Impact of off-pump coronary artery surgery on myocardial performance and beta-adrenoceptor function.

OBJECTIVE: To determine the hemodynamic changes during beating heart revascularization of the left anterior descending artery, the circumflex artery, and the right coronary artery as well as cardiovascular beta-adrenoceptor function before and after off-pump coronary artery bypass surgery. DESIGN: Prospective study. SETTING: University department of cardiothoracic anesthesia. PARTICIPANTS: Twenty patients scheduled for off-pump coronary artery bypass surgery using the Octopus 2 stabilizer system. INTERVENTIONS: Isoproterenol, 4 microg, was administered intravenously after induction of anesthesia and again after surgery to monitor cardiac beta-receptor function. MEASUREMENTS AND MAIN RESULTS: The hemodynamic responses to isoproterenol and cardiovascular variables were monitored before, during, and after immobilization of the target coronary artery with catheters in the radial and pulmonary arteries. During surgery on the left anterior descending artery (n = 23), stroke volume and cardiac index decreased 17 mL (21%) and 400 mL (17%). During revascularization of the circumflex artery (n = 9), stroke volume and cardiac index decreased 19 mL (28%) and 300 mL (17%). During surgery on the posterior aspect of the heart (n = 13), stroke volume and cardiac index decreased 22 mL (29%) and 400 mL (17%). All the cardiovascular variables had returned to baseline values 5 minutes after releasing the heart. The hemodynamic responses to isoproterenol were equal before and after surgery. CONCLUSION: This study provides evidence that the hemodynamic changes associated with off-pump surgery on the 3 major coronary arteries are similar and of short duration. No desensitization of cardiovascular beta-adrenoceptors was found. This finding is in contrast to the deterioration in beta-adrenoceptor function seen after surgery with cardiopulmonary bypass.

Sequence-specific interaction between the disintegrin domain of mouse ADAM 3 and murine eggs: role of beta1 integrin-associated proteins CD9, CD81, and CD98.

ADAM 3 is a sperm surface glycoprotein that has been implicated in sperm-egg adhesion. Because little is known about the adhesive activity of ADAMs, we investigated the interaction of ADAM 3 disintegrin domains, made in bacteria and in insect cells, with murine eggs. Both recombinant proteins inhibited sperm-egg binding and fusion with potencies similar to that which we recently reported for the ADAM 2 disintegrin domain. Alanine scanning mutagenesis revealed a critical importance for the glutamine at position 7 of the disintegrin loop. Fluorescent beads coated with the ADAM 3 disintegrin domain bound to the egg surface. Bead binding was inhibited by an authentic, but not by a scrambled, peptide analog of the disintegrin loop. Bead binding was also inhibited by the function-blocking anti-alpha6 monoclonal antibody (mAb) GoH3, but not by a nonfunction blocking anti-alpha6 mAb, or by mAbs against either the alphav or beta3 integrin subunits. We also present evidence that in addition to the tetraspanin CD9, two other beta1-integrin-associated proteins, the tetraspanin CD81 as well as the single pass transmembrane protein CD98 are expressed on murine eggs. Antibodies to CD9 and CD98 inhibited in vitro fertilization and binding of the ADAM 3 disintegrin domain. Our findings are discussed in terms of the involvement of multiple sperm ADAMs and multiple egg beta1 integrin-associated proteins in sperm-egg binding and fusion. We propose that an egg surface "tetraspan web" facilitates fertilization and that it may do so by fostering ADAM-integrin interactions.

Sequence-specific interaction between the disintegrin domain of mouse ADAM 2 (fertilin beta) and murine eggs. Role of the alpha(6) integrin subunit.

Little is yet known about the biological and biochemical properties of the disintegrin-like domains of ADAM (a disintegrin and metalloprotease) proteins. Mouse ADAM 2 (mADAM 2; fertilin beta) is a sperm surface protein involved in murine fertilization. We produced recombinant proteins containing the disintegrin-like domain of mADAM 2 in both insect cells and in bacteria. The protein produced in insect cells (baculo D+C) contained a signal sequence followed by the disintegrin-like and cysteine-rich domains; it was purified from the medium of recombinant baculovirus-infected cells. A bacterial construct containing the disintegrin-like domain was produced in Escherichia coli as a glutathione S-transferase chimera. Baculo D+C, as well as the D domain of the bacterial construct (released with thrombin), bound to the microvillar surface of murine eggs. Using concentrations in the range of 1 to 5 microM, both recombinant proteins strongly inhibited sperm-egg binding and fusion; the baculovirus-produced protein exhibited a somewhat greater extent of inhibition (approximately 75 versus approximately 55% maximal inhibition). Substitution of alanine for each of the five charged residues within the disintegrin loop of mADAM 2 revealed a critical importance for the aspartic acid at position nine. Binding of both recombinant proteins to the egg was inhibited by the function blocking anti-alpha(6) monoclonal antibody, GoH3, but not by a nonfunction-blocking anti-alpha(6) monoclonal antibody. Binding was also inhibited by a peptide analogue of, and with an antibody against, the disintegrin loop of mADAM 2.

Role of the integrin-associated protein CD9 in binding between sperm ADAM 2 and the egg integrin alpha6beta1: implications for murine fertilization.

CD9 is a tetraspan protein that associates with several beta1 integrins, including alpha6beta1. Because alpha6beta1 is present on murine eggs and interacts with the sperm-surface glycoprotein ADAM 2 (fertilin beta), we first asked whether CD9 is present on murine eggs and whether it functions in sperm-egg binding and fusion. CD9 is present on the plasma membrane of oocytes in the ovary as well as on eggs isolated from the oviduct. The anti-CD9 mAb, JF9, potently inhibits sperm-egg binding and fusion in vitro in a dose-dependent manner. JF9 also disrupts binding of fluorescent beads coated with native fertilin or a recombinant fertilin beta disintegrin domain. (Both ligands bind to the egg via alpha6beta1.) Immunohistochemistry showed that CD9 is undetectable in the uterine epithelium, appears basolaterally and as prominent apical patches on the epithelium in the region between the uterus and the oviduct, and then persists apically in the oviduct. The integrin alpha6A subunit is found in similar apical patches in the region between the uterus and oviduct, but is confined to the basal aspect of the epithelium in the uterus and oviduct. Hence, alpha6A and CD9 both are expressed on the apical epithelial surface at the uterine-oviduct junction. These findings correlate with the observation that fertilin beta "knockout" sperm traverse the uterus but do not progress into the oviduct, contributing to the infertility of fertilin beta(-/-) male mice. Our results suggest that high-avidity binding between fertilin beta (ADAM 2) and alpha6beta1 requires cooperation between alpha6beta1 and CD9. Such cooperation may assist sperm passage into the oviduct as well as sperm-egg interactions.

Monitoring of beta-receptor sensitivity in cardiac surgery.

OBJECTIVE: To determine the repeatability of the hemodynamic response to repeated isoproterenol challenge doses to validate the standardized isoproterenol sensitivity test as an index of cardiovascular beta-receptor function. DESIGN: Prospective, single-blind, nonrandomized clinical trial. SETTING: University department of cardiothoracic anesthesia. PARTICIPANTS: Twenty middle-aged men scheduled for primary elective coronary artery bypass surgery, 10 of whom had been treated with cardioselective beta1-antagonists for more than 3 months. INTERVENTIONS: After induction of anesthesia and baseline hemodynamic evaluation, cardiac beta-receptor sensitivity was estimated from the chronotropic/inotropic responses to four intravenous 4-microg isoproterenol bolus doses. MEASUREMENTS AND MAIN RESULTS: Baseline cardiovascular function and pharmacodynamic response to the four isoproterenol challenge doses were monitored with catheters in the radial and pulmonary arteries (thermodilution). Heart rate was continuously recorded and calculated from the electrocardiogram. Baseline hemodynamic status and response to the first 4 microg of isoproterenol were similar in the 10 patients treated with beta1-antagonists and the rest of the patients. In all 20 patients, heart rate response to the three subsequent isoproterenol challenge doses decreased progressively by 28%. CONCLUSION: The standardized isoproterenol sensitivity test is unreliable for clinical monitoring of cardiac beta-adrenoceptor function.

A model for sperm-egg binding and fusion based on ADAMs and integrins.

Once a sperm meets an egg, several events must occur in order for fertilization to proceed. Sperm must bind to the zona pellucida, undergo the acrosome reaction, penetrate the zona pellucida and then bind to and fuse with the egg plasma membrane. Shortly thereafter, the egg must be activated for zygotic development. This review focuses on mammalian sperm-egg plasma membrane binding and fusion, and in particular on the roles of two families of cell-adhesion molecules, ADAMs and integrins, in this important union.

The effect of preoperative methylprednisolone on pulmonary function and pain after lung operations.

Thirty-six patients undergoing elective thoracotomy with pulmonary resection with the use of combined epidural and general anesthesia were randomized into a double-blind study to receive a single intravenous preoperative dose of methylprednisolone 25 mg/kg body weight or a placebo (saline solution). Postoperative pain relief consisted of epidural morphine 4 mg and paracetamol 1 gm three times a day for 4 days. Postoperative pulmonary function (peak expiratory flow rate, forced expiratory volume in first second, forced vital capacity) was evaluated on days 1, 2, 3, 4, and 7 and after 1 month. The value obtained after 1 month served as the control value. Pain score at rest and during cough was evaluated after 4 and 8 hours and on days 1, 2, 3, and 4. Pulmonary function was reduced after operation to the same degree in the steroid and placebo group: 42% versus 41% for forced expiratory volume in first second and 38% versus 39% for forced vital capacity, compared with control values after 1 month. Pain score was reduced in the steroid group after 4 hours and on day 1 during rest and after 4 and 8 hours and on day 2 during cough, compared with results in the placebo group (p < 0.05). In the steroid group three patients underwent reoperation because of leakage through the chest wall incision. In conclusion, administration of a single preoperative dose of methylprednisolone did not affect the postoperative reduction in pulmonary function after thoracotomy despite attenuated pain response, and the results do not warrant steroid administration before lung operation.

Effect of piroxicam in addition to continuous thoracic epidural bupivacaine and morphine on postoperative pain and lung function after thoracotomy.

Twenty-eight patients scheduled for lung resection with lateral thoracotomy and postoperative chest drains during combined thoracic epidural bupivacaine plus morphine and general anaesthesia were studied. Postoperative pain treatment was continuous epidural infusion of bupivacaine 0.25% 5 ml h-1 plus morphine 0.2 mg h-1 for 48 h and, in addition, the patients received rectal piroxicam 40 mg randomly and double-blind 12 h and 1 h before surgery and 20 mg 24 h-1 postoperatively or placebo. Pain was evaluated at rest, during cough and mobilisation, together with pulmonary function (FEV1, FVC, PEFR) and sensory level of analgesia repeatedly for 48 h. The results showed efficient pain relief, but without differences in pain scores or need for supplementary analgesics between the two groups. Pulmonary function decreased similarly in the two groups. Thus we were unable to show enhanced analgesia by supplementing an otherwise effective low-dose epidural bupivacaine and morphine treatment with piroxicam after thoracic surgery with chest drains.

[Changes in mental function after anesthesia and surgery]. / Aendringer i den mentale funktion efter anaestesi og kirurgi.

Minor short-term depression of mental function is seen after anaesthesia and surgery. However, general anaesthesia does not seem to cause permanent damage or depress mental function beyond the first 2-4 postoperative days and no significant advantages of regional anaesthesia, as regards to cerebral function, are found after this period. Severe cases of long term mental deterioration after surgery and anaesthesia may be explained by other factors such as per- and postoperative complications. The risk of mental disturbance is increased in patients with psychiatric disease or presenile dementia and may be due to ongoing treatment with tricyclic antidepressant and neuroleptic drugs. Centrally acting cholinergic drugs, hypotension and hypoxia together with postoperative pain and sleep deprivation should be avoided.

Effect of combined prednisolone, epidural analgesia, and indomethacin on the systemic response after colonic surgery.

Twenty patients undergoing colonic resection were randomized to either conventional postoperative pain treatment with morphine chloride and acetaminophen (group 1, n = 9) or methylprednisolone sodium succinate 90 minutes before surgery plus intraoperative neural blockade, with a postoperative analgesic regimen with combined bupivacaine hydrochloride-morphine and indomethacin sodium for systemic effect (group 2, n = 11). Assessments of pain, pulmonary function, convalescence, and various injury factors were done several times until 8 days after surgery. Postoperative pain and hyperthermic response were eliminated in group 2. Conventional reduction in pulmonary function measures was improved in group 2, and fatigue and mobility were less pronounced. Prostaglandin E2, interleukin 6, and C-reactive protein levels increased in both groups, but significantly less in group 2. These results suggest that a combined neural and humoral blockade may more effectively inhibit the global stress response to elective surgery than previously observed with neural blockade with or without indomethacin.

[Treatment of postoperative pain]. / Postoperativ smertebehandling.

Intensive research during recent years concerning treatment of postoperative pain has demonstrated that the majority of operation patients can be rendered free from pain but that this is far from being the case in clinical practice. This article reviews the physiological mechanisms of acute pain and the methods available for treatment of pain related to acute physiology of pain. Postoperative treatment of pain should be aggressive with the object of preventing pain and normalizing the vital functions with the object of reducing the perioperative morbidity and mortality. A series of recommendations are given for treatment of pain after surgical intervention.

Morphine, morphine-6-glucuronide and morphine-3-glucuronide concentrations in plasma and cerebrospinal fluid during long-term high-dose intrathecal morphine administration.

The kinetics of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) were studied in a 56-year-old female with lung cancer. Long-term treatment with morphine intrathecally 28 mg every 6 h was used for pain control. Cerebrospinal fluid (CSF) concentrations of morphine were high with an elimination half-life of 2.1 h. The plasma/CSF ratios for M6G and M3G were 1:0.8 and 4:1, respectively, suggesting that M6G penetrates the blood-brain barrier more easily than M3G. The low CSF concentrations indicate that M6G played hardly any major analgetic role in the patient studied.

Comparative bioavailability of a morphine suppository given rectally and in a colostomy.

In eight patients with a colostomy, plasma morphine levels were followed for 8 h after administration of 20 mg morphine chloride as a suppository, first rectally and after at least 48 h via the colostomy. The bioavailability after administration in the colostomy showed very great variation; the mean value compared to rectal bioavailability was only 43% (range 0.1-127%). In four patients the plasma concentrations of morphine after colostomy administration were lower at all times than after rectal administration, and in three only small amounts of morphine were detectable. One patient showed higher plasma concentrations after colostomy application than after rectal administration. It is concluded that administration of morphine suppositories in a colostomy cannot be recommended.

Comparison of the effects of continuous intrapleural vs epidural administration of 0.5% bupivacaine on pain, metabolic response and pulmonary function following cholecystectomy.

Twenty patients undergoing elective cholecystectomy were prospectively randomised to receive either intrapleural (bolus 20 ml followed by 10 ml/h) or thoracic epidural (bolus 9 ml followed by 5 ml/h) bupivacaine 0.5% for 8 h postoperatively to assess the effect of these two techniques on pain, pulmonary function and the surgical stress response. As assessed by the visual analogue scale (VAS), both groups received good but not total pain relief. Both groups had a 50% reduction in forced expiratory volume (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) after operation, and there was no observed effect on the stress response as measured by plasma glucose and cortisol. It is concluded that while both techniques provide good analgesia, the degree and extent of nerve blockade are not sufficient to affect the afferent neurogenic stimuli responsible for the observed effects on pulmonary function and the stress response.

Effects of thoracic paravertebral block with bupivacaine versus combined thoracic epidural block with bupivacaine and morphine on pain and pulmonary function after cholecystectomy.

Twenty patients undergoing elective cholecystectomy via a subcostal incision were randomized in a double-blind study to either thoracic paravertebral blockade with bupivacaine 0.5% (15 ml followed by 5 ml/h) or thoracic epidural blockade with bupivacaine 7 ml 0.5% + morphine 2 mg followed by 5 ml/h + 0.2 mg/h, respectively for 8 h postoperatively. Mean initial spread of sensory analgesia on the right side was the same (Th3,4-Th11 versus Th2,6-Th11), but decreased (P less than 0.05) postoperatively in the paravertebral group. All patients in the epidural group had bilateral blockade, compared with three patients in the paravertebral group. In both groups only minor insignificant changes in blood pressure and pulse rate were seen postoperatively. Pain scores were significantly higher in the paravertebral group, as was the need for systemic morphine (P less than 0.05). Pulmonary function estimated by forced vital capacity, forced expiratory volume and peak expiratory flow rate decreased about 50% postoperatively in both groups. In conclusion, the continuous paravertebral bupivacaine infusion used here was insufficient as the only analgesic after cholecystectomy. In contrast, epidural blockade with combined bupivacaine and low dose morphine produced total pain relief in six of ten patients.

[Long-term treatment with intrathecal morphine in severe painful cancer]. / Langtidsbehandling med morfin intratekalt ved svaere cancersmertetilstande.

Intrathecal treatment with morphine was instituted in seven cancer patients with severe pain. All of the patients had already received treatment with epidural morphine and the reason for the change in treatment was insufficient effect, side effects and/or pain connected with the injections in the epidural form of therapy. The duration of treatment was 5-136 days (median 40 days). The daily intrathecal dosage of morphine which was administered by 1-4 daily injections was initially 2.4-16.0 mg (median 3.6 mg) and had to be increased to 3.2-112 mg (median 16 mg) at the conclusion of treatment. Five patients became free from pain and one had acceptable relief of pain on this treatment. One patient received accidentally too great a dose of morphine intrathecally as compared with the usual dose and required treatment for respiratory insufficiency. Apart from postural headache on account of leakage of cerebro-spinal fluid, which could be treated by epidural blood "patch", the method was without complications which could be attributed to the intrathecally placed catheter. Treatment of pain with opioids injected intrathecally may thus be recommended in the cases in which epidural treatment cannot be carried out on account of the reasons mentioned above.

Continuous thoracic extradural 0.5% bupivacaine with or without morphine: effect on quality of blockade, lung function and the surgical stress response.

Twenty-two patients undergoing upper abdominal surgery were entered into a randomized, double-blind study to receive extradural (T7-T8) 0.5% bupivacaine 9 ml followed by 25 mg h-1 with or without additional extradural morphine (bolus 4 mg plus 0.5 mg h-1), for 16 h after operation. Addition of morphine was associated with total alleviation of pain, and a stable level of sensory analgesia, but not with changes in blood glucose and cortisol concentrations or postoperative impairment of lung function (PEFR, FEV1, FVC). Two patients were withdrawn because of hypotension or respiratory depression.

The roles of acute and chronic pain in regression of sensory analgesia during continuous epidural bupivacaine infusion.

The purpose of this study was to investigate whether regression of sensory analgesia during constant epidural bupivacaine infusion was different in postoperative patients with acute pain than in patients with chronic nonsurgical pain. Sensory levels of analgesia (to pinprick) and pain (on a five-point scale) were assessed hourly for 16 hours during continuous epidural infusion of 0.5% plain bupivacaine (8 ml/hr) in 12 patients with chronic nonsurgical pain and in 30 patients after major abdominal surgery performed under combined bupivacaine and halothane--N2O general anesthesia. No opiates were given. If sensory analgesia decreased more than five segments from the initial level or if the pain score reached 2 (moderate pain), the patient was removed from the study. Initial levels of sensory analgesia after loading doses of 21.8 +/- 0.5 and 19.3 +/- 0.8 ml bupivacaine 0.5% were similar (T3.8 +/- 0.3 and T3.8 +/- 0.5) in the surgical and chronic pain patients, respectively (mean +/- SEM). Of the surgical patients, only 4 of the 30 (13%) maintained the initial level of sensory analgesia, and a pain score below 2 throughout the study compared with 7 of the 12 patients with chronic pain (58%) (P less than 0.01). Mean duration of sensory blockade was significantly longer (P less than 0.005) in the patients with chronic pain than in surgical patients (13.1 +/- 1.2 and 8.5 +/- 0.7 hours, respectively). Thus, surgical injury hastens regression of sensory analgesia during continuous epidural bupivacaine infusion. The underlying mechanism remains to be determined.

Unpredictability of regression of analgesia during the continuous postoperative extradural infusion of bupivacaine.

Twenty-four otherwise healthy patients scheduled for elective major abdominal surgery received general anaesthesia plus lumbar extradural analgesia. A loading dose of 0.5% plain bupivacaine was given to produce sensory analgesia (pin prick) from T4 to S5 and followed by a continuous infusion of 0.5% plain bupivacaine 8 ml h-1. Pain, scored on a 5-point scale, and sensory analgesia were assessed hourly for 16 h after skin incision. If sensory analgesia decreased by more than 5 segments from its preoperative level, or if the pain score reached 2 (moderate pain), the patients were removed from the study, and pain was treated otherwise. Only three patients maintained their initial levels of sensory analgesia and a pain score of less than 2. In the remaining patients sensory analgesia decreased at least 5 segments or pain score reached 2 between 4 and 16 h after skin incision. We found a weak correlation between increasing age and the duration of sensory analgesia (r = 0.46, P less than 0.05), but no significant correlations between duration of sensory analgesia and sex, weight, height, body surface area, serum albumin concentration, duration or site of operation.