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.     

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.     

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.     

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.     

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.     

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.     

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.     

Endoscopic Duodenal–Jejunal Bypass Liner Rapidly Improves Type 2 Diabetes

Background

Bariatric procedures excluding the proximal small intestine improve glycemic control in type 2 diabetes within days. To gain insight into the mediators involved, we investigated factors regulating glucose homeostasis in patients with type 2 diabetes treated with the novel endoscopic duodenal–jejunal bypass liner (DJBL).

Methods

Seventeen obese patients (BMI 30–50 kg/m²) with type 2 diabetes received the DJBL for 24 weeks. Body weight and type 2 diabetes parameters, including HbA_1c and plasma levels of glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon, were analyzed after a standard meal before, during, and 1 week after DJBL treatment.

Results

At 24 weeks after implantation, patients had lost 12.7?±?1.3 kg (p?<?0.01), while HbA_1c had improved from 8.4?±?0.2 to 7.0?±?0.2 % (p?<?0.01). Both fasting glucose levels and the postprandial glucose response were decreased at 1 week after implantation and remained decreased at 24 weeks (baseline vs. week 1 vs. week 24: 11.6?±?0.5 vs. 9.0?±?0.5 vs. 8.6?±?0.5 mmol/L and 1,999?±?85 vs. 1,536?±?51 vs. 1,538?±?72 mmol/L/min, both p?<?0.01). In parallel, the glucagon response decreased (23,762?±?4,732 vs. 15,989?±?3,193 vs. 13,1207?±?1,946 pg/mL/min, p?<?0.05) and the GLP-1 response increased (4,440?±?249 vs. 6,407?±?480 vs. 6,008?±?429 pmol/L/min, p?<?0.01). The GIP response was decreased at week 24 (baseline—115,272?±?10,971 vs. week 24—88,499?±?10,971 pg/mL/min, p?<?0.05). Insulin levels did not change significantly. Glycemic control was still improved 1 week after explantation.

Conclusions

The data indicate DJBL to be a promising treatment for obesity and type 2 diabetes, causing rapid improvement of glycemic control paralleled by changes in gut hormones.     

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.     

Quantifying the effect of enflurane on atracurium infusion requirements

The present study was designed to evaluate the interaction between atracurium and enflurane in 40 adult surgical patients using closed-loop feedback control of infusions of atracurium. Anaesthesia was induced with thiopentone and fentanyl and intubation was facilitated with atracurium 0.5 mg· kg^?1 lean body mass. During the first 90 min, anaesthesia was maintained with nitrous oxide in oxygen (2:1) and fentanyl. For the following 90 min the patients were randomly assigned to receive enflurane at different end-tidal concentrations: Group I, control, fentanyl-nitrous oxide anaesthesia; Group II, enflurane 0.3%-nitrous oxide; Group III, enflurane 0.6%-nitrous oxide; Group IV, enflurane 0.9%-nitrous oxide. The possible interaction of atracurium with enflurane was quantified by determining the asymptotic steady-state rate of infusion (I_ss) of atracurium necessary to produce a constant 90% neuromuscular block. This was accomplished by applying nonlinear curve fitting to data on the cumulative dose requirements. Every patient served as his/her own control and the changes in the infusion rates were determined individually. Patient characteristics and controller performance, i.e., the ability of the controller to maintain the neuromuscular blockade constant at the setpoint, did not differ among groups. In Group II I_ss decreased from 0.33 ± 0.12 to 0.26 ± 0.08 mg· kg^?1· hr^?1 (P < 0.01), in Group III from 0.32 ± to 0.12 to 0.24 ± 0.08 mg· kg^?1· hr^?1 (P < 0.001) and in Group IV from 0.29 ± 0.09 to 0.21 ± 0.09 mg· kg^?1 · hr^?1 (P < 0.001). In the control group atracurium requirements remained unchanged throughout the study. Enflurane reduces atracurium requirements in a dose-dependent manner. During enflurane anaesthesia the rate of atracurium infusion should be reduced but because of interindividual differences the monitoring of the neuromuscular function is important to ensure the appropriate level of neuromuscular block.     

Blood sugar,serum insulin and serum non-esterified fatty acid levels during thiopentone anaesthesia in dogs

The purpose of this study was to determine the effect of thiopentone anaesthesia on glucose metabolism. Blood sugar (BS), serum immunoreactive insulin (IRI) and serum non-esterified fatty acid (NEFA) concentrations were measured during the course of (1) an intravenous glucose tolerance test (IVGTT), and (2) an intravenous insulin test (ITT), in conscious and anaesthetized fasted dogs. The IVGTTs were repeated in dogs under alpha-or beta-adrenergic blockade, induced by phentolamine or propranolol. During the IVGTT, the anaesthetized dogs showed glucose intolerance (blood sugar levels were higher than in the control group) and little serum IRI response to hyperglycaemia was detected. An attenuated initial decrease and a slower rebound of NEFA concentration was observed in anaesthetized animals than in controls. Phentolamine administration (5 mg · kg^?1 iv) partly restored the IRI response without affecting the BS levels; propanolol (1 mg · kg^?1 iv) had no effect. Anaesthetized dogs showed a moderate resistance to insulin induced hypoglycaemic action and a lack of serum NEFA response during counter-regulation of hypoglycaemia, while in conscious controls an intense rebound was observed. Hyperinsulinaemia after iv insulin administration was longer in anaesthetized dogs than in controls. The insulin distribution space was 78% of body weight and insulin t_1/2 in blood group compared with 54% and 16 min, in controls. We conclude that thiopentone provokes disturbances in glucose and serum NEFA metabolisms and abolishes the serum IRI response to hyperglycaemia. These effects are influenced by extrapancreatic factors regulating serum IRI levels and by an alpha-adrenergic mechanism, via the inhibition of insulin secretion.     

Choice of anaesthetic regimen influences haemodynamic response to cemented arthroplasty

Haemodynamic changes during bilateral cemented arthroplasty (BCA) were compared in dogs anaesthetized with isoflurane/ N₂O (ISOF) or diazepam/fentanyl (100 μg · kg^{? 1})/N₂O (FENT). Eight animals were anaesthetized with each regimen. After establishing monitoring and recording baseline values, BCA was performed Haemodynamic measurements included aortic blood pressure (ABP), pulmonary artery pressure (PAP), right and left atrial pressures, and cardiac output. These were recorded at 30, 60, 180 and 300 sec after BCA. Lungs were removed and examined postmortem using quantitative morphometry. Groups demonstrated similar increases in PAP (ISOF 15 ± 2 to 32 ± 7, FENT 19 ± 4 to 38 ± 13; P > 0.05 between groups, P < 0.05 vs baseline). The proportion of lung vasculature occluded by fat was not different between groups (ISOF 9.63 ± 3.38%, FENT 8.85 ± 2.20%). Stroke volume decreased similarly in both groups (P > 0.05 between groups, P < 0.05 vs baseline). However, ABP decreased within one minute of BCA in ISOF (111 ± 17 to 55 ± 27 mmHg, P < 0.05) and two of eight dogs died. All FENT dogs survived and hypotension (118 ± 20 to 102 ± 24 mmHg) was transient and less severe (P < 0.05 vs ISOF). Increased heart rate (HR) was noted in FENT following BCA (73 ± 8 to 108 ± 25 beats · min^{? 1}; P < 0.05). Baseline HR was higher in ISOF (P < 0.05) and no increase in HR was noted. Systemic vascular resistance decreased in ISOF (P < 0.05), but not FENT (P > 0.05 vs baseline, P < 0.05 vs ISOF). To assess the role of slower baseline HR in FENT (73 ± 8) versus ISOF (131 ± 5), six FENT dogs were paced (130 beats · min^{? 1}) with epicardial leads and an AV sequential pulse generator to simulate the ISOF group’s baseline HR. Haemodynamic stability was maintained in this group in spite of a more rapid baseline HR. The choice of anaesthetic regimen strongly influenced acute haemodynamic changes in response to BCA.     

Changes inPetCO2 and pulmonary blood flow after bronchial occlusion in dogs

The use ofPetCO₂ in detecting accidental bronchial intubation was investigated. ThePetCO₂ was measured in six mongrel dogs after occluding the left mainstem bronchus in three conditions; pentobarbital anaesthesia, 0.8% halothane insufflation together withpentobarbital anaesthesia, and simultaneous left pulmonary artery and bronchial airway occlusion with intravenous pentobarbital anaesthesia. An external flow probe measured left pulmonary artery blood flow. ThePetCO₂ decreased after bronchial occlusion during pentobarbital (35 ± 3 vs 30 ± 5 mmHg) and halothane-pentobarbital (30 ± 6 vs 25 ± 6 mmHg) conditions (P < 0.05). However, within three minutes of bronchial occlusion, the values ofPetCO₂ had returned to their pre-occlusion values. After five minutes of bronchial occlusion pulmonary artery blood flow in the non-ventilated lung decreased (P < 0.05) during pentobarbital (770 ± 533 ml · min^?1 vs 575 ± 306 ml · min^?1) and halothane-pentobarbital (495 ± 127 ml · min^?1 vs 387 ± 178ml · min^?1) conditions. Simultaneous bronchial and pulmonary artery occlusion prevented any changes inPetCO₂. It was concluded that accidental one- lung ventilation results in small and transient decreases inPetCO₂. A redistribution of blood flow from the nonventilated to ventilated lung occurs which restoresPetCO₂ to the original values observed with twolung ventilation.     

Interaction between succinylcholine and ranitidine in rats

The hypothesis that the histamine H₂ receptor blocker ranitidine potentiates neuromuscular paralysis during anaesthesia was tested in vivo in urethane anaesthetised and mechanically ventilated rats. Succinylcholine was administered as a bolus and constant-rate infusion to maintain 48.5% (±2.5 SEM) tibialis anterior muscle paralysis in 14 rats. Ranitidine 2.5, 5, 10, or 20 mg · kg^?1 iv, was then administered into groups of three or five rats. Ranitidine produced an immediate potentiation of neuromuscular paralysis followed by a transient reversal and then a continued steady-state potentiation. Peak potentiation occurred within 20 (±3.3) sec and was maintained in all the rats to steady-state. Peak reversal was evident 70 (±8.1) sec after ranitidine administration. There was an excellent relationship (r² = 0.98, P < 0.001) between peak potentiation and serum ranitidine concentration with 50% potentiation occurring at 25.8 (±1.1) μg · ml^?1. There was a weak relationship (r² = 0.39, P < 0.05) between peak reversal and serum ranitidine but potentiation at steady-state was not correlated to serum ranitidine concentration (r² = 0.19, P > 0.05). These results show that ranitidine alters the neuromuscular action of succinylcholine in rats in a similar manner to cimetidine.     

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.     

A comparison of pentamorphone and fentanyl in balanced anaesthesia during general surgery

The purpose of our randomized, double-blind study of 64 unpremedicated healthy patients undergoing surgical procedures with a duration of at least 60 min was to compare 0.75 μg · kg^?1 and 1 μg · kg^?1 pentamorphone with 5 μg · kg^?1 and 7.5 μg · kg^?1 fentanyl to determine which dose of opioid would reduce the requirement for isoflurane supplementation needed to maintain haemodynamic stability. At 21 points during the procedure, the haemodynamic variables of heart rate and systolic, diastolic, and mean arterial pressures were recorded. The use of isoflurane was quantified; the number of patients requiring inhaled anaesthetic, concentration peaks, MAC minutes, and duration of isoflurane use were noted. The number of equal-volume supplemental opioid analgesic doses, postoperative analgesics, occurrence of postoperative nausea, emesis, and antiemetic doses were compared. The four groups exhibited similar patient demographics, total dose of muscle relaxants, types of surgical procedures, and duration of surgery or anaesthesia. Haemodynamic variables were stable with no difference among the four study groups. The patients given pentamorphone demonstrated both delayed requirement (P < 0.05) and shorter duration (P < 0.05) of isoflurane supplementation. Patients given either 5 μg · kg^?1 or 7.5 μg · kg^?1 fentanyl needed isoflurane supplementation within 12 ± 16 min and 12 ± 17 min from induction respectively; while patients given either 0.75 μg · kg^?1 or 1 μg · kg^?1 pentamorphone did not require isoflurane supplementation for 37 ± 10 min and 43 ± 26 min respectively. In addition, the 1 μg · kg^?1 pentamorphone group had significantly (P < 0.05) lower peak isoflurane concentrations than the 5 μg · kg^?1 fentanyl study group (0.9 ± 0.5 MAC% vs 1.5 ± 0.3 MAC%). In conclusion, we found pentamorphone to be a haemodynamically stable, isofluranesparing opioid analgesic. Pentamorphone’s major advantage over fentanyl was its lower requirement for inhalation agent in a balanced anaesthesia technique.     

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.     

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.     

The effect of free fatty acids on insulin-mediated glucose uptake

Free fatty acids (FFA) have been shown in vitro to inhibit insulin-mediated glucose uptake by muscle and have been proposed as in vivo mediators of peripheral insulin resistance. Twenty percent fat emulsion and heparin were administered to six awake healthy dogs during 3-hr insulin clamp studies. Lipid infusion resulted in a fivefold increase in FFA concentration over control (2371 ± 331 vs 439 ± 65, P < 0.002), but did not importantly alter glucose and insulin concentrations. No change was observed in glucose disposal (13.30 ± 1.41 vs 13.76 ± 1.51 mg/kg · min control), hindquarter A–V glucose concentration difference (9 ± 2 vs 9 ± 1 mg/dl), or hindquarter glucose uptake (3.42 ± 0.84 vs 3.71 ± 0.65 mg/kg · min). These observations suggest that FFA may not be important mediators of peripheral insulin resistance in critically ill patients.     

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).