Endocrine Emergencies

In depth

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Thyroid physiology, the HPT axis and nonthyroidal illness

Hypothalamic TRH drives pituitary TSH, and TSH drives the thyroid to secrete mostly T4. About 80% of circulating T3, the active hormone, comes from deiodination of T4 in liver, kidney and muscle, while type 3 deiodinase inactivates T4 to reverse T3. Over 99% of both is protein bound; only the free fraction acts. T4 lasts about 7 days and T3 about 1 day, so blocking T4-to-T3 conversion lowers T3 within a day, while TSH, which moves about 100-fold for a 2-fold change in free T4, lags by weeks.

Nonthyroidal illness (sick euthyroid, low T3 syndrome) begins within hours of severe illness or surgery as T4-to-T3 conversion falls and inactivation rises; in prolonged illness, cytokines and suppressed TRH lower TSH and T4 too, and a low T4 tracks with mortality. Dopamine, dobutamine and glucocorticoids suppress TSH (ATA 2014), amiodarone raises T4 and reverse T3, and in recovery TSH can overshoot for weeks, mimicking primary hypothyroidism.

ATA 2014 recommends against T4 or T3 for NTIS. IV T4 in acute renal failure raised mortality (43% vs 13%; Acker 2000, 59 patients), and in 838 unstable brain-dead donors IV levothyroxine did not increase hearts transplanted (54.9% vs 53.2%) and caused more hypertension and tachycardia (Dhar 2023).

Thyroid storm: scoring, drug sequence and rescue

Storm is decompensated thyrotoxicosis, not a higher hormone level: a trigger tips a hyperadrenergic, hypermetabolic state into organ failure, with high output, low SVR, AF and heart failure. In 356 Japanese patients (JTA 2016) the leading triggers were stopping antithyroid drugs and infection, mortality was about 11%, and heart rate ≥150 and AF were linked to death.

The Burch-Wartofsky Point Scale (1993) sums seven features; ATA 2016 treats BWPS ≥45 or JTA TS1–TS2 with organ decompensation aggressively and leaves BWPS 25–44 to judgment. The JTA criteria (Akamizu 2012) require thyrotoxicosis; definite storm (TS1) is CNS signs (delirium, agitation, GCS ≤14) plus fever ≥38 °C, heart rate ≥130, heart failure or GI-hepatic signs (bilirubin ≥3 mg/dL), or three of those four without CNS signs; two of the four is suspected storm (TS2). In a US cohort, altered mentation alone separated true storm from patients who merely scored as storm (Angell 2015).

JTA 2016 prefers β₁-selective landiolol, esmolol or bisoprolol to propranolol, because every Killip III–IV death on a β-blocker involved a nonselective agent; it targets heart rate ≤130 and considers stopping at heart rate <80, SBP <80 or cardiac index ≤2.2. ATA 2016 gives iodine at least 1 h after the thionamide, while JTA 2016 gives potassium iodide (about 200 mg/day) at the same time in Graves disease, citing Japanese trials.

Fever, tachycardia and mentation usually improve within 12–24 h; if not by 24–48 h, JTA 2016 suggests therapeutic plasma exchange, which strips hormone-carrying proteins (1–1.5 plasma volumes daily or every 2–3 days, FFP preferred because it supplies TBG; ASFA 2023 category II, grade 2C). Its effect is temporary, so it bridges to thionamides or, when agranulocytosis or liver injury rules them out, to surgery. Total thyroidectomy is the definitive rescue (5 of 49 refractory patients died after emergency surgery in a series cited by JTA 2016); afterward watch calcium, voice and the neck.

Myxedema coma and the T4 versus T3 debate

Myxedema coma is decompensated hypothyroidism, typically in an older woman in winter after infection, cold, sedatives or opioids, stroke, heart failure, GI bleeding or stopped levothyroxine. Heat production, heart rate and contractility fall and SVR rises; ventilatory drive falls, and macroglossia, effusions and weak muscles worsen hypercapnia. Impaired free-water excretion causes hyponatremia, low gluconeogenesis causes hypoglycemia, and slow drug clearance prolongs sedatives. In-hospital mortality was 29.5% in 149 Japanese patients, higher with age and catecholamine use (Ono 2017).

No trial compares regimens. ATA 2014: IV levothyroxine 200–400 mcg load (less for small, older or cardiac patients), then 1.6 mcg/kg/day reduced to 75% while IV; IV liothyronine may be added, 5–20 mcg load then 2.5–10 mcg every 8 h, because T4-to-T3 conversion falls in critical illness. T3 acts faster but provokes arrhythmia and ischemia: in pooled cases, T4 ≥500 mcg/day or T3 ≥75 mcg/day, older age and cardiac disease predicted death (Yamamoto 1999), yet hormone type and dose did not affect mortality in the Japanese database (Ono 2017). Many centers give T4 alone; others add low-dose T3.

• Hydrocortisone (commonly 100 mg IV every 8 h) before the first thyroid dose; draw cortisol first (ATA 2014)
• Early intubation for hypercapnia; expect a difficult airway and a slow wean
• Hypotension responds poorly to pressors until thyroid hormone acts
• Endpoints: mentation, temperature, heart and lung function; free T4 and T3 every 1–2 days, since TSH lags (ATA 2014)

Adrenal physiology, adrenal crisis and stress-dose steroids

CRH and vasopressin drive pituitary ACTH, which drives cortisol with a morning peak; aldosterone answers mainly to angiotensin II and potassium. Cortisol is permissive for vascular tone (it sustains α₁ and angiotensin responsiveness and restrains NO), raises glucose and lets the kidney excrete free water; resting output is about 9–10 mg/day (ESE/ES 2024) and rises several-fold with major stress. Primary insufficiency loses cortisol and aldosterone (hyperkalemia, salt wasting, pigmentation); secondary insufficiency, most often from prior glucocorticoids, spares aldosterone, but cortisol deficiency still releases vasopressin and causes hyponatremia that mimics SIADH.

Among 423 educated patients with known insufficiency, crises ran 8.3 per 100 patient-years and about 6% were fatal; GI infection, fever and emotional stress each triggered 20% (Hahner 2015). Other triggers: surgery, missed doses, levothyroxine started before steroids, adrenal hemorrhage and stopping long-term steroids. After the one-pager regimen, Endocrine Society 2016 drops to 100 mg the next day and tapers to oral doses as the patient recovers. Above 50 mg/day, hydrocortisone covers mineralocorticoid needs; dexamethasone has none.

ESE/ES 2024 assumes suppression is possible after 3–4 weeks or more above a physiologic dose (prednisone 4–6 mg/day) unless testing shows recovery. Minor illness: double the physiologic dose (hydrocortisone 40 mg/day or prednisone 10 mg/day). Surgery under general or regional anesthesia, or admission with severe illness: hydrocortisone 100 mg IV, then 200 mg/24 h; after surgery, double the oral dose for 48 h once eating. No extra is needed on hydrocortisone ≥200 mg, prednisone ≥50 mg or dexamethasone ≥6–8 mg daily, and the guideline notes that lower doses are widely used.

Critical illness–related corticosteroid insufficiency

CIRCI (SCCM/ESICM 2017) is corticosteroid activity inadequate for the severity of illness, from HPA dysregulation, altered cortisol metabolism and tissue resistance. Cortisol is usually high, and not only from production: in 158 ICU patients production rose 83% while clearance fell by more than half, ACTH was suppressed, and slow clearance blunted the cosyntropin response (Boonen 2013). The 2017 cutoffs are a rise below 9 mcg/dL 60 min after cosyntropin 250 mcg or a random cortisol below 10 mcg/dL, but in CORTICUS the cosyntropin response did not predict benefit, so septic shock treatment does not wait for it. Draw any level before hydrocortisone: it is cortisol, so the assay measures the dose given (dexamethasone does not interfere).

SSC 2026 suggests IV corticosteroids for septic shock with an ongoing vasopressor need and sets no threshold; the classic start (SSC 2021) is norepinephrine or epinephrine ≥0.25 mcg/kg/min for at least 4 h, as hydrocortisone 200 mg/day. Fludrocortisone is unsettled: APROCCHSS used it and ADRENAL did not; adding it did not significantly lower death in COIITSS (2010, 509 patients; 42.9% vs 45.8%), while a US target-trial emulation favored it (Bosch 2023).

Pituitary apoplexy and the triphasic response

Apoplexy is hemorrhage or infarction of a pituitary adenoma, often the first sign of the tumor. Sudden severe retro-orbital headache, vomiting, visual field loss (classically bitemporal), reduced acuity and ophthalmoplegia from cavernous sinus compression (CN III most often) mimic subarachnoid hemorrhage; MRI is the test of choice. Triggers include anticoagulation, cardiac surgery on bypass, dynamic pituitary testing, pregnancy and head trauma. About two-thirds have acute ACTH deficiency, the main cause of death (Endotext 2026).

UK guidelines (Rajasekaran 2011) give hydrocortisone 100–200 mg IV, then 2–4 mg/h by infusion or 50–100 mg IM every 6 h, for hemodynamic instability, altered consciousness, reduced acuity or severe field defects. Transsphenoidal decompression is favored for severe or worsening visual loss or falling consciousness, ideally within 7 days; isolated ocular palsy usually recovers without surgery, and no trial compares the two. Add visual acuity, fields and eye movements to neuro checks, and follow sodium and urine output.

After transsphenoidal surgery or stalk injury, posterior pituitary failure can run in three phases: DI from axonal shock on days 1–2; SIADH-like hyponatremia around days 5–10 as degenerating nerve endings leak stored vasopressin; then permanent DI if most hypothalamic neurons are lost. The full sequence is uncommon. After endoscopic surgery DI was transient in 13.6% and permanent in 2.7% (Sigounas 2008); delayed hyponatremia occurred in 10.5%, often after discharge, and caused 44% of 30-day readmissions (Lee 2021); postoperative fluid restriction (1–2.5 L/day) cut it (RR 0.34, Perez-Vega 2021).

SIADH, cerebral salt wasting and DI in depth

Confirm hypotonic hyponatremia (serum osmolality below 275 mOsm/kg), then read urine osmolality: below 100 mOsm/kg means vasopressin is suppressed (polydipsia, low solute intake). SIADH requires clinical euvolemia, urine osmolality above 100, urine sodium above 30 mmol/L on normal intake, no recent diuretics and normal thyroid and adrenal function (European 2014). Cerebral salt wasting is renal sodium loss after SAH, TBI, meningitis or neurosurgery, probably from natriuretic peptides and reduced renal sympathetic tone, and causes true volume depletion.

Treat the cause (SSRIs, carbamazepine, pain, nausea, lung or CNS disease). Fluid restriction tends to fail when (urine Na + urine K) ÷ serum Na exceeds 1 or urine osmolality exceeds 500 (Verbalis 2013); then add solute: oral urea 0.25–0.5 g/kg/day or salt tablets with a loop diuretic (European 2014). Tolvaptan (oral V₂ blocker) starts at 15 mg daily in hospital and titrates to 30–60 mg, with no fluid restriction for the first 24 h, a 30-day limit for liver injury, and no use in hypovolemia or a patient who cannot sense thirst (Samsca label). US experts (Verbalis 2013) accept vaptans when restriction fails; the European guideline (2014) advises against them.

In SALSA (2021, 178 patients), 3% saline boluses overcorrected no more often than slow infusion (17.2% vs 24.2%).

Central DI (renamed arginine vasopressin deficiency in 2022) follows pituitary surgery, TBI, SAH, stalk injury and brain death; nephrogenic DI follows lithium, hypercalcemia or hypokalemia and resists desmopressin. Before treating polyuria, exclude mannitol, glucosuria, diuretics and mobilized resuscitation fluid, which leave sodium normal or low. An awake patient with intact thirst may need only free water.

• Desmopressin 1–2 mcg IV or SC per dose (label maintenance 2–4 mcg/day in two doses); onset within about 1 h, effect 6–12 h or longer
• Redose when polyuria and dilute urine return rather than on a fixed schedule
• Hourly urine output and specific gravity; serum Na every 4–6 h (every 2 h if moving fast); daily weight
• Replace free water to match losses; lower chronic hypernatremia by no more than about 10 mmol/L per day

Pheochromocytoma crisis

A pheochromocytoma or paraganglioma can present as hypertensive crisis, pressure swinging into shock, tachyarrhythmias, catecholamine (takotsubo-like) cardiomyopathy with pulmonary edema, lactic acidosis, hyperglycemia and fever. Triggers include tumor manipulation, anesthesia induction, glucocorticoids, metoclopramide, β-blockers without α-blockade, tricyclics, MAO inhibitors and sympathomimetics. Plasma free or urine fractionated metanephrines confirm it (Endocrine Society 2014), but critical illness and drugs raise them, so only large elevations convince.

Lower pressure with α-blockade or an arterial vasodilator: phentolamine 1–5 mg IV boluses or infusion, nicardipine, clevidipine or nitroprusside. Add esmolol for tachycardia only after α-blockade; labetalol alone is a poor choice because its IV β effect is about 7 times its α effect. Patients are volume-contracted, so expand volume as vessels relax. Catecholamine cardiomyopathy with shock may need mechanical support until the tumor is controlled.

Elective resection follows 7–14 days of α-blockade with liberal salt and fluid, then β-blockade (Endocrine Society 2014); in PRESCRIPT (2020, 134 patients), phenoxybenzamine and doxazosin left pressure off target for similar time during surgery. Some centers now operate without routine α-blockade, which guidelines still require. After removal, expect hypotension (vasodilation, residual blockade, low volume) and rebound hypoglycemia; monitor BP, heart rate and glucose closely for 24–48 h.

ICU glycemic control and hypoglycemia

Stress hyperglycemia comes from cortisol, glucagon, epinephrine and cytokines, which drive hepatic gluconeogenesis and block insulin-mediated uptake in muscle, plus steroids, catecholamines, dextrose and nutrition. Hyperglycemia, hypoglycemia and glucose variability are each linked to death.

SCCM 2024 starts a protocol at persistent glucose ≥180 mg/dL, advises against titrating to 80–139 rather than 140–200, suggests IV insulin over subcutaneous in the acute phase, and suggests hourly or more frequent checks while glucose is unstable. ADA uses 140–180 for most critically ill patients and accepts 110–140 for selected patients if hypoglycemia is avoided. Whether patients with poorly controlled diabetes need higher targets is unsettled.

Sedation and β-blockers hide hypoglycemia; risks include sepsis, renal or liver failure, steroid tapers and insulin running after feeds stop. For glucose below 70 mg/dL, stop the insulin, give D50 12.5–25 g IV per protocol and recheck in 15 min. Fingersticks misread in shock, edema and vasopressor use, so use arterial or venous blood and confirm extremes in the lab; maltose (icodextrin dialysate) and high-dose vitamin C falsely raise some meters.

Exam pearls

• Thyroid storm (BWPS ≥45): β-blocker, thionamide, iodine at least 1 h later, hydrocortisone; acetaminophen, never aspirin
• Myxedema coma: hydrocortisone before IV levothyroxine, passive rewarming, early airway
• Low T3 with normal TSH in critical illness is nonthyroidal illness; do not replace hormone
• Adrenal crisis: hydrocortisone 100 mg IV now, then 200 mg/24 h; high potassium only in primary disease
• Septic shock on persistent pressors: hydrocortisone 200 mg/day without a cosyntropin test
• Pituitary apoplexy: sudden headache, visual loss, ophthalmoplegia; steroids first
• Salt wasting and SIADH share labs; volume separates them; never fluid-restrict in SAH
• DI: polyuria, SG <1.005, rising sodium; hyponatremia around day 7 after pituitary surgery
• Pheochromocytoma: α-blockade before any β-blocker
• ICU glucose target 140–180 mg/dL; tighter control raised deaths in NICE-SUGAR