Klinische Wochenschrift
KlinWochenschr (1990) 68:207-212
9 Springer-Verlag 1990
Originals Skin Surface Oxygen Pressure Fields During Administration of Prostaglandin E1 in Patients with Arterial Occlusive Disease A. Creutzig, L. Caspary, and K. Alexander Abteilung Angiologie, Medizinische Hochschule Hannover
Summary. Prostaglandin Ea is offered as a new therapeutic agent in the treatment of severe peripheral arterial occlusive disease. Especially when treating patients with ulcers or gangrene, the oxygen tension of the skin should improve during PGE~ administration. The new technique of assessing skin surface oxygen pressure histograms allows study of the skin microcirculation in vivo. Oxygen histograms were determined on the forefeet of 19 patients with different degrees of disease and different occlusion levels before and during a single intraarterial infusion of PGE1 at a dosage of 1.5ng/kg body weight/min. Only 9 patients showed improvement during the infusion period. Skin oxygen pressure was increased to a large extent only in patients assumed to suffer from diabetic microangiopathy. The effect of a long-term therapy with PGEt on skin microcirculation remains to be settled. Key words: Skin surface oxygen pressure fields - Skin microcirculation - Diabetic microangio-
pathy - Arterial occlusive disease - Prostaglandin E1
Prostaglandin E1 (PGE1) has some pharmacological properties that may be of benefit in the treatment of peripheral arterial occlusive disease. It is a strong vasodilator, inhibits aggregation of platelets, and influences the metabolism of the ischemic skeletal muscle by switching from oxydation of fatty acids to glucose oxydation [5, 13]. Intraarterial therapy has been proven to be effective in some clinical trials with patients with peripheral arterial Abbreviations: PGE~ =prostaglandin E~; TcPO2=transcutan-
eous oxygen pressure
occlusive disease [1, 14]. Its efficacy was assumed to be caused by microcirculatory changes [5]. Our previous investigations could demonstrate an increase of muscle surface oxygen pressure of the gastrocnemius muscle of patients with severe arterial occlusive disease when treated with PGE1; during exercise calf muscle circulation measured by the xenon clearance technique was improved [5]. This investigation was initiated to study skin microcirculation during PGE1 therapy which seems to be of utmost importance in patients with ulcers or gangrene. We used a new technique in assessing skin microcirculation by establishing oxygen pressure fields. Patients and M e t h o d s
Nineteen patients (2 female, 17 male) with peripheral arterial circulation disorders of the lower limbs aged between 32 and 80 years (average 58.8 years) were studied. The patients were treated in our angiological division because of severe claudication with maximal walking distances under 100 m (stage II according to Fontaine [I0], n = 5) or ulcers or gangrene of the toes (stage IV, n = 14) but without edema or infections of the forefoot (Table 1). Ten patients had diabetes and were treated with insulin or oral antidiabetics. Nine patients were smokers, 6 were treated with antihypertensive drugs (nifidepine, diuretics), and 4 had hyperlipoproteinemia treated dietetically (Table 1). Fourteen patients underwent angiography; in 7 patients the superficial femoral artery and one to three calf arteries were occluded, whereas the deep femoral artery was patent (type 1, Table 1). Their mean ankle pressure was 51 mmHg, mean brachiopedal pressure gradient (systolic pressure of the brachial artery minus systolic pressure of the posterior tibial artery) was 68 mmHg. In 7
A. C r e u t z i g et al. : P r o s t a g l a n d i n E l a n d Skin Surface O x y g e n Pressure H i s t o g r a m s
208 Table 1. P a t i e n t s ' d a t a Patient
Sex
Age
Stage
Type
dm
nic
hl p
hypt
AP
BP-AP
Result
1 2 3
Male Male Male
60 65 78
II II II
1 1 1
+
+ + -
-
+
90 60 Mediascl
40 65
NR R R
4 5
Female Male
45 58
II II
2 2
-
+ +
+ -
+
85 65
45 70
NR NR
6 7 8 9
Male Male Male Male
67 44 36 62
IV IV IV IV
1 1 1 1
+ -
+ + +
+ -
+
20 55 60 20
95 75 50 80
NR NR NR NR
10 11 12 13 14
Male Female Male Male Male
44 80 67 78 62
IV IV IV IV IV
2 2 2 2 2
+ + +
+ +
+ + -
+ + + -
40 80 100 115 50
80 80 60 45 80
R NR R R NR
15 16 17 18 19
Male Male Male Male Male
50 48 52 74 48
IV IV IV IV IV
3 3 3 3 3
+ + + + +
-
-
-
Mediascl 120 160 160 145
0 0 0 0
R R R R NR
Stage of disease ( F o n t a i n e ) : II i n t e r m i t t e n t c l a u d i c a t i o n , IV ulcer or g a n g r e n e ; t ype of o c c l u s i o n : 1 superficial f e m o r a l a r t e r y a n d o ne to th ree calf arteries, 2 one to three calf arteries, 3 no m a j o r arteries o c c l u d e d ; d m : d i a b e t e s m e l l i t u s ; nic: n i c o t i n e c o n s u m p t i o n , ; hlp: h y p e r l i p o p r o t e i n e m i a ; h y p t : h y p e r t e n s i o n ; A P : systolic a n k l e p r e s s u r e ( m m H g ) ; B P - A P : systolic b l o o d pr es s u r e m i n u s systolic a n k l e pressure ( m m H g ) ; m e d i a s c l : no pre s s ure m e a s u r e m e n t possible b e c a u s e o f m e d i a s c l e r o s i s ; R : r e s p o n d e r : significan t c h a n g e o f PO2 h i s t o g r a m w i t h increase o f m e d i a n PO2 d u r i n g P G E 1 i n f u s i o n ( P < 0 . 0 5 ) ; N R : n o n r e s p o n d e r : no sig nifican t c h a n g e d u r i n g i n f u s i o n p e r i o d
cases both thigh arteries were patent and one to three calf arteries occluded (type 2, Table 1).Their mean ankle pressure was 91 m m H g and mean brachiopedal pressure gradient 54 mmHg. In 5 diabetics oscillographic examinations of the limbs and pulse wave recordings of the toes were normal; their mean ankle pressure was 146 m m H g and mean brachiopedal pressure gradient was zero; they were assumed to have no occlusions of larger arteries and to suffer from diabetic microangiopathy (type 3, Table 1). Transcutaneous oxygen pressure (tcPO2) measurements have been recognized as a useful tool in characterizing skin microcirculation of patients with chronic arterial occlusive disease [7]. In order to standardize the investigation procedure most studies were undertaken with maximal vasodilatation due to hyperemization by an electrode core temperature of 44 ~ C. The reproducibility of these measurements was excellent [7]. However, in the state of maximal hyperemia pathophysiological or pharmacological studies could be performed only to a small extent. That is why we tried to study skin microcirculation at a moderate hyperthermia with an electrode core temperature of 37 ~ C where reagibility of skin capillaries is still present so that drug-induced changes of skin capillary flow can
be recorded [7]. However, with a single t c P O 2 (37 ~ C) measurement skin microcirculation is not sufficiently characterized; the reproducibility is poor. Corresponding to muscle surface oxygen pressure fields assessment of skin oxygen histograms proved to be useful to give a full and reproducible overview of local microcirculation [8]. To determine skin surface oxygen pressure fields we simultaneously used four commercially available tcPO2 electrodes (TCM 2, Radiometer, Copenhagen, Denmark) with a platinum electrode of 25 gm in diameter covered by a polypropylene membran. The room temperature was kept constant at 220-23 ~ C. The electrodes were calibrated by 20.9% oxygen. The subjects who had been asked not to smoke on the day of the examination were in a comfortable supine position. Five adhesive rings to fit the electrodes in were fixed on the forefoot in a circle with a diameter of about 7 cm. The electrodes were put in four of the rings; after reading their PO2 values which took about 5 min all electrodes were changed into the next rings by moving clockwise (Fig. 1); this procedure was repeated until more than 50 PO2 values were obtained which took about 2 h. Then PGE1 was given into the femoral artery via an infusion pump. The dose was 1.5
A. Creutzig et al. : Prostaglandin E~ and Skin Surface Oxygen Pressure Histograms
209
The results are presented a s P O 2 frequency histograms for groups of patients. They were statistically analyzed using the Kolmogorov-Smirnov test which is independent of mean values [11].
Results
Blood pressure or heart rate were not altered by PGE1 infusions. The reaction of skin surface oxygen pressure during PGE1 administration was very inhomogeneous. In nine patients it increased during the infusion period (responder), in ten patients it was unchanged or decreased (nonresponder, Table 2). In the responder group the sum histogram initially was left-shifted to POz values close to zero. During PGE1 administration the distribution type changed significantly ( P < 0.01), the histogram got a more bell-shaped form, and the median P O 2 increased from 4 to 6 mmHg (Fig. 2 a, b). The initial histogram of the nonresponders, which did not differ from that of the responders, did not change throughout the infusion period. When dividing into subgroups four out of five patients with diabetic microangiopathy (type 3, Table 1) demonstrated a steep increase in skin oxygen pressure during PGE1 infusion. The initial histogram of the whole group was characterized by only a few values close to zero and a good proportion above 10 mmHg (Fig. 3 a). Their median POz was 5 mmHg (Table 2). When infusing PGEa the histogram was shifted to the right; now even PO2 values above 20 mmHg could be found (Fig. 3b). Median POz rose up to 10 mmHg ( P < 0.001). The group of diabetics with occluded major arteries had only a slight but not significant increase of P O 2 . In patients without diabetes it even
Fig. 1. Simultaneous assessment of trancutaneous oxygen pressure by means of four electrodes fixed to the forefoot
ng/kg body weight/min according to our recommendation for clinical use [5]. It was dissolved in 50 ml sodium chloride. During the infusion period skin P O 2 measurements were repeated. Blood pressure and heart rate were determined before and at the 10th min of PGE~ infusion and at the end of the infusion period.
Table 2. Data of skin surface sum histograms from the forefeet before and during PGE1 infusion stratified to response, diabetes, stage of disease, and occlusion level (values in mmHg) Before P G E I
Responder ( n = 9 ) Nonresponder (n = 10) Diabetic microangiopathy ( n = 5 ) Diabetic macroangiopathy (n = 5) Macroangiopathy without diabetes (n = 9) Stage II ( n = 5 ) Stage IV (n = 14) Thigh/calf occlusion (n = 7) Calf occlusion ( n = 7 )
During PGE1
n*
Mean
SD
Median
627 756 479 350 554
4.2 4.4 5.6 3.2 5.3
3.2 3.1 3.5 3.2 3.0
4 4 5 2 5
369 1014 461 443
4.1 4.3 3.7 5.1
2.7 3.1 2.9 3.1
4 4 3 5
n*
Mean
SD
Median
P
KlinWochenschr (1990) 68:207-212
9 Springer-Verlag 1990
Originals Skin Surface Oxygen Pressure Fields During Administration of Prostaglandin E1 in Patients with Arterial Occlusive Disease A. Creutzig, L. Caspary, and K. Alexander Abteilung Angiologie, Medizinische Hochschule Hannover
Summary. Prostaglandin Ea is offered as a new therapeutic agent in the treatment of severe peripheral arterial occlusive disease. Especially when treating patients with ulcers or gangrene, the oxygen tension of the skin should improve during PGE~ administration. The new technique of assessing skin surface oxygen pressure histograms allows study of the skin microcirculation in vivo. Oxygen histograms were determined on the forefeet of 19 patients with different degrees of disease and different occlusion levels before and during a single intraarterial infusion of PGE1 at a dosage of 1.5ng/kg body weight/min. Only 9 patients showed improvement during the infusion period. Skin oxygen pressure was increased to a large extent only in patients assumed to suffer from diabetic microangiopathy. The effect of a long-term therapy with PGEt on skin microcirculation remains to be settled. Key words: Skin surface oxygen pressure fields - Skin microcirculation - Diabetic microangio-
pathy - Arterial occlusive disease - Prostaglandin E1
Prostaglandin E1 (PGE1) has some pharmacological properties that may be of benefit in the treatment of peripheral arterial occlusive disease. It is a strong vasodilator, inhibits aggregation of platelets, and influences the metabolism of the ischemic skeletal muscle by switching from oxydation of fatty acids to glucose oxydation [5, 13]. Intraarterial therapy has been proven to be effective in some clinical trials with patients with peripheral arterial Abbreviations: PGE~ =prostaglandin E~; TcPO2=transcutan-
eous oxygen pressure
occlusive disease [1, 14]. Its efficacy was assumed to be caused by microcirculatory changes [5]. Our previous investigations could demonstrate an increase of muscle surface oxygen pressure of the gastrocnemius muscle of patients with severe arterial occlusive disease when treated with PGE1; during exercise calf muscle circulation measured by the xenon clearance technique was improved [5]. This investigation was initiated to study skin microcirculation during PGE1 therapy which seems to be of utmost importance in patients with ulcers or gangrene. We used a new technique in assessing skin microcirculation by establishing oxygen pressure fields. Patients and M e t h o d s
Nineteen patients (2 female, 17 male) with peripheral arterial circulation disorders of the lower limbs aged between 32 and 80 years (average 58.8 years) were studied. The patients were treated in our angiological division because of severe claudication with maximal walking distances under 100 m (stage II according to Fontaine [I0], n = 5) or ulcers or gangrene of the toes (stage IV, n = 14) but without edema or infections of the forefoot (Table 1). Ten patients had diabetes and were treated with insulin or oral antidiabetics. Nine patients were smokers, 6 were treated with antihypertensive drugs (nifidepine, diuretics), and 4 had hyperlipoproteinemia treated dietetically (Table 1). Fourteen patients underwent angiography; in 7 patients the superficial femoral artery and one to three calf arteries were occluded, whereas the deep femoral artery was patent (type 1, Table 1). Their mean ankle pressure was 51 mmHg, mean brachiopedal pressure gradient (systolic pressure of the brachial artery minus systolic pressure of the posterior tibial artery) was 68 mmHg. In 7
A. C r e u t z i g et al. : P r o s t a g l a n d i n E l a n d Skin Surface O x y g e n Pressure H i s t o g r a m s
208 Table 1. P a t i e n t s ' d a t a Patient
Sex
Age
Stage
Type
dm
nic
hl p
hypt
AP
BP-AP
Result
1 2 3
Male Male Male
60 65 78
II II II
1 1 1
+
+ + -
-
+
90 60 Mediascl
40 65
NR R R
4 5
Female Male
45 58
II II
2 2
-
+ +
+ -
+
85 65
45 70
NR NR
6 7 8 9
Male Male Male Male
67 44 36 62
IV IV IV IV
1 1 1 1
+ -
+ + +
+ -
+
20 55 60 20
95 75 50 80
NR NR NR NR
10 11 12 13 14
Male Female Male Male Male
44 80 67 78 62
IV IV IV IV IV
2 2 2 2 2
+ + +
+ +
+ + -
+ + + -
40 80 100 115 50
80 80 60 45 80
R NR R R NR
15 16 17 18 19
Male Male Male Male Male
50 48 52 74 48
IV IV IV IV IV
3 3 3 3 3
+ + + + +
-
-
-
Mediascl 120 160 160 145
0 0 0 0
R R R R NR
Stage of disease ( F o n t a i n e ) : II i n t e r m i t t e n t c l a u d i c a t i o n , IV ulcer or g a n g r e n e ; t ype of o c c l u s i o n : 1 superficial f e m o r a l a r t e r y a n d o ne to th ree calf arteries, 2 one to three calf arteries, 3 no m a j o r arteries o c c l u d e d ; d m : d i a b e t e s m e l l i t u s ; nic: n i c o t i n e c o n s u m p t i o n , ; hlp: h y p e r l i p o p r o t e i n e m i a ; h y p t : h y p e r t e n s i o n ; A P : systolic a n k l e p r e s s u r e ( m m H g ) ; B P - A P : systolic b l o o d pr es s u r e m i n u s systolic a n k l e pressure ( m m H g ) ; m e d i a s c l : no pre s s ure m e a s u r e m e n t possible b e c a u s e o f m e d i a s c l e r o s i s ; R : r e s p o n d e r : significan t c h a n g e o f PO2 h i s t o g r a m w i t h increase o f m e d i a n PO2 d u r i n g P G E 1 i n f u s i o n ( P < 0 . 0 5 ) ; N R : n o n r e s p o n d e r : no sig nifican t c h a n g e d u r i n g i n f u s i o n p e r i o d
cases both thigh arteries were patent and one to three calf arteries occluded (type 2, Table 1).Their mean ankle pressure was 91 m m H g and mean brachiopedal pressure gradient 54 mmHg. In 5 diabetics oscillographic examinations of the limbs and pulse wave recordings of the toes were normal; their mean ankle pressure was 146 m m H g and mean brachiopedal pressure gradient was zero; they were assumed to have no occlusions of larger arteries and to suffer from diabetic microangiopathy (type 3, Table 1). Transcutaneous oxygen pressure (tcPO2) measurements have been recognized as a useful tool in characterizing skin microcirculation of patients with chronic arterial occlusive disease [7]. In order to standardize the investigation procedure most studies were undertaken with maximal vasodilatation due to hyperemization by an electrode core temperature of 44 ~ C. The reproducibility of these measurements was excellent [7]. However, in the state of maximal hyperemia pathophysiological or pharmacological studies could be performed only to a small extent. That is why we tried to study skin microcirculation at a moderate hyperthermia with an electrode core temperature of 37 ~ C where reagibility of skin capillaries is still present so that drug-induced changes of skin capillary flow can
be recorded [7]. However, with a single t c P O 2 (37 ~ C) measurement skin microcirculation is not sufficiently characterized; the reproducibility is poor. Corresponding to muscle surface oxygen pressure fields assessment of skin oxygen histograms proved to be useful to give a full and reproducible overview of local microcirculation [8]. To determine skin surface oxygen pressure fields we simultaneously used four commercially available tcPO2 electrodes (TCM 2, Radiometer, Copenhagen, Denmark) with a platinum electrode of 25 gm in diameter covered by a polypropylene membran. The room temperature was kept constant at 220-23 ~ C. The electrodes were calibrated by 20.9% oxygen. The subjects who had been asked not to smoke on the day of the examination were in a comfortable supine position. Five adhesive rings to fit the electrodes in were fixed on the forefoot in a circle with a diameter of about 7 cm. The electrodes were put in four of the rings; after reading their PO2 values which took about 5 min all electrodes were changed into the next rings by moving clockwise (Fig. 1); this procedure was repeated until more than 50 PO2 values were obtained which took about 2 h. Then PGE1 was given into the femoral artery via an infusion pump. The dose was 1.5
A. Creutzig et al. : Prostaglandin E~ and Skin Surface Oxygen Pressure Histograms
209
The results are presented a s P O 2 frequency histograms for groups of patients. They were statistically analyzed using the Kolmogorov-Smirnov test which is independent of mean values [11].
Results
Blood pressure or heart rate were not altered by PGE1 infusions. The reaction of skin surface oxygen pressure during PGE1 administration was very inhomogeneous. In nine patients it increased during the infusion period (responder), in ten patients it was unchanged or decreased (nonresponder, Table 2). In the responder group the sum histogram initially was left-shifted to POz values close to zero. During PGE1 administration the distribution type changed significantly ( P < 0.01), the histogram got a more bell-shaped form, and the median P O 2 increased from 4 to 6 mmHg (Fig. 2 a, b). The initial histogram of the nonresponders, which did not differ from that of the responders, did not change throughout the infusion period. When dividing into subgroups four out of five patients with diabetic microangiopathy (type 3, Table 1) demonstrated a steep increase in skin oxygen pressure during PGE1 infusion. The initial histogram of the whole group was characterized by only a few values close to zero and a good proportion above 10 mmHg (Fig. 3 a). Their median POz was 5 mmHg (Table 2). When infusing PGEa the histogram was shifted to the right; now even PO2 values above 20 mmHg could be found (Fig. 3b). Median POz rose up to 10 mmHg ( P < 0.001). The group of diabetics with occluded major arteries had only a slight but not significant increase of P O 2 . In patients without diabetes it even
Fig. 1. Simultaneous assessment of trancutaneous oxygen pressure by means of four electrodes fixed to the forefoot
ng/kg body weight/min according to our recommendation for clinical use [5]. It was dissolved in 50 ml sodium chloride. During the infusion period skin P O 2 measurements were repeated. Blood pressure and heart rate were determined before and at the 10th min of PGE~ infusion and at the end of the infusion period.
Table 2. Data of skin surface sum histograms from the forefeet before and during PGE1 infusion stratified to response, diabetes, stage of disease, and occlusion level (values in mmHg) Before P G E I
Responder ( n = 9 ) Nonresponder (n = 10) Diabetic microangiopathy ( n = 5 ) Diabetic macroangiopathy (n = 5) Macroangiopathy without diabetes (n = 9) Stage II ( n = 5 ) Stage IV (n = 14) Thigh/calf occlusion (n = 7) Calf occlusion ( n = 7 )
During PGE1
n*
Mean
SD
Median
627 756 479 350 554
4.2 4.4 5.6 3.2 5.3
3.2 3.1 3.5 3.2 3.0
4 4 5 2 5
369 1014 461 443
4.1 4.3 3.7 5.1
2.7 3.1 2.9 3.1
4 4 3 5
n*
Mean
SD
Median
P
