THE EFFECTS OF MEDROXYPROGESTERONE ACETATE AND ACETAZOLAMIDE ON THE NOCTURNAL OXYGEN SATURATION IN COPD PATIENTS

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1 THE EFFECTS OF MEDROXYPROGESTERONE ACETATE AND ACETAZOLAMIDE ON THE NOCTURNAL OXYGEN SATURATION IN COPD PATIENTS Wagenaar, M., Vos, P., Heijdra, Y., Herwaarden, C. van, Folgering, H. Departement of Pulmonary diseases, University of Nijmegen, Dekkerswald, The Netherlands INTRODUCTION Some patients with severe chronic obstructive pulmonary disease (COPD) are not able to keep their bloodgas values at a normal level and will become hypercapnic and/or hypoxic. The mechanism of this deterioration is multi-factorial: hypoventilation, ventilation/perfusion mismatch, an increased Functional Residual Capacity (FRC), reduced inspiratory muscle strength and blunted ventilatory responses to CO2/O2 possibly play a part. Several studies have shown that during sleep a deterioration of hypoxaemia and hypercapnia is induced due to hypoventilation (1-3). The hypoventilation is caused by diminished respiratory muscle function, especially during Rapid Eye Movement (REM)-sleep, when the diaphragm is the only inspiratory muscle, and by a diminution of the hypoxic and hypercapnic ventilatory response. During the last years several options of treatment have been suggested. SUPPLEMENT OXYGEN The restrospective study of Cooper et al.(4) has shown, that long term oxygen therapy (LTOT) improved hypoxaemia However, the last three years before death of these patients, hypoxaemia and hypercapnia worsened, due to hypoventilation. This may have influenced the prognosis for survival adversily. Therefore, it is of interest to keep minute ventilation and arterial bloodgas values as normal as possible. TARGET FLOW INSPIRATORY MUSCLE TRAINING (TF-IMT) Using TF-IMT Heydra et al.(5) has shown that mean nocturnal S a O 2 can be improved by approximately 2%. NON INVASIVE POSITIVE PRESSURE VENTILATION (NIPPV) NIPPV is believed to be effective in reducing P a CO 2, improving quality of life, and prolonging survival in hypercapnic, hypoventilating COPD patients. However, to optimize effectiveness (i.e selection of patients) and cost efficiency further research is needed (6). 139

2 RESPIRATORY STIMULANTS Respiratory stimulants such as Medroxyprogesterone acetate (MPA) and Acetazolamide (ACET) may have a benificial effect on hypoxia/hypercapnia by improvement of ventilation. MPA improves ventilation via progesterone receptors in the pre-optic area, N. Suprachiasmaticus and eminentia mediana of the hypothalamus (7,8). In humans ACET stimulates ventilation by inducing a metabolic acidosis. Animal studies showed that the working mechanism of ACET is probably via the central and peripheral chemoreflex loops and via an action on cerebral vessels resulting in an altered brain tissue PCO 2 (9). A study in COPD patients (10) showed that both acetazolamide and chlormadinon acetate (another synthetic progesteron, which effect on ventilation is comparable to that of MPA) decreased mean daytime and nocturnal PCO 2 and that ACET improved mean nocturnal oxygen saturation. AIM OF THE STUDY Aim of the present study was to investigate the effects of MPA and ACET on the nocturnal ventilation, oxygen saturation and PCO 2. METHODS Twelve hypercapnic COPD patients (daytime P a CO 2 > 6 kpa)(8 males and 4 females) participated in this study. COPD was defined according to the definition of the American Thoracic Society (11). All patients were clinically stable and were studied in a randomised double blind cross over and placebo controlled fashion. measurements: a. The arterial oxygen saturation (S a O 2 ) was measured by a pulse-oximeter (Oxyshuttle, SensorMedics). The S a O 2 data of the whole night were stored, digitized, and analysed by a computer to provide the mean and lowest S a O 2 as well as the standard deviation around the mean S a O 2. The baseline awake was defined as the mean S a O 2 15 minutes before falling asleep. Desaturation was defined as a decrease in S a O 2 from baseline awake S a O 2 of more than 4%. b. The end-tidal PCO 2 (PE T CO 2 ) was determined by introducing a cannula through the nose into the naso-pharyngeal cavity. An air sample was taken via a perma-pure drying tube connected to a sampling capnograph (Mijnhart capnolyser). c. The thoracoabdominal movements were assessed by respiratory inductance plethysmography (Vitalog) and an Electro-oculogram was performed with surface electrodes to indicate REM sleep. 140

3 EXPERIMENTAL PROTOCOL Prior to the study, an arterial blood gas sample was taken and pulmonary function tests were performed. All patients were studied during four nights: prior to every change of medication. The first night consisted of control measurements. Next, a placebo was given for two weeks in order to investigate the intra-individual variability. Then, a second study night was performed. After the second night, patients recieved either ACET (twice daily 250mg) or MPA (twice daily 30mg). After two more weeks, measurements of the third night were performed followed by another two week treatment with the opposite medication. At the end of the study measurements of the final (fourth) night were recorded (fig 1). Control X Placebo X Control 1 Placebo 2 ACET X MPA X (2x250mg) 3 4 MPA X ACET X (2x30MG) 3 4 Figure 1: Study-protocol. Figure 1: X= measurement, ACET= acetazolamide (twice daily 250mg), MPA= medroxyprogesterone acetate (twice daily 30mg), time x--x= 2 weeks STATISTICAL ANALYSIS Statistical analysis for paired comparisons was performed using the Wilcoxon signed rank test. The Mann-Whitney U test was performed to determine possible statistically significant differences between the two groups and to determine possible carry over effects. p-values less then 0.05 were considered to be significant. RESULTS Table 1. shows the daytime characteristics. As can be seen the group of patients consists of patients with severe airway obstruction (i.e low FEV1 and FEV1/VC). The blood gas values show that these patients were hypoxic as well as hypercapnic. 141

4 Table 1: Patient s daytime characteristics (mean±sd). total (n=12) reference values/ predicted values(*) general age (years) 68.3 ± weight (kg) 67.8 ± length (cm) ± Body Mass Index (kg/cm 2 ) 23.4 ± ± 2.5 lung function FEV 1 (l) 00.9 ± 0.4 =33 ± 4% pred.(*) VC (l) 02.6 ± 1.0 =72 ± 5% pred.(*) FEV 1 /VC (%) 34.2 ± 11.4 =45 ± 4% pred.(*) arterial blood sample ph 7.40 ± ± 0.05 P a O 2 (kpa) 08.8 ± ± 1 P a CO 2 (kpa) 06.3 ± ± 0.5 BE (mmol/l) 03.9 ± ± 2 HCO 3 -(mmol/l) 27.8 ± ± 2 S a O 2 awake (%) 92.4 ± ± 2 *)=[time spent at S a O 2 < (baseline awake-4%)] Analyzing the daytime parameters and nocturnal saturation parameters, no carry over effects were found when MPA was administered after ACET treatment and when ACET was given after MPA treatment. So both arms were analyzed together. Table 2 shows the intra individual variability. As can be seen no differences between control and placebo were observed. Table 2: Nocturnal parameters (Intra individual variability) (mean±sd).. n=12 CONTROL PLACEBO Mean nocturnal S a O 2 (%) 90.6 ± ± 3.5 Lowest S a O 2 (%) 83.4 ± ± 4.8 % time S a O 2 <90% 29.3 ± ± 37.0 % time desaturated*) 23.4 ± ± 25.2 Mean nocturnal P ET CO 2 (kpa) 05.7 ± ± 1.1 *)=[time spent at S a O 2 < (baseline awake-4%)] 142

5 As shown in table 3, a trend toward improvement of the mean nocturnal S a O 2 was apparent by both ACET and MPA. Lowest S a O 2 was slightly, not significantly, decreased with both treatments. The percentage of time that S a O 2 was beneath 90% was significantly decreased by ACET. Desaturation time (%time S a O 2-4% baseline awake) did not change significantly by both ACET and MPA. Mean nocturnal P ET CO 2 decreased significantly. Table 3: Nocturnal parameters of patients (mean±sd) n=12 PLAC ACET MPA Mean nocturnal S a O 2 (%) 90.7 ± ± ± 3.5 Lowest S a O 2 (%) 84.9 ± ± ± 7.1 %time S a O 2 <90% 34.9 ± ± 26.0* 23.8 ± 39.8 %time desaturated 23.4 ± ± ± 16.6 Mean nocturnal P ET CO 2 (kpa) 5.6 ± ± 0.9* 4.6 ± 0.5* (*significance between treatment and placebo) SIDE-EFFECTS The main complaints of the patients were gastro-intestinal discomfort (Plac:n=3, ACET:n=5 MPA:n=3) headache and dizziness (Plac:n=2, ACET: n=2 MPA n=2) and paraesthesia (Plac:n=0, ACET:n=4 MPA:n=1). CONCLUSION This study shows that acetazolamide has a favourable effect on nocturnal desaturation and on the mean nocturnal P ET CO 2. Although both acetazolamide and medroxyprogesterone acetate tend to improve mean nocturnal saturation and decreased. The severity of the nocturnal hypoxia (% time S a O 2 <90%) and the nocturnal hypoventilation (P ET CO 2 ) both were improved significantly. Further studies will be performed to evaluate the effects of combined treatment with both drugs in order to search for optimal treatment of these patients. 143

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