Tissue stiffness can be altered in various pathologic conditions, such as neoplasia, inflammation, fibrosis, and vascular congestion.1–3 Shear wave elastography (SWE) is an emerging imaging modality for noninvasive evaluation of tissue stiffness.4,5 In SWE, tissue stiffness is estimated by measuring the shear wave velocity (SWV) generated by irradiating the tissue with acoustic radiative force.6 Shear wave velocity correlates positively with tissue stiffness, because it is associated with the elastic restorative forces in the tissue that act against shear deformation.7,8 The recently introduced 2-D SWE allows the evaluation of tissue stiffness based on the exact location of the lesions on a color-coded map superimposed over the conventional ultrasound image in real time.9,10
Several technical factors can affect the SWV, including the respiratory phase, motion-related artifacts, and external pressure of the transducer.11,12 In human medicine, SWE guidelines recommend measuring the SWV during a transient breath held by the patients, avoiding deep inspiration with maximal extension of the arms.9,11 Concurrently, the transducer is applied, preventing excessive pressure on the abdomen.11 However, obtaining strict cooperation from pediatric patients during SWE examination can be difficult.13,14 In pediatric patients who do not cooperate to allow proper examination, the guidelines recommend performing elastography when they are asleep or sedated to maximize the success rate.13 Similarly, in veterinary medicine, strict cooperation during 2-D SWE examination cannot be expected because of uncontrolled breathing and movement.12
The kidneys are located deep inside the retroperitoneum; therefore, excessive pressure may be needed, and respiration-related motion artifacts may be exaggerated in the kidneys compared to those in the superficial organs during the SWE examination.12,15 The pancreas is located adjacent to the stomach and the cranial aspect of the transverse colon. Therefore, the presence of intestinal gas and surrounding organs can compromise consistent visualization of the pancreas.15 Moreover, epigastric pain in dogs with pancreatitis can increase abdominal pressure and induce irregular respiration.16 Therefore, performing SWE of the kidneys and pancreas requires more strict cooperation than other organs. Thus, when examining 2-D SWE of the kidneys and pancreas, the use of a sedation protocol is even more essential than for other organs.
Establishing a sedation protocol that does not affect the SWV in 2-D SWE is important.15,17 The degree of sedation may affect hemodynamic change, which is related to SWV.15,17 Although the effect of sedation on renal or pancreatic SWV in 2-D SWE has not yet been assessed, the effect of a sedative drug on the SWV of the canine spleen has been evaluated.15,18 A combination of zolazepam hydrochloride-tiletamine hydrochloride and medetomidine hydrochloride increased splenic SWV in the 2-D SWE of dogs.15 The stiffness of the splenic nodules did not differ significantly between nonsedated and sedated dogs using a butorphanol and midazolam combination, a fentanyl and midazolam combination, a butorphanol and acepromazine combination, or methadone in strain elastography.19 Butorphanol has an agonistic interaction with the central nervous opiate receptor site, predominant at the k-receptor and only partial at the μ-receptor.20 Therefore, it results in systemic analgesic effects without significant changes in vascular tone and myocardial contractility.19 Midazolam is a benzodiazepine agonist acting on the γ-aminobutyric acid A receptor with minimal cardiovascular changes at clinically relevant doses.20,21 The combination of butorphanol and midazolam is commonly used because of its rapid onset, short duration, and minimal cardiovascular effects.22–24 Consequently, this combination is expected to be applied to the 2-D SWE examination without affecting SWV significantly.
The effect of butorphanol and midazolam on SWV in dogs remains unclear. Therefore, our study aimed to investigate the effect of this sedative combination on 2-D SWE examination of the kidneys and pancreas by comparing the SWV of the 2 organs between sedated and nonsedated dogs. We hypothesized that the combination of butorphanol and midazolam would not influence SWV and could be used as an adequate sedative agent during the 2-D SWE examination.
Materials and Methods
The study protocol was approved by the Institutional Animal Care and Use Committee of Chonnam National University, and the protocol for the care of dogs adhered to the Guidelines for Animal Experiments of Chonnam National University (CNU IACUC-YB-2021-55).
Animals
We enrolled 8 client-owned dogs, including the breeds Chihuahua (n = 2), Maltese (n = 2), Poodle (n = 2), Bull Terrier (n = 1), and Pomeranian (n = 1). Informed consent was obtained from all owners. All dogs were clinically healthy, based on physical examination, CBC, serum chemistry, electrolyte levels, thoracic and abdominal radiography, and abdominal ultrasonography on the same day of 2-D SWE examination, although healthy canine kidneys and pancreas were not confirmed by histological examination.
Study protocols
In each dog, conventional ultrasonography and 2-D SWE were performed using the same ultrasound machine (EPIQ 5; Philips Healthcare) with a linear 4- to 18-MHz array transducer by 1 veterinarian (HC) with 7 years of experience in radiology. Conventional ultrasonography of the entire abdomen, including the kidneys and pancreas, was performed during a general checkup for about 20 minutes. Subsequently, 2-D SWE examinations of the bilateral kidneys and right pancreatic lobe were conducted to obtain SWV data. Immediately after presedation 2-D SWE, a combination of 0.2 mg/kg butorphanol and 0.1 mg/kg midazolam was administered IV. Postsedation 2-D SWE was performed when at least mild sedation was achieved in the dog based on the evaluation criteria (Table 1).25
Criteria for evaluation of sedation.
| Degree of sedation | Criteria |
|---|---|
| No sedation | No discernable effect of sedation |
| Mild sedation | Signs of sedation but remains standing or sitting; appears calm; aware of surrounding environment and reactive to verbal stimulation |
| Moderate sedation | Appears sleepy but remains sitting or assumes sternal recumbency; no reaction to verbal stimulation but can be aroused with physical examination |
| Heavy sedation | Inactive; assumes lateral recumbency; difficult to arouse with physical examination |
2-D SWE examinations
Pre-and postsedation 2-D SWE examinations were performed using an identical method according to recommended guidelines and previous reports.11,15,26–29 After clipping the abdominal hair and applying adequate ultrasonic gel, the dog was positioned in the lateral recumbent position, with the four limbs extended maximally. We performed 2-D SWE of the left kidney via the subcostal approach with the dog in right lateral recumbency. We performed 2-D SWE of the right kidney via the intercostal approach with the dog in left lateral recumbency, and that of the right pancreatic lobe was performed via the subcostal approach. Care was taken not to compress the kidneys and pancreas with the transducer, and to place the ultrasound beam perpendicular to the organs during the 2-D SWE. The installed software (ElastQ Imaging version 4.0; Philips Healthcare) was launched at the end of expiration. Subsequently, B-mode images and a color-coded map were displayed side by side in the dual-screen mode. In the color-coded map, a rectangular, color-coded elastographic box was placed over the sagittal plane of the left and right kidneys and right pancreatic lobe. A confidence map was generated simultaneously within an elastographic box. An area with a confidence value of less than the confidence threshold (50%) was displayed as color defects in the color-coded map. Insufficient color-coded areas acquired as a result of the presence of color defects was considered a technical failure. Frames that showed consistent and sufficient color-coded maps were selected as the region of interest (ROI). A circular ROI, 3 mm in diameter, was placed in the right pancreatic lobe and the middle third cortical region of each kidney. During the placement of each ROI, care was taken not to include the large vessels or regions of the rib shadows. Subsequently, the SWV was measured in meters per second from each ROI. The ratio of the interquartile range (IQR) to the median value (MED) was calculated automatically and used to assess the quality of the measurements by evaluating the variability of the data. The SWV in each ROI was considered valid data when the IQR/MED was < 30%. We performed 2-D SWE by obtaining 5 valid data sets for each organ, and the median value of these data sets was used as the representative SWV. An unreliable measurement was defined as an IQR/MED of > 30% of the 5 valid data sets.
Statistical analysis
Statistical analyses were performed using a commercial statistical program (SPSS Statistics 25; IBM Corp) by 1 veterinarian (HC) under the supervision of a statistician. Normal distribution was tested using the Kolmogorov–Smirnov test. The Wilcoxon signed-rank test was used to evaluate the difference in SWV and IQR/MED between pre-and post-sedation 2-D SWE. Data are presented as mean ± standard deviation. Statistical significance was set at P < 0.05.
Results
Pre- and postsedation 2-D SWE examinations of 8 dogs were performed successfully without technical failure or unreliable measurements. The average body weight of the 8 dogs was 5.10 ± 4.89 kg, and their average age was 7.13 ± 4.78 years. The 8 dogs included 4 neutered females, 2 intact females, and 2 neutered males. Administration of a combination of butorphanol and midazolam led to mild sedation in all dogs, with muscle relaxation and regular respiration, which provided an effective performance of postsedation 2-D SWE examination compared to presedation 2-D SWE examination.
The quality of the measurements was evaluated based on the variability of the data—that is, the IQR/MED score. The mean IQR/MED values in the left kidney, right kidney, and pancreas were less in the postsedation 2-D SWE examination than in the presedation SWE examination. However, there was no significant difference in the IQR/MED values of the left kidney (P = .167), right kidney (P = .075), and pancreas (P = 0.236; Table 2).
Interquartile range of median values of renal and pancreatic shear wave velocity in pre- and postsedation 2-D shear wave elastography (SWE) in healthy dogs.
| Organ | Interquartile range of median values | |
|---|---|---|
| Pre-sedation 2-D SWE | Post-sedation 2-D SWE | |
| Left kidney | 7.00 ± 4.10 | 5.12 ± 1.24 |
| Right kidney | 7.50 ± 4.62 | 4.50 ± 2.50 |
| Pancreas | 7.75 ± 3.57 | 5.00 ± 2.77 |
In the qualitative evaluation, the pancreas was shown as homogenous blue-to-green color mapping on pre-and postsedation 2-D SWE (Figure 1), along with the kidneys, which also revealed a uniform blue-to-green color in all dogs.
Elastographic images of the pancreas (A, B) and kidney (C, D) using 2-D shear wave elastography (SWE). B-mode image and color-coded map of 2-D SWE are displayed before (A, C) and after (B, D) sedation in each organ. In the color-coded maps, the rectangular colored box and region of interest are indicated. The shear wave velocity obtained from the region of interest is presented in the left corner of the display.
Citation: American Journal of Veterinary Research 84, 3; 10.2460/ajvr.22.10.0187
The data for the SWV of the kidneys and pancreas obtained from pre- and postsedation 2-D SWE are presented (Table 3). There was no significant difference in SWV before and after sedation in the left kidney (P = .779), right kidney (P = .400), and pancreas (P = .483).
Renal and pancreatic shear wave velocity of pre- and postsedation 2-D shear wave elastography (SWE) in healthy dogs.
| Organ | Shear wave velocity (m/s) | |
|---|---|---|
| Presedation 2-D SWE | Postsedation 2-D SWE | |
| Left kidney | 2.77 ± 0.14 | 2.79 ± 0.15 |
| Right kidney | 2.78 ± 0.21 | 2.81 ± 0.13 |
| Pancreas | 2.30 ± 0.15 | 2.25 ± 0.16 |
Discussion
In our study, the sedative effect of a combination of butorphanol and midazolam was evaluated by a 2-D SWE examination of healthy canine kidneys and pancreas. The sedation had no significant effect on the color map and SWV measurement of the bilateral kidneys and pancreas.
SWV, which increases according to the increase in tissue stiffness, reflects not only the tissue composition, but also the perfusion of the organ.30 Many studies15,31 have shown that the stiffness change is related to tissue perfusion in various organs and that sedative or anesthetic agents can alter the blood supply to the organ and affect the tissue stiffness. For example, in humans, liver stiffness increased after propofol administration, which was explained by the pharmacologic effect of propofol on increasing the splanchnic blood flow.15,31,32 Under pathologic conditions, the changed blood flow can also affect tissue stiffness.33,34 Alterations in portal blood flow resulting from portal hypertension affect the splenic SWV values in humans.33 Similarly, a canine study34 suggested that splenic SWV can change after alterations in portal flow resulting from portal hypertension.
However, our study reveals that the sedative dose of the combination of butorphanol and midazolam had no significant effect on pancreatic SWV in healthy dogs. The pancreas shares a common blood supply with other splanchnic organs, such as the liver, spleen, stomach, and small intestine.35 This splanchnic circulation is perfused through the cranial, caudal mesenteric, and celiac arteries, and drains into the portal vein. It accommodates about one-fifth of the cardiac output, and its major determinant is total peripheral vascular resistance and systemic arterial blood pressure.36,37 Therefore, the splanchnic circulation interacts closely with systemic hemodynamics.38 Consequently, the sedatives that can affect systemic hemodynamics may cause regional changes in blood flow to the splanchnic circulation.38,39 Although butorphanol induces only minimal changes in cardiopulmonary function, midazolam can reduce systemic blood pressure by inhibiting the release of norepinephrine and inducing smooth muscle contraction.23,40 However, when the combined effect of 0.2 mg/kg butorphanol and 0.1 mg/kg midazolam on canine splanchnic blood flow was assessed using contrast-enhanced ultrasonography (CEUS), no significant difference was observed in the perfusion parameters of the duodenum, another splanchnic organ,23 which is comparable to our result.
Sedation did not affect renal SWV significantly on 2-D SWE in our study. Several studies41–43 have investigated the effect of sedation on renal blood flow using noninvasive imaging techniques. In a feline study,42 0.4 mg/kg butorphanol exhibited no significant influence on renal blood flow using CEUS. The medetomidine-midazolam-butorphanol combination and tiletamine-zolazepam-medetomidine combination also did not change renal cortical blood flow significantly in canine studies41,43 using Doppler ultrasonography and CEUS. However, the combination of 0.2 mg/kg butorphanol and 0.1 mg/kg midazolam increased the resistive and pulsatility indices in dogs significantly, and the result was considered to be related to the effect of midazolam on renal blood flow, because resistive and pulsatility of kidneys is also associated with amount of renal blood flow.44 The discrepancy between our study and a previous study45 may be related to the dose of midazolam used, because it has dose-dependent pharmacokinetics. Kidneys can maintain renal blood flow by renal autoregulation, unless severe cardiac dysfunction occurs.46,47 In our study, a sedative dose of 0.2 mg/kg butorphanol and 0.1 mg/kg midazolam was used, and renal autoregulation may be effective in maintaining renal blood flow.
The mean IQR/MED values were less in postsedation 2-D SWE. In human medicine, IQR/MED is affected by patient factors, such as the inability of patients to hold their breath optimally or obesity.13,48 Therefore, regular respiration and reduced abdominal pressure induced by sedatives might have influenced IQR/MED values in our study.
Our study had some limitations. First, we included only a small number of animals and the statistical power was not calculated to determine sample size. Thus, the possibility that sample size would affect the statistical significance of this study cannot be ruled out completely. Further study is needed to confirm our results for a greater number of dogs. Second, we did not include a positive control, which might have influenced the cardiovascular system significantly, such as dexmedetomidine.15,19 Further studies are needed to investigate the effects of other sedatives on 2-D SWE. Third, pancreatic SWV was obtained only from the right pancreatic lobe; however, the reproducibility of 2-D SWE at the right pancreatic lobe is superior to that of other lobes.15
In conclusion, our study assessed the sedative effect of IV administration of a combination of 0.2 mg/kg butorphanol and 0.1 mg/kg midazolam on 2-D SWE of the pancreas and kidneys. Our results show that this combination does not change significantly the SWV and color map of the pancreas and kidneys on 2-D SWE. Therefore, the combination of butorphanol and midazolam can be used in healthy dogs to evaluate 2-D SWE of the pancreas and kidneys, especially when the patient is uncooperative in performing 2-D SWE.
Acknowledgments
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (NRF-2021R1A2C200573011).
The authors thank Jinkyung Kim for statistical assistance with this work.
The authors declare that there were no conflicts of interest.
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