Br.J. Anaesth. (1979), 51, 359
LABETALOL IN CONTROLLED HYPOTENSION Administration of labetalol when adequate hypotension is difficult to achieve D. H. P. COPE AND M. C. CRAWFORD SUMMARY
The introduction of halothane (Johnstone, 1956; Raventos, 1956) greatly facilitated the attainment of controlled hypotension during anaesthesia (Payne, 1963; Prys-Roberts et a l , 1974). Its use with tubocurarine and controlled ventilation is now widely practised to reduce blood loss during major surgery, and in those operations where even a small amount of bleeding mitigates against a successful operative result, for example, middle ear surgery. Nevertheless, there are a number of patients in whom this technique fails to produce adequate hypotension unless an undesirably high concentration of halothane is administered. In these circumstances, a ganglion blocking agent such as hexamethonium bromide (Walther, Slack and Chew, 1964) or trimetaphan (Hellewell and Potts, 1966) may be used in addition to gain the desired hypotension. However, these drugs are not entirely satisfactory; tachyphylaxis occurs and undesirable tachycardia is often induced. Propranolol (Hellewell and Potts, 1966; Hewitt, Lord and Thorton, 1967; Enderby, 1974) has been used to combat the increase in heart rate, but it is at the expense of an appreciable decrease in cardiac output (Prichard et al., 1975). Furthermore, hexamethonium has a prolonged duration of action so that, if the operation finishes earlier than expected, the arterial pressure may not be increased readily to a value at which obvious bleeding may be controlled unless vasopressor drugs are given. Sodium nitroprusside (Bascombe and Lewis, 1968; Taylor, Styles and Lamming, 1970; Macrae, 1971; Griffiths et al., 1974) is an alternative hypotensive agent but it too may produce tachycardia D. H. P. COPE, M.B., B.S., F.F.A.R.C.S., D.A. ; M. C. CRAWFORD,
M.B., CH.B., D.A.; Anaesthetic Department, The Middlesex Hospital, Mortimer Street, London Wl. 0007-0912/79/04O359-O7 §01.00
(Moraca et al., 1962; Wildsmith et al., 1973). It is potentially toxic in that it produces a metabolic acidosis (Macrae and Owen, 1974) which may be lethal (Jack, 1974; Merrifield and Blundell, 1974). This acidosis occurs when large doses are given because of resistance or tachyphylaxis. Patients in whom controlled hypotension is difficult to produce during surgery include younger patients with high sympathetic tone, anxious patients with tachycardia and those for whom halothane is contraindicated. The introduction of labetalol (Boakes, Knight and Prichard, 1971; Richards et al., 1974), a combined alpha- and beta-adrenoceptor antagonist, in the medical treatment of hypertension was described by Prichard and others (1975) and Rosei and others (1975). It seemed that this drug might be pharmacologically useful for the production of controlled hypotension during anaesthesia in the types of patient described above. The alpha-adrenoceptors of the capacitance vessels may be blocked with resultant vasodilatation, and a reflex increase in heart rate and cardiac output may be prevented by the simultaneous blocking of the beta-receptors. Scott and others (1978) have investigated its use in anaesthesia for induced hypotension with halothane. We describe the use of labetalol in 50 patients in the above categories. PHARMACOLOGY AND METABOLISM
Labetalol hydrochloride (fig. 1) is an amide with competitive alpha- and beta-adrenoceptor antagonist properties (Richards, 1976). Compared with propranolol, the $x antagonist effects are four to six times less potent on a weight basis and the (32 (bronchial and vascular) blocking © Macmillan Journals Ltd 1979
Downloaded from http://bja.oxfordjournals.org/ at UB der LMU Muenchen on June 21, 2014
A study of controlled hypotension was undertaken in 50 major surgical patients using labetalol, a drug with both alpha- and beta-adrenoceptor blocking activity. The patients were such that difSculty in achieving controlled hypotension could be anticipated: the young, the anxious and those for whom halothane was contraindicated. The administration of labetalol quickly induced hypotension which was controlled easily and was rapidly antagonized.
BRITISH JOURNAL OF ANAESTHESIA
360
TABLE I.
OH
CH
3 FIG. 1. Structure of labetalol.
/>
HCI
PATIENTS AND TECHNIQUE
The average age of the patients was 40.9 yr (range 9-77 yr). If those to whom halothane was not administered are extracted, the average age was 38.8 yr. There were 29 males and 21 females. The operations in the study are shown in table I. All patients recieved i.m. premedication 1 h before surgery (table II). Anaesthesia was induced with thiopentone 2.5% solution, the average dose being 360 mg and in most instances (46) the trachea was intubated following suxamethonium i.v. In 29 patients the lungs were ventilated manually with nitrous oxide 3 litre and oxygen 1.5 litre. A Manley ventilator was used for 15 patients and six breathed spontaneously. Halothane was introduced in increasing concentration up to 2% and, as soon as there was evidence of
Operation
No. of patients Total
Total hip replacement Pin and plate Pin and plate, osteotomy Girdlestone
12 2 1 1
16
Lumbo-sacral laminectomy Lumbo-sacral fusion Cervical fusion
10 4 2
16
Other Putti Platt operation orthopaedic Hindquarter amputation Disarticulation hip Replacement elbow + humerus
2 1 1 1
5
Nasal
Excision naso-pharyngeal angiofibroma Rhinoplasty +septoplasty Ethmoidectomy Hypophysectomy Excision biopsy cyst under eye
1 1 1 1 1
5
Myringoplasty Mastoidectomy
4
Laryngectomy Block dissection neck Parotidectomy
1 1 1
3
Abdominoperineal resection
1
1
Hip
Spinal
Ear Neck
General
TABLE II.
Types of premedication
No. of patients
Pethidine, promethazine, hyoscine Physeptone, promethazine, hyoscine Papaveretum, hyoscine Papaveretum, perphenazine, hyoscine Papaveretum, promethazine, hyoscine Pethidine, promethazine, atropine Pethidine, perphenazine, hyoscine
39 3 2 2 2 1 1
muscle tone returning, tubocurarine 30 mg was given i.v. where necessary. The patients were transferred to the operating table and positioned for the operation. Arterial pressure measurements were made using the Von Recklinghausen oscillotonometer. We aimed to maintain arterial systolic pressure of 60-80 mm Hg during controlled hypotension. If it appeared that young or anxious patients would require more than 1 % halothane to achieve this level then labetalol was administered.
Downloaded from http://bja.oxfordjournals.org/ at UB der LMU Muenchen on June 21, 2014
effects are 11-17 times less potent. The alphaantagonist effects are seven times less potent in comparison with phentolamine. Overall, the betablocking effects of labetalol are seven times as potent as the alpha-blocking effects. Metabolism in man (Martin, Hopkins and Bland, 1976) is mainly associated with the first pass effect through the liver. Thus labetalol is metabolized to a greater extent following oral administration than when given i.v. The major glucuronide metabolite is as yet unidentified but a minor one already identified is O-phenylglucuronide. Both metabolites are found to have mild alpha- and beta-antagonist effects. About 50% of labetalol is protein-bound. The major sites in the body where labetalol is found include the lungs, liver and kidneys. Labetalol is less lipophilic than propranolol or oxprenolol and virtually none has been found in brain tissue, whereas the other two drugs have been found in considerable quantities (Riess et al., 1970; Baker and Foulkes, 1973). This suggests that labetalol has probably only minimal central effects if any. Sixty per cent of the metabolic products of labetalol are excreted in the urine and 40% in the faeces. Five per cent of that found in the urine is in the unchanged form. The half-life of elimination in man is 3.5-4.5 h (Martin, Hopkins and Bland, 1976).
Type of surgery
to to
CH CH2NHCH CH2 CH 2 —
LABETALOL IN CONTROLLED HYPOTENSION Administration of labetalol when adequate hypotension is difficult to achieve D. H. P. COPE AND M. C. CRAWFORD SUMMARY
The introduction of halothane (Johnstone, 1956; Raventos, 1956) greatly facilitated the attainment of controlled hypotension during anaesthesia (Payne, 1963; Prys-Roberts et a l , 1974). Its use with tubocurarine and controlled ventilation is now widely practised to reduce blood loss during major surgery, and in those operations where even a small amount of bleeding mitigates against a successful operative result, for example, middle ear surgery. Nevertheless, there are a number of patients in whom this technique fails to produce adequate hypotension unless an undesirably high concentration of halothane is administered. In these circumstances, a ganglion blocking agent such as hexamethonium bromide (Walther, Slack and Chew, 1964) or trimetaphan (Hellewell and Potts, 1966) may be used in addition to gain the desired hypotension. However, these drugs are not entirely satisfactory; tachyphylaxis occurs and undesirable tachycardia is often induced. Propranolol (Hellewell and Potts, 1966; Hewitt, Lord and Thorton, 1967; Enderby, 1974) has been used to combat the increase in heart rate, but it is at the expense of an appreciable decrease in cardiac output (Prichard et al., 1975). Furthermore, hexamethonium has a prolonged duration of action so that, if the operation finishes earlier than expected, the arterial pressure may not be increased readily to a value at which obvious bleeding may be controlled unless vasopressor drugs are given. Sodium nitroprusside (Bascombe and Lewis, 1968; Taylor, Styles and Lamming, 1970; Macrae, 1971; Griffiths et al., 1974) is an alternative hypotensive agent but it too may produce tachycardia D. H. P. COPE, M.B., B.S., F.F.A.R.C.S., D.A. ; M. C. CRAWFORD,
M.B., CH.B., D.A.; Anaesthetic Department, The Middlesex Hospital, Mortimer Street, London Wl. 0007-0912/79/04O359-O7 §01.00
(Moraca et al., 1962; Wildsmith et al., 1973). It is potentially toxic in that it produces a metabolic acidosis (Macrae and Owen, 1974) which may be lethal (Jack, 1974; Merrifield and Blundell, 1974). This acidosis occurs when large doses are given because of resistance or tachyphylaxis. Patients in whom controlled hypotension is difficult to produce during surgery include younger patients with high sympathetic tone, anxious patients with tachycardia and those for whom halothane is contraindicated. The introduction of labetalol (Boakes, Knight and Prichard, 1971; Richards et al., 1974), a combined alpha- and beta-adrenoceptor antagonist, in the medical treatment of hypertension was described by Prichard and others (1975) and Rosei and others (1975). It seemed that this drug might be pharmacologically useful for the production of controlled hypotension during anaesthesia in the types of patient described above. The alpha-adrenoceptors of the capacitance vessels may be blocked with resultant vasodilatation, and a reflex increase in heart rate and cardiac output may be prevented by the simultaneous blocking of the beta-receptors. Scott and others (1978) have investigated its use in anaesthesia for induced hypotension with halothane. We describe the use of labetalol in 50 patients in the above categories. PHARMACOLOGY AND METABOLISM
Labetalol hydrochloride (fig. 1) is an amide with competitive alpha- and beta-adrenoceptor antagonist properties (Richards, 1976). Compared with propranolol, the $x antagonist effects are four to six times less potent on a weight basis and the (32 (bronchial and vascular) blocking © Macmillan Journals Ltd 1979
Downloaded from http://bja.oxfordjournals.org/ at UB der LMU Muenchen on June 21, 2014
A study of controlled hypotension was undertaken in 50 major surgical patients using labetalol, a drug with both alpha- and beta-adrenoceptor blocking activity. The patients were such that difSculty in achieving controlled hypotension could be anticipated: the young, the anxious and those for whom halothane was contraindicated. The administration of labetalol quickly induced hypotension which was controlled easily and was rapidly antagonized.
BRITISH JOURNAL OF ANAESTHESIA
360
TABLE I.
OH
CH
3 FIG. 1. Structure of labetalol.
/>
HCI
PATIENTS AND TECHNIQUE
The average age of the patients was 40.9 yr (range 9-77 yr). If those to whom halothane was not administered are extracted, the average age was 38.8 yr. There were 29 males and 21 females. The operations in the study are shown in table I. All patients recieved i.m. premedication 1 h before surgery (table II). Anaesthesia was induced with thiopentone 2.5% solution, the average dose being 360 mg and in most instances (46) the trachea was intubated following suxamethonium i.v. In 29 patients the lungs were ventilated manually with nitrous oxide 3 litre and oxygen 1.5 litre. A Manley ventilator was used for 15 patients and six breathed spontaneously. Halothane was introduced in increasing concentration up to 2% and, as soon as there was evidence of
Operation
No. of patients Total
Total hip replacement Pin and plate Pin and plate, osteotomy Girdlestone
12 2 1 1
16
Lumbo-sacral laminectomy Lumbo-sacral fusion Cervical fusion
10 4 2
16
Other Putti Platt operation orthopaedic Hindquarter amputation Disarticulation hip Replacement elbow + humerus
2 1 1 1
5
Nasal
Excision naso-pharyngeal angiofibroma Rhinoplasty +septoplasty Ethmoidectomy Hypophysectomy Excision biopsy cyst under eye
1 1 1 1 1
5
Myringoplasty Mastoidectomy
4
Laryngectomy Block dissection neck Parotidectomy
1 1 1
3
Abdominoperineal resection
1
1
Hip
Spinal
Ear Neck
General
TABLE II.
Types of premedication
No. of patients
Pethidine, promethazine, hyoscine Physeptone, promethazine, hyoscine Papaveretum, hyoscine Papaveretum, perphenazine, hyoscine Papaveretum, promethazine, hyoscine Pethidine, promethazine, atropine Pethidine, perphenazine, hyoscine
39 3 2 2 2 1 1
muscle tone returning, tubocurarine 30 mg was given i.v. where necessary. The patients were transferred to the operating table and positioned for the operation. Arterial pressure measurements were made using the Von Recklinghausen oscillotonometer. We aimed to maintain arterial systolic pressure of 60-80 mm Hg during controlled hypotension. If it appeared that young or anxious patients would require more than 1 % halothane to achieve this level then labetalol was administered.
Downloaded from http://bja.oxfordjournals.org/ at UB der LMU Muenchen on June 21, 2014
effects are 11-17 times less potent. The alphaantagonist effects are seven times less potent in comparison with phentolamine. Overall, the betablocking effects of labetalol are seven times as potent as the alpha-blocking effects. Metabolism in man (Martin, Hopkins and Bland, 1976) is mainly associated with the first pass effect through the liver. Thus labetalol is metabolized to a greater extent following oral administration than when given i.v. The major glucuronide metabolite is as yet unidentified but a minor one already identified is O-phenylglucuronide. Both metabolites are found to have mild alpha- and beta-antagonist effects. About 50% of labetalol is protein-bound. The major sites in the body where labetalol is found include the lungs, liver and kidneys. Labetalol is less lipophilic than propranolol or oxprenolol and virtually none has been found in brain tissue, whereas the other two drugs have been found in considerable quantities (Riess et al., 1970; Baker and Foulkes, 1973). This suggests that labetalol has probably only minimal central effects if any. Sixty per cent of the metabolic products of labetalol are excreted in the urine and 40% in the faeces. Five per cent of that found in the urine is in the unchanged form. The half-life of elimination in man is 3.5-4.5 h (Martin, Hopkins and Bland, 1976).
Type of surgery
to to
CH CH2NHCH CH2 CH 2 —
