364 At anti-factor-VIII levels between 10 and 50 BU, porcine factor VIII is of therapeutic benefit because there is only partial cross-reactivity between the patient’s anti-factor-VIII antibody and the porcine factor.10 However, with repeated infustions, antibody specificity can shift further towards the porcine material, making subsequent infusions less effective. In patients with a severe haemorrhage, or electively before surgery, the antibody level can be reduced by plasmapheresis or by extracorporeal passage of plasma over a Sepharose A column." Patients with high levels of antibody (>50 BU) benefit from infusions of prothrombin complex concentrates (PCCs), particularly "activated" concentrates (APCCs) such as ’Feiba’ (factor eight inhibitor bypassing activity) or ’Autoplex’.12,13 Their mechanism of action is unknown, but efficacy may be related to their content of activated clotting factors (eg, factor Xa). Alternatively, a small amount of factor VIII may be bound to phospholipid present in the concentrates; in bound form it would be protected from neutralisation by antibody but could still participate in haemostasis.14 Such APCCs are not as effective as factor VIII in stopping bleeding in patients without inhibitors. Another exciting development is the potential for using factor VIla which, when combined with tissue factor, activates factor X directly, so bypassing the factor-VIII-dependent step in the coagulation cascade. Infusions of plasma-derived factor VI Ia have secured haemostasis in patients with inhibitors. 15 Recombinant factor VIla has been synthesised, and in a single case-report was effective in maintaining haemostasis during a synovectomy;16 an international multicentre trial is now underway. Three other new treatments appear promising. Routine infusion of small doses of factor VIII on alternate days, whether or not the patient has a haemorrhage, gradually reduces the inhibitor level. This induction of immune tolerance may be useful in patients with low-level inhibitors but it seems not to be suitable for high responders because the antibody may reappear after regular therapy is discontinued.l’ Alternatively, massive doses of factor VIII and feiba 10. Kernoff PBA, Thomas ND, Lilley PA, et al. Clinical experience with polyelectrolyte fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII. Blood 1984; 63: 31-41. 11. Nilsson IM, Berntrop E, Zettervall O. Induction of split tolerance and clinical cure in high-responding hemophiliacs with factor IX antibodies. Proc Natl Acad Sci USA 1986; 83: 9169-73. 12. Sjamsoedin LJM, Heijnen L, Mauser-Bonschoten JL, et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII: a double blind clinical trial. N Engl J Med 1981; 305: 717-21. 13. Lusher JM, Shapiro S, Palascak JE, et al. Autoplex versus Proplex: a controlled double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII. Blood 1983; 62: 1135-38. 14. Barrowcliffe TW, Kemball-Cook G, Gray E. Factor VIII inhibitor bypassing activity: a suggested mechanism of action. Thrombosis Research 1981; 21: 181-86. 15. Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors. J Clin Invest 1983; 71: 1836-41. 16. Hedner U, Glazer S, Pingel K, et al. Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy. Lancet 1988; ii: 1193. 17. Wensley RT, Burn AM, Redding OM. Induction of tolerance to factor VIII in haemophilia A with inhibitors using low doses of human factor VIII. Thrombosis Haemostas 1985; 54: 227. can be given several times a day for many months; such a regimen is very expensive in the short-term but seems to lead to complete disappearance of the antibody in many patients, who subsequently respond well to conventional doses of factor VIII.18 Although intravenous IgG, cyclophosphamide, and regular factor VIII I infusions are not very effective in reducing antibody levels when used alone or as any pair, the use of all three together looks beneficial. Such therapy eradicated the antibody in 9 of 11 patients; this approach was most successful when combined with a reduction in antibody level by first passing the patients’ plasma extracorporeally over protein A Sepharose.19 Development of an anti-factor-VIII inhibitor is greatly feared by patients with haemophilia, who are well aware of the limitations of therapy. In the near future it should be possible to suppress inhibitors or to provide haemostatically effective treatment even in their presence. Brain Damage and Open-heart Surgery ADVANCES in anaesthetic and surgical techniques and in equipment have all contributed to the reduction in mortality from open-heart surgery with cardio- pulmonary bypass. Nonetheless, there is still a considerable morbidity associated with this type of surgery; postoperative renal, respiratory, hepatic, and haematological dysfunctions are well recognised. Cerebral injury following heart surgery has also received considerable attention in the past and has now been drawn back into the limelight. Focal lesions such as stroke, retinal emboli and infarction, and new seizure activity occur in about 05—2% of patients after open-heart surgery. Such lesions are more common with valve than with coronary artery surgery (CAS), with advancing age, and in patients with a history of peripheral vascular disease. Of more interest, and potentially of more concern, are the results from studies conducted in Newcastle1 and at the Middlesex Hospital, London,2 in patients undergoing otherwise routine, uncomplicated CAS. Shaw and her colleagues1 prospectively investigated neurological complic- ations in 312 patients undergoing CAS and found that 191 (61 %) had such abnormalities. Three-quarters of the patients were not seriously disabled by these subtle 18. Brackman HH. In: Hoyer LW, ed. Factor VIII inhibitors. New York: Liss, 1984: 189-95. 19. Nilsson IM, Bemtorp E, Zetterrall O. Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII. N Engl J Med 1988; 318: 947-50. 1. Shaw PJ, Bates D, Cartlidge NEF, et al. Neurological and neuopsychological morbidity following major surgery: a comparison between coronary artery bypass and peripheral vascular surgery. Stroke 1987; 18: 700-07. 2. Smith PLC, Treasure T, Newman S, et al. Cerebral consequences of cardiopulmonary bypass. Lancet 1986; i: 823-25.
Transcript
364
At anti-factor-VIII levels between 10 and 50 BU,porcine factor VIII is of therapeutic benefit becausethere is only partial cross-reactivity between thepatient’s anti-factor-VIII antibody and the porcinefactor.10 However, with repeated infustions, antibodyspecificity can shift further towards the porcinematerial, making subsequent infusions less effective.In patients with a severe haemorrhage, or electivelybefore surgery, the antibody level can be reduced byplasmapheresis or by extracorporeal passage of plasmaover a Sepharose A column." Patients with high levelsof antibody (>50 BU) benefit from infusions ofprothrombin complex concentrates (PCCs),particularly "activated" concentrates (APCCs) suchas ’Feiba’ (factor eight inhibitor bypassing activity) or’Autoplex’.12,13 Their mechanism of action is
unknown, but efficacy may be related to their contentof activated clotting factors (eg, factor Xa).Alternatively, a small amount of factor VIII may bebound to phospholipid present in the concentrates; inbound form it would be protected from neutralisationby antibody but could still participate inhaemostasis.14 Such APCCs are not as effective asfactor VIII in stopping bleeding in patients withoutinhibitors.
Another exciting development is the potential forusing factor VIla which, when combined with tissuefactor, activates factor X directly, so bypassing thefactor-VIII-dependent step in the coagulationcascade. Infusions of plasma-derived factor VI Ia havesecured haemostasis in patients with inhibitors. 15Recombinant factor VIla has been synthesised, and ina single case-report was effective in maintaininghaemostasis during a synovectomy;16 an internationalmulticentre trial is now underway.Three other new treatments appear promising.
Routine infusion of small doses of factor VIII onalternate days, whether or not the patient has ahaemorrhage, gradually reduces the inhibitor level.This induction of immune tolerance may be useful in
patients with low-level inhibitors but it seems not tobe suitable for high responders because the antibodymay reappear after regular therapy is discontinued.l’Alternatively, massive doses of factor VIII and feiba
10. Kernoff PBA, Thomas ND, Lilley PA, et al. Clinical experience with polyelectrolytefractionated porcine factor VIII concentrate in the treatment of hemophiliacs withantibodies to factor VIII. Blood 1984; 63: 31-41.
11. Nilsson IM, Berntrop E, Zettervall O. Induction of split tolerance and clinical cure inhigh-responding hemophiliacs with factor IX antibodies. Proc Natl Acad Sci USA1986; 83: 9169-73.
12. Sjamsoedin LJM, Heijnen L, Mauser-Bonschoten JL, et al. The effect of activatedprothrombin-complex concentrate (FEIBA) on joint and muscle bleeding inpatients with hemophilia A and antibodies to factor VIII: a double blind clinicaltrial. N Engl J Med 1981; 305: 717-21.
13. Lusher JM, Shapiro S, Palascak JE, et al. Autoplex versus Proplex: a controlleddouble-blind study of effectiveness in acute hemarthroses in hemophiliacs withinhibitors to factor VIII. Blood 1983; 62: 1135-38.
14. Barrowcliffe TW, Kemball-Cook G, Gray E. Factor VIII inhibitor bypassing activity:a suggested mechanism of action. Thrombosis Research 1981; 21: 181-86.
15. Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia Apatients with high-titer inhibitors. J Clin Invest 1983; 71: 1836-41.
16. Hedner U, Glazer S, Pingel K, et al. Successful use of recombinant factor VIIa inpatient with severe haemophilia A during synovectomy. Lancet 1988; ii: 1193.
17. Wensley RT, Burn AM, Redding OM. Induction of tolerance to factor VIII inhaemophilia A with inhibitors using low doses of human factor VIII. ThrombosisHaemostas 1985; 54: 227.
can be given several times a day for many months;such a regimen is very expensive in the short-term butseems to lead to complete disappearance of theantibody in many patients, who subsequently respondwell to conventional doses of factor VIII.18
Although intravenous IgG, cyclophosphamide,and regular factor VIII I infusions are not very effectivein reducing antibody levels when used alone or as anypair, the use of all three together looks beneficial. Suchtherapy eradicated the antibody in 9 of 11 patients; thisapproach was most successful when combined with areduction in antibody level by first passing thepatients’ plasma extracorporeally over protein ASepharose.19Development of an anti-factor-VIII inhibitor is
greatly feared by patients with haemophilia, who arewell aware of the limitations of therapy. In the nearfuture it should be possible to suppress inhibitors or toprovide haemostatically effective treatment even intheir presence.
Brain Damage and Open-heartSurgery
ADVANCES in anaesthetic and surgical techniquesand in equipment have all contributed to the reductionin mortality from open-heart surgery with cardio-pulmonary bypass. Nonetheless, there is still a
considerable morbidity associated with this type ofsurgery; postoperative renal, respiratory, hepatic, andhaematological dysfunctions are well recognised.Cerebral injury following heart surgery has alsoreceived considerable attention in the past and hasnow been drawn back into the limelight.
Focal lesions such as stroke, retinal emboli andinfarction, and new seizure activity occur in about05—2% of patients after open-heart surgery. Suchlesions are more common with valve than with
coronary artery surgery (CAS), with advancing age,and in patients with a history of peripheral vasculardisease. Of more interest, and potentially of moreconcern, are the results from studies conducted inNewcastle1 and at the Middlesex Hospital, London,2in patients undergoing otherwise routine,uncomplicated CAS. Shaw and her colleagues1prospectively investigated neurological complic-ations in 312 patients undergoing CAS and found that191 (61 %) had such abnormalities. Three-quarters ofthe patients were not seriously disabled by these subtle
18. Brackman HH. In: Hoyer LW, ed. Factor VIII inhibitors. New York: Liss, 1984:189-95.
19. Nilsson IM, Bemtorp E, Zetterrall O. Induction of immune tolerance in patients withhemophilia and antibodies to factor VIII by combined treatment with intravenousIgG, cyclophosphamide, and factor VIII. N Engl J Med 1988; 318: 947-50.
1. Shaw PJ, Bates D, Cartlidge NEF, et al. Neurological and neuopsychologicalmorbidity following major surgery: a comparison between coronary artery bypassand peripheral vascular surgery. Stroke 1987; 18: 700-07.
2. Smith PLC, Treasure T, Newman S, et al. Cerebral consequences of
cardiopulmonary bypass. Lancet 1986; i: 823-25.
365
changes. However, 4 patients (2%) were unable tolead an independent existence and the remaining 25 %had sufficient impairment in the immediate
postoperative period to compromise their everydayactivities. Six months after surgery only about 2% ofthese moderately impaired patients had residualdeficits.
In both studies,1,2 the investigators also focused on adeficit in neuropsychological outcome. The patientsfaced a battery of ten tests of neuropsychologicalfunction (one verbal memory, two non-verbal
memory, one visuospatial, one perceptuomotor, andfour attention and concentration). Deterioration inpostoperative performance by one standard deviationof the preoperative group value was taken to besignificant. If this deterioration occurred in two ormore tests the patient was said to have a
neuropsychological deficit.3 By use of this definition,about three-quarters of CAS patients had a significantneuropsychological deficit in the days followingsurgery. In contrast to the time-course of recovery of
neurological deficit, there was evidence of a significantneuropsychological deficit in about a third of thosestudied at eight weeks after operation.4 This
proportion was not reduced at six months5 or one year6postoperatively. These data confirm earlier less
comprehensive reports of subtle cerebral impairmentafter open-heart surgery,.7,8How important are these observations? There are
anecdotal accounts of occasional patients whosespouse or immediate family complained that a relativedid not have the same speed of thought or had greatermood swings. Should one infer from the results of theNewcastle and London studies that 60-70% of
patients will be transiently brain damaged and a thirdpermanently impaired after open-heart surgery? If so,what is the cause of this mayhem and how can it bestopped? The second question is slightly easier toaddress. Cerebral hypoperfusion and microemboli arethe two prime candidates as causal agents.
In conscious man, cerebral blood flow is effectivelymaintained constant by autoregulation down to amean perfusion pressure of 50-70 mm Hg. There isconsiderable debate about the relation between flowand driving pressure during cardiopulmonary bypassat moderate hypothermia (28-30°C). The prevailingview is that by maintaining the temperature-correctedblood carbon dioxide tension (by adding carbon
3. Newman S. The incidence and nature of neuropsychological morbidity followingcardiac surgery. Perfusion 1989; 4: 93-100.
4. Smith PL. The cerebral complications of coronary artery bypass surgery. Ann R CoilSurg Engl 1988; 70: 212-16.
5. Shaw PJ, Bates D, Cartlidge NEF, et al. Long term intellectual dysfunction followingcoronary artery bypass surgery; a six month follow up study. Quart J Med 1987;239: 259-68.
6. Venn GE, Klinger L, Newman S, et al. The neuropsychological sequelae of bypass 12months following coronary surgery. Br Heart J 1987; 57: 565 (abstr).
8. Savageau JA, Stanton BA, Jenkins CD, Frater RWM. Neuropsychologicaldysfunction following elective cardiac operations. II: A six month reassessment. JThorac Cardiovasc Surg 1982; 84: 595-600.
dioxide into the oxygenator; so-called "pH stat")cerebral blood flow becomes directly related to
perfusion pressure. This leads to a state of excess or"luxury" perfusion at higher pressures and potentiallysevere hypoperfusion at low pressures. If control ofacid-base balance during hypothermia is based on theassumption that the patient is a poikilotherm, andtemperature is not corrected (alpha stat), then
autoregulation is maintained.9 Some evidence
suggests that the lack of control of carbon dioxidetension before and management of such tension
throughout perfusion, together with reduced cerebralperfusion pressures, may contribute to the observedneuropsychological outcome.10Some workers believe that microemboli are
responsible for neurological impairment.11,12Microemboli have been found in the arterialcirculation during perfusion with dopplerultrasound13 and in the retinal circulation withfluorescein angiography.14 These emboli can be
composed of gas; activated formed elements of blood,especially platelets; and a multiple of particulatesoriginating from the pump-oxygenator system.12The importance of certain aspects of the
neurological morbidity, such as impairedcoordination and the development of primitivereflexes, is unclear, especially since most are short-lived.15 The long-lived neuropsychological defects aremore difficult to interpret for several reasons. Acritical issue that has not been adequately addressed isthat a postoperative neuropsychological deficit, as
defined,1-3 is not unique to patients undergoingopen-heart surgery. In one study, the frequency ofmild defects in the control, vascular surgery, patientseight days postoperatively was 31% vs 55% in thecardiac group.1 In another series of patients from adifferent centre,4 moderate and severe deficits werepresent eight weeks postoperatively in 37% of cardiacand 46% of control, thoracic and vascular surgery,patients. This high proportion of non-cardiac-surgerypatients with the same deficit received scant attention.Another study of 312 patients undergoing CAS also
raises questions about the relevance of theseobservations to open-heart surgery alone.15 The onlyvariable related to extracorporeal circulation that was
9. Murkin JM. Cerebral hyperfusion during cardiopulmonary bypass: the influence ofPaCO2. In: Hiderman J, ed. Brain injury and protection during heart surgery.Boston: Martinus Nijhoff, 1988: 47-66.
10. Nevin M, Adams S, Colchester ACF, Pepper JR. Evidence for involvement ofhypocapnia and hypotension in aetiology of neurological deficit after
cardiopulmonary bypass. Lancet 1988; ii: 1943-45.11. Brennan RW, Patterson RH, Kessler J. Cerebral blood flow and metabolism during
cardiopulmonary bypass: evidence of microembolic encephalopathy. Neurology1971; 21: 665-72.
12. Editorial. Brain damage after open-heart surgery. Lancet 1982; i: 1161-62.13 Pugsley WB, Klinger L, Paschalis C, Newman S, Harrison M, Treasure T. Does
arterial line filtration affect the bypass related cerebral impairment in patientsundergoing coronary artery surgery. Clin Sci 1988; 76: 30-31.
14. Blauth C, Arnold J, Schulenberg WE, McCartney A, Taylor KM. Cerebralmicroembolism during cardiopulmonary bypass. Retinal microvascular studies invivo with fluorescein angiography. J Thorac Cardiovasc Surg 1988; 95: 668-76.
15. Shaw PJ, Bates D, Cartlidge NEF, et al. An analysis of factors predisposing toneurological injury in patients undergoing coronary bypass operations. Quart JMed 1989; 72: 633-46.
366
significantly associated with neuropsychologicaloutcome was the fall in haemoglobin concentrationduring the procedure. This latter variable was alsoassociated with the development of retinal infarctspostoperatively. The lack of any association of thedefect with any aspect of extracorporeal support seemssurprising. The investigators were also unable toestablish that use of a membrane-type oxygenator (in66 % of patients) rather than a bubble oxygenatorconferred any neuropsychological benefit. This resultaccords with preliminary data obtained by mechanicalmethods such as arterial line filtration16 and also with aflat sheet membrane vs a bubble-type oxygenator17 toreduce arterial microemboli. Although the quantitiesof particulate and probably gaseous microembolidelivered to the patient were significantly reduced, butnot abolished, by these methods16,17 there was nodramatic improvement in neuropsychologicaloutcome. Two years after CAS, Klonoff et ap8
reported an improvement in patients’ physicalactivity, personal satisfaction, and work ability,attributed to the success of the operation in relievingangina and preoperative anxiety; these researcherssuggest that, overall, the anxiolytic action outweighsany neurological defect.Why has cerebral impairment after open-heart
surgery not been the subject of a barrage of
pharmacological interventions, especially as there isnow considerable scope for such approaches?19,20 Useof antiaggregatory agents such as the prostacyclins hasnot been beneficial, probably because the desiredaction is unobtainable without severe hypotension."Nussmeyer and her colleagues reported that
neuropsychological outcome was vastly improved ifthe patients were given thiopentone for
cerebroprotection,z2 but the dose used (35 mg/kg)meant that all patients required postoperativecatecholamines to support their arterial pressure andthe profound sedation produced by such a doseimposed the need for prolonged ventilatory support(typically 24 hours). This latter effect brings its owndangers--eg, inadvertent disconnection leading tohypoxia. In addition, the need for prolonged intensivecare would reduce the available beds and might lead tolonger hospital stays and longer waiting lists.What do you says to your patient or close relative
who requires cardiac surgery and is worried about
16. Treasure T. Intervennons to reduce cerebral injury during cardiac surgery-the effectof artenal line filtration. Perfusion 1989; 4: 147-52.
17. Smith PLC. Interventions to reduce cerebral injury during cardiac surgery-introduction and the effect of oxygenator type. Perfusion 1989; 4: 139-45
18. Klonoff H, Clark C, Kavanagh-Gray D, Meigala H, Munro I. Two year follow upstudy of coronary bypass surgery. J Thorac Cardiovasc Surg 1989; 97: 78-85.
19. Weir DL, Jones JG. Cerebral ischaemia; pathophysiology and treatment. In.Kaufmann L, ed. Anaesthesia review 5. London: Churchill Livingstone, 1988:131-44.
20 Royston D. Interventions to reduce cerebral injury during cardiac surgery-the effectof physical and pharmacological agents. Perfusion 1989; 4: 153-61.
21 Blauth C, Brady A, Arnold J, Schulenberg WE, Frackowiak R, Taylor KM A doubleblind clinical trial of Iloprost during cardiopulmonary bypass. Perfusion 1987; 2:271-76.
22. Nussmeyer NA, Arlund C, Slogoff S Neuropsychological complications after
cardiopulmonary bypass: cerebral protection with a barbiturate. Anesthesiology1986; 64: 165-70.
brain damage? First, neurological damage sometimesoccurs, for which there are several risk factors.i5
However, the risk of permanent damage is probablyonly 0-2%.23 Second, there is a risk, probably greaterafter cardiac than after general surgery, of subtleintellectual impairment. Although such effectsbecome more likely with increasing age and durationof surgery,2,4 there are apparently no absolute
predictors for development. is There is much to besaid for conducting bypass under alphastat acid-basecontrol, with continuous online monitoring of arterialcarbon dioxide tension, a membrane oxygenator, andan arterial line filter; but to exclude any or all of theseaspects of technique is not negligent. Postoperativecerebral dysfunction deserves more thoroughinvestigation after all types of surgery.
LESSONS IN THE SURGICAL TREATMENT OFEPILEPSY
A DYSEMBRYOPLASTIC neuroepithelial tumour has latelybeen described in a group of 39 patients from Paris and fromRochester, Minnesota, all of whom had medicallyintractable partial complex seizures with secondarygeneralisation in 6 patients (15%).1 Total or subtotalremoval of these tumours led to complete freedom fromseizures in 81 % of the 37 patients available for follow-upover a mean of 9 years and to improvement in the remainder.The patients had had seizures for 2-18 years. In most casesthe tumour was in the frontal lobe (31 %) or in the temporallobe (62%), and it was visible on a computerisedtomographic (CT) scan in 91 % of the 22 patients who wereexamined. In the Paris group, the patients represented 75%of those undergoing epilepsy surgery between 1964 and1983.This report should draw attention to certain guidelines
for the surgical treatment of epilepsy. First, the principlethat focal seizures suggest focal pathology is well illustratedby this group of patients. The original study of 471 epilepticsby Gastaut showed that in only 11 % of patients withgeneralised seizures could a CT scan abnormality bedemonstrated, compared with 63% of those with partialcomplex seizures.2 Similar findings have been described byYang et al in children.3 Experience in the use of magneticresonance imaging (MRI) for detection of such lesions isgrowing, and reports suggest that tumours may be shown bythis technique when they are unrecognised or invisible byCT scanning.4 In specialist epilepsy centres the frequency ofsuch lesions is probably 20-25%.5 Unfortunately, the
3 Yang PJ, Berger PE, Cohen ME, Duffner PK. Computed tomography and childhoodseizure disorders. Neurology 1979; 29: 1084-88.
4. Sperling MR, Wilson G, Engel J, Babb TL, Phelps M, Bradley W. Magneticresonance imaging in intractable partial epilepsy: correlative studies. Ann Neurol1986; 20: 57-62
5. Adams CBT, Anslow OWP, Molyneux A, Oxbury J Radiological detection ofsurgically treatable lesions. In: Engel J, ed Surgical treatment of the epilepsies.New York: Raven, 1987: 213-33.
