|Year : 2008 | Volume
| Issue : 1 | Page : 70
Intra-operative Patient-Controlled Sedation (PCS):Propofol versus Midazolam Supplementation During Epidural Analgesia (Clinical and Hormonal Study)
Hassan S Al-khayat1, Abhay Patwari2, Mohamed S El-khatib1, Hassan Osman3, Khairy Naguib3
1 Consultant(W.Germany), Department, of Anaesthesia and Intensive Care, Farwania Hospital, Kuwait., Kuwait
2 Senior Registrar(Egypt), Department, of Anaesthesia and Intensive Care, Farwania Hospital, Kuwait., Kuwait
3 Chairman, Department, of Anaesthesia and Intensive Care, Farwania Hospital, Kuwait., Kuwait
|Date of Acceptance||28-Dec-2007|
|Date of Web Publication||19-Mar-2010|
P.O.Box 26228, Safat 13123, State of Kuwait, Arabian Gulf.
Source of Support: None, Conflict of Interest: None
This study was done on sixty adult males scheduled to have an epidural analgesia for elective inguinal hernia repair. The study was designed to compare propofol and midazolam with regard to their suitability for the patient-controlled sedation (PCS) technique during epidural analgesia. Patients were divided into three equal groups and premedicated with 0.2mg.kg -1 oral midazolam. Group I (G1) served as control. Using PCS technique, the pump was programmed to deliver on demand a bolus dose of 0.5 mg.kg 1 of propofol in Group II (G2) or 0.1mg.kg -1 midazolam in Group III(G3). Patient's sedation status was assessed by sedation score, comfort scale and by psychometric testing. The total delivered dose of each tested drug was calculated. Serum concentrations of propfol and midazolam, plasma cortisol and free fatty acids were measured. Propofol and midazolam PCS technique produced excellent and easily controllable sedation. The dose needed to produce steady state sedation was 2.8±1.42 and 0.11±0.6 mg.kg -1 .h 1 for propofol and midazolam respectively. Propofol was more suitable than midazolam for PCS because of its rapid onset, favorable recovery profile and low side effects. PCS proved to be a stress-free and acceptable technique.
Keywords: Patient controlled sedation, Midazolam, Propofol, Epidural analgesia
|How to cite this article:|
Al-khayat HS, Patwari A, El-khatib MS, Osman H, Naguib K. Intra-operative Patient-Controlled Sedation (PCS):Propofol versus Midazolam Supplementation During Epidural Analgesia (Clinical and Hormonal Study). Indian J Anaesth 2008;52:70
|How to cite this URL:|
Al-khayat HS, Patwari A, El-khatib MS, Osman H, Naguib K. Intra-operative Patient-Controlled Sedation (PCS):Propofol versus Midazolam Supplementation During Epidural Analgesia (Clinical and Hormonal Study). Indian J Anaesth [serial online] 2008 [cited 2019 Jan 20];52:70. Available from: http://www.ijaweb.org/text.asp?2008/52/1/70/60601
| Introduction|| |
Successful epidural analgesia requires not only intra-operative pain relief, but also an adequately sedated co-operative patient. To allay fear and anxiety and to ease any discomfort and apprehension associated with the performance of the epidural block and/or the surgical procedure, sedatives are often administered intravenously by different techniques in the operation room. 
Intra-operative sedation to augment local or regional analgesia should include optimal patient satisfaction with minimal risk of morbidity. Satisfactory intra-operative sedation should also include suitable post-operative recovery characteristics. Delay in recovery of mental function and memory may be considered a disadvantage of the technique used. 
Because of wide individual variations in response to sedatives, over -or under- sedation is not infrequent. In addition, there is considerable variation in the level of sedation desired by the patient.
Intra-operative sedation can be provided by inhalation or intravenous technique, the latter either by repeated bolus doses, manually operated,  patient-controlled  and computer-controlled infusion.  Many different agents have been used for this purpose, but infusion of a short acting, readily controllable, individually titrable agent has theoretical advantages. The advantages of patient-controlled sedation (PCS) technique may include: (1) a more constant serum level of the sedative agent, (2) improved sedation quality and (3) the abilty of the patient to modulate the final sedative dose to achieve the optimal sedation. 
The pharmacokinetic properties of propofol, particularly its rapid onset, redistribution, metabolism, high clearance, favorable recovery profile and its low incidence of side effects in the lipid formulation makes it a suitable agent for PCS. It also allows maximum flexibility and responsiveness to the patient's need. 
The high lipid solubility of midazolam at physiological pH allows for rapid brain entry and relatively fast onset of action. This makes it another suitable drug for PCS. 
This study was designed to compare propofol and midazolam with regard to their suitability for the PCS technique during epidural analgesia and to evaluate the feasibility, advantages and/or disadvantages of PCS if any.
| Methods|| |
Sixty adult male patients scheduled to have the same standard epidural analgesia for proposed elective surgery of inguinal hernia repair were enrolled in the study. Patients with any previous adverse experience of anaesthesia or sedation or those who were receiving drugs likely to interfere with the course of sedation were excluded. All operations were performed by the same surgeon.
The anaesthesiologists assigned to the case, the recovery room staff and the anaesthesiologist doing the post-operative testing were blinded from the drug used for PCS.
Permission to conduct this study was obtained from the Hospital's ethics research review committee, and patient's informed consent was taken. Patients were allocated randomly and blindly into three equal groups (20 each): Group1 (G1) served as control, Group 2 (G2) received propofol PCS and Group 3 (G3) received midazolam PCS. All patients were premedicated with 0.2 mg.kg -1 oral midazolam two hours before the operation.
On arrival to the operating room, the degree of sedation from premedication was rated jointly by anaesthesiologist assigned to the case and by the investigator using the sedation scale,  (1-10, 1 = fully awake, 5 = moderate sedation; resting comfortably with eyes closed but responsive to verbal stimuli, 10 = heavy sedation; unresponsive to verbal stimuli but responsive to gentle tactile stimuli). Two intravenous cannulae (18 G) were inserted (left dorsal venous arch) for fluid therapy and venous blood sampling. Electrocardiography (ECG), oxygen saturation (SpO2), non-invasive blood pressure and body temperature were monitored from arrival to the anaesthetic room. All patients received intravenous infusion of Ringer's lactate solution (6 ml.kg -1 over 20 minutes) as preload.
Epidural blockade was established with 20 ml of 2% plain lidocaine via a catheter inserted in L2-L3 interspace. Oxygen (3 L.min -1 ) was administered by nasal cannulae throughout the surgical procedure. If the epidural block was adequate regarding the sensory and motor levels with absence of unblocked segments and the cardiovascular system stable, PCS was commenced. All patients were instructed before premedication as to how to self-administer their sedation. The pump was programmed to deliver on demand a bolus dose of 0.5 mg.kg -1 of propofol using the standard 10mg.ml lipid formulation (G2) or 0.1mg.kg -1 midazolam (G3), or 0.05 ml.kg 1 or of Ringer's lactate solution (G1). The bolus delivery time was 20 seconds. The lockout time estimated from the completion of the bolus infusion was 5 minutes in G1, G2 and 15 minutes in G3. The patient-controlled pump (Patient controlled analgesia pump PCAM, IVAC, Model P 5000), delivered the drug through a minimal volume side arm attached to the Y-piece of an infusion set, the other arm of which was fitted with a one-way valve. At the end of the surgical procedure, the pump was disconnected and readings were taken from the PCS pump display: total dose of drug administered, number of attempts at self-drug administration and the number of successful attempts were noted. The length of time PCS was available to the patient was taken as "procedure duration". Any side effects or complications pre- and post- operatively were recorded.
| Measurements and Timing|| |
- Sedation Assessment:
- Sedation score: five points scoring system by Wilson et al.  (1 = fully awake, 2 = drowsy with eyes open, 3 = drowsy with eyes shut, responding to verbal command, 4 = rousable to mild physical stimulation and 5 = unarousable). Assessment was made just before PCS, at 15 minutes intra-operative intervals and at the time of any intra-operative event. The time of each patient's sedation score was related to the total infusion time to estimate the percentage of total steady state time (tsst).
- Comfort scale  , on the first postoperative day, the patients were asked to rate the overall comfort they had experienced in the operating room using the comfort scale (1-10, 1 = very uncomfortable, 5 = moderately comfortable, 10 = very comfortable).
- Psychomotor test:
- Ball bearing test  : The patient had to use a pair of forceps to place ball bearing in vertical tube, the score was number of ball bearings inserted in 40 seconds.
- Free recall test  : lists of 20 uncategorized words at a fixed space (one word every 2 seconds) were mentioned to the patient. After the last word was presented, the patient was asked to recall the words aloud. The score was the success percentage of word recall.
The psychomotor tests were done pre-operatively just before the premedication and every one hour during the first two post-operative hours.
- Total dose of each tested drug was calculated against the operative time to estimate the dose in mg.kg -1 .h required to produce satisfactory sedation under epidural analgesia.
- Serum propofol  and midazolam  levels were measured. Blood samples for drug estimation by the gasliquid chromatography were drawn from a separate indwelling 16 G cannula in the contralateral arm 5 minutes after commencement of the PCS and half hourly thereafter until the infusion was discontinued. The mean serum level was related to sedation score to estimate the drug concentration required for satisfactory sedation.
- Hormonal study: plasma cortisol (by radio-immunoassay method)  and free fatty acids (by colorimetric method)  levels were measured pre-operatively (just before starting PCS), at every 30 minute intervals and immediately post-operatively.
- Cardiovascular, respiratory and central nervous system parameters were observed and monitored. The patient was observed for any of the following complications:
- Respiratory rate < 6 breaths/minute,
- Oxygen saturation < 90% when nasal oxygen was administered at a rate of 3 L.min -1 .
- Hypotension (systolic pressure < 80 mmHg)
- Nausea or vomiting
- Restlessness and excitement
- Post-operative amnesia
- Pain at infusion site
The results were analyzed statistically using Student "t" and chi-square tests where appropriate. Differences were considered to be statistically significant when the probability value was < 0.05.
| Results|| |
Patients were between 20-60 years of age (mean 42±12.92 years), weighing between 45 and 100 kg (mean 74±19.91 kg), and their anaesthetic risk was classified as ASA grade 1.
I Sedation assessment:
- The target sedation scores (3 or 4) were achieved during 6.6%, 83.6% and 78.7% of total infusion time in G1, G2 and G3 respectively. Propofol by PCS technique provided more significant sedation than midazolam using the same technique [Table 1].
- Post-operative patient self-assessment of PCS tech nique, and drug used using the "comfort scale"  showed significant patient acceptance of propofol (9±0.13) as compared to midazolam (7±2.51) and control (5±0.05) groups [Table 2].
- Using the psychomotor tests, the means of ball bearing test in the second post-operative hour were (18±1.61), (12±2.16) and (9±1.95) in G1,G2 and G3 respectively, while the means of free call test were (96±4.1), (70±4.8) and (64±5.5)% in G1, G2 and G3 respectively [Table 3].
II During epidural analgesia, the supplementation dose of propofol and midazolam using PCS technique required to produce satisfactory sedation was (2.8±1.42), and (0.11±0.06) mg.kg-1. h-1 respectively [Table 4].
III The mean measured serum propofol and midazolam concentration necessary to achieve sedationto level 3 or 4 was (0.87±0.51), (1.32±0.63), (0.41±0.43) and (0.63±0.52) mcg.ml -1 respectively [Table 5].
- The mean plasma cortisol level [Figure 1] was in significantly increased up to 120 minutes (p<0.05) in both propofol and midazolam PCS.
- Free fatty acids were insignificantly increased (p<0.05) in both propofol and midazolam PCS groups [Figure 2].
V Pain at infusion site was recorded in one patient (5%) from the propofol PCS group, while nausea alone was recorded in one patient (5%) from the midazolam PCS group in the immediate post-operative period. Nausea (5%), retching (5%) and restlessness (20%) were recorded in the control group [Table 6]
| Discussion|| |
PCS has become a widely accepted technique for supplementing regional blocks to allay fear, anxiety and to ease any discomfort and apprehension that may occur  . The current study results showed satisfactory clinical performance as 83.6% and 78.7% of total operative time was spent at the target sedation scores of 3 or 4 in propofol and midazolam PCS groups respectively. Undesirable over-sedation, corresponding to a sedation score of 5 occurred for an average of only 5.2% and 4% in propofol and midazolam PCS groups respectively. This degree of over-sedation may be further reduced as experience with the system increases.
Propofol PCS provided significant sedation at desired score 3 or 4 than midazolam PCS. Murdoch et al  showed in a similar study that eighy-eight per cent of the total infusion time under propofol PCS was at the desired sedation level with no over-sedation. Annemiek et al  concluded that the level of satisfactory sedation (3 or 4) was maintained by most of the patients (75%) who received midazolam PCS; the others (25%) showed wide individual variations.
Despite the fact that comparable doses of propofol and midazolam were used by PCS technique, patients in propofol group indicated by their rating on the comfort scale that they were more comfortable intra-operatively than patients in the midazolam group. This can be explained by the rapid onset and easily controllable sedation effect of propofol as compared to midazolam . All patients in the study significantly accepted the PCS technique. It seems likely that this could be attributed to the positive psychological effect of allowing the patients to feel that they have some control over their situations as they fine tune and maintain the level of sedation themselves. Myles et al  studied the psychological characteristics and the effectiveness of the PCS technique and concluded that most of the patients were accepting the technique, because it provided a more constant sedative serum level with optimal patient satisfaction and minimal risk of morbidity.
The current study showed that post-operative mental performance (using psychomotor test) of propfol group was better than the midazolam group. This may be due to the shorter duration of action, higher clearance rate and rapid redistribution of propofol  . Janzen et al  in their similar study showed significantly impaired postoperative mental performance in the midazolam PCS but with significant improvement with time in recovery. Midazolam may produce dose-dependent impairment of mental function with no significant improvement with time over similar recovery intervals  .
The pump assembled for this study performed satisfactorily and demonstrated the advantages of rapid bolus infusion for PCS. The present study showed less favorable demand ratio of successful to unsuccessful attempts in midazolam group of patients, in spite of patients being apparently sedated to level similar to those in the propofol group. This may be related to the differences between the drugs for dose-dependent anxiolysis, mood alteration or analgesia.
The current study estimated the dose required for satisfactory sedation under epidural block for propofol and midazolam PCS. It was (2.80±1.42) and (0.11±0.06) mg.kg -1 .h -1 respectively. Nearly similar doses were estimated (2.62±1.17) and (0.13±0.15) mg.kg -1 .h -1 by Annemiek et al  and 2.72±1.37 and 0.11±0. 05 mg.kg 1. h -1 by Janzen et al  in their studies.
In the present study, the mean measured serum propofol and midazolam levels necessary to achieve desirable sedation score of 3 or 4 were (0.87±0.51), (1.32±0.63), (0.41±0.43) and (0.63±0.52) mcg.ml -1 respectively. This suggests that doses of PCS technique are capable of achieving the desired level of sedation in a readily controllable manner as 83% and 78.7% of total procedure time was spent at the desired sedation level in propofol and midazolam groups respectively. Murdoch et al  found similar serum propofol level to achieve sedation to level 3 and 4 (0.80±0.48 mcg.ml -1 ). Kim et al  estimated that, patient with a blood propofol level around 1 mcg.ml -1 will respond to verbal stimulation.
Stress-free technique using propofol and midazolam PCS was confirmed, as was evident by insignificant increase in the mean plasma level of both cortisol and free fatty acids. Such findings can be explained by the well maintained serum level of the sedative drug used in PCS producing a steady state of sedation and by the underlying epidural analgesia.
The complications related to the current study were post-operative unexplained nausea in one patient from the midazolam group, that was relieved spontaneously within two minutes. Intra-operative pain at the site of infusion was recorded in one patient from the propofol group. It immediately disappeared after flushing with 5 ml of normal saline. That the study failed to detect any other complications may be due to the limited number of cases.
To conclude, propofol and midazolam by PCS technique produced excellent and easily controllable sedation during epidural analgesia. The dose needed was (2.8±1.42) and (0.11±0.06) mg.kg -1 .h -1 for propofol and midazolam respectively using PCS to produce steady state sedation. Onset of sedation was smooth and depth was easily controlled. The frequency of side effects was low and negligible in both groups. However recovery (as judged by immediate return of consciousness, orientation and by performance in psychometric testing) was significantly faster with propofol. Propofol was more suitable than midazolam for PCS due to its more rapid response to fluctuating patient requirements, as shown by a more favorable ratio of successful to unsuccessful demand, without over-sedation. However, more studies with PCS are needed to determine the best choice of drug(s), its dose(s) and the optimum lock-out intervals.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]