Methylprednisolone inhibits increase of interleukin 8 and 6 during open heart surgery

It has been reported that interleukin 8 (IL-8) and interleukin 6 (IL-6) are two of the chemical mediators causing myocardial injury. It is not clear whether treatment with corticosteroids in vitro in these patients can prevent the production of interleukin 8 and 6. This prospective study was conducted to investigate whether methylprednisolone (MP) pretreatment (30 mg · kg^?1 before CPB and before declamping of aorta) influenced the production of IL-8 and 6 in the peripheral circulation in 27 patients undergoing elective coronary artery bypass surgery. The IL-8 and IL-6 concentrations were measured by ELISA kit. We also studied the effect of MP pretreatment on postoperative cardiac Junction. Serum concentration of IL-8 in non-MP-treated patients (37 ± 44 pg · ml^?1 preoperatively) increased to 169 ± 86 pg · ml^?1 60 min after declamping of the aorta (P < 0.001). The increase was greater than the increase from 22 ± 8.9 pg · ml^?1 to 52 ± 35 pg · ml^?1 in the MP-treated patients (P < 0.01). Serum IL-6 concentration in non-MP-treated patients increased from the preoperative value of 59 ± 30 pg · ml^?1 to 436 ± 143 pg · ml^?1 60 min after declamping of the aorta (P < 0.001). The increase was greater than the increase from 36 ± 15 pg · ml^?1 to 135 ± 55 pg · ml^?1 in the MP-treated patients (P < 0.01). Furthermore, postoperative cardiac index in MP-treated patients (3.6 ± 1.1 L · min^?1· m^?2) was higher than 2.3 ± 0.8 L · min^?1 · m^?2 of non MP-treated patients (P < 0.05). The levels of IL-8 max during surgery correlated negatively with postoperative cardiac index (γ = ?0.67). These results suggest that methylprednisolone suppresses production of IL-8 and 6.     

Interleukin-10 and Interleukin-1 receptor antagonists increase during cardiac surgery

Background

It has been reported that inflammatory cytokines such as interleukin-8 and 6 (IL-8, IL-6) increase during cardiac surgery and cause postoperative cardiac dysfunction. Therefore, it is important to investigate changes of suppressive cytokines such as IL-10, interleukin-4 (IL-4) and interleukin-1 receptor antagonist (IL-1 ra) dunng cardiac surgery.

Method

Serum levels of cytokines and IL-1 ra were measured in 10 patients during cardiac surgery with cardiopulmonary bypass. Six blood samples were drawn after inducing anaesthesia. In each sample, serum IL-10, IL-4, IL-8, IL-6 and IL-1 ra were measured by enzyme linked immunosorbent assay.

Results

Serum IL-6 and IL-8 concentration (19.1 ±8.8 pg · ml^?1, and 13.4±5.2 pg · ml^?1, preoperatively) increased to 227.5± 191 pg · ml^?1 and 81.0±56 pg · ml^?1 at 60 min after declamping the aorta (P< 0.01, respectively). Serum IL-10 concentration increased at 60 min after dedamping the aorta compared with the preoperative value (from 1.0±0 pg · ml^?1 to 552.0± 158 pg · ml^?1 P< 0.001]). Similarly, serum IL-1 ra concentration increased from the preoperative value of 1331±896 pg · ml^?1 to 43353±12812 pg · ml^?1 at 60 min after dedamping the aorta (P< 0.00l). Positive correlations were obtained between IL-10 and IL-8. and between IL-10 and IL-6 (γ=0.7, γ=0.8, P< 0.001, respectively).

Conclusion

These findings demonstrate that pro-and anti-inflammatory cytokines increase to maintain their balance during cardiac surgery.     

Ulinastatin reduces elevation of cytokines and soluble adhesion molecules during cardiac surgery

Purpose

To investigate whether ulinastatin pretreatment (6000 U · kg^?1 before CPB and before declamping of aorta) influenced the production of cytokines and adhesion molecules in the peripheral circulation.

Methods

This prospective randomized study was performed in 22 patients undergoing cardiac surgery. They were divided into two groups. Patients in Group I were untreated and in Group II treated with ulinastatin. The soluble intercellular adhesion molecule-1 (S-ICAM-1), soluble endothelial leukocyte adhesion molecule-1 (S-ELAM-1), interleukin8 and 6 (IL-8, 6) were measured using ELISA kits.

Results

Serum S-ICAM-1 concentration in Group I increased from the preoperative value of 297 ± 27 ng · kg^?1 to 418 ± 106 ng · kg^?1 at 60 min after declamping of the aorta (P < 0.01) but did not change in Group II. Serum S-ELAM-1 concentration did not change in either group. Serum concentration of IL-8 and IL-6 in Group I (37 ± 44 pg · kg^?1, and 59 ± 59 pg · kg^?1, preoperatively) increased to 169 ± 86 pg · kg^?1 and 436 ± 143 pg · kg^?1 at 60 min after declamping of the aorta (P < 0.001, P < 0.001). The increases were greater than those from 25 ± 6 pg · kg^?1 and 30 ± 26 pg · kg^?1 to 56 ± 36 pg · kg^?1 and 132 ± 78 pg · kg^?1 in Group II (P < 0.001, P < 0.001). The levels of S-ICAM-1 correlated with those of IL-8 (r = 0.5, P < 0.001).

Conclusion

These results suggest that ulinastatin may suppress the increase in IL-8 production and the expression of ICAM-1 during cardiac surgery.     

Adrenocorticotrophic hormone,cortisol and catecholamine concentrations during insulin hypoglycaemia in dogs anaesthetized with thiopentone

Glucose homeostasis is maintained by complex neuroendocrine control mechanisms. Increases in plasma concentrations of various glucose-raising hormones such as glucagon, catecholamines, adrenocorticotrophic hormone (ACTH), and cortisol are observed under certain conditions associated with stress (haemorrhage and hypoglycaemia). The purpose of this study was to determine the effect of thiopentone anaesthesia on the cathecholamine, ACTH and cortisol response to insulin hypoglycaemia in dogs. Blood sugar (BS), plasma cathecholamine, and ACTH, and serum cortisol concentrations were measured during the course of (1) an intravenous insulin test (ITT) and (2) an ACTH test in conscious and in anaesthetized fasted dogs. During the ITT, the anaesthetized dogs showed a moderate resistance, compared with conscious dogs, to the hypoglycaemic action induced by insulin (blood sugar concentration 30 min after insulin injection: 2.91 ± 0.25 vs 1.93 ± 0.12 mM · L^?1; P < 0.01). In addition, decreased epinephrine (220 ± 27 vs 332 ± 32 pg · ml^?1 ACTH (65 ± 6 vs 90 ± 5 pg · ml^?1) and cortisol (4.48 ± 0.3 vs 6.25 ± 0.5 μg · ml^?1) concentrations were detected 60 min after insulin injection (P < 0.01). The norepinephrine response to hypoglycaemia was not altered by anaesthesia (273 ± 33 vs 325 ± 25 pg · ml^?1). Anaesthetized dogs showed a decreased cortisol response to ACTH at 45 min (5.68 ± 0.54 vs 8.87 ± 0.47 μg · ml^?1) when compared with control dogs (P < 0.001). Haemodynamic variables during anaesthesia showed little changes (P < NS); while respiratory rate was altered (P < 0.01 between 60 and 105 min). Arterial pH was decreased (7.29 ± 0.03 vs 7.36 ± 0.04; P < 0.05) and PaCO₂ was increased (6.8 ± 0.3 vs 5.2 ± 0.3; P < 0.01) at 30 min from induction of anaesthesia but little change was seen after the beginning of the ITT and ACTH tests. We conclude that thiopentone anaesthesia provokes a moderate resistance to the hypoglycaemic action of insulin. This does not appear to be related to increases in plasma concentrations of cathecholamines, cortisol or ACTH. Since the hyperglycaemic effects of cathecholamines and glucagon are synergistic it is possible that glucagon plays an important role in the altered blood sugar response to insulin administration.     

Stress hormone responses to major intra-abdominal surgery during and immediately after sevoflurane-nitrous oxide anaesthesia in elderly patients

We studied the responses of plasma epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), cortisol, and antidiuretic hormone (ADH) during and immediately after sevoflurane-nitrous oxide anaesthesia supplemented with vecuronium in seven elderly patients (mean 76.6 ± 1.7 SEM) who underwent major intra-abdominal surgery. The plasma concentrations of norepinephrine, ACTH, cortisol, and ADH increased in response to surgical procedures (P <0.05). The plasma concentration of ADH increased to a peak concentration of 189.1 ± 20.7 pg · ml^?1 30 min after skin incision (P < 0.05). the plasma concentrations of epinephrine, norepinephrine, ACTH, and cortisol increased to peak concentrations of 408.6 ± 135.5 pg · ml^?1, 635.7 ± 167.8 pg · ml^?1, 222.6 ± 48.0 pg · ml^?1, and 113.6 ± 67.5 μg · dI^?1, respectively immediately after tracheal extubation (P <0.05). We conclude that, in the elderly patients, the responses of stress hormones to major intraabdominal surgery were preserved during sevoflurane-nitrous oxide anaesthesia sufficient to prevent increases in arterial pressure and heart rate. The strongest responses of epinephrine, norepinephrine, ACTH, and cortisol were elicited immediately after treacheal extubation.     

Kinetics of bupivacaine after clonidine pretreatment in mice

Previous studies have reported that clonidine pretreatment causes an increase in the local anaesthetic activity of bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, desbutylbupivacaine, PPX, in mice after a single, 0.1 mg · kg^?1, injection of clonidine. Kinetic variables of bupivacaine were determined after a single 20 mg · kg^?1 ip dose of bupivacaine in controls (Group I) and in clonidine (0.1 mg · kg^?1 ip) pretreated mice (Group 2). The maximal concentration in serum (Cmax, 2.553 ± 0.862 μg · ml^?1 versus 0.962 ± 0.141 μg · ml^?1 for. Groups 2 and 1, respectively, P = 0.01) and the area under the concentration curve (AUC, 3.530 ± 0.330 μ · ml^?1·^?1 versus 1.755 ± 0.252 Hg · ml^?1 · hr^?1 for Groups 2 and 1, respectively, P < 0.01) of bupivacaine were higher in clonidine pretreated mice while the Clearance (Cl) was decreased in clonidine pretreated animals (0.603 ± 0.054 μ · ml^?1 versus 1.264 ± 0.447 μg · ml^?1 for Groups 2 and 1, respectively, P < 0.01). The ratio of AUC PPX/AUC bupivacaine (which may partially indicate the rate of metabolism) was lower in presence of clonidine (0.220 ± 0.019 against 0.425 ± 0.033 for Groups 2 and 1, respectively, P < 0.01). Our data indicate decreased metabolism in the clonidine-treated mice which suggests altered hepatic metabolism of bupivacaine by clonidine. This may explain the previously reported enhanced anaesthetic activity of bupivacaine in the presence of clonidine.     

Haemodynamic,diuretic and hormonal responses to prostaglandin E1, infusion in halothane anaesthetized dogs: comparison among epidural lidocaine,epidural fentanyl and epidural saline

Deliberate hypotension decreases blood loss and transfusion but it may be accompanied by adverse effects due either to the hypotensive agents themselves or to haemodynamic alterations. Prostaglandin E₁ (PGE₁) has the advantage of a diuretic effect coupled with systemic hypotension. To elucidate the mechanisms by which PGE₁ induces diuresis we compared the haemodynamic, diuretic and hormonal responses to PGE₁ infusion simultaneously with epidural lidocaine (EP-L n = 7), epidural fentanyl (EP-F n = 8) or epidural saline (CONT n = 7) in halothane anaesthetized mongrel dogs. All groups developed a decrease in mean arterial pressure during PGE₁ infusion (from 105 ± 24 to 77 ± 18 mmHg in EP-L; 106 ± 19 to 79 ± 13 mmHg in the EP-F; and 129 ± 14 to 106 ± 18 mmHg in the CONT groups (mean ± SD)) (P < 0.05). In the EP-F and CONT groups urinary output increased during PGE₁ infusion (from 4.31 ± 1.89 to 6.15 ± 2.03 ml · min^?1 and 2.71 ± 1.23 to 4.48 ± 1.66 ml · min^?1 (P < 0.05), respectively) and was accompanied by increases in renal blood flow (from 87.0 ± 40.7 to 111.0 ± 42.8 ml · min^?1 and from 121.6 ± 46.6 to 158.4 ± 64.9 ml · min^?1 (P < 0.05), respectively) and in fractional excretion of sodium (FE_Na) (from 4.78 ± 3.88 to 7.63 ± 5.20% in CONT group). Plasma epinephrine concentration increased after laparotomy in the CONT group (from 0.09 ± 0.08 to 0.17 ± 0.14 pg · min^?1) (P < 0.05) and antidiuretic hormone (ADH) concentration increased after laparotomy (from 6.9 ± 5.2 to 21.0 ± 13.0 pg · ml^?1 in EP-F and from 8.1 ± 6.2 to 45.8 ± 29.9 pg · ml^?1 in CONT groups). Plasma renin activity increased after laparotomy in the EP-L group (from 2.00 ± 1.37 to 4.72 ± 2.73 mg · ml^?1 hr^?1) (P < 0.05). The results suggest that the mechansim of the PGE_1? induced diuretic effect includes increases in renal blood flow while renal sympathetic innervation is maintained and in FE_Na in the presence of elevated plasma ADH concentration.     

Clonidine does not affect lidocaine seizure threshold in rats

We investigated the effect of clonidine on intravenous (iv) lidocaine-induced haemodynamic changes and convulsions in awake rats. Wistar rats (200–250 g) were divided into three groups of eight and were pretreated with iv clonidine or normal saline 15 min before lidocaine infusion. Group 1 received normal saline; Group 2, 1 μg · kg^?1 clonidine; and Group 3, 10 μg · kg^?1 clonidine. After surgical preparation and recovery from anaesthesia, all groups received a continuous iv infusion of lidocaine (15 mg · ml^?1) at a rate of 4 mg · kg^?1 · min^?1 until generalized convulsions occurred. Oxygenation was well maintained in all groups. Pretreatment with clonidine changed neither cumulative convulsant doses (Group 1: 41.8 ± 2.2, Group 2: 43.8 ± 2.6, Group 3: 42.3 ± 2.0 mg · kg^?1, respectively) nor plasma concentrations of lidocaine at the onset of convulsions (Group 1: 10.5 ± 0.3, Group 2: 10.8 ± 0.3, Group 3: 10.6 ± 0.3 μg · ml^?1, respectively). The mean arterial blood pressures in Groups 2 and 3 were decreased after clonidine pretreatment (Group 2: 93 ± 1, P < 0.01, Group 3: 90 ± 1%, P < 0.01, respectively) and they gradually increased during lidocaine infusion. The heart rates decreased after clonidine pretreatment (Group 2: 94 ± 2, P < 0.05, Group 3: 86 ± 2%, P < 0.01, respectively) and the combination of clonidine and lidocaine potentiated the bradycardic effect of lidocaine at a subconvulsant dose. Our results indicate that clonidine has neither anticonvulsant nor proconvulsant effects on lidocaineinduced convulsions. However, the interactions of clonidine and lidocaine on blood pressure and heart rate should be investigated further.     

Haemodynamic changes during induced hypotension — comparison of trimethaphan with prostaglandin E1 assessed using transoesophageal echocardiography

Haemodynamic changes during induced hypotension depend upon the hypotensive agent used. We investigated if, using transoesophageal echocardiography (TEE), we could identify the haemodynamic differences between trimethaphan and prostaglandin E₁. Twenty-nine patients undergoing total hip replacement were selected for study. Hypotension was induced to a mean arterial pressure of 8.0– 9.3 kPa with either trimethaphan (5–20 μg · kg^?1 min^?1) or prostaglandin E₁ (0.5–2.0 μg · kg^?1 min^?1). The left atrial dimension, cardiac output, fractional shortening, pulmonary venous flow and mitral valve flow were evaluated using TEE. During induced hypotension, left atrial dimension decreased in both trimethaphan and prostaglandin E₁ groups (P < 0.05). In the trimethaphan-treated patients systolic velocity in pulmonary venous flow decreased from 41.9 ± 4.8 cm · sec^?1 before induced hypotension to 27.8 ± 4.2 cm · sec^?1 by 30 min after stable hypotension had been established (P < 0.01). The late/early ratio of peak velocity in mitral blood flow decreased in prostaglandin E₁ treated patients. Cardiac output increased from 4.2 ± 0.5 L · min^?1 to 5.3 ± 0.4 L · min^?1 during 30 min hypotension with prostaglandin E₁ administration (P < 0.05), but cardiac output decreased from 5.0 ± 0.5 to 3.5 ± 0.4 L · min^?1 with trimethaphan (P < 0.01). The differences in haemodynamic variables could be attributed to the venule dilatation effect of trimethaphan. We conclude that it was possible to detect the haemodynamic differences between trimethephan and prostaglandin E₁ using TEE.     

Midazolam reverses histamine-induced bronchoconstriction in dogs

Purpose

Midazolam has been used clinically as a sedative and as an anaesthetic induction agent. However, the bronchodilating effects of midazolam have not been comprehensively evaluated. We sought to determine relaxant effects of midazolam on the airway.

Methods

After our Animal Care Committee approved the study, eight mongrel dogs were anaesthetized with 30 mg · kg^?1 pentobarbitoneiv, and were paralysed with 200 μg · kg^?1 · hr^?1 pancuronium. The trachea was intubated with an endotracheal tube (ID 7 mm) that had a second lumen for insertion of a superfine fibreoptic bronchoscope (OD 2.2 mm) to measure the bronchial cross-sectional area (BCA) continuously. The tip of the bronchoscope was placed at the level of the second or third bronchial bifurcation of the nght bronchus. A videopnnter printed the BCA which was then measured with a NIH Image program. Bronchoconstnction was produced with histamine (H) 10 μg · kg^?1 followed by 500 μg · kg^?1 · hr^?1. Thirty minutes later, 0 [saline], 0.01, 0.1 and 1.0 mg · kg^?1 midazolam and 25 μg · kg^?1 flumazenil were given. The BCA was assessed before (basal area) and 30 min after the start of H infusion, and was also measured five minutes after each midazolam and flumazeniliv. At the same time, arterial blood was sampled for plasma catecholamine measurement.

Results

Histamine infusion decreased BCA to 49.7 ± 17.3% of basal BCA More than 0.1 mg · kg^?1 midazolam increased BCA up to 71.7 ± 15.3% of the basal (1.0 mg · kg^?1) (P < 0.01). Plasma adrenaline concentration was decreased from 6.9 ± 3.8 to 3.7 ± 1.9 ng · ml^?1 by 1.0 mg · kg^?1 midazolam (P < 0.05). Flumazenil did not antagonize the relaxant effect of midazolam but reversed the inhibitory effect of midazolam on histamine-induced adrenaline release.

Conclusion

Midazolam has a spasmolytic effect on constricted airways but this bronchodilatation was not reversed by flumazenil.     

Displacement of lidocaine from the lung after bolus injection of bupivacaine

The purpose of this study was to determine whether lidocaine was displaced from the lung after bolus injection of bupivacaine. Fourteen anaesthetized rabbits were randomly assigned to either a bupivacaine or a control group. Lidocaine was infused at a rate of 10 mg · kg^?1 hr^?1. After one hour of infusion, a bolus of bupivacaine (1 mg · kg^?1) in normal saline (0.2 ml · kg^?1) was injected into the central venous circulation in the bupivacaine group. The control group was injected with normal saline. After bolus injection, arterial blood samples were collected serially from an internal carotid artery at 1.2-sec intervals for 24 sec. The baseline concentration of lidocaine was 3.0 ±0.1 μg · ml^?1 in the bupivacaine group and 3.2 ±0.1 μg · ml^-1 in the control group (NS). Arterial concentrations of lidocaine increased to a maximum of 4.7 ±0.2 μg · ml^?1 in the bupivacaine group (P = 0.0001). No increases were seen in the control group. These findings indicate that lidocaine was displaced from the lung into the blood after bolus injection of bupivacaine. The amount of lidocaine displaced during the first passage of bupivacaine through the lung was calculated to be 92.3 ±9.7 μg. It is concluded that lidocaine is displaced from the lung after bolus injection of bupivacaine.     

Plasma concentrations after high-dose (45 mg · kg−1) rectal acetaminophen in children

Although the recommended dose of rectal acetaminophen (25–30 mg · kg^?1) is twice that for oral administration (10–15 mg · kg^?1), the literature justifies the use of a higher dose when acetaminophen is administered via the rectal route. We measured’ venous plasma acetaminophen concentrations resulting from 45 mg · kg^?1 of rectal acetaminophen in ten ASA 1, 15 kg paediatric patients undergoing minor surgery with a standardized anaesthetic. After induction of anaesthesia, a single 650 mg suppository (Abenol®, SmithKline Beecham Pharma Inc.) was administered rectally. Plasma was sampled at t = 0, 15, 30, 45, 60, 90, 120, 180, 240 min in the first five patients and at t = 0, 30, 60, 90, 120, 180, 240, 300, 420 min in the subsequent five. Acetaminophen plasma concentrations were determined’ using a TDxFLx® fluorescence polarization immunoassay (Abbott Laboratories, Toronto, Ontario). The maximum plasma concentration was 88 ± 39 μmol · L^?1 (13 ± 6 μg · ml^?1) and the time of peak plasma concentration was 198 ± 70 min (mean ± SD). At 420 min, the mean plasma concentration was 46 ± 18 μmol · L^?1 (7.0 ± 0.9 μg · ml^?1). No plasma concentrations associated with toxicity (> 800 μmol · L^?1) were identified. A 45 mg · kg^?1 rectal dose of acetaminophen resulted in peak plasma concentrations comparable with those resulting from 10–15 mg · kg^?1 of oral acetaminophen at three hours after suppository insertion. It is concluded that the delayed and erratic absorption of acetaminophen after rectal administration leads to unpredictable plasma concentrations. Rectal acetaminophen will not be consistently effective for providing rapid onset of analgesia in children.     

Effets de la lidocaïne aux concentrations plasmatiques obtenues par voie péridurale sur les troubles de la conduction auriculo-ventriculaire

The aim of this study was to measure plasma concentrations obtained during lidocaine extradural blocks, and to determine whether these concentrations were able to induce high degree AV blocks in patients with impaired AV conduction. In a preliminary study, 12 patients were given an extradural block with an initial bolus of 3.4 mg · kg^?1 lidocaine. After repeat injections, the mean total dose was 4.7 mg · kg^?1. Plasma lidocaine concentrations were determined over an 8 h period after the first injection. The study itself was carried out in 14 patients with conduction disturbances undergoing His-bundle exploration. After informed consent had been obtained, the patients received an intravenous bolus of lidocaine (1.6 mg · kg^?1 over 30 s). After baseline values had been measured, His conduction and lidocaine plasma concentrations were recorded 2, 5, 10, 30 and 60 min after lidocaine injection. In the preliminary study, the peak plasma lidocaine concentration was obtained at the 15th min (1.22 ± 0.81 μg · ml^?1). In the second series, no clinical disturbance was seen after the i.v. injection of lidocaine. The peak plasma lidocaine concentration was obtained at the 2nd min (3.05 ± 1.44 μg · ml^?1). No significant alteration of conduction occurred after intravenous lidocaine. It is therefore possible to conclude that bifascicular AV disturbances do not constitute a contraindication to extradural anaesthesia with lidocaine.     

Change in plasma endotoxin titres and endotoxin neutralizing activity in the perioperative period

Purpose

To elucidate whether endotoxaemia detected during major surgery was a specific or non-specific reaction.

Methods

Prospective clinical study in the operating theatre and multidisciplinary intensive care unit in a university hospital. A series of plasma samples was obtained from 21 patients, including eight after cardiopulmonary bypass (CPB), until 48 hr after surgery. The endotoxin titres in these samples were compared by the two chromogenic limulus amebocyte lysate (LAL) assays; one is factor C containing and the other factor G-free, endotoxin-specific test. The endotoxin neutralizing activity of the plasma was determined by adding the endotoxin to the plasma (1,000 pg · ml^?1), and by assaying how much the potency of the endotoxin to activate LAL was lost during incubation for 120 min at 37°C.

Results

Although endotoxin litres measured using the test including factor G showed a marked elevation during and after surgery, which were 3 ± 5 (4 ± 10), 14 ± 13 (20 ± 17**), 133 ± 13* (46 ± 29*), 89 ± 72* (48 ± 35*), 62 ± 40** (37 ± 29*), 50 ± 54 (39 ± 36) pg · ml^?1 in patients with CPB (without CPB), mean ± SD, at 0, 3, 6, 9, 24, and 48 hr after start of surgery (*P < 0.01, **P < 0.05 compared with 0 hr), those measured by the endotoxin-specific test did not show any changes. Plasma neutralized 95% of endotoxin potency after five minutes incubation at 37°C.

Conclusion

Using an endotoxin-specific assay, endotoxin could not be deleted in the blood stream during or after major surgery.     

Glucose intolerance during prolonged sevoflurane anaesthesia

Purpose

The effects of prolonged sevoflurane anaesthesia on insulin sensitivity were investigated by two successive intravenous glucose tolerance tests (IVGTT) in eight patients who underwent prolonged surgery.

Methods

The first IVGTT was administered (25 g glucose as 20% dextrose in water iv) over two minutes 35 min after initiation of surgery. Arterial blood samples were obtained at 0, 5, 10, 30, 60, and 120 min after glucose administration for blood glucose and plasma insulin determination. A second IVGTT was performed six hours following the initiation of surgery.

Results

The disappearance rate of glucose (k-value) for the first IVGTT was 0.887 ± 0.436 (mean ± SD) % · min^?1, and 0.784 ± 0.289 for the second IVGTT. Both k-values are lower than the normal value. The maximum insulin response to glucose (ΔIRI · ΔBS^?1) of the second IVGTT was lower than the first IVGTT (0.124 ± 0.092 vs 0.071 ± 0.056, P < 0.05). The total insulin output of the first IVGTT was higher than the second IVGTT (1,161 ± 830 vs 568 ± 389 μU · min · ml^?1, P < 0.05).

Conclusion

Glucose intolerance is enhanced by diminished insulin output in response to blood glucose elevation during prolonged anaesthesia and surgery.     

Modification of intravenous lidocaine-induced convulsions by epinephrine in rats

We studied intravenous lidocaine-induced convulsions in rats to determine whether added epinephrine influences the provocation of lidocaine toxicity. Wistar rats (200–250 g) were divided into three groups of ten, depending on the concentration of epinephrine added to lidocaine. Group 1: plain 1.5% lidocaine; Group 2: 1.5% lidocaine with 1∶200,000 epinephrine; Group 3: 1.5% lidocaine with 1∶100,000 epinephrine. After surgical preparation and recovery from anaesthesia, all rats received a continuous iv infusion of lidocaine (15 mg·ml^?1) at a rate of 4.0 mg·kg^?1·min^?1 until generalized convulsions occurred. The epinephrine-treated animals developed acute hypertension after one minute of lidocaine infusion (105±2 to 141±2 mmHg in Group 2 and 103±2 to 151±2 mmHg in Group 3). The PaO₂ values in the epinephrine groups at the onset of convulsions were decreased significantly (88.3±1.0 to 84.0 ±1.5 mmHg in Group 2 P < 0.05 and 86.9±1.2 to 78.1±2.4 mmHg in Group 3 P<0.01). However, these values were still within physiological ranges. Serum potassium concentrations in all groups were decreased P<0.05, (4.24±0.09 to 3.52±0.12 mEq·L^?1 in Group 1, 4.02±0.09 to 3.63±0.17 mEq·L^?1 in Group 2, and 4.15±0.10 to 3.69 ±0.17 mEq·L^?1 in Group 3). Blood sugar concentrations in all groups were increased at the onset of convulsions, and the levels in the epinephrine groups were higher than in Group 1 P<0.01 (119±4 to 149±7 mg·dl^?1 in Group 1: 120±4 to 195±10 mg·dl^?1 in Group 2, and 127±3 to 190±6 mg·dl^?1 in Group 3). There were differences in the cumulative convulsant doses of lidocaine among the groups, as follows: Group 1=41.9±1.3 > Group 2=30.0±0.7 > Group 3=24.2±0.9 mg·kg^?1; P<0.01. At the onset of convulsions, not only the plasma lidocaine concentrations (Group 1=10.7±0.3 > Group 2=8.3±0.2 (P<0.01) > Group 3=7.5±0.2 μg·ml^?1 (P<0.01 vs Group 1, P < 0.05 vs Group 2), but also the brain lidocaine concentrations which were extracted from the whole brain homogenates: Group 1=48.7±1.9 > Group 2=38.2±1.1 (P<0.01) > Group 3=33.0±1.3 μg·g^?1 (P <0.01 vs Group 1, P<0.05 vs Group 2) showed differences. The brain/plasma lidocaine concentration ratios were, however, similar in the three groups (Group 1=4.5±0.1; Group 2=4.6±0.1; Group 3=4.4±0.2). Our data show that added epinephrine decreases the threshold of lidocaine-induced convulsions dose-dependently; however, the added ephinephrine does not cause a greater proportion of the infused lidocaine to enter the CNS.     

Cigarette smoke increases bupivacaine metabolism in rats

This study was designed to document possible changes in bupivacaine kinetics in rats after exposure to cigarette smoke. Rats (n = 15) were exposed to cigarette smoke (Borgwaldt type Hamburg II) for ten minutes per day during four days (C) or eight days (B); controls (A) were used simultaneously without exposure to cigarette smoke. After bupivacaine 20 mg · kg^?1 ip at day 4 (C) or day 8 (B), blood was sampled (0.5 ml of blood collected by puncture at the retro-orbital sinus 0.25, 0.5, 1, 2, 4, 6 and 8 hours after administration) and bupivacaine and its main metabolite i.e., desbutylbupivacaine (PPX) were determined by gas liquid chromatography. The sensitivity of the method was 15 ng · ml^?1 and the reproductibility was <6%. Serum bupivacaine concentrations were plotted against time and the pharmacokinetic variables were determined assuming a two compartment open model: Cmax, Tmax were derived directly from individual data. The β phase elimination halflives (T_1/2β), the area under the serum concentration curve (AUC₀ ^∞), the total plasma clearance (Cl) and the total volume of distribution (Vd) were calculated. These variables were assessed according to non-linear fitting method. Cigarette smoking exposure did not change the pharmacokinetic variables of bupivacaine. However, the pharmacokinetic parameters of PPX, Cmax (0.175 ± 0.007 μg · ml^?1, 0.119 ± 0.014 μg · ml^?1 and 0.312 ± 0.023 μg · ml^?1, for groups A, B and C, respectively), AUC (0.170 ± 0.006 μg · ml^?1 · hr^?1, 0.104 ± 0.013 μg · ml^?1 · hr^?1 and 0.433 ± 0.017 μgv· ml^?1 · hr^?1 for groups A, B and C, respectively) and the ratio AUC PPX/ AUC bupivacaine (0.306 ± 0.042, 0.153 ± 0.021 and 0.660 ± 0.054 for groups A, B and C, respectively) were higher (P < 0.0001) for group C. These results indicate an enzymatic induction after only short exposure to cigarette smoking and justify further studies to document possible variations of the metabolism of bupivacaine induced by exposure to cigarette smoke in humans.     

Epidural and intravenous bolus morphine for postoperative analgesia in infants

Purpose

To compare two doses of bolus epidural morphine with bolus iv morphine for postoperative pain after abdominal or genitourinary surgery in infants.

Methods

Eighteen infants were randomly assigned to bolus epidural morphine (0.025 mg · kg^?1 or 0.050 mg · kg^?1) or bolus iv morphine (0.050–0.150 mg · kg^?1). Postoperative pain was assessed and analgesia provided, using a modified infant pain scale. Monitoring included continuous ECG, pulse oximetry, impedance and nasal thermistor pneumography. The CO₂ response curves and serum morphine concentrations were measured postoperatively.

Results

Postoperative analgesia was provided within five minutes by all treatment methods. Epidural groups required fewer morphine doses (3.8 ± 0.8 for low dose [LE], 3.5 ± 0.8 for high dose epidural [HE] vs. 6.7 ± 1.6 for iv, P < 0.05) and less total morphine (0.11 ± 0.04 mg · kg^?1 for LE, 0.16 ± 0.04 for HE vs 0.67 ± 0.34 for iv, P < 0.05) on POD1 Dose changes were necessary in all groups for satisfactory pain scores. Pruritus, apnoea, and haemoglobin desaturation occurred in all groups. CO₂ response curve slopes, similar preoperatively (range 36–41 ml · min^?1 · mmHg ETco ₂ ^?1 · kg^?1) were generally depressed (range, 16–27 ml · min^?1 · mmHg ETco ₂ ^?1 · kg^?1) on POD1. Serum morphine concentrations, negligible in LE (<2 ng · ml^?1), were similar in the HE and iv groups (peak 8.5 ± 12.5 and 8.6 ± 2.4 ng · ml^?1, respectively).

Conclusion

Epidural and iv morphine provide infants effective postoperative analgesia, although side effects are common. Epidural morphine gives satisfactory analgesia with fewer doses (less total morphine); epidural morphine 0.025 mg · kg^?1 is appropriate initially. Infants receiving epidural or iv morphine analgesia postoperatively need close observation in hospital with continuous pulse oximetry.     

Dose-response relationships for edrophonium antagonism of mivacurium-induced neuromuscular block during N2O-enflurane-alfentanil anaesthesia

The purpose of this study was to determine the dose-response relationships for edrophonium antagonism of mivacuriuminduced neuromuscular block. Seventy-five ASA I or II adults were given mivacurium 0.15 mg · kg^{? 1} followed by an infusion (7 μg · kg^{? 1} · min^{? 1}) during alfentanil-propofol-N₂O-enflurane anaesthesia. Train-of-four stimulation (TOF) was applied to the ulnar nerve every 20 sec and the response of the adductor pollicis was recorded (Relaxograph NMT-100. Datex, Helsinki, Finland). Mivacurium infusion was modified at five-minute intervals in order to keep the height of the first twitch in TOF (T₁) at 5% of its control value. At the end of surgery, edrophonium (0.0. 0.125, 0.25, 0.5. or 1.0 mg · kg^{? 1}) combined with glycopyrrolate (0.0, 0.0012, 0.0025, 0.005, or 0.01 mg · kg^{? 1}) were administered by random allocation. Edrophonium doses of 0.25, 0.5 and 1.0 mg · kg^{? 1} were different from placebo with regard to time to attain a TOF ratio (fourth twitch in TOF/ T,) = 0.7 (13.8 ± 4.5, 11.1 ± 3.5, 11.4 ± 3.0 vs 19.7 ± 4.7 min P < 0.05). Doses of 0.5 and 1.0 mg · kg^{? 1} permitted faster recovery time of T₁ from 10 to 95% (T_{10– 95}) than did placebo (7.5 ± 3.8,8.9 ± 3.5 vs 14.5 ± 5.0 min P < 0.05). Edrophonium 0.5 mg · kg^{? 1} was different from placebo with regard to recovery time of T₁ from 25 to 75% (T_{25– 75}) (3.3 ± 2.0 vs 6.7 ± 2.0 min P < 0.05). Only edrophonium 0.5 mg · kg^{? 1} provided faster recovery than placebo with regard to all three indices. It is concluded that edrophonium 0.5 + glycopyrrolate 0.005 mg · kg^{? 1} allow the fastest recovery from a mivacurium-induced block during enflurane-N₂O anaesthesia.     

Serum bupivacaine concentrations during continuous extrapleural infusion

Purpose

To determine the rate of increase in serum bupivacaine concentration during continuous extrapleural infusion.

Methods

After thoracotomy for lobectomy under general anaesthesia, nine patients had an extrapleural catheter inserted, before chest closure, in a costovertebral gutter constructed surgically by lifting the panetal pleura. Bupivacaine 0.5% with epinephnne 1:200.000 was injected through the catheter as 0.3 ml·kg^?1 bolus followed by 0.1 ml· kg^?1·hr^?1 for five days. Serum bupivacaine (free and total), albumin, alpha-1 acid glycoprotein concentrations were measured 15 min after injection and at 24 hr intervals for five days. Bupivacaine concentrations were determined by column liquid chromatography using solid phase extraction. Serum alpha-1 acid glycoprotem concentration was determined by nephelometry on QM 300 protein analyzer. Serum albumin concentration was determined by bromocresol green dye binding procedure on Hitachi 717 Autoanalyzer.

Results

A continuous elevation in total serum bupivacaine was observed, with an average value of 0.75 μg· ml on day 1 to 2.77 μg· ml on day 4 (P< 0.05). There was no increase in postoperative free serum bupivacaine concentration; average value of 177 pcg· ml^?1 on day 1 and 249 pcgml^?1 on day 4 (P=0.92). Postoperative serum alpha-1 acid glycoprotein concentration showed a steady rise with an average value of 0.94 μg· ml^?1 on day 1 and 1.47 μg·ml^?1 on day 4 (P< 0.05). No change was observed in post-operative serum albumin with an average value of 31.4 g· l^?1 on day 1 and 31.3 g· l^?1 on day 4.

Conclusion

Continuous extrapleural infusion of bupivacaine over five days after thoracotomy is associated with a steady increase in total serum bupivacaine concentration and no elevation in free serum bupivacaine concentration.