Effects of ephedrine, dobutamine and dopexamine on cerebral haemodynamics: transcranial Doppler studies in healthy volunteers

I. K. Moppett*,1, M. J. Wild2, R. W. Sherman2, J. A. Latter2, K. Miller3 and R. P. Mahajan1,2

1 University Department of Anaesthesia, Queen’s Medical Centre, Nottingham, UK. 2 Nottingham City Hospital, Nottingham, UK. 3 Medical School, Nottingham University, Nottingham, UK

*Corresponding author. E-mail: iain.moppett@nottingham.ac.uk

Accepted for publication: July 14, 2003


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Sympathomimetic drugs are assumed to have no direct effects on cerebral haemodynamics on the basis of animal experiments; there is little evidence of their direct effects in humans. This study aimed to address this issue.

Methods. The effects of ephedrine, dobutamine, and dopexamine on cerebral autoregulation, cerebral vascular reactivity to carbon dioxide, estimated cerebral perfusion pressure, and zero flow pressure (ZPF) were studied in 10 healthy volunteers using transcranial Doppler ultrasound. The strength of autoregulation was measured using the transient hyperaemic response test. The reactivity to carbon dioxide was measured as the change in middle cerebral artery flow velocity with a step change in end-tidal carbon dioxide. For the estimated cerebral perfusion pressure and the ZFP, established formulae were used which utilized instantaneous values of arterial pressure and middle cerebral artery flow velocity. Measurements were made at baseline and after i.v. infusion of the study drug to an endpoint of 25% increase in mean arterial pressure (MAP) (ephedrine, dobutamine) or cardiac index (dopexamine).

Results. There was no significant change in the strength of autoregulation (from (mean (SD)) 1.07 (0.16) to 1.07 (0.18); from 1.07 (0.16) to 1.03 (0.19); from 1.04 (0.12) to 1.04 (0.25)), reactivity to carbon dioxide (from 40% (8) to 36 (10); from 37 (12) to 37 (11); from 45 (12) to 43 (11)) with ephedrine, dobutamine, or dopexamine, respectively. Despite a clinically significant increase in MAP with ephedrine and dobutamine and a clinically significant increase in cardiac index with dopexamine, the estimated cerebral perfusion pressure did not change significantly (from 81 (38) to 60 (16) mm Hg with ephedrine; from 67 (22) to 63 (11) mm Hg with dobutamine; from 87 (27) to 79 (17) mm Hg with dopexamine). The ZFP increased significantly with ephedrine (from 29 (10) to 44 (11) mm Hg) and dobutamine (from 35 (14) to 43 (10) mm Hg) but not dopexamine (from 3 (23) to 11 (22) mm Hg).

Conclusions. Sympathomimetic agents do not significantly change cerebrovascular homeostasis as assessed by the transient hyperaemic response test, reactivity to carbon dioxide and estimated cerebral perfusion pressure.

Br J Anaesth 2004; 92: 39–44

Keywords: blood, flow, zero flow pressure; measurement techniques, transcranial Doppler; sympathetic nervous system, beta-sympathomimetic


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Sympathomimetic drugs are used widely in intensive care and anaesthesia to manipulate cardiovascular variables. Many of these patients have a disordered cerebral circulation either because of trauma,1 sepsis,2 sub-arachnoid haemorrhage,3 or pre-existing cerebrovascular disease.4 Although sympathomimetic drugs are assumed to have little direct effect on the cerebral circulation,57 the effects of these drugs on cerebral autoregulation, reactivity to carbon dioxide, estimated cerebral perfusion pressure and zero flow pressure (ZFP), as assessed by transcranial Doppler ultrasonography are not well documented. A knowledge of any such effects is important for judicious use of these drugs in patients with neurological disorders. Alteration of cerebrovascular tone can affect cerebral autoregulation8 and can also influence estimated cerebral perfusion pressure and ZFP;9 10 cerebral perfusion pressure may therefore be changed independently of changes in intracranial pressure.10 The overall effects of sympathomimetic agents are dependent on their balance of {alpha}, ß, and dopaminergic effects, and their mode of action. Before assessing the effects of these drugs in subjects with neurological disorders, it is first necessary to know what effect they might have in healthy subjects. In the present study, we aimed to assess the effects of clinically significant doses of ephedrine, dobutamine, and dopexamine, all commonly used, predominantly ß agonists, at steady state on cerebral autoregulation, reactivity to carbon dioxide, estimated cerebral perfusion pressure, and ZFP in healthy volunteers.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
To allow for the relative lack of pressor effect of dopexamine, two slightly different protocols were followed. Protocol A assessed the effects of ephedrine and dobutamine; protocol B assessed dopexamine.

The local Ethics Committee approved the study. All subjects were enrolled after giving informed, written consent. Subjects were healthy volunteers. Criteria for exclusion were:

age less than 18 yr or more than 40 yr;

history of hypertension (or measured arterial pressure >130/85 mm Hg) or neurological disease;

drugs—any vaso-active substances, for example calcium channel blockers, antidepressants;

history of migraine;

smokers;

pregnancy/potential pregnancy.

The 10 subjects for protocol A were different subjects to the 10 for protocol B as the studies were carried out on different sites. Subjects were studied in the supine position (protocol A) or sat at 45° (protocol B). Cerebral blood flow is not known to be influenced by position. The subjects sat up in protocol B for comfort and ease of positioning of the Doppler probe. Each subject lay with his or her head in a comfortable position on a pillow. The left middle cerebral artery was identified using standard criteria,7 via the subjects’ temporal window, using a 2 MHz pulsed transcranial Doppler ultrasonography probe (SciMed PCDop 842 (protocol A) and QVL (protocol B), SciMed, Bristol, UK). The position of the probe was held constant throughout the study by the application of a headband, to ensure a constant angle of insonation. The middle cerebral artery flow velocity waveform was recorded continuously onto digital audiotape for subsequent analysis using specific software (SciMed). Following application of a nose clip, constant end-tidal carbon dioxide monitoring was instituted via a mouthpiece connected to a capnograph (Datex Capnomac (protocol A) or Marquette (protocol B)). The arterial pressure was measured non-invasively at 1-min intervals for the duration of the test (Dinamap (protocol A) or Marquette (protocol B)). Further monitoring consisted of continuous pulse oximetry and electrocardiography. For protocol B, the cardiac index was determined using a trans-oesophageal Doppler probe (Deltex, Chichester) inserted nasally under local anaesthesia. All transcranial Doppler ultrasonography measurements were taken with the probe removed to avoid confounding effects of discomfort from the probe.

Middle cerebral artery flow velocity, cerebral autoregulation, reactivity to carbon dioxide, and arterial pressure were measured with the subject receiving no drug (baseline values) and then following titration of the drug to a predetermined cardiovascular endpoint. Each drug was studied on a separate day. For protocol A, the order of drug was chosen at random, and the endpoint was an increase in mean arterial pressure (MAP) of 25% above baseline values. For protocol B, dopexamine was titrated to an increase in cardiac index of 25% over baseline. The drugs were studied in an open label fashion as pilot studies had shown that subjects were likely to be aware of the drug infusion as a result of peripheral ß-stimulation leading to tremulousness. The starting infusion rate was 0.3 µg kg–1 min–1 for ephedrine, 1.25 µg kg–1 min–1 for dobutamine and 0.125 µg kg–1 min–1 for dopexamine. Each drug was titrated to the arterial pressure or cardiac index endpoint by increasing the rate of infusion every 2–5 min. Cerebral haemodynamic measurements were repeated only after achieving a steady state at the cardiac index or arterial pressure endpoint; steady state was defined as less than 5 mm Hg change in MAP on successive recordings or less than 0.1 litre min–1 m–2 change in cardiac index over 5 min.

Transcranial Doppler flow velocity measurements
Cerebral autoregulation. This was assessed by performing the transient hyperaemic response test. The details of this test have been described previously.1113 Briefly, it consists of compression of the common carotid artery ipsilateral to the insonated middle cerebral artery for 10 s and then sudden release; with intact autoregulation a transient hyperaemic response is seen at the release of compression.

The criteria for the acceptance of a transient hyperaemic response test were: (i) a sudden and maximal decrease in flow velocity at the onset of compression; (ii) stable heart rate for the period of compression; (iii) steady Doppler signal for the duration of compression; and (iv) absence of flow transients following release of compression.13 Two indices were calculated to assess autoregulation, the transient hyperaemic response ratio and the strength of autoregulation. Analysis was performed by selecting three waveforms from each period of compression: (i) the middle cerebral artery waveform immediately before compression, F1; (ii) the first waveform following compression, F2; and (iii) the waveform immediately following release of compression, F3.13

The time-averaged mean of the outer envelope of the flow velocity profile was used for performing the analysis.

The transient hyperaemic response ratio (THRR) was calculated as:

THRR=F3/F1(1)

The strength of autoregulation (SA) was calculated as:

SA=(F3xP2)/(MAPxF1)(2)

where, P2 is the greater value of either the estimated arterial pressure in the middle cerebral artery at the onset of common carotid artery compression, as calculated by:

P2=MAPxF2/F1(3)

or 60 mm Hg (the assumed lower limit of autoregulation). Details of the derivation of these formulae have been published previously.13 The strength of autoregulation is considered to be a better measure of autoregulation as it takes into account the variable decrease in perfusion pressure on compression as a result of (i) variable amounts of flow around the circle of Willis and (ii) incomplete occlusion of the carotid artery.

Reactivity to carbon dioxide. After baseline measurements of arterial pressure, end tidal carbon dioxide and middle cerebral artery flow velocity breathing room air, subjects were asked either to raise or lower their end tidal carbon dioxide. To lower the end tidal carbon dioxide, subjects were asked to increase the rate and depth of their breathing sufficient to reduce their end tidal carbon dioxide by 1 kPa from baseline. Once this had been achieved at steady state (1 min of lowered end tidal carbon dioxide) repeated measurements of arterial pressure, end tidal carbon dioxide and middle cerebral artery flow velocity were made. To raise end tidal carbon dioxide subjects breathed through a Mapleson D circuit with low flows of air and oxygen to allow a degree of re-breathing sufficient to increase end tidal carbon dioxide by 1 kPa. Again, once this had been achieved at steady state (1 min of raised end tidal carbon dioxide) repeated measurements of arterial pressure, end tidal carbon dioxide and middle cerebral artery flow velocity were made. The order of hypo- or hypercapnia was made at random. Subjects were allowed to breath room air to normalise their end tidal carbon dioxide between measurements. The reactivity to carbon dioxide was calculated as the percentage change of mean middle cerebral artery flow velocity per kPa change in end tidal carbon dioxide.13

Estimated cerebral perfusion pressure and ZFP. These were calculated using the method described by Belfort.14 Simultaneous measurements of arterial pressure and transcranial Doppler ultrasonography velocities were recorded. The estimated cerebral perfusion pressure, eCPP, was derived from:

eCPP=[MFV/(MFV – DFV)]x(MAP – DAP)14 15(4)

where, MAP and DAP are mean and diastolic arterial pressures, and MFV and DFV are mean and diastolic middle cerebral artery flow velocities.

ZFP was calculated using the following formula:

ZFP=MAP – eCPP14 15(5)

Statistics
The calculated range for strength of autoregulation in healthy volunteers is 0.88–1.12 with a coefficient of variation of less than 10% on repetitive measurements within the same subject.11 12 We calculated that 10 subjects would be required to detect an absolute difference of 0.15 in strength of autoregulation with a power of 0.8 and {alpha} of 0.05. This is a clinically relevant change of similar magnitude to that seen with impairment of autoregulation with inhalation anaesthetics.11 Post hoc testing indicated that the study had the same power to detect clinically significant differences in reactivity to carbon dioxide (30% relative change). Changes of up to 50% may be seen with high doses of anaesthetics,11 cerebrovascular disease,16 and traumatic brain injury.17

The data were tested for normality of distribution using the Anderson–Darling test. Cerebrovascular and cardiovascular variables were analysed using multivariate ANOVA comparing data before and after administration of each drug for each subject. Where the null hypothesis was rejected, significant differences between the means were analysed using Tukey’s test. All statistical analyses were performed using SPSS 11.0 for Windows. Control measurements were always from the period immediately preceding the administration of the study drug.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Subjects were aged between 22 and 38 yr. In protocol A, seven were males, three females: all were males in protocol B.

The endpoint of increase in MAP or cardiac index was reached in all subjects (Table 1). The oxygen saturation was greater than or equal to 98% for all subjects throughout the study. The median dose (range) of drug required was: ephedrine 30 (9–54) µg kg–1 min–1, dobutamine 12.5 (10–25) µg kg–1 min–1, dopexamine 0.25 (0.125–0.5) µg kg–1 min–1. The median (range) time to reach steady state was: ephedrine 15 (11–33) min, dobutamine 15 (6–24) min, and dopexamine 20 (15–35) min. There were no adverse events. Some subjects reported slight tremulousness with ephedrine, dobutamine, and dopexamine.


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Table 1. The effect of experimental drugs on cerebrovascular and haemodynamic. Variables: CI, cardiac index; CPP, cerebral perfusion pressure; CR, compression ratio; CRCO2, cerebral vascular reactivity to carbon dioxide; HR, heart rate; MCAFV, time-averaged mean middle cerebral artery flow velocity; SA, strength of autoregulation; THRR, transient hyperaemic response ratio. All values are given as mean (SD) All results are non-significant unless stated otherwise. *P<0.05 vs control values
 
The effects of each drug on middle cerebral artery flow velocity, transient hyperaemic response ratio, strength of autoregulation, reactivity to carbon dioxide, estimated cerebral perfusion pressure, and ZFP are detailed in Table 1. The middle cerebral artery flow velocity, strength of autoregulation, transient hyperaemic response ratio, and reactivity to carbon dioxide remained within the normal range before and during infusion of each drug. None of the drugs had a statistically significant effect on the strength of autoregulation, reactivity to carbon dioxide, or estimated cerebral perfusion pressure. The ZFP increased significantly with ephedrine and dobutamine, but not dopexamine.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We have shown that the sympathomimetic drugs tested in this study have little effect on the strength of autoregulation or reactivity to carbon dioxide in healthy volunteers. In addition, we have shown that despite having achieved a clinically significant increase in MAP, ephedrine and dobutamine did not significantly increase estimated cerebral perfusion pressure, and were associated with statistically significant increases in ZFP suggesting an increase in the tone of the cerebral vasculature.

There is an abundant sympathetic innervation of the cerebral vasculature.18 In animals with normal blood–brain barriers, adrenergic drugs have been shown to have no effect on cerebral blood flow measured by xenon clearance, thermoclearance, and tissue gas tensions.1921 If the blood–brain barrier is disrupted or bypassed, the effects of such agents can be either vasodilatory (ß) or vasoconstrictive ({alpha}) depending upon the drug profile and the size of the vessels.22 Chronic cervical sympathectomy in baboons reduces the lower limit of autoregulation suggesting a role for the sympathetic nervous system in modulating cerebrovascular tone indirectly.23 24 Acute cervical sympathectomy in baboons reduces the upper limit of the autoregulatory plateau.23 24

In humans, the evidence for the effect of sympathomimetic agents is less direct. Some of the methods of assessing cerebral autoregulation rely on pharmacological means of manipulating arterial pressure.7 The results of these tests could be taken to be confounded by the direct effects of vasoactive agents, unless it is assumed that these agents have no direct effect on cerebral autoregulation. Berre and colleagues25 showed that dobutamine (10 µg kg–1 min–1) given to septic patients with an altered conscious level increased middle cerebral artery flow velocity in parallel with increases in cardiac index and MAP. In contrast to much of the animal work, ß-block in humans has no effect on cerebral blood flow measured by xenon clearance or transcranial Doppler ultrasonography suggesting that, at least in normal individuals, ß-adrenergic stimulation is not important.26

The transient hyperaemic response test provides an ideal opportunity to study direct effects of vasoactive agents on cerebral autoregulation. Unlike some other commonly used tests of autoregulation7 the transient hyperaemic response test does not rely on the use of vasoactive substances to change systemic arterial pressure. Therefore, its use avoids any confounding interactions between the direct effects of a drug and autoregulatory influences on the vascular tone. We found no statistically significant change in the strength of autoregulation with any of the drugs.

Cerebral vascular reactivity to carbon dioxide is a marker of the ability of the cerebral vasculature to respond to metabolic demands, normally independent of perfusion pressure.27 Patients with head injuries may have reduced reactivity to carbon dioxide, which in some may show a return of reactivity to carbon dioxide to normal with increased MAP.17 Using transcranial Doppler ultrasonography experiments with changes in carbon dioxide and head up tilt/ganglionic block to augment/diminish sympathetic tone, Jordan and colleagues28 suggested that sympathetic tone may attenuate the carbon dioxide-induced increase in cerebral blood flow. Studies in patients with autonomic neuropathy secondary to diabetes mellitus show increased reactivity to carbon dioxide in the presence of postural hypotension and decreased reactivity to carbon dioxide in its absence.29 However, labetalol does not affect reactivity to carbon dioxide in volunteers.26

Our results suggest that ß-sympathomimetic drugs do not cause a significant change in reactivity to carbon dioxide in normal, young subjects. The difference between our results and those of Jordan and colleagues28 may be a result of difference in experimental technique. We gave steady-state infusions of single drugs, whereas Jordan and colleagues assessed the effect of sympathetic activation or block, which is a more subtle process. The same arguments apply to the results found in diabetic autonomic neuropathy.29 The labetalol results are consistent with ours, although again this is a pharmacological rather than physiological approach.

There is no single accepted definition of cerebral perfusion pressure. Taking the orthodox view of:

CPP=MAP – (greater of) ICP or CVP(6)

where, CPP is cerebral perfusion pressure, ICP is intracranial pressure and CVP is central venous pressure, any increase in MAP will increase cerebral perfusion pressure provided intracranial pressure or central venous pressure remain unchanged; indeed, in clinical practice vasopressors are used to increase cerebral perfusion pressure by increasing MAP.31 However, recently it has been shown that in patients/subjects with normal intracranial pressure, cerebrovascular tone is the major determinant of the downstream component of cerebral perfusion pressure.9 10 Thus, a more general concept of ZFP has been introduced, where ZFP is defined as the pressure at which flow in a vessel would cease. In the cerebral circulation the ZFP is a function of intracranial pressure, central venous pressure, and vascular tone3033 and the cerebral perfusion pressure can be estimated from the difference between MAP and ZFP. In conditions of relatively low intracranial pressure and central venous pressure, vascular tone may be the dominant component of ZFP. Thus, if a drug or manoeuvre, which is designed to increase MAP also results in a similar increase in ZFP, it will fail to have any effect on estimated cerebral perfusion pressure. In the present study, both ephedrine and dobutamine, despite causing significant increases in MAP, failed to increase estimated cerebral perfusion pressure presumably a result of simultaneous increases in ZFP. The increase in ZFP with ephedrine and dobutamine suggests that use of these drugs is associated with increased cerebrovascular tone. Given the lack of effect on reactivity to carbon dioxide, an indirect effect as a result of changes in MAP is the most likely explanation, although a direct effect of these drugs on the vascular bed cannot be excluded. Whatever the cause, this is an interesting finding as it tends to challenge the frequently recommended use of vasopressors to increase cerebral perfusion pressure.34 However, further studies are required with different vasoactive drugs in healthy subjects and in patients with head injury to define the place of estimated cerebral perfusion pressure.

We have used the term ß-sympathomimetics within this study as that reflects the predominant action of these drugs. The choice of drugs used in this study was based on their common clinical use and spectrum of associated {alpha}-receptor activity; dopexamine is known to have no effect on {alpha} receptors, dobutamine has some {alpha}-agonistic effect, and ephedrine has significant {alpha}-agonistic effect. We used two different endpoints (MAP or cardiac index) for drug titration. This was appropriate because dopexamine could not be expected to significantly increase MAP. Furthermore, the aim of the endpoint was to reach a measurable, repeatable and clinically relevant cardiovascular change with each drug. The range of drug doses required was relatively wide, but this reflects clinical and experimental experience. We chose not to attempt to define a dose–response relationship for each drug as using smaller cardiovascular changes was even less likely to produce cerebrovascular change and 25–30% changes are commonly used in cerebrovascular studies. Transoesophageal Doppler estimation of cardiac output has been validated against indicator dilution methods;35 changes correlate better than absolute values.35

This study was not designed to investigate the effects of sympathomimetic agents in head injury or sepsis, but rather to clarify what is ‘normal’. Extrapolation of these results to patients with neurological disease will be inappropriate. However, these results will serve as the point of reference for further studies in patients with neurological disorders.

In conclusion, we have found that a range of ß-sympathomimetic agents, given systemically, do not affect the cerebral haemodynamics as assessed by transient hyperaemic response tests, cerebral reactivity to carbon dioxide, or cerebral perfusion pressure using transcranial Doppler studies. If changes in these variables are seen in pathological states when using these drugs then clinicians should seek the cause.


    Acknowledgements
 
The Transcranial Doppler ultrasound equipment was purchased with a grant from the Association of Anaesthetist of Great Britain and Ireland. The Oesophageal Doppler probes were kindly donated by Deltex Medical, UK.


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 Introduction
 Methods
 Results
 Discussion
 References
 
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