DL Bowton, DA Stump, DS Prough, JF Toole, DS ...

Pentoxifylline increases cerebral blood flow in patients with cerebrovascular disease DL Bowton, DA Stump, DS Prough, JF Toole, DS Lefkowitz and L Coker Stroke 1989, 20:1662-1666 Stroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 Copyright © 1989 American Heart Association. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628

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Pentoxifylline Increases Cerebral Blood Flow in Patients With Cerebrovascular Disease David L. Bowton, MD, David A. Stump, PhD, Donald S. Prough, MD, James F. Toole, MD, David S. Lefkowitz, MD, and Laura Coker, BSN We determined the immediate effects of pentoxifylline on cerebral bloodflowin 10 patients with cerebrovascular disease; four received 400 mg and six received 800 mg pentoxifylline orally. Regional cerebral blood flow was measured before (baseline) and 2, 4, and 6 hours after pentoxifylline administration using the xenon-133 clearance technique with 16 detectors (eight per hemisphere). Global cerebral blood flow as a percentage of the baseline value increased significantly after 800 mg but not 400 mg pentoxifylline (p=0.017 and/>=0.29, respectively). Regional cerebral bloodflowas a percentage of the baseline value at the detector with the lowest baseline value increased significantly 2 hours after both 400 mg and 800 mg pentoxifylline (p=0.038 and />=0.010, respectively). Cerebrovascular reactivity to carbon dioxide was preserved despite the increases in cerebral blood flow. Pentoxifylline increases cerebral blood flow and is not associated with "intracerebral steal" in patients with cerebrovascular disease. (Stroke 1989;20:1662-1666)

P

entoxifylline (Hoechst-Roussel, Somerville, New Jersey) is a methylxanthine recently approved by the Food and Drug Administration for the symptomatic relief of intermittent claudication due to peripheral vascular disease. Although its mechanisms of action have been incompletely elucidated, it is known that pentoxifylline decreases blood viscosity and inhibits platelet aggregation by inhibiting membrane-bound phosphodiesterase. 1 ' 2 Pentoxifylline also appears to increase the synthesis of prostacyclin, a vasodilatory eicosanoid that inhibits platelet aggregation.3 Previous studies have demonstrated that pentoxifylline increases cerebral blood flow (CBF) after 2-4 weeks of therapy. 4 - 6 Only one study has reported on the acute effects of pentoxifylline on CBF. 7 That study reported a 17% increase in CBF immediately following a large intravenous bolus dose of pentoxifylline in three subjects; CBF was measured with only two detectors (one over each hemisphere) and therefore the effects of pentoxifylline on regional cerebral blood flow (rCBF) and the From the Departments of Anesthesia (Critical Care) (D.L.B., D.S.P.), Neurology (D.A.S., D.S.P., J.F.T., D.S.L., L.C.), and Medicine (Pulmonary) (D.L.B.), Wake Forest University Medical Center, Winston-Salem, North Carolina. Supported in part by Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey. Address for correspondence: David L. Bowton, MD, Department of Anesthesia (Critical Care), Wake Forest University Medical Center/Bowman Gray School of Medicine, 300 South Hawthorne Road, Winston-Salem, NC 27103. Received March 15, 1989; accepted June 9, 1989.

development of "intracerebral steal" could not be assessed. The effect of pentoxifylline on cerebrovascular reactivity to CO2 (CRCO2) was also not assessed. Our study was undertaken to ascertain the acute effects of orally administered pentoxifylline on global CBF, rCBF, and CRCO2 in patients with cerebrovascular disease. Subjects and Methods We studied 10 patients (two women, eight men; mean age 68.8 [range 57-88] years) in a project approved by the institutional clinical review board. All patients provided informed consent. They had had an acute vascular neurologic insult (nonhemorrhagic focal cerebral infarction in eight and reversible ischemic neurologic deficit lasting >24 but x vy

* ci - 2

Inhaled gas

Time Low dose (400 mg) Baseline

(mm Hg)

Air

34.8+1.4 42.5±1.6

2 hours

CO 2 Air

4 hours

CO 2 Air

6 hours

CO 2 Air

MABP (mm Hg)

Global CBF ml/100 g/min

Lowest rCBF

% baseline

ml/100 g/min

34.0±2.0 43.6+1.3

95±3 103±9 91+6 95+4

33.7±1.9

93±5 92±5 102±7

54.9±10.1 69.3±18.3t 60.1 + 13.5

101±15

44.7±1.5 33.6+2.3

110±15

51.3±10.0 64.0±12.7 60.8±10.7*

CO 2

44.0±1.2

106+10

70.6±14.2*

116+7f

70.0±13.7

Baseline

Air

31.6±2.6

100

43.2±12.5

101+8 104+12

63.7±21.0 59.4±12.9* 70.1 ±14.2

100

2 hours

41.2+3.5 32.0±2.6 41.1±5.8 31.5±2.9

102+13 111±26

52.5 ± 15.2

CO 2 Air

99±9 104±8 103±16 106±10

58.2±12.3t 74.0+19.4f 62.4±10.7* 78.1 + 15.7*

114±14t 120±18f 125 ±27* 131±33*

54.5±17.6 53.8±6.7* 64.2±8.9 54.0+10.6* 70.2+13.1*

55.5 ± 13.9

100 100

61.5±15.8 55.6±13.8 63.7±15.0

101 + 8 104+11

113±8t

% baseline

44.3±11.3 58.8±12.9 59.8±3.6* 59.8+16.1

100 100 143±37* 104±33 119±24 110±13 144±39* 121 ± 13

High dose (800 mg)

CO2 4 hours

Air

6 hours

CO 2 Air

41.6±4.5 31.8±2.6 42.0±4.9

CO 2

116±16t 116+22

100 100 132±31t 128±37 131+32f 139±43f 146±40* 140±41*

58.8+7.9* 70.5±12.7*

Petco2, end-tidal carbon dioxide tension; MABP, mean arterial blood pressure; CBF, cerebral blood flow; rCBF, regional cerebral blood flow. Data are mean±SD. *tps0.01, 0.02, respectively, different from baseline by / test.

lowing 400 mg i.v. pentoxifylline in three subjects with "chronic cerebrovascular" disease, and those of Hartmann,4-6 who described increases in CBF following 2-6 weeks of pentoxifylline administration. It is unlikely that the increase in CBF following pentoxifylline is secondary to variability or "drift" in our CBF measurement technique. Repeated determination of CBF is usually associated with a slight decrease, and the change in baseline CBF over 24 hours and the CBF response to placebo are considerably smaller than the response to pentoxifylline that we observed.11 In our laboratory, the mean± SEM difference in resting "baseline" CBF (flow

gray) between two determinations 24 hours apart in 15 healthy adult volunteers with a mean age of 45 years was —2.4±2.4 ml/100 g/min (95% confidence interval -7.1-2.3 ml/100 g/min)11; the mean±SEM change in CBF 2 hours after placebo administration was 1.4±1.3 ml/100 g/min (95% confidence interval -1.2-4.0 ml/100 g/min).11 Hence, our observed increases in CBF after pentoxifylline administration appear to be drug-related. Intracerebral steal, the redistribution of blood flow away from ischemic regions, is a potential adverse effect of cerebral vasodilator drugs.12-13 Intracerebral steal was not observed with pentoxifylline as lowest

TABLE 2. Global Cerebral Blood Flow at Each Time in Each Patient With Cerebrovascular Disease Treated With Low or High Dose of Pentoxifylline Baseline Patient Low dose (400 mg) 1 2 7 8 High dose (800 mg) 3 4 5 6 9 10

4 hours

2 hours

6 hours

Air

CO 2

Air

CO 2

Air

CO 2

Air

CO 2

61.2 36.4 56.7 67.8

71.2

59.1 39.6

64.5 44.5 63.6 82.3

63.0 44.2 49.4 62.9

73.3

42.9 53.8 78.2

51.3 58.6 93.9

63.6 46.7

77.6 53.2 65.1 86.7

46.6 84.9 82.4

37.9 67.6

28.9 72.0 66.0 52.1 52.0 44.0

31.8 87.0 87.2 63.9 64.8 47.4

51.8 72.0 40.9 72.1 73.4 62.6 52.5 54.8

73.8 66.4 66.5

71.1 63.3 54.9 54.6

40.1 93.5 90.9 70.4 76.4 72.3

Data are ml/100 g/min.


53.1 77.0 49.9 73.0 73.1 60.9 56.2 60.9

60.8 97.9 93.6 79.9 67.2 69.1

Bowton et al 225 n W

tn 200o a: a. g

1i

175-

fc fe 150" 125-

m o

100 75 TIME

1. Regional cerebral bloodflow(CBF) at detector with lowest baseline value for each patient (o) at each time after 400 mg (mean A) and 800 mg (mean •) pentoxifylline. FIGURE

rCBF increased at least as much as global CBF. Further, cerebrovascular responses to metabolic change, specifically Pco2, appear to be unaffected by pentoxifylline at either a global or a regional level. Pentoxifylline has been approved for the relief of claudication in patients with peripheral vascular disease. It is likely that many of these patients also have cerebrovascular disease, and it appears unlikely that pentoxifylline would have deleterious effects on the cerebral circulation in these patients. In fact, it is possible that the CBF increase caused by pentoxifylline could be beneficial. Theoretically, cerebral vasodilators are an attractive therapeutic option in patients with symptomatic cerebrovascular disease and reduced rCBF. Studies in polycythemic patients14-15 and cigarette smokers16 support the hypothesis that reduced CBF is associated with impaired and increased CBF is associated with improved neuropsychologic function. To date, however, clinical improvement in neuropsychologic function produced by cerebral vasodilators has been largely anecdotal and difficult to substantiate. 12'13'17 Whether this is related to the magnitude of the CBF increase, to intracerebral steal and worsening dysfunction in areas already most severely compromised, to impairment of metabolic vascular reactivity, or to demonstration of the error of the underlying hypothesis is not known. A large, placebo-controlled, international, multicenter trial of pentoxifylline in acute nonhemorrhagic stroke has been published recently.18 Pentoxifylline therapy was begun as a 50-mg i.v. bolus within 12 hours after the onset of symptoms; therapy continued as an intravenous infusion at 16 mg/ TABLE 3. Cerebrovascular Reactivity at Each Time for Patients With Cerebrovascular Disease Treated With Low or High Dose of Pentoxifylline

Dose Low (400 mg) High (800 mg)

Baseline 0.8±0.7 1.3±0.8

2 hours 0.9±0.4 2.5±3.3

4 hours

6 hours

1.4±1.0

1.0±0.3 1.7±0.7

Data are mean±SD ml/100 g/min/mm Hg.

Pentoxifylline Increases CBF

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kg/day for 72 hours and then as 400 mg orally t.i.d. for 25 days. There were no differences in mortality nor in motor strength or ataxia scores between the placebo and pentoxifylline groups at the conclusion of the study. There was a trend toward improved level of consciousness in the pentoxifylline group, though this difference did not achieve significance. However, early in the study, while subjects received intravenous infusion, the pentoxifylline group had significantly higher level of consciousness, motor strength, cranial nerve function, and total neurologic deficit scores than did the control group; CBF was not measured. It is interesting to speculate that a higher oral dose of pentoxifylline, one more likely to increase global CBF, might have resulted in sustained neurologic improvement. Further carefully designed trials are indicated to determine whether the increased CBF following pentoxifylline is associated with improved neuropsychologic function in patients with cerebrovascular disease. References 1. Hammerschmidt DE, Kotasek D, McCarthy T, Huh PW, Freyburger G, Vercellotti GM: Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor. / Lab Clin Med 1988; 112:254-263 2. Ward A, Clissold SP: Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 1987;34:50-97 3. Santos MT, Martinez Sales V, Valles J, Aznar J, Yaya R, Vaya A, Villa P: Prostacyclin production by rat aorta "in vitro" is increased by the combined action of dipyridamole plus pentoxifylline. Prostaglandins 1985;29:113-122 4. Hartmann A, Tsuda Y: A controlled study on the effect of pentoxifylline and an ergot alkaloid derivative on regional cerebral blood flow in patients with chronic cerebrovascular disease. Angiology 1988;39:449-457 5. Hartmann A: Cerebral blood flow in patients with cerebrovascular disorders: Study with pentoxifylline. Ric Clin Lab 1981;ll:243-246 6. Hartmann A: Effect of pentoxifylline on regional cerebral blood flow in patients with cerebral vascular disorders. Eur Neurol 1983;22(Suppl):108-115 7. Passero S, Nardini M, Battistini N: Effect of pentoxifylline on cerebral blood flow in patients with chronic cerebrovascular disease. / Intern Med Res 1981;9:211-214 8. Obrist WD, Thompson HK Jr, Wang HS, Wilkinson WE: Regional cerebral blood flow estimated by 133-Xenon inhalation. Stroke 1975;6:245-256 9. Obrist WD, Wilkinson WE: Stability and sensitivity of CBF indices in the noninvasive 133Xe method, in Hartmann A, Hoyer S (eds): Cerebral Blood Flow and Metabolism Measurement. New York, Springer Verlag, 1985, pp 30-36 10. Ackerman RH: The relationship of regional cerebrovascular CO2 reactivity to blood pressure and regional resting flow. Stroke 1973;4:725-731 11. McHenry LC Jr, Stump DA, Howard G, Novack TT, Bivins DH, Nelson AO: Comparison of the effects of intravenous papaverine hydrochloride and oral Pavabid HP capsulets on regional cerebral blood flow in normal individuals. J Cereb Blood Flow Metab 1983;3:442-447 12. Lehmann HE: Psychopharmacological approaches to the organic brain syndrome. Comp Psychiatry 1983;24:412-430 13. Cook P, James I: Cerebral vasodilators (first of two parts). N EnglJ Med 1981;305:1508-1513 14. Bornstein R, Menon D, York E, Sproule B, Zak C: Effects of venesection on cerebral function in chronic lung disease. J Can Soc Neurol 1980;7:293-296


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15. York EL, Jones RL, Menon D, Sproule BJ: Effects of secondary polycythemia on cerebral blood flow in chronic obstructive pulmonary disease. Am Rev Respir Dis 1980; 121:813-818 16. Meyer JS, Judd BW, Tawaklna T, Rogers RL, Mortel KF: Improved cognition after control of risk factors for multiinfarct dementia. JAMA 1986;256:2203-2209 17. Cook P, James I: Cerebral vasodilators (second of two parts). NEnglJMed 1981;305:1560-1564

18. Hsu CY, Norris JW, Hogan EL, Bladin P, Dinsdale HB, Yatsu FM, Earnest MP, Scheinberg P, Caplan LR, Karp HR, Swanson PD, Feldman RG, Cohen MM, Mayman CI, Cobert B, Savitsky JP: Pentoxifylline in acute nonhemorrhagic stroke. Stroke 1988; 19:716-722

KEYWORDS • cerebral blood flow • pentoxifylline • xenon
