Phenylephrine versus EPhedrine on cerebral Perfusion during Carotid EndarteRectomy

Carotid endarterectomy (CEA) is the recommended treatment for patients with a
symptomatic high degree stenosis of the internal carotid artery (ICA). Besides
these symptoms, stenosis of the ICA jeopardizes the cerebral perfusion and may
affect cerebral autoregulation (CA), implicating that cerebral perfusion
becomes dependent of changes in blood pressure (BP).1 Therefore, to preserve
cerebral perfusion during surgery and to prevent *watershed* stroke,
intraoperative hypotension needs to be avoided and the suggested BP that should
be maintained intraoperatively is a systolic arterial pressure between normal
and 20% above baseline.2
To do so, different short-acting vasopressor agents can be used, such as
phenylephrine or ephedrine. If existing at all, preference for either of these
agents is purely based on a personal basis. Furthermore, both agents are
internationally accepted and, when heart rate is in the normal range, randomly
applied in cardiovascular surgery. Despite that the effect on blood pressure is
more or less identical, both agents have a different mechanism of action.
Phenylephrine (an *-agonist) increases BP by vasoconstriction, whereas
ephedrine (a combined *- and *-agonist) increases BP with a combination of
vasoconstriction and an increase in heart rate and therefore cardiac output.3
Besides this difference in systemic hemodynamics also the perfusion of the
brain react different. In healthy subjects, with intact CA, cerebral tissue
oxygenation decreases during phenylephrine administration while it is preserved
with ephedrine use.3, 4 It is suggested that the increase in cardiac output
observed during ephedrine use can explain this difference in cerebral
oxygenation.5 It is unknown how in status of impaired CA, as often observed in
patients undergoing a CEA, the cerebral vessels react on phenylephrine or
ephedrine. The optimal agent to maintain cerebral perfusion in CEA patients,
with an impaired CA is unknown. If during the use of one of the two agents
cerebral perfusion would be better maintained or even increase this would
clearly influence the choice for the optimal agent.

In our center during CEA, we routinely monitor rSO2 using near infrared
spectroscopy (NIRS) and middle cerebral artery blood velocity (VMCA). To study
the effect of both vasopressors on these parameters we have retrospectively
analysed the effect of phenylephrine and ephedrine induced changes in BP on
rSO2 and Vmca in 19 patients. We noticed that phenylephrine and ephedrine both
increased blood pressure and VMCA in patients undergoing carotid
endarterectomy. However, an increase in blood pressure induced by phenylephrine
has lowering effect on the cerebral perfusion, while ephedrine had an
increasing effect on the cerebral perfusion.
This pilot study indicated that the use of ephedrine should be preferred above
the use of phenylephrine for correction of hypotension during CEA. However, the
numbers of patients were small and the dose of agent applied not standardized.
Therefore a prospective study to analyze the effect of both ephedrine and
phenylephrine on cerebral perfusion during CEA is needed to make a
recommendation.

(1) Ederle J et al. Carotid artery stenting compared with endarterectomy in
patients with symptomatic carotid stenosis (International Carotid Stenting
Study): an interim analysis of a randomised controlled trial. Lancet 2010
20;375(9719):985-97.
(2) Stoneham MD et al. Arterial pressure management and carotid endarterectomy.
Br J Anaesth 2009 April;102(4):442-52.
(3) Dyer RA et al. Hemodynamic effects of ephedrine, phenylephrine, and the
coadministration of phenylephrine with oxytocin during spinal anesthesia for
elective cesarean delivery. Anesthesiology 2009 ;111(4):753-65.
(4) Nissen P. et al. Phenylephrine but not ephedrine reduces frontal lobe
oxygenation following anesthesia-induced hypotension. Neurocrit Care 2010
February;12(1):17-23.

Primary Objective:
Our primary objective is to study the influence of two routinely used drugs to
increase systemic blood pressure (phenylephrine and ephedrine) on cerebral
oxygenation and perfusion, estimated by changes in cerebral oxygenation (NIRS)
and middle cerebral artery blood velocity, in patient undergoing carotid
endarterectomy.

Secondary Objective:
To study whether the influence of phenylephrine and ephedrine on cerebral
perfusion and oxygenation is different between patients with and without an
adequate functioning cerebral autoregulation.

A prospective randomized trial in symptomatic patients undergoing CEA because
of a hemodynamically significant stenosis of the ICA.
Currently, the preference of administering either phenylephrine or ephedrine
for correction of relative intraoperative hypotension (which is required in
virtually all carotid procedures) is mainly based on physician*s preferences.
For this trial randomization will be performed preoperatively between these two
agents:
For this trial randomization will be performed peroperatively between 1)
phenylephrine (50-100 µg), or 2) ephedrine (5-10 mg), to increase blood
pressure.
If relative hypotension persists 5 minutes after administration of either
phenylephrine or ephedrine, the patient will classified as a non-responder and,
escape medication preferred by the anesthesiologist will be administered.
Before surgery all patients will be informed about the trial procedure and
written informed consent will be obtained from all patients.
As part of the standard of care for patients undergoing CEA in our hospital,
cerebral monitoring including transcranial Doppler (TCD), Near Infrared
Spectroscopy (NIRS) and electroencephalography (EEG) will be provided. To
quantify whether the intra-operative cerebral autoregulation is impaired or
not, the breathing frequency will be decreased from the normal 12 breaths per
minute to 6 breaths per minute for an episode of three minutes.

Medication
During surgery randomization will be performed for treatment with either
phenylephrine (50-100µg) or ephedrine (5-10mg) for correction of relative
hypotension after tracheal intubation.
Relative hypotension requiring intervention is defined as a decrease in mean BP
>20% of baseline BP (as reported on the nursing ward the day before surgery).

Measurements
As part of the standard of care a radial artery catheter is placed in each
patient for continuous blood pressure measurement and cerebral monitoring
including transcranial Doppler (TCD), Near Infrared Spectroscopy (NIRS) and
electroencephalography (EEG) will be provided.

Intervention:
To quantify whether the intra-operative cerebral autoregulation is impaired or
not, the breathing frequency is decreased from the normal 12 breaths per minute
to 6 breaths per minute for an episode of three minutes.

Phenylephrine and ephedrine are two of the most commonly used short acting
agents to increase blood pressure in clinical anesthesiologic practice.
Monitoring of middle cerebral artery blood velocity with TCD and frontal lobe
cerebral tissue oxygenation with NIRS are part of the standard of care.
Furthermore, there are no reports that the three minute modification in
breathing frequency described in the *intervention*-section is harmful.
Therefore risks for participating patients are negligible and the burden
minimal.