Oropharyngeal and esophageal dysphagias are common in humans and dogs and are classified into 2 broad etiologic categories: structural and neuromyogenic disorders.1–7 Structural causes of dysphagia, including cricopharyngeal bars, esophageal strictures or webs, extrinsic compression, tumors, and foreign bodies, are generally easy to diagnose in dogs; however, diagnosis of neuromyogenic disorders, including neuropathies, myopathies, neuromuscular junctionopathies, and esophageal dysmotility disorders, can be challenging. Conventional assessment of dysphagic dogs includes collection of a thorough history, physical (including oropharyngeal) and neurologic examinations, survey radiography of the thorax and neck, biochemical analyses (including measurement of creatine kinase activity), videofluoroscopy during swallowing, and esophagoscopy. Advanced diagnostic procedures implemented in dysphagic dogs with an underlying neuromyogenic cause include electrodiagnostic testing such as electromyography, nerve conduction velocity testing, and muscle biopsy. Videofluoroscopy is the only diagnostic technique used in veterinary medicine that provides information about the functional integrity of the esophagus.1
Esophageal manometry is the test of choice to evaluate disorders of esophageal motor function. Manometric techniques have evolved immensely since the 1970's, when water-perfused catheters were in use. Those catheters had pressure-sensing ports spaced at wide (3- to 5-cm) intervals. Therefore, a great deal of esophageal pressure data could not be obtained. Water-perfused catheters also had a short sensing segment, making it impossible to simultaneously observe the entire esophageal motor pattern from the pharynx to the stomach. These problems were obviated with the advent of HRM catheters with pressure sensors spaced at 7.5- to 10-mm intervals along a 36-cm sensing segment. This facilitates simultaneous assessment of motor function of the UES, esophagus, and LES with each swallow. Pressure data are converted into a topographical plot to provide a complete spatial and temporal depiction of esophageal motor function termed HREPT.8 In HRM catheters, the small diameter (ranging from 2.75 to 4.2 mm) facilitates the transnasal intubation of the esophagus in fully awake people; thus, they can be evaluated on an outpatient basis.9–13
To our knowledge, HRM has been assessed in dogs, in only 2 studies,14,15 which indicated that HRM is feasible in awake dogs; however, both studies were conducted on Beagles only. Additionally, repeated evaluations in awake, healthy dogs following placebo administration were not performed.14,15 However, no conclusions could be drawn from either study regarding the variability and reproducibility of HREPT in dogs, and the usefulness of several important outcome variables, including residual LES pressure following cisapride administration,15 UES recovery time, and pharyngeal contractile integral, were not assessed.14
The objective of the study reported here was to validate the use of HRM in awake, healthy dogs of various breeds and body sizes and compare the effects of bolus type (liquid vs solid) and drug treatment (saline [0.9% NaCl] solution vs cisapride) on esophageal pressure profiles. We hypothesized that cisapride, a 5-hydroxytryptamine 4 receptor agonist, would increase LES tone as a result of its effects on gastrointestinal smooth muscle.16,17 As in studies of HRM performed in humans,18–22 our intent was to establish a set of variables to guide interpretation of canine deglutitive physiology.
Materials and Methods
Dogs
Fifteen apparently healthy dogs were screened to determine their eligibility for the study. Dogs that were > 1 year of age and weighed < 25 kg that had no history of gastrointestinal tract disease within the preceding 6 months were eligible for inclusion. All animals were pet dogs owned by staff or students from the University of California-Davis School of Veterinary Medicine, and all dogs had not undergone any previous experimental procedure. None of the dogs were hospitalized prior to the HRM procedure. Owners brought their dogs to the William R. Pritchard Veterinary Medical Teaching Hospital for the procedure after food had been withheld from the dogs for 12 to 16 hours. The Institutional Animal Care and Use Committee, as well as the Clinical Trial Review Board at the University of California-Davis, approved the study protocol. Informed consent was obtained from each dog's owner. The screening process comprised a comprehensive history and results of a physical examination, CBC, serum biochemical panel, and thoracic and cervical radiography. In addition, a videofluoroscopic barium swallow examination was performed for each dog.
HRM
A solid-state 8-F (outer diameter, 2.75 mm) manometric cathetera with 36 pressure channels spaced at 1-cm intervals was used for the procedure. Each pressure channel had 12 pressure sensors spaced equally around the circumference of the catheter to detect pressure along the length of the 2.5-mm channel. Before use, thermal in vivo calibration followed by sensor calibration in a sealed chamberb was performed. Immediately prior to placement of the catheter in the esophagus, the catheter was removed from the pressure chamber and all channels were zeroed in reference to atmospheric pressure.
Catheter placement
Food was withheld from each dog for 12 to 16 hours before the start of the procedure. Three or 4 drops of a nasal decongestant (oxymetazoline hydrochloride)c and 3 drops of tetracaine hydrochloride ophthalmic solutiond were placed in the right naris of the dog. Lidocaine gele was then applied to the outer surface of the catheter to facilitate its passage. The dog was carefully restrained in a sitting position by animal health technicians, and the same investigator (SLM) placed the catheter in all dogs throughout the study. The tip of the catheter was directed ventromedially and passed into the ventral meatus. Two to 3 mL of distilled water was administered orally to stimulate esophageal peristalsis and relaxation of the LES, thereby facilitating passage of the catheter down the esophagus and into the stomach. A survey lateral thoracic radiographic view was obtained to verify correct placement of the probe in the first dog (Figure 1); however, for all dogs, correct catheter placement was confirmed by means of software,f which depicted the UES and LES at areas of high pressure (Figure 2).
Survey lateral thoracic radiographic view of a 7.2-kg terrier cross after placement of an HRM probe. In this dog, the probe traverses both the UES and LES. The brighter rectangular regions spaced equally along the probe represent each of the 36 probe sensors.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Survey lateral thoracic radiographic view of a 7.2-kg terrier cross after placement of an HRM probe. In this dog, the probe traverses both the UES and LES. The brighter rectangular regions spaced equally along the probe represent each of the 36 probe sensors.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Survey lateral thoracic radiographic view of a 7.2-kg terrier cross after placement of an HRM probe. In this dog, the probe traverses both the UES and LES. The brighter rectangular regions spaced equally along the probe represent each of the 36 probe sensors.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of esophageal motor activity generated by the administration of a single liquid bolus (5 mL of water) in a 7.2-kg terrier cross. Pressure is represented by color coding (interpreted on the basis of the color bar on the right), sensor location (distance from the nares) is on the y-axis, and time is on the x-axis. Resting UES and EGJ or LES pressures are seen as horizontal bands of color that are several centimeters in width. Their hues indicate pressures that are greater than those in the adjacent portion of the pharynx, esophagus, or stomach. Opening of the UES (arrow) and EGJ (asterisk) are depicted as changes of color to hues that represent a lower pressure. The diagonal bars of color in the pharynx (arrowhead) represent pharyngeal peristaltic contractions produced by swallows of liquid. A diagonal band of color running from just below the UES to the EGJ represents the esophageal peristaltic pressure wave generated by swallows of liquid. Notice that several pharyngeal swallows occur before esophageal peristalsis is triggered. In humans, this pattern is called deglutitive inhibition. Although its genesis is well characterized in the smooth muscle of the human esophagus, it is unclear how it occurs in the striated muscle esophagus of dogs.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of esophageal motor activity generated by the administration of a single liquid bolus (5 mL of water) in a 7.2-kg terrier cross. Pressure is represented by color coding (interpreted on the basis of the color bar on the right), sensor location (distance from the nares) is on the y-axis, and time is on the x-axis. Resting UES and EGJ or LES pressures are seen as horizontal bands of color that are several centimeters in width. Their hues indicate pressures that are greater than those in the adjacent portion of the pharynx, esophagus, or stomach. Opening of the UES (arrow) and EGJ (asterisk) are depicted as changes of color to hues that represent a lower pressure. The diagonal bars of color in the pharynx (arrowhead) represent pharyngeal peristaltic contractions produced by swallows of liquid. A diagonal band of color running from just below the UES to the EGJ represents the esophageal peristaltic pressure wave generated by swallows of liquid. Notice that several pharyngeal swallows occur before esophageal peristalsis is triggered. In humans, this pattern is called deglutitive inhibition. Although its genesis is well characterized in the smooth muscle of the human esophagus, it is unclear how it occurs in the striated muscle esophagus of dogs.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of esophageal motor activity generated by the administration of a single liquid bolus (5 mL of water) in a 7.2-kg terrier cross. Pressure is represented by color coding (interpreted on the basis of the color bar on the right), sensor location (distance from the nares) is on the y-axis, and time is on the x-axis. Resting UES and EGJ or LES pressures are seen as horizontal bands of color that are several centimeters in width. Their hues indicate pressures that are greater than those in the adjacent portion of the pharynx, esophagus, or stomach. Opening of the UES (arrow) and EGJ (asterisk) are depicted as changes of color to hues that represent a lower pressure. The diagonal bars of color in the pharynx (arrowhead) represent pharyngeal peristaltic contractions produced by swallows of liquid. A diagonal band of color running from just below the UES to the EGJ represents the esophageal peristaltic pressure wave generated by swallows of liquid. Notice that several pharyngeal swallows occur before esophageal peristalsis is triggered. In humans, this pattern is called deglutitive inhibition. Although its genesis is well characterized in the smooth muscle of the human esophagus, it is unclear how it occurs in the striated muscle esophagus of dogs.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Data acquisition
In smaller dogs that weighed < 15 kg, the entire length of the catheter traversed both the UES and LES. In larger dogs that weighed ≥ 15 kg, the catheter was not sufficiently long to traverse the UES and LES concurrently; thus, separate measurements were obtained from each sphincter. All dogs received an IV injection of saline solution (placebo) administered via a butterfly catheterg in a lateral saphenous vein. Subsequently, 10 separate boluses of water were administered via syringe into the side of the dog's mouth at intervals of approximately 60 seconds. To standardize the procedure and facilitate ease of swallowing, 5 mL of water was administered in each bolus. Pressure measurements from the pharynx to the gastroesophageal junction were recorded during each swallow. The next swallow was not initiated until the water bolus had passed beyond the LES. Following the administration of 10 boluses of water, each dog was offered 10 separate boluses of canned foodh meatballs (5 g each).
Incomplete swallows (induced by coughing, sneezing, or gagging) were excluded from the data analysis. For larger dogs that underwent separate measurements of the UES and LES, 5 swallows of liquid followed by 5 swallows of canned food were recorded at the LES. The catheter was then moved proximally to the level of the pharynx and UES, and 5 swallows of liquid followed by 5 swallows of canned food were recorded. Cisapridei at a dose of 1 mg/kg with 60 mL of saline solution was then administered IV via a cephalic catheterj with an infusion devicek and a syringe pumpl over a 15-minute period. After 10 minutes, oral administration of the liquid and solid boluses was repeated for HRM assessment of the esophagus.
The injectable cisapride solution (3 mg/mL) was formulated in batches of 100 mg at North Carolina State University College of Veterinary Medicine Pharmacy according to the United States Pharmacopeia (USP) compounded preparation monograph, Cisapride, Compounded, Injection, Veterinary.m Cisapride monohydrate (USP powder) was obtained from the Professional Compounding Centers of America with a stated potency assay of 99.9% on the certificate of analysis for the batch. Following preparation of the cisapride injection, it was submitted for potency testing and sterility testing to an analytical research laboratory.n Potency of the batch was determined to be 2.921 mg/mL (97.4% of label), which was within the limits established in the USP monograph.m Sterility was assessed for up to 90 days and was maintained throughout the study period. The cisapride solution was kept refrigerated for up to 7 days following its arrival from the pharmacy before being discarded.
On completion of the experimental procedures, the catheter was wiped down with enzymatic cleanero and immersed in disinfectantp for 12 minutes. Feedback from the owners regarding signs of discomfort (rubbing of the nose, pawing of the nose, or head shaking) and epistaxis during the 48-hour period following completion of the procedures was collected. For 4 of the 8 dogs, experimental procedures were repeated 2 to 4 weeks following initial HRM after food had been withheld from the dogs as before; however, cisapride was not administered during the repeated procedures. Pressure data were captured and converted to HREPT profiles with an acquisition program.f Ease of placement of the catheter, retention of the catheter once it was placed in the correct location, willingness of the dogs to receive water boluses, and willingness of the dogs to receive solid boluses were scored semi-quantitatively by 2 of the investigators (SLM and TVU) with a scoring system of 1 through 5, in which 1 represented the greatest ease of placement, tolerance to retention of the catheter, or willingness to receive water and solid boluses, and 5 represented the least ease of placement, tolerance to retention of the catheter, or willingness to receive water and solid boluses.
Data analysis
Interpretation of HREPT profiles for liquid (Figure 2) and solid (Figure 3) boluses was accomplished with specialized analysis software.10,q The analysis was also applied to high-resolution pharyngeal pressure topography (Figure 4). Eleven outcome variables were analyzed for each swallow. Pharyngeal and UES functions were characterized by the CFVp and PCI (Figure 5), resting UES pressure (mean of UES pressure during a 30-second period when no swallowing occurred), residual UES pressure (the lowest mean pressure in the UES when it was open), time to UES nadir (interval from opening of the UES to the lowest residual UES pressure), duration of UES opening (interval from UES opening to UES closure), and UES recovery time (interval from UES nadir to UES closure). Esophageal motor function was characterized by peristaltic CFVe and the ECI (Figure 6). Function of the LES was characterized by the resting LES pressure and residual LES pressure (a measure of the extent of EGJ opening during swallowing). Resting LES pressure was defined as the respiratory minimum LES pressure (ie, the mean of the lowest EGJ pressures during expirations in the 30-second period when no swallowing occurred).10 This excluded pressures produced by diaphragmatic crural contraction, thereby yielding true resting LES pressure. To determine residual LES pressure, upper and lower margins of the EGJ were demarked and a 10-second period was identified, beginning at the start of UES relaxation initiated by swallowing. A program functionr measured pressure simultaneously over a 6-cm length of the catheter. An algorithm calculated maximum pressure along the 6-cm segment at each time point within the 10-second period. The lowest of these pressures over 4 continuous or discontinuous seconds were averaged; the calculated mean was the residual LES pressure.10
Representative HREPT profile of esophageal motor activity generated by a swallow of a solid bolus (canned food meatball [5 g]) in a 7.2-kg terrier cross. Notice that the esophageal peristaltic pressure wave appears of greater amplitude and longer duration than that generated by swallows of liquid. It also appears to have a lower propagation velocity. There are rhythmic contractions of the UES just prior to the swallow (arrow). The genesis of this contractile pattern is unclear, but might represent mastication. See Figure 2 for key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of esophageal motor activity generated by a swallow of a solid bolus (canned food meatball [5 g]) in a 7.2-kg terrier cross. Notice that the esophageal peristaltic pressure wave appears of greater amplitude and longer duration than that generated by swallows of liquid. It also appears to have a lower propagation velocity. There are rhythmic contractions of the UES just prior to the swallow (arrow). The genesis of this contractile pattern is unclear, but might represent mastication. See Figure 2 for key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of esophageal motor activity generated by a swallow of a solid bolus (canned food meatball [5 g]) in a 7.2-kg terrier cross. Notice that the esophageal peristaltic pressure wave appears of greater amplitude and longer duration than that generated by swallows of liquid. It also appears to have a lower propagation velocity. There are rhythmic contractions of the UES just prior to the swallow (arrow). The genesis of this contractile pattern is unclear, but might represent mastication. See Figure 2 for key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of pharyngeal motor function generated by a swallow of a liquid bolus (5 mL of water) in a 15.1-kg Border Collie. The brackets indicate location of the velopharynx and mesopharynx. The nasopharynx is superior to the velopharynx. The pharyngeal pressure wave starts with velopalatine closure (velopharynx), followed by pharyngeal peristalsis produced by contraction of the tongue and pharyngeal musculature (mesopharynx). Normally, during swallow-induced opening of the UES, pharyngeal pressure approximates that in esophagus. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of pharyngeal motor function generated by a swallow of a liquid bolus (5 mL of water) in a 15.1-kg Border Collie. The brackets indicate location of the velopharynx and mesopharynx. The nasopharynx is superior to the velopharynx. The pharyngeal pressure wave starts with velopalatine closure (velopharynx), followed by pharyngeal peristalsis produced by contraction of the tongue and pharyngeal musculature (mesopharynx). Normally, during swallow-induced opening of the UES, pharyngeal pressure approximates that in esophagus. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profile of pharyngeal motor function generated by a swallow of a liquid bolus (5 mL of water) in a 15.1-kg Border Collie. The brackets indicate location of the velopharynx and mesopharynx. The nasopharynx is superior to the velopharynx. The pharyngeal pressure wave starts with velopalatine closure (velopharynx), followed by pharyngeal peristalsis produced by contraction of the tongue and pharyngeal musculature (mesopharynx). Normally, during swallow-induced opening of the UES, pharyngeal pressure approximates that in esophagus. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Respresentative HRM profiles of pharyngeal motor function generated by a swallow of a liquid bolus (5 mL of water) in a 15.1-kg Border Collie to illustrate determination of CFVp (A) and PCI (B). In panel A, the thin black line outlining pressure events is a 30-mm Hg isobaric contour line. The outline identifies all loci in the profile where the pressure is 30 mm Hg; within the outline, pressures are > 30 mm Hg and outside the line, pharyngeal pressures are < 30 mm Hg. The CFVp, which is a measure of peristaltic velocity, is obtained by calculating velocity from a best linear fit along the 30-mm Hg contour line at the leading edge of the peristaltic pressure wave (white dashed line). The solid white line on the x-axis represents 2 seconds. In panel B, the PCI (a measure of how robust peristalsis is in the pharynx) is determined by first marking a box (white dashed line) that encompasses all swallow-induced motor activity from the upper border of velopalatine closure to the upper border of the UES. Next, a 20-mm Hg isobaric contour line (thin black line) is created. The PCI is calculated by summing pressures from all of the time-length foci within the field delineated by the box and 20-mm Hg isobaric contour line. The solid white line on the x-axis represents 2 seconds. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Respresentative HRM profiles of pharyngeal motor function generated by a swallow of a liquid bolus (5 mL of water) in a 15.1-kg Border Collie to illustrate determination of CFVp (A) and PCI (B). In panel A, the thin black line outlining pressure events is a 30-mm Hg isobaric contour line. The outline identifies all loci in the profile where the pressure is 30 mm Hg; within the outline, pressures are > 30 mm Hg and outside the line, pharyngeal pressures are < 30 mm Hg. The CFVp, which is a measure of peristaltic velocity, is obtained by calculating velocity from a best linear fit along the 30-mm Hg contour line at the leading edge of the peristaltic pressure wave (white dashed line). The solid white line on the x-axis represents 2 seconds. In panel B, the PCI (a measure of how robust peristalsis is in the pharynx) is determined by first marking a box (white dashed line) that encompasses all swallow-induced motor activity from the upper border of velopalatine closure to the upper border of the UES. Next, a 20-mm Hg isobaric contour line (thin black line) is created. The PCI is calculated by summing pressures from all of the time-length foci within the field delineated by the box and 20-mm Hg isobaric contour line. The solid white line on the x-axis represents 2 seconds. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Respresentative HRM profiles of pharyngeal motor function generated by a swallow of a liquid bolus (5 mL of water) in a 15.1-kg Border Collie to illustrate determination of CFVp (A) and PCI (B). In panel A, the thin black line outlining pressure events is a 30-mm Hg isobaric contour line. The outline identifies all loci in the profile where the pressure is 30 mm Hg; within the outline, pressures are > 30 mm Hg and outside the line, pharyngeal pressures are < 30 mm Hg. The CFVp, which is a measure of peristaltic velocity, is obtained by calculating velocity from a best linear fit along the 30-mm Hg contour line at the leading edge of the peristaltic pressure wave (white dashed line). The solid white line on the x-axis represents 2 seconds. In panel B, the PCI (a measure of how robust peristalsis is in the pharynx) is determined by first marking a box (white dashed line) that encompasses all swallow-induced motor activity from the upper border of velopalatine closure to the upper border of the UES. Next, a 20-mm Hg isobaric contour line (thin black line) is created. The PCI is calculated by summing pressures from all of the time-length foci within the field delineated by the box and 20-mm Hg isobaric contour line. The solid white line on the x-axis represents 2 seconds. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profiles of esophageal motor activity generated by a swallow of a liquid bolus (5 mL of water) in a 7.2-kg terrier cross to illustrate determination of CFVe (A) and ECI (B). In panel A, the thin black line outlining pressure events is a 30-mm Hg isobaric contour line. The outline identifies all loci in the HREPT profile where the pressure is 30 mm Hg; within the outline, pressures are > 30 mm Hg and outside the line, esophageal pressures are < 30 mm Hg. The CFVe, which is a measure of peristaltic velocity, is obtained by calculating velocity from a best linear fit along the 30-mm Hg contour line at the leading edge of the peristaltic pressure wave (dashed black line). In panel B, the ECI (a measure of how robust peristalsis is in the esophagus) is determined by first marking a box (dashed white line) that encompasses all swallow-induced motor activity from the lower border of the UES to where the peristaltic contraction ends at the EGJ. Next, a 20-mm Hg isobaric contour line (thin black line) is created. The ECI is calculated by summing pressures from all of the time-length foci within the field delineated by the box and 20-mm Hg isobaric contour line. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profiles of esophageal motor activity generated by a swallow of a liquid bolus (5 mL of water) in a 7.2-kg terrier cross to illustrate determination of CFVe (A) and ECI (B). In panel A, the thin black line outlining pressure events is a 30-mm Hg isobaric contour line. The outline identifies all loci in the HREPT profile where the pressure is 30 mm Hg; within the outline, pressures are > 30 mm Hg and outside the line, esophageal pressures are < 30 mm Hg. The CFVe, which is a measure of peristaltic velocity, is obtained by calculating velocity from a best linear fit along the 30-mm Hg contour line at the leading edge of the peristaltic pressure wave (dashed black line). In panel B, the ECI (a measure of how robust peristalsis is in the esophagus) is determined by first marking a box (dashed white line) that encompasses all swallow-induced motor activity from the lower border of the UES to where the peristaltic contraction ends at the EGJ. Next, a 20-mm Hg isobaric contour line (thin black line) is created. The ECI is calculated by summing pressures from all of the time-length foci within the field delineated by the box and 20-mm Hg isobaric contour line. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Representative HREPT profiles of esophageal motor activity generated by a swallow of a liquid bolus (5 mL of water) in a 7.2-kg terrier cross to illustrate determination of CFVe (A) and ECI (B). In panel A, the thin black line outlining pressure events is a 30-mm Hg isobaric contour line. The outline identifies all loci in the HREPT profile where the pressure is 30 mm Hg; within the outline, pressures are > 30 mm Hg and outside the line, esophageal pressures are < 30 mm Hg. The CFVe, which is a measure of peristaltic velocity, is obtained by calculating velocity from a best linear fit along the 30-mm Hg contour line at the leading edge of the peristaltic pressure wave (dashed black line). In panel B, the ECI (a measure of how robust peristalsis is in the esophagus) is determined by first marking a box (dashed white line) that encompasses all swallow-induced motor activity from the lower border of the UES to where the peristaltic contraction ends at the EGJ. Next, a 20-mm Hg isobaric contour line (thin black line) is created. The ECI is calculated by summing pressures from all of the time-length foci within the field delineated by the box and 20-mm Hg isobaric contour line. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 77, 8; 10.2460/ajvr.77.8.818
Statistical analysis
The following predictive variables were assessed: procedure type (initial or repeated), bolus type (liquid or solid), and drug (saline solution or cisapride). The effects on the 11 outcome variables were analyzed by mixed-effects ANOVA, with dog used as the random effect, and either procedure type and bolus type (saline solution-only model) or drug and bolus type (initial procedures-only model) used as fixed effects. Main effects and 2-way interactions were fit, and marginal means for each combination of the 2 variables were predicted from the model. If the interaction was significant, each of the 6 possible pairwise contrasts were tested and dichotomized as significant or not significant following use of a Bonferroni adjustment for multiple comparisons to preserve a nominal type I error probability of 0.05. Logarithmic transformations were evaluated with normal probability plots of residuals to check for improvement in model fit. An exact Wilcoxon signed-rank test was used to compare scores of dogs that were evaluated twice. To assess repeatability, dog-specific coefficients of variation were calculated from the replicates, and averaged across dogs to obtain means and SDs of the mean coefficients of variation for each of the dependent physiologic measurements. A value of P < 0.05 was considered significant.
Results
Dogs
Five of 15 dogs were excluded from the study on the basis of results of the preliminary screening. One dog was excluded because of panhypoproteinemia consistent with a subclinical protein-losing enteropathy. The other 4 dogs were excluded on the basis of the videofluoroscopic findings during swallowing. Of those 4 dogs, 3 had subclinical sliding (type I) hiatal hernias and 1 had evidence of reduced esophageal motility. Of the 10 dogs deemed suitable for enrollment, 1 was excluded after screening because of foreign body ingestion and an acute episode of vomiting and 1 dog did not tolerate placement of the catheter.
Among the 8 dogs in which the initial experimental procedures were successfully completed, there were 3 males (2 were castrated and 1 was sexually intact) and 5 females (4 were spayed and 1 was sexually intact). Breeds represented included Duck Tolling Retriever (n = 1), Border Collie (1), shepherd cross (3), terrier cross (3), and Jack Russell Terrier (1). The dogs ages ranged from 1.5 to 7 years (mean ± SD, 4.3 ± 1.7 years). Body weights ranged from 7.1 to 23.5 kg (mean ± SD, 15.5 ± 6.5 kg); 4 dogs weighed 7.1 to 15.1 kg and 4 dogs weighed 18.1 to 23.5 kg. For the 8 dogs, body condition score ranged from 4 to 6 (mean ± SD, 4.9 ± 0.8) on a scale of 1 to 9. Cisapride administration was not performed in 1 of the 8 dogs (terrier cross) owing to lack of tolerance of the catheter. Two of the 8 dogs (shepherd cross and Border Collie) had mild serosanguineous discharge following removal of the catheter that resolved within 3 to 4 minutes following completion of the initial procedures. The length of the esophagus in the dogs of the present study ranged from 22 to 41 cm. Two of the shepherd crosses, the Duck Tolling Retriever, and the Border Collie underwent separate assessments of the UES and LES because of the length of their esophagus.
Four dogs (a Duck Tolling Retriever, 2 terrier crosses, and a Border Collie) underwent repeated procedures. The mean age of the 4 dogs was 4.9 years, mean body weight was 13.4 kg, and mean body condition score was 5/9.
Ease of catheter placement, catheter retention, and willingness to receive water or food boluses
Comparing the initial study scores in all 8 dogs to repeat procedure scores in 4 dogs, the scores for ease of catheter retention once placed in the correct location (mean, 1.75; median, 1.5) were subjectively lower than scores for ease of catheter placement (mean, 2.25; median, 2 [Table 1]). Scores for ease of administration of liquid boluses were similar to scores for ease of administration of solid boluses. Body weights of the 4 dogs that underwent repeated HRM were 7.2, 11.1, 15.1, and 20.2 kg; separate measurements of the UES and LES were necessary in the 2 dogs that weighed 15.1 kg and 20.2 kg because the catheter was not long enough to traverse the UES and LES simultaneously. In the 4 dogs that underwent repeated HRM, the scores for each category were decreased, compared with the scores from the initial procedures in the same 4 dogs; however, P values from hypothesis tests comparing scores were not significant owing to the inadequate sample size (data not shown).
Scores for ease of catheter placement, catheter retention once placed in the correct location, and willingness to receive liquid and solid boluses in awake healthy dogs undergoing HRM.
| Variable | Initial procedures (n = 8) | Repeated procedures only (n = 4) | |||
|---|---|---|---|---|---|
| Range | Mean ± SD | Median | Range | Median | |
| Catheter placement | 1–5 | 2.25 ± 1.5 | 2 | 1–1 | 1 |
| Catheter retention | 1–3 | 1.75 ± 1.5 | 1.5 | 1–1 | 1 |
| Liquid boluses | 1–3 | 2.63 ± 0.9 | 2 | 1–3 | 2 |
| Solid boluses | 1–5 | 2.25 ± 0.7 | 1.5 | 1–2 | 1 |
The range, mean and SD, and median were calculated for each category. In a crossover study, each dog received saline (0.9% NaCl) solution (10 mL) IV and HRM was performed during oral administration of 10 boluses (5 mL each) of water or 10 boluses (5 g each) of canned food. Cisapride (1 mg/kg in 60 mL of saline solution) was subsequently administered IV to 7 dogs; HRM and bolus administration procedures were repeated. Two to 4 weeks later, HRM was repeated following administration of saline solution and water and food boluses in 4 dogs. Ease of placement of the catheter, tolerance to retention of the catheter, willingness of the dogs to receive water boluses, and willingness of the dogs to receive solid boluses were scored semi-quantitatively by 2 investigators with a scoring system of 1 through 5, in which 1 represented the greatest ease, tolerance, or willingness, and 5 represented the least ease, tolerance, or willingness.
Repeatability of HRM procedures
Seven of the 11 outcome variables demonstrated concordance between findings from the initial and repeated procedures (Table 2). In contrast, means for ECI (P = 0.027), residual LES pressure (P < 0.001), residual UES pressure (P < 0.001), and PCI (P = 0.003) from the initial and repeated procedures differed significantly. Coefficients of variation were < 0.5 for 10 of the 11 outcome variables; the exception was a coefficient of variation of 0.60 for UES recovery after cisapride administration and during food bolus swallows.
Predicted means (SE) for 11 outcome variables in a study to validate the use of HRM in awake, healthy dogs and compare the effects of bolus type (liquid vs solid) on pharyngeal and esophageal pressure profiles.
| Variable | Initial procedures (n = 8) | Repeated procedures only (n = 4) | P value | ||||
|---|---|---|---|---|---|---|---|
| Liquid | Solid | Liquid | Solid | Procedure type | Bolus type | Interaction | |
| PCI (cm/mm Hg/s) | 97.7 (7.0) | 151.5 (7.6) | 75.1 (8.6) | 116.6 (8.7) | 0.003 | < 0.001 | 0.230 |
| CFVp (cm/s) | 20.7 (2.0) | 16.7 (2.0) | 20.1 (2.2) | 13.5 (2.2) | 0.69 | < 0.001 | 0.125 |
| Resting UES pressure (mm Hg) | 22.9 (4.9) | 27.0 (4.9) | 20.9 (5.5) | 33.4 (5.7) | 0.735 | 0.411 | 0.271 |
| Residual UES pressure (mm Hg) | −6.4 (1.0) | −2.5 (1.1) | −1.3 (1.1) | 1.3 (1.3) | < 0.001 | < 0.001 | 0.401 |
| Time to UES pressure nadir (ms) | 91.2 (7.5) | 93.8 (7.7) | 83.4 (8.0) | 87.5 (9.6) | 0.451 | 0.802 | 0.923 |
| Duration of UES opening (ms) | 198.7 (12.4) | 210.2 (12.7) | 209.8 (13.2) | 183.3 (15.8) | 0.506 | 0.478 | 0.126 |
| UES recovery (ms) | 121.2 (10.7) | 120.0 (10.9) | 128.0 (11.4) | 96.8 (13.3) | 0.593 | 0.924 | 0.106 |
| ECI (cm/mm Hg/s) | 660.3 (133.7) | 850.4 (134.2) | 552.0 (138.4) | 824.8 (136.8) | 0.027 | < 0.001 | 0.184 |
| CFVe (cm/s) | 6.2 (0.46) | 5.6 (0.46) | 6.0 (0.48) | 5.6 (0.48) | 0.322 | < 0.001 | 0.450 |
| Resting LES pressure (mm Hg) | 19.7 (2.1) | 19.1 (2.1) | 17.2 (2.9) | 22.2 (2.9) | 0.418 | 0.825 | 0.184 |
| Residual LES pressure (mm Hg) | 17.06 (2.25)a | 10.07 (2.24)b | 24.15 (2.58)c | 11.22 (2.44)b | < 0.001 | < 0.001 | 0.005 |
Each dog received saline (0.9% NaCl) solution (10 mL) IV and HRM was performed during oral administration of 10 boluses (5 mL each) of water or 10 boluses (5 g each) of canned food. Cisapride (1 mg/kg in 60 mL of saline solution) was subsequently administered IV to 7 dogs; HRM and bolus administration procedures were repeated. Two to 4 weeks later, HRM was repeated following administration of saline solution and water and food boluses in 4 dogs. Data were obtained via a manometric catheter that was placed in awake dogs. In smaller dogs that weighed < 15 kg, the entire length of the catheter traversed both the UES and LES. In larger dogs that weighed ≥ 15 kg, the catheter was not sufficiently long to traverse the UES and LES concurrently; thus, separate measurements were obtained from each sphincter. The P values provided for procedure type and bolus type relate to differences between procedure types and between bolus types for each outcome variable. The P values provided for interaction relate to effects between procedure types and between bolus types for each outcome variable. A value of P < 0.05 was considered significant.a,b,cWithin a variable, different letters are indicative of significant (P < 0.05) differences in predicted means (ie, no significant difference was found between residual LES pressures in either procedure period during swallows of solid boluses, but a significant difference was found during swallows of liquid boluses).
Comparison of liquid versus solid boluses on esophageal pressure profiles
Logarithmic transformations did not meaningfully change the fits or interpretations of the respective statistical models; thus, results are reported without transformation (ie, in their original units [Tables 2 and 3]). For 6 of the 11 outcome variables, significant differences were identified between solid and liquid boluses: PCI, CFVp, residual UES pressure, ECI, CFVe, and residual LES pressure.
After saline solution administration, the PCI, ECI, and residual UES pressure were significantly (P < 0.001) higher for solid boluses than for liquid boluses, and CFVe and CFVp were significantly (P < 0.001) faster for liquid boluses than solid boluses in both the initial and repeated procedures (ie, there were no significant interactions between bolus type and procedure type [Table 2]). A significant (P = 0.005) interaction between bolus type and procedure type was identified for residual LES pressure. Liquid boluses resulted in significantly higher residual LES pressures than did solid boluses, although the magnitude of the differences varied between initial and repeated procedures. Following both saline solution and cisapride administration, residual LES pressure and CFVp were significantly (P < 0.001) higher for liquid boluses, compared with findings for solid boluses; moreover, PCI was significantly higher (P < 0.001) for solid boluses, compared with findings for liquid boluses (ie, there were no significant interactions between bolus type and drug type [Table 3]).
Predicted means (SE) for 11 outcome variables in the dogs in Table 1 to compare the effects of drug type (saline solution vs cisapride) and bolus type (liquid vs solid).
| Variable | Liquid bolus | Solid bolus | P value | ||||
|---|---|---|---|---|---|---|---|
| Saline solution | Cisapride | Saline solution | Cisapride | Drug type | Bolus type | Interaction | |
| PCI (cm/mm Hg/s) | 97.8 (9.7) | 103.6 (11.1) | 151.8 (10.3) | 150.2 (11.2) | 0.498 | < 0.001 | 0.532 |
| CFVp (cm/s) | 19.4 (1.7) | 20.7 (1.8) | 15.4 (1.7) | 14.3 (1.9) | 0.269 | < 0.001 | 0.121 |
| Resting UES pressure (mm Hg) | 21.3 (4.6) | 18.5 (4.8) | 25.4 (4.6) | 26.8 (4.8) | 0.422 | 0.211 | 0.378 |
| Residual UES pressure (mm Hg) | −6.0 (0.97)a | −5.3 (1.0)a | −2.1 (0.98)b | −5.5 (1.0)a | 0.460 | < 0.001 | 0.003 |
| Time to UES pressure nadir (ms) | 96.1 (12.7) | 104.2 (13.3) | 96.3 (12.9) | 110.6 (13.4) | 0.512 | 0.985 | 0.724 |
| Duration of UES opening (ms) | 203.9 (22.8) | 219.5 (23.8) | 213.3 (23.1) | 227.6 (23.9) | 0.441 | 0.633 | 0.963 |
| UES recovery (ms) | 119.6 (14.7) | 121.0 (15.7) | 19.1 (15.0) | 125.2 (15.7) | 0.933 | 0.974 | 0.840 |
| ECI (cm/mm Hg/s) | 654.7 (134.6)a | 781.2 (136.8)b | 848.8 (135.4)b | 1107.1 (136.7)c | 0.007 | < 0.001 | 0.047 |
| CFVe (cm/s) | 6.2 (0.44)a | 5.4 (0.44)b | 5.6 (0.44)b | 5.6 (0.44)b | < 0.001 | < 0.001 | 0.005 |
| Resting LES pressure (mm Hg) | 19.7 (4.2) | 33.6 (4.4) | 19.1 (4.2) | 29.7 (4.4) | 0.003 | 0.905 | 0.60 |
| Residual LES pressure (mm Hg) | 16.9 (1.9) | 27.0 (2.0) | 10.0 (1.9) | 16.9 (2.0) | < 0.001 | < 0.001 | 0.088 |
The P values provided for drug type and bolus type relate to differences between drug types and between bolus types for each outcome variable. The P values provided for interaction relate to effects between drug types and between bolus types for each outcome variable.
See Table 2 for key.
The CFVe was significantly faster for liquid boluses after saline solution administration, but there was almost no bolus type difference for CFVe following cisapride administration (interaction P = 0.005 [Table 3]). Furthermore, residual UES pressure was significantly higher for solid versus liquid boluses after saline solution administration, but not after cisapride administration (interaction P = 0.003).
Comparison of the effect of cisapride versus saline solution on esophageal pressure profiles
Five of the 11 outcome variables were significantly different after cisapride and saline solution administration: resting LES pressure, residual LES pressure, CFVe, ECI, and residual UES pressure (Table 3). Resting and residual LES pressures were significantly higher under cisapride administration versus saline solution administration (P = 0.003 and P < 0.001, respectively), regardless of bolus type (ie, there were no significant interactions between drug type and bolus type). Three outcome variables had significant interactions between drug type and bolus type: CFVe (interaction P = 0.005), ECI (interaction P = 0.047), and residual UES pressure (interaction P = 0.003). Compared with findings after cisapride administration, CFVe following saline solution administration was significantly faster for liquid boluses than it was for solid boluses. The ECI was significantly higher when dogs received cisapride, although the magnitude of the difference varied by bolus type. Compared with findings after cisapride administration, residual UES pressure after saline solution administration was significantly higher for solid boluses than it was for liquid boluses.
Discussion
In the present study, HRM was found to be highly feasible in fully awake dogs, paralleling the findings of Kempf et al.14,15 However, the HRM procedure was successfully completed in 8 of 9 dogs in which it was attempted in our study, which was a greater proportion than that in the study by Kempf et al (14 of 22 dogs of the same breed).14 Furthermore, in the present study, the ease of the procedure was semi-quantitatively scored, thereby creating a system with which to evaluate its success in dogs. The successful implementation of HRM in alert dogs is influenced by the experience and skillset of the operator placing the catheter, the temperament of the dog, and the ability of trained technicians to gently restrain the animal while the procedure is being completed. However, the increased ease of catheter placement observed during the repeated procedures in 4 dogs in the present study underscored the learning curve that was inherent to successfully completing this procedure. It is plausible that selection bias could have played a role in the improved scores for catheter placement and catheter retention; however, the scores for the repeated HRM procedures decreased from scores obtained for the initial procedures for all 4 dogs.
The anatomic differences between the human and canine esophagus also presented inherent challenges to the implementation of HRM in dogs. The length of the esophagus in large-breed dogs is much longer than that in humans, in whom the esophagus is typically 23 cm in length.23 The length of the esophagus in the dogs of the present study ranged from 22 to 41 cm, and all dogs were considered small to medium-sized breeds. This precluded the ability to obtain data for both the UES and LES at the same time with a 36-cm-long cathetera in dogs weighing > 15 kg. The body of the canine esophagus also differs in muscular structure. The entire length of the canine esophagus to the LES is composed of skeletal muscle24; in the human esophagus, the proximal 5% is composed of skeletal muscle, the middle 35% to 40% is a mixture of striated and smooth muscle known as the transition zone, and the remaining 50% to 60% is smooth muscle.25 Peristalsis in the striated muscle of the esophagus is controlled by vagal motor neurons that originate in the brainstem and end as motor endplates on the striated muscle. Peristalsis in the striated muscle results from patterned activation of brainstem neurons that sequentially innervate and activate the striated esophageal musculature. Peristalsis in the smooth muscle of the esophagus is controlled differently. Sandwiched between the longitudinal and circular muscle layers is a flat plexus of neurons called the myenteric plexus. It has neural inputs from the CNS, and supplies the smooth muscle with its terminal motor innervation.25 In the smooth muscle of the esophagus, activation of vagal motor fibers originating in the brainstem triggers a peripheral peristaltic sequence in the myenteric plexus and circular smooth muscle. Because the neuromuscular control of distal esophageal peristalsis differs in humans and dogs, we might expect to find differences in motor characteristics. In humans, the CFVe is in the range of 3 to 4 cm/s,26 whereas in the dogs of the present study, the CFVe was in the range of 5 to 6 cm/s. In humans, the analog of the ECI is the distal contractile integral, which measures the vigor of contraction in the smooth muscle portion of the esophagus. In dogs, the ECI measures the vigor of contraction of the entire esophagus. In general, the distal contractile integral in humans is 2 to 3 times that in dogs.26 Although no statistical comparison can be made as part of the present study, visual inspection of human and canine esophageal peristalsis profiles obtained via HRM appears to support this difference. Despite identifiable anatomic differences, the human and canine spatiotemporal plots appeared similar, and certain phenomena were consistent in both humans and dogs. For example, episodes of belching and deglutitive inhibition (Figure 2) have been observed in manometric studies performed in humans27,28 and were readily identified on the spatiotemporal plots in the present study.
In the present study, repeated HRM revealed that 7 of the 11 outcome variables initially analyzed had appropriate reproducibility. The remaining 4 outcome variables may not be reliable for future HRM studies in dogs; however, further assessment of their repeatability in a larger cohort of dogs is warranted. Additionally, a few of the variables describing UES relaxation (time to UES nadir, duration of UES opening, and UES recovery) were not significantly different between liquid and solid boluses or in response to saline solution or cisapride administration. However, these variables may be clinically useful in the identification of disorders associated with dysmotility of the UES.4,5 Results of studies13,19–22 of large numbers of humans have facilitated the creation of the Chicago classification system that provides reference ranges. The low mean coefficients of variation (< 0.5) for most outcome variables in the present study reflected the largely ignorable variability of the data within and across all 8 dogs. In addition, there were no consistent differences in measurements from dogs weighing < 15 kg and dogs weighing ≥ 15 kg. Therefore, it may be possible to establish reference guidelines for each outcome variable and potentially facilitate the creation of a classification system in dogs similar to the Chicago system in humans.
In the dogs of the present study, the CFVe for liquid boluses was significantly more rapid than that for solid boluses, and the ECI for solid boluses was significantly greater than that for liquid boluses. These results parallel data for humans in whom drinking water led to more rapid clearance times but less vigorous peristaltic contractions, compared with findings after swallowing bread.29,30 Research in humans suggests that this finding is clinically relevant because more viscous boluses seemingly enhance the accuracy of diagnosis of esophageal motility disorders.31,32 The study14 in dogs by Kempf et al revealed a stronger peristaltic contractile integral for solid boluses and a faster velocity for liquid boluses in both awake and sedated dogs, although statistical comparisons were not made between liquid and solid bolus variables.
The significant increases in both residual and resting LES pressure following cisapride administration in dogs of the present study supported findings from studies performed in humans17,33 and 2 other manometric studies in dogs.15,16 These increases confirm the ability of HRM to accurately and reproducibly discern alterations in sphincter pressure profiles and support the application of cisapride for management of gastroesophageal reflux in dogs. Cisapride labeled for human use was withdrawn from the United States and Canadian markets on July 14, 2000 because of reports of drug-associated torsade de pointes and prolonged QT interval in humans with deaths of 4 patients.34 To our knowledge, there have been no reported cases of serious arrhythmias associated with cisapride administration in other animals; however, medicinal or analytic grade cisapride must be purchased from an approved source and compounded for veterinary use.
The present study expanded on findings from a previous canine HRM study15 by identifying important interaction effects between cisapride administration and bolus viscosity, which were not assessed in the previous study wherein only liquid boluses were administered. Another important difference between the present study and that of Kempf et al15 is that we administered cisapride to the dogs parenterally rather than orally. In addition, resting LES pressure but not residual LES pressure was measured in the previous study. Resting LES pressure is measured over a 30-second period when the dog is not swallowing, whereas residual LES pressure is a measure of LES pressure during swallow-induced LES relaxation.10 Residual LES pressure provides more prognostic information, particularly in humans being evaluated for achalasia.35
High-resolution manometry, as performed in the present study, provided a complete spatiotemporal view of esophageal motor function in awake healthy dogs of various breeds and sizes. High-resolution manometry was also repeatable and findings could be analyzed on the basis of reliable outcome variables. In healthy dogs, peristaltic contractions were stronger for solid boluses than for liquid boluses and contraction velocities were faster for liquid boluses than for solid boluses. Compared with data obtained after saline solution administration, LES pressures were found to be significantly increased after cisapride administration. The results of the present study have illustrated the potential of HRM technology to facilitate the diagnosis and improve our understanding of functional esophageal disorders in dogs, particularly those that cannot be routinely diagnosed via esophagoscopy or videofluoroscopy. High-resolution manometry should be further evaluated to assess pharyngeal and UES function in dogs with cricopharyngeal dysphagia,36,37 esophageal dysmotility,38 and EGJ abnormalities with and without hiatal hernias.39
Acknowledgments
Supported in part by the Comparative Gastroenterology Society (CGS) and Students Training in Advanced Research (STAR) Program at the School of Veterinary Medicine, University of California-Davis.
Dr. Conklin is a consultant and speaker for Covidien. Presented in part as an oral presentation at the IGPS (Interdisciplinary Graduate and Professional Symposium) at the University of California-Davis in April 2014.
ABBREVIATIONS
| CFVe | Esophageal contraction front velocity |
| CFVp | Pharyngeal contraction front velocity |
| ECI | Esophageal contractile integral |
| EGJ | Esophagogastric junction |
| HREPT | High-resolution esophageal pressure topography |
| HRM | High-resolution manometry |
| LES | Lower esophageal sphincter |
| PCI | Pharyngeal contractile integral |
| UES | Upper esophageal sphincter |
Footnotes
ManoScan 360TM, Given Imaging Inc, Duluth, Ga.
ManoScan 360TM, calibration chamber, Given Imaging Inc, Duluth, Ga.
Oxymetazoline hydrochloride 0.05%, Major, Livonia, Mich.
Tetracaine hydrochloride ophthalmic solution USP, 0.5%, Bausch & Lomb, Rochester, NY.
Lidocaine hydrochloride jelly USP, 2%, Akorn, Lake Forest, Ill.
ManoScan acquisition software, Given Imaging Inc, Duluth, Ga.
Surflo winged infusion set, Terumo, Tokyo, Japan.
Hill's i/d, Hill's Pet Nutrition Inc, Topeka, Kan.
Compounded cisapride, North Carolina State University College of Veterinary Medicine, Veterinary Teaching Hospital Pharmacy, Raleigh, NC.
BD Insyte sterile catheter, Becton Dickinson Infusion therapy, Franklin Lakes, NJ.
Buretrol, Baxter HealthCare Corp, Deerfield, Ill.
3010 Syringe pump, Medfusion, Medex Inc, Duluth, Ga.
United States Pharmacopeia (USP) compounded preparation monograph, Cisapride, Compounded, Injection, Veterinary. 2016.
Analytical Research Laboratories, Oklahoma City, Okla.
Enzymatic cleaner, Metrex, Orange, Calif.
Cidex activated glutaraldehyde solution, ASP (Advanced Sterilization Products), Miami, Fla.
ManoView analysis software, Given Imaging Inc, Duluth, Ga.
E-sleeve function, ManoView analysis software, Given Imaging Inc, Duluth, Ga.
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