Biomedical subjects
Publications and source records attributed to D Lundberg.
In a 69-year-old man with severe tetanus, sympatho-adrenal overactivity was successfully treated with a lumbar epidural block. Cardiovascular disturbances were reduced and fluctuations in plasma catecholamines were decreased. The duration of other manifestations of tetanus was, however, not influenced by the epidural block in this case.
An experimental model was designed to study circulatory drug effects with or without barostatic reflex influences. In dogs anaesthetized with chloralose, both carotid sinuses were perfused from a femoral by-pass either with systemic arterial pressure or with a pump in order to control the sinus pressure. Cardiac and aortic baroreceptors were denervated. I.v. metoprolol (240 micrograms X kg-1 + 102 micrograms X kg-1 X h-1) with constant carotid sinus pressure and thereby constant baroreceptor activation reduced cardiac output, heart rate, cardiac contractility and left ventricular stroke work index. Systemic vascular resistance increased. This response was independent of the degree of baroreflex activation. During the combined administration of enflurane (1.6% end-tidal concentration) and metoprolol, cardiac performance (cardiac output, stroke volume, heart rate, cardiac contractility and left ventricular stroke work index) was depressed independent of the degree of baroreflex activation. Barostatic reflexes, however, counteracted an observed decrease in systemic vascular resistance. This reflex vascular response was, during metoprolol-enflurane administration, associated with an increased left ventricular end-diastolic pressure.
Local effects of enflurane on intestinal vascular resistance were studied in vivo in cats. A jejunal segment was prepared and perfused at constant flow with blood from the femoral arteries. The intestine was either: (1) left with intact sympathetic innervation, (2) denervated and exposed to electrical post-ganglionic vasoconstrictor nerve stimulation, or (3) excluded from neurogenic remote control by post-ganglionic denervation. Enflurane dissolved in lipid and intra-arterially administered to the jejunal segment in doses comparable to those clinically encountered, decreased intestinal vascular resistance in relation to the intra-arterial concentration of the drug. The vasodilator response was, at the highest enflurane doses studied (blood concentration: 400 and 800 mg X 1(-1], most pronounced in the intestine with intact sympathetic innervation. Otherwise, no differences were observed in vasodilator responses between the three different investigated modes of neurogenic influence on the intestine. In vitro enflurane (-in-lipid) did not affect the vasoconstrictor response to electrical field stimulation in the rat mesenteric arterioles. Enflurane, however, dose-dependently reduced spontaneous contractile activity in the rat portal veins.
The effects of enflurane on intestinal vascular resistance and blood flow in the intestine were studied in cats during basal chloralose anaesthesia. A jejunal segment was prepared and perfused with blood from both femoral arteries, allowing control of intestinal inflow pressure. Mesenteric venous blood flow was measured with an optical drop recorder. During constant intestinal arterial pressure (75 mmHg; 10 kPa), intestinal vascular resistance was calculated during enflurane inhalation at MAC 0.5 and 1.0 before and after postganglionic denervation of the jejunal segment. Inhalation of enflurane reduced intestinal vascular resistance in a dose-dependent fashion. The decrease in vascular resistance was attenuated but not abolished by post-ganglionic denervation, indicating both peripheral and central nervous sites of action for enflurane. Furthermore, with the intestinal segment perfused at systemic arterial pressure, the effects of locally intraarterially infused enflurane dissolved in a fat emulsion was studied. A vasodilator response was elicited in the intestine when exposed to local arterial enflurane concentrations in the same range as encountered during surgical anaesthesia in man, supporting the hypothesis of a peripheral site of action.
The haemodynamic effects of enflurane (1.7% and 3.4% expiratory concentrations) were investigated in sheep (n = 6) pretreated with an infusion of metoprolol (0.2 mg X kg-1 X h-1 for 5 days) and in control animals (n = 6). Chloralose was used as basal anaesthetic. A 90 s apnoea period was included in the experiment to evaluate further the possible side-effects of long-term metoprolol treatment in combination with enflurane anaesthesia. MAC 1.0 for enflurane in the sheep was found at 1.45% end-tidal concentration by separate measurements. Before enflurane administration, the only significant differences between the two groups of animals were a lower systemic vascular resistance and a higher stroke volume during metoprolol treatment. Enflurane abolished these discrepancies in a dose-dependent fashion and similar cardiovascular depression was observed in both groups of animals at 3.4% expiratory concentration of enflurane. Metoprolol did not significantly affect the hypertensive response to apnoea during chloralose anaesthesia alone. At enflurane 1.7% expiratory concentration the apnoea response was small and only the metoprolol-treated animals showed a significant increase in left ventricular end-diastolic pressure. We conclude that 5 days of pretreatment with metoprolol in the sheep model does not significantly impair cardiovascular performance during enflurane anaesthesia.
It is somewhat difficult to reconcile the contrasting findings regarding the hemodynamic actions of high doses of corticosteroids in shock. The studies differ according to type of shock (hypovolemic, septic or cardiogenic), animal species, shock model, type of corticosteroid, etc. Beneficial hemodynamic effects (e.g. myocardial improvement, vasodilation) of steroids given alone are not consistently observed and when so often mild and transient. This might indicate that the hemodynamic changes of corticosteroids are not due to primary actions on the cardiovascular system but rather represent the hemodynamic consequences of the metabolic response to corticosteroid therapy. If, however, the corticosteroid therapy is combined with an alpha-adrenoreceptor blocker the nutritive tissue blood flow is distinctly increased.
It is evident that the majority of studies concerning the use of high dose corticosteroids (HDC) in circulatory shock hitherto published, in a pharmacological sense, are mainly descriptive. However, some of the studies have none the less provided valuable information about the mechanisms of action and a few investigations have primarily been designed to study the pharmacodynamics of HDC in different shock settings. The research has shown that HDC interferes with various pathophysiological mechanisms including cell membrane stability, granulocyte aggregability, oxygen delivery, peripheral circulation and metabolism. Less is known about the pharmacokinetics of HDC, a subject which has been more or less neglected until very recently. However, some basic facts are known. Hence, the mean elimination half life of methylprednisolone (MP) administered i.v. ranges from 2.4 to 3.5 hours in normal healthy adults. The drug is distributed widely throughout the body including the central nervous system and is metabolized mainly in the liver to inactive metabolites.
Respiratory activity was studied in rats during light halothane anesthesia. Thyrotropin releasing hormone (TRH) and two TRH analogues: the desamidated form (TRH-OH) and gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN 1417) were administered intracerebroventricularly. TRH 0.5-5 micrograms induced a marked tachypnoea with a rapid onset and a duration of at least 20 min. DN 1417, a potent analogue of TRH with a very low TSH (thyroid stimulating hormone) releasing activity was more effective in stimulating respiratory frequency, while TRH-OH, regarded to have neither TSH releasing nor extra hypothalamic effects, at equimolar doses was unable to induce any changes in the respiratory pattern. When TRH was given into the fourth ventricle the dose response curve was slightly shifted to the left. In experiments employing the occluded breath technique, P0.1 was increased in the same magnitude as the mean inspiratory flow (VT/T1). The results also indicated an increase in the gain of the inflation reflex loop whereas the central bulbopontine setting for T1 and TTOT were not significantly changed. Local injection of TRH into the nucleus tractus solitarii induced a stimulation of respiratory frequency which was slower in onset compared to the response seen after injection into the lateral or fourth ventricles. Concomitantly to the respiratory changes, i.c.v. TRH injection induced a hypocarbia and an alkalosis. No changes in blood pressure or heart rate were seen. The respiratory stimulant effect of TRH could be potentiated by pretreatment with naloxone, methylatropine or a low dose of GABA. Haloperidol or propranolol did not significantly change the respiratory effects of TRH, while reserpine pretreatment seemed to blunt some of the ventilatory effects of TRH. It seems likely that TRH has few direct effects on brain stem neurones involved in the central regulation of respiration, but the main effects seem to be elicited in areas rostral to the brain stem. The respiratory stimulating effect of TRH is unrelated to TSH. Furthermore, other neurotransmitter systems might also be involved in modulation of the respiratory stimulation evoked by TRH.
Deaths in septic shock continue to occur at a high frequency despite current treatment programs. However, the mortality can be substantially decreased with a close bedside attendance of patients at risk and if the patient is transferred to an intensive care unit for intensive treatment and monitoring as soon as shock is suspected or established. The treatment program consists of adequate antibiotic administration in combination with massive doses of steroids and aggressive infusion therapy supplemented with cardiovascular drugs according to the hemodynamic response to the initial treatment.
Respiratory activity was studied in adult rats during light halothane anesthesia. Dopamine agonists and antagonists were injected intracerebroventricularly (i.c.v.) or systemically. The respiratory parameters were recorded after exposure to O2 or to CO2 in O2. Apomorphine (i.c.v. 300 microgram) induced a biphasic response with an initial decrease in respiratory frequency (f) followed by pronounced tachypnoea after 5 min. The changes in tidal volume (VT) showed an inverse pattern. When apomorphine was administered into the fourth ventricle, only the later phase of the biphasic response was observed. Haloperidol (2 mg/kg i.p.) antagonized the apomorphine-induced response in contrast to domperidone (2 mg/kg i.v.), a dopamine receptor blocking agent which does not pass the blood brain barrier. Administered i.c.v., haloperidol as well as domperidone induced a decrease in f while VT was increased. The same response was observed after the presynaptic dopamine receptor agonist 3-PPP, 3-(3-hydroxyphenyl)-N-n-propylpiperidine. Hypercapnea was found to decrease the tachypnea in apomorphine-treated animals. Apomorphine also induced a decrease in blood pressure and heart rate, which was not reversed by haloperidol. It is concluded that there is a centrally located, tonically activated dopamine system involved in respiratory regulation. The predominant effect seems to be of a respiratory stimulating nature. The possible role of presynaptic and different postsynaptic dopamine receptor mechanisms is discussed.
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The hemodynamic effects of massive doses of dexamethasone in combination with the alpha-adrenergic blocking agent phenoxybenzamine were studied in dogs subjected to hemorrhagic hypotension. Previously it has been shown that the glucocorticoid methylprednisolone, but not the glucocorticoid betamethasone, induces a pronounced vasodilation in combination with phenoxybenzamine. In the present study it was found that also dexamethasone (a stereoisomer of betamethasone) is unable to increase the peripheral blood flow after phenoxybenzamine. Since equivalent doses were used in relation to glucocorticoid activity, it seems reasonable to conclude that the different hemodynamic patterns are unrelated to the glucocorticoid ability of the drugs. Furthermore, it is unlikely that possible beneficial effects of dexamethasone in hypovolemic shock are due to a direct vascular influence.
Twenty-six patients on chronic (greater than 3 months) beta-receptor blocking therapy due to ischaemic heart disease and/or hypertension were randomly distributed to a 4-day gradual withdrawal (n = 13) or a continuation of ordinary therapy until a planned cholecystectomy under neurolept anaesthesia (n = 13). Plasma-adrenaline, -noradrenaline, -potassium, -glycerol, -FFA, -insulin and b-glucose were determined perioperatively. The metabolic response to surgery was as expected with hyperglycaemia and depressed insulin levels, which did not differ significantly between the two groups of patients. Plasma-catecholamines showed the highest mean values during emergence from anaesthesia. Plasma-adrenaline and -potassium were constantly highest in the beta-receptor-blocked patients, who also showed indices of a relatively depressed lipolysis compared to patients in whom beta-receptor blockers had been withdrawn. These discrepancies between withdrawal versus continuation of preoperative beta-receptor blockade seemed to be of small clinical importance and did not oppose the present view that beta-receptor blockers should generally be continued during surgery. However, findings in individual patients suggest that beta-receptor blockade may maintain hypoglycaemia in catabolic patients.
Forty-eight chronically (greater than 3 months) beta-receptor-blocked patients with ischaemic heart disease and/or hypertension were studied on 49 occasions after random distribution to a 4-day, gradual preoperative withdrawal (n = 26) or a continuation (n = 23) of beta-receptor blockers. The patients were scheduled for either a cholecystectomy (n = 28) or a carotid thrombendarterectomy (n = 21) under neurolept anaesthesia. Three patients were excluded from the randomized part of the study due to complications (tachycardia, hypertension, severe angina) after therapy withdrawal. In subgroups, central haemodynamics (beta-receptor blockers withdrawn n = 6, continued n = 8) and creatinine-kinase B (beta-receptor blockers withdrawn n = 9, continued n = 11) were studied. Withdrawal of beta-receptor blockers was associated with high heart rates, supraventricular tachyarrhythmias and a hyperkinetic circulation during pain stimuli. Significantly more postoperative ECG changes (P less than 0.02) indicative of myocardial ischaemia were found than in beta-receptor blocked patients. These patients had low heart rates but also pronounced increases in pulmonary capillary wedge pressures, which in single patients could be associated with myocardial damage. These results imply that beta-receptor blockers should be continued before surgery and that a concomitant vasodilatatory therapy is likely to avoid the drawbacks of an increased cardiac afterload.
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.
In normal rats lightly anesthetized with halothane apomorphine increased both resting and CO2-dependent minute ventilation (VM) by stimulating respiratory frequency (RF) whereas tidal volume (VT) was slightly decreased. Acute bilateral glossopharyngectomy, which impaired carotid body function, did not change the apomorphine effects in contrast to bilateral vagotomy, which abolished the RF response of the drug, but now increased VT. Intravenous infusion of dopamine increased VM by elevating RF, and this effect was only slightly blunted by bilateral glossopharyngectomy but nearly abolished by vagotomy and totally eliminated by the combined procedures. The respiratory response to dopamine was depressed in rats with chronically destroyed central catecholaminergic neurons. These findings indicate that there may be two different dopaminergic stimulatory mechanisms that modulate RF-one peripheral and one central-and both depend upon afferent vagal activity. With impaired vagal function, however, two other dopaminergic stimulatory mechanisms effecting VT are evident-one central, and one peripheral which involves the carotid body.
The respiratory activity in newborn preterm (29 days gestation) rabbits was studied after administration of thyrotropic releasing hormone. Intraperitoneal injection induced an increase in respiratory frequency (f) and a decrease in tidal volume (VT) resulting in a slight increase in pulmonary ventilation (VE). These effects were seen in parallel to a decrease in expiratory time (TE) and respiratory time (TTOT). An increase in the TI/TTOT ratio but (unaffected) VT/TI ratio indicates that thyrotropic releasing hormone affects "respiratory timing" mechanisms rather than "inspiratory drive." The changes in respiratory parameters are most probably due to an effect on the central respiratory controlling centers in the brain stem.
At the Hospital of Physical Medicine, Hornbaek, we analysed in retrospect 52 cases of myositis ossificans circumscripta (MOC) among 605 patients with para/tetraplegia. MOC proved significantly more common after total than after subtotal spinal cord injuries. MOC was not observed in any case above the motor level of the spinal cord lesion. This neurological relationship appears to "explain" the finding that MOC is more common in para/tetraplegia of traumatic origin (more complete spinal cord lesions) than among those caused by slipped discs or tumours. Twenty-five per cent of the patients ended up with fairly mild and 12% with more severe hip contractures, the latter causing recurrent, contralateral decubital ulcers over the ischial tuberosity and protracted hospitalization. To aid diagnosis, the authors suggest a simple programme for all para/tetraplegics. In our opinion, routine X-ray examination is not necessary. Intensified research into the causative factors and treatment is needed, not only to facilitate these patients' social adaptation, but also for socio-economic reasons.