928

adenosine may play a part in regulation of cerebral" andskeletal muscles 14 blood flow.

In the kidney, adenosine seems not to be a vasodilator but avasoconstrictor. 1, " This accords with the concept ofNewby9because oxygen demand in the kidney is due to glomerularfiltration and tubular processes.’6 By limiting renal bloodflow, adenosine would reduce glomerular filtration and

energy demands.When given intravenously to human beings, adenosine is

reported to stimulate respiration.1’ If the suggestion that thenucleoside is involved in the ventilatory response to hypoxiais proved, this will extend Newby’s concept of adenosine as aregulator of oxygen delivery.

In the central and peripheral nervous systems the diverseactions of adenosine and its related nucleotides’ are ofuncertain relevance to neural physiology and patho-physiology. One intriguing observation is that the centralstimulant action of caffeine and other methylxanthines is

probably due to antagonism of the sedative effects ofadenosine. 19,20

Possible pathophysiological roles for adenosine are nowbeing investigated. In asthmatic subjects adenosine, wheninhaled, is a bronchoconstrictor but in normal subjects it hasno such effect. 21 The bronchoconstrictor effect of adenosineis antagonised by theophylline, 22 perhaps explaining in partthe effectiveness of theophylline, a competitive adenosineantagonist, in the management of asthmatic patients.Adenosine may be involved in the genesis of

bradyarrhythmias seen in inferior myocardial infarction.23 Itslows the sinus rate and can block conduction throughthe atrioventricular node.24 The adenosine antagonisttheophylline can reverse the atrioventricular block producedby adenosine or by hypoxia of the isolated heart.25,26 Localischaemia of the sinoatrial and atrioventricular nodes

following right coronary artery occlusion may lead to

raised adenosine concentrations and bradyarrhythmias.23 .Lately Watt has proposed that impaired or enhancedadenosine action may be causally related to other cardiacdisorders-hypertrophic cardiomyopathy2’ and the sicksinus syndrome28-but these speculations have yet to betested experimentally.Adenosine is an effective acute treatment for

14. Proctor KG. Reduction of contraction-induced arteriolar vasodilation by adenosinedeaminase or theophylline. Am J Physiol 1984; 247: H195-H205.

15. Osswald H. Adenosine and renal function. In: Berne RM, Rall TW, Rubio R, eds.Regulatory function of adenosine. Boston: Martinus Nijhoff, 1983: 399-415.

16. Spielman WS, Thompson CI. A proposed role for adenosine in the regulation of renalhemodynamics and renin release. Am J Physiol 1982; 242: F423-F435.

17. Watt AH, Routledge PA. Adenosine stimulates respiration in man. Br J ClinPharmacol 1985; 20: 503-06.

18 Stone TW. Physiological roles for adenosine and adenosine 5’-triphosphate in thenervous system. Neuroscience 1981; 6: 523-55.

19. Daly JW, Bruns RF, Snyder SH. Adenosine receptors in the central nervous system:relationship to the central actions of methylxanthines. Life Sci 1981; 28: 2083-97.

20. Snyder SH, Katims JJ, Annau Z, Bruns RF, Daly JW. Adenosine receptors andbehavioural actions of methylxanthmes. Proc Natl Acad Sci USA 1981; 78:3260-64.

21. Cushley MJ, Tattersfield AE, Holgate ST. Inhaled adenosine and guanosine on airwayresistance in normal and asthmatic subjects. Br J Clin Pharmacol 1983; 15: 161-65.

22. Cushley MJ, Tattersfield AE, Holgate ST. Adenosine-induced bronchoconstriction inasthma: antagonism by inhaled theophylline. Am Rev Resp Dis 1984; 129: 380-84.

23. Berne RM, Di Marco JP, Belardinelli L. Dromotropic effects of adenosine andadenosine antagonists in the treatment of cardiac arrhythmias involving theatrioventricular node. Circulation 1984; 69: 1195-97.

24. Di Marco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine:

electrophysiologic effects and therapeutic use for terminating paroxysmalsupraventricular tachycardia. Circulation 1983, 68: 1254-63.

25. Belardinelli L, Belloni FL, Rubio R, Berne RM. Atrioventricular conductiondisturbances during hypoxia: possible role of adenosine in rabbit and guinea pigheart Circ Res 1980; 47: 684-91.

26. Belardinelli L, Mattos EC, Berne RM. Evidence for adenosine mediation ofatrioventricular block in the ischemic canine myocardium J Clin Invest 1981; 68:195-205

27. Watt AH Hypothesis. Hypertrophic cardiomyopathy: a disease of impaired adenosine-mediated autoregulation of the heart Lancet 1984; i: 1271-73.

supraventricular tachycardia induced in the electro-

physiology laboratory,24 and also of the spontaneouslyarising arrhythmia.29,30 The mechanism of action seems to betransient atrioventricular block, breaking the re-entrant

circuit within the atrioventricular node (a mechanism

commonly underlying supraventricular tachycardia24).Adenosine is probably without effect in the treatment ofarrhythmias involving atrial re-entry, such as atrialflutter. 24,30 Adenosine did restore sinus rhythm in

experimental studies of atrial fibrillation by Drury andSzent-Gyorgyil-an observation that has yet to be fullyexplored in man.The vasodilator action of adenosine has been exploited

in the production of controlled hypotension. In animalshypotension was induced rapidly, smoothly, and withouttachyphylaxis or rebound hypertension.3’-33 These desirablefeatures have been confirmed in patients undergoingneurosurgery.

Fifty-six years after the pioneering work of Drury andSzent-Gyorgyi, the research effort on adenosine is gatheringpace.

SPLENECTOMY—A LONG-TERM RISK OFINFECTION

SERIOUS bacterial infection should be well known as a

complication of splenectomy: it has been reported manytimes since 1952’ and is clearly described in recent surgicalreviews.2,3 Pneumococci are the cause of at least half thereported cases and deaths; meningococci and Haemophilusinfluenzae feature amongst the other microorganismsassociated with fulminant infection in asplenic patients. Mostattention has been paid to those at most risk-that is, youngchildren and patients with underlying malignancies. The riskis greatest within two years of splenectomy. However, anyconsideration of prevention encounters the question as tohow long the risk lasts. Scattered case-reports,4-6 togetherwith a claim settled last year by a medical defence

organisatiQn,7 serve to remind us that life-threatening sepsiscan arise ten or more years after splenectomy, in adultswithout underlying disease. Some of these may have beenchance events, but the evidence that there is a long-term riskis more than a collection of case-reports. In a follow-up of740American servicemen who had splenectomies because of

28. Watt AH. Hypothesis. Sick sinus syndrome: an adenosine-mediated disease. Lancet1985; i: 786-88.

29. Munoz A, Leenhardt A, Sassine A, Galley P, Puech P. Therapeutic use of adenosine forterminating spontaneous supraventricular tachycardia. Eur Heart J 1984; 5:735-38.

30. Watt AH, Bernard MS, Webster J, Passani SL, Stephens MR. Intravenous adenosinein the treatment of supraventricular tachycardia (abstr). Br Heart J 1985; 53: 678.

31. Hoffman WE, Satinover I, Miletich DJ, Albrecht RF, Gans BJ. Cardiovascularchanges during sodium nitroprusside or adenoside triphosphate infusion in the rat.Anesth Analg 1982; 61: 99-103.

32. Fukunaga AF, Flacke WE, Bloor BC. Hypotensive effects of adenosine and adenosinetriphosphate compared with sodium nitroprusside Anesth Analg 1982; 61: 273-78.

33 Newberg LA, Milde JH, Michenfelder JD. Cerebral and systemic effects of

hypotension induced by adenosine or ATP in dogs. Anesthesiology 1985, 62:429-36

34. Sollevi A, Lagerkranser M, Irestedt L, Gordon E, Lindquist C. Controlled

hypotension with adenosine in cerebral aneurysm surgery. Anesthesiology 1984; 61:400-05.

1. King H, Shumacker HB. Splenic studies 1. Susceptibility to infection after

splenectomy performed in infancy. Ann Surg 1952; 136: 239-42.2. Ellison EC, Fabri PJ. Complications of splenectomy. Etiology, prevention and

management. Surg Clin N Am 1983; 63: 1313-30.3. Cooper MJ, Williamson RCN. Splenectomy: indications, hazards and alternatives. Br

J Surg 1984; 71: 173-80.4 Bisno AL. Hyposplenism and overwhelming pneumococcal infection: a reappraisal.

Am J Med Sci 1971; 262: 101-075. Zarrabi MH, Rosner F. Serious infections in adults following splenectomy for trauma

Arch Intern Med 1984; 144: 1421-24.6. Evans DIK Postsplenectomy sepsis 10 years or more after operation. J Clin Pathol

1985; 38: 309-11.7. Medical Defence Union Annual report, 1985. London: MDU: 1985, 29.

929

injuries in 1944-45 and the same number of controls, it wasfound that 6 asplenic men, but no controls, had died ofpneumonia by 1974.8 Babesiosis is a rare protozoal infection,but a third of the reported clinical cases have been associatedwith asplenism,9 in one instance with an interval of thirty-sixyears from splenectomy to infection. A cohort of 193 asplenicadults, followed for a total of 1090 patient years, experienced7 serious infections per hundred patient years.’° Half of theinfections were. in the first post-splenectomy year, butthereafter the episodes of infection accumulated at a steadyrate for at least ten years.The reasons for an increased risk of infection after

splenectomy lie in loss of the ability to remove

microorganisms by phagocytosis from the blood." r

Concentrations of IgM and the opsonising factors, tuftsinand properdin, become IOW.12-15 In the absence of systemicdisease, the remainder of the reticuloendothelial system mayadapt and produce normal antibody responses to antigenssuch as bacterial polysaccharide vaccines,16,17 but the IgMresponse is suboptimal. 18 Accessory spleens and splenictissue settling in the peritoneum or implanted in theabdominal wall may regain some function-the "born-again"spleen.19 Yet, without the high blood-flow past macrophagesin the normal spleen, clearance of opsonised bacteria isdeficient. 20,21The long-term prophylaxis in asplenism remains a

conundrum, to be avoided by preserving the spleen wheneverpossible.22 Prophylactic penicillin and pneumococcal vaccinehave been recommended for asplenic patients,5,23 but withreservations about the degree and duration of their effects.How many youngsters who lose their spleens because ofinjury or idiopathic thrombocytopnia will take penicillinregularly for ten years and more? Pneumococci may becomepenicillin-resistant, and a range of other organisms lesssensitive to penicillin also cause post-splenectomy sepsis.There have been fatal pneumococcal infections in asplenicpatients despite vaccination and penicillin prophylaxis.24-26It is too soon to know how long the increase in pneumococcalantibodies induced by vaccination will last. The increase inthe incidence of pneumococcal infection from middle age

8. Robinette CD, Fraumeni JF. Splenectomy and subsequent mortality in veterans of the1939-45 war. Lancet 1977; ii: 127-29.

9 Rosner F, Zarrabi MH, Benach JL, Habicht GS. Babesiosis in splenectomized adults.Am J Med 1984; 76: 696-701.

10. Schwartz PE, Sterioff S, Mucha P, Melton LJ, Offord KP. Postsplenectomy sepsis andmortality in adults. JAMA 1982; 248: 2279-83.

11. Ellis EF, Smith RT. The role of the spleen in immunity, with special reference to thepost-splenectomy problem in infants. Pediatrics 1966; 37: 111-16.

12 Schumacher MJ Serum immunoglobulin and transferrin levels after childhood

Splenectomy. Arch Dis Child 1970; 45: 114-1713. Chaimoff C, Dover D, Pick IA, Pmkhas J. Serum immunoglobulin changes after

accidental splenectomy in adults. Am J Surg 1978; 136: 332-33.14. Constantopoulos A, Najjar VA, Wish JB, Necheles TH, Stolbach LL. Defective

phagocytosis due to tuftsin deficiency in splenectomized subjects. Am J Dis Child1973; 125: 663-65.

15. Carlisle HN, Saslaw S. Properdin levels in splenectomized persons. Proc Soc Exp BiolMed 1959; 102: 150-54.

16 Caplan ES, Boltansky H, Snyder MJ, et al. Response of traumatized splenectomizedpatients to immediate vaccination with polyvalent pneumococcal vaccine. J Trauma1983; 23: 801-05.

17 Ruben FL, Hankins WA, Zeigler Z, et al. Antibody responses to meningococcalpolysaccharide vaccine in adults without a spleen. Am J Med 1984; 76: 115-21

18. Aaberge IS, Heier HE, Hem E, Giercksky KE, Groeng EC. IgM and IgG response topneumococcal polysaccharide vaccine in normal individuals and individualssplenectomised due to trauma Acta Path Microbiol Immunol Scand, Sect C 1984; 92:11-16.

19 Pearson HA, Johnston D, Smith KA, Touloukian RJ The born-again spleen. Return ofsplenic function after splenectomy for trauma. N Engl J Med 1978; 298: 1389-92.

20 Hosea SW, Brown EJ, Hamburger MI, Frank MM. Opsonic requirements forintravascular clearance after splenectomy. N Engl J Med 1981; 304: 245-50.

21 Rice HM, James PD. Ectopic splenic tissue failed to prevent fatal pneumococcalsepticaemia after splenectomy for trauma. Lancet 1980; i: 565-66.

22 Roy D. The spleen preserved. Br Med J 1984; 289: 70-71.23 Austrian R. Prevention of fatal bacterial infection in patients with anatomic or

functional asplenia Ann Intern Med 1982; 96: 117-19.

onwards suggests a waning of natural immunity acquired inchildhood. Therefore boosters of pneumococcal vaccine maybe needed. All that can be firmly recommended is anincreased awareness that asplenism carries a long-term risk ofinfection. Patients-or, in the case of children, their

parents-should be told of the condition, which might berecorded on a locket or bracelet. Unknown or forgottenasplenism may be detected by the presence of Howell-Jollybodies in red blood cells, by which haematologists can alertphysicians.27 Case notes in hospital and general practice canbe clearly marked that there is an infection risk, so that fever isnot diagnosed as a minor viral infection before pneumococcalsepsis is excluded.

DEFENCES AGAINST MENINGOCOCCALINFECTIONS

A FASCINATING and infuriating feature of many infectiousdiseases is their unpredictability. Where control can beexercised by vaccination, the incidence of infection can beinfluenced sometimes profoundly (in smallpox, to the extentof complete eradication); but in the absence of vaccination avariety of known and unknown factors can combine toproduce peaks and troughs of infection year by year. Exceptin the so-called meningitis belt of sub-Saharal Africa,meningococcal infections are unpredictable in their extent,although their seasonal incidence is well recognised.The meningococcus is the only bacterial cause of large-

scale epidemics of meningitis and these are usually due toNeisseria meningitidis of groups A or C. Group Crneningococci have given rise to a large outbreak in Brazilland are increasing in prevalence in Africa,2,3 but large-scaleepidemics are usually due to group A. Such was seen

following the group C outbreak in Brazil,4 has been a regularevent in Africa, and in Europe was most notable in Finlandin 1974.6 Outbreaks have occurred in Mongolia, and Nepaland parts of India are still experiencing brisk upsurges ofdisease.7 Disease due to meningococci of groups A and C canbe controlled by vaccination with material containing theirgroup-specific capsular polysaccharide. The chemical

structure of most of the capsular polysaccharides is known8 8

and those of groups Y and W 135 have been incorporated with

24. Evans DIK. Fatal post-splenectomy sepsis despite prophylaxis with penicillin andpneumococcal vaccine Lancet 1984; i: 1124.

25. Brivet F, Herer B, Fremaux A, Dormont J, Tchernia G. Fatal post-splenectomypneumococcal sepsis despite pneumococcal vaccine and penicillin prophylaxis.Lancet 1984; ii: 356-57.

26. Gonzaga RAF. Fatal post-splenectomy pneumococcal sepsis despite prophylaxis.Lancet 1984; ii: 694-95.

27. Brigden ML, Preece E. Preventing post-splenectomy sepsis Can Med Assoc J 1984;130: 344.

1. Morais JS, Munford RS, Risi JP, Antezana E, Feldman RA Epidemic disease due toserogroup C Neisseria meningitidis in Sao Paulo, Brazil. J Inf Dis 1974; 129: 568-71.

2. Greenwood BM, Wali SS. Control of meningococcal infection in the African

meningitis belt by selective vaccination. Lancet 1980; i: 729-32.3. Rey JL, Adamov. Etienne J, Picq JJ. Time and space related changes of the various

meningococcal serogroups in tropical Africa. Méd Trop 1983; 43: 60.4. Guedes J da S. Results observed during the vaccination campaign against

meningococcal meningitis, Sao Paulo, Brazil, 1975. Paper presented at the 2ndInternational Conference on Immunity and Immunization in Cerebro-spinalMeningitis, Torremolinos, 1977.

5. Galazka A. Meningococcal disease and its control with meningococcal vaccines. BullWHO 1982; 60: 1-7

6. Salmi I, Pettay O, Simula I, Kallio A-K, Waltimo O. An epidemic due to sulphonamide-resistant Group A meningococci in the Helsinki area (Finland). Scand J Infect Dis1976; 8: 249-54.

7. WHO. Meningococcal diseases. Meningococcal meningitis outbreaks in Delhi andKathmandu Valley. Wkly Epidem Rec 1985, no 16: 122.

8. Fallon RJ. Meningococcal diseases; pathogenesis and prevention. In: Reeves D,Geddes A, eds. Recent advances in infection 1. Edinburgh: Churchill Livingstone,1979.

9. Andre FE, Safary A, Karanko U, Peltola H. Reactogenicity and immunogenicity of atetravalent meningococcal vaccine in different age groups Méd Trop 1983; 43:201-02.