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transforming growth factor beta superfamily, parts ofwhich may control bone turnover.1O,11

Clinical studies with BMP have been hindered bythe difficulty of obtaining sufficient amounts of theactive product. Urist’s group12 showed that BMPalone placed in diaphyseal defects in dogs consistentlyresulted in union which would otherwise not take

place, and in a small uncontrolled series of humanimplants they used autogenous bone with BMP forestablished non-union with good results.13

Purification of the various BMPs anddetermination of their precise role in osteoinductionand their relation with other growth factors in theproduction and homoeostasis of bone will lead to agreater understanding of how bone changesthroughout life. The potential for BMP to be

produced commercially will surely interest anyonewho has a bony defect to fil1.14

1. Lacroix P. Recent investigations on the growth of bone. Nature 1945; 156:576.

2. Khouri RK, Koudsi B, Reddi H. Tissue transformation into bone in vivo.JAMA 1991; 266: 1953-55.

3. Urist MR, Strates BS. Bone formation in implants of partially and whollydemineralized bone matrix. Clin Orthop 1970; 71: 271-78.

4. Urist MR. Bone: formation by autoinduction. Science 1965; 150: 893-99.5. Sampeth TK, Reddi AH. Dissociative extraction and reconstitution of

extracellular matrix components involved in local bone differentiation.Proc Natl Acad Sci USA 1981; 78: 7599-603.

6. Ma S, Chen G, Reddi AH. Collaboration between collagenous matrixand osteogenin is required for bone induction. Ann N Y Acad Sci 1990;580: 524-25.

7. Luyten FP, Cunningham NS, Ma S, et al. Purification and partial aminoacid sequence of osteogenin, a protein initiating bone differentiation.J Biol Chem 1989; 264: 13370-80.

8. Wang EA, Rosen V, D’Allessandro JS, et al. Recombinant human bonemorphogenetic protein induces bone formation. Proc Natl Acad SciUSA 1990; 87: 2220-24.

9. Bessho K, Tagawa T, Murata M. Analysis of bone morphogeneticprotein (BMP) derived from human and bovine bone matrix. ClinOrthop 1991; 268: 226-34.

10. Hauschka PV, Mavrakos AE, lafrati MD, et al. Growth factors in bonematrix. J. Biol Chem 1986; 261: 12665-74.

11. Centrella M, McCarthy TL, Canalis E. Transforming growth factor-betaand remodeling of bone. J Bone Jt Surg 1991; 73A: 1418-28.

12. Nilsson OS, Urist MR, Dawson EG, et al. Bone repair induced by bonemorphogenetic protein in ulnar efects in dogs. J Bone Jt Surg 1986;68B: 635-42.

13. Johnson EE, Urist MR, Finerman GAM. Repair of segmental defects ofthe tibia with cancellous bone grafts augmented with human bonemorphogenetic protein. Clin Orthop 1988; 236: 249-57.

14. Reddi AH, Cunningham NS. Recent progress in bone induction byosteogenin and bone morphogenetic proteins: challenges forbiomechanical and tissue engineering. J Biomech Eng 1991; 113:189-90.

Adenosine and the diagnosis oftachycardias

Adenosine is an endogenous purine nucleosidewhich, when injected intravenously, causes transientheart block by slowing atrioventricular nodalconduction.1,2 This action makes it highly effectivefor termination of paroxysmal supraventriculartachycardias with re-entrant circuits that include theatrioventricular node.3-6 Use of adenosine has latelybeen approved in the UK not only for this therapeuticindication but also as an aid to the diagnosis oftachycardias. Adenosine-induced atrioventricularnodal block may reveal an atrial tachyarrhythmia--eg,

atrial flutter-by slowing the ventricular response.3-5Ventricular tachycardia, by contrast, would beunaffected by adenosine. The extreme brevity ofaction of adenosine (half-life less than 2 s’) may meanthat it is safer for this purpose than verapamil, a drugcommonly used to treat supraventriculartachycardia,8,9 but is there any need for a

pharmacological diagnostic aid when we already haveelectrocardiographic10-13 and clinical13,14 criteria forthe diagnosis of tachycardias?

Despite the availability of diagnostic criteria,arrhythmias are commonly misdiagnosed.8,14-16 It is

important to establish the correct diagnosis, not onlybecause of the long-term therapeutic and prognosticimplications but also to ensure proper emergencytreatment. For example, tachycardia with broad QRScomplexes may be supraventricular tachycardia withaberrant conduction (eg, bundle branch block) orventricular tachycardia. Adverse effects, includingcardiac arrest, may occur when verapamil isadministered to patients with ventricular tachycardiathat has been misdiagnosed as supraventriculartachycardia. 8,9,16 Misdiagnosis also occurs with

narrow-complex tachycardias. In a multicentre studyof adenosine for paroxysmal supraventriculartachycardia,615 % of patients were excluded from theanalysis of efficacy because they were found to haveother arrhythmias. Thus, an additional diagnostic aid,such as the response to adenosine, may be helpful-but only if sensitivity and specificity are high and,most important, safety has been established.

Intravenous adenosine, administered as a rapidbolus injection into a large peripheral vein, restoredsinus rhythm in over 90% of patients with paroxysmalsupraventricular tachycardia. In patients with

broad-complex tachycardia, response to adenosinedifferentiated supraventricular from ventricular

tachyarrhythmias with a sensitivity of 90%, a

specificity of 93%, and a positive predictive accuracyof 92 % .4,17 Transient side-effects, including chestdiscomfort, dyspnoea, and flushing, are common, butlast less than a minute and are usually tolerated.Serious adverse effects have not been reported.Additional diagnostic information may also beobtained. For example, in patients with paroxysmalsupraventricular tachycardia, Wolff-Parkinson-White syndrome may be revealed by adenosine in thefirst sinus beats following termination of tachycardia.Adenosine induces atrioventricular nodal block, butdoes not affect accessory pathway conduction,resulting in pronounced ventricular pre-excitationwhich is apparent on the surface electrocardiogram.4,18Administration of adenosine during sinus rhythmmay likewise establish the presence of an accessorypathway in patients with latent pre-excitation.19Use of adenosine as a diagnostic aid is not without

potential drawbacks. The electrophysiological effectsof adenosine are not confined to the atrioventricularnode. The drug shortens the atrial action potentialand has antiadrenergic actions on ventricular

465

myocardiwn .20 A few atrial arrhythmias, includingatrial flutter, may respond to adenosine,4,17 andadenosine-sensitive ventricular tachycardias havebeen reported in patients with structurally normalhearts who have exercise-induced arrhythmias.21 Bycontrast, ventricular tachycardia is not the onlyexplanation for lack of effect. The rapid metabolism ofadenosine makes the rate and route of injectioncritically important. The minimal effective dose islower when the drug is administered via large orcentral veins4 and, conversely, peripheraladministration may be ineffective. Because of theshort half-life, incremental doses should be given--eg,3 mg followed by 6 mg, and then 12 mg; a few patientsrefuse further increments because of transient side-effects with ineffective lower doses. Some patientswith supraventricular tachycardia require higher thanthe maximum recommended dose of 12 mg;3,4 highdoses may likewise be needed in patients on

theophylline, which antagonises the effects ofadenosine.3 3

There are uncommon broad-complex tachycardias,other than ventricular tachycardia, that may not

respond to adenosine. Examples include pre-excitedatrial flutter or fibrillation, with conduction of activityfrom atria to ventricles via an accessory pathway.Verapamil administered to such patients can causeserious side-effects, including cardiac arrest.22,23

Experience with adenosine in pre-excited atrialfibrillation or flutter is limited, but there have been noreports of adverse effects despite transient increases inaccessory pathway conduction and atrial rate. 17,24

Experience with adenosine in patients withventricular tachycardia is likewise limited and is

mainly confined to patients with induced ventriculartachycardia in the electrophysiology laboratory. 4,17,25Again, no serious adverse effects have been reported.Whether this apparent safety of adenosine will beconfirmed with more widespread use remains to beseen. In patients with supraventricular arrhythmiasthere have been reports of adenosine-induced

bradycardia with ventricular standstill of severalseconds’ duration. 3,4 4 Normal rhythm returnedthereafter without longer term sequelae. However,actions of adenosine are potentiated four-fold bydipyridamole,26 an adenosine uptake blocker, andduration of adverse effects may be prolonged in

patients taking this commonly prescribed drug and inthose with sinus node dysfunction. 3Thus adenosine should be used as an adjunct to,

and not a replacement for, clinical and

electrocardiographic observations. A history ofmyocardial infarction, or evidence of dissociated atrialactivity from the jugular venous pulse, supports thediagnosis of ventricular tachycardia.13,14 Every patientwith tachycardia should have a full 12-lead

electrocardiogram before treatment. Diagnosis ofventricular tachycardia from the electrocardiogramcan include analysis of the QRS morphology, 10,13 butsimpler criteria (eg, atrioventricular dissociation,

QRS duration > 140 ms, or QRS axis more negativethan - 30 degrees) will indicate the diagnosis in manycases.27 Adenosine should be tried in cases where

supraventricular tachycardia has been diagnosed orwhere doubt persists.

1. Honey RM, Rithchie WT, Thomson WAR. The action of adenosineupon the human heart. QJ Med 1930; 23: 485-90.

2. Favale S, DiBase M, Rizzo U, Belardinelli L, Rizzon P. Effect ofadenosine on atrioventricular conduction in patients. JACC 1985; 5:1212-19.

3. DiMarco JP, Sellers TD, Lerman BB, Greenberg ML, Berne RM,Belardinelli L. Diagnostic and therapeutic use of adenosine in patientswith supraventricular tachyarrhythmias. JACC 1985; 6: 417-18.

4. Rankin AC, Oldroyd KG, Chong E, Rae AP, Cobbe SM. Value andlimitations of adenosine in the diagnosis and treatment of narrow andbroad complex tachycardias. Br Heart J 1989; 62: 195-203.

5. Till J, Shinebourn EA, Rigby ML, Clarke B, Ward DE, Rowland E.Efficacy and safety of adenosine in the treatment of supraventriculartachycardia m infants and children. Br Heart J 1989; 62: 204-11.

6. DiMarco JP, Miles W, Akhtar M, et al. Adenosine for paroxysmalsupraventricular tachycardia: dose ranging and comparison withverapamil. Ann Intern Med 1990; 113: 104-10.

7. Moser GH, Schrader J, Deussen A. Turnover of adenosine in plasma ofhuman and dog blood. Am J Physiol 1989; 256: C799-C806.

8. Rankin AC, Rae AP, Cobbe SM. Misuse of intravenous verapamil inpatients with ventricular tachycardia. Lancet 1987; ii: 472-74.

9. Buxton AE, Marchlinski FE, Doherty JU, Flores B, Josephson ME.Hazards of intravenous verapamil for sustained ventricular

tachycardia. Am J Cardiol 1987; 59: 1107-10.10. Wellens HJJ, Bar FWHM, Lie KI. The value of the electrocardiogram in

the differential diagnosis of a tachycardia with a widened QRScomplex. Am J Med 1978; 64: 27-33.

11. Bar FW, Brugada P, Dassen WRM, Wellens HJJ. Differential diagnosisof tachycardia with narrow QRS complex (shorter than 0·12 seconds).Am J Cardiol 1984; 54: 555-60.

12. Kindwall KE, Brown J, Josephson ME. Electrocardiographic criteria forventricular tachycardia in wide complex left bundle branch block

morphology tachycardias. Am J Cardiol 1988; 61: 1279-83.13. Griffith MJ, de Belder MA, Linker NJ, Ward DE, Camm AJ.

Multivariate analysis to simlify the differential diagnosis of broadcomplex tachycardia. Br Heart J 1991; 66: 166-74.

14. Tchou P, Young P, Mahmud P, Denker S, Jazayeri M, Akhtar M. Usefulclinical criteria for the diagnosis of ventricular tachycardia. Am J Med1988; 84: 53-56.

15. Dancy M, Camm AJ, Ward D. Misdiagnosis of chronic recurrentventricular tachycardia. Lancet 1989; ii: 320-23.

16. Stewart RB, Bardy GH, Greene HL. Wide complex tachycardia:misdiagnosis and outcome after emergent therapy. Ann Intern Med1986; 104: 766-71.

17. Griffith MJ, Linker NJ, Ward DE, Camm AJ. Adenosine in thediagnosis of broad complex tachycardia. Lancet 1988; i: 672-75.

18. Garratt C, Linker N, Griffith M, Ward D, Camm AJ. Comparison ofadenosine and verapamil for termination of paroxysmal junctionaltachycardia. Am J Cardiol 1989; 64: 1310-16.

19. Garratt CJ, Antoniou A, Griffith MJ, Ward DE, Camm AJ. Use ofintravenous adenosine in sinus rhythm as a diagnostic test for latentpreexcitation. Am J Cardiol 1990; 65: 868-73.

20. Belardinelli L, Linden J, Beme RM. The cardiac effects of adenosine.Prog Cardiovasc Dis 1989; 32: 73-97.

21. Lerman BB, Belardinelli L, West A, Berne RM, DiMarco JP.Adenosine-sensitive ventricular tachycardia: evidence suggestingcyclic AMP-mediated triggered activity. Circulation 1986; 74: 270-80.

22. McGovern B, Garan H, Ruskin JN. Precipitation of cardiac arrest byverapamil in pre-excited atrial fibrillation. Ann Intern Med 1986; 104:791-94.

23. Garratt C, Antoniou A, Ward D, Camm AJ. Misuse of verapamil inpre-excited atrial fibrillation. Lancet 1989; i: 367-69.

24. Garratt CJ, Griffith MJ, O’Nunain S, Ward DE, Camm AJ. Effects ofintravenous adenosine on antegrade refractoriness of accessoryatrioventricular connections. Circulation 1991; 84: 1962-68.

25. Griffith MJ, Linker NJ, Garratt CJ, Ward DE, Camm AJ. Relativeefficacy and safety of intravenous drugs for termination of sustainedventricular tachycardia. Lancet 1990; 336: 670-73.

26. Lerman BB, Wesley RC, Belardinelli L. Electrophysiologic effects ofdipyridamole on atrioventricular nodal conduction and

supraventricular tachycardia: role of endogenous adenosine.Circulation 1989; 80: 1536-43.

27. Dancy M, Ward D. Diagnosis of ventricular tachycardia: a clinicalalgorithm. Br Med J 1985; 291: 1036-38.