Substrate Report for: Remifentanil

We present a case of anesthesia for electroconvulsive (ECT) therapy that was complicated by emetic sensitivity to etomidate, fragile ictal threshold, and mild pseudocholinesterase deficiency. The anesthetic was designed in this patient taking all his issues in consideration. The mild pseudocholinesterase deficiency necessitated a (50-75%) reduction in succinylcholine dosage, careful monitoring of the train of four, and postictal amnestic coverage to prevent paralysis upon waking. The significant emetic response to etomidate prompted substitution to propofol and preemptive ondansetron. Propofol significantly raised the ictal threshold but significantly reduced the postprocedural emesis. Eventually, this clinical challenge was resolved with adjunctive use of low-dose etomidate and remifentanil. This combination preserved the ictal parameters, providing patient comfort, good clinical response, and therapeutic efficacy. Although seizure duration and quality often are restored with hyperventilation and caffeine, this case necessitated a return to etomidate for the restoration of satisfactory ictal parameters. Although this effect of remifentanil has been described with methohexital, and etomidate with alfentanil, to the best of our knowledge, this is the first reported case of adjunctive remifentanil with etomidate for preserving ictal threshold. The outpatient course of ECT was thus completed with all psychiatric and anesthetic goals satisfied: adequate seizure quality and duration, no paralysis upon waking, no post-ECT nausea and vomiting, and patient satisfaction. Anesthesiologists should be aware of factors influencing the seizure duration and, keeping in mind the coexisting medical conditions of the patient, adjustments should be made to get the best possible outcome.

STUDY OBJECTIVE: The present report investigates the rate of arousal following remifentanil-based anesthesia associated with the coadministration of pancuronium, which inhibits butyrylcholinesterase, or cisatracurium, which is partially metabolized by nonspecific esterases, versus vecuronium that is eliminated independently of ester hydrolysis. DESIGN, SETTING AND PATIENTS: Sixty patients, ASA I-II, scheduled for elective abdominal surgeries were enrolled in a double-blinded prospective study. In fact, patients were equally divided into three Groups with each Group receiving remifentanil and either one of the following three muscle relaxants: pancuronium, vecuronium or cisatracurium. MEASUREMENTS: The rate of arousal following discontinuation of anesthesia was assessed by Modified Aldrete Score. Time to eye opening on verbal command, tracheal extubation, Modified Aldrete Score >9, and time to discharge from the recovery room were recorded. MAIN
RESULTS: Time to eye opening on verbal command, tracheal extubation, Modified Aldrete Score >9, and time to discharge from the recovery room were not significantly different between the three groups. CONCLUSION: The results suggest that recovery following remifentanil-based anesthesia is not delayed by the coadministration of pancuronium, cisatracurium versus vecuronium; and by the use of neostigmine for reversal of neuromuscular blockade.

We designed this in vitro study to determine whether the half-life of remifentanil was altered in butyrylcholinesterase-deficient patients. Test tubes containing Krebs buffered solution, whole blood, plasma, or red cells from both normal and butyrylcholinesterase-deficient patients were incubated with remifentanil. Remifentanil concentrations were determined by using gas chromatography and mean half-lives were calculated by using a nonlinear regression analysis. There were no differences in whole blood, red cells, or plasma half-life between normal and butyrylcholinesterase-deficient volunteers. In both normal and butyrylcholinesterase-deficient volunteers, whole blood and plasma had a significantly longer half-life than the red cell component. Extrapolation to the in vivo setting would suggest that a butyrylcholinesterase-deficient patient should not have altered remifentanil kinetics. IMPLICATIONS: This was a test-tube-designed study to determine whether an enzyme deficiency (butyrylcholinesterase deficiency) changes the way remifentanil is metabolized. It seems that remifentanil dosage does not need to be changed in patients with butyrylcholinesterase deficiency.

Remifentanil is a synthetic opioid derivative that was introduced into clinical practice in the United States in 1996. The unique modification of its chemical structure to include a methyl-ester ring allows its hydrolysis by non-specific plasma and tissue esterases. This molecular configuration results in its rapid metabolism thereby providing a rapid onset, easy titration by continuous infusion, and a short context-sensitive half-life with rapid elimination. These principles are stable and consistent across all age groups regardless of the infusion characteristics. Owing to these pharmacokinetic characteristics, it is an effective agent in the neonatal population allowing the provision of intense analgesia and anesthesia with a rapid recovery profile in various clinical scenarios. Here, we review the pharmacokinetics of remifentanil in neonates, discuss its clinical applications including intraoperative administration for anesthetic care, unique applications for procedural sedation including endotracheal intubation, and its potential use for sedation in the Intensive Care Unit setting during mechanical ventilation.

We present a case of anesthesia for electroconvulsive (ECT) therapy that was complicated by emetic sensitivity to etomidate, fragile ictal threshold, and mild pseudocholinesterase deficiency. The anesthetic was designed in this patient taking all his issues in consideration. The mild pseudocholinesterase deficiency necessitated a (50-75%) reduction in succinylcholine dosage, careful monitoring of the train of four, and postictal amnestic coverage to prevent paralysis upon waking. The significant emetic response to etomidate prompted substitution to propofol and preemptive ondansetron. Propofol significantly raised the ictal threshold but significantly reduced the postprocedural emesis. Eventually, this clinical challenge was resolved with adjunctive use of low-dose etomidate and remifentanil. This combination preserved the ictal parameters, providing patient comfort, good clinical response, and therapeutic efficacy. Although seizure duration and quality often are restored with hyperventilation and caffeine, this case necessitated a return to etomidate for the restoration of satisfactory ictal parameters. Although this effect of remifentanil has been described with methohexital, and etomidate with alfentanil, to the best of our knowledge, this is the first reported case of adjunctive remifentanil with etomidate for preserving ictal threshold. The outpatient course of ECT was thus completed with all psychiatric and anesthetic goals satisfied: adequate seizure quality and duration, no paralysis upon waking, no post-ECT nausea and vomiting, and patient satisfaction. Anesthesiologists should be aware of factors influencing the seizure duration and, keeping in mind the coexisting medical conditions of the patient, adjustments should be made to get the best possible outcome.

STUDY OBJECTIVE: The present report investigates the rate of arousal following remifentanil-based anesthesia associated with the coadministration of pancuronium, which inhibits butyrylcholinesterase, or cisatracurium, which is partially metabolized by nonspecific esterases, versus vecuronium that is eliminated independently of ester hydrolysis. DESIGN, SETTING AND PATIENTS: Sixty patients, ASA I-II, scheduled for elective abdominal surgeries were enrolled in a double-blinded prospective study. In fact, patients were equally divided into three Groups with each Group receiving remifentanil and either one of the following three muscle relaxants: pancuronium, vecuronium or cisatracurium. MEASUREMENTS: The rate of arousal following discontinuation of anesthesia was assessed by Modified Aldrete Score. Time to eye opening on verbal command, tracheal extubation, Modified Aldrete Score >9, and time to discharge from the recovery room were recorded. MAIN
RESULTS: Time to eye opening on verbal command, tracheal extubation, Modified Aldrete Score >9, and time to discharge from the recovery room were not significantly different between the three groups. CONCLUSION: The results suggest that recovery following remifentanil-based anesthesia is not delayed by the coadministration of pancuronium, cisatracurium versus vecuronium; and by the use of neostigmine for reversal of neuromuscular blockade.

BACKGROUND A short hospital stay is nowadays desirable and affordable for a wide range of surgical pathology, respecting safety of care and home discharge. In the present study, the Authors investigated the use of TIVA with propofol/remifentanil during microsurgical vertebral disc resection to maintain a controlled vascular hypotension for bloodless surgical field aiming to reduce the operating time and consequently recovery room length of stay and morbility related to anaesthesia. METHODS: The study took place in a 300 bed Orthopaedics hospital over a period of 3 months and 50 ASA I-II patients were enrolled in this trial; further data are presented for comparison of 50 ASA I-II patients homogeneous for age and sex to the studied population, operated under a standard TIVA with propofol and boluses of fentanyl. Duration of anaesthesia and surgery, time for awakening after cessation of TIVA, incidence of postoperative nausea and vomiting (PONV), amount and quality of postoperative analgesia, length of stay in the recovery room are reported in statistical presentation. RESULTS: Time of surgery and anaesthesia were reduced in the remifentanil group compared with the fentanyl group, thanks to an easily reachable and durable state of controlled hypotension in the first group without the use of any other drug. The recovery profile was shorter in the remifentanil group the drug being rapidly metabolised by plasma cholinesterase.
CONCLUSIONS: No difference occurred between the two groups regarding quality and amount of postoperative analgesia, while PONV presented more in the fentanyl group and shivering more in the remifentanil group.

We designed this in vitro study to determine whether the half-life of remifentanil was altered in butyrylcholinesterase-deficient patients. Test tubes containing Krebs buffered solution, whole blood, plasma, or red cells from both normal and butyrylcholinesterase-deficient patients were incubated with remifentanil. Remifentanil concentrations were determined by using gas chromatography and mean half-lives were calculated by using a nonlinear regression analysis. There were no differences in whole blood, red cells, or plasma half-life between normal and butyrylcholinesterase-deficient volunteers. In both normal and butyrylcholinesterase-deficient volunteers, whole blood and plasma had a significantly longer half-life than the red cell component. Extrapolation to the in vivo setting would suggest that a butyrylcholinesterase-deficient patient should not have altered remifentanil kinetics. IMPLICATIONS: This was a test-tube-designed study to determine whether an enzyme deficiency (butyrylcholinesterase deficiency) changes the way remifentanil is metabolized. It seems that remifentanil dosage does not need to be changed in patients with butyrylcholinesterase deficiency.

BACKGROUND: Opioids inhibit the rapid eye movement (REM) phase of sleep and decrease acetylcholine (ACh) release in medial pontine reticular formation (mPRF) regions contributing to REM sleep generation. It is not known whether opioids decrease ACh release by acting on cholinergic cell bodies or on cholinergic axon terminals. This study used in vivo microdialysis to test the hypothesis that opioids decrease ACh levels at cholinergic neurons in the laterodorsal tegmental nuclei (LDT) and LDT axon terminals in the mPRF.
METHODS: Nine male cats were anesthetized with halothane, and ACh levels within the mPRF or LDT were assayed using microdialysis and high-pressure liquid chromatography (HPLC). ACh levels were analyzed in response to dialysis of the mPRF and LDT with Ringer's solution (control), followed by dialysis with Ringer's solution containing morphine sulfate (MSO4) or naloxone. ACh in the mPRF also was measured during either dialysis delivery or intravenous infusion of remifentanil and during dialysis delivery of fentanyl.
RESULTS: Compared with dialysis of Ringer's solution, microdialysis with MSO4 decreased ACh by 23% in the mPRF and by 30% in the LDT. This significant decrease in ACh was antagonized by naloxone. MSO4 and fentanyl each caused a dose-dependent decrease in mPRF ACh when delivered by dialysis. Remifentanil delivered by continuous intravenous infusion or by dialysis into the mPRF did not alter mPRF ACh.
CONCLUSIONS: Morphine inhibits ACh at the cholinergic cell body region (LDT) and the terminal field in the mPRF. ACh in the mPRF was not altered by remifentanil and was significantly decreased by fentanyl. Thus, MSO4 and fentanyl disrupt cholinergic neurotransmission in the LDT-mPRF network known to modulate REM sleep and cortical electroencephalographic activation. These data are consistent with the possibility that inhibition of pontine cholinergic neurotransmission contributes to arousal state disruption by opioids.

This review discusses concepts of isomers, stereoisomers, chirality, and enantiomers as applied to drugs used in anaesthesia. The inhalational anaesthetics enflurane and isoflurane are examples of stereoisomers. A chiral centre is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral centre is then present in one of two possible configurations termed enantiomers. A racemate is a mixture of both enantiomers in equal proportions. Many of the drugs used in anaesthesia are racemic mixtures (the inhalation anaesthetics, local anaesthetics, ketamine, and others). The shape of the atracurium molecule is comparable to that of a dumb-bell:the two isoquinoline groups representing the two bulky ends connected by an aliphatic chain. In each isoquinoline group there are two chiral centres, one formed by a carbon and the other by a quaternary nitrogen atom. From a geometric point of view, the connections from the carbon atom to a substituted benzene ring and from the quaternary nitrogen to the aliphatic chain may point in the same direction (cis configuration) or in opposite directions (trans configuration). The two isoquinoline groups in atracurium are paired in three geometric configurations: cis-cis, trans-trans, or cis-trans. However, the two chiral centres allow each isoquinoline group to exist in one of four stereoisometric configurations. In the symmetrical atracurium molecule, the number of possible stereoisomers is limited to ten. Among these, 1 R-cis, 1'R-cis atracurium was isolated and its pharmacologic properties studied. This isomer, named cis-atracurium, offers clinical advantages over the atracurium mixture, principally due to the lack of histamine-releasing propensity and the higher neuromuscular blocking potency. The ester groups appear in one of two steric configurations true and reverse esters. In the true esters, oxygen is positioned between the nitrogen atom and the carbonyl group, while in the reverse esters in its positioned on the other side of the carbonyl group. True esters, suxamethonium and mivacurium, are hydrolysed by the enzyme plasma cholinesterase (butyrylcholinesterase), albeit at different rates. The more rapid degradation of suxamethonium is responsible for its fast onset and short duration of action in comparison with mivacurium. The reverse esters, atracurium, cisatracurium, and remifentanil, are hydrolysed by nonspecific esterases in plasma (carboxyesterases). Remifentanil is hydrolysed rapidly; the degradation leads to its inactivation and short duration of action. Cis-atracurium is preferentially degraded and inactivated by a process known as Hofmann elimination. In a second step, one of the degradation products, the monoester acrylate, is hydrolysed by a nonspecific esterase.