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The cardiopulmonary effects of dexmedetomidine infusions in dogs during isoflurane anesthesia
Veterinary Anaesthesia and Analgesia, 2014
doi:10.1111/vaa.12220
RESEARCH PAPER
The cardiopulmonary effects of dexmedetomidine infusions in dogs during isoflurane anesthesia Peter J Pascoe Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
Correspondence: Peter J Pascoe, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. E-mail: [email protected]
Abstract Objective To determine the cardiopulmonary changes associated with intravenous (IV) infusions of dexmedetomidine at equipotent isofluranedexmedetomidine concentrations compared with isoflurane alone. Study design Prospective, randomized, crossover experiment. Animals Six adult intact female mixed-breed dogs weighing (mean SD [range]) 23.3 3.8 (17.8– 29.4) kg. Methods Anesthesia was induced and maintained with isoflurane in oxygen. Measurements of respiratory rate (fR), heart rate (HR), systemic and pulmonary arterial pressures (SAP, DAP, MAP, MPAP), central venous pressure (CVP), pulmonary arterial occlusion pressure (PAOP), cardiac index (CI), left and right ventricular stroke work index (LVSWI, RVSWI), systemic and pulmonary vascular resistance index (SVRI, PVRI), arteriovenous shunt _ Qt), _ _ 2 ), oxygen extraction (Qs= oxygen delivery (DO ratio (O2ER), oxygen consumption, arterial and mixed venous blood gases, and arterial packed cell volume (PCV) were obtained 30 minutes after instrumentation at an end-tidal isoflurane concentration (FE′Iso) of 1.73 0.02% (1.3 MAC). Dexmedetomidine was administered IV at 0.5 or 3 lg kg 1 over 6 minutes followed by an infusion at 0.5 (LD) or 3 lg kg 1 hour 1 (HD), respectively, with FE′Iso at 1.41 0.02 (LD) or 0.72 0.09%
(HD). Measurements were taken at 10, 30, 60, 90, 120, 150 and 180 minutes after the start of the infusion. Results The low dose produced significant decreases in HR, increases in SAP, DAP, CVP, MPAP, PAOP and LVSWI, but no change in CI. HD produced significant increases in SAP, MAP, DAP, CVP, PAOP, SVRI, LVSWI, O2ER and PCV and significant _ 2 . There were significant decreases in CI and DO differences between treatments in HR, MAP, DAP, _ 2 , O2ER CVP, MPAP, PAOP, CI, SVRI, HCO3 , SBE, DO _ Qt. _ and Qs= Conclusions and clinical relevance Cardiopulmonary changes associated with LD were within clinically accepted normal ranges whereas HD produced clinically significant changes. The LD may be useful as an anesthetic adjunct in healthy dogs. Keywords dexmedetomidine, infusion, isoflurane.
dogs,
intravenous
Introduction The halogenated inhalant anesthetics cause significant depression of cardiopulmonary function and so there has been an interest in finding anesthetic adjuncts that would allow the use of decreased concentrations of these drugs. In dogs, fentanyl, nitrous oxide, ketamine and lidocaine have all been shown to reduce the dose of inhalant needed to maintain the same plane of anesthesia with a 1
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
resulting improvement in cardiovascular function (Steffey et al. 1975; Ilkiw et al. 1994; Boscan et al. 2005; Ortega & Cruz 2011). These drugs have antinociceptive properties and may benefit the animal during surgical procedures by contributing to an overall blunting of nociceptive input (Macintyre et al. 2010). The alpha2-adrenergic agonists are also analgesics but have profound effects on the cardiovascular system at doses used commonly in veterinary practice (Pypendop & Verstegen 1998). Even at a dose of medetomidine at 1 lg kg 1 intravenously (IV) the cardiac index decreased to <50% of the baseline value (Pypendop & Verstegen 1998), when a dose in the range of 5–10 lg kg 1 is frequently used for premedication prior to general anesthesia. However, in human anesthesia the alpha2-adrenergic agonists are commonly used at low doses with minimal effect on cardiac output and reduced likelihood of mortality, tachycardia or myocardial ischemia has been reported (Talke et al. 1995; Wijeysundera et al. 2009; Kabukcu et al. 2011). The purpose of this study was to establish a dose of dexmedetomidine that would reduce the concentration of inhalation agent necessary to maintain anesthesia without severely decreasing cardiac output. When used as an IV infusion during anesthesia in dogs, medetomidine infusions have ranged from 0.2–12 lg kg 1 hour 1 (Kaartinen et al. 2010) and the cardiovascular effects reported have been dose related. Factors that may alter the cardiovascular response include prior administration of drug, loading dose and the rate at which it is administered, infusion rate and inhalant concentration. In Congdon et al. (2013), the dogs were premedicated with 10 lg kg 1 dexmedetomidine and the intraoperative infusions of dexmedetomidine had no further effect on the cardiovascular response. In Kaartinen et al. (2010), a low dose of medetomidine (0.2 lg kg 1 loading dose with a 0.2 lg kg 1 hour 1 infusion) had minimal effect on cardiovascular function, medetomidine (0.5 lg kg 1 hour 1) induced small, but statistically significant effects, and higher dose rates resulted in increasingly depressant effects. In the latter study, the isoflurane concentration was maintained at the same level throughout the infusion, which may have altered the hemodynamic response. The effect of dexmedetomidine on the minimum alveolar concentration (MAC) of isoflurane has been measured with infusion rates of 0.5, 1 and 3 lg kg 1 hour 1 that were documented to 2
decrease MAC by 5–31%, 18%, and 42–59%, respectively (Pascoe et al. 2006; Kulka et al. 2012; Ebner et al. 2013). The aim of this study was to determine the cardiopulmonary effects of IV infusions of dexmedetomidine (a loading dose of 0.5 or 3 lg kg 1 followed by infusions of 0.5 or 3 lg kg 1 hour 1, respectively) when administered with isoflurane at equipotent doses to 1.3 MAC. The hypothesis was that these two dose rates of dexmedetomidine administered at equipotent isoflurane concentrations would have no effect on cardiopulmonary function in dogs. Materials and methods This research was approved by the Institutional Animal Care and Use Committee. Six conditioned adult intact female dogs weighing 23.3 3.8 kg were acclimated to the housing facility for 3 weeks. The dogs were assessed as being healthy based on physical, hematological and biochemical examinations. The dogs were fasted for 12 hours and water was available until the dogs were brought to the laboratory for the study. The study was carried out by one investigator and was a randomized, crossover design such that dogs were assigned to one treatment using a web based random assignment (www. randomizer.org) and then received the other treatment after a 2 week washout period. A standard circle anesthetic system was used. The dogs were anesthetized with isoflurane using a mask to deliver 5% isoflurane in oxygen (5 L minute 1). Once anesthetized the dogs were endotracheally intubated and allowed to breathe spontaneously and the oxygen flow rate was decreased to 1 L minute 1. The dogs were placed in lateral recumbency. The endotracheal tube was equipped with a catheter whose tip was close to the distal end of the tube. This was used to draw end-tidal gas samples into a 6 mL glass syringe, by hand, for the measurement of endtidal isoflurane concentration (FE′Iso) using an infrared analyzer calibrated to 1/100th% (LB- 2 Medical Gas Analyzer; Beckman Instruments, CA, USA) as described previously (Steffey & Eger 1974; Steffey et al. 1994). In between these samples the catheter was connected to an analyzer (Raman gas spectroscopy, Rascal II; Ohmeda, UT, USA), which displayed the changes in carbon dioxide concentration with breathing as well as the concentrations of oxygen, nitrogen and isoflurane. This was used to monitor minute-to-minute changes but the only value recorded was respiratory rate (fR, breaths minute 1).
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia
Cardiopulmonary effects of dexmedetomidine PJ Pascoe Anesthesia was maintained with isoflurane alone to allow instrumentation. A 20 gauge catheter (4.8 cm, Insyte; Becton Dickinson, UT, USA) was placed percutaneously into a dorsal pedal artery. A 20 gauge catheter (4.8 cm Insyte; Becton Dickinson) was placed in a cephalic vein and this was used to deliver lactated Ringer’s solution (Hospira Inc., IL, USA) at 3 mL kg 1 hour 1 and the infusion of dexmedetomidine. Three pressure transducers (DTX plus; Becton Dickinson) were prepared and calibrated against a mercury manometer at pressures appropriate for the pressure they needed to measure (200, 50 and 20 mmHg for the systemic arterial, pulmonary arterial and central venous sites, respectively). A 7 Fr 110 cm Swan-Ganz catheter (Arrow balloon thermodilution set; Arrow International, NC, USA) was introduced through a jugular vein using an introducer (Introducer kit; Arrow International). The distal port of this catheter was connected to a pressure transducer and advanced into the pulmonary artery using the characteristic pressure changes associated with the right ventricle and pulmonary artery. A transducer was attached to the arterial catheter for measurement of systemic arterial systolic (SAP), mean (MAP), and diastolic (DAP) pressures. Transducers were connected to the distal and proximal ports of the Swan-Ganz catheter to allow measurement of mean pulmonary arterial pressure (MPAP) at the distal port, pulmonary arterial occlusion pressure (PAOP) at the distal port, and central venous pressure (CVP) at the proximal port. All pressure transducers were zeroed at the level of the manubrium. Pulmonary arterial occlusion pressures were taken after inflation of the distal balloon on the Swan-Ganz catheter at the end of expiration. The Swan-Ganz catheter was used to measure cardiac output (CO) by thermodilution (COM-1 cardiac output computer; Edwards Lifesciences, CA, USA). For this purpose 5 mL of dextrose (5%, 1–4 °C) was rapidly hand-injected into the proximal port of the Swan-Ganz catheter at end-expiration. At each measurement time, three consecutive measurements that were within 10% of each other were recorded and the average taken as the CO (L minute 1). Arterial and mixed venous (pulmonary arterial) blood samples were drawn anerobically and simultaneously for the measurement of pH and the partial pressures of oxygen (PO2) and carbon dioxide (PCO2), bicarbonate (HCO3 ) and standard base excess (SBE) (ABL505; Radiometer, Denmark), packed cell volume (PCV) total protein
(TP) and hemoglobin (Hba and Hbv) concentration (OSM-3, Co-oximeter; Radiometer). The thermistor on the Swan-Ganz catheter was used to measure core body temperature (T) which was maintained between 37.5 and 38.8 °C using warm water and warm air blankets. Each blood gas measurement was corrected to T. Previously published formulae and measured values were used for calculation of cardiac index (CI), systemic (SVRI) and pulmonary vascular resistance index (PVRI), oxygen delivery _ 2 ), oxygen consumption (VO _ 2 ), arteriovenous (DO _ _ shunt fraction (Qs=Qt), oxygen extraction ratio (O2ER) (Haskins et al. 2005) and left and right stroke work index (LVSWI, RVSWI) (Schramm 2010). After the dogs were instrumented the FE′Iso was adjusted to 1.73 0.02% (1.3 9 MAC) (Steffey & Howland 1977) and the concentration maintained for 30 minutes. All cardiopulmonary measurements were recorded at this time and these values were used as the baseline. Dogs were randomly assigned to receive one of two dose rates of dexmedetomidine (Precedex; Hospira). The dexmedetomidine was diluted to either 0.5 or 3 lg mL 1 using sterile saline (0.9% NaCl, Hospira) and administered using an infusion pump (Medfusion 2010i; Medex Inc., GA, USA). For each treatment an IV loading dose of dexmedetomidine (1 mL kg 1) was administered over 6 minutes followed by an infusion at 1 mL kg 1 hour 1 for 180 minutes. The low dose (LD) dexmedetomidine treatment was 0.5 lg kg 1 loading dose and 0.5 lg kg 1 hour 1 infusion and high dose (HD) was 3 lg kg 1 loading dose and 3 lg kg 1 hour 1 infusion. The FE′Iso was decreased to 1.41 0.02% and 0.72 0.09% for the LD and HD, respectively, based on previous work with these infusions, in order to maintain isofluranedexmedetomidine administration equipotent between treatments and to 1.3 MAC isoflurane administered alone (Pascoe et al. 2006). All the cardiopulmonary measurements were repeated at 10, 30, 60, 90, 120, 150 and 180 minutes after the beginning of the infusion. The values measured during the infusion were compared with the baseline values using a Friedman test for each dose (Prism; Graphpad, CA, USA). A Wilcoxon signed rank test was used to test the difference between doses (JMP 11 Pro; SAS Institute, NC, USA). The data were visually inspected for a relationship between change in CI and change in other variables. A correlation coefficient was calculated for the relationship between HR and CI.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia
3
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
Results There were no significant differences between variables at baseline between the two treatments with the exception of the PVRI, which was lower for the HD dogs (Tables 1 & 2). There were significant decreases in HR, and increases in SAP, MAP, DAP, CVP and MPAP at some time points with the LD (Table 1, Fig. 1). During the HD there were significant increases in all three systemic arterial pressures, CVP, MPAP, PAOP, SVRI and PCV while HR, _ 2 decreased (Table 2, Figs 2 & 3). CI and DO _ 2, There were significant decreases in HR, CI, DO _ _ O2ER and Qs=Qt at all time points during the dexmedetomidine infusions with HD compared with LD. The HCO3 and SBE were decreased at all time points except T60 in HD compared with LD. The following variables were significantly increased at all time points during the infusion in HD compared with LD: SAP, MAP, DAP, CVP, and PAOP. The SVRI was higher at all times in HD compared with LD except for 120 minutes and the PVRI was only increased at 180 minutes (p = 0.031). The plot of % change in HR versus % change in CI (Fig. 4) revealed a good correlation with a coefficient (R2) of 0.8447. Discussion The effect of many of the traditional anesthetics in dogs is a negative inotropy combined with some peripheral vasodilation. These lead to decreased perfusion pressures and oxygen delivery to the tissues. In a healthy animal such decreases are usually well tolerated because of the physiological reserve but in the sick or compromised patient such depression may lead to significant morbidity or even mortality. Studies examining the mortality rate of increasingly sick patients (increasing American Society of Anesthesiologists [ASA] status) have reported worse outcomes in ASA 3–5 compared to ASA 1–2 dogs (Clarke & Hall 1990; Brodbelt et al. 2008). Hence it is a common research endeavor to find techniques that provide a promise of decreased cardiovascular compromise while also aiming to decrease patient stress and pain, which may also contribute to this increased mortality. The results of this study demonstrated that a low infusion rate of dexmedetomidine (0.5 lg kg 1 hour 1), when administered at the previously documented MAC reduction of isoflurane (Pascoe et al. 2006), had minimal effect on cardiopulmo4
nary function. Another study that investigated a slightly higher infusion rate of dexmedetomidine during isoflurane anesthesia (dexmedetomidine loading dose of 25 lg m 2 with an infusion at 25 lg m 2 hour 1, which is equivalent to about 1.2 lg kg 1 hour 1 for the size of dogs used in the current experiment) measured approximately 30% decrease in CO with increased MAP and SVR (Lin et al. 2008). The FE′Iso used in that study was higher, estimated to be equivalent to 1.5 9 MAC, than that used for the LD in the current experiment. These data suggest that the major changes in cardiovascular effects occur between 0.5 and 1.2 lg kg 1 hour 1. The expectation that a reduction in isoflurane concentration in combination with the dexmedetomidine infusion would lead to increased CO was not realized. This is in contrast to reported benefits of fentanyl or ketamine infusions as adjunct agents to inhalation anesthesia. Infusion of fentanyl produced a 65% reduction in the MAC of enflurane in one study in dogs (Murphy & Hug 1982), and when fentanyl infusion and enflurane were administered at doses equipotent to 1.3 MAC, the CI was increased by almost 100% when compared with enflurane anesthesia alone (Ilkiw et al. 1994). Infusion of ketamine resulted in a similar reduction in the MAC of isoflurane at plasma concentrations of about 3 lg mL 1, and when administered at an equipotent dose to isoflurane alone, resulted in a 67% increase in CI (Boscan et al. 2005). Fentanyl is the only one of these three drugs to reduce oxygen consumption while increasing oxygen delivery (Ilkiw et al. 1994; Boscan et al. 2005) which may be a significant advantage in a compromised patient where oxygen delivery is already reduced. A disadvantage to infusion of opioids such as fentanyl is that they induce significant respiratory depression, which was not evident with the dexmedetomidine in this experiment. The cardiopulmonary effects reported in this experiment are typical of those seen in many studies examining the effects of alpha2-agonists. The initial dose of dexmedetomidine causes a vasoconstriction in both the pulmonary and systemic circulations that then elicits a decrease in HR and CO, with a slight depressive effect on ventilation (Honkavaara et al. 2011). That the initial cardiovascular changes are mainly due to peripheral rather than central actions of the drug is supported by evidence gained from the use of a peripherally acting alpha2antagonist (Honkavaara et al. 2011). In this and
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia 11.7 (7.3–14.8) 1.4 (0.6–1.5) 546 (418–660) 84 (66–100) 0.15 (0.12–0.23) 12 (6–15)
8.0 (6.3–11.8) 1.0 (0.7–1.6) 559 (476–710) 91 (74–105) 0.15 (0.13–0.20) 11 (7–16)
11.0 (7.1–16.8) 1.3 (0.6–1.7) 632 (422–677) 93 (53–131) 0.17 (0.08–0.24) 11 (4–17)
1.42 0.01 10 (6–17) 98 (54–108) 118 (95–170) 67 (56–74) 5 (2–8) 12 (12–16) 7 (4–10)* 38.1 (37.9–38.2) 39 (35–45) 4.9 (4.6–5.6) 7.34 (7.27–7.38) 46 (39–54) 6.1 (5.2–7.2) 537 (484–603) 71.6 (64.5–80.4) 24 (22–28) 2 ( 2 to +2) 13.7 (12.5–15.1) 166 (91–176)
30
11.2 (7.7–15) 1.3 (0.6–2.0) 568 (416–758) 104 (81–198) 0.18 (0.17–0.27) 10 (5–12)
1.42 0.02 10 (6–16) 100 (52–112) 117 (105–162) 67 (59–71)* 5 (2–7)* 13 (12–16) 7 (4–11)* 38.1 (37.8–38.3) 38 (35–42) 4.8 (4.6–5.6) 7.34 (7.28–7.38) 44 (37–55) 5.9 (4.9–7.3) 544 (489–567) 72.5 (65.2–75.6) 24 (21–28) 3 ( 3 to +2) 14.1 (12.9–15.0) 169 (91–194)
60
10.1 (8.2–16.6) 1.2 (0.7–2.1) 533 (431–839) 83 (68–108) 0.14 (0.12–0.23) 11 (7–15)
1.42 0.01 12 (7–14) 100 (48–116) 124 (105–162) 67 (58–83) 5 (2–8) 13 (11–17)* 7 (3–10) 38.1 (38.0–38.3) 38 (35–42) 4.8 (4.5–5.7) 7.36 (7.28–7.39) 43 (40–55) 5.7 (5.3–7.3) 550 (477–601) 73.3 (63.6–80.1) 24 (22–27) 2 ( 3 to +2) 13.7 (12.7–14.9) 185 (108–207)
90
11.1 (8–18.7)* 1.3 (0.9–2.1) 601 (459–817) 97 (87–114) 0.16 (0.13–0.21) 11 (5–17)
1.41 0.01 10 (6–16) 96 (52–104)* 124 (105–168)* 67 (60–72)* 6 (1–8) * 13 (11–17)* 7 (3–11) 38.1 (38.0–38.2) 38 (35–42) 4.8 (4.6–5.5) 7.34 (7.29–7.40) 44 (36–54) 5.9 (4.8–7.2) 536 (486–598) 71.5 (64.8–79.7) 24 (21–27) 2 ( 3 to +2) 14.3 (12.8–15) 176 (91–187)
120
11.9 (7.8–15.8)* 1.0 (0.7–2.1) 557 (440–836) 88 (57–118) 0.14 (0.11–0.21) 11 (4–17)
1.42 0.01 11 (5–15) 100 (48–104)* 124 (105–168)* 67 (59–70)* 6 (2–8) 12 (11–17)* 7 (4–10) 38.2 (38.0–38.4) 39 (34–43) 4.8 (4.5–5.5) 7.35 (7.28–7.40) 44 (35–56) 5.9 (4.7–7.5) 524 (498–615) 69.9 (66.4–82.0) 24 (20–28) 2 ( 3 to +2) 14.2 (12.5–15.6) 173 (61–196)
150
12.2 (7–18.1)* 1.0 (0.8–2.2) 521 (443–837) 99 (81–113) 0.17 (0.12–0.22) 9 (4–17)
1.41 0.02 9 (5–14) 100 (40–100)* 125 (102–166)* 67 (59–70) 6 (2–8)* 13 (11–17) 7 (4–10)* 38.3 (37.9–38.4) 39 (34–42) 4.8 (4.5–5.2)* 7.36 (7.27–7.39) 43 (36–57) 5.7 (4.8–7.6) 532 (503–617) 70.9 (67.1–82.3) 24 (21–27) 1 ( 3 to +2) 14.4 (12.5–15.3) 158 (22–198)
180
fR, respiratory rate; HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; CVP, central venous pressure; MPAP, mean pulmonary arterial pressure; PAOP, pulmonary arterial occlusion pressure; T, core body temperature; PCV, packed cell volume; TP, total protein; pHa, arterial pH; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; SBE, _ 2, standard base excess; Hba, arterial concentration of hemoglobin; PVRI, pulmonary vascular resistance index; LVSWI, left ventricular stroke work index; RVSWI, right ventricular stroke work index; DO _ Qt, _ arteriovenous shunt. *Significant difference from baseline (p ≤ 0.05). _ 2 , oxygen consumption; Qs= oxygen delivery; O2ER, oxygen extraction ratio; VO
1.39 0.02 11 (7–20) 94 (56–108)* 127 (95–170)* 67 (56–74)* 6 (3–8)* 14 (12–16)* 7 (5–12)* 38.2 (37.9–38.3) 36 (35–38) 4.9 (4.3–5.7) 7.34 (7.28–7.37) 45 (36–53) 6.0 (4.8–7.1) 546 (424–616) 72.8 (55.5–82.1) 24 (20–28) 2 ( 4 to +3) 14.1 (12.5–14.5) 187 (129–228)
1.73 0.02 12 (7–16) 114 (100–124) 102 (96–157) 56 (51–70) 3 (1–5) 11 (11–15) 5 (3–7) 38.1 (38.0–38.4) 36 (35–38) 4.9 (4.5–6.0) 7.33 (7.29–7.39) 49 (39–58) 6.5 (5.2–7.7) 560 (417–583) 74.7 (55.6–77.7) 24 (22–29) 2 ( 3 to +4) 13.3 (12.8–14.1) 176 (110–207)
FE′Iso % fR (breaths minute 1) HR (beats minute 1) SAP (mmHg) DAP (mmHg) CVP (mmHg) MPAP (mmHg) PAOP (mmHg) T (°C) PCV (%) TP (g dL 1) pHa PaCO2 (mmHg) PaCO2 (kPa) PaO2 (mmHg) PaO2 (kPa) HCO3 (mmol L 1) SBE (mmol L 1) Hba (g dL 1) PVRI (dynes seconds cm 5 m 2) LVSWI (mJ kg 1) RVSWI (mJ kg 1) _ 2 (mL minute 1 m 2) DO _ 2 (mL minute 1 m 2) VO O2ER _ Qt _ (%) Qs=
10
Baseline
Variable
Time (minutes)
Table 1 Cardiopulmonary variables (median and range) following a loading dose of 0.5 lg kg 1 dexmedetomidine, administered over 6 minutes, and an infusion of 0.5 lg kg 1 hour 1 in six spontaneously breathing dogs. The end-expired concentration of isoflurane (FE′Iso, mean SD) was decreased by 18% from baseline for the dexmedetomidine-isoflurane treatment to be equipotent to 1.3 MAC
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
5
6 12.8 0.8 345 93 0.29 6
1.73 0.03 9 (9–21) 110 (76–128) 112 (98–151) 62 (45–74) 3 (1–7) 11 (9–16) 6 (4–9) 38.4 (37.5–38.5) 36 (28–41) 5.0 (4.6–5.4) 7.32 (7.26–7.36) 46 (38–52) 6.1 (5.1–6.9) 541 (479–572) 72.1 (63.9–76.3) 23 (21–24) 3 ( 5 to 1) 13.5 (10.4–14.2) 116 (48–173)
8.9 (6.0–13.5) 1.0 (0.3–2.1) 559 (404–872) 86 (50–187) 0.14 (0.10–0.32) 13 (7–18)
FE′Iso (%) fR (breaths minute 1) HR (beats minute 1) SAP (mmHg) DAP (mmHg) CVP (mmHg) MPAP (mmHg) PAOP (mmHg) T (°C) PCV (%) TP (g dL 1) pHa PaCO2 (mmHg) PaCO2 (kPa) PaO2 (mmHg) PaO2 (kPa) HCO3 (mmol L 1) SBE (mmol L 1) Hba (g dL 1) PVRI (dynes seconds cm 5 m 2) LVSWI (mJ kg 1) RVSWI (mJ kg 1) _ 2 (mL minute 1) DO _ 2 (mL minute 1 m 2) VO O2ER _ Qt _ (%) Qs= 13.6 (9.0–23.7)* 0.9 (0.4–2.6) 334 (252–577)* 98 (68–126) 0.27 (0.22–0.33) 7 (4–9)
0.73 0.03 14 (11–18) 56 (28–64) 155 (125–198) 81 (70–104)* 10 (7–11) 15 (14–19) 11 (10–17)* 38.5 (37.8–38.8) 42 (35–46) 5.0 (4.7–5.3) 7.36 (7.29–7.38) 41 (37–44) 5.5 (4.9–5.9) 547 (498–599) 72.9 (66.4–79.9) 22 (20–22) 3 ( 5 to 3) 15.2 (12.4–17.0) 143 44
30
12.7 (9.5–20.7) 0.9 (0.3–1.9) 331 (278–510)* 101 (75–134) 0.29 (0.21–0.34)* 5 (3–7)*
0.69 0.01 16 (6–16) 54 (32–56) 162 (123–199) 80 (70–98) 10 (7–11) 15 (14–20) 12 (10–17) 38.3 (38.1–38.5) 42 (36–47) 5.0 (4.5–5.5) 7.35 (7.28–7.39) 42 (36–47) 5.6 (4.8–6.3) 571 (549–605) 76.1 (73.2–80.7) 23 (21–24) 3 ( 4 to 1) 15.8 (13.9–17.4) 176 (32–206)
60
13.2 0.9 328 94 0.27 5
(8.5–24.2) (0.5–3.0) (266–535)* (73–126) (0.23–0.31) (4–8)*
0.69 0.01 15 (7–18) 52 (28–56)* 161 (124–200) 81 (66–94) 10 (8–11)* 16 (14–20)* 12 (11–17)* 38.3 (38.0–38.4) 42 (36–48) 4.9 (4.7–5.5) 7.35 (7.27–7.38)* 41 (36–44) 5.5 (4.8–5.9) 562 (539–596) 74.9 (71.9–79.5) 22 (21–23) 3 ( 5 to 2) 15.7 (14.0–17.8) 171 (84–221)
90
14.2 1.0 365 99 0.28 5
(10.0–21.7)* (0.6–2.7) (285–552) (89–113) (0.20–0.32) (3–12)*
0.69 0.01 13 (10–16) 48 (28–56)* 164 (124–206)* 75 (67–98) 10 (7–11) 16 (14–20)* 12 (11–17)* 38.3 (38.1–38.6) 42 (36–49)* 5.1 (4.6–5.5) 7.36 (7.29–7.39)* 40 (35–45)* 5.3 (4.7–6.0) 554 (502–606) 73.9 (66.9–80.8) 22 (21–22) 3 ( 5 to 2) 15.7 (13.9–18.1) 176 (143–184)
120
14.6 (9.4–22.5)* 1.0 (0.5–2.0) 341 (287–523) 94 (85–127) 0.27 (0.22–0.32) 6 (4–10)
0.69 0.01 11 (6–16) 50 (24–52)* 158 (123–210)* 84 (75–99) 10 (7–11)* 16 (14–18)* 12 (11–16)* 38.3 (38.1–38.6) 43 (37–50)* 5.1 (4.7–5.3) 7.36 (7.31–7.39)* 39 (34–44)* 5.2 (4.5–5.9) 551 (519–595) 73.5 (69.2–79.3) 22 (20–22) 4 ( 5 to 3) 16.4 (14.4–18.4)* 171 (131–198)
150
15.5 1.0 335 95 0.28 5
(7.3–20.4) (0.4–2.2) (284–487)* (90–116) (0.21–0.33) (3–7)*
0.70 0.01 15 (7–17) 48 (32–52)* 166 (128–208)* 80 (71–98)* 10 (7–12)* 16 (14–19)* 12 (11–16) 38.3 (38.1–38.6) 43 (38–49)* 5.1 0.4 7.35 (7.30–7.38) 42 (39–44) 5.6 (5.2–5.9) 576 (505–623) 76.8 (67.3–83.1) 22 (21–22) 3 ( 4 to 2) 16.5 (15.0–18.3)* 199 (135–233)*
180
fR, respiratory rate; HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; CVP, central venous pressure; MPAP, mean pulmonary arterial pressure; PAOP, pulmonary arterial occlusion pressure; T, core body temperature; PCV, packed cell volume; TP, total protein; pHa, arterial pH; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; SBE, _ 2, standard base excess; Hba, arterial concentration of hemoglobin; PVRI, pulmonary vascular resistance index; LVSWI, left ventricular stroke work index; RVSWI right ventricular stroke work index; DO _ Qt, _ arteriovenous shunt. *Significant difference from baseline (p ≤ 0.05). _ 2 , oxygen consumption; Qs= oxygen delivery; O2ER, oxygen extraction ratio; VO
(9.0–18.5) (0.4–1.2) (262–568)* (75–147) (0.22–0.35)* (4–10)
0.80 0.26 14 (7–20) 60 (36–68) 156 (129–194)* 82 (75–105)* 11 (9–11)* 16 (9–19) 12 (9–19)* 38.5 (37.8–38.8) 39 (34–46) 5.0 (4.6–5.6) 7.32 (7.27–7.38) 43 (36–49) 5.7 (4.8–6.5) 536 (499–591) 71.5 (66.5–78.8) 22 (20–23) 3 ( 6 to 2) 14.4 (13.4–16.8) 140 86
Baseline
Variable
10
Time (minutes)
Table 2 Cardiopulmonary variables (median and range) following a loading dose of 3 lg kg 1 dexmedetomidine, administered over 6 minutes, and an infusion of 3 lg kg 1 hour 1 in six spontaneously breathing dogs. The end-expired concentration of isoflurane (FE′Iso, mean SD) was decreased by 59% for the dexmedetomidine-isoflurane treatment to be equipotent to 1.3 MAC
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
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Cardiopulmonary effects of dexmedetomidine PJ Pascoe
Figure 1 Median (line), interquartile range (box) and range (whiskers) of mean arterial pressures (mmHg) at baseline and at times indicated following an IV loading dose and infusion of dexmedetomidine at either 0.5 µg kg 1 over 6 minutes and 0.5 µg kg 1 hour 1 infusion (LD; white boxes) or 3 µg kg 1 over 6 minutes and 3 µg kg 1 hour 1 infusion (HD; speckled boxes) in six dogs. *Significant difference from baseline for that infusion rate (p ≤ 0.05).
Figure 2 Median (line), interquartile range (box) and range (whiskers) of systemic vascular resistance index (dynes seconds cm 5 m 2) at baseline and at times indicated following an IV loading dose and infusion of dexmedetomidine at either 0.5 µg kg 1 over 6 minutes and 0.5 µg kg 1 hour 1 infusion (LD; white boxes) or 3 µg kg 1 over 6 minutes and 3 µg kg 1 hour 1 infusion (HD; speckled boxes) in six dogs. *Significant difference from baseline for that infusion rate (p ≤ 0.05).
other studies the infusion of dexmedetomidine has been associated with an increased Hba and/or PCV (Lin et al. 2008). The reasons for this have not been elucidated but could be due to release of red cells from the spleen (alpha-agonist effect) or be due to a loss of circulating volume associated with the diuresis caused by the alpha2-agonist. In this study, and in others (Lin et al. 2008), the decrease in CI _ 2 despite contributed to a significant decrease in DO an increase in oxygen content of the blood.
Figure 3 Median (line), interquartile range (box) and range (whiskers) of cardiac index (L minute 1 m 2) at baseline and at times indicated following an IV loading dose and infusion of dexmedetomidine at either 0.5 µg kg 1 over 6 minutes and 0.5 µg kg 1 hour 1 infusion (LD; white boxes) or 3 µg kg 1 over 6 minutes and 3 µg kg 1 hour 1 infusion (HD; speckled boxes) in six dogs. *Significant difference from baseline for that infusion rate (p ≤ 0.05).
Figure 4 Plot of % change in heart rate (HR) versus % change in cardiac index (CI) using data from both treatments. The line represents the best line of fit for these data using a linear function as represented by the equation (Y=). The correlation coefficient is shown (R2).
Considerable individual variation in cardiovascular responses to the dexmedetomidine infusions was noted between dogs in this experiment. Average decreases in CI over the 180 minutes ranged from 1 to 17% with LD and 27–56% with HD treatments. This might suggest that the safest way to use these drugs would be to titrate the dose rate to a certain end point. Examining the data from this study, HR might be the best guide, such that any change in HR less than a 20% decrease from before the start of the infusion would be indicative of minor changes in CI (+7 to 6%). However, the range of data is limited as only two doses of dexmedetomidine were used. In a
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Cardiopulmonary effects of dexmedetomidine PJ Pascoe
study in cats a range of doses were used to determine dose-response curves for a number of cardiovascular variables (Pypendop et al. 2011). The dexmedetomidine concentration needed to decrease CI by 50% of the maximum effect (IC50) was 0.45 ng mL 1 and the IC50 for HR was 0.75 ng mL 1. Of the concentrations reported in that paper for a 50% of maximum change in clinically monitored cardiovascular variables CI and HR were closest, supporting the idea that a change in HR might be a good indication of a change in CI. Concentrations of dexmedetomidine, measured in dogs using the same protocol for the IV infusion, reported mean concentrations of about 0.19 and 1.9 ng mL 1 for the LD and HD, respectively (Pascoe et al. 2006). The loading dose in this experiment was administered over 6 minutes. This is a shorter time than in two other studies, where the loading dose was administered over 10 minutes (Kaartinen et al. 2010; Kulka et al. 2012) but may be longer than in some other studies where loading doses have been administered but the time taken to give them was not stated (Lin et al. 2008; Lamont et al. 2012). The elimination half-life (T1/2) for dexmedetomidine was reported to be 0.46 hours (Lin et al. 2008), therefore, steady state would be reached in 1.84– 2.3 hours (4–5 9 T1/2) if an infusion was started without a loading dose. Given the observed increase in diastolic pressure in this study during the loading dose, a longer duration, such as 10 minutes, might be less likely to cause immediate vasoconstriction. In Kaartinen et al. (2010), where the loading dose of medetomidine (1 lg kg 1) was administered over 10 minutes, there was a 12% decrease in mean HR and a 4% decrease in CI compared with 20 and 9%, respectively, in the present study at 10 minutes into the infusion. While these comparisons might suggest that the longer time for the loading dose had less effect, the MAP only increased by 13% in the present study whereas it increased by 19% in the Kaartinen et al. (2010) study. It is likely that there would be little clinical importance to the differences between these times used for the loading doses. The infusions were continued for 3 hours in this study to determine if there was any change with time in the variables measured. At both doses there were minimal changes with time. Other studies reporting infusions over 2 hours (Lin et al. 2008; Kaartinen et al. 2010) have found similar results and further changes in HR or fR were not reported when the infusion was continued for 24 hours (Lin et al. 2008). 8
Limitations of this experiment include the lack of blinding, the failure to calibrate the syringe pump, and the use of a relatively limited number of animals. Since all the measurements recorded were objective it is unlikely that a lack of blinding would have introduced bias into the experiment. The syringe pump was not calibrated prior to use but the amounts infused were consistent with the expected volumes and any inaccuracy with regard to the infusion would have been very minor. It is possible that some of the changes seen with both doses could have shown statistical significance if more dogs had been used in the experiment. Conclusion The LD appeared to have minimal overall effect on the cardiopulmonary values measured whereas the HD caused typical changes expected with an alpha2adrenergic agonist. This LD may be useful as an adjunct to anesthesia to allow a reduction in inhalant concentration with minimal change in cardiopulmonary function. Acknowledgements The funding for this work was provided by the Center for Companion Animal Health at the University of California, Davis, CA, USA. The author thanks Dr. Phil Kass for assistance with statistical analysis and Linda Tripp for technical assistance. References Boscan P, Pypendop BH, Solano AM et al. (2005) Cardiovascular and respiratory effects of ketamine infusions in isoflurane-anesthetized dogs before and during noxious stimulation. Am J Vet Res 66, 2122– 2129. Brodbelt DC, Blissitt KJ, Hammond RA et al. (2008) The risk of death: the confidential enquiry into perioperative small animal fatalities. Vet Anaesth Analg 35, 365–373. Clarke KW, Hall LW (1990) A survey of anaesthesia in small animal practice: AVA/BSAVA report. J Ass Vet Anaesth 17, 4–10. Congdon JM, Marquez M, Niyom S et al. (2013) Cardiovascular, respiratory, electrolyte and acid-base balance during continuous dexmedetomidine infusion in anesthetized dogs. Vet Anaesth Analg 40, 464–471. Ebner LS, Lerche P, Bednarski RM et al. (2013) Effect of dexmedetomidine, morphine-lidocaine-ketamine, and dexmedetomidine-morphine-lidocaine-ketamine constant rate infusions on the minimum alveolar
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Cardiopulmonary effects of dexmedetomidine PJ Pascoe concentration of isoflurane and bispectral index in dogs. Am J Vet Res 74, 963–970. Haskins S, Pascoe PJ, Ilkiw JE et al. (2005) Reference cardiopulmonary values in normal dogs. Comp Med 55, 156–161. Honkavaara JM, Restitutti F, Raekallio MR et al. (2011) The effects of increasing doses of MK-467, a peripheral alpha(2) -adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. J Vet Pharmacol Ther 34, 332–337. Ilkiw JE, Pascoe PJ, Haskins SC et al. (1994) The cardiovascular sparing effect of fentanyl and atropine administered to enflurane anesthetized dogs. Can J Vet Res 58, 248–253. Kaartinen J, Pang D, Moreau M et al. (2010) Hemodynamic effects of an intravenous infusion of medetomidine at six different dose regimens in isoflurane-anesthetized dogs. Vet Ther 11, E1–E16. Kabukcu HK, Sahin N, Temel Y et al. (2011) Hemodynamics in coronary artery bypass surgery: effects of intraoperative dexmedetomidine administration. Anaesthesist 60, 427–431. Kulka AM, Otto KA, Bergfeld C et al. (2012) Effects of isoflurane anesthesia with and without dexmedetomidine or remifentanil on quantitative electroencephalographic variables before and after nociceptive stimulation in dogs. Am J Vet Res 73, 602–609. Lamont LA, Burton SA, Caines D et al. (2012) Effects of 2 different infusion rates of medetomidine on sedation score, cardiopulmonary parameters, and serum levels of medetomidine in healthy dogs. Can J Vet Res 76, 308–316. Lin GY, Robben JH, Murrell JC et al. (2008) Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs. Vet Anaesth Analg 35, 141–153. Macintyre PE, Scott DA, Schug SA et al. (2010) APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. In: Acute Pain Management: Scientific Evidence. AaNZCoAaFoP (ed.). ANZCA & FPM, Melbourne. pp. 12–15.
Murphy MR, Hug CC Jr (1982) The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 57, 485–488. Ortega M, Cruz I (2011) Evaluation of a constant rate infusion of lidocaine for balanced anesthesia in dogs undergoing surgery. Can Vet J 52, 856–860. Pascoe PJ, Raekallio M, Kuusela E et al. (2006) Changes in the minimum alveolar concentration of isoflurane and some cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs. Vet Anaesth Analg 33, 97–103. Pypendop B, Verstegen J (1998) Hemodynamic effects of medetomidine in the dog: a dose titration study. Vet Surg 27, 612–622. Pypendop BH, Barter LS, Stanley SD et al. (2011) Hemodynamic effects of dexmedetomidine in isofluraneanesthetized cats. Vet Anaesth Analg 38, 555–567. Schramm W (2010) The units of measurement of the ventricular stroke work: a review study. J Clin Monit Comput 24, 213–217. Steffey EP, Eger EI 2nd (1974) Hyperthermia and halothane MAC in the dog. Anesthesiology 41, 392– 396. Steffey EP, Howland D Jr (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833–1836. Steffey EP, Gillespie JR, Berry JD et al. (1975) Circulatory effects of halothane and halothane-nitrous oxide anesthesia in the dog: spontaneous ventilation. Am J Vet Res 36, 197–200. Steffey EP, Baggot JD, Eisele JH et al. (1994) Morphineisoflurane interaction in dogs, swine and rhesus monkeys. J Vet Pharmacol Ther 17, 202–210. Talke P, Li J, Jain U et al. (1995) Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group. Anesthesiology 82, 620–633. Wijeysundera DN, Bender JS, Beattie WS (2009) Alpha-2 adrenergic agonists for the prevention of cardiac complications among patients undergoing surgery. Cochrane Database Syst Rev, CD004126. Received 21 November 2013; accepted 26 June 2014.
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doi:10.1111/vaa.12220
RESEARCH PAPER
The cardiopulmonary effects of dexmedetomidine infusions in dogs during isoflurane anesthesia Peter J Pascoe Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
Correspondence: Peter J Pascoe, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. E-mail: [email protected]
Abstract Objective To determine the cardiopulmonary changes associated with intravenous (IV) infusions of dexmedetomidine at equipotent isofluranedexmedetomidine concentrations compared with isoflurane alone. Study design Prospective, randomized, crossover experiment. Animals Six adult intact female mixed-breed dogs weighing (mean SD [range]) 23.3 3.8 (17.8– 29.4) kg. Methods Anesthesia was induced and maintained with isoflurane in oxygen. Measurements of respiratory rate (fR), heart rate (HR), systemic and pulmonary arterial pressures (SAP, DAP, MAP, MPAP), central venous pressure (CVP), pulmonary arterial occlusion pressure (PAOP), cardiac index (CI), left and right ventricular stroke work index (LVSWI, RVSWI), systemic and pulmonary vascular resistance index (SVRI, PVRI), arteriovenous shunt _ Qt), _ _ 2 ), oxygen extraction (Qs= oxygen delivery (DO ratio (O2ER), oxygen consumption, arterial and mixed venous blood gases, and arterial packed cell volume (PCV) were obtained 30 minutes after instrumentation at an end-tidal isoflurane concentration (FE′Iso) of 1.73 0.02% (1.3 MAC). Dexmedetomidine was administered IV at 0.5 or 3 lg kg 1 over 6 minutes followed by an infusion at 0.5 (LD) or 3 lg kg 1 hour 1 (HD), respectively, with FE′Iso at 1.41 0.02 (LD) or 0.72 0.09%
(HD). Measurements were taken at 10, 30, 60, 90, 120, 150 and 180 minutes after the start of the infusion. Results The low dose produced significant decreases in HR, increases in SAP, DAP, CVP, MPAP, PAOP and LVSWI, but no change in CI. HD produced significant increases in SAP, MAP, DAP, CVP, PAOP, SVRI, LVSWI, O2ER and PCV and significant _ 2 . There were significant decreases in CI and DO differences between treatments in HR, MAP, DAP, _ 2 , O2ER CVP, MPAP, PAOP, CI, SVRI, HCO3 , SBE, DO _ Qt. _ and Qs= Conclusions and clinical relevance Cardiopulmonary changes associated with LD were within clinically accepted normal ranges whereas HD produced clinically significant changes. The LD may be useful as an anesthetic adjunct in healthy dogs. Keywords dexmedetomidine, infusion, isoflurane.
dogs,
intravenous
Introduction The halogenated inhalant anesthetics cause significant depression of cardiopulmonary function and so there has been an interest in finding anesthetic adjuncts that would allow the use of decreased concentrations of these drugs. In dogs, fentanyl, nitrous oxide, ketamine and lidocaine have all been shown to reduce the dose of inhalant needed to maintain the same plane of anesthesia with a 1
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
resulting improvement in cardiovascular function (Steffey et al. 1975; Ilkiw et al. 1994; Boscan et al. 2005; Ortega & Cruz 2011). These drugs have antinociceptive properties and may benefit the animal during surgical procedures by contributing to an overall blunting of nociceptive input (Macintyre et al. 2010). The alpha2-adrenergic agonists are also analgesics but have profound effects on the cardiovascular system at doses used commonly in veterinary practice (Pypendop & Verstegen 1998). Even at a dose of medetomidine at 1 lg kg 1 intravenously (IV) the cardiac index decreased to <50% of the baseline value (Pypendop & Verstegen 1998), when a dose in the range of 5–10 lg kg 1 is frequently used for premedication prior to general anesthesia. However, in human anesthesia the alpha2-adrenergic agonists are commonly used at low doses with minimal effect on cardiac output and reduced likelihood of mortality, tachycardia or myocardial ischemia has been reported (Talke et al. 1995; Wijeysundera et al. 2009; Kabukcu et al. 2011). The purpose of this study was to establish a dose of dexmedetomidine that would reduce the concentration of inhalation agent necessary to maintain anesthesia without severely decreasing cardiac output. When used as an IV infusion during anesthesia in dogs, medetomidine infusions have ranged from 0.2–12 lg kg 1 hour 1 (Kaartinen et al. 2010) and the cardiovascular effects reported have been dose related. Factors that may alter the cardiovascular response include prior administration of drug, loading dose and the rate at which it is administered, infusion rate and inhalant concentration. In Congdon et al. (2013), the dogs were premedicated with 10 lg kg 1 dexmedetomidine and the intraoperative infusions of dexmedetomidine had no further effect on the cardiovascular response. In Kaartinen et al. (2010), a low dose of medetomidine (0.2 lg kg 1 loading dose with a 0.2 lg kg 1 hour 1 infusion) had minimal effect on cardiovascular function, medetomidine (0.5 lg kg 1 hour 1) induced small, but statistically significant effects, and higher dose rates resulted in increasingly depressant effects. In the latter study, the isoflurane concentration was maintained at the same level throughout the infusion, which may have altered the hemodynamic response. The effect of dexmedetomidine on the minimum alveolar concentration (MAC) of isoflurane has been measured with infusion rates of 0.5, 1 and 3 lg kg 1 hour 1 that were documented to 2
decrease MAC by 5–31%, 18%, and 42–59%, respectively (Pascoe et al. 2006; Kulka et al. 2012; Ebner et al. 2013). The aim of this study was to determine the cardiopulmonary effects of IV infusions of dexmedetomidine (a loading dose of 0.5 or 3 lg kg 1 followed by infusions of 0.5 or 3 lg kg 1 hour 1, respectively) when administered with isoflurane at equipotent doses to 1.3 MAC. The hypothesis was that these two dose rates of dexmedetomidine administered at equipotent isoflurane concentrations would have no effect on cardiopulmonary function in dogs. Materials and methods This research was approved by the Institutional Animal Care and Use Committee. Six conditioned adult intact female dogs weighing 23.3 3.8 kg were acclimated to the housing facility for 3 weeks. The dogs were assessed as being healthy based on physical, hematological and biochemical examinations. The dogs were fasted for 12 hours and water was available until the dogs were brought to the laboratory for the study. The study was carried out by one investigator and was a randomized, crossover design such that dogs were assigned to one treatment using a web based random assignment (www. randomizer.org) and then received the other treatment after a 2 week washout period. A standard circle anesthetic system was used. The dogs were anesthetized with isoflurane using a mask to deliver 5% isoflurane in oxygen (5 L minute 1). Once anesthetized the dogs were endotracheally intubated and allowed to breathe spontaneously and the oxygen flow rate was decreased to 1 L minute 1. The dogs were placed in lateral recumbency. The endotracheal tube was equipped with a catheter whose tip was close to the distal end of the tube. This was used to draw end-tidal gas samples into a 6 mL glass syringe, by hand, for the measurement of endtidal isoflurane concentration (FE′Iso) using an infrared analyzer calibrated to 1/100th% (LB- 2 Medical Gas Analyzer; Beckman Instruments, CA, USA) as described previously (Steffey & Eger 1974; Steffey et al. 1994). In between these samples the catheter was connected to an analyzer (Raman gas spectroscopy, Rascal II; Ohmeda, UT, USA), which displayed the changes in carbon dioxide concentration with breathing as well as the concentrations of oxygen, nitrogen and isoflurane. This was used to monitor minute-to-minute changes but the only value recorded was respiratory rate (fR, breaths minute 1).
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Cardiopulmonary effects of dexmedetomidine PJ Pascoe Anesthesia was maintained with isoflurane alone to allow instrumentation. A 20 gauge catheter (4.8 cm, Insyte; Becton Dickinson, UT, USA) was placed percutaneously into a dorsal pedal artery. A 20 gauge catheter (4.8 cm Insyte; Becton Dickinson) was placed in a cephalic vein and this was used to deliver lactated Ringer’s solution (Hospira Inc., IL, USA) at 3 mL kg 1 hour 1 and the infusion of dexmedetomidine. Three pressure transducers (DTX plus; Becton Dickinson) were prepared and calibrated against a mercury manometer at pressures appropriate for the pressure they needed to measure (200, 50 and 20 mmHg for the systemic arterial, pulmonary arterial and central venous sites, respectively). A 7 Fr 110 cm Swan-Ganz catheter (Arrow balloon thermodilution set; Arrow International, NC, USA) was introduced through a jugular vein using an introducer (Introducer kit; Arrow International). The distal port of this catheter was connected to a pressure transducer and advanced into the pulmonary artery using the characteristic pressure changes associated with the right ventricle and pulmonary artery. A transducer was attached to the arterial catheter for measurement of systemic arterial systolic (SAP), mean (MAP), and diastolic (DAP) pressures. Transducers were connected to the distal and proximal ports of the Swan-Ganz catheter to allow measurement of mean pulmonary arterial pressure (MPAP) at the distal port, pulmonary arterial occlusion pressure (PAOP) at the distal port, and central venous pressure (CVP) at the proximal port. All pressure transducers were zeroed at the level of the manubrium. Pulmonary arterial occlusion pressures were taken after inflation of the distal balloon on the Swan-Ganz catheter at the end of expiration. The Swan-Ganz catheter was used to measure cardiac output (CO) by thermodilution (COM-1 cardiac output computer; Edwards Lifesciences, CA, USA). For this purpose 5 mL of dextrose (5%, 1–4 °C) was rapidly hand-injected into the proximal port of the Swan-Ganz catheter at end-expiration. At each measurement time, three consecutive measurements that were within 10% of each other were recorded and the average taken as the CO (L minute 1). Arterial and mixed venous (pulmonary arterial) blood samples were drawn anerobically and simultaneously for the measurement of pH and the partial pressures of oxygen (PO2) and carbon dioxide (PCO2), bicarbonate (HCO3 ) and standard base excess (SBE) (ABL505; Radiometer, Denmark), packed cell volume (PCV) total protein
(TP) and hemoglobin (Hba and Hbv) concentration (OSM-3, Co-oximeter; Radiometer). The thermistor on the Swan-Ganz catheter was used to measure core body temperature (T) which was maintained between 37.5 and 38.8 °C using warm water and warm air blankets. Each blood gas measurement was corrected to T. Previously published formulae and measured values were used for calculation of cardiac index (CI), systemic (SVRI) and pulmonary vascular resistance index (PVRI), oxygen delivery _ 2 ), oxygen consumption (VO _ 2 ), arteriovenous (DO _ _ shunt fraction (Qs=Qt), oxygen extraction ratio (O2ER) (Haskins et al. 2005) and left and right stroke work index (LVSWI, RVSWI) (Schramm 2010). After the dogs were instrumented the FE′Iso was adjusted to 1.73 0.02% (1.3 9 MAC) (Steffey & Howland 1977) and the concentration maintained for 30 minutes. All cardiopulmonary measurements were recorded at this time and these values were used as the baseline. Dogs were randomly assigned to receive one of two dose rates of dexmedetomidine (Precedex; Hospira). The dexmedetomidine was diluted to either 0.5 or 3 lg mL 1 using sterile saline (0.9% NaCl, Hospira) and administered using an infusion pump (Medfusion 2010i; Medex Inc., GA, USA). For each treatment an IV loading dose of dexmedetomidine (1 mL kg 1) was administered over 6 minutes followed by an infusion at 1 mL kg 1 hour 1 for 180 minutes. The low dose (LD) dexmedetomidine treatment was 0.5 lg kg 1 loading dose and 0.5 lg kg 1 hour 1 infusion and high dose (HD) was 3 lg kg 1 loading dose and 3 lg kg 1 hour 1 infusion. The FE′Iso was decreased to 1.41 0.02% and 0.72 0.09% for the LD and HD, respectively, based on previous work with these infusions, in order to maintain isofluranedexmedetomidine administration equipotent between treatments and to 1.3 MAC isoflurane administered alone (Pascoe et al. 2006). All the cardiopulmonary measurements were repeated at 10, 30, 60, 90, 120, 150 and 180 minutes after the beginning of the infusion. The values measured during the infusion were compared with the baseline values using a Friedman test for each dose (Prism; Graphpad, CA, USA). A Wilcoxon signed rank test was used to test the difference between doses (JMP 11 Pro; SAS Institute, NC, USA). The data were visually inspected for a relationship between change in CI and change in other variables. A correlation coefficient was calculated for the relationship between HR and CI.
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Cardiopulmonary effects of dexmedetomidine PJ Pascoe
Results There were no significant differences between variables at baseline between the two treatments with the exception of the PVRI, which was lower for the HD dogs (Tables 1 & 2). There were significant decreases in HR, and increases in SAP, MAP, DAP, CVP and MPAP at some time points with the LD (Table 1, Fig. 1). During the HD there were significant increases in all three systemic arterial pressures, CVP, MPAP, PAOP, SVRI and PCV while HR, _ 2 decreased (Table 2, Figs 2 & 3). CI and DO _ 2, There were significant decreases in HR, CI, DO _ _ O2ER and Qs=Qt at all time points during the dexmedetomidine infusions with HD compared with LD. The HCO3 and SBE were decreased at all time points except T60 in HD compared with LD. The following variables were significantly increased at all time points during the infusion in HD compared with LD: SAP, MAP, DAP, CVP, and PAOP. The SVRI was higher at all times in HD compared with LD except for 120 minutes and the PVRI was only increased at 180 minutes (p = 0.031). The plot of % change in HR versus % change in CI (Fig. 4) revealed a good correlation with a coefficient (R2) of 0.8447. Discussion The effect of many of the traditional anesthetics in dogs is a negative inotropy combined with some peripheral vasodilation. These lead to decreased perfusion pressures and oxygen delivery to the tissues. In a healthy animal such decreases are usually well tolerated because of the physiological reserve but in the sick or compromised patient such depression may lead to significant morbidity or even mortality. Studies examining the mortality rate of increasingly sick patients (increasing American Society of Anesthesiologists [ASA] status) have reported worse outcomes in ASA 3–5 compared to ASA 1–2 dogs (Clarke & Hall 1990; Brodbelt et al. 2008). Hence it is a common research endeavor to find techniques that provide a promise of decreased cardiovascular compromise while also aiming to decrease patient stress and pain, which may also contribute to this increased mortality. The results of this study demonstrated that a low infusion rate of dexmedetomidine (0.5 lg kg 1 hour 1), when administered at the previously documented MAC reduction of isoflurane (Pascoe et al. 2006), had minimal effect on cardiopulmo4
nary function. Another study that investigated a slightly higher infusion rate of dexmedetomidine during isoflurane anesthesia (dexmedetomidine loading dose of 25 lg m 2 with an infusion at 25 lg m 2 hour 1, which is equivalent to about 1.2 lg kg 1 hour 1 for the size of dogs used in the current experiment) measured approximately 30% decrease in CO with increased MAP and SVR (Lin et al. 2008). The FE′Iso used in that study was higher, estimated to be equivalent to 1.5 9 MAC, than that used for the LD in the current experiment. These data suggest that the major changes in cardiovascular effects occur between 0.5 and 1.2 lg kg 1 hour 1. The expectation that a reduction in isoflurane concentration in combination with the dexmedetomidine infusion would lead to increased CO was not realized. This is in contrast to reported benefits of fentanyl or ketamine infusions as adjunct agents to inhalation anesthesia. Infusion of fentanyl produced a 65% reduction in the MAC of enflurane in one study in dogs (Murphy & Hug 1982), and when fentanyl infusion and enflurane were administered at doses equipotent to 1.3 MAC, the CI was increased by almost 100% when compared with enflurane anesthesia alone (Ilkiw et al. 1994). Infusion of ketamine resulted in a similar reduction in the MAC of isoflurane at plasma concentrations of about 3 lg mL 1, and when administered at an equipotent dose to isoflurane alone, resulted in a 67% increase in CI (Boscan et al. 2005). Fentanyl is the only one of these three drugs to reduce oxygen consumption while increasing oxygen delivery (Ilkiw et al. 1994; Boscan et al. 2005) which may be a significant advantage in a compromised patient where oxygen delivery is already reduced. A disadvantage to infusion of opioids such as fentanyl is that they induce significant respiratory depression, which was not evident with the dexmedetomidine in this experiment. The cardiopulmonary effects reported in this experiment are typical of those seen in many studies examining the effects of alpha2-agonists. The initial dose of dexmedetomidine causes a vasoconstriction in both the pulmonary and systemic circulations that then elicits a decrease in HR and CO, with a slight depressive effect on ventilation (Honkavaara et al. 2011). That the initial cardiovascular changes are mainly due to peripheral rather than central actions of the drug is supported by evidence gained from the use of a peripherally acting alpha2antagonist (Honkavaara et al. 2011). In this and
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia 11.7 (7.3–14.8) 1.4 (0.6–1.5) 546 (418–660) 84 (66–100) 0.15 (0.12–0.23) 12 (6–15)
8.0 (6.3–11.8) 1.0 (0.7–1.6) 559 (476–710) 91 (74–105) 0.15 (0.13–0.20) 11 (7–16)
11.0 (7.1–16.8) 1.3 (0.6–1.7) 632 (422–677) 93 (53–131) 0.17 (0.08–0.24) 11 (4–17)
1.42 0.01 10 (6–17) 98 (54–108) 118 (95–170) 67 (56–74) 5 (2–8) 12 (12–16) 7 (4–10)* 38.1 (37.9–38.2) 39 (35–45) 4.9 (4.6–5.6) 7.34 (7.27–7.38) 46 (39–54) 6.1 (5.2–7.2) 537 (484–603) 71.6 (64.5–80.4) 24 (22–28) 2 ( 2 to +2) 13.7 (12.5–15.1) 166 (91–176)
30
11.2 (7.7–15) 1.3 (0.6–2.0) 568 (416–758) 104 (81–198) 0.18 (0.17–0.27) 10 (5–12)
1.42 0.02 10 (6–16) 100 (52–112) 117 (105–162) 67 (59–71)* 5 (2–7)* 13 (12–16) 7 (4–11)* 38.1 (37.8–38.3) 38 (35–42) 4.8 (4.6–5.6) 7.34 (7.28–7.38) 44 (37–55) 5.9 (4.9–7.3) 544 (489–567) 72.5 (65.2–75.6) 24 (21–28) 3 ( 3 to +2) 14.1 (12.9–15.0) 169 (91–194)
60
10.1 (8.2–16.6) 1.2 (0.7–2.1) 533 (431–839) 83 (68–108) 0.14 (0.12–0.23) 11 (7–15)
1.42 0.01 12 (7–14) 100 (48–116) 124 (105–162) 67 (58–83) 5 (2–8) 13 (11–17)* 7 (3–10) 38.1 (38.0–38.3) 38 (35–42) 4.8 (4.5–5.7) 7.36 (7.28–7.39) 43 (40–55) 5.7 (5.3–7.3) 550 (477–601) 73.3 (63.6–80.1) 24 (22–27) 2 ( 3 to +2) 13.7 (12.7–14.9) 185 (108–207)
90
11.1 (8–18.7)* 1.3 (0.9–2.1) 601 (459–817) 97 (87–114) 0.16 (0.13–0.21) 11 (5–17)
1.41 0.01 10 (6–16) 96 (52–104)* 124 (105–168)* 67 (60–72)* 6 (1–8) * 13 (11–17)* 7 (3–11) 38.1 (38.0–38.2) 38 (35–42) 4.8 (4.6–5.5) 7.34 (7.29–7.40) 44 (36–54) 5.9 (4.8–7.2) 536 (486–598) 71.5 (64.8–79.7) 24 (21–27) 2 ( 3 to +2) 14.3 (12.8–15) 176 (91–187)
120
11.9 (7.8–15.8)* 1.0 (0.7–2.1) 557 (440–836) 88 (57–118) 0.14 (0.11–0.21) 11 (4–17)
1.42 0.01 11 (5–15) 100 (48–104)* 124 (105–168)* 67 (59–70)* 6 (2–8) 12 (11–17)* 7 (4–10) 38.2 (38.0–38.4) 39 (34–43) 4.8 (4.5–5.5) 7.35 (7.28–7.40) 44 (35–56) 5.9 (4.7–7.5) 524 (498–615) 69.9 (66.4–82.0) 24 (20–28) 2 ( 3 to +2) 14.2 (12.5–15.6) 173 (61–196)
150
12.2 (7–18.1)* 1.0 (0.8–2.2) 521 (443–837) 99 (81–113) 0.17 (0.12–0.22) 9 (4–17)
1.41 0.02 9 (5–14) 100 (40–100)* 125 (102–166)* 67 (59–70) 6 (2–8)* 13 (11–17) 7 (4–10)* 38.3 (37.9–38.4) 39 (34–42) 4.8 (4.5–5.2)* 7.36 (7.27–7.39) 43 (36–57) 5.7 (4.8–7.6) 532 (503–617) 70.9 (67.1–82.3) 24 (21–27) 1 ( 3 to +2) 14.4 (12.5–15.3) 158 (22–198)
180
fR, respiratory rate; HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; CVP, central venous pressure; MPAP, mean pulmonary arterial pressure; PAOP, pulmonary arterial occlusion pressure; T, core body temperature; PCV, packed cell volume; TP, total protein; pHa, arterial pH; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; SBE, _ 2, standard base excess; Hba, arterial concentration of hemoglobin; PVRI, pulmonary vascular resistance index; LVSWI, left ventricular stroke work index; RVSWI, right ventricular stroke work index; DO _ Qt, _ arteriovenous shunt. *Significant difference from baseline (p ≤ 0.05). _ 2 , oxygen consumption; Qs= oxygen delivery; O2ER, oxygen extraction ratio; VO
1.39 0.02 11 (7–20) 94 (56–108)* 127 (95–170)* 67 (56–74)* 6 (3–8)* 14 (12–16)* 7 (5–12)* 38.2 (37.9–38.3) 36 (35–38) 4.9 (4.3–5.7) 7.34 (7.28–7.37) 45 (36–53) 6.0 (4.8–7.1) 546 (424–616) 72.8 (55.5–82.1) 24 (20–28) 2 ( 4 to +3) 14.1 (12.5–14.5) 187 (129–228)
1.73 0.02 12 (7–16) 114 (100–124) 102 (96–157) 56 (51–70) 3 (1–5) 11 (11–15) 5 (3–7) 38.1 (38.0–38.4) 36 (35–38) 4.9 (4.5–6.0) 7.33 (7.29–7.39) 49 (39–58) 6.5 (5.2–7.7) 560 (417–583) 74.7 (55.6–77.7) 24 (22–29) 2 ( 3 to +4) 13.3 (12.8–14.1) 176 (110–207)
FE′Iso % fR (breaths minute 1) HR (beats minute 1) SAP (mmHg) DAP (mmHg) CVP (mmHg) MPAP (mmHg) PAOP (mmHg) T (°C) PCV (%) TP (g dL 1) pHa PaCO2 (mmHg) PaCO2 (kPa) PaO2 (mmHg) PaO2 (kPa) HCO3 (mmol L 1) SBE (mmol L 1) Hba (g dL 1) PVRI (dynes seconds cm 5 m 2) LVSWI (mJ kg 1) RVSWI (mJ kg 1) _ 2 (mL minute 1 m 2) DO _ 2 (mL minute 1 m 2) VO O2ER _ Qt _ (%) Qs=
10
Baseline
Variable
Time (minutes)
Table 1 Cardiopulmonary variables (median and range) following a loading dose of 0.5 lg kg 1 dexmedetomidine, administered over 6 minutes, and an infusion of 0.5 lg kg 1 hour 1 in six spontaneously breathing dogs. The end-expired concentration of isoflurane (FE′Iso, mean SD) was decreased by 18% from baseline for the dexmedetomidine-isoflurane treatment to be equipotent to 1.3 MAC
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
5
6 12.8 0.8 345 93 0.29 6
1.73 0.03 9 (9–21) 110 (76–128) 112 (98–151) 62 (45–74) 3 (1–7) 11 (9–16) 6 (4–9) 38.4 (37.5–38.5) 36 (28–41) 5.0 (4.6–5.4) 7.32 (7.26–7.36) 46 (38–52) 6.1 (5.1–6.9) 541 (479–572) 72.1 (63.9–76.3) 23 (21–24) 3 ( 5 to 1) 13.5 (10.4–14.2) 116 (48–173)
8.9 (6.0–13.5) 1.0 (0.3–2.1) 559 (404–872) 86 (50–187) 0.14 (0.10–0.32) 13 (7–18)
FE′Iso (%) fR (breaths minute 1) HR (beats minute 1) SAP (mmHg) DAP (mmHg) CVP (mmHg) MPAP (mmHg) PAOP (mmHg) T (°C) PCV (%) TP (g dL 1) pHa PaCO2 (mmHg) PaCO2 (kPa) PaO2 (mmHg) PaO2 (kPa) HCO3 (mmol L 1) SBE (mmol L 1) Hba (g dL 1) PVRI (dynes seconds cm 5 m 2) LVSWI (mJ kg 1) RVSWI (mJ kg 1) _ 2 (mL minute 1) DO _ 2 (mL minute 1 m 2) VO O2ER _ Qt _ (%) Qs= 13.6 (9.0–23.7)* 0.9 (0.4–2.6) 334 (252–577)* 98 (68–126) 0.27 (0.22–0.33) 7 (4–9)
0.73 0.03 14 (11–18) 56 (28–64) 155 (125–198) 81 (70–104)* 10 (7–11) 15 (14–19) 11 (10–17)* 38.5 (37.8–38.8) 42 (35–46) 5.0 (4.7–5.3) 7.36 (7.29–7.38) 41 (37–44) 5.5 (4.9–5.9) 547 (498–599) 72.9 (66.4–79.9) 22 (20–22) 3 ( 5 to 3) 15.2 (12.4–17.0) 143 44
30
12.7 (9.5–20.7) 0.9 (0.3–1.9) 331 (278–510)* 101 (75–134) 0.29 (0.21–0.34)* 5 (3–7)*
0.69 0.01 16 (6–16) 54 (32–56) 162 (123–199) 80 (70–98) 10 (7–11) 15 (14–20) 12 (10–17) 38.3 (38.1–38.5) 42 (36–47) 5.0 (4.5–5.5) 7.35 (7.28–7.39) 42 (36–47) 5.6 (4.8–6.3) 571 (549–605) 76.1 (73.2–80.7) 23 (21–24) 3 ( 4 to 1) 15.8 (13.9–17.4) 176 (32–206)
60
13.2 0.9 328 94 0.27 5
(8.5–24.2) (0.5–3.0) (266–535)* (73–126) (0.23–0.31) (4–8)*
0.69 0.01 15 (7–18) 52 (28–56)* 161 (124–200) 81 (66–94) 10 (8–11)* 16 (14–20)* 12 (11–17)* 38.3 (38.0–38.4) 42 (36–48) 4.9 (4.7–5.5) 7.35 (7.27–7.38)* 41 (36–44) 5.5 (4.8–5.9) 562 (539–596) 74.9 (71.9–79.5) 22 (21–23) 3 ( 5 to 2) 15.7 (14.0–17.8) 171 (84–221)
90
14.2 1.0 365 99 0.28 5
(10.0–21.7)* (0.6–2.7) (285–552) (89–113) (0.20–0.32) (3–12)*
0.69 0.01 13 (10–16) 48 (28–56)* 164 (124–206)* 75 (67–98) 10 (7–11) 16 (14–20)* 12 (11–17)* 38.3 (38.1–38.6) 42 (36–49)* 5.1 (4.6–5.5) 7.36 (7.29–7.39)* 40 (35–45)* 5.3 (4.7–6.0) 554 (502–606) 73.9 (66.9–80.8) 22 (21–22) 3 ( 5 to 2) 15.7 (13.9–18.1) 176 (143–184)
120
14.6 (9.4–22.5)* 1.0 (0.5–2.0) 341 (287–523) 94 (85–127) 0.27 (0.22–0.32) 6 (4–10)
0.69 0.01 11 (6–16) 50 (24–52)* 158 (123–210)* 84 (75–99) 10 (7–11)* 16 (14–18)* 12 (11–16)* 38.3 (38.1–38.6) 43 (37–50)* 5.1 (4.7–5.3) 7.36 (7.31–7.39)* 39 (34–44)* 5.2 (4.5–5.9) 551 (519–595) 73.5 (69.2–79.3) 22 (20–22) 4 ( 5 to 3) 16.4 (14.4–18.4)* 171 (131–198)
150
15.5 1.0 335 95 0.28 5
(7.3–20.4) (0.4–2.2) (284–487)* (90–116) (0.21–0.33) (3–7)*
0.70 0.01 15 (7–17) 48 (32–52)* 166 (128–208)* 80 (71–98)* 10 (7–12)* 16 (14–19)* 12 (11–16) 38.3 (38.1–38.6) 43 (38–49)* 5.1 0.4 7.35 (7.30–7.38) 42 (39–44) 5.6 (5.2–5.9) 576 (505–623) 76.8 (67.3–83.1) 22 (21–22) 3 ( 4 to 2) 16.5 (15.0–18.3)* 199 (135–233)*
180
fR, respiratory rate; HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; CVP, central venous pressure; MPAP, mean pulmonary arterial pressure; PAOP, pulmonary arterial occlusion pressure; T, core body temperature; PCV, packed cell volume; TP, total protein; pHa, arterial pH; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; SBE, _ 2, standard base excess; Hba, arterial concentration of hemoglobin; PVRI, pulmonary vascular resistance index; LVSWI, left ventricular stroke work index; RVSWI right ventricular stroke work index; DO _ Qt, _ arteriovenous shunt. *Significant difference from baseline (p ≤ 0.05). _ 2 , oxygen consumption; Qs= oxygen delivery; O2ER, oxygen extraction ratio; VO
(9.0–18.5) (0.4–1.2) (262–568)* (75–147) (0.22–0.35)* (4–10)
0.80 0.26 14 (7–20) 60 (36–68) 156 (129–194)* 82 (75–105)* 11 (9–11)* 16 (9–19) 12 (9–19)* 38.5 (37.8–38.8) 39 (34–46) 5.0 (4.6–5.6) 7.32 (7.27–7.38) 43 (36–49) 5.7 (4.8–6.5) 536 (499–591) 71.5 (66.5–78.8) 22 (20–23) 3 ( 6 to 2) 14.4 (13.4–16.8) 140 86
Baseline
Variable
10
Time (minutes)
Table 2 Cardiopulmonary variables (median and range) following a loading dose of 3 lg kg 1 dexmedetomidine, administered over 6 minutes, and an infusion of 3 lg kg 1 hour 1 in six spontaneously breathing dogs. The end-expired concentration of isoflurane (FE′Iso, mean SD) was decreased by 59% for the dexmedetomidine-isoflurane treatment to be equipotent to 1.3 MAC
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia
Cardiopulmonary effects of dexmedetomidine PJ Pascoe
Figure 1 Median (line), interquartile range (box) and range (whiskers) of mean arterial pressures (mmHg) at baseline and at times indicated following an IV loading dose and infusion of dexmedetomidine at either 0.5 µg kg 1 over 6 minutes and 0.5 µg kg 1 hour 1 infusion (LD; white boxes) or 3 µg kg 1 over 6 minutes and 3 µg kg 1 hour 1 infusion (HD; speckled boxes) in six dogs. *Significant difference from baseline for that infusion rate (p ≤ 0.05).
Figure 2 Median (line), interquartile range (box) and range (whiskers) of systemic vascular resistance index (dynes seconds cm 5 m 2) at baseline and at times indicated following an IV loading dose and infusion of dexmedetomidine at either 0.5 µg kg 1 over 6 minutes and 0.5 µg kg 1 hour 1 infusion (LD; white boxes) or 3 µg kg 1 over 6 minutes and 3 µg kg 1 hour 1 infusion (HD; speckled boxes) in six dogs. *Significant difference from baseline for that infusion rate (p ≤ 0.05).
other studies the infusion of dexmedetomidine has been associated with an increased Hba and/or PCV (Lin et al. 2008). The reasons for this have not been elucidated but could be due to release of red cells from the spleen (alpha-agonist effect) or be due to a loss of circulating volume associated with the diuresis caused by the alpha2-agonist. In this study, and in others (Lin et al. 2008), the decrease in CI _ 2 despite contributed to a significant decrease in DO an increase in oxygen content of the blood.
Figure 3 Median (line), interquartile range (box) and range (whiskers) of cardiac index (L minute 1 m 2) at baseline and at times indicated following an IV loading dose and infusion of dexmedetomidine at either 0.5 µg kg 1 over 6 minutes and 0.5 µg kg 1 hour 1 infusion (LD; white boxes) or 3 µg kg 1 over 6 minutes and 3 µg kg 1 hour 1 infusion (HD; speckled boxes) in six dogs. *Significant difference from baseline for that infusion rate (p ≤ 0.05).
Figure 4 Plot of % change in heart rate (HR) versus % change in cardiac index (CI) using data from both treatments. The line represents the best line of fit for these data using a linear function as represented by the equation (Y=). The correlation coefficient is shown (R2).
Considerable individual variation in cardiovascular responses to the dexmedetomidine infusions was noted between dogs in this experiment. Average decreases in CI over the 180 minutes ranged from 1 to 17% with LD and 27–56% with HD treatments. This might suggest that the safest way to use these drugs would be to titrate the dose rate to a certain end point. Examining the data from this study, HR might be the best guide, such that any change in HR less than a 20% decrease from before the start of the infusion would be indicative of minor changes in CI (+7 to 6%). However, the range of data is limited as only two doses of dexmedetomidine were used. In a
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia
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Cardiopulmonary effects of dexmedetomidine PJ Pascoe
study in cats a range of doses were used to determine dose-response curves for a number of cardiovascular variables (Pypendop et al. 2011). The dexmedetomidine concentration needed to decrease CI by 50% of the maximum effect (IC50) was 0.45 ng mL 1 and the IC50 for HR was 0.75 ng mL 1. Of the concentrations reported in that paper for a 50% of maximum change in clinically monitored cardiovascular variables CI and HR were closest, supporting the idea that a change in HR might be a good indication of a change in CI. Concentrations of dexmedetomidine, measured in dogs using the same protocol for the IV infusion, reported mean concentrations of about 0.19 and 1.9 ng mL 1 for the LD and HD, respectively (Pascoe et al. 2006). The loading dose in this experiment was administered over 6 minutes. This is a shorter time than in two other studies, where the loading dose was administered over 10 minutes (Kaartinen et al. 2010; Kulka et al. 2012) but may be longer than in some other studies where loading doses have been administered but the time taken to give them was not stated (Lin et al. 2008; Lamont et al. 2012). The elimination half-life (T1/2) for dexmedetomidine was reported to be 0.46 hours (Lin et al. 2008), therefore, steady state would be reached in 1.84– 2.3 hours (4–5 9 T1/2) if an infusion was started without a loading dose. Given the observed increase in diastolic pressure in this study during the loading dose, a longer duration, such as 10 minutes, might be less likely to cause immediate vasoconstriction. In Kaartinen et al. (2010), where the loading dose of medetomidine (1 lg kg 1) was administered over 10 minutes, there was a 12% decrease in mean HR and a 4% decrease in CI compared with 20 and 9%, respectively, in the present study at 10 minutes into the infusion. While these comparisons might suggest that the longer time for the loading dose had less effect, the MAP only increased by 13% in the present study whereas it increased by 19% in the Kaartinen et al. (2010) study. It is likely that there would be little clinical importance to the differences between these times used for the loading doses. The infusions were continued for 3 hours in this study to determine if there was any change with time in the variables measured. At both doses there were minimal changes with time. Other studies reporting infusions over 2 hours (Lin et al. 2008; Kaartinen et al. 2010) have found similar results and further changes in HR or fR were not reported when the infusion was continued for 24 hours (Lin et al. 2008). 8
Limitations of this experiment include the lack of blinding, the failure to calibrate the syringe pump, and the use of a relatively limited number of animals. Since all the measurements recorded were objective it is unlikely that a lack of blinding would have introduced bias into the experiment. The syringe pump was not calibrated prior to use but the amounts infused were consistent with the expected volumes and any inaccuracy with regard to the infusion would have been very minor. It is possible that some of the changes seen with both doses could have shown statistical significance if more dogs had been used in the experiment. Conclusion The LD appeared to have minimal overall effect on the cardiopulmonary values measured whereas the HD caused typical changes expected with an alpha2adrenergic agonist. This LD may be useful as an adjunct to anesthesia to allow a reduction in inhalant concentration with minimal change in cardiopulmonary function. Acknowledgements The funding for this work was provided by the Center for Companion Animal Health at the University of California, Davis, CA, USA. The author thanks Dr. Phil Kass for assistance with statistical analysis and Linda Tripp for technical assistance. References Boscan P, Pypendop BH, Solano AM et al. (2005) Cardiovascular and respiratory effects of ketamine infusions in isoflurane-anesthetized dogs before and during noxious stimulation. Am J Vet Res 66, 2122– 2129. Brodbelt DC, Blissitt KJ, Hammond RA et al. (2008) The risk of death: the confidential enquiry into perioperative small animal fatalities. Vet Anaesth Analg 35, 365–373. Clarke KW, Hall LW (1990) A survey of anaesthesia in small animal practice: AVA/BSAVA report. J Ass Vet Anaesth 17, 4–10. Congdon JM, Marquez M, Niyom S et al. (2013) Cardiovascular, respiratory, electrolyte and acid-base balance during continuous dexmedetomidine infusion in anesthetized dogs. Vet Anaesth Analg 40, 464–471. Ebner LS, Lerche P, Bednarski RM et al. (2013) Effect of dexmedetomidine, morphine-lidocaine-ketamine, and dexmedetomidine-morphine-lidocaine-ketamine constant rate infusions on the minimum alveolar
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Cardiopulmonary effects of dexmedetomidine PJ Pascoe concentration of isoflurane and bispectral index in dogs. Am J Vet Res 74, 963–970. Haskins S, Pascoe PJ, Ilkiw JE et al. (2005) Reference cardiopulmonary values in normal dogs. Comp Med 55, 156–161. Honkavaara JM, Restitutti F, Raekallio MR et al. (2011) The effects of increasing doses of MK-467, a peripheral alpha(2) -adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. J Vet Pharmacol Ther 34, 332–337. Ilkiw JE, Pascoe PJ, Haskins SC et al. (1994) The cardiovascular sparing effect of fentanyl and atropine administered to enflurane anesthetized dogs. Can J Vet Res 58, 248–253. Kaartinen J, Pang D, Moreau M et al. (2010) Hemodynamic effects of an intravenous infusion of medetomidine at six different dose regimens in isoflurane-anesthetized dogs. Vet Ther 11, E1–E16. Kabukcu HK, Sahin N, Temel Y et al. (2011) Hemodynamics in coronary artery bypass surgery: effects of intraoperative dexmedetomidine administration. Anaesthesist 60, 427–431. Kulka AM, Otto KA, Bergfeld C et al. (2012) Effects of isoflurane anesthesia with and without dexmedetomidine or remifentanil on quantitative electroencephalographic variables before and after nociceptive stimulation in dogs. Am J Vet Res 73, 602–609. Lamont LA, Burton SA, Caines D et al. (2012) Effects of 2 different infusion rates of medetomidine on sedation score, cardiopulmonary parameters, and serum levels of medetomidine in healthy dogs. Can J Vet Res 76, 308–316. Lin GY, Robben JH, Murrell JC et al. (2008) Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs. Vet Anaesth Analg 35, 141–153. Macintyre PE, Scott DA, Schug SA et al. (2010) APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. In: Acute Pain Management: Scientific Evidence. AaNZCoAaFoP (ed.). ANZCA & FPM, Melbourne. pp. 12–15.
Murphy MR, Hug CC Jr (1982) The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 57, 485–488. Ortega M, Cruz I (2011) Evaluation of a constant rate infusion of lidocaine for balanced anesthesia in dogs undergoing surgery. Can Vet J 52, 856–860. Pascoe PJ, Raekallio M, Kuusela E et al. (2006) Changes in the minimum alveolar concentration of isoflurane and some cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs. Vet Anaesth Analg 33, 97–103. Pypendop B, Verstegen J (1998) Hemodynamic effects of medetomidine in the dog: a dose titration study. Vet Surg 27, 612–622. Pypendop BH, Barter LS, Stanley SD et al. (2011) Hemodynamic effects of dexmedetomidine in isofluraneanesthetized cats. Vet Anaesth Analg 38, 555–567. Schramm W (2010) The units of measurement of the ventricular stroke work: a review study. J Clin Monit Comput 24, 213–217. Steffey EP, Eger EI 2nd (1974) Hyperthermia and halothane MAC in the dog. Anesthesiology 41, 392– 396. Steffey EP, Howland D Jr (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833–1836. Steffey EP, Gillespie JR, Berry JD et al. (1975) Circulatory effects of halothane and halothane-nitrous oxide anesthesia in the dog: spontaneous ventilation. Am J Vet Res 36, 197–200. Steffey EP, Baggot JD, Eisele JH et al. (1994) Morphineisoflurane interaction in dogs, swine and rhesus monkeys. J Vet Pharmacol Ther 17, 202–210. Talke P, Li J, Jain U et al. (1995) Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Research Group. Anesthesiology 82, 620–633. Wijeysundera DN, Bender JS, Beattie WS (2009) Alpha-2 adrenergic agonists for the prevention of cardiac complications among patients undergoing surgery. Cochrane Database Syst Rev, CD004126. Received 21 November 2013; accepted 26 June 2014.
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