Perioperative Evaluation and Management of Patients on Glucocorticoids

Stanley M. Chen Cardenas; Prasanna Santhanam; Lilah Morris-Wiseman; Roberto Salvatori; Amir H. Hamrahian

J Endo Soc. 2023;7(2)

Abstract and Introduction

Abstract

Myriad questions regarding perioperative management of patients on glucocorticoids (GCs) continue to be debated including which patients are at risk for adrenal insufficiency (AI), what is the correct dose and duration of supplemental GCs, or are they necessary for everyone? These questions remain partly unanswered due to the heterogeneity and low quality of data, studies with small sample sizes, and the limited number of randomized trials. To date, we know that although all routes of GC administration can result in hypothalamic-pituitary-adrenal (HPA) axis suppression, perioperative adrenal crisis is rare. Correlation between biochemical testing for AI and clinical events is lacking. Some of the current perioperative management recommendations based on daily GC dose and duration of therapy may be difficult to follow in clinical practice. The prospective and retrospective studies consistently report that continuing the daily dose of GCs perioperatively is not associated with a higher risk for adrenal crises in patients with GC-induced AI. Considering that oral GC intake may be unreliable in the early postoperative period, providing the daily GC plus a short course of IV hydrocortisone 25 to 100 mg per day based on the degree of surgical stress seems reasonable. In patients who have stopped GC therapy before surgery, careful assessment of the HPA axis is necessary to avoid an adrenal crisis. In conclusion, our literature review indicates that lower doses and shorter duration of supplemental GCs perioperatively are sufficient to maintain homeostasis. We emphasize the need for well-designed randomized studies on this frequently encountered clinical scenario.

Introduction

Glucocorticoids (GCs) are one of the most commonly prescribed drugs with an estimated use prevalence of approximately 1% of the US population.^[1] They are very effective anti-inflammatory medications and considered first-line treatment for many autoimmune conditions. One important consequence of supraphysiological and/or long-term GC treatment is the potential for hypothalamic-pituitary-adrenal (HPA) axis suppression leading to GC-induced adrenal insufficiency (AI), which is associated with increased morbidity and mortality.^[2] When associated with a stressor such as a surgical procedure, HPA axis suppression can result in adrenal crisis. This outcome was recognized in early-20th-century studies when adrenalectomized dogs experienced circulatory shock after laparotomy that could be prevented by administering GCs.^[3,4] In the 1950s, multiple reports described patients on chronic GC therapy for rheumatoid arthritis who died shortly after orthopedic surgery. Postmortem examinations consistently revealed bilateral adrenal atrophy, leading to the conclusion that the adrenal glands' inability to respond to surgical stress was the cause of death.^[5–7] The resultant concern about postoperative adrenal crisis in patients on GCs led to the routine use of high-dose perioperative GC replacement in clinical practice.

Currently, there is little high-quality evidence supporting routine perioperative use of high-dose GCs.^[8–11] While underdosing perioperative GCs may place patients at risk for cardiovascular collapse, high doses carry a risk of hyperglycemia, hypertension, opportunistic infections, bone loss in a state of immobility, venous thromboembolism, and poor wound healing.^[12–14] This review outlines the key physiologic aspects of the stress response to surgery, the effect of different forms of GCs on the HPA axis, the evidence for perioperative GC administration, and our personalized approach to perioperative management in adults with GC-induced AI.

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Table 1. Surgical stress associated with common surgical procedures, based on the modified Johns Hopkins surgical criteria [32]
Grade	General Characteristics	Characteristic Operations
Grade I (Minor)	Minimal to mild risk independent of anesthesia Minimal to moderately invasive procedure Potential blood loss of < 500 mL	Minor general surgical procedures (skin/subcutaneous tissue procedures, inguinal hernia repair, breast biopsy) Endoscopy (including cystoscopy, hysteroscopy, bronchoscopy, minor laparoscopy, arthroscopy) Minor gynecologic procedures (tubal ligation, dilation, and curettage) Minor otolaryngology procedures (myringotomy tubes, tonsillectomy/rhinoplasty)
Grade II (Moderate)	Moderate risk independent of anesthesia Moderately to significantly invasive procedures Potential blood loss of 500–1500 mL	Open or laparoscopic resection/reconstruction of the digestive tract; cholecystectomy Thyroidectomy Cystectomy, nephrectomy Hysterectomy or myomectomy Laminectomy Joint replacement
Grade III (Major)	Major to critical risk independent of anesthesia Highly invasive procedure Potential blood loss >1500 mL Usual postoperative intensive care unit stay with invasive monitoring	Any major orthopedic-spinal, oropharyngeal, or genitourinary repair or reconstruction Any intracranial, major vascular, or cardiothoracic procedure

Table 2. Pharmacological properties of frequently used glucocorticoids [65–68]
Classification	Equivalent Glucocorticoid Dose (mg)	Glucocorticoid Activity	Mineralocorticoid Activity	Biological Half-Life (hours)	Plasma Half- Life (hours)	Bound in Plasma (%)
Short Acting
Hydrocortisone	20	1	1	8–12	1.3–2.3	90
Cortisone acetate	25	0.8	0.8	8–12	0.5	—
Deflazacort	5	4	1	<12	1.3–1.9	40
Intermediate-Acting
Prednisone	5	4	0.8	12–36	2–4	75
Prednisolone	5	4	0.8	12–36	2–4	95
Methylprednisolone	4	5	0.5	12–36	2–4	78
Triamcinolone	4	5	Negligible	12–36	0.5	68
Long-Acting
Betamethasone	0.6	25–30	Negligible	36–72	5	64
Dexamethasone	0.375–0.75	30–40	Negligible	36–72	3.5–5	68

Table 3. Common drugs affecting the hypothalamic-pituitary adrenal axis [92, 97, 110, 111]
Drugs Affecting CRH and ACTH Synthesis or Secretion
Opioids (morphine, oxycodone, fentanyl, tramadol, methadone, heroin) Benzodiazepines (midazolam, oxazepam, alprazolam, diazepam) Megestrol Acetate Medroxyprogesterone
Drugs Affecting Cortisol Synthesis
Azoles (Ketoconazole/Levoketoconazole, Posaconazole, fluconazole) Etomidate Metyrapone, Aminoglutethimide Trilostane
Drugs Affecting Cortisol Action
Mifepristone
Drugs Affecting Cortisol Metabolism
Cytochrome P450 3A4 Inhibitors (Decrease Cortisol Metabolism)	Cytochrome P450 3A4 Inducers (Increase Cortisol Metabolism)
Protease inhibitors (darunavir, indinavir, lopinavir, nelfinavir, telaprevir, ritonavir)	Antiepileptic drugs (phenytoin, fosphenytoin, phenobarbital, primidone)
Cobicistat, Azoles (itraconazole, voriconazole), clarithromycin, Grapefruit juice, mifepristone	Carbamazepine, rifampin, and mitotane
Calcium channel blockers (verapamil, diltiazem), amiodarone, cimetidine, conivaptan, erythromycin, and imatinib^b	Nafcillin, rifabutin, bosentan, dorafenib, efavirenz, rifabutin, St John's wort^a

^aLess potent inducers.
^bLess potent inhibitors.

Table 4. Studies addressing supplemental perioperative glucocorticoid treatment
Source	Type of Study	Population	Perioperative Glucocorticoid Regimen	Total Dose per Day	Duration of the Protocol	Type of Surgery	Outcome
Solem 1962 [136]	Prospective	Heterogeneous (n = 78)	Group 1: A 7-day cortisone regimen for those under chronic glucocorticoid at the time of surgery vs Group 2: As needed therapy for those who stopped glucocorticoids > 4 weeks pre-op	100 mg 1 day pre-op 300–400 mg day 1 200 mg day 2 150 mg days 3–4 100 mg days 5–6 Baseline dose day 7	7 days	Various Mostly major stress	No AI in either group
Lloyd 1981 [137]	Prospective	RA (n = 61)	Group 1: Hydrocortisone once, then only if post-op hypotension vs Group 2: PRN hydrocortisone Patients in both groups were on their chronic glucocorticoid regimen	100 mg day 1	1 day	Various orthopedic procedures	PRN regimen was favored
Symbreg 1981 [118]	Prospective	Heterogeneous (n = 22)	Group 1: Controls not previously exposed to glucocorticoids Group 2: Hydrocortisone treatment if abnormal CST vs Group 3: Monitoring if normal CST^b	125 mg day 1	1 day	Various Mostly major stress	No AI in either group^a
Shapiro 1990 [139]	Prospective	Renal transplant (n = 13)	Group 1: Continued their daily dose of prednisone (no supplemental glucocorticoids were given)	5–20 mg	n/a	Allograft Nephrectomy	No AI with continuing daily dose of prednisone
Bromberg 1991 [138]	Prospective (Cohort)	Renal Transplant (n = 40)	Group 1: Same population Controls Group 2: Continue daily dose of prednisone (no supplemental glucocorticoids were given)	5–10 mg	n/a	Various surgical and non-surgical stress	No AI with continuing daily dose of prednisone
Friedman 1995 [140]	Prospective	RA, renal transplant (n = 28)	Group 1: Continued their daily dose of prednisone (no supplemental glucocorticoids were given)	1–20 mg	n/a	Major orthopedic surgeries	No AI with continuing daily dose of prednisone
Bromberg 1995 [143]	Prospective	Renal transplant (n = 52)	Group 1: Continued their daily dose of prednisone (no supplemental glucocorticoids were given)	5–15 mg	n/a	Various	No AI with continuing daily dose of prednisone
Glowniak 1997 [133]	Randomized controlled trial	Heterogeneous (n = 17)	Group 1: Daily dose + stress dose hydrocortisone vs Group 2: Daily dose + saline (placebo)	200 mg day 1 100 mg day 2 50 mg day 3	3 days	Various	No additional benefit from stress dose hydrocortisone
Thomason 1999 [135]	Randomized controlled trial Crossover	Organ transplant (n = 20)	Group 1: Daily dose + single stress dose hydrocortisone vs Group 2: Daily dose + saline (placebo)	100 mg	1 day	Gingival surgeries Minor stress	No additional benefit from stress dose hydrocortisone No AI in either group
Mathis 2004 [141]	Retrospective	Renal Transplant (n = 58)	Group 1: Stress dose glucocorticoids vs Group 2: No stress dose^b	n/a	n/a	Lymphocele drainage	No additional benefit from stress dose glucocorticoids and more hyperglycemia was reported
Zaghiyan 2011 [144]	Retrospective	IBD (n = 49)	Group 1: Stress dose glucocorticoids vs Group 2: No stress dose	100 mg (incision) 300 mg day 1 Taper to prednisone 20 mg per day	4 days	Major abdominal surgeries	No additional benefit from stress dose glucocorticoids No AI in either group
Zaghiyan 2012 [145]	Prospective	IBD (n = 32)	Group 1: Patient not currently on glucocorticoid (but previously exposed during the past 12 months) received no treatment perioperatively vs Group 2: Patients currently on glucocorticoids receiving low-dose supplemental glucocorticoids perioperatively	One-third of pre-op dose (incision) One-third of the dose Q8hrs day of surgery One-fourth Q8hr day 1 One-sixth Q8hr day 2 One-fourth Q12hr day 3 Prednisone equivalent day 4	4 days	Major abdominal surgeries	No AI in either group Low-dose supplemental glucocorticoid regimens seem safe
Zaghiyan 2012 [146]	Retrospective	IBD (n = 97)	Group 1: High (stress) dose glucocorticoids vs Group 2: Low-dose supplemental glucocorticoid (see [145])	100 mg (Incision) 300 mg day 1 Taper to prednisone	4 days	Major abdominal surgeries	No AI in either group No additional benefit from high-dose stress glucocorticoids
Ayatac 2013 [147]	Retrospective	IBD (n = 235)	Group 1: Daily dose + Stress dose glucocorticoids vs Group 2: Daily dose (unless off glucocorticoids preoperatively) + no stress dose	100 mg (operating room) 300 mg day 1 Then taper	n/a	Major abdominal surgeries	One case of AI in group 1. No additional benefit or harm was seen from stress dose glucocorticoids
Zaghiyan 2014 [134]	Single blinded randomized controlled trial	IBD (n = 92)	Group 1: Stress dose hydrocortisone vs Group 2: Hydrocortisone equivalent to oral daily dose	100 mg (incision) 300 mg day 1 225 mg day 2 150 mg day 3 100 mg day 4 20 mg Prednisone	5 days	Major abdominal surgeries	No additional benefit from stress dose glucocorticoids

Excluded studies where both chronic glucocorticoids and supplemental treatment were not provided [33, 148].
AI, adrenal insufficiency; CST, cosyntropin stimulation test; IBD, inflammatory bowel disease; n/a, not available; RA, rheumatoid arthritis.
^a125 mg resulted in higher cortisol levels than nonexposed.
^bUnclear if patients were receiving or stopped chronic glucocorticoids at the time of surgery.

Table 5. Perioperative treatment regimens suggested for patient with glucocorticoid-induced AI
Regimen	Degree of Surgical Stress	Glucocorticoid Regimen
Patients currently on glucocorticoids	Garde I Minor	• Continue daily dose of glucocorticoid • 25 mg of IV hydrocortisone at induction if not able to tolerate PO • Resume oral daily preoperative glucocorticoid regimen
	Grade II Moderate	• Continue daily dose of glucocorticoid • 25–50 mg of hydrocortisone IV at induction • 15–25 mg hydrocortisone every 6 hours. until PO is tolerated and hemodynamically stable^a • Resume oral daily preoperative glucocorticoid regimen
	Grade III Major	• Continue daily dose of glucocorticoid • 50 mg of hydrocortisone IV at induction • 25 mg of hydrocortisone IV every 6 hours on day 1 and until hemodynamically stable, then 15 mg IV every 6 hours until PO is tolerated^a • Resume oral daily preoperative glucocorticoid regimen
Patients who stopped or plan to stop glucocorticoids before surgery		• Assess HPA axis in patients with intermediate to high risk (see Table 4) • The closer the date of discontinuing glucocorticoids before surgery, the higher the risk of AI • Treat based on the degree of surgical stress in those who have abnormal HPA axis
Adrenal crisis		• 100 mg of hydrocortisone IV (IM if no IV access) • 50 mg every 6 hours until hemodynamically stable and then taper^a • Taper depending on clinical response-intravenous fluids (normal saline), dextrose 5% if hypoglycemia

These recommendations include the authors' personalized approach to perioperative management in patients with glucocorticoid-induced AI.
AI, adrenal insufficiency; HPA, hypothalamic-pituitary-adrenal; IM, intramuscular; IV, intravenous; PO, by mouth.
^aSome experts favor continuous glucocorticoid infusion.

Table 6. Review articles that commented on perioperative glucocorticoid treatment regimen
Source	Year	Comments from the Authors	Conclusions on Treatment
Kehlet [151]	1975	"Glucocorticoid should only be given in a necessary and adequate dose" to avoid side effects	Most regimens are founded on empirical basis
Salem [8]	1994	The risk should be individualized based on the glucocorticoid preoperative dose, duration, and type of surgery	We are giving too much glucocorticoids
De Lange [157]	2008	There is no evidence to support excessive dosing (>200 mg hydrocortisone equivalent/day) or extensive duration in uncomplicated cases	We are giving too much glucocorticoids
Marik [158]	2008	"Stress doses are not routinely required as long as the patient continues their usual daily dose of glucocorticoids"	We are giving too much glucocorticoids
Fleager [155]	2010	"There are no evidence-based treatment guidelines that provide firm recommendations for the administration of perioperative steroids"	No evidence for current practice
Kelly [159]	2013	Based on the existing evidence, patients on long-term glucocorticoids do not require the once-standard high doses; just continue their maintenance doses perioperatively. Treat refractory hypotension with rescue doses of steroids	We are giving too much glucocorticoids
Hicks [160]	2015	"Current prescribing practices are highly variable, likely because of a lack of randomized controlled data and a wide range of preoperative treatment regimens"	"Recent data suggest that additional corticosteroid supplementation in the perioperative period may be unnecessary and may serve only to increase the risk of poor wound healing and infectious"
MacKenzie [161]	2016	"Despite little evidence for this practice (supraphysiological supplemental perioperative glucocorticoids), few have challenged this treatment paradigm"	"With few exceptions, the use of supraphysiologic glucocorticoid therapy for adults with presumed adrenal insufficiency due to exogenous glucocorticoid use should be regarded as unnecessary"
Liu [156]	2017	"Recommendations in major textbooks are confusing, inconsistent, and lacking in class A or B evidence"	There is no universal agreement regarding dose, duration, or regimen of supplemental glucocorticoid
Groleau [9]	2018	"It is not possible to conclude that perioperative administration of corticosteroids, compared to placebo, reduced the incidence of adrenal insufficiency"	Providing the daily maintenance dose without supplemental glucocorticoids may be sufficient
Khazen [162]	2018	"We found no evidence to support the use of supraphysiologic dose of glucocorticoid therapy provided the patient receive their usual dose of glucocorticoid preoperatively"	"A well-designed, large multicenter RCT is warranted"
Chilkoti [66]	2019	"There are no dogmatic guidelines regarding perioperative "stress dose" of steroids in patients on chronic steroid therapy; however, there is enough evidence that patients on long-term exogenous steroid therapy do not require the conventional high-dose perioperative corticosteroid, instead must be kept on their baseline maintenance dose"	We are giving too much glucocorticoids
Manou-Stathopoulou [163]	2019	"Clinical trials exploring glucocorticoid supplementation have provided conflicting data, reflecting the lack of understanding of the cortisol biology during the perioperative period"	More personalized targeted therapies are needed
Seo [11]	2021	Many clinical trials have low level of evidence, lack of power, without clear criteria for AI that results in high variation in the recommendations	No evidence for current practice
Laugesen [10]	2021	"Current evidence indicates substantial variation regarding risk and course of glucocorticoid-induced adrenal insufficiency … more research is needed to refine the diagnosis and to support evidence-based clinical decision-making"	No evidence for current practice

Many review articles discuss the topic and make recommendations without specific comments about the current practice.
AI, adrenal insufficiency; RCT, randomized controlled trial.

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Perioperative Evaluation and Management of Patients on Glucocorticoids

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