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    Mean ± SD plasma concentration of ketamine in 12 healthy Dorset-crossbred adult sheep anesthetized and maintained with sevoflurane at the minimum alveolar concentration that blunts adrenergic responses (MACBAR). Each animal underwent 2 separate anesthetic events (MACBAR and noninvasive cardiac output [NICO]) and received either a bolus of ketamine at 1.5 mg/kg IV followed by a constant rate infusion of 1.5 mg/kg/h IV or an equal volume of sterile saline as a placebo. No difference was found in the ketamine plasma concentration between the 2 anesthetic events (P = 0.663)

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The effect of a ketamine constant rate infusion on cardiovascular variables in sheep anesthetized at the minimum alveolar concentration of sevoflurane that blunts adrenergic responses

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  • 1 Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA
  • | 2 Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA
  • | 3 Department of Molecular and Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

Abstract

OBJECTIVE

To evaluate the effect of a constant rate infusion of ketamine on cardiac index (CI) in sheep, as estimated using noninvasive cardiac output (NICO) monitoring by partial carbon dioxide rebreathing, when anesthetized with sevoflurane at the previously determined minimum alveolar concentration that blunts adrenergic responses (MACBAR).

ANIMALS

12 healthy Dorset-crossbred adult sheep.

PROCEDURES

Sheep were anesthetized 2 times in a balanced placebo-controlled crossover design. Anesthesia was induced with sevoflurane delivered via a tight-fitting face mask and maintained at MACBAR. Following induction, sheep received either ketamine (1.5 mg/kg IV, followed by a constant rate infusion of 1.5 mg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (placebo). After an 8-day washout period, each sheep received the alternate treatment. NICO measurements were performed in triplicate 20 minutes after treatment administration and were converted to CI. Blood samples were collected prior to the start of NICO measurements for analysis of ketamine plasma concentrations. The paired t test was used to compare CI values between groups and the ketamine plasma concentrations with those achieved during the previous study.

RESULTS

Mean ± SD CI of the ketamine and placebo treatments were 2.69 ± 0.65 and 2.57 ± 0.53 L/min/m2, respectively. No significant difference was found between the 2 treatments. Mean ketamine plasma concentration achieved prior to the NICO measurement was 1.37 ± 0.58 µg/mL, with no significant difference observed between the current and prior study.

CLINICAL RELEVANCE

Ketamine, at the dose administered, did not significantly increase the CI in sheep when determined by partial carbon dioxide rebreathing.

Abstract

OBJECTIVE

To evaluate the effect of a constant rate infusion of ketamine on cardiac index (CI) in sheep, as estimated using noninvasive cardiac output (NICO) monitoring by partial carbon dioxide rebreathing, when anesthetized with sevoflurane at the previously determined minimum alveolar concentration that blunts adrenergic responses (MACBAR).

ANIMALS

12 healthy Dorset-crossbred adult sheep.

PROCEDURES

Sheep were anesthetized 2 times in a balanced placebo-controlled crossover design. Anesthesia was induced with sevoflurane delivered via a tight-fitting face mask and maintained at MACBAR. Following induction, sheep received either ketamine (1.5 mg/kg IV, followed by a constant rate infusion of 1.5 mg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (placebo). After an 8-day washout period, each sheep received the alternate treatment. NICO measurements were performed in triplicate 20 minutes after treatment administration and were converted to CI. Blood samples were collected prior to the start of NICO measurements for analysis of ketamine plasma concentrations. The paired t test was used to compare CI values between groups and the ketamine plasma concentrations with those achieved during the previous study.

RESULTS

Mean ± SD CI of the ketamine and placebo treatments were 2.69 ± 0.65 and 2.57 ± 0.53 L/min/m2, respectively. No significant difference was found between the 2 treatments. Mean ketamine plasma concentration achieved prior to the NICO measurement was 1.37 ± 0.58 µg/mL, with no significant difference observed between the current and prior study.

CLINICAL RELEVANCE

Ketamine, at the dose administered, did not significantly increase the CI in sheep when determined by partial carbon dioxide rebreathing.

Introduction

Sheep are routinely anesthetized in clinical practice, and they are also frequently used in research settings as translational models for a variety of disease processes and surgical techniques. An adequate plane of general anesthesia with unconsciousness, analgesia, and immobility is essential prior to invasive procedures. This is commonly achieved using inhalational anesthetics, with isoflurane and sevoflurane as frequently used agents.1 The minimum alveolar concentration (MAC) is a measure of potency for inhalational anesthetics and is characterized by the concentration of anesthetic that prevents movement in response to a supramaximal noxious stimulus in 50% of a population.2 Additionally, hemodynamic stability should be maintained during anesthesia, with minimal sympathetic stimulation and activation of the neuroendocrine stress response. The MAC that blunts adrenergic responses (MACBAR) is defined as the minimum alveolar concentration of an anesthetic required to block an autonomic response to noxious stimulus in 50% of a population.3 MACBAR of sevoflurane has been shown to be higher than MAC in humans4,5 and dogs.6,7 The MAC and MACBAR for sevoflurane in sheep are 1.92% to 2.74%8,9 and 2.77%,10 respectively.

Ketamine is a dissociative anesthetic phencyclidine derivative that acts as a noncompetitive antagonist at N-methyl-d-aspartate receptors.11 Drugs within this class also exhibit activity at opioid, muscarinic, monoaminergic receptors, and voltage-gated calcium channels.12 Ketamine has been used as an adjunctive drug during inhalational anesthesia to provide analgesia, reduce MAC, and minimize dose-dependent cardiopulmonary depression of inhalational anesthetics in dogs,13,14,15 cats,16 goats,17 sheep,18 and horses.19 Ketamine has also been shown to reduce the MACBAR of sevoflurane in dogs6 and rats.20 Despite acting as a direct negative inotrope at the myocardium,21 systemic administration of ketamine leads to increases in heart rate, cardiac output (CO), and blood pressure secondary to central sympathetic stimulation and increased sympathetic tone.22,23,24 Improvements in CO secondary to ketamine use have been demonstrated in humans,25 rats,26 and dogs.23

Optimization of CO is a goal of perianesthetic management, as low CO has been associated with increased patient mortality.27 Conventional methods of CO monitoring are invasive, reliant on specialized equipment, or require advanced training, which has limited their clinical use in veterinary medicine. Noninvasive cardiac output monitoring methods, such as transesophageal Doppler echocardiography,28 partial carbon dioxide rebreathing,29 and thoracic bioimpedance,30 have been developed for use in human patients. Partial carbon dioxide rebreathing is minimally invasive, is resistant to electromagnetic interference, and is not reliant on user skill. It calculates CO by applying the indirect Fick principle to the elimination of carbon dioxide following intermittent periods of partial rebreathing.31 Cardiac output estimated using noninvasive cardiac output monitoring by partial carbon dioxide rebreathing (NICO) has been shown to be in agreement with COs obtained using conventional methods (lithium dilution and pulmonary arterial catheter thermodilution) in dogs,31,32 horses,33 and pigs.34 However, to the authors’ knowledge, the use of NICO has not been studied in sheep.

The objective of this study was to evaluate the effects of a constant rate infusion (CRI) of ketamine on cardiac index (CI) in sheep, as estimated using NICO, when anesthetized with sevoflurane at the previously determined MACBAR. We hypothesized that ketamine CRI may affect heart rate, mean arterial blood pressure (MAP), and CI in sheep anesthetized with sevoflurane and receiving ketamine, compared with those receiving the placebo.

Materials and Methods

Study design

A randomized, masked, balanced, placebo-controlled crossover design was used for this study. Each sheep was anesthetized twice for NICO determination while receiving either a ketamine CRI or an equivalent volume of 0.9% sodium chloride solution. The 2 treatments were administered following a minimum washout period of 8 days.

Animals

Twelve healthy Dorset-crossbred adult sheep (2 castrated males and 10 sexually intact females) between 1.5 and 6 years of age and weighing between 56 and 88 kg were enrolled in the study. This group of sheep was enrolled in a previous study10 in which the individual MACBAR of sevoflurane with and without IV administration of ketamine was determined in duplicate. These animals were also concurrently enrolled in a separate study. Data collection for the unrelated study was performed following collection of NICO data.

Subjects were determined to be healthy based on physical examination findings and blood work results, which included a complete blood count and a serum biochemical analysis. Sheep were housed in groups of 2 or 3 at an approved research facility at the University of Georgia and allowed to acclimate to the housing environment for a minimum of 7 days prior to the start of the study. Food and water were withheld for 24 and 18 hours before general anesthesia, respectively. The study was approved by the Institutional Animal Care and Use Committee at the University of Georgia.

Anesthetic protocol and instrumentation

Before induction of general anesthesia, 2 mL of 2% lidocaine (Lidocaine HCl; Hospira) was injected SC on the right site of the neck to facilitate the insertion of a jugular catheter. A 16-gauge, 83-mm (2.35-inch) catheter was placed in the jugular vein, secured with skin sutures, and used for administration of experimental treatments and a balanced electrolyte solution. General anesthesia was induced using sevoflurane (Sevoflo; Zoetis), with the vaporizer set at 8%, in 100% oxygen at 2 L/min delivered through a rebreathing system and a tight-fitting face mask. Orotracheal intubation was performed with a cuffed Murphy-type endotracheal tube to secure the airway, and the cuff was inflated until no leak was detected at a peak inspiratory pressure of 20 cm H2O. Anesthesia was maintained with sevoflurane in oxygen delivered through an adult, semiclosed circle system with an oxygen flow rate of 1 L/min. Animals were placed in lateral recumbency, and an orogastric tube was placed in the rumen to prevent tympany and evacuate residual ruminal content. Intermittent positive-pressure ventilation was performed using a mechanical ventilator (Hallowell EMC Model 2000; Hallowell Engineering & Manufacturing Corp) to maintain end-tidal partial pressure of carbon dioxide (PETCO2) levels between 35 and 45 mm Hg.

An additional 18-gauge, 32-mm (1.25-inch) IV catheter was inserted in the cephalic vein for blood sample collection for determination of plasma concentrations of ketamine. A 20-gauge, 32-mm (1.25-inch) catheter was placed in the medial intermediate branch of the rostral auricular artery for invasive monitoring of arterial blood pressure and blood gas analysis. The catheter was connected to a disposable pressure transducer using noncompliant tubing filled with heparinized saline. The transducer was positioned at the level of the heart using the manubrium as a reference point and was calibrated and zeroed according to the manufacturer's instructions. Heart rate, respiratory rate, invasive arterial blood pressure, hemoglobin oxygen saturation, body temperature, and a lead II ECG were continuously monitored using a multiparameter monitor (SurgiVet Advisor Vital Signs Monitor; Smiths Medical). An esophageal probe was used to measure body temperature, and normothermia was maintained using a forced-air warming device (Bair Hugger Warming Unit; Augustine Medical Inc) with an over-the-body blanket.

End-tidal partial pressure of carbon dioxide and concentration of sevoflurane were measured using a sidestream infrared gas analyzer (POET IQ 602; Criticare Systems Inc) at a sampling rate of 150 mL/min. The monitor was calibrated prior to each experiment with calibration gases (nitrous oxide 60%, oxygen 34%, carbon dioxide 5%, and sevoflurane 1%) and using a refractometer gas analyzer (Riken Optical Gas Indicator Model FI-21; Riken Keiki Co Ltd) as described elsewhere.35 In brief, the gas analyzer and the refractometer were connected simultaneously to the common gas outlet of the anesthesia machine. The infrared analyzer was calibrated against the refractometer at sevoflurane concentrations of 0, 2, 3, 4, and 6 vol%. During the entire anesthetic event, a balanced electrolyte solution (lactated Ringer solution) was administered IV to all sheep at a rate of 5 mL/kg/h.

Two sheep were euthanized with IV sodium pentobarbital at the end of the experiment for tissue collection as part of a separate study. The remainder of the sheep were positioned in sternal recumbency and allowed to recover from anesthesia. The endotracheal tube was removed once each sheep regained the swallowing reflex. All indwelling catheters were removed, and the sheep were returned to their stalls once they were able to ambulate.

Experimental protocol

After induction of general anesthesia, a bolus of either ketamine (VetaKet; Akorn Animal Health) at 1.5 mg/kg or an equivalent volume of 0.9% NaCl was administered IV over 30 seconds. A CRI of ketamine at 1.5 mg/kg/h or 0.9% NaCl was started immediately after the loading dose. The ketamine CRI was diluted with 0.9% NaCl to allow both treatments to be administered at a rate of 10 mL/h. The predetermined individual MACBAR values of sevoflurane with or without ketamine10 were achieved and maintained for at least 20 minutes prior to the NICO measurement.

An arterial blood sample was collected for blood gas analysis before each NICO determination, and the following parameters were entered into the monitor: arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen, hemoglobin concentration, and hematocrit. The NICO determinations were performed using a commercially available monitor (NICO; Novametrix Medical Systems Inc) assembled according to the manufacturer's guidelines. A combined carbon dioxide and volume sensor was connected between the endotracheal tube and anesthetic circuit, and a transmittance pulse oximeter probe was placed on the tongue. Cardiac output determinations were performed in 3-minute cycles, and each cycle consisted of the following 3 phases: 1) 60 seconds of normal controlled ventilation to establish baseline volume of carbon dioxide eliminated over time (VCO2), PaCO2, and PETCO2; 2) 50 seconds of rebreathing, during which VCO2 was reduced, PaCO2 and PETCO2 were increased, and mixed venous carbon dioxide remained unchanged; and 3) 70 seconds of stabilization without rebreathing when all values returned to baseline.

During the rebreathing phase, each sheep temporarily inhaled a reduced portion of the exhaled gases. Cardiac output was calculated using the differences in VCO2 and PETCO2 during the normal and rebreathing phases and applying them to the modified Fick equation:
CO=ΔVCO2/ΔCaCO2
where ΔVCO2 is the difference in carbon dioxide elimination and PETCO2 between the normal and rebreathing phases and ΔCaCO2 is the difference in arterial content of carbon dioxide between the normal and rebreathing phases. Cardiac output determinations were performed in triplicate for each sheep and reported as the mean. If the difference between any of the 3 values was greater than 10%, a fourth reading was obtained. Cardiac output results were converted to CI for statistical analysis using the following equation to calculate body surface area (A3D) from body weight (W)36:
A3D=0.1177W0.6122

Blood sample collection for drug analysis

Blood samples were collected from the jugular catheter before the induction of anesthesia for CBC, serum biochemical analysis, and plasma concentration analysis baseline values. The subsequent blood samples were collected from the cephalic catheter immediately prior to the NICO data collection. For each sample, 3 mL of blood was discarded, and 6 mL was collected in lithium heparin tubes (Whatman Mini-Uni Prep). The samples were immediately placed on ice and centrifuged at 1960 × g for 10 minutes within 15 minutes of collection. The plasma was separated, homogenized by pipetting, aliquoted in 1.5 mL cryovials, and stored at–80 °C. Plasma concentrations of ketamine were quantified with ultrahigh liquid chromatography and mass spectrometry using an assay as described in previous studies.10

Statistical analysis

A power analysis was conducted to determine the number of subjects needed to show an increase in MAP and heart rate of 10% in sheep receiving ketamine versus placebo with a power set at 0.8 and α at 0.05.

Heart rate, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), MAP, stroke index, CI, respiratory rate, PETCO2, hemoglobin oxygen saturation, VCO2, and ketamine plasma concentrations were assessed for normality by examination of a histogram, normal plot of the residuals, and the Shapiro-Wilk test. All variables met the assumption of normality except for respiratory rate and hemoglobin oxygen saturation. The paired t test and the Wilcoxon signed rank test were used to compare the parametric and nonparametric variables of the ketamine and placebo group, respectively.

A paired t test was used to compare ketamine plasma concentrations of the current study with those collected during the previous study,10 in which the sevoflurane MACBAR values with ketamine infusion were determined.

Parametric and nonparametric data were expressed as mean ± SD and median and interquartile range, respectively. All statistical analyses were carried out using a commercially available statistical software program (JMP Pro 15.0.0; SAS Institute Inc). Significance was set at P < 0.05.

Results

The power analysis showed that a minimum of 10 subjects was needed. However, to increase the power, 12 sheep were enrolled in this study. Induction of general anesthesia via face mask and orotracheal intubation were successfully completed in all subjects without complications. Ten of the 12 subjects recovered from both anesthetic events without complications, and the remaining 2 subjects were euthanized for tissue collection as part of an unrelated study.

Cardiac index of ketamine and placebo treatments was 2.69 ± 0.65 mL/m2/min and 2.57 ± 0.53 mL/m2/min, respectively, with no statistical significance noted between the 2 groups (P = 0.576). Heart rate, SAP, DAP, MAP, stroke index, PETCO2, and VCO2 were not significantly different between the 2 groups (Table 1).

Table 1

Mean ± SD for select hemodynamic and respiratory variables for 12 healthy adult Dorset-cross sheep that were anesthetized with sevoflurane at the minimum alveolar concentration that blunts adrenergic responses (MACBAR) alone and sevoflurane at MACBAR with a ketamine constant rate infusion.

VariableKetaminePlaceboP value
Cardiac output (L/min)4.33 ± 0.883.99 ± 0.740.315
Cardiac index (L/min/m2)2.69 ± 0.652.57 ± 0.530.576
Heart rate (beats/min)81 ± 1778 ± 150.563
Systolic arterial pressure (mm Hg)98 ± 1490 ± 110.050
Diastolic arterial pressure (mm Hg)70 ± 1465 ± 140.138
Mean arterial pressure (mm Hg)79 ± 1473 ± 130.098
PETCO2 (mm Hg)41 ± 638 ± 40.150
VCO2 (mL/min)128 ± 5126 ± 230.760

MACBAR of sevoflurane was individually predetermined in a previous study. Sheep either received ketamine at 1.5 mg/kg IV followed by a constant rate infusion of 1.5 mg/kg/h or an equal volume of sterile saline as a placebo. All sheep were anesthetized twice and received both treatments, with a minimum washout period of 8 days between treatments. Increases in cardiac output, cardiac index, heart rate, systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, and stroke index were noted for the ketamine group, but these differences were not significant.

PETCO2 = End-tidal partial pressure of carbon dioxide. VCO2 = Volume of carbon dioxide eliminated over time.

Ketamine plasma concentration achieved prior to the NICO measurement was 1.37 ± 0.58 µg/mL, and no difference was found between the current study and the previous report10 (P = 0.663; Figure 1).

Figure 1
Figure 1

Mean ± SD plasma concentration of ketamine in 12 healthy Dorset-crossbred adult sheep anesthetized and maintained with sevoflurane at the minimum alveolar concentration that blunts adrenergic responses (MACBAR). Each animal underwent 2 separate anesthetic events (MACBAR and noninvasive cardiac output [NICO]) and received either a bolus of ketamine at 1.5 mg/kg IV followed by a constant rate infusion of 1.5 mg/kg/h IV or an equal volume of sterile saline as a placebo. No difference was found in the ketamine plasma concentration between the 2 anesthetic events (P = 0.663)

Citation: American Journal of Veterinary Research 83, 3; 10.2460/ajvr.21.08.0129

Discussion

In the present study, significant differences in CI, MAP, and heart rate were not achieved between sheep receiving ketamine versus a placebo while anesthetized at MACBAR of sevoflurane. The lack of improvements in MAP and CO has been attributed to CNS depression associated with anesthesia or sedation since many of the cardiovascular effects of ketamine are centrally mediated by the autonomic nerve sytem.23,24,37,38 These findings have been demonstrated in similar studies with other veterinary species. Dogs sedated with a combination of dexmedetomidine, buprenorphine, and ketamine did not show an increase in CO, compared with those receiving only dexmedetomidine and buprenorphine, despite an increase in heart rate.38 Awake goats receiving a single dose of 2 mg/kg of IV ketamine showed increases in MAP and CO up to 15 minutes following administration. However, the same goats anesthetized with pentobarbital prior to administration of the same dose of ketamine showed no change in MAP and CO.39 Similarly, dogs premedicated with dexmedetomidine prior to induction of anesthesia with ketamine showed no change in MAP and CO and a small increase in heart rate compared with those induced without premedication.24 Since the sheep in our study were maintained with sevoflurane at MACBAR, the sympathomimetic effects of ketamine were likely attenuated, resulting in a lack of significant improvement in MAP, heart rate, and CI.

Interestingly, no sheep in our study exhibited a reduction in cardiovascular function. Since the sheep were maintained at MACBAR of sevoflurane, it would be reasonable to expect the negative inotropic effects of ketamine to predominate due to the depression of sympathetic tone. This observation has been reported in similar studies. Goats that received a 4-mg/kg dose of IV ketamine following anesthetic induction with pentobarbital showed a consistent decrease in MAP and CO.39 In anesthetized humans, CO was significantly decreased up to 30 minutes following administration of 2 mg/kg of IV ketamine.37 The doses used in both studies were higher than those tested in the current study, suggesting that the cardiodepressant effects of ketamine are likely dose dependent.11,39

Ketamine plasma concentrations were measured in the current study to ensure that the concentrations achieved were similar to those of the previous study at the same MACBAR. Plasma concentrations associated with the cardiovascular effects of ketamine have not been studied in veterinary species. In humans, a plasma S-ketamine concentration of 0.4 µg/mL has been correlated with a 25% increase in CI.25 The mean racemic ketamine plasma concentrations achieved in the present study during the NICO data collection were 3 times greater, compared with those reported in the human literature. Despite this, no significant difference in the cardiovascular variables was found between treatment groups.

Routine use of CO monitoring has been challenging in clinical veterinary practice due to the invasive nature of traditional techniques. Implementation of new minimally invasive techniques, such as NICO, has been studied in veterinary patients. The NICO method was found to produce comparable estimates of CO when compared with pulmonary artery thermodilution and lithium dilution in humans,40 dogs,31,32 pigs,34 and foals.33 This method is also less dependent on operator skill compared with other minimally invasive techniques, such as transesophageal Doppler echocardiography. The use of the partial carbon dioxide rebreathing method has not been investigated or validated in sheep; however, given the good correlation with other techniques and ease of implementation, NICO was selected for the present study. The CI range previously reported in anesthetized sheep using the direct Fick method, which derives CO based on the patient's oxygen consumption,41 was 2.7 to 5.4 mL/min/m2.42 The CO ranges reported when using dye dilution, lithium dilution, and ultrasonic flowmetry of the pulmonary artery were 2.79 to 5.33 L/min, 3.8 to 9.6 L/min, and 4.0 to 9.2 L/min, respectively.44 The CI of the present study fell within the range of those obtained using the direct Fick method. Furthermore, the CO was within the ranges obtained using dye dilution; however, it was underestimated when compared with lithium dilution and electromagnetic flowmetry.

One of the major limitations of the present study was that neither thermodilution nor lithium dilution was determined for comparison with the NICO results. To account for this, each sheep served as its own control for comparison. The CO and CI values in our study were also compared with published values in sheep using either thermodilution or lithium dilution. Additionally, NICO estimations were performed during a discrete time period, and possible changes in CO occurring outside these readings would not have been detected.

Only a single ketamine loading dose followed by CRI was tested in this study. This dose was selected based on published data on ketamine administered to sheep10,45 and to reproduce the same experimental setting as the previous study. Ketamine plasma concentrations reported to increase CO45 were achieved but did not produce any changes in CI, heart rate, and MAP in our study. Higher doses may have produced significant results but could have led to suboptimal recoveries, with effects such as emergence delirium, myoclonus, and incoordination.11

Norketamine is an active metabolite of ketamine, with an estimated 10% to 30% activity of the original drug.46 Plasma concentrations of norketamine were not measured since they did not have a detectable effect on MACBAR in our previous study. Additionally, no difference in ketamine plasma concentrations was observed between the 2 studies; therefore, it is reasonable to assume that norketamine plasma concentrations were similar as well.

The power analysis for this study was performed based on heart rate and MAP rather than CO due to the lack of data in sheep. It is possible that this study was underpowered; however, 2 additional subjects were added to increase power. Despite this, no difference in any variables, including heart rate and MAP, was detected.

The results of the present study suggested that 1.5 mg/kg of ketamine IV followed by 1.5 mg/kg/h CRI is ineffective in increasing heart rate, MAP, and CI in sheep anesthetized at sevoflurane MACBAR. Given the slight increases observed in our study, future studies investigating the effects of higher doses on CI in sheep are warranted. Additional studies validating the use of NICO as a method of CO determination in sheep may also be beneficial.

Acknowledgments

The authors declare that there were no conflicts of interest.

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Contributor Notes

Corresponding author: Dr. Barletta (mbarlett@uga.edu)