Propofol Sedation in Orthopaedic Surgery Under Central Neuraxial Block: Patient-controlled Sedation Versus Target-controlled Infusion
Phase: NA
Conditions: Patient-controlled Sedation
Sponsor: Universiti Kebangsaan Malaysia Medical Centre

Dept of Anaesthesiology And Intensive Care UKMMC 
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PROPOFOL SEDATION IN ORTHOPAEDIC 
SURGERY UNDER CENTRAL NEURAXIAL  
BLOCK: PATIENT-CONTROLLED SEDATION 
VERSUS TARGET-CONTROLLED INFUSION  
 
 
 
 
 
 
 
 
 
DR. LIM SHIN HOEI 
BM (University of Southampton, UK) 
 
 
 
 
 
 
UNIVERSITI KEBANGSAAN MALAYSIA 
 
 
 

Dept of Anaesthesiology And Intensive Care UKMMC 
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INTRODUCTION 
 
Regional anaesthesia is one of the mainstays of anaesthesia methods in various disciplines 
particularly orthopaedic surgeries. Patient communication intra-operatively is one of its main 
forte, not to mention reduced cost with less complications and faster patient recovery.1,2 
However, the state of consciousness can potentially cause patient anxiety and non-
cooperation which may interfere with surgery, therefore reduce surgeon and patient 
satisfaction. Sedation has an essential role in balancing the pros and cons of regional 
anaesthesia. 
 
Sedation has its spectrum ranging from anxiolysis to deep sedation.3 Within this range, 
conscious sedation or monitored anaesthesia care sedation is usually provided by the 
anaesthetist to supplement regional anaesthesia. It aims for a comfortable and pain-free 
patient who is sedated but remains arousable, able to obey commands and maintain their 
airway independently.4 However, it is difficult to judge precisely the amount of sedative 
required for adequate patient sedation, comfort and analgesia as patients’ needs differ.5,6 
 
Propofol remains the most attractive choice of drug for sedation due to its favourable 
pharmacokinetic profile, which results in fast induction, easy control of depth of sedation and 
rapid recovery.7  Apart from its rapid onset and offset, propofol has anxiolytic, amnesic and 
anti-emetic effects, making it the nearest to ideal agent for sedation during surgery under 
regional anaesthesia.7  Propofol can be infused by a manually controlled volumetric infusion 
pump, or targeted to a specific plasma or effect site concentration using target-controlled 
infusion (TCI) devices.8 Target-controlled infusion allows the anaesthetist to set the desired 
target plasma or effect site concentration and the TCI pump adjusts infusion rate according to 
the pharmacokinetic model of the drug.9 Target-controlled infusion improve drug titration as 
it better matches the drug concentration profile to the rapidly changing intra-operative drug 
requirement compared to manually controlled infusion.10 
 
Patient-controlled sedation (PCS) is a valid option for surgeries or procedures under regional 
anaesthesia. It is a well-established technique, initially adapted from post-surgery patient 
controlled analgesia.11,12  First reported in 1991, Rudkin et al studied PCS with propofol in 
patients undergoing dental extractions under local anaesthesia.13 Park and Watkins studied 
the efficacy of anaesthetist-controlled sedation (ACS) versus PCS, both using bolus delivered 

Dept of Anaesthesiology And Intensive Care UKMMC 
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midazolam and fentanyl, in patients undergoing lower extremity and lower abdominal 
procedures under epidural anaesthesia.14 In both studies, PCS resulted in significant 
satisfactory response from the patients. In 2000, Girdler et al reported that patients utilizing 
PCS with propofol reached target sedation faster, though not significant, than patients with 
ACS of continuous propofol infusion in surgeries under local anaesthesia.15 In 2008, Wahlen 
et al reported significantly lower plasma and effect-site propofol concentration with high 
degree of patient satisfaction among patients on PCS compared to ACS of continuous 
propofol infusion in patients undergoing total knee and hip replacements under spinal 
anaesthesia.16  
 
This study aims to compare the effectiveness of ACS using TCI sedation (TCIS), versus PCS 
in patients undergoing lower limb orthopaedic surgery under central neuraxial block (CNB). 
If PCS could be shown to be superior in terms of reduced propofol requirement, in addition to 
improved safety, sedation quality and patient satisfaction, it could be an alternative sedation 
option, or replace ACS as the current means of sedation in surgeries under CNB. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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OBJECTIVES 
Primary objective 
To compare total propofol requirement between propofol sedation using patient-controlled 
sedation versus target-controlled infusion, in patients undergoing lower limb orthopaedic 
surgery under central neuraxial block. 
 
Secondary objective 
To compare complications, sedation quality and patient satisfaction.  
 
 
 
 
 

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MATERIALS AND METHODS 
 
This prospective, randomised clinical trial will be submitted for approval from the Research 
Committee of the Department of Anaesthesiology & Intensive Care, Universiti Kebangsaan 
Malaysia Medical Centre (UKMMC) and the Medical Research & Ethics Committee, 
UKMMC. Once ethical approval has been obtained, the subjects will be screened by the 
principal investigator during the pre-operative visit. Patient inclusion and exclusion criteria 
include: 
  
 Inclusion Criteria: 
 
1. 
American Society of Anesthesiologists (ASA) I or II. 
2. 
Aged 18-65 years. 
3. 
Elective lower limb orthopaedic surgery under CNB anticipated to last for 1.5 to 2 
hours 
 
Exclusion Criteria: 
 
1. 
Body Mass Index (BMI)  > 30kg/m2 
2. 
Unable to cooperate (eg. mental disorders, language barrier) 
3. 
Drug abuse 
4. 
Alcoholism (chronic daily alcohol intake greater than 75 g of pure alcohol for ≥ 2 
years17, where 75g of alcohol = 5 cans of beer, 1 bottle of wine or half a pint of 
distilled spirit) 
5. 
Contraindications to the study drugs 
6. 
Pregnancy 
7. 
Significant pulmonary or cardiovascular diseases, including Obstructive Sleep 
Apnoea (OSA) and Obesity Hypoventilation Syndrome (OHS) 
8. 
Features of difficult airway  
 
During the pre-operative visit, the patient will be briefed on the study and informed consent 
obtained. They will also be assessed for pre-operative anxiety by using the Amsterdam Pre-
operative Anxiety and Information Scale (APAIS; Appendix 1)18, where only the anxiety 
components of the original questionnaire will be assessed. Patients will be graded on a five-
point Likert scale from 1 = not at all, to 5 = extremely anxious. A patient with score ≥ 11 is 
considered anxious.18  
 

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All patients will be given pre-medication of oral midazolam 3.75 or 7.5 mg accordingly. 
Subjects will be randomised via computer generated block randomisation into Group PCS 
and Group TCIS. The study will be conducted by multiple anaesthesia medical officers. In 
the operating theatre, standard monitoring will include electrocardiogram (ECG), non-
invasive blood pressure, pulse oximetry and transthoracic impedance pneumography. 
Baseline readings will be recorded. Intravenous access will be established with an18G 
cannula and normal saline 0.9% infused. 
 
Central neuraxial block will be performed under aseptic technique by the anaesthesia medical 
officer in-charge and the L2-3 or L3-L4 intervertebral space sought with the patient sitting. 
The subarachnoid space will be located using a pencan 27G (B Braun, Germany) spinal 
needle and hyperbaric bupivacaine 0.5% plus fentanyl 15-25 µg will be administered. In the 
case of combined spinal-epidural anaesthesia (CSE), the epidural space will be located with a 
Tuohy 18G epidural needle, and the epidural catheter secured in place (Espocan®, B Braun, 
Germany). After establishing an adequate sensory level, surgery will be allowed to proceed, 
and PCS or TCIS commenced. Patients with failed subarachnoid block or sensory block 
inadequate for surgery will be dropped out from the study. All patients will receive oxygen 
supplement of 5L/min via a face mask. Heart rate (HR), blood pressure (BP), oxygen 
saturation (SpO2) and respiratory rate (RR) will be monitored and documented every 5 
minutes. Patients will be kept warm with standard intra-operative warming devices during the 
surgery.  
 
Propofol will be premixed with lignocaine where 10 mg of lignocaine will be added to every 
100 mg propofol 1% to reduce the intensity of pain on injection with propofol.19,20 Patients in 
Group PCS will receive intravenous (IV) propofol (Lipuro® 1%, B.Braun, Germany) via a 
Graseby® Omnifuse patient controlled analgesia (PCA) (Smith’s Medical, UK) infusion 
pump. The machine will be set to deliver a demand bolus dose of 0.25 mg/kg with no lockout 
interval or basal infusion.12 The patient will be instructed to press on a hand-held device as 
often as required to achieve their desired level of comfort or sedation. The sedation level will 
be assessed using the Observer's Assessment of Alertness/Sedation Scale (OAA/S; Appendix 
2) every 5 minutes in the first 30 minutes, followed by every 20 minutes thereafter. 
 
Patients in Group TCIS will receive IV propofol (Lipuro® 1%, B.Braun, Germany) via a 
Graseby® Omnifusion target-controlled infusion (TCI) pump (Graseby Medical, Watford, 

Dept of Anaesthesiology And Intensive Care UKMMC 
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U.K) targeting an initial effect site concentration (Cet) of 0.6 μg /ml, using the Schnider 
pharmacokinetic model.12   Upon attainment of 0.6 μg /ml Cet, the patient’s sedation level 
will be assessed. The Cet will be increased or reduced accordingly by 0.2 μg/ml to attain an 
OAA/S score of 3. After equilibrium between predicted and set concentration is achieved, 
OAAS score is re-assessed and adjustment of Cet is made until OAA/S score of 3 achieved. 
The induction time, which is the time taken to reach OAA/S of 3, will be documented in both 
groups. Thereafter the OAS/S will be assessed every 20 minutes. 
 
Complications from sedation will be managed as follows: 
1. 
Hypotension (systolic BP 20% below baseline) will be treated with administration of 
IV fluid and titrated bolus doses of IV ephedrine 6 mg or IV phenylephrine 100 μg as 
required. 
2. 
Bradycardia (HR < 40bpm) will be treated with IV atropine 0.6mg. 
3. 
Respiratory depression (RR< 8 breaths/min) and oxygen desaturation (SpO2 < 95%) 
will be managed by verbal or tactile stimuli, and titrating down Cet by 0.2 μg/ml in 
the TCI group, delivering 100% oxygen by applying airway maintenance manoeuvres 
and assisted ventilation as necessary. 
4. 
Over-sedation (OAS/S score ≤ 2) will be managed by verbal or tactile stimuli, and 
titrating down Cet by 0.2 μg/ml. 
 
The use of airway adjuncts or intubation will be considered depending on the severity of 
respiratory compromise. These patients will be excluded from analysis of recovery 
characteristics. 
 
Sedative administration will be terminated (T0) at the completion of surgery. At the recovery 
area, standard monitoring will be employed. The medical officer in the recovery room will 
assess the OAS/S score every 5 minutes. The recovery time, which is the time taken to reach 
OAS/S 5 from T0 will be documented. Total propofol requirement in both groups will be 
calculated in mg/kg/hour. 
 
Before discharge from the recovery room, patient satisfaction with sedation was measured 
using a 10-point verbal rating scale, 1 being extremely dissatisfied and 10 being extremely 
satisfied. 

Dept of Anaesthesiology And Intensive Care UKMMC 
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STATISTICAL ANALYSIS 
Sample size calculation 
The α value is set at 0.05 and power of study at 80%. Sample size calculation was based on  
mean propofol requirement for sedation in a study by Singh T et al. 21  We expect a difference 
of 0.5 mg/kg/hour of propofol between Groups PCS and TCIS. 
 
The sample size was calculated using the ‘Power and Sample Size Calculations’ program. 
Sample size calculated using t- test. 
Requested output: Sample size 
Independent 
Alpha = 0.05; power = 0.8; δ = 0.5; σ = 0.74; M = 1 
Case sample size for t-test = 35 
Total sample size: 35 x 2 plus 10% drop-out rate = 78 
Sample size = 39 per study group. 
 
Statistical tests 
Demographic data and total propofol requirement will be analysed using the student’s t-test 
(or Mann Whitney-U test for non-parametric data). Patients’ satisfaction score will be 
compared using the student’s t-test. The satisfaction level of anxious patients in PCS group 
and TCIS group is compared by using the t-test. A p-value < 0.05 will be considered 
statistically significant. 
 
 
 
 
 
 
 
 
 
 

Dept of Anaesthesiology And Intensive Care UKMMC 
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FLOW CHART 
 
 
 
 
 
 
 
 
 
Patients for elective lower limb orthopaedic surgery 
ASA I or II patients 
Aged 18-65 years 
Lower limb orthopaedic surgery 
under CNB 
 
BMI > 30 kg/m2 
Unable to cooperate (eg. mental disorders, language barrier) 
Contraindications to the study drugs 
Pregnancy 
Significant pulmonary or cardiovascular diseases, OSA or OHS 
Features of difficult airway 
 
Written Consent 
EXCLUDED 
Random Allocation into Group PCS or Group TCIS 
GROUP PCS 
Propofol 1% administered via a 
PCA device: bolus dose 0.25 
mg/kg, no lockout interval or basal 
infusion 
 
GROUP TCIS 
Propofol 1% administered via 
TCI pump (Schnider model) 
with initial Cet 0.6 μg /ml, 
titrated by 0.2 μg /ml 
accordingly 
In OT 
 CNB administered  
 Patients commenced on PCS or TCIS as per protocol 
 Continuous monitoring of BP, HR, ECG, SpO2, RR and documented every 5 minutes 
 OAS/S score every 5 minutes in the first 30 minutes (PCS group) and after  attainment of 
OAS/S score of 3 in TCI group, subsequently monitored every 20 minutes 
 Complications documented  
 

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DATA COLLECTION FORM 
Study ID: 
 
Study group 
 PCS 
 TCIS 
Age: 
 
Gender: 
 
Race: 
 
Height (m): 
 
Weight (kg): 
 
BMI: 
 
ASA: 
 
Diagnosis: 
 
Surgical 
procedure: 
 
 
Time surgery commeneced:  
Time sedation commenced: 
Time to reach OASS score 3: ____________ min 
 
Time surgery ended: 
Time sedation terminated (To): 
Total propofol requirement: _________ mg 
 
 
Time of arrival at the recovery room: 
Time to reach OASS score 5: ______________ min 
Time discharged from recovery room: 
 
COMPLICATIONS  
YES 
NO 
RESCUE/REMARKS 
Systolic BP < 20% baseline 
 
 
 
HR < 40 bpm 
 
 
 
RR < 8/min  
 
 
 
SpO2 < 95% 
 
 
 
OAS/S ≤ 2 
 
 
 

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Monitoring chart 
Time (min) 
Baseline 
5 
10 
15 
20 
25 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
95 
100 
BP (mmHg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HR  (bpm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SpO2 (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RR(per min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OAS/S score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cet (ng/ml) 
*TCIS only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time (min) 
 
105 
110 
115 
120 
125 
130 
135 
140 
145 
150 
155 
160 
165 
170 
175 
180 
185 
190 
195 
200 
BP (mmHg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HR(bpm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SpO2 (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RR(per min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OAS/S score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cet (ng/ml) 
*TCIS only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(OAS/S charting for PCS: Every 5 mins for 30 mins, thereafter every 20 mins. TCIS: Adjustent of targeted effect site concentration until OASS score 3, thereafter every 20 mins)   

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REFERENCES 
1. 
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Miller RD (Ed.), Anesthesia. 4th edition 1994. p. 269-274. 
2. 
Abdulselam E, Ferah D, Vildan T, Bayazit D. Patient-controlled sedation in 
orthopedic surgery under regional anesthesia: a new approach in procedural 
sedation. Brazilian Journal of Anesthesiology  2013. 63: 5.  
3. 
American Society of Anesthesiologists Task Force on Sedation and Analgesia by 
Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-
anesthesiologists. Anesthesiology 2002. 96: 1004–17. 
4. 
Sa Rego MM, Watcha MF, White PF. The changing role of monitored anesthesia 
care in the ambulatory setting. Anesthesia and Analgesia 1997. 85: 1020–36. 
5. 
Jowell PS, Eisen G, Onken J, et al.. Patient-controlled analgesia for conscious 
sedation during endoscopic retrograde cholangiopancreatography: a randomized 
controlled trial. Gastrointestinal Endoscopy 1996. 43: 490 -4. 
6. 
Stermer E, Gaitini L, Yudashkin M, et al. Patient-controlled analgesia for 
conscious sedation during colonoscopy: a randomized controlled study. 
Gastrointestinal Endoscopy 2000. 51: 278 -81. 
7. 
Ho¨hener D, Blumenthal S, Borgeat A. Sedation and regional anaesthesia in the 
adult patient. British Journal of Anaesthesia 2008. 100(1): 8–16. 
8. 
Goudra BG,  Jeff EM. Target-controlled infusions/patient-controlled sedation. 
Techniques in Gastrointestinal Endoscopy 2009. 11(4): 181-187.  
9. 
Barakat AR, Sutcliffe N, Schwab M. Effect site concentration during propofol 
TCI sedation: a comparison of sedation score with two pharmacokinetic models. 
Anaesthesia  2007.  62: 661–666. 
10. 
Schnider TW, Minto CF, Struys MM, Absalom AR. The safety of Target-
Controlled Infusions. Anesthesia and analgesia 2016. 122(1): 79-85. 
11. 
Owen H, Mather LE, Rowley K. The development and clinical use of patient-
controlled analgesia. Anaesthesia and Intensive Care 1988. 16: 437-447. 
12. 
Ferrante FM. Patient-controlled analgesia. Anesthesiology Clinics of North 
America 1992. 10: 287-298. 
13. 
Rudkin GE, Osborne GA, Curtis NJ. Intra-operative patient-controlled sedation. 
Anaesthesia 1991. 46: 90-92.  
14. 
Park WY, Watkins PA. Patient-controlled sedation during epidural anesthesia. 
Anesthesia and Analgesia 1991. 72: 304-307. 

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15. 
Girdler NM, Rynn D, Lyke JP, Wilson KE. A prospective randomised study of 
patient controlled propofol sedation in phobic dental patients. Anaesthesia 2000. 
55: 327-33. 
16. 
Wahlen BM, Kilian M, Schuster F,  Muellenbach R,  Roewer N, Kranke P. 
Patient-controlled versus continuous anesthesiologist-controlled sedation using 
propofol during regional anesthesia in orthopaedic procedures – a pilot study. 
Expert Opinion on Pharmacotherapy 2008. 9(16): 2733-2739. 
17. 
Liang C, Chen J, Gu W, Wang H, Xue Z. Chronic alcoholism increases the 
induction dose of propofol. Acta Anaesthesiol Scand 2011. 55: 1113–1117. 
18. 
Moerman N, Van Dam FS, Muller MJ, et al. The Amsterdam preoperative anxiety 
and information scale (APAIS). Anesthesia and analgesia 1996. 82(3): 445-51. 
19. 
Euasobhon P, Dej-arkom S, Siriussawakul A, Muangman S, Sriraj W, Pattanittum 
P, Lumbiganon P. Lidocaine for reducing propofol-induced pain on anaesthesia in 
adults. Cochrane Database of Systematic Reviews 2016. 2: CD007874. 
20. 
Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O et al. Prevention of 
pain on injection of propofol: systematic review and meta-analysis. British 
Medical Journal 2011. 342: d1110 
21. 
Tejinder S, Ravishankar M. Conscious sedation with propofol for surgeries under 
spinal anaesthesia: Anaesthesiologist Versus Patient Controlled. Journal of 
Anaesthesiology Clinical Pharmacology 2005. 21(2): 169-173. 
22. 
Mohd FZ, L Lai, PS Loh, Validation of the Malay version of the Amsterdam 
Preoperative Anxiety and Information Scale (APAIS). The Medical journal of 
Malaysia, 2015. 70(4): p. 243 
 
 
 

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Appendix 1: The Amsterdam Preoperative Anxiety and Information Scale (APAIS) 
(The measure of agreement with these statements is graded on a five-point Likert scale from 
1 = not at all, to 5 = extremely) 
English version18 
1. I am worried about the anesthetic. 
2. The anesthetic is on my mind continually. 
3. I am worried about the procedure. 
4. The procedure is on my mind continually. 
(Licensed permission granted by Wolters Kluwer Health, Inc.) 
 
Malay version 22 
1. Saya bimbang tentang pembiusan saya. 
2. Pembiusan sentiasa berada di fikiran saya. 
3. Saya bimbang tentang prosedur pembedahan saya. 
4. Prosedur pembedahan sentiasa berada di fikiran saya. 
 
 
 

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Appendix 2: Observer's Assessment of Alertness/Sedation (OAA/S) Scale 
Score  
Observation 
5 
Responds readily to name spoken in normal tone 
4 
Lethargic response to name spoken in normal tone 
3 
Responds only after name is called loudly and/or repeatedly 
2 
Responds only after mild prodding or shaking 
1 
Does not respond to mild prodding or shaking