Clinical Study Propofol Requirement for Induction of...

Clinical StudyPropofol Requirement for Induction ofUnconsciousness Is Reduced in Patients withParkinson’s Disease: A Case Control Study

Xiao-ping Xu,1,2 Xi-ya Yu,1 Xi Wu,3 Xiao-wu Hu,3 Jian-chun Chen,3

Jin-bao Li,1 Jia-feng Wang,1 and Xiao-ming Deng1

1Department of Anesthesiology and Intensive Care Medicine, The Second Military Medical University,168 Changhai Road, Shanghai 200433, China2Department of Anesthesiology, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road,Fuzhou, Fujian 350001, China3Department of Neurosurgery, Changhai Hospital, The Second Military Medical University, 168 Changhai Road,Shanghai 200433, China

Correspondence should be addressed to Jia-feng Wang; [email protected] and Xiao-ming Deng; deng [email protected]

Received 26 June 2015; Accepted 7 September 2015

Academic Editor: Paola Aceto

Copyright © 2015 Xiao-ping Xu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, but whether the neurodegenerative processinfluences the pharmacodynamics of propofol remains unclear. We aimed to evaluate the effect of PD on pharmacodynamicsof propofol. A total of 31 PD patients undergoing surgical treatment (PD group) and 31 pair-controlled non-PD patientsundergoing intracranial surgery (NPD group) were recruited to investigate the propofol requirement for unconsciousnessinduction. Unconsciousness was induced in all patients with target-controlled infusion of propofol. The propofol concentration atwhich unconsciousness was induced was compared between the two groups. EC

50and EC

95were calculated as well. Demographic

data, bispectral index, and hemodynamic values were comparable between PD and NPD groups.Themean target concentration ofpropofol when unconsciousness was achieved was 2.32 ± 0.38 𝜇g/mL in PD group, which was significantly lower than that in NPDgroup (2.90± 0.35 𝜇g/mL).The EC

50was 2.05 𝜇g/mL (95%CI: 1.85–2.19 𝜇g/mL) in PD group,much lower than the 2.72 𝜇g/mL (95%

CI: 2.53–2.88 𝜇g/mL) in NPD group. In conclusion, the effective propofol concentration needed for induction of unconsciousnessin 50% of patients is reduced in PD patients. (This trial is registered with NCT01998204.)

1. Introduction

Parkinson’s disease (PD) is the second most prevalent neu-rodegenerative disease in the world, with an increasingincidence among the elderly [1]. It is reported that theincidence is about 0.3% in the general population, but ashigh as 3% in patients over 65 years [2]. Anesthesia inPD patients has been considered a challenge because ofdisability of the patients and interactive reaction betweenanesthetics and anti-PD medications or PD symptoms[3, 4].

Deep brain stimulator (DBS) was first introduced totreat PD in 1987 [5, 6], sending electrical impulses to thala-mus, subthalamic nucleus, and globus pallidus. Anesthesiaconcerns have been focused on the anesthesia type andwithdrawal of anti-PD medications [7–9], but there is littleinformation about the pharmacodynamic changes of anes-thetic agents in PD patients undergoing DBS implantationbecause of the degenerate brain. We speculated that theimbalance of neurotransmitter might change the amount ofanesthetics that patients required for anesthesia. The aim ofthe present study was to determine whether the requirement

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 953729, 5 pageshttp://dx.doi.org/10.1155/2015/953729

2 BioMed Research International

for propofol to induce unconsciousness was reduced inpatients with Parkinson’s disease.

2. Materials and Methods

2.1. Study Design. This prospective case control study wasperformed in our hospital from January 2012 to June 2013upon the approval from theEthicsCommittee of BiomedicineResearch of The Second Military Medical University (Shang-hai, China). Informed consent was obtained from all patientsor their surrogates before recruitment. The trial protocol wasregistered as NCT01998204 in clinicaltrial.gov.

2.2. Subjects. A total of 31 adult PD patients undergoing DBSimplantation and pulse generator placement were recruitedin the Parkinson’s disease group (PD group). The exclusioncriteria included ASA score higher than class III, predicteddifficult airway, hearing impairment, inability to followinstructions, alcohol or drug abusers, and patients whorefused to provide informed consent.

Additional 31 patients undergoing intracranial surgery fortumors were assigned as non-PD (NPD) group based on a1 : 1 pairing principle. Subjects in NPD group should be of thesame sex and similar age (±3 years) to the counterparts in PDgroup.

2.3. Trial Protocol. All patients fasted for 8 h before surgeryand received no premedication.They were administered with10mL/kg Ringer’s solution and monitored with noninva-sive blood pressure (BP), heart rate (HR), pulse oximetry(SpO2), electrocardiography (ECG), and bispectral index

(BIS). Oxygen was provided at a 6 L/min rate before propofol(AstraZeneca, Italy) administration through a target con-trolled infusion (TCI) pump (Fresenius, German) using theMarsh model. A Chinese study reported that when plasmaconcentration of propofol was set to 2.0𝜇g/mL, a concentra-tion of 1.9 𝜇g/mL would induce unconsciousness in the pop-ulation [10]; therefore, the target effect-site concentration ofpropofol was started at 1.4𝜇g/mL. If unconsciousness was notinduced when the target concentration was stabilized for onemin, the target concentration was added by 0.2 𝜇g/mL. Con-sciousness was assessed again 20 s after unconsciousness wasachieved, based on the observer’s assessment of alertness andsedation score (OAA/S).The target concentration of propofolat the time of achieving unconsciousness was consideredas the dose of propofol required to induce unconsciousnessfor this patient. Unconsciousness was defined as an OAA/Sscore not higher than 1 [11, 12]. Assisted respiration wasperformed by the anesthetic machine if SpO

2was lower than

92%. The vasopressor agent or atropine was administered ifhypotension or bradycardia occurred.

2.4. Outcome. The primary outcome is the target concen-tration of propofol when unconsciousness was induced. BISand hemodynamic variables were recorded before and afterpropofol induction.

Table 1: Demographic data of the patients.

Parameters PD group(𝑛 = 31)

NPD group(𝑛 = 31) 𝑃 value

Age (years) 57.4 ± 9.1 57.7 ± 8.5 0.99Sex (male/female) 17/14 17/14 1.00Body mass index(kgm−2) 22.2 ± 2.9 22.1 ± 4.1 0.97

ASA score (classII/III) 12/19 17/14 0.203

BIS 96.2 ± 2.5 95.2 ± 3.7 0.67HR (bpm) 80.0 ± 8.7 77.2 ± 15.2 0.94SBP (mmHg) 136.4 ± 17.6 132.8 ± 17.4 0.96DBP (mmHg) 80.3 ± 12.1 78.3 ± 13.2 0.96Values are presented as mean ± standard derivation or counts. Data wereanalyzed using paired Student’s 𝑡-test or chi-square test. ASA: AmericanSociety of Anesthesiologists; BIS: bispectral index; HR: heart rate; SBP:systolic blood pressure; DBP: diastolic blood pressure.

Table 2:The anti-Parkinson medications taken by the patients withParkinson’s disease.

Medications Number of uses (%)Levodopa/benserazide 30 (96.8)Trihexyphenidyl 10 (32.3)Levodopa/carbidopa 6 (19.4)Amantadine 6 (19.4)Pramipexole 5 (16.1)Entacapone 3 (9.7)Bromocriptine 1 (3.2)Rasagiline 1 (3.2)

2.5. Power Estimation. According to a clinical trial in aChinese population [10], the mean standard derivation (SD)of propofol to reach an OAA/S score of 1 was 0.3–0.4 𝜇g/mL.In order to detect a disparity of 0.3 𝜇g/mL, at least 28 patientsin each group should be included for a power of 0.8 and 𝛼 =0.05.

2.6. Statistical Analysis. All statistical analyses were per-formed in SPSS 16.0. Continuous data were expressed asmean ± SD. Intergroup comparison was accomplished bypaired 𝑡-test or chi-square analysis between the two groups.The effective propofol concentrations needed for induction ofunconsciousness in 50% (EC

50) and 95% (EC

95) of patients

were calculated by probit regression, and EC50

of differentgroups was compared using the relative median potencyestimates. A 𝑃 < 0.05 was considered statistically significant.

3. Results

All the 62 patients completed the study and none wasexcluded during the trial. General demographic data areshown in Table 1. Age, gender, body mass index (BMI), ASAclassification, BIS, HR, and BP were comparable between PDand NPD groups. The medications that the PD patients weretaking were listed in Table 2. As shown in Figure 1, propofol

BioMed Research International 3

120

100

80

60

40

20

0Before induction

Time points

After induction

∗

BIS

PDNPD

100

90

80

70

60

50

40

30

20

10

0Before induction

Time points

After induction

Hea

rt ra

te (b

pm)

PDNPD

180

160

140

120

100

80

60

40

20

0Before induction

Time points

After induction

∗

Systo

lic b

lood

pre

ssur

e (m

mH

g)

PDNPD

100

90

80

70

60

50

40

30

20

10

0Before induction

Time points

After induction

∗

Dia

stolic

blo

od p

ress

ure (

mm

Hg)

PDNPD

Figure 1: BIS, heart rate, systolic blood pressure, and diastolic blood pressure before and after propofol induction (𝑛 = 31 for both groups).PD: Parkinson’s disease; NPD: non-Parkinson’s disease; BIS: bispectral index. Results are given as mean (standard derivation). ∗𝑃 < 0.05compared with before induction in both groups.

administration reduced BIS, systolic BP, and diastolic BPsignificantly (𝑃 < 0.05), but there was no significantdifference between the 2 groups regarding BIS, HR, systolicBP, and diastolic BP.

The target concentration of propofol for induction ofunconsciousness was 2.32 ± 0.38 𝜇g/mL in PD group, whichwas significantly lower than 2.90±0.35 𝜇g/mL in NPD group(𝑃 < 0.05) (Figure 2). EC

50and EC

95were 2.05 𝜇g/mL (95%

CI: 1.85–2.19 𝜇g/mL) and 2.91 (95% CI: 2.75–3.15𝜇g/mL)in PD group and 2.72 𝜇g/mL (95% CI: 2.53–2.88𝜇g/mL)and 3.59 𝜇g/mL (95% CI: 3.39–3.88 𝜇g/mL) in NPD group.Comparison of EC

50between the two groups showed that

EC50

in PD group was significantly lower than that in NPDgroup, since the relative median potency estimate was 0.677(95% confidential interval: 0.368, 1.156).

4. Discussions

Our study demonstrated that the propofol requirement forinduction of unconsciousness was reduced in PD patients

undergoing DBS implantation and pulse generator place-ment.Themean target concentration at the time of achievingunconsciousness and EC

50of propofol for unconsciousness

induction were lower in PD patients than those in NPDpatients.

Our data is important for clinical anesthesia, because theprevalence of PD is reported to be as high as 3% in patientsolder than 65 years [2], which raises concerns over theanesthesia management in PD patients. Unfortunately, mostof these concerns were focused on the anesthetic techniquesfor DBS implantation or interaction between anesthetics andchronicmedications or PD symptoms [3, 4]. To the best of ourknowledge, this is the first work showing that the propofolrequirement for unconsciousness induction was reduced inPD patients, which might change our anesthetic techniquesamong a proportion of patients older than 65 years. Theconventional pharmacodynamic concept may lead to therelative overdose of propofol in this population and furtherresult in compromise of cardiovascular function, delayedemergence, and postoperative delirium due to oversedation

4 BioMed Research International

3.5

3

2.5

2

1

1.5

0.5

0

Targ

et co

ncen

trat

ion

of p

ropo

fol (𝜇

g/m

L)

GroupsPD NPD

∗

Figure 2: The target concentration of propofol when unconscious-ness is induced by propofol. PD: Parkinson’s disease; NPD, non-Parkinson’s disease (𝑛 = 31 for both groups). Results are given asmean (standard derivation). ∗𝑃 < 0.05 compared with NPD group.

[13]. Deep anesthesia with a BIS lower than 20 has beendemonstrated as an independent predictor for postoperativedelirium. Moreover, BIS-guided anesthesia to reduce propo-fol delivery during anesthesia was believed to be protectiveagainst postoperative cognitive dysfunction [14]. Therefore,oversedation produced by the relatively lower requirement ofpropofol should be concerned in PD patients.

It remained unclear why PD patients required a lowerdose of propofol than did NPD patients. The reason mightinclude neurodegenerative changes during PD progressionand anti-PD medications. The loss of dopaminergic neuronsand reduced dopamine production in the substantia nigraof basal ganglia are basic pathophysiological changes thatincrease the activity of inhibitory nuclei, mainly includingthe activity of 𝛾-aminobutyric acidergic neurons [15]. It wasreported that 𝛾-aminobutyric acid (GABA) in the corpusstriatum of PD animals was increased with the decrease ofdopamine [16]. It is well recognized that GABA is involvedin the mechanism of general anesthesia. Recent evidence hasdemonstrated that propofol potentiates GABA (A) receptoron 𝛽3 homopentamers and 𝛼1𝛽3 heteropentamers [17, 18],which might be one of the targets for general anesthesia.Muscimol, a GABA (A) receptor agonist, prolonged theduration of loss of the righting reflex and loss of the tail-pinchresponse after propofol administration in rats. Therefore,excessive activation of GABAergic neurons might enhancethe anesthetic effect of propofol, thus reducing the propofolrequirement for unconsciousness induction in PD patients.

Chronic medications in PD patients might also par-ticipate in the reduced propofol requirement for uncon-sciousness induction in PD patients. It was reported thatlevodopa, the mainstay of PD treatment, upregulated NMDAreceptor subunit in several neuronal loci, which is oneof the reasons for levodopa-induced dyskinesia [19, 20].Knockout of NMDA receptor subunit in mice attenuated thehypnotic effect of propofol, indicating that NMDA receptor

is an important target of propofol during anesthesia [21].Therefore, levodopa administered to PD patients might alsoreduce the propofol requirement by increasing the density ofNMDA receptor in the brain.

There are three main limitations in our study. The firstone is that the sample size was relatively small, which mightresult in a false positive result. Secondly, we did not determinethe real concentration of propofol in the patients’ blood. Thepharmacokinetic model of propofol used in theMarshmodelmight be not suitable for PD patients, and the predictedconcentration of propofol might vary greatly from real con-centration.Thus our conclusion must be based on the theorythat PD patients shared the same propofol pharmacokineticcharacters as the patients with intracranial tumor. Whetherthe pharmacokinetic model of propofol in PD patients isdifferent from the others should be further investigated.Thirdly, patients with brain tumors were chosen as control,but not patients without PD undergoing DBS implantationfor other reasons, because DBS has seldom been used inour hospital for other diseases. However, what we want toinvestigate is the propofol requirement for unconsciousnessbefore surgery in PD andNPDpatients.What kind of surgerywould be performed should not be critical.

5. Conclusions

In conclusion, the present study demonstrates that theeffective propofol concentration needed for induction ofunconsciousness in 50% patients is reduced in PD patients.In otherwords, propofol requirement for induction of uncon-sciousness is reduced in PDpatients.Themechanism remainsto be explained by further studies.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Authors’ Contribution

Xiao-ping Xu and Xi-ya Yu contributed equally to this work.

Acknowledgments

This study was supported by the National Natural ScienceFoundation of China (81201493) and the 1255 Scientific Grantof Changhai Hospital, Shanghai, China (CH125541600).

References

[1] L. M. L. de Lau, P. C. L. M. Giesbergen, M. C. de Rijk, A.Hofman, P. J. Koudstaal, and M. M. B. Breteler, “Incidence ofparkinsonism and Parkinson disease in a general population:the Rotterdam study,” Neurology, vol. 63, no. 7, pp. 1240–1244,2004.

[2] S. Moghal, A. H. Rajput, C. D’Arcy, and R. Rajput, “Prevalenceof movement disorders in elderly community residents,” Neu-roepidemiology, vol. 13, no. 4, pp. 175–178, 1994.

BioMed Research International 5

[3] G.Nicholson, A. C. Pereira, andG.M.Hall, “Parkinson’s diseaseand anaesthesia,”British Journal of Anaesthesia, vol. 89, no. 6, pp.904–916, 2002.

[4] A. Kalenka and A. Schwarz, “Anaesthesia and Parkinson’sdisease: how to manage with new therapies?” Current Opinionin Anaesthesiology, vol. 22, no. 3, pp. 419–424, 2009.

[5] A. L. Benabid, P. Pollak, A. Louveau, S. Henry, and J. de Rouge-mont, “Combined (thalamotomy and stimulation) stereotacticsurgery of the VIM thalamic nucleus for bilateral Parkinsondisease,” Applied Neurophysiology, vol. 50, pp. 344–346, 1987.

[6] G. Deuschl, C. Schade-Brittinger, P. Krack et al., “A randomizedtrial of deep brain stimulation for Parkinson’s disease,”TheNewEngland Journal of Medicine, vol. 355, no. 9, pp. 896–908, 2006.

[7] A. M. Harries, J. Kausar, S. A. G. Roberts et al., “Deep brainstimulation of the subthalamic nucleus for advanced Parkinsondisease using general anesthesia: Long-term results,” Journal ofNeurosurgery, vol. 116, no. 1, pp. 107–113, 2012.

[8] D. A. Burton, G. Nicholson, and G. M. Hall, “Anaesthesia inelderly patients with neurodegenerative disorders,” Drugs andAging, vol. 21, no. 4, pp. 229–242, 2004.

[9] A.Machado, A. R. Rezai, B. H. Kopell, R. E. Gross, A. D. Sharan,and A.-L. Benabid, “Deep brain stimulation for Parkinson’sdisease: surgical technique and perioperative management,”Movement Disorders, vol. 21, no. 14, pp. S247–S258, 2006.

[10] S.-H. Liu, W. Wei, G.-N. Ding, J.-D. Ke, F.-X. Hong, and M.Tian, “Relationship between depth of anesthesia and effect-siteconcentration of propofol during induction with the target-controlled infusion technique in elderly patients,” ChineseMedical Journal, vol. 122, no. 8, pp. 935–940, 2009.

[11] K. Bauerle, C.-A. Greim, M. Schroth, M. Geisselbrecht, A.Kobler, and N. Roewer, “Prediction of depth of sedation andanaesthesia by the Narcotrend EEG monitor,” British Journal ofAnaesthesia, vol. 92, no. 6, pp. 841–845, 2004.

[12] Y. Sun, C. Liu, Y. Zhang et al., “Low-dose intramusculardexmedetomidine as premedication: a randomized controlledtrial,”Medical Science Monitor, vol. 20, pp. 2714–2719, 2014.

[13] F. M. Radtke, M. Franck, J. Lendner, S. Kruger, K. D. Wer-necke, and C. D. Spies, “Monitoring depth of anaesthesia in arandomized trial decreases the rate of postoperative deliriumbut not postoperative cognitive dysfunction,” British Journal ofAnaesthesia, vol. 110, supplement 1, pp. i98–i105, 2013.

[14] M. T. V. Chan, B. C. P. Cheng, T. M. C. Lee, and T. Gin,“BIS-guided anesthesia decreases postoperative delirium andcognitive decline,” Journal of Neurosurgical Anesthesiology, vol.25, no. 1, pp. 33–42, 2013.

[15] A. E. Lang and A. M. Lozano, “Parkinson’s disease: first of twoparts,”The New England Journal of Medicine, vol. 33, no. 15, pp.1044–1053, 1998.

[16] H.-C. Gao, H. Zhu, C.-Y. Song et al., “Metabolic changesdetected by ex vivo high resolution 1H NMR spectroscopy inthe striatum of 6-OHDA-induced Parkinson’s rat,” MolecularNeurobiology, vol. 47, no. 1, pp. 123–130, 2013.

[17] G. M. S. Yip, Z.-W. Chen, C. J. Edge et al., “A propofolbinding site on mammalian GABAA receptors identified byphotolabeling,” Nature Chemical Biology, vol. 9, no. 11, pp. 715–720, 2013.

[18] R. W. Olsen and G.-D. Li, “GABAA receptors as moleculartargets of general anesthetics: identification of binding sitesprovides clues to allosteric modulation,” Canadian Journal ofAnesthesia, vol. 58, no. 2, pp. 206–215, 2011.

[19] M. J. Hurley, M. J. Jackson, L. A. Smith, S. Rose, and P. Jenner,“Immunoautoradiographic analysis of NMDA receptor sub-units and associated postsynaptic density proteins in the brainof dyskinetic MPTP-treated common marmosets,” EuropeanJournal of Neuroscience, vol. 21, no. 12, pp. 3240–3250, 2005.

[20] P. Jenner, “Molecular mechanisms of L-DOPA-induced dyski-nesia,” Nature Reviews Neuroscience, vol. 9, no. 9, pp. 665–677,2008.

[21] Y. Sato, E. Kobayashi, T. Murayama, M. Mishina, and N. Seo,“Effect of N-methyl-D-aspartate receptor epsilon1 subunit genedisruption of the action of general anesthetic drugs in mice,”Anesthesiology, vol. 102, no. 3, pp. 557–561, 2005.

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Clinical Study Propofol Requirement for Induction of...

Documents

Transcript of Clinical Study Propofol Requirement for Induction of...