M. Leone, P. Visintini, and C. Martin
Introduction
The modulation of arterial pressure is an important stage in the care of a patient with a cerebral lesion. International guidelines recommend a level of cerebral perfu- sion pressure (CPP = mean arterial pressure [MAP] – intracranial pressure [ICP]) that is superior to 60 mmHg. On the other hand, a level that exceeds 70 mmHg in the absence of cerebral ischemia must be avoided given the risk of acute respiratory distress syndrome (ARDS) [1]. Moreover, a single episode of hypotension defined as systolic arterial pressure ‹ 90 mmHg in a patient with severe head trauma is associ- ated with an increase in mortality and morbidity [2].
In fact, the variations induced by pharmacologic treatment of arterial or perfu- sion pressure have different effects depending on the preservation of cerebral vaso- motor reactivity (auto-regulation). Arterial pressure is not correlated to the velocity of cerebral blood flow (CBF) when auto-regulation is intact; in this case, its increase triggers vasoconstriction, a reduction in cerebral volume and, therefore, a decrease in ICP. On the other hand, the correlation between arterial pressure and the velocity of CBF is significant in patients who have lost self-regulation [3]. Treatment must, therefore, take the presence or absence of auto-regulation into account.
An analysis of a data bank of 392 patients with Glasgow Coma Scale (GCS) scores between 3 and 8 revealed that a MAP inferior to 70 mmHg was associated with a poor prognosis in patients with severe head trauma. It should be noted that the results were not the same when the level of MAP was fixed at 80 mmHg [4]. In such patients, it is, therefore, advisable to maintain a MAP that is superior to 70 mmHg with CPP between 60 and 70 mmHg.
The aim of this chapter is to define the role of catecholamines in the maintenance of these therapeutic objectives. For that, an analysis of the literature using the Pub- med database was performed using the following key words and their combinations:
catecholamines, norepinephrine, epinephrine, dopamine, dobutamine, dopexamine, isoprenoterol, head injury, cerebral perfusion pressure, intracranial pressure, cere- bral blood flow, trauma. Randomized clinical trials were specifically targeted.
The Effects of Hypertension on a Cerebral Lesion
Increasing CPP beyond 70 mmHg is inadvisable given the resulting extracranial complications. In one study, increasing CPP by 20 % using norepinephrine in head trauma patients reduced the volume of the ischemic zone, improved flow metabo- lism coupling and increased the ICP by 2 mmHg [5]. In another study, an increase
in MAP of 14 „ 5 mmHg triggered an increase in ICP from 16 „ 9 to 19 „ 9 mmHg.
In this population, a decrease in ICP of more than 20 % was observed in 77 % and 49 % of the patients treated by hyperventilation or metabolic suppression (propofol), respectively, whereas this occurred in only 5.5 % of the patients with induced hyper- tension [6].
The effects of arterial pressure variations were studied in 13 head trauma patients during the first three days of hospitalization. The initial MAP was 94 mmHg. It then decreased to 68 mmHg and subsequently went up again to 126 mmHg. In the six patients with an ICP 8 24 mmHg, the reduction in CPP increased ICP and reduced cerebral tissue oxygen partial pressure (PtiO2). The patients without intracranial hypertension did not present significant variations during the various tests [7].
A study of CBF around the contusion zone provided interesting data. The flow and the volume of the cerebral blood compartment increased in the region of the contusion. The increase in CPP from 70 to 90 mmHg had effects on the perilesional zone that were not significant. Overall, the ischemic regions remained ischemic [8].
Thus, the effects of hypertension on the hemodynamics of head trauma patients depend in part on self-regulation and the ICP level. Locally, a reduction in ischemic zones or a modification in (PtiO2) is sometimes observed. In any case, these modifi- cations have no clearly defined clinical consequences.
The Effects of Catecholamines and other Vasopressors The Systemic Effects of Catecholamines
The systemic effects of catecholamines depend on their affinity for [ - and q -recep- tors. Briefly, seven subtypes of [ -receptors have been described but only [ 1 and [ 2 are of practical interest. These receptors respond, in order of strength, to norepi- nephrine 8 epinephrine 8 isoprenoterol. Norepinephrine has a sensitivity that is higher for [ 1 than for [ 2 receptors. [ 1 receptors activate the Gq protein which increases intracellular calcium via phospholipase C. This results in muscle contrac- tion whereas stimulation of [ 2 receptors induces vasodilatation via inhibition of adenyl cyclase. In addition, [ 2 receptors have central effects such as sedation, anxio- lysis, and analgesia.
q -receptors are different from a pharmacologic point of view. The order of sensi- tivity for q -receptors is isoprenaline 8 epinephrine 8 norepinephrine. These recep- tors activate a Gs protein and increase the concentration of cyclic AMP via the acti- vation of adenyl cyclase which in turn triggers muscular relaxation.
The Cerebral Effects of Catecholamines
NorepinephrineNorepinephrine is a central nervous system (CNS) endogenous mediator. The administration of exogenous norepinephrine induces dose-dependent effects. At a low dose, the q 1 effect predominates, inducing an increase in cardiac output, whereas strong doses stimulate [ 1 receptors, inducing intense vasoconstriction of the arterial and venous territories. In head trauma patients, increasing arterial pres- sure with norepinephrine has no effect on renal function [9].
Old data suggest that norepinephrine reacts through a local mechanism during a cerebral lesion. The application of topical norepinephrine on large cerebral arteries induces vasoconstriction. This is not the case for small arteries [10]. The absence of
a response is probably due to a modest sympathetic innervation of the small arteries and to the liberation of nitrogen monoxide at their level [11, 12]. Intraventricular injection of a 40 µg/kg bolus of norepinephrine significantly increases CBF, oxygen and cerebral glucose consumption. After chemical rupture of the hemato-encephalic barrier, intra-carotid injection of 50 ng/kg/min of norepinephrine increased CBF, cerebral oxygen and glucose consumption. The response to norepinephrine is, there- fore, dependent on the integrity of the hemato-encephalic barrier and the increase in CBF is secondary to that of cerebral metabolism [13]. These results are in agree- ment with those of a study performed on a culture of astrocytes. The formation of CO2due to glucose oxidation increases in the presence of norepinephrine. Oxidative metabolism is linked to the stimulation of [ 1 and 2 receptors [14]. In an experiment on conscious rats, an elevation in arterial pressure induced by the administration of 10 µg/kg/min of norepinephrine did not modify the CBF/glucose utilization ratio or the blood brain barrier [15]. Another study performed in conscious rats reported a reduction in glucose metabolism with unchanged CBF during perfusion of norepi- nephrine which produced moderate hypertension [16]. However, the clinical rele- vance of these studies is debatable since experimental conditions are far from clini- cal practice. The doses of norepinephrine were 20 times more than those used in clinical practice, the injection sites were inappropriate, and the clinical condition of the animals did not mimic that of a cerebral lesion.
Two arguments suggest that the local effect of norepinephrine on cerebral hemo- dynamics is not significant. First of all, in healthy tissue, norepinephrine boutons are directly apposed to the capillary wall at sites of glial end-feet discontinuities, leading one to suppose that the latter are not very accessible (Fig. 1) [17]. In a head trauma animal model, self-regulation was stopped in the area of the lesion. During rupture of the blood brain barrier, the local effect of norepinephrine should induce vasoconstriction. However, elevated MAP increases local CBF with arteriolar vasodi- latation, confirming the abolition of auto-regulation [18]. Second, a study performed in healthy volunteers revealed that an increase in cerebral vascular resistance during perfusion of norepinephrine is the result of self-regulation with constant CBF despite the increase in MAP. In order to decouple the effects of MAP and norepi- nephrine, an antihypertensive agent (phentolamine) was used to normalize MAP, keeping the norepinephrine perfusion constant and, thereby, preserving the local effect. CBF remained constant and vascular resistances regained their initial values [19]. This study confirmed the specific local effect of norepinephrine when the blood brain barrier is intact. Although data remain uncertain in head trauma patients, it would appear that the local effect is not predominant.
Fig. 1. Relation between norepi- nephrine receptors and cerebral vessels.
Dopamine
Dopamine is the immediate precursor of norepinephrine. It has dose-dependent actions as a neurotransmitter via activation of the D1receptor and as an indirect agent by inhibiting the liberation of norepinephrine via the D2receptor. Doses that range from 2 to 10 µg/kg/min have positive chronotropic and inotropic effects by activating the q 1-receptor. Beyond 10 µg/kg/min, the [ 1-receptors trigger vasocon- striction.
In the large cerebral arteries, dopamine-induced relaxation appears to be linked to dopaminergic receptors which predominate over the [ vasoconstrictor effect at a low concentration [20]. In conscious rats treated with dopamine (200 µg/kg/min) in order to reach a MAP of 150 mmHg, the CBF/glucose utilization ratio and the blood brain barrier permeability increased with the administration of dopamine [15]. On the other hand, two animal studies revealed that dopamine perfusion triggered an increase in MAP without modifying CBF [21, 22].
Another study has clarified this contradiction by stressing the effect of the dose.
Rats were subjected to head trauma, then randomized to either a treatment group (dopamine at 40 – 50 µg/kg/min) or a placebo group (saline solution). CBF decreased by 46 % at the level of the cerebral contusion in all of the rats. The administration of dopamine at 10 – 12 µg/kg/min did not modify MAP or cortical cerebral blood pres- sure compared with the placebo. On the other hand, a dose of 40 – 50 µg/kg/min increased MAP from 89 to 120 mmHg and CBF in the contusion zone by 35 %. How- ever, flow was not modified in the contralateral hemisphere. Cerebral swelling, water content, and the concentration of glutamate and hypoxanthine in the cerebrospinal fluid (CSF) were not affected by the perfusion of dopamine. In fact, the administra- tion of dopamine revealed a local change in self-regulation [23].
In a rodent model, the effect of dopamine was determined using models of a rapid increase in ICP due to a secondary lesion and a cortical contusion. Dopamine restored cerebral perfusion in the first model with partial restoration of CBF. Mag- netic resonance imaging (MRI) showed an elevation in cerebral water content four hours after the lesion. Dopamine perfusion increased the quantity of water. In the contusion model, the administration of dopamine aggravated the edema in the homo- and controlateral zones [24].
In conclusion, dopamine is effective in restoring CPP but increases CBF depend- ing on the area of the lesion. Its effect on the volume of the lesion has not been defined but requires caution.
Other catecholamines
Epinephrine is an endogenous catecholamine which, at a low dose (0.015 µg/kg/
min), activates the q 1 (increase in cardiac output) and q 2 (bronchodilatation and vasodilatation) receptors. At high doses, the [ receptors are stimulated, leading to vasoconstriction. The cerebral effect of epinephrine was tested on a sheep model without cerebral lesion. In this model, the hypertension induced by a clinically sig- nificant dose of epinephrine did not alter CBF, ICP, or cerebral consumption of oxy- gen [25].
Among the agents that preferentially act on q -receptors, dobutamine is a syn- thetic catecholamine derived from dopamine that acts predominantly on q 1 recep- tors. The cerebral effects of dobutamine have been analyzed in a sepsis model excluding meningitis (loss of auto-regulation). Dobutamine perfusion increased CBF and MAP [26]. MAP modification was the only effect reported in healthy volunteers [27]. These results alone do not make it possible to make conclusions on the possi-
ble local effects of dobutamine although it would appear that this agent does not have an effect on healthy brain. Auto-regulation is probably stopped in the case of sepsis. The increase in CBF, parallel to that of MAP, suggests passive vasodilatation linked to the increase in flow. However, one cannot exclude the possibility that dobutamine, through its q effect, triggers vasodilatation due to the change in the blood brain barrier [26, 27]. In conclusion, since these agents have a predominant q receptor effect, they must be excluded from the therapeutic arsenal used to maintain adequate CPP.
A non-catecholamine vasopressor: Vasopressin
Vasopressin is a natural hormone secreted from the posterior pituitary gland. It is active via the V1, V2, and V3receptors. V1receptors activate a Gq protein which pro- duces an elevation in intracellular calcium concentration and consequently a con- traction of smooth muscle. This system is an alternative to the catecholamine system for strong vasoconstriction. V2receptors make up the antidiuretic system at the level of the kidneys whereas V3receptors are stimulated by adenocorticotropic hormone (ACTH).
Vasopressin has a marked local effect with a probable role in vasospasm via acti- vation of the V1receptors. In fact, in a goat model, incremental doses of vasopressin (0.03 – 1 µg) administered in the internal mammary artery significantly increased cerebral vascular resistance. This effect was not observed with desmopressin, which elicits V2receptor action [28]. In a murine model, vasopressin was implicated in the vasospasm secondary to subarachnoid hemorrhage (SAH) [29]. In a head trauma model followed by hemorrhagic shock, the effects of volemic expansion, with or without administration of a vasopressor (phenylephrine or vasopressin), were com- pared [30]. The addition of vasopressors prevented an increase in ICP and a reduc- tion in CPP. Lactate plasma levels remained elevated in the group treated with vaso- pressin whereas it decreased in the other groups [30]. The effects of vasopressin on cerebral hemodynamics remain to be clarified but its vasoconstrictive properties with its probable implication in vasospasm make its use advisable.
Comparison of Norepinephrine and Dopamine
Animal modelThe effects of norepinephrine and dopamine were studied in a murine model with cerebral lesion (by hammer) followed by hypoxic and hypotensive shock with the aim of maintaining CPP greater than 70 mmHg. In the control group, CPP decreased with an increase in ICP and a reduction in CBF. Surprisingly, the CPP objective was not achieved with either catecholamine. Moreover, ICP was higher in the catechol- amine groups than in the control animals. Local CBF fell in a similar manner in the three groups. According to the authors, hypovolemia, as an explanation for the resis- tance to catecholamines, was improbable given the volemic expansion performed [31].
Human studies
Four studies have compared norepinephrine and dopamine in head trauma patients (Table 1) [32 – 35]. The first study was prospective and not randomized with the choice left to the doctor who received the patient. Nineteen patients were included with an initial ICP of 29 „ 10 mmHg. Catecholamines were crossed over after the first data collection. The important result of this study was the significant increase
Table 1. Human studies comparing norepinephrine (NE) and dopamine (DA).
Reference Design Patients (n)
Objectives Dopamine Norepinephrine Conclusion
[32] Prospective (19)
CPP 8 60 mmHg
SjvO2 8 55 % →ICP NE 8 DA (effect ICP)
[33] Prospective, randomized (11)
65 mmHg→CPP 85 mmHg
Less
predictable →O2local
→ 2 O2art-vein
NE 8 DA (prediction)
[34] Prospective, randomized (10)
65 mmHg→CPP 85 mmHg
Less predictable
NE 8 DA (prediction)
[35] Prospective, randomized (15)
65 mmHg→CPP →HR, CI →creatinine clearance
→ pHi
No difference
CI: cardiac index; HR: heart rate; ICP: Intracranial pressure; CPP: cerebral perfusion pressure; SjvO2: oxygen jugular venous saturation
in ICP with a reduction in CPP in the dopamine group. Transcranial Doppler and oxygen saturation data, measured in the jugular vein, were similar in both groups.
Given the results, it was not possible to know how many patients lost cerebral auto- regulation. Norepinephrine, therefore, had a better performance than dopamine for the selected criteria [32].
In order to increase CPP from 65 to 85 mmHg, the effects of norepinephrine and dopamine were compared in a randomized study that included 11 patients with severe head trauma (GCS ‹ 10) [33]. A microdialysis system analyzed local oxygen exchange. An increase in CPP induced by norepinephrine significantly reduced the arterio-venous difference in oxygen and increased local oxygenation. This result was not obtained with dopamine. There was no difference between dopamine and nor- epinephrine in terms of ICP, although the response to dopamine was less predictable [33].
A cross-over randomized study was performed by the same team in 10 patients who had initially been treated with norepinephrine or dopamine [34]. CPP was set at 65 mmHg, was increased to 75 mmHg and finally to 85 mmHg, with a cross-over of catecholamines. On admission, GCS scores were between 3 and 8 (the study was performed three days after admission). Norepinephrine predictably increased the velocity of mean cerebral artery flow estimated by transcranial Doppler at each stage of the experiment whereas dopamine produced unpredictable results. However, no significant difference was observed in terms of the absolute value of ICP or CBF. The high levels of CPP required in this study are not currently recommended which lim- its the scope of these results [34].
In a study using the same protocol and performed in 15 patients with GCS scores from 3 to 8, the aim was to maintain CPP at 65 mmHg. Norepinephrine and dopa- mine doses were 0.27 „ 0.2 µg/kg/min and 11.3 „ 3 µg/kg/min, respectively. Heart rate and cardiac index were higher in the dopamine group and a reduction in intra- mucosal pH was observed in the norepinephrine group without hyperlactatemia.
Creatinine clearance was significantly increased in this same group. CPP and ICP on inclusion were 15 and 55 mmHg, respectively. The CPP target (8 65 mmHg) was
reached with no significant difference between the groups. The velocities measured by transcranial Doppler increased uniformly after treatment and ICP increased non- significantly (18 „ 9 mmHg) [35].
Of these studies, three concluded in favor of the use of norepinephrine in head trauma patients. The first study showed an elevation in ICP after the administration of dopamine but the absence of randomization obviously limits the interpretation of the results [32]. The second and third studies were published by the same group, the same year in two different journals. Both studies indicated better norepinephrine pre- dictability but the CPP objectives are no longer recommended in daily clinical prac- tice [33, 34]. The fourth study was published in abstract form [35]. The CPP target was 65 mmHg. No difference in cerebral hemodynamics was observed. None of these studies had a large enough cohort to make definitive conclusions. Moreover, there are no data on the effect of catecholamines on the recovery and mortality of patients with severe head trauma, which illustrates the need for future clinical studies. The results of the above studies encourage the use of norepinephrine given its better predictabil- ity, despite the fact that this result only appears indirectly in these studies.
Conclusion
The data on the effects of catecholamines on cerebral hemodynamics are complex and variable depending on the type of artery (large or small), the condition of the hemato-meningeal barrier, changes in self-regulation, and the objectives of the study. Agents with a predominantly q -adrenergic action (dobutamine, isoprenaline) should not be used in head trauma patients to increase CPP. Norepinephrine and dopamine are the two best studied catecholamines. Overall, a local effect probably exists when there is rupture of the hemato-meningeal barrier but does not appear to be prominant in clinical practice. Administration of a catecholamine for a cerebral lesion restores CBF in the injured zones but the repercussions in terms of oxygena- tion are less obvious. There are few human studies and their methodology limits their scope. However, norepinephrine appears to be more appropriate than dopa- mine for the maintenance of CPP in patients with a cerebral lesion.
References
1. Brain Trauma Foundation (2003) The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Guidelines for cerebral perfusion pressure.
At: http://www.braintrauma.org/guidelines; Accessed December 2006
2. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care (2000) Hypotension. J Neurotrauma 17:591 – 595 3. Lang EW, Lagopoulos J, Griffith J, et al (2003) Cerebral vasomotor reactivity testing in head
injury: the link between pressure and flow. J Neurol Neurosurg Psychiatry 74:1053 – 1059 4. Clifton GL, Miller ER, Choi SC, Levin HS (2002) Fluid thresholds and outcome from severe
brain injury. Crit Care Med 30:739 – 745
5. Coles JP, Steiner LA, Johnston AJ, et al (2004) Does induced hypertension reduce cerebral ischaemia within the traumatized human brain? Brain 127:2479 – 2490
6. Oertel M, Kelly DF, Lee JH, et al (2002) Efficacy of hyperventilation, blood pressure elevation, and metabolic suppression therapy in controlling intracranial pressure after head injury. J Neurosurg 97:1045 – 1053
7. Cremer OL, van Dijk GW, Amelink GJ, de Smet AM, Moons KG, Kalkman CJ (2004) Cerebral hemodynamic responses to blood pressure manipulation in severely head-injured patients in the presence or absence of intracranial hypertension. Anesth Analg 99:1211 – 1217
8. Steiner LA, Coles JP, Johnston AJ, et al (2003) Responses of posttraumatic pericontusional cerebral blood flow and blood volume to an increase in cerebral perfusion pressure. J Cereb Blood Flow Metab 23:1371 – 1377
9. Alban`ese J, Leone M, Garnier F, Bourgoin A, Antonini F, Martin C (2004) Renal effects of nor- epinephrine in septic and nonseptic patients. Chest 126:534 – 539
10. Wie EP, Raper AJ, Kontos HA, Patterson JL (1975) Determinants of response of pial arteries to norepinephrine and sympathetic nerve stimulation. Stroke 6:654 – 658
11. Faraci FM, Heistad DD (1990) Regulation of large cerebral arteries and cerebral microvascu- lar pressure. Circ Res 66:8 – 17
12. Bauknight GC Jr, Faraci FM, Heistad DD (1992) Endothelium-derived relaxing factor modu- lates noradrenergic constriction of cerebral arterioles in rabbits. Stroke 23:1522 – 1526 13. MacKenzie ET, McCulloch J, O’Kean M, Pickard JD, Harper AM (1976) Cerebral circulation
and norepinephrine: relevance of the blood-brain barrier. Am J Physiol 231:483 – 488 14. Subbarao KV, Hertz L (1991) Stimulation of energy metabolism by alpha-adrenergic agonists
in primary cultures of astrocytes. J Neurosci Res 28:399 – 405
15. Tuor UI, Edvinsson L, McCulloch J (1986) Catecholamines and the relationship between cere- bral blood flow and glucose use. Am J Physiol 251:H824-H833
16. Kuschinsky W, Suda S, Bunger R, Yaffe S, Sokoloff L (1983) The effects of intravenous norepi- nephrine on the local coupling between glucose utilization and blood flow in the rat brain.
Pflugers Arch 398:134 – 138
17. Paspalas CD, Papadopoulos GC (1998) Ultrastructural evidence for combined action of nor- adrenaline and vasoactive intestinal polypeptide upon neurons, astrocytes, and blood vessels of the rat cerebral cortex. Brain Res Bull 45:247 – 259
18. Kroppenstedt SN, Thomale UW, Griebenow M, et al (2003) Effects of early and late intrave- nous norepinephrine infusion on cerebral perfusion, microcirculation, brain-tissue oxygena- tion, and edema formation in brain-injured rats. Crit Care Med 31:2211 – 2221
19. Kimmerly DS, Tutungi E, Wilson TD, et al (2003) Circulating norepinephrine and cerebrovas- cular control in conscious humans. Clin Physiol Funct Imaging 23:314 – 319
20. Toda N (1983) Dopamine vasodilates human cerebral artery. Experientia 39:1131 – 1132 21. Gleason CA, Robinson R, Harris AP, Mayock DE, Traystman RJ (2002) Cerebrovascular
effects of intravenous dopamine infusions in fetal sheep. J Appl Physiol 92:717 – 724 22. Myburgh JA, Upton RN, Grant C, Martinez A (2003) The effect of infusions of adrenaline,
noradrenaline and dopamine on cerebral autoregulation under propofol anaesthesia in an ovine model. Intensive Care Med 29:817 – 824
23. Kroppenstedt SN, Stover JF, Unterberg AW (2000) Effects of dopamine on posttraumatic cere- bral blood flow, brain edema, and cerebrospinal fluid glutamate and hypoxanthine concen- trations. Crit Care Med 28:3792 – 3798
24. Beaumont A, Hayasaki K, Marmarou A, Barzo P, Fatouros P, Corwin F (2001) Contrasting effects of dopamine therapy in experimental brain injury. J Neurotrauma 18:1359 – 1372 25. Myburgh JA, Upton RN, Grant C, Martinez A (1998) A comparison of the effects of norepi-
nephrine, epinephrine, and dopamine on cerebral blood flow and oxygen utilisation. Acta Neurochir Suppl 71:19 – 21
26. Berre J, De Backer D, Moraine JJ, Melot C, Kahn RJ, Vincent JL (1997) Dobutamine increases cerebral blood flow velocity and jugular bulb hemoglobin saturation in septic patients. Crit Care Med 25:392 – 398
27. Moppett IK, Wild MJ, Sherman RW, Latter JA, Miller K, Mahajan RP (2004) Effects of ephed- rine, dobutamine and dopexamine on cerebral haemodynamics: transcranial Doppler studies in healthy volunteers. Br J Anaesth 92:39 – 44
28. Fernandez N, Martinez MA, Garcia-Villalon AL, Monge L, Dieguez G (2001) Cerebral vaso- constriction produced by vasopressin in conscious goats: role of vasopressin V(1) and V(2) receptors and nitric oxide. Br J Pharmacol 132:1837 – 1844
29. Trandafir CC, Nishihashi T, Wang A, Murakami S, Ji X, Kurahashi K (2004) Participation of vasopressin in the development of cerebral vasospasm in a rat model of subarachnoid hae- morrhage. Clin Exp Pharmacol Physiol 31:261 – 266
30. Feinstein AJ, Patel MB, Sanui M, Cohn SM, Majetschak M, Proctor KG (2005) Resuscitation with pressors after traumatic brain injury. J Am Coll Surg 201:536 – 545
31. Ract C, Vigue B, Bodjarian N, Mazoit JX, Samii K, Tadie M (2001) Comparison of dopamine
and norepinephrine after traumatic brain injury and hypoxic-hypotensive insult. J Neuro- trauma 18:1247 – 1254
32. Ract C, Vigue B (2001) Comparison of the cerebral effects of dopamine and norepinephrine in severely head-injured patients. Intensive Care Med 27:101 – 106
33. Johnston AJ, Steiner LA, Chatfield DA, et al (2004) Effect of cerebral perfusion pressure aug- mentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury. Intensive Care Med 30:791 – 797
34. Steiner LA, Johnston AJ, Czosnyka M, et al (2004) Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients. Crit Care Med 32:1049 – 1054
35. Boyadjiev I, Garnier F, Antonini F, Leone M, Alban`ese J, Martin C (2005) Comparaison des effets de la dopamine ou de la noradr´enaline sur les circulations r´egionales chez les traumati- s´es crˆaniens]. Ann Fr Anesth R´eanim 24:R375 (abst)
