1305

Treatment of biliary colic with nitroglycerin

SIR-The treatment of biliary colic with nitroglycerin, a donorof nitric oxide (NO) is not generally recognised although therelaxing effect of NO on all smooth muscle, including thevascular, bronchial, and biliary muscle, is mentioned in oldereditions of standard pharmacological textbooks.1 3 patients arepresented whose biliary colic was successfully treated withnitroglycerin.A 25-year-old woman, previously healthy, had acute and

severe pain in the right hypochondrium which radiated to theright scapula and was associated with vomiting and

restlessness. Palpation of the right hypochondrium elicited asharp pain that was worse on deep inspiration (Murphy’s sign).There was no fever or jaundice. Her older sister had hadcholecystectomy for choleliathisis 1 year earlier. 0-5 mgnitroglycerin as a sublingual tablet relieved the pain within 20 s.2 hours later, when the pain returned, she received 20 mgisosorbide dinitrate as an oral tablet, which kept her pain freefor at least 12 hours. Ultrasonography of the gallbladdershowed multiple stones.A 46-year-old man, with no family history of gallbladder

disease, had acute, severe pain in the right hypochondrium 30minutes after breakfast. The pain radiated to the back. He wasnauseated and restless. 1 month earlier he had a similar attackthat resolved spontaneously. His blood pressure was 150/90mm Hg, and pulse was 80 per minute. An electrocardiogramwas normal. Palpation of the right hypochondrium elicited thecharacteristic pain and Murphy’s sign was present. There wasno fever or jaundice. 0-4 mg nitroglycerin as a sublingual sprayrelieved the pain within 30 s. After 20 minutes the paingradually resumed. Another dose of nitroglycerin reduced thepain to a weak ache. Ultrasonography revealed multiple stonesin the gallbladder.A 70-year-old man with frequent attacks of biliary colic had a

positive cholecystogram and had had papillotomy, but stonesremained in the gallbladder. Cholecystectomy was

contraindicated because of severe bronchial asthma and

obesity. The attacks of biliary colic occurred within 15 minutesof a meal, lasted for 4-6 hours, and responded only moderatelyto oral opioids. 0-5 mg nitroglycerin as a sublingual tabletrelieved the pain completely within 60 s, and the effect lastedfor at least 12 hours.

These cases show that nitroglycerin is an effective and

rapidly-acting agent in the treatment of acute biliary colic,probably by relaxing spasms of the biliary smooth muscle.Nitroglycerin may be a useful alternative to analgesic treatmentin the acute situation and in the inoperable patient.

Bjørnar HasselNorwegian Defence Research Establishment, Division for Environmental Toxicology,N 2007 Kjeller, Norway

1 Nickerson M. Vasodilator drugs. In: Goodman LS, Gilman, eds. Thepharmacological basis of therapeutics, 5th ed. New York: Macmillan,1975; 733-35.

Asthma guidelines and evidence-basedmedicine

SIR-Many clinical management guidelines have been

produced in the 1990s, especially in asthma management.There are, however, concerns about the efficacy and validity ofguidelines. The impartiality of consensus statements has alsobeen questioned, as has their ability to improve clinical

practice.1.2 Against this background, a critical appraisal ofpublished asthma-management guidelines was done withcriteria based on clinical decision making.3Twenty-one asthma management guidelines were identified

*Those stating the criterion.

Table: Critical appraisal of asthma guidelines

from (i) A search of English-language publications cited inMedline from 1989 to June, 1993, with key words asthma,management, and guidelines, together with the MESH

heading practice guidelines; (ii) review of the reference lists ofretrieved publications; and (iii) review of the contents pages ofthe Medical Journal of Australia and New Zealand Journal ofMedicine for 1989-93. Where multiple publications describedthe same set of guidelines, only the original publication wasused (a list is available from The Lancet on request). Thisreview showed that there are major deficiencies with theassembly of evidence that forms the basis of asthma

management guidelines (table). Although most guidelinesrecommend some form of drug treatment, they seldom

reported the magnitude of the expected benefits, or the

potential side-effects of treatment according to the guidelines.The cost implications of the recommendations were notconsidered in any guidelines. The cost and side-effects oftherapy are two essential factors used by drug evaluating bodieswhen considering new treatments. These methodological flawsin present asthma-management guidelines will limit their

application by practitioners and administrative bodies.History has a habit of repeating itself. Second generation

asthma-management guidelines are starting to appear andthere is now an opportunity to improve guidelines to increasetheir usefulness. Unbiased methods should be used to obtainevidence on which to base practice recommendations. Weshould now expect that guidelines systematically evaluate theevidence, grade the strength of this evidence by use of the toolsof clinical epidemiology, and include this analysis in the

publication.

Peter Gibson

Respiratory Medicine Unit, John Hunter Hospital, Newcastle, NSW 2310, Australia

1 Haines A, Feder G. Guidance on guidelines. BMJ 1992; 305: 785-86.2 Sheldon TA, Smith GD. Consensus conferences as drug promotion.

Lancet 1993; 341: 100-02.3 Hayward RSA, Wilson MC, Tuhis SR, Bass EB, Rubin HR, Haynes

RB. More information abstracts of articles describing clinical practiceguidelines. Ann Int Med 1993; 118: 731-37.

&bgr;-agonists and asthma

SiR-Cockcroft and colleagues (Oct 2, p 833) show a smallincrease in the early asthmatic response to allergen but nochange in underlying methacholine responsiveness after 2weeks of regular salbutamol. They also record a small decreasein the protection afforded by salbutamol against methacholine-induced bronchoconstriction (3-2 down to 2-5 doubling doses)and allergen-induced bronchoconstriction (3-7 down to 2-5doubling doses). How important are these findings, with

1306

respect to clinical practice? As Cockcroft has commented,l therelevance of early asthmatic response for chronic asthma isprobably less important than the late asthmatic response andthe associated increase in non-specific responsiveness to agentssuch as methacholine. Furthermore, the study patients werevery mild asthmatics (who were able to cope without rescuebronchodilator for at least 4 weeks), who were then treatedquite artificially with regular salbutamol in a way that wouldnot be considered in this group.

In his accompanying commentary Britton (p 818) uses thesedata to question the regular use of the newer longer-acting betaagonist, salmeterol. The only study that has shown a fall in theprotective effect of salmeterol against inducedbronchoconstriction over time2 was also done in mild and

largely symptom-free so-called asthmatics, who were not oninhaled steroids. Even so, these patients remained less reactiveto methacholine after a dose of salmeterol while on regularsalmeterol compared with the value at entry, and no rebound inreactivity was noted. In asthma patients with symptomaticdisease and mainly on regular inhaled steroids-ie, the patientgroup for whom salmeterol might be considered in clinicalpractice, we showed no rebound or underlying change inmethacholine responsiveness after 6 weeks of therapy. 3

Protection against methacholine-induced bronchoconstrictionup to 12 hours was maintained after 4 and 8 weeks of regularsalmeterol, again with no rebound in underlying airwayreactivity.4

Cockcroft and colleagues are concerned about the possibleso-called proinflammatory effects of regular 0-agonists, andsuggest that enhanced mediator release from mast cells

accounts for the small increase in allergen responsiveness theyshow with regular salbutamol treatment. However, Taylor etaP showed that despite a 1 14 and 2-73 doubling dilutionprotection against allergen-induced bronchoconstriction withsalbutamol and salmeterol, respectively, there was no

suppression of urinary leukotriene E4, suggesting that themajor action of these drugs in protecting against earlyasthmatic response was by relaxation of smooth muscle and notby inhibition of mast cell mediator release. We6 and others havenot observed any detrimental or beneficial effects of 8 weeks of

regular salmeterol on inflammatory parameters in broncheolarlavage.The data on salmeterol seem reassuring, on the basis of small

but detailed studies of airway pathophysiology and largeclinical studies, which have failed to show any tachyphylaxis tothe bronchodilator activity of (3-agonists,b nor any diminutionin clinical efficacy6 or loss of asthma control7 with long term,regular salmeterol.

Helen Booth, E Haydn WaltersDepartment of Respiratory Medicine, Alfred Hospital and Monash University MedicalSchool, Melbourne, Victoria 3181, Australia

1 Cockcroft DW, Murdock KY. Comparative effects of inhaledsalbutamol, sodium cromoglycate, and beclomethasone dipropionateon allergen-induced early asthmatic responses, late asthmaticresponses, and increased bronchial responsiveness to histamine.J Allergy Clin Immunol 1987; 79: 734-40.

2 Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH,Sterk PJ. Long-term effects of a long-acting B2-adrenoceptor agonist,salmeterol, on airway hyperresponsiveness in patients with mildasthma. N Engl J Med 1992; 327: 1198-203.

3 Beach JR, Young CL, Harkawat R, et al. Effect on airwayresponsiveness of six weeks treatment with sameterol. Pulm Pharmacol1993; 6: 155-57.

4 Booth H, Fishwick K, Harkawat R, Devereux G, Hendrick DJ,Walters EH. Changes in methacholine induced bronchoconstrictionwith the long acting B2-agonist salmeterol in mild to moderateasthmatic patients. Thorax (in press).

5 Taylor IK, O’Shaughnessy KM, Choudry NB, Adachi M, PalmerJBD, Fuller RW. A comparative study in atopic subjects with asthmaof the effects of salmeterol and salbutamol on allergen-inducedbronchoconstriction, increase in airway reactivity, and increase in

urinary leukotriene E4 excretion. J Allergy Clin Immunol 1992; 89:575-83.

6 Pearlman DS, Chervinsky P, LaForce C, et al. A comparison ofsalmeterol with albuterol in the treatment of mild-to-moderate asthma.N Engl J Med 1992; 327: 1420-25.

7 Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillancestudy: comparison of salmeterol with salbutamol in asthmatic patientswho require regular bronchodilator treatment. BMJ 1993; 306:1034-37.

SiR-Cockcroft and colleagues’ report has once again fuelledthe continuing debate on the use of &bgr;2-agonists in asthma.’ Webelieve that their findings are of little clinical relevance withrespect to the general asthmatic population. They investigatedpatients with mild asthma who had not needed therapy, andhence by definition would not usually have been exposed toregular inhaled &bgr;2-agonists. Their findings should be

extrapolated with caution to patients with moderate or severeasthma who are likely to be taking inhaled corticosteroids aswell as &bgr;2-agonists. In this respect there is good evidence that itis safe to use regular inhaled &bgr;2-agonists in conjunction withinhaled corticosteroid, in terms of effects on FEV!, peak flowmeasurements, bronchial hyperreactivity, symptoms, andexacerbation rates.2,3 Furthermore, combined therapy withregular inhaled corticosteroid and 02-agonists protect againstboth the early and late responses to allergen challenge.4The British Thoracic Society guidelines recommend the

dose of inhaled steroid be titrated in stepwise fashion againstmarkers of disease activity, including requirements for

P2-agonist.s However, on the basis of the evidence, patientswho need to use their (32-agonists regularly can be reassuredthat it is safe to do so, provided that they are also using anoptimum dose of inhaled steroid. There has been a

considerable amount of coverage in both the medical and laypress about the dangers of 02-agonists, which has resulted inunneccessary anxiety in asthmatic patients. We emphasise that02-agonists remain an effective and safe first-linebronchodilator drug when used correctly.1

Brian J Lipworth, Alison GroveDepartment of Clinical Pharmacology, Ninewells Hospital and Medical School,Dundee DD1 9SY, UK

1 Lipworth BJ. Risks versus benefits of inhaled &bgr;2-agonists in themanagement of asthma. Drug Safety 1992; 7: 54-70.

2 Kerstjens HAM, Brand PLP, Hughes MD, et al. A comparison ofbronchodilator therapy with or without inhaled corticosteroid forobstructive airway disease. N Engl J Med 1992; 327: 1413-19.

3 Waalkens HJ, Gerritsen J, Koeter GH, Krouwels FH,Van Aalderen WMC, Knol K. Budesonide and terbutaline orterbutaline alone in children with mild asthma: effects on bronchial

hyperresponsiveness and diurnal variation in peak flow. Thorax 1991;46: 499-503.

4 Paggiaro PL, Dente FL, Vagaggini B, et al. Salbutamol plusbeclomethasone dipropionate but not salbutamol alone, completelyprevent early and late asthmatic responses to allergen. Respir Med1991; 85: 401-06.

5 British Thoracic Society guidelines for treatment of asthma. Thorax1993; 48 (suppl): S1-S24.

Young patients on inhaled steroids andcataract

SiR-Simons and colleagues (Sept 25, p 776) report no

posterior subcapsular cataracts with narrow-beam slit-lampexamination in 95 patients who received inhaled

glucocorticoids. This result is certainly encouraging for thesafety of the inhaled steroids, and they conclude that theroutine screening of the patients bn inhaled steroids is notwarranted. It is important that the patients with suspectedcataracts are examined with dilated pupils and with bothnarrow slit-lamp beam and retroillumination techniques.Failure to do so may mean undetected cataracts. All cataracts