Yes (1) Aldridge et al. (1981) Caffeine 50.1338 PO.

Yes (1, 2, 4) Knutti et al. (1981) Salbutamol 7.1633 IV, PO.

Yes (3, 4) Hutchings et al. (1987) Terbutaline 8.2735 IV.

Yes (4) Berg et al. (1984) Source: Little BB. Obstet Gynecol 1999; 93: 858.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , pleak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared with nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV, intravenous; IM, intramuscular.

a T.

Control groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female reatment regimens reatment regimens controls combined.

103.

104.

Antiasthma agents during pregnancy Table 5.2 Medication dosages for treatment of asthma during pregnancy Drug Medication dosages for treatment of asthma during pregnancy Drug Dosage Beclomethasone 25 puffs bid to qid (inhalation) Cromolyn sodium 2 puffs qid Epinephrine 0.30.5 mL of 1:1000 solution q 20 min Prednisone Burst for acute symptoms, 40 mg/day for 7 days, and then taper for 7 days Theophylline 400600 mg/day initial and increase to therapeutic level of 812 g/mL Terbutaline (inhaled) 23 puffs q 46 h prn Terbutaline (subcutaneous) 250 g q 15 min Cunningham, 1994; National Asthma Education Program, 1993.

Methylxanthines The xanthines and methylxanthines have a peculiar pharmac.o.kinetic profile during pregnancy, and it important to note their unusual behavior. Xanthines tend to increase their steady-state concentration during pregnancy (Table 5.1), and this effect is magni-fied during the third trimester. Consequently, achieving the desired plasma concentrations will require different doses throughout pregnancy, and physicians should antic.i.p.ate a decrease in doses required as the pregnancy advances (Table 5.2).

Theophylline Theophylline is a xanthine derivative with potent diuretic effects commonly used for its bronchodilating actions. Theophylline is a compet.i.tive inhibitor of the enzyme phospho-diesterase which inactivates cyclic 3 5-adenosine monophosphate (cAMP) (Feldman and McFadden, 1977). Increased in intracellular cAMP levels stimulates bronchodilation. For many years theophylline salts were the first line of therapy for control of asthma in the pregnant patient. The frequency of congenital anomalies was not increased among 606 infants whose mothers used theophylline during the first trimester, and among 1294 infants whose mothers used the drug any time during pregnancy (Heinonen et al et al., 1977; Schatz et al et al., 1997; Stenius-Aarniala et al et al., 1995).

Theophylline crosses the placenta readily and high maternal doses may result in toxicity in the neonate (Arwood et al et al., 1979; Horowitz et al et al., 1982; Labovitz and Spector, 1982; Omarini et al et al., 1993; Yeh and Pildes, 1977). Newborns may manifest tachycardia, jitteriness, vomiting, and occasional apneic episodes during theophylline withdrawal (Arwood et al et al., 1979; Horowitz et al et al., 1982; Spector, 1984; Turner et al et al., 1980; Yeh and Pildes, 1977).

Aminophylline Aminophylline is the only salt preparation available for parenteral use, but there are numerous oral theophylline preparations. The range for therapeutic plasma concentrations of theophylline is between 10 and 20 mg/mL. Wide variation in the dosage Beta-adrenergic agents Beta-adrenergic agents 105.

necessary to achieve this plasma concentration in patients is apparent. Caution should be used because of the potential for toxicity. Parenteral aminophylline is given as a loading dose of 56 mg/kg body weight infused over 2030 min followed by a continuous infusion of 0.20.9 mg/kg.h. The loading dose should be reduced by half or omitted for patients already taking oral theophylline preparations. Aminophylline was used in the past for initial therapy and as combination therapy with beta-adrenergic agonists. It has recently been replaced by corticosteroids (Dombrowski, 1997), but oral theophylline derivatives are still utilized by many clinicians (Cunningham, 1994; Weinberger and Hendeles, 1996). Intravenous aminophylline for the acute treatment of asthma in pregnant women 'offers no therapeutic advantages' and may be a.s.sociated with toxicity (Wendel et al et al., 1996).

Aminophylline is sometimes a.s.sociated with uterine activity at higher dosages than those required to treat asthma, but it was not an effective agent for the treatment of premature labor (Lips.h.i.tz, 1978). Theophylline may have an additional benefit in the pregnant asthmatic because it may be a.s.sociated with a decreased frequency of preeclampsia in these women (Dombrowski et al et al., 1986). As noted by Hankins and Cunningham (1992) as well as Wendel et al et al. (1996), aminophylline should no longer be 'the mainstay of therapy for severe asthma,' and the primary role of theophylline derivatives is for chronic outpatient therapy (Hankins and Cunningham, 1992; Wendel et al et al., 1996).

BETA-ADRENERGIC AGENTS.

Epinephrine, isoetharine, isoproterenol, metaproterenol, and terbutaline are included in this cla.s.s of drugs. These agents have beta receptor activity; epinephrine has alpha, 2 beta , and beta receptor activity (Table 5.3).

1.2.Table 5.3 Adrenergic drugs used for the treatment of asthma Drug Adrenergic drugs used for the treatment of asthma Drug Receptor Administration Recommended dosages Epinephrine , , .

Subcutaneous 0.30.5 mL 1:1000 solution q 20 1.2.min Inhaled 200300 g/puff, 12 puffs q 4 h Isoetharine .

Inhaled metered dose 340 g/puff, 37 puffs q 34 h 2.Aerosolized 0.5 mL of 1% solution, diluted 1:3 with saline Isoproterenol , .

Inhaled 1:100 solution, 37 inhalations q 1.2.46 h 1:200 solution, 515 inhalations q 46 h Intravenous 0.55 g/min by infusion Metaproterenol .

Inhaled metered dose 650 g/puff, 23 puffs q 34 h 2.Nebulizer 0.3 mL of 5% solution q 4 h Terbutaline .

Subcutaneous 250 g q 15 min 2.Oral 2.5 mg q 46 h From Cunningham, 1994, with permission.

106.

Antiasthma agents during pregnancy Epinephrine Epinephrine has alpha and beta-adrenergic actions, and is used to alleviate bronchospasm and other allergic reactions. During an acute asthma attack, 0.30.5 mL of a 1:1000 dilution of epinephrine is given subcutaneously every 30 min and may be repeated up to three times (Table 5.3). Relative contraindications to epinephrine use include severe hypertension, cardiac arrhythmias, and a heart rate more than 140 beats per minute. No convincing evidence that epinephrine causes congenital anomalies or adverse fetal effects has been published. Congenital anomalies were increased in frequency among 189 women who used epinephrine during the first trimester, but not among 508 who used the drug only during the first and second trimesters (Heinonen et al et al., 1977). However, these were minor birth defects that were not of clinical significance, and probably not causally related to the drug exposure. Maternal epinephrine crosses the placenta readily. Epinephrine occurs naturally and is released from the adrenal medulla in response to stress. Therefore, it seems reasonable to conclude that it is unlikely that epinephrine is a.s.sociated with an increased risk of malformations in the fetus when used in usual adult doses.

Epinephrine causes congenital anomalies in animal species, but only at doses hundreds to thousands of times greater than those administered to humans.

Isoproterenol Isoproterenol stimulates beta-adrenergic receptors and is the most potent of the group.

It is used in the treatment of asthma and cardiac arrhythmias. Isoproterenol is usually administered by inhalation although it has been used parenterally in the treatment of status asthmaticus (Table 5.3). There are no reports to date of an a.s.sociation between congenital anomalies and the use of isoproterenol. Congenital anomalies were not increased in frequency among 31 offspring exposed to this drug in the first trimester (Heinonen et al et al., 1977).

Isoetharine Isoetharine is a sympathomimetic drug taken orally or as an aerosol (1 percent solution) to treat bronchospasms. Isoetharine is the most selective beta agent of this cla.s.s, but it 2 has weak bronchodilating effects and does not stimulate the heart as much as other beta2 agents. No published studies are available on congenital anomalies in infants of mothers exposed to isoetharine during pregnancy. No animal teratology studies in animals have been published. Isoproterenol is a closely related drug.

Metaproterenol and albuterol Metaproterenol and albuterol are resorcinols, drugs that: (1) are acquired by manipula-tion of the catecholamine molecule; (2) confer more beta selectivity; and (3) have some-2 what longer duration of action than other agents in this cla.s.s. They are administered orally, parenterally, or as inhalants. Any risk to the embryo or fetus that may be a.s.sociated with these drugs is substantially reduced when the route of administration is inhalation.

Antiinflammatory agents 107.

Metaproterenol, albuterol, and terbutaline are the resorcinol agents available in the USA. Metaproterenol and albuterol are beta sympathomimetics used as bronchodilators and to arrest premature labor. In one series of 361 infants exposed to metaproterenol during the first trimester, the frequency of congenital anomalies was not increased in frequency (Rosa, personal communication, cited in Briggs et al et al., 2002). Among 1090 infants exposed to albuterol during the first trimester, the frequency of congenital anomalies was not increased (Rosa, personal communication). Fetal tachycardia has been reported with maternal albuterol therapy in the third trimester, but has not been a.s.sociated with any adverse neonatal effects (Hastwell et al et al., 1978; Ryden, 1977).

Terbutaline Terbutaline is a potent bronchodilator and has also been used to prevent or treat premature labor, although it does not have Food and Drug Administration (FDA) approval for this purpose. The oral dose of terbutaline is 2.55 mg three or four times daily. It can be administered subcutaneously (0.250.5 mg), but has less beta selectivity. Congenital 2 anomalies were not increased in frequency among 149 infants exposed to terbutaline during the first trimester (Rosa, personal communication, cited in Briggs et al. et al. , 2005). , 2005).

Terbutaline crosses the placenta readily (Ingemarsson et al et al., 1981) and has been a.s.sociated with fetal tachycardia and transient hypoglycemia in the neonatal period when used as a tocolytic agent (Epstein et al et al., 1979; Ingemarsson, 1976; Wallace et al et al., 1978).

In summary, metaproterenol, albuterol, and terbutaline do not pose a substantial risk of birth defects at therapeutic doses, and it seems unlikely that these drugs are a.s.sociated with an increased risk of congenital anomalies.

ANTIINFLAMMATORY AGENTS.

Glucocorticoids Glucocorticoids are a mainstay of asthma treatment. Several adrenal glucocorticoids are given to severely asthmatic pregnant women (Box 5.3). Steroids should be employed in acute exacerbations when severe airway obstruction persists or worsens despite optimal Box 5.3 Steroid use in pregnancy Box 5.3 Steroid use in pregnancy Patient unresponsive to bronchodilators Hydrocortisone 4 mg/kg body weight IV loading dose followed by 3 mg/kg IV q 6 h for 23 days. Switch to oral prednisone Methylprednisolone 0.51 mg/kg (approximately 125 mg) IV bolus followed by 60 mg IV q 6 h Prednisone 3060 mg PO daily Beclomethasone 2 puffs (100 g) tidqid Patients on maintenance dose of steroids Hydrocortisone 100 mg IM or IV q 68 h 24 h Methylprednisolone 125 mg IV bolus followed by 60 mg IV q 6 h From ACOG, 1996.

108.

Antiasthma agents during pregnancy bronchodilator therapy because severe asthma is dangerous to the mother. Chronic glucocorticoid use is of greatest benefit in patients with frequent recurrences and those with worsening disease despite a prior optimal regimen. Steroids act by inducing protein lipocortin production, thereby inhibiting phospholipase A and decreasing arachidonic 2 acid release (Townley and Suliaman, 1987). Enhancement of the bronchodilating effect of beta agonists occurs with steroid use, as well as a decrease in mucous gland secretions and an inflammatory response. In a prospective investigation of 503 pregnant patients with acute asthma, the risk of an attack when maintained on an inhaled steroid ( n n = 257) was reduced fivefold compared to those who did not receive an inhaled steroid (Stenius-Aarniala = 257) was reduced fivefold compared to those who did not receive an inhaled steroid (Stenius-Aarniala et al et al., 1996). Glucocorticoids effects are usually not felt until at least 68 h after initial administration. Therefore, it is of utmost importance to continue bronchodilator therapy.

Prednisone and prednisolone Prednisone and prednisolone are synthetic glucocorticoids. Prednisone is biologically inert and is metabolized to prednisolone in the liver. The maternal-to-fetal gradient of prednisone/prednisolone is 10:1, and thus the fetus is exposed to only approximately 10 percent of the drug (Beitins et al et al., 1972; Levitz et al et al., 1978). Prednisone is the glucocorticoid of choice for asthma treatment.

Prednisone and prednisolone are discussed in Chapter 4. It is important to reiterate that it is unlikely that prednisone or prednisolone exposure during the first trimester is a.s.sociated with an increased risk of congenital anomalies, particularly cleft palate.

Infants born to mothers who received prednisone throughout gestation usually had normal adrenocortical reserves and lacked symptoms of adrenal suppression (Arad and Landau, 1984). Additionally, in two other reports, no evidence of neonatal adrenal insufficiency was found in newborn infants of women who took prednisone daily (as much as 60 mg in one study) throughout pregnancy (Schatz et al et al., 1975; Weinberger et et al al., 1980).

Beclomethasone Beclomethasone is a synthetic glucocorticoid administered by inhalation to treat bronchial asthma. Beclomethasone is now considered one of the key therapeutic agents for asthma. Readmissions decreased 55 percent in pregnant asthmatics receiving this inhaled steroid (Wendel et al et al., 1996). As with other steroids, beclomethasone has been reported to be teratogenic (i.e., cleft palate) in animals (Esaki et al et al., 1976; Furuhashi et al et al., 1977; Nomura et al et al., 1977; Tamagawa et al et al., 1982). However, beclomethasone was not a.s.sociated with an increased frequency of congenital anomalies in 395 infants exposed to the drug during the first trimester (Rosa, personal communication, cited in Briggs et al. et al. , 2005; Schatz, 2001). In one prospective study of this agent in pregnancy, it was not a.s.sociated with an increase in the frequency of malformations (Greenberger and Patterson, 1983). , 2005; Schatz, 2001). In one prospective study of this agent in pregnancy, it was not a.s.sociated with an increase in the frequency of malformations (Greenberger and Patterson, 1983).

In a prospective study of 503 gravid patients with acute asthma, risk of an attack when maintained on a beclomethasone ( n n = 214) was significantly reduced compared to those who did not receive an inhaled steroid. No reduction in birth weight or increase = 214) was significantly reduced compared to those who did not receive an inhaled steroid. No reduction in birth weight or increase Antiinflammatory agents Antiinflammatory agents 109.

in the frequency of birth defects was found in the treated group compared to the untreated group (Stenius-Aarniala et al et al., 1996).

Cortisone Cortisone (hydrocortisone) is a glucocorticoid excreted by the adrenal cortex. Four of 27 newborns whose mothers were treated with cortisone had congenital anomalies, but no distinct patterns of malformations were found (Wells, 1953). No increase in the frequency of congenital anomalies was found among the small number of infants ( n n = 34) exposed to this steroid in the first trimester (Heinonen = 34) exposed to this steroid in the first trimester (Heinonen et al et al., 1977).

Animal studies have demonstrated the teratogenic effects of cortisone in several species (Loevy and Roth, 1968). The pertinence of these findings to the clinical use of cortisone in human pregnancy remains unclear. It seems unlikely that cortisone therapy substantially increases the risk of cleft palate in infants born to women who used the drug during the first trimester.

Betamethasone Betamethasone is a synthetic glucocorticoid that crosses the placenta readily (Ballard et al et al., 1975). No epidemiological studies of congenital anomalies in newborns of pregnant women exposed to the drug during the first trimester have been published. Betamethasone has been used to accelerate fetal lung maturation in pregnant women with premature labor. In a 6-year follow-up evaluation of children exposed to betamethasone treatment, no consistent alterations in growth or intellectual function were noted (MacArthur et al et al., 1982). Animal teratology studies with betamethasone have found effects similar to those of other corticosteroids, i.e., an increased frequency of cleft palate was observed among the offspring of pregnant rats, mice, and rabbits exposed to betamethasone during gestation (Ishimura et al et al., 1975; Mosier et al et al., 1982; Walker, 1971; Yamada et al et al., 1981). The frequency of omphaloceles was increased in frequency among the offspring of betamethasone-exposed pregnant rats (Mosier et al et al., 1982; Yamada et al et al., 1981).

Dexamethasone Dexamethasone has been used during pregnancy for the treatment of asthma and to stimulate fetal lung maturation. It crosses the placenta readily, resulting in therapeutic fetal serum levels (Osathanondh et al et al., 1977). The use of dexamethasone, as well as other steroids, in treating the pregnant asthmatic was not a.s.sociated with adverse maternal or fetal effects (Schatz et al et al., 1975). There were no adverse effects of in utero in utero exposure to dexamethasone observed in infants in a long-term follow-up by the Collaborative Group on Antenatal Steroid Therapy (1984). The teratogenic effects of dexamethasone in animal species are similar to those of cortisone. For example, neural tube defects were induced in rabbits (Buck exposure to dexamethasone observed in infants in a long-term follow-up by the Collaborative Group on Antenatal Steroid Therapy (1984). The teratogenic effects of dexamethasone in animal species are similar to those of cortisone. For example, neural tube defects were induced in rabbits (Buck et al et al., 1962) and cleft palates in mice (Pinsky and DiGeorge, 1965). Also, Jerome and Hendrickx (1988) administered 10 mg/kg dexamethasone daily between days 22 and 50 in six pregnant rhesus monkeys and observed cranium bifidum and aplasia cutis congenita in one and three fetuses, respectively.

As discussed with prednisone previously, first trimester exposure may be a.s.sociated with a very small risk of oral clefts (see Chapter 4).

110.

Antiasthma agents during pregnancy CHROMONES.

Cromolyn sodium Cromolyn sodium inhibits degranulation of mast cells and thus the release of the chemical mediators of anaphylaxis. It is given by inhalation for asthma prophylaxis (Cunningham, 1994). Congenital anomalies were not increased in frequency among infants born to 151 and 191 women who used cromolyn sodium during the first trimester (Rosa, personal communication) (Schatz et al et al., 1997). Older reports of its use during pregnancy indicate no adverse fetal effects (d.y.k.es, 1974; Wilson, 1982).

MISCELLANEOUS AGENTS.

Anticholinergics Anticholinergics, such as atropine, produce bronchodilation in asthmatics. Their systemic side effects limited their use (Van Arsdel and Paul, 1977). Atropine readily crosses the placenta to the fetal circulation and may cause fetal vagal blockade with subsequent fetal tachycardia (h.e.l.lman and Fillisti, 1965; Kanto et al et al., 1981; Kivalo and Saarikoski, 1977). No increase in congenital defects among 401 offspring of women with exposure to atropine during early pregnancy, or 1198 infants whose mothers used the drug any-time during pregnancy was found (Heinonen et al et al., 1977).

Antibiotics Upper respiratory infections should be treated aggressively in the pregnant asthmatic patient, as in the nonpregnant patient (see Chapter 2). Penicillins are considered safe for use during pregnancy. Erythromycin is probably a safe alternative in the patient who is allergic to penicillin. However, hepatotoxicity has been observed in pregnant patients treated with the estolate salt of erythromycin (McCormack et al et al., 1977).

Tetracyclines should be avoided during pregnancy (Table 5.4) because of their adverse effects on fetal teeth (permanent staining) and bones (abnormalities in bone formation) (Anthony, 1970; Cohlan et al et al., 1967; Harcourt et al et al., 1962; Rendle-Short, 1962; Swallow, 1964).

Table 5.4 Drugs that should be avoided in the treatment of asthma during pregnancy Agent Drugs that should be avoided in the treatment of asthma during pregnancy Agent Effects Beta-blockers Bronchospasm Cyclopropane Bronchoconstriction Iodide-containing mixtures Fetal goiter Congenital hypothyroidism Opiates, sedatives, tranquilizers Depress alveolar ventilation Prostaglandin F Bronchoconstriction 2.

Tetracyclines Stain fetal teeth Abnormalities in bone formation Risk summary 111.

Antihistamines and expectorants Antihistamines and expectorant use during pregnancy during pregnancy is discussed in Chapter 11. Briefly, diphenhydramine, chlorpheniramine, pheniramine, and tripelennamine are generally considered safe for use during pregnancy. A few studies have shown that expectorants and mucolytics are efficacious in the treatment of asthma. It is of utmost importance that these agents, as well as theophylline mixtures containing iodides, not be used during pregnancy, because the iodine blocks the synthesis of thyroxine in the fetus, resulting in hypothyroidism or congenital goiter (Carswell et al et al., 1970; Galina et al et al., 1962). Other drugs used to treat asthma are also contraindicated for use during pregnancy (Table 5.4).

RISK SUMMARY.

The FDA Pregnancy Risk Rating is compared to the Teratogen Information System (TERIS) risk rating in Table 5.5. Generally, the TERIS risk rating provides greater information than the FDA rating. However, the FDA rating is an aggregate risk of not only Table 5.5 Table 5.5 Summary of drugs used to treat asthma Summary of drugs used to treat asthma Drug TERIS risk FDA risk rating Albuterol Undetermined Cm Atropine Unlikely C.

Beclomethasone Unlikely Cm Betamethasone Undetermined C*

Chlorpheniramine Unlikely B.

Cortisone Unlikely C*

Cromolyn Unlikely Bm Dexamethasone Minimal C*

Ephedrine Unlikely C.

Epinephrine Unlikely C.

Erythromycin None Bm Hydrocortisone Unlikely C*

Isoetharine Undetermined C.

Isoproterenol Unlikely C.

Metaproterenol Undetermined Cm Methylprednisolone Unlikely Not in book Penicillin None Bm Pheniramine Unlikely C.

Prednisone Oral clefts: small C*

Other congenital anomalies: unlikely Terbutaline Unlikely Bm Tetracycline Unlikely D.

Theophylline None Cm NA, not available.

TERIS, Teratogen Information System; FDA, Food and Drug Administration.

Compiled from Friedman et al., Obstet Gynecol 1990; 75 75: 594; Briggs et al., 2005; Friedman and Polifka, 2006.

112.

Antiasthma agents during pregnancy birth defects, but also of possible adverse events during the second and third trimester.

The TERIS risk rating is directed toward the risk for birth defects (i.e., teratogenicity).

SPECIAL CONSIDERATIONS.

Acute asthma Patients with an acute asthma attack should have a clinical a.s.sessment, including evaluation for symptoms suggestive of complications such as pneumonia or pneumothorax and for the presence of agitation, pulse paradoxus, severe wheezing, or cyanosis. The beta-adrenergic agonists are a critical element of first-line pharmacological therapy (Cunningham, 1994). These include the medications listed in Table 5.3. During an acute asthma attack, 0.30.5 mL of epinephrine in a 1:1000 dilution is administered subcutaneously every 30 min. Alternatively, 0.25 mg of terbutaline in two to three doses can be given subcutaneously every 2030 min. Some physicians advocate the use of inhaled beta agonists initially. Each dose should be followed by spirometry. Evaluation should include forced expiratory volume in 1 s (FEV ) and peak expiratory flow rate (PEFR) (ACOG, 1 1996). Supplemental oxygen should be administered, as needed, to maintain a pO greater 2 than 60 mmHg. Intravenous hydration is also important, along with respiratory care to remove the tenacious secretions. If initial spirometry indicates severe obstruction, an intravenous bolus of 125 mg methylprednisolone should be considered. Methylprednisolone is indicated in patients who are on chronic corticosteroids. It has been recommended that corticosteroids should be part of the initial therapy for women with severe, acute asthma (Cunningham, 1994; National Heart, Lung and Blood Inst.i.tute, 1991).

After two or three doses of epinephrine or inhaled beta-agonists, if the wheezing is not corrected, then intravenous aminophylline may be indicated. Dosing should be based on theophylline levels, if the patient has been receiving oral theophylline (it should be noted that theophylline requirements decrease as pregnancy advances; see Table 5.1). The patient should be admitted to the hospital if she demonstrates a poor spirometric response to therapy, has no symptom improvement, or has pneumonia or pneumothorax.

Endotracheal intubation and mechanical ventilation should be considered when signs of respiratory failure present. Specifically, PaCO greater than 40 mmHg, PaO less than 2 2.70 mmHg and pH less than 7.38 are indicators of impending respiratory failure.

Immediate endotracheal intubation should be performed when (1) a PaCO of greater 2 than or equal to 55 mmHg or (2) a PaO of less than or equal to 65 mmHg is obtained.

2.Patients who respond quickly to such therapy should be discharged on an intensified regimen. A tapering schedule of oral corticosteroids should be given if intravenous steroids were used. Close follow-up should be arranged to rea.s.sess their clinical condition and possible adjustments in medication. In addition, precipitating factors (Box 5.1) should be avoided.