International Journal of ClinicalMonitoring and Computing9: 207-212, 1992. 9 1992KluwerAcademic Publishers. Printedin the Netherlands.

Postoperative analgesia using a computerised infusion of alfentanil following aortic bifurcation graft surgery F.W. Davies, Martin White & Gavin N.C. Kenny University Department of Anaesthesia, Royal Infirmary, 8-16 Alexandra Parade, Glasgow G43 2EF, UK Accepted 7 May 1992

Key words: alfentanil, postoperative analgesia, computer, pharmacokinetic, model

Summary A Psion microcomputer controlled infusion system for alfentanil was assessed for the provision of postoperative analgesia in 14 patients who had undergone aortic bifurcation graft surgery. The system employed a pharmacokinetic model working in real time to deliver any selected target plasma concentration of alfentanil. The alfentanil infusion system was used for a mean time of 39 hours and for 96% of this time, patients were scored as having no pain or only mild pain. Severe pain was recorded for only 0.05% of the study time. The use of a pharmacokinetic delivery system may offer a convenient and simple method of providing postoperative analgesia with alfentanil.

Introduction Postoperative analgesia after major vascular surgery is provided frequently by an intravenous infusion of morphine with the infusion rate altered by the nursing staff as required. The time to peak effect of a bolus dose of morphine is about 15-20 minutes so that an alteration in infusion rate will not achieve its full effect for a considerable time [1]. Alfentanil, with rapid onset and a short elimination half-life, has a desirable pharmacokinetic and pharmacodynamic profile for use as a variable rate infusion [2, 3]. It therefore offers the principal advantage over morphine of rapid onset of action with minimal sedation but has the drawback that it is also rapidly eliminated and distributed. The use of alfentanit to provide postoperative analgesia has been investigated using patient controlled analgesia (PCA) with bolus doses delivered in response to a patient demand but this technique

has not yet proved satisfactory [4, 5]. Patient con-trol of an infusion-demand system also proved to be of little value [6] and some form of constant alfentanil infusion is therefore required to provide adequate postoperative analgesia. Computer controlled infusion of alfentanil using a pharmacokinetic model has been used successfulty during anaesthesia [7, 8] but has not been investigated previously for the provision of postoperative analgesia. We have developed a computer controlled infusion system for alfentanil using a Psion microcomputer interfaced to the Ohmeda 9000 syringe pump similar to that used to control plasma concentrations of propofol [9]. This study was undertaken to assess the use of the pharmacokinetic based infusion system to control postoperative pain following aortic bifurcation graft surgery.

Abstract presented at the 6th International Symposiumon Computing in Anaesthesia and Intensive Care; Hammamatsu, Japan.

208 Methods

Fourteen patients weighing 48-85 kg and aged 4379 years, scheduled to undergo elective aortic bifurcation grafting were entered into the study which was approved by the hospital ethics committee. Demographic data are shown in Table 1. All patients gave written informed consent and received a standard anaesthetic in which premedication was oral temazepam 10-30mg. Anaesthesia was induced with thiopentone and the trachea was intubated following vecuronium. The lungs were ventilated artificially with 66% N20 and oxygen and anaesthesia was maintained with enflurane. The Psion computer controlled the Ohmeda 9000 syringe pump via the RS-232 interface and the program was stored in a removable EPROM. The anaesthetist entered the patient's body weight, age and sex into the system and the pharmacokinetic variables were calculated for each patient using data from Maitre and colleagues [10]. The selected target plasma alfentanil concentration was achieved by a rapid zero order infusion at a rate of 300 ml per hour. The program calculated the theoretical plasma concentration achieved approximately every second and once the predicted concentration was within 1% of the selected target, the target plasma concentration was maintained at the desired level by calculating the infusion rate of alfentanil necessary to compensate for elimination and redistribution of the drug to the peripheral compartments. The system was capable at all times of calculating the distribution of the drug between the three compartments of a mathematical pharmacokinetic model and allowed the target concentration to be manipulated in any direction at any point in time. In order to assess the performance of the pharmacokinetic model, venous blood samples were obtained via a dedicated sampling line. Samples were centrifuged and plasma frozen at - 2 0 degrees centigrade for analysis by radioimmunoassay. Intraoperative analgesia was achieved using the Psion control system set to an initial target plasma alfentanil concentration of 40 nanogml -~. Subsequent plasma concentrations were selected by the

anaesthetist as required during the operation. Patients were returned to the recovery area postoperatively for a short period of artificial ventilation and extubated when stable and their body temperature was within the normal range. The program allowed the anaesthetist to select the optimum target concentration of alfentanil in the recovery room to achieve satisfactory analgesia and to set the system so that further alterations could increase or decrease the concentration by only + 5 nanogm1-1. The nursing staff then altered the predicted alfentanil concentration by these increments to provide the necessary degree of analgesia for the rest of the postoperative period. The system was used for each patient until parenteral analgesia was no longer required. Ordered category pain scores and arterial oxygen saturation were recorded by the nursing staff during the study period. Oxygen saturation was measured using the Ohmeda, Biox 3700 Pulse Oximeter. Visual analogue pain scores were obtained from each patient on the day following surgery using a 100 millimetre scale, once in the morning and again in the evening.

Results

Analysis of pain scores demonstrated that patients who received postoperative analgesia with the computerised alfentanil infusion system had good quality of pain relief. The alfentanil infusion system was used for a mean time of 39 hours postoperatively (Table 1) and for 96% of this time, patients were scored as having no pain or only mild pain. Severe pain was recorded for only 0.05% of the study time (Table 2). Ordered category scores for the patient group are represented graphically in Fig. 1 and visual analogue scores are summarised in Table 3. Ordered category scores are shown at specific time intervals from operation, scores occurring between these times are not represented. Severe pain was controlled rapidly by increasing the target alfentanil level. Only two patients experienced severe pain, each for a period less than fifteen minutes and hence do not appear in the figure. The greatest frequency of plasma level al-

209 []

No Pain

[]

Mild Pa~n

300

Moderate Pain

'1

e"

~" ;i I

200 ~c ~c

100

0~,,,.Q

E Z

0

50

100

150

200

Predicted Plasma Alfentanil (ng/ml) _

0 1 2 3 4 5 6

8 910111214161820222426283032343638

Time Since Operation ( h o u r s ) Fig. 1. Ordered category scores at hourly intervals postoperatively. (No patient recorded severe pain at these times).

terations occurred in the immediate postoperative recovery phase. The median time spent in the recovery area was 3 hours (range 2 to 5). During this time a median of 10 alterations were made (range 4 to 22). Median time spent on the high dependency unit using the system was 47 hours (range 14 to 63). During this time a median of 13 alterations were made (range 9 to 26). Figure 2 shows the correlation between the target plasma alfentanil concentrations predicted by the pharmacokinetic model and those measured by radioimmunoassay: Measured = 21.26 + 1.26 x Predicted:r = 0.69 The median target plasma concentrations selected to provide postoperative analgesia was 71 nanog ml < with a range of 34 to 150 nanog ml-L Respiratory rate and oxygen saturation data are shown in Figs 3 and 4. These figures summarise the Table 1. Demographic data of patients studied. Values are expressed as mean (range). Weight Age Duration 04 operation Hours in study Male / female

66.1 (48-85) kg 62 (43-79) years 3.5 (2.5-5) hours 39 (14-68) hours 11 / 3

Fig. 2. Correlation between predicted and measured plasma concentrations of alfentanit.

data obtained for all patients using observations by nursing staff recorded at half hourly intervals for the first 24 hours and at hourly intervals thereafter. Respiratory rates of less than 10 per minute were noted in 3 patients but were not found to correspond with arterial oxygen desaturation. The range of oxygen saturation in these patients at these times was 95-100%. One other patient required insertion of a Guedel airway and reduction of the target plasma alfentanil concentration because of excessive sedation. This was quickly reversed by reduction of the predicted plasma alfentanil level and specific opiate antagonists were not required. In this case the respiratory rate was at all times greater than ten per minute and oxygen saturation greater than 95%. All patients received supplementary oxygen on the first postoperative day. Oxygen saturations less than 90% were not observed during this period. Oxygen therapy was discontinued on the morning of the second day resulting in saturation levels less than 90% in 3 patients associated with respiratory

Table2. Number of hours spent at different pain Jevels. Values are expressed as mean (range). none

mild

moderate

severe

27.55 (2.75-41.75)

9.98 (0.25-24,5)

1.4 (0-10)

0.05 (0-0.25)

210

i i

i

o

E i=

f

E I-.

6) e,-

E

,o

t,,_

I:1.

13,.

85

86

87

88

89

90

9~

92

93

94

95

96

97

98

99

100

Oxygen Saturation (Percent)

0

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22

Respiratory Rate

Fig. 3. Oxygen saturations for all patients as recorded by nursing staff following return to ward.

Fig. 4. Respiratory rates for all patients as recorded by nursing staff following return to ward.

rates of 14-18 per minute. In these patients supplementary oxygen was restarted. Two patients were withdrawn from the study. One patient was returned to theatre after 14 hours for emergency splenectomy, the other was withdrawn after 17 hours when the computer system was disabled during the repositioning of an intravenous infusion. No patient was withdrawn from the study because of adverse events or inadequate analgesia. A questionnaire was distributed to nursing staff on the high dependency unit following completion of the study. The system was scored as 'very easy' to use by 89% and 11% found it 'quite difficult'. All thought it an acceptable method of providing analgesia.

those obtained from the patients. This demonstrates that alfentanil, when delivered by this infusion system, is effective for longer term pain relief for surgery recognised to be associated with a high degree of postoperative pain. The use of alfentanil patient controlled analgesia, in one study, has resulted in an unacceptably high demand frequency [4] and in another, in an inability to control pain in the immediate postoperative period [5]. A recent study by Owen and colleagues [6] using a patient controlled infusiondemand system was unsuccessful in finding a dosage regime which would provide adequate analgesia. Only 24% of patients who received alfentanil completed the 24 hour study of postoperative analgesia after upper abdominal surgery. Twenty four of the 37 patients in Owen's evaluation of PCA had inadequate analgesia and 3 were withdrawn because of respiratory depression. In our study, we had the advantage that alfentanil was administered intraoperatively and immedi-

Discussion

Alfentanil produces rapid onset of analgesia but requires an appropriate infusion regime to maintain satisfactory pain relief. Studies by Andrews and colleagues [12] and O'Conner and colleagues [13] using alfentanil infusion postoperatively have demonstrated its ability to provide excellent analgesia. These two studies were however for short periods postoperatively and involved only superficial body surgery. In our study, pain scores comparing favourably with morphine PCA [14] were recorded by the nursing staff and are supported by

Table 3. Visual analogue scores taken on the day following surgery. Values are expressed in millimetres.

Morning 'pain since yesterday evening' Evening 'pain since this morning'

Median

Range

23.5 19 12.5 11

6-49 0-34 0-29 0-41

211 ate postoperative pain was not a problem. The pharmacokinetic model incorporated in the system m e a n t that if analgesia proved to be inadequate rapid control of pain was possible by alteration of the target alfentanil level. No patients were withdrawn from the study because of unacceptable respiratory depression. In the 3 patients with respiratory rates less than 10 per minute, satisfactory oxygen saturation was maintained. Carbon dioxide tension was not measured but it has been shown that such respiratory patterns postoperatively are not associated with a significant rise [11]. In all 3 patients, low respiratory rates occurred in a twelve hour period overnight in the first postoperative 24 hours and may have been due to lack of stimulation at a time when ward activity was low. The possibility of significant respiratory depression occurring cannot however be excluded. A high d e p e n d e n c y unit was chosen to operate the system because of the high degree of supervision that could be offered and the system may not yet be suitable for use in a wider context. I m p r o v e m e n t in safety for more widespread use m a y lie with the d e v e l o p m e n t of a predictive infusion system allied to a patient controlled system with automatic plasma level reduction with time. Target plasma alfentanil concentrations required by the patients in the present study ranged from 34 to 150 nanog m1-1 which is similar to values reported in previous studies [12, 13]. Measured and predicted plasma concentrations of alfentanil showed the degree of variability which can occur with pharmacokinetic-based systems. H o w e v e r , pharmacokinetic variability must be assessed in terms of the variation in pharmacodynamics which is d e m o n s t r a t e d by the variation in patient requirements for alfentanil. The variation in target atfentanil requirements from 34-150 nanog m1-1 represents a 5-fold variation c o m p a r e d with the differences found between the m e a s u r e d and predicted plasma concentrations. T h e range of alfentanil concentrations required in our patients was narrower than that found when morphine was used to provide postoperative analgesia using P C A [14]. In this study reported by Burns and her colleagues, a 30-fold interpatient variation was found which makes prediction of the probable morphine re-

quirements for postoperative analgesia difficult. The prediction of alfentanil requirements may, from this evidence be less difficult. The Psion control system functioned satisfactorily over the course of the study and was well accepted by the nursing staff. The high quality of postoperative analgesia after m a j o r vascular surgery suggests that this method of delivering alfentanil m a y offer advantages over other reported techniques.

References

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212 pression during and after infusion of alfentanil in man. Br J Anaesth 1983; 55: 217S-22S. 14. Burns JW, Hodsman NBA, McLintock TTC, Gillies GWA, Kenny GNC, McArdle CS. The influence of patient characteristics on the requirements for postoperative analgesia. Anaesthesia 1989; 44: 2-6.

Address for offprints: G.N.C. Kenny, University Department of Anaesthesia, Royal Infirmary, 8-16 Alexandra Parade, Glasgow G43 2EF, UK