Effects of gestational age on physical findings of immaturity, body weight, and survival in neonatal alpacas (2002-2010).

BACKGROUND: Gestational duration is highly variable in camelids (reference range 330-360 days), and a definition for prematurity has not been established. Anecdotally, it is suggested that crias born outside of this have increased incidence of physical findings of immaturity (tendon laxity, floppy ears, and unerupted teeth) and need increased intensive support in the neonatal period. OBJECTIVES: Low gestational age (<330 days) is associated with physical findings of immaturity, low birth weight, more intensive and expensive care, but not decreased short-term survival. ANIMALS: A total of 130 alpacas presented to the University of Wisconsin. METHODS: Retrospective study of all neonatal crias <1 month of age. RESULTS: Of 130 neonatal alpacas presented, 86 (66%) had gestational age recorded (range 312-393 days). There were 16 (18.6%) crias with gestational age below 330 days. Crias born before 330 days were lighter at birth (mean 6.4 kg, SD 1.3 kg) than those born after 330 days (mean 7.4 kg, SD 1.7 kg, P = .002). Clinically immature crias had lower birth weights (mean 6.5 kg, SD 1.5 kg) than physically mature crias (mean 8.8 kg, SD 3.2 kg, P = .05). Survival rates were similar in all groups (premature 77%, mature 88%, P = .12). However, treatment costs were higher in crias born prior to 330 days with physical findings at birth consistent with immaturity compared with gestationally mature crias and those born prior to 330 days but with a physically mature appearance. CONCLUSIONS: Crias born before 330 days and those with physical findings of immaturity have a good prognosis, but require more intensive care, resulting in higher treatment costs.

Clostridial myonecrosis in horses (37 cases 1985-2000).

REASONS FOR PERFORMING STUDY: Previous reports of clostridial myonecrosis have either focused on individual case reports or have been small retrospective studies reporting very high mortality rates. OBJECTIVES: The objective of this study was to describe the outcome of cases of clostridial myonecrosis submitted to 2 referral equine hospitals in the United States over a 15 year period. METHODS: A retrospective study of case material selected on the basis of positive Clostridium spp. culture or the identification of Clostridium spp. by specific fluorescent antibody testing from soft tissue wounds was performed at Cornell and Wisconsin. RESULTS: 37 cases of clostridial myonecrosis were documented. Twenty-seven horses survived, 8 were subjected to euthanasia and 2 died during treatment for an overall survival rate of 73%. Twenty-five cases (68%) were associated with Clostridium perfringens alone, 6 cases (16%) with Cl. septicum alone, 4 cases with mixed clostridial infections (11%), 1 case with Cl. sporogenes and 1 with an unspeciated Clostridium spp. The highest survival rate of 81% was documented for those cases from which Cl. perfringens alone was isolated. The most common antecedent condition prior to referral was colic. The myonecrotic lesion occurred within 6-72 h of a soft tissue injection in 34 cases but was associated with a wound or laceration in the remaining 3 cases. Of the 34 cases associated with recent injections, 24 were associated with i.m. injections in the cervical region, 4 in the semimembranosus/semitendinosus region, 3 in the gluteal region, 2 with perivascular leakage of drugs administered into the jugular vein and 1 case developed simultaneously in the gluteal and neck region following injections at both sites. CONCLUSIONS: Clostridial myonecrosis can occur following the i.m. or inadvertent perivascular administration of a wide variety of commonly administered drugs. It is most common in the neck musculature. Aggressive treatment can be associated with survival rates of up to 81% for cases due to Cl. perfringens alone. Survival rates for other Clostridial spp. tend to be lower. POTENTIAL RELEVANCE: A combination of high dose i.v. antibiotic therapy and surgical fenestration/debridement is the best approach to cases of clostridial myonecrosis. With rapid diagnosis and therapeutic intervention, horses may have up to an 81% chance of survival.

Alterations in clinical, hematological and metabolic variables in bovine neonatal endotoxemia.

Endotoxemia is an important cause of morbidity and mortality in the neonate. Although many models are used to study the problem, none completely simulates the natural disease. To more clearly define a bovine neonatal endotoxemia model we studied the effects of dose of endotoxin on clinical, hematological and biochemical variables. Thirty-four neonatal calves were administered Escherichia coli endotoxin (LPS) at 0 (0.9% saline solution), 0.2, 2.0 or 20 micrograms/kg, by either IV bolus or infusion over 50 minutes. Variables monitored included mean arterial blood pressure (MAP), leukocyte (WBC) count, plasma glucose and lactate concentrations and clinical status. All LPS-treated calves displayed similar clinical signs within one hour. Dose-dependent differences in response to LPS among groups became evident over time. Substantial dose-dependent changes in attitude, appetite, mucous membrane character, capillary refill time, MAP, plasma glucose and lactate concentrations, and WBC count were noted in LPS-treated calves. Higher doses of LPS induced a more prolonged clinical response and significantly (p < 0.05) greater hypotension, lacticemia and hypoglycemia. While dose altered the response to endotoxin, the method of administration had no overall effect on the variables measured.

Effect of repeated administration of tirilazad mesylate on healthy and endotoxemic calves: a pilot study.

Tirilazad mesylate (TM:U74006F), a nonglucocorticoid 21-aminosteroid (lazaroid), is beneficial in the treatment of experimentally-induced ischemic injury following brain and spinal cord trauma, subarachnoid hemorrhage, hypovolemic shock and endotoxemia. This study investigated the effects of TM following repeated administration in sixteen healthy and endotoxemic calves. Group A calves received TM 3 mg/kg IV; group B calves received Escherichia coli endotoxin in increasing doses (0.1 to 20 micrograms/kg IV); group C calves received TM and endotoxin and group D calves received sterile saline (10 mL). Endotoxin, TM and saline were given every eight hours for five days. Mild, transient tachypnea was observed following TM administration. The drug suppressed clinical signs of endotoxemia until larger doses of endotoxin were given. At necropsy no substantial lesions were observed in groups A and D. Groups B and C had lesions consistent with endotoxemia but only group C calves had evidence of abomasal and ruminal ulceration. Although TM may be of benefit in the treatment of endotoxemia, further studies are needed to determine the optimal dosage and potential side effects in the endotoxic bovine neonate.

Effect of endotoxin on tirilazad mesylate (U74006F) pharmacokinetic parameters in neonatal calves.

The pharmacokinetics of the 21-aminosteroid tirilazad mesylate (U74006F) were studied in both healthy and endotoxin-challenged neonatal calves. Group I calves received a 3-h intravenous (i.v.) infusion of sterile saline (250 ml) and tirilazad mesylate (1.5 mg/kg i.v.) 1 h after the start of the saline infusion. Group II calves received tirilazad mesylate 1 h after the start of a 3-h endotoxin (3.25 micrograms/kg) infusion. The data obtained indicate that tirilazad mesylate follows a biexponential equation in neonatal calves. The area-derived volume of distribution (Vdarea) was 9.68 +/- 0.759 l/kg in healthy calves and 6.53 +/- 1.20 l/kg in endotoxin-challenged calves (P < 0.05). Similarly, significant (P < 0.05) decreases in steady-state volume of distribution (Vdss) and central volume (Vc) were observed in endotoxin-challenged calves (5.32 +/- 0.979 l/kg and 1.68 +/- 0.189 l/kg, respectively) compared to healthy calves (7.58 +/- 0.834 l/kg and 2.43 +/- 0.452 l/kg, respectively). A and B were significantly larger in endotoxin-challenged calves than in healthy calves (P < 0.05). Rate constants and their associated half-lives, area under the curve and clearance were not significantly altered by endotoxin challenge. Serum thromboxane generation (ex vivo) was evaluated as a marker of the drug's physiologic activity. There was no significant difference in thromboxane generation during clotting of blood from healthy and endotoxemic calves treated with tirilazad mesylate.

Pharmacokinetics of and serum thromboxane suppression by flunixin meglumine in healthy foals during the first month of life.

Age and species reportedly affect the pharmacokinetic variables of nonsteroidal anti-inflammatory drugs. We determined the effect of age on flunixin pharmacokinetic variables in foals during the first month of life. We also estimated the physiologic activity of the drug in neonatal foals by determining the effect of flunixin on thromboxane production during clotting of blood taken from the foals. Flunixin disposition and clearance were determined after IV administration of 1.1 mg of drug/kg of body weight to 5 healthy foals when they were 24 to 28 hours, 10 to 11 days, and 27 to 28 days old. The area under the curve (2,471 micrograms.min/ml), mean residence time (477 minutes), and zero-time intercept of the elimination phase (4,853 ng/ml) were significantly (P = 0.05) greater, the elimination half-life (339 minutes) and slope of the elimination phase (0.002 L/min) were significantly (P = 0.05) longer, and total body clearance (0.482 ml/min/kg) and zero-time intercept for the distribution phase (2,092 ng/ml) were significantly (P = 0.05) lower at 24 to 28 hours. At each age, a biexponential equation was best fitted to the plasma flunixin concentration from each foal. Thromboxane B2 production during clotting of blood was significantly (P = 0.05) suppressed for 12 hours after flunixin meglumine administration at all ages. Therefore, it appears that although age does alter the disposition and elimination of flunixin in neonatal foals, this effect may be of little consequence because the drug's physiologic activity in foals appears similar to that in mature horses.

Effect of dose and method of administration of endotoxin on cell mediator release in neonatal calves.

The cellular response induced in the host animal by endotoxin contributes greatly to the morbidity and mortality of gram-negative infections in bovine neonates. We characterized the temporal sequence, magnitude, and duration of mediator release during endotoxemia and evaluated the effect of endotoxin dose and method of administration. Thromboxane B2 (TxB2), and 6-keto prostaglandin F1 alpha (PGF1 alpha) concentrations and tumor necrosis factor (TNF), and interleukin-1 beta (IL-1 beta) activities were measured in 34 newborn calves given Escherichia coli endotoxin at dosage of 0 (saline solution), 0.2, 2.0, or 20 micrograms/kg of body weight, either by IV administered bolus or infusion over 50 minutes. In all groups and at each lipopolysaccharide dosage, mediators peaked in this sequence: TxB2 and TNF, followed by PGF1 alpha, then IL-1 beta. Neither dose nor method of administration affected the sequence of mediator release. The magnitude of eicosanoid response to endotoxin was dose-dependent. During induced endotoxemia, duration and/or magnitude of mediator response reflected the dose of endotoxin administered, indicating that the outcome of endotoxemia, in neonatal calves, may be related to the amount of circulating endotoxin.

Effects of concurrent administration of phenylbutazone and flunixin meglumine on pharmacokinetic variables and in vitro generation of thromboxane B2 in mares.

Flunixin meglumine and phenylbutazone are nonsteroidal anti-inflammatory drugs commonly used for the management of colic, endotoxemia, and musculoskeletal disorders in equids. Although it is not usually recommended, there appears to be an increasing trend to use nonsteroid anti-inflammatory drugs in combination to enhance or prolong their effects. Therefore, we studied the effect of concurrent administration of flunixin (1.1 mg/kg of body weight, IV) as flunixin meglumine and phenylbutazone (2.2 mg/kg, IV) on the pharmacokinetics of each drug and on in vitro thromboxane B2 production. Pharmacokinetic variables calculated for each drug when given alone and in combination were similar to those reported. Serum thromboxane B2 production was significantly (P = 0.05) suppressed for 12, 8, and 24 hours after administration of flunixin, phenylbutazone, and the drugs in combination, respectively. These results indicate that although concurrent administration of these drugs at the aforementioned dosages does not alter either drug disposition or clearance, it prolongs their pharmacologic effect.

Pharmacokinetics and effects of repeated administration of phenylbutazone in neonatal calves.

Age, species, and disease state may substantially alter the disposition and clearance of pharmacologic agents. This is particularly important when drugs with low therapeutic index are used in ill neonates. Pharmacokinetic variables for phenylbutazone were determined in 24- to 32-hour-old healthy and endotoxemic calves after i.v administration of a single dose (5 mg/kg of body weight, i.v.). Elimination half-life was 207 and 168 hours, and clearance was 0.708 and 0.828 ml/kg/h in healthy and endotoxemic calves, respectively. Intravenous infusion of endotoxin at the dose (2 micrograms/kg over 4 hours) given did not significantly alter any of the calculated pharmacokinetic variables. Serum thromboxane B2 concentration was significantly (P = 0.05) suppressed for 3 hours after phenylbutazone administration in healthy calves and for 4 hours in endotoxin-challenged calves. Daily administration of phenylbutazone (10 mg/kg loading, then 5 mg/kg for 9 days) to healthy and endotoxemic calves failed to induce any lesions consistent with nonsteroidal anti-inflammatory drug toxicosis.

Comparative efficacy of flunixin, ketoprofen, and ketorolac for treating endotoxemic neonatal calves.

Saline (0.9% NaCl) solution or 1 of 3 nonsteroidal anti-inflammatory drugs (NSAID) was administered i.v. to 5 neonatal calves 15 minutes after the start of a 3-hour i.v. infusion of Escherichia coli lipopolysaccharide (LPS; 2 micrograms/kg/h). Four additional calves were given a 3-hour i.v. infusion of saline solution alone. Clinical attitude, mean arterial blood pressure, PCV, WBC, and plasma lactate, glucose, and eicosanoid concentrations (thromboxane B2, 6-keto-PGF1 alpha) were monitored for 12 hours. Flunixin meglumine (1.1 mg/kg of body weight, i.v.), ketoprofen (2.2 mg/kg, i.v.), and ketorolac tromethamine (1.1 mg/kg, i.v.) each ameliorated the clinical signs of endotoxemia and LPS-induced lacticemia, but failed to significantly alter the degree of leukopenia or hypoglycemia associated with infusion of LPS. Although the 3 NSAID prevented eicosanoid production, they provided only partial protection against LPS-induced hypotension. Each NSAID modified the response to LPS, but none was clearly superior to the others in modulating the clinical signs or physiologic alterations induced by infusion of LPS in neonatal calves.

Comparison of flunixin, prednisolone, dimethyl sulfoxide, and a lazaroid (U74389F) for treating endotoxemic neonatal calves.

Saline (0.9% NaCl) solution, flunixin meglumine (1.1 mg/kg), prednisolone sodium succinate (1.1 mg/kg), U74389F (1.5 mg/kg), and dimethyl sulfoxide (0.5 g/kg) were each administered i.v. to 5 neonatal calves 15 minutes after the start of a 3-hour infusion of Escherichia coli lipopolysaccharide (LPS; 2 micrograms/kg/hr). Four additional calves were given a 3-hour i.v. infusion of saline solution alone. Only flunixin significantly suppressed eicosanoid production and mitigated clinical signs associated with endotoxemia. Prednisolone provided partial protection against LPS-induced hypotension and lacticemia. Pronounced hypoglycemia and lacticemia were observed in U74389F-treated calves; LPS-induced hypotension and hypoglycemia were marked in dimethyl sulfoxide-treated calves.

Effect of tirilazad mesylate (U74006F) on eicosanoid and tumor necrosis factor generation in healthy and endotoxemic neonatal calves.

The effects of a 21-aminosteroid, tirilazad mesylate (U74006F; The Upjohn Co., Kalamazoo, MI), developed for treatment of central nervous system trauma in human beings, on eicosanoid and tumor necrosis factor (TNF) generation were evaluated in both healthy and endotoxin-challenged neonatal calves. Endotoxemia was induced in 24 neonatal calves by intravenous infusion of Escherichia coli lipopolysaccharide (3.25 micrograms/kg) over 3 hr. Group I calves received the endotoxin infusion alone; group II calves received an infusion of 0.9% saline and were treated with tirilazad mesylate (1.5 mg/kg) 1 hr after the infusion was started, group III and IV calves were treated with tirilazad mesylate 1 hr after or before endotoxin infusion was started. Tirilazad mesylate effectively suppressed production of plasma prostacyclin (6-keto-PGF1 alpha) and TNF in endotoxin-challenged neonatal calves. In addition, production of thromboxane B2 was mitigated by treatment with tirilazad mesylate both 1 hr before and 1 hr after initiation of endotoxin infusion. It appears that tirilazad mesylate effectively suppresses eicosanoid and TNF generation induced by endotoxin, and thus may be beneficial in the treatment of endotoxemia and septicemia in neonatal calves.

Effect of phenylbutazone and repeated endotoxin administration on hemostasis in neonatal calves.

Twenty newborn Holstein calves were allotted at random to 4 groups: group A received 0.9% sterile saline solution; group B received phenylbutazone (5 mg/kg of body weight, IV) and 0.9% sterile saline solution; group C received progressively increasing doses of endotoxin (0.1 to 15 micrograms/kg); and group D received phenylbutazone and endotoxin similarly as did calves of groups B and C, respectively. Phenylbutazone was given once daily and saline solution or endotoxin were given every 8 hours for 5 days. Clinical variables--PCV, plasma total protein and fibrinogen concentrations, platelet count, prothrombin time, activated partial thromboplastin time, and fibrin degradation products concentration were measured at 24-hour intervals. Necropsy was performed on each calf. Phenylbutazone suppressed the clinical response to endotoxin challenge until large doses (7.5 to 15 micrograms/kg) were administered. Calves of groups C and D remained stable until they abruptly developed severe dyspnea necessitating euthanasia. Thrombocytopenia and leukopenia developed after the initial endotoxin dose. Prothrombin time was prolonged and PCV suddenly decreased at 96 hours. Necropsy revealed consistent lesions in the vascular endothelium and lungs. Phenylbutazone administration did not enhance or ameliorate endotoxin-induced hemostatic alterations or pathologic lesions.

Clinical efficacy of tirilazad mesylate for treatment of endotoxemia in neonatal calves.

The clinical efficacy of the lazaroid, tirilazad mesylate, a new therapeutic agent for prophylaxis and treatment of endotoxemia, was evaluated in 24 neonatal Holstein calves. Endotoxemia was induced by IV infusion of commercial Escherichia coli lipopolysaccharide (3.25 micrograms/kg of body weight) over 3 hours. Group-1 calves were given endotoxin alone; group-2 calves were given an infusion of 0.9% sterile saline solution, then were treated with tirilazad mesylate (1.5 mg/kg) 1 hour after the infusion was started. Group-3 calves were treated with tirilazad mesylate 1 hour after the start of the endotoxin infusion, and group-4 calves were given tirilazad mesylate 1 hour before the start of the endotoxin infusion. Clinical signs of endotoxemia were mitigated by tirilazad mesylate. In addition, tirilazad mesylate protected calves from endotoxin-induced hyperglycemia; treatment after endotoxin infusion decreased the severity of hypoglycemia and prevented lactic acidosis. Treatment with tirilazad mesylate after initiation of endotoxin infusion was as protective as was pretreatment.

Efeitos de baixas doses de Flunixin Meglumine na endotoxemia experimental em cavalos / Low dose Flunixin Meglumine: effects on experimental endotoxaemia in horses

A aplicaçäo de Flunixin Meglumine antes do desafio endotoxínico causou significante supressäo na geraçäo plasmática de tramboxane e 6-Keto-prostaglandina F1 alfa em eqüinos. Na dose de 0,25 mg/kg de peso vivo, o produto provocou, em cavalos pré-medicados, significativa supressäo nos índices elevados de lactado sangüíneo. A reduçäo dos sintomas clínicos de endotoxemia por açäo do Flunixin Meglumine foi dependente, facilitando a avaliaçäo clínica do animal

Administration of bacterial lipopolysaccharide elicits circulating tumor necrosis factor-alpha in neonatal calves.

The presence of tumor necrosis factor-alpha (TNF-alpha) during endotoxemia in ruminants has not been reported previously. In this study, we detected the in vivo release of bovine TNF-alpha by using WEHI-164 murine fibrosarcoma cells as targets in an 18-h cytotoxicity assay. Treatment of the WEHI-164 cells with 1 microgram of actinomycin D (dactinomycin) enhanced approximately twofold the susceptibility of the cells to TNF-alpha activity. TNF-alpha activity in sera from neonatal calves injected intravenously with 2.7 micrograms of Escherichia coli lipopolysaccharide (LPS) increased rapidly within the first 2 h postinjection and then declined until it was undetectable by 4 h postinjection. Sera taken before LPS administration had no TNF-alpha activity. LPS (10 micrograms/ml) and fetal, newborn, and pooled adult bovine sera alone and in combination had no direct cytotoxic effects on WEHI-164 cells. TNF-alpha cytotoxic activity is probably not due to the presence of interleukin-1 (IL-1), alpha interferon, or gamma interferon in the sera since recombinant human IL-1, natural bovine IL-1, and recombinant bovine alpha and gamma interferons had no direct cytotoxic effects on WEHI-164 cells. A monoclonal antibody that neutralizes recombinant human TNF-alpha significantly reduced the cytotoxic activity of sera from LPS-injected calves.

Effects of a specific thromboxane synthetase inhibitor in equine endotoxaemia.

Thromboxane A2 may play a major role in circulatory shock. In some species, thromboxane synthetase inhibitors have a beneficial effect on shock induced by endotoxin, trauma, sepsis and administration of arachidonate. In some shock models, however, results with thromboxane synthetase inhibitors have been conflicting. The effect of UK-38,485, a selective thromboxane inhibitor, was evaluated in ponies injected with endotoxin intraperitoneally. Four groups of ponies were used to compare the effects of endotoxin alone, UK-38,485 alone, treatment with UK-38,485 before endotoxin challenge and treatment with UK-38,485 after endotoxin challenge. Haematological, metabolic, eicosanoid and clinical responses in each group were evaluated. The results indicated that UK-38,485 is an effective inhibitor of thromboxane A2 generation following endotoxin challenge. Prostacyclin values were elevated compared with baseline in ponies administered UK-38,485 and endotoxin. However, prostacyclin values were not significantly different from those of ponies receiving endotoxin alone. Furthermore, UK-38,485 failed to attenuate the haematological, metabolic and clinical manifestations commonly seen in the pony after endotoxin challenge.