Post Head Injury Endocrine Complications

Autopsy studies in fatal traumatic brain injury (TBI) cases demonstrate a fairly high prevalence of hypothalamic and pituitary abnormalities, including anterior lobe necrosis, posterior lobe hemorrhage, and traumatic lesions of the hypothalamic-pituitary stalk.[4] Some variability is noted in studies. Anterior pituitary infarction has been seen to occur in 9-38% of patients; posterior pituitary hemorrhage, in 12-45% of cases; and traumatic lesions of the stalk, in 5-30% of patients.

The traumatic rupture of the pituitary stalk results in anterior lobe infarction because of disruption of the portal blood supply between the hypothalamus and anterior pituitary. Ninety percent of the anterior lobe is nourished by the hypophyseal portal veins, which originate from and follow the pituitary stalk. An alternative explanation is that posttraumatic edema of the pituitary gland within the bony sella turcica compromises the portal blood supply, resulting in anterior lobe ischemia/necrosis. Both mechanisms may contribute to anterior lobe dysfunction following TBI.

Anterior hypothalamic trauma often is observed on postmortem studies and may be associated with pituitary hemorrhage or infarction related to TBI. Anterior pituitary hormones (eg, growth hormone [GH],[5] thyrotropin, corticotropin, gonadotropins) are released by the neuropeptide-releasing hormones from the hypothalamus. The posterior pituitary hormones (eg, vasopressin, oxytocin) are produced by the hypothalamus and are carried by long axonal projections into the posterior pituitary; they are released later. The posterior lobe vascular supply is not affected by pituitary stalk trauma, because it is supplied by the inferior hypophyseal arteries, which arise from the internal carotid artery below the level of the diaphragma sella. Infarction of the posterior lobe is therefore rare, and the mechanism of the development of diabetes insipidus (DI) is by denervation-losing neural integrity with the hypothalamus.[6, 7, 8, 9, 10, 11]

The most common endocrine complication after a TBI is syndrome of inappropriate antidiuretic hormone (SIADH). SIADH causes a dilutional hyponatremia secondary to inappropriate renal water conservation. Relatively less common post-TBI endocrinopathies include anterior hypopituitarism (AH), DI, cerebral salt wasting (CSW), and primary adrenal insufficiency (PAI).[12, 13, 14, 15, 16, 17, 18, 19] The most common endocrinopathies associated with hypopituitarism, in descending order, include hypogonadism, hypothyroidism, adrenal insufficiency, hyperprolactinemia, DI, and GH deficiency.[20] CSW and PAI are peripheral causes of hyponatremia after a TBI. SIADH, AH, and DI have central endocrine etiologies.

A study by Izzy et al indicated that endocrine complications can be associated with traumatic brain injuries (TBIs) of any severity. Patients with mild TBI and those with moderate to severe TBI both showed an increased risk for diabetes, with the hazard ratio (HR) for each group being 1.9. Diabetes risk was particularly high in persons aged 18-40 years, the HR being 4.6 in persons with mild TBI. Moreover, the risk for mortality was increased in patients with post-TBI adrenal insufficiency, the HR for those with moderate to severe TBI being 6.2.[21]

A study by Giuliano et al found that at 1-year follow-up, eight out of 23 patients (34.8%) with complicated mild TBI demonstrated GH deficiency, while in a second group, followed up at 5 years or longer postinjury, 12 out of 25 patients (48.0%) with complicated mild TBI showed GH deficiency. The study also found that the patients with GH deficiency, particularly those in the group followed up at 1 year, more frequently demonstrated visceral adiposity and an adverse metabolic profile than did patients who were not GH deficient. The investigators suggested that patients who have suffered complicated mild TBI be assessed for GH deficiency even several years postinjury.[22]

Frequency

United States

In the United States, the annual incidence of traumatic brain injury (TBI) is 1.5-2 million people.[23] Of that population, 70,000-90,000 persons sustain a chronic, significant disabling condition. A retrospective study demonstrated that 4% of patients with TBI sustained an associated neuroendocrine disorder of the hypothalamic-pituitary axis. This condition is underdiagnosed,[24, 25] as demonstrated by evidence that 40-63% of fatal cases of TBI reveal postmortem pathologic findings of the hypothalamus/anterior pituitary.

Mortality/Morbidity

According to data from the Centers for Disease Control and Prevention, state surveillance projects report the annual incidence of traumatic brain injury (TBI) to be 200 individuals per 100,000 people, with an estimated 52,000 fatalities each year. Estimates of prevalence suggest that a total of 2.5-6.5 million persons are living with the sequelae of TBI. These estimates may be inaccurate, because these data are limited to hospitalized patients with TBI and to prehospital fatalities from TBI.

Race

No known statistical racial predisposition exists in relation to traumatic brain injury (TBI). Approximately 20% of TBI cases are related to violence, especially firearm violence. In general, young African-American males are exposed to violent acts more frequently than other populations are, which may be reflected in a somewhat higher-than-average incidence of TBI in this group.

Sex

The male-to-female ratio for the incidence of traumatic brain injury (TBI) is greater than 2:1. The incidence of neuroendocrine complications following TBI is directly proportional to this ratio.

Age

The populations at greatest risk for traumatic brain injury are young people aged 15-24 years and individuals older than 75 years. Children aged 5 years or younger also are at risk.[5]

A study by Ortiz et al, using data drawn from the Arizona Health Care Cost Containment System (AHCCCS), indicated that children who sustain a TBI have approximately three times the risk of being subsequently diagnosed with a central endocrinopathy than do members of the general population.[26]

A study by Dassa et al indicated that permanent pituitary dysfunction can result from severe childhood TBI, with GH deficiency and central precocious puberty capable of appearing a number of years post-TBI.[27]

Approximately 30-50% of patients who survive post–traumatic brain injury (post-TBI) demonstrate endocrine complications. Most post-TBI endocrinopathies do not have typical specific history patterns.

Diabetes insipidus

Diabetes insipidus (DI) is an exception, as it does have a specific history. DI most commonly is associated with severe TBI and basilar skull fractures with cranial nerve involvement, craniofacial trauma, and postcardiopulmonary arrest. Delayed onset of DI is associated with a poor prognosis due to hypothalamic involvement causing permanent DI.

Acute DI following a mild to moderate TBI indicates a posterior pituitary lesion with only a temporary antidiuretic hormone (ADH) deficiency.

Hypopituiarism

Anterior hypopituitarism (AH) also has a specific history. AH usually is associated with moderate to severe TBI. With improvement of emergency and neurosurgical care for these patients, there are more survivors demonstrating AH. AH may present weeks to months after the TBI, typically in the acute or chronic rehabilitation phase. Any patient with unexplained malaise or a setback with regard to functional status should be examined and tested for AH or the other post-TBI endocrinopathies. In summary, risk factors for AH include relatively serious TBI (Glasgow Coma Scale score < 10), diffuse brain swelling, and hypotensive or hypoxic episode.

A literature review by the American Association of Clinical Endocrinologists and the American College of Endocrinology found that although TBI-induced hypopituitarism seems to occur most frequently in relation to severe TBI, hypopituitarism is also a risk for patients with mild TBI and for those who have suffered repeated TBIs or whose brain injury is sports or blast related.[28]

A study by Silva et al indicated that persons who sustain TBI in motor vehicle accidents, as well as those with posttraumatic seizures, focal cortical contusions, petechial brain hemorrhages, and/or intracranial hemorrhage, are more likely to suffer serious pituitary dysfunction, such as adrenal insufficiency and DI.[29]

Syndrome of inappropriate antidiuretic hormone

Syndrome of inappropriate antidiuretic hormone is the most common TBI-associated neuroendocrinopathy causing hyponatremia. The incidence is reportedly as high as 33%.[30]

Cerebral salt wasting

Cerebral salt wasting (CSW) is a less common cause of hyponatremia in the post-TBI population. These patients are dehydrated and lose weight.

Primary adrenal insufficiency

Primary adrenal insufficiency (PAI) is rare and presents with the superimposed psychiatric symptoms of depression, confusion, and apathy. PAI is associated with fatigue, weakness, anorexia, and weight loss. These problems may present insidiously over a prolonged period. The acute presentation of PAI includes nausea, vomiting, and hypertension.

Related Medscape Reference topics:

Adrenal Insufficiency

Adrenal Insufficiency and Adrenal Crisis

Cerebral Salt-Wasting Syndrome

Diabetes Insipidus [Endocrinology]

Diabetes Insipidus [Pediatrics: General Medicine]

Hypopituitarism [Emergency Medicine]

Hypopituitarism [Pediatrics: General Medicine]

Hypopituitarism (Panhypopituitarism)

Panhypopituitarism

Syndrome of Inappropriate Antidiuretic Hormone Secretion [Emergency Medicine]

Syndrome of Inappropriate Antidiuretic Hormone Secretion [Pediatrics: General Medicine]

Syndrome of Inappropriate Secretion of Antidiuretic Hormone [Nephrology]

See the list below:

• Physical examination findings may be obscured by the altered cognitive status of patients who have had a traumatic brain injury (TBI).

• Common post-TBI findings, such as lethargy, fatigue, and slowed mental processing time, also are associated with endocrine complications.

• In extreme cases, hyponatremia can cause seizures, confusion, and coma.

• Primary adrenal insufficiency (PAI) may present with acute psychiatric problems, such as psychosis, depression, apathy, or a schizophrenialike syndrome.

• General physical examination findings may include myxedematous, Addisonian-appearing, or slowed mentation.

• Vital signs include the following:

  • Slowed pulse

  • Hypothermia

  • Orthostatic hypotension

• Dermatologic findings include the following:

  • Pale, soft, waxy skin

  • Hyperpigmentation

  • Decreased axillary and pubic hair

  • Areolar depigmentation

  • Decreased male facial hair

  • Decreased sweating and sebum secretion

• Neurologic findings include the following:

  • Mental status changes (eg, lethargy, confusion, slowed mentation)[31]

  • Muscle weakness (may be proximal due to endocrine myopathy)

  • Hyporeflexia or areflexia

  • Hypotonia

The most common post–traumatic brain injury (post-TBI) endocrine complications are as follows:

• Syndrome of inappropriate antidiuretic hormone (SIADH)[30]

  • SIADH is the most common neuroendocrine complication following TBI, with a reported incidence of as high as 33%. In the TBI rehabilitation setting, SIADH is the most common cause of hyponatremia.

  • Hyponatremia often is seen in the rehabilitation setting among survivors of either traumatic or nontraumatic brain injury (eg, hemorrhagic stroke, brain tumors, CNS infections). This problem is associated most often with SIADH. Approximately 30% of patients who undergo neurosurgery demonstrate SIADH. SIADH also can be induced by medications such as carbamazepine, major tranquilizers, and antidepressants.[32]

  • Hyponatremia can cause several problems, including cerebral ischemia (by volume depletion), lassitude, seizures, confusion, and coma.

  • SIADH causes renal water conservation, with a secondary hyponatremia because of dilution. In patients who are not dehydrated or using diuretics, the laboratory diagnosis is based upon a urine osmolality greater than serum osmolality. The serum osmolality in patients with SIADH is less than 280 osm/kg, serum sodium is less than 135 mEq/L, and urine sodium is greater than 25 mEq/L.

  • The treatment in most cases is fluid restriction and, in unusual situations, IV hypertonic saline.

• Cerebral salt wasting (CSW)[18, 33]

  • Although most cases of hyponatremia due to brain injury are caused by SIADH, a less common etiology is CSW syndrome. Peters and colleagues first described CSW in 1950.[17] CSW is caused by impaired renal tube function that results in the inability of the kidneys to conserve salt. The etiology may be attributable to direct neural influence on renal tube function. Salt wasting with volume depletion is the hallmark of this syndrome. Clinically, patients manifesting CSW are dehydrated, lose weight, have orthostatic hypotension, and demonstrate a negative fluid balance. In cases of CSW and SIADH, the laboratory values often are the same for serum/urine osmolalities and electrolytes; however, elevated serum blood urea nitrogen (BUN), serum potassium, and serum protein concentration also are supportive of the diagnosis of CSW. Additionally, serum uric acid is normal in patients with CSW and is low in persons with SIADH.

  • Treatment of this type of hyponatremia with associated dehydration consists of replacement of fluids and salt, which is best managed by IV normal saline or, in rare cases, by IV hypertonic saline. Rehydration significantly reduces the risk of cerebral ischemia or cerebrovascular accident.

• Diabetes insipidus (DI)[6, 7, 8, 9, 10, 11, 34]

  • DI is rare, with an estimated 1 case per 100,000 hospital admissions. Posttraumatic DI occurs in 2-16% of all cases. The most common etiologies of posttraumatic DI include severe closed head injury, frequently with basilar skull fractures; craniofacial trauma; thoracic injury; postcardiopulmonary arrest; and intraventricular hemorrhage in neonatal patients. DI frequently is associated with cranial nerve injuries. The usual onset is 5-10 days following trauma.

  • Characteristic features of DI include polyuria, low urine osmolality, high serum osmolality, normal serum glucose, and normal to elevated serum sodium. Urine output usually is greater than 90 mL/kg/d, with a specific gravity of less than 1.010 and an osmolality of 50-200 mOsm.

• Anterior hypopituitarism (AH)[12, 13, 14, 15, 16]

  • AH, or panhypopituitarism, is not as rare a complication after a closed head injury; it usually follows moderate to severe craniocerebral trauma. With improvements in emergency and acute neurosurgical care for patients with head injuries, a greater number of severely involved patients are surviving than had previously done so. This subset of patients is most susceptible to the development of AH. The mechanism through which AH develops in patients with severe head injuries is an interruption of the major blood supply to the anterior lobe of the pituitary gland because of trauma to the unprotected stalk connecting the anterior pituitary to the median eminence of the hypothalamus.

  • Additionally, the hypothalamus secretes releasing and inhibitory hormones into the portal or stalk circulation, for controlling the release of the anterior pituitary hormones. Although the pituitary gland is well protected by the bony sella turcica, the pituitary stalk is not covered by dura mater and lies in the subarachnoid space. Severe craniocerebral injury may traumatize the stalk directly, or an anterior lobe infarction can occur due to impaired portal system circulation secondary to shock and cerebral edema.

  • The arterial blood supply of the posterior lobe of the pituitary comes directly from the inferior hypophyseal arteries branching from the internal carotid arteries. The posterior pituitary hormones are secreted by the hypothalamus.

  • Autopsy studies of 100 patients who died from craniocerebral trauma demonstrated pituitary lesions in approximately 60% of the group studied. Of those subjects with pituitary lesions, 59 demonstrated capsular hemorrhage, 42 demonstrated posterior lobe hemorrhages, and 22 revealed anterior lobe ischemic necrosis. Most patients (20 of 22) with anterior lobe ischemic necrosis died within the first 7 days following injury because of the severity of the craniocerebral trauma associated with shock and severe cerebral edema. Clinical AH is so rare in association with closed head injuries because most of these patients do not survive secondary to the severity of their injuries. This clinical syndrome presents itself only when two thirds of the anterior pituitary has been destroyed.

  • The syndrome of AH may manifest an insidious onset weeks to months after the original closed head injury. The patient may become progressively lethargic or anorexic and may demonstrate hypothermia, bradycardia, or hypotension with hyponatremia. These symptoms result in a significant setback if they occur during the acute phase of rehabilitation of a patient who has sustained a closed head injury. Any unexplained onset of malaise and generally decreased vital signs with associated stagnation of the rehabilitation progress in a patient following closed head injury should prompt the clinician to suspect the presence of AH.

  • AH following TBI can be obscured by the cognitive impairment of the patient and can contribute to delayed progress in rehabilitation.

  • The endocrine workup for AH includes serum hormonal assays, such as cortisol (0900), testosterone, triiodothyronine (T3), thyroxine (T4), thyrotropin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (females). Insulinlike growth factor-I (IGF-I) is a screening assay for growth hormone (GH) deficiency. Advanced provocative GH testing may be necessary to confirm this diagnosis. Also perform a complete blood cell (CBC) count and serum electrolyte evaluation.

  • Treatment involves multiple hormonal replacement therapy, as well as monitoring of the patient's serum levels and clinical response. The patient usually responds with improved vital signs, improved constitutional symptoms, and increased endurance for participation and progress in the rehabilitation program. The hormonal replacement therapy usually is required long-term.

• Primary adrenal insufficiency (PAI)[19]

  • PAI usually presents with the psychiatric symptoms of depression, confusion, and apathy.

  • Additional features include self-mutilation, paranoia, psychosis, and schizophrenic behaviors.

  • The mechanism of the psychiatric presentation is related to factors such as hypoglycemia, elevated exogenous endorphins, and axonal conduction changes.

  • Progressive deficiency of glucocorticoid and mineralocorticoid hormonal activity leads to hypotension, fatigue, anorexia/nausea, hyperpigmentation, and progressive, generalized weakness. Diagnosis of PAI is difficult in patients with TBI, because these particular symptoms may be ascribed to the TBI itself.

  • The most common cause of PAI is autoimmune or idiopathic adrenalitis (in 65-84% of cases). The next most common etiology is adrenal parenchymal destruction secondary to tuberculosis, sarcoidosis, malignancy, acute sepsis (including systemic fungal infections), and acquired immunodeficiency syndrome (AIDS).

  • Acute adrenal crisis may result from bilateral adrenal hemorrhage from trauma, sepsis, surgery, or acute burns. If this problem is unrecognized, acute adrenal crisis may lead to acute shock and death. Adrenal failure usually is permanent in patients who survive the acute phase of the adrenal crisis.

  • Several rare hereditary syndromes are associated with PAI, such as familial glucocorticoid insufficiency, adrenoleukodystrophy, and adrenomyeloneuropathy. PAI results from a deficiency of glucocorticoid and mineralocorticoid hormonal activity, combined with a reduction of feedback to the anterior pituitary gland. The cortisol deficiency results in excessive secretion of corticotropin from the anterior pituitary gland and excessive secretion of corticotropin-releasing hormone from the hypothalamus.

  • The presentation of PAI may be acute, characterized by nausea, vomiting, and hypertension. Alternatively, this clinical entity may present insidiously, with slow development of nonspecific symptoms over a prolonged period. The most common features include fatigue, weakness, anorexia, and weight loss. Additional findings include hyponatremia, hyperkalemia, skin hyperpigmentation, and gastric motility impairment that leads to complete gastric stasis.

  • Physiatrists must be aware of PAI, even though it is rare, because the presentation of adrenal insufficiency can be similar to the presentation of TBI. The symptoms limiting rehabilitation of patients following TBI can be attributed to the brain injury itself or to deconditioning secondary to prolonged bedrest. Treatment of this underlying problem by mineralocorticoid and glucocorticoid replacement therapy can result in a significant improvement of rehabilitation progress and outcome.

• Other post-TBI endocrine complications

  • Early puberty is defined as secondary sexual development in females younger than 8 years and in males younger than 9 years. Precocious puberty can occur in children with head injuries because of an inappropriate secretion of gonadotropin-releasing hormone (GRH), resulting in the subsequent release from the anterior pituitary of LH and FSH. These hormones cause the early onset of puberty by increasing levels of gonadal steroids and gametogenesis.[35]

  • Hypogonadism also can occur following head trauma. In one study, approximately one third of female patients who had head injuries (ie, 26 of 78) experienced temporary amenorrhea, usually for no longer than 3 months. This phenomenon is secondary to hypothalamic dysfunction, resulting in absent or decreased secretion of GRH.

  • In male patients, gonadotropin and testosterone levels are low immediately following head injury. Later, in response to exogenous GRH, the anterior pituitary responds with the release of high levels of LH and FSH, which is typical of hypothalamic dysfunction. At 3-6 months after the head injury, 5 of 21 male patients demonstrated persistently low serum testosterone levels. Depending on the clinical situation, consider appropriate testosterone replacement therapy.

• Summary

  • Approximately 30-50% of patients with moderate-to-severe head injury demonstrate endocrine complications. These problems may not present in a classic textbook fashion in persons who are severely impaired following TBI. The only clue to determining endocrine complications may be an unexplained failure to progress or a setback in the TBI rehabilitation program.

  • The most common endocrine abnormality is SIADH, followed by DI.

  • SIADH is the most common cause of hyponatremia; however, other causes include fluid overload or extracellular fluid depletion from GI or renal loss of sodium.

  • Criteria for diagnosis of SIADH include low serum osmolality, hyponatremia, and inappropriately concentrated urine (with urine sodium >25 mEq/L).

  • Hyponatremia that remains unresponsive to standard treatment for SIADH should point the clinician to other causes of hyponatremia.

  • Another clue to recognizing adrenal insufficiency is hyperkalemia associated with the hyponatremia secondary to a loss of mineralocorticoid activity at the kidney, causing urine sodium loss, impaired excretion of potassium, and hydrogen ion retention.

  • Azotemia also may be associated with adrenal insufficiency.

The hallmark of endocrine disorders is an abnormal serum level of either a particular hormone or the entire spectrum of associated hormones, such as in anterior hypopituitarism (panhypopituitarism).

Serial hormone assays may be used to determine the secretory pattern and to assess the hypothalamic regulation of pituitary function. All patients with traumatic brain injury (TBI) should undergo a baseline hormone evaluation at the time of hospital or intensive care unit (ICU) discharge, as well as at 3 months and 12 months post-TBI. The endocrinologist's workup may include provocative testing. Confirmatory testing of growth hormone (GH) deficiency is by assay of IGF-I. A low level of IGF-I in the absence of malnutrition is indicative of severe GH deficiency; however, aging or other factors (eg, liver disease, chronic renal disease, obesity, diabetes mellitus) can also cause a low level of IGF-I.

Careful clinical assessment of patients who have sustained TBI and who develop unexplained lethargy, generalized weakness, or anorexia should include an endocrine evaluation. Endocrine problems interfere with the progress of rehabilitation and are detrimental to the rehabilitation outcome if not recognized and treated promptly.

Laboratory/clinical screening studies of pituitary function include the following:

• GH - Height, weight, and bone age (< 18 y)

• IGF-I (0900)

• Thyrotropin - Free T4 and T3 by radioimmunoassay (0900)

• Corticotropin - Serum cortisol (0900 h)

• Gonadotropins - Serum estradiol or testosterone (0900)

• Prolactin - Serum prolactin

• ADH - Serum/urine sodium, serum/urine osmolalities, and urine output

A study by Salomón-Estébanez et al indicated that children who have suffered mild to moderate TBI may not require routine evaluation for endocrine dysfunction. In the study, 36 pediatric patients, all of whom had suffered skull fracture or intracranial hemorrhage, including 36.6% who had sustained moderate to severe TBI, were assessed for pituitary dysfunction after a mean postinjury period of 3.3 years (with a mean age at assessment of 7.2 years). No pituitary dysfunction was found in these patients at follow-up, including in 4 patients with low serum IGF-I levels and two patients in whom serum cortisol levels were low and plasma adrenocorticotropic hormone (ACTH) levels were inappropriately normal.[36]

See the list below:

• Cranial magnetic resonance imaging (MRI) provides the most specific cross-sectional views of the hypothalamus and pituitary gland.[37] The diagnosis and treatment of endocrine complications following traumatic brain injury (TBI) are based on clinical findings and laboratory studies of overall pituitary hormonal regulation and of each endocrine gland.

Endocrine complications following traumatic brain injury (TBI) are treated by medical management and usually do not require surgical intervention.

Endocrinology subspecialty consultation may be needed following traumatic brain injury (TBI) in patients who demonstrate subtle findings of underlying endocrine abnormalities, as evidenced by a slowdown or complete halt in the progression of a TBI rehabilitation program. This group of patients includes those who have a growth delay (eg, pediatric patients) or unexplained constitutional symptoms of lethargy/poor appetite following TBI, and young female patients with amenorrhea following TBI.

From the endocrinologist's perspective, patients with vital endocrinopathies, such as diabetes insipidus, secondary adrenal failure, and secondary hypothyroidism, should be promptly treated with hormone replacement therapy (HRT). Secondary hypogonadism and severe growth hormone (GH) deficiency should be considered later, after replacement of other deficits and after retesting. Patients who are severely involved in a persistent vegetative state would not likely benefit from HRT for secondary hypogonadism or GH deficiency. GH replacement therapy outcomes include increased muscle mass/exercise tolerance and improved quality of life/sense of wellness.

Post-TBI patients functioning at a very low level who are institutionalized should receive HRT only for vital endocrine hormones, including hydrocortisone, vasopressin, and T4. All patients with moderate to severe TBI should receive a baseline pituitary hormone deficiency evaluation, especially if they were hospitalized for at least 1 day post-TBI.

Electrolyte therapy for patients with hyponatremia following traumatic brain injury (TBI)

See the list below:

• Hyponatremia is a decrease in serum sodium concentration to less than 136 mmol/L. Dilutional hyponatremia (ie, SIADH) secondary to water retention is the most common form.

• Hypotonic hyponatremia also results from water retention with essentially normal sodium stores. Most of the symptoms of hyponatremia are attributable to sequelae of central nervous system (CNS) dysfunction, such as headaches, nausea, muscle cramping, lethargy, restlessness, disorientation, and depressed deep tendon reflexes.

• Slowly developing hyponatremia results in progressive cerebral edema and milder symptoms due to brain adaptation, with these patients experiencing minimal symptomatology. On the other hand, if the hyponatremia is characterized by a rapid onset, intracranial hypertension causes the more dangerous complications referred to above, especially in the more susceptible patient with brain injury. See the image below.

  Effects of hyponatremia on the brain and adaptive responses. Within minutes after the development of hypotonicity, water gain causes swelling of the brain and a decrease in osmolality of the brain. Partial restoration of brain volume occurs within a few hours as a result of cellular loss of electrolytes (rapid adaptation). The normalization of brain volume is completed within several days through loss of organic osmolytes from brain cells (slow adaptation). Low osmolality in the brain persists despite the normalization of brain volume. Proper correction of hypotonicity reestablishes normal osmolality without risking damage to the brain. Overly aggressive correction of hyponatremia can lead to irreversible brain damage.

• Aggressive treatment of hyponatremia, even by fluid restriction, can cause osmotic demyelination, a rare and serious complication. Brain shrinkage triggers pontine and extrapontine neuronal demyelination, causing disabling CNS dysfunction, including quadriplegia, pseudobulbar palsy, seizures, coma, and death. Hepatic failure, hypokalemia, and malnutrition are risk factors for osmotic demyelination.

• Management of hyponatremia

  • Patients with less serious symptoms of hyponatremia and dilute urine concentrations of less than 200 mmol/L usually require fluid retention and close monitoring. More serious symptoms of hyponatremia include urine concentrations of greater than 200 mmol/L.

  • Insensate fluid loss contributes to hyponatremia, assisted by dermal and respiratory losses. Associated endocrinopathies (eg, hypothyroidism, adrenal failure) develop slowly. Hypothyroidism can masquerade as SIADH.

  • The correction of hyponatremia is no more than 8 mmol/L per day.

  • The initial correction is 1-2 mmol/L/h for several hours in patients with severe symptoms of hyponatremia (see table below). Indications to stop the rapid correction of hyponatremia include the need to control life-threatening complications, moderation of other symptoms, and serum sodium concentrations of 125-130 mmol/L.

  • The most common treatment for SIADH is fluid restriction to less than 800 mL/d to induce a negative water balance. If necessary, loop diuretics may be instituted by causing excretion of electrolyte-free water. If this treatment fails, use 600-1200 mg of demeclocycline to cause nephrogenic diabetes insipidus (DI). Assessment of renal function is necessary, because the condition is nephrotoxic, especially in patients with cirrhosis. Table. Formulas for Use in Managing Hyponatremia and Characteristics of Infusates

    Table. (Open Table in a new window)

    Formula*		Clinical Use
    Change in serum Na+ =	Infusate Na+ — serum Na+ —————————— total body water +1	Estimate the effect of 1 L on any infusate serum Na+
    Change in serum Na+ =	(Infusate Na+ + infusate K+)—serum Na+ ———————————————— total body water +1	Estimate the effect of 1 L of any infusate containing Na+ and K+ on serum Na+
    Infusate	Infusate Na+	Extracellular—Fluid Distribution
    	mmol/L	%
    5% sodium chloride in water	855	100†
    3% sodium chloride in water	515	100†
    0.9% sodium chloride in water	154	100
    Ringer lactate solution	130	97
    0.45% sodium chloride in water	77	73
    0.2% sodium chloride in 5% dextrose in water	34	55
    5% dextrose in water	0	40
    *The number in formula 1 is a simplification of the expression (infusate Na+ —serum Na+) X 1 liter, with the value yielded by the equation in mmol/L. The estimated total body water (in liters) is calculated as a fraction of body weight. The fraction is 0.6 in children; 0.6 and 0.5 in nonelderly men and women, respectively; and 0.5 and 0.45 in elderly men and women, respectively.†In addition to its complete distribution in the extracellular compartment, this infusate induces osmotic removal of water from the intracellular compartment.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

Because most endocrinopathies following traumatic brain injury (TBI) are due to failure at the anterior pituitary level, treatment involves hormonal replacement. Individual hormonal replacement also is indicated, depending on the specific endocrine gland involved. Posterior pituitary failure also is treated by replacement therapy.

Levothyroxine (Levoxyl, Synthroid)

In the active form, this drug influences growth and maturation of tissues. Involved in normal growth, metabolism, and development. Primary use is for synthetic thyroid hormone replacement.

Secondary use is for suppression of pituitary thyrotropin for management of thyroid carcinoma or thyroid nodules. Titrate to degree of hypothyroidism.

Desmopressin acetate (DDAVP)

Synthetic analogue of hypothalamic/posterior pituitary hormone 8-arginine vasopressin (ADH) for treatment of central DI. Not for treatment of nephrogenic DI. Dose should be titrated to plasma/urine osmolality and urine volume.

Testosterone (Andro-LA, Androderm, Depo-Testosterone)

For treatment of primary hypogonadism or hypogonadotropic hypogonadism.

Hydrocortisone (Cortef, Solu-Cortef)

Used for treatment of primary or secondary adrenocortical insufficiency.

Used short-term to treat flare-ups of rheumatologic conditions. Used for prolonged maintenance of collagen diseases (eg, systemic lupus erythematosus, polymyositis/dermatomyositis). Also used for dermatologic (eg, pemphigus), allergic (eg, atopic dermatitis), and respiratory diseases (eg, sarcoidosis).

Pediatric growth and development may be suppressed and should be monitored.

Class Summary

Tetracycline antibiotics are used to treat Rocky Mountain spotted fever, typhus fever, psittacosis, relapsing fever, chancroid, and gram-negative microorganism infections (depending on specific culture/sensitivity results).

Demeclocycline (Declomycin)

Primarily used as an antibiotic but also used as a nephrotoxin to induce diabetes insipidus for the treatment of resistant SIADH.

Class Summary

These agents inhibit the resorption of sodium and chloride in the proximal and distal tubules and in the loop of Henle.

Furosemide (Lasix)

Potent diuretic that can cause massive diuresis and electrolyte depletion at high doses. Onset of diuresis is within 1 h, and the peak effect is during the first and second hour. Total diuretic effect is 6-8 h.

See the list below:

• The outpatient follow-up care of these patients is individualized, depending on the endocrine problem under treatment and the patient's metabolic stability.

See the list below:

• The clinical response of the patient after treatment has been instituted is the most important factor in determining the necessity of additional treatment. Follow-up endocrine studies (ie, hormonal levels) are necessary at least weekly until homeostasis has been achieved. Serum electrolytes, BUN, and creatinine levels need to be assessed at least daily until normalized, and then these levels should be monitored at routine intervals.

See the list below:

• As stated previously, medication management consists primarily of hormone replacement until clinical response and normal serum levels have been achieved. In most cases, the HRT continues on a long-term outpatient basis. Most inpatients with associated electrolyte disorders are stabilized with intravenous electrolyte therapy before hospital discharge, and no further medication management is necessary.

See the list below:

• No deterrence/prevention program exists for endocrine complications following traumatic brain injury (TBI). Early recognition of these problems through a high index of suspicion, close monitoring of serum electrolyte balance, and prompt corrective treatment minimizes any negative impact these complications have on the rehabilitation outcome.

See the list below:

• The most significant complication is failure to recognize these treatable endocrine complications, ultimately prolonging the rehabilitation program and decreasing the patient's functional outcome following traumatic brain injury (TBI).

• Osmotic demyelination of the CNS, caused by an excessively rapid correction of hyponatremia with IV hypertonic saline, is an unusual complication of TBI, albeit a serious and sometimes lethal one.

See the list below:

• The prognosis for the patient with endocrine complications following traumatic brain injury (TBI) is good to excellent, assuming these sometimes subtle problems are diagnosed and treated promptly. Failure to recognize and treat these problems negatively affects the rehabilitation progress and eventually the long-term functional outcome.[24, 25]

See the list below:

• Depending on the level of patient cognitive impairment, the patient and his or her caregivers/guardians are advised to be aware of any changes exhibited by the patients, such as unexplained patient lethargy, decreased tolerance to activity, or cold intolerance. These particular problems require immediate notification of the attending physician. The patient should undergo physician reevaluation and, if necessary, an endocrine workup. Rapid corrective hormonal replacement therapy then can be initiated and monitored at a follow-up session with the treating physician.

• For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism Center. Also, see eMedicineHealth's patient education article Anatomy of the Endocrine System.