How is hypothermia linked to Adrenocorticotropic Hormone (ACTH) and cortisol levels?

Hypothermia and the HPA Axis: Mechanisms and Clinical Implications

Hypothermia profoundly disrupts the hypothalamic-pituitary-adrenal (HPA) axis through multiple mechanisms: it directly impairs adrenal responsiveness to ACTH stimulation, triggers ACTH-independent cortisol secretion as a stress response, and causes temperature-dependent enzyme dysfunction that affects cortisol synthesis and metabolism.

Direct Adrenal Suppression During Hypothermia

The adrenal glands become functionally unresponsive to ACTH stimulation when body temperature drops below 32°C, with cortisol responses showing only minimal increases (mean rise of 12.5%) compared to normal responses after rewarming (mean rise of 166%). 1

• Below the critical threshold of 32°C, ACTH stimulation tests produce misleading results with depressed cortisol responses (mean absolute rise of only 5.0 μg/dL versus normal responses of >7-9 μg/dL) 1
• This represents a temperature-dependent threshold effect where adrenal responsiveness progressively deteriorates as core temperature falls 1
• ACTH stimulation testing should never be performed in hypothermic patients until body temperature normalizes, as results will falsely suggest adrenal insufficiency 1

ACTH-Independent Cortisol Secretion

During cold exposure, the adrenal glands shift to an ACTH-independent mechanism of cortisol secretion, breaking the normal inverse relationship between ACTH and cortisol levels. 2

• Autopsy studies of hypothermia deaths demonstrate maintained or elevated serum cortisol levels despite the absence of correlation with ACTH concentrations 2, 3
• Immunohistochemical analysis shows cortisol localizes primarily to the nucleus rather than cytoplasm of zona fasciculata cells during hypothermia, suggesting altered cellular trafficking 2
• Cell culture experiments confirm that cold exposure triggers slow, sustained corticosterone secretion (15-20 minutes) independent of ACTH stimulation 2
• Serum ACTH levels in fatal hypothermia cases remain similar to clinical reference values, while CSF ACTH levels are significantly lower than other causes of death 3

Physiological Effects of Therapeutic Hypothermia

Mild induced hypothermia (33-36°C) causes predictable endocrine changes including decreased insulin sensitivity, insulin secretion, and hyperglycemia, but the cortisol response pattern has prognostic significance. 4

• Hypothermia reduces drug clearance by up to 30% at 34°C, affecting sedatives, neuromuscular blockers, and potentially corticosteroid metabolism 4
• The bradycardia induced by mild hypothermia may be beneficial, similar to beta-blocker effects, and its occurrence associates with good neurological outcomes 4
• Electrolyte abnormalities are common, including hypophosphatemia, hypokalemia, hypomagnesemia, and hypocalcemia, which can confound interpretation of adrenal function 4

Cortisol as a Prognostic Biomarker in Neonatal Hypothermia

In neonates undergoing therapeutic hypothermia for birth asphyxia, persistently elevated cortisol levels after 24 hours of cooling predict adverse neurological outcomes at 18 months. 5

• Neonates with good neurological outcomes show significantly lower serum cortisol after 24 hours of hypothermia (28.7 ng/mL) compared to those with adverse outcomes (344 ng/mL, p=0.01) 5
• The cortisol concentration decreases more gradually during therapeutic hypothermia in infants who develop adverse neurological sequelae 5
• This suggests that monitoring cortisol trends during therapeutic hypothermia provides prognostic information beyond initial clinical assessment 5

Critical Illness-Related Corticosteroid Insufficiency (CIRCI) Considerations

Hypothermia complicates the diagnosis of CIRCI because both conditions can present with hypotension and altered cortisol dynamics, but the mechanisms differ fundamentally. 4

• During critical illness, plasma ACTH levels follow a dynamic pattern with transiently elevated levels and subsequent decline over weeks, making single measurements unreliable 4
• The 250-μg ACTH stimulation test remains the recommended diagnostic approach for CIRCI, but interpretation must account for temperature effects 4
• Corticotropin levels are not recommended for routine CIRCI diagnosis due to measurement complexity and lack of rapid turnaround time 4

Clinical Pitfalls and Management Implications

Never delay treatment of suspected adrenal crisis to perform diagnostic testing in hypothermic patients, as hypothermia itself mimics adrenal insufficiency and mortality is high if untreated. 4, 6

• Hypothermia in trauma patients increases mortality, blood loss, and transfusion requirements through combined effects on coagulation, enzyme function, and hemodynamics 4
• A core temperature <34°C in trauma patients requiring massive transfusion carries >80% mortality risk independent of shock severity and coagulopathy 4
• Forced air warming, warm fluid therapy, and in extreme cases extracorporeal rewarming should be initiated immediately 4
• If adrenal insufficiency is suspected in a hypothermic patient, administer stress-dose hydrocortisone (100 mg IV) immediately while initiating rewarming measures, then reassess adrenal function after normothermia is achieved 6, 1

Temperature-Dependent Enzyme Dysfunction

Hypothermia causes a 10% reduction in coagulation factor function for every 1°C drop in temperature, and similar temperature-dependent effects likely affect cortisol synthesis enzymes including 21-hydroxylase and 11β-hydroxylase. 4

• Standard laboratory coagulation tests (PT, aPTT) performed at 37°C fail to detect the functional impairment present at lower body temperatures 4
• This same principle applies to cortisol assays—measurements performed at standard laboratory temperatures may not reflect the actual functional cortisol activity at hypothermic body temperatures 4