The use of dexmedetomidine in neurosurgery

Abstracts

BACKGROUND AND OBJECTIVES: The use of alpha2-adrenergic agonists is increasingly more frequent in Anesthesiology, as adjuvant or the sole anesthetic drug. Currently, dexmedetomidine is gaining popularity due to its greater selectivity for the alpha2-adrenergic receptors and its pharmacokinetic profile. The aim of this review was to analyze the use of dexmedetomidine in neurosurgery. CONTENTS: Besides considerations and review of the literature regarding the use of dexmedetomidine, specifically in neurosurgical procedures, its effects on the different organ systems are described. CONCLUSIONS: The pharmacokinetic and pharmacodynamic profile of dexmedetomidine favors its use in several neurosurgical procedures. Its use in craniotomy for the treatment of aneurysms and tumor removal is recent. Besides, its use in functional surgical interventions is promising.

DRUGS, Adrenergic Agonists; SURGERY, Neurosurgery

JUSTIFICATIVA E OBJETIVOS: Os fármacos alfa2-agonistas são a cada dia mais utilizados em Anestesiologia, seja como adjuvantes ou como agentes anestésicos únicos. Atualmente, o emprego da dexmedetomidina vem se popularizando devido à sua maior seletividade aos receptores alfa2 e, também, ao seu perfil farmacocinético. O objetivo desta revisão foi fazer uma análise do emprego da dexmedetomidina em neurocirurgia. CONTEÚDO: Além das considerações e revisão da literatura quanto ao emprego da dexmedetomidina especificamente em procedimentos neurocirúrgicos, foi realizada descrição dos efeitos do fármaco nos diversos sistemas do organismo. CONCLUSÕES: A dexmedetomidina tem perfil farmacocinético e farmacodinâmico que favorece seu emprego em diversos procedimentos neurocirúrgicos. A utilização clínica em procedimentos cirúrgicos com craniotomia para pinçamento de aneurisma e remoção de tumores é crescente. Além disso, seu uso em intervenções cirúrgicas funcionais é promissor.

CIRURGIA, Neurocirurgia; DROGAS, Agonista adrenérgico

JUSTIFICATIVA Y OBJETIVOS: Los fármacos alfa2-agonistas son cada día más utilizados en Anestesiología, sea como adyuvantes o como agentes anestésicos únicos. Actualmente, el empleo de la dexmedetomidina se ha venido popularizando debido a su mayor selectividad a los receptores alfa2 y, también, a su perfil farmacocinético. El objetivo de esta revisión fue hacer una análisis del empleo de la dexmedetomidina en Neurocirugía. CONTENIDO: Además de las consideraciones y de la revisión de la literatura en cuanto al empleo de la dexmedetomidina específicamente en procedimientos neuro-quirúrgicos, fue realizada una descripción de los efectos del fármaco en los diversos sistemas del organismo. CONCLUSIONES: La dexmedetomidina tiene un perfil farmacocinético y farmacodinámico que favorece su empleo en diversos procedimientos neuro-quirúrgicos. La utilización clínica en procedimientos quirúrgicos con craneotomia para el pinzamiento de aneurisma y la retirada de tumores va en aumento. Además, su uso en intervenciones quirúrgicas funcionales es promisorio.

REVIEW ARTICLE

The use of dexmedetomidine in neurosurgery^*

Uso de dexmedetomidina en neurocirugía

Bernardo Aloisio Grings Herbert^I; Paulo Magalhães Gomes Ramaciotti^II; Fábio Ferrari, TSA^III; Laís Helena Camacho Navarro^IV; Giane Nakamura^IV; Geraldo Rolim Rodrigues Jr, TSA^III; Yara Marcondes Machado Castiglia, TSA^V; José Reinaldo Cerqueira Braz, TSA^V; Paulo do Nascimento Jr, TSA^VI

^IEx-ME₃ (2005) do CET/SBA do Departamento de Anestesiologia da FMB — UNESP

^IIME₃ do CET/SBA do Departamento de Anestesiologia da FMB — UNESP

^IIIProfessor Assistente; Co-Responsável pelo CET/SBA do Departamento de Anestesiologia da FMB — UNESP

^IVMédico Assistente do Departamento de Anestesiologia da FMB — UNESP

^VProfessor Titular; Co-Responsável pelo CET/SBA do Departamento de Anestesiologia da FMB — UNESP

^VIProfessor Adjunto Livre-Docente; Co-Responsável pelo CET/SBA do Departamento de Anestesiologia da FMB — UNESP

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: The use of a₂-adrenergic agonists is increasingly more frequent in Anesthesiology, as adjuvant or the sole anesthetic drug. Currently, dexmedetomidine is gaining popularity due to its greater selectivity for the a₂-adrenergic receptors and its pharmacokinetic profile. The aim of this review was to analyze the use of dexmedetomidine in neurosurgery.

CONTENTS: Besides considerations and review of the literature regarding the use of dexmedetomidine, specifically in neurosurgical procedures, its effects on the different organ systems are described.

CONCLUSIONS: The pharmacokinetic and pharmacodynamic profile of dexmedetomidine favors its use in several neurosurgical procedures. Its use in craniotomy for the treatment of aneurysms and tumor removal is recent. Besides, its use in functional surgical interventions is promising.

Key Words: DRUGS, Adrenergic Agonists: dexmedetomidine; SURGERY, Neurosurgery.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Los fármacos a₂-agonistas son cada día más utilizados en Anestesiología, sea como adyuvantes o como agentes anestésicos únicos. Actualmente, el empleo de la dexmedetomidina se ha venido popularizando debido a su mayor selectividad a los receptores a₂ y, también, a su perfil farmacocinético. El objetivo de esta revisión fue hacer una análisis del empleo de la dexmedetomidina en Neurocirugía.

CONTENIDO: Además de las consideraciones y de la revisión de la literatura en cuanto al empleo de la dexmedetomidina específicamente en procedimientos neuro-quirúrgicos, fue realizada una descripción de los efectos del fármaco en los diversos sistemas del organismo.

CONCLUSIONES: La dexmedetomidina tiene un perfil farmacocinético y farmacodinámico que favorece su empleo en diversos procedimientos neuro-quirúrgicos. La utilización clínica en procedimientos quirúrgicos con craneotomia para el pinzamiento de aneurisma y la retirada de tumores va en aumento. Además, su uso en intervenciones quirúrgicas funcionales es promisorio.

INTRODUCTION

Dexmedetomidine is a selective a₂-adrenergic agonist with an affinity ratio a₁:a₂ of 1,620:1, while the proportion of another a₂-agonist commonly used, clonidine, is 220:1 ¹. Its action is mainly through the pre-synaptic a₂-adrenoreceptors, inhibiting the release of noradrenaline by negative feed-back ², and in the postsynaptic region in several areas of the body, causing effects such as contraction of the vascular smooth muscle, hypertension, bradycardia, sedation, and analgesia. Due to its specificity ratio, low doses have a potent sedative effect without the undesirable cardiovascular effects originated by the activation of a₁ receptors ³.

Initially, dexmedetomidine was approved by the Food and Drug Administration (FDA) to promote sedation in intensive care units (ICUs). However, its pharmacological profile and different fields of action made it an agent that is increasingly used as adjuvant in Anesthesiology ^4-6, providing good hemodynamic stability during the anesthetic-surgical procedure ^4-7.

Preservation of intracranial homeostasis, hemodynamic stability, fast transition from sleep to awake, allow neurological evaluation even in the operating room, reduction in cerebral blood flow — which improves the relationship between oxygen supply and demand —, and neuroprotection capability ¹ are common goals in neuroanesthesiology that can be achieved using dexmedetomidine. The objective of this review was to demonstrate the particularities of this drug that frequently include it among the drugs that can be used in anesthesia, and more specifically in Neurosurgery.

PHARMACOLOGY

Similar to other a₂-adrenergic agonists, dexmedetomidine is an imidazol compound. It is the pharmacologically active enantiomer of medetomidine (commonly used in veterinary medicine), separated from the racemic form of L-medetomidine, an isomer with little activity (affinity ratio a₂:a₁ of 23:1). It has a very fast half-life of distribution, approximately 6 minutes, and elimination time of 2 hours ^1,8,9.

Alpha₂-receptors are widely distributed in the organism. In the brain, they are concentrated in the pons and spinal cord, and are involved in the transmission and activation of pathways in the central nervous system that connect cortical centers to the periphery. The release of noradrenaline is decreased by the activation of pre-synaptic a₂-adrenoreceptors, while the activation of postsynaptic a₂-adrenoreceptors increases regional cerebral blood flow ^10,11. In the spinal cord, postsynaptic a₂-adrenoreceptors are located in the dorsal horn, and their stimulation inhibits the transmission of the nociceptive signal ¹². They are also found in the smooth muscle of peripheral vessels, being responsible for vasoconstriction ¹¹.

MAIN EFFECTS ON SEVERAL SYSTEMS

The effects of dexmedetomidine can be explained by the knowledge of the location and function of a₂-adrenoreceptors throughout the body and, also, by the identification of their subtypes.

Hemodynamic effects are obtained both by central, such as increasing the activity of the vagus nerve by reducing the activity of the sympathetic nervous system (presynaptic a_2A-adrenoreceptors), and peripheral mechanisms, i.e., blockade of the sympathetic ganglions ¹³ and its activity on vascular smooth muscle (postsynaptic a₂-adrenoreceptors), leading to vasoconstriction. The rapid infusion of this drug can, initially, cause temporary hypertension due to the peripheral vasoconstriction ^6,14. However, hypotension, caused by a significant reduction in the levels of circulating catecholamines, is the main effect of this drug ¹⁵. This differentiated physiologic effect seems to have a temporal relationship with the dose (increasing doses of dexmedetomidine increase systemic vascular resistance and decrease cardiac output ¹⁶), speed of administration, presence of hypovolemia ¹⁷, or previous changes in the tonus of the sympathetic nervous system ¹⁸. Its sympatholytic effect decreases the heart rate ¹⁹. Due to the risk of bradycardia, dexmedetomidine is not recommended in patients with cardiac blocks, but its association with b-blockers does not seem to increase the risk of bradycardia ²⁰.

Since this class of drugs has tranquilizing and analgesic properties and is capable of controlling tremors, it can be useful in myocardial protection. A recent meta-analysis, as well as animal experiments, suggest that this type of drug can reduce significantly the risk of cardiac mortality ^21,22.

Dexmedetomidine has little effect on ventilation and, even in high doses, does not compromise lung function, and it can even cause bronchodilation ²³. Venn et al., studying patients in the postoperative period of general and cardiac surgeries in the ICU, did not detect significant differences between placebo and dexmedetomidine regarding lung function when pulse oxymetry, PaCO, PaO₂:FiO₂, and respiratory rate were analyzed. In this blind study, the mean doses of dexmedetomidine were 0.42 ± 0.18 and 0.17 ± 0.13 µg.kg^-1.h^-1 before and after tracheal intubation, respectively. The placebo group received a solution of sodium chloride and, in both groups, when necessary to maintain patients with a score equal or above 2, according to the Ramsay sedation scale, morphine was administered ²⁴.

Dexmedetomidine modulates the response to stress by reducing the neurohumoral response, with decreased serum levels of adrenaline and noradrenaline, as well as the activity of the sympathetic nervous system. However, if it is used for less than 24 hours, it does not seem to reduce significantly the inflammatory response, demonstrated by evaluating adrenocortical activity, cortisol production, and serum levels of interleukin-6 (IL-6) ²⁵.

This drug increases urine flow. It was demonstrated, in experimental models, that this effect is possibly due to a reduction in the efferent sympathetic stimulus from the renal innervation ²⁶, increased glomerular filtration rate, probably by the suppression of vasopressin ²⁷, increased secretion of the atrial natriuretic peptide, and decreased release of rennin ²⁸.

The analgesic action of dexmedetomidine is mainly due to its interaction with a₂-adrenoreceptors in the spinal cord, especially a_2A and a_2C^29,10. The a_2A receptors are also responsible for the analgesic action in synergy with opioids, when descending noradrenergic pathways are activated ³⁰. This drug causes a 30% to 50% reduction in the requirements of opioids, especially in the types of pain that have to be treated with high doses of these drugs, such as postoperative pain ³¹. It seems to exert its sedative-tranquilizing effect through the activation of a₂-receptors in the Locus coeruleus, the most important noradrenergic interventional area of the central nervous system. It produces a unique sedation, in which the patient is cooperative, with an easy transition from sleep to awake and back to sleep, when the patient is not stimulated ^32,33.

EFFECTS OF DEXMEDETOMIDINE ON THE CENTRAL NERVOUS SYSTEM

The a₂-adrenoreceptors are widely distributed on cerebral vessels, and the systemic administration of a₂-adrenergic agonists can reduce cerebral blood flow (CBF) by a direct action on the receptors in the vessels, causing contraction of the vessel smooth muscle, and indirectly, by its action on neurological pathways that modulate vascular effects. Karlsson et al. ³⁴ and Zornow et al. ³⁵ showed that, in dogs, the intravenous administration of a 10 µg.kg^-1 dose of dexmedetomidine caused a 40% to 45% reduction in CBF in anesthesia with halothane and isoflurane, which is not accompanied by a proportional reduction in brain metabolism. Reduction in CBF occurred despite a significant increase in mean arterial pressure, secondary to the activation of a_2B-recetors in the vascular smooth muscle.

McPherson et al. ³⁶ demonstrated that dexmedetomidine causes a 30% reduction in cerebral oxygen transportation, calculated by multiplying the CBF by the arterial oxygen content (CaO₂), but the reduction in CaO₂ secondary to hypoxia does not accentuates the reduction in cerebral oxygen transportation, since this drug does not hinder increase in CBF and compensatory vasodilation in response to hypoxia. Besides, they verified that the reduction in CBF caused by dexmedetomidine depends on the synthesis of nitric oxide. Lam et al.³⁷ demonstrated a reduction in flow velocity in the middle cerebral artery, in healthy volunteers, during the administration of dexmedetomidine, with preserved reactivity to CO₂ and self-regulation of cerebral blood flow.

Cerebral vasodilation induced by isoflurane or sevoflurane is decreased by the prior administration of dexmedetomidine ³⁸. Thus, the use of a₂-adrenergic agonists could be useful as adjuvant in inhalational anesthesia for neurosurgeries, in situations that an increase in CBF can be detrimental.

In subarachnoid hemorrhage, the increase in circulating cathecolamines and the massive sympathetic discharge contribute to the cerebral vasospasm, and the blockade of this adrenergic effect can be protective. In animals, a₂-adrenergic agonists are more potent venous vasoconstrictors than arterial in the brain vasculature ³⁹. Since the venous compartment encompasses most of the cerebral blood volume, a₂-adrenergic agonists could, probably, reduce intracranial pressure (ICP) without increasing significantly the cerebral arteriolar resistance. A minimal effect of clonidine on ICP in patients with brain tumors has been reported. In normocapnic rabbits without intracerebral changes, low doses of dexmedetomidine reduced the ICP by approximately 30% ⁴⁰. With high doses of this drug, the ICP remained unchanged, despite the significant increase in blood pressure. A clinical study by Talke et al. ⁴¹ showed that the target-controlled administration of dexmedetomidine during 60 minutes, to maintain a plasma concentration of 0.6 ng.mL^-1, in patients after transphenoidal hypophisectomy, had no effects on lumbar cerebrospinal fluid pressure, but reduced mean arterial pressure from 103 ± 10 mmHg to 86 ± 6 mmHg, and the heart rate from 77 ± 12 bpm to 64 ± 7 bpm.

Alpha₂-adrenergic agonists attenuate a and b waves on the electroencephalogram (EEG), and increase the activity of slow waves that are typically seen on deep anesthetic plane. Infusion of 0.6 µg.kg^-1.h^-1 of dexmedetomidine causes changes in the EEG that correspond to a bispectral index (BIS) of 60 (moderate to deep sedation) ⁴²; however, patients are easily awaken with verbal stimuli. This suggests that EEG parameters might be inadequate to evaluate the depth of anesthesia in the presence of a₂-adrenergic agonists.

Dexmedetomidine has neuroprotective properties that were observed in several experimental models of cerebral ischemia, attenuating the hypoxic-ischemic lesion in developing brains that are highly susceptible to neuronal lesions ^43-45. The exact mechanism of neuroprotection is not clear. Cerebral ischemia is associated with increased levels of catecholamines in the circulation and in the brain. Thus, treatment with agents that reduce the release of noradrenaline in the brain can be a protective factor against lesions caused by ischemia. Engelhard et al. ⁴⁶ suggested that the neuroprotective activity of dexmedetomidine results from the modulation of the balance between pro-apoptotic and anti-apoptotic proteins. Several studies demonstrated that a₂-adrenergic agonists reduce the release of excitatory neurotransmitters, especially glutamate ^47,48. High levels of glutamate depolarize the neuronal membrane and allow calcium to enter the cell, triggering events that may damage the cell. Therefore, agents that reduce the release of glutamate are considered neuroprotectors. Laudenbach et al. ⁴⁹ showed that both clonidine and dexmedetomidine protect developing brains against excitotoxic lesions.

CLINICAL APPLICATIONS

In neurosurgeries that require intraoperative functional evaluation, neurophysiological tests are necessary to determine the exact location of the surgical intervention or to evaluate the effect produced by the intended functional change, especially in situations in which the cortical surgery is done in eloquent areas of the brain ⁵⁰. For this reason, it is often necessary the cooperation of the patient for the functional evaluation.

The drugs administered in those surgeries should allow the prompt variation in the level of sedation and analgesia during the periods of surgical stimulation, but should also allow the patient to remain awake, calm, and cooperative during the functional tests. Besides, anesthetic drugs should not change the self-regulation of cerebral blood flow, reactivity to CO₂, or metabolism ⁵¹.

Besides those characteristics, the ideal drug for this type of intervention should also provide some degree of residual analgesia and produce minimal inhibition of the spontaneous epileptiform activity ⁵².

Propofol associated with remifentanil is the anesthetic combination used most often in functional neurosurgeries, and their infusion is interrupted to allow the patient to awake and cooperate with the surgical team. More recently, dexmedetomidine has also been used for this type of surgery ^50,52,53.

Dexmedetomidine can be an attractive alternative, as a single agent or adjuvant, for the usual anesthetic techniques. Its properties include sedation, analgesia, reduction in the need for other anesthetic drugs, and it does not depress ventilation. Besides, the continuous infusion of low doses promotes sedation that can be easily reversed with verbal stimuli ⁵⁴.

Dexmedetomidine has been successfully when used in patients undergoing carotid endarterectomy, allowing the realization of intraoperative neurological exam when a cooperative patient is needed. Patients sedated with dexmedetomidine were more comfortable and cooperative, and the incidence of postoperative hypertension was reduced than in patients sedated with midazolam, propofol, or fentanil ⁵⁵.

Dexmedetomidine has also had a great impact on MRIs, especially in patients with Parkinson disease, in whom, to avoid artifacts and eliminate tremors, general anesthesia or high doses of propofol were necessary, carrying the risk of respiratory depression. This drug proved to be a safe alternative, providing sedation and reducing movements without affecting the respiratory drive and without significant residual effects ⁵⁰.

Dexmedetomidine can also be used in interventional neuroradiological procedures, since the patient can cooperate, when requested, and, unlike other drugs, it does not cause respiratory depression. However, the ideal dose that provides sedation and, at the same time, avoids side effects such as hypotension has not been established. Besides, reports in the literature have not demonstrated whether this drug interferes with the cognitive tests used in these procedures. Most of the studies have shown that dexmedetomidine interferes with test results only in patients that already showed some difficulty to communicate in the preoperative period; thus, it has been suggested that further studies should be undertaken ^50,51,56,57.

For intracranial surgeries, the intense surgical stimulation associated with craniotomy frequently causes sympathetic activation and changes in BP, CBF, and ICP. The vascular response can cause an increase in ICP and a reduction in cerebral perfusion pressure, i.e., prevention and hemodynamic control in response to nociceptive stimuli are extremely important to preserve brain homeostasis in neurosurgical patients.

Antinociceptive and sympatholitic effects and a reduction in the doses of anesthetics are well documented ^9,14. This range of proprieties would be compatible with the goal of a neuroanesthesia with hemodynamic stability and modulation of the intraoperative sympathetic response, attenuating cerebral and myocardial vascular risk, avoiding intracranial hemorrhage, and allowing immediate neurological evaluation in emergency situations.

Studies on the use of dexmedetomidine in patients undergoing craniotomy for the removal of brain tumors under general anesthesia, demonstrated that its intraoperative administration reduces the need of opioids and anti-hypertensive drugs, and can provide good hemodynamic stability during the incision and craniotomy, and during the period the patient is regaining consciousness ⁵⁸.

Dexmedetomidine is frequently used in ICUs due to its sedative-analgesic action. Several studies demonstrated a significant reduction in the need for other sedative and analgesic drugs, besides providing hemodynamic stability without respiratory depression. This drug has also an unique sedation, described as similar to normal sleep, providing a state of tranquility while at the same time the patient is able to understand and communicate upon a simple verbal stimulus from the medical team. This characteristic allows a better evaluation of the neurological status of the patients in mechanical ventilation, especially when compared with other sedatives used in ICUs. Thus, dexmedetomidine should be considered an option for the sedation of neurosurgical patients who need continuous evaluation of their neurological status.

CONCLUSION

The objective of this study was to review some of the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine that are responsible for its applicability in specific situations and types of surgeries, especially neurosurgeries. It does not increase ICP, reduces CBF secondary to cerebral vasoconstriction, maintains hemodynamic stability, and reduces the need for other anesthetics, especially opioids. Besides, dexmedetomidine can provide sedation without respiratory depression, and allows the fast arousal and neurological evaluation. For all these reasons, dexmedetomidine is an interesting and promising drug to be used in Anesthesiology, especially in neurosurgeries.

REFERENCES

Submitted em 26 de abril de 2006

Accepted para publicação em 14 de novembro de 2006

• 01. Bhana N, Goa KL, McClellan KJ Dexmedetomidine. Drugs, 2000;59:263-268.
• 02. Virtanen R, Savola JM, Saano V et al. Characterization of selectivity, specificity and potency of medetomidine as an alpha₂-adrenoceptor agonist. Eur J Pharmacol, 1988;150:9-14.
• 03. Hall JE, Uhrich TD, Barney JA et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg, 2000;90:699-705.
• 04. Curtis FG, Castiglia YMM, Stolf AA et al. Dexmedetomidina e sufentanil como analgésicos per-operatórios. Estudo comparativo. Rev Bras Anestesiol, 2002;52:525-534.
• 05. Marangoni MA, Castiglia YMM, Medeiros TP Eficácia analgésica da dexmedetomidina comparada ao sufentanil em cirurgias intraperitoneais. Estudo comparativo. Rev Bras Anestesiol, 2005;55:19-27.
• 06. Bloor BC, Ward DS, Belleville JP et al. Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes. Anesthesiology, 1992;77:1134-1142.
• 07. Dyck JB, Maze M, Haack C et al. The pharmacokinetics and hemodynamic effects of intravenous and intramuscular dexmedetomidine hydrocholoride in adult human volunteers. Anesthesiology, 1993;78:813-820.
• 08. Karol MD, Maze M Pharmacokinetics and interaction of dexmedetomidine in humans. Ballière Clin Anesthesiol, 2000; 14:261-269.
• 09. Kamibayashi T, Maze M Clinical uses of alpha₂-adrenergic agonists. Anesthesiology, 2000;93:1345-1349.
• 10. Civantos Calzada B, Aleixandre de Artinano A Alpha-adrenoceptor subtypes. Pharmacol Res, 2001;44:195-208.
• 11. Scheinin M, Pihlavisis M Molecular pharmacology of a₂-adrenoceptor agonists. London, Balliere Tindall, 2000:247-260.
• 12. Hodgson PS, Liu SS New developments in spinal anesthesia. Anesthesiol Clin North Am, 2000;18:235-249.
• 13. McCallum JB, Boban N, Hogan Q et al. The mechanism of alpha₂-adrenergic inhibition of sympathetic ganglionic transmission. Anesth Analg, 1998;87:503-510.
• 14. Khan ZP, Ferguson CN, Jones RM Alpha₂ and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia, 1999;54:146-165.
• 15. Talke P, Chen R, Thomas B et al. The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery. Anesth Analg, 2000;90:834-839.
• 16. Ebert TJ, Hall JE, Barney JA et al. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology, 2000;93:382-394.
• 17. Jalonen J, Hynynen M, Kuitunen A et al. Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting. Anesthesiology, 1997;86:331-345.
• 18. Talke P, Lobo E, Brown R Systemically administered alpha₂-agonist-induced peripheral vasoconstriction in humans. Anesthesiology, 2003;99:65-70.
• 19. Villela NR, Nascimento Jr P, Carvalho LR Efeitos cardiovasculares de duas doses de dexmedetomidina. Estudo experimental em cães. Rev Bras Anestesiol, 2003;53:784-796.
• 20. Bekker A, Gold M, Basile J et al. Hemodynamic and respiratory changes related to the use of dexmedetomidine in patients undergoing awake carotid endarterectomy. Anesthesiology, 2003;100:A136.
• 21. Lawrence CJ, Prinzen FW, de Lange S The effect of dexmedetomidine on the balance of myocardial energy requirement an oxygen supply and demand. Anesth Analg, 1996;82:544-550.
• 22. Wijeysundera DN, Naik JS, Beattie WS Alpha₂ adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis. Am J Med, 2003;114:742-752.
• 23. Groeben H, Mitzner W, Brown RH Effects of the alpha₂-adrenoceptor agonist dexmedetomidine on bronchoconstriction in dogs. Anesthesiology, 2004;100:359-363.
• 24. Venn RM, Hell J, Grounds RM Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care. Crit Care Med, 2000;4:302-308.
• 25. Venn RM, Bryant A, Hall GM et al. Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine, and inflammatory responses in postoperative patients needing sedation in the intensive care unit. Br J Anaesth, 2001;86:650-656.
• 26. Xu H, Aibiki M, Seki K et al. Effects of dexmedetomidine, an alpha₂-adrenoceptor agonist, on renal sympathetic nerve activity, blood pressure, heart rate and central venous pressure in urethane-anesthetized rabbits. J Auton Nerv Syst, 1998; 71:48-54.
• 27. Villela NR, Nascimento Jr P, Carvalho LR et al. Efeitos da dexmedetomidina sobre o sistema renal e sobre a concentração plasmática do hormônio antidiurético. Estudo experimental em cães. Rev Bras Anestesiol, 2005;55:429-440.
• 28. Pettinger WA, Umemura S, Smyth DD et al. Renal alpha₂-adrenoceptors and the adenylate cyclase-cAMP system: biochemical and physiological interactions. Am J Physiol, 1987;252:F199-208.
• 29. Malmberg AB, Hedley LR, Jasper JR et al. Contribution of a₂ receptor subtypes to nerve injury-induced pain and its regulation by dexmedetomidine. Br J Pharmacol, 2001;132:1827-1836.
• 30. Stone LS, MacMillan LB, Kitto KF et al. The a_2A adrenergic receptor subtype mediates spinal analgesia evoked by a₂ agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci, 1997;17:7157-7165.
• 31. Unlugenc H, Gunduz M, Guler T et al. The effect of pre-anaesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anaesthesiol, 2005;22:386-391.
• 32. Martin E, Ramsay G, Mantz J et al. The role of alpha₂-adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit. J Intens Care Med, 2003;18:29-41.
• 33. Venn RM, Grounds RN Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions. Br J Anaesth, 2001;87:684-690.
• 34. Karlsson BR, Forsman M, Roald OK et al. Effect of dexmedetomidine, a selective and potent alpha₂-agonist, on cerebral blood flow and oxygen consumption during halothane anesthesia in dogs. Anesth Analg, 1990;71:125-129.
• 35. Zornow MH, Fleischer JE, Scheller MS et al. Dexmedetomidine, an alpha₂-adrenergic agonist, decreases cerebral blood flow in the isoflurane-aneshetized dog. Anesth Analg, 1990;70:624-630.
• 36. McPherson RW, Koehler RC, Traystman RJ Hypoxia, alpha₂-adrenergic, and nitric oxide-dependent interactions on canine cerebral blood flow. Am J Physiol, 1994;266:H476-H482.
• 37. Lam AM, Bhatia S, Lee LA et al. Influence of dexmedetomidine on CO₂ reactivity and cerebral autoregulation in healthy volunteers. Anesthesiology, 2001;95:A341.
• 38. Ohata H, Iida H, Dohi S et al. Intravenous dexmedetomidine inhibits cerebrovascular dilatation induced by isoflurane and sevoflurane in dogs. Anesth Analg, 1999;89:370-377.
• 39. Ulrich K, Kuschinsky W In vivo effects of alpha-adrenoreceptor agonists and antagonists on pial veins of cats. Stroke, 1985;16:880-884.
• 40. Zornow MH, Scheller MS, Sheehan PB et al. Intracranial pressure effects of dexmedetomidine in rabbits. Anesth Analg, 1992;75:232-237.
• 41. Talke P, Tong C, Lee HW et al. Effect of dexmedetomidine on lumbar cerebrospinal fluid pressure in humans. Anesth Analg, 1997;85:358-364.
• 42. Hall JE, Uhrich TD, Barney JA et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg, 2000;90:699-705.
• 43. Jolkkonen J, Puurunen K, Koistinaho J et al. Neuroprotection by the alpha₂-adrenoceptor agonist, dexmedetomidine, in rat focal cerebral ischemia. Eur J Pharmacol, 1999;372:31-36.
• 44. Paris A, Tonner PH Dexmedetomidine in anaesthesia. Curr Opin Anaesthesiol, 2005;18:412-418.
• 45. Kuhmonen J, Pokorny J, Miettinen R et al. Neuroprotective effects of dexmedetomidine in the gerbil hippocampus after transient global ischemia. Anesthesiology, 1997;87:371-377.
• 46. Engelhard K, Werner C, Eberspacher E et al. The effect of the alpha₂-agonist dexmedetomidine and the N-methyl-D-aspartate antagonist S (+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg, 2003;96:524-531.
• 47. Chen Y, Zhao Z, Code WE et al. A correlation between dexmedetomidine-induced biphasic increases in free cytosolic calcium concentration and energy metabolism in astrocytes. Anesth Analg, 2000;91:353-357.
• 48. Talke P, Bickler PE Effects of dexmedetomidine on hypoxia-evoked glutamate release and glutamate receptor activity in hippocampal slices. Anesthesiology, 1996;85:551-557.
• 49. Laudenbach V, Mantz J, Langercrantz H et al. Effects of alpha₂-adrenoceptor agonists on perinatal excitotoxic brain injury: comparison of clonidine and dexmedetomidine. Anesthesiology, 2002;96:134-141.
• 50. Bekker A, Sturaitis MK Dexmedetomidine for neurological surgery. Neurosurgery, 2005;57:1-10.
• 51. Mack PF, Perrine K, Kobylarz E et al. Dexmedetomidine and neurocognitive testing in awake craniotomy. J Neurosurg Anesthesiol, 2004;16:20-25.
• 52. See JJ, Manninen PH Anesthesia for neuroradiology. Curr Opin Anaesthesiol, 2005;18:437-441.
• 53. Everett LL, Van Rooyen IF, Warner MH et al. Use of dexmedetomidine in awake craniotomy in adolescents: report of two cases. Paediatr Anaesth, 2006;16:338-342.
• 54. Venkatraghavan L, Manninen P, Mak P et al. Anesthesia for functional neurosurgery. Review of complications. J Neurosurg Anesthesiol, 2006;18:64-67.
• 55. Bekker AY, Basile J, Gold M et al. Dexmedetomidine for awake carotid endarterectomy: efficacy, hemodynamic profile, and side effects. J Neurosurg Anesthesiol, 2004;16:126-135.
• 56. Lee CZ, Young WL Anesthetic considerations for interventional neuroradiology. ASA Refresher Courses in Anesthesiol, 2005;33:145-154.
• 57. Pasternak JJ, Lanier WL Neuroanesthesiology review. J Neurosurg Anesthesiol, 2005;17:2-8.
• 58. Sturatis M, Kroin J, Swamidoss CS et al. Effect of intraoperative dexmedetomidine infusion on hemodynamic stability during brain tumor resection. Anesthesiology, 2002;97:A310.

*

Received from Departamento de Anestesiologia da Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (FMB UNESP), Botucatu, SP

Publication Dates

• Publication in this collection
  15 Mar 2007
• Date of issue
  Apr 2007

History

• Accepted
  14 Nov 2006
• Received
  26 Apr 2006