journal oflnternal Medicine 1 9 9 0 ; 227: 107-1 1 4
Haemodilution with medium molecular weight hydroxyethyl starch in patients with peripheral arterial occlusive disease stage IIb H. KIESEWETTER, J. B L U M E t , F. J U N G , S. SPITZER*, & E. WENZEL Front the Department of Clinical Haemostasiology and Transfusion Medicine. the *Medical Clinic and Out-patient Department, Interrial Medicine III. University Hospitals of the Saarlurid. Homburg-Saw, arid the ?Center !or Cardiovascular Diseases, AacRen. West Germany
Abstract. Kiesewetter H, Blume J. Jung F, Spitzer S, Wenzel E (Department of Clinical Haemostasiology and Transfusion Medicine, the Medical Clinic and Outpatient Department, Internal Medicine 111. University Hospitals of the Saarland, Homburg-Saar, and Center for Cardiovascular Diseases, Aachen, West Germany). Haemodilution with medium molecular weight hydroxyethyl starch in patients with peripheral arterial occlusive disease stage IIb. journal of Internal Medicine 1 9 9 0 : 2 2 7 : 107-1 14. The basic therapy of peripheral arterial occlusive disease stage IIb, according to Fontaine, is exercise. It should be determined whether a mild hypervolaemic haemodilution with hydroxyethyl starch or Ringer lactate can produce a further increase in walking distance. For this purpose, three groups of 2 5 patients each were formed. One group exercised three times weekly and the second group, in addition to exercise, underwent a mild hypervolaemic to isovolaemic dilution therapy with HES for a period of 6 weeks. In the final group the haematocrit was reduced to the same extent by venesections and volume substitution using Ringer lactate. The walking distance in the HES group increased from 216 m to 31 1 m (44%), in the Ringer lactate group from 214 m to 258 m (20%). and in the exercise group from 21 3 m to 242 m ( 1 4%). On comparison of the groups, the increase in pain-free walking distance in the HES group differs significantly ( P < 0.05) from that achieved in the other groups. It was demonstrated that haemodilution with HES in combination with exercise brings about a clinical effect three times that achieved by exercise alone. Venesection with subsequent administration of Ringer lactate and exercise is superior to exercise alone but markedly inferior to the combination therapy with HES.
Keywords: arterial occlusive disease, haemodilution. hydroxyethyl starch. peripheral arterial occlusive disease.
Introduction Haemodilution with hydroxyethyl starch has been employed for a number of years by various angiological centres as an effective therapy in patients suffering from peripheral arterial occlusive disease [l-s]. We could demonstrate that isovolaemic haemodilution is superior to venesections [6]. Furthermore, HES 200/0.5 10%combined with exercise leads to clinically much better results in the case of isovolaemic and hypervolaemic haemodilution [ 71 than Dextran 40 10%. In patients presenting
dissimilar rheological morphology, haemodilution combined with exercise has proved to be significantly more favourable than physical therapy alone [ 3 ] . The aim of this study was to answer the question whether haemodilution with HES 200/0.5 10%plus exercise (given only moderately elevated haematocrit values of up to 46 %, and tested in isomorphic patient groups) is clinically more effective than haemodilution with Ringer lactate plus exercise or exercise alone. The study was designed according to the recommendations for clinical therapeutic studies concerning peripheral arterial occlusive disease 107
108
H. KIESEWETTEK et al.
initially drawn up at an international symposium in Biarritz in 1985 [S].
Methods The study was randomized, double-blind and placebo-controlled including 50 patients and a control group of 2 5 patients. Peripheral arterial occlusive disease stage IIb according to Fontaine (PAOD IIb) has been evident for at least 6 months prior to the study.
Criteria for inclusion Out-patients of both sexes and aged between 4 0 and 75 years were chosen. Criteria included peripheral arterial occlusive disease of the femoral and/or tibia1 type, presence of a stenosis or an occlusion of the superficial femoral artery with or without haemodynamically inactive stenosis (less than 50%) of the anterior iliac artery and/or the deep femoral artery with angiographically demonstrated localization. mean stable walking distance without pain on admission of between 80 and 300 m, fluctuation in walking distance during wash-out phase of not more than 30% (guidelines for clinical therapy studies for peripheral arterial occlusive disease [S]) between three values recorded on different days, Doppler pressure values over peripheral arteries at rest greater than 50 mmHg, haematocrit values less than or equal to 46%, or greater than or equal to 42%. and plasma viscosity greater than or equal to 1.34 mPas. The criteria for exclusion are described by Heidrich and Boccalon, [S].
Implementation of the study The test phase for each patient was 10 weeks (4 weeks of wash-out phase and 6 weeks of treatment phase). All patients received physical therapy for 10 weeks (10 x 3 workdays). The increase in walking distance after the wash-out phase was not allowed to exceed 50% in relation to the initial condition. The physical therapy consisted of 4 5 min of interval training in the gym three times weekly (10 min of limbering-up ball exercises, 20 min of three times the pain-free walking distance at 90 to 1 2 0 strides min-I. followed by 1 5 min of gymnastic exercise, designed specifically for the type of occlusion). During the 6 weeks of the treatment phase only the patients in the HES and Ringer group were diluted in addition to physical therapy. The double-blind design relates to the two dilution groups. The third group was the basis control group. The dilutions were performed five times during the first 3 weeks, but only three times weekly in the final 3 weeks. At haematocrit values of 42 % and above an isovolaemic haemodilution with venesection was performed and at haematocrit values equal to or less than 4 2 % a hypervolaemic dilution. On isovolaemic haemodilution, 250 ml blood were removed and substituted for 2 5 0 m l HES 200/0.5 10% (HES steril" 100/0, Fresenius AG) or Ringer lactate solution. On hypervolaemic haemodilution, 250 ml HES 200/0.5 10%or Kinger lactate solution were infused without prior venesection. Under this therapy, care was taken to ensure that the blood pressures prior to the hypervolaemic dilution were less than 160/90 mmHg. The study schedule is illustrated in Fig. 1.
Selection of patients The 75 patients were selected at random from 108 out-patients in accordance with the criteria for inclusion. Prior to the planned study, the patients were informed of possible side-effects, and all gave their written consent. Data record sheets were drawn up for the tests before the study commenced, and the pain-free walking distance was determined as the confirmatory parameter. The patients were then allocated by means of a second randomization to three groups of 25 each: group 1: HES, group 2: Kinger and group 3 : exercise group.
Patients The demographic data, risk factors, and concomitant diseases of the patients were given in Tables 1-3. The concomitant medication did not change between the wash-out and test phases. All patients received the following drugs which were distributed equally among the three groups : clonidine, digoxin, sulphonyl urea, nifedipine, insulin, verapamil, sulphinpyrazone, acetylsalicylic acid, nitrates. The localizations of the stenoses and occlusions are shown in Table 4.
H A E M O D I L U T I O N I N A R T E R I A L OCCLUSIVE D I S E A S E
I
Wash-out phase
Test phase 3/week according to Weidinger
iso- and iso-/hypervolaemically Hct > 42% isov .; Hct 42% hyperv.)
3/week
Haemodilution with medium molecular weight hydroxyethyl starch in patients with peripheral arterial occlusive disease stage IIb H. KIESEWETTER, J. B L U M E t , F. J U N G , S. SPITZER*, & E. WENZEL Front the Department of Clinical Haemostasiology and Transfusion Medicine. the *Medical Clinic and Out-patient Department, Interrial Medicine III. University Hospitals of the Saarlurid. Homburg-Saw, arid the ?Center !or Cardiovascular Diseases, AacRen. West Germany
Abstract. Kiesewetter H, Blume J. Jung F, Spitzer S, Wenzel E (Department of Clinical Haemostasiology and Transfusion Medicine, the Medical Clinic and Outpatient Department, Internal Medicine 111. University Hospitals of the Saarland, Homburg-Saar, and Center for Cardiovascular Diseases, Aachen, West Germany). Haemodilution with medium molecular weight hydroxyethyl starch in patients with peripheral arterial occlusive disease stage IIb. journal of Internal Medicine 1 9 9 0 : 2 2 7 : 107-1 14. The basic therapy of peripheral arterial occlusive disease stage IIb, according to Fontaine, is exercise. It should be determined whether a mild hypervolaemic haemodilution with hydroxyethyl starch or Ringer lactate can produce a further increase in walking distance. For this purpose, three groups of 2 5 patients each were formed. One group exercised three times weekly and the second group, in addition to exercise, underwent a mild hypervolaemic to isovolaemic dilution therapy with HES for a period of 6 weeks. In the final group the haematocrit was reduced to the same extent by venesections and volume substitution using Ringer lactate. The walking distance in the HES group increased from 216 m to 31 1 m (44%), in the Ringer lactate group from 214 m to 258 m (20%). and in the exercise group from 21 3 m to 242 m ( 1 4%). On comparison of the groups, the increase in pain-free walking distance in the HES group differs significantly ( P < 0.05) from that achieved in the other groups. It was demonstrated that haemodilution with HES in combination with exercise brings about a clinical effect three times that achieved by exercise alone. Venesection with subsequent administration of Ringer lactate and exercise is superior to exercise alone but markedly inferior to the combination therapy with HES.
Keywords: arterial occlusive disease, haemodilution. hydroxyethyl starch. peripheral arterial occlusive disease.
Introduction Haemodilution with hydroxyethyl starch has been employed for a number of years by various angiological centres as an effective therapy in patients suffering from peripheral arterial occlusive disease [l-s]. We could demonstrate that isovolaemic haemodilution is superior to venesections [6]. Furthermore, HES 200/0.5 10%combined with exercise leads to clinically much better results in the case of isovolaemic and hypervolaemic haemodilution [ 71 than Dextran 40 10%. In patients presenting
dissimilar rheological morphology, haemodilution combined with exercise has proved to be significantly more favourable than physical therapy alone [ 3 ] . The aim of this study was to answer the question whether haemodilution with HES 200/0.5 10%plus exercise (given only moderately elevated haematocrit values of up to 46 %, and tested in isomorphic patient groups) is clinically more effective than haemodilution with Ringer lactate plus exercise or exercise alone. The study was designed according to the recommendations for clinical therapeutic studies concerning peripheral arterial occlusive disease 107
108
H. KIESEWETTEK et al.
initially drawn up at an international symposium in Biarritz in 1985 [S].
Methods The study was randomized, double-blind and placebo-controlled including 50 patients and a control group of 2 5 patients. Peripheral arterial occlusive disease stage IIb according to Fontaine (PAOD IIb) has been evident for at least 6 months prior to the study.
Criteria for inclusion Out-patients of both sexes and aged between 4 0 and 75 years were chosen. Criteria included peripheral arterial occlusive disease of the femoral and/or tibia1 type, presence of a stenosis or an occlusion of the superficial femoral artery with or without haemodynamically inactive stenosis (less than 50%) of the anterior iliac artery and/or the deep femoral artery with angiographically demonstrated localization. mean stable walking distance without pain on admission of between 80 and 300 m, fluctuation in walking distance during wash-out phase of not more than 30% (guidelines for clinical therapy studies for peripheral arterial occlusive disease [S]) between three values recorded on different days, Doppler pressure values over peripheral arteries at rest greater than 50 mmHg, haematocrit values less than or equal to 46%, or greater than or equal to 42%. and plasma viscosity greater than or equal to 1.34 mPas. The criteria for exclusion are described by Heidrich and Boccalon, [S].
Implementation of the study The test phase for each patient was 10 weeks (4 weeks of wash-out phase and 6 weeks of treatment phase). All patients received physical therapy for 10 weeks (10 x 3 workdays). The increase in walking distance after the wash-out phase was not allowed to exceed 50% in relation to the initial condition. The physical therapy consisted of 4 5 min of interval training in the gym three times weekly (10 min of limbering-up ball exercises, 20 min of three times the pain-free walking distance at 90 to 1 2 0 strides min-I. followed by 1 5 min of gymnastic exercise, designed specifically for the type of occlusion). During the 6 weeks of the treatment phase only the patients in the HES and Ringer group were diluted in addition to physical therapy. The double-blind design relates to the two dilution groups. The third group was the basis control group. The dilutions were performed five times during the first 3 weeks, but only three times weekly in the final 3 weeks. At haematocrit values of 42 % and above an isovolaemic haemodilution with venesection was performed and at haematocrit values equal to or less than 4 2 % a hypervolaemic dilution. On isovolaemic haemodilution, 250 ml blood were removed and substituted for 2 5 0 m l HES 200/0.5 10% (HES steril" 100/0, Fresenius AG) or Ringer lactate solution. On hypervolaemic haemodilution, 250 ml HES 200/0.5 10%or Kinger lactate solution were infused without prior venesection. Under this therapy, care was taken to ensure that the blood pressures prior to the hypervolaemic dilution were less than 160/90 mmHg. The study schedule is illustrated in Fig. 1.
Selection of patients The 75 patients were selected at random from 108 out-patients in accordance with the criteria for inclusion. Prior to the planned study, the patients were informed of possible side-effects, and all gave their written consent. Data record sheets were drawn up for the tests before the study commenced, and the pain-free walking distance was determined as the confirmatory parameter. The patients were then allocated by means of a second randomization to three groups of 25 each: group 1: HES, group 2: Kinger and group 3 : exercise group.
Patients The demographic data, risk factors, and concomitant diseases of the patients were given in Tables 1-3. The concomitant medication did not change between the wash-out and test phases. All patients received the following drugs which were distributed equally among the three groups : clonidine, digoxin, sulphonyl urea, nifedipine, insulin, verapamil, sulphinpyrazone, acetylsalicylic acid, nitrates. The localizations of the stenoses and occlusions are shown in Table 4.
H A E M O D I L U T I O N I N A R T E R I A L OCCLUSIVE D I S E A S E
I
Wash-out phase
Test phase 3/week according to Weidinger
iso- and iso-/hypervolaemically Hct > 42% isov .; Hct 42% hyperv.)
3/week
![[Pharmacology of low molecular weight hydroxyethyl starch].](/assets/img/hold.png)
