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Obstetrics & Gynecology 2001;98:313-318
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Skin Flux During Reactive Hyperemia and Local Hyperthermia in Patients With Preeclampsia

Ernst Beinder, MD and Dietmar Schlembach, MD

From the University Hospital of Erlangen/Nuremberg, Department of Obstetrics, Erlangen, Germany.

Address reprint requests to: Ernst Beinder, MD, University of Erlangen/Nuremberg, Department of Obstetrics and Gynecology, Universitätsstr. 21-23, 91054 Erlangen, Germany; E-mail: ernst.beinder{at}gyn.med.uni-erlangen.de.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To test the contribution of the endothelium to the maximum vasodilatation in patients with preeclampsia and healthy pregnant controls.

METHODS: Laser-Doppler flowmetry, which is a noninvasive method for the continuous measurement of skin blood flow, was used to test the response of skin microcirculation to the above-mentioned stimuli in 14 patients with preeclampsia and 20 normotensive pregnant controls.

RESULTS: In normotensive pregnant controls, the reactive hyperemic response after a 3-minute ischemia in the forearm reaches values of 77 ± 16% of the maximum vasodilatation, which was induced by local hyperthermia of 42C. In patients with preeclampsia, this response was significantly (P < .05) reduced (43 ± 9%).

CONCLUSION: Vascular reactivity is altered in skin vessels of patients with preeclampsia in vivo. This alteration seems to be attributable mainly to the endothelium.

The main hemodynamic characteristic of preeclampsia is vascular dysfunction with the consequence of altered vascular reactivity, proteinuria and, in advanced disease, marked increase in peripheral vascular resistance.1,2 Endothelial dysfunction with an imbalance of vasodilating and vasoconstricting factors was found to play a major part in altered vascular reactivity in preeclampsia,3,4 and underlying maternal vascular diseases and genetic factors may confer susceptibility.5,6 Moreover, central nervous influences, such as enhanced sympathetic activity, are reported in preeclampsia and may cause or enhance vasoconstriction.7

It remains uncertain as to what extent vascular dysfunction in preeclampsia is a result of endothelial dysfunction, central nervous influences, local neuronal defects, myogenic impairment, or microangiopathy.

The hyperemic response to an ischemic block is thought to primarily reflect endothelial function and is mediated mainly by the release of nitric oxide and prostacyclin from the endothelium.8–12 The hyperemia caused by local hyperthermia, however, is an intrinsic property of cutaneous vascular smooth muscles and results both from relaxation of sympathetic tone and active neurogenic vasodilatative mechanisms.13–16 The ratio of vasodilatation after ischemia and vasodilatation after heating therefore gives an estimate of the endothelium-dependent contribution in the maximum vasodilatory reserve of vessels. It was the aim of our study to test in vivo the contribution of the endothelium in vascular dysfunction in preeclampsia.


   MATERIALS AND METHODS
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ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
During a 6-month period, 20 consecutive patients with preeclampsia, who were otherwise healthy, and 20 normotensive pregnant controls matched for gestational age were asked to participate in the study. The criteria for preeclampsia were diastolic blood pressure (BP) over 90 mmHg (Korotkoff V) and systolic BP over 140 mmHg in two measurements at least 4 hours apart occurring after the 20th week of pregnancy, which subsequently regressed after delivery and proteinuria of over 300 mg per day. The clinical details of the patients are given in Table 1Go.


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  		Table 1. Clinical Characteristics of the Control and Study Group
 
All patients with preeclampsia agreed to participate in the study. Three of the preeclamptic patients received antihypertensive treatment with dihydralazine or metoprolol. The medication was discontinued on the day before the measurements. Therefore, the interval between the last dose of these drugs and the microcirculatory study was at least 12 hours in all cases. Three of the healthy controls received thyroxin, which should not interfere with the microcirculatory measurements because all of these controls were euthyreotic. No medication other than iron, vitamins, and minerals was taken regularly by the other women in the study and the control groups.

The patients with preeclampsia were recruited from the perinatal ward of the University Hospital of Erlangen-Nuremberg. The healthy controls were outpatients who came to our hospital for routine prenatal care. Only patients and controls with singleton pregnancies and without a history of diabetes, angiopathy, and autoimmunopathy were included in the study. Six patients with preeclampsia had to be excluded from the study because blood pressure after delivery did not regress to normal values.

The study protocol was approved by the local ethic committee of the University of Erlangen-Nuremberg, and all the women gave informed consent.

The patients were examined between 9 AM and noon. Before study, they were allowed 20 minutes to acclimatize to room temperature of 21–23C in a recumbent, comfortable position. Forearm blood flow was measured noninvasively using a laser-Doppler flowmeter (MBF3D Laser Blood Flow Monitor, Moor Instruments, Axminster, England). The blood flow recordings are based on the Doppler effect.17 Light from a He-Ne Laser ({lambda} 810 nm) is applied to the skin via a flexible fiberoptic cable and irradiates the tissue. In the measurement area, this light is reflected both by fixed tissue structures and moving particles. The reflected light, which consists of a mixture of shifted and nonshifted frequencies, is transmitted back via a flexible fiberoptic cable to the laser-Doppler photodiode, amplified and transformed into an analog signal. Signal deflection is proportional to mean velocity and number of erythrocytes in a measurement volume of approximately 1 mm,3 making it possible to record flow changes not only in capillaries but also in arteriovenous shunt vessels of the skin. The measurement is not influenced by underlying muscle blood flow.18 The entire spectrum of reflected frequencies is in the range of 0–8 kHz. Quantification of the measurement signal in absolute blood flow values is not possible with this method because neither the vessel density in the measurement area nor the hematocrit in the target vessels is known. Because of the low weight of the probe and the low energy of the laser, an influence of the probe on skin microcirculation in the area under investigation can be excluded.

The output of the He-Ne laser is 3 mW, which, as we found using a high sensitivity thermography camera with a temperature resolution of 0.07C, has no detectable warming effect on the skin. Our measurements were performed in the forearm where the skin volume under investigation contains both subepidermal capillaries and skin arterioles, and the main function of skin blood flow is nutritive. In other skin areas, such as the palmar hand or fingertips, however, where the skin perfusion serves primarily thermoregulatory purposes, arteriovenous shunt blood flow predominates and enormous functional differences in comparison with other skin areas exist. Reactive hyperemia, for example, is abolished in the skin of the fingertip in normotensive pregnant patients in most cases.19

To investigate the response of skin blood flow to local hyperthermia of 42C, the laser-Doppler probe was incorporated in a thermostatically controlled heater coil with a diameter of 3 cm, which could be fixed onto the skin of the forearm by double adhesive tapes. A BP cuff was applied to the upper arm. During the entire investigation period, the laser-Doppler curve was recorded on a multichannel recorder at a paper speed of 6 cm/min. The recordings (laser-Doppler flux) were expressed in arbitrary units (AU) because the signal cannot be expressed in terms of quantitative blood flow. The arbitrary units correspond to the voltage of the analog signal of the laser-Doppler flowmeter with the zero value corresponding with the blood flow value during arterial occlusion. The recording was considered acceptable when pulse-synchronous signals were clearly detectable and the peak flow during reactive hyperemia and local hyperthermia was not disturbed by the patient’s movements.

After a 10-minute baseline period, ischemia in the forearm was induced by a BP cuff, which was inflated to 50 mmHg above the subject’s systolic BP for 3 minutes. Then the BP cuff was released and the reactive hyperemia recorded until the preischemic baseline value was restored. Hyperthermia was induced by the heater coil with the integrated laser-Doppler probe, which was heated to 42C. The recording was continued until a maximum value was reached.

For analysis, the maximal peak flux during reactive hyperemia and local hyperthermia was measured on the recording. The ratio between peak flux during reactive hyperemia and local hyperthermia was calculated as a measure of the contribution of the endothelium in maximum vasodilatation.

A representative recording of blood flow changes during reactive hyperemia and local hyperthermia of the skin of the forearm in a normotensive pregnant control is shown in Figure 1Go. On the left side of the recording, the blood flow during arterial occlusion, which is near zero, is shown. The arterial occlusion is induced by a BP cuff around the upper arm, which is inflated to a suprasystolic pressure. After release of the BP cuff, the blood flow increases to a maximum value (peak flux during reactive hyperemia) and afterwards decreases again to the basal blood flow level. Local warming of the surroundings of the probe to 42C induces a second blood flow increase to a maximum value (peak flux during local warming). The magnitude of the peak flux value is given in AU in relation to the zero-flow during arterial occlusion.



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  		Figure 1. Representative recording of laser-Doppler flux during reactive hyperemia and local hyperthermia in a normotensive pregnant woman (AU = arbitrary units).

Beinder. Vascular Reactivity in Preeclampsia. Obstet Gynecol 2001.

 
The Mann-Whitney U test was applied to test differences between the two groups of healthy pregnant controls and women with preeclampsia. Differences were considered significant with P < .05. In cases where no significant difference was found, the power of the test to detect significant differences was evaluated. The graphic data are presented with box-plots, showing the median, the 10th, 25th, 75th, and 90th percentile of the data distribution. Circles represent values over the 90th or below the 10th percentile. The Fisher exact test was used to test differences of nominal data in Table 1Go. Values in Table 1Go are presented as means ± standard deviations.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The group with preeclampsia did not differ significantly from the controls with respect to gestational age, weight, hematocrit, and number of primigravidae, but was younger (30.8 ± 5.2 compared with 34.9 ± 4.7 years) (Table 1Go). The normotensive pregnant women had a mean arterial pressure of 87.4 ± 8.7 mmHg, which was, as expected, significantly lower than that in the group of patients with preeclampsia (118.4 ± 9.6 mmHg). Seven patients with preeclampsia had blood flow abnormalities measured by Doppler ultrasound (defined as a pulsatility index over 97th percentile) either in the uteroplacental circulation (n = 4), the fetoplacental circulation (n = 2), or in both (n = 1) (Table 1Go).

The variability of the absolute flux values during reactive hyperemia and local hyperthermia is high, both in the group of preeclamptic patients (coefficient of variation is 60% for reactive hyperemia and 50% for local hyperthermia) and healthy controls (coefficient of variation is 27% for reactive hyperemia and 33% for local hyperthermia). The peak flux value during reactive hyperemia was slightly higher in normotensive pregnant women, but the difference was not significant (17.1 ± 4.7 AU compared with 13.7 ± 8.2 AU) (Figure 2Go). The peak flux value during local hyperthermia was higher in patients with preeclampsia, but again the difference was not significant (30.6 ± 15.4 AU compared with 23.0 ± 7.7 AU) (Figure 2Go). Because of the small sample size, the power of the test to detect significant differences was small (40% for reactive hyperemia and 42% for local hyperthermia).



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  		Figure 2. Peak laser-Doppler flux values in the skin of the forearm during reactive hyperemia and local hyperthermia (AU = arbitrary units).

Beinder. Vascular Reactivity in Preeclampsia. Obstet Gynecol 2001.

 
More importantly, the coefficient of variation decreased to 21% both in preeclamptic patients and healthy controls, when the ratio of peak flux during reactive hyperemia and local hyperthermia was calculated. This ratio was significantly higher in pregnant controls compared with patients with preeclampsia (0.77 ± 0.16 compared with 0.43 ± 0.09) (Figure 3Go).



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  		Figure 3. Ratio between peak flux during reactive hyperemia and local hyperthermia in the study and control group. The difference is statistically significant (P < .05).

Beinder. Vascular Reactivity in Preeclampsia. Obstet Gynecol 2001.

 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Gant et al demonstrated that vascular reactivity in patients with preeclampsia is altered in comparison with healthy pregnant controls even before the onset of the disease.20 In the meantime, altered vascular reactivity in preeclamptic patients was demonstrated in many in vitro studies using isolated umbilical and maternal vessels in organ chambers or animal models with induced conditions resembling preeclampsia.2,21 However, there are very few in vivo studies with respect to the control of vascular reactivity in preeclamptic patients compared with normal pregnancy. Moreover, most of these in vivo studies give no information on vascular reactivity in circumscript vascular beds because they measure blood flow in the whole body (eg, with the angiotensin-II sensitivity assay) or in a whole extremity (eg, with plethysmography).

In our study, we evaluated two different microcirculatory responses in every patient. Reactive hyperemia is mainly controlled by the endothelium, whereas local heating abolishes completely the cutaneous vascular smooth muscle tone independent of the presence of endothelium.22,23 Strong experimental evidence in the literature suggests that cutaneous vasodilatation is at its maximal level when skin temperature is at or above 42C,16,22 the temperature used in our study. Neither the absence of sympathetic tone nor the direct relaxation of the smooth muscle with a nitric oxide donor nor a 10-minute tourniquet ischemia induces greater vasodilatation.22,23

The postischemic reactive hyperemia results mainly from the release of endothelium-derived relaxing factors and by the stimulation of adenin-triphosphate-sensitive potassium channels.8–12 Nitric oxide, the most important endothelium-derived relaxing factor, contributes to all phases of reactive hyperemia including the peak velocity in normal human peripheral vasculature.10,11 Prostaglandins appear to be important factors in peak flow. Prostaglandins and nitric oxide together potentiate their vasodilatory functions in reactive hyperemia.9

In our study, we calculated the ratio of the peak flux after ischemia and during local hyperthermia to evaluate vascular reactivity. This ratio gives an estimate of the contribution of the endothelium to the maximum vasodilatory reserve of vessels. We found that normotensive pregnant subjects had a reactive hyperemia response nearly as pronounced as the maximal vasodilatation of these vessels induced by local heating. In patients with preeclampsia, however, reactive hyperemia reached only half of the maximal vasodilatory capacity. This result suggests impaired endothelium-dependent vasodilatation in small subcutaneous vessels in vivo in preeclampsia.

In vitro data on isolated vessels from patients with preeclampsia describe rather uniformly a reduced endothelium-dependent vasodilatation in comparison with vessels from normal pregnant controls. Cockell and Poston demonstrated with myography in isolated small subcutaneous arteries from healthy pregnant women that flow-mediated vasodilatation, which is endothelium-dependent, is reduced in preeclampsia.24 Other authors confirmed a decrease in endothelium-dependent relaxation in subcutaneous fat resistance vessels25 and isolated myometrial resistance arteries26 in patients with preeclampsia. Pascoal et al have shown that acetylcholine, but not bradykinin, is ineffective to induce vasodilatation in resistance-size omental arteries in patients with preeclampsia.27 Because both acetylcholine and bradykinin dilate vessels by the stimulation of endothelial nitric oxide production, a specific receptor-defect in the endothelium-dependent vasorelaxation in these vessels was suggested.27

There are only few and contradictory in vivo studies on vascular reactivity in preeclampsia. Anumba et al28 and Eneroth-Grimfors et al29 found no difference, whereas Yoshida et al30 and Foong et al31 demonstrated changes in vascular reactivity between preeclampsia and normal pregnancy.

These discrepancies might result from different methods used for the measurement of blood flow in these studies. Forearm plethysmography, which was used by Anumba et al,28 is a method to register absolute blood flow volumes, but it does not provide continuous measurements, which are critical in early phases of reactive hyperemia, when flow changes rapidly. Another drawback of plethysmography is the fact that it is not possible to distinguish between reactive hyperemia in skin-, muscle- or bone-microcirculation. Iontopheresis, which was used by Eneroth-Grimfors et al29 to induce blood flow changes, is difficult to apply in a standardized manner. High-resolution sonography and Doppler sonography30 can measure blood flow only in larger vessels but not in the resistance arteries, which are the main target of the disease in preeclampsia.

A drawback of laser-Doppler flowmetry, which was used in our study, is the fact that absolute blood flow measurements are not possible. However, this method is noninvasive and measurements can be performed in well-defined, circumscribed vascular beds. The application of different stimuli in the same person allows the separate evaluation of muscular and endothelial factors in vascular reactivity.


   Footnotes
 
Supported by Deutsche Forschungsgemeinschaft (DFG, Be 1119/2-1).

PII S0029-7844(01)01456-9

Received January 4, 2001. Received in revised form April 25, 2001. Accepted May 4, 2001.


   REFERENCES
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Groenendijk R, Wallenburg H. Hemodynamic measurements in preeclampsia: Preliminary observations. Am J Obstet Gynecol 1984;150:232–6.[Medline]

2. Vedernikov Y, Saade GR, Garfield RE. Vascular reactivity in preeclampsia. Semin Perinatol 1999;23:34–44.[Medline]

3. Roberts JM, Redman CWG. Preeclampsia: More than pregnancy-induced hypertension. Lancet 1993;341: 1447–51.[Medline]

4. Baylis C, Beinder E, Sü tö T, August P. Recent insights into the roles of nitric oxide and renin-angiotensin in the pathophysiology of preeclamptic pregnancy. Semin Nephrol 1998;18:208–30.[Medline]

5. Caritis S, Sibai B, Hauth J, Lindheimer M, VanDorsten P, Klebanoff M, et al. Predictors of preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine. Am J Obstet Gynecol 1998;179:946–51.[Medline]

6. Dekker GA, de-Vries JI, Doelitzsch PM, Huijgens PC, von-Blomberg BM, Jakobs C, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–8.[Medline]

7. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Preeclampsia—a state of sympathetic overactivity. N Engl J Med 1996;335:1480–5.[Abstract/Free Full Text]

8. Bannit PF, Smits P, Williams SB, Ganz P, Creager MA. Activation of ATP-sensitive potassium channels contributes to reactive hyperemia in humans. Am J Physiol 1996; 271:H1594–8.

9. Engelke KA, Halliwill HR, Proctor DN, Dietz NM, Joyner MA. Contribution of nitric oxide and prostaglandins to reactive hyperemia in the human forearm. J Appl Physiol 1996;81:1807–41.[Abstract/Free Full Text]

10. Meredith IT, Currie KE, Anderson TJ, Roddy MA, Ganz P, Creager MA. Postischemic vasodilatation in human forearm is dependent on endothelium-derived nitric oxide.Am J Physiol 1996;270:H1435–40.

11. Dadak N, Husain S, Mulcahy D, Andrews NP, Panza JA, Waclawiw M, et al. Contribution of nitric oxide to reactive hyperemia: Impact of endothelial dysfunction. Hypertension 1998;32:9–15.[Abstract/Free Full Text]

12. Koller A, Kaley G. Role of endothelium in reactive dilatation of skeletal muscle arterioles. Am J Physiol 1990;259: H1313–6.

13. Kellogg DL, Liu Y, Kosiba IF, O’Donnell D. Role of nitric oxide in the vascular effects of local warming of the skin in humans. J Appl Physiol 1999;86:1185–90.[Abstract/Free Full Text]

14. Pergola PE, Kellogg DL, Johnson JM, Kosiba WA, Solomon DE. Role of sympathetic nerves in the vascular effects of local temperature in human forearm skin. Am J Physiol 1993;265:H785–92.

15. Saumet JL. Cutaneous vasodilation induced by local warming, sodium nitroprusside, and bretylium iontophoresis on the hand. Microvasc Res 1998;56:212–7.[Medline]

16. Taylor WF, Johnson JM, O’Leary D, Park MK. Effect of high local temperature on reflex cutaneous vasodilatation.J Appl Physiol 1984;57:191–6.[Abstract/Free Full Text]

17. Nilsson GE, Tenland T, Ö berg PA. Evaluation of a laser-Doppler flowmeter for measurement of tissue flood flow. IEEE Trans Biomed Eng BME 1980;27:597–604.

18. Saumet JL, Kellogg DL, Taylor WF, Johnson JM. Cutaneous laser-Dopper flowmetry: Influence of underlying muscle blood flow. J Appl Physiol 1988;65:478–81.[Abstract/Free Full Text]

19. Beinder E, Lang N. Veränderung der mikrozirkulato-rischen Reaktivität bei Patientinnen mit Gestose. Geburtsh u Frauenheilk 1994;54:268–72.

20. Gant NF, Daley GL, Chand S, Walley PJ, MacDonald PC.A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest 1973;52:2682–9.

21. Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Physiol 1997;272:R441–63.

22. Savage MV, Brengelmann GL. Reproducibility of the vascular response to heating in human skin. J Appl Physiol 1994;76:1759–63.[Abstract/Free Full Text]

23. Johnson JM, O’Leary D, Taylor WF, Kosiba W. Effect of local warming on forearm reactive hyperemia. Clin Physiol 1986;6:337–46.[Medline]

24. Cockell AP, Poston L. Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia. Hypertension 1997;30:247–51.[Abstract/Free Full Text]

25. McCarthy AL, Woolfson RG, Raju SK, Poston L. Abnormal endothelial cell function in resistance arteries from women with preeclampsia. Am J Obstet Gynecol 1993; 168:1323–30.[Medline]

26. Ashworth JR, Warren AY, Baker PN, Johnson IR. Loss of endothelium-dependent relaxation in myometrial resistance arteries in preeclampsia. Am J Obstet Gynecol 1997; 104:1152–8.

27. Pascoal IF, Lindheimer MD, Nalbantian-Brandt C, Umans JG. Preeclampsia selectively impairs endothelium-dependent relaxation and leads to oscillatory activity in small omental arteries. J Clin Invest 1998;101:464–70.[Medline]

28. Anumba DO, Robson SC, Boys RJ, Ford GA. Nitric oxide activity in the peripheral vasculature during normotensive and preeclamptic pregnancy. Am J Physiol 1999;277: H848–54.

29. Eneroth-Grimfors E, Lindblad LE, Westgren M, Ihrman-Sandahl C, Bevegard S. Noninvasive test of microvascular endothelial function in normal and hypertensive pregnancies. Br J Obstet Gynaecol 1993;100:469–71.[Medline]

30. Yoshida A, Nakao S, Kobayashi H, Kobayashi M. Noninvasive assessment of flow-mediated vasodilatation with a 30-MHz transducer in pregnant women. Hypertension 1998;31:1200–1.[Free Full Text]

31. Foong LC, Chong YS, Chua S, Johnson P, De Swiet M.Impaired vasoconstriction in pregnancy-induced hypertension assessed using Doppler fluximetry. Obstet Gynecol 2000;95:491–5.[Abstract/Free Full Text]




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