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.     

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.     

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.     

Elevation of cytokines during open heart surgery with cardiopulmonary bypass: participation of interleukin 8 and 6 in reperfusion injury

Myocardial ischaemia is one of the major causes of low output syndrome during open heart surgery. Injury associated with ischaemia and reperfusion has been considered to result, in part, from the action of neutrophils, the interaction of neutrophils with vascular endothelial cells, and the effects of cytokines which are mediators that induce and modify reactions between these substances. We investigated cell injury in relation to the concentrations of interleukins 6 and 8 (IL-6 and IL-8), which have recently received attention as neutrophil activators. Neutrophil counts, granulocyte elastase (GEL), IL-6, IL-8, tumour necrosis factor-α (TNF-α), CK, and CK-MB concentrations were determined serially in 11 patients undergoing open heart surgery with cardiopulmonary bypass (CPB). Neutrophil counts (mean ±SD 2717 ±2421 μl^?1 preoperatively) peaked 60 min after declamping the aorta at 7432 ±4357 μl^?1 (P < 0.01) and remained elevated 7136 ±5194 μl^?1 at 180 min (P < 0.01). Plasma GEL level (168 ±71 μg sd L^?1 preoperatively) peaked at 1134 ±453 μg · L^?1 120 min after declamping of the aorta (P < 0.01) and remained elevated, 1062 ±467 μg · L^?1, after 180 min (P < 0.01). Serum IL-6 level (118 ±59 pg · ml^?1 preoperatively) peaked at 436 ±143 pg · ml^?1 60 min after declamping of the aorta (P < 0.01) and remained elevated, 332 ±109 pg · ml^?1, after 180 min. Serum IL-8 level (37 ±44 pg · ml^?1 preoperatively) peaked at 169 ±86 pg · ml^?1 at 60 min after declamping of the aorta (P < 0.001) and remained elevated at 113 ±78 pg · ml^?1 180 min after declamping of the aorta. Serum TNF-α was decreased at 60 min after aortic occlusion but otherwise did not change. Plasma GEL concentrations correlated with serum IL-8 levels (R = 0.7, P = 0.001) and the IL-6 and IL-8 concentrations correlated with the duration of aortic clamping (R = 0.64, P = 0.01, R = 0.7, P = 0.01). We conclude that the increases of IL-6 and IL-8 occur as a result of ischaemia, and suggest that these cytokines participate in reperfusion injury by activating neutrophils.     

Intraoperative mild hypothermia does not increase the plasma concentration of stress hormones during neurosurgery

PURPOSE: To determine how mild hypothermia (34 degrees C) affects the hemodynamic and the stress hormonal responses intraoperatively and during extubation in patients undergoing cerebral aneurysm surgery. METHODS: After induction, anesthesia was maintained with 1.2% isoflurane and 50% nitrous oxide. For the normothermia and the hypothermia groups, the body temperature was maintained at 36.9 +/- 0.3 degrees C and 34.2 +/- 0.2 degrees C respectively up to the recovery room. Hemodynamic changes were recorded continuously. Stress hormones comprising epinephrine, norepinephrine, ADH, ACTH, and cortisol were measured at the awake control, intraoperative, and extubation periods. RESULTS: Vital signs of the intraoperative and postextubation time periods were not significantly different between the normothermia and hypothermia groups except for a statistically lower pulse rate intraoperatively in the hypothermia group (P <0.05). In the control awake state, all five hormonal concentrations were similar between the two groups. Intraoperatively, all of the hormonal levels tended to be lower in the hypothermia group compared to the normothermia group, but only the epinephrine level decreased sufficiently to reach statistical significance (P <0.05). During extubation, all stress hormone concentrations, except norepinephrine, were lower in the hypothermia group (epinephrine: P <0.05; ADH: P <0.05; ACTH: P <0.05; cortisol: P <0.05). CONCLUSIONS: Our data suggest that intraoperative mild hypothermia neither significantly affects the blood pressure response nor increases the concentrations of stress hormones intraoperatively. Furthermore, mild hypothermia significantly decreased the plasma concentrations of stress hormones during the extubation period.     

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.     

The role of catecholamines in the pathogenesis of neurogenic pulmonary edema associated with subarachnoid hemorrhage

Background

Neurogenic pulmonary edema (NPE) occurs frequently after aneurysmal subarachnoid hemorrhage (SAH), and excessive release of catecholamines (epinephrine/norepinephrine) has been suggested as its principal cause. The objective of this retrospective study is to evaluate the relative contribution of each catecholamine in the pathogenesis of NPE associated with SAH.

Methods

Records of 63 SAH patients (20 men/43 women) whose plasma catecholamine levels were measured within 48?h of SAH onset were reviewed, and the clinical characteristics and laboratory data of those who developed early-onset NPE were analyzed thoroughly.

Results

Seven patients (11?%) were diagnosed with NPE on admission. Demographic comparison revealed that the NPE+ group sustained more severe SAH than the NPE? group. Cardiac dysfunction was also significantly more profound in the former, and the great majority of the NPE+ group sustained concomitant cardiac wall motion abnormality. There was no significant difference in the plasma epinephrine levels between NPE+ and NPE? group (324.6?±?172.8 vs 163.1?±?257.2?pg/ml, p?=?0.11). By contrast, plasma norepinephrine levels were significantly higher in the NPE+ group (2977.6?±?2034.5 vs 847.9?±?535.6?pg/ml, p?<?0.001). Multivariate regression analysis revealed that increased norepinephrine levels were associated with NPE (OR, 1.003; 95?% CI, 1.002–1.007). Plasma epinephrine and norepinephrine levels were positively correlated (R?=?0.48, p?<?0.001). According to receiver operating characteristic curve analysis, the threshold value for plasma norepinephrine predictive of NPE was 2,000?pg/ml, with an area under the curve value of 0.85.

Conclusions

Elevated plasma norepinephrine may have more active role in the pathogenesis of SAH-induced NPE compared with epinephrine, although both catecholamines may be involved via multiple signaling pathways.     

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.     

Postoperative analgesia with “3-in-1” femoral nerve block after prosthetic hip surgery

Purpose

To evaluate the efficacy of a single shot “3-in-1” femoral nerve block for prosthetic hip surgery in association with general anaesthesia on post-operative analgesia.

Methods

Forty patients, ASA 1 to 3, received sham block or “3-in-1” femoral nerve block, following Winnie’s landmarks with a nerve stimulator, and 40 ml bupivacaine 0.5% with epinephrine were injected after induction of anaesthesia. Vecuronium, 0.1 mg· kg^?1, was added after performing the block and anaesthesia was maintained with isoflurane, oxygen 40% and nitrous oxide 60%. Fentanyl, 1.5 μg· kg^?1, was administered before incision to all patients. Heart rate, blood pressure, fentanyl requirements and F_ETiso were measured throughout surgery. During the post-operative period, 75 mg diclofenacim and/or 0.1 mg· kg^?1 morphine sc were administered when pain score was > 3/10 and repeated when necessary. Pain scores at first analgesic intervention, at 24 hr and 48 hr as well as diclofenac and morphine requirements after surgery were recorded.

Results

There was no difference in anaesthetic requirements during surgery. The time from performance of sham or “3-in-1” femoral nerve block to the first analgesic intervention (261 ± 49 min versus 492 ± 40 min,P < 0.05) and time from extubation to the first analgesic intervention (61 ± 44 minvs 298 ± 39 min,P < 0.05) were prolonged in the study group. However, pain scores and the analgesic requirements in the postoperative periods (24 and 48 hr) were similar.

Conclusion

There is a short-term benefit during the first few postoperative hours in using a single shot “3-in-1” femoral nerve block to complement general anaesthesia for elective hip surgery.     

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.     

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.     

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.     

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.     

Plasma lipid concentrations correlate inversely with CPB-induced interleukin-6 release

Purpose

Cardiopulmonary bypass (CPB) is characterized by translocation of intestinal endotoxin and subsequent endogenous production of the pro-inflammatory cytokine interleukin-6 (IL-6). Plasma lipid fractions, especially high density lipoproteins, bind and neutralize endotoxin and, therefore, inhibit endotoxin-induced macrophage cytokine production, including IL-6. Increased IL-6 plasma levels have been implicated in adverse consequences associated with CPB. Previous studies demonstrated large interpatient variability in IL-6 plasma levels after CPB. The purpose of this study was to evaluate the relationship between plasma lipid concentrations and the concentrations of IL-6 following CPB in humans.

Methods

In a prospective study, a group of 15 patients selected to exclude variables known to influence post-CPB plasma levels of IL-6 (preoperative left ventricular ejection fraction > 45%, similar durations of aortic cross clamping and total CPB time, similar temperature control during CPB, and avoidance of platelet transfusion and shed mediastinal blood re-infusion), IL-6 was measured at baseline, one and 24 hr post-CPB.

Results

Interleukin-6 plasma concentrations (mean ± SD) increased at one (142 ± 89 pg·ml^?1,P < 0.05) and 24 (129 ± 82 pg·ml^?1,P < 0.05) hr post-CPB compared with baseline (1,5 ± 1 pg·ml^?1) concentrations. An inverse correlation was found between IL-6 plasma concentrations at one hour post-CPB and plasma cholesterol concentrations (r = -0.592,P = 0.02), high density lipoprotein (r = -0.595,P = 0.02), and low density lipoprotein (r = -0.656,P = 0.01).

Conclusions

These results suggest that plasma lipids attenuate the production of IL-6 during CPB and may partly explain the variability of interpatient levels of IL-6 reported post-CPB by others.     

Densities of cerebrospinal fluid and spinal anaesthetic solutions in surgical patients at body temperature

Purpose

To determine the densities of cerebrospinal fluid (CSF) in patients for surgery under spinal anaesthesia. The densities of the CSF were compared with the densities of local anaesthestic solutions and their mixtures with commonly used spinal opioids.

Method

One ml of CSF was collected from 131 consecutive patients that consented to the study at the time of spinal anaesthesia. Densities were measured at 37°C in a Density Meter that displayed density to the fourth decimal point and was accurate to 0.00003 g·ml^?1 The densities of a selection of spinal anaesthetic drugs were also measured.

Results

The mean CSF density in the study population was 1.00059 ± SD 0.00020. In men of all ages, the mean CSF density was 1.00067 ± 0.0001 8 g·ml^?1; in postmenopausal women 1.00060 ± 0.00015 g·ml^?1; in premenopausal non-pregnant women 1.00047 ± 0.00076 g·ml^?1; and in pregnant women 1.00033 ± 0.00010 g·ml^?1 There were differences between the CSF densities in pregnant women compared with men (P = 0.0001), postmenopausal women (P = 0.0001) and non-pregnant premenopausal women (P = 0.03). Local anaesthetic solutions that contain sugar (glucose or dextrose) were all hyperbaric. In the absence of sugar, all local anaesthetic solutions were hypobaric except for lidocaine CO₂ which was slightly hyperbaric. Opioids were all hypobaric except meperidine which was hyperbaric.

Conclusion

Pregnant women have slightly lower CSF densities than do men and postmenopausal women, and non-pregnant premanopausal women. In the absence of sugar all spinal anaesthetic solutions measured were hypobaric except for lidocaine CO₂ and meperidine, both of which were hyperbaric.     

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 the apnoea test for diagnosis of brain death

Haemodynamic responses to the apnoea test jor the diagnosis of brain death were investigated in nine patients with severe head injury or cerebrovascular disease. To prove apnoea, the ventilator was disconnected for ten minutes and oxygen was insufflated to avoid hypoxaemia. No respiratory movement was séen in any patient. Ten minutes after disconnecting the ventilator, PaCO₂ was increased to 78 ± 3 mmHg and pH was reduced to 7.17 ± 0.02. Adequate oxygenation was maintained in all patients. Cardiac output increased from 4.8 ± 0.7 to 5.7 ± 0.8 L · min^{? 1} (P < 0.05), and mean pulmonary artery pressure increased from 11 ± I to 17 ± 2 mmHg (P < 0.01). However, mean arterial pressure, heart rate, pulmonary artery wedge pressure and right a trial pressure did not change. Plasma catecholamines were measured in three patients. Plasma norepinephrine concentrations increased in all three patients but the changes in plasma epinephrine were minimal. These circulatory responses to acute hypercapnia were less than those reported in awake volunteers and in patients during general anaesthesia. However, since plasma norepinephrine concentration increased during the test, some sympathoadrenal response, probably of spinal origin, was present, and may have prevented the direct depressant circulatory effects of acute hypercapnia. In conclusion, the apnoea test did not produce haemodynamic disturbances when respiratory acidosis was limited toapH 7.17±0.02 and PaCO₂ 60–80 mmHg.     

Plasma concentrations of bupivacaine in young infants after continuous epidural infusion

This study reports plasma bupivacaine concentration in seven infants who during major abdominal surgery received lumbar epidural or caudal block anaesthesia. Plasma concentrations (CP) were measured postoperatively after six and twelve h of continuous infusion. Postnatal age ranged from one day to seven months. The local anaesthetic block was performed after induction of anaesthesia. Postoperatively bupivacaine 1.25-2.5 mg·ml^?1 without adrenaline was infused at a rate of 0.5 to 0.83 mg·kg^?1·h^?1. After six h of infusion the mean value measured was 1.59 μg·ml^?1 (range 1.2-1.94 μg·ml^?1). After 12 h the mean value measured was 2.06 μg·ml^?1 (range 1.53-2.98 μg·ml^?1). A marked increase in bupivacaine plasma concentration was seen between six and 12 hours of infusion. Bupivacaine plasma concentration never exceeded 4 μg·ml^?1. Adverse effects that possibly were due to a toxic reaction to bupivacaine were seen in three patients. In conclusion, the dose administered in this study appears to be high and cannot be recommended as safe dosage in this age group.;     

Sufentanil transfer in the human placenta during in vitro perfusion

Purpose

Sufentanil, a lipophilic opioid, is used to provide analgesia for labour and Caesarean section, but may cause neonatal depression. Factors affecting placental transfer of sufentanil were investigated using human placentas.

Study design

Transfer and uptake of sufentanil by the human placenta were studied using a single pass (open)in vitro perfusion model. The effects of change in sufentanil concentration (1–100 ng· ml^?1) and change in fetal pH (range 7.4–6.8) on placental transfer were studied. Placental metabolism of sufentanil and the effects of maternal protein content (fresh human plasma, albumin 4%, Media 199) on placental transfer were also investigated utilizing a closed (recirculated)in vitro perfusion system.

Results

Sufentanil transfer was 2% at five minutes and plateaued at 12% by 45 min. The clearance index (Cl =sufentanil clearance/antipyrine clearance) was 0.56 ± 0.2 for maternal to fetal (MTF) and 0.44 ± 0.2 in the fetal to maternal (FTM) directions (P=NS). The Cl was 0.5 ± 0.2 for 1 ng· ml^?1 and 0.61 ± 0.3 for 100 ng· ml^?1 sufentanil concentration (P=N.S.). The placenta contained 7.1 ± 2 and 9.8 ± 3 ng· g^?1 sufentanil following MTF and FTM perfusions for 90 min at 1 ng· ml^?1. The placenta did not metabolize sufentanil. After one hour MTF washout, placental sufentanil content was 2.3 ±.5 ng· g^?1 with 0.08 ng· ml^?1 sufentanil in the umbilical vein. Maternal plasma decreased MTF Cl from 0.41 ± 0.1 for albumin and 0.4 ± 0.1 for Media 199 to 0.17 ±.06 for plasma (P < 0.05). Decreasing fetal pH increased MTF Cl from 0.57 ±.13 at pH 7.4 to 1.6 ±.4 at pH 6.8 (P < 0.05).

Conclusion

Sufentanil crossed the placenta by passive diffusion and accumulated in placental tissue, which acted as a drug depot, slowing the initial transfer. Placental transfer was decreased by maternal plasma proteins, but not by albumin. Fetal acidosis increased placental transfer. Due to its low initial umbilical vein concentration, sufentanil may be the opioid of choice when delivery is imminent (< 45 min).