Acta Anaesthesiol Scand 1992: 36: 779-783

Clinical and metabolic responses to different kinds of premedication in ASA I11 patients 0. KIRVELAand J. H. KANTO Department of Anaesthesiology, Turku University Hospital Turku, Finland

Clinical and metabolic responses to atropine plus pethidine and to scopolamine plus morphine premedication were studied in 45 ASA physical status 111 patients undergoing gynaecological procedures. Atropine 0.5 mg plus pethidine 50 mg intramuscularly (Group I ) , scopolamine 0.24 mg plus morphine 8 mg (Group 2), or intramuscular placebo (Group 3) premedication were given in random, double-blind fashion. Scopolaminemorphine premedication caused a significant decrease in energy expenditure (EE) and oxygen consumption (To,) (from 1229 f 193 to 1184 f 221 kca1/24 h, P=0.004 and from 105 f 11 to 102 f 12 ml/min/m2,P= 0.006, respectively) simultaneously with a decrease in rate-pressure product (RPP) (P=0.0001) and an increase in pressure-rate quotient (PRQ) (P=0.034). Atropine-pethidine premedication induced a decrease in RPP but not in EE or To?.In the placebo group both RPP and vo2 first increased and then slowly returned to the levels measured prior to premedication. The RPP was significantly lower in Group 2 than in Groups 1 and 3 at both 30 and 60 min. The degrees of subjective tiredness and anxiolysis were significantly greater in Groups 1 and 2 (showing good sedative and anxiolytic effect) than in Group 3. These results show that in ASA 111 patients, atropine-pethidine premedication does not decrease the sympathoadrenal reaction to the degree its anxiolytic and sedative effect would suggest. This may indicate neuroendocrine stress induced by atropine-pethidine. Received 15 September 1991, accepted f o r publication 20 March 1992

Key words: Anesthesia, premedication; metabolism: energy expenditure, oxygen consumption; pharmacology: opioids, parasympathicolytics.

Opiates and anticholinergic agents have been used as premedication to control fear and anxiety, and to suppress the reaction to anaesthesia and surgery (1, 2). The relationships between self-reported assessments of acute preoperative anxiety and several biochemical and physiological indicators of stress reaction have been evaluated in many studies (3-9), but the metabolic effects of different types of premedication have not been as thoroughly studied. Indirect calorimetry has been used to measure metabolic needs and changes in various patient populations (10) and the compact and easy-to-use metabolic monitors (10-12) now offer an accurate and noninvasive way to measure the metabolic state of patients also in the operating room. We have previously shown in ASA I patients that the combination of atropine and pethidine results in higher levels of energy expenditure (EE) as well as oxygen consumption (00,)than diazepam premedication (13). These findings indicate that atropine plus pethidine is an iatrogenic stress factor which may be of importance in high-risk patients. Scopolamine (l-hyoscine) is another anticholinergic agent widely used as part of premedication (2, 3, 8, 14-16). It is a tertiary amine like atropine and has anti-sialogogic, sedative and amnesic effects. The present study compares the

effects of atropine plus pethidine to those of scopolamine plus morphine premedication in ASA I11 patients in terms of EE, Vo,, and cardiovascular and subjective estimates of tiredness, anxiolysis, fear and dry mouth.

PATIENTS AND METHODS Forty-five ASA I11 patients scheduled for gynaecological procedures under spinal anaesthesia were studied (Table 1). The study was approved by the Ethics Committee of Turku University Hospital and written informed consent was obtained from each patient. The patients were randomly allocated to receive one of three premedications: (a) Group 1 were given 0.5 mg of atropine and 50 mg of pethidine intramuscularly, (b) Group 2 were given 0.24 mg of scopolamine and 8 mg of morphine, and (c) Group 3 received intramuscular placebo (2 ml of NaC10.9). There were 15 patients in each group, and the study was conducted in a double-blind fashion. On the evening before operation no hypnotic medication was given. After fasting overnight, the patients received their premedication 30 min before they were transferred to the operating room. After premedication the patients remained resting supine. Upon arrival in the operating room area, patients were placed in a quiet corner of the recovery room where they remained for the entire study period. Continuous monitoring of the electrocardiogram (ECG) and heart rate (HR), together with noninvasive recording of systolic (SAP) and diastolic (DAP), and mean (MAP) arterial blood pressures (Datascope Accutor 3, Paramus NJ, USA) at 5-min intervals

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Table I Patient characteristics (mean f s.d.).

Group 1 (atropine+ pethidine) Group 2 (scopolamine+morphine) Group 3 (placebo)

Age (years)

BSA (m')

6 3 f 15 67 f 12 6 6 5 13

1.77t0.21 1.73 f 0.21 1.76t0.15

were started. Rate pressure product (RPP) was defined as SAP times H R (mmHg x beats per minute [bpm]) and pressure-rate quotient (PRQ) was defined as the MAP divided by H R (mmHg/bpm). Sao, was monitored continuously with a pulse oximeter (Satlite, Datex/ Instrumentarium, Helsinki, Finland). Ten minutes after arrival, ungraded visual analog scales (VAS) were used to collect subjective data (17) concerning fear, anxiety, tiredness and dry mouth (Table 2). After the VAS evaluation the metabolic measurements were started. Patients were resting in bed undisturbed and the lights were dimmed. The entire measurement period for metabolic parameters was 30 min. The first 10 min and the remaining 20 min were analysed separately to get a better understanding of the effects of premedication. A recently validated ( 1 1, 12) portable metabolic cart system (Deltatrac, with good overall accuracy [2* 1 % (12), 1.9% ( I I ) for oxygen consumption (Vo,) with a tidal volume of 500 ml] was used. The Deltatrac is an open system, indirect calorimetry device designed to measure Vo, and carbon dioxide production (Vco,). For the measurements the patient's head is placed under a plastic cone (canopy) connected to the analyser. The canopy is manufactured of a 1mm-thick transparent PVC plastic and has the basic geometry of a half ellipsoid. It is provided with adapters for tubings and with a wide edge of soft plastic cloth to make the construction air-tight under the head and around the neck of the patient. Minor leakages do not affect the results since they are inwards due to the slight underpressure inside the canopy because of the constant airflow (40 I/min) drawn through the canopy to the gas analysers, and thus all expired gases will be captured. The difference between inspired (sampling at the entry valve of the canopy) and expired oxygen fractions (Fro,, F E O ~is) measured with a fast-response paramagnetic differential oxygen sensor (OM-101, DatexIInstrumentarium, Helsinki, Finland). The expired C O , fraction (FEco?) is measured with an infrared CO, sensor. A microcomputer controls a set of magnetic valves for the automatic control of the absolute FIO,, FICO,, and gas analyser baselines. Vco2 is calculated as the product of the constant flow and the fraction of CO, in the diluted expiratory flow: Vco,= QX FECO,. Vo, is calculated using the Haldane transformation: Vo, = (QJ1Fro,] x (FIo,-FEo,-FIo~ x [F~co,-Frco,], where Q is the constant flow, and FEO, and FECO, the fractions of oxygen and CO, in the mixed expiratory gas flowing through the monitor. Energy expenditure (EE) is calculated from the measured rates of Vo, and bco,:

EE (kcal/day)=3.581 x Vo, (I/day)+ 1.448 x Vco, (l/day)-32.4 (10, 12). All calculations are made at I-min intervals and the results are stored for further processing. The instrument allows for real time graphics of VO,, oco,, and EE. Hard copies are obtained from an attached printer. The results of metabolic measurements were analysed separately for the first 10 min [energy expenditure ( E E I ) , oxygen consumption (Vo,I)], and for the following 20 min (EE2, V0,2). Deltatrac was calibrated before every measurement according to the procedures suggested by the manufacturer of the device. Basal Metabolic Rate (BMR) is defined as the energy expenditure of a subject at rest and at least 10 h postprandially in a thermally neutral environment (10). The Deltatrac calculates BMR by means of the empirical Harris-Benedict formula: (females) BMR=655+9.6 W + 1.8 H-4.7 A (kca1/24 h ) where W=Weight (kg), H=Height (cm), A=Age (yr) The data were analysed using the SYSTAT system (Evanston, IL, USA). Analysis of variance was performed with post-hoc comparisons by the Tukey test. Paired and unpaired analyses were also performed on appropriately grouped data. For the VAS data, Kruskal-Wallis analysis of variance with Mann-Whitney U-test was performed and Bonferroni correction was made for the P-values. A P-value of 0.05 was considered as significant.

RESULTS Demographic data (Table 1) in the three groups were similar with regard to age, and body surface area (BSA). Premedication in Groups 1 and 2 was associated with greater degrees of subjective tiredness (P= 0.004 and P= 0.0001, respectively), and anxiolysis ( P = 0.028 and P= 0.0001, respectively) than placebo as measured by VAS (Table 2). The patients in Group 3 felt more fear than those in Groups 1 and 2 (P=O.O22 and P= 0.0001, respectively). The degrees ofsubjective tiredness and anxiolysis were greater in Group 2 than in Group 1 (P=O.O31 for tiredness and P=0.002 for anxiolysis). The patients in Group 1 experienced more subjective fear than patients in Group 2 (P=O.OOl). Dry mouth was more frequent and severe in Groups 1 and 2 than in Group 3 (P=O.O02 and P=O.O27). There were no differences between the groups in heart rate or blood pressures or R P P or PRQprior to premedication (Table 3). At the time of VAS evaluation (40min after premedication) patients in Group

Table 2 Subiectively estimated tiredness, anxiety and fear, and dry mouth. ~~

~~

Group 1 (atropine+ pethidine) Group 2 (scopolamine+ morphine) Group 3 (placebo)

Tiredness

Anxiety

Fear

Dry mouth

30 )15-75)" 60 (10-90)h 15 (1-30)'

20 (IO-70)d 10 (5-40)' 40 (5-80)'

15 (10-50)g 10 (5-30)h 40 ( 10-80)'

70 (30-90)' 70 (10-90)' 20 (0-75)'

a < b , P=0.031; a > c , P ~ 0 . 0 0 4 b; > c , e e , j > l , P=0.002; d < f , P=0.028; g > h , P = O . O O l ; g < i , P=0.022; k > l , P=0.027. Tiredness, as mm on a 100-mm-long ungraded visual analog scale: 0 =fully alert, 100 =asleep; anxiety and fear, 0 = not at all, 100 =worst possible; dry mouth, 0 =normal, 100= intolerable. All values are given as medians (range).

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METABOLIC RESPONSE TO PREMEDICATION Table 3 Cardiovascular responses*. ~~~~~

RPPl (mmHg x bpm Group 1 2 3

x

11.4f2.6 1O.Of l.gd 11.7 5 2.6

~

RPPS (mmHg x bpm x 10-3)

RPPS (mmHg x bpm 10-3)

PRQl (mmHg/bpm)

PRQ2 (mmHg/bpm)

PRQ3 (mmHg/bpm)

Sao,

11.7 f 3.7" 8. I f 2.5' 12.8 f 3.9'

10.3 f 2.7b 7.3 f 2.8' 11.3 f 2 . 9

1.29 f 0.19 1.27 + 0.188 1.43 + 0.29

1.19fO.19' 1.45 f 0.30h 1.39 k 0.32

1.19 f 0.26 1.42 f 0.36 1.41 kO.29

95 k 2 94+3 96f2

(YO)

a > e , P=0.02; a > b , d > e , P=O.O1; b>f, P=0.012; e < i , P=0.002; c < h , P=0.038; f f , P=0.003; e > f , P=O.OOOl; i>j, P=0.017, j < h , P=0.034. *Rate-pressure product (RPP), and pressure-rate quotient (PRQ in the morning before premedication (RPP1, PRQl), 40 min after premedication (RPP2, PRQ2), and 70 min after premedication (RPP3, PRQ3). Sao, is the lowest oxygen saturation level during the study period. All values as mean f s.d.

2 had statistically significantly lower levels of RPP than patients in Group 1 (P=O.O12) and Group 3 ( P = 0.002). At the end of the metabolic measurements (70 min after premedication), RPP levels remained lower in Group 2 than in Group 1 (P=0.012) and in Group 3 (P=O.OOl) (Table 3). I n Group 2 the RPP decreased significantly from the premedication levels (from 10.0 & 1.9 mmHg * beats/min x to 8.1 k 2.5 mmHg x beats/min x at 40 min, and to 7.3 f 2.8 mmHg x beatslmin x at 70 rnin after premedication; P=O.Ol and P=0.003, respectively). The pressure-rate quotient ( P R Q was significantly lower in Group 1 than in Group 2 after premedication (P= 0.038). The premedication in Group 2 caused a significant rise in P R Q ( P = 0 . 0 3 4 ) . There were no differences in the Sao,-levels between the groups. The calculated (for weight, height, and age) BMR values did not differ significantly between the three groups (Table 4),showing a successful randomization also in this respect. In Groups 2 and 3 energy expenditure decreased significantly during the 30-min measurement period (P=0.004 and P=O.OOl, respectively). fro, decreased significantly during the metabolic measurement period in Groups 2 and 3 (P= 0.006 for Group 2, and P=O.O03 for Group 3). Interestingly, in Group 2 the measured energy expenditures (EE1 and EE2) were significantly lower than the predicted BMR (P=O.Ol and P=O.OOl, respectively). No significant correlation was found between VAS

data and cardiovascular or metabolic data in any of the groups (by Pearson correlation matrix).

DISCUSSION Premedication with i.m. atropine plus pethidine or scopolamine plus morphine produced a greater subjective sense of tiredness with a significantly better anxiolysis than did placebo. The subjective VAS estimates of patients given scopolamine plus morphine indicate a better anxiolysis and sedative effect compared to atropine plus meperidine. This difference was not unexpected since scopolamine is known to have more pronounced central effects than atropine (16, 17). Whether the better anxiolytic and sedative effects explain the more pronounced cardiovascular effects of scopolamine plus morphine is not clear from these data. However, there was no significant correlation between the VAS data and cardiovascular response. The metabolic measurement was divided into two periods. The first 10 min served as an adaptation period. When normal non-sedated subjects are first placed under the canopy, Vo, and OCO,are somewhat increased and then decrease over 5 to 15 min to a fairly stable plateau ( l o ) , which was the case in the placebo group. Since body 0, stores are small compared to 002, an increase in VO, represents an increase in tissue 0, consumption. Thus, the values for the first

Table 4 Results of metabolic measurements*.

BMR Group I (atropine+ pethidine) Group 2 (scopolamine+ morphine) Group 3 (placebo)

1349 f 220 1306 f 188" 1329f 120'

EEI 1359 f 366 1229 f 194b 1437 f 250g

EE2

v o 21

v0,2

1325 f 327 1 184 f 221' 1366f218h

112f 18 106 + 1 I d I19 + 16'

109+ 18 102* 12' 113k 1 %

a > b , P=O.Ol; a > c , g > h , P=O.OOl; b>c, P=0.004; d z e , P=0.006; fj, P=0.003. *Energy expenditure as measured for the first 10 min of the measurement period (EEI, kca1/24 h ) and for the following 20 min (EE2, kcal/ 24 h), predicted basal metabolic rate (BMR, kca1/24 h), oxygen consumption (ml x min-' x m-') for the first 10 rnin ( V O , ~and ) for the following 20 rnin ( V O , ~ )All . values are mean f s.d.

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10 min reflect the anxiolytic and sedative effects of premedication. However, the better anxiolytic effect of scopolamine plus morphine in comparison with atropine plus pethidine may be of minor importance with respect to the metabolic response. BMR, after an overnight sleep, is remarkably constant for normal subjects of similar age, height, weight and sex. In this study the patients were of ASA physical status 111, a fact that to some degree may decrease the reliability of the Harris-Benedict equation. However, there was no difference between the groups in this respect. The observation that the EE1 values (30 min after premedication) in Group 2 were significantly lower than the estimated BMR values suggests a rapid and profound effect of scopolamine plus morphine on metabolic rate. Both energy expenditure and oxygen consumption decreased over the entire study period in Group 2, while there was no change in these values in Group 1. Accordingly, the significantly decreased energy expenditure values with scopolamine plus morphine premedication indicate a favourable effect on metabolic response to stress. Atropine plus pethidine premedication did not decrease the metabolic demands to the degree that the anxiolytic and sedative effects would suggest. This can be explained either by fear (indicating absence of anxiolysis) or by a pharmacologic effect, or both. Both atropine and pethidine have significant anticholinergic actions and, originally, pethidine was studied as an atropine-like agent (18). Thus the combination of atropine plus pethidine may change the balance between the sympathetic and parasympathetic nervous system more than other generally used premedicants (2, 14-19), and therefore a sympathoadrenal reaction may be the best explanation for our findings of elevated metabolic activity. The changes in both RPP and RPQsupport this view. It appears that the neuroendocrine stress induced by atropine plus pethidine is rather a high cost for the sedative and/or anxiolytic effect achieved. Although myocardial oxygen consumption represents only 10-15% of the total body oxygen consumption (20), it may be critical in patients with poor coronary reserve. PRQis a good indicator for myocardial ischaemia (21). Although the P R Q d i d not reach the critical value of 1.0, the PRQvalues in Group 1 were significantly lower than those in Group 2. It should be noted that the P R Q values in Group 2 increased significantly after premedication. Accordingly, use of premedications causing increased EE rates and thus increased fro, values should be reconsidered in cardiac-compromised patients and, if an anticholinergic agent is needed, atropine may not be the first choice.

In conclusion, our results show that the metabolic effects of premedication should be borne in mind. Premedication with atropine plus pethidine does not decrease oxygen consumption as a n effective premedication should, while scopolamine plus morphine premedication attenuates the metabolic response to preoperative stress.

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METABOLIC RESPONSE T O PREMEDICATION 19. Kanto J. New aspects in the use of atropine. I n t J Clin Phanacol Ther Toxic01 1983: 21: 92-94. 20. Finch C E, Lenfant C. Oxygen transport in man. N Engl J Med 1972: 286: 407-415. 21. Shiraki H, Lee S, Hong Y, et al. Diagnosis ofmyocardial ischemia by the pressure-rate quotient and diastolic time interval during coronary artery bypass surgery. J Cardiothorac Anesth 1989: 3: 592-596.

Address: ONi Kirvela, M. D., Ph. D. Department of Anaesthesiology Turku University Hospital Kiinamyllynkatu 4-8, SF-20520, Turku Finland

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