A recent study1 found that abomasal emptying rate is decreased in cows with LDA and is further decreased immediately after surgical correction of the condition. Postoperative decreases in gastrointestinal tract motility are common in many species and have been reported for humans, rats, mice, dogs, cats, sheep, monkeys, and horses.2,3,4,5,6,7,8 Complex pathophysiologic mechanisms contribute to this postoperative hypomotility of the gastrointestinal tract, including inhibitory reflexes9; pain; endogenous catecholamine release; stimulation of the sympathetic nervous system9,10,11; inflammation; endotoxemia; release of nitric oxide, prostaglandins, interleukins 1 and 6, tumor necrosis factor α, and vasoactive intestinal peptide12,13,14,15,16,17; and ischemia-reperfusion injury.18,19,20
A variety of drugs have been tested to determine whether they can be used to prevent or treat postoperative hypomotility of the gastrointestinal tract, including adrenoceptor antagonists4,11; cholinergic agents such as carbachol,21 cisapride,22 and metoclopramide23; spasmoanalgesic and anti-inflammatory drugs24,25,26; and local anesthetics administered epidurally9 or IV.27 However, we are not aware of any studies describing the prevention or treatment of postoperative hypomotility in cows undergoing surgical correction of abomasal displacement. It is possible that effective prevention or treatment of postoperative hypomotility in cows undergoing surgical correction of LDA could improve abomasal motility and thereby increase dry matter intake, rumen motility, and milk production. Previous studies found that administration of erythromycin (8.8 to 10.0 mg/kg [4.0 to 4.5 mg/lb], IM) accelerates abomasal emptying in healthy preruminant calves28,29 and healthy dairy cows,30 and erythromycin improves postoperative gastrointestinal tract motility in humans with ileus after gastric or duodenal surgery.31,32,33 In addition, erythromycin has a positive effect on ileocecocolic myoelectric activity and cecal transit time in healthy horses.34 However, these effects are not consistently present in horses after abdominal surgery.35
Nonsteroidal anti-inflammatory drugs have been administered after surgery for pain relief and to reduce inflammation and prostaglandin synthesis.24,26 Previous reports have indicated that nonsteroidal anti-inflammatory drugs have limited or no effects on postoperative hypomotility in monkeys7 and human patients.25 In contrast, in 1 study,36 administration of flunixin meglumine resulted in significant improvements in postoperative food intake and milk production in dairy cows. Although abomasal emptying rate was not measured, the findings suggest that flunixin may be an effective treatment for postoperative hypomotility in cattle.
On the basis of the previous findings, we hypothesized that preoperative administration of erythromycin or flunixin to cows with LDA would provide an effective method for ameliorating hypomotility of the gastrointestinal tract in the immediate postoperative period. We also hypothesized that erythromycin and flunixin would facilitate normalization of the rumen contraction rate and increase milk production. The purpose of the study reported here was to determine whether preoperative administration of erythromycin or flunixin altered postoperative abomasal emptying rate, rumen contraction rate, or milk production in dairy cattle undergoing surgical correction of LDA.
Materials and Methods
Animals—The study involved 45 lactating dairy cows (German Black Pied–Holstein Friesian cross) admitted to the Leipzig University Veterinary Hospital for surgical correction of LDA between January and May 2006. Cows ranged from 2 to 8 years old and came from 27 dairy farms in Middle Germany. All cows had recently calved (mean ± SD time since parturition, 22 ± 19 days).
A routine physical examination was performed on admission, including determination of rectal temperature, respiratory rate (obtained by counting the number of thoracic excursions for 30 seconds), pulse rate (obtained by palpating the facial artery for 30 seconds), and body weight. Animals with signs of systemic illness (eg, rectal temperature > 39.5°C [103.1°F]), clinical mastitis, watery diarrhea, or retained fetal membranes and cows with evidence of peritonitis or abomasal ulceration during surgery were excluded from the study. In all cows, a 20-cm-long, 14-gauge catheter was placed aseptically in the left jugular vein, and venous blood was obtained for measurement of RBC and WBC counts and serum biochemical variables, including total protein, glucose, total bilirubin, urea, β-hydroxybutyrate, and total calcium concentrations. The catheter was subsequently used for administration of drugs and fluids and for collection of blood samples for analysis of D-xylose concentration.
In all cows, the diagnosis of LDA was made on the basis of results of physical examination (ie, simultaneous percussion and auscultation of the left side of the abdomen) and confirmed at surgery. Left displacement of the abomasum was defined as displacement of the abomasal body to the left dorsal abdominal quadrant between the left body wall and rumen.37
Study protocol—The study was approved by the institutional animal use and protection committee. As cows were admitted to the hospital, they were sequentially assigned to 1 of 3 groups. Cows in the control group (n = 15) were not given any specific treatments to prevent postoperative hypomotility of the gastrointestinal tract, cows in the erythromycin treatment group (15) were given a single dose of erythromycin (10 mg/kg [4.5 mg/lb], IM) 1 hour prior to surgery, and cows in the flunixin treatment group (15) were given a single dose of flunixin (2.2 mg/kg [1.0 mg/lb], IV) 1 hour prior to surgery. The erythromycin dosage was selected on the basis of results of previous studies involving suckling calves28,29 and adult cows.30 Erythromycin and flunixin were administered 1 hour prior to surgery because prokinetic agents are usually administered to human patients 15 to 30 minutes before meals,38 and plasma concentrations of flunixin remain high enough to have analgesic and anti-inflammatory effects for several hours after IV administration.39,40
All cows received 10 L of 0.9% NaCl solution containing 700 g of glucose IV as a constant-rate infusion over 12 hours, beginning 1 hour before surgery. The right flank was prepared for laparotomy, and regional anesthesia was achieved by use of procaine hydrochloride administered as a distal paravertebral block in combination with a reverse-L block caudal to the 13th rib.
The abdominal cavity was explored, and the abomasum was identified. Prior to repositioning of the abomasum, D-xylose was injected into the abomasal lumen to allow postoperative measurement of abomasal emptying rate, as described.1,41 The D-xylose solution was freshly prepared by dissolving sufficient D-xylose in warm tap water to obtain a 50% solution; this solution was stored in a water bath (39°C [102°F]) for < 4 hours prior to administration. A 14-gauge needle attached to a flexible tube inserted into the dorsal abomasal lumen was used to administer D-xylose solution (1 mL/kg [0.45 mL/lb]; equivalent to 0.5 g/kg [0.23 mg/lb]) and remove excess gas from the abomasum. The abomasum was then returned to its normal position, and omentopexy of the greater omentum was performed 4 to 5 cm caudal to the pylorus, as described for correction of LDA.42 The abdomen was closed routinely. Total surgical time did not exceed 45 minutes.
Following surgery, rumen contraction rate (number of contractions detected during auscultation of the left flank for 3 minutes) was determined twice daily. In addition, cows were milked twice daily, and milk production was recorded. Personnel who performed postoperative physical examinations and milkings were masked to group assignment. Cows were discharged after a minimum of 3 days of hospitalization.
Measurement of abomasal emptying rate—Venous blood samples (5 mL) were obtained immediately before administration of D-xylose solution (0 minutes) and 30, 60, 90, 120, 150, 180, 240, 300, 360, 480, 600, and 720 minutes after administration. Samples were allowed to clot at 4°C (39.2°F) for 30 minutes and then were centrifuged at 1,800 × g for 10 minutes. Serum was harvested and stored at −21°C for up to 3 months before determination of D-xylose concentration.
Serum D-xylose concentration was measured by means of a spectrophotometric procedure, as described,41 because the enzymatic test kit used to measure D-xylose concentration in a previous study1 was no longer being manufactured. In brief, samples were boiled under acidic conditions to convert D-xylose to furaldehyde, and an orcinol–ferric chloride solution43 was added to cause the furaldehyde to form a yellow-green dye, which was then measured spectrophotometrically at a wavelength of 665 nm. This method does not differentiate D-xylose from other pentose sugars, such as D-arabinose and D-ribose, but because pentose sugars appear only in trace amounts in mammalian serum,44 the measured pentose sugar concentration was assumed to represent the true D-xylose concentration. Concentrations of hexoses (eg, glucose) and other substrates have minimal effect on pentose sugar concentrations measured with this method.44
Following measurement of D-xylose concentrations in serum samples, maximal serum concentration (Cmax) and time to obtain the maximal serum concentration (Tmax) were identified and pharmacokinetically calculated (Cmax-model, Tmax-model) for each cow. The serum D-xylose concentration versus time curve was modeled by means of the first derivative of the Siegel modified power exponential formula, as described,45 with the following formula: C(t) = m × k × β × e−kt × (1 − e−kt)β − 1, where C(t) is the serum D-xylose concentration at time t, m is the total cumulative recovery of D-xylose, k is an estimate of the rate constant for abomasal emptying, and β is an estimate of the duration of the lag phase before an exponential rate of emptying was reached. The value of Tmax-model was obtained by differentiating the first derivative equation and solving for 0, at which time t = Tmax-model, and Tmax-model = ln(β)/k. The value for Cmax-model was then calculated by applying the values for m, k, β, and Tmax-model to the first derivative of the Siegel modified power exponential formula.45 An estimate for oral bioavailability (F) was calculated as F = m/D, where D was the dose of D-xylose administered.
Statistical analysis—Data are summarized as mean and SD. Variables that were not normally distributed were log transformed before analysis. Analysis of variance was used to examine whether there was a significant effect of group on physical examination findings, RBC count, WBC count, serum biochemical variables, Cmax, Cmax-model, Tmax, or Tmax-model. If a significant effect was found, the Dunnett post hoc test was used to compare values for the erythromycin treatment group versus the control group and for the flunixin treatment group versus the control group. Repeated-measures ANOVA was used to analyze data for rumen contraction rate (morning measurements) obtained prior to surgery (day 0) and daily for the first 3 days after surgery. Daily milk production for the first 3 days after surgery was expressed as a percentage of milk production the day of surgery (day 0), and ANOVA was used to analyze values for relative milk production. When indicated by a significant F test, Bonferroni adjusted comparisons were conducted as a post hoc test. Standard softwarea was used for all analyses. Values of P < 0.05 were considered significant.
Results
All cows were successfully treated and were discharged from the veterinary hospital between 3 and 7 days after admission. Cows in the 3 groups did not differ in regard to age, parity, or time since parturition. Rectal temperature, heart rate, respiratory rate, and body weight prior to surgery also did not differ among the 3 groups. For all 45 cows, mean ± SD rectal temperature prior to surgery was 39.0° ± 0.5°C (102.2° ± 0.9°F), mean heart rate was 78 ± 9 beats/min, mean respiratory rate was 29 ± 13 breaths/min, and mean body weight was 551 ± 55 kg (1,212 ± 121 lb). Values were also not significantly different among groups on the first day after surgery.
Serum biochemical abnormalities commonly identified prior to surgery included hyperketonemia (mean ± SD β-hydroxybutyrate concentration, 2.7 ± 2.1 mmol/L; reference range, < 0.6 mmol/L), hyperbilirubinemia (mean total bilirubin concentration, 19.9 ± 11.7 μmol/L; reference range, 3 to 5 μmol/L), and hyperglycemia (mean glucose concentration, 5.3 ± 1.8 mmol/L; reference range, 2.2 to 3.3 mmol/L); mean values for serum total protein concentration, total calcium concentration, RBC count, and WBC count prior to surgery were within reference limits. Results of hematologic and serum biochemical analyses performed prior to surgery did not differ significantly among groups.
Maximum serum D-xylose concentration did not differ significantly among groups (Table 1; Figure 1). However, time to maximum concentration was significantly (P < 0.001) shorter for cows treated with erythromycin than for cows in the control group, although time to maximum concentration for cows treated with flunixin was not significantly (P = 0.26) different from time for control cows. Calculated mean values for k, m, and apparent oral availability did not differ significantly among groups, but the calculated mean value for β (ie, the estimated duration of the lag phase before an exponential rate of abomasal emptying was achieved) was significantly lower for cows treated with erythromycin than for control cows.
Mean serum D-xylose concentration (Cmax), mean time to maximum concentration (Tmax), and results of pharmacokinetic modelling (Cmax-model, Tmax-model) of serum D-xylose concentrationversus-time curves for 45 dairy cows undergoing surgical correction of LDA that were not given any specific treatments to prevent postoperative hypomotility of the gastrointestinal tract (control group; n = 15), were given a single dose of erythromycin (10 mg/kg [4.5 mg/lb], IM) 1 hour prior to surgery (erythromycin group; 15), or were given a single dose of flunixin meglumine (2.2 mg/kg [1.0 mg/lb], IV) 1 hour prior to surgery (flunixin group; 15).
Mean serum D-xylose concentration in 45 dairy cows undergoing surgical correction of LDA that were not given any specific treatments to prevent postoperative hypomotility of the gastrointestinal tract (control group; n = 15), were given a single dose of erythromycin (10 mg/kg [4.5 mg/lb], IM) 1 hour prior to surgery (erythromycin group; 15), or were given a single dose of flunixin meglumine (2.2 mg/kg [1.0 mg/lb], IV) 1 hour prior to surgery (flunixin group; 15). A 50% solution of D-xylose (1 mL/kg [0.45 mL/lb]) was injected into the abomasal lumen at the time of surgery (time 0). Error bars represent SD.
Citation: Journal of the American Veterinary Medical Association 232, 3; 10.2460/javma.232.3.418
Rumen contraction rate was not significantly different among groups prior to surgery and increased in all groups after surgery (Figure 2). On the first day after surgery, rumen contraction rates for cows treated with erythromycin (P = 0.001) or flunixin (P = 0.001) were significantly higher than for control cows. However, no significant differences among groups were detected on the second and third days after surgery.
Mean rumen contraction rate (ie, number of contractions in 3 minutes) for dairy cows undergoing surgical correction of LDA that were not given any specific treatments to prevent postoperative hypomotility of the gastrointestinal tract or were given a single dose of erythromycin or flunixin. Error bars represent SD. *Significantly (P < 0.05) different from value for control group cows on the same day. †Significantly (P < 0.005) different from value obtained on day 0 for the same group.
Citation: Journal of the American Veterinary Medical Association 232, 3; 10.2460/javma.232.3.418
Mean relative daily milk production (ie, milk production as a percentage of production on day 0 [horizontal dotted line]) for dairy cows undergoing surgical correction of LDA that were not given any specific treatments to prevent postoperative hypomotility of the gastrointestinal tract or were given a single dose of erythromycin or flunixin. Error bars represent SD. *Significantly (P < 0.05) different from value for control group cows on the same day. †Significantly (P < 0.005) different from baseline value (100%) for the same group.
Citation: Journal of the American Veterinary Medical Association 232, 3; 10.2460/javma.232.3.418
Mean values for daily milk production the day of surgery (day 0) for cows in the control, erythromycin treatment, and flunixin treatment groups were 8.9 ± 4.5 kg (19.6 ± 9.9 lb), 7.5 ± 3.2 kg (16.5 ± 7.0 lb), and 9.2 ± 4.1 kg (20.2 ± 9.0 lb), respectively, and did not differ significantly among groups. In all 3 groups, milk production, relative to day 0 production, increased after surgery (Figure 3). However, relative milk production (ie, milk production as a percentage of day 0 production) was significantly greater on the first (P < 0.001) and second (P < 0.001) days after surgery in cows treated with erythromycin than in control cows. No difference in milk production was detected between cows treated with flunixin and control cows.
Discussion
Results of the present study suggested that preoperative IM administration of a single dose of erythromycin to cows with LDA increased abomasal emptying rate, rumen contraction rate, and milk production in the immediate postoperative period, relative to values for untreated control cows. In contrast, preoperative IV administration of a single dose of flunixin had no effect on postoperative abomasal emptying rate or milk production, relative to values for untreated control cows, but increased rumen contraction rate the first day after surgery. Our findings confirmed those of a previous study1 that found that abomasal hypomotility was present in cattle after surgical correction of LDA because abomasal emptying rate after surgery for cows in the present study was much slower than that reported for healthy cows.
Mean time to pharmacokinetically calculated maximum D-xylose concentration for control cows in the present study (mean ± SD, 277 ± 95 minutes) was similar to that reported previously for cows undergoing surgical correction of LDA (268 ± 35 minutes), although D-xylose concentrations were measured with a different analytical method, but greater than that reported for healthy cows in early lactation (108 ± 14 minutes).1 Results of the present study, in conjunction with reports46,47,48 of disturbed abomasal electromyographic activity and diminished abomasal smooth muscle contraction in vitro, indicate that hypomotility of the gastrointestinal tract is common in cows immediately after surgical correction of LDA. However, we do not know how long abomasal hypomotility persists after surgical correction of LDA.
In the present study, mean Tmax-model for cows treated with erythromycin (149 ± 48 minutes) was significantly shorter than that for control cows. However, it was substantially longer than the previously reported Tmax-model for healthy cows in early lactation (108 ± 14 minutes).1 This suggests that erythromycin ameliorates some, but not all, of the abomasal hypomotility associated with LDA. Erythromycin binds to motilin receptors and initiates gastrointestinal myoelectric activity similar to phase III of the migrating motor complex, which results in increased gastric and duodenal motility.49 Erythromycin is much more effective at promoting gastric and proximal small intestine motility than large intestinal motility, and the differential response is thought to be associated with the decrease in motilin receptor density from cranial to caudal in the gastrointestinal tract.50,51,52
Nonsteroidal anti-inflammatory drugs can be an effective treatment for postoperative gastrointestinal tract hypomotility, with efficacy varying depending on the particular drug and species.24,26,53 In a previous study,36 flunixin (2.2 mg/kg, IV, q 24 h for 7 days) was reported to improve food intake, rumination, and fecal characteristics, compared with values for untreated control cows, but specific information was lacking in this report. Nevertheless, this finding, coupled with our finding that rumen contraction rate was increased on the first postoperative day among cows treated with flunixin, suggests that flunixin may have some minor effects on postoperative hypomotility in cows that have undergone surgical correction of LDA, possibly because of its analgesic effects.7,24 Our finding that flunixin did not increase postoperative abomasal emptying rate relative to the rate in control cows may suggest that abomasal hypomotility after surgical correction of LDA is not mainly due to pain. However, it is possible that perioperative regional anesthesia may have decreased the importance of systemic analgesia during the immediate postoperative period.
Increased endotoxin absorption as a result of surgically induced damage to the gastrointestinal tract mucosa54 contributes to the pathogenesis of postoperative hypomotility in dogs and rats.12,16 Endotoxemia is associated with a marked decrease in abomasal emptying rate in cattle,55 and flunixin is effective in treating endotoxininduced reticulorumen stasis in cattle.56 However, abomasal displacement and surgical correction was not accompanied by an increased frequency of endotoxemia in peripheral venous blood or blood from the right epigastric vein, which drains the abomasum, in dairy cows.57
Similar to results of a previous study36 in cattle with LDA, flunixin increased rumen contraction rate in the immediate postoperative period in the present study. In contrast to results of that previous study,36 however, daily milk production for cows treated with flunixin in the present study was not significantly greater than daily milk production for control cows. The lack of a significant difference in daily milk production in the present study may have been a result of wide variations in milk production and the low number of cattle in each group. Studies involving larger numbers of cattle are needed to more clearly determine the effect of analgesics on milk production in the postoperative period.
Antimicrobials are commonly administered during the perioperative period when surgical correction of LDA is performed on the farm because surgery is often performed in a less-than-ideal environment and because many cattle with LDA have concurrent diseases such as metritis, retained fetal membranes, and mastitis.58 Antimicrobials commonly administered to lactating dairy cattle in the perioperative period include penicillin G procaine, amoxicillin, ceftiofur, and oxytetracycline, with antimicrobials selected on the basis of treatment efficacy and milk withdrawal times. Results of the present study raise the interesting question of whether erythromycin is the preferred antimicrobial for perioperative administration in cattle with LDA. However, studies are needed to compare the cost and efficacy of erythromycin with the cost and efficacy of other antimicrobial agents.
We do not believe that results of the present study were confounded by IV glucose administration to cows in all 3 groups. Given that cows in the study weighed at least 500 kg, administration of 10 L of fluids over a period of 12 hours resulted in a maximum fluid administration rate of 1.7 mL/kg/h (0.77 mL/lb/h) and maximum glucose administration rate of 58 g/h; both are below maintenance requirements for lactating dairy cows. In the unlikely case that this glucose infusion had an effect on plasma D-xylose concentration by, for instance, inducing diuresis, the effect would have been consistent for all 3 groups. Moreover, visual inspection of the terminal phase of the D-xylose concentration versus time curves indicated that the rate of D-xylose clearance was similar for all 3 groups.
In the present study, Cmax-model for cows treated with erythromycin was not significantly different from Cmax-model for control cows. However, maximum plasma concentration is considered a poor indicator of the rate of absorption because it is dependent on the rate of absorption, the rate of elimination, the extent of absorption, and the volume of distribution.59 It is reasonable to assume that the rates of elimination and volume of distribution were similar for all 3 groups; however, it is likely that the extent of absorption varied among groups as a result of group differences in abomasal emptying rate. We have previously reported that the apparent oral bioavailability of D-xylose in lactating dairy cattle is low (10% to 17%) but is increased in cattle immediately after surgical correction of LDA (31%).1 The results of the present study and the previous study1 also suggest that there is substantial animal-to-animal variation in apparent oral bioavailability, as indicated by the high SD relative to the mean.
ABBREVIATIONS
| LDA | Left displacement of the abomasum |
SAS, version 8.2, SAS Institute Inc, Cary, NC.
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