Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses.

BACKGROUND: Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2 -adrenoceptors. Vatinoxan, a peripheral α2 -antagonist, has been shown experimentally to alleviate the adverse effects of some α2 -agonists in horses. However, vatinoxan has not been investigated during constant-rate infusion (CRI) of medetomidine in standing horses. OBJECTIVES: To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine. STUDY DESIGN: Experimental, randomised, blinded, cross-over study. METHODS: Six healthy horses were given medetomidine hydrochloride, 7 µg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 µg/kg i.v., followed by CRI of medetomidine at 3.5 µg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t-tests as appropriate. RESULTS: Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001) respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01). MAIN LIMITATIONS: Experimental study with healthy, unstimulated animals. CONCLUSIONS: Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min.. The Summary is available in Portuguese - see Supporting Information.

Effects of dexmedetomidine and MK-467 on plasma glucose, insulin and glucagon in a glibenclamide-induced canine hypoglycaemia model.

The commonly used sedative α2-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting α2-adrenoceptor antagonist MK-467. An ancillary effect of dexmedetomidine is to decrease insulin release from the pancreas, whereas MK-467 stimulates insulin release. This study assessed the effects of co-administered dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model. In a randomised, cross-over experiment, eight beagle dogs received five intravenous treatments, comprising two administrations of saline, with dexmedetomidine or dexmedetomidine and MK-467, and three administrations of glibenclamide, with saline, dexmedetomidine or dexmedetomidine and MK-467. Plasma concentrations of glucose, lactate, insulin, glucagon and the test drugs were monitored. Administration of glibenclamide significantly increased insulin secretion and decreased blood glucose concentrations. Dexmedetomidine counteracted glibenclamide-evoked hypoglycaemia. This was opposed by the α2-adrenoceptor antagonist MK-467, but the glibenclamide-evoked hypoglycaemia was not potentiated by co-administration of dexmedetomidine and MK-467. None of the dogs developed uncontrolled hypoglycaemia. Thus, the combination of dexmedetomidine and MK-467 appeared to be safe in this canine hypoglycaemia model. Nevertheless, when MK-467 is used to alleviate the undesired cardiovascular effects of α2-adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects.

The impact of medetomidine on the protein-binding characteristics of MK-467 in canine plasma.

This study determined the unbound fraction of the peripheral α2 -adrenoceptor antagonist MK-467 alone and combined with medetomidine. MK-467 (0.1, 1 and 10 µm) was incubated in canine plasma with and without medetomidine (molar ratio 20:1), with human serum albumin (HSA) and with α1-acid glycoprotein (AGP). Rapid equilibrium dialysis was used for the measurement of protein binding. All samples were analysed by liquid chromatography and tandem mass spectrometry to obtain the unbound fraction (fu ) of MK-467. Unbound fractions (fu ) of MK-467 in canine plasma (mean ± standard deviation) were 27.6 ± 3.5%, 26.6 ± 0.9% and 42.4 ± 1.2% at 0.1, 1.0 and 10 µm concentrations, respectively. In the presence of medetomidine, fu were 27.5 ± 0.4%, 26.6 ± 0.9% and 41.0 ± 2.4%. The fu of MK-467 in HSA were 50.1 ± 2.5% at 0.1 µm, 49.4 ± 1.2% at 1.0 µm and 56.7 ± 0.5% at 10 µm. fu of MK-467 in AGP was 56.3 ± 3.7% at 0.1 µm, 54.6 ± 5.6% at 1.0 µm and 65.3 ± 0.4% at 10 µm. Protein binding of MK-467 was approximately 70% between 0.1 and 1.0 µm. Medetomidine had no apparent effect on the protein binding of MK-467.

Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs.

We investigated the influence of the peripherally acting α2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an α2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 µg/kg) or medetomidine with MK-467 (250 µg/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK-467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine.

Tension pneumothorax secondary to nasojejunal feeding tube misplacement in a mechanically ventilated dog.

CASE REPORT: An 11-year-old female terrier-cross underwent general anaesthesia and mechanical ventilation for insulinoma resection. Following tumour removal, three consecutive but unsuccessful attempts were made to place a wire-guided nasojejunal feeding tube (NJFT), using both nostrils, with one tube eventually left in situ in the right nostril. A final successful attempt using a smaller NJFT was made via the left nostril. On withdrawal of the previously, unsuccessfully placed NJFT, the dog developed an acute tension pneumothorax. Severe cardiorespiratory dysfunction ensued, including decreasing arterial haemoglobin O2 saturation, increasing end-tidal CO2, hypotension and tachycardia. Immediate thoracocentesis with air evacuation from the pleural cavity followed by continuous air drainage through bilateral thoracostomy tubes produced marked improvement of cardiorespiratory function. During exploratory thoracotomy performed 1 day later, two lung lesions were identified and over sewn, one in the right middle lobe and the other in the accessory lobe. CONCLUSIONS: This is the first case report to describe in an anaesthetised and mechanically ventilated dog the occurrence and management of a tension pneumothorax as a life-threatening complication secondary to parenchymal injury after NJFT misplacement into the tracheobronchial tree. It illustrates that presence of a cuffed endotracheal tube does not protect against passing a NJFT into the bronchial system.

The effect of omeprazole on oesophageal pH in dogs during anaesthesia.

OBJECTIVES: Intra-operative, gastro-oesophageal reflux may be associated with post-anaesthestic complications such as oesophagitis and oesophageal stricture in dogs. The aim of this study was to investigate the effect of preoperative administration of omeprazole, a proton pump inhibitor, on oesophageal pH in anaesthetised dogs. METHODS: Forty-seven dogs undergoing elective pelvic limb orthopaedic surgery were enrolled into the study. These were randomly allocated to treatment group (n=22) or control group (n=25). The treatment group received one dose of omeprazole (1 mg/kg po) at least 4 h before anaesthesia. All dogs were anaesthetised by the same standardised protocol. A pH probe was inserted into the distal oesophagus after induction of anaesthesia and oesophageal pH was continuously monitored. RESULTS: In the treatment group, four animals (18 per cent) showed a sudden decrease in oesophageal pH (<4). In the control group the same phenomenon was detected in 13 animals (52 per cent). Gastro-oesophageal reflux occurred more frequently in the control group compared with the omeprazole group (odds ratio 4.7, 95 per cent C.I. 1.1 to 24.7, P=0.032). CLINICAL SIGNIFICANCE: This study suggests that the preoperative administration of omeprazole is effective in reducing the incidence of gastro-oesophageal reflux during anaesthesia in dogs.

Comparison of sevoflurane and isoflurane in dogs anaesthetised for clinical surgical or diagnostic procedures.

OBJECTIVES: To assess attributes of sevoflurane for routine clinical anaesthesia in dogs by comparison with the established volatile anaesthetic isoflurane. METHODS: One hundred and eight dogs requiring anaesthesia for elective surgery or diagnostic procedures were studied. The majority was premedicated with 0.03 mg/kg of acepromazine and 0.01 mg/kg of buprenorphine or 0.3 mg/kg of methadone before induction of anaesthesia with 2 to 4 mg/kg of propofol and 0.5 mg/kg of diazepam. They were randomly assigned to receive either sevoflurane (group S, n=50) or isoflurane (group I, n=58) in oxygen and nitrous oxide for maintenance of anaesthesia. Heart rate, respiratory rate, indirect arterial blood pressure, haemoglobin saturation, vaporiser settings, end-tidal carbon dioxide and anaesthetic concentration and oesophageal temperature were measured. Recovery was timed. Data were analysed using analysis of variance and non-parametric tests. RESULTS: Heart rate (85 to 140/minute), respiratory rate (six to 27/minute) and systolic arterial blood pressure (80 to 150 mmHg) were similar in the two groups. End-tidal carbon dioxide between 30 and 60 minutes (group S 6.4 to 6.6 and group I 5.8 to 5.9 per cent) and vaporiser settings throughout (group S 2.1 to 2.9 and group I 1.5 to 1.5 per cent) were higher in group S. There was no difference in time to head lift (18+/-16 minutes), sternal recumbency (28+/-22 minutes) or standing (48+/-32 minutes). No adverse events occurred. CLINICAL SIGNIFICANCE: Sevoflurane appeared to be a suitable volatile anaesthetic for maintenance of routine clinical anaesthesia in dogs.

Radical surgery with omental flap for uncontrolled locally recurrent breast cancer.

BACKGROUND: Uncontrolled chest wall disease due to breast cancer is a highly morbid condition causing pain, ulceration, malodour and the need for frequent dressings. Aggressive surgical approaches are rarely justified because most patients will succumb to metastatic breast cancer within a short period. A highly selected group of patients with minimal or no evidence of metastatic disease and good performance status may benefit from radical chest wall surgery. Omental transposition flaps are ideal for reconstructing extensive surgical defects following chest wall surgery. METHODS: A retrospective review was carried out of 61 female patients treated consecutively between 1980 and 1995. The surgical technique is described herein. RESULTS: All patients were symptomatic preoperatively. Symptoms included ulceration (80%), pain (44%) and malodour (40%). Twenty-nine patients had uncontrolled local recurrence following initial treatment for locally advanced breast cancer and 32 patients developed uncontrolled recurrence after treatment for operable breast cancer by mastectomy or conservation surgery. Median survival following chest wall surgery was 21 months and the median local recurrence-free interval was 20 months. Morbidity was -limited. There were no cases of major flap loss. Twenty-nine patients (48%) had no further local disease. Eighteen patients (30%) developed soft-tissue recurrence at the edge of the omental flap or in surrounding skin and 14 (23%) developed recurrence beneath the flap. CONCLUSION: In a highly selected group of patients with symptomatic uncontrolled chest wall recurrence who are fit and have an expectation of at least moderate-term survival, radical chest wall surgery and omental flap transposition offers excellent palliation and local control in the majority of patients

Comparison of detomidine and romifidine as premedicants before ketamine and halothane anesthesia in horses undergoing elective surgery.

OBJECTIVE: To compare detomidine hydrochloride and romifidine as premedicants in horses undergoing elective surgery. ANIMALS: 100 client-owned horses. PROCEDURE: After administration of acepromazine (0.03 mg/kg, IV), 50 horses received detomidine hydrochloride (0.02 mg/kg of body weight, IV) and 50 received romifidine (0.1 mg/kg, IV) before induction and maintenance of anesthesia with ketamine hydrochloride (2 mg/kg) and halothane, respectively. Arterial blood pressure and blood gases, ECG, and heart and respiratory rates were recorded. Induction and recovery were timed and graded. RESULTS: Mean (+/- SD) duration of anesthesia for all horses was 104 +/- 28 minutes. Significant differences in induction and recovery times or grades were not detected between groups. Mean arterial blood pressure (MABP) decreased in both groups 30 minutes after induction, compared with values at 10 minutes. From 40 to 70 minutes after induction, MABP was significantly higher in detomidine-treated horses, compared with romifidine-treated horses, although more romifidine-treated horses received dobutamine infusions. In all horses, mean respiratory rate ranged from 9 to 11 breaths/min, PaO2 from 200 to 300 mm Hg, PaCO2 from 59 to 67 mm Hg, arterial pH from 7.33 to 7.29, and heart rate from 30 to 33 beats/min, with no significant differences between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine and romifidine were both satisfactory premedicants. Romifidine led to more severe hypotension than detomidine, despite administration of dobutamine to more romifidine-treated horses. Both detomidine and romifidine are acceptable alpha2-adrenoceptor agonists for use as premedicants before general anesthesia in horses; however, detomidine may be preferable when maintenance of blood pressure is particularly important.

The Pacific Islands Project: the first 3 years.

BACKGROUND: The Pacific Island countries consist of widely scattered, small, underdeveloped islands which require considerable international assistance, particularly in health care. In 1995, the Pacific Islands Project was established and funded by AusAID to provide tertiary medical assistance to 10 island countries over a 3-year period. The programme was later expanded to include Papua New Guinea. METHODS: The Royal Australasian College of Surgeons was appointed manager of the project, which involved voluntary input from members of several specialist medical colleges and societies. Assistance was provided through short-term visits of multidisciplinary teams according to predetermined priorities. The delivery of medical services was combined with a transfer of skills and educational activities. Feedback was obtained from the recipient countries and each visit evaluated by an independent committee. RESULTS: One hundred and thirty-one visits in ten disciplines were conducted in 11 countries by 255 participants on a voluntary basis between March 1995 and March 1998: 15 784 patients were seen and 3424 operations performed. CONCLUSIONS: The programme was very successful on all counts. It has now been extended for a further 3 years and will be conducted in parallel with postgraduate educational programmes in the Pacific region and Papua New Guinea.

Comparison of detomidine/ketamine and guaiphenesin/thiopentone for induction of anaesthesia in horses maintained with halothane.

This prospective clinical study compared the physiological effects of two commonly used anaesthetic induction techniques in horses maintained with halothane. One hundred horses admitted for elective surgery were randomly allocated to receive either guaiphenesin (to effect) and thiopentone (5 mg/kg), or detomidine (20 microg/kg) and ketamine (2 mg/kg) for the induction of anaesthesia after acepromazine premedication. Anaesthesia was maintained with halothane in oxygen. There were no significant differences in breed, age, sex, weight, type of surgery and duration of anaesthesia between the groups. Immediately after induction of anaesthesia heart rate was higher after guaiphenesin and thiopentone, and arterial blood pressure was higher after detomidine and ketamine. Thereafter hypotension, often necessitating an infusion of dobutamine, developed in both groups. Arterial blood gases and respiratory rates were similar in the two groups. There were no significant differences between the groups in the subjectively scored quality of induction and recovery, or in recovery time.

Infrarenal aortic aneurysm surgery in a rural surgical service: risk factors for mortality.

BACKGROUND: An audit of both the emergency and elective abdominal aortic surgery that was performed in a rural surgical service, was carried out. METHODS: Retrospective data analysis was performed on 41 patients who were treated for abdominal aortic aneurysms (AAA) during an 8-year period from 1989 to 1996. Postoperative outcomes were analysed with respect to patient age, mode of presentation (elective or emergency), transfusion requirements and pre-existing cardiac and respiratory disease. Univariate analysis was performed using Fisher's exact test, and the odds ratio for adverse outcome was calculated. RESULTS: A postoperative mortality rate of 5.8% in elective repairs and 68% in cases of rupture was noted. Pre-existing respiratory disease, transfusion requirements of more than six units and presentation with retroperitoneal leak or rupture correlated with postoperative mortality, while age and pre-existing cardiac disease were shown not to be predictive of adverse outcome following surgery. CONCLUSIONS: An overall improvement in operative outcomes in the institution (Wimmera Base Hospital) that was audited would be affected by earlier referral for elective repair in selected patients. Like others, the authors believe that age on its own is not a contraindication to elective AAA repair.

Preliminary investigations of pain and analgesia assessment in horses administered phenylbutazone or placebo after arthroscopic surgery.

Twenty-five horses undergoing arthroscopic surgery were studied to develop a scheme for assessing pain in horses while investigating the effects of phenylbutazone (PBZ) analgesia. Fifteen of the 25 horses received PBZ 4 mg/kg intravenously (IV) before surgery and 2 mg/kg (IV) every 12 hours thereafter until 60 hours; the remaining 10 (placebo group) were given a corresponding volume of saline. In both groups, venous blood samples were collected for catecholamine, beta-endorphin, and cortisol assays before premedication and up to 72 hours after surgery. Postoperative pain was evaluated by measuring predefined behavioral and physiological variables. A total postoperative pain severity index (TPPSI) was calculated using all variables. There were no differences between PBZ and placebo groups in plasma beta-endorphin or catecholamine concentrations, but the TPPSI was higher in the placebo group than in the PBZ group, suggesting that perioperative treatment with PBZ has some analgesic benefit. This study shows the difficulties associated with pain assessment in horses.

Parathyroid hormone related protein in breast cancers of widely varying prognosis.

Parathyroid hormone related protein (PTHrP) is a novel calcium regulating hormone that may have a significant role in the pathophysiology of breast cancer. We have previously demonstrated a relationship between immunohistochemically detectable PTHrP in primary breast tumours and the subsequent development of bone metastases and hypercalcaemia. The aim of this study was to compare the PTHrP status in the primary tumours from three groups of patients with widely varying prognosis. (1) The favourable outcome group; all patients had a favourable prognosis and minimum 3 years disease free follow up (n = 30). (2) The unfavourable outcome group; all patients presented with localized breast cancer but developed distant disease within 3 years (n = 26). (3) The unfavourable presentation group; all had distant disease at first presentation (n = 26). No differences in PTHrP status of the primary tumour amongst the three patient groups were found (66%, 65% and 61% positive respectively). The development of bone with liver metastases and hypercalcaemia was associated with increased positive PTHrP status of the primary tumor.

Detection and significance of occult metastases in node-negative breast cancer.

The clinical value of lymph node immunohistochemistry was assessed in 343 consecutive patients with apparently node-negative breast cancer using antimucin monoclonal antibodies BC2, BC3 and 3E1.2. Occult metastases were detected in 41 patients (12 per cent). Although most of these were micrometastatic (< 2 mm in diameter), larger or diffuse deposits were found in ten patients. Blind assessment of repeat haematoxylin and eosin stained sections detected metastases in ten of the 41 patients with occult metastases. After a median follow-up of 79 months, patients with occult metastases had a shorter time to disease recurrence (P < 0.05) but not to death. After adjustment for other prognostic factors, the presence of occult metastases in two or more nodes was the most significant predictor of both disease recurrence (P < 0.01) and death (P < 0.01). When the ten patients with positive haematoxylin and eosin sections were excluded from the analysis, the presence of occult metastases in two or more nodes was still associated with a reduced disease-free interval (P < 0.05) and survival (P < 0.05). Lymph node immunohistochemistry is a simple technique affording more accurate definition of nodal involvement than conventional methods.

Rearrangement of chromosome 1p in breast cancer correlates with poor prognostic features.

In a cytogenetic study of breast cancer biopsies, clonal abnormalities of chromosome 1p were identified in 56% (14) of 25 informative patients. Translocations predominated, involving 1p22 (n = 1), 1p35 (n = 1) or 1p36 (n = 10) breakpoints. Chromosome 1p abnormalities were associated with estrogen receptor (ER) negativity (P = 0.03, 2-tailed Fisher Exact Probability test), high histological grade (P = 0.02, 2-tailed Mann-Whitney U-test) and an unfavourable Melbourne Prognostic Score (NEPA P = 0.02, SEPA P = 0.04, 2-tailed Mann-Whitney U-tests). These findings are consistent with the possibility that a gene located on chromosome 1p is implicated in tumour progression.

Breast cancer in the elderly: treatment of operable disease.

Between 1976 and 1985 122 elderly patients aged 70 years and over, were treated for 'operable' invasive breast cancer (UICC stage I-IIB). A tendency towards less aggressive investigation and treatment was noted in the elderly. Of 117 patients undergoing surgery, 79 (68%) had 'full' conventional treatment, either mastectomy with axillary clearance, sampling or radiotherapy, or local excision with radiotherapy. In 38 patients (32%) management of the breast or axilla was considered to have been less complete than the usual practice for younger patients ('limited' treatment group), either local excision without radiotherapy or simple mastectomy alone. The 'limited' treatment group were significantly older than the 'full' treatment group but were comparable for tumour size, clinical nodal status and oestrogen and progesterone receptor levels. Although there was no survival difference between the groups, those in the 'limited' treatment group were more likely to develop locoregional recurrence (chi 1(2) = 9.2, P = 0.002, log rank test). In practice, management of the elderly often appears to be influenced by chronological age rather than clinical or biological factors. It is suggested that elderly patients sufficiently fit to undergo surgery should be treated along the lines applicable to younger patients.

Breast cancer in the elderly: pattern of disease.

The elderly (aged 70 years or more) constituted 201 (37%) of 548 first-time admissions to a single institution for breast cancer between 1976 and 1985. The pattern of disease was studied and contrasted with that seen in younger patients (less than 70 years old). Currently, 5000 new breast cancers are diagnosed in Australia each year. It is projected that the proportion of new breast cancer patients who are elderly will rise from 37 to 60% by the year 2031. In general, the disease was similar to that seen in younger patients. Minor histological differences occurred and there were tendencies towards late presentation and clinically less aggressive disease. Tumour size, the presence of metastases and UICC staging were useful predictors of outcome but nodal status and hormone receptor levels did not discriminate. An unexpected finding was the relative longevity of elderly patients with breast cancer. The stage-specific 5-year survival rates (UICC stages: I--73%; II--65%; III--42%; IV--10%;) did not differ significantly from those seen in younger patients.