponatremic encephalopathy.

We initially recommended using a 100 cc bolus of 3% NaCl for the treatment of exercise-associated hyponatremic encephalopathy in 2005 (Ayus et al. 2005), and this approach has since been adopted by the Second International Exercise-Associated Hyponatremia Concensus Development Conference. (Hew-Butler et al. 2008) Our approach has now been recommended by other experts for the treatment of adults with hyponatremic encephalopathy. (Palmer and Sterns 2009; Sterns et al. 2009) Recommended safe limits for the correction of hyponatremia vary among experts depending on the setting of hyponatremia, including 6–8 mEq/l in 24 h (Sterns et al. 2009), 10 mEq/l in 24 h (Decaux and Soupart 2003), 15 mEq/24 h (Lauriat and Berl 1997) or 20 mEq/l in 48 h (Moritz and Carlos Ayus 2007), as do recommendations for using hypertonic saline. Our recommendation to use bolus therapy is a unifying approach that would stay well within all recommended limits of correction and can be used safely in any setting. It can be used safely in children and adults, in chronic or acute symptomatic hyponatremia and in the outpatient or inpatient setting. Our approach is simple, as it does not rely on formulas or complicated calculations, and it can be administered safely and quickly in the emergency department or at the bedside, prior to transfer to a monitored setting.

Risk factors for cerebral demyelination

A significant barrier to the use of hypertonic saline has been the perceived risk of developing cerebral demyelination from overcorrection of hyponatremia. Cerebral demyelination is a rare condition that has been reported in patients with chronic hyponatremia (>48 h) who have additional risk factors such as liver disease or alcoholism, severe malnutrition, hypoxia, or correction in serum sodium > 25 mEq/L in the first 24–48 h of therapy. (Ayus et al. 1987) In these high-risk patients, it is not clear that cerebral demyelination is completely preventable, as there have been multiple reports of cerebral demyelination occurring both with careful correction and in cases unassociated with hyponatremia. (Pradhan et al. 1995; Germiniani et al. 2002; Tan and Onbas 2004; Dellabarca et al. 2005; Savasta et al. 2006; Georgy et al. 2007; Nagaishi et al. 2007; Hagiwara et al. 2008; Orakzai 2008; Yoon et al. 2008; Schuster et al. 2009) Patients with acute symptomatic hyponatremia are at minimal risk for developing cerebral demyelination. Recent studies have revealed that poor outcome in hyponatremic patients is associated with inadequate therapy. Studies in chronically hyponatremic animals have revealed that it is the magnitude rather then the rate of correction that produces brain injury, with the threshold for brain injury being an acute elevation in serum sodium of approximately 25 mEq/L within 24 h. (Ayus et al. 1985; Ayus et al. 1989; Verbalis and Martinez 1991; Soupart et al. 1992; Gankam Kengne et al. 2009) Chronically hyponatremic rats can be corrected with hypertonic saline by as much as 20 mEq/L in 1 h without developing brain pathology. (Soupart et al. 1992) There is no data to suggest that an acute elevation in serum sodium of < 20 mEq/L is associated with brain injury.

Preventing overcorrection of hyponatremia

Preventing an extreme rise in serum sodium (> 25 mEq/L in 48 hrs) can be difficult, particularly in the severely hyponatremic patient (SNa ≤ 115 mEq/L). Under most circumstances, hyponatremia develops due to a state of high AVP production. Once the stimulus for AVP production abates, there will be brisk urinary excretion of free water and hyponatremia will correct rapidly. The overall rate of correction of hyponatremia is primarily a determinant of the renal response to fluid therapy, more so than the composition of fluids administered. Even 0.9% NaCl could result in an overcorrection of hyponatremia if a free water diuresis develops. A patient receiving 100 cc/hr of 0.9% NaCl over 48 h would receive 4.8 L of fluid containing 739 mEq of Na. This could result in a 30 mEq/L rise in serum sodium if the sodium was retained and water excreted in the urine. In general, if the serum sodium is greater than 115 mEq/L, then even if there is a brisk free water diuresis, the absolute rise in serum sodium will not be likely to exceed 25 mEq/L, and the risk of brain injury is small.

We recommend that the following measures be taken in order to prevent overcorrection of hyponatremia: 1) Patients with a serum sodium < 115 mEq/l should be monitored to see if a water diuresis follow treatment, as evidenced by an increase in serum sodium of > 1 mEq/l/hr accompanied by a urine flow rate of > 1 ml/kg/hr. In general a urine tonicity (urine sodium plus potassium) less than 80 mEq/L or urine osmolality less than that of the plasma is consistent with a significant free water diuresis during the correction phase of hyponatremia. 2) Hydration with either 3% NaCl or 0.9% NaCl should be limited to the minimal amount necessary to correct the serum sodium to a safe level or correct volume depletion. 3) Sodium-containing intravenous fluid should be restricted once a free water diuresis commences, and oral intake should be encouraged. 4) Parenteral fluids, when needed, should be hypotonic, Na concentration < 80 mEq/l, if there is a free water diuresis. When a patient with severe hyponatremia fails these above measures, the administration of dDAVP could be considered.

dDAVP administration was first suggested to prevent the overcorrection of hyponatremia in 1993 (Ayus and Arieff 1993) and has subsequently been used successfully in adult patients. (Goldszmidt and Iliescu 2000; Perianayagam et al. 2008) DDAVP has also been used successfully to therapeutically relower the serum sodium in adult patients and animals with overcorrection of chronic hyponatremia. (Perianayagam et al. 2008; Gankam Kengne et al. 2009) dDAVP should be used with caution and in consultation with someone familiar with this therapy as it can result in inadvertent hyponatremia. If used, hypotonic fluid administration should be avoided following the administration of dDAVP, and isotonic saline should be administered at a restricted rate when needed. An inadvertent lowering of the serum sodium following dDAVP administration can be corrected with a bolus of 3% NaCl.

Special situations: dDAVP-induced hyponatremia

Hyponatremia caused by dDAVP is particularly difficult to manage. A common and dangerous way to manage dDAVP-induced hyponatremia is by stopping dDAVP and administering 0.9% NaCl. This can result in an overcorrection of hyponatremia, as withdrawal of dDAVP will result in a free-water diuresis, and in combination with 0.9% NaCl or 3% NaCl hypernatremia could develop, especially in the case of central diabetes insipidus, where there will not be endogenous AVP production in response to hyperosmolality. (Ayus and Arieff 2002a) This is particularly likely to occur when the serum sodium is < 115 mEq/l. We have previously reported on cases of brain injury from overcorrection of hyponatremia following dDAVP withdrawal. (Ayus and Arieff 2002b) The safer approach is to continue the dDAVP in order to allow a controlled correction in serum sodium. 3% NaCL boluses can be administered as needed to correct the serum sodium. Fluid restriction should then be instituted with isotonic fluids used in parenteral fluids if needed. Once the serum sodium has been corrected to mildly hyponatremic values, dDAVP could be discontinued.

Preventing hospital-acquired hyponatremic encephalopathy

There have been numerous reports of death or permanent neurological injury from hospital acquired hyponatremic encephalopathy in otherwise healthy children and adults, with the majority occurring in the post-operative setting. (Arieff, Ayus et al. 1992; Ayus et al. 1992; Ayus and Arieff 1996; Moritz and Ayus 2005) The primary reason for this complication is the routine administration of hypotonic fluids in patients at risk for high argenine vasopressin (AVP) production, such as patients with pulmonary and central nervous system disease, volume depletion, or cancer, or following surgery.

There is good reason to believe that post-operative hyponatremic encephalopathy could be virtually eliminated by administering 0.9% NaCl in patients at high risk for AVP excess when parenteral fluids are needed. In 2003 (Moritz and Ayus 2003), we proposed that 0.9% NaCl be administered for the prevention of hospital-acquired hyponatremia in children, and we have since extended these recommendations to include adults. (Moritz and Ayus 2003; Moritz and Carlos Ayus 2007) Numerous studies have confirmed that hypotonic fluid results in hyponatremia. There have been three recent prospective randomized studies in almost 300 post-operative children which have confirmed that 0.9% NaCl effectively prevents the development of post-operative hyponatremia and that hypotonic fluids consistently produce a fall in serum sodium. (Montanana et al. 2008; Neville et al. 2009; Yung and Keeley 2009)

No single intravenous fluid can be used safely in all situations. Fluid overload could develop if excessive amounts of 0.9% NaCl were administered in the presence of a fluid overload state such as significant renal impairment or congestive heart failure. Similarly, 0.9% NaCl could result in hypernatremia if administered to a patient with renal or extrarenal free water losses as are seen with nephrogenic diabetes insipidus or high nasogastric output. We have thus recommended that hypotonic fluids be restricted in their use to patients with either hypernatremia (Na >145 mEq/l) or ongoing urinary or extrarenal free water losses and that patients at risk for fluid overload have their volume of fluid restricted.

In summary, use of a 100 cc 3% NaCl bolus provides a safe, effective and simple method of treating hyponatremic encephalopathy when it develops. Its use results in an acute and controlled rise in serum sodium without the need for complex formulas and minimizes the risk for overcorrection. Precautions should be taken in patients with a serum sodium < 115 to prevent overcorrection (> 25 mEq/L in 48 hrs) of hyponatremia. The most important measure which can be taken to prevent hospital-acquired hyponatremia is the avoidance of hypotonic fluids and the administration of 0.9% NaCl to patients at high-risk for AVP excess when parental fluids are indicated.

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