Effects of norepinephrine and glyceryl trinitrate on cerebral haemodynamics: transcranial Doppler study in healthy volunteers
1 University Department of Anaesthesia and Intensive Care, Queen's Medical Centre, Nottingham, UK
2 Nottingham University Hospitals NHS Trust, Nottingham, UK
* Corresponding author. E-mail: iain.moppett{at}nottingham.ac.uk
Accepted for publication November 25, 2007.
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Background: The effects of vasoactive substances on cerebral haemodynamics are not fully known. We studied the effects of norepinephrine and glyceryl trinitrate (GTN) on cerebral haemodynamics in healthy volunteers.
Methods: The effects of norepinephrine (n=10) and GTN (n=10) on the middle cerebral artery flow velocity (MCAFV), cerebral autoregulation, reactivity to carbon dioxide, and estimated cerebral perfusion pressure (eCPP) were studied using transcranial Doppler ultrasound. Established methods were used for calculating zero flow pressure (ZFP). Measurements were made at baseline, and after i.v. infusion of the study drug to the endpoints of 25% increase in mean arterial pressure (MAP) for norepinephrine (0.02–0.1 µg kg–1 min–1), or 15% decrease in MAP for GTN (0.5–2.5 µg kg–1 min–1).
Results: The MCAFV remained unchanged with norepinephrine, but decreased slightly with GTN {from [median (inter-quartile range)] 53 (38, 62) to 48 (33, 52) cm s–1}. Cerebrovascular reactivity did not change significantly with either drug. The eCPP did not change significantly with norepinephrine, but increased significantly with GTN [from 49 (32, 54) to 62 (47, 79) mm Hg]. ZFP increased with norepinephrine [from 39 (28, 48) to 56 (46, 62) mm Hg] and decreased with GTN [from 35 (30, 49) to 12 (–7, 20) mm Hg].
Conclusions: Norepinephrine, despite increasing arterial pressure, did not increase the eCPP. The eCPP increased significantly with GTN, despite decreased MAP. Cerebral vascular tone is an important determinant of CPP during pharmacologically induced changes in arterial pressure.
Keywords: brain, blood flow; pharmacology, agonists adrenergic; pharmacology, nitroglycerin
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The use of transcranial Doppler ultrasonography (TCD) to assess middle cerebral artery blood flow velocity (MCAFV), cerebral autoregulation, and cerebral vascular reactivity to carbon dioxide (CRCO2) is well established.1 Recently, its use has been extended to estimate cerebral perfusion pressure (CPP) and zero flow pressure (ZFP); this estimation is based on extrapolating the relationship between instantaneous values of MCAFV and the arterial pressure during pulsatile blood flow to calculate arterial pressure at which the blood flow would cease (i.e. ZFP).1 In subjects without raised intracranial pressure, ZFP is determined mainly by cerebral vascular tone.1 2 In terms of cerebral perfusion, ZFP is considered to be the effective downstream pressure such that the estimated CPP (eCPP) is taken as the difference between the mean arterial pressure (MAP) and the ZFP (eCPP=MAP–ZFP).2–4
Vasoactive drugs are commonly used during anaesthesia and in intensive care. The effects of these drugs on cerebral haemodynamic parameters, such as MCA FV, cerebral autoregulation, CRCO2, eCPP, and ZFP, are not well documented. This information is important for safe and appropriate use of these drugs, particularly in neuroanaesthesia and neuro-intensive care. The concept of the role of cerebrovascular tone in determining eCPP evokes interesting possibilities regarding the effects of the vasoactive substances. Because the net change in eCPP would depend on the relative changes in MAP and ZFP, the change in eCPP may or may not follow the change in MAP induced by a vasoactive agent.
In the intensive care unit, norepinephrine is commonly used for its vasoconstrictive action to increase arterial pressure, and glyceryl trinitrate (GTN) is commonly used for its vasodilatory action to decrease arterial pressure. The effects of these agents on cerebral haemodynamic parameters have not been described in the literature. We aimed to study the effects of these agents on MCAFV, cerebral autoregulation, CRCO2, eCPP, and ZFP as assessed by TCD.
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The study was approved by the local ethics committee. Twenty healthy volunteers were recruited. Informed written consent was obtained from all the subjects. The exclusion criteria were as in the following: age <18 or >40 yr, history of hypertension (or measured arterial pressure >140/90 mm Hg), neurological disease, history of migraine, smoking, pregnancy/potential pregnancy, and history of intake of vasoactive drugs (antidepressants, anti-hypertensives).
The subjects were studied in the supine position with their heads resting on a pillow. A 2 MHz pulsed TCD probe (SciMed PCDop 842, SciMed, Bristol, UK) was used to insonate left middle cerebral artery (MCA) using temporal window. The artery was identified using standard criteria.5 A custom-built head band was used to hold TCD probe in a constant position throughout the study to ensure a constant angle of insonation. The MCAFV waveform was recorded continuously onto digital audiotape for subsequent analysis using specific software (SciMed). All subjects used a nose clip and a mouthpiece to allow accurate and continuous end-tidal carbon dioxide (E'CO2) monitoring (Datex Capnomac). In addition, continuous monitoring of pulse oximetry and electrocardiography was established. The arterial pressure was measured non-invasively at 1 min intervals for the duration of the study (Dinamap).
At least 5 min after establishing all the monitoring, the baseline measurements of MCAFV, cerebral autoregulation, CRCO2, and arterial pressure (for calculating eCPP and ZFP—see below) were taken at steady state with the subject receiving no drug. The steady state was defined as <10% change in the heart rate and arterial pressure and <0.5 kPa change in the E'CO2 over a period of 3 min. After baseline measurements, an i.v. infusion of norepinephrine or GTN was started. The infusions were prepared using standard dilutions as per local intensive care unit protocols. The norepinephrine infusion was prepared by diluting 4 mg in 100 ml of saline 0.9%, and was started to deliver 0.02 µg kg–1 min–1. The rate of infusion was increased gradually up to 0.1 µg kg–1 min–1 to titrate it to a predetermined 25% increase in MAP. The GTN infusion was prepared by diluting 100 mg in 100 cc of 0.9% saline and was started to deliver 0.5 µg kg–1 min–1. The rate of infusion was increased gradually to a maximum of 2.5 µg kg–1 min–1 to achieve a predetermined 15% decrease in MAP. Cerebral haemodynamic measurements were repeated after achieving a steady state at the arterial pressure endpoints.
Cerebral haemodynamics
Cerebral autoregulation
The transient hyperaemic response (THR) test was performed to assess cerebral autoregulation; the details of this test have been described previously.6–8 This test involves a 10 s compression of the common carotid artery ipsilateral to the insonated MCA followed by a sudden release. If the autoregulation is intact, a THR is seen at the release of compression.
The THR tests were accepted only if they met certain predefined criteria. These criteria were:
- a sudden and maximal decrease in flow velocity at the onset of compression;
- stable heart rate for the period of compression;
- steady Doppler signal for the duration of compression;
- absence of flow transients after release of compression.7
The strength of autoregulation (SA) was calculated using previously described formulae. Three waveforms from each period of compression were taken for analysis. These were the MCA waveform immediately before compression (F1), the first waveform after compression (F2), and the waveform immediately after the release of compression (F3).7 The time-averaged mean of the outer envelope of the FV profile was used for performing the analysis. SA was calculated as:
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Cerebral vascular reactivity to carbon dioxide
CRCO2 was calculated as % change of mean MCAFV per mm Hg change in E'CO2.9 The changes in MCAFV were recorded at rest (baseline), during induced hypocapnia [voluntary hyperventilation to an E'CO2 of 7.5 mm Hg (1 kPa) below baseline] and hypercapnia [rebreathing through a Mapleson D circuit with oxygen-enriched air to achieve an E'CO2 of 1 kPa (7.5 mm Hg) above baseline]. At baseline and after induced changes in E'CO2, MCAFV was averaged more than 12 s to include at least two complete respiratory cycles.
Estimated cerebral perfusion pressure and zero flow pressure
The method described by Belfort and colleagues10 was used to calculate eCPP and ZFP. Taking simultaneous measurements of arterial pressure and TCD velocities at steady state, the following formulae were used:8 10
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The calculated range for SA in healthy volunteers is 0.88–1.12 with a coefficient of variation of <10% on repetitive measurements within the same subject.7 We calculated that 10 subjects would be required to detect an absolute difference of 0.15 in SA with a power of 0.8 and
of 0.05. This is a clinically relevant change of similar magnitude to that seen with impairment of autoregulation with inhalational anaesthetics.11 On the basis of the previous studies,2 4 8 similar sample size would also be sufficient to determine significant changes in ZFP. Data were analysed for normal distribution using Anderson–Darling test. Since some data were not distributed normally, cerebrovascular and cardiovascular variables were analysed using non-parametric tests; Wilcoxon signed rank test was used to analyse within-group changes before and after drug infusions; Mann–Whitney U-test was used for comparing corresponding values between the two groups.
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Seven males and three females received norepinephrine, and six males and four females received GTN. The subjects were aged between 22 and 38 yr. The endpoints of increase or decrease in MAP were 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 norepinephrine required to achieve endpoint was 0.06 (0.04–0.1), and that for GTN was 2 (1.5–2.5) µg kg–1 min–1. The median (range) time to reach steady state was 15 (11–33) min for norepinephrine and 20 (15–24) min for GTN. There were no adverse events with either of the agents. Some subjects reported increased awareness of their heart beat with GTN.
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The heart rate decreased significantly with norepinephrine and it increased significantly with GTN (Table 1). The MCAFV remained unchanged with norepinephrine and it decreased by a small but significant amount with GTN. The CRCO2 and SA remained unchanged with both the drugs.
In the subjects who received norepinephrine, despite significant increases in MAP, the eCPP did not change significantly, and there was an associated significant increase in ZFP. On the other hand, with GTN, despite significant decreases in MAP, eCPP increased significantly with an associated significant decrease in ZFP.
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We have shown that neither norepinephrine nor GTN have significant effects on SA or CRCO2. In addition, we have shown that despite having significantly increased MAP, norepinephrine did not increase eCPP, and was associated with significant increases in ZFP. This is consistent with the hypothesis that ZFP is a function of the tone of cerebral vasculature. Cerebrovascular tone increases in response to the increase in MAP. GTN had the opposite effect; despite significant decreases in MAP, eCPP increased, and was associated with significant decreases in ZFP, suggesting a decrease in the tone of cerebral vasculature in response to the decrease in MAP. The study shows that in awake subjects with no neurological disorder, simply increasing MAP with norepinephrine may not achieve an increase in CPP. Equally importantly, it also shows that reducing cerebral vascular tone may be an effective strategy to significantly increase eCPP, despite a moderate decrease in systemic arterial pressure.
The effects of different vasoactive substances on cerebral haemodynamics are not well documented. The cerebral vasculature is known to be abundantly innervated by sympathetic nerves.12 We have recently reported the effects of ephedrine, dobutamine, and dopexamine on cerebral haemodynamics using a study protocol similar to the present study.4 We concluded that neither of these agents significantly affected MCAFV, SA, CRCO2, or eCPP. These agents are predominantly β-sympathomimetics, although ephedrine can also have significant -agonistic effect. On the other hand, norepinephrine is predominantly an -agonist. However, the present study shows that its effects on cerebral haemodynamics are similar to those reported earlier for ephedrine or dobutamine. Strebel and colleagues13 have reported the effects of norepinephrine and phenylephrine on anaesthetized individuals. The increase in arterial pressure with these agents was associated with increases in MCAFV, indicating disturbed autoregulation. These authors believed this to be the effects of anaesthetics rather than the vasoactive agents. We chose to study the effects in awake volunteers so as to avoid the confounding effects of anaesthetics. Our results with norepinephrine, when interpreted along with the findings of previous study with ephedrine and dobutamine,4 suggest that an increase in MAP with these agents is also associated with an increase in ZFP so that eCPP remains unchanged.
Assessment of ZFP using TCD is indirect since cerebral blood flow is not measured directly. Rather, blood flow velocity is measured. However, the original work on ZFP was performed using directly cannulated vessels in animals allowing direct measurement of flow and pressure throughout the cardiac cycle. Subsequent indirect work in both placental and cerebral flow has been consistent with the original studies. Changes in MCAFV are only directly proportional to cerebral blood flow if the diameter of the insonated vessel does not change. There is no evidence that -agonists affect directly the diameter of basal cerebral arteries. -Adrenoceptors are scarce on basal cerebral arteries and phenylephrine appeared to have no effect when the vessels were viewed directly.14–16 Various studies have suggested, however, that GTN acts as a vasodilator of the MCA,17 18 leading to reduced flow velocities but maintained or increased cerebral blood flow secondary to intracranial vasodilatation. In this study, we did not measure cerebral blood flow directly, although given that the doses used were similar to previous studies,17 18 we assume in the present study, a slight decrease in MCAFV with GTN reflects slight dilatation on the MCA, rather than a decrease in cerebral blood flow. The calculations of various cerebral haemodynamic variables such as CRCO2 and SA are determined by the per cent change in flow velocity after a stimulus, and that of eCPP is determined by the ratio of pulsatilities of arterial pressure and flow velocity, and not the absolute values of flow velocity. Hence, dilatation of MCA per se is unlikely to influence the values of these variables.
The increase in eCPP after GTN is consistent with its effects on cerebral vessels leading to a reduction in tone, similar to that seen during hypercapnia, or inhalation of nitrous oxide.2 19 However, in contrast to hypercapnia and inhalation of nitrous oxide, which are known to impair cerebral autoregulation,7 20 GTN infusion in this study was not associated with impairment of cerebral autoregulation. This is consistent with previous work investigating the effect of GTN21 which also found no effect on autoregulation.
The concept of estimating ZFP using TCD has been published previously, supporting its use and validity both in vitro and in vivo.2 3 19 We used Belfort's method10 of calculating ZFP. Previously, we have shown that this method is sensitive in calculating changes in ZFP, despite variability in individual measurements.2 However, so far these studies have been performed in healthy volunteers without evidence of cerebrovascular disease. Further clinical studies will be required to determine the effect of vasoactive substances in the presence of intracranial pathology, particularly reduced intracranial compliance.
This is a volunteer study in young subjects without overt cardiovascular or cerebral disease. Willmot and colleagues22 found that in patients with ischaemic stroke, despite reductions in systemic arterial pressure, GTN did not decrease cerebral blood flow. Previous workers have found that GTN may be beneficial in vasospasm after sub-arachnoid haemorrhage.23 Our study provides support to the concept that the effects of vasodilators on cerebrovascular tone (effective downstream pressure or ZFP) are important determinants of maintenance of adequate eCPP, despite reductions in systemic arterial pressure. In summary, we have demonstrated that during infusion of vasoactive drugs, changes in cerebrovascular tone play an important role in determining eCPP. Changes in systemic arterial pressure do not necessarily equate with changes in CPP.
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Association of Anaesthetists of Great Britain and Ireland.
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1 Moppett IK, Mahajan RP. Transcranial Doppler ultrasonography in anaesthesia and intensive care. Br J Anaesth (2004) 93:710–24.
2 Hancock SM, Mahajan RP, Athanassiou L. Noninvasive estimation of cerebral perfusion pressure and zero flow pressure in healthy volunteers: the effects of changes in end-tidal carbon dioxide. Anesth Analg (2003) 96:847–51.
3 Athanassiou L, Hancock SM, Mahajan RP. Doppler estimation of zero flow pressure during changes in downstream pressure in a bench model of a circulation using pulsatile flow. Anaesthesia (2005) 60:133–8.[CrossRef][Web of Science][Medline]
4 Moppett IK, Wild MJ, Sherman RW, Latter JA, Miller K, Mahajan RP. Effects of ephedrine, dobutamine and dopexamine on cerebral haemodynamics: transcranial Doppler studies in healthy volunteers. Br J Anaesth (2004) 92:39–44.
5 Aaslid R. Transcranial Doppler examination techniques. In: Transcranial Doppler Sonography—Aaslid R, ed. (1986) Vienna: Springer-Verlag. 36–59.
6 Harrison JM, Girling KJ, Mahajan RP. Effects of target-controlled infusion of propofol on the transient hyperaemic response and carbon dioxide reactivity in the middle cerebral artery. Br J Anaesth (1999) 83:839–44.
7 Mahajan RP, Cavill G, Simpson EJ. Reliability of the transient hyperemic response test in detecting changes in cerebral autoregulation induced by the graded variations in end-tidal carbon dioxide. Anesth Analg (1998) 87:843–9.
8 Sherman RW, Bowie RA, Henfrey MME, Mahajan RP, Bogod D. Cerebral haemodynamics in pregnancy and pre-eclampsia as assessed by transcranial Doppler ultrasonography. Br J Anaesth (2002) 89:687–92.
9 Matta BF, Stow PJ. Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies. Br J Anaesth (1996) 76:790–4.
10 Belfort MA, Saade GR, Grunewald C, et al. Association of cerebral perfusion pressure with headache in women with pre-eclampsia. Br J Obstet Gynaecol (1999) 106:814–21.[Web of Science][Medline]
11 Bedforth NM, Girling KJ, Harrison JM, Mahajan RP. The effects of sevoflurane and nitrous oxide on middle cerebral artery blood flow velocity and transient hyperemic response. Anesth Analg (1999) 89:170–4.
12 Duckles SP. Innervation of the cerebral vasculature. Ann Biomed Eng (1983) 11:599–605.[CrossRef][Web of Science][Medline]
13 Strebel SP, Kindler C, Bissonnette B, Tschaler G, Deanovic D. The impact of systemic vasoconstrictors on the cerebral circulation of anesthetized patients. Anesthesiology (1998) 89:67–72.[CrossRef][Web of Science][Medline]
14 Bevan JA, Duckworth J, Laher I, Oriowo MA, McPherson GA, Bevan RD. Sympathetic control of cerebral arteries: specialization in receptor type, reserve, affinity, and distribution. FASEB J (1987) 1:193–8.[Abstract]
15 Duckworth JW, Wellman GC, Walters CL, Bevan JA. Aminergic histofluorescence and contractile responses to transmural electrical field stimulation and norepinephrine of human middle cerebral arteries obtained promptly after death. Circ Res (1989) 65:316–24.
16 Giller CA, Bowman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery (1993) 32:737–41.[Web of Science][Medline]
17 Dahl A, Russell D, Nyberg-Hansen R, Rootwelt K. Effect of nitroglycerin on cerebral circulation measured by transcranial Doppler and SPECT. Stroke (1989) 20:1733–6.
18 Bednarczyk EM, Wack DS, Kassab MY, et al. Brain blood flow in the nitroglycerin (GTN) model of migraine: measurement using positron emission tomography and transcranial Doppler. Cephalgia (2002) 22:749–57.[CrossRef][Web of Science][Medline]
19 Hancock SM, Eastwood JR, Mahajan RP. Effects of inhaled nitrous oxide 50% on estimated cerebral perfusion pressure and zero flow pressure in healthy volunteers. Anaesthesia (2005) 60:129–32.[CrossRef][Web of Science][Medline]
20 Girling KJ, Cavill G, Mahajan RP. The effects of nitrous oxide and oxygen on transient hyperemic response in human volunteers. Anesth Analg (1999) 89:175–80.
21 Endoh H, Honda T, Ohashi S, Hida S, Shibue C, Komura N. The influence of nitroglycerin and prostaglandin E1 on dynamic cerebral autoregulation in adult patients during propofol and fentanyl anaesthesia. Anaesthesia (2001) 56:947–52.[CrossRef][Web of Science][Medline]
22 Willmot M, Ghadami A, Whysall B, Clarke W, Wardlaw J, Bath PMW. Transdermal glyceryl trinitrate lowers blood pressure and maintains cerebral blood flow in recent stroke. Hypertension (2006) 47:1209–15.
23 Nakao K, Murata H, Kanamaru K, Waga S, Katusic ZS. Effects of nitroglycerin on vasospasm and cyclic nucleotides in a primate model of subarachnoid hemorrhage. Stroke (1996) 27:1882–8.
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