Delayed emergence is an unpredictable complication of general anesthesia. None of the clinical cases of delayed emergence reported in patients under propofol anesthesia were associated with genetic background. However, genetic variations of propofol-metabolizing enzymes may be a causal factor linked to interpatient variability in emergence from general anesthesia. We explored the influence of genetic polymorphisms of the key propofol-metabolizing enzymes, cytochrome P450 2B6 (CYP2B6), and uridine 5′-diphospho-glucuronosyltransferase 1A9 (UGT1A9) in an elderly woman with unusual delayed emergence from propofol. Written consent was obtained from the patient to publish this report.
A 71-year-old Japanese woman (weight, 68.6 kg; height, 156 cm; and body mass index, 28.2 kg/m2; American Society of Anesthesiology physical status II) underwent lumbar spine partial laminectomy under general anesthesia. Her medical history included lumbar spinal canal stenosis, hypertension, diabetes mellitus, breast cancer, and multiple, uneventful surgeries. Her home medications included pregabalin, duloxetine, clonazepam, neurotropin, acetaminophen/tramadol, tizanidine, mirabegron, sennosides, amlodipine, insulin lispro, and tamoxifen. Preoperative measurements of blood urea nitrogen, creatinine, and electrolyte levels and liver function were all within the normal range.
Anesthesia was performed according to the standard protocol followed by the Anesthesiology Department of Nagoya City University. No premedication was administered. Patient monitoring included electrocardiography, invasive blood pressure, pulse oximetry, capnography, and peripheral temperature measurements. After preoxygenation, her tracheal intubation was facilitated with remifentanil (0.3 μg/kg/min), 1% propofol (Diprivan, AstraZeneca, Brussels, Belgium) using target-controlled infusion (TCI; TE-371, Termo, Tokyo, Japan), and rocuronium (0.6 mg/kg). TCI was used for induction and anesthesia maintenance targeting a plasma concentration of 2.0 to 3.0 μg/mL, according to bispectral index (BIS; Monitor IntelliVue MP60, Philips, Amsterdam, The Netherlands). The intraoperative BIS was 40 to 60, with no abnormal electroencephalographic findings. Propofol infusion duration and dose were 274 minutes and 1700 mg, respectively. Supplemental fentanyl (300 μg) and acetaminophen (1000 mg) were administered intraoperatively, without any additional muscle relaxants; we have not used atropine. Microsurgical laminectomy (L3–L5) was performed with the patient in the prone position with no complications, and the patient’s vital parameters remained normal. The surgical and anesthesia durations were 238 and 297 minutes, respectively. In total, 1500 mL of crystalloid fluids was administered. After discontinuation of anesthesia, rocuronium was antagonized with 2.0 mg/kg of sugammadex; however, the patient remained unconscious. Because adequate oxygenation, adequate ventilation (tidal volume exceeded 6 mL/kg), hemodynamically stable, full reversal of muscle relaxation, intact gag/cough reflex, normothermia, and no anticipated difficult airway were observed, the extubation criteria were thought to be satisfactory except for the patient’s state of consciousness, and tracheal extubation was performed. At tracheal extubation, the calculated effect-site concentrations (Ce) were 1.2 μg/mL for propofol using Marsh’s model and 0.57 μg/mL for fentanyl using Shafer’s model. After tracheal extubation, we observed the patient closely in the postanesthesia care unit (PACU). On arrival, the patient was still unresponsive to intense tactile and painful stimuli. Her breathing was unremarkable (12–18 breaths/min), with unlabored respiration. Her other vital signs were normal. A specimen for arterial blood gas analysis was obtained by femoral artery puncture, but it did not elicit any pain response. Blood gas analysis showed a pH of 7.38, Paco2 of 42.6 mmHg, Pao2 of 82.2 mmHg, and HCO3− 24.8 mmol/L in 3 L of oxygen supplement. Serum electrolytes and hemoglobin levels were normal. Postoperatively, measured renal and liver function parameters were within normal limits, with no deterioration. To exclude residual opioid effects, 0.2 mg naloxone was administered without any improvement in consciousness. After 90 minutes of unconsciousness, the patient was admitted to the intensive care unit, and a neurologist was consulted. Her Richmond Agitation-Sedation Scale (RASS)1 was −5 (unarousable), but her clinical neurologic findings and brain imaging (computed tomography and magnetic resonance imaging) revealed no organic abnormalities. Two hours after the surgery, the patient began to move her extremities in response to pain (RASS, −4); 3 hours after the surgery, the patient gradually woke up and opened her eyes in response to her name and completely obeyed all commands (RASS, −1). Neurologists excluded the possibilities of intracranial events, including stroke and seizure, but the cause of delayed emergence from anesthesia could not be confirmed. After full awakening, the patient showed no clinical evidence of any psychologic abnormalities and no neurologic sequelae. Her postoperative course was uneventful, and she was discharged on postoperative day 11.
A careful review of the patient’s past medical records revealed that intravenous propofol anesthesia had been administered for breast surgery performed 2 years previously. Continuous propofol infusion (TCI; plasma target concentration, 2.2–3.0 μg/mL) and remifentanil had been administered without any intraoperative events. The surgical duration and total propofol infusion dose were 87 minutes and 800 mg, respectively. However, during the postoperative PACU stay, the patient was unarousable and unresponsive to loud voices for >30 minutes. At 70 minutes after surgery, the patient opened her eyes and began to obey commands. Her duration of stay at the PACU was 101 minutes, which is longer than usual.
After obtaining written informed consent from the patient, a 5-mL heparinized blood sample was obtained for analysis. DNA was prepared from the blood cells and then analyzed as described previously.2 Genotyping for CYP2B6 516 G>T (CYP2B6*9 or CYP2B6*6) and CYP2B6 785 A>G (CYP2B6*4 or CYP2B6*6) was performed by subjecting polymerase chain reaction products to restriction enzyme digestion. UGT1A9 was genotyped by direct sequencing using sequencing primers. This patient was genotyped for CYP2B6*4/*6, which was heterozygous for CYP2B6 516 G/T and homozygous for CYP2B6 785 G/G, along with UGT1A9 I399 C/C (wild type). The propofol risk index score proposed by Kansaku et al2 was a maximum of 3 points (0–3); when subjects carried the CYP2B6 516 G/T or T/T and UGT1A9 I399 T/C or C/C genotypes and if they were >65 years of age, 1 point each was added to the proposed index score.
We described a patient who was administered general anesthesia twice over 2 years and developed delayed emergence (70 minutes to 3 hours) both times, which resembled a comatose state. All organic causes were excluded. Similar drugs had been used for general anesthesia, and opioids had not been administered at excessive doses. Pharmacologic reversal with naloxone did not result in emergence. Therefore, we presumed that the most probable etiology of delayed emergence was propofol accumulation. Intraoperatively, we used a pharmacokinetic simulation software that calculated the concentration of the drug and the BIS monitor, but the measured parameters did not correlate with the clinical course. Therefore, we suspected a genetic polymorphism in propofol-metabolizing enzymes, which may cause interpatient variability in pharmacokinetics or drug metabolism.
Propofol is a frequently administered intravenous sedative for inducing and maintaining anesthesia. Although awakening is usually rapid and the drug has a favorable safety profile, a delay in emergence and recovery from propofol anesthesia can still occur. Propofol is metabolized mainly by the enzymes CYP2B6 (responsible for propofol hydroxylation) and UGT1A9 (that catalyzes propofol glucuronidation).3,4CYP2B6 and UGT1A9 are highly polymorphic genes. The CYP2B6 516G>T polymorphism may reduce CYP2B6 activity and may consequently decrease propofol breakdown and thereby prolong propofol plasma concentrations, leading to prolonged sedation.2,5 The intronic single-nucleotide polymorphism (SNP) UGT1A9 I399C>T is associated with increased UGT1A9 protein levels and glucuronidation activities toward propofol.6 The association of these polymorphisms with propofol-associated interpatient variability was described previously.2 These authors reported that the CYP2B6*6 allele is a useful biomarker for drug disposition. They proposed that the maximum plasma concentration of propofol, after normalizing with the duration of infusion, was affected by the CYP2B6 G516T variant (related to impaired function) and was significantly affected by a 3-point propofol risk index score that incorporated CYP2B6 G516T and UGT1A9 I399C>T (high expression) genotypes and advanced age. Herein, DNA analysis revealed CYP2B6 G/T and UGT1A9 C/C. This polymorphism may increase propofol plasma concentrations during continuous propofol infusion, leading to delayed emergence from anesthesia. Our patient’s propofol risk index score was 3 points (advanced age was incorporated to the genotypes), and this result was consistent with her clinical course. Prospective large-scale genetic analyses can confirm propofol risk index validity for estimating the risk of delayed emergence from propofol anesthesia.
SNPs in CYP2B6 and UGT1A9 genes might contribute to the interindividual variability in the propofol metabolite formation rates. However, with >100 described SNPs, numerous complex haplotypes, and distinct ethnic and racial frequencies, CYP2B6 is one of the most polymorphic CYP genes in humans.7 The amount of CYP enzyme also may make a difference, as well as the genetic variant present.4 There are no consistent reports concerning the association between the CYP2B6 and UGT1A9 genotypes and interpatient variability in propofol biotransformation in vitro and in vivo.2,5,8,9 Mastrogianni et al5 reported that the CYP2B6 516G>T polymorphism was associated with high blood concentration of propofol in Greek women. In contrast, Loryan et al9 found no significant effects of CYP2B6 or UGT1A9 SNPs or age on propofol metabolism rate in their pilot study, although they reported a pronounced effect of the sex, suggesting patient sex as another important factor in systemic clearance of propofol. Several studies8,9 have suggested that the sex of the patient is a highly significant predictor of recovery time after propofol anesthesia. Faster emergence times have been observed in women. In addition, women have been described to have a higher incidence of awareness during surgery than men.10 Interestingly, Mukai et al11 suggested that the kinetic profile of propofol glucuronidation by liver microsomes differed markedly among species and sex, and UGT isoforms including UGT1A9 were involved in its metabolism. No consistent associations have yet been found using the pharmacogenetic approach. The power of these analyses could have been diminished by the conversion of the study outcome data to a categorical level because the group size for some rare genetic polymorphisms was small.12
Our study has some limitations. First, we could not measure the plasma propofol concentrations during delayed emergence; therefore, increased propofol concentrations could not be confirmed. However, because all organic causes were excluded, we presumed that the most probable etiology of delayed emergence was abnormal propofol pharmacokinetics. Other possibilities for the delayed emergence could be postoperative central anticholinergic syndrome (CAS).13 Clinical features of postoperative CAS are nonspecific, leading to difficult clinical diagnosis. Diagnosis of CAS depends on the exclusion of other conditions and a positive response to a centrally acting cholinesterase inhibitor, usually physostigmine.13 Unfortunately, physostigmine was not administered in the present case because it was not available in Japan. In this case, the patient’s symptoms were not very consistent with CAS, and we had used sugammadex as an agent to reverse muscle relaxation instead of neostigmine and atropine, which were reported to cause CAS.13 In addition, the patient experienced similar delayed emergence from propofol anesthesia in previous breast surgery. Although we could not completely exclude the possibility of CAS, we considered that propofol accumulation was more likely a cause of delayed emergence than CAS in this case. Second, we used the Diprifusor pump based on pharmacokinetic variables developed by Marsh et al14 (Ke0 = 0.26/min). Calculations in Marsh’s model are based only on the patient’s weight, resulting in propofol overdose.15 Marsh’s model does not make any adjustments for age and underpredicts the plasma propofol concentrations in the elderly.16 Advancing age is also associated with increased pharmacodynamic sensitivity to the effects of propofol.17 The time course of estimated propofol concentrations was calculated using the Tivatrainer 10 software (GuttaBV, Aerdenhout, NL), based on the pharmacokinetic parameters from Marsh’s model14 as shown in the Figure. We plotted the expected time course of propofol and the anticipated return of consciousness (ROC) in contrast to the observed ROC. Shafer et al18 reported the effective propofol concentrations at which 50% and 95% of patients were awake as 1.07 and 0.52 μg/mL, respectively. In this case, at intensive care unit admission, Ce of propofol was 0.34 μg/mL, which was below effective concentrations at which 95% of patients are awake and low enough for the patient to be awakened. Three hours after surgery, the patient woke up, and her observed Ce ROC was 0.26 μg/mL. We adjusted the dose of propofol according to BIS; therefore, it was unlikely that we administered an excessive dose. These discrepancies between the pharmacokinetics/pharmacodynamic model and clinical course that cannot be explained by the pharmacokinetic model alone can imply the presence of some abnormal genetic variability of propofol metabolism.
In conclusion, we encountered a case of delayed emergence of a patient from general anesthesia because of abnormal propofol metabolism. Because genetic analysis confirmed a high propofol risk index score (advanced age, CYP2B6 516 G/T, and UGT1A9 I399 C/C), propofol should be avoided in this patient. Genetic variance of propofol metabolism must be considered in patients with unexplained delayed emergence from propofol anesthesia.
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