Enalaprilat decreases plasma endothelin and atrial natriuretic peptide levels and preload in patients with left ventricular dysfunction after cardiac surgery.

OBJECTIVE: To study the acute effects of angiotensin-converting enzyme inhibition by intravenous enalaprilat infusion in patients with left ventricular dysfunction after cardiac surgery. DESIGN: Prospective, consecutive sample, before-after trial. SETTING: Surgical intensive care unit in a tertiary care university hospital. PARTICIPANTS: Eight patients with left ventricular dysfunction after cardiac surgery. Patients were defined as having left ventricular dysfunction if the pulmonary capillary wedge pressure persisted above 18 mmHg in spite of conventional vasoactive medication (inotropic or vasodilating and diuretic drugs) and intermittent mandatory ventilation during the first postoperative week. INTERVENTIONS: Enalaprilat was infused initially at 1 mg/ hour. The rate was doubled every 30 minutes until pulmonary capillary wedge pressure decreased at least 20% or until a maximum total dose of 10 mg was achieved. MEASUREMENTS AND RESULTS: Central hemodynamics, systemic oxygenation, and hormonal regulation of circulation (plasma renin activity, plasma endothelin, atrial natriuretic peptide, norepinephrine, epinephrine, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum levels of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly over 2 hours after the infusion. Enalaprilat infusion (median dose, 2.0 mg; infusion time, 48 minutes) caused a significant decrease in pulmonary capillary wedge pressure (p = 0.004), lasting until the end of the 2 hours' follow-up. This coincided with inhibition of serum angiotensin-converting enzyme activity (p < 0.001), an increase in plasma renin activity (p = 0.022), and decreases in plasma endothelin (p = 0.035), atrial natriuretic peptide (p = 0.005), and serum aldosterone (p = 0.001) concentrations. Cardiac output, venous admixture, and oxygen delivery and consumption remained unchanged. CONCLUSIONS: Adding enalaprilat to conventional therapy makes it possible to unload the left ventricle and to relieve overt neurohormonal activation temporarily while maintaining cardiac function and systemic oxygenation.

beta-blockade, atrial natriuretic peptide and exercise.

Changes in the release of atrial natriuretic peptide (ANP) and vasopressin (VP) may contribute to the final outcome of beta-adrenoceptor blocking therapy. Therefore, we administered 2 hours before a bicycle exercise test (a 30-minute exercise with 100 W work load) in a randomized, double-blind, placebo-controlled crossover study orally 50 mg atenolol, 80 mg propranolol or 10 mg pindolol to 15 healthy volunteers. Hormone release and sympathoadrenal activation were estimated by measuring plasma ANP-, VP-, adrenaline and noradrenaline concentrations. beta-blockade and -antagonism were estimated by measuring the reduction of exercise-induced tachycardia and the extent to which the drugs occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in the circulating plasma. We noticed clear differences in the animal beta 1- and beta 2-receptor occupancy between these agents. The agents and placebo during the exercise augmented plasma ANP level similarly, on average by 34-72%. Pindolol administration enhanced the decline of plasma ANP level after exercise (ANCOVA rep meas, pindolol vs placebo, p < 0.05). Although pindolol increased the mean plasma VP level by 25% (ANCOVA rep meas for the increase, pindolol vs placebo, p < 0.05), drug effects on plasma VP-level were generally negligible. In conclusion, in healthy volunteers beta 1- and beta 2-antagonism by pindolol, atenolol and propranolol do not markedly potentiate plasma ANP- and VP-responses to physical exercise. The responses are, however, slightly influenced presumably by the beta-agonist activity of pindolol.

Blood transfusion with autologous and leukocyte-depleted or standard allogeneic red blood cells and the immune response to open heart surgery.

Allogeneic blood transfusions have been associated with impaired outcome in surgical patients. This effect may be mediated by leukocytes. Animal experiments have shown that at least some of the effect can be modified by removal of leukocytes from transfused blood. Therefore, we compared the effects of autologous + leukocyte-depleted against standard allogeneic red blood cell transfusion on postoperative immunosuppression in 24 men undergoing coronary artery bypass surgery. In the autologous + leukocyte-depleted red blood cell transfusion group, patients received 800 +/- 200 mL (mean +/- SD) autologous blood and 2.2 +/- 2.0 units (mean +/- SD) of leukocyte-depleted saline-adenine-glucose-mannitol (SAGM) red blood cells. In the standard red blood cell transfusion group, patients were transfused with 5.5 +/- 1.4 units (mean +/- SD) of SAGM red blood cells. Leukocyte and differential counts; percentages of lymphocyte subpopulations (CD3-, CD4-, CD8-, CD16-, CD20-, CD25-, and B5-positive lymphocytes) and monocytes (CD14); phytohemagglutinin-, concanavalin A-, and pokeweed mitogen-induced and unstimulated proliferation of separated lymphocytes; unstimulated and pokeweed mitogen-stimulated production of IgG, IgM, or IgA; and serum interleukin-6, interleukin-1 beta, and serum C-reactive protein concentrations were measured preoperatively and on postoperative Days 1, 7, and 21. Significant changes were seen in these variables, but there were no differences between the groups. Three of the 12 patients in the allogeneic leukocyte-containing red blood transfusion group became human lymphocyte antigen (HLA) alloimmunized. No infections or other complications occurred in any patients. We conclude that HLA alloimmunization was the only effect that could be modified by use of autologous blood.

Enalaprilat in acute intractable heart failure after myocardial infarction: a prospective, consecutive sample, before-after trial.

OBJECTIVE: To evaluate the acute effects of intravenous enalaprilat infusion in critically ill patients with intractable heart failure after acute myocardial infarction. DESIGN: Prospective, consecutive sample, before-after trial. SETTING: Medical intensive care unit in a university hospital. PATIENTS: Eight consecutive patients with intractable acute heart failure after acute myocardial infarction. All study patients continued receiving inotropic, vasodilating, and diuretic medication at a constant rate. Six patients received steady intermittent mandatory ventilation and two patients were on a continuous positive airway pressure mask during the investigation, all with constant positive end-expiratory pressure. Heart failure was defined as intractable if the pulmonary artery occlusion pressure remained > 20 mm Hg despite this conventional therapy. INTERVENTIONS: Enalaprilat was infused at a rate of 1 mg/hr until the pulmonary artery occlusion pressure decreased by > or = 20%. MEASUREMENTS AND MAIN RESULTS: Central hemodynamics, oxygenation, and hormonal regulation (plasma renin activity, plasma norepinephrine, epinephrine, endothelin, atrial natriuretic peptide, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum concentrations of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly during 2 hrs after the infusion. The statistical analysis was performed with analysis of variance for repeated measurements. Enalaprilat infusion (median dose 0.3 mg and infusion time 21 mins) caused significant but short-lasting decreases in pulmonary artery occlusion pressure (p = .007), mean arterial pressure (p = .003), mean pulmonary arterial pressure, and rate pressure product. These findings coincided with inhibition of serum angiotensin-converting enzyme activity, an increase in plasma renin activity, and a decrease in plasma endothelin concentrations (p = .041). Enalaprilat had no significant effects on the other hormones studied. Cardiac output and stroke volume index, venous admixture, oxygen extraction ratio, and mixed venous and arterial oxygen saturations remained unchanged. CONCLUSIONS: Adding enalaprilat to conventional therapy makes it possible to transiently relieve pulmonary congestion while maintaining cardiac function and systemic oxygenation. The decrease in plasma endothelin concentrations may have further clinical implications, because endothelin is known to have potent vasoconstricting effects on the coronary circulation and it may also contribute to the extension of myocardial infarction. Whether these observed benefits can be maintained with repeated bolus injections or with continuous infusion of enalaprilat, remains to be settled.

Enalapril premedication attenuates the blood pressure response to tracheal intubation and stabilizes postoperative blood pressure after controlled hypotension with sodium nitroprusside in neurovascular patients.

Oral premedication with enalapril, 0.1 mg/kg was compared with placebo in 22 patients subjected to craniotomy and ligation of an intracranial aneurysm or extirpation of an arteriovenous malformation. Balanced hypotensive anesthesia was used with sodium nitroprusside (SNP) as the main hypotensive agent. The hypertensive response to laryngoscopy and tracheal intubation was significantly attenuated by enalapril (p = 0.020). The mean blood pressure was lower and more stable in the intensive care unit after enalapril than after placebo (p = 0.044). The median SNP dose rate tended to be lower in the enalapril-pretreated patients [0.6 (range of 0-3.5) micrograms/kg/min] compared to the placebo group [1.4 (0.4-5.8) micrograms/kg/min] (p = 0.12). Concentrations of plasma catecholamines, vasopressin, and endothelin as well as serum osmolality, arterial blood gases, and plasma electrolytes and level of consciousness were repeatedly measured. Enalapril had no significant effects on these variables. Plasma renin activity was increased and serum angiotensin converting enzyme (ACE) activity was reduced in the expected manner by enalapril. We found premedication with an ACE inhibitor favorable for hypotensive anesthesia in neurovascular patients as assessed by the circulatory responses.

Effect of thermal stress on serum prolactin, cortisol and plasma arginine vasopressin concentration in the pregnant and non-pregnant state.

The thermal responses of serum prolactin, cortisol and plasma arginine vasopressin were studied on pregnant and non-pregnant women. Group I consisted of 15 healthy non-pregnant women, group II of 23 women 13-14 weeks pregnant and group III of 23 women 36-37 weeks pregnant. Blood samples were taken before the stress (21-23 degrees C), at the end of a 20 min stay in a heat chamber (70 degrees C, 15% relative humidity) and 20 min and 45 min after the stress (21-23 degrees C). The rectal temperature increased 0.3-0.4 degrees C. Serum concentration of prolactin increased from the pre-stress level by 82% in group I (NS), by 25% in group II (P less than 0.05) by the end of the stress but declined steadily in group III by 12% till the end of the recovery period (P less than 0.001). The cortisol concentration increased only in group II during the recovery period (54-72%, P less than 0.05). In this group the subjects who felt discomfort after the stress had higher cortisol levels already before the stress. Arginine vasopressin levels increased significantly only in group I by 17% (P less than 0.05) and there were no differences in the proportional changes between the groups. The response of prolactin to thermal stress seems to be abolished at late pregnancy while the responses of cortisol and arginine vasopressin are not influenced by pregnancy.

The effect of hydration status on plasma vasopressin release during physical exercise in man.

The effect of hydration status on plasma vasopressin release was studied in six healthy volunteers undergoing a 15-min bicycle ergometer exercise. The hydration states were dehydration, produced by a 14-h abstinence from fluids, euhydration, and hyperhydration caused by drinking 20 ml kg-1 water 2 h before the exercise. The exercise load was individually adjusted to 70% of maximal oxygen uptake. Exercise resulted in a significant increase in plasma vasopressin only during euhydration, in spite of the marked increase in plasma osmolality in all hydration states. The vasopressin concentrations during hyperhydration were significantly lower than during euhydration. Plasma volume and serum sodium were significantly affected by the exercise. The highest responses were obtained in euhydration and the lowest in hyperhydration. On this basis, the body's drive towards normal homeostasis and to the best ability to respond to the challenges of the environment is rational.

Propofol infusion for sedation in outpatient oral surgery. A comparison with diazepam.

An infusion of propofol was compared with intravenous boluses of diazepam as sedation for minor oral surgery under local anaesthesia in 12 healthy patients who had elective bilateral surgical extraction of lower third molars; the patients served as their own controls. Plasma catecholamine, vasopressin and cortisol concentrations were determined from repeated blood samples. The total administered dose of propofol was 3.93 (SD 1.34) mg/kg and of diazepam 0.28 (SD 0.07) mg/kg. No cardiovascular depression or airway problems occurred. Other side effects were also rare but some discomfort on injection was frequent with propofol. Recovery times were faster after propofol than after diazepam as assessed by the Maddox wing and visual analogue scales. Propofol also provided better amnesia compared to diazepam at the time of the extraction of the teeth. Eight of the 12 patients subjectively preferred propofol sedation. There was no hormonal stress response in either group.

Hormonal, haemodynamic, and subjective effects of intravenously infused indomethacin: no change in the physiological response to hypertonic saline challenge.

This double-blind, placebo-controlled human study was performed to determine the endocrine responses to intravenously administered indomethacin at two dose rates (0.36 or 0.72 mg/kg bolus followed by 0.071 or 0.143 mg/kg/hr for 150 min.). A 5% hypertonic saline infusion was used for further assess the hormonal systems regulating body fluid and electrolyte balance. Plasma renin activity (PRA) and concentrations of aldosterone and vasopressin (AVP) were unaffected by indomethacin. Hypertonic saline caused a 5% increase in plasma sodium and a 4.2% increase in serum osmolality, with a concomitant two-fold rise in plasma AVP levels and significant declines in PRA and aldosterone. Indomethacin had no effects on these responses, and did not affect plasma catecholamine concentrations, but the hypertonic saline infusion doubled the noradrenaline levels in plasma. Atrial natriuretic peptide (ANP)-like immunoreactivity in plasma was not affected by indomethacin nor by hypertonic saline. The higher dose rate of indomethacin resulted in significant stimulation of growth hormone release, but plasma prolactin levels were not influenced. Thus acute intravenous administration of indomethacin proved to be devoid of significant effects on the multihormonal system regulating fluid and electrolyte balance.

Hemodynamic and hormonal changes in patients pretreated with captopril for surgery of the abdominal aorta.

Cardiovascular and hormonal responses to aortic cross-clamping (ACC) and declamping (ADC) were studied in 20 patients undergoing reconstructive aortic surgery anesthetized with fentanyl and droperidol. Ten of the patients served as a control group, and 10 patients were treated with oral captopril (25 mg the day before operation and 25 mg one hour before anesthesia) to prevent intraoperative and postoperative hypertension. After the induction of anesthesia in the captopril group, hypotension was seen in four patients and bradycardia in three patients. In both groups, the most important changes in hemodynamics after the ACC were an increase in systemic vascular resistance and decreases in cardiac and stroke index. After the ADC, the cardiac index (CI) improved nearly to the level before the ACC. The urine output during anesthesia was 46 +/- 5 mL/h in the control group and 73 +/- 11 mL/h (P less than 0.05) in the captopril group. Postoperatively, patients in both groups were hypertensive and tachycardic. In the control group, plasma renin activity rose significantly during the ACC, indicating activation of the renin-angiotensin system (RAS). In both groups, significant increases in plasma vasopressin (PAVP), epinephrine, and norepinephrine were also observed before the ACC and during the postoperative period. The results suggest that oral captopril increases the risk of hypotension and bradycardia after induction of anesthesia, and does not prevent postoperative hypertension.

Effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on hemodynamic control mechanisms.

Dexmedetomidine, a selective alpha 2-adrenoceptor agonist, was administered to five healthy male volunteers in single intravenous doses of 12.5, 25, 50, and 75 micrograms as part of a placebo-controlled study. The drug caused dose-dependent decreases in systolic and diastolic blood pressure. A small initial hypertensive response was observed after injection of the two highest doses. Heart rate was decreased. The concentration of norepinephrine in plasma was decreased significantly (by up to 92%), and the decrease was dose-dependent. No significant drug-induced alterations were observed in plasma renin activity or in the concentrations of atrial natriuretic peptide and arginine vasopressin in plasma. Other drug effects included dose-dependent impairment of vigilance and stimulation of growth hormone secretion. Plasma cortisol levels were unaffected. Dexmedetomidine is a potentially useful tool for studies of the physiology and pharmacology of alpha 2-adrenoceptors in human beings and may have therapeutic applications in clinical conditions in which sedative and sympatholytic effects are considered beneficial, such as premedication for anesthesia and surgery.

Glucose polymer syrup attenuates prolonged endurance exercise-induced vasopressin release.

We investigated the effect of glucose and glucose polymer ingestion on plasma arginine vasopressin (pAVP) levels, on plasma osmolality (p-osm), and on performance during two prolonged endurance events. The study subjects were 37 Finnish elite endurance athletes, of whom 18 were orienteers and 19 cross-country skiers. Plasma AVP increased in both combined glucose and glucose polymer groups, but the increase in the glucose polymer group was significantly smaller (P less than 0.001) than that in the glucose group. A significant change in p-osm caused a significant change in pAVP and vice versa. Both the orienteers and the skiers on glucose polymer tended to have more success in the competition; the orienteers on glucose polymer ran the last third of the competition significantly faster than those on glucose (P less than 0.05). It is suggested, in the light of the smaller pAVP response, that after glucose polymer ingestion the physical stress in prolonged endurance exercise is smaller than after ingestion of glucose.

Role of pulmonary diseases and physical condition in the regulation of vasoactive hormones.

Lungs have many non-respiratory metabolic functions, of which some take place in the capillary endothelium, while others are in parenchymal lung tissue. We have studied the role of the lungs in the metabolism of vasoactive and some other hormones by comparing patients who have undergone lung resection to those having various obstructive or fibrotic lung diseases. We have also compared these groups with persons in good physical health. The data suggested that lung resection patients had low angiotensin II levels in plasma but the response of angiotensin II to exercise was normal. Also adrenalin concentration was low in the lung resection group while dopamine did not show any significant difference between the groups. When hormone levels were correlated to the exercise data, renin levels were especially related to physical condition. Serum post-exercise renin values were inversely related to the uneven distribution of lung perfusion, possibly thus reflecting the diminished pulmonary vascularization. A negative association was found between angiotensin II and diffusion capacity. Thus, the angiotensin II levels may preferably be controlled by the non-circulatory functions of the lungs.

Renin-angiotensin-aldosterone system and plasma vasopressin in surgical patients anaesthetized with halothane or isoflurane.

The effects of halothane and isoflurane anaesthesia on plasma renin activity and plasma concentrations of aldosterone and vasopressin were investigated in 20 cholecystectomy patients. Plasma renin activity rose significantly during both halothane and isoflurane anaesthesia without surgery, and increased further after the commencement of operation. Plasma aldosterone increased slightly during halothane and isoflurane anaesthesia, but the highest concentrations, three times the control values, were measured during surgery in both groups. Plasma vasopressin decreased during halothane and isoflurane anaesthesia to half of the control values, but rose significantly during cholecystectomy. During anaesthesia and surgery there were no significant differences in the mean arterial pressures of the groups. The results demonstrate that isoflurane stimulates the renin-angiotensin system to a similar extent as halothane, although it causes hypotension by a different mechanism. The activation of the renin-angiotensin-aldosterone system may be an essential compensatory mechanism, which antagonizes the decrease of blood pressure. Plasma vasopressin probably has no role in regulating blood pressure during anaesthesia.

Continuous positive airway pressure with and without high-frequency ventilation: hemodynamics, oxygenation, and endocrine response.

After 18 h of mechanical ventilation following open heart surgery, central hemodynamics, systemic oxygen delivery (DO2), and oxygen consumption were assessed in ten consecutive patients receiving continuous positive airway pressure (CPAP) therapy. Plasma vasopressin, norepinephrine, and epinephrine levels were analyzed. While maintaining the mean airway pressure, two CPAP methods were studied: a demand CPAP with continuous flow without (CPAP) and one with high-frequency ventilation (CPAP-HFV). The frequency used during CPAP-HFV was 300 cycle/min. The spontaneous ventilatory rate was found to be equal during CPAP and CPAP-HFV. The cardiac and stroke volume indices were slightly higher (p less than .05) during CPAP-HFV, which accounted for the finding that DO2 was also slightly higher (p less than .05) during CPAP-HFV. The epinephrine and norepinephrine levels did not differ, whereas the vasopressin level was somewhat higher during CPAP-HFV, which might indicate a higher level of vigilance. It is concluded that cardiac output was slightly higher during CPAP-HFV compared to that during CPAP. This may be due to an effect of the oscillations on circulation or to differences in the level of vigilance.

Temazepam versus flunitrazepam as an oral premedication in adult surgical patients.

In a randomized study, 20 patients received temazepam 20 mg orally the night before and 20 mg in the morning of an operation performed under spinal analgesia (Group I); 20 patients received flunitrazepam I mg similarly (Group 2). Different aspects of the premedication were evaluated verbally, with the aid of a visual analogue scale, Maddox wing apparatus, the critical flicker fusion threshold test, blood pressure and heart rate measurements, serum and CSF cortisol and plasma ADH measurements, as well as CSF drug level determinations. Clinically, temazepam 20 mg proved to be comparable with flunitrazepam I mg, although the latter more effectively prevented cardiovascular changes and pre-operative hormonal stress reaction. No correlation was found between the CSF drug level (bioassayed by radioreceptor assay) and the clinical response of the two benzodiazepines, nor was there any correlation between the cortisol or ADH levels versus the CSF drug levels. On the whole, flunitrazepam proved to be marginally better than temazepam as an oral premedicant.

Meptazinol and pentazocine: effects on prolactin, growth hormone and vasopressin levels in plasma.

The effects of two partial agonist opioid analgesics, meptazinol (at doses 0.7 and 1.4 mg/kg intravenously) and pentazocine (at doses 0.3 and 0.6 mg/kg), on anterior and posterior pituitary hormone secretion were studied in six normal human volunteers. Both drugs stimulated the secretion of prolactin dose-dependently, as expected. This effect was seen in all subjects, although two of the six subjects reacted more sensitively to both drugs. Plasma growth hormone concentrations were increased only after the higher dose of meptazinol. This was also seen in all subjects suggesting a specific pharmacological effect. Vasopressin (AVP) in plasma was greatly increased (up to 76 pg/ml) in three of the six subjects after the higher dose of meptazinol, but remained on a low level in the other three and after all other drug doses. The increase in AVP occurred only in those individuals who reported nausea after meptazinol. It was concluded that the augmented AVP release following meptazinol administration was likely to be a non-specific response induced by nausea and not an effect mediated by opiate receptors.

Oral premedication with clonidine: effects on stress responses during general anaesthesia.

The effect of clonidine (4.5 micrograms kg-1) on haemodynamics and hormonal stress responses was evaluated in 21 female patients undergoing breast surgery. The standardized general anaesthesia included diazepam as premedicant, thiopentone, enflurane, N2O, fentanyl and vecuronium. Venous plasma concentrations of noradrenaline, adrenaline, growth hormone, vasopressin, and cortisol were assayed at various times before, during and after surgery. Clonidine attenuated the sympathoadrenal response; arterial blood pressure and heart rate increases in association with intubation were lower in clonidine-premedicated patients. Noradrenaline levels were lower throughout and 3 h after surgery in the clonidine group (P less than 0.05). Adrenaline levels were lower in this group 2 min after intubation (P less than 0.05). Growth hormone, vasopressin and cortisol plasma levels were increased at the end of and after surgery, with no differences between the groups. In spite of the effect on sympathoadrenal response, clonidine did not have any significant additive anxiolytic effect. Statistically significant differences were not found as to need for postoperative analgesics.

Reduction of pain at venous cannulation in children with a eutectic mixture of lidocaine and prilocaine (EMLA cream): comparison with placebo cream and no local premedication.

The local analgesic efficacy of a cream formulation of lidocaine and prilocaine (EMLA) in reducing pain at venous cannulation was investigated in children scheduled for elective surgery. Forty children participated in a double-blind, randomized comparison between EMLA and inactive placebo cream. Another group of 18 children without any local treatment was studied as an additional control material. Subjective pain scores, expressed with a visual analogue scale, were significantly lower in the EMLA group compared with both the group treated with placebo cream (P less than 0.001) and the open control group (no cream; P less than 0.01). Local pallor and slight oedema were the only side-effects, registered in both cream-treated groups. A preliminary study was also carried out with 10 children (five with EMLA and five without) in order to determine whether catecholamine and vasopressin levels in venous blood are affected by the stress and anxiety associated with venepuncture in children premedicated with oral flunitrazepam. No significant hormone responses were, however, detected. The lidocaine concentrations measured in venous blood taken from the application site of EMLA cream were low, and there were no measurable levels of lidocaine in simultaneous blood samples from the opposite extremity. In our opinion EMLA cream is safe and alleviates effectively the pain associated with venepuncture, and thus deserves a place in the routine premedication of children.

Sympatho-adrenal and pituitary hormone responses during and immediately after thoracic surgery--modulation by four different pain treatments.

Four different pain treatments (single intercostal block with bupivacaine, repeated intercostal block, epidural morphine and epidural bupivacaine infusions) were compared in 39 patients subjected to lung surgery under general anaesthesia. The patients' own estimate of the postoperative pain was not significantly different between the groups, but the epidurally treated patients required fewer doses of supplementary analgesic than those given just a single dose of intercostal bupivacaine. Bupivacaine levels in blood were below the toxic range in all groups. The concentration of antidiuretic hormone in blood was increased early during the operation, and had only partly returned to normal on the first postoperative morning. Growth hormone in plasma was increased only at the end of the operation. Catecholamine levels in blood increased gradually, reaching their peak postoperatively. There were only slight differences between the groups in these posterior and anterior pituitary and sympatho-adrenal responses to surgical stress. Thus, neither repeated intercostal blockade nor epidural administration of morphine or bupivacaine could prevent the endocrine responses to thoracic surgery, in spite of significant, albeit incomplete, pain relief. This was probably caused in part by residual pain, and also by poor access of the extradural medications to the autonomic afferent pathways mediating nociceptive signals from thoracic organs and tissues.