Artículo de Revisión

Andrés García Botero*, Leonardo Rodríguez**, Félix Arturo Salazar Pérez***, Alberto Venegas Saavedra****

* Médico residente III de Anestesiología y Reanimación, Universidad Nacional de Colombia, Bogotá, Colombia. Correspondencia: Calle 47B sur No. 23B-70, int 22 apto 344 Bogota - Colombia. Correo electrónico: andresgarciabotero@yahoo.com

** Médico residente III de Anestesiología y Reanimación, Universidad Sur Colombiana, Huila, Colombia. Correo electrónico: leoroci@yahoo.com

*** Médico residente II de Anestesiología y Reanimación, Universidad Colegio Mayor Nuestra Señora del Rosario, Bogotá, Colombia. Correo electrónico: fe_ar@yahoo.com.ar

**** Coordinador nacional del Comité de Anestesia Intravenosa (Scare), Anestesiólogo Clínica el Country. Docente en: Universidad Nacional de Colombia, Universidad Mayor Nuestra Señora del Rosario, Universidad Javeriana, Fundación Universitaria de Ciencias de la Salud. Instructor Universidad el Bosque. Bogotá, Colombia. Correo electrónico: avanegass@hotmail.com

Recibido: abril 29 de 2011. Enviado para modificaciones: septiembre 28 de 2011. Aceptado: mayo 18 de 2011.

Dexmedetomidine was used initially for sedation in intensive care units. However, because of its sedative, analgesic and anti-anxiety effects and the fact that it does not alter ventilatory function, its use may be expanded as an intravenous agent in surgery. There are reports in the literature about its effective use in specific surgical populations, although further studies are required in order to support its use in all situations where total intravenous anesthesia (TIVA) is applied. The purpose of this review is to describe the role of dexmedetomidine in this form of anesthesia.

Materials y methods. A literature search was conducted in PubMed, Medline, EMBASE, Cochrane and LILACS. The search was expanded based on the references found in the articles reviewed initially and analyzed by the authors; the search was conducted under the MeSH included as key words below.

Dexmedetomidine is an alpha-2 adrenergic receptor agonist (A2ARA) used for sedation and analgesia, and as an adjunct in anesthesia to reduce anesthetic requirements in procedures requiring total intravenous anesthesia (TIVA) (1,2,3). It also provides autonomic protection, anti-anxiety effects, and it has predictable dose-dependent cardiovascular and respiratory effects. Likewise, it allows to lower the use of analgesics in postoperative pain, provides memory-preserving sedation (4), helps suppress shivering, and improves postoperative recovery (1).

This review explores the use of dexmedetomidine in TIVA, and its emergence as an option to consider in special patient populations (5).

Problem definition: Use of dexmedetomidine in TIVA.

Thesaurus selection and search in MeSH terms under ‘dexmedetomidine’ and ‘total intravenous anesthesia, in reference databases (PubMed, Medline, EMBASE, Cochrane and LILACS), that were added in a unified PubMed search in “Search Box with AND” with no limitations, resulting in a total of 72 texts. The search was expanded to other books and texts, and a comprehensive review of the literature was conducted together. Studies were selected and also excluded on the basis of irrelevance or impossibility to access the abstract and/or content.

This paper was prepared using the all-literature review methodology.

The use of dexmedetomidine dates back to the use of medetomidine in veterinary medicine. It is an imidazole combination of levomedeto midine (pharmacologically inactive) and dexmedetomidine (pharmacologically active) that shares affinity for alpha-2 adrenergic receptors (A2AR) (5,6,7). It was approved by the Food & Drug Administration for use as sedative and analgesic in intensive care units (1,2,8), but its use has been expanded to other areas (5). Its use was derived from the observation of the effect of clonidine on anesthetized patients (9,10). It has not been approved for use in pediatrics or obstetrics (11).

These are mainly postsynaptic receptors distributed throughout multiple areas, in particular the Locus Caeruleus (12,13) and the solitary nucleus. Their sympatholytic, sedative and analgesic effects result from the action of agonist substances on central A2AR.

These metabotropic receptors associated with the G inhibitory protein (Gi/o) reduce cyclic adenosine monophosphate (AMP) through adenyl cyclase inhibition, and induce an increase in potassium (14) by enhanced permeability of inflow and outflow channels, hyperpolarizing the postsynaptic neuron. Moreover, they lower citosol calcium levels because they reduce ion channel permeability, limiting presynaptic neurotransmitter release (6). There are different types of adrenoreceptors:

• Alfa 2A: These receptors are found in peripheral blood vessels and produce vasoconstriction

• Alfa 2B and 2C: These receptors are present in the spinal chord and in the brain in noradrenergic neurons of the central nervous system (mainly in the locus coeruleus and the dorsal spinal chord motor complex). They inhibit the release of noradrenaline, mediating hypertension and bradycardia. They are also found in the dorsal horns, the ventrolateral nuclei of the spinal chord and in the ascending reticular activating system. Their presence has also been reported in the liver, pancreas, platelets, kidneys, adipose tissue, and the eyes (2).

• Type C: These receptors mediate vascular tone control, provide analgesia of spinal origin, down-regulating the activity of pain transmitter neurons.

• Type D: They are similar to type A receptors (with lower affinity for ligands).

Chemical structure: It is a medetomidine dextro enantiomer with a basic imidazole structure and a 1600:1 alpha-2:alpha-1 affinity (compared, for example, with clonidine, with a 200:1 affinity) (5,7,15,16). For this reason, it is considered a pure alpha-2 adrenergic agonist. It is highly water-soluble (2).

Pharmacodynamics: The alpha-2 adrenergic agonist activity (A2A) of desmedetomidine blocks the afferent activity of A and C fibers, associated with somato-sympathetic reflexes and spotaneous somatic flow, offering protection against stress. Moreover, it diminishes preganglionar cholinergic sympathetic tone and mediates the release and production of other excitatory neurotransmitters.

Peripherally, it is associated with initial hypertension after the administration of a loading dose. It lowers noradrenaline secretion and cerebral oxygen metabolic consumption, and inhibits histamine release (2,13). Its analgesic activity is additive and synergistic in relation to respiratory depression. It may show cross-tolerance with opioid agonists, leading to minimal ventilatory and hypoxic depression (1). Its hypnotic effect is similar to slow sleep (4); it is associated with a capacity for preserving immune and cognitive function (2).

No adrenal suppression due to the imidazole structure has been reported with infusions of up to 40 hours (6). Its central alpha-2 effect is dose-dependent; with low and medium doses, or infusions with no loading dose, the alpha-2 effect predominates, whereas the alpha-1 effect predominates with high doses, loading doses, or rapid infusions (11).

eurologic effects: Its neuroprotective effect is not well known (21); sedation has been de scribed as “cooperative” and “wakable”. Memory disturbances may occur at high doses (11).

Respiratory effects: There is no respiratory depression associated with its use (22,23) (dose dependent effect). Infusions at a concentration of 15ng/ml (TCI system) at the effective site in healthy volunteers did not produce changes in pH or PaCo2, but gave rise to an increase in respiratory rate, from 10 to 25 breaths per minute (4). The ventilatory response to hypercapnia was not affected when compared with remifentanil at a dexmedetomidine dose that produced a negative response to vigorous stimulation (2). A bolus dose of 2 mcg/kg may produce transient apnea (11).

Cardiovascular effects: A2A may have anti-arrhythmic effects and mediate a reduction in systemic blood pressure; it also reduces heart rate and produces vasoconstriction (24,25,26). It must be used with caution in hypovolemic patients because of a 22% increase in peripheral vascular resistance and a 27% drop in heart rate. These parameters return to baseline fifteen minutes later, although there is a 15% drop in blood pressure afterwards (27). There may be a reduction in myocardial contractility and cardiac output.

Its use has been associated with lower cardiovascular complications such as myocardial ischemia during the perioperative period (28), and it is also associated with a higher need for drugs required to maintain blood pressure (2,29).

USE OF DEXMEDETOMIDINE IN TIVA

The use of dexmedetomidine in total intravenous anesthesia has shown to potentiate analgesia and sedation in surgery (at a dose of 0.5-1 mcg/kg/hour), when given over a 10-15 period as adjunct to other intravenous anesthetics before the procedure. It may be administered at the same infusion rate 15-20 minutes before the end of the procedure in order to reduce anxiety during extubation, the occurrence of postoperative shivering, as well as the need for analgesics (1).

It may be used as a single agent at a dose of 1 - 5 mcg/kg/hour during periods of 10-15 minutes initially, followed by a dose of 0.25 - 1 mcg/kg/hour (1,2,3).

As a result of a diminished autonomic response to laryngoscopy (30,31), the risk of increased intraocular pressure is reduced (31,32) and salivary secretion is inhibited; for this reason, it is indicated in orotracheal intubation (OTI) while the patient is awake. Dexmedetomidine is associated with an improved hemodynamic response to OTI when compared to fentanyl at 2 mcg/kg (30,31) and has anti-anxiety effects similar to those of midazolam when given 90 minutes before the procedure (2). Additionally, it minimizes cardiovascular effects and reduces the need for thiopental and opioids by 30 % (33,34).

It must be used with caution in patients with vagal tone predominance and atrial-ventricular blocks, because of its association with bradycardia and cardiac arrest (1,11).

Dexmedetomidine is a weak analgesic, in particular for thermal or electric painful stimuli (2).

Premedication doses must range between 0.33 and 0.67 mcg/kg and must be given 15 minutes before surgery. It is useful in neurosurgery of eloquent areas with the patient awake because it permits intra-operative neurologic assessment. This drug appears promising for use as sedative and analgesic outside the operating room both in adults as well as in children (35,36).

Dexmedetomidine has also been shown to be useful in cardiovascular anesthesia (37,38); infusions of up to 0.4 mcg/kg/hour have shown to be effective and offer hemodynamic stability. In 2003, a meta-analysis of 23 clinical trials comprising 3,395 patients concluded that the use of alpha-2 adrenergic agonists reduced mortality and myocardial infarction during and after cardiovascular surgery; additionally, lower rates of ischemia were also found, probably accounting for lower mortality rates (39). However, it may increase predisposition to hypotension (40).

It may be used for the management of patients with pulmonary hypertension during mitral valve replacement surgery; in those cases, dexmedetomidine was associated with a lower need for fentanyl, and attenuated the increase in post-sternotomy systemic vascular and pulmonary resistance. Likewise, it lowered mean blood pressure, mean pulmonary blood pressure and wedge pressure, when compared to placebo (41). In coronary heart disease, a meta-analysis showed that in order to achieve a 25% reduction in cardiovascular events with adequate statistical significance, a sample size of 4,000 patients was required, something that has not been attained so far (42).

Neuroanesthesia: There are certain neurosurgery procedures that require patient participation for response assessment, for example, after profound stimulation in the treatment of Parkinson’s disease, electrode implantation, electrocorticography in epilepsy surgery, and procedures around the Broca and Wernicke area (43). Dexmedetomidine is of value in those situations because it provides sedation while the patient is awake during craniectomies (44).

In cases of laminectomy, TIVA with dexmedetomidine at 0.2 mcg/kg/hour as an adjunct provides adequate cardiovascular stability, as well as similar extubation time when compared with other anesthetic techniques (propofol-remifentanil or propofol-fentanyl). Lower morphine requirements have been reported when a dexmedetomidine infusion is maintained (45).

Ventilatory failure may increase during the postoperative period with the concomitant use of opioids and the presence of conditions such as obesity, sleep apenea hypopnea syndrome, or in airway procedures.

Dexmedetomidine reduces the need for propofol, opioids and other analgesics, as well as the risk of respiratory depression. At the same time, it ensures shorter extubation time and fast recovery. The dose is a 0.8 mcg/kg bolus followed by a 0.4 mcg/kg/hour maintenance dose (46).

TIVA with dexmedetomidine as single agent: In 2004, Ramsay (3), reported a case series using dexmedetomidine up to 10 mcg/kg/hour, with satisfactory analgesia and hypnosis, as well as ventilatory and hemodynamic stability in cases

of laser tracheal ablation, facial tumor resection and tracheal prosthesis exchange. Boluses of 2-5 mcg/kg were used in four pediatric patients undergoing laryngoscopy and bronchoscopy, with cardiovascular and ventilatory stability during and after the surgical procedure (47).

In a study with propofol and dexmedetomidine in TIVA performed with the purpose of replacing the latter with remifentanil in patients undergoing gynecological video laparoscopy, no significant differences were found in terms of adverse events, recall, cortisol levels, serum glucose, blood pressure and heart rate. This led to the conclusion that, despite no indication for replacing the opioid, there are some differences pertaining to extubation time, although the total recovery time was similar in both groups.

TIVA in pediatrics: A review of the status of TIVA in pediatrics was conducted in 2010 (49), documenting the use of dexmedetomidine for interventional radiology, endoscopy, spine surgery and airway instrumentation procedures. Propofol plasma concentrations required for anesthesia when remifentanil is replaced with dexmedetomidine in endoscopic procedures in pediatrics are not affected (in effective concentrations: 50 of 3.7mcg/ml). The conclusion was that the analgesic effectiveness of dexmedetomidine in those procedures is limited (41). Dexmedetomidine has also been reported to be successful in pediatric patients with dysautonomy, reducing anxiety after surgery and the risk of triggering hypertensive crises (42).

Other uses of dexmedetomidine: It provides analgesia in chronic neuropathic pain, reduces postoperative shivering, and is used for opioid detoxification and to control anxiety after weaning from sedation and analgesia in intensive care units (ICUs), at a dose of 0.6 mcg/kg/hora. In those cases, its action is similar to that of propofol given at a dose of 3 mg/kg/hour. The bispectral index for the two groups was 50 with 5 points on the Ramsay scale. A lower use of opioids (2,17,34) as well as a reduction in extubation time and length of stay in the ICU were observed.

Infusions of more than 24 hours were not recommended (1,2,8).

When dexmedetomidine and propofol were titrated equally for sedation, there were no changes in respiratory rate with a bispectral index of 85 (50).

SIDE EFFECTS

The most frequent side effects are: bradycardia (4.4%), hypotension (16-23 %), nausea (11 %), atrial fibrillation (7 %), anemia (3 %), pulmonary edema (2 %), oliguria (2 %) and thirst (2 %), but they tend to disappear after interrupting the 1 mcg /kg bolus dose.

Dryness of the mouth has been proposed as an advantange in fiberoptic tracheal intubation (OTI). (11,51,52)

Atipamezol (Antisedan, Pfizer), a dexmedetomidine antagonist available at present, has a similar pharmacokynetic profile, but it is not used widely because dexmedetomidine’s side effects (bradycardia, hypotension, etc.) may be reverted easily with the use of anticholinergics or pympathomimetics.

Dexmedetomidine is a relatively new drug approved for use only in intensive care for periods of no more than 24 hours. Off-label uses have been reported. Likewise, there are not sufficient clinical trials or sample sizes supporting its use or precise indication in the practice of anesthesia.

Dexmedetomidine blocks the deleterious adrenergic response during the perioperative period, provides low-potency analgesia and shows a stable cardiovascular profile at doses that are still to be defined appropriately.

For the time being, it is useful in special patient populations, where its advantages are greater than its side effects, for example, patients with a risk of opioid accumulation, ventilatory depression and, in recent years, the pediatric population.

There is no absolute indication to replace opiods with dexmedetomidine or to use it as a “single universal anesthetic”. The current role of dexmedetomidine is as and adjunct in the armamentarium of intravenous anesthetics, with the best possible evidence in specific populations.

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