One of the corner stones in the management of head-injured patients is maintaining cerebral perfusion pressure (CPP) at an adequate level to restore or preserve cerebral blood flow (CBF). Besides fluid resuscitation, catecholamines are frequently used to augment mean arterial pressure (MAP) and hence CPP. This review will summarize the current literature regarding the cerebrovascular effects of catecholamines on the traumatized brain. It is based on a literature search (PubMed) for the years 1997-2006 using combinations of the MeSH search terms ‘traumatic brain injury', ‘catecholamines', ‘epinephrine', ‘norepinephrine', ‘dopamine', ‘phenylephrine', ‘dobutamine', ‘dopexamine' and ‘isoprenaline'. Publications concentrating on the disruption of cerebral catecholaminergic transmission after brain injury and papers investigating the role of drugs related to catecholamines to enhance recovery from brain injury were excluded.
In both pial and intracerebral vessels, α1- and α2-adrenoceptors have been found to mediate vasoconstriction. Prejunctional α2-adrenoceptors are also responsible for the inhibition of norepinephrine release and endothelial vasodilatation. β1-adrenoreceptors and β2-adrenoceptors are also found in cerebral vessels where they mediate vasodilatation. Sympathomimetic agents such as epinephrine, norepinephrine and phenylephrine contract pial arterial segments in vitro and pial arteries, arterioles and veins in situ. Norepinephrine leads to a stronger contraction in veins than in arterioles. Systemically applied catecholamines generally cause a minor reduction in normocapnic CBF (approximately 5-15%). The comparative non-reactivity of the cerebral circulation to blood-borne catecholamines is best explained by the existence of the blood-brain barrier to monoamines. The interpretation of cerebrovascular effects of dopamine is difficult. Dopamine acts on the various dopamine receptor sub-types, and at higher concentrations it can also activate α-adrenoreceptors and β-adrenoceptors and 5-hydroxytryptamine receptors. For an extensive review see .
Many factors need to be considered when interactions between catecholamines and cerebral blood vessels are studied. Six such factors are addressed here. (1) The larger ‘inflow tract' vessels are innervated by adrenergic fibres and the sympathetic tone influences the limits of autoregulation . (2) The presence or absence of autoregulation or an intervention exceeding the range of autoregulation will profoundly influence any attempt to manipulate CBF through a change in MAP . In healthy volunteers, ephedrine, dobutamine and dopexamine have been shown not to influence dynamic autoregulation . (3) Other factors such as CO2 and O2 reactivity need to be considered. Instability in PaCO2 or PaO2 during studies on cerebrovascular effects of vasoactive drugs may influence CBF measurements profoundly . (4) The blood-brain barrier should be thought of not only as a structural barrier but also as an enzymatic barrier. As cerebral microvessels contain monoamino oxidase, it is likely that catecholamines are unable to transverse the blood-brain barrier in their intact form. Furthermore, intrinsic adrenergic nerves that innervate cerebral microvessels seem to modulate the permeability of the blood-brain barrier . (5) Some studies suggest that there is metabolic stimulation of the brain through β-adrenoceptors, e.g. a study in conscious rats without brain injury investigated systemic infusions of phenylephrine, norepinephrine and epinephrine. The achieved changes in MAP were within the range of autoregulation, and only epinephrine led to an increase in CBF. This was interpreted as a metabolic effect due to a β-adrenoreceptor stimulation . In contrast, in an intact physiological sheep model, hypertension induced by epinephrine and norepinephrine was associated neither with global changes in CBF nor with cerebral oxygen utilization, both of which remained constant. At equivalent doses, dopamine caused cerebral hyperaemia and increased global cerebral oxygen utilization . (6) In human and animal studies, background effects of anaesthetics and interactions between catecholamines and anaesthetics need to be considered. In an ovine model comparing animals without an intracranial pathology in the awakened state and anaesthetized with either propofol or isoflurane, epinephrine, norepinephrine and dopamine did not change pressure autoregulation [8,9]. Work by Strebel and colleagues  in patients without cerebral pathology indicated that norepinephrine and phenylephrine do not directly affect intracranial haemodynamics in patients anaesthetized with isoflurane or propofol. Rather, haemodynamic changes observed with vasoconstrictors reflect the effect of the background anaesthetic agents on cerebral pressure autoregulation . Large doses of propofol have been shown to have paradoxical effects on autoregulation in patients with severe head injury, i.e. static autoregulation deteriorated with higher propofol infusion rates . A very interesting study in sheep showed that epinephrine, norepinephrine and dopamine significantly reduced mean arterial propofol concentrations, which may affect CBF. There were parallel reductions of concentrations in sagittal sinus blood leaving the brain. The data were consistent with a mechanism based on increased first-pass dilution and clearance of propofol, secondary to the increased cardiac output. . Such changes in propofol concentration may directly affect CBF.
Effects on cerebral perfusion
Studies reporting on the effects of catecholamines on CBF and cerebral perfusion in the traumatized brain are difficult to compare. Many different models and methods are used.
Using a cortical impact injury model in rats, Kroppenstedt and colleagues  showed an increase in regional cerebral perfusion measured by laser Doppler flowmetry after MAP was increased with dopamine. CBF increased significantly and there was no evidence of a dopamine-mediated vasoconstriction . In a later study, by the same group using similar methods, the authors infused either norepinephrine or dopamine to increase MAP. Both substances significantly increased cerebral perfusion. However, despite similar MAP values, the effect on cerebral perfusion was more sustained under norepinephrine. There was no evidence of cerebrovascular vasoconstriction with either substance . Based on electroencephalographic (EEG) activity and glutamate levels, the authors conclude that this sustained effect was due to a metabolically driven increase, which was found in norepinephrine but not in dopamine . In a further study the same group compared the effects of early and late intravenous norepinephrine on cerebral perfusion. Again a rat model and a focal cortical contusion model were used. Early (4 h) and late (24 h) after-injury norepinephrine significantly improved pericontusional perfusion . Ract and colleagues  used a weight drop model in rats in which the animals were also exposed to a severe hypoxic hypotensive insult. They were not able to increase CPP through the administration of either dopamine or norepinephrine, whereas CBF actually decreased. However, it is conceivable that the hypoxic insult led to a severe acidosis that prevented the restoration of CPP despite the administration of catecholamines . Stubbe and colleagues  used a sheep model with a blunt non-penetrating injury to compare the effects of hydroxyethylstarch and norepinephrine. CPP was stabilized with either approach until 60-70 mmHg was reached. Identical carotid blood flow was reached in both groups . Cherian and colleagues  investigated the effects of phenylephrine in rats using a cortical impact model and found that phenylephrine restored CPP and CBF.
A comparison between norepinephrine and dopamine using a randomized cross-over design showed predictable increases in transcranial Doppler flow velocity when norepinephrine was used to augment CPP. However, when dopamine was used in the same patients the changes were variable and inconsistent. The authors concluded that norepinephrine may be the more predictable agent to augment cerebral perfusion . A clinical study by Ract and colleagues showed that after MAP elevation with dopamine, intracranial pressure (ICP) was higher than when the same MAP was achieved with norepinephrine in the same patient. CBF measured as transcranial Doppler flow velocity was identical in both groups. This suggests intact autoregulation in this group of patients. The study focused on ICP, and targeted MAP rather than CPP. Consequently, the comparison between the two drugs was made at significantly different CPPs, and the reported increase in ICP may possibly be a reflection of intact pressure reactivity rather than of a specific effect of dopamine . These two studies measured flow velocity in the middle cerebral artery as a surrogate marker of CBF. Only few studies addressed the question of regional changes in CBF in head-injured patients. Using Xenon computed tomography (CT) and norepinephrine in seven patients with severe head injury, Chieregato and colleagues  found that an acute increase from 65 to 88 mmHg of CPP only marginally affected regional CBF in the intracontusional low-density area. However, in their study they found a decrease in regional CBF in the unaffected hemisphere in some patients . Using positron emission tomography (PET), Steiner and colleagues have quantified the response to an increase in CPP in and around contusions in 18 head-injured patients. Regional CBF was measured with PET at CPPs of 70 and 90 mmHg using norepinephrine to control CPP. Based up CT, regions of interest were placed as two concentric ellipsoids, each of 1-cm width, around the core of the contusions. Measurements were compared with a control region of interest in tissue with normal anatomic appearance. Baseline CBF increased significantly with increasing distance from the core of the lesion. The increase in CPP led to small increases in CBF in all regions of interest except the core. The largest absolute CBF increase was found in the control region. Relative CBF increases did not differ between regions so that ischaemic areas remained ischaemic .
In summary, norepinephrine, dopamine and phenylephrine have all been shown to increase CBF in various animal models of head injury and in patients. The available evidence suggests that norepinephrine is possibly more predictable than dopamine. Phenylephrine has never been directly compared to norepinephrine or dopamine. The effects on regional CBF have only been studied in very few patients. The revised Brain Trauma Foundation Guidelines suggest that CPP should be maintained at a minimum of 60 mmHg and that in the absence of cerebral ischaemia, aggressive attempts to maintain CPP above 70 mmHg with fluids and pressors should be avoided . Most studies report results from a CPP range that lies outside these recommendations.
Effects on cerebral oxygenation and metabolism
The rationale behind the increase in CBF is to improve cerebral oxygenation. An increase in CBF leading to hyperaemia is not desirable. This aspect of CPP augmentation has been addressed by several investigators. Work by Stubbe and colleagues , cited above, comparing the specific effects of each hydroxyethylstarch and norepinephrine, reports that despite identical carotid blood flow in both groups only norepinephrine decreased the oxygen extraction fraction. Similar results were reported by Malhotra and colleagues  In anaesthetized swine they induced a head injury followed by a 45% volume bleed. All animals were fluid resuscitated with NaCl 0.9%, and the experimental group received phenylephrine in addition to NaCl 0.9% to maintain CPP > 80 mmHg. Only the experimental group had improved brain oxygenation.
In head-injured patients, a randomized cross-over study using norepinephrine and dopamine to achieve a CPP of 65 and 85 mmHg found that only the intervention with norepinephrine leads to a significant improvement in global and regional brain oxygenation measured as arterio-venous oxygen difference and brain tissue oxygen, respectively . In one study, increasing CPP with phenylephrine did not increase oxygen availability in a majority of patients despite marked increases in CPP . In a PET study, an increase in CPP from 70 to 90 mmHg, due to norepinephrine, led to significantly increased levels of brain tissue oxygen and also significantly reduced the regional oxygen extraction fraction. However, these changes did not translate into predictable changes in regional chemistry as determined by microdialysis . In a further PET study, Coles and colleagues  found that although CPP elevation from 70 to 90 mmHg produced a significant drop in the ischaemic brain volume, this volume was small and clinically insignificant in most of these patients. The reduction in ischaemic brain volume, however, was directly related to the baseline ischaemic brain volume, and patients with large baseline ischaemic brain volume showed substantial and clinically significant reductions .
Effects on brain oedema and intracranial pressure
In view of the possibility that catecholamines influence the blood-brain barrier permeability, the question of secondary brain oedema and increased ICP needs to be addressed. In rats, after controlled cortical impact, Kroppenstedt and colleagues  found no evidence for brain oedema induced by either norepinephrine or dopamine in several series of experiments [13-16]. However, when dopamine was used to achieve a very high MAP (140 mmHg) the same investigators found an increase in contusion volume in rats with a cortical impact injury . Stover and colleagues . found that in rats with focal contusions norepinephrine and dopamine significantly increased pericontusional glucose concentrations. However, this did not translate into elevated extracellular lactate or aggravate oedema formation . In contrast, using a rodent model of cortical contusion and MRI to assess brain tissue water, Beaumont and colleagues [32,33] found in two series of experiments that dopamine may significantly worsen oedema. In the study by Cherian and colleagues , described above, the increase in CBF due to phenylephrine was associated with a significant increase in ICP.
In patients, one comparison of norepinephrine and dopamine showed increased ICP when dopamine was used to increase MAP. However, as stated above, this is most likely due to autoregulation and a vascular phenomenon rather than an increase in brain oedema . The two previously cited studies by Johnston and Steiner [20,26] did not show an increase in ICP with either norepinephrine or dopamine.
There is one experimental study investigating brain tissue outcome in relation to the resuscitation strategy used in swine with a splenic laceration and a cryogenic brain injury. The authors compared fluid resuscitation with Ringer's lactate either to delayed fluid resuscitation or to phenylephrine to maintain baseline MAP. Ringer's lactate restored CBF earlier and was associated with less secondary neuronal ischaemia than the other two regimens . There are no patient data on the relationship between the substances used to maintain CBF and outcome.
When attempting to synthesize the available data on which catecholamines should be used to maintain CPP, systemic complications need to be addressed. Dopamine has hypophysiotropic properties and suppresses the circulating concentrations of all anterior pituitary-dependent hormones, except cortisol. Available evidence suggests that the major effect of dopamine administration on the endocrine system is unlikely to be beneficial for the threatened metabolic and immunologic homoeostasis of the severely ill patient. This pattern of hypopituitarism induced by chronic, severe illness and exogenous dopamine administration is reminiscent of the hormonal profiles obtained in experimental models of chronic stress, suggesting that endogenous dopamine may play a role in the endocrine and metabolic response to critical illness . In the study by Malhotra and colleagues , cited earlier, the use of phenylephrine did improve brain oxygenation when compared to fluids. However, the phenylephrine-treated swine had more lung oedema, suggesting a propensity for phenylephrine to cause pulmonary complications . When comparing an ICP-orientated management strategy with a CBF-oriented strategy in head-injured patients, Robertson and colleagues  found that patients in the CBF strategy arm received more fluids, dopamine and phenylephrine than those in the ICP arm and that the rate of adult respiratory distress syndrome (ARDS) in the CBF arm was unexpectedly high. Later, logistic regression analysis was used to study the interaction of the factors that were related to the development of ARDS in these patients. In the final exact logistic regression model, it was found that administration of epinephrine and dopamine was significantly associated with an increased risk of ARDS. The authors concluded that although the clinical trial by Robertson and colleagues was not designed to study the association of management strategy and the occurrence of ARDS, the data strongly indicated that induced hypertension was associated with the development of ARDS . Finally, based on a case report of a patient who developed propofol infusion syndrome and received norepinephrine, dopamine and phenylephrine, it has been suggested that catecholamines may be a triggering factor for this syndrome .
In summary, based on the data presented, norepinephrine seems to be the substance that may have some advantages over the other catecholamines as far as predictability and metabolic effects are concerned. There is also less evidence for potential cerebral and systemic side-effects for norepinephrine than for dopamine. However, there are no data linking norepinephrine to improved patient outcome and the data are insufficient to formulate a guideline.
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