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Urine Body

Figure 7. Desalination type of hyponatremia. The rectangles represent 1 L volumes. The [Na+] in each L is shown in the rectangle. The left rectangle represents 2 L if IV infusions. The first rectangle to the right of the arrow represents the hypertonic urine, and the second rectangle to the right of the arrow represents the 1 L of EFW generated and retained in the body due to AVP actions. Reproduced with permission [55].

Urine Body

Figure 7. Desalination type of hyponatremia. The rectangles represent 1 L volumes. The [Na+] in each L is shown in the rectangle. The left rectangle represents 2 L if IV infusions. The first rectangle to the right of the arrow represents the hypertonic urine, and the second rectangle to the right of the arrow represents the 1 L of EFW generated and retained in the body due to AVP actions. Reproduced with permission [55].

glucose in water (D5W), or hypotonic saline as intravenous fluids (virtually always occur-ing in the perioperative period); (2) the intake of ice-chips or sips of water (also perioperative period); (3) the generation of EFW from the kidney excreting urine that is hypertonic to the infusate (or to body fluid in the absence of intravenous infusions [30]) (Figure 7).

Prevention: The best way to avoid acute postoperative hyponatremia is to avoid giving solutions that are hypotonic to the urine if polyuria is present, or hypotonic to body fluids in the oliguric patient. In addition, isotonic fluids should only be given to maintain systemic hemodynamics during surgery and to replace losses if they occur. One should be very suspicious of a "good" urine output because this might be hypertonic to the infused solutions and generate EFW (Figure 7). The plasma [Na+] should be monitored in settings associated with AVP release (Table 4), particularly in patients who excrete more than 1 - 2 L of urine/day. Finally, caution should be used with the volume of fluid given to a small patient, as a large volume of fluid in a small patient translates into more EFW generation if the urine is hypertonic to the fluids administered. This is especially important in men-struous females, in whom acute hyponatremia may be more dangerous [31].

Emergency therapy: The immediate goal of therapy is to shrink the expanded ICF volume of the brain sufficiently to curtail the serious CNS symptoms. If hyponatremia is severe (< 120 mM) or symptoms are present, one should administer hypertonic saline until the plasma [Na+] is close to 130 mM. When calculating the amount of Na+ required, one must assume that its volume of distribution behaves as if the Na+ will be dissolved in TBW, since the cell membrane is permeable to water, but not to Na+ [32]. To clarify these points, consider the following illustrative case.

- Case example: Hyponatremia (plasma [Na+] 120 mM) developed in a 50-kg person 24 hours after surgery; a seizure has just occurred. Therefore, the initial aim of therapy is to shrink the size of brain cells over 1 - 2 hours to the pre-sei-zure level. A reasonable target is to raise the plasma [Na+] by 5 mM over the next 1-2 hours. In order to achieve this, 125 mmoles of Na+ should be administered, given a TBW of 25 L (50% of body weight). Since 1 L of 3% saline contains close to 450 mmoles Na+, 0.3 L of this solution should be administered. After the seizure is controlled, the rate of infusion may be slowed, with the goal of raising the [Na+] to 130 mM. Careful observation is required to avoid the development of pulmonary edema.

Maintenance Therapy: Once the plasma [Na+] has been raised to 130 mM, one should ensure that it does not fall any further. The tonicity balance approach (Figure 8) uses 2 general strategies to prevent a further fall in sodium in a patient who is excreting a large volume of hypertonic urine.

- Input: If the input is equal to the output with respect to Na+, K+, and water, there will be no change in the plasma [Na+]. Since hypertonic saline is being excreted,

Figure 8. Tonicity balance. The rectangle represents all body compartments. To calculate a tonicity balance, one must have separate balances for water and Na+ + K+. The data can predict how the [Na+] in plasma should change; this should be compared to measured values. Reproduced with permission [55].

Figure 8. Tonicity balance. The rectangle represents all body compartments. To calculate a tonicity balance, one must have separate balances for water and Na+ + K+. The data can predict how the [Na+] in plasma should change; this should be compared to measured values. Reproduced with permission [55].

the same volume and the same composition of hypertonic saline must be administered.

- Output: Here the aim is to lower the concentration of Na+ and K+ ([Na+ + K+]) in the urine so that isotonic fluids can be administered. If the [Na+ + K+] in the urine is very high [30], one can render it isotonic with the administration of a loop diuretic (e.g. furosemide) [33, 34] or an osmotic diuretic (e.g. urea) [35]. Isotonic intravenous fluids should be given at the same rate as that of the urine output. Once the reason for the release of AVP is no longer present, this therapy will not be required. The patient will begin to excrete dilute urine and hence the plasma [Na+] will rise [30].

Specific Examples

Acute hyponatremia in females: Most commonly, this follows otherwise uneventful gynecological surgery which leads to the sustained release of AVP for a number of reasons, such as pain, anxiety or drugs [31]. The ill-ad vised infusion of D5W, the most common source of EFW in this setting, exacerbates the problem. Even isotonic saline can present the body with a large infusion of EFW [30] (Figure 7). The severity of hyponatremia may be worsened if the volume of fluid given is not scaled down to body size. This form of acute hyponatremia leads to brain cell swelling and rarely, death due to high ICP in some patients. A quantitative example is provided in Table 4.

Acute hyponatremia in males: The list of causes of acute hyponatremia in males reflects the type of surgical procedure they are likely to undergo. The most common surgery for males is TURP [36]. The main reason for hyponatremia in this setting is that large volumes of half-isotonic solutions of organic compounds are used to lavage the prostatic bed, some of which may be absorbed. The development of hyponatremia becomes clear when the absorbed fluid is divided into its two constituent parts (Table 4).

- Gain ofosmol-free (and electrolyte-free) water: This simple EFW gain causes cells to swell, but it is not the major cause for the hyponatremia (fall of 7 mM in the plasma [Na+] in the example provided in Table 4).

- Gain of isosmolar fluid: Solutes such as mannitol, glycerol, or glycine distribute in the ICF compartment at a slow rate [37]. When they remain in the ECF, they cause hyponatremia because these solutions are Na+-free. This transient form of hyponatremia is not associated with a change in brain cell volume, and so does not pose a threat of brain herniation [38]. A low plasma osmolality in the setting of acute hyponatremia following a TURP poses a threat of brain cell swelling. If that osmolality is close to normal, one should not be alarmed with the severity of the hyponatremia and the rapidity of its correction (Table 5). The symptoms

Table 5. Causes of High AVP Levels in Patients with Hyponatremia

1. AVP release in response to physiologic stimuli:

- Low "effective" circulating volume

- ECF volume depletion

- Blood loss

- Hypoalbuminemia

- Low cardiac output.

- Excessive pain, nausea, vomiting. or anxiety.

2. AVP release without a physiologic stimulus:

- CNS or lung lesions.

- Neoplasms and granulomas such as tuberculosis.

- Metabolic lesions such as acute intermittent porphyria.

- Administration of agents that simulate AVP

- DDAVP (e.g. treatment for diabetes insipidus or urinary incontinence)

- Oxytocin for labor induction.

- Drugs that augment or stimulate AVP release:

- Examples include nicotine, morphine, clofi-brate, tricyclic antidepressants, antineoplastic agents, (probably via nausea and emesis), anticonvulsants such as tegretol.

- Drugs that promote the actions of AVP on the kidney by increasing cyclic AMP levels or augmenting its bioactivity:

- Examples include oral hypoglycemics (e.g. chlorpropamide), methylxanthines (e.g. caffeine, aminophylline), analgesics that inhibit prostaglandin synthesis (e.g. aspirin, non-steroidal anti-inflammatory drugs).

associated with hyponatremia when glycine is used as the lavage fluid during a TURP may be the consequence of hy-perammonemia rather than swelling of cells of the brain [36].

Hyponatremia with primary polydipsia: Normally one cannot become hyponatremic simply from drinking EFW, because AVP will be absent and in this setting, normal kidneys can excrete close to 1 L of EFW/hour, more than almost anyone can drink and absorb [39

- 41]. Nevertheless, if there is a reason for AVP release, such as an appreciably low ECF volume, anxiety, pain, psychosis, or the intake of certain drugs (Table 4), the intake of EFW will result in hyponatremia [30].

Hyponatremia in an infant: Apart from unique disorders such as inborn errors, hy-ponatremia in this setting is most commonly due to a loss of Na+ (e.g. diarrhea). This form of hyponatremia may be acute. AVP is released in response to the contracted ECF volume, and this leads to the retention of EFW that is ingested by the infant. If a hyponatremic infant is fed sugar water to rest the GI tract and avoid dehydration, this EFW will be retained. Thus, hyponatremia has 2 components: loss of Na+ and gain of EFW. Its degree may be very severe. The 2 considerations for therapy include rapid re-expansion of the contracted ECF volume by infusing "isotonic to the patient" saline and avoidance of any further addition of EFW (this includes the generation of EFW by the kidneys if the rate of excretion of Na+ were to rise while AVP is still acting, Figure 7).

Summary

- Do not give EFW to a subject with a plasma [Na+] <138 mM. Give a smaller volume if the patient is likely to have AVP released for nonosmotic reasons.

- Do not give more isotonic saline during surgery and in the acute postoperative time than is needed to maintain normal hemodynamics.

- Be careful if the urine output is larger than expected.

- Use a tonicity balance calculation to help understand the basis of hyponatremia and to plan therapy. Emphasis can be placed on changing the input or the output.

Figure 9. Steps to take in the patient with chronic hyponatremia. The focus in chronic hyponatremia is to determine why AVP is present. If the reason for the release of AVP is reversible, patients might be at risk of having a water diuresis if the release of AVP is suppressed -e.g. when their ECF volume is re-expanded. Reproduced with permission [55].

Figure 9. Steps to take in the patient with chronic hyponatremia. The focus in chronic hyponatremia is to determine why AVP is present. If the reason for the release of AVP is reversible, patients might be at risk of having a water diuresis if the release of AVP is suppressed -e.g. when their ECF volume is re-expanded. Reproduced with permission [55].

Clinical Approach to a Patient with Chronic Hyponatremia

Chronic hyponatremia is the most common electrolyte abnormality in hospitalized patients [42], but it rarely leads to significant symptoms (Figure 9). The patient with chronic hyponatremia is often identified by the determination of routine electrolytes, in which case the duration of the disorder is unknown. The fundamental issue here is that adaptive responses have had time to occur, the most important of which are in the brain. Brain cells have returned their volume virtually to normal (for review see [9]). The initial mechanism is the export of ions (K+), providing that electroneutrality was not the result of the entry of Na+ into their ICF (it is not clear which anion might be exported with K+, but the defense of the ICF volume of cells of the brain would be most efficient if Cl- were also exported from these cells). Over the next few days, organic molecules such as myoinositol, amino acids, and taurine are exported. Brain cells must reaccumulate solutes that were lost to achieve a normal ICF volume and composition; this provides the rationale for deciding the rate of correction of hyponatremia. The critical issue is that these cells, which have undergone volume regulation, are at risk of an acute decline in their volume if the plasma

[Na+] is raised before these solutes are taken up. This is even more important if these cells do not have available organic osmolytes to re-establish their normal ICF osmole composition. For example, a patient with poor nutrition or a large deficit of K+ may take longer to regain these intracellular organic osmolytes [43]. Correction of hyponatremia exceeding 6 - 8 mM/24 hours, can lead to the devastating neurologic syndrome, ODS [44].

Diagnostic Issues

To develop hyponatremia, a source of EFW (usually ingestion of water) coupled with a limitation to its excretion (release of AVP) must be present. Virtually everyone drinks EFW, so one need not dwell on this for diagnostic purposes unless the intake is very large. The diagnostic issue focuses on why the rate of excretion of EFW is so low. The challenge to the physician is to identify why AVP was released despite a low plasma "effective" osmolality (Table 5, Figure 9). The objective at the bedside is to determine whether AVP levels will decline rapidly, leading to an overly rapid rate of hyponatremia correction, thus predisposing the patient to ODS.

Several examples where the level of AVP might decline abruptly include chronic nau sea, vomiting, anxiety, and/or stress, or when desmopressin (DDAVP) is given to patients in a nursing home to minimize bed wetting. In addition, the apparent on-again, off-again release of AVP may be the result of a decreased "effective" circulating volume. When the "effective" circulating volume is low enough, AVP will be released, even if hyponatremia is present. This helps to defend the ECF volume at the price of an expanded ICF volume. Since thirst is also stimulated by a low "effective" circulating volume, both a source of EFW and the release of AVP to prevent its excretion are present. The problem is that a clinician may have great difficulty in deciding whether the "effective" circulating volume is contracted unless the changes are marked. One can use clues from the history. First, there may be excessive renal loss of Na+. Its most common cause is the ingestion of a diuretic. Less often, renal salt wasting and/or an osmotic diuretic (e.g. glucose or urea) may cause excessive excretion of Na+. In patients with renal salt wasting, examining the rate of excretion of K+ may help determine the nephron site with defective handling of Na+. A low rate of excretion of K+ in the face of renal Na+ loss and ECF volume contraction should suggest that there is a lesion in the CCD, for example a low aldosterone bioactivity. In contrast, a high rate of excretion of K+ with renal Na+ wasting suggests that an abnormal loss of Na+ occurred in the PCT (usually with metabolic acidosis), the loop of Henle (as in patients with Bartter's syndrome), or the early DCT (as in patients with Gitelman's syndrome). Although one would expect a low rate of excretion of Na+ and Cl- when the ECF volume is low, there are notable exceptions to this rule. Na+ may be excreted if there is a high rate of excretion of another anion such as HCO3-in the patient who has vomited recently. In this case, the excretion of Cl- should be low. In contrast, if the loss of NaCl was due to diar-

Table 6. Urine Electrolytes in the Differential Di

agnosis of Hyponatremia. (These urine electrolyte

levels do not apply to polyuric states.)

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