The utility of parenteral glucocorticoids in the emergency department

The Journal of EImergency Medicine,Vol 12, No 4, pp 507-519,1994 Copyright 0 1994ElsevierScienceLtd Printedin the USA. All rightsreserved 0736~4679/94$6.00 + .OO

Pergamon

073&4679(94)E0031-P

THE UTILITY OF PARENTERA GLUCOCC?RT~COIDS IN THE EMERGENCY DEPAR~NT Kim D. Hoang, MD, and Charles V. Pollack, Jr., MA, MD Department of Emergency Medicine, Maricopa Medical Center, Phoenix, Arizona Reprint Address: Kim Hoang, MD, Department of Emergency Medicine, Maricopa Medical Center, P.O. Box 5099, Phoenix, AZ 85010

and de-emphasizesthe use of GCS in the continuity care setting.

Cl Abstract-Exogenous giucocorticoids have wide clinical appikabiiity in emergency medicime. Many uses reported for this ciass of drugs are supported by only anecdotal evidence of efficacy, while otbers have been proven or disproven by weii-designed studies; this evidence is evaluated here. Because adverse effects are relatively common and may be serious after initiation of steroid therapy in the emergency department, it is important for the emergency physician to review systematicaiiy the indications, contraindications, amd precautions for the use of parenterai giucocorticoids.

PHARMACOLOGY

There are two classesof steroids synthesizedin the adrenal cortex: the corticosteroids, with 21 carbon atoms, and the androgens, with 19. The corticosteroids are classedas glucocorticoidsor mineralocorticoids basedon their different physiologicalactivities. Hydrocortisone (cortisol) and cortisone are the naturally occurring GCS; the latter is more physiologically significant. Over the years, there have been concertedefforts by the pharmaceutical industry to synthesizeanalogues of cortisone that, given exogenously,would produce ever greater beneficialeffects with lesstoxicity. Thus far, the search has fallen short of its ultimate goal. Among the commonly usedsyntheticGCS in clinical practice are prednisone, prednisolone, methylprednisolone,triamcinolone, and dexamethasone. Hydrocortisone and cortisone are relatively short-acting GCS, whereas prednisone, prednisolone, methylprednisolone, and triamcinolone have intermediate durations of action; dexamethasoneis relatively long-acting. It is traditionally held that the longer the half-life, the more potent is the agent (1,2). Table 1 lists the commonly used GCS and their relative antiinflammatory potenciesbasedon this supposition. A

El Keywords - glucocorticoid steroids; dexamethasone; methyl prednisoione; hydrocortisone

INTRODUCTION

Over four decadesin clinical practice, exogenousglucocorticoids (GCS) have becomewidely used by physiciansin all specialties.The emergencyphysician, in facing a variety of medical problems, must recognize the usefulnessof GCS. Despite the vast amount of information available on GCS and their beneficial as well as their deleterious effects, however, there remain controversiesregarding their proper utilization. This survey examinesthe available data and reviews the indications and contraindications for GCS use in the treatment of specific illnesses.Only parenteral usesof GCS will be considered;oral and topical uses will be excluded. The information presentedis directed toward the practice of emergencymedicine, RECEIVED: ACCEPTED:

7 June 1993;FINAL SUBMISSION 15 November 1993

RECEIVED:

OF GLUCOCORTICOIDS

29 October 1993; 507

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K. D. Hoang and C. V. Pollack, Jr.

Table 1. Relative Potencies of Glucocorticoids (modified from reference 2) Glucocorticoid Short-acting Hydrocortisone Cortisone Intermediate-acting Prednisone Prednisolone Methylprednisolone Triamcinolone Long-acting Dexamethasone

Relative Anti-inflammatory Effect 1

in the production of proteins translated by these mRNAs. These proteins are frequently enzymesor other biologically active molecules. SIDE-EFFECTS OF GLUCOCORTICOIDS

0.8 4 4 5 5 27

more contemporary view is that potency dependson the affinity of the steroid for the GCS receptors (which will be discussedlater), as well as its half-life. Over a short period, affinity for the receptor is a major factor. Over a longer period, both affinity and half-life are important (3). For example, over the first few hours after administration, prednisone is only slightly more potent than hydrocortisone (instead of being fourfold more potent as it is usually considered), becauseits affinity for the receptor is only about twice as strong as that of hydrocortisone (4). The physiological and pharmacological effects of GCS are numerous and widespread.They affect protein, carbohydrate, and lipid metabolism; electrolyte and water balance; the functions of the immune system and the cardiovascular system; renal function; skeletal muscle; and the nervous system. Nevertheless, the single most important property of GCS that makes them useful in clinical practice is their antiinflammatory effect. Glucocorticoids inhibit the recruitment of neutrophils and monocyte-macrophages into the inflammatory area (5,6). They also inhibit the formation of prostaglandins and leukotrienes, which play an important role in inflammation (7). Great progress has been made in understanding the fundamental mechanismof GCS action. While a discussionof the molecular biology of GCS action is beyond the scopeof this paper, interestedreadersare referred to a review by Baxter (3). The basic concept is that GCS appear to mediate their actions through an intracellular receptor - the GCS receptor. Glucocorticoid receptors are believed to be present in all tissuesof the body, though probably in widely varying concentrations.The binding of GCS to the receptor leads to activation of the receptor through conformational changes. The complex then enters the nucleus where it induces changesin the rate of transcription of specific mRNAs, resulting in changes

Becausealmost all organ systems are affected by GCS, the side effects of their therapeutic use are wide-ranging. These unwanted effects of GCS can be divided into two categories:those resulting from withdrawal and those resulting from continued use of large doses. Therapy with GCS for a period of weeks reliably results in suppression of pituitaryadrenal function. Adrenal insufficiency therefore occurs upon rapid withdrawal of GCS after prolonged therapy; Graber and colleagues(8) found that the recovery of pituitary-adrenal function required as long as 9 months in some patients following prolonged therapy. During this recovery period, the patient may need exogenous GCS for protection in stressful situations such as surgery or severeinfection. The developmentof iatrogenic adrenal insufficiency is usually gradual, but can be acute. Patients may present with generalizedweaknessand fatigue, weight loss, anorexia, nausea, vomiting, hypotension, and postural dizziness.More acutely, presentation may be marked by profound nauseaand vomiting, severeabdominal pain, hypotension, and shock that is incompletely responsive to fluid resuscitation (9). In addition to pituitary-adrenal suppression,prolonged therapy with GCS is also complicated by an increasedsusceptibility to infection (a result of immunosuppression);fluid and electrolyte disturbances (mineralocorticoid effect); hyperglycemia and glycosuria (increasedgluconeogenesisand decreasedperipheral uptake of glucose);osteoporosis(osteoblast inhibition); peptic ulcers (increased gastrin secretion); cataract formation (complex mechanism, possibly direct binding of GCS to lenses causing opacity); and the Cushing’shabitus (altered lipid metabolism) (10). In children, inhibition or arrest of growth can result from relatively small dosesof GCS (11). Glucocorticoid therapy has also been known to cause behavioral disturbances (12). The most frequent psychiatric side effects are mood changesranging from mild euphoria to hypomania. Other possible manifestation are depression, dementia, and psychosis. Becauseof these potentially deleterious effects, steroids should be used only when necessaryand in the smallestdosesand for the shortestperiod of time possible. Furthermore, local use is preferred to sys-

Glucocorticoids

temic use whenever possible. Alternate-day therapy can minimize some of the side effects such as pituitary-adrenal suppressionand suppressionof growth in children (3). However, alternate-day treatment is not useful as acute therapy and may not be effective for all indications for GCS use. When it is employed, a short-acting GCS should be used; otherwise the effect would last into the “off day” and hence, in effect, it would not be alternate-daytherapy. Once the therapy is no longer necessary,the dosage of GCS is usually tapered off gradually. This practice servestwo purposes. The first is that by tapering the steroid dose, there is less chance for a flare-up of the condition being treated. The secondis to avoid problems with suppressedpituitary-adrenal function. However, if GCS therapy has been given for less than 5-10 days, then pituitary-adrenal suppressionshould be minimal and transient, and tapering dosesare generally not necessary.This is of particular interest to the emergencyphysician, for whose patients follow-up is not alwaysassured. CLINICAL APPLICATIONS

Pulmonary Emergencies Asthma. Asthma is an episodic diseasewith acute exacerbationsinterspersedwith symptom-free periods. It is characterizedby airway narrowing causing obstruction to air flow. Three pathologic processes account for this obstruction: constriction of airway smooth muscle,thickening of airway epithelium, and secretionof mucus in airway lumen. Becauseof their anti-inflammatory effect, GCS reduce mucous secretions that contribute to airway narrowing. Multiple studieshave supported the use of GCS in acute asthmatic exacerbation.Haskell, Wong, and Hansen(13) compared methylprednisolone(MP) at low dose (15 mg), medium dose (40 mg), and high dose (125 mg) in 25 patients admitted with status asthmaticus. Methylprednisolonewas given intravenously (IV) every 6 hours for 3 days. Together, the high- and medium-dose groups improved significantly as measured by pulmonary function testing (FEV, > 50% of predicted). The high-dose group showed significant improvement by the end of the first day, whereasthe medium-dosegroup reachedthis level by the middle of the secondday. Littenberg and Gluck (14) in 1986 reported that MP 125 mg IV given on admissionto the emergency department (ED) decreasesthe need for hospital admissions as compared to placebo control (19% vs 47%). There was, however, no objective spirometric

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improvement in the steroid group. Similarly, Schneider et al (15) reported that high-doseIV MP (30 mg/ kg body weight) reducesthe need for hospital admission in patients with acute asthma exacerbation, independentof current use of oral GCS (19% rate of hospitalization vs 44% in the control group). A more recent randomized double-blind placebocontrolled trial with 81 patients (16) demonstratedno benefit from high-dose IV MP (125 mg given as a single dose initially) compared to placebo controls. The criteria for comparison included subjective symptoms, peak expiratory flow rate (PEFR), and frequency of hospital admission. It is possible, however, that the beneficial effects of GCS are delayed and relate primarily to prevention of relapse.Because of contradicting resultsin this study to previous ones, further investigation would be helpful. However, weighing all the available data, the literature supports the use of IV GCS in acute asthma exacerbation, and they continue to enjoy widespreadclinical use. The use of GCS intramuscularly (IM) has also been evaluated. The primary advantage of using a single high-doseintramuscular depot injection is the avoidanceof noncompliance.Hoffman and Fiel(17) demonstratedthat an 80 mg dose of MP sodium acetate given IM is at least as effective as oral MP at 64 mg per day, tapering to zero over 8 days. The success of the treatments was evaluated in terms of recurrenceof symptomson follow-up 5 to 7 days later. Ogirala and colleagues(18) comparedintramuscular triamcinolone 120 mg per day for 3 days to lowdose prednisone(median dose 12.5 mg per day) over 2 to 3 months. The study showed improvement in pulmonary function, and significant reduction in the number of ED visits, hospitalization, and need for intubation. Both studiesreported an increasein side effects with the useof IM steroids, though most were minor. Although it is premature to make firm conclusions, IM GCS therapy appears promising for long-term managementof reactiveairway disease. Chronic obstructive pulmonary disease (COPD). COPD exists as two clinical types-chronic bronchitis and emphysema- which often present in combination. Chronic bronchitis is associatedwith excessive airway mucus production, while alveolar wall destruction is the basic abnormality in emphysema. Both may be complicated by acute bronchospasm and broncho-inflammation, for which GCS might offer therapeutic benefit. The use of GCS in acute COPD is, at the present time, basedupon very little scientific data. In 1980, Albert, Martin, and Lewis (19) published a. study comparing treatment of

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COPD with IV aminophylline, inhaled isoproterenol, antibiotics, and either IV MP (0.5 mg/kg body weight) or placebo every 6 hours for 72 hours, Fortyfour patients were enrolled in the study. They found that MP improves air flow as measured by FEVl more than does placebo. The improvement, however, did not appear until about 12 hours after initiation of treatment and continued over the next 2 to 3 days. A larger study by Emerman et al (20) published in 1989 included 96 subjects with acute exacerbation of COPD. Patients received aminophylline, hourly aerosolized isoetharine, and either IV MP (100 mg) or saline, all given within one-half hour of admission to the ED. These investigators found no difference in improvement in FEV, or the rate of hospitalization between the two groups after 5 hours of observation in the ED. Based on these two studies, it appears that GCS may not improve outcomes acutely in the ED, but may be of benefit over the next few days. At the present time, physicians are encouraged to use GCS after bronchodilator and bronchopulmonary drainage measures have failed. Further studies are necessary before any rational conclusion can be made. Pediatric viral respiratory infection. Croup (laryngotracheitis) is a common illness in children. It is characterized by inflammation of the upper airway in the region of the larynx. Glucocorticoids have been used for many years for the treatment of severe croup. A meta-analysis by Kairys, Olmstead, and O’Connor (21) of nine randomized clinical trials between 1960 and 1983 analyzed data on GCS treatment of croup in 1,286 patients. Dexamethasone (DXM) was used in seven studies, while prednisolone or MP was used in the others. Routes of administration varied: IM in five studies, subcutaneously (SC) in one, and orally in three. All of the steroid doses were converted to cortisone dose-equivalent. There were five studies using “high-dose” (> 125 mg of cortisone equivalent). Results were evaluated in terms of clinical improvement at 12 and 24 hours as well as by incidence of endotracheal intubation. Overall, the analysis demonstrates that the use of GCS is associated with clinical improvement and a significantly reduced incidence of endotracheal intubation. Furthermore, there appears to be a positive relationship between the steroid dose and the proportion of improved patients. The benefit of GCS in croup was also demonstrated by Kuusela and Vesikari (22) in a more recent study in 1988. The study involved 72 children in a randomized double-blind placebo controlled trial. Dexamethasone was given IM at 0.6 mg/kg body

K. D. Hoang and C. V. Pollack, Jr.

weight as a single dose upon admission to the ED. Subjective symptom evaluation was done at 6 and 12 hours postadmission. There was a significant clinical improvement as well as a decreasein length of hospital stay in the DXM-treated children. Super et al (23) similarly demonstrated the beneficial effects of parenteral DXM (0.6 mg/kg) in a prospective randomized double-blind study. Thus far, the literature supports the use of GCS in children with croup. Another common viral respiratory infection encountered in pediatric patients is bronchiolitis. Contrary to their usefulness in croup, GCS appear to have no objective beneficial effect in bronchiolitis. Early studies in the 1960sreported favorable results; however, these were uncontrolled studies involving small numbers of patients. In 1969, Leer et al (24) reported a large, double-blind controlled collaborative study involving 297 patients from five hospitals. Betamethasone was used with an initial dose of 1 mg/5 lbs body weight either IM or IV. Subsequently, doses of 0.5 mg/5 lbs body weight were given IM every 12 hours for a total of six doses. The results show no statistical difference between the control and experimental groups in terms of duration of symptoms, severity of respiratory distress, and complication rate. This well-designed study suggeststhat there is no basis for the routine administration of GCS in bronchiolitis. Pneumocystis cariniipneumonia (PCP). Pneumocystis curinii is an opportunistic pathogen causing pneumonia in a compromised host. With the acquired immunodeficiency syndrome (AIDS) epidemic, PCP has become a relatively common disease. Two recent randomized clinical trials demonstrate the benefits of GCS in PCP in patients with AIDS. Twenty-three patients in a study by Gagnon et al (25) were randomized to receive either 40 mg of MP or placebo IV every 6 hours for 7 days. The diagnosis of PCP was confirmed histologically in all patients based on sputum, bronchoalveolar lavage, or transbronchial biopsy. Furthermore, all patients received standard PCP therapy with trimethoprim-sulfamethoxazole for 21 days. Nine of 12 patients (75%) treated with steroids survived until hospital discharge, as compared with only two of 11 patients (18%) in the control group. The study was terminated short of the objective 80 patients when a statistically significant difference in survival became evident. A larger study (26) involved 59 AIDS patients with histologically proven first episodesof PCP. Inclusion criteria included an arterial pOZ of less than 67.5 torr or an arterial pCOZ of less than 30 torr. All patients received standard therapy with cotrimoxazole. Thirty

Glucocorticoids

subjectswere randomized to receiveIV MP 2 mg/kg daily in four divided dosesfor 10 days. Compared to the control group, the MP-treated group had a higher rate of survival to discharge (90% vs 69%), a decreasein the requirement for mechanicalventilation (10% vs 41%), and an improved 90-day survival rate (87% vs 69Vo). Oral prednisone, beginning at 40 mg twice daily then tapering, has also been shown to be effective as adjunctive therapy for PCP (27). There has been no study comparing oral to parenteraltreatment. At this time, adjunctive GCS therapy, whether oral or parenteral, is recommendedin the treatment of moderate to severePCP, and should be initiated in the ED when the diagnosisis established. Pulmonary burns. The use of steroids in inhalation injury has been suggestedto decreaseinflammatory and edematous changes. Early studies indicated a beneficial effect of MP and DXM in experimental inhalation injury in rats (28). In 1978, Levine et al (29) published one of the first prospective randomized placebo-controlled trials. Thirty patients with both smoke inhalation and thermal cutaneousinjury were enrolled in the study. Flexible fiberoptic bronchoscopyin all patients confirmed pulmonary injury. Half of the patients received 20 mg IV DXM daily for 3 days, while control patients received normal saline. The mean percent body surface burn in both groups was similar. There was no significant differencebetweenthe two groups in terms of pulmonary functions, mortality, or morbidity. The effect of steroids in isolated inhalation injury without associatedcutaneousinjury was first investigated by Robinson et al (30) following two hotel fires in Las Vegasin the early 1980s.Two hundred twentyfive patients met criteria to be included in this retrospective study. The steroid-treated group consisted of 141 patients who receiveda dosageequivalent 10 mg DXM every 6 hours for 48 hours. The steroidtreated and nonsteroid-treated groups were similar in terms of gender, previous cardiac or pulmonary diseases,presenting symptoms, arterial blood gases, and carboxyhemoglobin levels. No differences in outcome with respectto morbidity or mortality were detected. Consistentwith these two studies, the current viewpoint is that GCS are not indicated in the ED managementof inhalation injury. Fat embolism syndrome. Although well known for its associationwith fractures of long bones, the fat embolism syndrome (FES) also occurs in prosthetic joint replacement, suction lipectomy, bone marrow transplantation, acute hemorrhagic pancreatitis, car-

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bon tetrachloride poisoning, and external cardiac massage.The pathophysiologyof FES is still unclear, though it is believedto involve microvascular occlusion and the formation of free fatty acids that are damaging to lung tissue. By the time the clinical symptomsof FES are evident, pathologic changesof tissueshave beenin progressfor 24-72 hours. Therefore, it is of interest to prophylactically treat patients at high-risk for FES. Methylprednisolone has been used in the treatment and prophylaxis of FES. Two prospectivedouble-blind randomized studies were published in the 1980s.Schonfeld et al (31) enrolled 64 patients with long bone fractures; 21 patients were randomized to receiving MP 7.5 mg/kg IV every 6 hours for 12 doses (total dose 90 mg/kg). All patients were assigneda fracture index score and FES diagnosiswas determinedby a strict scoring systembasedon physical examination and degree of hypoxemia. No patient with clinical FES was noted in the MP-treated group as opposedto nine (21%) of the controls. Futhermore, the MP-treated group had a lower FES score(mean 1.24 vs 3.34). Lindeque and colleagues(32) usedMP at a dosage of 30 mg/kg body weight IV on admission and a single repeat dose after 4 hours. Twenty-sevenof 55 patients with tibial or femoral fractures were randomizedto receivethe glucocorticoid. Diagnostic criteria for FES were based on pulmonary function (PO, < 60 torr, pCOZ > 55 torr or pH < 7.3, and respiratory rate > 35 per minute). Three patients (11070)in the steroid group met the criteria for FES comparedto 13 (46%) in the control group. At present, MP appearsto be beneficial in reducing the incidence of FES in high-risk patients when used prophylactically. Emergencyphysiciansshould review these data with their consulting orthopedists and trauma surgeonsbecauseGCS administration in the ED may be of benefit to selectedpatients. Any benefit afforded by GCS in the treatment of FES once it has developed,however, has not been established. Neurologic Emergencies Bacterial meningitis. Despite great progress in its treatment, bacterial meningitis is still a serious diseasewith high morbidity and mortality, especiallyin the pediatric age group. The presenceof bacteria in the subarachnoidspacecausesan inflammatory reaction in the pia and arachnoid membranes and the cerebrospinalfluid. The infective agent as well as the inflammatory processinjure those structuresthat lie

512 within the subarachnoid space (cranial and spinal roots) or ventricles (choroid plexuses). Cranial nerve palsy, usually third, sixth, seventh, or eighth, occurs in lo-20% of cases. Unilateral or bilateral hearing loss occurs in about 10% of infants and children who have bacterial meningitis. Furthermore, approximately 30% of children with bacterial meningitis eventually develop subtle learning deficits. Glucocorticoids are postulated to decrease the frequency and severity of these complications by reducing the inflammatory response. In recent years, GCS have become increasingly recognized as an adjunct therapeutic agent that decreases undesired sequelae. The beneficial effect of GCS probably resides in an anti-inflammatory property that decreases injury to intracranial structures. Lebel and colleagues conducted three well-designed double-blind placebo-controlled studies in 260 infants and children with bacterial meningitis (33,34). All patients were 2 months of age or older. Huemophilus influenza type b was the causative organism in most cases. Patients randomized to the experimental group received DXM 0.6 mg/kg/day in four divided doses IV for 4 days. The first dose was given at the time antibiotic therapy was initiated. The DXMtreated group exhibited earlier clinical improvement (afebrile at 1.6 vs 5 days) and a lower rate of bilateral sensorineural hearing loss (3.3 vs 15.5%). Furthermore, there were fewer neurologic complications (e.g., seizures and hemiparesis) in patients who received DXM. A more recent study by Odio et al (35) in 1991 employed a different antibiotic, but nonetheless demonstrates a similar beneficial effect from DXM. The role of GCS in the treatment of bacterial meningitis in adults or children with pneumococcal or meningococcal meningitis has not yet been clearly established. The current recommendation is to consider DXM for bacterial meningitis in infants and children 2 months of age or older. The recommended dosage is 0.6 mg/kg per day, in four divided doses, given IV for 4 days, with the first dose administered at the time of the first dose of antibiotic (36). Cerebral edema. Increased intracranial pressure (ICP) is the common pathophysiology leading to neurologic damage in cerebral injury. Among the insults to the brain commonly encountered in the ED are closed head injury (CHI), primary or metastatic brain tumor, and brain abscess. As early as 1961, Galicich and French reported an uncontrolled study involving 21 comatose patients with either gliomas (13 patients), meningiomas (l), or metastatic tumors (7). All patients received DXM 10 mg IV, followed

K. D. Hoang and C. V. Pollack, Jr,

by 4 mg IM every 6 hours until maximal response was achieved. Eighteen patients showed improvement within 12 to 18 hours of treatment. Of these, 13 showed definite resolution of neurologic deficit. The three patients who did not improve and remained comatose had slowly growing astrocytomas (37). In 1972, Maxwell, Long, and French (38) reported the results of a 1Zyear study involving 1,361 patients with cerebral edema secondary to neoplasm (815 patients), perioperative craniotomy (194), intracranial hemorrhage (189), closed head injury (142), or brain abscess (21). Dexamethasone was given as a 10 mg loading dose IV, followed by 4 mg IM every 6 hours. The dosage was tapered over 5 to 7 days and, in certain patients, converted to oral form. Outcome was evaluated clinically based on resolution of symptoms such as headache, nausea, vomiting, visual disturbances, and mental depression. The study was controlled and double-blinded initially, but was terminated soon after when the efficacy of DXM appeared to be obvious. The researchers found that DXM is highly effective in the treatment of brain tumor and brain abscesses. Furthermore, patients with metastatic tumors and glioblastomas respond better to the therapy than do patients with astrocytomas and meningiomas. On the other hand, severe CHI-associated edema does not appear to benefit from DXM therapy. In 1976, Meinig et al (39) studied the combined effects of DXM and diuretics in the treatment of cerebral edema secondary to tumors. Patients were randomized to receiving DXM 4 mg IM every 6 hours for 4 to 6 days; or DXM at the same dosages in combination with oral furosemide 120 mg per day for 4 to 6 days; or no treatment (control). Computed tomography (CT scan) was used to evaluate the extent of cerebral edema. There was improvement in both experimental groups compared to the controls, though there was substantially greater improvement in the combined therapy group. The current recommendation is in favor of the use of DXM, whether alone or in combination with diuretics, in treatment of cerebral edema with focal lesions such as tumor or abscess. This treatment should ideally be initiated in the ED. On the other hand, the role of GCS in CHI is not established. Cooper et al (40) published a review of 76 comatose patients who were managed by hyperventilation, ICP monitoring, and IV mannitol. Twenty-five patients had been randomized to receive DXM at 16 mg/day (low dose) and 27 to receive DXM 98 mg/day (high dose), with the first dose given within 6 hours of injury. There was no significant benefit in mortality and morbidity immediately

Glucocorticoids

or at 6-month follow-up in either group comparedto the placebo-controlgroup. A prospective double-blind study was also reported by Saul et al (41). One hundred patients were randomized into two groups: the steroid group received MP 5 mg/kg/day, and the control group received no drug. All patients had a Glasgow coma scaleof 7 or less on admission. There were no other injuries. Patients were reassessed on day 3 and were classifiedinto either early responders(Glasgowcoma scalehad improved to more than 8) or nonresponders. There was no statistically significant difference in the outcome of. the steroid and control groups at 6 months. However, there was a higher incidence of good recovery among the early respondersin the steroid group. The authors suggestthat the effect of steroids may be different in different patients, and that steroids should be given for 3 days and be continued thereafter only in early responders. Still later, Braakman et al (42) in 1983 published the results of a prospective double-blind trial using “megadose”GCS. One hundred sixty-one patients were randomized into a placebo group or a GCS group that received 100 mg/day of DXM IV or IM, tapering to 4 mg/day over 10 days. The first dose of DXM was given within 6 hours of injury. There was no difference between the two groups in terms of mortality and morbidity acutely or at l-month and (j-month follow-up. The most recent trial, also using high-doseDXM, by Dearden and colleaguesin 1986, involved 130 patients (43). Similar to previous studies, the 6-month outcome did not differ betweenthe GCS and placebo groups. Basedon available data, GCS cannot be recommendedin the acute managementof CHI. Acute spinai cord injury. Acute spinal cord injury (ASCI) is a heterogenouscondition with a high degree of variability in the characteristicsof the injury. The injury may occur as a result of trauma, ischemia, or compressionby metastatictumor, epidural abscess or hemorrhage. For many years, GCS have been investigated as a pharmacologic treatment for ASCI becauseof an anti-inflammatory effect that probably helps reduce swelling and compressionof the spinal cord. The first American National Acute Spinal Cord Injury Study (NASCIS 1) was launched in the late 1970s and compared two doses of MP. The “low dose”consistedof a bolus of 100 mg followed by 25 mg IV every 6 hours over the next 10 days. The “high dose”was IO-fold higher in dosage,given at similar intervals. There was no control arm in the study. The resultsrevealno significant difference in neurological recoveryat 6 weeksor 6 months (44) or at 1 year (45).

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In 1985, NASCIS 2, a randomized double-blind controlled study, was initiated and eventually enrolled 487 patients at 10 centers. Based on previous work with animal models, high-dose MP was used. Patients were randomizedto receiveMP at 30 mg/kg bolus, then 5.4 mg/kg/hour for 24 hours. The controls receivedno GCS treatment. Neurological functions (motor and sensory)were evaluatedby a complex protocol on admissionand at 6 weeks,6 months, and 1 year later, Patients who started MP treatment within 8 hours of injury demonstrateda statistically better functional recovery at 6 weeksand 6 months (46) and at 1 year (47) when comparedto the placebotreated patients. Such improvement in outcome was observedboth in patients who initially presentedwith complete (no motor or sensoryfunction) and incomplete (someresidual distal motor or sensoryfunction) spinal cord injuries. On the other hand, patients who started treatment more than 8 hours after injury showed a worse outcome than the placebo group, though this was not statistically significant. Basedon this large randomized controlled study, MP is thus recommendedfor ASCI, but only if it can be started within 8 hours of injury. Guillain-Barrt! syndrome. In the 196Os,GCS were used routinely for the treatment of Guillain-Barre syndrome(GBS). However, by the 1970sit appeared that GCS did not change the course of the disease and their use, therefore, declined. Becausethe diseaseis relatively rare, it is difficult to conduct clinical trials. Nevertheless,Hughes et al (48) were able to enroll 40 patients with acute polyneuropathy of undetermined etiology (GBS) in a randomized controlled trial. About half of the patients were randomized to receiveprednisolone60 mg daily, tapering to 30 mg, then off, over 2 weeks. The others received no GCS treatment. Neurologic evaluations at 1, 3, and 12 months consistentlyshowedgreater improvement in the control than in the GCS-treatedgroup, although the difference was not statistically significant. The authors suggestthat GCS can be detrimental and should not be given to patients with GBS. The sameconclusionis made earlier in a similar study by Goodall, Kosmidis, and Geddes, who demonstrated prolonged mean hospital stay in the group receivingGCS (49). Immunologic Emergencies Acute allergic reaction. The severity of allergic reactions ranges from mild cutaneous rash to frank anaphylacticshock. The cornerstonesof the pharma-

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cologic treatment of anaphylaxis are adrenergic agonists (e.g., epinephrine) and antihistamines. Other potentially useful agents are the GCS. To date, there have been no controlled studies to support the use of GCS in anaphylaxis, although a wealth of anecdotal evidence suggests potential benefits. Most authors recommend GCS in treating refractory cases, especially in the presence of on-going bronchospasm or hypotension. Hydrocortisone 100 mg IV every 6 hours is commonly used, albeit without much experimental support (50). Although not life threatening, urticaria and angioedema are more common manifestations of acute allergic reactions. Similar to anaphylaxis, the pharmacologic treatment for these conditions is epinephrine (usually given subcutaneously) and antihistamines. Glucocorticoids are not generally used in urticaria and angioedema, but in patients with severe or recurrent symptoms who do not respond to conventional measures, GCS are sometimes beneficial; an abbreviated course of oral prednisone is usually sufficient (51). Contrast media allergy (anaphylactoid reactions). Immediate generalized reactions to radiographic contrast media (RCM) occur in 1-2070of unselected patients. However, in patients who previously have had allergic reaction to RCM, the risk increases to 1760% on repeat exposure (52). These reactions are manifest by pruritus, urticaria, angioedema, dyspnea, and, occasionally, frank shock. It is, therefore, of interest to the emergency physician to prevent the occurrence of these reactions in high-risk patients. For routine RCM studies, a regimen of oral prednisone started at up to 13 hours before the anticipated procedures, in conjunction with diphenhydramine, has been recommended (52,53). However, emergent procedures requiring RCM preclude prolonged prophylactic treatment. Greenberg et al (54) report the prophylactic use of hydrocortisone, 200 mg IV, immediately and every 4 hours subsequently until the procedure is completed, plus diphenhydramine 50 mg IV 1 hour before the procedure. No reactions were reported in the 10 high-risk patients enrolled in this uncontrolled study. Despite the success of this regimen, the authors recommend that advanced airway and life support personnel and equipment be available in the radiology department when such patients are being studied. Endocrinologic Emergencies Acute adrenal insufficiency. Acute adrenal insufficiency (AAI), or Addison’s crisis, most often results

K. D. Hoang and C. V. Pollack, Jr.

from the rapid withdrawal of GCS from patients with suppressedadrenal glands secondary to chronic GCS administration. Other conditions that may precipitate AA1 include stressful situations such as infection and surgery in patients with primary adrenal insufficiency. Rarely, acute adrenal destruction secondary to hemorrhage in septicemia or anticoagulant therapy is the causeof AAI. Hypovolemic shock is the most significant presenting symptom of AAI. Other signs and symptoms include severeabdominal pain, nausea, vomiting, fever, and lethargy. Hyponatremia, hyperkalemia, and acidosis are common. Besides IV fluid resuscitation, immediate GCS replacement is life-saving. Intravenous hydrocortisone should be given as a 100 mg bolus and repeated every 6 hours until symptoms improve (usually within 24 hours), then tapered to oral maintenance levels over 2 to 3 days (9,55). Alternatively, continuous IV infusion of hydrocortisone at 10 mg/hr is administered following an initial 100 mg bolus (56). Once the acute problems have been stabilized, mineralocorticoid supplement should be started becausethese patients are generally also deficient in mineralocorticoids. Hypercalcemia. The causesof hypercalcemia are numerous, but hyperparathyroidism and malignancy account for most cases (57). The primary treatment for hypercalcemia is fluid resuscitation and loop diuretics (forced saline diuresis), intravenous phosphates, a combination of calcitonin and GCS, and, if necessary, dialysis. Mundy and Martin (58) recommend urgent treatment in any patient with serum calcium of 13 mg/dL or more or in any patient who is symptomatic. When serum calcium is 15 mg/dL or higher, coma and cardiac arrest may occur. Both calcitonin and GCS are effective inhibitors of bone resorption. Calcitonin is a rapidly acting agent and is useful initially. Its effect, however, is lost within 24-72 hours, probably due to a downregulation of calcitonin receptors on bone cells. Glucocorticoids, on the other hand, have a delayed effect on bone resorption that usually starts at 24 hours. For these reasons, calcitonin and GCS are used in combination. Glucocorticoids can be used IV or orally. The recommended doses are calcitonin lOO400 Medical Research Council units IM or SC every 12 hours, and hydrocortisone 100 mg IV every 6 hours (58). Alternatively, prednisone 10 mg to 20 mg orally three times a day can be used (59). These regimens, in conjunction with fluids and diuretics, are most effective in hypercalcemia of malignancy, especially myeloma; other conditions of hypercalcemia (e.g., hyperparathyroidism, granulomatous dis-

Glucocorticoids

ease,etc.) generallydo not respond as well to calcitonin and GCS therapy. Hypothyroidism and myxedema. When patients with

hypothyroidism or myxedema are treated with thyroid hormone supplement, adrenal insufficiency sometimesoccurs due to an increasedmetabolic rate that overtaxes the pituitary-adrenal reserve. Therefore, it is common practice to give thesepatients supplemental GCS. Hydrocortisone 100 mg IV daily in divided dosesis recommendeduntil the hypothyroid condition is corrected, then tapered off gradually (60). The first dose of supplementalGCS (hydrocortisone 25-50 mg IV) may be given in the ED. There have been no studies investigating this apparently beneficial practice. Thyroid storm. Fulminant hyperthyroidism-acute thyrotoxicosis or “thyroid storm”-may present in the ED with fever, marked tachycardia, diaphoresis, and alteredlevel of consciousness.Untreated, thyroid storm may progressto congestiveheart failure, severe pulmonary edema,and circulatory collapse.Immediate initiation of resuscitativeand support measuresis required. In addition to antithyroid drugs, iodide, and beta-adrenergicblockers,GCS are indicated in the ED managementof thyroid storm (61). Glucocorticoids are beneficial in this syndrome both becauseadrenocortical reserveis reduced, and becauseGCS (particularly DXM) interfere with the conversion of circulating thyroxine (TJ to triiodothyronine (T3), which is more metabolically active (62-64). This effect is additive to that of propylthiouracil (65). Dexamethasoneshould be given parenterally at initiation of therapy (equivalent to 300 mg HC per day), followed by DXM 2 mg orally every 6 hours (66). The effects of reduced circulating T, are evident within 24-36 hours (6266).

Other Emergencies Caustic ingestions. Caustic materials are widely used

for household cleaning and are likely to be accidentally ingested by children. Although less common, adult ingestionsare usually intentional and therefore more severe.Caustic materials causeliquefactive necrosis (alkalis) or coagulation necrosis(acids) of the mucous membrane in the mouth, the pharynx, and the esophagusupon ingestion. Esophagealstricture formation is a late sequelaof severecausticingestion, and develops3 to 4 weeksafter the injury. Immediate treatment involves administration of diluent (water or milk) orally to wash the materials off the mucous

515 membranes (67). Esophagoscopyis recommended within 24-48 hours to evaluate the extent of the injury (67,68). In the 1950sand 196Os,GCS were thought to be the mainstay of therapy to decreasethe incidenceof stricture formation. However, the trend has reversed, and many people have questioned the efficacy of GCS in caustic ingestions (69-71). One recent prospective controlled trial by Anderson, Rouse, and Randolph (71) involved 60 children with severecaustic injuries of the esophagus.Esophagealstrictures developedin 10 of the 31 children treated with GCS (prednisolone IV 2 mg/kg per day, then orally and tapered off over 2 to 3 weeks),as compared to 11 of the 29 controls. With no proven benefit and potential seriousside effects, GCS should not be administered in the ED managementof causticingestion. Pharyngitis. Acute exudative pharyngitis frequently

causesmuch discomfort and difficulty swallowing. Adjunctive therapy with DXM has been recommended to hasten recovery and pain relief (72). A single 10 mg doseof DXM IM in adjunct to standard therapy with penicillin or erythromycin was found to be effective in relieving pain in one prospective randomized double-blinded placebo-controlled trial involving 58 patients with exudativepharyngitis. Patients with immunocompromising conditions or suspicion of peritonsillar abscesswere excluded from the study. This regimenmay deserveconsiderationin the treatment of acute pharyngitis. Brown recluse spider bite. There is no specific therapy for brown reclusespider (Loxosc&s reclusa) en-

venomation, which causestissue necrosisand, in severe cases,systemicsymptoms such as fever, chills, nausea, vomiting, and joint pain. Parenteral GCS have been used by some, despitethe lack of evidence and controlled trials. Sporadic case reports suggest that HC 100 mg IV or IM given every 8 hours for 1 to 2 days helps ameliorate the necrotic effect of the venom (73,74), however, there are other casereports showing no benefit in the use of systemicGCS (75). Studies in animals also show no support for GCS therapy (76). It is difficult to draw any conclusion without further data available. Autoimmune diseases.These disorders have poorly

understood etiologiesand pathophysiologiesthat involve the immune system. They include a variety of diseaseentities such as systemiclupus erythematosus (SLE), rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s and Behcet’s syndromes, and the vasculitides. With few exceptions, GCS therapy

516

K. D. Hoang and C. V. Pollack, Jr.

alone or in combination with cytotoxic agents (e.g., colchicine and methotrexate) is useful in the acute treatment as well as the chronic management of these diseases. Oral GCS such as prednisone are usually given and parenteral administration is rarely necessary. However, patients who present with acute life-threatening manifestations of SLE (i.e., nephritis, pneumonitis, myocarditis, cerebritis, vasculitis, thrombocytopenic purpura, or severehemolytic anem ia and granulocytopenia) require emergent therapy. Methylprednisolone 1 gram IV daily for 3 to 5 days, followed by maintenance oral GCS, is generally used in these situations. Such treatment may be initiated in the ED and continued during hospitalization (77,78). Acute gouty polyarthritis. Systemic GCS have been studied in patients with gouty polyarthritis who are Table 2. Potential Utility of Glucocotticoids

in the Emergency Department

indication Asthma exacerbation COPD exacerbation Croup Pneumocystis pneumonia Fat emboli syndrome prophylaxis Bacterial meningitis Cerebral edema

unable to tolerate oral nonsteroidal agents (NSAIDs) or colchicine. Alloway et al (79) compared indomethacin 50 mg three times daily with triamcinolone acetonide (TC) 60 mg one dose IM plus acetaminophen with codeine pm in 27 patients with known crystalline gout. Patients given TC experienced symptom resolution faster than those given indomethacin, with no difference in side-effects. There was likewise no difference in symptom rebound. Groff and colleagues (80) compared a tapering regimen of oral prednisone in 15 patients with acute gouty polyarthritis and also report prompt (mean, 3.8 days) symptom resolution, no side effects attributable to GCS, and no higher incidence of rebound than with conventional (NSAIDs * colchicine) therapy. Two patients, unable to tolerate oral medications at the beginning of the study, were given M P IV 30-160 mg. Although these studies were not per-

Dose MP125mgiVq6h TC12OmgiMq24h x 3 MP 0.5 mg/kg IV q 6 h uptolOOmgq6h DXM 0.6 mglkg lV/lM single dose MP4OmgIVq6h x 7-10d MP75mglkgq6h x 12d or3Omglkgq4h x 2 DXM 0.15 mg/kg q 6 h x 4

Anaphylaxis

DXM 10 mg IV, then4mgIVq6h MP 30 mglkg IV boius, then 5.4 mglkglh x 24 h HClOOmgiVq6h

Contrast media reaction prophylaxis Acute adrenal insufficiency

HC 200 mg IV, then repeat q 4 h until procedure complete HClOOmgIVq6h

Malignant hypercalcemia Hypothyroidism

HClOOmgiVq6h HC25-50mgiVq6-12h

Thyroid storm

DXM 10 mg IV, then 2-4 mg IVlpo q 6 h DXM 10 mg IM

Acute spinal cord injury

Acute pharyngitis Lupus exacerbation Acute gouty polyarthritis inflammatory joints

MP 1000 mg IV daily in divided doses x 3-5 d TC 60 mg IM TC 2.5-80 mg intra-articular

MP = Methylprednisolone. TC = Triamcinoione. DXM = Dexamethasone. COPD = Chronic obstructive pulmonary disease.

Comments Further studies necessary immediate benefit controversial

Unknown benefit once symptoms have developed First dose to be given with first dose of antibiotics No proven benefit in edema due to head trauma Should be initiated within 8 hours of acute injury in addition to adrenergic agents and antihistamines In addition to diphenhydramine May use HC 10 mglh infusion after initial bolus In conjunction with calcitonin In conjunction with thyroid replacement In conjunction with antithyroid drugs, beta blockers, iodide To date recommended in only one study

References 13-16 17-18 19 21-23 25-26 31-32 33-36 37-39 44-47 50 52-54 9,55,56 58-59 60 61-66 72 77-78

May add narcotic analgesic

79-80 81-86

Glucocorticoids

517

formed in a blinded fashion, they provide evidence that parenteral GCS may be of benefit in patients with acute gouty arthritis. Emergency physicians should consider this option in patients with known gout who cannot tolerate more typical therapy. Adhesive capsulitis and other inflammatory joint disorders. A variety of GCS preparations are available

for local injection. The two most potent and longestacting GCS preparations for this purpose are triamcinolone acetonide (Kenalog@)and triamcinolone hexacetonide(Aristopan@‘).Methylprednisolone acetate (Depo-Medrol@)is another commonly used GCS for this indication. The purported advantageof local injection of inflammatory joints is to minimize the systemicside effects while maximizing the local effects. Furthermore, local injection can be usedin addition to systemic therapy to improve its efficacy. For large joints (knee and hip), injection of 80 mg of triamcinolone should be adequate. Medium-sized joints (elbow and wrist) require smaller injections of 5-15 mg; and small joints (metacarpophalangealand interphalangealjoints) require about 2.5-5 mg (81). Local injection, however, is not without adverseeffects. Soft tissue atrophy, periarticular calcification, tendon rupture, osteonecrosis,and septic arthritis have all been reported (81). Adhesive capsulitis, also known as frozen shoulder, is a relatively common condition of unknown etiology. Patients with this condition experienceconstant and progressiveshoulder pain that results in disabling restriction of joint motion. In addition to physical therapy, local anestheticand GCS injection are frequently used for treatment. Prospective randomized trials have shown conflicting results, with

some demonstrating improved joint motion and some failing to demonstrate any benefit following intra-articular injection of GCS (82-86). With potential serious side effects, one should weigh the risks and benefits carefully before initiating local injection therapy in the ED. Topical GCS. A discussionof the indications for and usesof topical corticosteroidsis beyond the scopeof this survey. The interestedreader is referred to a review article by Sterry (87).

SUMMARY

Table 2 lists conditions in which parenteral GCS therapy may be useful in the ED setting. The benefit of GCS has been demonstrated in asthma and COPD exacerbation,croup, PCP, pediatric bacterial meningitis, cerebraledemadue to brain tumor and abscess, hypothyroidism, thyroid storm, and Addisonian crisis. Potential benefits for GCS therapy are found in pulmonary fat embolism prophylaxis, acute spinal cord injury, acute allergic reaction, contrast media allergy prophylaxis, hypercalcemia(especiallysecondary to malignancy), acute pharyngitis, inflammatory joint disease,and brown reclusespider bite. The autoimmune diseasesas a group are generallytreated with oral GCS, except for acute flare-ups in SLE that involve major organs, in which caseparenteral therapy is indicated. On the other hand, GCS have no proven benefit in bronchiolitis, pulmonary burn, CHI, Guillain-Barre syndrome, and caustic ingestion. These conclusions may be modified as more studiesare reported and new data becomeavailable.

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