Supplemental Corticosteroids for Dental Patients with Adrenal

DENTISTRY & MEDICINE ABSTRACT

Background. Dental patients with primary or secondary adrenal

insufficiency, or AI, may be A D A at risk of experiencing J ✷ ✷ adrenal crisis during or 

after invasive procedures. O N I Since the mid-1950s, sup- T T Supplemental I A N U C I U plemental steroids in A N G E D R 3 corticosteroids for rather large doses have TICLE been recommended for patients with AI to prevent adrenal crisis. dental patients with Methods. To evaluate the need for supplemental steroids in these patients, the adrenal insufficiency authors searched the literature from 1966 to 2000 using MEDLINE and textbooks for Reconsideration of the information that addressed AI and adrenal crisis in dentistry. Reference lists of rele- problem vant publications and review articles also were examined for information about the topic. CRAIG S. MILLER, D.M.D., M.S.; JAMES W. LITTLE, Results. The review identified only four D.M.D., M.S.; DONALD A. FALACE, D.M.D. reports of purported adrenal crisis in dentistry. Factors associated with the risk of adrenal crisis included the magnitude of or more than 50 years, medicine and dentistry surgery, the use of general anesthetics, the have appreciated the importance of the adrenal health status and stability of the patient, glands in maintaining physiological integrity. and the degree of pain control. This appreciation grew from studies1,2 in the Conclusions. The limited number of 1930s that demonstrated that adrenocortical reported cases strongly suggests that insufficiencyF was associated with electrolyte disturb- adrenal crisis is a rare event in dentistry, ances, and a decade later3 that cortisol prevented hypo- especially for patients with secondary AI, volemia and circulatory collapse associ- and most routine dental procedures can be ated with adrenalectomy. During the performed without glucocorticoid Adrenal crisis is 1940s, organic chemists isolated and supplementation. Clinical Implications. The authors a rare event in elucidated the structures of 28 steroids 4 identify risk conditions for adrenal crisis dentistry, from the adrenal cortex. It was against this background that Hench and col- and suggest new guidelines to prevent this and most leagues5,6 reported the beneficial effects problem in dental patients with AI. routine dental of cortisone in the treatment of diseases procedures can other than adrenocortical insufficiency be performed (for example, rheumatoid arthritis). without These findings ushered in the era of glu- became the standard of care for many 8 glucocorticoid cocorticoid therapy for patients with pri- years. mary adrenal insufficiency, or AI, and Although these recommendations have supplementation. inflammatory connective-tissue disease. served as important guidelines, knowl- The concept of secondary AI evolved edge of the adrenal cortical response to in the early 1950s from reports of patients experiencing physical stressors has been refined refractory hypotension at the end of routine surgical during the past 30 years.9-11 Based on procedures and dying hours later as a consequence of these more recent findings, reconsidera- glucocorticoid therapy withdrawal and resultant AI.7,8 tion of the guidelines for perioperative These outcomes resulted in a list of recommendations glucocorticoid supplementation in den- for perioperative glucocorticoid supplementation that tistry appears needed. We consider gluco-

corticoid supplementation in dentistry by ad- istered at a target equal to, or less than, the dressing AI, current medical recommendations, normal daily output of cortisol (that is, 20 to 30 adrenal crisis and identification of risk in den- milligrams per day).18 For example, hydrocorti- tistry, and prescribing guidelines for periopera- sone, which has the equivalent anti-inflammatory tive coverage. potency of cortisol, usually is administered at 20 mg/day; prednisone and prednisolone, which ADRENAL INSUFFICIENCY have four times the anti-inflammatory potency of The adrenal cortex produces mineralocorticoids cortisol, usually are administered at 5 mg/day; and glucocorticoids that are important in main- and dexamethasone, which has 25 times the taining fluid volume. Cortisol, the principal glu- anti-inflammatory potency of cortisol, is admin- cocorticoid, maintains extracellular fluid, istered at 0.75 mg/day. whereas aldosterone, the principal mineralocorti- Such regimens, when administered as a coid, regulates salt and water balance.12 Insuffi- morning dose, are less suppressive because of cient production of these hormones can result the diurnal rhythm of cortisol secretion, from primary or secondary adrenal disease. Pri- resulting in highest levels in the morning. mary adrenocortical insufficiency, also known as Higher and divided daily doses are more sup- Addison’s disease, is uncommon, occurring in pressive, and often begin producing clinical man- about eight people per million population per ifestations of glucocorticoid excess (that is, year, with a prevalence of about 40 to 100 per Cushing’s syndrome) after three weeks of use.20 million.13-15 Although the level of cortisol production in It is caused by a progressive destruction of the patients with secondary AI due to hypothalamic adrenal cortex, usually of an idiopathic nature or pituitary disease can be low because of its (most commonly autoimmune), but also results dependence on the level of circulating ACTH, the from hemorrhage, sepsis, infectious diseases administration of corticosteroids alone does not (such as tuberculosis, human immunodeficiency determine which patients secrete sufficient virus, cytomegalovirus and fungal infection), levels of cortisol in response to stress. For malignancy, adrenalectomy, amyloidosis or example, the average cortisol production rate in drugs.16 Clinical evidence of the deficiency gener- patients with Cushing’s syndrome has been ally arises only after 90 percent of the adrenal reported to be 36 mg/day.21 cortices have been destroyed.17 Affected patients The table presents the signs and symptoms have high levels of adrenocorticotropic hormone, associated with AI and corticosteroid treatment. or ACTH, in blood, and a very low to undetect- The manifestations of primary AI (Addison’s dis- able level of aldosterone and cortisol in blood. ease) relate to a deficiency of aldosterone and Cortisol levels during this disease do not cortisol. The most common complaints are weak- increase in response to stress and ACTH. ness, fatigue and nausea. The most common sign Secondary adrenocortical insufficiency results is melanin hyperpigmentation of the skin and from hypothalamic or pituitary disease, or from mucous membranes. Hypotension, anorexia, the administration of exogenous corticosteroids. fever and weight loss are common findings. Although classified together, these two entities In secondary AI, the severity of symptoms is have different physiological effects. In the ab- often less marked, and normal mineralocorticoid sence of hypothalamic or pituitary function, the function is preserved. The preservation of miner- adrenal cortex undergoes irreversible atrophy.18 alocorticoid function makes it less likely for In contrast, long-term administration of cortico- patients with secondary AI to experience adrenal steroids blunts adrenal cortical function, with crisis than it is for patients with primary AI. variable and reversible effects.19 Cases of Cushing’s syndrome, which is due to chronic glu- hypothalamic-pituitary disease are less common cocorticoid excess, produces several features rec- than those induced by use of corticosteroids. Re- ognizable to the dentist, including plethora (red searchers estimate that 5 percent of adults in the face), moon face, hirsutism, acne, capillary United States regularly use corticosteroids20 and fragility and bruising, hypertension, osteoporosis are at risk of developing secondary adrenocor- and muscle weakness. tical insufficiency. Depending on the inflammatory condition, ADRENAL CRISIS corticosteroids in medicine generally are admin- The most significant acute adverse outcome of AI

TABLE FEATURES OF ADRENAL INSUFFICIENCY.

VARIABLE PRIMARY ADRENAL SECONDARY ADRENAL CUSHING’S SYNDROME ADRENAL CRISIS INSUFFICIENCY INSUFFICIENCY

Underlying Glucocorticoid and Glucocorticoid Potential glucocor- Severe glucocorticoid Problem mineralocorticoid deficiency due to ticoid insufficiency deficiency with or deficiency due to hypothalamic or due to long-term without mineralo- destruction or pituitary disease administration of corticoid deficiency due atrophy of corticosteroid for to stress (for example, adrenal gland inflammatory surgery, infection) and condition or organ inability of adrenal transplantation cortex to meet demand

Clinical Weakness, Similar to Cushingoid Major categories: Features fatigability, weight primary adrenal features: weight dGastrointestinal loss, hypotension insufficiency gain, moon face, (nausea, vomiting, (may be ortho- except less thin skin, buffalo diarrhea, stomach static), hyperpig- dramatic, no hump (that is, fat cramps) mentation of skin, hyperpigmenta- pad on neck), dHypotension, weak mucous mem- tion and patients central obesity, pulse, profuse branes and creases; tend not to be acne, bruisability, sweating, weak- less common are salt-depleted hypertension ness, fatigue anorexia, nausea, or extracellular dHeadache, sunken vomiting, abdom- volume–depleted eyes, cyanosis inal pain, salt dFever, dehydration, craving, myalgia, dyspnea progres- personality sing to hypothermia changes, diarrhea, dMyalgias, malaise; body hair arthralgia loss in women; history of HIV* or TB† infection

Laboratory Hyponatremia, Fluid and Can be normal or Hyponatremia and Features hyperkalemia, electrolyte abnormal based on eosinophilia, elevated BUN,‡ disturbances are underlying hypoglycemia, occasionally less common than condition azotemia hypercalcemia, low in primary dis- serum glucose level ease except mild with sensitivity to hyponatremia, fasting, mild hypoglycemia, anemia, mild anemia and eosinophilia eosinophilia

Therapy Glucocorticoid and Glucocorticoid Addition of steroid- Intravenous bolus of mineralocorticoid sparing drugs 100 milligrams of (azathioprine, hydrocortisone, fluid methotrexate can and electrolyte reduce the adverse replacement effects of steroids)

* HIV: Human immunodeficiency virus. † TB: Tuberculosis. ‡ BUN: Blood urea nitrogen.

is adrenal crisis. This event can occur when a myalgias, arthralgia, hyponatremia and patient with AI, most commonly in the form of eosinophilia. If not treated rapidly, the patient Addison’s disease, is challenged by stress (for may develop hypothermia, severe hypotension, example, illness, infection or surgery), and, in hypoglycemia, confusion and circulatory collapse response, is unable to synthesize adequate that can culminate in death.22 amounts of cortisol and aldosterone. This poten- Adrenal crisis is rare in patients with sec- tially life-threatening emergency usually evolves ondary AI, because the majority of these patients slowly during a few hours and then is manifested have normal aldosterone levels.17 Since the mani- by severe exacerbation of the condition, includ- festations usually are limited to those of gluco- ing profuse sweating, hypotension, weak pulse, corticoid deficiency, the features of rapid cyanosis, nausea, vomiting, weakness, headache, hypotension, dehydration and shock seldom are dehydration, fever, sunken eyes, dyspnea, encountered in patients with secondary AI.12

Features more commonly involve hypoglycemia, General anesthesia. General anesthesia in weakness, gastrointestinal complaints and a corticosteroid-treated patients significantly slowly evolving hypotension. depresses the plasma cortisol response to surgery Adrenal crisis requires immediate intravenous compared with that in patients who have not administration of a glucocorticoid—usually a received corticosteroid drugs.31,32 This may be an 100-mg hydrocortisone bolus—and intravenous effect of steroid-induced AI or the use of barbitu- fluid and electrolyte replacement to restore the rate anesthetic drugs that can lower cortisol blood pressure. Intramuscular injection of gluco- production.30,33 corticoid is less desirable for emergency treatment Although the role of these factors has not been because it results in slow absorption. After the ini- fully determined, several prospective studies have tial treatment, 100 mg of hydrocortisone is admin- shown that the vast majority of patients who reg- istered slowly intravenously every six to eight ularly take the daily equivalent dose of steroid or hours during the first 24 hours, along with fluid less (that is, mean dose, 5 to 10 mg of prednisone replacement, vasopressors and correction of hypo- daily) for renal transplantation or rheumatoid glycemia, if needed. Resolution of the event or con- arthritis maintain adrenal function and do not dition that precipitated the crisis also is required. require supplementation for minor surgical procedures.31,34,35 Furthermore, for minor surgery, the MEDICAL RECOMMENDATIONS risk of adrenal crisis appears to be low. A signifi- Since the mid-1950s, supplemental steroids have cant proportion of patients receiving prednisone been recommended before and during surgery to therapy (5 to 50 mg daily) for between six days prevent adrenal crisis in patients who receive and 10 years who stopped therapy before surgery steroid therapy.7,8 The consensus among the med- produced plasma cortisol levels similar to those of ical community has been to provide “stress cov- healthy subjects for up to seven days after minor erage” of 200 mg of hydrocortisone or its equiva- or major surgery, and followed a normal postoper- lent in the morning and 100 mg in the evening ative course.29,32,34 during periods of acute stress (such as surgery), Salem and colleagues26 suggested that clini- trauma or illness.16,17 This regimen is based on cians replace glucocorticoids only in an amount clinical inferences from case reports that the cor- equivalent to the normal physiological response tisol secretion rate increases during acute stress to surgical stress, and that the risk of an adverse and can reach levels in the range of 100 to 300 mg outcome depends on the duration and severity of per day.17,23-25 However, cortisol secretion in the the surgery, the preoperative glucocorticoid dose first 24 hours after surgery rarely exceeds 200 and the overall health of the patient. Kehlet and mg,10,26 and the plasma cortisol level required to Binder10 and Hume and colleagues24 estimated maintain homeostasis following stress has not that an average adult secretes 75 to 150 mg a been defined precisely. day in response to major surgery, and 50 mg a The recommendations described above recently day during minor procedures. Based on these have undergone revision,9,26 with emphasis placed findings, Salem and colleagues26 made the fol- on reducing the dose of supplemental steroid lowing general surgery and general anesthesia based on factors that influence cortisol demand. recommendations. We review some of these factors below. Minor surgical stress. For minor surgical Surgery. Surgery is known to cause increased stress, the glucocorticoid target is about 25 mg plasma corticosteroid levels during and after opera- of hydrocortisone equivalent on the day of sur- tions, with plasma cortisol levels reaching their gery. For example, an asthmatic patient who peak (twofold to 10-fold above baseline) between takes 5 mg of prednisone every other day should four and 10 hours after surgery.27,28 The level receive 5 mg of prednisone before surgery. of response is based on the magnitude of the Moderate surgical stress. For moderate sur- surgery10,29 and whether general anesthetic is gical stress, the glucocorticoid target is about 50 used.28,30 Postoperative pain also is contributory, to 75 mg per day of hydrocortisone equivalent for as is evident from the fact that urine levels of 17- up to one to two days. For example, a patient with hydroxycorticosteroids remain increased during systemic lupus erythematosus who takes 10 mg of the recuperative phase (three to six days after prednisone daily should receive 10 mg of pred- surgery),28 and the plasma cortisol levels decline nisone (or parenteral equivalent) before surgery after postoperative administration of an analgesic.29 and 50 mg of hydrocortisone intravenously during

surgery. On the first postoperative day, 20 mg of risk of experiencing adrenal crisis during dental hydrocortisone is administered intravenously procedures?” This question, unfortunately, has every eight hours (that is, 60 mg per day). The not been addressed fully despite the presence of patient returns to his or her preoperative gluco- several excellent review articles in the dental lit- corticoid dosage on postoperative day 2. erature.38-41 These reports have provided recom- Major surgical stress. For major surgical mendations for preventing adrenal crisis in den- stress, the glucocorticoid target is 100 to 150 mg tistry based, in large part, on medical reports; per day of hydrocortisone equivalent for two to however, few people have analyzed the risks asso- three days. For example, a patient with Crohn’s ciated with dental procedures. disease who has taken 40 mg of prednisone daily To this end, we searched the medical literature for several years should receive his or her usual using MEDLINE from 1966 through 2000 for 40 mg of prednisone (or the parenteral equiva- reports in English that addressed adrenal crisis lent) before surgery (within two hours) and 50 mg in dentistry. In MEDLINE, we searched the key of hydrocortisone intravenously every eight hours words adrenal, adrenal crisis and dentistry alone after the initial dose for the first 48 to 72 hours and in combination. Reference lists of relevant after surgery. In comparison, a patient who takes publications and review articles were examined to 5 mg of prednisone daily and is undergoing a sim- identify further studies. We analyzed the infor- ilar major operation should receive 5 mg of pred- mation in these reports on the basis of the nisone (or the parenteral equivalent) as a preop- reported features, quality of documentation and erative dose, with 25 mg of hydrocortisone response to therapy. administered intraoperatively and 25 mg admin- The significance of each report was based on istered within the first eight hours after surgery. evidence that the clinical or laboratory features or The clinician should prescribe hydrocortisone both were consistent with adrenal crisis,17,41 as (25 mg) every eight hours for the next 48 hours. shown in the table; the condition responded to The above protocol accounts for individual dif- glucocorticoid therapy; and factors such as ferences in glucocorticoid coverage based on the hypotension, hypovolemia and hypoglycemia were patient’s current daily steroid regimen and the reasonably dispelled. These criteria were impor- severity of surgery or other stresses, and recom- tant since hypotension, fever and nausea are non- mends that the preoperative steroid dose be taken specific signs of disorders (such as unrecognized within two hours of surgery (to afford high blood loss, septicemia, myocardial infarction and plasma levels during and after surgery). The pro- the effects of general anesthesia) that could be tocol also recommends advising the surgeon, confused with the clinical picture of adrenal anesthetist and nurses of the potential for compli- crisis. cations. If the postoperative course is uneventful, Our analysis resulted in the identification of the patient receives his or her usual glucocorti- only four reports42-45 published in peer-reviewed coid dosage on completion of the regimen. journals that purported that an adrenal crisis Factors that can complicate the postoperative related to dental treatment had occurred. This course and exacerbate AI include liver dysfunc- limited number of reported cases (four in 35 tion, sepsis and certain drugs.36 Drugs that can years) indicates that this medical emergency is lower plasma cortisol levels include amino- seldom encountered in dentistry. Features glutethimide (an adrenolytic), etomidate (an common in three of the four reports included AI anesthetic agent), ketoconazole and inducers of in patients who were at least 40 years of age and hepatic cytochrome P-450 oxygenases (that is, who had multiple extractions performed with phentyoin, barbiturates or rifampin) that accel- administration of general anesthetic, or in whom erate degradation of cortisol. In contrast, the an oral infection was present. The authors action of oral anticoagulants can be potentiated reported a significant drop in blood pressure in by intravenous high-dose methylprednisolone,37 the postoperative phase of each case, a feature which can contribute to increased bleeding and suggestive of adrenal crisis. However, these three the potential for hypovolemia. reports had one or more of the following: dclinical features of the “crisis” were poorly ADRENAL CRISIS AND IDENTIFICATION documented; OF RISK IN DENTISTRY dother disorders (that is, hypovolemia, bleeding, The above discussion leads one to ask, “Who is at infection or hypoglycemia) were not ruled out

adequately; dinadequate evidence was DENTAL PROCEDURES AND RECOMMENDED provided that patients would CORTICOSTEROID SUPPLEMENTATION IN PATIENTS have responded to fluids, glu- WITH ADRENAL INSUFFICIENCY.* cose and/or vasopressors alone. These inadequacies call into question the validity of these NEGLIGIBLE RISK CATEGORY three reports. The fourth dNonsurgical dental procedures report appears to document a Regimen: No supplementation required hypotensive-hypoglycemic MILD RISK CATEGORY event—a common finding in dMinor oral surgery: A few simple extractions, biopsy primary AI—because there dMinor periodontal surgery was evidence of undiagnosed Regimen: The glucocorticoid target is about 25 milligrams of AI that responded to dextrose, hydrocortisone equivalent (5 mg of prednisone) the day of surgery fluids and vasopressors, but did not require corticosteroids MODERATE-TO-MAJOR RISK CATEGORY for resolution.44 dMajor oral surgery: Multiple extractions, quadrant periodontal Although all four reports surgery, extraction of bony impactions, osseous surgery, lacked adequate documenta- osteotomy, bone resections, cancer surgery, surgical procedures involving general anesthesia, procedures lasting more than one tion, it is possible that these hour, procedures associated with significant blood loss cases, individually or as a Regimen: The glucocorticoid target is about 50 to 100 mg per group, truly represented day of hydrocortisone equivalent the day of surgery and for at adrenal crises. Either way, a least one postoperative day significant hypotensive event * General anesthesia, infection and pain can increase the risk of adrenal crisis in susceptible patients. occurred that required emergency treatment. We analyzed the overlapping features of these cases to identify trials have been conducted in patients who have risk factors potentially contributing to the pur- AI to definitively establish that corticosteroids ported crisis. The overlapping features identified are required for dental procedures, guidelines were primary or secondary AI, use of a general rely on evidence from the above-mentioned anesthetic, extraction of multiple teeth, low blood studies and the few purported adrenal crisis pressure at the end of the appointment, a crisis cases associated with dentistry.42-45 From these 1 developing 1 ⁄2 to five hours after surgery and an studies, four factors appear to contribute to the uncertainty about whether postoperative anal- risk of adrenal crisis during the perioperative gesia was obtained. period of oral surgery. These include the magni- We identified the following additional factors tude of surgery, use of general anesthetic, overall that could have increased the patients’ risk of health of the patient (for example, stable vs. developing hypotension and features of adrenal ongoing infection) and the degree of pain control. crisis: Based on these data, we suggest guidelines for dthe stress of multiple extractions and the risk stratification of patients who have AI (Box, presence of oral infection; “Dental Procedures and Recommended Cortico- dhypovolemia resulting from recent diarrhea or steroid Supplementation in Patients With Ad- bleeding from the surgical site; renal Insufficiency”). Three categories are intro- dinadequate circulating plasma cortisol (or glu- duced, primarily on the basis of the type and cose) levels as a result of AI, a fasting state, use magnitude of the procedure performed and the of a barbiturate-containing general anesthetic risk of adrenal crisis. However, the clinician also that can metabolize circulating cortisol,46 or in- should realize that risk is influenced by drugs adequate or inappropriate dosing of hydrocorti- administered, health of the patient and degree sone before and during the procedure. of pain control. We realize that these recommendations are a departure from current common ap- GUIDELINES FOR PERIOPERATIVE proaches. However, available evidence no longer COVERAGE IN DENTISTRY supports routine recommendations for cortico- Because no carefully controlled, randomized steroid supplementation for all dental procedures

for patients who potentially have AI or who are period, approximately one to five hours after currently receiving or have recently stopped the start of the procedure. The postoperative receiving steroid therapy.47 increase in plasma cortisol levels likely is a response to pain, since postoperative increases NEGLIGIBLE RISK: NONSURGICAL DENTAL in cortisol levels correlate with the loss of PROCEDURES local anesthesia54 and are blunted by the use Available evidence11,34,35,48 indicates that the vast of analgesics.27 majority of patients with AI can undergo routine, Clinicians can reduce the risk of adrenal crisis nonsurgical dental treatment without the need by requesting that the patient take his or her for supplemental glucocorticoids. This conclusion usual steroid dose before coming to the dental is supported by the fact that routine, nonsurgical office, scheduling the appointment in the dental procedures do not stimulate cortisol pro- morning when cortisol levels are highest, and duction at levels comparable to those of oral providing stress reduction measures with appro- surgery,49 and local anesthetic blocks neural priate postoperative analgesia. Consistent with stress pathways required for ACTH secretion.50,51 this, Ziccardi and colleagues reported41,55 that In presenting this guideline, however, we do supplementation is not required for patients who not advocate the performance of dental treat- receive corticosteroid therapy when uncompli- ment in patients whose AI is uncontrolled or cated minor surgical procedures of the orofacial undiagnosed (see Table for clinical features). complex are performed with local anesthesia, However, patients with AI who are in stable con- with or without conscious sedation (V. Ziccardi, dition, and those with a history of steroid use D.D.S., oral communication, November 2000). who have had their glucocorticoid therapy dis- Controversy surrounds the need for supple- continued before surgery have withstood general mental steroid therapy in patients who are surgical procedures without experiencing adrenal undergoing oral surgery and have recently dis- crisis.10,29,34 continued steroid therapy. A conservative approach is to wait two weeks for the normal MILD RISK: MINOR ORAL SURGERY adrenal function to return56-59 before performing Patients at risk of experiencing adrenal crisis are elective oral surgical procedures. However, this those who undergo stressful surgical procedures conservative waiting period appears to be un- and have no, or extremely low, adrenal function needed for patients who are receiving 30 mg of as a result of primary or secondary AI. Evi- hydrocortisone (that is, 5 mg of prednisone) or dence10,14,26 indicates that the risk of adrenal less per day.48 Alternatively, biochemical testing crisis is greater for primary AI than for sec- (that is, ACTH stimulation test, the insulin hypo- ondary AI due to hypothalamic or pituitary dis- glycemia test or the corticotropin-releasing hor- ease or destruction. This secondary AI carries a mone test)19,20 can be performed if surgical pro- risk equal to or greater than that for secon- cedures are required within the two-week dary AI associated with steroid administration window, with the need for supplemental steroid (30 mg/day or more of cortisol equivalent) and therapy determined on the basis of low adrenal recent failure to take the medication, which in response. However, the clinical response is not turn presents a greater risk than that for sec- always well-correlated with test results.19 ondary AI associated with current steroid administration. Patients who receive less than 30 MILD RISK REGIMEN mg/day of cortisol equivalent, or who receive top- For minor oral and periodontal surgery (for ical or inhaled steroid therapy rarely have example, a few simple extractions, soft-tissue adrenal suppression unless the topical agents surgery), evidence suggests that AI is prevented cover large inflamed areas with occlusive dress- when circulating levels of glucocorticoids are ings52 or the inhalation doses exceed 1.5 mg of about 25 mg of hydrocortisone equivalent per beclomethasone equivalent per day.53 day.26 This is equivalent to a dose of about 5 mg Studies27,29,48,54 that have investigated the stress of prednisone. The clinician should confirm that response to minor general and oral surgical pro- the patient has taken the recommended dose of cedures have concluded that significant cortisol steroid within two hours of the surgical pro- increases generally are not seen before or during cedure, and should schedule the surgery in the the operation, but occur in the postoperative morning when normal cortisol levels are highest.

Stress reduction measures should be implemented. DENTAL MANAGEMENT GUIDELINES FOR PATIENTS WITH Benefits can be gained from ADRENAL INSUFFICIENCY. use of the following: d dDefine the risk of adrenal insufficiency through medical history oral, inhalation or intra- and clinical examination. An increased risk of adrenal insuf- venous sedation that pro- ficiency exists when there is a history of tuberculosis or vides stress reduction; human immunodeficiency virus infection, since opportunistic dintravenous fluids (that infectious agents can attack the adrenal glands.20,60 is, 5 percent dextrose) that dEnsure that patients with adrenal insufficiency take their usual glucocorticoid dose before a stressful surgical procedure. can prevent hypovolemia dSchedule surgery in the morning, when cortisol levels usually are and hypoglycemia; highest. dlong-acting local dProvide proper stress reduction, since anxiety can increase anesthetics; cortisol demand. dadequate postoperative dMinor surgeries require minimal steroid coverage. The patient’s usual daily dose typically is sufficient. analgesics. dMajor surgeries and those lasting more than one hour or involving general anesthesia should be performed in a hospital MODERATE-TO-MAJOR with steroid supplementation. RISK: MAJOR ORAL dUse of nitrous oxide-oxygen or intravenous or oral benzodiaze SURGERY pine sedation61 is helpful, since plasma cortisol levels are not reduced by these agents.28 Patients who have AI and dAvoid general anesthesia for outpatient procedures, since it are undergoing major oral increases glucocorticoid demand.61,62 Avoid the use of surgery are at increased barbiturates, since these drugs increase the metabolism of risk of experiencing adrenal cortisol and reduce blood levels of cortisol.30 crisis compared with the dDiscontinue drug therapy that decreases cortisol levels (for example, ketoconazole) at least 24 hours before surgery, with risk associated with minor the consent of the patient’s physician. surgery. Major surgical pro- dProvide adequate pain control during the operative and cedures are more stressful postoperative phases of care. Clinicians should ensure good than minor surgical pro- postoperative pain control by administering long-acting local cedures.26 They increase the anesthetics (for example, bupivicaine) at the end of the procedure, as well as regular analgesic dosing. demand for cortisol because dBlood and other fluid volume loss, as well as the use of anticoagu- of postoperative pain. Also, lants can exacerbate hypotension and increase the risk of blood loss is greater, thus adrenal insufficiency-like symptoms. Thus, methods to reduce increasing the risk of devel- blood loss should be used. oping hypovolemia and dMonitor blood pressure throughout the procedure and before the patient leaves the dental office. Patients whose blood pressure is hypotension. at or below 100/60 millimeters of mercury should receive fluid replacement (5 percent dextrose), vasopressors or, if needed, MODERATE-TO-MAJOR glucocorticoids. RISK REGIMEN dRecognize the signs of hypotension, hypoglycemia and hypovo- For major oral surgical lemia and take corrective action quickly. stress (for example, multiple extractions, quadrant periodontal surgery, extraction of bony leagues.26 Higher doses may be needed if exces- impactions, osseous surgery, osteotomy, bone sive bleeding or complications are encountered. resections, oral cancer surgery), surgical proce- Patients should take their usual steroid dose dures involving the use of general anesthetic, pro- before the procedure, and supplemental intra- cedures lasting more than one hour, or proce- venous hydrocortisone should be administered dures associated with significant blood loss, the during surgery to achieve a total glucocorticoid glucocorticoid target is about 50 to 100 mg per level of 100 mg. Clinicians should consider hospi- day of hydrocortisone equivalent for the day of talizing these patients since blood pressure can be surgery and for at least one postoperative day. more closely monitored after surgery in this set- For reasons of simplicity, our guideline represents ting.48 Hydrocortisone (25 mg) usually is pre- a merger of the moderate and major surgical scribed every eight hours after surgery for 24 to stress categories proposed by Salem and col- 48 hours, depending on the procedure and the

anticipated level of postoperative pain. 15. Nomura K, Demura H, Saruta T. Addison’s disease in Japan: characteristics and changes revealed in a nationwide survey. Intern The box (“Dental Management Guidelines for Med 1994;33:602-6. Patients With Adrenal Insufficiency,” page 16. Loriaux D, McDonald W. Adrenal insufficiency. In: Degroot LJ, ed. Endocrinology. 3rd ed. Philadelphia: Saunders; 1995:1731-40. 60-62 1577) provides further recommendations for 17. Chin R. Adrenal crisis. Crit Care Clin 1991;7:23-42. reducing the risk of adrenal crisis associated with 18. Haynes R Jr . Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and surgical stress in patients with AI. actions of adrenocortical hormones. In: Gilman A, Rall T, Nies A, Taylor P, eds. Goodman and Gilman’s the pharmacological basis of CONCLUSION therapeutics. 8th ed. New York: Pergamon Press; 1990:1431-62. 19. Schlaghecke R, Kornely E, Santen R, Ridderskamp P. The effect Our analysis of the literature suggests that of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. N Engl J Med 1992;326: adrenal crisis is rare in dentistry, specific risk 226-30. factors increase the risk of an adverse event 20. Loriaux D. The adrenal cortex. In: Goldman LB, ed. Cecil textbook of medicine. 21st ed. Philadelphia: Saunders; 2000:1250-7. developing in patients who have AI, and perioper- 21. Esteban N, Loughlin T, Yergey A, et al. Daily cortisol production ative glucocorticoid supplementation can be pre- rate in man determined by stable isotope dilution, mass spectrometry. J Clin Endocrinol Metabl 1991;71:39-45. scribed in a more rationale manner than is cur- 22. Williams G, Dluhy R. Diseases of the adrenal cortex. In: Facui A, rently the case. As new evidence becomes Braunwald E, Isselbacher K, et al., eds. Harrison’s principles of internal medicine. 14th ed. New York: McGraw-Hill; 1998:2034-56. available, the suggested recommendations for 23. Hardy J, Turner M. Hydrocortisone secretion in man: studies of perioperative glucocorticoid supplementation in adrenal vein blood. Surgery 1957;42:195. 24. Hume D, Bell C, Bartter F. Direct measurement of adrenal secre- dentistry may need to be modified. tion during operative trauma and convalescence. Surgery 1962;52:174- 87. 25. Melmon K, Morrelli H. Clinical pharmacology: basic principles in therapeutics. 2nd ed. New York: MacMillan; 1978:598-626. Dr. Miller is a professor of Oral Medicine, MN118 Oral Health Prac- 26. Salem M, Tainsh R, Bromberg J, Loriaux D, Chernow B. Periop- tice, University of Kentucky College of Dentistry, 800 Rose St., Lex- erative glucocorticoid coverage: a reassessment 42 years after emer- ington, Ky. 40536-0297, e-mail “[email protected]”. Address reprint gence of a problem. Ann Surg 1994;4:416-25. requests to Dr. Miller. 27. Banks P. 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