Pharmacokinetics/Pharmacodynamics
Melatonin and Clonidine Premedication Has Similar Impact on the Pharmacokinetics and Pharmacodynamics of Propofol Target Controlled-Infusions
The Journal of Clinical Pharmacology 2015, 55(3) 307–316 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.401
Agnieszka Bienert, PhD1, Katarzyna Wawrzyniak, MD, PhD2, Paweł Wiczling, PhD3, Krzysztof Przybyłowski, MSc1, Zenon J. Kokot, PhD4, Jan Matysiak, PhD4, Agnieszka Pachutko, MSc1, Martyna Józefowicz, MSc3, Krzysztof Kusza, MD, PhD2,5, and Edmund Grzeskowiak, PhD1
Abstract Recently oral melatonin has been proposed as an agent for premedication. In this study, we compared melatonin with clonidine, considering its anxiolytic properties as well as the influence of both agents on the pharmacokinetic, hypnotic, and hemodynamic effects of propofol during propofol– remifentanil total intravenous anesthesia (TIVA). The dataset under analysis included 32 patients scheduled for a functional endoscopic sinus surgery. The population pharmacokinetic modeling was done with NONMEM. The PK of propofol was described with a two-compartment disposition model, whereas the BIS and AAI were described with a sigmoidal Emax model linked with the propofol concentration via the biophase compartment. The anxiolytic effect was assessed by means of the visual analog scale for anxiety (VAS-A). The population PK/PD model was successfully developed to describe the data. No significant differences in the PK/PD of propofol were noted due to the premedication with clonidine and melatonin. Melatonin was less effective than clonidine in reducing patients’ anxiety at the induction of anesthesia, whereas clonidine premedication was associated with greater decrease in heart rate and blood pressure. A decreased EC50 (2.47 vs. 3.17 mg/L) and increased slope (2.71 vs. 1.30) of the sigmoidal Emax relationship was observed for the AAI index, as compared with the BIS measurements.
Keywords melatonin, clonidine, propofol, pharmacokinetics, pharmacodynamics
Recently oral melatonin has been proposed as a preoperative medication in both adult and pediatric surgical patients. Melatonin has a significant anxiolytic effect and thus it may be useful for highly anxious patients undergoing painful surgeries. In comparison with midazolam, melatonin has similar anxiolytic efficacy but it causes less psychomotor impairment and fewer side effects.1–4 Also, it has been demonstrated that oral premedication with 0.2 mg/kg melatonin significantly reduces the propofol and thiopental doses required for the loss of responses to verbal commands and eyelash stimulation,5 whereas exogenously administered melatonin acts as an anesthetic agent on the rat model.6 Thus, it is possible that melatonin may influence the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol used during anesthesia. However, this hypothesis has not been confirmed yet. In this study, we compared melatonin with clonidine, a drug used for premedication, considering the influence of both agents on the pharmacokinetics as well as the hypnotic and hemodynamic effects of propofol during propofol–remifentanil TIVA. Both clonidine and melatonin have been used as premedication agents and may have some advantages over
midazolam in patients undergoing ESS: they do not cause respiratory depression and have a favorable side-effects profile. In particular, clonidine can also decrease
1 Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, ul. Marii Magdaleny 14, 61 - 861 Poznan, Poland 2 Department of Anesthesiology and Intensive Therapy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Marii Skłodowskiej - Curie 9, 85-094 Bydgoszcz, Poland 3 Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdansk, ul. Hallera 107, 80-401 Gdansk, Poland 4 Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, ul. Grunwaldzka 6, 60 - 780 Poznan, Poland 5 Department of Anesthesiology and Intensive Therapy, Poznan University of Medical Sciences, ul. Marii Magdaleny 14, 61 - 861 Poznan, Poland
Submitted for publication 12 July 2014; accepted 17 September 2014. Corresponding author: Agnieszka Bienert, Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, ul. Sw. Marii Magdaleny 14, 61-861 Poznan, Poland Email: [email protected]
308 intraoperative bleeding due to its effect on the blood flow in the nasal mucosa.7,8 Both agents have been successfully used as premedication and their effects resemble midazolam to some extent.4,9,10
Methods Patients After approval by the Research Ethics Committee at the Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland (KB 693/2011), and with informed, written consent received from 32 patients with the ASA physical status I and II they were scheduled for functional endoscopic sinus surgery (FESS) and they were prospectively randomized into one of three groups. In group I (n ¼ 9) oral melatonin (Melatonina, Lekam, Poland) (5 mg on the night before the surgery and 5 mg 60 minutes before the surgery) was used for premedication and a Bispectral Index (BIS) monitor was used to monitor the depth of anesthesia. The anxiolytic effects of both premedication agents were assessed according to the visual analog scale for anxiety (VAS-A) during the preoperative visit and shortly before the induction of anesthesia. In group II (n ¼ 10) oral melatonin (5 mg on the night before the surgery and 5 mg 60 minutes before the surgery) was used for premedication and A-Line Auditory Evoked Potential Index (AAI index) (AEP/2, Danmeter, Denmark) was used to monitor the depth of hypnosis, whereas in group III (n ¼ 13) oral clonidine (Iporel, WZF Polfa, Poland) (150 mg, 60 minutes before the induction of anesthesia) and bispectral index monitor (BIS; A-2000, Aspect Medical System, Newton, MA, USA) were used, respectively. On the morning of surgery, the patients were NPO > 6 hours based on American Society of Anesthesiologist 2011 practice guidelines. In all the three groups, intravenous anesthesia (TIVA) consisted of target-controlled infusions (TCI) of remifentanil (Ultiva, GlaxoSmithKline, Australia) and propofol (Propofol 1% MCT/LCT, Fresenius, Germany) with a pump (Orchestra Base Primea, Fresenius Kabi AG, Germany) in order to achieve the estimated target effectsite concentration of remifentanil (Ce) of 1.5 ng/mL. When the steady-state equilibrium for remifentanil was achieved, the infusion of propofol started to reach the target Ce concentration of 3 mg/mL. The TCI of propofol was carried out according to the Schneider model, and the infusion of remifentanil was carried out according to the Minto model. During the surgery the infusion of remifentanil was titrated to achieve a favorable hemodynamic profile and the infusion of propofol was titrated to maintain the BIS index within the range of 45–60 or the AAI index within the range of 15–25. The exclusion criteria were as follows: significant cardiovascular disease, epilepsy, smoking (>10 cigarettes
The Journal of Clinical Pharmacology / Vol 55 No 3 (2015)
daily), excessive alcohol intake (>30 g daily), and neurological diseases that could affect the CNS monitoring, immunodeficiency, use of melatonin, clonidine, benzodiazepines, rifampicin, cimethidine, neuroleptics, tricyclic, and selective serotonin reuptake inhibitors (SSRI) antidepressants; actual body weight less than 50 kg or more than 100 kg, alcohol abuse, and pregnancy. During the induction of anesthesia an arterial catheter was inserted for blood sampling. Vecuronium bromide 0.1 mg/kg was administered to facilitate intubation. The ECG, arterial blood pressure, heart rate, peripheral oxygen saturation, and end-tidal carbon dioxide (Fabius, Draeger, Germany) were monitored continuously throughout the study. Blood samples for propofol assay were collected from the radial artery 5 and 45 minutes after the beginning of the infusion, on stopping the infusion, and also after 2.5, 5, 8, 10, 30, 60, 120, and 150 minutes after the termination of the infusion of propofol. The blood samples were transferred into heparinized tubes and they were centrifuged immediately after the collection. The plasma was stored at 4 °C. The concentration of propofol in the plasma was measured within 8 weeks by means of highperformance liquid chromatography with a fluorescence detector.11,12 The analytical procedure was validated. The lower limit of quantification (LLOQ) was 0.01 mg/mL. The within-day and between-day variation coefficients were 0.01). Also the total doses of propofol administrated during anesthesia was similar in the studied groups (P ¼ 0.274 and 0.725 for the Melatonin/BIS and Melatonin/AEP groups, respectively). In the current study we demonstrated that, in clinical conditions the influence of both premedication agents on the sedative response to propofol is similar. We also assessed the preoperative anxiolytic effect of both premedication agents. Several studies reported that melatonin is as effective as
midazolam in reducing preoperative anxiety in adults.4 On the contrary, Kain et al.25 noted that midazolam is more effective than melatonin in reducing anxiety at the induction of anesthesia to children. Similarly to Kain et al., our analysis seems to indicate that the anxiolytic effect of melatonin is lesser than that of clonidine. However, further studies are required on this field taking into account the influence of dosing time of melatonin efficacy, because literature data suggests that the anxiolytic effect of this sleep hormone may be lesser if it is given during the morning hours.26,27 Our aim was to understand the usefulness of melatonin as a premedicant for routine clinical practice and chronobiological aspect was not of our concern. The mean time of the premedication in our study was similar in all studied groups (median 9.41 AM, 9.53 AM, and 9.37 AM for the melatonin/BIS, melatonin/AEP, and clonidine/BIS groups, respectively with P-value > 0.01), therefore, the results of our study are not influenced by the differences in the dosing time of both premedication agents. The patients who received clonidine had considerably lower values of their systolic (SYS) and diastolic (DIAS) arterial pressure and their heart rate (HR) than those who received melatonin (Table 1). These results are in agreement with the data reported in the literature.23,28–31 However, it is noteworthy that the lower SYS/DIAS and HR values did not cause a decrease in propofol clearance.
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According to the literature data, the pharmacokinetics of propofol is influenced by changes in the distribution of blood volume, cardiac output, and hepatic blood flow,10 because the drug is characterized by a high hepatic extraction ratio (over 0.7).32 Clonidine affects the cardiac output (CO), and simultaneously it affects the regional blood flow. Thus, it can modify the pharmacokinetics of propofol. As was discussed above, in both groups under investigation the values of this parameter were similar and no statistically significant difference was found between them. Ismail & Mowafi33 observed that an oral premedication with melatonin at a dose of 10 mg may cause a drop in the MAP in the patients undergoing a cataract surgery under local anesthesia and they suggested that melatonin might have a mild hypotensive effect. We cannot definitely confirm or exclude these findings, however, if this hormone reduces the arterial pressure, it definitely does it to a lesser extent than clonidine. Another factors, which may influence propofol sedative effects as well as patient’s hemodynamics are the doses of propofol and remifentanil titrated during anesthesia. Similarly to the propofol median dose, the dose of titrated remifentanil was comparable in the studied groups (P ¼ 0.253 and 0.289 for the Melatonin/BIS and Melatonin/AEP group, respectively). The differences in the patients’ hemodynamics observed in this study may be therefore attributed to different premedication agents. The use of AAI index and BIS monitors enabled us to compare those two common instruments used to assess the depth of anesthesia. We observed that the AAIderived EC50 was lower by 0.72 mg/L, and the gamma was 1.41 greater than the BIS-derived values. We concluded that the AAI is more sensitive to changes in propofol biophase concentrations than the BIS, and that the half-maximal response is achieved at lower propofol concentrations for the AAI than for the BIS. Similar observations were made by Nishiyama,34 who compared composite auditory evoked potentials (cAAI), auditory evoked potentials (AAI), and bispectral index (BIS) during propofol – fentanyl anesthesia and noted, that the AAI may discriminate the anesthetic depth better than the cAAI and BIS. Kreuer et al.35 obtained the opposite results. They observed wide variations in the AAI index and considerable overlap of AAI values between consciousness and unconsciousness, which were less evident for the BIS monitoring. Similarly to Kreuer et al.,35 we noted a larger unexplained variability for the AAI than for the BIS (Table 2). The presence of a steeper relationship between the AAI and biophase concentrations is beneficial for the anesthesiologist as it enables quicker observation of changes in propofol concentrations. However, the observed higher residual variability (the larger deviations between predictions and observations) for the AAI monitoring makes it less reliable in assessing the depth of patient’s anesthesia than the BIS.
Limitations of the Study The limitation of the study is mainly the absence of the placebo group. Due to this fact we were unable to confirm the effects of melatonin and clonidine on propofol PK/PD as well as patients’ recovery profile per se. The goal of the current study was to compare the influence of both agents on propofol TCI as well as different EEG monitors used during anesthesia, which was covered by the third group of patients (Group II melatonin/AEP). It is also noteworthy that the surgery without premedication (the placebo group) may arise ethical reservations and in the current study it was considered not in the best interest of the patients. Another limitation is that the concentrations of both melatonin and clonidine were not measured in the study, so the interaction between both agents and endogenous melatonin could not be assessed. Also the patients’ number may be found too small to interchangeably conclude about the preoperative anxiolytic effect of clonidine and melatonin. At last the promptness of recovery of the psychomotor functions after surgery was not assessed, so it is difficult to compare our recovery parameters with some literature data. To conclude, the population PK/PD model was successfully developed to describe the time course of propofol concentrations and measurements of the AAI and BIS index. The BIS monitoring did not reveal differences in PK/PD related with different premedication. In comparison with the BIS monitoring the AAI showed a decrease in EC50 and increased slope in the sigmoidal Emax relationship. The dose of melatonin applied to the population under study had similar influence on the hypnotic effect and pharmacokinetics of propofol as clonidine. Thus, the application of both drugs does not involve the need to correct the dosage of propofol. Premedication with melatonin has different influence on the hemodynamic parameters of patients anesthetized with propofol than premedication with clonidine. The research findings prove that melatonin may be an attractive alternative to clonidine drugs used in premedication, especially in patients with low blood pressure or those with contraindications for clonidine. However, it is justified to continue research on the subject, as the preoperative anxiolytic effect of melatonin seems to remain an open question, especially that the dosing time of the sleeping hormone seems to be of great importance. Also, the interactions between melatonin and various anesthetics assessed in clinical conditions should be further examined. This is important for the optimization of dosage of the drugs with a narrow therapeutic index, e. g. propofol. Also, the application of different EEG monitors may lead to different propofol plasma and biophase concentrations due to the different sigmoidal Emax relationships.
316 Declaration of Conflicting Interests The authors declare that there are no conflicts of interest.
References 1. Naguib M, Gottumukkala V, Goldstein PA. Melatonin and anesthesia: a clinical perspective. J Pineal Res. 2007;42:12–21. 2. Samarkandi A, Naguib M, Riad W. Melatonin vs midazolam premedication in children: a double-blind placebo – controlled study. Eur J Anesthesiol. 2005;22:189–196. 3. Naguib M, Samarkandi MH. The comparative dose-response effects of melatonin and midazolam for premedication in adult patients: a double-blind placebo-controlled study. Anesth Analg. 2000;91: 473–479. 4. Yousaf F, Seet E, Venkatraghavan L, et al. Efficacy and Safety of melatonin as an anxiolytic and analgesic in the perioperative period. Anesthesiology. 2010;113:968–976. 5. Naguib M, Samarkandi AH, Moniem MA, et al. The effects of melatonin premedication on propofoland thiopental induction dose– response curves: a prospective, randomized, double-blind study. Anesth Analg. 2006;103:1448–1452. 6. Naguib M, Schmid PG, Baker MT. The electroencephalographic effects of IV anesthetic doses of melatonin: comparative study with thiopental and propofol. Anesth Analg. 2003;97:238–243. 7. Folkow LP. Adrenergic vasomotor responses in nasal mucosa of hooded seals. Am J Physiol. 1992;263:1291–1297. 8. Talke PO, Lobo EP, BROWN R. et al. Clonidine- induced vasoconstriction in awake volunteers. Anesth Analg. 2001;93:271– 276. 9. Paris A, Kaufmann M, Tonner P, et al. Effects of clonidine and midazolam premedication on bispectral index and recovery after elective surgery. EJA. 2009;26:603–610. 10. Morris J, Acheson M, Reeves M, et al. Effect of clonidine premedication on propofol requirements during lower extremity vascular surgery: a randomized controlled trial. Br J Anaesth. 2005;95:183–188. 11. Dawidowicz AL, Fornal E, Fijalkowska A. Determining the influence of storage time on the level of propofol in blood samples by means of chromatography. Biomed Chromatogr. 2000;14:249. . 12. Dawidowicz AL, Kality nski R. HPLC investigation of free and bound propofol in human plasma and cerebrospinal fluid. Biomed Chromatogr. 2003:17–447. 13. Bergstrand M, Hooker AC, Wallin JE, et al. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13:143–151. 14. Parke J, Holford NH, Charles BG. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed. 1999;59:19–29. 15. Higuchi H, Adachi Y, Arimura S, et al. Oral clonidine premedication reduces the awakening concentration of propofol. Anesth Analg. 2002;94:609–614. 16. Goyagi T, Tanaka M, Nishikawa T. Oral clonidine premedication reduces induction dose and prolongs awakening time from propofol-nitrous oxide anesthesia. Can J Anesth. 1999;46:894–896. 17. Imai Y, Mammoto T, Murakami K, et al. The effects of preanesthetic oral clonidine on total requirement of propofol for general anesthesia. J Clin Anesth. 1998;10:660–665. 18. Caumo W, Torres F, Moreira NL, et al. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg. 2007;105: 1263–1271.
The Journal of Clinical Pharmacology / Vol 55 No 3 (2015) 19. Naguib M, Baker MT, Spadoni G, et al. The hypnotic and analgesic effects of 2-bromomelatonin. Anesth Analg. 2003;97:763–768. 20. Naguib M, Hammond Dl, Schmid PG, et al. Pharmacological effects of intravenous melatonin: comparative studies with thiopental and propofol. Br J Anaesth. 2003;90:504–507. 21. Kurdi MS, Patel T. The role of melatonin in anaesthesia and critical care. Indian J Anaesth. 2013;57:137–144. 22. Ghosh I, Bithal PK, Dash HH, Chaturvedi A, Prabhakar H. Both clonidine and metoprolol modify anesthetic depth indicators and reduce intraoperative propofol requirement. J Anesth. 2008;22:131– 134. 23. Khafagy HF, Ebied RS, Osman ES, et al. Perioperative effects of various anesthetic adjuvants with TIVA guided by bispectral index. Korean J Anesthesiol. 2012;63:113–119. 24. Higuchi H, Adachi Y, Dahan A, et al. Interaction between propofol and clonidine for loss of consciousness. Anesth Analg. 2002;94: 886–891. 25. Kain ZN, MacLaren JE, Herrmann L, Mayes L, Rosenbaum A, Hata J, Lerman J. Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery. Anesthesiology. 2009;111(1):44–49. 26. Almenrader N1, Haiberger R, Passariello M. Steal induction in preschool children: is melatonin as good as clonidine? A prospective, randomized study. Paediatr Anaesth. 2013;23(4): 328–333. 27. Lewy AJ, Siever LJ, Uhde TW, Markey SP. Clonidine reduces plasma melatonin levels. J Pharm Pharmacol. 1986;38(7):555– 556. 28. Taittonen MT, Kirvela OA, Aantaa R, Kanto JH. Effect of clonidine and dexmedetomidine premedication on perioperative oxygen consumption and haemodynamic state. Br J Anaesth. 1997;78: 400–406. 29. Singh S, Arora K. Effect of oral clonidine premedication on perioperative haemodynamic response and postoperative analgesic reqiurement for patients undergoing laparoscopic cholecystectomy. Indian J Anaesth. 2011;55:26–30. 30. Altan A, Turgut N, Yildiz F, et al. Effects of magnesium sulphate and clonidine on propofol consumption, haemodynamics and postoperative recovery. Br J Anaesth. 2005;94:438–441. 31. Park J, Forrest J, Kolesar R, et al. Oral clonidine reduces postoperative PCA morphine requirements. Can J Anaesth. 1996;43:900–906. 32. Favetta P, Degoute C-S, Perdrix J-P, Dufresne C, Boulieu R, Guitton J. Propofol metabolites in man following propofol induction and maintenance. Br J Anaesth. 2002;88:653–658. 33. Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg. 2009;108:1146–1151. 34. Nishiyama T. Composite auditory evoked potentials index is not a good indicator of depth of anesthesia in propofol-fentanyl anesthesia: randomized comparative study. J Anesthesiol Clin Pharmacol. 2013;29:333–336. 35. Kreuer S, Bruhn J, Larsen R, et al. Comparison of alaris AEP index and bispectral index during propofol-remifentanilanaesthesia. Br J Anaesth. 2003;91(3):336–340.
Supporting Information Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Melatonin and Clonidine Premedication Has Similar Impact on the Pharmacokinetics and Pharmacodynamics of Propofol Target Controlled-Infusions
The Journal of Clinical Pharmacology 2015, 55(3) 307–316 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.401
Agnieszka Bienert, PhD1, Katarzyna Wawrzyniak, MD, PhD2, Paweł Wiczling, PhD3, Krzysztof Przybyłowski, MSc1, Zenon J. Kokot, PhD4, Jan Matysiak, PhD4, Agnieszka Pachutko, MSc1, Martyna Józefowicz, MSc3, Krzysztof Kusza, MD, PhD2,5, and Edmund Grzeskowiak, PhD1
Abstract Recently oral melatonin has been proposed as an agent for premedication. In this study, we compared melatonin with clonidine, considering its anxiolytic properties as well as the influence of both agents on the pharmacokinetic, hypnotic, and hemodynamic effects of propofol during propofol– remifentanil total intravenous anesthesia (TIVA). The dataset under analysis included 32 patients scheduled for a functional endoscopic sinus surgery. The population pharmacokinetic modeling was done with NONMEM. The PK of propofol was described with a two-compartment disposition model, whereas the BIS and AAI were described with a sigmoidal Emax model linked with the propofol concentration via the biophase compartment. The anxiolytic effect was assessed by means of the visual analog scale for anxiety (VAS-A). The population PK/PD model was successfully developed to describe the data. No significant differences in the PK/PD of propofol were noted due to the premedication with clonidine and melatonin. Melatonin was less effective than clonidine in reducing patients’ anxiety at the induction of anesthesia, whereas clonidine premedication was associated with greater decrease in heart rate and blood pressure. A decreased EC50 (2.47 vs. 3.17 mg/L) and increased slope (2.71 vs. 1.30) of the sigmoidal Emax relationship was observed for the AAI index, as compared with the BIS measurements.
Keywords melatonin, clonidine, propofol, pharmacokinetics, pharmacodynamics
Recently oral melatonin has been proposed as a preoperative medication in both adult and pediatric surgical patients. Melatonin has a significant anxiolytic effect and thus it may be useful for highly anxious patients undergoing painful surgeries. In comparison with midazolam, melatonin has similar anxiolytic efficacy but it causes less psychomotor impairment and fewer side effects.1–4 Also, it has been demonstrated that oral premedication with 0.2 mg/kg melatonin significantly reduces the propofol and thiopental doses required for the loss of responses to verbal commands and eyelash stimulation,5 whereas exogenously administered melatonin acts as an anesthetic agent on the rat model.6 Thus, it is possible that melatonin may influence the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol used during anesthesia. However, this hypothesis has not been confirmed yet. In this study, we compared melatonin with clonidine, a drug used for premedication, considering the influence of both agents on the pharmacokinetics as well as the hypnotic and hemodynamic effects of propofol during propofol–remifentanil TIVA. Both clonidine and melatonin have been used as premedication agents and may have some advantages over
midazolam in patients undergoing ESS: they do not cause respiratory depression and have a favorable side-effects profile. In particular, clonidine can also decrease
1 Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, ul. Marii Magdaleny 14, 61 - 861 Poznan, Poland 2 Department of Anesthesiology and Intensive Therapy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Marii Skłodowskiej - Curie 9, 85-094 Bydgoszcz, Poland 3 Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdansk, ul. Hallera 107, 80-401 Gdansk, Poland 4 Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, ul. Grunwaldzka 6, 60 - 780 Poznan, Poland 5 Department of Anesthesiology and Intensive Therapy, Poznan University of Medical Sciences, ul. Marii Magdaleny 14, 61 - 861 Poznan, Poland
Submitted for publication 12 July 2014; accepted 17 September 2014. Corresponding author: Agnieszka Bienert, Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, ul. Sw. Marii Magdaleny 14, 61-861 Poznan, Poland Email: [email protected]
308 intraoperative bleeding due to its effect on the blood flow in the nasal mucosa.7,8 Both agents have been successfully used as premedication and their effects resemble midazolam to some extent.4,9,10
Methods Patients After approval by the Research Ethics Committee at the Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland (KB 693/2011), and with informed, written consent received from 32 patients with the ASA physical status I and II they were scheduled for functional endoscopic sinus surgery (FESS) and they were prospectively randomized into one of three groups. In group I (n ¼ 9) oral melatonin (Melatonina, Lekam, Poland) (5 mg on the night before the surgery and 5 mg 60 minutes before the surgery) was used for premedication and a Bispectral Index (BIS) monitor was used to monitor the depth of anesthesia. The anxiolytic effects of both premedication agents were assessed according to the visual analog scale for anxiety (VAS-A) during the preoperative visit and shortly before the induction of anesthesia. In group II (n ¼ 10) oral melatonin (5 mg on the night before the surgery and 5 mg 60 minutes before the surgery) was used for premedication and A-Line Auditory Evoked Potential Index (AAI index) (AEP/2, Danmeter, Denmark) was used to monitor the depth of hypnosis, whereas in group III (n ¼ 13) oral clonidine (Iporel, WZF Polfa, Poland) (150 mg, 60 minutes before the induction of anesthesia) and bispectral index monitor (BIS; A-2000, Aspect Medical System, Newton, MA, USA) were used, respectively. On the morning of surgery, the patients were NPO > 6 hours based on American Society of Anesthesiologist 2011 practice guidelines. In all the three groups, intravenous anesthesia (TIVA) consisted of target-controlled infusions (TCI) of remifentanil (Ultiva, GlaxoSmithKline, Australia) and propofol (Propofol 1% MCT/LCT, Fresenius, Germany) with a pump (Orchestra Base Primea, Fresenius Kabi AG, Germany) in order to achieve the estimated target effectsite concentration of remifentanil (Ce) of 1.5 ng/mL. When the steady-state equilibrium for remifentanil was achieved, the infusion of propofol started to reach the target Ce concentration of 3 mg/mL. The TCI of propofol was carried out according to the Schneider model, and the infusion of remifentanil was carried out according to the Minto model. During the surgery the infusion of remifentanil was titrated to achieve a favorable hemodynamic profile and the infusion of propofol was titrated to maintain the BIS index within the range of 45–60 or the AAI index within the range of 15–25. The exclusion criteria were as follows: significant cardiovascular disease, epilepsy, smoking (>10 cigarettes
The Journal of Clinical Pharmacology / Vol 55 No 3 (2015)
daily), excessive alcohol intake (>30 g daily), and neurological diseases that could affect the CNS monitoring, immunodeficiency, use of melatonin, clonidine, benzodiazepines, rifampicin, cimethidine, neuroleptics, tricyclic, and selective serotonin reuptake inhibitors (SSRI) antidepressants; actual body weight less than 50 kg or more than 100 kg, alcohol abuse, and pregnancy. During the induction of anesthesia an arterial catheter was inserted for blood sampling. Vecuronium bromide 0.1 mg/kg was administered to facilitate intubation. The ECG, arterial blood pressure, heart rate, peripheral oxygen saturation, and end-tidal carbon dioxide (Fabius, Draeger, Germany) were monitored continuously throughout the study. Blood samples for propofol assay were collected from the radial artery 5 and 45 minutes after the beginning of the infusion, on stopping the infusion, and also after 2.5, 5, 8, 10, 30, 60, 120, and 150 minutes after the termination of the infusion of propofol. The blood samples were transferred into heparinized tubes and they were centrifuged immediately after the collection. The plasma was stored at 4 °C. The concentration of propofol in the plasma was measured within 8 weeks by means of highperformance liquid chromatography with a fluorescence detector.11,12 The analytical procedure was validated. The lower limit of quantification (LLOQ) was 0.01 mg/mL. The within-day and between-day variation coefficients were 0.01). Also the total doses of propofol administrated during anesthesia was similar in the studied groups (P ¼ 0.274 and 0.725 for the Melatonin/BIS and Melatonin/AEP groups, respectively). In the current study we demonstrated that, in clinical conditions the influence of both premedication agents on the sedative response to propofol is similar. We also assessed the preoperative anxiolytic effect of both premedication agents. Several studies reported that melatonin is as effective as
midazolam in reducing preoperative anxiety in adults.4 On the contrary, Kain et al.25 noted that midazolam is more effective than melatonin in reducing anxiety at the induction of anesthesia to children. Similarly to Kain et al., our analysis seems to indicate that the anxiolytic effect of melatonin is lesser than that of clonidine. However, further studies are required on this field taking into account the influence of dosing time of melatonin efficacy, because literature data suggests that the anxiolytic effect of this sleep hormone may be lesser if it is given during the morning hours.26,27 Our aim was to understand the usefulness of melatonin as a premedicant for routine clinical practice and chronobiological aspect was not of our concern. The mean time of the premedication in our study was similar in all studied groups (median 9.41 AM, 9.53 AM, and 9.37 AM for the melatonin/BIS, melatonin/AEP, and clonidine/BIS groups, respectively with P-value > 0.01), therefore, the results of our study are not influenced by the differences in the dosing time of both premedication agents. The patients who received clonidine had considerably lower values of their systolic (SYS) and diastolic (DIAS) arterial pressure and their heart rate (HR) than those who received melatonin (Table 1). These results are in agreement with the data reported in the literature.23,28–31 However, it is noteworthy that the lower SYS/DIAS and HR values did not cause a decrease in propofol clearance.
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According to the literature data, the pharmacokinetics of propofol is influenced by changes in the distribution of blood volume, cardiac output, and hepatic blood flow,10 because the drug is characterized by a high hepatic extraction ratio (over 0.7).32 Clonidine affects the cardiac output (CO), and simultaneously it affects the regional blood flow. Thus, it can modify the pharmacokinetics of propofol. As was discussed above, in both groups under investigation the values of this parameter were similar and no statistically significant difference was found between them. Ismail & Mowafi33 observed that an oral premedication with melatonin at a dose of 10 mg may cause a drop in the MAP in the patients undergoing a cataract surgery under local anesthesia and they suggested that melatonin might have a mild hypotensive effect. We cannot definitely confirm or exclude these findings, however, if this hormone reduces the arterial pressure, it definitely does it to a lesser extent than clonidine. Another factors, which may influence propofol sedative effects as well as patient’s hemodynamics are the doses of propofol and remifentanil titrated during anesthesia. Similarly to the propofol median dose, the dose of titrated remifentanil was comparable in the studied groups (P ¼ 0.253 and 0.289 for the Melatonin/BIS and Melatonin/AEP group, respectively). The differences in the patients’ hemodynamics observed in this study may be therefore attributed to different premedication agents. The use of AAI index and BIS monitors enabled us to compare those two common instruments used to assess the depth of anesthesia. We observed that the AAIderived EC50 was lower by 0.72 mg/L, and the gamma was 1.41 greater than the BIS-derived values. We concluded that the AAI is more sensitive to changes in propofol biophase concentrations than the BIS, and that the half-maximal response is achieved at lower propofol concentrations for the AAI than for the BIS. Similar observations were made by Nishiyama,34 who compared composite auditory evoked potentials (cAAI), auditory evoked potentials (AAI), and bispectral index (BIS) during propofol – fentanyl anesthesia and noted, that the AAI may discriminate the anesthetic depth better than the cAAI and BIS. Kreuer et al.35 obtained the opposite results. They observed wide variations in the AAI index and considerable overlap of AAI values between consciousness and unconsciousness, which were less evident for the BIS monitoring. Similarly to Kreuer et al.,35 we noted a larger unexplained variability for the AAI than for the BIS (Table 2). The presence of a steeper relationship between the AAI and biophase concentrations is beneficial for the anesthesiologist as it enables quicker observation of changes in propofol concentrations. However, the observed higher residual variability (the larger deviations between predictions and observations) for the AAI monitoring makes it less reliable in assessing the depth of patient’s anesthesia than the BIS.
Limitations of the Study The limitation of the study is mainly the absence of the placebo group. Due to this fact we were unable to confirm the effects of melatonin and clonidine on propofol PK/PD as well as patients’ recovery profile per se. The goal of the current study was to compare the influence of both agents on propofol TCI as well as different EEG monitors used during anesthesia, which was covered by the third group of patients (Group II melatonin/AEP). It is also noteworthy that the surgery without premedication (the placebo group) may arise ethical reservations and in the current study it was considered not in the best interest of the patients. Another limitation is that the concentrations of both melatonin and clonidine were not measured in the study, so the interaction between both agents and endogenous melatonin could not be assessed. Also the patients’ number may be found too small to interchangeably conclude about the preoperative anxiolytic effect of clonidine and melatonin. At last the promptness of recovery of the psychomotor functions after surgery was not assessed, so it is difficult to compare our recovery parameters with some literature data. To conclude, the population PK/PD model was successfully developed to describe the time course of propofol concentrations and measurements of the AAI and BIS index. The BIS monitoring did not reveal differences in PK/PD related with different premedication. In comparison with the BIS monitoring the AAI showed a decrease in EC50 and increased slope in the sigmoidal Emax relationship. The dose of melatonin applied to the population under study had similar influence on the hypnotic effect and pharmacokinetics of propofol as clonidine. Thus, the application of both drugs does not involve the need to correct the dosage of propofol. Premedication with melatonin has different influence on the hemodynamic parameters of patients anesthetized with propofol than premedication with clonidine. The research findings prove that melatonin may be an attractive alternative to clonidine drugs used in premedication, especially in patients with low blood pressure or those with contraindications for clonidine. However, it is justified to continue research on the subject, as the preoperative anxiolytic effect of melatonin seems to remain an open question, especially that the dosing time of the sleeping hormone seems to be of great importance. Also, the interactions between melatonin and various anesthetics assessed in clinical conditions should be further examined. This is important for the optimization of dosage of the drugs with a narrow therapeutic index, e. g. propofol. Also, the application of different EEG monitors may lead to different propofol plasma and biophase concentrations due to the different sigmoidal Emax relationships.
316 Declaration of Conflicting Interests The authors declare that there are no conflicts of interest.
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