Steroids and Croup

1134

ventricular dilatation in the rat model, since the selective arterial vasodilator hydralazine has no apparent influence on ventricular size. Sharpe et als were the first to describe prophylactic post-infarction ACE inhibition in man: sixty symptom-free patients with ejection fractions of less than 45 % were randomised to receive captopril, frusemide, or placebo a week after infarction. Patients taking captopril showed a progressive reduction in left ventricular end-systolic volume index (LVESVI) and a progressive improvement in ejection fraction (EF) and stroke volume index (SVI) over a year of follow-up. In contrast, patients given frusemide or placebo showed small increases in LVESVI, no change in SVI, and a slight reduction in EF. In the only other study in man published so far Pfeffer and co-workers16 randomised sixty patients to captopril or placebo at a mean of 18 days after first anterior infarction. Again none was in overt cardiac failure but all had an ejection fraction below 45%. There was no change in end-systolic volume between baseline and one year in either group, but end-diastolic volume increased in the placebo group. Comparison of the end-diastolic volume changes in the two groups revealed no significant differences. Among patients taking placebo, volume enlargement was more pronounced in those with an extensive wall-motion abnormality or with an occluded infarct-related artery. These relations were not seen in patients taking captopril-an indication that in high-risk patients remodelling had been favourably influenced. In a subgroup of males without exercise-limiting ischaemia, exercise capacity was greater in those patients taking captopril; however, when this group was further subdivided on the basis of abnormalities in ventricular morphology at entry to the study, only in the tercile with the most abnormal ventricles did captopril improve exercise capacity and functional

status The number of patients in these studies is too small and follow-up is too short for any conclusions to be drawn about sustained attenuation of cardiac dilatation. However, there is sufficient evidence of

benefit, particularly in high-risk patients, to justify large-scale investigations. The SAVE study (Survival And Ventricular Enlargement) is enrolling more than two thousand patients with an ejection fraction less than 40%. They are randomised to captopril or placebo between three and sixteen days after infarction and follow-up will be for a median of more than three years. This study will provide important data on the longer term effects of ACE inhibition on ventricular function. However, even with this number of patients it may be difficult to assess survival changes

Sharpe N, Murphy J, Smith H, Hannon S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988, i: 255-59. 16. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J 15.

Med 1988; 319: 80-86.

in view of the low late mortality already achieved with conventional treatment. Other questions remain unanswered-not least that of the optimum time for initiation of therapy. A week after infarction ventricular enlargement is already well under way,ls and a greater influence might be achieved with earlier intervention. Interest is now extending to use of ACE inhibitors in the acute phase of infarction as primary therapy. In animals both captopril and enalapril have been reported to limit infarct size but contrary results have also been obtained and extrapolation to man is difficult. 18-20 Nevertheless, both captopril and enalaprilat (the active metabolite of enalapril) have been used safely in patients with acute left ventricular failure after infarction, and oral captopril has been given in combination with streptokinase. 21-23 Use of ACE inhibitors in the early stages of infarction is therefore a reasonable proposition. Perhaps a more important issue, however, is whether ACE inhibitors are any more effective than conventional vasodilators in preventing progressive ventricular dilatation. Intravenous nitrates reduce both preload and afterload and in one study produced impressive limitations of ventricular dilatation-though this may have been due at least in part to reduction in infarct size.24 In an ISIS pilot study captopril, oral nitrate, and placebo are being compared. For limitation of ventricular in the dilatation progressive presymptomatic phase of ventricular failure the balance of evidence at present favours ACE inhibitors. However, there is no case yet for routine use of these agents.

Steroids and

Croup

CROUP is the commonest cause of acute upper airway obstruction in children, leading to 2-3% of young children being admitted to hospital.1 Many aspects of management remain controversialZ Although corticosteroids have been given for croup for over 30 years, it is still unclear whether they are beneficial. Results of published studies are conflicting Vaughan DE, Parisi AF, Pfeffer MA. Effects of left ventricular shape and captopril therapy on exercise capacity after anterior wall acute myocardial infarction Am J Cardiol 1989; 63: 1167-73 18. Ertl G, Kloner RA, Alexander RW, Braunwald E Limitation of experimental infarct size by an angiotensin converting enzyme inhibitor. Circulation 1982; 65: 40-48 19 Lefer AM, Peck RC Cardioprotective effects of enalapril in acute myocardial ischaemia. Pharmacology 1984; 29: 61-69. 20. Daniell HB, Cason RR, Ballard KD, Thomas GR, Privitera PJ Effects of captopril on limiting infarct size in conscious dogs J Cardiovasc Pharmacol 1984; 6: 1043-47 21 McAlpine HM, Morton JJ, Leckie B, Dargie HJ. Haemodynamic effects of captopnl in acute left ventricular failure complicating myocardial infarction J Cardiovasc Pharmacol 1987; 9 (suppl 2): S25-S30 22. Taylor SH, Verma SP. Treatment of post myocardial infarction left ventricular failure with intravenous enalaprilat. In: Sever P, McGregor GA, eds. Current advances in ACE inhibition. Edinburgh. Churchill Livingstone, 1989 23 Kingma JH, van Gilst WH, de Graeff P, Louwerenborg HW, Six AJ, Wesseling H Captopril during thrombolysis in myocardial infarction. Feasibility, tolerance and beneficial neurohumoral effects. In Sever P, McGregor GA, eds. Current advances in ACE inhibition. Edinburgh Churchill Livingstone, 1989 24. Jugdutt BI, Warnicka JW. Intravenous nitroglycerine therapy to limit myocardial infarct size, expansion and complications. Circulation 1988; 78: 906-19 1. Phelan PD, Landau LI, Olinsky A. Respiratory illness in children 2nd ed Oxford 17. Lamas GA,

Blackwell, 1982 32-33. 2. Couriel JM. Management of croup. Arch Dis Child 1988; 63: 1305-08.

1135

and

confusing: differences

in

patient selection,

assessment of severity, and treatment regimens hinder

comparison of these reports.3-Q Kairys and colleagues’ lately conducted a metaanalysis of ten randomised controlled trials of steroids in the management of childhood croup published since 1960. After excluding one study because randomisation was not double-blind, they amassed data on 1126 children admitted to hospital with croup, of whom 575 had received steroids and 551 placebo. They concluded that a significantly higher proportion of patients who received steroids showed clinical improvement 12 hours (odds ratio 225, 95 % confidence interval [CI] 1-66, 3-06) and 24 hours (odds ratio 3-19, 95% CI 1-70, 5-99) after treatment than did control subjects. The need for endotracheal intubation was reduced in those receiving steroids (odds ratio 0-21, 95% CI 0-05, 084). Higher initial doses of steroid ( > 100 mg hydrocortisone) were more effective than smaller doses. Although these results support the use of steroids in children with croup who require hospital admission, there are important deficiencies in the original studies, and some assumptions made in the meta-analysis may not be valid.8,9 The first difficulty lies with patient selection-did all the children diagnosed as having croup in these studies have the same disease? Croup is not a single entity, but an acute clinical syndrome with inspiratory stridor, barking cough, hoarseness, and signs of respiratory distress due to laryngeal or tracheal obstruction. This defmition embraces several distinct conditions with different pathogeneses, clinical courses, and responses to treatment.2 The commonest cause of croup (60-85 % of cases) is viral laryngotracheobronchitis, in which the features of croup are usually preceded by coryza and fever for 1-2 days. Some children have repeated episodes (recurrent or spasmodic croup) without preceding coryza, often with a rapid onset at night and a shorter duration than that of viral croup. Because of the association with atopic disease, and an abnormal response to histamine challenge, hyperreactivity of the upper airway is thought to be the underlying mechanism.10,11 Less common, but potentially life-threatening, causes of bacterial include tracheitis (pseudocroup

3.

Cherry J. The treatment of croup: continued controversy due to failure of recognition of historic, ecologic, etiologic and clinical perspectives. J Pediatr 1979; 94: 352-54. 4. Tunnessen WW, Feinstein AR. The steroid-croup controversy an analytic review of methodologic problems. J Pediatr 1980; 96: 751-56. 5. Olinsky A, Phelan PD. Diagnosis and management of upper airway obstruction In: Milner AD, Martin RJ, eds. Neonatal and paediatric respiratory medicine. London: Butterworths, 1985: 111-25. 6. Smith DS. Corticosteroids in croup: a chink in the ivory tower? J Pediatr 1989; 115: 256-57. 7. Kairys

SW, Olmstead EM, O’Connor GT. Steroid treatment of laryngotracheitis: a meta-analysis of the evidence from randomized trials. Pediatrics 1989; 83: 683-93. 8. Editorial Whither meta-analysis? Lancet 1987; i: 897-98. 9. Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Meta-analysis of randomized controlled trials. N Engl J Med 1987; 316: 450-55 10. Zach M, Erben A, Olinsky A. Croup, recurrent croup, allergy and airways hyperreactivity. Arch Dis Child 1981; 56: 336-41. 11. Zach M, Schnall RP, Landau LI.Upper and lower airway hyperreactivity in recurrent croup. Am Rev Respir Dis 1980; 121: 979-83.

membranous

croup), and inhaled laryngeal foreign

body. Clear inclusion and exclusion criteria were not given in all the studies reviewed by Kairys et al. In some studies, all children admitted to hospital with croup were included; in others, children with mild symptoms,12 or some of those with severe symptoms, were excluded.13 Only one trial distinguished between laryngotracheobronchitis and spasmodic croup;14 in that study, the 35% of the subjects with the diagnosis of spasmodic croup improved more rapidly with steroids, whereas those with laryngotracheobronchitis showed no such benefit. These results have subsequently been challenged.l6 Different clinical scores were used to assess the initial condition of the children and the response to treatment. These scores were based on signs such as heart and respiratory rate, chest wall recession, stridor, dyspnoea, cyanosis, and restlessness. Whilst such features are helpful in the assessment of individual patients, there is no evidence that they are a valid measure for comparisons. It is illogical to give the same score to tachycardia, which may be present in mild croup, and to cyanosis, which indicates lifethreatening obstruction. Newth16 compared physical signs with arterial blood gases in children with croup: respiratory rate was the most reliable indicator of

hypoxaemia. Hypercapnia, indicating severe obstruction, was not reflected by any clinical signs. There are important variations in the ways in which steroids were given in the various trials reviewed. Dexamethasone

used in

studies and in others. To the methylprednisolone prednisolone allow comparison of the different treatment regimens, Kairys et al expressed all doses as cortisone equivalents. The initial dose for an average 2-year-old ranged from a minute 4-2 mg to a generous 267 mg of cortisone. In six studies, further doses of steroids were Intramuscular, given at variable intervals. intravenous, and oral routes of administration were used in different studies. In addition to steroids or placebo, patients received several other treatments, including antibiotics, mist, sedatives, and nebulised racemic adrenaline. Details of these treatments are not presented in the meta-analysis. The trials lack an agreed end-point against which the response to treatment can be assessed. Kairys et al used three end-points: the proportion of subjects who had improved at 12 hours and at 24 hours, and the was

seven

or

Leipzig B,

Stockman JA, Swender P. A prospective determine the efficacy of steroids in treatment of croup. J Pediatr 1979; 94: 194-96. 13. Muhlendahl KE, Kahn D, Spohr HL, Dressler F. Steroid treatment of pseudo-croup. Helvet Paediatr Acta 1982; 37: 431-36. 14. Koren G, Frand M, Barziley Z, Macleod SM. Corticosteroid treatment of laryngotracheitis versus spasmodic croup in children. Am J Dis Child 1983; 137: 941-44. 15. Lacroix J, Massicote P. Corticosteroid treatment of croup. Am J Dis Child 1984; 138: 699. 16. Newth CJL, Levison H, Bryan AC. The respiratory status of children with croup. J Pediatr 1972; 81: 1068-73 17. Wagener JS, Landau LI, Olinsky A, Phelan PD. Management of children hospitalized for laryngotracheobronchitis. Pediatr Pulmonol 1986; 2: 159-62. 12.

Oski FA, randomized study

Cummings CW,

to

1136

proportion needing endotracheal intubation. Data on the improvement at 12 and 24 hours were available from only seven of nine and four of nine of the studies, respectively. The conclusion that steroids significantly reduced intubation was based on only 8 subjects (7 placebo, 1 steroid) from four studies. There

evidence that steroids reduced the of hospital admission, or about possible

was no

length toxicity.

of steroids in children admitted with croup cannot be justified on the basis of the available information. Perhaps the most important message from Kairys and colleagues’ analysis is that 82% of children admitted to hospital who did not receive steroids had improved within 24 hours. Wagener et al 17 showed that the presence of chest wall retraction and stridor at rest on admission identifies those children who will have a severe or prolonged illness. If steroids are to be of any clinical relevance in croup, it will be in this minority of patients, and any further studies should focus on this group. Measurement of oxygen saturation, which is valuable in the assessment of acute asthma,18 may give a useful objective alternative to clinical scores in the assessment of response to treatment in croup. There is still a need for randomised controlled double-blind studies of steroids in severe croup. Such studies would need clear diagnostic criteria, stratification into laryngotracheobronchitis and spasmodic croup, a validated index of severity, an adequate dose of steroid, and a clinically relevant measurement of outcome in a statistically adequate number of subjects.4Although the latest trial,19 which concludes that dexamethasone is of some benefit in the first 24 hours, comes close to meeting these criteria, the case for the routine use of steroids in croup remains

Routine

use

unproven.

CHEMOTHERAPY AND HEPATITIS B DURING the past decade slow but positive progress has been made towards antiviral therapy for chronic hepatitis B virus (HBV) infection. Interferon-a is currently the favoured drug, and several studiesl-3 have shown that among HBsAg-positive adult Caucasians (as distinct from Orientals) who are HBeAg and DNA polymerase positive and have raised aminotransferase levels, about 30-40% will lose HBe positivity 8-12 weeks after starting interferon 18. Geelhoed GC, Landau LI, LeSouef PN. Predictive value of oxygen saturation in emergency evaluation of asthmatic children. Br Med J 1988; 297: 395-96. 19 Super DM, Cartelli NA, Brooks LJ, Lembo RM, Kumar ML. A prospective randomized double-blind study to evaluate the effect of dexamethasone in acute laryngotracheitis. J Pediatr 1989; 115: 323-29. 1. Davis GL, Hoofnagle JH. Interferon m viral hepatitis: role in pathogenesis and treatment. Hepatology 1986; 6: 1038-41. 2 Alexander GJM, Brahm J, Fagan EA, et al. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet 1987; ii: 66-68. 3 Brook MG, Chan G, Yap I, et al. Randomised controlled trial of lymphoblastoid interferon alfa in Europid men with chronic hepatitis B virus infection. Br Med J 1989, 299: 652-56.

A smaller proportion will also lose HBsAg and become anti-HBs positive; clearance of either antigen is almost invariably accompanied by substantial and sustained improvement in liver inflammation. Seroconversion is generally associated with acute hepatocellular damage, with both clinical and biochemical evidence of hepatitis, and for this reason interferon therapy is not recommended for patients with advanced liver disease in whom such an episode might well result in decompensation and even death. The role of corticosteroids in chronic HBV infection has been debated for many years. Long before the widespread introduction of antiviral agents, Lam et al’ in Hong Kong reported that the administration of prednisone to patients with HBsAg-positive chronic active hepatitis hastened biochemical relapse. Moreover, subsequent studies have shown that withdrawal after a course of steroids induces an immunological "rebound", leading to a reduction in HBV-associated DNA polymerase and serum HBV DNA. 5,6 In some patients these changes result in acute hepatitis and liver decompensation 7" but they may also be associated with a significant frequency of HBeAg clearance. Several ongoing studies have been designed to examine whether the combination of corticosteroids and subsequent interferon administration might improve the therapeutic

therapy.

response rate. Two reports

now

draw attention

to

the hazards of

administering cytotoxic or immunosuppressive drugs to hepatitis B carriers for conditions unrelated to liver disease. Lau and colleagues9 report 4 Chinese patients with nonHodgkin lymphoma in whom, after several courses of chemotherapy, fulminant hepatitis developed with simultaneous reactivation of hepatitis B infection. 5 cases are described from London by Bird and colleagues,10 who observed similar changes in patients treated for both malignant and non-malignant disorders. 7 of the 9 patients were initially anti-HBe positive but became HBe antigen positive with the development of the hepatic necrosis. Although 2 patients were found to have previously unrecognised cirrhosis at necropsy, the others appear to have been truly symptom-free HBsAg carriers with no clinically important liver damage before chemotherapy. The observation that cytotoxic and immunosuppressive drugs may interfere with hepatitis B status is not new: Wands et alll surveyed 85 patients with myeloproliferative and lymphoproliferative disorders and observed that after chemotherapy, HBsAg titres often increased. In 2 patients 4. Lam KC, Lai CL, Ng R, Trepo C, Wu PC. Deletenous effect of prednisone in HBsAg positive chronic active hepatitis N EnglJ Med 1981; 304: 380-86. 5 Scullard GH, Smith CI, Mengan TC, Robinson WS, Gregory PB Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B Gastroenterology 1981; 81: 987-91. 6. Rakela J, Redeker AG, Weliky B. Effect of short-term prednisone therapy on aminotransferase levels and hepatitis B virus markers in chronic type B hepatitis. Gastroenterology 1983; 84: 956-60. 7. Nair PV, Tong MJ, Stevenson D, Roskamp D, Boone C. A pilot study on the effects of prednisone withdrawal on serum hepatitis B virus, DNA and HBeAg in chronic active hepatitis B. Hepatology 1986; 6: 1319-24. 8. Hess G, Manns M, Hutteroth M, Meyer zum, Buschenfelde KH. Discontinuation of immunosuppressive therapy in hepatitis B surface antigen-positive chronic hepatitis: effect on viral replication and on liver cell damage Digestion 1987, 36: 47-54. 9. Lau JYN, Lai CL, Lin HJ, et al. Fatal reactivation of chronic hepatitis B vitus infection following withdrawal of chemotherapy in lymphoma patients. Q J Med 1989, 73: 911-17. 10. Bird GLA, Smith H, Portmann B, Alexander GJM, Williams R Acute liver decompensation on withdrawal of cytotoxic therapy and immunosuppressive therapy in hepatitis B carriers. QJ Med 1989; 73: 895-902. 11. Wands JR, Chura CM, Roll FJ, Maddrey WC Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders Gastroenterology 1975, 68: 105-12