Central Adrenal Insufficiency

The hypothalamic-pituitary-adrenal (HPA) axis involves hypothalamic secretion of corticotropin-releasing hormone, which travels through the hypophyseal portal system and triggers corticotrophs in the anterior pituitary to secrete ACTH. ACTH travels to the adrenal glands through the blood stream and stimulates epinephrine and norepinephrine. Acute CAI occurs due to disruption of the hypothalamus or pituitary gland. Incidence of posttraumatic CAI varies widely, ranging from 9.8% to 78%, reflecting discrepancies in thresholds for inpatient cortisol testing and different testing modalities. Relative adrenal insufficiency may develop due to acute illness, making the diagnosis more challenging. Cortisol-binding globulin levels may also fluctuate in the setting of TBI, which can confound standard laboratory assays. Due to these factors, the gold standard cosyntropin stimulation test for CAI is often inaccurate within the first 6 weeks post-TBI. Chronic adrenal insufficiency (AI) is less common (ranging from 8.2% to 9.9% in adults and 2% in children) as the HPA axis tends to recover at 3 to 6 months. ^{, ,}

Adrenal insufficiency after TBI has notable clinical significance as it may contribute to hemodynamic instability, hyponatremia, and hypoglycemia. However, there are multiple other causes of hyponatremia and hemodynamic instability in trauma patients including cerebral salt wasting, SIADH, septic shock, or hemorrhagic shock, which may be present concurrently with or in isolation from CAI. If basal cortisol levels are low (ie, <7 μg/dL), a low-dose ACTH stimulation test can be performed. Taken together, hyponatremia, hypoglycemia, hypotension, and low 8:00 am serum cortisol strongly indicate adrenal insufficiency, which can be performed with an ACTH stimulation test.

Management of CAI includes vasopressor support and may include corticosteroids at stress-dosages during the acute phase of illness. This highlights an important detail that corticosteroid administration is associated with worse outcomes in TBI as a whole, but may be indicated for a select population with acute CAI. Dosing is typically hydrocortisone 50 mg every 6 to 8 hours. In the chronic phase, it is recommended for patients to undergo a supervised steroid taper with serial cortisol testing to assess need for long-term steroid replacement.

Diabetes Insipidus

ADH is produced and secreted by hypothalamic neurons (supraoptic and paraventricular nuclei), which send axons through the pituitary stalk with axon terminals at the posterior pituitary gland. Thus, DI can be caused by damage to the posterior pituitary gland, pituitary stalk, or hypothalamus. Injury to the hypothalamic neurons can lead to permanent DI, while injury to the stalk may produce the triphasic response involving DI for a few days, followed by transient SIADH as the secretory granules in the posterior pituitary containing ADH are released into circulation, followed by transient or permanent DI. Damage to the posterior pituitary gland itself typically does not lead to permanent DI as hypothalamic neurons can secrete ADH into circulation through capillaries of the median eminence.

Acute central DI is seen in 14% to 26% of patients with TBI. This is typically transient, and resolves after several days, but may proceed to chronic DI in a small percentage (6.9% in 1 study) of patients. One study looking at incidence of severe cases of DI with plasma sodium concentration greater than 160 mEq/L found an incidence of 2.9%. Risk factors included lower Glasgow Coma Scale (GCS) and cerebral edema. Clinically, patients produce large volumes of dilute urine, which can lead to rapid onset of hypovolemic hypernatremia. This tends to occur within the first few days following the trauma, but can occur up to day 10. ^, DI seldom occurs in the delayed phase, although there have been rare case examples published in the literature. ^, The precise definition of DI differs in the literature, but generally involves polyuria (>3–3.5 L in 24h) with dilute urine (osmolality < 30 mOsm/kg) and hypernatremia (Na >145). Management includes fluid replacement to avoid dehydration (intravenous fluids in comatose patients, while conscious patients may replace fluids lost by drinking to thirst). Desmopressin (ddAVP), a synthetic analog of ADH may be administered to correct hypernatremia as well, although care must be taken to avoid overcorrecting or correcting too quickly, as this may predispose the patient to worsening cerebral edema or central pontine myelinolysis.

Growth Hormone Deficiency

GHD is the most common chronic endocrinopathy after TBI, likely due to the susceptibility of their blood supply (the long portal vessels) to traumatic injury. GHD ranges from 2% to 30% in the acute phase and from 10% to 63.6% in the chronic stage. The incidence is similar in children (4% to 31%). Although acute GHD may occur in up to 30% of patients in the acute stage, insulin-like growth factor-1 (IGF-1) testing is generally inaccurate in the acute phase of TBI, and 1 study found only 17% to 30% of adult patients with GHD had low IGF-1. Other tests performed in the delayed setting include tolerance test; pyridostigmine-growth hormone releasing hormone (GHRH) or GHRH-Arginine agents, which have variable sensitivity and specificity.

The primary manifestations of GHD include metabolic and cognitive issues. Metabolic manifestations of GHD include increased adiposity, reduced height and hypoglycemia in children, reduced lean body mass and bone mineral density, and increased fat stores in adults. Cognitive deficits include simple attention, verbal memory, visual memory, reaction time, and emotional stability. ^, Growth hormone (GH) replacement has been shown to improve cognitive deficits after TBI. One double-blinded randomized controlled trial (RCT) performed in adults with TBI found improvements in verbal learning, information-processing speed, dominant-hand finger tapping speed, and executive function in the group receiving growth hormone replacement. Another RCT on moderate and severe TBI patients found improvements in memory and information-processing speed, but no improvement in attention, executive function, or language. Overall, these results suggest that routine GH testing should be performed after TBI and that GH replacement may be beneficial to help individuals with posttraumatic metabolic and cognitive deficits.

Central Hypothyroidism

The hypothalamus produces and secretes thyroid-releasing hormone (TRH), which travels to the anterior pituitary gland through the hypophyseal portal system and triggers release of TSH by thyrotrophs in the anterior pituitary. TSH triggers production of T3 and T4, which feedback and inhibit TRH/TSH production. Routine thyroid testing involves a free T4 and TSH level. In central hypothyroidism, TSH may be normal (rather than elevated) in the setting of a low free T4 level. Thyroid dysfunction is frequently observed immediately after TBI, in a pattern consistent with nonthyroidal illness (low T3, high rT3, low/normal T4, low/normal TSH). Thus, the acute diagnosis of central hypothyroidism is difficult to make. Hypothyroidism is diagnosed in 2% to 15% of TBI patients, and the diagnosis is more reliably made at 3-months or 12-months post injury. ^,

Clinical manifestations of hypothyroidism include hair loss, constipation, generalized weakness and fatigue, dry skin, hypothermia, weight gain, hyperlipidemia, irregular menses, cognitive issues, and hoarse voice. Treatment generally involves thyroid hormone replacement with levothyroxine.

Gonadotropin Deficiency

Gonadotropin deficiency (FSH/LH) after TBI occurs in high proportions of both men and women in the acute phase after TBI (it is the second most common endocrinopathy after GH), although management is typically reserved for a period after the patient recovers from their traumatic injuries. One study looking at men found low serum testosterone in 100% of TBI patients at 4 days after TBI. Around 58% of subjects had low luteinizing hormone (LH), and 37.9% had low follicle stimulating hormone (FSH) at the same time point. Another study looking at men and women found similar suppression of FSH, LH, and testosterone in men and low estradiol in 43% of premenopausal women. Other studies have found 68% to 80% of patients had hypogonadotropic hypogonadism after sustaining a TBI in the acute setting. ^, In the long term, most patients had improvements in their gonadotropin suppression, with studies reporting that only 4% to 37% of patients had long-term hypogonadotropic hypogonadism. ^,

Gonadotropin deficiency has multiple manifestations, including infertility, menstrual irregularities, sexual dysfunction, osteoporosis, reduced muscle mass, hair loss, breast atrophy, galactorrhea, and fatigue. Management is reserved for the chronic setting and typically includes careful monitoring and replacement of hormonal deficits.

Hyperprolactinemia

Elevated prolactin may be observed after TBI due to damage to the pituitary stalk interrupting the dopaminergic inhibition of lactotrophs of the anterior pituitary. Posttraumatic hyperprolactinemia tends to be transient and usually resolves within 12 months of injury. Elevated prolactin has not been associated with increased mortality, poor outcome, GCS, or intracranial pressure. ^, Compared to rates of hyperprolactinemia in 77% of individuals on day 4 after TBI, at 1 year, this dropped to 5.7% of patients. Hyperprolactinemia may present with symptoms of hypogonadism (prolactin inhibits FSH/LH secretion), as well as galactorrhea.

Paroxysmal Sympathetic Hyperactivity

Paroxysmal sympathetic hyperactivity (PSH) is a clinical syndrome of sympathetic hyperactivity that occurs primarily following severe TBI featuring brief, sudden onset of concurrent tachycardia, hypertension, tachypnea, hyperthermia, and decerebrate posturing in response to often disproportionately benign stimulus. Dr. Wilder Penfield first described this syndrome in 1929, and it was formally defined and titled PSH in 2014. PSH has been reported to occur in between 8% and 33% of patients with severe TBI, and while approximately 80% of PSH cases are associated with TBI, other forms of severe brain injury may also produce these episodes including ischemic stroke and hypoxic-ischemic encephalopathy.

PSH onset is usually within a week after injury, ^, and it may last from weeks to months. On average, episodes occur 5 times per day. Duration of each episode varies widely, from minutes to hours-one study found on average 30 minutes. ^, In the majority of patients with PSH, episodes are triggered by stimulus, which in the intensive care unit (ICU) typically includes neurologic examinations, lab draws, urinary retention, and repositioning. ^,

There are 2 major theories for the pathophysiology of PSH, which may both contribute. One is increase in descending sympathetic activation signals. This may occur secondary to either direct structural damage to the areas where sympathetic activity originates, such as the hypothalamus and medulla, or injury to inhibitory fibers from cortex and forebrain areas that terminate on these areas. ^, This is consistent with radiographic findings of frequent white matter damage in patients with PSH. ^,

An alternative or complementary theory is the excitatory:inhibitory ratio (EIR) model. The EIR model proposes that damage to inhibitory centers of the brainstem and diencephalon reduces tonic inhibition to afferent sensory pathways from the spinal cord. This amplifies afferent input that would typically be non-nociceptive and leads to a disproportional sympathetic response. ^,

There is no consensus on the magnitude of the effect of PSH on clinical outcomes; while 1 retrospective study of 35 PSH patients with controls matched for GCS on day of injury demonstrated longer hospital stays and worse clinical outcomes in patients with PSH, other studies have failed to demonstrate a consistent effect. Studies of how PSH affects outcomes are often confounded by the association between PSH and greater injury severity. Although the published evidence on outcomes is equivocal, PSH poses undeniable dangers to patients and challenges to clinicians during recovery from brain injury. Sympathetic hyperactivity over a prolonged period can lead to cardiac damage, cardiac arrhythmias, and in severe cases myocardial infarction. Patients may suffer from pulmonary edema, intracranial hypertension, and rhabdomyolysis. PSH produces a hypermetabolic state, which can lead to malnutrition. ^, PSH may be easily mistaken in the acute phase for sepsis, seizure, or withdrawal, which may lead to delay in optimal treatment.

The PSH assessment measure was developed in 2014 by consensus among a multidisciplinary group, and includes tools for evaluating diagnostic likelihood of PSH, PSH severity, and monitoring clinical trends during treatment. Avoiding stimulation is a mainstay of treatment, with reduction of examinations involving noxious stimulus, adequate analgesia during procedures, and minimizing discomfort during repositioning. Episodes can be aborted using benzodiazepines, beta blockers, opioids, alpha-2 agonists, and baclofen, most often in combination. Additional medications that have been used include gabapentin, bromocriptine, and dantrolene. In patients requiring sedative drips, dexmedetomidine may be more useful than propofol. Practices vary widely and there is no standard treatment algorithm for aborting PSH episodes. There remains a great need for further research into the pathophysiology and treatment of PSH, which may improve recovery of some of the most critically ill patients.

Dysautonomia in Spinal Cord Injury

The autonomic nervous system is comprised of sympathetic and parasympathetic systems, with the parasympathetic system arising from cranial and sacral nerves, whereas the sympathetic nervous system arises from the spine at T1-L2. Spinal cord injury may produce parasympathetic dominance, with cardiac dysrhythmias, systemic hypotension, bronchoconstriction, copious respiratory secretions, and uncontrolled bowel, bladder, and sexual dysfunction. Conversely, noxious afferent signals to the sympathetic cord may cause an unchecked reflexive response without any cortical inhibition, producing sympathetic hyperactivity similar to PSH.

In the acute phase after spinal cord injury (SCI), neurogenic shock may occur in SCI above T6, with areflexia and unopposed parasympathetic dominance due to blunting of the sympathetic system. Neurogenic shock occurs in 19% of cervical injuries, and 7% of thoracic injuries. Neurogenic shock uniquely produces bradycardia with orthostatic hypotension, bronchiolar constriction, mucus secretion, and priapism. In the setting of polytrauma, it may be difficult to identify concurrent neurogenic and hypovolemic shock, which would have opposing effects on heart rate and could lead to dangerously low cardiac output. Following SCI, maintaining mean arterial pressure of greater than 85 for 7 days to improve spinal cord perfusion is an independent predictor of neurologic recovery.

Chronically, the sympathetic nervous system may be blunted by disconnection from supraspinal sympathetic centers. This may produce parasympathetic dominance, with bradycardia and high risk of atrioventricular (AV) block. Parasympathetic vasodilation in the viscera and extremities produces orthostatic hypotension in 74% of SCI patients. An abdominal binder and compression stockings are recommended, as well as avoiding vasodilatory stress due to heat, large meals, and alcohol. If refractory to these conservative measures, fludrocortisone or midodrine are used.

Autonomic dysreflexia is uninhibited sympathetic response to noxious stimulus, similar to that observed in PSH, and occurs in up to 90% of patients with high thoracic and cervical injuries. Autonomic dysreflexia develops after the neurogenic shock period when reflexes have recovered, usually within the first year after injury. Complete spinal cord injuries are 3 times more likely to produce autonomic dysreflexia than incomplete injuries. Lack of supraspinal inhibition of preganglionic sympathetic neurons produces diffuse vasoconstriction and hypertension in response to stimulus below the level of injury. Normal compensatory parasympathetic signals arise from the medulla and cannot travel below the level of injury, thus vasoconstriction below the level of injury continues unchecked and vasodilation above the level of the injury is often insufficient to offset hypertension. Autonomic dysreflexia is rarely seen in SCI below the level of T10 because the splanchnic innervation remains intact, allowing compensatory parasympathetic dilation of the splanchnic vascular network. Bladder and rectal distension are the most common triggering stimulus, but other triggers include traumatic injuries, pressure ulcers, and infections. The mainstay of treatment is removing triggering stimulus, but if trigger cannot be identified and blood pressure cannot be controlled, preferred emergency antihypertensives include nitroglycerine, nifedipine, captopril, and clonidine.