Comparison of two benzodiazepines for anaesthesia induction: midazolam and diazepam

NH-- CH) 0 0 J .G. REVES, GUENTER CORSSEN, AND CLIFFORD HOLCOMB 1 Presented in part at the Annual Meeting of the American Society of Anaesthesiologists at New Or- leans , October 1977. J.G. Reves, M.D., Associate Professor, Guenter Corssen, M.D., Professor, and Clifford Holcomb, M.D. , Assistant Professor. Department of Anaes- thesiology, University of Alabama Medical Center , Birmingham, Alabama 35294. Reprint requests to Dr. J.G. Reves Ro 21-3981 OR MIDAZOLAM MALEATE is a benzodiazepine derivative closely related to diazeDam. The structural formulae of Ro 21-3981 and of three other c o m m o n l y used b e n z o d i a z e p i n e 6~H~ Chlordiozepolldr { Librium ) patients agreed to receive d i a z e p a m 0.3 mg/kg and serve as a comparison group. All patients c a m e to the operating room unpremedicated. The standard lead Ii electr0cardiogram was monitored continuously and blood pressure was measured every minute by the Riva-Rocci method. A metal Butterfly ~ needle was placed into a vein on the d o r s u m o f the hand* for injection of the anaesthetic drug. The patients were divided into four groups o f t e n patients each according to drug and dosage (Table I). Each Group I Group II Group III Group ]V TABLE I RO zi-39al FIGURE 1. Structural formulae of three commonly used benzodiazepine derivatives and the newly synthesized water soluble compound, Ro 21-3981. - 0.10 mg/kg 0.15 mg/kg 0.20 mg/kg 0.30 mg/kg drugs are shown in Figure 1. The major difference b e t w e e n the physical properties o f Ro 21-3981 and diazepam is that Ro 21-3981 is water soluble, w h e r e a s diazepam is not. Because of its water solubility and o t h e r pharmacological properties c o m m o n to the b e n z o d i a z a p i n e s , Ro 21-3981 is a promising drug for induction of anaesthesia. The purpose o f this clinical investigation was to estabtish the effective sleep dose o f Ro 21-3981 and to c o m p a r e it with d i a z e p a m 0.3 mg/kg. M E T H O D S Thirty patients o f A S A status I or II scheduled for elective surgical p r o c e d u r e s were selected tbr study. The patients were informed of the possible risks associated with Ro 21-3981 and agreed to participate in the investigation. Ten additional agent was given o v e r 15 s e c o n d s and flushed in with an infusion o f 50 ml of five per c e n t d e x t r o s e in water. Patients breathed r o o m air until after induction, w h e n ventilation was assisted with 100 per c e n t oxygen. Induction o f anaesthesia was defined as c o m p l e t e with loss o f lid reflex and failure to r e s p o n d to oral c o m m a n d s . The n u m b e r of patients in each group and the time required for induction were recorded. T h e patients were observed for signs of pain with injection o f the drugs and graded according to a scale o f increasing severity : 0 = none; I = slight; 2 = m o d e r a t e ; 3 = severe. Post-operative visits were m a d e for three d a y s to e x a m i n e the injection site and to ascertain the patients' subjective evaluation o f injection pain, if any. Signs o f v e n o u s irritation were graded according to increasing severity on a scale o f 0 to 3 and patients graded the severity o f burning pain on injection o f the a n a e s t h e t i c on a scale of I to 3. T h o s e patients who had undergone anaesthesia in the past were asked to c o m p a r e the induction with their previous anaesthetic experie n c e s as either the same, better, or worse. *Two patients in Group I did not have the metal needle, and received fluids and subsequent drugs through the same plastic cannula. CANADIAN ANAESTHETISTS' SOCIETY JOURNAL DEMOGRAPHICDATA OF PATIENTS No significant difference in any category. Mean age T h e p e r t i n e n t d e m o g r a p h i c d a t a c o n c e r n i n g the s u b j e c t s are g i v e n in T a b l e I1 a n d s h o w no d i f f e r e n c e b e t w e e n the g r o u p s as far as s e x , age, RELATION OF DRUG AND DOSAGE TO EFFEC'rlVENE~ AND TIME OF INDUCTION Per cent induced TABLE Ill 153 4- 14.5 107 _+ 19.1 weight, d u r a t i o n o f a n a e s t h e s i a or history of previous a n a e s t h e s i a are c o n c e r n e d . T h e effectiven e s s o f R o 21-3981 and d i a z e p a m for i n d u c t i o n is s h o w n in T a b l e III w h e r e the s u c c e s s o f induction is directly related to d o s a g e a n d time of induction i n v e r s e l y related to dosage. M e a n time o f induction w a s 80 -+ 8.6 s e c o n d s for the t e n patients in G r o u p III, significantly P < 0.05) less t h a n for G r o u p I in w h o m a n a e s t h e s i a w a s i n d u c e d with a m e a n time of 153 - 14.5 s e c o n d s in three patients. T h e r e w a s no significant d i f f e r e n c e in induction t i m e s b e t w e e n G r o u p s Ii, III, a n d IV. T h e c o m p a r i s o n of objective and subjective pain s c o r e s on induction is s h o w n in Table IV along with post-operative s e v e r i t y o f vein and tissue irritation a n d the p a t i e n t s ' c o m p a r i s o n o f a n a e s t h e t i c e x p e r i e n c e s . T h e r e w a s a d o s e related i n c r e a s e in pain in patients r e c e i v i n g Ro 21-3981, but significantly (P < 0.05) less t h a n t h a t e n c o u n t e r e d with d i a z e p a m . T h e r e w a s no differe n c e in vein irritation or phlebitis a m o n g t h e *P < 0.05 Group llI vs Groups I and II 1"P < 0.05 Group IV vs Groups I and IL 0.3 4- 0.15 0.5 4- 0.27 0.5 + 0.27 0 . 5 + 0 . 2 2 0.5 _+ 0.17 0.2 _+ 0.13 1.55--+0.17 0 . 8 ~ - + 0 . 2 5 Comparison with previous anaesthesia (per cent) groups. The two patients in Group [ who received multiple drugs and other fluids had some mild signs of tissue irritation consistent with extravenous infiltration. One patient each in Groups III and IV had evidence of mild venous and tissue irritation at the injection site. Patient acceptance was high (over 60 per cent) in Groups 1I, 111,and IV; and unfavourable responses coincided with patients who had the greatest degree of discomfort on injection of the drugs. The benzodiazepines have common properties of sedation, hypnosis amnesia, anticonvulsant, and muscle relaxation.~ As a class of drugs they are used as premedicants, 2 anaesthesia induction ,agents~ and adjuvants in neuroleptanaesthesia. + Of the benzodiazepine derivatives, diazepam has been used most frequently for induction of anaesthesia. It has minimal effects on the cardiovascular systemfl causes some respiratory depression, 6 but is a suitable induction agent particularly in patients with ischaemic heart disease in whom there is evidence that coronary blood flow is maintained or increased. 7,s A major disadvantage ofdiazepam is its insolubility in water, which necessitates the aqueous preparation in a vehicle of organic solvents which may irritate the vein and cause pain on injection. The synthesis of Ro 21-3981 produced a benzodiazepine that is water soluble, yet is still closely related to diaz (...truncated)