Abstract: Nifedipine does not usually provoke cardiac failure in man' despite having a negative inotropic effect on isolated heart muscle. On the other hand, nifedipine treatment may help patients with heart failure because it reduces after-load.2 3 Nifedipine, however, brought on heart failure in a patient with fixed outflow tract obstruction4 in whom after-load could not be reduced. We report on a patient who developed pulmonary oedema after nifedipine treatment in the absence of a fixed outflow tract obstruction.

Abstract: Summary The author's first 500 caudal anaesthetics in children up to the age of 10 years are reviewed. Emphasis is laid upon sedation, both by premedication and by the anaesthetic technique. Nearly all the children were anaesthetised briefly for the sacral injection. Despite high levels of blockade, cardiovascular stability was well maintained, particularly in the younger children. There was a good correlation between volume of injection per unit of body weight and level of blockade. Dosage can be calculated on this basis for operations on the perineum, lower limb and groin with 97 to 98% confidence. The volume of solution appeared to be more important than its concentration in determining extent of blockade.

Abstract: The modifying effect of anesthetic procedures on the endocrine-metabolic response to surgery is reviewed. Administration of intravenous or volatile agents in normal “low” doses has no major effect on endocrine-metabolic parameters in themselves or on the surgically induced metabolic changes. In contrast, “high-dose” opiate anesthesia or administration of volatile agents at high minimum alveolar concentration (MAC) values suppress the intraoperative endocrine-metabolic response to surgery but without a persistent effect on postoperative responses or on nitrogen balance. Regional anesthesia prevents a predominant part of the endocrine-metabolic response to surgery, and postoperative nitrogen balance is improved. This inhibitory effect of neurogenic blockade (combined afferent blockade of stimuli from the surgical area and blockade of efferent pathways to the adrenal medulla) on the surgically induced endocrine-metabolic changes is most consistent during lower abdominal surgery and operations on the lower extremities. During upper abdominal surgery, regional anesthesia has a lesser modifying influence on the stress response, probably because of insufficient afferent blockade. Epidural administration of opiates has no influence on the intraoperative stress response, but partially inhibits the normal postoperative increase in plasma cortisol and glucose. Posttraumatic application of regional anesthesia prevents further amplification of the stress response. Future studies should consider the influence of regional anesthesia on the stress response during major abdominal surgery, the relative importance of sensory analgesia versus blockade of sympathetic afferent and efferent pathways. Existing data should lead to randomized clinical studies on the effect of regional anesthesia on postoperative morbidity, based upon the hypothesis that inhibition of the surgically induced endocrine-metabolic response will reduce postoperative morbidity.

Abstract: In a prospective double-blind clinical study, single-dose lumbar epidural blockade was instituted in 60 healthy patients undergoing lower abdominal surgery. Patients were randomly assigned to one of five groups. Each group received treatment with a different local anesthetic solution containing 1:200,000 epinephrine. Local anesthetic solutions used were 0.5 per cent bupivacaine HCl, 2 per cent lidocaine HCl, and lidocaine-bupivacaine mixtures in the ratios of 1:3, 1:1 or 3:1 by volume. Onset and complete spread of sensory blockade were similar in all five groups. Time to regression to two segments of partial and complete sensory blockade was positively correlated (P less than 0.05) with increasing dose of bupivacaine in the solutions and ranged from 84 min (partial) and 70 min (complete) for lidocaine, to 128 min (partial) and 101 min (complete) for bupivacaine. Using skin temperature as a criterion of sympathetic blockade, all three mixtures demonstrated a duration of action intermediate between the two single drugs, lidocaine (124 +/- 13 min) and bupivacaine (286 +/- 32 min). Onset of complete motor blockade was fastest and the degree of motor blockade was most profound with the mixture containing equal proportions of lidocaine and bupivacaine. Pharmacokinetics of individual drugs were unaltered in any of the mixtures.

Abstract: Perivascular axillary block was performed on 80 patients by a catheter technique. All patients had a standard dose of 40 ml mepivacaine 1% with adrenaline. Thirty minutes after the injection, the motor and sensory blockade was determined. Eighty-six per cent of the patients had a distinct motor blockade, whereas the remaining 14% had only a slight motor blockade. The sensory blockade was complete in 63%, whereas 37% had lack of analgesia in one or several cutaneous areas. Lack of analgesia was most often found in the cutaneous area of the axillary, musculocutaneous and radial nerves. The frequency of analgesia in the three areas of innervation was analysed with reference to the influence of the age, height and weight of the patient, and of differences in technique: paraesthesias, position of catheter, and unintended puncture of blood vessels. None of these variables seems to be important for the low frequency of analgesia in the three areas of innervation.

Abstract: THE INCREASING USE of calcium-entry blocking agents requires that their pharmacologic interaction with other cardiovascular drugs be carefully investigated. Although marketed in this country for its antiarrhythmic properties, verapamil is a potent dilator of vascular smooth muscle and has proved effective in the management of stable angina pectoris, both alone'13 and in combination with f3-adrenergic blocking agents.4' In vitro studies have shown that verapamil has significant negative inotropic, chronotropic and dromotropic effects.6 Clinical studies in patients with wellpreserved ventricular function have documented reflex sympathetic stimulation in response to vasodilation that usually compensates for any expected depression of left ventricular performance.7 8 However, verapamil has produced marked depression of left ventricular function in patients with poor left ventricular function.9 Beta-adrenergic blocking drugs also have negative chronotropic and dromotropic properties, as well as potentially negative inotropic properties. Although these effects are similar to those of the calcium blockers, their pharmacologic site of action is different. At the cellular level, calcium-entry blockers uncouple excitation-contraction, whereas 3-adrenergic blockers competitively antagonize the f-adrenergic membrane receptor. There is legitimate concern about the potential deleterious effects of combination of these independently useful antianginal therapies. Addition of a 3-adrenergic blocking drug may blunt the reflex f-adrenergic stimulation that occurs with calcium-entry blockers, thereby unmasking the latter drug's myocardial depressant effect. Two articles published in the current issue1'O 11 assess the effect of combined 3-adrenergic and calcium-entry blockade on left ventricular performance. Kieval and associates'0 studied patients with well-preserved left ventricular function (mean ejection fraction 59.9 ± 11.2%) who were receiving maintenance doses of oral propranolol (plasma range 65.7-81.7 ng/ml). After left ventriculography, the patients were given short infusions of i.v. verapamil, and standard hemodynamic variables and several determinants of left ventricular function were assessed. Kieval et al. found no change in left ventricular performance as assessed by cardiac index, stroke volume index, left ventricular ejection fraction and mean velocity of circumferential fiber shortening, despite several dosing

Abstract: One hundred sixty-nine normal men received varying propranolol dosage regimens and placebo. Dose level and frequency were compared with plasma propranolol levels and beta blockade, as assessed by reduction of exercise tachycardia. Propranolol levels above 20 ng/ml induced significant beta blockade. An average daily propranolol dose slightly in excess of 160 mg led to a minimum plasma level above 20 ng/ml. Approximately 50% of subjects achieved 20 bpm or greater decrease in exercise tachycardia with 160 mg per day. The degree of beta blockade at the daily minimum propranolol level was related to dose and not dose frequency. The relation of propranolol dose and plasma levels to beta blockade in normal subjects appears to reflect observations in large clinical trials. Clinical Pharmacology and Therapeutics (1982) 32, 692–700; doi:10.1038/clpt.1982.225

Abstract: The interaction of a bromoacetylated derivative of alprenolol (Alm-CO-CH2Br) with cardiac and lung beta adrenoreceptors was partially characterized. After a short incubation period, the concentration of Alm-CO-CH2Br that inhibited specific [3H]dihydroalprenolol binding by 50% in cardiac and lung membranes was 0.5 and 0.11 microM, respectively. The blockade was time-dependent and Scatchard analysis showed no change in the KD value for specific (-)-[3H]dihydroalprenolol binding but a loss of beta adrenoreceptor content after membrane pretreatment with Alm-CO-CH2Br. The blockade was not reversed by extensive membrane washing, although concurrent treatment with alprenolol fully protected whereas phentolamine had no protective effect. Alm-CO-CH2Br produced a dose-dependent blockade of heart and lung beta adrenoreceptors in vivo and the compound had little or no effect on the growth rate of the rat. Four hours after a single i.p. injection of Alm-CO-CH2Br at 35 mg/kg, the heart and lung beta adrenoreceptor content was decreased by 88 and 90%, respectively. The time required for complete recovery from irreversible beta adrenoreceptor blockade was about 200 hr in the heart and 650 hr in the lung. These results suggest that Alm-CO-CH2Br may be a useful probe for the beta adrenoreceptor both in vitro and for recovery studies in vivo.

Abstract: The acute haemodynamic effects of beta-blockade with propranolol and combined alpha-blockade and beta-blockade with labetalol were compared in a randomised study in 12 patients with coronary artery disease proved by angiography. Propranolol induced significantly greater depression of left ventricular function both at rest and during exercise than labetalol. This difference was probably attributable to the vasodilator activity of labetalol and the associated reduction in afterload offsetting the haemodynamic disadvantages of blockade of cardiac beta-adrenoceptors alone. The haemodynamic advantages of combined alpha-blockade and beta-blockade over beta-blockade alone may thus have therapeutic implications for the use of these treatments in patients with coronary heart disease.

Abstract: To examine whether H 2 blockade might prevent development of allergen-induced nasal congestion, we subjected 18 volunteers with allergic rhinitis to nasal allergen challenge after pretreatment with cimetidine or with placebo. Response after cimetidine was more severe than that which followed placebo. H 2 blockade has a subtle adverse effect on nasal allergic response.

Abstract: A prospective study was performed in 43 men scheduled for transurethral resections under spinal anaesthesia. All patients were on chronic beta-receptor blockade because of hypertension and/or ischaemic heart disease. The patients were randomly subjected to either a gradual preoperative withdrawal or a continuation of the beta-receptor blockade. Haemodynamics were measured non-invasively. Spinal anaesthesia was performed and an i.v. injection of atropine given. The patients were then placed in a lithotomy position. Mean anaesthetic level included T6. After beta-receptor blocker withdrawal consistently elevated heart rates, a high incidence of arhythmias, angina pectoris and postoperative ST-T changes indicating myocardial ischaemia were seen. These changes were not seen in patients with continued beta-receptor blockade. Withdrawal of beta-receptor blockers was also associated with an increased total peripheral vascular resistance in connection with spinal anaesthesia. These results suggest that patients on long-term beta-receptor blockade should continue the therapy during and after spinal anaesthesia.

Abstract: The effect of head-up tilt upon subcutaneous and skeletal muscle blood flow in the crus was studied before and during epidural blockade in 10 subjects. Relative changes in blood flow were estimated by the local 133Xe washout technique. In subcutaneous tissue head-up tilt induced a decrease in blood flow of about 40% and there was no difference in the vascular response to head-up tilt before and during epidural blockade. In skeletal muscle tissue essentially the same was found as head-up tilt decreased blood flow by about 26% the response being uninfluenced by epidural blockade. In 3 patients local nervous blockade was induced by Lidocaine in 133Xe labelled subcutaneous tissue on one side. During epidural blockade and tilt blood flow increased by 12% whereas blood flow decreased by 30% on the control side. Thus epidural blockade had no influence on the vasoconstrictor response in subcutaneous tissue and skeletal muscle to head-up tilt whereas local blockade was able to prevent the response. Local mechanisms including the local veno-arteriolar reflex appear to play an important role for the observed maintenance of arterial blood pressure in the tilted position during central sympathetic blockade.

Abstract: lised in the liver. Subjects with a low capacity for paracetamol detoxication have been described.3 In such subjects larger quantities of the drug would reach the kidneys and could exert toxicity there by the formation of arylating metabolites. Perhaps this occurred in the two patients described above. Nevertheless, the paracetamol ingestion may have played no part in the pathogenesis of the renal failure of these patients. The symptoms which led the patients to take analgesics may have been due to some other process, which also caused tubular necrosis; and the paracetamol intake could have been coincidental. If a careful drug history were taken from all patients with cryptogenic renal failure additional subjects might be found in whom paracetamol appears to be nephrotoxic with little or no hepatotoxicity. ROGER GABRIEL

Abstract: A prospective randomized study was performed in 91 patients scheduled for general surgery on 99 occasions. The patients were chronically (greater than 3 months) treated with beta-receptor blockers because of ischaemic heart disease and/or hypertension and the beta-receptor blockade was either gradually withdrawn (n = 51) during 4 days preoperatively or continued until surgery (n = 48). The effects on arterial blood pressure (BP), heart rate (HR) and rate-pressure product (RPP) at rest and the incidence of chest pain during daily activities were registered. A withdrawal of the beta-receptor blockade was associated with increases of HR (in eight patients greater than 30 beats min-1) and RPP and in patients treated for hypertension there were also increases of systolic and diastolic BP (in five patients greater than or equal to 30/15 mmHg). Patients who continued the beta-receptor blockade until surgery showed no changes. Nine out of 23 patients with a previous history of ischaemic heart disease had an increase of chest pain after withdrawal of the beta-receptor blockers, whereas none of the corresponding 25 patients who continued the therapy suffered from an increased chest pain. Due to the severity of symptoms after beta-receptor blocker withdrawal, surgery had to be postponed in 4 patients. The observations suggest that a 4-day preoperative withdrawal of long-term beta-receptor blockade is potentially hazardous in ischaemic and/or hypertensive patients.

Abstract: Haemodynamic effects of a cold pressor test (foot immersion for 6 min in water at 5 degrees C) without medication and after the non-selective beta-adrenoceptor blocker propranolol and the selective beta-adrenoceptor blocker metoprolol were studied in 17 volunteers. In the control study as well as in the study with the beta-adrenoceptor blockers cold exposure caused comparable changes, namely a blood pressure rise and a reduction of forearm blood flow. The increase in heart rate during cold exposure was clearly and equally reduced by both beta-adrenoceptor blockers. Plasma noradrenaline rose significantly by 47%, plasma adrenaline did not change. It is concluded, that as to this kind of stress, beta 1-selective-adrenoceptor blockade confers no important advantage over non-selective beta-adrenoceptor blockade.

Abstract: Exercise electrocardiograms must be interpreted with the understanding that not every positive test is indicative of coronary artery disease. Mitral valve prolapse mimics coronary heart disease clinically and often in the electrocardiographic response to exercise. Twelve patients with mitral valve prolapse in whom exercise testing was positive underwent a repeat study after beta blockade. All tracings returned to normal after adequate blockade, evidenced by 17 to 22% reduction of resting and exercise heart rates. To the best of our knowledge, this is the first such report in the English literature. The results of this study suggest that an exercise test after beta blockade should become part of the routine procedure in such patients. The elimination of false positive electrocardiographic responses by beta blockade should help improve the specificity of the exercise test. Moreover, similar responses should lead to the suspicion of mitral valve prolapse.

Abstract: 1 The effects of a single oral dose of 5 mg pindolol (P) and 100 mg metoprolol (M) were assessed in a double-blind study in 30 patients undergoing oral surgery. 2 Systolic and diastolic blood pressures and heart rate were reduced 90 min after oral medication and did not exceed initial values at rest during the procedure. 3 Noradrenaline, adrenaline and c-AMP concentrations did not differ at any time from the control values at rest after P, but were increased after local anaesthesia and during oral surgery after M as were the metabolic responses reflected by plasma concentrations of glucose and free-fatty acids. 4 Plasma levels of ACTH and cortisol showed the typical increase during the procedure, being independent of beta-adrenoceptor blockade. In contrast to the cardioselective antagonist M, prophylactic administration of the non-selective drug P prevented the sympathetic and metabolic responses to the stress of oral surgery. 5 Hypothalamic and adrenal stimulation were not reduced by either selective or non-selective beta-adrenoceptor blockade.

Abstract: The effect of beta-adrenergic receptor blockade (with propranolol) on exercise-induced glycogen mobilization in rat skeletal muscles was studied. Treatment with propranolol either fully or partly prevented glycogen mobilization or had no effect at all on the process. The effects of propranolol depended on the intensity and duration of exercise and on the fiber composition of the muscle studied.

Abstract: The effect of intravenous regional sympathetic blockade with guanethidine on total forearm blood flow and on muscle and skin blood flow in the forearm was studied in healthy humans, using venous occlusion plethysmography, 133Xe-clearance technique and skin temperature recordings. The total blood flow tripled in response to the blockade and the rise persisted for 2-3 days. The increase in blood flow was confined to the skin, with no demonstrable steal effect on muscle blood flow. The observations imply that this type of sympathetic blockade may be of therapeutic value in some vascular disorders of the hand, and as supportive treatment in vascular surgery on the extremities.

Abstract: outpatient follow-up consultations. Many of the departments listed in the study would encompass disorders requiring potentially toxic medication. The hospital specialists concerned might rightly feel they have a responsibility in monitoring such treatment. Although \"nothing new might be learnt\" both the patient and the doctors concerned might be reassured that no harm is being done. Alternatively, the consultant may on occasions wish to obtain first-hand feed back on a patient's progress at a follow-up consultation. Hospital specialists, like all doctors, must be allowed the chance of learning from their successes or failures. Also, a patient's problem may remain undiagnosed and the consultant feel that he could still contribute something to that patient's management at a further consultation. The data required to draw the conclusions stated by Dr Marsh are missing from this study. The results could equally be used to support the opposite conclusions. In 90o of patients a \"new diagnosis\" was made. We do not know how important this might have been, but possibly in some patients it may have been lifesaving. In 1500 a \"new treatment\" was tried. If this had resulted in a dramatic response (data not given) surely the consultation would not have been \"futile.\" In 102 consultations (49 %) the general practitioner learnt \"something useful.\" Certainly thought must be given to the problem of unnecessary outpatient follow-ups, particularly if waiting lists for new patient referrals accumulate. Many factors not mentioned by Dr Marsh, however, need to be considered. Also, any study such as this should be conducted in an unbiased manner, preferably as a joint venture with hospital specialists. Finally, although Dr Marsh states that one of his aims was to ascertain the value ofthe consultation \"to the patient,\" no attempt was made to record the patients' own views. These surely would need to be included in further studies. 0 E EADE