Abstract
OBJECTIVE
To evaluate the effects of rocuronium and sugammadex on the patient state index (PSI) in dogs anesthetized with propofol.
ANIMALS
6 intact healthy male Beagles.
PROCEDURES
Anesthesia was induced with and maintained on a propofol infusion. The estimated plasma propofol concentration (ePC) was recorded. Baseline PSI and train-of-four ratio (TOFR) readings were collected for 2 minutes in stable general anesthesia. Neuromuscular blockade (NMB) was induced with 0.6 mg/kg, IV, rocuronium, and full NMB was confirmed with a TOFR of 0. After 5 minutes, the neuromuscular function was restored with 4 mg/kg sugammadex, IV (reversal), and monitored for 5 minutes. Throughout the data collection, ePC, PSI, and TOFR were recorded every 15 seconds and compared with mixed-effect ANOVA.
RESULTS
Baseline ePC, PSI, and TOFR were 3.63 ± 0.38, 41 ± 6, and 0.97 ± 0.08 µg/mL, respectively. There was no difference between the baseline of ePC and PSI from NMB or reversal. Compared to the baseline, the TOFR decreased to 0 with NMB (P < .001) and returned to 0.96 ± 0.08 (P = .721) on reversal. After 5 minutes, sugammadex fully reversed 5 out of 6 dogs to TOFR > 0.90 and partially reversed 1 animal to TOFR = 0.80.
CLINICAL RELEVANCE
There was no evidence that NMB with rocuronium and sugammadex-induced reversal interfered with PSI readings under steady-state total intravenous anesthesia with propofol. Further evaluation of PSI is warranted to assess its utility in a clinical population to detect changes in levels of consciousness during NMB.
Electroencephalogram (EEG)-based anesthetic monitors estimate levels of anesthetic depth by interpreting the raw electrical potentials at the os frontalis (forehead). They are used in human medicine as a corroborating method to assess consciousness, as hemodynamic changes are not always predictive of the patient’s anesthetic depth.1 The use of EEG monitors reduces the anesthetic dosage and improves anesthetic depth assessment and recovery of human patients.2–4
The patient state index (PSI) is an EEG index3 that generates a unitless number from 0 to 100. A PSI of 0 indicates a deep level of hypnosis, and 100 indicates a fully awake state.3 The recommended PSI values in adequately anesthetized humans are between 25 and 50.2,5 Similar values were observed in anesthetized chimpanzees.2 The application of PSI in dogs has been reported with PSI decreasing from 89 to 47 after propofol administration.6
The utility of an EEG index such as PSI can become particularly important when neuromuscular blocking agents (NMBAs) are administered and assessing the level of consciousness with muscle tone and reflexes dependent on the skeletal musculature becomes unreliable. However, there is no current literature that has evaluated whether NMBAs affect the PSI in anesthetized dogs. A study in fully conscious human volunteers found significant decreases in another EEG-based index after administering rocuronium.7 There are no studies in anesthetized dogs that evaluate the effects of NMBA in PSI readings. If a similar decrease in PSI happens after rocuronium-induced neuromuscular blockade, the PSI would also not be reliable in anesthetized dogs.
This study aimed to determine if PSI values were altered after administering rocuronium and its reversal agent under steady-state total intravenous anesthesia (TIVA) with propofol in dogs. We hypothesized that canine PSI values would not change significantly when rocuronium induces neuromuscular blockade or when sugammadex restores the neuromuscular function assuming hypnosis was properly measured before administration of rocuronium.
Materials and Methods
This study was approved by the University of Georgia Institutional Animal Care and Use Committee (IACUC), protocol A2021 04-010-Y1-A1. The study took place on February 21, 2021.
Animals
Six intact male Beagles were enrolled. Dogs were assessed as healthy based on physical exams as well as a CBC and serum biochemical analysis. The investigators used the same dogs from a surgical study8 performed in tandem with this experiment to reduce the number of animals in research, following the “Three Rs” tenet for animal welfare. We estimated that a sample size of 6 animals would render the power of 95.9% with an alpha of 4.1% in a compromise 2-tailed paired t test power analysis. For this analysis, we considered the PSI of 40 ± 5 and 30 ± 5 for dogs with and without neuromuscular blockade, respectively.
Sedation
Dogs were fasted 8 to 12 hours before anesthesia with water available ad libitum. The forehead of each dog was previously clipped for another study for EEG placement. A 20-gauge peripheral IV catheter was placed in the cephalic vein on the morning of anesthesia. Each dog received 1 mg/kg maropitant (Cerenia; Zoetis), 0.03 mg/kg acepromazine (PromAce; Boehringer Ingelheim), and 0.1 mg/kg hydromorphone (Hydromorphone HCl; West-Ward Pharmaceuticals), IV.
Measurement of the PSI
The EEG pads were placed over the forehead (Root Patient Monitoring and Connectivity Platform, Masimo Corporation) on the positions F3, F4, Fz, T3, T4, and Cz. A self-adherent bandage was used to cover the electrodes (Vetrap 4” Bandaging Tape; 3M) and increase contact with the dog as previously described.6 Anesthesia was induced with propofol (PropoFlo 28; Zoetis) if proper surface contact was confirmed by a green indicator light on the monitor.
Anesthetic protocol
Oxygen supplementation was provided by a tight-fitting facemask attached to a rebreathing circuit with an oxygen flow rate of 2 L/min. Dogs received oxygen supplementation for 5 minutes before anesthetic induction. Anesthesia was induced and maintained with 2 mg/kg, IV, propofol administered over 2 minutes, followed by an infusion of 13.2 mg/kg/h. Orotracheal intubation was performed, and ventilation of the lungs was performed with intermittent positive pressure ventilation (Hallowell EMC Model 2002; Halowell Engineering & Manufacturing Corp), with peak inspiratory pressure set at 10 to 12 cm H2O and respiratory rate between 8 and 14 breaths per minute, aiming for an end-tidal carbon dioxide pressure between 35 and 45 mm Hg.
The propofol infusion rate was adjusted for an adequate surgical anesthesia depth: ventromedial rotation of the eye globes, absence of palpebral reflexes, relaxed jaw tone, and heart rate and blood pressure not changing by more than 20% with surgical stimulation. The propofol dose was increased if the heart rate and blood pressure increased by more than 20% with surgical stimulation. The PSI was maintained between 25 and 50 during the surgical procedure. The plasma propofol concentration was estimated (ePC) with pharmacokinetic software (CCIP V2.5; Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong) by tracking the initial bolus and the adjustments of the infusion rates of propofol in real-time simulation. Pharmacokinetic parameters described for propofol anesthesia in dogs were inserted into the software.9 The total dosage of propofol delivered by baseline measurements and the rate of propofol delivered during data collection were recorded.
Each dog was monitored with an electrocardiogram, esophageal temperature probe, oscillometric blood pressure (VetTRENDS V Plus Monitor; VetTRENDS), and a reflectance pulse oximetry probe placed on a shaved region of the plantar surface of the tarsus (Root Patient Monitoring and Connectivity Platform; Masimo Corporation). A heated circulating water blanket was used for temperature support. The propofol infusion was decreased by 10% if the mean arterial pressure was < 65 mm Hg. Palpebral reflexes, jaw tone, and eye globe position were assessed during the surgical procedure but not in the data collection window to avoid motion artifacts.
Surgical procedure
The dogs underwent a surgical procedure for an independent study8 before the instrumentation for neuromuscular function measurements.
The study evaluated sildenafil citrate hydrogel and its effects on wound healing. These experiments occurred 21 days after 4 full-thickness 3-by-3-centimeter wounds were created in the dorsum of each dog. The surgeons obtained 4-millimeter punch biopsies and closed the wounds before the data collection of the anesthetic study. The surgical procedure duration, the time from procedure end to baseline, and the time from anesthesia induction to baseline were recorded.
Measurement of the neuromuscular function
The dogs were positioned in sternal recumbency with the pelvic limbs towards the right side to allow free movement of the tarsus. A peripheral nerve stimulator was used to apply train-of-four (TOF) stimuli over the peroneal nerve and elicit the cranial tibial muscle contraction. The positive electrode was placed proximally 3 cm apart from the negative electrode over the lateral aspect of the femorotibial joint with stimulating subcutaneous needles. The acceleration-sensitive crystal (TOF-Watch SX; Organon Ireland) was placed dorsally, 2 cm proximal to the metatarsal pad. The current was set at 40 mA, and the device was calibrated for train-of-four ratio (TOFR; the peak acceleration of the fourth twitch over the first twitch) measurements in CAL1 mode. The device was configured to stimulate every 15 seconds (4 square stimuli at 2 Hz and 0.2-millisecond duration each). The TOFR was displayed and recorded manually.
Experimental design
The heart rate, mean arterial pressure (MAP), oxygen hemoglobin saturation (Spo2), and end-tidal partial pressure of carbon dioxide (Petco2) were recorded immediately before baseline and after 5 minutes from sugammadex administration. The respiratory rate was recorded immediately before baseline and kept constant throughout data collection. Esophageal temperature was recorded before rocuronium administration and after sugammadex administration.
The ePC was recorded every 15 seconds during the data collection simultaneously with PSI and TOFR. Once the PSI and TOFR readings were stable for 10 minutes during a constant estimated propofol plasma concentration, the baseline data were collected for 2 minutes. Neuromuscular blockade was induced with 0.6 mg/kg, IV, rocuronium (Zemuron; Merck & Co) at time 0. At 5 minutes, the dogs received 4 mg/kg, IV, sugammadex (Bridion; Merck & Co), and data were collected for an additional 5 minutes (Figure 1). The neuromuscular blockade onset (time from rocuronium administration to TOFR = 0) and neuromuscular function recovery (time from sugammadex administration to TOFR > 0.9) were recorded. The peripheral nerve stimulator was adjusted, and additional TOFR readings were performed if the TOFR was < 0.9. The propofol infusion ceased when the TOFR was confirmed to be above 0.9. The animals were extubated when strong swallowing reflexes were observed. When the animals were fully conscious, the intravenous catheter was removed, and they were returned to the housing facility.
Flow diagram of the perianesthetic period. Patient state index (PSI) instrumentation for electroencephalography and peripheral nerve stimulation as well as a surgical procedure for another study was performed on each dog before train-of-four (TOF) instrumentation and stabilization. The PSI and train-of-four ratio (TOFR) were measured for 12 minutes. Baseline TOFR and PSI were collected for 2 minutes. Afterward, each dog underwent neuromuscular blockade with 0.6 mg/kg, IV, rocuronium, and then reversal with 4 mg/kg, IV, sugammadex while TOFR and PSI were monitored for 5 minutes after administration of each agent. The estimated plasma propofol concentration (ePC) was obtained via real-time tracking pharmacokinetics software.
Citation: American Journal of Veterinary Research 84, 7; 10.2460/ajvr.23.03.0050
Statistical analysis
Normality was evaluated with Shapiro-Wilk tests. The baseline heart rate, MAP, Spo2, and Petco2 were compared with the postexperiment values with paired t tests. The responses ePC concentration, PSI, and TOFR were evaluated with mixed-effect models. The initial 3 minutes after the administration of rocuronium or sugammadex were excluded from the analysis to ensure the evaluation of only a fully relaxed or recovered dog. The fixed effects were (1) the neuromuscular condition: baseline, paralyzed (after the administration of rocuronium), and reversed (after the administration of sugammadex); (2) time; and (3) interaction of time with the neuromuscular condition. The individual animal was added as a random effect in the model. Multiple pairwise comparisons were performed with Tukey’s honest significance difference tests if necessary. Parametric data are expressed as mean ± standard deviation. Alpha was set at 5%. All statistical analysis was performed using standard software (JMP version 16.2.0; SAS Institute Inc).
Results
The mean ± SD age and weight for dogs enrolled was 14.1 ± 0.2 months old and 12.3 ± 0.4 kg, respectively. The physiological variables (heart rate, MAP, Spo2, and Petco2) were stable during the experiment (Table 1). The surgical length was 35.3 ± 3.2 minutes, and the time from induction to the end of data collection was 82.3 ± 5.3 minutes. The respiratory rate was 11.2 ± 2.6 breaths/minute, and the esophageal temperature was 35.6 ± 0.6 °C. Two dogs developed hypothermia, defined as a temperature below 35 °C (95 °F).
Physiologic variables recorded during patient state index monitoring at baseline and the end of the data collection window.
| Variable | Baseline | End of data recording | P value |
|---|---|---|---|
| Heart rate (beats/min) | 59.5 ± 5.2 | 60.0 ± 4.9 | .802 |
| MAP (mm Hg) | 78.7 ± 17.0 | 75.5 ± 15.0 | .151 |
| Spo2 (%) | 98 ± 0.9 | 97.8 ± 1.3 | .611 |
| Petco2 (mm Hg) | 40 ± 5.5 | 39.2 ± 6.1 | .363 |
Data are means ± SD.
The dogs received 14.5 ± 1.1 mg/kg/h of propofol before baseline. The infusion rate for data collection was 13.9 ± 1.6 mg/kg/h. The mean ePC at baseline was 3.63 ± 0.38 µg/mL. There was an effect of time, with an increase of 0.005 µg/mL/min (P < .001). The final estimated ePC, 5 minutes after sugammadex administration, was 3.67 ± 0.42 µg/mL, 1.1% higher than the baseline. The estimated plasma concentration at baseline was not different than in paralyzed and reversed statuses (P = .278). The time with the neuromuscular condition interaction was not significant (P = .405).
The PSI before the induction of anesthesia was > 90 in the sedated dogs. The mean baseline PSI ± SD after anesthetic induction was 41 ± 6. Time (P = .794), neuromuscular condition (P = .864), and the interaction of time with the neuromuscular condition were insignificant (P = .636; Figure 2).
Data collection of 6 dogs for 12 minutes. TOFR (A) and PSI (B). The baseline was obtained for 2 minutes. Neuromuscular blockade was achieved with 0.6 mg/kg of rocuronium at time 0. Sugammadex at 4 mg/kg reversed neuromuscular blockade at 5 minutes. Anesthesia was maintained with a propofol infusion. Individual data points are represented with open circles. Bold lines are the mean of the variables. The shaded areas were included in the mixed-effect analysis, with times 0 to 3 and 5 to 8 excluded from the analysis. P values were calculated by comparing neuromuscular states (baseline, paralyzed, and reversed). *Statistical significance.
Citation: American Journal of Veterinary Research 84, 7; 10.2460/ajvr.23.03.0050
The baseline TOFR was 0.97 ± 0.08, and a complete neuromuscular blockade was confirmed with TOFR = 0 in all dogs 45.0 ± 13.4 seconds after rocuronium (P < .001). Sugammadex successfully reversed NMB in 5 out of 6 dogs (TOFR = 0.96 ± 0.09; P = .721) (Figure 2). The neuromuscular function recovery time was 54.0 ± 13.4 seconds. One dog reached a TOFR of 0.70 at 60 seconds and peaked and plateaued at a TOFR of 0.80 from 210 to 300 seconds from sugammadex administration. In this animal, the TOFR was above 0.9 immediately after the sensor was readjusted after the data collection time window. No effect of time (P = .587) or interaction of time with neuromuscular conditions (P = .448) was observed.
All dogs recovered uneventfully from anesthesia and were returned to the housing facility. Additional data were collected for the surgical study8 for 1 week. The animals were transferred to another research protocol, following the proper approval of the IACUC.
Discussion
Our results demonstrated that PSI values remained steady in dogs anesthetized with propofol during neuromuscular blockade with rocuronium and after neuromuscular blockade reversal with sugammadex. To the authors’ knowledge, this is the first study that evaluated the effects of rocuronium and sugammadex on PSI in dogs anesthetized with a propofol infusion.
During the data collection, 2 dogs presented body temperatures below 35 °C (95 °F). The guidelines for neuromuscular blockade research recommend maintaining the temperature above 35 °C and normoventilation10 to obtain consistent data. Hypothermia11 and hypoventilation12 prolong the duration of the neuromuscular blockade. One dog did not reach TOFR > 0.9 and had a rectal temperature between 34.9 to 35.2 °C (94.8 to 95.3 °F) between baseline and reversal. Ventilation was controlled with intermittent mechanical ventilation and Petco2 was within normal limits and should not have potentiated the neuromuscular blockade.
The ePC of 3.7 µg/mL in this study was similar to the target used for induction of general anesthesia13 and within the range reported for surgical anesthesia in dogs.14 The rate of infusion of 13.9 mg/kg/h during the data collection window is near the minimum propofol infusion rate to prevent the movement of dogs that received 10 µg/kg, IV, fentanyl, followed by 12 µg/kg/h.15
Adequate anesthetic depth with absent palpebral reflexes, light jaw tone, ventromedial rotation of the eye globes, and stable heart rate and blood pressure were observed during the surgery with the PSI between 25 and 50. Murillo et al16 reported a mean PSI of 19.7 when propofol anesthesia was maintained at 2.4 mg/kg/min for 15 minutes in dogs that were not sedated. The authors16 reported that the animals did not have auditory responses to clicker noise, lack of palpebral reflex, and relaxed jaw tone. In our study, the propofol dosage was 10-fold lower with similar clinical signs observed by Murillo et al.16 However, the dogs in this experiment were sedated with acepromazine and hydromorphone, and the PSI was maintained at around 40. Based on our observations, a PSI < 50 suggests appropriate anesthetic depth for surgery during propofol-based anesthesia. The reliability of PSI for predicting anesthetic depth with propofol has been noted in the human literature.1,17
Rocuronium is a nondepolarizing neuromuscular blocker with a short onset.18 As rocuronium has an aminosteroidal structure, its NMB effects can be reversed with sugammadex. The rocuronium onset time was less than 1 minute in this study, similar to what was reported previously.18–20 Sugammadex is a cyclodextrin molecule that encapsulates rocuronium rendering it inactive rapidly. Therefore, a major advantage of sugammadex over conventional reversal with acetylcholinesterase inhibitors is the capacity to reverse deep neuromuscular blockade in under 2 minutes.21,22 The sugammadex dose in this experiment was half of what was previously reported by Mosing et al.20 A dose of 8 mg/kg reversed 0.6 mg/kg of rocuronium within 2 minutes in anesthetized dogs.20 It was possible to fully reverse the neuromuscular blockade of 0.6 mg/kg rocuronium with 4 mg/kg of sugammadex in 5 of 6 animals in less than 1 minute. Whether the partial paralysis was truly existent or a technical error occurred is unknown. Unfortunately, a second dose of sugammadex was not administered to confirm the partial reversal. It has been reported that 4 mg/kg sugammadex successfully reversed the neuromuscular blockade in a dog refractory to reversal with neostigmine.21
Based on the human literature, there is no evidence of rocuronium or sugammadex being affected by propofol.23,24 Opioids and acepromazine can have an effect on EEG readings,25,26 but their effects on the PSI in dogs were not evaluated.
The absence of PSI changes during the neuromuscular blockade of Beagles reported here is consistent with a recent human study.27 Kim et al27 found that neither PSI nor the bispectral (BIS) indexes changed significantly during steady-state propofol anesthesia when paralyzed with rocuronium and reversed with sugammadex. However, opposing reports show that nondepolarizing neuromuscular blocking agents and neuromuscular blockade reversal drugs affect BIS. The BIS index declined in awake volunteers when paralyzed.7,28 The inconsistency in the findings can be attributed to the different algorithms used to calculate BIS and PSI indexes and testing the EEG-based monitors in awake instead of anesthetized humans. The PSI is more accurate in detecting intraoperative awareness than BIS based on receiver operating characteristic analysis.1 To date, this is the only study in the veterinary literature, to the authors’ knowledge, that has evaluated the effects of NMBAs on PSI in dogs.
There are limitations in our study to note. The dogs in this study were not exposed to surgical stimulation under general anesthesia that could alter PSI values. In addition, our study population was homogenous. Breed, age, and health status were similar for all dogs. The sensitivity to neuromuscular blocking agents, pharmacokinetic and pharmacodynamics of relaxants, and neuromuscular block reversal agents are age dependent.29–31 Furthermore, we only evaluated changes to PSI for 12 minutes, and it is possible that changes to PSI could have been observed if the dogs had been anesthetized for a longer period of time with varying levels of surgical stimulation and anesthetic depth. However, this time interval for testing is consistent with previous literature.27 The dogs in this study received sildenafil for the surgical procedure research and phosphodiesterase type 5 inhibitor drugs can produce EEG slowing of delta and theta frequencies.32 Therefore, this could have affected our results. Finally, we did not study the effects of rocuronium and sugammadex on PSI in awake dogs due to ethical concerns.
In conclusion, PSI is unaffected in dogs given rocuronium or sugammadex during total intravenous propofol anesthesia. PSI can be considered a valuable tool for evaluating anesthetic depth in dogs with or without neuromuscular blockade during total propofol intravenous anesthesia.
Acknowledgments
The authors declare that there were no conflicts of interest.
Dr. Martin-Flores is a member of the Journal of the American Veterinary Medical Association (JAVMA) scientific review board. He declares that he had no role in the editorial direction of this manuscript.
This study was supported by the Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia.
The authors thank A. Bullington, MS, C. Caster, and L. Moss for their technical support and logistics throughout all aspects of this study.
Current address of H. N. Trenholme: Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL.
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