THROMBOSIS RESEARCH 68; 435-440, 1992 0049-3848192 $5.00 + .OOPrinted in the USA. Copyright (c) 1992 Pergamon Press Ltd. All rights reserved.
BRIEF COMMUNICATION IMPROVEMENT OF BLOOD GAS LEVELS AFTER CALCIUM-HEPARIN TREATMENT IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Corrado Cordova, *Francesco Violi, *Cesare Alessandri, Stefania Basili, Roberto Barsi, *Mirella Saliola, Michele Paradiso. Istituto di Terapia Medica and *Istituto di I Clinica Medica, University of Rome (Universith di Roma "La Sapienza", Italy).
(Received 27.12.1991; accepted in revised form 12.10.1992 by Editor S. Coccheri)
INTRODUCTION Autoptic studies (1) performed in patients who had died from chronic obstructive pulmonary disease (COPD) showed that microthrombosis may occur in lung vessels. Clinical studies confirmed these preliminary findings suggesting that during the clinical occurrence of course of COPD the pulmonary microthrombosis could be a warning sign of death (2-4), These findings prompted many researchers to investigate whether a prothrombotic condition was present in COPD patients. They observed a shortened platelet half-life, in vitro and in vivo platelet activation,high values of blood fibrinogen and an accelerated fibrinogen polymerization curve (5-11). In addition, uncontrolled studies showed that heparin treatment was able to values in patients with improve clinical course and blood gas study severe COPD, non responders to common therapy (10,12). To further the effect of heparin in COPD , we have evaluated whether this therapy given subcutaneously for a short period of time could be able to influence blood gas values. --_----------------Key words: chronic obstructive pulmonary disease, hypercapnia, hypoxia, calcium-heparin.
435
436
CALCIUM-HEPARIN
AND BLOOD GAS
Vol. 68, Nos. 4/S
MATERIALS AND METHODS Eighteen patients (10 males , 8 females ; age range from 52 to 85 years) suffering from COPD were included into ten days study. COPD diagnosis was based on clinical and laboratory findings including chest-X-ray, ECG, arterial blood gas and spirometry. Criteria for inclusion was FEVl < 1.2 litres, PaC02 2 46 mmHg, Pa02 I 65 mmHg, pH between 7.28 and 7.42 at rest and Hct < 50%; patients with acute inflammatory diseases, episodes of pulmonary embolism, metabolic acidosis, peptic ulcer, chronic hepatitis, before haemorrhage (one month cancer, recent history of platelet coagulant or anti anti admission to the study), treatment, contraindication for corticosteroids were excluded. All patients gave informed consent to participate in the study, which was approved by the appropriate hospital administration board. weeks run-in period underwent a four All the patients included during which blood gas analysis and FEVl were as out-patients, This pre-randomisation phase did not periodically performed. show changes in blood gas values or in FEVl >15% During the run-in phase as well as the randomisation period all patients were given a standard therapy , which consisted of cardiac glycosides, corticosteroids, salbutamol, aminophilline, and oxygen therapy ( l-2 litres / min for 15 hours daily by 0.24 Venturi's mask). Thirty apparently healthy subjects matched for sex and age were used as control group. Studv design 18 patients were randomly allocated After one month of run-in to receive standard therapy plus calcium-heparin given subcutaneously (5000 IU t.i.d) [Group I ; n = 91 or standard therapy alone [Group II; n = 91 for 10 days. The FEVl and forced vital capacity (FVC) were measured with a dry spirometer before and at the end of treatment period. Blood analvsis Blood was taken from the radial artery between 8 and 9 a.m. in each patient who had fasted for at least 12 hours and had not been given oxygen therapy in the previous 4 hours and analysed for gas tension on a Radiometer ABL3 (Detta, Copenhagen, Denmark) before and at the end of treatment period. Between 8 and 9 a.m. another blood sample was taken from patients, whitout stasis ,from the anticubital vein. Nine parts of blood were mixed directly in a vacutainer (Be&on Dickinson Vacutainer System, France) with 1 part of 3.8% Na citrate and treated for the study of clotting factor activities, as reported below. Citrated blood samples were immediately centrifuged for 20' at 2000 xg. The following blood coagulation screening tests were performed on each sample before and at the end of each treatment period: , assessed -Prothrombin activity by Normotest (Nyegaard & C, Oslo, Norway, ref. val. 70-120%), which explores vitamin K dependent factors, used according to the manufactures' instructions. -Activated partial thromboplastin time (aPTT), evaluated by Cephotest (IItuTIUnO Diagnostics, Pisa,Italy, ref. val. 25-33 set).
Vol. 68, Nos. 45
CALCIUM-HEPARIN
AND BLOOD GAS
437
-Plasma fibrinogen (Baldacci, Pisa, ref. val. 180-400 mg/dl), was studied according to the Clauss method. A Schnitger und Gross coagulometer was employed for the Normotest, aPTT and plasma clottable fibrinogen assays. D-dimer was evaluated in patients plasma using Ortho Dimertest (Ortho Diagnostics, Milan, Italy, ref. val. 4200 ng/ml). Antithrombin III plasma activity was assayed by "Coatest antithrombinl' (Ortho Diagnostics, Milan, Italy, ref. val. 70120%). Platelet count, Haematocrit and Haemoglobin were measured using standard laboratory methods. Statistical Analysis The effect of treatment was assessed with appropriate (13-14). Data was showed as mean f standard deviation 95% confidence limits (95% CL). Level of significance (Stat View II. Abacus Concepts, Berjeley, CA).
t-tests (SD) and is 0.05
RESULTS Eighteen patients were included in the study and all completed the trial. Nine had been randomised to calcium-heparin plus standard therapy [Group I] and 9 to standard therapy [Group II]. Nine patients were currently smoking, three (17%) we!re exsmokers. Eleven (61%) showed electrocardiographic evidence of right heart strain. None of these characteristics differed significantly between the two groups. After ten days of treatment Group I showed a significant increase of Pa02 and a significant decrease of PaC02 while Group II showed a significant increase of Pa02 and no changes of PaC02 (Table 1,2). PaCo2 and Pa02 baseline values did not differ between the two groups; after treatment period group I had of Pa02 and lower values of PaC02 significantly higher values than group II. Table 1 ~Standard Therapy Plus Pa02 Values (mmHg) Before And After Alone And Standard Therapy Calcium-Heparin (Group I) (Group II). (*p
BRIEF COMMUNICATION IMPROVEMENT OF BLOOD GAS LEVELS AFTER CALCIUM-HEPARIN TREATMENT IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Corrado Cordova, *Francesco Violi, *Cesare Alessandri, Stefania Basili, Roberto Barsi, *Mirella Saliola, Michele Paradiso. Istituto di Terapia Medica and *Istituto di I Clinica Medica, University of Rome (Universith di Roma "La Sapienza", Italy).
(Received 27.12.1991; accepted in revised form 12.10.1992 by Editor S. Coccheri)
INTRODUCTION Autoptic studies (1) performed in patients who had died from chronic obstructive pulmonary disease (COPD) showed that microthrombosis may occur in lung vessels. Clinical studies confirmed these preliminary findings suggesting that during the clinical occurrence of course of COPD the pulmonary microthrombosis could be a warning sign of death (2-4), These findings prompted many researchers to investigate whether a prothrombotic condition was present in COPD patients. They observed a shortened platelet half-life, in vitro and in vivo platelet activation,high values of blood fibrinogen and an accelerated fibrinogen polymerization curve (5-11). In addition, uncontrolled studies showed that heparin treatment was able to values in patients with improve clinical course and blood gas study severe COPD, non responders to common therapy (10,12). To further the effect of heparin in COPD , we have evaluated whether this therapy given subcutaneously for a short period of time could be able to influence blood gas values. --_----------------Key words: chronic obstructive pulmonary disease, hypercapnia, hypoxia, calcium-heparin.
435
436
CALCIUM-HEPARIN
AND BLOOD GAS
Vol. 68, Nos. 4/S
MATERIALS AND METHODS Eighteen patients (10 males , 8 females ; age range from 52 to 85 years) suffering from COPD were included into ten days study. COPD diagnosis was based on clinical and laboratory findings including chest-X-ray, ECG, arterial blood gas and spirometry. Criteria for inclusion was FEVl < 1.2 litres, PaC02 2 46 mmHg, Pa02 I 65 mmHg, pH between 7.28 and 7.42 at rest and Hct < 50%; patients with acute inflammatory diseases, episodes of pulmonary embolism, metabolic acidosis, peptic ulcer, chronic hepatitis, before haemorrhage (one month cancer, recent history of platelet coagulant or anti anti admission to the study), treatment, contraindication for corticosteroids were excluded. All patients gave informed consent to participate in the study, which was approved by the appropriate hospital administration board. weeks run-in period underwent a four All the patients included during which blood gas analysis and FEVl were as out-patients, This pre-randomisation phase did not periodically performed. show changes in blood gas values or in FEVl >15% During the run-in phase as well as the randomisation period all patients were given a standard therapy , which consisted of cardiac glycosides, corticosteroids, salbutamol, aminophilline, and oxygen therapy ( l-2 litres / min for 15 hours daily by 0.24 Venturi's mask). Thirty apparently healthy subjects matched for sex and age were used as control group. Studv design 18 patients were randomly allocated After one month of run-in to receive standard therapy plus calcium-heparin given subcutaneously (5000 IU t.i.d) [Group I ; n = 91 or standard therapy alone [Group II; n = 91 for 10 days. The FEVl and forced vital capacity (FVC) were measured with a dry spirometer before and at the end of treatment period. Blood analvsis Blood was taken from the radial artery between 8 and 9 a.m. in each patient who had fasted for at least 12 hours and had not been given oxygen therapy in the previous 4 hours and analysed for gas tension on a Radiometer ABL3 (Detta, Copenhagen, Denmark) before and at the end of treatment period. Between 8 and 9 a.m. another blood sample was taken from patients, whitout stasis ,from the anticubital vein. Nine parts of blood were mixed directly in a vacutainer (Be&on Dickinson Vacutainer System, France) with 1 part of 3.8% Na citrate and treated for the study of clotting factor activities, as reported below. Citrated blood samples were immediately centrifuged for 20' at 2000 xg. The following blood coagulation screening tests were performed on each sample before and at the end of each treatment period: , assessed -Prothrombin activity by Normotest (Nyegaard & C, Oslo, Norway, ref. val. 70-120%), which explores vitamin K dependent factors, used according to the manufactures' instructions. -Activated partial thromboplastin time (aPTT), evaluated by Cephotest (IItuTIUnO Diagnostics, Pisa,Italy, ref. val. 25-33 set).
Vol. 68, Nos. 45
CALCIUM-HEPARIN
AND BLOOD GAS
437
-Plasma fibrinogen (Baldacci, Pisa, ref. val. 180-400 mg/dl), was studied according to the Clauss method. A Schnitger und Gross coagulometer was employed for the Normotest, aPTT and plasma clottable fibrinogen assays. D-dimer was evaluated in patients plasma using Ortho Dimertest (Ortho Diagnostics, Milan, Italy, ref. val. 4200 ng/ml). Antithrombin III plasma activity was assayed by "Coatest antithrombinl' (Ortho Diagnostics, Milan, Italy, ref. val. 70120%). Platelet count, Haematocrit and Haemoglobin were measured using standard laboratory methods. Statistical Analysis The effect of treatment was assessed with appropriate (13-14). Data was showed as mean f standard deviation 95% confidence limits (95% CL). Level of significance (Stat View II. Abacus Concepts, Berjeley, CA).
t-tests (SD) and is 0.05
RESULTS Eighteen patients were included in the study and all completed the trial. Nine had been randomised to calcium-heparin plus standard therapy [Group I] and 9 to standard therapy [Group II]. Nine patients were currently smoking, three (17%) we!re exsmokers. Eleven (61%) showed electrocardiographic evidence of right heart strain. None of these characteristics differed significantly between the two groups. After ten days of treatment Group I showed a significant increase of Pa02 and a significant decrease of PaC02 while Group II showed a significant increase of Pa02 and no changes of PaC02 (Table 1,2). PaCo2 and Pa02 baseline values did not differ between the two groups; after treatment period group I had of Pa02 and lower values of PaC02 significantly higher values than group II. Table 1 ~Standard Therapy Plus Pa02 Values (mmHg) Before And After Alone And Standard Therapy Calcium-Heparin (Group I) (Group II). (*p
