The cortisol stress response induced by surgery: A systematic review and meta‐analysis
Open accessAbstract
Summary: Objective: Surgery is a stressor that can be categorized by duration and severity and induces a systemic stress response that includes increased adrenal cortisol production. However, the precise impact of surgical stress on the cortisol response remains to be defined. Design: We performed a systematic review and meta‐analysis to assess the cortisol stress response induced by surgery and to stratify this response according to different parameters. Methods: We conducted a comprehensive search in several databases from 1990 to 2016. Pairs of reviewers independently selected studies, extracted data and evaluated the risk of bias. Cortisol concentrations were standardized, pooled in meta‐analysis and plotted over time. Results: We included 71 studies reporting peri‐operative serum cortisol measurements in 2953 patients. The cortisol response differed substantially between moderately/highly invasive and minimally invasive surgical procedures. Minimally invasive procedures did not show a peri‐operative cortisol peak, whereas more invasive surgeries caused a cortisol surge that was more pronounced in older subjects, women and patients undergoing open surgery and general anaesthesia. The duration of the procedure and the use of etomidate for induction of anaesthesia did not affect the cortisol response. Conclusions: The peri‐operative cortisol stress response is dynamic and influenced by patient‐specific, surgical and anaesthetic features. However, the available evidence is derived from highly heterogeneous studies, with only two of 71 studies measuring cortisol by mass spectrometry, which currently prevents a precise and reproducible definition of this response.
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A five-fold increase in cortisol secretion, to about 100 mg per day, is common following uncomplicated major elective surgery.
“A fi ve-fold increase in secretion, to about 100 mg of cortisol per day, is common.”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [10]
Section 3.2 and the Discussion report that first-day cortisol output after moderate and highly invasive surgery was about four-fold and 3.5-fold, respectively, relative to healthy unstressed adults—not five-fold. The Discussion’s 100 mg figure refers to a recommended hydrocortisone bolus for patients with adrenal insufficiency, not measured daily cortisol secretion. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPlasma cortisol concentration typically returns to baseline within 24-48 h after uncomplicated major elective surgery.
“Plasma cortisol concentration typically returns to baseline within 24 -48 h [9, 10].”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [10]
The Discussion (§4) identifies return to baseline within 24–48 hours as a suggestion from pre-1990 studies, then says the review's data show the contrary. The Results (§3.2) report that mean cortisol after grade II and III surgery remained elevated relative to baseline up to postoperative day 7. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredFollowing uncomplicated major elective surgery there is a proportionate increase in pro-inflammatory cytokines, CRH, ACTH and cortisol.
“Following uncomplicated major elective surgery there is a proportionate increase in pro-in fl ammatory cytokines, CRH, ACTHandcortisol.”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [10]
The Introduction (page unavailable) describes surgery as activating inflammatory and neurohormonal responses, including CRH release followed by ACTH and cortisol secretion. Section 3.2 (page unavailable) reports increased cortisol output after moderately and highly invasive surgery. The paper does not establish a proportionate increase in pro-inflammatory cytokines, CRH and ACTH alongside cortisol; its reported cortisol output is also slightly lower for grade III than grade II surgery. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn that systematic review, the evidence base was highly heterogeneous and only two of the seven studies employed reference standard mass spectrometry for the measurement of cortisol.
“However, the evidence base was highly heterogeneous and only two of the seven studies employed reference standard mass spectrometry for the measurement of cortisol [10].”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [10]
The Abstract describes the included studies as highly heterogeneous and says that only two measured cortisol by mass spectrometry. But it gives the total as 71 studies, not seven; Results §3.6 also reports two studies using LC-MS/MS. (LLM, conf=0.94)
Experimental — accuracy not yet measuredA recent systematic review and meta-analysis of 71 studies reporting perioperative cortisol concentrations in almost 3000 individuals showed the peri-operative cortisol surge to be most prominent with procedures involving open surgery and general anaesthesia.
“This showed the peri-operative cortisol surge to be most prominent with procedures involving open surgery and general anaesthesia.”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [10]
A recent systematic review of more than 2900 patients undergoing surgery revealed that the perioperative cortisol response is influenced by patient-specific factors in addition to the type of surgery performed.
“A recent systematic review of more than 2900 patients undergoing surgery revealed that the perioperative cortisol response is influenced by patient specific factors in addition to the type of surgery performed.31”
From Adrenal crisis: prevention and management in adult patients (2019) · cites this paper as [31]
Serum total cortisol concentrations in all examined conditions of psychological and physical stress were increased above those observed in healthy, unstressed controls.
“In line with previously reported findings (18–20), we documented that serum total cortisol concentrations in all examined conditions of psychological and physical stress were increased above those observed in healthy, unstressed controls.”
From Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery (2020) · cites this paper as [20]
Indirect calculation of serum free cortisol utilizing cortisol-binding globulin is often inaccurate in the context of acute surgery and critical illness.
“We also used mass spectrometry for the direct measurement of serum free cortisol, an important strength in comparison to studies who only employed indirect calculation of serum free cortisol utilizing cortisol-binding globulin, which is often inaccurate in the context of acute surgery and critical illness (20, 25, 26).”
From Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery (2020) · cites this paper as [20]
An initial decrease in serum cortisol occurs during elective surgery.
“Consistent with our previous systematic review and meta-analysis of the cortisol response to surgery (20), we observed an initial decrease in serum cortisol during elective surgery, which is likely to be linked to the induction of anesthesia.”
From Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery (2020) · cites this paper as [20]
The diurnal rhythm of cortisol can be lost in severe illness or stress, with significant increases in circulating cortisol throughout the entire 24-h period observed in patients with sepsis and during surgical procedures.
“This rhythm can be lost in times of severe illness or stress, with significant increases in circulating cortisol throughout the entire 24-h period observed in patients with sepsis and during surgical procedures [243,244].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [244]
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Cited by
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“throughout the entire 24-h period observed in patients with sepsis and during surgical procedures [243,244].”
Self-citationWoodcock, T., Barker, P., Daniel, S., Fletcher, S., Wass, J. A. H., Tomlinson, J. W., Misra, U., Dattani, M., Arlt, W., & Vercueil, A. (2020) · Anaesthesia · doi:10.1111/anae.14963 · Cited by 163 · see citing works
“However, the evidence base was highly heterogeneous and only two of the seven studies employed reference standard mass spectrometry for the measurement of cortisol [10].”
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Self-citationPerioperative evaluation and management of patients on glucocorticoids
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- Authors
- Prete, A., Yan, Q., Al‐Tarrah, K., Akturk, H. K., Prokop, L. J., Alahdab, F., Foster, M. A., Lord, J. M., Karavitaki, N., Wass, J. A., Murad, M. H., Arlt, W., & Bancos, I.
- Affiliations
- University of Birmingham (GB)
- Mayo Clinic (US)
- Barbara Davis Center for Diabetes University of Colorado School of Medicine Aurora Colorado
- Queen Elizabeth Hospital Birmingham (GB)
- Churchill Hospital (GB)
- Corresponding author
- Bancos, Irina
- ORCID
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2018-08-23
- Volume
- 89
- Issue
- 5
- Pages
- 554-567
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2883038239
- Semantic Scholar
- 624bdd833567a86b286dfe9c1ee12e8647eba72c
- Cited by
- 192
- References
- 122
- Citations by year
- 2026: 35 · 2025: 21 · 2024: 21 · 2023: 24 · 2022: 25 · 2021: 32 · 2020: 20 · 2019: 13
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- cortisol, surgical stress response, minimally invasive surgery, open surgery, general anesthesia, etomidate, age and sex differences
- MeSH terms
- Female, Humans, Hydrocortisone, Male, Postoperative Complications, Mass Spectrometry
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