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Rev. Bras. Anestesiol. vol.57 no.2 Campinas Mar./Apr. 2007
The use of dexmedetomidine in neurosurgery*
Uso de dexmedetomidina en neurocirugía
Bernardo Aloisio Grings HerbertI; Paulo Magalhães Gomes RamaciottiII; Fábio Ferrari, TSAIII; Laís Helena Camacho NavarroIV; Giane NakamuraIV; Geraldo Rolim Rodrigues Jr, TSAIII; Yara Marcondes Machado Castiglia, TSAV; José Reinaldo Cerqueira Braz, TSAV; Paulo do Nascimento Jr, TSAVI
(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
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.
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.
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.
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 a2A-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 a2A and a2C 29,10. The a2A 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 a2B-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.
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.
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.
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Dr. Paulo do Nascimento Jr
Departamento de Anestesiologia da FMB UNESP
Distrito de Rubião Junior
18618-970 Botucatu, SP
Submitted em 26
de abril de 2006
Accepted para publicação em 14 de novembro de 2006
* Received from Departamento de Anestesiologia da Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (FMB UNESP), Botucatu, SP