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Effects of Vasopressors on Cerebral Circulation and Oxygenation: A Narrative Review of Pharmacodynamics in Health and Traumatic Brain Injury

Thorup, Line MD*; Koch, Klaus U. MD*; Upton, Richard N. BSc, PhD; Østergaard, Leif MD, PhD, DMSC; Rasmussen, Mads MD, PhD*

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Journal of Neurosurgical Anesthesiology: January 2020 - Volume 32 - Issue 1 - p 18-28
doi: 10.1097/ANA.0000000000000596
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The clinical use of vasoactive drugs aims to improve hemodynamic variables in end organ(s) and thereby maintain or restore adequate perfusion and oxygenation in accordance with metabolic demands. Normally, the cerebral circulation is maintained at homeostatic levels, tightly coupled to neuronal activity through a complex and not completely understood cerebral autoregulatory system involving cardiovascular, respiratory, and neural mechanisms. Thus, under constantly changing physiological conditions, regional and global cerebral blood flows (CBF) are preserved to maintain the function and survival of brain tissue. The main focus in the management of patients with brain injury during surgery and neurointensive care is restoring and/or maintaining adequate cerebral perfusion pressure (CPP) in order to ensure CBF in accordance with metabolic demands.1 One commonly used clinical strategy is the administration of vasoactive drugs aiming to increase mean arterial blood pressure (MABP) and thereby CPP. However, in some circumstances, MABP correlates poorly with the microcirculatory flow.2 Elevation in MAPB may, paradoxically, result in reduced microvascular perfusion and cerebral oxygenation, possibly due to capillary flow disturbances, despite meeting recommended endpoints of CPP.3,4 Here, we first describe the anatomic and physiological basis for the cerebrovascular effects of vasopressor agents. Next, we review the pharmacodynamics of commonly used vasopressors under normal circumstances and in the presence of head injury. We further discuss the role of blood-brain barrier (BBB) disruption and microvascular dysfunction with regard to the effects of the reviewed vasopressor agents.



The brain’s extracerebral arteries are encircled by a perivascular plexus of nerve fibers originating from peripheral ganglia (extrinsic innervation). The sympathetic nerves of this “extrinsic innervation” have contractile effects on cerebral vasculature, whereas the parasympathetic innervation has cerebrovascular dilatory effects (Fig. 1).9,10

Neural regulation of cerebrovascular tone. The “extrinsic” innervations are perivascular nerves that originate from peripheral ganglia (superior cervical ganglion, SCG; sphenopalatine ganglion, SPG; otic ganglion, OG; trigeminal ganglion, TG) and surround the extracerebral vessels located on the base and the surface of the brain. Upon entry into the brain parenchyma, pial arterioles lose their peripheral nerve supply. Instead, they and brain capillaries receive fibers that project from central neuronal pathways (intrinsic innervation) and interneurons. Glia (astrocytes, microglia, and oligodendrocytes), vascular cells (endothelial cells, vascular smooth muscle cells, and pericytes), and neurons are organized into well-structured and functionally integrated neurovascular units.5–7 The anatomic and chemical relationships between these cellular components form a functional unit and blood-brain barrier (BBB) that maintain cerebral microenvironment and detect and regulate CBF according to neuronal demand by transducing neuronal signals into vasomotor responses (neurovascular coupling).5–7 The glycocalyx lining the endothelial cells should be considered a part of the BBB and neurovascular unit and is a meshwork layer consisting of molecules including hyaluronic acid, proteoglycans, and glycoproteins.8 The glycocalyx is mainly involved in the maintenance of vascular wall integrity.

Upon entering the cerebral parenchyma, the arterioles lose their peripheral nerve innervation and instead receive innervation from cerebral neurons (intrinsic innervation),9 all of which project to the perivascular space surrounding the arteriole (Fig. 1).

Normal brain function necessitates a narrow regulated parenchymal environment different in composition and strictly separated from the peripheral circulation. The highly specialized endothelial cells that form the BBB are coated with glycocalyx, a matrix of glycosylated proteins lining the lumen of the vasculature, and with the basement membrane and astrocytic end-feet on the abluminal side (Fig. 1).8 These barriers constitute part of a physical and functional BBB.8 Shedding of the glycocalyx and increased BBB permeability is commonly seen in traumatic brain injury (TBI) and may influence drug delivery and the effects of vasoactive drugs.11 The endothelium is further encircled by mural cells with direct vasodilative and vasoconstrictive properties: smooth muscle cells at arterioles and pericytes at capillaries5 (Fig. 1). Studies suggest that astrocytes, pericytes, neurons, microglia, and endothelium are organized into well-structured and intimately linked neurovascular units.5 The anatomic and chemical relationships between these cellular components form a functional unit and a BBB that detects and regulates CBF according to neuronal demand by transducing neuronal signals into vasomotor responses.5–7 In concert with other components, for example, vasoactive metabolic substances and ion gradients, this neurovascular unit adapts the cerebral perfusion to spatial and temporal changes in neuronal activity.5,6


In the healthy brain, CBF and tissue oxygenation are tightly regulated by metabolic, vasomotor, respiratory, and neurogenic factors in a complex and not yet fully understood manner. A major site of active regulation of CBF is at the level of pial and intracerebral resistance vessels. Here, β1-adrenoceptors and β2-adrenoceptors mediate vasodilatation, whereas α1-adrenoceptors and α2-adrenoceptors mediate vasoconstriction.10,12,13 α2-adrenoceptors also mediate prejunctional inhibition of norepinephrine release and are further associated with endothelial-mediated vasodilatation (Table 1).

Cerebrovascular Adrenergic Receptor (α, β) Distribution and Effects of Vasopressors in Awake or Anesthetized Subjects Without Cerebral Pathology

Sympathetic stimulation of CBF can occur in 2 ways: (i) via the sympathetic innervation of the vessel wall (above) and (ii) via circulating, sympathetically acting mediators. A relative nonreactivity of the cerebral circulation to blood-borne catecholamines is attributed partly to the relative impermeability of the endothelial lining to polar, lipid-insoluble substances, and partly to the endothelial enzymatic apparatus capable of degrading monoamines.10 The extent to which sympathetic activity is involved in the regulation of CBF in healthy humans during rest, however, remains debated.10,29 In the event of increasing blood pressure, sympathetic neural activity is likely to protect the brain by vasoconstriction, shifting the upper limit of the autoregulation curve toward higher pressures.10,29 Parasympathetic influence on cerebrovascular alterations is still debated. However, the parasympathetic innervation seems important in mediating vasodilation in response to sympathetic innervations, and strong interdependence between the sympathetic and parasympathetic innervations exist.30

The regulation of vascular tone affects regional CBF, but tissue oxygenation is further determined by the microscopic distribution of blood along individual capillaries.31 Accordingly, any deviations from a uniform, capillary flow distribution reduce oxygen availability, and it is suggested that reduction in red blood capillary transit-time heterogeneity, which is high in resting brain tissue, improves oxygen extraction from blood to the tissue. Indeed, capillary pericytes have contractile properties and may affect both CBF32 and extraction efficacy through capillary transit-time heterogeneity.31 From the perspective of neurogenic blood flow control (above), nerve fibers not only innervate resistance vessels to control CBF but also capillaries to control their permeability and tone.33

Although difficult to monitor, capillary patency and function is just as important to brain oxygenation as it is to that of resistance vessels.4,31 Accordingly, the effect of vasopressors on cerebral oxygenation cannot be gleaned from their effects on arterial tone alone, but rather the effects of the vasoconstrictors on capillary flow patterns have to be considered, both under circumstances with intact BBB, and as they cross a leaking BBB, where vasopressor effects seem to be different.


When evaluating the cerebrovascular effects of vasoactive agents, one must consider these effects in the context of the influence and heterogeneity of other factors involved in the regulation of cerebrovascular tone.

Functional or absent cerebral autoregulation may influence the action of vasopressors. When an intervention caused by an adrenoceptor agonist or antagonist exceeds the limits of cerebral autoregulation, then CBF increases linearly with MABP.34 Other factors, such as CO2 and O2 reactivity of cerebral vessels and the concomitant use of sedatives and anesthetics must be taken into account.35 It appears that cerebral metabolism can be stimulated through adrenergic β-adrenoceptors; thus, some catecholamines, adrenaline, in particular, may affect vascular tone directly as well as indirectly through stimulation of cerebral metabolism with secondary alterations in CBF.36 Further, the absence of an intact BBB may allow the entry of administered drugs into intracerebral tissue, where they may exhibit altogether different effects on the cerebral circulation (see below).37


Phenylephrine is a selective α1-agonist and commonly used as an arterial vasoconstrictor to increase MABP (Table 1). Reflex bradycardia is often seen after administration and may be associated with a decrease in cardiac output (CO)14 (Fig. 2).

Proposed mechanisms of how vasopressors may influence cerebral tissue oxygen saturation (SctO2) and cerebral metabolism under normal and pathologic circumstances. A, Administration of phenylephrine in anesthetized normal subjects is likely associated with an increase in mean arterial blood pressure (MABP), subsequent reflex bradycardia, and reduced cardiac output (CO), which increases sympathetic activity and possibly elicits cerebral vasoconstriction with a reduction in SctO2.15,38–40 The increase in MABP may also cause autoregulatory vasoconstriction and reduce the cerebral arterial to venous blood volume ratio with a decrease in SctO2.35 The autoregulatory response may be modulated by the degree of ventilation.35 B, In circumstances with blood-brain barrier (BBB) disruption due to trauma or other pathology, noradrenaline may cross the BBB and enter the brain.22,37,41–43 Beta receptor stimulation is associated with an increase in cerebral metabolism (CMRO2) and possibly regional cerebral vasoconstriction through alpha-receptor stimulation.22,37,41–43 Pure alpha agonists such as phenylephrine may only be associated with vasoconstriction under circumstances with BBB disruption; however, this has not been demonstrated. C, After head injury, elevated intracranial pressure (ICP), astrocytic end-feet swelling, pericyte injury, and blood breakdown products are all expected to disturb capillary morphology and function, reducing tissue oxygenation for a given CBF.4,31 Oxygenated blood may thus be ‘shunted’ through the microvasculature, and increasing CPP may paradoxically be associated with poorer net oxygenation of brain tissue, potentially causing cerebral ischemia.4,31,44 D, The decrease in SctO2 after phenylephrine and noradrenaline may partly be caused by vasoconstriction of vessels in extracranial tissue contaminating the SctO2 measurement.

Recent studies in both awake and anesthetized patients have showed that administration of phenylephrine causes decreased near-infrared spectroscopy (NIRS)-derived estimate of frontal lobe cerebral tissue oxygen saturation (SctO2) despite marked increases in MABP.15,38,45 A study on anesthetized human subjects showed that phenylephrine induced concordant reductions in global hemodynamics (CO) and regional hemodynamics (SctO2), even though MABP was significantly increased.15 Whether the reduction in SctO2 is associated with a decrease in CBF has not been clarified. However, phenylephrine did not appear to influence CBF during hypothermic (28°C) cardiopulmonary bypass where CO was kept constant.39 This suggests that the cerebrovascular effects of phenylephrine may be secondary to changes in CO (Fig. 2). Whether this finding is present in normothermic subjects with spontaneous circulation remains to be identified.

Both phenylephrine and norepinephrine are associated with an increase in middle cerebral artery (MCA) flow velocity (Vmean) during isoflurane, but not during propofol anesthesia in patients without intracranial pathology.46 This finding suggested that the effects of vasoconstrictive agents on MCA flow velocity merely reflect background anesthetic-induced impairment of cerebral autoregulation rather than intrinsic vasoconstrictive effects on the cerebral vasculature. Notably, flow velocity is an indirect measure of flow, and increased MCA flow velocity does not necessarily imply increased CBF, especially if associated with the actions of vasoactive drugs.

The mechanism behind the reduction in SctO2 induced by phenylephrine is not fully clarified and remains controversial. It is suggested that phenylephrine constricts cerebral resistance vessels indirectly via reflexively increased sympathetic nerve activity subsequent to a decreased CO15 (Fig. 2). It has previously been proposed that acute arterial hypertension may activate a sympathetically mediated reflex from the superior cervical ganglion, causing constriction of cerebral resistance vessels47 (Fig. 2). The effect of phenylephrine-induced hypertension on MCA Vmean and SctO2 was examined in healthy subjects during rest and exercise.48 The authors reported that, during rest, MABP and MCA Vmean increased, whereas SctO2 paradoxically decreased. It was suggested that a combination of a baroreceptor-mediated decrease in CO, a direct effect of phenylephrine on cerebral vessels facilitated through temporary hypertension-induced breach of the BBB, and an autoregulatory response due to an increase in MABP could explain the SctO2 decrease.48 Interestingly, the effect of phenylephrine on SctO2 was abolished during increasing levels of exercise. This was interpreted as a possible consequence of the increased cerebral metabolism, thus indicating a context-dependent balance between cerebral metabolism and sympathetic regulation of cerebral perfusion.48 The negative effect of phenylephrine on SctO2 appears to be enhanced by hypocapnia and blunted by hypercapnia and suggests that the effect of vasoactive agents is possibly modulated by carbon dioxide partial pressure (PaCO2)35 (Fig. 2).

Studies suggest that the effects of phenylephrine on CO may be preload dependent,49 and CO should be considered an integrated physiological regulator within the framework of cerebral perfusion40,49 (Fig. 2). The evidence is based on studies demonstrating alternations in CBF caused by acute induced changes in CO that seem independent from other CBF-regulating parameters like MABP and PaCO2.16,50 An approximate 10% CBF decrease for a 30% CO reduction was estimated.40 Under circumstances with stable MABP, the conventional hemodynamic model dictates that, in order for increases in CO to alter CBF, both peripheral resistance and cerebral resistance must decrease. For a given CO, the CBF will ultimately be determined by the balance between cerebral vascular resistance and systemic vascular resistance (SVR).

Interpreting data on the phenylephrine-induced effect on cerebral oxygenation on the basis of NIRS-derived SctO2 is potentially subject to pitfalls and needs careful considerations. NIRS-derived cerebral oxygenation estimate is related to the balance between arterial and venous blood saturation in the brain.17 Thus, it has been suggested that phenylephrine administration induces cerebral autoregulatory vasoconstriction and a change in the balance between cerebral arterial and venous blood flow, which may in part explain the paradox of decreased SctO2, while there is increased CBF velocity35,51 (Fig. 2). Other experimental studies suggest extracranial contamination (soft tissue vasoconstriction) of the NIRS signal by α-agonists as an alternative or contributing explanation for the decreased NIRS signal during catecholamine administration17 (Fig. 2).


Ephedrine stimulates α-adrenergic and β-adrenergic receptors directly and indirectly by promoting the endogenous release of norepinephrine. Ephedrine has positive inotropic and chronotropic effects and thus augments MABP through an increase in both SVR and CO (Table 1).14

In comparison with phenylephrine, ephedrine shows no negative effects on SctO2.15,45 A study in anesthetized human subjects compared ephedrine and phenylephrine to correct for anesthesia-induced hypotension.45 Both vasopressors augmented MABP above the considered lower limit of autoregulation, but only ephedrine managed to restore CO and preserve SctO2.45 Similarly, a randomized cross-over trial on anesthetized humans comparing ephedrine and phenylephrine found preserved SctO2 and CO after ephedrine administration.15 In contrast, CO and SctO2 were reduced after phenylephrine administration despite a marked increase in MABP. Among the physiological variables considered (MABP, CO, HR, end-tidal CO2, peripheral saturation [SpO2], and BIS), CO was most significantly associated with SctO2. The authors suggested a cause-effect relationship between global hemodynamics and regional hemodynamics under circumstances where changes in CO are induced by sympathomimetic agents15 (Fig. 2). Accordingly, the elevated SctO2 appears to be associated with an increase in CO, whereas an increase in MABP seems not to be an absolute prerequisite to ensure adequate SctO2.

Despite an increase in MABP, ephedrine did not change MCA Vmean in a study on healthy subjects.52 The lack of MCA Vmean increase was ascribed to augmented cerebral vascular tone (characterized as zero-flow pressure [ZFP]). ZFP is regarded as a function of ICP, central venous pressure, and vascular tone. Supported by others,18 the authors speculate that, in subjects with relatively low ICP and central venous pressure, cerebrovascular tone is the foremost determinant of downstream CPP. Thus, CPP can be estimated as the difference between MABP and ZFP. In the study by Moppett el al,52 calculated ZFP increased significantly, while CPP was maintained. In conclusion, the use of ephedrine (and dobutamine) was regarded to be associated with increased cerebrovascular tone, but without effect on CPP and other measures for cerebrovascular homeostasis including transient hyperaemic response test, and reactivity to carbon dioxide.52 Thus, it appears that ephedrine may not affect dynamic autoregulation. In a trial comparing the effect of phenylephrine and ephedrine on cerebral oxygenation on anesthetized subjects undergoing carotid endarterectomy, the authors found a higher rate of restoration of SctO2 (ipsilateral and contralateral to the planned site of surgery) in the ephedrine group than in the phenylephrine group.19 While postoperative clinical outcomes were similar among the 2 groups, the postoperative plasma concentration of S100B protein was lower in the ephedrine group than in the phenylephrine group. Ephedrine was suggested as the drug of choice in the treatment of hypotension; however, the concentration of S100B was a secondary outcome parameter, and there was potential for confounding.19


Norepinephrine has predominantly α1, but also β1 adrenoceptor agonist properties, causing vasoconstriction and inotropic and chronotropic effects (Table 1).14 Norepinephrine is widely used in neurointensive care to maintain CPP in patients with TBI and other cerebral pathologies. In studies of patients with intact BBB, pioneering studies suggested that norepinephrine has only minor (approximately 5% to 10% decrease in CBF) or no influence on normocapnic CBF or cerebral metabolic rate of oxygen (CMRO2).20,53 In accordance with these findings, a contemporary study reported constant MCA flow velocity during norepinephrine infusion in awake healthy subjects despite an increase in MABP by 25%.54 Sustained MCA Vmean under norepinephrine infusion is also supported by other studies.21 From these studies, it was concluded that MABP augmentation with norepinephrine may not achieve increases in CPP in subjects with intact autoregulation.54 If the BBB is disrupted, however, or MABP is increased above the upper limit of the cerebral autoregulation, norepinephrine will increase CBF and CMRO222,37 (see below).

Contrasting evidence exists as to whether the norepinephrine-induced increase in MABP is associated with a decrease or increase in CO and whether norepinephrine, like phenylephrine, has a negative influence on SctO2. In healthy awake subjects, infusion of norepinephrine (0.1 μg/kg/min) increased MABP simultaneously with a reduction in MCA Vmean, SctO2, and internal jugular venous saturation (SvjO2), while CO remained constant.55 Norepinephrine-induced stimulation of arterial chemoreceptors and augmentation of pulmonary ventilation was suggested as a partial explanation of the reduction in SctO2. In addition, as SctO2 mainly reflects the venous compartment, it was proposed that the decrease in SctO2 in part represents a decrease in SvjO2.55 Furthermore, a contribution from extracranial contamination of the NIRS-signal was suggested. The authors speculate that the observed norepinephrine-induced reduction in cerebral oxygenation may be associated with a constant CO in the face of increasing MABP; suggesting that preservation of cerebral oxygenation depends on the ability of CO to increase with MABP.55 In contrast, however, a recent study on anesthetized patients during cardiopulmonary bypass reported no significant association between norepinephrine dose and SctO2.56 Level of sedation, use of extracorporeal circulation, and patient comorbidity may explain the different findings. In anesthetized patients, norepinephrine and phenylephrine infusion caused a decrease in SctO2 and cardiac index despite increased MABP.24 Likewise, the effects of calcium chloride, ephedrine, phenylephrine, epinephrine, and norepinephrine on SctO2 were studied in the treatment anesthesia–induced hypotension in patients scheduled for abdominal surgery.57 When data were analyzed as effects of β-adrenoceptor agonists (ephedrine and epinephrine) and α-adrenoceptor agonist (phenylephrine and norepinephrine), the authors found preserved SctO2 in the β-adrenoceptor agonist group and following calcium chloride administration, but a slight (2%) reduction in SctO2 in the α-adrenoceptor agonist group.57 The administered drugs all increased MABP, but CO increased only in the β-adrenoceptor group. Thus, an attempt to improve cerebral perfusion by augmentation of MABP without knowledge of the consequent change in CO seems to render the clinician potentially blinded to the subsequent effects on cerebral oxygenation. In addition, CBF is a major component of CO, and hence any analysis should recognize that the two flows are intrinsically correlated.


Dopamine is an endogenous catecholamine and a major neurotransmitter of the brain. When administered as an exogenous agent, dopamine is associated with heterogenous cardiovascular effects.58 Low doses of dopamine exert effects via the various dopamine receptor subtypes, mainly causing a decrease in vascular resistance and vasodilation.59 Higher doses of dopamine hold mainly β-adrenoceptor and α-adrenoceptor agonist properties in addition to affecting 5-hydroxytryptamine (5-HT) receptors, which may lead to both an increase or a decrease in CO, heart rate, and SVR.58

These complex pharmacological actions make interpretation of the cerebrovascular effects challenging. Early in vitro studies have shown that dopamine has contractile effects on major cerebral arteries.25 The contractile effect appears to be the result of α-adrenoceptor and 5-HT receptor stimulation.25–27 Animal studies have reported that dopamine is associated with both dose-dependent increases and decreases in CBF, while CMRO2 remains virtually unchanged.28,60 It has also been reported from animal studies that dopamine increases ICP.60,61 The mechanism by which dopamine in these studies seems to exert effects on cerebral perfusion remains elusive. Dopamine may exert an effect on cerebral vasculature via nonadrenergic mechanisms or by passing the BBB. In animal models with breached BBB and animal studies using dopamine agonists capable of crossing the BBB, increased CBF and CMRO2 have been found.62,63 In a series of studies on awake and anesthetized animals, dopamine, norepinephrine, and epinephrine were not associated with alteration of cerebral pressure autoregulation.64,65


The current guideline on the management of TBI from The Brain Trauma Foundation recommends maintaining CPP between 60 and 70 mmHg (evidence level IIB).1 The guideline provides no recommendation on the potential choice of vasopressor. Currently, only a limited number of studies compare the effectiveness and associated complications of commonly used vasopressor agents in patients with TBI, and the findings seem conflicting. To our knowledge, there are no studies available on the cerebrovascular effects of ephedrine in patients with TBI, and, consequently, the sections below only focus on the effects of phenylephrine, norepinephrine, and dopamine.

Influence of BBB Permeability on Cerebrovascular Effects of Vasopressors

Under normal circumstances, the major effects of exogenous catecholamines on CBF and CMRO2 are prevented by the intact BBB. However, TBI is often associated with increased BBB permeability, and there is experimental evidence of paradoxical effects of vasopressors with increases in CBF and CMRO2 in subjects with BBB disruption.22,37,41 Early animal studies examined the effects of systemic norepinephrine on cerebral perfusion in subjects with osmotic opening of the BBB or by methodological bypassing of the BBB and found increased regional CBF22,37,41 and increased cerebral metabolism and glucose utilization (Fig. 2).37,41 Stimulation of β-receptors appears to be the mechanism responsible for the reported increase in CMRO2 and CBF when norepinephrine gains direct access to the brain42 (Fig. 2). Whether this effect then is absent during stimulation with a selective α1-agonist (phenylephrine) has not been confirmed. Clinical evidence of different cerebrovascular effects of vasopressors under circumstances with BBB disruption is very limited. A paradoxical reduction in intracontusional regional CBF was reported after norepinephrine-induced elevation of CPP in patients with TBI.23 The authors speculated that the paradoxical reduction in CBF with CPP augmentation might be a consequence of increased BBB permeability with transendothelial diffusion of norepinephrine and a direct vasoconstrictive effect on the cerebral vessels.23 Similarly, norepinephrine was associated with vasoconstriction of cerebral vessels in an animal model with induced disruption of the BBB, and the authors speculated that the BBB hinders a potential α-adrenoceptor-mediated vasoconstrictive effect of norepinephrine.43

Thus, under circumstances with BBB disruption, the effects of vasopressors may include increases in both CMRO2 and CBF in addition to direct vasoconstrictive effects on cerebral vessels.


Few clinical studies have described the cerebrovascular effects and effectiveness of phenylephrine in patients with TBI. In a retrospective study, including 114 adult TBI patients, phenylephrine was associated with higher MABP than dopamine and higher CPP than norepinephrine when adjusting for different baseline parameters.66 There was no statistically significant difference in baseline ICP or ICP during vasopressor treatment between the vasopressor groups. However, increasing CPP may not necessarily improve cerebral oxygenation. In a study including moderately or severely head-injured patients, CPP was augmented by phenylephrine.3 The marked increase in CPP was, however, not associated with increased cerebral oxygenation, measured as brain tissue oxygen (PtiO2). This is similar to the findings in experimental head injury in swine, which showed that phenylephrine was as effective as arginine vasopressin in maintaining CPP, but the ICP was higher and cerebral oxygenation lower in the phenylephrine group.67

In contrast, an experimental study reported that phenylephrine was associated with improved cerebral oxygenation compared with a control group in a similar head injury model in swine.68 However, the phenylephrine-treated group had more lung edema, suggesting an inclination for adverse systemic effects, such as pulmonary congestion. The propensity of such adverse systemic effects must be considered, when selecting the appropriate vasoactive agent.

The cerebrovascular effects of vasopressors may be different in the immature brain. In a pediatric head injury model, the efficacy of norepinephrine was compared with phenylephrine to target a CPP of 70 mm Hg.69 In the group receiving norepinephrine, there was higher PtiO2 with no statistically significant difference in CBF between the 2 groups. Animals receiving phenylephrine experienced a greater reduction in metabolic crisis (lactate/pyruvate ratio) and less ischemic injury. The authors speculated that the increased PtiO2 in the norepinephrine group might be the result of norepinephrine-induced reduction in oxygen utilization or partly by a not statistically significant higher CBF.

In subjects with TBI and increased BBB permeability, the question of vasopressor-induced secondary edema and increased ICP becomes a matter of concern. In a cortical impact model, phenylephrine increased CBF and CPP, with a concomitant increase in ICP, which was associated with extensive neurological injury compared with the control group.70 To our knowledge, no clinical studies have convincingly demonstrated whether augmentation of MABP with phenylephrine is associated with increased cerebral edema.


In neurointensive care, norepinephrine may by some be regarded as the first-line vasopressor when an increase in CPP is warranted to improve cerebral oxygenation. Using norepinephrine to augment CPP from 70 to 90 mm Hg in TBI patients, CBF and CBV were increased (consistent with impaired cerebral autoregulation), whereas CMRO2 and OEF (oxygen extraction fraction) were reduced.71 The reduced OEF was attributed to increased oxygen supply through augmented CBF in addition to reduced CMRO2. Further, the authors reported a significant reduction in ischemic brain volume (IBV), this being linearly related to baseline IBV with clinically significant reductions in patients with large baseline IBV.71 Similarly, the effects of CPP augmentation with norepinephrine were studied in patients with TBI.72 In this study, norepinephrine was associated with a significant increase in PtiO2 and CBF and a significant decrease in OEF. Measurements were predominantly made in areas of the brain appearing normal on computed tomography scan. These findings were, however, not accompanied by predicted changes in regional chemistry determined by microdialysis. Interestingly, CPP augmentation led to a greater percentage increase in PtiO2 than percentage decrease in OEF. The authors speculated that CPP augmentation may recruit cerebral capillaries and thereby reduce the oxygen gradients between tissue and vascular compartments. Another study, on patients with TBI, compared the effects of CPP augmentation with dopamine and norepinephrine on regional and global cerebral oxygenation.73 Norepinephrine significantly increased regional and global oxygenation expressed as PtiO2 and arterial-jugular venous oxygen difference, respectively. No significant differences in cerebral oxygenation or metabolism on either CPP level was found between dopamine and norepinephrine.73 Thus, there is clinical evidence that norepinephrine increases CBF and brain tissue oxygenation in patients with TBI. Notably, the degree of BBB permeability was not reported in the above studies, and whether these findings are associated with improved outcome remains to be elucidated.

Augmentation of CPP imposes a risk of increased ICP. In a randomized, cross-over trial carried out on TBI patients, predictable increases in CBF, as estimated by TCD flowmetry, were demonstrated during norepinephrine-induced CPP augmentation.74 The CPP augmentation did not significantly affect ICP. Likewise, Johnston et al73 did not find increased ICP during CPP augmentation by either norepinephrine or dopamine in TBI patients. Further, lower ICP was reported with norepinephrine when compared with dopamine infusion in a cross-over trial targeting the same MABP in head-injured patients.75 Thus, norepinephrine does not appear to have a major impact on ICP in patients with TBI.


In head injury, few clinical data exist on the influence of dopamine on the cerebral circulation and oxygenation and have already been mentioned in the “norepinephrine” section above. Experimental data are therefore reviewed in the following section. In a cortical impact model in rats, MABP augmentation (MABP, 89 to 120 mm Hg) with dopamine caused a significant increase in regional CBF measured by laser Doppler flowmetry.76 Hemispheric swelling and water content (using wet-weight/dry-weight method) were not significantly affected in the dopamine group 8 hours after injury. In an additional study by the same group, comparable MABP augmentation with dopamine did not increase ICP significantly, but an increase in experimental contusion volume was reported when CPP was maintained at 120 mm Hg.77 Similarly, in an experimental head injury model, dopamine worsened cerebral edema formation, which was associated with an increase in ICP.78 Impaired BBB function permitting transmission of induced hypertension may explain the exacerbated vasogenic edema formation and evolving contusion volume in these studies.


Cerebral blood supply and its microscopic distribution are particularly crucial in conditions of elevated ICP and BBB leakage. After a head injury, astrocytic end-feet swelling, pericyte injury, and blood breakdown products are all expected to disturb capillary morphology and function, reducing tissue oxygenation for a given CBF.4 Elevated ICP is expected to cause further deterioration of brain oxygenation, as capillaries begin to be compressed at far lower pressures than arterioles. Even for ICPs lower than 20 mm Hg, oxygenated blood may thus be “shunted” through the microvasculature, and increasing CPP, paradoxically, may be associated with poorer net oxygenation of brain tissue4 (Fig. 2). Biophysical models predict that, for severely affected capillary function, the most efficient oxygen extraction from blood is achieved by maintaining CBF slightly above the ischemic threshold,79 providing more time for oxygen to be extracted from microvessels with fast “shunt” flow, while letting tissue oxygen tension drop to provide the highest possible blood-tissue concentration gradients for oxygen extraction. In fact, unattenuated CBF increases, both in response to dynamic changes in perfusion pressure and in the form of so-called “luxury perfusion,” have been reported to carry a particularly poor prognosis in head-injured patients.4 Under such circumstances, temporary maintenance of a low intracranial blood volume and blood flow may thus be warranted. Currently, there are limited data on the influence of vasopressors on the cerebral microcirculation, both in normal brain and in conditions of elevated ICP. In particular, knowledge of vasopressor agents’ relative effects, if any, on smooth muscle cell and pericyte tone seem particularly useful, given their impact on blood supply and oxygen extraction efficacy, respectively. Moreover, the potential, direct effects of individual vasopressor agents on the microcirculation in areas of BBB breakdown deserve further scrutiny to understand their effects on tissue fate in the injured brain.


Phenylephrine is in awake and anesthetized healthy subjects associated with an increase in MABP and simultaneous reductions in CO and SctO2. However, under circumstances with constant CO, phenylephrine appears to maintain CBF and possibly SctO2 unaltered. Thus, the cerebrovascular effects of phenylephrine may be secondary to cardiovascular changes and need further investigation. In contrast, ephedrine is consistently associated with an increase in MABP, CO, and SctO2. In healthy subjects, norepinephrine is associated with a small reduction in CBF. However, contrasting evidence exists on the effects on cerebral oxygenation, as augmentation of MABP and CPP with norepinephrine is associated with both a decrease and a neutral effect on SctO2. Future studies will determine whether the reported changes in SctO2 after vasopressor treatment are in fact associated with changes in cerebral oxygenation. In healthy subjects, dopamine is associated with a dose-dependent increase in CBF, while CMRO2 remains unaltered. In head injury, contrasting effects have been reported on the influence of phenylephrine and norepinephrine on CBF parameters and oxygenation. Whether the choice of vasopressor can influence outcome after TBI has not been investigated. Under circumstances with BBB disruption, vasopressors may be associated with an increase in CMRO2 and CBF. However, solid clinical evidence for different effects of vasopressors in conditions with BBB disruption is still lacking and should be further investigated. Vasopressors may affect capillary flow and thereby oxygenation. Experimental and clinical evidence is lacking concerning the influence of vasopressors on microcirculation in the normal brain and in subjects with brain pathology, and clinical studies are highly warranted.44 Overall, until further clinical evidence is available, we cannot recommend one of the reviewed vasopressors over another.


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vasoconstrictor agents; cerebrovascular circulation; blood pressure; craniocerebral trauma

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