Sedation with dexmedetomidine is associated with transient gallbladder wall thickening and peritoneal effusion in some dogs undergoing abdominal ultrasonography

Abstract Background Dexmedetomidine often is used for sedation before or during abdominal ultrasonography. The effect of dexmedetomidine on gallbladder wall thickness is unknown. Hypothesis/Objectives To investigate the relationship between dexmedetomidine administration and gallbladder wall thickening in dogs. The hypothesis was that sedation with dexmedetomidine will cause transient gallbladder wall thickening. Gallbladder wall thickness will be associated with duration of sedation and recumbency position. Animals Seventy‐nine client owned dogs and 10 healthy research dogs. Methods A prospective observational study (n = 79) was used to establish the prevalence of gallbladder wall thickening (> 2.0 mm) after sedation with dexmedetomidine. A randomized, crossover study (n = 10) was used to evaluate the effect of time and recumbency position on the development of gallbladder wall thickening. Linear mixed models were used. Results The proportion of client‐owned dogs that developed gallbladder wall thickening was 24.05% (19/79; 95% confidence interval [CI], 15.1%‐35.0%) with a median dose of dexmedetomidine of 5.0 μg/kg (range, 2.0‐12.5 μg/kg). After sedation, the proportion of research dogs that developed gallbladder wall thickening in left lateral (5/10, 50%; 95% CI, 18.7%‐81.3%) and dorsal (7/10, 70%; 95% CI, 34.8%‐93.3%) recumbency did not differ significantly (P = .45). Gallbladder wall thickening developed within 20 to 40 minutes. Duration of sedation was significantly associated with thickening of the gallbladder wall (P < .001). Five dogs developed 9 instances of peritoneal effusion in both lateral (5) and dorsal (4) recumbency. Conclusions and Clinical Importance Sedation with dexmedetomidine is associated with gallbladder wall thickening (> 2.0 mm) and peritoneal effusion that could be confused with pathologic etiologies.


| INTRODUCTION
Ultrasonography is commonly used to evaluate the hepatobiliary system in dogs. The normal gallbladder wall in dogs is visible ultrasonographically as a thin hyperechoic line measuring 1 to 2 mm thick. 1 Gallbladder wall thickening is often the result of gallbladder wall edema and most commonly appears as a hypoechoic band of variable thickness surrounded by inner and outer hyperechoic lines. 2 This appearance has been referred to as a "double rim sign" or a "gallbladder halo." 3 Gallbladder wall edema is well established in the veterinary literature and has been reported with numerous etiologies that cause inflammation, venous congestion, or a combination of both. Examples include cholecystitis, hepatopathy, pancreatitis, hepatobiliary neoplasia, biliary obstruction, portal hypertension, right-sided heart failure (including pericardial effusion), hypoproteinemia, chemotherapeutic drugs, renal failure, and more recently anaphylaxis, blood transfusion, immune-mediated hemolytic anemia, sepsis, systemic inflammatory response syndrome, and disseminated intravascular coagulation. 2,[4][5][6] The presence of peritoneal effusion surrounding the gallbladder may mimic true gallbladder wall thickening. 2 The proposed pathophysiology of gallbladder wall edema is explained by aberrations of Starling's forces, including increased vascular permeability, increased hydrostatic pressure in the portal venous system, decreased oncotic pressure, or lymphatic obstruction. 2,5 Although gallbladder wall edema is a common cause of gallbladder wall thickening, other factors such as cystic mucosal hyperplasia or fibrosis also may contribute to the thickened appearance. A review of the literature identified no reports of gallbladder wall thickening after administration of dexmedetomidine or other alpha-2 agonists.
Many dogs tolerate abdominal ultrasonography with only physical restraint, but periprocedural sedation often is required in noncompliant patients or for ultrasound-guided procedures. Dexmedetomidine, an alpha-2 agonist, often is chosen for sedation because of its reversible sedative, anxiolytic, and analgesic properties. 7 On several occasions, we have observed variable and progressive gallbladder wall thickening during abdominal ultrasonography in dogs sedated with dexmedetomidine that was neither present before sedation nor explained by anaphylaxis or other pathology. Our purpose was to investigate the relationship between sedation with dexmedetomidine and gallbladder wall thickening in dogs as well as factors contributing to its formation. One hypothesis was that sedation with dexmedetomidine will cause transient gallbladder wall thickening in dogs. A second hypothesis was that increased gallbladder wall thickness will be associated with increasing sedation dose, a longer duration of sedation, recumbency in a dorsal position, obesity, increased congestion index, and increased portal blood flow volume (PBFV) but not associated with other secondary variables.

| MATERIALS AND METHODS
Two phases were planned to investigate the study's purpose. Both phases were approved by the Mississippi State University Institutional Animal Care and Use Committee (IACUC-19-024 and IACUC-19-026).
Phase 1 had a prospective observational design whereas phase 2 had a randomized, crossover design. For all-client owned animals, owners signed an informed consent form before recruitment into phase 1.

| Phase 1
Phase 1 was designed to establish the proportion of client-owned dogs that develop gallbladder wall thickening (> 2.0 mm) when sedated with dexmedetomidine (IV or IM) alone or in combination with other drugs.
Based on our clinical experience before the study, the estimated proportion of dogs that develop gallbladder wall thickening after being sedated with dexmedetomidine was approximately 6% to 12%. Assuming the proportion of dogs developing gallbladder wall thickening was 6% and an α level of .05, sample size calculation identified that 79 patients will allow an estimate of this proportion with precision of ±5.3%. If gallbladder wall thickening was not detected in any of the 79 dogs, then it was estimated with 95% confidence that this finding occurs at a level < 3.7%.
Dogs eligible for inclusion were those > 1 year of age that presented to the diagnostic imaging service for routine nonabdominal radiographic imaging studies that required sedation with dexmedetomidine (Dexdomitor, Zoetis, Troy Hills, New Jersey) alone or in combination with other drugs. A history, physical examination, CBC, and serum biochemical profile were performed the same day as the ultrasound examinations for all dogs. Dogs were not included if they had a history of clinical signs related to potential abdominal pathology (eg, anorexia, vomiting, diarrhea, abdominal pain), muffled heart sounds, dyspnea, increased liver function test results (eg, alanine aminotransferase, alkaline phosphatase, total bilirubin), a platelet count < 60, 000/μL, or an ultrasonographically abnormal liver, gallbladder wall thickening, or bile duct dilatation (> 3 mm) on presedation examination. Dogs also were not included in the study if they had diseases or treatments reported to cause gallbladder wall thickening, including hepatic or gallbladder disease, anaphylaxis or any other kind of shock, right-sided heart failure, pericardial effusion, pancreatitis, hypoalbuminemia, peritoneal effusion, portal hypertension, sepsis, systemic inflammatory response syndrome, or had received fluid therapy, iodinated contrast, chemotherapeutics, sedatives, or anesthesia within 24 hours before presentation.
Dogs were sedated using a drug protocol chosen by the attending veterinarian. The following vital signs were monitored and recorded every 5 to 10 minutes: heart rate, respiratory rate, pulse quality, mucous membrane color, capillary refill time, and temperature. All dogs received a focused ultrasound examination of the liver, gallbladder, and porta hepatis before and at the end of the sedation period, and before the administration of any reversal agents (eg, atipamezole). All ultrasound examinations were performed with the dog in left lateral recumbency by the same second year radiology resident (M.A. Seitz) under the supervision of a board-certified radiologist.
The results of the presedation ultrasound examination served as an internal control and to screen for pre-existing gallbladder wall thickening. The same ultrasound machine (LOGIQ S8, General Electric Healthcare, Chicago, Illinois) was used for all examinations. The same microconvex transducer (C3-10 D broad-spectrum microconvex trans- were measured using pulse wave Doppler with an angle of interrogation < 60 . Still images and cine loops were obtained for documentation purposes. Gallbladder wall thickening was defined as a gallbladder wall thickness > 2 mm. Each gallbladder wall and vessel cross-sectional area were measured twice by a single observer (a radiology resident under supervision of a board-certified veterinary radiologist) and the measurements averaged. Congestion index and PBFV were calculated as previously described. 8 Additionally, the medical record was used to collect the following variables: final diagnosis, breed, sex, neuter status, age, weight, body condition score (BCS), sedation duration, other drugs used, and heart rate during sedation.  (Table 1) was assessed in a separate logistic regression model using the logistic procedure in the statistical software program. For some secondary measures, there were no dogs with gallbladder wall thickening in 1 of the levels of the variable leading to quasi-complete separation of data points. Firth's penalized maximum likelihood estimation was used in these models.

| Phase 1: Statistical analysis
The level of significance was set at an α level of .05.

| Phase 1: Study population
Seventy-nine client-owned dogs were eligible for inclusion in phase 1.
The study was terminated before the prestudy goal of 100 dogs because interim analysis indicated a much higher prevalence than expected and because of unanticipated recruitment challenges arising from the COVID-19 pandemic. The study population consisted of a variety of dogs presented primarily for orthopedic conditions. Reasons for imaging included diagnosis or re-evaluation of the following conditions: cranial cruciate ligament injury (n = 46), osteoarthrosis (8) (1), and routine wellness screening (1). Thirty-nine dogs were female and 40 were male. Sixty-seven dogs were neutered whereas 12 were intact. The age range was 1 to 14 years with a median of 5 years. Age was further categorized as follow: young = 1 to 4 years (33), middle-aged = 5 to 8 years (37), and geriatric ≥ 9 (9).
The following breeds were represented: mixed (14), Labrador retriever (11), English bulldog (7), Golden retriever (7), German shepherd dog  (1), toy T A B L E 1 Summary of variables measured in phase 1 to assess their association with the formation of gallbladder wall thickening in a population of 79 client-owned pets presenting for routine nonabdominal imaging using univariate logistic regression

| Phase 1: Results
The proportion of dogs developing gallbladder wall thickening in  Table 1

| Phase 2: Study population
A research colony of 10 healthy bloodhounds was used for phase 2.
The body weight range was 22.3 to 36.1 kg, with a median of 25.1 kg.
All dogs had an ideal BCS of 4 or 5. The age range was 3 to 6 years, with a median of 5 years. Seven dogs were female and 3 were male.
Seven dogs were intact and 3 of the female dogs were spayed.

| Phase 2: Results
Duration of sedation was significantly associated with thickening of the twice that of those that did not (1.53 ± 0.25 mm). Similar to phase 1, asymmetric thickening was seen first along the dorsal aspect of the gallbladder wall, regardless of recumbency position. Inconsistently, the thickening would spread to a more diffuse pattern as time progressed in some, but not all dogs (see Figure 1).
Gallbladder wall thickness also was increased significantly in dogs with peritoneal effusion (P = .01). Four dogs had gallbladder sludge whereas 6 dogs did not. Secondary variables (see Table 2) not associated with gallbladder wall thickness included body weight, heart rate, systolic blood pressure, mean arterial blood pressure, presence of gall- supply to the liver is 2-fold with approximately 75% to 80% coming from the PV and the remainder supplied by the hepatic arteries. 13 The increased PBFV may be offset by decreased blood supply via the hepatic arteries secondary to a dexmedetomidine-mediated decrease in cardiac output. For example, 1 study 14 found that dexmedetomidine caused a significant decrease in flow volume of the abdominal AO, the cranial mesenteric artery, and the celiac artery until reversal with atipamezole.
However, it is also possible that the increased PBFV represents a statistically spurious result and is not truly clinically relevant because numerous secondary variables were analyzed.
T A B L E 2 Summary of variables measured in phase 2 to assess their association with the formation of gallbladder wall thickening in a population of 10 healthy research bloodhounds using separate linear mixed models with position within dog as a repeated effect and dog as a random effect