Anthony J. Cunningham

Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo

The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, is limited by cardiotoxicity, particularly when combined with herceptin, an antibody that blocks the HER2 receptor. Doxorubicin induces cyclooxygenase-2 (COX-2) activity in rat neonatal cardiomyocytes. This expression of COX-2 limits doxorubicin-induced cardiac cell injury, raising the possibility that the administration of a prostaglandin may protect the heart during the in vivo administration of doxorubicin. Doxorubicin (15 mg/kg) administered to adult male Sprague Dawley rats induced COX-2 expression and activity in cardiac tissue. Prostacyclin generation measured as the excretion of 2,3-dinor-6-keto-PGF(1alpha) also increased, and this was blocked by a COX-2 inhibitor, SC236. In contrast, administration of a COX-1 inhibitor SC560 at a dose that reduced serum thromboxane B2 by more than 80% did not prevent the doxorubicin-induced increase in prostacyclin generation. Doxorubicin increased cardiac injury, detected as a rise in plasma cardiac troponin T, serum lactate dehydrogenase, and cardiomyocyte apoptosis; this was aggravated by coadministration of SC236 but not SC560. The degree of injury in animals treated with a combination of doxorubicin and SC236 was attenuated by prior administration of the prostacyclin analogue iloprost. These data raise the possibility of protecting the heart during the administration of doxorubicin by prior administration of prostacyclin.

Laparoscopic surgery ― anesthetic implications

Laparoscopic cholecystectomy is a relatively new surgical procedure which is enjoying everincreasing popularity and presenting new anesthetic challenges. The advantages of shorter hospital stay and more rapid return to normal activities are combined with less pain associated with the small limited incisions and less postoperative ileus compared with the traditional open cholecystectomy. The efficacy of laparoscopic appendectomy and hemicolectomy has been recently evaluated. However, there have been no prospective randomized studies to date comparing laparoscopic with traditional laparotomy techniques. The physiological effects of prolonged pneumoperitoneum and the longer duration of surgery with the laparoscopic techniques are of concern. The application of laparoscopic inguinal hernia repair may be limited because, unlike traditional surgical hepair, general anesthesia is required and concerns have been expressed about the duration of surgery and the possibility of hernia recurrence. Notwithstanding case reports and series describing successful diaphragmatic and hiatus hernia repair using a laparoscopic surgical technique, the frequently encountered complications of cervical surgical emphysema, pneumothorax, and pneumomediastinum, attributed to passage of insufflating gas through weak points or defects in the diaphragm, must be of major concern. Anesthesiologists must maintain a high index of suspicion for these potential complication and must undertake appropriate monitoring. If there is clinical evidence of a tension pneumothorax, immediate chest tube decompression is indicated.Intraoperative complications of laparoscopic surgery are mostly due to traumatic injuries sustained during blind trocar insertion and physiological changes associated with patient positioning and pneumoperitoneum creation. The choice of anesthetic technique for upper abdominal laparoscopic procedures is most frequently limited to general anesthesia. Controlled ventilation avoids hypercarbia, and an anesthetic technique incorporating antiemetics and nonsteroidal anti-inflammatory agents has reduced postoperative nausea and vomiting following laparoscopic cholecystectomy. The use of nitrous oxide during laparoscopic procedures remains controversial.Laparoscopic cholecystectomy is a major advance in the management of patients with symptomatic gallbladder disease. However, in the present era of cost containment, older and sicker patients may present for this procedure on the day of surgery without adequate preoperative evaluation. Anesthesiologists should thus be prepared to recommend deflation of the pneumoperitoneum and possibly conversion to an open procedure if hemodynamic, oxygenation, or ventilation difficulties arise during the procedure.

Anaesthesia for abdominal aortic surgery — a review (Part II)

Patients presenting for abdominal aortic surgery have a high incidence of vascular disease elsewhere, manifested primarily by hypertension, coronary and cerebrovascular disease, as well as co-existing respiratory, renal and metabolic disorders. Routine clinical assessment, electrocardiogram, chest roentgenograms, resting and exercise radionuclide ventriculography and echocardiography, dipyrdiamole-thallium scanning are all designed to assess the functional status of the myocardium and to detect the presence of significant coronary artery disease. Patients with no abnormalities on physical examination, routine evaluation and no redistribution on dipyridamole-thallium scanning should proceed to surgery with the expectation of very low perioperative cardiac risk. Patients with evidence of coronary artery disease and significant redistribution on dipyridamole-thallium scan should undergo coronary angiography and possible myocardial revascularization before definitive aortic vascular surgery. For high cardiac risk patients with no bypassable lesions presenting for abdominal aortic aneurysm resection a conservative policy of serial three monthly ultrasound or CT assessment may be adopted, with selective resection for rapid aneurysm expansion or symptom development. A variety of extra-anatomical and angioplastic techniques is available for similar high cardiac risk patients with aortoiliac occlusive disease. The haemodynamic consequences of aortic cross-clamping, especially in aneurysm patients, include a significant reduction in stroke volume, cardiac index, and myocardial oxygen consumption with an increased systemic vascular resistance. Patients with coronary artery disease may respond to aortic cross-clamping by increasing pulmonary capillary wedge pressure and by demonstrating ECG evidence of myocardial ischaemia. Pulmonary artery catheterization is especially indicated in patients with a history of previous myocardial infarction, angina or signs of cardiac failure and in patients with evidence of diminished ejection fraction, abnormal ventricular wall motion or myocardial redistribution on preoperative scanning. The more widespread application of intraoperative transoesophageal two-dimensional echocardiography and radionuclide cardiography monitoring techniques into anaesthetic practice will enable measurement of left ventricular dimensions, myocardial performance and wall motion. Suggested guidelines for anaesthetic management are presented in Table VI. A combined opiate-oxygen-volatile anaesthetic agent technique will best ensure a hypodynamic circulation with preservation of myocardial oxygenation.(ABSTRACT TRUNCATED AT 400 WORDS)

Interscalene brachial plexus blockade with lidocaine in chronic renal failure - a pharmacokinetic study

Plasma lidocaine concentrations, latency of onset, and duration of anaesthesia, were determined after interscalene brachial plexus block in 16 patients presenting for elective upper limb surgery. Eight patients had normal renal function and eight had chronic renal failure, as determined by creatinine clearance. Significantly higher plasma lidocaine levels were recorded ten minutes after infiltration in patients with chronic renal failure (p < 0.05). Cmax plasma levels for normal patients (5.6 ±1.1 μg · ml-1) and for patients with chronic renal failure (6.6 ± 1 .6 μg · ml-1) were not significantly different. The latency of onset and duration of anaesthesia were similar in both groups. One per cent lidocaine solution may be administered to patients with normal and impaired renal function to provide effective brachial plexus blockade for short surgical procedures.

The influence of collateral vascularisation on haemodynamic performance during abdominal aortic surgery.

The extent of periaortic collateral vascularisation has been proposed as a possible mechanism of an altered haemodynamic response to infra-renal aortic cross-clamp in patients undergoing by-pass grafting for aorto-iliac occlusive disease (AOD) compared with patients undergoing abdominal aortic aneurysm (AAA) resection. The haemodynamic responses following clamping, during the clamp time and following clamp release were studied in 18 patients undergoing AAA resection and 12 patients undergoing bypass grafting for AOD. The role of preoperative aortography in predicting cardiovascular performance during aortic vascular surgery was assessed. During the cross-clamp period LVSWI and CI decreased while SVR increased in the AAA group while the AOD group showed an improved CI, stable LVSWI and reduced SVR, which correlated with the extent of periaortic vascularisation on preoperative aortography. Chronic collateral circulation associated with AOD may permit continuous lower extremity perfusion during aortic cross-clamp. The extent of periaortic collateralisation may influence the choice of monitoring techniques and anaesthetic management.RésuméĽimportance de la vascularisation collatérale périaortique a été proposée comme étant un mécanisme pouvant altérer les réponses hémodynamiques au clampage aortique infra-rénal chez les patients devant subir une greffe aorto-iliaque comparativement aux patients devant subir une résection de ľanévrisme de ľaorte abdominale. Les réponses hémodynamiques après clampage, durant le clampage ainsi qu’après déclampage ont été étudiées chez 18 patients subissant une résection ďanévrisme de ľaorte abdominale et 12 patients subissant un pontage aorto-iliaque. Le rôle de ľaortographie préopératoire dans la prédiction de la performance cardiovasculaire durant la chirurgie fut évalué. Lors du clampage aortique, le travail ďéjection indexé du ventricule gauche ainsi que ľindex cardiaque ont diminué alors que la résistance vasculaire systémique a augmenté chez les patients ayant subi une résection de ľanévrisme de ľaorte abdominale. Les patients ayant subi une greffe aorto-iliaque pour maladie athérosclérotique obstructive ont démontré une amélioration de ľindex cardiaque, un travail ďéjection indexé du ventricule gauche stable et une diminution de la résistance vasculaire systémique qui était reliée à ľimportance de la vascularisation péri-aortique telle que démontrée par ľaortographie préopératoire. Ľétablissement ďune circulation collatérale chronique en présence de maladie athérosclérotique obstructive de ľaorte peut permettre une perfusion continue des extrémités lors du clampage aortique. Ľétendue de la collatéralisation péri-aortique peut influencer le choix des techniques de surveillance ainsi que la conduite anesthésique.

Myocardial contractility and ischaemia in the isolated perfused rat heart with propofol and thiopentone

The effects of propofol and thiopentone on myocardial contractility and global ischaemia were evaluated using an isolated non-working perfused rat heart preparation. Contractility was assessed using a tension transducer linked to the cardiac apex, and the contractility was expressed as a ratio of the deflection size before and after infusion of the drug. Ischaemia-induced leakage of myocardial proteins and ions (potassium and magnesium) was assessed by comparing the concentrations in the effluent perfusate immediately before and after 60 min of isothermic ischaemia, in the presence of propofol, thiopentone or plain Krebs’ buffer solution (control). Mean contractility ratios of 1.15 and 1.3 were obtained with control and propofol groups respectively (NS), but were reduced to 0.5 in the thiopentone group (P < 0.001). The magnitude of the postischaemic leakage of proteins and potassium was similar in each group; however, the post-ischaemic leakage of magnesium was greater in the thiopentone group than in the propofol or control groups. These data suggest that, compared with thiopentone, propofol is not a potent negative inotrope, and that it may cause less disturbance of myocardial magnesium homeostasis during myocardial ischaemia.RésuméLes effets du propofol el du thiopentone sur la contractilité myocardique et l’ischémie globale furent évalués utilisant une préparation isolée de cœur de rat perfusé au repos. La contractilité fut évaluée utilisant un transducteur de pression lié à l’apex et la contractilité fut exprimée par le ratio de la déflection avant et après perfusion des médicaments. La fuite des protéines myocardiques et des ions (potassium et magnésium) induite par ischémie fut évaluée en comparant des concentrations à la sortie dans le liquide de perfusion immédiatement avant et après 60 minutes d’ischémie isothermique en présence de propofol, thiopentone ou une solution de Krebs (contrôle). Des ratios de contractilité moyenne de 1.15 et 1.3 furent obtenus dans les groupes controle et propofol respectivement (NS), mais furent diminués à 0.5 dans le groupe thiopentone (P < 0.001). L’étendue de la fuite post-ischémique des protéines et du potassium était similaire dans chaque groupe, cependant elle etait plus grande pour le magnésium dans le groupe thiopentone comparativement aux groupes controle et propofol. Ces données suggèrent que comparativement au thiopentone, le propofol ne possède pas un effet inotrope négatif puissant et qu’il peut causer moins de perturbation de l’homéostasie du magnésium myocardique lors de l’ischémie myocardique.

Protective Role of Cyclooxygenase (COX)-2 in Experimental Lung Injury: Evidence of a Lipoxin A4-Mediated Effect

BACKGROUND Polymorphoneutrophils (PMNs) are activated by inflammatory mediators following splanchnic ischemia/reperfusion (I/R), potentially injuring organs such as the lung. As a result, some patients develop respiratory failure following abdominal aortic aneurysm repair. Pulmonary cyclooxygenase (COX)-2 protects against acid aspiration and bacterial instillation via lipoxins, a family of potent anti-inflammatory lipid mediators. We explored the role of COX-2 and lipoxin A(4) in experimental I/R-mediated lung injury. MATERIALS AND METHODS Sprague-Dawley rats were assigned to one of the following five groups: (1) controls; (2) aortic cross-clamping for 45 min and reperfusion for 4 h (I/R group); (3) I/R and SC236, a selective COX-2 inhibitor; (4) I/R and aspirin; and (5) I/R and iloprost, a prostacyclin (PGI(2)) analogue. Lung injury was assessed by wet/dry ratio, myeloperoxidase (MPO) activity, and bronchoalveolar lavage (BAL) neutrophil counts. BAL levels of thromboxane, PGE(2), 6-keto-PGF(1)α (a hydrolysis product of prostacyclin), lipoxin A(4), and 15-epi-lipoxin A(4) were analyzed by enzyme immunoassay (EIA). Immunostaining for COX-2 was performed. RESULTS I/R significantly increased tissue MPO, the wet/dry lung ratio, and neutrophil counts. These measures were significantly further aggravated by SC236 and improved by iloprost. I/R increased COX-2 immunostaining and both PGE(2) and 6-keto-PGF(1α) levels in BAL. SC236 markedly reduced these prostanoids and lipoxin A(4) compared with I/R alone. Iloprost markedly increased lipoxin A(4) levels. The deleterious effect of SC236 and the beneficial effect of iloprost was associated with a reduction and an increase, respectively, in lipoxin A(4) levels. CONCLUSIONS Lipoxin A(4) warrants further evaluation as a mediator of COX-2 regulated lung protection.

Spinal Cord Perfusion Pressure in Dogs after Control of Proximal Aortic Hypertension during Thoracic Aortic Cross-clamping with Esmolol or Sodium Nitroprusside

Background:Spinal cord perfusion pressure may be reduced when sodium nitroprusside is used to control proximal aortic hypertension during thoracic aortic clamping. The effect of esmolol infusion on spinal cord perfusion pressure during thoracic aortic clamping is unknown. This study compares spinal cord perfusion pressure following control of proximal hypertension with either sodium nitroprusside or esmolol during thoracic aortic clamping. Methods:The thoracic aorta was cross-clamped for 30 min in 18 dogs anesthetized with halothane. A control group (n = 6) received no treatment of proximal hypertension during cross-clamping. In two other groups, proximal arterial pressure was controlled (100 mmHg) by infusion of either sodium nitroprusside (n = 6) or esmolol (n = 6). Brachial and femoral arterial pressures, spinal cord perfusion pressure, pulmonary artery occlusion, central venous pressures, and cardiac output were monitored. Neurologic assessment was performed 24 h following surgery. Results:Femoral arterial pressure was lower with nitroprusside (14 ± 3 mmHg) compared to esmolol (24 ± 4 mmHg) after 15 min of aortic cross-clamping. Cerebrosplnal fluid pressure Increased during aortic cross-clamping in the sodium nitroprusside group (from 7 ± 5 to 16 ± 6 mmHg) but not in esmolol or control groups. Spinal cord perfusion pressure was lower with nitroprusside at 15 min of aortic cross-clamping (2 ± 4 mmHg) compared to control (15 ± 7 mmHg) and esmolol groups (17 ± 11 mmHg). Esmolol Infusion reduced cardiac output and increased ventricular filling pressures compared to control and nitroprusside groups. Conclusions:Esmolol was associated with greater spinal cord perfusion pressure, but adverse hemodynamic effects, when compared with nitroprusside during thoracic aortic cross-damping. When only surviving dogs (4 control, 5 esmolol, 6 nitroprusside) are considered, the Incidence of neurologic deficit was greater in nitroprusside-treated dogs than in either control or esmolol-treated dogs. No difference in outcome was present when all dogs are considered.

The sitting position in neurosurgery: Unresolved hemodynamic consequences!

ONTROVERSY continues to surround use of the sitting position for neurosurgical procedures. 1–3 The seated position, while presenting a number of challenges for the anesthesiologist, offers many surgical advantages for patients undergoing posterior fossa and cervical spine procedures. Specifically, the upright position improves operator orientation and surgical access to midline lesions in many posterior fossa cases. Gravitational drainage of venous blood from the surgical field and lowering of intracranial pressure increases technical ease and allows more rapid access to bleeding points. 4 An unobstructed view of the face allows motor responses to cranial nerve stimulation to be directly observed in the sitting position, and access to the anterior chest wall is facilitated in the event of cardiovascular collapse. Despite the many advantages offered from the surgical perspective, the sitting position presents unique physiological challenges for the anesthesiologist with the potential for serious complications. 1,5 Venous air embolism, with or without paradoxical air embolism, is a major concern in relation to the use of this position. 2,6 Hemodynamic instability with hypotension and potential compromise of cerebral and myocardial perfusion may occur. Reduction of inhaled volatile anesthetic agent and decreasing depth of anesthesia may predispose the seated patient to the risk of intraoperative awareness. Peripheral neuropathy 1 tension pneumocephalus, 7 and quadriplegia 1,2 are additional reported associated complications. The hemodynamic effects of anesthesia in the sitting position may be influenced by choice of ventilatory technique. Spontaneous ventilation with a volatile anesthetic agent in nitrous oxide/oxygen was popular in the 1960’s to provide signs of surgical encroachment on vital medullary and pontine structures. 8 The problems of cardiovascular instability and arterial hypotension associated with the upright position may be aggravated by the depressant effects of intravenous induction and volatile agents on myocardial contractility during general anesthesia and changes in venous return following intermittent positive pressure ventilation. 9 The volume of blood accumulating in the venous system may be influenced by patient factors - body mass index, intravascular volume status, pre-existing hypertension and mode of ventilation. As much as 1500 mL may be sequestered in the venous system of the lower limbs due to the effect of gravity 10 and increased diffusion through the capillary walls and venous dilatation associated with the use of volatile anesthetic agents. 11 Indicator dilution technique studies have confirmed a 14% redistribution of blood volume from the intra- to the extrathoracic compartment in anesthetized patients after a change from the supine to the sitting position. 12 Concomitant changes in arterial pressure and stroke volume index were thus attributed to alterations in cardiac preload. A number of techniques have been advocated to attenuate the hemodynamic effects of patient placement in the sitting position. Colloid preloading (10 mL·kg –1 ) 30 min before starting general anesthesia was reported to prevent decreases in systolic and central venous pressures during sitting patient positioning without adverse effects. 13 Compensatory mechanisms, perhaps mediated by the renin-angiotensin-aldosterone system or the sympathetic nervous system, may be operative in the awake or anesthetized state to attenuate adverse hemodynamic changes associated with the sitting position. Wrapping of the legs, application of anti-gravity suits and positioning of the knees at right heart level may all have potential benefits.

The effect of local anaesthetics on epine-phrine absorption following rectal mucosal infiltration

This study was undertaken to investigate the effects of lidocaine and bupivacaine on epinephrine absorption following rectal mucosal infiltration, to assess the cardiovascular and metabolic effects of the absorbed epinephrine and to compare the systemic absorption of the local anaesthetics employed. Three groups of five greyhounds received 1.5 μg · kg−1 of epinephrine 1:200,000 in lidocaine 0.5 per cent, bupivacaine 0.5 per cent or 0.9 per cent saline. Plasma epinephrine, lidocaine, bupivacaine, lactate, glucose and potassium concentrations were measured at 1, 2, 5, 10, 15 and 30 minutes following infiltration. Plasma epinephrine concentrations were significantly higher in the lidocaine group at one and two minutes following infiltration. Plasma bupivacaine concentrations were significantly higher than plasma lidocaine concentrations throughout the study period. There were no significant differences in metabolic or biochemical indices within or between the three groups. A local vasodilatory action of lidocaine may enhance epinephrine absorption. Differences in hepatic uptake and rate of metabolism may explain the increased plasma bupivacaine measured. Lidocaine may be the local anaesthetic of choice for ano-rectal procedures, especially when large volumes of local anaesthetic are being infiltrated.RésuméCe travail avait pour but de comparer la lidocaine et la bupivacaïne injectées dans la muqueuse rectale quant à leur absorption et à leur effet sur l’absorption de l’adrénaline. On voulait aussi mesurer l’impact cardiovasculaire et métabolique de l’adrénaline. Nous avons injecté 1.5 μg · kg−1 d’adrénaline 1:200,000 avec soit de la lidocaine 0.5 pour cent, soit de la bupivacaïne 0.5 pour cent ou du NaCl 0.9 pour cent chez trois groupes de cinq lévriers. Les mesures sériées des concentrations sériques d’adrénaline, de lidocaïne, de bupivacaïne, de lactate, de glucose et de potassium étaient faites 1, 2, 5, 10, 15 et 30 minutes après l’infltraiton de la muqueuse. Nous avons mesuré des concentrations sériques d’ adrénaline plus élevées dans le groupe lidocaïne à une et deux minutes et trouvé que les niveaux plasmatiques de bupivacaine étaient systématiquement supérieurs à ceux de lidocaïne. Les variables métaboliques et biochimiques étaient semblables d’un groupe à l’autre. En vasodilatant, la lidocaïne peut faciliter l’absorption de l’adrénaline alors qu’une captation hépatique et un métabolisme plus faibles pourraient expliquer les niveaux plasmatiques élevés de bupivacaïne. La lidocaïne est probablement le meilleur choix pour les infiltrations locales de grands volumes d’anesthésique lors de chirurgies ano-rectales.