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.     

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.     

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.     

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.     

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.     

40 Hz Auditory steady-state response and EEG spectral edge frequency during sufentanil anaesthesia

Purpose

The auditory steady-state evoked response (ASSR) is an evoked potential which provides a sensitive measure of the effects of general anaesthetics on the brain. We used pharmacokinetic-pharmacodynamic (PK-PD) modelling to compare the effects of sufentanil on the amplitude of the ASSR with its effect on spectral edge frequency (SEF) of the electroencephalogram.

Methods

Nine patients scheduled for elective cardiac surgery participated. Midazolam (70 μg·kg^?1 im) was given 60 min before entering the operating room. Anaesthesia was induced with 5 μg·kg^?1 sufentanil at a rate of 0.83 μg·kg^?1·min^?1. The ASSR, SEF and plasma sufentanil concentrations were measured for 30 min ater induction of anaesthesia before surgery. The half-life between the central and effect site compartments (t_1/2K_eo), the 50% inhibitory concentration (IC₅₀) and the slope factor (gamma) were computed.

Results

The amplitude of the ASSR increased during the first three minutes of infusion of sufentanil by up to 40%. This was followed by a rapid decrease between the fourth and fifth minutes to 16% of baseline. The SEF decreased progressively during the first five minutes of infusion to 18% of baseline. Both measures subsequently showed modest recovery. The parameters gamma, IC₅₀ and t_1/2K_eofor ASSR were (mean ±SD) 6,0 ±3.7, 2.1 ±1,2 ng·ml^?1 and 7.3 ±2.4 min. For SEF the values were 5.9 ±5.2, 1.4 ±0.7 ng·ml^?1 (P < 0.05 compared with ASSR) and 6.8 ±2,4 min.

Conclusion

The sensitivity of ASSR to sufentanil is less than that of the SEF.     

Residual neuromuscular blockade after cardiac surgery: pancuroniumvs rocuronium

Purpose

To determine the incidence of residual neuromuscular blockade after cardiac surgery in patients receiving either rocuronium or pancuronium for muscle relaxation.

Methods

In a prospective, controlled, double-blind study, 20 patients undergoing coronary artery bypass were randomized to receive either rocuronium (n= 10) or pancuronium (n = 10) dunng surgery. Anaesthesia was induced with sufentanil, benzodiazepine and propofol or ketamine, and maintained with air/O₂/sufentanil/isoflurane. Neuromuscular blockade was induced with 0.1 ml·kg^?1 from blinded synnges containing rocuronium (6 mg·ml^?1) (Group R) or pancuronium (I mg·ml^?1) (Group P). Relaxants were administered according to clinical criteria and reversal agents were not given. After surgery, neuromuscular transmission was assessed by train-of-four stimulation of the ulnar nerve/adductor pollicis EMG (Datex Relaxograph). Mean values from three trains of stimuli were recorded and repeated 30 min later if TOF ratio was < 0.7. Time to extubation was recorded.

Results

On arrival in the ICU, nine of 10 patients in group R but only three of 10 patients in group P demonstrated four visible responses (P < 0.05). Mean TOF ratio in group P, 0.03 ± 0.05, was less than in group R, 0.68 ± 0.34 (P < 0.001). All patients in group P and 4 of 10 patients in group R had TOF ratio < 0.7 (P = 0.01). Time to extubation in group P (median 18, range 6–48 hr) was not statistically different from that in group R (14, 5–44 hr).

Conclusion

Residual neuromuscular block, TOF ratio < 0.7, is common after cardiac surgery but the incidence is less when pancuronium is replaced by rocuronium.     

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.     

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.     

Postoperative patientcontrolled epidural analgesia with opioid bupivacaine mixtures

Purpose

To determine the efficacy and safety of patient-controlled epidural analgesia of morphine or fentanyl in combination with bupivacaine for postoperative pain relief.

Methods p]Forty ASA 1–11 patients scheduled for major abdominal surgery were studied. After insertion of a lumbar epidural catheter, patients were given a non-opioid general anaesthetic. After surgery patients complaining of pain, received a loading dose of 2 mg morphine (Group I) or 50 μg fentanyl (Group II). For continuing pain, 1 mg morphine in 4 ml bupivacaine 0.125% (0.25 mg·ml^?1 morphine and 1 mg·ml^?1 bupivacaine, Group I) or 20 μg fentanyl in 4 ml bupivacaine 0.125% (5 μg·ml^?1 fentanyl and 1 mg·ml^?1 bupivacaine Group II) were administered. Blood pressure, heart rate, respiratory rate and SpO₂ were monitored. Assessments of pain (VAS), nausea-vomiting, motor block, pruritus and sedation were recorded for 24 hr.

Results

No difference in pain or sedation was observed between groups, The 24 hr postoperative opioid consumption was 15.50 ± 7.53 mg morphine and 555.10 ± 183.85μg fentanyl. Total bupivacaine 0.125% consumption was 58.00 ± 30.14 ml in Group I and 101.05 ± 36.77 ml in Group II. One patient in Group II complained of motor weakness in one leg. The incidence of nausea (Group I 45%, Group II 10%P < 0.05) and pruritus (Group I 30%, Group II 5%P < 0.05) was less in patients receiving fentanyl. Conclusion: Both methods were effective in the prevention of pain but, because of fewer side effects, fentanyl may be preferable to morphine.     

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.     

Relationship Between Cytokine Gene Polymorphisms and Risk of Postoperative Pneumonia with Esophageal Cancer

Background

We retrospectively evaluated the relationship between cytokine gene polymorphisms and development of postoperative pneumonia after esophagectomy.

Methods

In 120 patients who underwent esophagectomy, serum samples were obtained to measure levels of serum interleukin (IL)-6 and IL-10 at four time points (preoperatively, postoperative day (POD)0, POD1, and POD3). DNA extracted from peripheral blood in all patients was analyzed to determine polymorphisms of cytokines such as tumor necrosis factor-α -1031 T/C, IL-1β -511C/T, IL-6 -634C/G, and IL-10 -819 T/C.

Results

Postoperative pneumonia arose in 34 patients (28.3 %). Perioperative serum IL-10 levels were significantly higher for IL-10 -819 C/T?+?C/C genotypes than for T/T genotypes (POD0 16.7?±?2.84 vs. 8.54?±?0.87 pg/ml, p?=?0.0002; POD1 14.0?±?2.64 vs. 8.8?±?0.87 pg/ml, p?=?0.0143; POD3 8.9?±?2.67 vs. 4.4?±?0.52 pg/ml, p?=?0.0076). The frequency of the IL-10 -819 T/T genotype was significantly higher in patients with postoperative pneumonia than in patients without pneumonia (p?=?0.0323). Multivariate analysis of factors such as sex, smoking, length of operation, field of lymph node dissection, and IL-10 polymorphism identified IL-10 polymorphism as independent predictor of postoperative pneumonia.

Conclusions

Patients with IL-10 -819 T/T genotype may be at high risk for postoperative pneumonia after esophagectomy.     

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).     

Paricalcitol reduces basal and lipopolysaccharide-induced (LPS) TNF-α and IL-8 production by human peripheral blood mononuclear cells

Introduction

Vitamin D and its analogues proved to exert immunomodulatory effects. Paricalcitol is a vitamin D analogue that is safe. It has been used for years in the treatment of secondary hyperparathyroidism in hemodialysis patients and, importantly, it is less calcemic than vitamin D. In this study the immunomodulatory/anti-inflammatory properties of paricalcitol were evaluated in vitro.

Subject and methods

Ten healthy volunteers enrolled into the study. Peripheral blood mononuclear cells (PBMC) at a concentration of 10⁶ cells per well were cultured for 48 h in the presence or not of lipopolysaccharide (LPS) (100 ng/ml) and in the presence or not of paricalcitol (10^?8 M). TNF-α and IL-8 were measured in the supernatants by ELISA.

Results

Basal TNF-α concentration (50.3 ± 22 pg/ml) was reduced by paricalcitol (44.1 ± 23.2 pg/ml). LPS increased TNF-α concentration (150.0 ± 81.7 pg/ml), but paricalcitol reduced it (121.1 ± 69.0 pg/ml). The effect of paricalcitol on IL-8 production was more profound. Basal IL-8 concentration (1926 ± 455 pg/ml) was reduced by paricalcitol (1273 ± 472 pg/ml). LPS increased IL-8 concentration (2361 ± 385 pg/ml), but paricalcitol returned it to its basal level (1849 ± 417 pg/ml).

Conclusion

The in vitro inhibition of transforming growth factor alpha and interleukin 8 by paricalcitol confirms the immunomodulatory properties of this vitamin D analogue.     

Heart rate changes in cardiac transplant patients and in the denervated cat heart after edrophonium

Purpose

The effect of edrophonium on heart rate in cardiac transplant patients and in an animal model of acute cardiac denervation were studied, to evaluate the functional state of the peripheral parasympathetic pathway fol lowing cardiac denervation.

Methods

Edrophonium was studied in patients with normally innervated hearts (controls) and m cardiac trans plants. Edrophonium was also studied in vagotomized. beta-blocked cats. In Group I animals, the vagus nerve was not stimulated. In Groups 2 & 3 the right vagus nerve was electrically stimulated to produce approximately 20% and 40% reductions in baseline heart rate, respectively.

Results

Maximum heart rate reduction in transplants (7.3 ± 0.8 beats·min^?1 with 0.6 ± 0.08 mg·kg^?1) was less than in controls (13.3 ± 1.6 beatsmm with 0.4 + 0.05 mg·kg^?1, P < 0.01). In Group I animals heart rate decreased maximally by 20.9 ± 2.5 beats·min^?1 with 9.0 ± 1.9 mg·kg^?1. In Groups 2 and 3, with doses < 15 mg·kg^?1, reduc tions m heart rate were greater than in Group I and maximual reductions were obtained with lower doses (Group 2: maximum reduction by 20.3 ± 2.8 beats·min^?1 with 1.3 ± 0.1 mg·kg^?1: Group 3: 22.6 ± 4.0 beats·min^?1 with 0.8±0.2 mg·kg^?1, P < 0.001) Doses > 1.5 mg·kg^?1 in Groups 2 and 3 produced increases in heart rate.

Conclusion

Edrophonium produced bradycardia in cardiac transplants suggesting spontaneous release of acetylcholinee from parasympathetic postganglionic neurons m the transplanted heart. The magnitude of the brady cardia was less in transplant than in control patients. Findings from animal studies suggest that the reduction in transplants can be attributed to diminution or absence of tonic cardiac parasympathetic drive. At high doses, edrophonium may interfere with parasympathetic neuron activation.     

Density determination of local anaesthetic opioid mixtures for spinal anaesthesia

Purpose

To measure the density of hyperbaric and isobaric local anaesthetics before and after addition of neuroaxial opioids to define a method for calculating any local anaesthetic/opioid mixture density based on individual component densities.

Methods

Density was determined using a volumetric pycnometer (25.0281 ± 0.0013 ml). The density of local anaesthetics (bupivacaine, lidocaine), opioids (fentanyl, morphine) and multiple anaesthetic/opioid mixtures were measured in quadruplicate and expressed in g·ml^?1, at 37°C (mean ± SD). Regression analysis was used to derive a formula for calculating the density of any anaesthetic/opioid mixture.

Results

Individual components had the following densities (g·ml^?1): bupivacaine 0.75%; 1.0252 ± 0.0001, lidocaine 5%; 1.0249 ± 0.0001, bupivacaine 0.5%; 0.9994 ± 0.0001, lidocaine 2%; 1.0000 ± 0.0001, 50μg·ml^?1 fentanyl; 0.9936 ± 0.0001, and 0.5 mg·ml^?1 morphine; 1.0001 ± 0.0001. Using regression analysis, linear relationships were demonstrated between density (D) of anaesthetic/opioid mixture and the proportion of anaesthetic in the mixture (fractional volume of anaesthetic) (r = 0.9999,P < 0.001). The following formula was derived; Density_Mixture = (D_{Local anaesthetic} ? D_Opioid) × Fractional Volume Anaesthetic + D_Opioid Comparison of calculated and measured densities for multiple clinically relevant anaesthetic/opioid mixtures showed a significant degree of correlation (r = 0.9996,P < 0.001).

Conclusion

Density of spinal anaesthetic/opioid mixtures can be calculated from the component densities and the proportion of anaesthetic in the mixture.     

Thoracic epidural block attenuates cardiovascular response to apnea in rabbits

Purpose

Apnea is one of the potential complications during anaesthesia. If sympathetic nerve activity is blocked by epidural anaesthesia, circulatory responses to apnea might change. Our objective was to assess the potential modifying effects of epidural anaesthesia on the cardiovascular responses to apnea in the animals.

Methods

Twenty rabbits anaesthetised with pentobarbital (25 mg·kg^?1 iv, 8 mg·kg^?1·hr^?1) and pacuronium bromide (0.2 mg·kg^?1·hr^?1 iv) were randomly assigned to one of two groups: control (n = 10) and epidural (n = 10). In the control group, 0.6 ml saline, and in the epidural group, 0.6 ml lidocaine 1% was injected into the epidural space respectively. After mechanical ventilation with FIO₂ 0.4, apnea was induced by disconnecting the anaesthetic circuit from the endotracheal tube, and mean arterial pressure (MAP), heart rate (HR), and time to cardiac arrest were measured.

Results

Before apnea MAP was lower in the epidural than in the control group (73 ± 10vs 91 ± 10 mmHg,P < 0.05). Heart rate was not different between groups (264 ± 36vs 266 ± 24 bpm). Mean arterial pressure increased in the control group after apnea, but not in the epidural group. The time to cardiac arrest was less in the epidural group than in the control group (420 ± 67vs 520 ± 61 sec,P < 0.05). Heart rate decreased markedly after apnea in the control group whereas it decreased gradually in the epidural group.

Conclusion

Thoracic epidural anaesthesia attenuated cardiovascular response to apnea and reduced the time to cardiac arrest.     

Neostigmine decreases heart rate in heart transplant patients

Purpose

This study evaluated the effect of neostigmine on heart rate in cardiac transplant patients.

Methods

Neostigmine (2.5–50 μg · kg^?1) was administered to ASA 1 or 2 patients with normally innervated hearts (controls), and to patients who had undergone recent (<six months before study) or remote (> six months before study) cardiac transplantation.

Results

Baseline heart rate was 66 ± 3 beats · min^?1 in controls (n = 10, mean ± SEM), which was slower than that observed in recently (95 ± 4 beats · min^?1, n = 15, P < 0.001) and in remotely (88 ± 3 beats · min^?1, n = 16, P < 0.001) transplanted patients. Neostigmine produced a dose-dependent decrease in heart rate in all patients. Controls were the most sensitive to neostigmine, with a 10% decrease in heart rate produced by an estimated dose of 5.0 ± 1.0 μg · kg^?1. The recently transplanted group was the least sensitive, with the maximum dose producing only an 8.3 ± 0.9% reduction. The response to neostigmine of the remotely transplanted patients was variable. The estimated dose to produce a 10% decrease in heart rate in this group was 24 ± 6 μg · kg^?1 which was greater than that for controls (P = 0.008). Administration of atropine (1.2 mg) reversed the neostigmine-induced bradycardia in all three groups. Reversal of the bradycardia consisted of a transient peak increase in heart rate in controls to 145 ± 6% of baseline, a value which was greater than that observed in recent (103 ± 1%, P < 0.001) and in remote (109 ± 3%, P < 0.001) transplants.

Conclusions

Neostigmine produces a dose-dependent brady-cardia in heart transplant patients. Some remotely transplanted patients may be particularly sensitive to the bradycardic effects of neostigmine.     

Dose-response to anaesthetic induction with sufentanil: haemodynamic and electroencephalographic effects

Purpose

To determine the effect of a five-fold variation in sufentanil dose on the haemodynamic and electroencephalo graphic (EEG) response to anaesthetic induction and tracheal intubation.

Methods

Thirty-four patients undergoing elective coronary artery bypass grafting (CABG) participated in this randomized double-blind study. Patients in Group L (n= 17) received 3 μg · kg^?1 sufentanil and those in Group H (n= 17) 15 μg · kg^?1. Premedication was 60 μg · kg^?1 lorazepam po. Anaesthesia and neuromuscular blockade were induced by infusing sufentanil and 0.15 mg · kg^?1 vecuronium iv over five minutes. Haemodynamic data and the electroencephalographic (EEG) spectral edge were acquired by computer and compared at Control, Induction and Intubation.

Results

Sufentanil dose did not affect the haemodynamic or EEG response at end-induction. No bradyarrhythmias occurred, and the incidence of hypotension was 12% in both groups. However, during induction apparent electromyographic artifacts and a transiently greater increase in heart rate were observed in Group H. The serum sufentanil concentration at Induction was 6.1 ± 1.8 ng · ml^?1 in Group L and 25.4 ± 8.8 ng · ml^?1 in Group H, and did not correlate with haemodynamic changes. No patient recalled any intraoperative event.

Conclusion

Increasing sufentanil dose from 3 to 15 μg · kg^?1 does not influence the ultimate haemodynamic response to induction. Combined with lorazepam premedication, 3 μg · kg^?1 sufentanil produces near-maximal haemodynamic and EEG effects and is adequate for induction and tracheal intubation of patients undergoing CABG. Sufentanil 15 μg · kg^?1 is no more efficacious, and causes transient cardiovascular stimulation.     

Continuous oesophageal aortic blood flow echo-Doppler measurement during general anaesthesia in infants

Purpose

Invasive haemodynamic monitoring during general anaesthesia in infants is usually limited to very high risk operations, such as cardiac surgery Nevertheless, different surgical procedures and/or anaesthetic techniques justify additional monitoring for children, as for adults. The aim of this preliminary study was to evaluate the feasibility of using a new echo-Doppler device (Dynemo 3000®) capable of measuring continuous aortic blood flow during general anaesthesia in infants.

Methods

Aortic blood flow (ABF) was measured with a small oesophageal probe designed for newborns and infants. The aortic flowmeter was connected with satellite devices to visualise the haemodynamic profile which included ABE pre-ejection period (PEPi), left ventricular ejection time (LVETi), mean artenal pressure, heart rate, stroke volume and systemic vascular resistance. Twelve infants, aged 8–26 mo, undergoing surgery under general anaesthesia were successively included in the evaluation of this device. Isoflurane (1 % end-expired concentration) was introduced to maintain anaesthesia after induction with halothane, midazolam, fentanyl and atracurium.

Results

Correct positioning of the probe was easily obtained in all cases and the recording quality was excellent, whatever the operative position. Recordings of haemodynamic data showed some myocardial depression from isoflurane: decreased ABF (indexed to body surface area) and lengthened PEP/LVET (2.24 ± 0.53 L · min^?1 · m^?2 and 0.32 ± 0.05 respectively, before introduction of isoflurane and 1.71 ± 0.53 L · min^?1 · m^?2 (P = 0.027) and 0.39 ± 0.06 (P ± 0.007) with isoflurane).

Conclusion

These preliminary results suggest that this continuous ABF echo Doppler device may be valuable for pen anaesthetic monitonng in infants.