Corticosteroids have been the cornerstone for treatment of many inflammatory and immune disorders with these beneficial effects well recognized by the medical community. It also possesses many undesirable clinical adverse effects that can occur within 2 weeks of use. Moreover, in the past decade, chronic users of corticosteroids have been linked to skeletal (vertebral and hip) osteoporosis/osteonecrosis with some patients requiring adjunctive antiresprotive medications to counteract fracture prevention. Additionally, two case reports have implicated daily prednisone user to cause osteonecrosis of the mandible. This chapter highlights current adrenal suppression classifications, pathophysiology, drug interactions, and perioperative surgical and anesthesia management.
Key points
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Corticosteroids have beneficial therapeutic properties but it also has a wide range of adverse clinical side effects.
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Most clinicians consider 3 weeks of continuous use of 20 mg of prednisone or its equivalent or higher to cause tertiary adrenal insufficiency and this phenomenon will likely cease after 12 months of drug discontinuation.
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Good perioperative pain control, especially during the postoperative phase, is crucial to decrease cortisol demand.
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High-quality randomized control trials are needed to determine if perioperative “stress dose” steroid is necessary for minor, moderate, and major surgeries.
Introduction
Corticosteroids have been used to treat a variety of anti-inflammatory and immunosuppression conditions such as arthritis (juvenile idiopathic arthritis, psoriatic arthritis, rheumatoid arthritis), polymyalgia rheumatica, autoimmune disease (ie, systemic lupus erythematosus, giant cell arteritis), chronic obstructive pulmonary disease (COPD)/asthma, dermatologic lesions, inflammatory bowel disease, oral mucocutaneous lesions, adjunctive chemotherapy regimen, and organ transplant recipients. It is estimated that 1.2% of the US population is on chronic steroids. With an aging population, OMFS clinicians will likely encounter these patients in their daily practice. Currently, physicians have been reconditioned to prescribe the lowest dose and the shortest course for targeted therapy to avoid numerous undesirable side effects, but unfortunately, some patients may require a lifelong treatment regimen. The purpose of this article is to highlight some of the current adrenal insufficiency classifications, significant drug-to-drug interactions, adverse effects, and current perioperative recommendations for patients taking long-term corticosteroids suffering from these chronic ailments.
Pathophysiology and effects on the hypothalamus-pituitary-adrenal axis
Daily endogenous cortisol production by the adrenal gland is approximately 8 to 10 mg/d or 20 mg/d with a higher output in the morning than in the evening. Cortisol helps regulate a variety of normal physiologic functions in response to stress. It provides anti-inflammatory properties by suppressing prostaglandin production. Impairment of chemotaxis and adequate immune cellular recruitment in particular polymorphonucleocytes and leukocytes, respectively. Hyperglycemia results from gluconeogenesis by the liver and the dysfunction of insulin’s ability to reuptake serum blood glucose into adipose tissue. Enhancement of the cardiovascular system through catecholamine stimulation resulting in increased cardiac output and blood pressure. Promotion of osteoclasts and prevention of osteoblasts function on bone remodeling.
All 3 forms of adrenal insufficiencies can result in a net decrease in cortisol production. Secondary adrenal insufficiency is related to the inability of the anterior pituitary to produce adrenocorticotropic hormone (ACTH) due to the pituitary gland’s dysfunction (ie, tumor, irradiation, surgery, and genetic alterations), whereas tertiary adrenal insufficiency reflects the lack of corticotropin-releasing hormone, and/or arginine vasopressin released by the hypothalamus with chronic steroid administration being the most common etiology. One of vasopressin’s roles is to promote vasoconstriction in response to low blood pressure when sensed by the host’s baroreceptors. Daily consumption of corticosteroids will trigger a negative feedback mechanism aimed to “halt” the body’s natural cortisol production. Currently, most clinicians consider 3 weeks of continuous use of 20 mg of prednisone per day or its equivalent or higher to cause tertiary adrenal insufficiency and this phenomenon will likely cease after 12 months of drug discontinuation. ,
Patients with primary adrenal insufficiency (Addison’s disease), however, lack the inability of the adrenal gland to produce 3 major hormones: mineralocorticoid (aldosterone), glucocorticoids (cortisol), and androgens (dehydroepiandrosterone) predominantly from autoimmune disease when a significant amount of the adrenal gland has been destroyed. Mineralocorticoid deficiency causes hyponatremia, hyperkalemia, and low intravascular volume (blood pressure). In a healthy individual, aldosterone normally stimulates the reabsorption of sodium and water and excretion of potassium at the distal and collecting tubules to help increase blood pressure via the renin-angiotensin-aldosterone-system. Cortisol’s availability is also devoid of its essential properties which are to maintain cardiac output and increase vascular tone to catecholamine during a stressful response. An inadequate amount of these functioning hormones could result in adrenal crisis—a rare condition with potential for fatal outcome with vasodilation and severe hypotension with eventual cardiovascular collapse , , ( Fig. 1 ).
Medication dosages
Prednisone is the most commonly prescribed corticosteroid on the market. Relative potency of 5 mg of prednisone is equivalent to 20 mg of hydrocortisone corresponding to the daily endogenous production. Dexamethasone is 25 times more potent than cortisol and only requires 0.75 mg to have the same equivalency or approximately 4 mg = 100 mg of hydrocortisone ( Table 1 ). Inhalation preparation is commonly prescribed for asthmatics and COPD patients with recommended adult dosing in metered-dose inhaler preparation provided ( Table 2 ).
| Name of Drug | Anti-Inflammatory Potency | Mineralocorticoid Potency | Equivalent Dose (mg) | Duration of Action |
|---|---|---|---|---|
| Cortisol | 1 | 2 | 20 | Short acting < 12 h |
| Hydrocortisone | 0.8 | 2 | 20 | Short acting < 12 h |
| Prednisone | 4 | 1 | 5 | Intermediate acting 12–36 h |
| Prednisolone | 4 | 1 | 5 | Intermediate acting 12–36 h |
| Triamcinolone | 5 | 0 | 4 | Intermediate acting 12–36 h |
| Methylprednisolone | 5 | 0.5 | 4 | Intermediate acting 12–36 h |
| Dexamethasone | 25 | 0 | 0.75 | Long acting > 36 h |
| Inhalation Corticosteroids | Dosages in Metered-Dose Inhaler Preparation | Brand Names | Adult Dosing |
|---|---|---|---|
| Fluticasone propionate | 50, 100, 250 mcg | Flovent | 2 puffs BID |
| Becalometasone Dipropionate | 40 or 80 mcg | Qvar | 1–4 puffs BID |
| Ciclesonide | 80 or 160 mcg | Alvesco | 1–2 puffs BID |
| Triamcinolone acetonide | Azmacort | ||
| Budesonide | 80 or 160 mg | Symbicort | 2 puffs BID |
Adverse reaction/events of corticosteroids
There is no Black Box Warning Label associated with corticosteroids.
Glucocorticoids and Nonsteroidal Anti-Inflammatory Drugs
The combination will increase the risk for gastrointestinal (GI) issues (ie, peptic ulcers and GI bleed). Two separate meta-analyses have demonstrated the adverse effects when these 2 drugs are used together. One study showed 4 times relative increased risk with the combination of glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) when compared to nonusers. Similarly, a second analysis showed a 3 times relative increased risk when this combination is used when compared to nonusers. It also demonstrated an odds ratio of 1.8 when compared to NASIDs user group suggesting approximately twice the relative risk.
Glucocorticoids and Inducers of Cytochrome-450 (CYP3A4)
These inducers of CYP (ie, barbiturate, phenobarbital, phenytoin, carbamazepine, rifampicin, and troglitazone) increase the breakdown of cortisol and therefore will have decreased levels of circulating cortisol. If permissible by physician, these drugs should be discontinued 24 hours before surgery. ,
Glucocorticoids and Inhibitors of Cytochrome-450 (CYP3A4)
The inhibitors of CYP such as the antifungal class of azole (ie, fluconazole and ketoconazole) and antiviral class (ie, ritonavir) decrease the breakdown of cortisol and therefore will have increased levels of circulating cortisol. ,
Despite its effectiveness, chronic systemic steroid therapy has been documented to have numerous major adverse events and a wide range of clinical manifestations from mild to severe forms. These manifestations include dermatologic (cushingoid appearance, weight gain and skin atrophy, ecchymosis, acne), ophthalmologic (cataract, glaucoma), cardiovascular (hypertension, fluid retention, arrhythmia [atrial fibrillation, atrial flutter], premature arteriosclerosis), GI (gastritis, peptic ulcer disease), musculoskeletal (osteoporosis, avascular necrosis, bone fracture), myopathy, psychiatric (mania, depression, euphoria, akathisia, memory impairment, dementia), endocrine (hyperglycemia), immune system (increase risk of infection), and hematological (leukocytosis). Also, recent case reports of medication-related osteonecrosis of the jaw (MRONJ) have been documented.
Chronic inhaled corticosteroids have been shown to induce several intraoral adverse effects such as oral candidiasis, oral hairy leukoplakia, angina bulla hemorrhagic, and Churg-Strauss syndrome with oral candidiasis being the most common finding. The direct local effects of corticosteroids to the oropharyngeal region are from over suppression leading to overgrowth of Candida albicans and the condition is fully reversible upon discontinuation of the drug. For those who are reliant on this therapy, oral water rinses after each use and/or attaching a spacer for these inhalers could significantly reduce these occurrences. If needed, nystatin and fluconazole can be prescribed to treat these fungal infections. Angina bullosa hemorrhage are blood-filled lesions with soft palate being the most common site and are self-limiting within 1 weeks with rupture noted within 48 hours of onset. Churg-Strauss syndrome is a rare inflammatory condition of the blood vessels. Patients with a history of asthma or allergies may display intraoral findings commonly seen as “strawberry gingivitis” secondary to inflamed gingival tissue. Prolonged tongue ulceration is another finding associated with this syndrome.
Patients with rheumatoid arthritis on daily oral prednisone have dose and duration-dependent related adverse effects based on several retrospective studies. Those who took 5 to 10 mg/d of prednisone developed adverse effects such as severe infections, GI bleed, skeletal fracture, and cataract 10 years after the 10 to 15 mg/d group. A nationwide retrospective study in Taiwan investigated 2,623,327 people aged between 20 and 65 years who consumed 5 mg of prednisone per day or its equivalent within 14 days were found to have increased association with (GI bleed, sepsis, and heart failure) within 30 days, which dissipated after 31 to 90 days. Users of high dose with short-term duration have also been implicated. Of the 327,452 adults surveyed in the study for the under 65-year-old group, approximately 47% of these patients developed (sepsis, venous thromboembolism, and fractures) within 30 days only after a 6-day course of medrol-dose pack (105 mg of prednisone equivalent).
Glucocorticoid-induced osteoporosis (GIOP) and osteonecrosis has been well-documented in medical literature in the past decade but not within the dental community. , Specifically, vertebral and hip fractures are directly linked with chronic prednisone users with onset noted as early as 3 months. Excess corticosteroids cause decreased osteoblast production by blocking the Wingless (Wnt)/B-catenin signaling pathway along with osteoblast apoptosis resulting from an increased level of reactive oxygen species. Simultaneously, glucocorticoid exerts a direct effect on osteoblast to increase production of receptor activator of nuclear factor kappa-B (ligand) RANKL available for RANK binding on preosteoclasts cells. Upon forming an RANKL/RANK complex, the osteoclast will differentiate and develop into mature osteoclasts ready for bone resorption. Additionally, osteoblast decreases the secretion of osteoprotegerin (OPG) making it less available to bind with RANKL further tipping the scale toward bone resorption. Lastly, osteocyte’s apoptosis is enhanced thus altering normal bony remodeling resulting in poorer bone quality and increased risk for fracture despite maintaining bone mineral density (BMD) values. The net effect is less bone formation (decrease quantity of osteoblasts, osteocytes, and OPG), more bone resorption (increased osteoclast’s action), decreased vascular endothelial growth factor (less VEGF) resulting in osteoporosis or osteonecrosis bony architecture , ( Fig. 2 ).
