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moment for the pharmacologist. There have beenmany studies of receptors in circulating blood cells buttheir relevance is widely questioned. Why should aneutrophil beta-2-receptor reflect the behaviour of thecardiac beta-1-receptor? Regulation of beta-receptorsmay not be uniform for beta-1 and beta-2 subtypes.This would not be surprising since beta-1-receptorsare mainly influenced by neuronally releasednoradrenaline and beta-2-receptors by circulatingadrenaline. Indeed there is increasing evidence ofseparate regulation of different receptor subtypes. 12So, could the study of Davies et al imply that thecardiac beta-receptor is not so different after all fromthe neutrophil receptor?

Several radioligand binding studies have nowshown that 25-50% of cardiac beta-receptors arebeta-2, autoradiography has revealed that thesereceptors are on myocardial cells and are possiblymore numerous around the sinoatrial andatrioventricular nodes;12 and isolated cat hearts showan increase in heart rate in response to selective beta-2

receptor stimulation by salbutamol.15 During the pastyear, it has become apparent that these cardiac

beta-2-receptors may be much more important inman than in other species, and that the majority ofadenylate cyclase may indeed be linked to beta-2 notbeta-1 receptors .16 Since most of the inotropic actionof isoprenaline is, however, beta-1-receptor mediated,the implication is that beta-2-receptor stimulationmay be largely wasteful. If beta-2-receptors are

especially liable to up-regulation or supercoupling,this would attach greater importance to studies ofbeta-2-receptors on white cells and possibly explainthe paradoxical benefit which some patients withcardiac failure receive from beta-blockadeP If one

questions the survival value of such potentiallyharmful receptors in the heart this may be to protectagainst excessive down-regulation; adrenaline is theendogenous agonist for beta-2-receptors andtherefore these are less likely than beta-1-receptors tobe chronically down-regulated, since release ofadrenaline from the adrenal medulla is paroxysmal.The question of whether MVPS is a disease in its

own right remains. Some authorities believe that the"hyperadrenergic symptoms" are due to a coexistentanxiety disorder .18 Finding autonomic dysfunction in

12. O’Donnel SR, Wanstall JC. Functional evidence for differential regulation ofbeta-adrenoreceptor subtypes. Trends Pharmacol Sci 1987; 8: 265-68.

13. Stiles GL, Taylor S, Lefkowitz RJ. Human cardiac beta-adrenergic receptors. subtypeheterogeneity delineated by direct radioligand binding. Life Sci 1983; 33: 467-73.

14. Hedberg A, Minneman KP, Molinoff PB. Co-existence of beta-1 and beta-2 receptorsin human heart: effect of treatment with beta blockers and calcium antagonists.J Pharm Exp Ther 1985; 234: 561-68.

15. Carlsson E, Ablad B, Branstrom A, Carlsson B. Differentiated blockade of thechronotropic effects of various adrenergic stimuli in the cat heart. Life Sci 1972; 11(part 1): 953-58.

16. Kaumann AJ, Lemoine H. Beta-2 adrenoreceptor mediated positive inotropic effect ofadrenaline in human ventricular myocardium. Naunyn-Schmiedeberg’s ArchPharmacol 1987; 335: 403-11.

17. Anderson JL, Lutz JR, Gilbert EM, et al. A randomized trial of low dose beta blockadetherapy for idiopathic dilated cardiomyopathy. Am J Cardiol 1985; 55: 471-75.

18. Leatham A, Brigden W. Mild mitral regurgitation and the mitral prolapse fiasco. AmHeart J 1980; 99: 659-64.

MVPS does not disprove this hypothesis sinceautonomic dysfunction is also found in patients withanxiety disorders. 19 In order to test whetherautonomic dysfunction is related to MVPS or to

anxiety disorders it would be necessary to apply thesame tests of autonomic function in four groups-patients with MVPS; patients with anxiety; patientswith symptomless MVP; and normals.2o

Physicians who have followed the evolution of theevidence linking the sympathetic system to MVPSmay sometimes feel that they are pursuing ever-receding goal posts-first it was increased release ofnoradrenaline that was incriminated, then adrenaline,then increased beta-receptor number, and now

supercoupling of post-receptor events. To someextent this sequence reflects progress inunderstanding the sympathetic system itself, andstudies such as that of Davies et al may prove relevantto other "hyperadrenergic states", such as

thyrotoxicosis, beta-blocker withdrawal, and heartfailure.

Obstructive Sleep Apnoea andLower Airways Obstruction

OBSTRUCTIVE sleep apnoea (OSA) and chronicairways obstruction (CAWO) are very differentdisorders but the relationship between them hasprovoked much research. They probably coincidemore often than would be expected by chance, butwhether this is because they have aetiological factors incommon (excessive eating, alcohol consumption, andsmoking) or true cause and effect is not clear. There isno doubt, however, that when these two conditionscoexist they exacerbate each other.

Early work suggested that patients with CAWOand respiratory failure (low Pa02 and raised PaCOz)had excessive nocturnal hypoxaemia, possibly due to aform of sleep apnoea. 14 It was even suggested that thissleep hypoxaemia might be the cause of the

respiratory failure, thus providing an explanation forthe variability of blood gas disturbances in CAWO-the so called blue-bloater/pink-puffer spectrum.5,6

19. Nesse RM, Cameron OG, Curtis GC, McCann DS, Huber-Smith MJ. Adrenergicfunction in patients with panic anxiety. Arch Gen Psychiatry 1984; 41: 771-76.

20. Rudd CO, Taylor AA, Pool JL, Nelson EB, Mitchell JR. Decreased vascular responseto alpha-adrenergic agonists m mitral valve prolapse syndrome. Clin Res 1982; 30:258A.

1. Wynne JW, Block AJ, Hemenway J, Hunt LA, Flick MR. Disordered breathing andoxygen desaturation during sleep in patients with chronic obstructive lung disease(COPD). Am J Med 1979; 66: 573-79.

2. Douglas NJ, Calverley PMA, Leggett RJE, Brash HM, Flenley DC, Brezinova V.Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet1979; i: 1-4.

3. Guilleminault C, Cummiskey J, Motta J. Chronic obstructive airflow disease and sleepstudies. Am Rev Respir Dis 1980; 122: 397-406.

4. DeMarco FJ, Jr, Wynne JW, Block AJ, Boysen PG, Taasen VC. Oxygen desaturationduring sleep as a determinant of the "blue and bloated" syndrome. Chest 1981; 79:621-25.

5. Block AJ, Boysen PG, Wynne JW. The origins of cor pulmonale. A hypothesis. Chest1979; 75: 109.

6. Flenley DC. Clinical hypoxia. causes, consequences, and correction. Lancet 1978; i:542-46.

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Reports of patients with both CAWO and OSA withrespiratory failure seemed to support this

hypothesis,3,7.9 and indeed some of these patients had areturn of PaC02 to normal after the OSA had beentreated. 3,8These early papers tended to report patients whose

main disorder was OSA but who had moderateCAWO in addition. However, when random series ofpatients with CAWO and a large range of daytimePa02 values were examined there was no suggestionthat the blue bloaters were more prone to excessivenocturnal hypoxaemia than pink puffers.1o,1l Anyapparent extra hypoxaemia in the blue bloaters

(measured by non-invasive oximetry as %Sa02) was afunction of lower starting arterial oxygen saturationlevels and the shape of the haemoglobin dissociationcurve, the drop in nocturnal arterial oxygen pressurebeing the same irrespective of daytime Sa0° Twoof these reports suggested that the degree of nocturnalhypoxaemia was related to PaC02 as well as basalSa02 but it was unclear whether extra nocturnal

hypoventilation (causing the hypoxaemia) had led togreater COZ retention over the years or vice versa.1O,12A 1987 report13 on a large series of patients withCAWO who were all hypoxic (PaOz mostly less than7-3 kPa) showed that despite similar waking Sa02values the group with a mean daytime PaC02 of 6-6kPa had a little more nocturnal hypoxaemia than thegroup with a mean value of 5-0 kPa (2-3 versus 1 -9 kPa,respectively). Again it is impossible to say which camefirst-the greater nocturnal hypoxaemia or the higherdaytime PaCO—or whether they evolved together.Although variations in nocturnal hypoxaemia

cannot account for the observed variations in the

degree of cor pulmonale, there is a small group ofpatients with CAWO and associated OSA who dohave more pronounced nocturnal hypoxaemia andhigher diurnal PaC02 levels3,9,lo than would be

expected from their degree of chronic airwaysobstruction alone.14 The percentage of incidentalcases of OSA in series of randomly selected patientswith primarily CAWO is disputed, partly because ofthe lack of agreement over the diagnosis of OSA. The

7. Hensley MJ, Read DJC. Intermittent obstruction of the upper airway during sleepcausing profound hypoxaemia. A neglected mechanism exacerbating chronicrespiratory failure. Aust NZ J Med 1976; 6: 481-86.

8. Sullivan CE, Berthon-Jones M, Issa FG. Remission of severe obesity hypoventilationsyndrome after short-term treatment during sleep with nasal continuous positivepressure. Am Rev Respir Dis 1983; 128: 177-81.

9. Alford NJ, Fletcher EC, Nickeson D. Acute oxygen in patients with sleep apnea andCOPD. Chest 1986; 89: 31-38.

10. Stradling JR, Lane DJ. Nocturnal hypoxaemia in chronic obstructive pulmonarydisease. Clin Sci 1983; 64: 213-22.

11. Catterall JR, Douglas NJ, Calverley PMA et al. Transient hypoxemia during sleep inchronic obstructive pulmonary disease is not a sleep apnea syndrome. Am RevRespir Dis 1983; 128: 24-29.

12. Fleetham JA, Mezon B, West P, Bradley CA, Anthonisen NR, Keyger MH. Chemicalcontrol of ventilation and sleep arterial oxygen desaturation in patients with COPD.Am Rev Respir Dis 1980; 122: 583-89.

13. Perez-Padilla R, Conway W, Roth T, Anthonisen N, George C, Kryger M.Hypercapnia and sleep SaO2 desaturation in chronic obstructive pulmonarydisease. Sleep 1987; 10: 216-23.

14. Lane DJ, Howell JBL, Giblin B. The relation between airways obstruction and CO2tension in chronic obstructive airways disease. Br Med J 1968; iii: 707-09.

prevalence of OSA diagnosed by arbitrary-physiological criteria will be much higher than

symptomatic OSA but even so will probably be muchless than 5%...-i8How important is it to recognise OSA in a patient

whose main trouble is CAWO? Apart from relievingsleepiness, we might expect treatment of the OSA toreduce the severity of nocturnal hypoxaemia (and thusthe occurrence of malignant arrhythmias19-21) and toimprove blood gases with regression of cor pulmonaleand lessening of dyspnoea.3,7,8 No controlled trials,however, have been done. Long-term home oxygentherapy for hypoxic CAWO in the presence of OSAleads to morning headaches with greater CO2retention during sleep (2-5 kPa versus 1 kPa)9,17 but theeffect on life expectancy is uncertain. Excessivenocturnal hypoxaemia seems to have little if any effecton long-term survival. 22,23 Sullivan et all reported that,in patients with severe cor pulmonale due to CAWOand associated symptomatic OSA, treatment withbronchodilators, diuretics, oxygen, and nasalcontinuous airway pressure improved the OSA as wellas other indices. This is surprising since it suggeststhat the CAWO and cor pulmonale might have causedthe OSA, possible mechanisms being the productionof oedema in the pharyngeal tissues or some generaleffect on respiratory drive (both decreasing the

pharyngeal lumen). Should sleep studies be done toidentify unsuspected OSA in patients with CAWO?There is no evidence that this is worthwhile. If thereare findings in the history and examination suggestiveof OSA-such as heavy snoring, sleepiness, andobesity-then a sleep study is justified for thesereasons alone. If treatment of the associated OSA issuccessful then there may be some lessening of any corpulmonale present. -A more subtle and reversed relation between OSA

and airways obstruction is emerging. Obese patientswith pure OSA seldom progress to diurnal respiratoryfailure with permanent hypoxaemia and hypercapnia.Two centres have now shown that it is the presence of

15. Kline NW, De Lancey DA, Giblin EC. Sleep apnea in patients with chronicobstructive pulmonary disease. Am Rev Respir Dis 1978; 117 (suppl): 140.

16. Arand DL, McGinty DJ, Littner MR. Respiratory patterns associated with

hemoglobin desaturation during sleep in chronic obstructive pulmonary disease.Chest 1981; 80: 183-90.

17. Goldstein RS, Ramcharan V, Bowes G, McNicholas WT, Bradley D, Philipson EA.Effect on supplemental nocturnal oxygen on gas exchange in patients with severeobstructive lung disease. N Engl J Med 1984; 310: 425-29.

18. Smyth ML, Giblin EC. Sleep apnoea and obstructive lung disease. Am Rev Respir Dis1980; 121 (suppl): 191.

19. Flick MR, Block AJ. Nocturnal vs diurnal cardiac arrhythmias in patients with chronicobstructive pulmonary disease. Chest 1979; 75: 8-11.

20. Tirlapur VG, Mir MA. Nocturnal hypoxemia and associated electrocardiographicchanges in patients with chronic obstructive airways disease. N Engl J Med 1982;306: 125-30.

21. Shepard JW, Garrison MW, Grither DA, Evans R, Schweitzer PK. Relationshipbetween ventricular ectopy to nocturnal oxygen desaturation in patients withCOPD. Am J Med 1985; 78: 28-34.

22. Connaughton JJ, Catterall JR, Douglas NJ. Does nocturnal hypoxia in patients withchronic bronchitis and emphysema predict survival? Clin Respir Physiol 1986; 22(suppl 8): 448.

23. Stradling JR, Cookson W, Warley A, Lane DJ. The amount of nocturnal hypoxaemiadoes not affect the survival of patients with chronic airways obstruction. Am RevRespir Dis 1987; 135: A149.

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additional diffuse airways obstruction and daytimehypoxaemia in such patients (sometimes only ofmild-to-moderate severity) rather than obesity thatprovokes CO2 retention, pulmonary hypertension,and cor pulmonale.24,26 The reasons are not clear.Small airways disease will tend to raise functionalresidual capacity (FRC) and residual volume, whichto some extent offsets the expected airway closure andreduced gas exchange. In addition, a rise in FRC willincrease the size of the pharynx27 (thus reducing thetendency to OSA) and the size of the O2 reserve duringapnoea. However, obesity will push the FRC downagain towards residual volume (particularly when thepatient is supine) and airway resistance will be high atthis lower lung volume.24,28 Thus the obese patientwith mild airways obstruction will have a reduceddaytime Pa02, small airway closure, and a lower FRCthan expected-all factors worsening the degree ofarterial desaturation for a given length of apnoea. 29The presence of moderate airways obstruction mayalso limit the patient’s ability to hyperventilate andrestore blood gases to normal between apnoeas: over

many years this extra hypoxic and hypercapnic loadmay provoke resetting of Pa02 and PaC02 controlmechanisms, 21,30 with consequent diurnal respiratoryfailure. The "pickwickian" patient is likely to be anobese individual having OSA with some CAWO andconsequent diurnal respiratory failure. Thus,vigorous treatment of even moderate diffuse airwaysobstruction will lessen some of the physiologicalconsequences of OSA by improving waking andsleeping oxygenation, though benefit in terms of

symptoms such as sleepiness is uncertain. Fletcher eta131 have also shown that, if the primary problem ofsleep apnoea is treated (by tracheostomy) in patientswith associated moderate CAWO, then the raisedpulmonary artery pressure and pulmonary vascularresistance improve. Another interesting possiblerelationship, recently reported to the British ThoracicSociety, exists between asthma and OSA. Chan et al32treated asthmatics with nocturnal asthma and OSA or

very heavy snoring by continuous nasal positiveairway pressure. The nocturnal asthma symptoms

24. Bradley TD, Rutherford R, Lue F, Moldofsky H, Grossman RF, Zamel N, PhillipsonEA. Role of diffuse airway obstruction in the hypercapnia of obstructive sleepapnea. Am Rev Respir Dis 1986; 134: 920-24.

25. Weitzenblum E, Kneger J, Oswald M, Vallee E, Ehrhart M, Kurtz D. Pulmonaryhypertension in patients with obstructive sleep apnea syndrome Clin Respir Physiol1987; 23 (suppl 12): 419S.

26. Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky H. Role ofdaytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleepapnea syndrome. Am Rev Respir Dis 1985; 131: 835-39.

27. Hoffstein V, Phillipson EA, Zamel N. Lung volume dependence of pharyngealcross-sectional area in patients with obstructive sleep apnea. Am Rev Respir Dis1984; 130: 175-78.

28. Onal E, Leech JA, Lopata M. Relationship between pulmonary function andsleep-induced respiratory abnormalities. Chest 1985; 87: 437-41.

29. Bradley TD, Martinez D, Rutherford R, Lue F, Grossman R, Moldofsky H, ZamelN, Phillipson EA. Physiological determinants of nocturnal arterial oxygenation inpatients with obstructive sleep apnoea. J Appl Physiol 1985, 59: 1364-68.

30. Rapoport DM, Garay SM, Epstein H, Goldring RM. Mechanism of chronichypercapnia in obstructive sleep apnea. Am Rev Respir Dis 1982; 125: A252.

31. Fletcher EC, Schaaf JW, Miller J, Fletcher JG Long-term cardiopulmonary sequelaein patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987; 135:525-33.

32. Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring andobstructive sleep apnoea (OSA). Presented at British Thoracic Society Meeting,Edinburgh, 1987

improved, as did the morning peak flows. Themechanism is far from clear, but these workers suggestthat a pharyngeal reflex may be operative, althoughhypoxia itself can provoke bronchoconstriction.At present the clinical implications of these findings

on the interrelations between CAWO and OSA aredebatable. Most patients will have one or other, notboth. A spectrum must exist within the small grouphaving both-some predominantly CAWO, somepredominantly OSA. Symptoms that may be due toOSA are worth investigation, whether or not CAWOis present as well. On existing evidence there is no casefor routine sleep studies in all patients with CAWO.

SCHIZOPHRENIA AND ORGANIC DISEASE

SINCE Kraepelin first introduced the term dementiapraecox to describe the condition that subsequently becameschizophrenia there has been a constant debate about therelation between this condition and organic disease.Kraepelin1 was unequivocal in regarding it as an organicdementia "in which the faculty of comprehension and therecollection of knowledge previously acquired are much lessaffected than judgement, emotional impulses and acts ofvolition". Kraepelin’s views are now known to have beensubstantially correct, in that a significant proportion ofpatients with schizophrenia have cerebral abnormalities,particularly in the temporal lobe .2-6 Despite these findingsthe cause or causes of schizophrenia remain elusive. In thesecircumstances it is sometimes helpful to look carefully atcoexisting diagnosable organic disease. Although suchassociations might be fortuitous or independent of the cause,the degree of association between organic disease andschizophrenia exceeds that expected by chance7,8 and itseems likely that at least in some cases the organic disease isof major aetiological importance. Interpretation of data ismade more difficult by the prolonged course of

schizophrenia and the development of secondarycomplications, including alcohol abuse,9 depressiontardive dyskinesia," and personality change.

Because there is dispute over whether these secondaryfeatures are part of the natural history of schizophrenia or aconsequence of management there are merits in studyingschizophrenia at first presentation. Results of such inquirieshave shown that schizophrenia is associated relatively

1. Kraepelin E. Lectures on clinical psychiatry. Revised and edited by T. Johnstone.London: Baillière, Tindall and Cox, 1906: 26.

2. Johnstone EC, Crow TJ, Frith CD, Husband J, Kreel L. Cerebral ventricular size andcognitive impairment in chronic schizophrenia. Lancet 1976; ii: 924-26.

3. Weinberger DR, Torrey EF, Neophytides A, Wyatt RJ. Structural abnormalities ofthe cerebral cortex in chronic schizophrenia. Arch Gen Psychiatry 1979; 36: 935-39.

4. Reveley AM, Reveley MA, Clifford CA, Murray RM. Cerebral ventricular size intwins discordant for schizophrenia. Lancet 1982; i: 540-42.

5. Weinberger DR, Wagner RL, Wyatt RJ. Neuropathological studies of schizophreniaa selective review. Schizophr Bull 1983; 9: 193-212.

6. Brown R, Colter N, Corselhs JAN, et al. Postmortem evidence of structural brainchanges in schizophrenia: differences in brain weight, temporal hom area, andparahippocampal gyrus compared with affective disorder. Arch Gen Psychiatry1986; 43: 36-42.

7. Davison K, Bagley CR. Schizophrenia-like psychoses associated with organicdisorders of the central nervous system: a review of the literature. In: HerringtonRN, ed. Current problems in neuropsychiatry. Ashford: Headley Bros, 1969:113-84.

8. Slater E, Beard AW, Glithero E. The schizophrenia-like psychoses of epilepsy. Br JPsychiatry 1963; 109: 95-150.

9. Freed EX. Alcoholism and schizophrenia: the search for perspectives. J Stud Alcohol1975; 36: 853-81.

10. Virkkunen M. Suicides in schizophrenia and paranoid psychoses. Acta Psychiat Scand1974 (suppl 250).

11. Crane GE. Persistent dyskinesia. Br J Psychiatry 1973; 122: 395-405.