Is there a role for bisphosphonates in vascular calcification in chronic kidney disease?

Theoretically bisphosphonates could accelerate or retard vascular calcification. In subjects with low GFR, the position is further confounded by a combination of uncertain pharmacokinetics (GI absorption is poor and inconsistent at all levels of renal function and the effect of low GFR generally is to increase bioavailability) and a highly variable skeletal substrate with extremes of turnover that increase unpredictably further. Although bisphosphonates reduce bone formation by 70-90% in subjects with normal GFR and reduce the ability of bone to buffer exogenous calcium fluxes, in bisphosphonate treated postmenopausal women accelerated vascular calcification has not been documented. The kidneys assist with this buffering, but the capacity to modulate calcium excretion declines as GFR falls, increasing the risk of hypercalcaemia in the event of high calcium influx. In the ESRD patient, decreased buffering capacity substantially increases the risk of transient hypercalcaemia, especially in the setting of dialysis, and as such may promote vascular calcification which is highly prevalent in the CKD population. Low bone turnover may thus be less of a vascular problem in patients with preserved renal function and a bigger problem when the GFR is low. In patients with stage 4 and 5 CKD, adynamic bone disease associates with the severity and progression of arterial calcification, including coronary artery calcification, and further suppression of bone turnover by a bisphosphonate might exacerbate an already high predisposition to vascular calcification. No convincing signal of harm has emerged from clinical studies thus far. For example 51 individuals with CKD stage 3-4 treated with either alendronate 70 mg per week or placebo for 18 months showed no difference in the rate of vascular calcifications. Conversely an observational study of women with stage 3-4 CKD with pre-existing cardiovascular disease found an increased risk of mortality with a hazard ratio of 1.22 (1.04-1.42) in those given bisphosphonates. Direct suppression of vascular calcification by bisphosphonates is probably confined to etidronate - treatment of soft tissue calcification was a recognized indication for this drug and etidronate markedly reduced progression of vascular calcification in CKD patients. Bisphosphonates are analogues of pyrophosphate, a potent calcification inhibitor in bone and soft tissue. Thus the efficacy of etidronate as treatment for soft tissue calcification brought with it a problematic tendency to cause osteomalacia. In contrast, conventional doses of nitrogen-containing bisphosphonates fail to yield circulating concentrations sufficient to exert direct anti-calcifying effects, at least in patients with good renal function and studies using alendronate and ibandronate have yielded inconsistent vascular outcomes.

Impact of the American College of Cardiology/American Heart Association guidelines for interpretability of continuous electrocardiography on the association of silent ischemia with troponin release after major noncardiac surgery.

INTRODUCTION: Preexisting electrocardiographic abnormalities may limit accuracy of continuous electrocardiography (cECG) for ischemia determination. The American College of Cardiology/American Heart Association published criteria for the exclusion of unsuitable cECG curves from ST-segment interpretation. These criteria consider medication and 12-lead ECG findings (medication- and 12-lead ECG-based criteria) and cECG lead characteristics (cECG-based criteria). METHODS: We recorded cECG in 300 patients undergoing major noncardiac surgery. We determined postoperative troponin and 12-month outcome. We compared the associations of cECG-detected ischemia with troponin and 12-month outcome with and without adherence to the criteria. RESULTS: Adherence to the medication- and 12-lead ECG-based criteria enhanced the association between troponin and perioperative ischemia in CM5 (odds ratio, 3.74; 95% confidence interval, 1.88-7.44) and 7.03 (2.67-18.49), respectively; P = .049). Similarly, the association between ischemia in CM5 and 12-month outcome tended to increase (P = .081). CONCLUSIONS: Applying the guideline criteria for the interpretation of cECG enhanced cECG diagnostic value in surgical patients.

Sevoflurane decreases bispectral index values more than does halothane at equal MAC multiples.

At the minimum alveolar concentration (MAC) of inhaled anesthetics, 50% of subjects move in response to noxious stimulation. Similarly, at MAC-awake, 50% of subjects respond appropriately to command. The bispectral index (BIS) nominally measures the effect of anesthetics on wakefulness or consciousness. We postulated that the use of halothane with a larger MAC-awake/MAC ratio than sevoflurane would produce higher BIS values at comparable levels of MAC. We studied 33 unpremedicated patients anesthetized by inhalation, 18 with sevoflurane and 15 with halothane. We measured BIS before and during anesthesia at 1 MAC, both before and after tracheal intubation facilitated by fentanyl and rocuronium and then at 1.5 MAC. BIS measurements were made after meeting steady-state conditions. No surgery was performed during this study. BIS values in awake patients did not differ between the sevoflurane and halothane groups (96 +/- 2 and 96 +/- 2, mean +/- sd, respectively). At 1 MAC without and with neuromuscular blockade and at 1.5 MAC, BIS values for patients anesthetized with halothane (54 +/- 7, 56 +/- 7, and 49 +/- 7, respectively) exceeded those for patients anesthetized with sevoflurane (34 +/- 6, 34 +/- 6, and 29 +/- 5, respectively) (P < 0.0001). This finding adds to other evidence indicating that BIS is drug specific.

Morphologic changes and xanthine oxidase activity in the equine jejunum during low flow ischemia and reperfusion.

OBJECTIVE: To determine whether xanthine oxidase and dehydrogenase activities are altered during low flow ischemia and reperfusion of the small intestine of horses. ANIMALS: 5 clinically normal horses without histories of abdominal problems. PROCEDURE: With the horse under general anesthesia, a laparotomy was performed and blood flow to a segment of the distal jejunum was reduced to 20% of baseline for 120 minutes and was then reperfused for 120 minutes. Biopsy specimens were obtained before, during, and after ischemia for determination of xanthine oxidase and dehydrogenase activities, and for histologic and morphometric analyses. RESULTS: Percentage of xanthine oxidase activity (as a percentage of xanthine oxidase and dehydrogenase activity) was not altered during ischemia and reperfusion. An inflammatory response developed and progressed during ischemia and reperfusion. Mucosal lesions increased in severity after ischemia and reperfusion. Mucosal surface area and volume decreased during ischemia and continued to decrease during reperfusion. Submucosal volume increased slightly during ischemia, and continued to increase during reperfusion. CONCLUSIONS AND CLINICAL RELEVANCE: Evidence for conversion of xanthine dehydrogenase to xanthine oxidase during ischemia was not found. Factors other than production of reactive oxygen metabolites may be responsible for progressive epithelial loss, decrease in mucosal surface area and volume, and increase in submucosal volume observed in this study. Other methods of determining xanthine oxidase activity that detect the enzyme in sloughed epithelial cells should be used to better define the importance of this pathway in jejunal reperfusion injury in horses.

Surgical treatment for colic in the foal (67 cases): 1980-1992.

Sixty-seven foals age < 150 days underwent a ventral celiotomy for colic. Of the 67 foals, 51 foals (82%) recovered from anaesthesia and 42 (63%) were subsequently released from the hospital. Three (6%) of the 51 foals were subjected to a repeat celiotomy. Long term follow-up was available on 36 foals. Twenty-nine (57%) of the 51 foals recovered from anaesthesia, were alive at least 2 years following surgery. Adhesions were identified in 8 (17%) of the foals which recovered from general anaesthesia but were subsequently subjected to euthanasia due to recurrent colic. Strangulating lesions were associated with a lower survival rate. Nineteen per cent of foals with strangulating intestinal lesions survived > 2 years following surgery, compared to 69% of foals with nonstrangulating lesions. The age of foals on admission had a significant effect on survival. Only 10% of foals less than 14 days of age survived, compared to 45.8% of foals between age 15 and 150 days.

[Minimally invasive surgery of large bullous pulmonary emphysema]. / Minimal invasive Chirurgie beim grossbullösen Lungenemphysem.

An enormous pulmonary cyst (phi approx. 20 cm) in a 72-year-old male patient with large bullous pulmonary emphysema caused compression of the right lung and the mediastinum with consecutive, O2-dependent dyspnoea at rest. The symptoms did not improve under conservative therapy of an accompanying COPD. Thus, in spite of two heart attacks in the previous history, an operation with bullectomy was indicated. A thoracotomy had to be avoided because of the very high cardiac risk. In the present case, a minimally invasive procedure enabled the complete cyst resection with a smooth postoperative course and an excellent functional therapeutic result.

Effects of the 21-aminosteroid U-74389G on ischemia and reperfusion injury of the ascending colon in horses.

Sixteen horses were allotted at random to 3 groups: vehicle only; low dosage (vehicle and 3 mg of U-74389G/kg of body weight); high dosage (vehicle and 10 mg of U-74389G/kg). These solutions were given prior to reperfusion. The ascending colon was subjected to 2 hours of ischemia followed by 2 hours of reperfusion. Before, during, and after ischemia, full-thickness colonic tissue biopsy specimens were obtained for measurement of malondealdehyde (MDA) concentration and myeloperoxidase activity and for morphologic evaluation. Although increases were not significant, MDA concentration and myeloperoxidase activity increased during ischemia and reperfusion. Administration of U-74389G did not have significant effects on MDA concentration and myeloperoxidase activity. However, the lower dosage tended (P = 0.08) to reduce myeloperoxidase activity at 30 and 60 minutes of reperfusion. In horses of the vehicle-only group, ischemia induced a decrease in mucosal surface area that was continued into the reperfusion period (P < or = 0.05). Administration of U-74389G at both dosages (3 and 10 mg/kg) prevented the reperfusion-induced reduction in mucosal surface area, which was significant at 60 minutes (high dosage; P = 0.05) and 90 minutes (low and high dosages; P = 0.02). After initial reduction in horses of all groups, mucosal volume increased for the initial 60 minutes of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuromuscular blocking agents in equine anesthesia.

In summary, neuromuscular blocking agents can be used safely and to advantage in equine anesthesia. Muscle-relaxant use in equine anesthesia has been helped by the development of new relaxants such as atracurium, which has a reliable and reproducible duration of action. There are certain cases that benefit particularly by the use of relaxants but their use is not limited to these cases. These cases involve horses that experience persistent movement and hypotension during anesthesia, are undergoing ophthalmic or abdominal surgery or fracture repair, or are severely ill. Horses receiving muscle relaxants during anesthesia require mechanical ventilation, and neuromuscular blockade should be monitored with a peripheral-nerve stimulator.

A comparison of xylazine-diazepam-ketamine and xylazine-guaifenesin-ketamine in equine anesthesia.

After sedation with xylazine (0.3 mg/kg intravenously [IV]), anesthesia was induced in six healthy horses with ketamine (2.0 mg/kg IV) and guaifenesin (100 mg/kg IV), diazepam (0.05 mg/kg IV), or diazepam (0.10 mg/kg IV). Anesthesia was maintained with halothane for 30 minutes. Heart rate, respiratory rate, direct arterial blood pressure, arterial blood gas, and pH measurements were made before, and at set intervals after, induction of anesthesia. Quality and characteristics of induction and recovery were evaluated objectively by an independent observer unaware of the protocol used. There were no significant differences among the three protocols from pre-induction values for arterial blood pressure, blood gas values, and pH. There was significantly greater ataxia at induction with the use of guaifenesin. The nature of induction, transition to and recovery from general anesthesia were comparable between guaifenesin and the higher dose of diazepam. Because of movements and difficulty with intubation, the lower dose of diazepam was considered unsatisfactory. It was concluded that diazepam (0.10 mg/kg) could be substituted for guaifenesin (100 mg/kg) to produce comparable quality of anesthesia in horses.

Contracture test and histologic and histochemical analyses of muscle biopsy specimens from horses with exertional rhabdomyolysis.

Biopsy specimens of the cutaneous omobrachialis muscle were obtained from 10 horses with a problem of myositis from mild exercise. One horse had been evaluated previously and malignant hyperthermia-like contractures developed in its muscle biopsy specimen during the contracture test. In this study, the halothane-caffeine contracture test and histologic and histochemical evaluations were performed on muscle biopsy specimens. In the contracture test, no muscle biopsy specimen developed contracture in the presence of 2 or 4% halothane alone. The mean (+/- SEM) caffeine-specific concentration in the presence of halothane was 5.23 +/- 0.5 mM for 2% halothane, and 4.46 +/- 0.6 mM for 4% halothane. The caffeine-specific concentration values were not significantly different. Contracture response for any muscle specimen did not resemble contracture associated with malignant hyperthermia. The cutaneous omobrachialis muscle was composed of type-II fibers, with type-I fibers seldom seen. For 9 of the 10 horses, overall fiber morphology was normal; 1 horse had necrotic fibers. Of the 10 muscle specimens, 9 had fibers that had positive reaction for alkaline phosphatase activity; 3 muscle specimens contained ringed myofibers. Three horses of this study were administered general anesthesia; 2 were research horses, anesthetized with halothane and succinylcholine, and 1 was a clinical case given halothane anesthesia plus a non-depolarizing muscle relaxant. One research horse developed a malignant hyperthermia-like reaction to anesthesia, with severe rhabdomyolysis evident after anesthesia, and an episode of muscle cramping in its stall 2 days after anesthesia. The other 2 horses had unremarkable postanesthetic periods.

Blood pressure response to tourniquet use in anesthetized horses.

Blood pressure during anesthesia and surgery was compared for 2 groups of horses. Group A, consisting of 23 horses, had a tourniquet placed on the distal portion of a limb. The other group of 20 horses (group B) had surgery of comparable nature and duration as did group-A horses, but a tourniquet was not used. There was a statistical difference (P less than 0.05) in the peak systolic arterial blood pressure between the groups; group-A horses had a mean (+/- SEM) peak of 151 +/- 6 mm of Hg and group-B horses had a peak of 118 +/- 4 mm of Hg. In addition, group-A horses had immediate decrease in blood pressure, coincident with tourniquet deflation. The blood pressure decrease of 23 +/- 3 mm of Hg represented 16% of immediate predeflation blood pressure. Comparable blood pressure decrease was not observed at the end of surgery in group-B horses. Significant difference was not found when other factors that could affect blood pressure were considered. These factors included preanesthetic medication, anesthetic agents, mode of ventilation, pretourniquet inflation blood pressure, and duration of tourniquet inflation. Significant (P less than 0.05) difference in peak blood pressure was observed when the tourniquet was placed on the dependent, compared with the uppermost, limb, with changes more pronounced when the tourniquet was placed on the dependent limb. Tourniquet placement was associated with hypertension, and tourniquet deflation was associated with blood pressure decrease in these anesthetized horses.

Clinical use of the neuromuscular blocking agents atracurium and pancuronium for equine anesthesia.

Neuromuscular blocking agents (muscle relaxants) are useful and common adjuncts to general anesthesia for human beings, but have not been used extensively during anesthesia of large animal species. Over a 3-year period, atracurium or pancuronium were used as adjuncts to general anesthesia for 89 anesthetic procedures in 88 equids (of 18 breeds and age ranging in age from 5 weeks to 25 years) at the teaching hospital. Forty-one of the anesthetic procedures were for abdominal surgery, and orthopedic (n = 19), ophthalmologic (n = 17), thoracotomy (n = 1), and soft tissue (n = 14) procedures composed the rest. Most equids were given atracurium because it was less expensive than pancuronium. Initial dosage of either relaxant ranged from 0.12 to 0.2 mg/kg of body weight IV, and repeat doses ranged from 10 to 30 mg. Relaxants were used for as long as 205 minutes. Muscles of the face or hind limb digital extensor muscles were used to monitor relaxation. Muscles of the hind limb were more sensitive to the effects of relaxants than were muscles of the face. At the end of a surgical procedure, just prior to being taken to the recovery stall, a relaxant antagonist, edrophonium (0.5 to 1 mg/kg), was administered IV to each equid. Edrophonium caused blood pressure to increase in most of the equids. Heart rate change was variable, with approximately half the equids having no change or increased heart rate and the remainder having decreased heart rate. Recovery to standing after anesthesia was rated excellent or good for 72 equids, fair for 11, and poor for 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Unusual response following use of succinylcholine in a horse anesthetized with halothane.

A syndrome similar to malignant hyperthermia developed in a 545-kg Quarter Horse while anesthetized with halothane for cataract removal. Succinylcholine administration caused prolonged, severe muscle fasciculations followed by tachycardia, and an elevated blood pressure. Later, while the horse was still under anesthesia, its body temperature rose 2 degrees C, and respiratory acidosis developed. Myositis developed after surgery, but the horse recovered.

Succinylcholine infusion associated with hyperthermia in ponies anesthetized with halothane.

Succinylcholine was administered by infusion to halothane-anesthetized ponies to determine dosage requirements for surgical relaxation up to 3 hours' duration. This was not possible to do, since 4 of 6 ponies studied developed severe reactions characterized by prolonged muscle fasciculations after the initial succinylcholine dose, muscle rigidity, hyperthermia, hypercapnia, tachycardia, increasing pulse pressure, and metabolic acidosis. The reactions resembled those associated with malignant hyperthermia, a disease recognized in persons and swine. Two ponies showed signs of the phase II or desensitization block of succinylcholine. All ponies recovered from anesthesia without signs of muscle injury.