Ephedrine, a mixed α-adrenergic and β-adrenergic agonist,1 and phenylephrine, a pure α-1-adrenergic agonist,2 are both effective in counteracting vasoplegia induced by spinal anaesthesia. Although changes in skin blood flow (SBF) induced by sympathetic blockade have been studied, the effects of these two vasopressors have not yet been described in the setting of spinal anaesthesia.
Patients and methods
With Clinical Research Ethics Committee approval and written informed consent, 20 American Society of Anesthesiologists (ASA) status I–II adult patients scheduled for elective surgery under spinal anaesthesia were enrolled in this prospective, randomised, double-blind study. Neurologic and cardiovascular diseases, diabetes, autonomic dysfunction, treatment with β-blocking or vasoconstricting agents and pregnancy were all considered as exclusion criteria.
After oral premedication with 7.5 mg of midazolam, patients were installed in the operating room and standard monitoring was applied. While quiet and motionless, in the supine position, the patient's arterial blood pressure was measured once by the automatic non-invasive monitor, and this value was defined as the baseline blood pressure. An intravenous (i.v.) preload of 500 ml Lactated Ringer's solution was then started and spinal anaesthesia was delivered in the lateral jack-knife position. Hyperbaric 0.5% bupivacaine (12.5–15 mg) was injected intrathecally over 20 s. The patient was then placed in the supine position and his arterial pressure measured at intervals of 1 min. Dermatomal sensory block was assessed at 10, 30 and 60 min. As soon as mean arterial blood pressure decreased by 10% from baseline, an i.v. bolus dose of ephedrine 7.5 mg or phenylephrine 75 μg was injected by the anaesthetist in charge, who was unaware of the vasopressor administered. This procedure was repeated if necessary. SBF was assessed by a non-invasive dual-channel laser Doppler (Periflux PF-4001; Perimed, Stockholm, Sweden) flowmetry technique.3 To avoid blood flow changes induced by skin temperature variations, local warming was performed. One laser probe was positioned on one forearm and the second one in an area under spinal anaesthesia blockade (upper part of the thigh), both in glabrous skin areas. The continuous laser Doppler flowmeter signal expressing blood flow in arbitrary perfusion units was analysed by the Perisoft software (Perimed).
Mean SBF was averaged during 1 min before spinal anaesthesia (baseline value), 20 min after completion of spinal anaesthesia, then immediately before vasopressor injection and finally a few minutes (at maximal effect on SBF) after the injection of a vasopressor. To avoid the possible effects of cumulative doses, only the first administration of vasopressor was analysed.
Cutaneous vascular conductance (CVC) was calculated as mean SBF divided by mean arterial pressure. We calculated for each patient the ‘variation of perfusion’ as follows:
Data are expressed as mean (SD) unless stated otherwise. Demographic, haemodynamic and SBF characteristics of both groups were compared by using Fisher's exact test and unpaired Student's t-test when appropriate. An analysis of variance for repeated measures in the same participants followed by Bonferroni correction was used to identify differences within the two groups.
Patients' characteristics and dermatomal sensory levels after spinal anaesthesia are presented in Table 1. All patients received 12.5 mg of hyperbaric bupivacaine, except one in the phenylephrine group who received 15 mg. All patients required administration of vasopressor. Haemodynamic variables, mean SBF measured before and 20 min after spinal anaesthesia in the forearm and in the thigh, along with calculated CVC show no differences between the two groups (Tables 2 and 3).
In the phenylephrine group, the perfusion variation is increased following spinal anaesthesia by 105% (150%) [mean (SD)] at the upper limb and by 75% (55%) at the lower limb; in the ephedrine group, the perfusion variation is increased by 34% (74%) and 78% (56%), respectively. There are no differences between groups.
When considering the variation of perfusion [mean (SD)], phenylephrine shows an increase in the upper and lower limbs by 44% (79%) and 34% (24%), respectively. After ephedrine injection, the decrease of SBF in the upper and lower limbs was 16% (15%) and 22% (11%), respectively. When we compare them (Fig. 1), the variation of perfusion in both limbs between ephedrine and phenylephrine injections is significant (P < 0.05).
The effect of the administration of vasopressor on the mean arterial pressure is presented in Fig. 2.
Our study shows that an i.v. bolus of phenylephrine increases the SBF, whereas ephedrine decreases it, without any influence of the sympathetic blockade.
These findings could be explained by the distribution of the α-adrenoreceptor subtypes, and their relative predominance, among veins and arteries of different sizes in the subcutaneous tissue and in the skin.
Postjunctional α-2 adrenoreceptors are predominant over the α-1 adrenoreceptor subtype in human subcutaneous resistance arteries.4 Vasoconstricting postjunctional α-2 adrenoreceptors contribute more to basal vascular tone than α-1 adrenoreceptors.5 Therefore, ephedrine is a potent subcutaneous arterial vasoconstrictor.
Phenylephrine, a pure α-1-adrenergic agonist, is known to constrict mainly arterioles with a diameter larger than 110 μm.6 Because of their more prominent α-2 adrenoreceptor population, smaller skin arterioles do not respond to systemic infusion of phenylephrine.4 We can, therefore, postulate that phenylephrine administration, by its vasoconstrictive effect, reduces muscle blood flow, diverting it to the skin, where arterioles are less constricted. This hypothesis is only partly supported by our data, as we did not measure muscular blood flow.
A mixture of α-1 and α-2 adrenoreceptors has also been found in vein, with a functional predominance of α-2 adrenoreceptors.7 For this reason, ephedrine can increase the venous tone more than phenylephrine, contributing to a further decrease in SBF.
This study has several limitations. A single dosage of vasopressors was used; whether lower or higher doses would act similarly on SBF is unknown. As we did not have any previous data on the SBF variations induced by phenylephrine and ephedrine, we could not calculate an appropriate sample size for each group.
Further studies are needed for a better understanding of the physiology of blood flow regulation in the skin and other organs (placenta, kidney), in order to choose the most suitable vasopressor for clinical practice.
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