Hypernatremia is a condition with a serum sodium concentration above the normal range of meq/l.

Definition

Serum sodium concentration and osmolality are closely regulated by water homeostasis. This is mediated by thirst, arginine vasopressin, and the kidneys. A disruption in water homeostasis is manifested by an abnormal serum sodium concentration—either hyponatremia or hypernatremia. The former is defined as a serum sodium concentration less than 135 mEq/L, with severe hyponatremia occurring at values less than 120 mEq/L. The patient described in the case synopsis had hypo-osmotic hyponatremia and was euvolemic with normal thyroid and adrenal function. Causes of true hyponatremia are listed in Table 103-1; causes of pseudohyponatremia are listed in Table 103-2. The case presented is due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) related to small cell lung carcinoma (Table 103-3).

Treatment of Hyponatremia.

If serum sodium concentration is less than 120 mEq/L, correction of hyponatremia is recommended with 3% saline solution (513 mEq of sodium per liter) up to 120 mEq/L of serum sodium concentration over 4 to 6 hours depending on the severity of hyponatremia (Avner, 1995). Although rapid intravenous bolus administration of 4 to 6 mL/kg of 3% saline solution has been effective in children with seizures or coma (Sarnaik et al, 1991), one must keep in mind that rapid and complete correction of low serum sodium concentration in adults with chronic hyponatremia has been shown to be associated with pontine and extrapontine myelinolysis. Therefore, once the risk of central nervous system symptoms has been minimized and serum sodium concentration has reached 120 mEq/L, complete correction of hyponatremia should be performed more slowly, over 24 to 48 hours. In patients with asymptomatic hyponatremia whose serum sodium concentration exceeds 120 mEq/L, hypertonic infusions are not indicated. The use of 5% dextrose in water with 0.45% to 0.9% saline is reasonable. Figure 30-5 summarizes the clinical evaluation and therapy of neonates with hyponatremia.

19. How should correction be monitored?

The serum sodium should be monitored every 2 to 4 hours during hypertonic saline infusion. Urine volume should also be closely watched during this period. Patients with hypovolemic or thiazide-induced hyponatremia may experience a spontaneous water diuresis once volume depletion has been corrected, sometimes after only a modest amount of normal saline given for volume repletion. The occurrence of such a water diuresis will put the patient at risk for ODS. In some patients, spontaneous correction is so rapid that the major therapeutic consideration is how to limit the rise in serum sodium concentration. Although initiation of hypertonic saline infusion in patients with severe symptoms should not be delayed until intensive care unit (ICU) transfer, monitoring urine output on an hourly basis and serum sodium concentration every 2 hours is most readily accomplished in the ICU.

Serum Electrolytes, Albumin, and Volume Homeostasis

Plasma sodium and bicarbonate are slightly reduced, potassium is at the lower end of the normal range, and albumin and urate are lower than in the nonpregnant state. Increases in plasma sodium to levels of nonpregnant women should raise the possibility of (reversible) pregnancy-specific diabetes insipidus (due to excess placental vasopressinase). In general, this is a mild disorder, but DDAVP should be given if plasma sodium rises above 150 mmol/l.

Adequate intravascular volume is essential to preservation of GFR and good pregnancy outcome for mother and baby. Clinically, it is difficult to assess maternal volume homeostasis. Edema is an unhelpful sign in pregnancy, so hematocrit should be measured in women with underlying CKD at the initial first-trimester visit, along with serum albumin. Both measures should fall slightly as pregnancy progresses. A rise in either value strongly suggests intravascular volume contraction, although there is no absolute discriminant value. Conversely, a significant fall in either value does not by itself diagnose excessive volume expansion because the hematocrit depends on other factors, and serum albumin may fall in patients with nephrotic syndrome, who in turn may have reduced intravascular volume.

In practice, volume excess, provided there is no respiratory compromise and BP can be controlled, is more favorable than volume depletion for maternal renal function and fetal growth.

When there is concern about fetal growth or deteriorating GFR in women with CKD and reduced intravascular volume is suggested by the change in hematocrit and albumin from baseline, a trial of intravenous normal saline (no more than 1 liter) under observation in the hospital is a reasonable clinical approach.

Maintaining eunatremia

Serum sodium concentration and osmotic gradient play a critical role in maintaining ICP and nervous system physiology. Neurosurgical patients are prone to fluctuations in serum sodium and will need to be monitored closely for these derangements because severe shifts in either direction can result in seizures, altered mental status, or coma. Hyponatremia in the setting of posterior fossa edema can precipitate a rapid downward cycle of localized swelling, obstructive hydrocephalus, and declining neurological examination.

The most common cause for hyponatremia in this population of patients is the syndrome of inappropriate release of antidiuretic hormone (SIADH), which results in retention of free water by renal collecting ducts. This represents a euvolemic state that can be noted by high urine osmolarity relative to serum osmolarity. The treatment of SIADH is fluid restriction and, in refractory cases, sodium supplementation through oral tablets or peripheral hypertonic saline infusions. Importantly, the correction of sodium should not be more rapid than 0.5 mEq/hour due to concern for central pontine myelinolysis. Cerebral salt wasting (CSW) also manifests as hyponatremia that can be difficult to distinguish from SIADH. CSW is a hypovolemic state that responds to fluid resuscitation. Hypernatremia can be a result of central diabetes insipidus from diminished antidiuretic hormone (ADH) release. This can be a consequence of manipulations of the hypothalamus or pituitary gland. The clinical syndrome is marked by high output of dilute urine, which requires repletion with isotonic normal saline. Desmopressin, a synthetic vasopressin analog, can be administered intranasally, orally, intravenously, or subcutaneously to augment this impaired endogenous secretion of ADH.

Cerebral salt wasting (CSW)

CSW is a rare endocrine condition characterized by hyponatremia and dehydration in response to CNS disease. CSW may occur after neurosurgery, head injury and particularly in patients with subarachnoid hemorrhage. CSW is characterized by hyponatremia and ECF depletion due to inappropriate sodium wasting in the urine. CSW may occur after the first days or week from the cerebral injury event, and it takes usually 2–4 weeks, but may continue for months. The central nervous system damage can directly cause CSW by oversecretion of atrial natriuretic hormone (ANH), resulting in natriuresis and polyuria, leading to hyponatremia and reduced effective volume mass. Alternatively, CSW can be a secondary response to SIADH by stimulation of ANH secretion via AVP or plasma volume expansion. The abnormal sympathetic outflow to the kidney with a pressure natriuresis as well as abnormal secretion of AVP or brain natriuretic peptide (BNP) have been proposed as potential causes (Edate and Albanese, 2015; Yee et al., 2010; Bettinelli et al., 2012).

Plasma Sodium, Plasma, and Urine Osmolality

Measurements of plasma sodium, plasma, and urinary osmolality should be immediately available at various intervals during dehydration procedures. Plasma sodium is easily measured by flame photometry or with a sodium-specific electrode [243]. Plasma and urinary osmolalities are also reliably measured by freezing point depression instruments with a coefficient of variation at 290 mmol/kg of less than 1%.

At variance with published data [79,116], we have found that plasma and serum osmolalities are equivalent (i.e., similar values are obtained). Blood taken in heparinized tubes is easier to handle because the plasma can be more readily removed after centrifugation. The tube used (green-stoppered tube) contains a minuscule concentration of lithium and sodium, which does not interfere with plasma sodium or osmolality measurements. Frozen plasma or urinary samples can be kept for further analysis of their osmolalities because the results obtained are similar to those obtained immediately after blood sampling, except in patients with severe renal failure. In the latter patients, plasma osmolality measurements are increased after freezing and thawing but the plasma sodium values remain unchanged.

Plasma osmolality measurements can be used to demonstrate the absence of unusual osmotically active substances (e.g., glucose and urea in high concentrations, mannitol, ethanol). With this information, plasma or serum sodium measurements are sufficient to assess the degree of dehydration and its relationship to plasma AVP. Nomograms describing the normal plasma sodium/plasma AVP relationship (Fig. 8.10) are equally as valuable as classic nomograms describing the relationship between plasma osmolality and effective osmolality (i.e., plasma osmolality minus the contribution of “ineffective” solutes: glucose and urea).

Osmoregulation in Normal Pregnancy

Plasma sodium levels decrease 4–5 mEq/L in normal gestation.145 This decrement is often mistaken as a sign of changing sodium balance but in reality PNa is but a surrogate for plasma osmolality (Posmol), the latter decreasing ~10 mosm/kg during pregnancy.67 The decrease commences during the luteal phase,48 falling to a new steady state (~10 mosm/kg) very early in pregnancy and remaining at this new lower level until term.11,64,65,67 Analysis of data from both human and rodent pregnancy leads to the following explanation of how this occurs.146,147 The osmotic thresholds for thirst and arginine vasopressin (AVP) release decrease in parallel (Fig 16.5). Lowering the thirst threshold stimulates increased water intake and dilution of body fluids. Because inhibition of AVP release also occurs at a lower level of body tonicity, the hormone continues to circulate and the ingested water is retained. Posmol then declines until it is below the new osmotic thirst threshold and a new steady state is established with only modest retention of water.

Figure 16.5 further reveals that the rate of rise in PAVP as Posmol increases decreases as pregnancy progresses. There are two possible interpertations for this finding. The first is that the sensitivity of the system may be decreasing (i.e., less secretion per unit rise in Posmol), and the second that the disposal rate (the metabolic clearance, MCR) of AVP is increasing. It is the latter that appears to be the case, AVP’s MCR rising four-fold between early and midgestation.148 This rise in MCR also parallels the increase in trophoblast mass accompanied by a concomitant rise in circulating levels of cystine aminopeptidase (vasopressinase), the latter phenomenon being the most likely explanation of the striking increase in the MCR of AVP as gestation progresses. This hypothesis is strongly supported by the observation that the disposal rate of infused 1-desamino-8-d-arginine vasopressin (DDAVP: desmopressin), an AVP analog resistant to inactivation by vasopressinase, is virtually unaltered in pregnancy.149

Mechanisms responsible for altered osmogegulation are obscure though hCG,65,67,150 constuitive NOS,129 and relaxin69,70 have all been implicated. Relaxin, though, being a hormone secreted by the corpus luteum, is the prime candidate as it explains the effects of hCG decreasing Posmol and osmotic thresholds in premenopausal women, but not men,65,149 the osmoregulatory changes during the menstrual cycle,48 and the alterations in osmoregulation during rodent gestation described earlier in this chapter. Also the decrease in Posmol is blunted in women with primary ovarian failure who successfully carry donated ova,85 and sheep, which lack relaxin due to a stop codon in the coding sequence, do not show reductions in Posm during pregnancy.151,152

It has also been argued that the osmoregulatory changes reflect changes in how gravidas sense their altered volume, and that hypoosmolality relates to nonosmotic stimuli, the pregnant woman sensing her effective volume as “underfilled.” This relative hypovolemia is then said to be the reason for AVP secretion at lower Posmol. Volume regulation is detailed further in Chapter 15 but of interest here is a report that there are borderline or undetectable elevations in vasopressin levels in gravid rats that lead to upregulation of aquaporin-2 mRNA and its water channel protein in the apical membranes of collecting ducts.153 These observations, though, appear inconsistent with patterns of renal water handling of both pregnant rodents and humans, who handle water loads similar to the they way they do in the nonpregnant state (unlike patients with cirrhosis and heart failure, who are prototypes for decreased “effective circulating volume” and where nonosmotic AVP secretion leads to decreased abilities to excrete water loads rapidly). That is, there should be a decreased response to water loading tests in human and rodent pregnancies if the density of the water channels was increased and this does not appear to be the case.

3 Does hyponatremia simply mean there is too little sodium in the body?

No. The serum sodium concentration is not a reflection of the total body sodium content; instead, it is more representative of changes in the total body water. With hyponatremia, defined as serum sodium level less than 135 mEq/L, there is too much total body water relative to the amount of total body sodium, thereby lowering its concentration. Despite this key observation, the serum sodium concentration is not a reflection of volume status, and it is possible for hyponatremia to develop in states of volume depletion, euvolemia, and volume excess. Assessing a patient's volume status is therefore the key step in identifying the underlying cause of hyponatremia (Fig. 45-1). Helpful physical findings include tachycardia, dry mucous membranes, orthostatic hypotension, increased skin turgor (associated with hypovolemia) or edema, an S3 gallop, jugular venous distention, and ascites (present in hypervolemic states).

Diagnosis