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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.54 no.1 Campinas Jan./Feb. 2004
Remifentanil in the clinical practice*
Remifentanil en la práctica clínica
Rogério Luiz da Rocha Videira, TSA, M.D.I; José Roquennedy Souza Cruz, TSA, M.D.II
IAnestesiologista da Clínica
Médica e Anestesiológica (CMA) do Hospital e Maternidade São
Luiz, Anestesiologista do HC-FMUSP, Membro do Comitê de Anestesia Venosa/SBA
IIAnestesiologista da CMA do Hospital e Maternidade São Luiz, Anestesiologista da Disciplina de Anestesiologia, Dor e Terapia Intensiva da UNIFESP
BACKGROUND AND OBJECTIVES: Remifentanil
is the newest opioid for anesthetic procedures. This study aimed at reviewing
the literature, with emphasis on information of clinical interest published
from January 2000 to December 2002.
CONTENTS: Major remifentanil studies are described and grouped by areas of interest for clinical anesthesia. Issues such as recommended dose, equipment and their correct use, transitional analgesia, as well as controversial indications, such as sedation, pediatric or obstetric surgery and intensive care, are discussed.
CONCLUSIONS: Remifentanil is currently the best opioid for continuous intravenous infusion and may improve anesthesiologist's efficiency provided usage recommendations are followed.
Key Words: ANALGESICS, Opioids: remifentanil
JUSTIFICATIVA Y OBJETIVOS: El remifentanil
es el opioide más recientemente introducido en la práctica anestésica.
El objetivo de ese estudio fue rever la literatura, con énfasis en la
información de interés clínico publicada en el período
de enero de 2000 a diciembre de 2002.
CONTENIDO: Los principales estudios sobre remifentanil son descritos y agrupados por áreas de interés para la anestesia clínica. Aspectos como dosis recomendada, equipamiento y forma de uso, analgesia de transición y áreas en que el uso aún es controvertido, como para sedación, cirugía pediátrica, obstétrica y terapia intensiva, son discutidos.
CONCLUSIONES: El remifentanil es actualmente el opioide más adecuado para la administración por infusión venosa continua y puede hacer más eficiente la práctica clínica del anestesista a partir del momento en que sean seguidas las recomendaciones para su uso.
Analgesia is part of general anesthesia and opioids are currently the most common drugs to induce analgesia during intravenous or balanced anesthesia. The adequate use of opioids depends on pharmacokinetics and pharmacodynamics understanding 1, in addition to knowing its adverse effects and how to prevent them. Remifentanil is the newest opioid in Brazilian market, since 1999. There are three remifentanil reviews in the Brazilian literature 2-4, but after the publication of those studies, the number of scientific articles on remifentanil listed in Medline has almost tripled.
This study aimed at reviewing the literature on remifentanil with emphasis on clinical interest information published from January 2000 to December 2002.
WHAT IS REMIFENTANIL?
Remifentanil is a selective µ-agonist opioid of the phenylpiperidine group, the same of fentanyl, alfentanil and sufentanil. Pharmacodynamic characteristics are similar to other opioids of this group, but its pharmacokinetics is totally different. It has a lateral methylester chain which provides metabolism by unspecific blood and tissues esterases (carboxiesterase). Onset after intravenous administration is fast (1 to 2 minutes) because the balance between plasma and action site in the central nervous system (biophase) is fast and similar to alfentanil. Remifentanil does not release histamine 2.
Remifentanil effect duration is short, with 9 to 10 minutes excretion half-life, as a consequence of extensive extra-hepatic metabolism, differently from other opioids which depend on tissue redistribution for the end of effect and on liver metabolism for excretion 2-4. It is the fastest action opioid in the market 4. Recovery is fast, even after prolonged infusion, because its plasma concentration is 50% decreased 3 to 10 minutes after, regardless of infusion time 5. After 3 hours infusion in equipotent doses, there has been 50% recovery of ventilatory depression 5 minutes after remifentanil withdrawal, as compared to 54 minutes after alfentanil withdrawal 6.
Acid remifentanil is the major metabolite, produced by ester binding hydrolysis, with analgesic action approximately 4 thousand times lower than remifentanil and urinary excretion representing more than 90% of administered remifentanil 7.
Patients with the atypical form or deficiency in plasma pseudocholinesterase (butyryl-cholinesterase), or even after receiving anticholinesterases, normally metabolize remifentanil 8. It has already been used in acute intermittent porphyry patients without causing any problem 9.
It is available lyophilized in 1, 2 or 5 mg vials. Reconstituted in water with 1 mg.ml-1, its pH is close to 3. For clinical use, it should be diluted in saline solution or 5% glucose and should be used in up to 24 hours. Lactated Ringer's should be avoided because there is loss of action 6 hours after dilution. Final dilution should be at least 1 mg in 20 ml, resulting in 50 µg.ml-1 concentration. More diluted solutions should be used especially when patients are maintained in spontaneous ventilation. Dilution in propofol should be avoided, because this drug promotes remifentanil ester group hydrolysis 10.
Its fast excretion prevents build up and longer action time even after prolonged infusion, but makes bolus doses inconvenient except for some specific indications.
This characteristic makes remifentanil the best opioid for continuous intravenous infusion when a fast return to spontaneous ventilation is planned after surgery or when there is the need to awaken the patient during surgical procedure. On the other hand, the fast analgesic recovery is a negative characteristic, because there is virtually no residual analgesia.
The association of remifentanil and low doses of more prolonged action opioid, such as morphine, fentanyl or methadone, has been proposed to avoid bolus doses, help maintaining intraoperative analgesia and allow for less painful emergence 11-13.
It is counterindicated for neuraxial block because its formulation contains glycine (13 mg/1 mg remifentanil) which is neurotoxic and may induce transient paralysis 14.
Conventional recommendation is 1 µg.kg-1 intravenous bolus injected in at least 30 seconds, followed by 0.5 µg.kg-1.min-1 infusion titrated according to surgical stimulation 2,15, but American pharmacopoeia considers these doses excessive 16.
Blood concentration analgesic potency reached by intravenous infusion is somewhat higher than fentanyl (approximately 1.2 times) 5. However, when this same potency ratio is applied to bolus dose there is a relative overdose because biophase balance is faster than with fentanyl. This bolus, as with any other opioid, may cause apnea, chest stiffness, bradycardia or arterial hypotension. Bolus doses equivalent to 0.2 µg.kg-1 have been indicated for sedation 17.
Other proposals with 0.1 to 0.5 µg.kg-1.min-1 infusions without bolus have already been described 3,4, because they prevent bolus side-effects and benefit from the fact that 10 to 15 minutes after a constant infusion, biophase concentration reaches more than 80% of balanced state concentration, as compared to less than 30% with other opioids 5.
When remifentanil is diluted in 50 µg.ml-1 (1 mg in 20 ml syringe), infusion pump rate in ml.h-1 may be initially set to 10% of body weight in kg because this is equivalent to slightly less than 0.1 µg.kg-1.min-1 infusion. For example: in a 60 kg patient, initial infusion rate may be 6 ml.h-1.
On the other hand, remifentanil-induced blood pressure and heart rate decrease (mean 25% to 40%) is dose-independent even after excessive dose (30 µg.kg-1), when administered to healthy people who had previously received anticholinergics 18.
As opposed to other opioids, time to return to spontaneous ventilation is almost not changed after high intravenous infusion doses 19. Based on this characteristic, the intentional use of remifentanil overdose has already been proposed 20. This practice, however, has already been charged as responsible for the development of acute tolerance 21.
Care with equipment is critical. Although the use of remifentanil through manually controlled equipment with microdrops and continuous anesthesiologist monitoring has been suggested as similar to the use through infusion pumps 22, there are no extensive prospective studies evaluating the safety of such proposal. The use of flow controllers, or preferably infusion pumps, is recommended 16.
Infusion system volume, considered between remifentanil solution entry point and patient's vein, should be as low as possible to prevent remifentanil build up in this space if hydration flow is too slow or inadvertently interrupted. When fluid infusion is restarted or increased, there might be inadvertent bolus injection of remifentanil built up in this space. This mechanism has been considered the cause for postoperative apnea and intraoperative arterial hypotension and bradycardia 23,24. At the end of remifentanil infusion, all venous extension or connection should be purged with the hydration solution to prevent such problem 16.
Blood and hemoderivatives infusion by the same remifentanil infusion line has not been recommended because there might be remifentanil metabolism by blood esterases, but such metabolization is slow with 1.8 hours half-life in blood maintained at 37 ºC, which probably markedly decreases the clinical meaning of this metabolization 25. So, in the absence of other venous access, remifentanil may be injected through the same hemoderivatives infusion line.
Interaction with Inhalational and Intravenous Anesthetics
Effective remifentanil use decreases inhalational anesthetics to hypnotic doses only, in a concentration close to 50% of minimum alveolar concentration (MAC).
Associated to 67% nitrous oxide (N2O), the dose preventing autonomic response to skin incision in 50% of patients (DE50) was 0.02 to 0.09 µg.kg-1.min-1; however, even with 0.6 µg.kg-1.min-1 infusion, which is DE50 for any surgical stimulation, 1/3 of patients presented movement or eye opening without hemodynamic changes or intraoperative memory 19. Blood concentration equivalent to DE50 of remifentanil associated to N2O has varied from 3.8 hg.ml-1 for prostatectomy to 7.5 hg.ml-1 for abdominal surgery 26. It has to be reminded that after 10 to 15 minutes there is correspondence between remifentanil infusion rate (in µg.kg-1.min-1) and its blood concentration (in hg.ml-1), being the latter approximately 20 to 30 times higher than the former; for example: 0.1 µg.kg-1.min-1 infusion corresponds to 2 to 3 hg.ml-1 plasma concentration 5. Isoflurane MAC was decreased 50% with 1.2 hg.ml-1 remifentanil blood concentration (± 0.06 µg.kg-1.min-1) 27. Halogenate anesthetic used as hypnotic only has allowed faster and more foreseeable emergence, in addition to decreasing these agents' consumption in 40% to 50% 28.
Remifentanil has little effect on propofol plasma concentration and bispectral index (BIS) ratio, not only potentiating propofol sedative action but rather promoting less motor response to surgical stimulation in the same BIS value and inhibits its increase in response to painful stimulation 29,30.
When propofol target-concentration was decreased from 5 to 2 µg.ml-1, mean intraoperative remifentanil infusion had to be increased from 0.13 to 0.21 µg.kg-1.min-1 and emergence time was decreased from 14 to 6 minutes after end of infusion 31. However, propofol target-concentration in the operative period with total intravenous anesthesia should be at least 3 µg.ml-1, approximately equivalent to 100 µg.kg-1.min-1 maintenance infusion to prevent intraoperative awareness 32.
Remifentanil infusions lower than 0.05 µg.kg-1.min-1 associated to inhalational anesthetics (1 to 1.5 MAC) or propofol (up to 130 µg.kg-1.min-1) have been used to maintain intraoperative spontaneous ventilation 33.
As to recovery, patients receiving remifentanil and propofol had better neuro-psychomotor performance as compared to sevoflurane and N2O, but this difference was only observed in the first post-anesthetic recovery hour 34.
Intraoperative association with propofol, as compared to desflurane, allowed 20% less analgesics consumption and 3 times less nausea in the PACU after laparoscopic cholecystectomy 35.
This phenomenon has been observed with different opioids 36. However its incidence in the clinical practice is controversial, having been observed with remifentanil associated to desflurane 37, but not with sevoflurane 21 or propofol 38. Low ketamine doses (total of 0.6 mg.kg-1) associated to remifentanil have been proposed to decrease this desflurane-related problem 39.
In volunteers receiving 1 µg.kg-1.min-1 remifentanil and submitted to painful stimulation by skin pressure, there has been 75% decrease in analgesic action 3 hours after infusion 40. However, no acute tolerance has been observed in a study with volunteers submitted to thermal stimulation, hot and cold, and to electric stimulation 41.
On the other hand, no tolerance was observed in intensive care patients maintained with continuous remifentanil infusion to help mechanical ventilation 42.
Fast remifentanil recovery requires other analgesics before its withdrawal. For chest, abdominal or orthopedic surgeries anti-inflammatory drugs are unable to assure painless emergence and require the association of intravenous opioids of more prolonged action, such as fentanyl (up to 150 µg) or morphine (up to 0.15 mg.kg-1), of regional blocks or of local anesthetic infiltration before surgery completion 43,44. When morphine is used for cholecystectomy it is more effective if administered during induction, together with remifentanil, due to its prolonged onset time 45.
A different way to maintain immediate postoperative analgesia is to maintain 0.05 to 0.15 µg.kg-1.min-1 remifentanil infusion, but this technique is related to a higher incidence of respiratory depression and requires resources and monitoring equipment only available in recovery or intensive care units 11,23. In this technique, the simultaneous use of intravenous nalbuphine should be avoided because it antagonizes remifentanil analgesic action 46. Remifentanil bolus injection for postoperative analgesia is not recommended 16.
Although in theory remifentanil may be used in any situation in which an intravenous opioid is indicated during anesthesia, its more effective and safer use depends on some aspects described below.
Tracheal Intubation without Neuromuscular Blocker
This technique is indicated for myasthenia and myopathy patients, in surgeries where evoked potential will be monitored, when peripheral nerve stimulator is used for regional block or when muscle relaxation is not necessary during surgery. Intravenous atropine (0.5 to 1 mg) should be previously administered to prevent bradycardia.
Remifentanil (2 µg.kg-1) associated to propofol (2 mg.kg-1) has allowed good tracheal intubation conditions to 90% of patients, but has prolonged apnea from 6 to 9 minutes, as compared to 1 mg.kg-1 succinylcholine 47. Remifentanil associated to 1 mg.kg-1 lidocaine has allowed tracheal intubation dose to be decreased from 2 to 1 µg.kg-1.min-1 with consequent decrease in apnea from 8 to 5 minutes 48. A different study comparing different remifentanil bolus doses associated to propofol, has shown tracheal intubation reaction in 30% of patients with 3 µg.kg-1, while 4 µg.kg-1 has provided good tracheal intubation conditions in 95% of patients 49.
For tracheal intubation with awaken patients, remifentanil was used in bolus dose of 3 µg.kg-1 associated to midazolam (2 mg) 50. As single agent during fiber optics endoscopic intubation, up to 0.5 µg.kg-1.min-1 infusion was associated to better comfort, but with a higher incidence of memory as compared to combined intravenous midazolam (10 mg) and fentanyl (1.5 µg.kg-1) 51.
It has to be highlighted that these studies were performed with young and healthy patients being inadequate for elderly patients in the above-described doses.
Up to 0.1 to 0.15 µg.kg-1.min-1 remifentanil continuous infusion may be used for sedation. During spinal anesthesia or brachial plexus block, 0.04 µg.kg-1.min-1 infusion associated to midazolam (3 mg) has induced satisfactory sedation in 50% of patients 52. However, it has promoted more respiratory depression and a higher incidence of nausea and vomiting as compared to propofol, being recommended only to complement incomplete blocks with pain referred by the patient 53.
Remifentanil alone is less effective and produces more emesis in lithotripsy than when associated to propofol for patient-controlled analgesia 54. Associated to 50 µg.kg-1.min-1 propofol, 12.5 µg bolus remifentanil has promoted faster post-lithotripsy recovery as compared to other opioids 17. In a different study comparing propofol and bolus fentanyl, a higher incidence of post-lithotripsy emesis was observed 55.
Remifentanil has been used for analgesia during ophthalmologic blocks. It promotes faster recovery as compared to propofol, but with a higher incidence of nausea. Remifentanil-induced nausea may be prevented with 10 µg.kg-1.min-1 propofol infusion 56. The association of 0.5 µg.kg-1 bolus remifentanil and 0.5 mg.kg-1 propofol has been recommended for ophthalmologic block 57.
To complement local anesthesia for breast biopsy, the association of intravenous midazolam (2 mg) has decreased mean remifentanil infusion from 0.11 to 0.07 µg.kg-1.min-1, with lower incidence of anxiety, deeper sedation and lower incidence of injection memory 58.
It is believed that sedation with remifentanil should only be induced after anesthesiologists' have enough experience with this drug in general anesthesia in intubated patients, never forgetting that pulse oximetry will only provide late respiratory depression signals in patients receiving oxygen 59.
Remifentanil should be carefully used in pediatric surgeries because the lower is patient's body weight, the more critical are the issues recommended in the section "Infusion Equipment". In children with central venous access, this administration route may be preferred to the peripheral vein 60.
Differently from all other opioids, remifentanil has a higher plasma concentration in children aged 2 to 6 months as compared to adults 61. Preliminary studies with children above 2 years of age have shown pharmacokinetic and pharmacodynamic profiles similar to adults 62; but in a more recent study, mean infusion necessary to block cardiovascular responses to skin incision was at least twice as that observed in adults 63.
A multicentric study evaluating term babies (> 37 weeks) with less than 9 weeks of life and submitted to pyloromyotomy has shown that there has been no new postoperative apnea episodes with remifentanil/N2O, although it was seen in children receiving halothane 64.
In tonsillectomy, remifentanil has provided faster extubation but with a higher incidence of postoperative pain as compared to fentanyl 65.
In strabismus correction surgery with remifentanil, there has been a lower incidence of postoperative hypoxemia with no need for naloxone, used in 20% of children receiving fentanyl. However, there has been higher incidence of postoperative pain 62. A more recent study has observed a lower incidence of postoperative vomiting as compared to fentanyl 66.
In elderly patients (above 65 years of age) a 50% decrease in remifentanil dose is recommended. DE50 is decreased to half (pharmacodynamic change), while central distribution volume and plasma clearance are 25% to 33% decreased (pharmacokinetic change), respectively as compared to young adults 67.
Remifentanil associated to N2O has provided early emergence with less residual psychomotor effect as compared to isoflurane/N2O/fentanyl, but with higher incidence of post lumbar laminectomy nausea 68. In a different study with N2O, patients above 60 years of age had recovery time twice as higher than patients below 60 years of age, after remifentanil infusion in the same mean infusion rate 69.
It is recommended to decrease the infusion dose in up to 50% in liver failure patients 4,70. There are minor pharmacokinetic changes in liver failure patients. Even in patients in the no liver phase during liver transplantation, remifentanil plasma clearance was similar to healthy adults 25. There is, however, pharmacodynamic change in liver failure patients, because a certain analgesic or respiratory depressing action is obtained with plasma concentration 40% lower than that observed in healthy people 70.
No remifentanil pharmacokinetic or pharmacodynamic changes were observed in renal failure patients. However, prolonged infusions should be avoided because acid remifentanil excreted by kidneys has its half-life prolonged from 1.5 to 26 hours. Clinical relevance of this build up has not yet been established, but computer simulation with 2 µg.kg-1.min-1 remifentanil for 12 hours was unable to increase acid remifentanil to concentrations higher enough to induce significant hypnosis. Approximately 35% acid remifentanil is excreted 3 to 5 hours after hemodialysis 71. Remifentanil mild plasma clearance decrease and excretion half-life increase was observed after hemodialysis, probably due to decreased distribution volume, and of minor clinical significance 72.
Remifentanil associated to other short-duration anesthetics has been recommended for obese patients 73. Pharmacokinetics is similar to non-obese patients, but ideal weight should be used to calculate remifentanil dose rather than actual weight 74.
In equipotent doses, obese patients receiving alfentanil, fentanyl or remifentanil had similar hemodynamic changes during tracheal intubation 75. In obese patients submitted to laparoscopic cholecystectomy with sevoflurane, remifentanil has shortened emergence time from 11 to 6 minutes, as compared to bolus fentanyl 73.
There are still not enough studies to determine the role of remifentanil in intensive care. Most studies have evaluated the immediate postoperative period of neurological and cardiothoracic surgeries 76. In other prolonged surgeries, its use has been reported as a major factor to accelerate extubation and decrease the need for intensive care even after liver transplantation 77. Dose should be decreased in hemorrhagic shock although there is minor pharmacokinetic change 76.
In the mean dose of 0.14 µg.kg-1.min-1, remifentanil used for up to 78 hours has helped mechanical ventilation, has required additional sedation in 63% of patients and has provided extubation to be scheduled only 15 minutes in advance 42. In neurosurgical intensive care, remifentanil has helped intracranial propofol and mannitol-refractory pressure control, as well as has allowed for neurological evaluation few minutes after infusion withdrawal 78.
In carotid surgery with desflurane, remifentanil has decreased emergence time in half (from 8 to 4 minutes) as compared to fentanyl and with an even lower psychomotor deficit, thus allowing earlier neurological evaluation 79. As compared to sufentanil, remifentanil has provided better blood pressure control after tracheal intubation, has decreased the need for hypnotics and has presented similar hemodynamic response at surgery completion when associated to b-blocker and calcium blocker 80. It has also been used as a single maintenance agent in the dose of 0.35 to 1.5 µg.kg-1.min-1 after tracheal intubation under topic anesthesia and bolus propofol (1 mg.kg-1) 81.
As superficial and deep cervical plexus block complementation for carotid endarterectomy, it has been used in the dose of 0.04 µg.kg-1.min-1 82.
In intracranial mass excision surgeries with mean duration of 5 hours, more than 90% of patients under remifentanil infusion were extubated in 15 minutes as compared to approximately 60% after bolus fentanyl 83. In a different study, all patients receiving remifentanil were extubated in up to 20 minutes, while approximately 15% of patients receiving alfentanil have needed almost 1 hour for extubation, although mean extubation time has been similar for both groups 84. Associated to 3% desflurane, 0.12 µg.kg-1.min-1 remifentanil maintenance dose has been recommended for craniotomy 85.
Remifentanil has been used in stereotactic neurosurgeries to help intraoperative emergence, when needed 86. Bolus remifentanil (2.5 µg.kg-1) during electrocorticography helps intraoperative location of epilepsy focus because it increases its discharge while decreasing electric manifestations in areas around the focus, which helps decreasing non-epileptic brain tissue resection 87. On the other hand, 0.01 µg.kg-1.min-1 infusion for 15 minutes has not promoted changes in epileptic patients electrocorticographies 88.
In cervical ankylosing spondylitis correction surgeries, it has promoted intentional intraoperative emergence (wake-up test) in 3 to 5 minutes after infusion withdrawal and has not hindered somatosensory evoked potential monitoring, when associated to 0.3% isoflurane 89.
In children below 1 year of age, 0.25 µg.kg-1.min-1 remifentanil was used in the intraoperative period and maintained for 12 hours to help pain control and intensive care treatment after surgical craniosynostosis correction 90. Bolus 1 µg.kg-1 doses have also been useful to decrease hemodynamic and metabolic responses observed at subcutaneous catheter insertion in the ventricular-peritoneal lead during pediatric anesthesia with isoflurane and N2O 91.
Bolus remifentanil should not be used in elderly patients under b-blockers because there may be severe bradycardia, arterial hypotension and even asystole 92.
During cardiopulmonary bypass with hypothermia, plasma clearance has decreased approximately 20%, but there has been no need to adjust remifentanil infusion during this period 93. Remifentanil has decreased the incidence of arterial hypertension, tachycardia and intraoperative vasodilators, but there has been no change in extubation time as compared to bolus fentanyl to complement isoflurane and propofol anesthesia 94.
Associated to propofol and compared to fentanyl, it has been observed a longer extubation time due to higher incidence of shivering and arterial hypertension in the ICU 95. However, another author has not observed differences in tracheal extubation time, but has observed a lower incidence of arterial hypertension as compared to low dose fentanyl (< 15 µg.kg-1), which might be associated to a lower incidence of myocardial infarction 96.
In minimally invasive myocardial revascularization surgeries and associated to propofol without cardiopulmonary bypass, remifentanil has decreased emergence time from 75 to 25 minutes as compared to alfentanil, but there has been higher morphine consumption in the first 3 post-emergence hours 97.
For heart catheterization, 0.2 to 0.3 µg.kg-1.min-1 doses associated to 0.6 MAC sevoflurane were used in children with congenital cardiomyopathies 98.
Remifentanil has been used in general anesthesia for high-risk pregnant women, with cardiomyophathy or intracranial tumor 99-101. Remifentanil plasma clearance in pregnant women is twice as that observed in adults. As other opioids, it crosses the uterus-placental barrier but is rapidly metabolized by the fetus. Remifentanil umbilical vein/uterine artery concentration ratio of 0.88 shows that there is fast transfer of maternal blood to fetal blood, while umbilical artery and vein concentrations ratio of 0.29 suggests major fetal metabolization and/or redistribution 102. There might be neonatal respiratory depression, but there is a fast return to spontaneous ventilation when ventilatory assistance is maintained, which probably decreases the need for administering naloxone to the neonate.
For labor analgesia, remifentanil has been used in PCA 103 or in titrated continuous intravenous infusion 104 in patients with counterindications for regional anesthesia and with low platelet counts. In a preliminary study with intravenous bolus remifentanil (0.25 µg.kg-1) in the beginning of uterine contraction, analgesia was ineffective and there has been a high incidence of side-effects, such as nausea and maternal respiratory depression 105. Analgesia was satisfactory with PCA and mean remifentanil consumption was 0.07 µg.kg-1.min-1 with mean 0.4 µg.kg-1 bolus administered for 1 minute as compared to 20 traditional seconds with 1-minute block interval, with patient oriented to ask for the bolus at the first sign of uterine contraction. However, side-effects, such as respiratory depression between contractions and loss of fetal heart rate variability at cardiotocography have limited the use of this technique 106.
Remifentanil infusion has also been used for a short period to help epidural catheter insertion in poorly cooperative pregnant patients 107.
Other Surgical Procedures
Remifentanil associated to local anesthesia has been used to correct urinary incontinence with TVT - tension-free vaginal tape, because in this new surgical technique, patients have to be maintained awaken to be able to cough or increase abdominal pressure while tape tension is adjusted 108. However, preventive antiemetics were recommended.
Controlled arterial hypotension for middle ear surgery with propofol was obtained with 0.25 to 0.5 µg.kg-1.min-1 remifentanil and there has been no heart rate or PaCO2 increase or arterial blood pH decrease observed with nitroprusside 109.
As to billiary ways action, 0.1 mg.kg-1.min-1 infusion has prevented the crossing of intravenous contrast to the duodenum, what was observed only 20 minutes after infusion withdrawal, same time needed to enhance duodenum without remifentanil 110.
Associated to epidural anesthesia and sevoflurane for upper abdomen surgeries, it has provided faster extubation and higher SpO2 values up to 7 hours after surgery completion, as compared to sufentanil 111.
In laryngeal microsurgeries and associated to propofol, 79% of patients have reached Aldrete's score 9 or 10, already 10 minutes after surgery completion, as compared to 40% after fentanyl, and this difference has persisted even after 30 minutes (95% versus 65%) 112. In a different study with this same procedure, associated to propofol and compared to fentanyl, there has been lower incidence of tachycardia, arterial hypertension, lower propofol consumption, but higher incidence of bradycardia 113.
Remifentanil has pharmacokinetic characteristics which differentiate it from other opioids and make it the most flexible drug to be titrated as compared to all intravenous agents available for clinical anesthesia, but it requires a learning period for the anesthesiologist to understand how to best use it and prevent or minimize side-effects 114. In the clinical practice, however, anesthesiologists intuitively use the so-called "temporal reference system" to decide when to withdraw infusion or administer the last bolus of more prolonged action opioids before surgery completion 115. With remifentanil, this is no longer necessary and its infusion may be maintained until surgery completion, making its use particularly interesting when the estimated duration of a certain procedure is considered inadequate. Surgeries in which the operating field cannot be observed, the surgical team is not well-known by the anesthesiologist or in which there is severe painful stimulation until surgery completion are some examples of procedures in which remifentanil would be the best indication.
Its association to hypnotic doses of inhalational or intravenous general anesthetics often allows for faster return to consciousness and certainly in a more foreseeable manner than with other general anesthetic techniques. The cost of this more accurate forecasting is represented by closer attention to postoperative analgesia and by the use of equipment, such as infusion pumps, and care with infusion lines, which make its administration safer and more accurate.
Information of this review may be used by anesthesiologists to better use this drug in the clinical practice.
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Dr. Rogério Luiz da Rocha Videira
Address: Rua Oscar Freire 1546/194
ZIP: 05409-010 City: São Paulo, SP
Submitted for publication 13, 2003
Accepted for publication May 14, 2003
* Received from Hospital e Maternidade São Luiz, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC FMUSP) e da Disciplina de Anestesiologia, Dor e Terapia Intensiva da Universidade Federal de São Paulo (UNIFESP), SP