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Use of ephedrine and dopamine in dogs for the management of hypotension in routine clinical cases under isoflurane anesthesia
Veterinary Anaesthesia and Analgesia, 2007, 34, 301–311
doi:10.1111/j.1467-2995.2006.00327.x
RESEARCH PAPER
Use of ephedrine and dopamine in dogs for the management of hypotension in routine clinical cases under isoflurane anesthesia Hui C Chen*
DVM, MVM, DVSc,
Melissa D Sinclair
DVM, DVSc, Diplomate ACVA
& Doris H Dyson
DVM, DVSc, Diplomate ACVA
Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
Correspondence: Doris Dyson, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada. E-mail: [email protected]
Abstract Objective To determine the cardiovascular responses of ephedrine and dopamine for the management of presurgical hypotension in anesthetized dogs. Study design Prospective, randomized, clinical trial. Animals Twelve healthy client-owned dogs admitted for orthopedic surgery; six per group Methods Prior to surgery, 58 anesthetized dogs were monitored for hypotension [mean arterial pressure (MAP) <60 mmHg] that was not associated with bradycardia or excessive anesthetic depth. Ephedrine (0.2 mg kg)1, IV) or dopamine (5 lg kg)1 minute)1, IV) was randomly assigned for treatment in 12 hypotensive dogs. Ten minutes after the first treatment (Tx1-10), ephedrine was repeated or the dopamine infusion rate was doubled. Cardiovascular assessments taken at baseline, Tx1-10, and 10 minutes following treatment adjustment (Tx2-10) were compared for differences within and between treatments (p < 0.05). Results Ephedrine increased cardiac index (CI), stroke volume index (SVI), oxygen delivery index *Present address: Hui C Chen, Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor DE, Malaysia.
(DO2I), and decreased total peripheral resistance (TPR) by Tx1-10, while MAP increased transiently (<5 minutes). The second ephedrine bolus produced no further improvement. Dopamine failed to produce significant changes at 5 lg kg)1 minute)1, while 10 lg kg)1 minute)1 increased MAP, CI, SVI significantly from baseline, and DO2I compared with Tx1-10. The improvement in CI, SVI, and DO2I was not significantly different between treatments at Tx2-10. Conclusions and clinical relevance In anesthetized hypotensive dogs, ephedrine and dopamine improved cardiac output and oxygen delivery. However, the pressure-elevating effect of ephedrine is transient, while an infusion of dopamine at 10 lg kg)1 minute)1 improved MAP significantly by additionally maintaining TPR. Keywords blood pressure, cardiovascular effects, inotropes, lithium dilution cardiac output, sympathomimetic.
Introduction Hypotension during general anesthesia has arbitrarily been defined as a mean arterial pressure (MAP) <60 mmHg, corresponding to a systolic arterial pressure (SAP) <80–90 mmHg (Haskins 1996). Below these pressures, vital organs such as the brain and the kidney may lose their ability to autoregulate their own blood supply (Guyton & Hall 2000). In addition, it is speculated that organ blood 301
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flow declines in proportion to the decrease in blood pressure (BP) and the extent of organ damage associated with poor oxygen delivery is assumed to be proportional to the duration of hypotension. Hypotension has been reported in some studies as one of the most common complications observed in small animal anesthesia (Hosgood 1998; Gaynor et al. 1999). At the Ontario Veterinary College, the small animal anesthesia database (1998–2001) revealed that 36% of all ASA II, dogs, during maintenance of anesthesia were hypotensive (as defined above). Although the consequences of low BP are difficult to quantify in morbidity studies, early recognition and treatment of hypotension is a logical expectation of safe anesthetic management when actual measurements of perfusion are unavailable, and may be important in preventing adverse effects if associated with decreased oxygen delivery. The causes of hypotension during anesthesia are multifactorial, with major contributing factors related to the cardiovascular depression of the anesthetic agents themselves and the clinical conditions of the patient. Management of hypotension during anesthesia includes assessment and correction of errors in anesthetic depth, arrhythmias (bradycardia, supraventricular, or ventricular premature contractions) and obvious or potential volume deficits. If hypotension persists despite these steps, then administration of inotropic drugs may be necessary to maintain BP. Ephedrine and dopamine are two inotropic agents commonly used to manage hypotension in small animals. Ephedrine is commonly used to treat hypotension associated with inhalation and spinal anesthesia in humans (Bernards 1996; Stoelting 1999), and has been recommended for use in small animals and horses (Wagner & Brodbelt 1997; Wagner 2000; Mazzaferro & Wagner 2001). It is a noncatecholamine sympathomimetic that can stimulate a- and b-adrenergic receptors directly, as well as indirectly, by causing endogenous release of norepinephrine (Stoelting 1999; Hoffman 2001). Ephedrine has the advantages of being inexpensive and convenient to use, as an intravenous (IV) bolus. Previous experimental work in Beagles demonstrated an improvement in MAP, cardiac output (CO), and stroke volume (SV) without producing arrhythmias (Wagner et al. 1993). However, these dogs were not hypotensive and the effectiveness of ephedrine in the management of clinically hypotensive patients that have received premedicants and injectable induction agents is not known. 302
Dopamine is an endogenous catecholamine that exerts its effects through stimulation of the dopaminergic, a-adrenergic and b-adrenergic receptors. Rapid metabolism of dopamine and its brief duration of action mandate its use as a continuous IV infusion (constant rate infusion, CRI) (Stoelting 1999; Moss & Renz 2000), which may make it less convenient to use in the clinical setting. The receptor and hemodynamic effects of exogenous administration of dopamine are dose-dependent within the typical infusion rates recommended (2–10 lg kg)1 minute)1) (Hosgood 1990; Wagner & Brodbelt 1997; Stoelting 1999; Moss & Renz 2000; Muir et al. 2000). Higher infusion rates or an accidental IV bolus injection may result in tachycardia, vasoconstriction, and hypertension, with the potential for arrhythmias. An increase in BP achieved when either dopamine or ephedrine is administered clinically is presumed to indicate an increase in CO, although changes in vascular tone could also affect BP. This study was undertaken to determine the cardiovascular responses of ephedrine at 0.2 mg kg)1, IV (repeated if inadequate response) and dopamine CRI at 5 lg kg)1 minute)1, IV (rate doubled if inadequate response) to manage hypotension in otherwise healthy client-owned dogs during routine anesthetic management prior to orthopedic surgery. Materials and methods Animals and selection criteria This study was approved by the University of Guelph’s Animal Care Committee. Clinical cases presented to the Veterinary Teaching Hospital of the Ontario Veterinary College were used with client consent. Initial selection criteria for dogs consisted of ASA II cases, 6 months to 8 years of age and weighing 20–35 kg, and anesthetized for orthopedic procedures. They were judged to be healthy based on history, physical examination and standard, minimal, preoperative blood work (hematocrit, total protein, and blood urea nitrogen). Anesthesia and instrumentation The anesthetic protocols were tailored to the individual case: premedication with acepromazine and hydromorphone, with or without glycopyrrolate, given by intramuscular injection; induction with thiopental or ketamine-diazepam (1:1)
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administered IV via a 20 SWG catheter (BD Insyte-W; Becton Dickinson, Sandy, UT, USA) placed in a cephalic vein; and anesthetic maintenance with isoflurane (Iso) in 100% oxygen. Following induction the Iso concentration was adjusted according to the requirement of the individual dog as judged by the anesthetist, who was not involved in the study. An epidural injection of morphine and bupivacaine was routinely administered in cases undergoing hindlimb procedures. Bupivacaine was used for blockade of the brachial plexus in dogs undergoing forelimb procedures. All dogs were allowed to breathe spontaneously and received a balanced electrolyte solution (Plasma-Lyte A; Baxter Corp., Toronto, ON, Canada), administered IV at 10 mL kg)1 hour)1. A multi-channel patient monitor (Criticare Model 1100; Criticare Systems Inc., Waukesha, WI, USA) was used to assess all physiologic parameters and airway gas concentrations. A 20 SWG catheter (BD Insyte-W, Becton Dickinson) was placed percutaneously in a dorsal pedal artery and connected to a disposable transducer system (Model DT-36; Ohmeda Medical Devices Division Inc., Madison, WI, USA) to monitor the BP directly and to allow for lithium dilution measurement of CO. The pressure transducer and the pressure channel were calibrated with a mercury manometer prior to each use and zero was set at the level of the heart. A lead II ECG was placed to monitor heart rate (HR) and rhythm, and an esophageal temperature probe was inserted to measure body temperature (Temp). An 8-French sampling line was inserted within the endotracheal tube to the level of the carina to perform gas sampling near its tracheal end for endtidal CO2 (PE¢CO2) and end-tidal Iso (ETIso). The spectrometry component of the patient monitor was calibrated with a commercial calibration gas (Anesthesia Calibration Gas; Criticare Systems Inc.) prior to each use. Inclusion criteria and design of treatment intervention Inclusion criteria for the inotropic treatment intervention were hypotension, defined as MAP <60 mmHg, not associated with bradycardia (HR <65 beats minute)1) or excessive anesthetic depth (as judged by the anesthetist according to typical reflexes and appropriate Iso concentration). Only dogs that developed hypotension prior to onset of surgery were studied further. Once the animal was
deemed hypotensive, the Iso concentration was not altered and baseline (T-0) measurements were taken. Random assignment of the ephedrine and dopamine treatments was computer-generated based on a target of six cases per treatment group. Ephedrine (Ephedrine sulfate injection 50 mg mL)1 USP; SABEX INC., Boucherville, QC, Canada) was diluted to 5 mg mL)1 with normal saline immediately prior to use. Dopamine (Intropin; Bristol-Myers Squibb Canada, Montreal, Canada) was pre-diluted in 5% dextrose to 0.4 mg mL)1 and kept in the refrigerator at 4C for up to 30 days. It was administered with fully primed lines using a syringe or a fluid pump. The target MAP was selected as 70 mmHg. The ephedrine treatment consisted of an IV bolus of 0.2 mg kg)1. If the MAP remained below the target at 10 minutes after the initial dose (Tx1-10), the ephedrine dose (0.2 mg kg)1, IV) was repeated. The dopamine treatment consisted of an IV infusion of 5 lg kg)1 minute)1 for 10 minutes, administered by syringe or fluid pump through the injection port on the IV fluid line closest to the patient (approximately 1.5 mL dead space existed before reaching patient). This infusion rate was maintained if the target MAP was achieved, but was doubled to 10 lg kg)1 minute)1 if MAP remained lower than 70 mmHg at Tx1-10. Dogs were monitored for an additional 10 minutes following the second dose or CRI adjustment, and final measurements were repeated (Tx2-10). Transfer of the animal into the operating room, or surgery did not commence until all measurements were completed. Other supportive treatments were administered, if necessary, following complete data collection. Data collection Measurements consisted of HR, SAP, MAP, diastolic arterial pressure (DAP), CO, PE¢CO2, ETIso, Temp, arterial blood gases, sodium (Na), and hemoglobin (Hb) concentration. Blood gases were temperaturecorrected and analyzed immediately after sampling (ABL 700 series, Radiometer, Copenhagen, Denmark). All parameters were measured at T-0, Tx1-10, and Tx2-10, although BP and HR were measured every 2.5 minutes following treatment interventions. A single determination of CO was carried out following all other data collection (at T-0, Tx1-10, and Tx2-10) and a lithium dilution technique (LidCO plus Hemodynamic Monitor; LiDCO Ltd,
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differences from T-0. Difference of least squares means was used to compare values at Tx1-10 and Tx2-10 within treatment. Contrast between the two treatments was applied to examine how the cardiovascular responses changed over time and whether they changed in the same way. For all tests, residuals plots were examined for equality of variances. Normality was tested using Shapiro– Wilk test. Data were log-transformed when necessary. p < 0.05 was considered significant.
London, UK) as described by Mason et al. (2002) was used. Arterial blood was sampled 3 minutes prior to the CO determination to obtain the Na and Hb values as required by the LiDCO system. The peripheral vein for IV fluid administration was also used for the bolus injection of the lithium indicator (1 mL, 0.15 mmol) through a three-way stopcock (IV Set Stopcock, 3-Way, 10-1000; Benlan Inc., Oakville, Ontario, Canada) attached directly to the catheter. Dopamine infusion was stopped (for 1–1.5 minutes) during CO determination to ensure that the catheter dead space was free of dopamine during the bolus lithium injection. Cardiac index (CI), stroke volume index (SVI), arterial oxygen content (CaO2) and oxygen delivery index (DO2I) were calculated using standard formulae (Boyd et al. 1991). Total peripheral resistance (TPR) was calculated as 79.9 · MAP CO)1.
Results Data are presented as mean ± SD unless otherwise noted. A total of 58 dogs were recruited in the study and of these, 12 developed hypotension (MAP ¼ 56 ± 4 mmHg), while none of the animals were excluded because of HR or rhythm abnormalities. The ephedrine group consisted of five females and one male, 2.7 ± 1.6 years of age and 30.1 ± 4.4 kg. Five were scheduled for repair of ruptured anterior cruciate ligaments and one was presented for radial osteotomy. The dopamine group consisted of two females and four males, 2.6 ± 2.5 years and 30.7 ± 6.4 kg. One of the following procedures was scheduled for each dog: elbow arthrotomy, triple pelvic osteotomy, radialulnar osteotomy, tibial plateau leveling osteotomy, forelimb amputation, and bilateral shoulder joint arthroscopy. Anesthetic drugs and doses used are summarized in Table 1. Time from induction to the diagnosis of hypotension ranged from 25 to 85 (48 ± 22)
Statistical analysis A mixed model (Proc Mixed, SAS Version 8; SAS Institute Inc., Cary, NC, USA) for the split-plot design was used to analyze the cardiovascular parameters for significant treatment, time, and interactions between treatment and time effect. Time was considered the repeated measure and the dog, a random effect. An autoregressive covariance structure of order 1 was included in the analyses to account for correlations between measurements at different time points. When there was a significant time effect within treatment, a Dunnett’s test was applied to compare for
Drugs
Premedication Glycopyrrolate* Acepromazine Hydromorphone Induction Ketamine† Thiopental Diazepam Supplemental analgesia Morphine (epidural) Bupivacaine 0.5% (epidural) Bupivacaine 0.5% (brachial plexus neural blockade)
Dose range (mg kg)1)
Ephedrine
Dopamine
0.005–0.01 0.010–0.05 0.050–0.10
5 6 6
5 6 6
3.75–5.0 3.3–12.5 0.2–0.25
2 4 2
2 4 4
0.1–0.26 (mg kg)1) 0.75–1.15 (mg kg)1) 1–1.5 (mg kg)1)
5 5 1
3 2 1
Table 1 Dose range and number of cases that received the drug in each treatment group prior to development of hypotension
*One dog in the dopamine group received glycopyrrolate during the study period; †ketamine was mixed with diazepam (1:1 by volume; 100 mg:5 mg, respectively)
304
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minutes in the ephedrine group, and 17–50 (31 ± 12) minutes in the dopamine group. The ETIso concentration was not significantly different (0.92 ± 0.20% and 0.87 ± 0.16%, for the dopamine and ephedrine groups, respectively). Dogs in the ephedrine group tended to have a lower Temp (36.1 ± 1.2 C) than those in the dopamine group (37.3 ± 0.9 C) at T-0, and Temp continued to drop over time in all the dogs. All other variables at baseline were not different between groups. None of the dogs achieved the target MAP following either treatment at Tx1-10. Blood pressures (SAP, MAP, and DAP) increased immediately following the first ephedrine bolus (Table 2; Fig. 1a), with significant differences from baseline at 2.5 minutes. The BP decreased rapidly, returning to near or below baseline within 5 minutes. The second bolus of ephedrine did not significantly change BP. Dopamine at 5 lg kg)1 minute)1 did not improve BP significantly by Tx1-10. By doubling the dopamine infusion rate to 10 lg kg)1 minute)1, significant improvement was detected at Tx2-5, Tx2-
7.5, and Tx2-10. By the end of the study period, the target MAP was attained in four dogs in the dopamine group compared with one dog in the ephedrine group, and the improvement in MAP from baseline and Tx1-10 was significantly greater with the dopamine treatment than with ephedrine (p ¼ 0.0007 and 0.0076, respectively). An MAP of less than 50 mmHg following administration of the initial dose of the inotrope was noted in three dogs in the ephedrine group and in one dog in the dopamine group. Five animals in the ephedrine group had an MAP at Tx1-10 that was lower than baseline, and the MAP at the end of the study period remained lower than baseline in four of them. One dog in the dopamine group had an MAP at Tx1-10 that was lower than baseline, but by the end of the study period, MAP was higher than baseline in all six cases. There was no overall treatment or time effect on HR, but an interaction between treatment and time was significant (p ¼ 0.0016). This significance was related to the readings at Tx1-2.5 when HR
Table 2 Cardiovascular responses (mean ± SD) following detection of hypotension (T-0) and following each intervention: Tx1 – ephedrine bolus (E) (0.2 mg kg)1, IV) or dopamine infusion (D) (5 lg kg)1 minute)1, IV); Tx2 – repeated ephedrine bolus (0.2 mg kg)1, IV), or dopamine at 10 lg kg)1 minute)1, IV
First treatment intervention (Tx1)
Second treatment intervention (Tx2)
Baseline Variables
T-0
HR (beats minute)1) E 93 ± 14 D 96 ± 24 SAP (mmHg) E 100 ± 22 D 94 ± 14 DAP (mmHg) E 43 ± 6 D 44 ± 3 SVI (mL beat)1 kg)1) E 1.15 ± 0.22 D 1.33 ± 0.32 Hb (g dL)1) E 12.4 ± 1.0 D 12.7 ± 1.2 CaO2 (mL L)1) E 190 ± 13 D 193 ± 15
Tx1-2.5
Tx1-5
Tx1-7.5
Tx1-10
Tx2-2.5
Tx2-5
Tx2-7.5
Tx2-10
105 ± 18* 86 ± 19
101 ± 19 92 ± 21
103 ± 24 88 ± 19
102 ± 21 86 ± 20
109 ± 22* 87 ± 20
102 ± 23 90 ± 16
106 ± 19 98 ± 23
106 ± 19 96 ± 21
125 ± 24* 86 ± 15
107 ± 24 91 ± 15
104 ± 38 103 ± 18
98 ± 31 102 ± 23
108 ± 38 106 ± 17
106 ± 39 133 ± 37*
108 ± 29 140 ± 40*
108 ± 31bc 147 ± 39*#
56 ± 15* 42 ± 7
48 ± 9 44 ± 5
43 ± 5 48 ± 3
42 ± 6 48 ± 4
44 ± 8 46 ± 4
45 ± 12 56 ± 10*
43 ± 10 61 ± 15*
43 ± 19bc 59 ± 10*#
– –
– –
– –
1.4 ± 0.53* 1.49 ± 0.26
– –
– –
– –
1.38 ± 0.43* 1.71 ± 0.44*
– –
– –
– –
12.0 ± 0.7* 11.9 ± 1.1*
– –
– –
– –
12.3 ± 1.0 11.8 ± 1.4*
– –
– –
– –
181 ± 16* 182 ± 15*
– –
– –
– –
188 ± 13 181 ± 20*
HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; SVI, stroke volume index; Hb, hemoglobin concentration; CaO2, arterial oxygen content. Tx1-y (time in minutes following first treatment); Tx2-y (time in minutes following second treatment). Significant differences (p < 0.05) are denoted as follows: within the same treatment, *value differs from baseline (T-0), # value at Tx2-10 differs from Tx1-10; between treatments, afirst response (T-0 to Tx1-10) differs, bsecond response (Tx1-10 to Tx2-10) differs, and csum of responses (T-0 to Tx2-10) differs.
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increased after the ephedrine bolus (p ¼ 0.0434), but tended to decrease in the dopamine group (p ¼ 0.1558). The increase in HR was significant at Tx2-2.5 following the repeated dose of ephedrine (p ¼ 0.0326). Sinus arrhythmia was observed following administration of ephedrine (n ¼ 1) and escape beats (ventricular beat following a short sinus arrest) with dopamine when it was increased to 10 lg kg)1 minute)1 (n ¼ 1). Glycopyrrolate (0.005 mg kg)1, IV) was administered to the latter case, resulting in a dramatic increase in HR and BP. If the data points following treatment with glycopyrrolate in this dog were excluded from the statistical analysis, the increase in HR from T-0 to Tx2-10 in the ephedrine group was higher than that in the dopamine group (p ¼ 0.0436), but all other results were not affected. Following this incident,
glycopyrrolate was included in the premedication of subsequent cases (10/12 dogs). The first dose of ephedrine significantly improved CI (p ¼ 0.0040), SVI (p ¼ 0.0472), and DO2I (p ¼ 0.0131), while the repeat dose of ephedrine did not change these parameters further and values at Tx2-10 remained higher than baseline (Table 2; Figs 1b & c). Dopamine at 5 lg kg)1 minute)1 did not change the CI, SVI, or DO2I, but improvement was seen when the infusion rate was increased to 10 lg kg)1 minute)1, although the increase in DO2I did not reach statistical significance (p ¼ 0.0078, 0.0006, and 0.0526, respectively). In addition, Tx210 values were greater than Tx1-10 (p ¼ 0.0020, 0.0798, and 0.0045, respectively). The improvement in CI and DO2I from baseline to Tx1-10 was greater following the first ephedrine bolus compared
Figure 1 Effects (mean ± SD) of ephedrine (————) and dopamine (_ _ _ _ _) treatments on mean arterial pressure (MAP), cardiac index (CI), oxygen delivery index (DO2I) and total peripheral resistance (TPR) following detection of hypotension (T-0) and following each intervention: Tx1 – ephedrine bolus (0.2 mg kg)1, IV) or dopamine infusion (5 lg kg)1 minute)1, IV); Tx2 – repeated ephedrine bolus (0.2 mg kg)1, IV) or dopamine at 10 lg kg)1 minute)1, IV (arrows indicate commencement of treatments). Significant differences (p < 0.05) are denoted as follows: within the same treatment, *value differs from baseline (T-0), #value at Tx1-10 differs from Tx2-10; between treatments, afirst response (T-0 to Tx1-10) differs, bsecond response (Tx1-10 to Tx2-10) differs, csum of responses (T-0 to Tx2-10) differs. 306
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with dopamine at 5 lg kg)1 minute)1 (p ¼ 0.0495 and 0.0353, respectively). By the end of the study period, there was no significant difference in the increases in CI, SVI, or DO2I between treatments. Following the first dose of ephedrine, TPR at Tx110 was significantly lower than baseline (p ¼ 0.0004) (Fig. 1d). The repeated dose of ephedrine did not change TPR further, and TPR at Tx2-10 remained lower than baseline (p ¼ 0.0033). Dopamine at both infusion rates did not change the TPR significantly at Tx1-10 and Tx2-10 when compared with baseline. In general, the Hb concentration decreased over time in both groups. The repeated dose of ephedrine tended to increase the Hb concentration toward the baseline value, but these changes were not statistically significant. Arterial oxygen content followed a trend similar to Hb concentration. There were no significant treatment, time, or interaction effects in arterial Na (148 ± 2 and 147 ± 2 mmol L)1), pH (7.253 ± 0.082; 7.268 ± 0.054), carbon dioxide tension (54.4 ± 10.0 and 53.2 ± 6.1 mmHg), oxygen tension (548.6 ± 31.6 and 532.7 ± 36.5 mmHg), bicarbonate (23.2 ± 2.2 and 23.5 ± 1.3 mmol L)1), or base excess values ()4.3 ± 3.0 and )3.5 ± 2.2 mmol L)1) for ephedrine and dopamine groups, respectively (pooled data for the three time points). All dogs had an uneventful recovery from anesthesia. Discussion Our study showed presurgical hypotension in 21% of these ASA II dogs. This number is lower than the 36% recorded from our whole database but the latter represents the whole period of anesthesia compared with just the pre-surgical period in this study. No evidence of volume deficits was noted in the preoperative evaluations, although subclinical dehydration could have existed. Additional fluid administration may have been effective in some of these animals. The prolonged preoperative time in our dogs was likely a contributor to the development of this hypotension. The lack of stimulation during radiography, clipping, and surgical preparation is likely to result in lower BP than that associated with surgery. Although benefits were shown with the use of inotropes in this study, their use in clinical cases should be reserved for those animals known to have poor contractility or following more directed treatment of the suspected problem. However, this study
confirmed that in hypotensive dogs exposed to various anesthetic agents both ephedrine and dopamine improved perfusion as demonstrated by a significant increase in CI, SVI, and DO2I. However, ephedrine at 0.2 mg kg)1 IV increased BP transiently and was not improved with a repeated dose. The initial effect lasted less than 5 minutes and appeared to be countered by a significant decrease in TPR. Dopamine at 10 lg kg)1 minute)1 significantly improved BP with a similar rise in CI, SVI, and DO2I. Most of the cardiovascular responses following ephedrine administration in our study were similar to those reported by Wagner et al. (1993). However, the increase in BP in their dogs was longer and more intense at the higher dose. Ephedrine at 0.1 mg kg)1 IV increased MAP significantly for 5 minutes while at 0.25 mg kg)1 IV, the effect lasted for 15 minutes. The shorter duration and intensity in our dogs could be attributable to the addition of other drugs as part of the anesthetic management and the presence of baseline hypotension prior to treatment, although the overall BP achieved was not remarkably different. Our premedication may have been the most likely cause for the difference in response to ephedrine. Acepromazine is a potent a1 antagonist producing peripheral vasodilation and resulting in a dosedependent decrease in BP (Coulter et al. 1980; Muir & Hubbell 1985). Previous work has demonstrated that with prior administration of acepromazine in dogs anesthetized with halothane, the amount of phenylephrine required to increase MAP by 50% increased in a dose-dependent manner (Ludders et al. 1983). A higher dose of ephedrine may have resulted in a better BP response. This a1 antagonist effect may also explain the lack of increase in Hb concentrations in response to ephedrine as noted with both ephedrine (Wagner et al. 1993) and higher doses of dopamine (Abdul-Rasool et al. 1987). The other drugs used for premedication and induction (hydromorphone, thiopental, ketamine, and diazepam) do not have direct effects on a- or b-adrenergic receptors. Although Iso causes a dosedependent decrease in BP associated with a decrease in systemic vascular resistance (SVR) and CI (Steffey & Howland 1977; Pagel et al. 1991), it is expected that this decrease in BP will respond to a- and/or b-adrenergic stimulation. Spinal anesthesia and, to a lesser degree, epidural anesthesia in humans has been shown to produce hypotension as a result of venous and arterial
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dilation induced by the sympathetic blockade (Bernards 1996). However, Torske et al. (1999) studied the effects of epidural administration of oxymorphone and bupivacaine (at similar doses to the ones used in the current study) in halothane anesthetized dogs and reported no significant change in SVR when the concentration was appropriately reduced according to the MAC-sparing effect. Other studies demonstrated reductions in BP following epidural bupivacaine (0.36 mL kg)1) in conscious dogs (Franquelo et al. 1995), and epidural lidocaine (0.1 mL kg)1) in dogs anesthetized with 1.5% sevoflurane (Hirabayashi et al. 1996). It is unlikely that more sympathetic blockade was present in both these studies as these doses are above and below (respectively) our dose and that used by Torske et al. (1999). Epidural bupivacaine could have influenced the vascular response produced by ephedrine in our study, although the same effect was shown in the dog that received the brachial plexus neural blockade. Additional clinical research is required to substantiate any confounding effect. The variability of time from drug administration to actual ephedrine treatment in each dog may have contributed to some difference in the effect of ephedrine. However, BP improvement was not maintained even when the time for hypotension development was delayed. This study provided no evidence that the effect of BP from ephedrine would last beyond 5 minutes in hypotensive dogs or be maintained with a repeated bolus. In our study, HR increased immediately following both the first and second bolus doses of ephedrine, while HR decreased significantly for up to 15 minutes in the study by Wagner et al. (1993). This difference is likely due to a baroreceptor response to the acute and prolonged increase in BP in their dogs. The two dogs in our study, that demonstrated the best BP response following ephedrine, also showed a decrease in HR. The HR gradually increased as BP decreased. Although it is possible that glycopyrrolate may have predisposed the dogs to an increased HR following ephedrine, this increase in HR also fits with the underlying mechanism of action of ephedrine to stimulate the cardiac b1-receptors (Lawson & Meyer 1996; Stoelting 1999; Hoffman 2001). The increase in CI and reduction in TPR with ephedrine treatment in dogs is consistent with other studies (Grandy et al. 1989; Wagner et al. 1993; Lee et al. 2002). Although the increase in CO has also been shown to be due to increased venous 308
return caused by selective venoconstriction (Butterworth et al. 1986; Lawson & Meyer 1996), the effect on cardiac b1-receptors is the primary mechanism (Lawson & Meyer 1996; Stoelting 1999; Hoffman 2001). We did not measure central venous pressure in these dogs and thus have no estimation of alterations in venous return. Moreover, the inability to use this value in the TPR calculation may have contributed to some error in this measurement, but it is unlikely to have made a significant impact on these results due to the narrow range for central venous pressures. The reduced response observed with the repeated bolus of ephedrine may be an indication of tachyphylaxis. This is explained by persistent occupation of both the adrenergic receptors by the first dose of ephedrine or depletion of norepinephrine stores (Stoelting 1999). It is also possible that a better response may have been obtained if a higher dose of ephedrine was used in the repeated bolus (Butterworth et al. 1986). Alternatively, an infusion of ephedrine could be considered as has been used in humans (Gajraj et al. 1993; Critchley et al. 1995; Chan et al. 1997). Research to substantiate the appropriate dose and overall cardiovascular effect with a CRI of ephedrine in dogs requires further investigation. Our work indicates that ephedrine would be useful when a very short-lived increase in BP is sufficient, such as in the face of significant hypotension immediately before surgery or when a delay exists in starting other treatments (e.g., if preparation is required). Ephedrine should be able to increase CO when used in hypotensive dogs at these doses, although evidence for the degree of change in CO is unlikely to be easily measured. The cardiovascular responses to the dopamine infusion in hypotensive dogs were in agreement with the general descriptions of dose-dependent receptor and hemodynamic effects reported by others (Robie & Goldberg 1975; Abdul-Rasool et al. 1987; Raner et al. 1995; Moss & Renz 2000). The lack of response to the 5 lg kg)1 minute)1may be due to the pharmacokinetics of dopamine. Although no data have been reported in dogs, the elimination half-life reported in humans is 12.3 minutes (MacGregor et al. 2000) which would mean that the plasma concentration of dopamine achieved after 5 minutes would be less than 50% of the value expected under steady-state conditions. A significant increase in BP was noted at 5 minutes following the start of 10 lg kg)1 minute)1 of
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dopamine. The improvement in BP appeared to plateau at 7.5 minutes with no further change after this time at either infusion rate. This provided evidence that the patient should be reassessed, the infusion rate changed, or the IV line checked for obstructions if the desired BP is not achieved within 7.5 minutes of dopamine therapy. However, it is not possible to define the impact from the administration of 5 lg kg)1 minute)1 for the first 10 minutes on the response time or on the effect produced by 10 lg kg)1 minute)1 of dopamine. The reason for using this design was to mimic the clinical situation. In humans (MacGregor et al. 2000) and cats (Pascoe et al. 2006) it has also been observed that the plasma concentration of dopamine achieved with a given infusion rate is highly variable providing another impetus to increase the infusion rate if the desired goal is not achieved within a reasonable time period. Although the improvement in CI and SVI associated with dopamine administration at 10 lg kg)1 minute)1 was not different from that produced by ephedrine, the lack of change in TPR resulted in a better BP response. Although it might be suggested that a reduction in TPR is preferential for perfusion and reduces cardiac workload, this must be considered in light of the fact that both Iso and acepromazine cause some vasodilation and thus, there may be little advantage to a further reduction in TPR. Unfortunately, without the measurement of CO there may be little evidence during anesthesia of a drug effect on this parameter unless a change in BP is produced. The improvement in BP with dopamine administration is evidence of its effect and a reflection of the increase in CO. Maintenance of adequate systemic BP influences perfusion pressure and organ blood flow (Guyton & Hall 2000) and thus, the ability of dopamine to increase MAP above 60 mmHg in all our dogs while ephedrine was only effective in one animal provided some evidence for the preferred use of dopamine in clinical cases. Only two dogs in the dopamine group received epidural bupivacaine compared with five in the ephedrine group. This may reduce the comparability of the groups, but both the dogs in the dopamine group responded well to dopamine at 10 lg kg)1 minute)1. If epidural administration of bupivacaine contributed to the poorer BP response of ephedrine boluses in this study, dopamine, at 10 lg kg)1 minute)1 may be preferable in such situations.
Variation in the actual activity of the dopamine solution used in this study cannot be ruled out, it was not diluted immediately before each use. The dopamine was pre-diluted and stored in the refrigerator. Commercial availability of pre-diluted dopamine (DOPamine HCl and 5% Dextrose injection, 800 lg mL)1, 250 mL bags; Baxter Corp.) provided some evidence that our preparation was likely to be effective. We have obtained good results with our pre-diluted dopamine in clinical cases and are confident in the efficacy of the dopamine. Despite this shortcoming, an expected dose–response was shown in the present study. Individual variation was apparent in the cardiovascular responses to the treatment in this study. This variability could be the result of differences in age, sex, cardiac condition, volume status, ETIso, PE¢CO2, residual effects of prior administered drugs, degree of physical stimulation, differences in the sensitivity of specific receptor types, existing endogenous catecholamine, and variation in the pharmacokinetics, and thus, plasma concentrations of the drugs used (MacGregor et al. 2000). Although all data were collected prior to surgery, maneuvers such as extending and hanging of the limb for surgical preparation, and changes in position may have produced stimulation of the dogs, as anesthesia was maintained at a light plane. All the dogs in this study hypoventilated, with PE¢CO2 values higher than 45 mmHg. Hypercapnia augments BP and CO through stimulation of the sympathetic nervous system and release of catecholamines (Cullen & Eger 1974; Wagner et al. 1990). The degree of hypercapnia was unlikely to have influenced the cardiovascular values significantly. In addition, it was similar over the assessment time, between dogs and between groups. Ideally all variables would have been controlled. However, the intention of this study was to apply the treatments in the face of the variation that occurs in clinical cases. In conclusion, the results of this study suggest that ephedrine (0.2 mg kg)1, IV), repeated at a 10minute interval was less effective than a dopamine infusion to augment BP pre-surgically in hypotensive dogs during routine anesthetic management. However, the degree of improvement in CI, SVI, and DO2I was not different between the two treatments and hence perfusion may be increased with either. A dopamine infusion may be more useful clinically, as the rate can be adjusted according to individual BP responses.
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Acknowledgements This study was supported by the Pet Trust Fund, Ontario Veterinary College. Statistical consultation was provided by William C Sears, MS (Zoology), MSc (Statistics), Department of Population Medicine, University of Guelph, Guelph, Canada. References Abdul-Rasool IH, Chamberlain JH, Swan PC et al. (1987) Cardiorespiratory and metabolic effects of dopamine and dobutamine infusions in dogs. Crit Care Med 15, 1044– 1050. Bernards CM (1996) Epidural and spinal anesthesia. In: Clinical Anesthesia (3rd edn). Barash PG, Cullen BR, Stoelting SK (eds). Lippincott-Raven Publishers, Philadelphia, PA, USA, pp. 645–668. Boyd CJ, McDonell WN, Valliant A (1991) Comparative hemodynamic effects of halothane and halothane-acepromazine at equipotent doses in dogs. Can J Vet Res 55, 107–112. Butterworth JF, Piccione W Jr, Berrizbeitia LD et al. (1986) Augmentation of venous return by adrenergic agonists during spinal anesthesia. Anesth Analg 65, 612–616. Chan WS, Irwin MG, Tong WN et al. (1997) Prevention of hypotension during spinal anaesthesia for caesarean section: ephedrine infusion versus fluid preload. Anaesthesia 52, 908–913. Coulter DB, Whelan SC, Wilson RC et al. (1980) Determination of blood pressure by indirect methods in dogs given acetylpromazine maleate. Cornell Vet 71, 76–84. Critchley LA, Stuart JC, Conway F et al. (1995) Hypotension during subarachnoid anaesthesia: haemodynamic effects of ephedrine. Br J Anaesth 74, 373–378. Cullen DJ, Eger EI 2nd (1974) Cardiovascular effects of carbon dioxide in man. Anesthesiology 41, 345–349. Franquelo C, Toledo A, Manubens J et al. (1995) Bupivacaine disposition and pharmacologic effects after intravenous and epidural administration in dogs. Am J Vet R 56, 1087–1091. Gajraj NM, Victory RA, Pace NA et al. (1993) Comparison of an ephedrine infusion with crystalloid administration for prevention of hypotension during spinal anesthesia. Anesth Analg 76, 1023–1026. Gaynor JS, Dunlop CI, Wagner AE et al. (1999) Complications and mortality associated with anesthesia in dogs and cats. J Am Anim Hosp Assoc 35, 13–17. Grandy JL, Hodgson DS, Dunlop CI et al. (1989) Cardiopulmonary effects of ephedrine in halothane-anesthetized horses. J Vet Pharmacol Ther 12, 389–396. Guyton AC, Hall JE (2000) Textbook of Medical Physiology (10th edn). WB Saunders, Philadelphia, PA, USA, pp. 210–710. Haskins SC (1996) Monitoring the anesthetized patients. In: Lumb and Jones’ Veterinary Anesthesia (3rd edn).
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Thurmon JC, Tranquilli WJ, Benson GJ (eds). Williams & Wilkins, Philadelphia, PA, USA, pp. 409–499. Hirabayashi Y, Shimizu R, Fukuda H et al. (1996) Effects of thoracic vs. lumbar epidural anaesthesia on systemic haemodynamics and coronary circulation in sevoflurane anaesthetized dogs. Acta Anaesthesiol Scand 40, 1127–1131. Hoffman BB (2001) Catecholamines, sympathomimetic drugs & adrenergic receptor antagonists. In: Goodman & Gilman’s The Pharmacologic Basis of Therapeutics (10th edn). Hardman JG, Limbird LE (eds). McGraw-Hill, New York, NY, USA, pp. 215–268. Hosgood G (1990) Pharmacologic features and physiologic effects of dopamine. J Am Vet Med Assoc 197, 1209– 1211. Hosgood G (1998) Evaluation of age as a risk factor for perianesthetic morbidity and mortality in the dog. J Vet Emerg Crit Care 8, 222–236. Lawson NW, Meyer DJ (1996) Autonomic nervous system: physiology and pharmacology. In: Clinical Anesthesia (3rd edn). Barash PG, Cullen BR, Stoelting SK (eds). Lippincott-Raven Publishers, Philadelphia, PA, USA, pp. 243–309. Lee Y-H, Clarke KW, Alibhai HIK et al. (2002) The effects of ephedrine on intramuscular blood flow and other cardiopulmonary parameters in halothane-anesthetized ponies. Vet Anaesth Analg 29, 171–181. Ludders JW, Reitan JA, Martucci R et al. (1983) Blood pressure response to phenylephrine infusion in halothane-anesthetized dogs given acetylpromazine maleate. Am J Vet Res 44, 996–999. MacGregor DA, Smith TE, Prielipp RC et al. (2000) Pharmacokinetics of dopamine in healthy male subjects. Anesthesiology 92, 338–346. Mason DJ, O’Grady M, Woods PJ et al. (2002) Comparison of a central and a peripheral (cephalic vein) injection site for the measurement of cardiac output using the lithium-dilution cardiac output technique in anesthetized dogs. Can J Vet Res 66, 207–210. Mazzaferro E, Wagner AE (2001) Hypotension during anesthesia in dogs and cats: recognition, causes and treatment. Compend Contin Educ Pract Vet 23, 728–736. Moss J, Renz CL (2000) The autonomic nervous system. In: Anesthesia (5th edn). Miller RD (ed.). Churchill Livingstone, Philadelphia, PA, USA, pp. 523–577. Muir WW, Hubbell JAE (1985) Blood pressure response to acetylpromazine and lenperone in halothane anesthetized dogs. J Am Anim Hosp Assoc 21, 285–289. Muir WW, Hubbell JAE, Skarda RT et al. (2000) Handbook of Veterinary Anesthesia (3rd edn) Mosby, St Louis, MO, USA. Pagel PS, Kampine JP, Schmeling WT et al. (1991) Comparison of the systemic and coronary hemodynamic actions of desflurane, isoflurane, halothane and enflurane in the chronically instrumented dog. Anesthesiology 74, 539–551.
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Pascoe PJ, Ilkiw JE, Pypendop BH (2006) Effects of increasing infusion rates of dopamine, dobutamine, epinephrine, and phenylephrine in healthy anesthetized cats. Am J Vet 67, 1491–1499. Raner C, Biber B, Henriksson BA et al. (1995) Are the cardiovascular actions of dopamine altered by isoflurane? Acta Anaesthesiol Scand 39, 678–684. Robie NW, Goldberg LI (1975) Comparative systemic and regional hemodynamic effects of dopamine and dobutamine. Am Heart J 90, 340–345. Steffey EP, Howland D (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833–1836. Stoelting RK (1999) Pharmacology & Physiology in Anesthetic Practice (3rd edn) Lippincott Williams & Wilkins, Philadelphia, PA, USA, pp. 259–276. Torske KE, Dyson DH, Conlon PD (1999) Cardiovascular effects of epidurally administered oxymorphone and oxymorphone-bupivacaine combination in halothaneanesthetized dogs. Am J Vet Res 60, 194–200.
Wagner AE (2000) Focused supportive care: blood pressure and blood flow during equine anesthesia. In: Recent Advances in Anesthetic Management of Large Domestic Animals. Steffey EP (ed.). International Veterinary Information Service (http://www.ivis.org). Wagner AE, Brodbelt DC (1997) Arterial blood pressure monitoring in anesthetized animals. J Am Vet Med Assoc 210, 1279–1285. Wagner AE, Bednarski RM, Muir WW 3rd (1990) Hemodynamic effects of carbon dioxide during intermittent positive-pressure ventilation in horses. Am J Vet Res 51, 1922–1929. Wagner AE, Dunlop CI, Chapman PL (1993) Effects of ephedrine on cardiovascular function and oxygen delivery in isoflurane-anesthetized dogs. Am J Vet Res 54, 1917–1922. Received 27 July 2004; accepted 15 December 2005.
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doi:10.1111/j.1467-2995.2006.00327.x
RESEARCH PAPER
Use of ephedrine and dopamine in dogs for the management of hypotension in routine clinical cases under isoflurane anesthesia Hui C Chen*
DVM, MVM, DVSc,
Melissa D Sinclair
DVM, DVSc, Diplomate ACVA
& Doris H Dyson
DVM, DVSc, Diplomate ACVA
Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
Correspondence: Doris Dyson, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada. E-mail: [email protected]
Abstract Objective To determine the cardiovascular responses of ephedrine and dopamine for the management of presurgical hypotension in anesthetized dogs. Study design Prospective, randomized, clinical trial. Animals Twelve healthy client-owned dogs admitted for orthopedic surgery; six per group Methods Prior to surgery, 58 anesthetized dogs were monitored for hypotension [mean arterial pressure (MAP) <60 mmHg] that was not associated with bradycardia or excessive anesthetic depth. Ephedrine (0.2 mg kg)1, IV) or dopamine (5 lg kg)1 minute)1, IV) was randomly assigned for treatment in 12 hypotensive dogs. Ten minutes after the first treatment (Tx1-10), ephedrine was repeated or the dopamine infusion rate was doubled. Cardiovascular assessments taken at baseline, Tx1-10, and 10 minutes following treatment adjustment (Tx2-10) were compared for differences within and between treatments (p < 0.05). Results Ephedrine increased cardiac index (CI), stroke volume index (SVI), oxygen delivery index *Present address: Hui C Chen, Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor DE, Malaysia.
(DO2I), and decreased total peripheral resistance (TPR) by Tx1-10, while MAP increased transiently (<5 minutes). The second ephedrine bolus produced no further improvement. Dopamine failed to produce significant changes at 5 lg kg)1 minute)1, while 10 lg kg)1 minute)1 increased MAP, CI, SVI significantly from baseline, and DO2I compared with Tx1-10. The improvement in CI, SVI, and DO2I was not significantly different between treatments at Tx2-10. Conclusions and clinical relevance In anesthetized hypotensive dogs, ephedrine and dopamine improved cardiac output and oxygen delivery. However, the pressure-elevating effect of ephedrine is transient, while an infusion of dopamine at 10 lg kg)1 minute)1 improved MAP significantly by additionally maintaining TPR. Keywords blood pressure, cardiovascular effects, inotropes, lithium dilution cardiac output, sympathomimetic.
Introduction Hypotension during general anesthesia has arbitrarily been defined as a mean arterial pressure (MAP) <60 mmHg, corresponding to a systolic arterial pressure (SAP) <80–90 mmHg (Haskins 1996). Below these pressures, vital organs such as the brain and the kidney may lose their ability to autoregulate their own blood supply (Guyton & Hall 2000). In addition, it is speculated that organ blood 301
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flow declines in proportion to the decrease in blood pressure (BP) and the extent of organ damage associated with poor oxygen delivery is assumed to be proportional to the duration of hypotension. Hypotension has been reported in some studies as one of the most common complications observed in small animal anesthesia (Hosgood 1998; Gaynor et al. 1999). At the Ontario Veterinary College, the small animal anesthesia database (1998–2001) revealed that 36% of all ASA II, dogs, during maintenance of anesthesia were hypotensive (as defined above). Although the consequences of low BP are difficult to quantify in morbidity studies, early recognition and treatment of hypotension is a logical expectation of safe anesthetic management when actual measurements of perfusion are unavailable, and may be important in preventing adverse effects if associated with decreased oxygen delivery. The causes of hypotension during anesthesia are multifactorial, with major contributing factors related to the cardiovascular depression of the anesthetic agents themselves and the clinical conditions of the patient. Management of hypotension during anesthesia includes assessment and correction of errors in anesthetic depth, arrhythmias (bradycardia, supraventricular, or ventricular premature contractions) and obvious or potential volume deficits. If hypotension persists despite these steps, then administration of inotropic drugs may be necessary to maintain BP. Ephedrine and dopamine are two inotropic agents commonly used to manage hypotension in small animals. Ephedrine is commonly used to treat hypotension associated with inhalation and spinal anesthesia in humans (Bernards 1996; Stoelting 1999), and has been recommended for use in small animals and horses (Wagner & Brodbelt 1997; Wagner 2000; Mazzaferro & Wagner 2001). It is a noncatecholamine sympathomimetic that can stimulate a- and b-adrenergic receptors directly, as well as indirectly, by causing endogenous release of norepinephrine (Stoelting 1999; Hoffman 2001). Ephedrine has the advantages of being inexpensive and convenient to use, as an intravenous (IV) bolus. Previous experimental work in Beagles demonstrated an improvement in MAP, cardiac output (CO), and stroke volume (SV) without producing arrhythmias (Wagner et al. 1993). However, these dogs were not hypotensive and the effectiveness of ephedrine in the management of clinically hypotensive patients that have received premedicants and injectable induction agents is not known. 302
Dopamine is an endogenous catecholamine that exerts its effects through stimulation of the dopaminergic, a-adrenergic and b-adrenergic receptors. Rapid metabolism of dopamine and its brief duration of action mandate its use as a continuous IV infusion (constant rate infusion, CRI) (Stoelting 1999; Moss & Renz 2000), which may make it less convenient to use in the clinical setting. The receptor and hemodynamic effects of exogenous administration of dopamine are dose-dependent within the typical infusion rates recommended (2–10 lg kg)1 minute)1) (Hosgood 1990; Wagner & Brodbelt 1997; Stoelting 1999; Moss & Renz 2000; Muir et al. 2000). Higher infusion rates or an accidental IV bolus injection may result in tachycardia, vasoconstriction, and hypertension, with the potential for arrhythmias. An increase in BP achieved when either dopamine or ephedrine is administered clinically is presumed to indicate an increase in CO, although changes in vascular tone could also affect BP. This study was undertaken to determine the cardiovascular responses of ephedrine at 0.2 mg kg)1, IV (repeated if inadequate response) and dopamine CRI at 5 lg kg)1 minute)1, IV (rate doubled if inadequate response) to manage hypotension in otherwise healthy client-owned dogs during routine anesthetic management prior to orthopedic surgery. Materials and methods Animals and selection criteria This study was approved by the University of Guelph’s Animal Care Committee. Clinical cases presented to the Veterinary Teaching Hospital of the Ontario Veterinary College were used with client consent. Initial selection criteria for dogs consisted of ASA II cases, 6 months to 8 years of age and weighing 20–35 kg, and anesthetized for orthopedic procedures. They were judged to be healthy based on history, physical examination and standard, minimal, preoperative blood work (hematocrit, total protein, and blood urea nitrogen). Anesthesia and instrumentation The anesthetic protocols were tailored to the individual case: premedication with acepromazine and hydromorphone, with or without glycopyrrolate, given by intramuscular injection; induction with thiopental or ketamine-diazepam (1:1)
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administered IV via a 20 SWG catheter (BD Insyte-W; Becton Dickinson, Sandy, UT, USA) placed in a cephalic vein; and anesthetic maintenance with isoflurane (Iso) in 100% oxygen. Following induction the Iso concentration was adjusted according to the requirement of the individual dog as judged by the anesthetist, who was not involved in the study. An epidural injection of morphine and bupivacaine was routinely administered in cases undergoing hindlimb procedures. Bupivacaine was used for blockade of the brachial plexus in dogs undergoing forelimb procedures. All dogs were allowed to breathe spontaneously and received a balanced electrolyte solution (Plasma-Lyte A; Baxter Corp., Toronto, ON, Canada), administered IV at 10 mL kg)1 hour)1. A multi-channel patient monitor (Criticare Model 1100; Criticare Systems Inc., Waukesha, WI, USA) was used to assess all physiologic parameters and airway gas concentrations. A 20 SWG catheter (BD Insyte-W, Becton Dickinson) was placed percutaneously in a dorsal pedal artery and connected to a disposable transducer system (Model DT-36; Ohmeda Medical Devices Division Inc., Madison, WI, USA) to monitor the BP directly and to allow for lithium dilution measurement of CO. The pressure transducer and the pressure channel were calibrated with a mercury manometer prior to each use and zero was set at the level of the heart. A lead II ECG was placed to monitor heart rate (HR) and rhythm, and an esophageal temperature probe was inserted to measure body temperature (Temp). An 8-French sampling line was inserted within the endotracheal tube to the level of the carina to perform gas sampling near its tracheal end for endtidal CO2 (PE¢CO2) and end-tidal Iso (ETIso). The spectrometry component of the patient monitor was calibrated with a commercial calibration gas (Anesthesia Calibration Gas; Criticare Systems Inc.) prior to each use. Inclusion criteria and design of treatment intervention Inclusion criteria for the inotropic treatment intervention were hypotension, defined as MAP <60 mmHg, not associated with bradycardia (HR <65 beats minute)1) or excessive anesthetic depth (as judged by the anesthetist according to typical reflexes and appropriate Iso concentration). Only dogs that developed hypotension prior to onset of surgery were studied further. Once the animal was
deemed hypotensive, the Iso concentration was not altered and baseline (T-0) measurements were taken. Random assignment of the ephedrine and dopamine treatments was computer-generated based on a target of six cases per treatment group. Ephedrine (Ephedrine sulfate injection 50 mg mL)1 USP; SABEX INC., Boucherville, QC, Canada) was diluted to 5 mg mL)1 with normal saline immediately prior to use. Dopamine (Intropin; Bristol-Myers Squibb Canada, Montreal, Canada) was pre-diluted in 5% dextrose to 0.4 mg mL)1 and kept in the refrigerator at 4C for up to 30 days. It was administered with fully primed lines using a syringe or a fluid pump. The target MAP was selected as 70 mmHg. The ephedrine treatment consisted of an IV bolus of 0.2 mg kg)1. If the MAP remained below the target at 10 minutes after the initial dose (Tx1-10), the ephedrine dose (0.2 mg kg)1, IV) was repeated. The dopamine treatment consisted of an IV infusion of 5 lg kg)1 minute)1 for 10 minutes, administered by syringe or fluid pump through the injection port on the IV fluid line closest to the patient (approximately 1.5 mL dead space existed before reaching patient). This infusion rate was maintained if the target MAP was achieved, but was doubled to 10 lg kg)1 minute)1 if MAP remained lower than 70 mmHg at Tx1-10. Dogs were monitored for an additional 10 minutes following the second dose or CRI adjustment, and final measurements were repeated (Tx2-10). Transfer of the animal into the operating room, or surgery did not commence until all measurements were completed. Other supportive treatments were administered, if necessary, following complete data collection. Data collection Measurements consisted of HR, SAP, MAP, diastolic arterial pressure (DAP), CO, PE¢CO2, ETIso, Temp, arterial blood gases, sodium (Na), and hemoglobin (Hb) concentration. Blood gases were temperaturecorrected and analyzed immediately after sampling (ABL 700 series, Radiometer, Copenhagen, Denmark). All parameters were measured at T-0, Tx1-10, and Tx2-10, although BP and HR were measured every 2.5 minutes following treatment interventions. A single determination of CO was carried out following all other data collection (at T-0, Tx1-10, and Tx2-10) and a lithium dilution technique (LidCO plus Hemodynamic Monitor; LiDCO Ltd,
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differences from T-0. Difference of least squares means was used to compare values at Tx1-10 and Tx2-10 within treatment. Contrast between the two treatments was applied to examine how the cardiovascular responses changed over time and whether they changed in the same way. For all tests, residuals plots were examined for equality of variances. Normality was tested using Shapiro– Wilk test. Data were log-transformed when necessary. p < 0.05 was considered significant.
London, UK) as described by Mason et al. (2002) was used. Arterial blood was sampled 3 minutes prior to the CO determination to obtain the Na and Hb values as required by the LiDCO system. The peripheral vein for IV fluid administration was also used for the bolus injection of the lithium indicator (1 mL, 0.15 mmol) through a three-way stopcock (IV Set Stopcock, 3-Way, 10-1000; Benlan Inc., Oakville, Ontario, Canada) attached directly to the catheter. Dopamine infusion was stopped (for 1–1.5 minutes) during CO determination to ensure that the catheter dead space was free of dopamine during the bolus lithium injection. Cardiac index (CI), stroke volume index (SVI), arterial oxygen content (CaO2) and oxygen delivery index (DO2I) were calculated using standard formulae (Boyd et al. 1991). Total peripheral resistance (TPR) was calculated as 79.9 · MAP CO)1.
Results Data are presented as mean ± SD unless otherwise noted. A total of 58 dogs were recruited in the study and of these, 12 developed hypotension (MAP ¼ 56 ± 4 mmHg), while none of the animals were excluded because of HR or rhythm abnormalities. The ephedrine group consisted of five females and one male, 2.7 ± 1.6 years of age and 30.1 ± 4.4 kg. Five were scheduled for repair of ruptured anterior cruciate ligaments and one was presented for radial osteotomy. The dopamine group consisted of two females and four males, 2.6 ± 2.5 years and 30.7 ± 6.4 kg. One of the following procedures was scheduled for each dog: elbow arthrotomy, triple pelvic osteotomy, radialulnar osteotomy, tibial plateau leveling osteotomy, forelimb amputation, and bilateral shoulder joint arthroscopy. Anesthetic drugs and doses used are summarized in Table 1. Time from induction to the diagnosis of hypotension ranged from 25 to 85 (48 ± 22)
Statistical analysis A mixed model (Proc Mixed, SAS Version 8; SAS Institute Inc., Cary, NC, USA) for the split-plot design was used to analyze the cardiovascular parameters for significant treatment, time, and interactions between treatment and time effect. Time was considered the repeated measure and the dog, a random effect. An autoregressive covariance structure of order 1 was included in the analyses to account for correlations between measurements at different time points. When there was a significant time effect within treatment, a Dunnett’s test was applied to compare for
Drugs
Premedication Glycopyrrolate* Acepromazine Hydromorphone Induction Ketamine† Thiopental Diazepam Supplemental analgesia Morphine (epidural) Bupivacaine 0.5% (epidural) Bupivacaine 0.5% (brachial plexus neural blockade)
Dose range (mg kg)1)
Ephedrine
Dopamine
0.005–0.01 0.010–0.05 0.050–0.10
5 6 6
5 6 6
3.75–5.0 3.3–12.5 0.2–0.25
2 4 2
2 4 4
0.1–0.26 (mg kg)1) 0.75–1.15 (mg kg)1) 1–1.5 (mg kg)1)
5 5 1
3 2 1
Table 1 Dose range and number of cases that received the drug in each treatment group prior to development of hypotension
*One dog in the dopamine group received glycopyrrolate during the study period; †ketamine was mixed with diazepam (1:1 by volume; 100 mg:5 mg, respectively)
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minutes in the ephedrine group, and 17–50 (31 ± 12) minutes in the dopamine group. The ETIso concentration was not significantly different (0.92 ± 0.20% and 0.87 ± 0.16%, for the dopamine and ephedrine groups, respectively). Dogs in the ephedrine group tended to have a lower Temp (36.1 ± 1.2 C) than those in the dopamine group (37.3 ± 0.9 C) at T-0, and Temp continued to drop over time in all the dogs. All other variables at baseline were not different between groups. None of the dogs achieved the target MAP following either treatment at Tx1-10. Blood pressures (SAP, MAP, and DAP) increased immediately following the first ephedrine bolus (Table 2; Fig. 1a), with significant differences from baseline at 2.5 minutes. The BP decreased rapidly, returning to near or below baseline within 5 minutes. The second bolus of ephedrine did not significantly change BP. Dopamine at 5 lg kg)1 minute)1 did not improve BP significantly by Tx1-10. By doubling the dopamine infusion rate to 10 lg kg)1 minute)1, significant improvement was detected at Tx2-5, Tx2-
7.5, and Tx2-10. By the end of the study period, the target MAP was attained in four dogs in the dopamine group compared with one dog in the ephedrine group, and the improvement in MAP from baseline and Tx1-10 was significantly greater with the dopamine treatment than with ephedrine (p ¼ 0.0007 and 0.0076, respectively). An MAP of less than 50 mmHg following administration of the initial dose of the inotrope was noted in three dogs in the ephedrine group and in one dog in the dopamine group. Five animals in the ephedrine group had an MAP at Tx1-10 that was lower than baseline, and the MAP at the end of the study period remained lower than baseline in four of them. One dog in the dopamine group had an MAP at Tx1-10 that was lower than baseline, but by the end of the study period, MAP was higher than baseline in all six cases. There was no overall treatment or time effect on HR, but an interaction between treatment and time was significant (p ¼ 0.0016). This significance was related to the readings at Tx1-2.5 when HR
Table 2 Cardiovascular responses (mean ± SD) following detection of hypotension (T-0) and following each intervention: Tx1 – ephedrine bolus (E) (0.2 mg kg)1, IV) or dopamine infusion (D) (5 lg kg)1 minute)1, IV); Tx2 – repeated ephedrine bolus (0.2 mg kg)1, IV), or dopamine at 10 lg kg)1 minute)1, IV
First treatment intervention (Tx1)
Second treatment intervention (Tx2)
Baseline Variables
T-0
HR (beats minute)1) E 93 ± 14 D 96 ± 24 SAP (mmHg) E 100 ± 22 D 94 ± 14 DAP (mmHg) E 43 ± 6 D 44 ± 3 SVI (mL beat)1 kg)1) E 1.15 ± 0.22 D 1.33 ± 0.32 Hb (g dL)1) E 12.4 ± 1.0 D 12.7 ± 1.2 CaO2 (mL L)1) E 190 ± 13 D 193 ± 15
Tx1-2.5
Tx1-5
Tx1-7.5
Tx1-10
Tx2-2.5
Tx2-5
Tx2-7.5
Tx2-10
105 ± 18* 86 ± 19
101 ± 19 92 ± 21
103 ± 24 88 ± 19
102 ± 21 86 ± 20
109 ± 22* 87 ± 20
102 ± 23 90 ± 16
106 ± 19 98 ± 23
106 ± 19 96 ± 21
125 ± 24* 86 ± 15
107 ± 24 91 ± 15
104 ± 38 103 ± 18
98 ± 31 102 ± 23
108 ± 38 106 ± 17
106 ± 39 133 ± 37*
108 ± 29 140 ± 40*
108 ± 31bc 147 ± 39*#
56 ± 15* 42 ± 7
48 ± 9 44 ± 5
43 ± 5 48 ± 3
42 ± 6 48 ± 4
44 ± 8 46 ± 4
45 ± 12 56 ± 10*
43 ± 10 61 ± 15*
43 ± 19bc 59 ± 10*#
– –
– –
– –
1.4 ± 0.53* 1.49 ± 0.26
– –
– –
– –
1.38 ± 0.43* 1.71 ± 0.44*
– –
– –
– –
12.0 ± 0.7* 11.9 ± 1.1*
– –
– –
– –
12.3 ± 1.0 11.8 ± 1.4*
– –
– –
– –
181 ± 16* 182 ± 15*
– –
– –
– –
188 ± 13 181 ± 20*
HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; SVI, stroke volume index; Hb, hemoglobin concentration; CaO2, arterial oxygen content. Tx1-y (time in minutes following first treatment); Tx2-y (time in minutes following second treatment). Significant differences (p < 0.05) are denoted as follows: within the same treatment, *value differs from baseline (T-0), # value at Tx2-10 differs from Tx1-10; between treatments, afirst response (T-0 to Tx1-10) differs, bsecond response (Tx1-10 to Tx2-10) differs, and csum of responses (T-0 to Tx2-10) differs.
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increased after the ephedrine bolus (p ¼ 0.0434), but tended to decrease in the dopamine group (p ¼ 0.1558). The increase in HR was significant at Tx2-2.5 following the repeated dose of ephedrine (p ¼ 0.0326). Sinus arrhythmia was observed following administration of ephedrine (n ¼ 1) and escape beats (ventricular beat following a short sinus arrest) with dopamine when it was increased to 10 lg kg)1 minute)1 (n ¼ 1). Glycopyrrolate (0.005 mg kg)1, IV) was administered to the latter case, resulting in a dramatic increase in HR and BP. If the data points following treatment with glycopyrrolate in this dog were excluded from the statistical analysis, the increase in HR from T-0 to Tx2-10 in the ephedrine group was higher than that in the dopamine group (p ¼ 0.0436), but all other results were not affected. Following this incident,
glycopyrrolate was included in the premedication of subsequent cases (10/12 dogs). The first dose of ephedrine significantly improved CI (p ¼ 0.0040), SVI (p ¼ 0.0472), and DO2I (p ¼ 0.0131), while the repeat dose of ephedrine did not change these parameters further and values at Tx2-10 remained higher than baseline (Table 2; Figs 1b & c). Dopamine at 5 lg kg)1 minute)1 did not change the CI, SVI, or DO2I, but improvement was seen when the infusion rate was increased to 10 lg kg)1 minute)1, although the increase in DO2I did not reach statistical significance (p ¼ 0.0078, 0.0006, and 0.0526, respectively). In addition, Tx210 values were greater than Tx1-10 (p ¼ 0.0020, 0.0798, and 0.0045, respectively). The improvement in CI and DO2I from baseline to Tx1-10 was greater following the first ephedrine bolus compared
Figure 1 Effects (mean ± SD) of ephedrine (————) and dopamine (_ _ _ _ _) treatments on mean arterial pressure (MAP), cardiac index (CI), oxygen delivery index (DO2I) and total peripheral resistance (TPR) following detection of hypotension (T-0) and following each intervention: Tx1 – ephedrine bolus (0.2 mg kg)1, IV) or dopamine infusion (5 lg kg)1 minute)1, IV); Tx2 – repeated ephedrine bolus (0.2 mg kg)1, IV) or dopamine at 10 lg kg)1 minute)1, IV (arrows indicate commencement of treatments). Significant differences (p < 0.05) are denoted as follows: within the same treatment, *value differs from baseline (T-0), #value at Tx1-10 differs from Tx2-10; between treatments, afirst response (T-0 to Tx1-10) differs, bsecond response (Tx1-10 to Tx2-10) differs, csum of responses (T-0 to Tx2-10) differs. 306
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with dopamine at 5 lg kg)1 minute)1 (p ¼ 0.0495 and 0.0353, respectively). By the end of the study period, there was no significant difference in the increases in CI, SVI, or DO2I between treatments. Following the first dose of ephedrine, TPR at Tx110 was significantly lower than baseline (p ¼ 0.0004) (Fig. 1d). The repeated dose of ephedrine did not change TPR further, and TPR at Tx2-10 remained lower than baseline (p ¼ 0.0033). Dopamine at both infusion rates did not change the TPR significantly at Tx1-10 and Tx2-10 when compared with baseline. In general, the Hb concentration decreased over time in both groups. The repeated dose of ephedrine tended to increase the Hb concentration toward the baseline value, but these changes were not statistically significant. Arterial oxygen content followed a trend similar to Hb concentration. There were no significant treatment, time, or interaction effects in arterial Na (148 ± 2 and 147 ± 2 mmol L)1), pH (7.253 ± 0.082; 7.268 ± 0.054), carbon dioxide tension (54.4 ± 10.0 and 53.2 ± 6.1 mmHg), oxygen tension (548.6 ± 31.6 and 532.7 ± 36.5 mmHg), bicarbonate (23.2 ± 2.2 and 23.5 ± 1.3 mmol L)1), or base excess values ()4.3 ± 3.0 and )3.5 ± 2.2 mmol L)1) for ephedrine and dopamine groups, respectively (pooled data for the three time points). All dogs had an uneventful recovery from anesthesia. Discussion Our study showed presurgical hypotension in 21% of these ASA II dogs. This number is lower than the 36% recorded from our whole database but the latter represents the whole period of anesthesia compared with just the pre-surgical period in this study. No evidence of volume deficits was noted in the preoperative evaluations, although subclinical dehydration could have existed. Additional fluid administration may have been effective in some of these animals. The prolonged preoperative time in our dogs was likely a contributor to the development of this hypotension. The lack of stimulation during radiography, clipping, and surgical preparation is likely to result in lower BP than that associated with surgery. Although benefits were shown with the use of inotropes in this study, their use in clinical cases should be reserved for those animals known to have poor contractility or following more directed treatment of the suspected problem. However, this study
confirmed that in hypotensive dogs exposed to various anesthetic agents both ephedrine and dopamine improved perfusion as demonstrated by a significant increase in CI, SVI, and DO2I. However, ephedrine at 0.2 mg kg)1 IV increased BP transiently and was not improved with a repeated dose. The initial effect lasted less than 5 minutes and appeared to be countered by a significant decrease in TPR. Dopamine at 10 lg kg)1 minute)1 significantly improved BP with a similar rise in CI, SVI, and DO2I. Most of the cardiovascular responses following ephedrine administration in our study were similar to those reported by Wagner et al. (1993). However, the increase in BP in their dogs was longer and more intense at the higher dose. Ephedrine at 0.1 mg kg)1 IV increased MAP significantly for 5 minutes while at 0.25 mg kg)1 IV, the effect lasted for 15 minutes. The shorter duration and intensity in our dogs could be attributable to the addition of other drugs as part of the anesthetic management and the presence of baseline hypotension prior to treatment, although the overall BP achieved was not remarkably different. Our premedication may have been the most likely cause for the difference in response to ephedrine. Acepromazine is a potent a1 antagonist producing peripheral vasodilation and resulting in a dosedependent decrease in BP (Coulter et al. 1980; Muir & Hubbell 1985). Previous work has demonstrated that with prior administration of acepromazine in dogs anesthetized with halothane, the amount of phenylephrine required to increase MAP by 50% increased in a dose-dependent manner (Ludders et al. 1983). A higher dose of ephedrine may have resulted in a better BP response. This a1 antagonist effect may also explain the lack of increase in Hb concentrations in response to ephedrine as noted with both ephedrine (Wagner et al. 1993) and higher doses of dopamine (Abdul-Rasool et al. 1987). The other drugs used for premedication and induction (hydromorphone, thiopental, ketamine, and diazepam) do not have direct effects on a- or b-adrenergic receptors. Although Iso causes a dosedependent decrease in BP associated with a decrease in systemic vascular resistance (SVR) and CI (Steffey & Howland 1977; Pagel et al. 1991), it is expected that this decrease in BP will respond to a- and/or b-adrenergic stimulation. Spinal anesthesia and, to a lesser degree, epidural anesthesia in humans has been shown to produce hypotension as a result of venous and arterial
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dilation induced by the sympathetic blockade (Bernards 1996). However, Torske et al. (1999) studied the effects of epidural administration of oxymorphone and bupivacaine (at similar doses to the ones used in the current study) in halothane anesthetized dogs and reported no significant change in SVR when the concentration was appropriately reduced according to the MAC-sparing effect. Other studies demonstrated reductions in BP following epidural bupivacaine (0.36 mL kg)1) in conscious dogs (Franquelo et al. 1995), and epidural lidocaine (0.1 mL kg)1) in dogs anesthetized with 1.5% sevoflurane (Hirabayashi et al. 1996). It is unlikely that more sympathetic blockade was present in both these studies as these doses are above and below (respectively) our dose and that used by Torske et al. (1999). Epidural bupivacaine could have influenced the vascular response produced by ephedrine in our study, although the same effect was shown in the dog that received the brachial plexus neural blockade. Additional clinical research is required to substantiate any confounding effect. The variability of time from drug administration to actual ephedrine treatment in each dog may have contributed to some difference in the effect of ephedrine. However, BP improvement was not maintained even when the time for hypotension development was delayed. This study provided no evidence that the effect of BP from ephedrine would last beyond 5 minutes in hypotensive dogs or be maintained with a repeated bolus. In our study, HR increased immediately following both the first and second bolus doses of ephedrine, while HR decreased significantly for up to 15 minutes in the study by Wagner et al. (1993). This difference is likely due to a baroreceptor response to the acute and prolonged increase in BP in their dogs. The two dogs in our study, that demonstrated the best BP response following ephedrine, also showed a decrease in HR. The HR gradually increased as BP decreased. Although it is possible that glycopyrrolate may have predisposed the dogs to an increased HR following ephedrine, this increase in HR also fits with the underlying mechanism of action of ephedrine to stimulate the cardiac b1-receptors (Lawson & Meyer 1996; Stoelting 1999; Hoffman 2001). The increase in CI and reduction in TPR with ephedrine treatment in dogs is consistent with other studies (Grandy et al. 1989; Wagner et al. 1993; Lee et al. 2002). Although the increase in CO has also been shown to be due to increased venous 308
return caused by selective venoconstriction (Butterworth et al. 1986; Lawson & Meyer 1996), the effect on cardiac b1-receptors is the primary mechanism (Lawson & Meyer 1996; Stoelting 1999; Hoffman 2001). We did not measure central venous pressure in these dogs and thus have no estimation of alterations in venous return. Moreover, the inability to use this value in the TPR calculation may have contributed to some error in this measurement, but it is unlikely to have made a significant impact on these results due to the narrow range for central venous pressures. The reduced response observed with the repeated bolus of ephedrine may be an indication of tachyphylaxis. This is explained by persistent occupation of both the adrenergic receptors by the first dose of ephedrine or depletion of norepinephrine stores (Stoelting 1999). It is also possible that a better response may have been obtained if a higher dose of ephedrine was used in the repeated bolus (Butterworth et al. 1986). Alternatively, an infusion of ephedrine could be considered as has been used in humans (Gajraj et al. 1993; Critchley et al. 1995; Chan et al. 1997). Research to substantiate the appropriate dose and overall cardiovascular effect with a CRI of ephedrine in dogs requires further investigation. Our work indicates that ephedrine would be useful when a very short-lived increase in BP is sufficient, such as in the face of significant hypotension immediately before surgery or when a delay exists in starting other treatments (e.g., if preparation is required). Ephedrine should be able to increase CO when used in hypotensive dogs at these doses, although evidence for the degree of change in CO is unlikely to be easily measured. The cardiovascular responses to the dopamine infusion in hypotensive dogs were in agreement with the general descriptions of dose-dependent receptor and hemodynamic effects reported by others (Robie & Goldberg 1975; Abdul-Rasool et al. 1987; Raner et al. 1995; Moss & Renz 2000). The lack of response to the 5 lg kg)1 minute)1may be due to the pharmacokinetics of dopamine. Although no data have been reported in dogs, the elimination half-life reported in humans is 12.3 minutes (MacGregor et al. 2000) which would mean that the plasma concentration of dopamine achieved after 5 minutes would be less than 50% of the value expected under steady-state conditions. A significant increase in BP was noted at 5 minutes following the start of 10 lg kg)1 minute)1 of
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dopamine. The improvement in BP appeared to plateau at 7.5 minutes with no further change after this time at either infusion rate. This provided evidence that the patient should be reassessed, the infusion rate changed, or the IV line checked for obstructions if the desired BP is not achieved within 7.5 minutes of dopamine therapy. However, it is not possible to define the impact from the administration of 5 lg kg)1 minute)1 for the first 10 minutes on the response time or on the effect produced by 10 lg kg)1 minute)1 of dopamine. The reason for using this design was to mimic the clinical situation. In humans (MacGregor et al. 2000) and cats (Pascoe et al. 2006) it has also been observed that the plasma concentration of dopamine achieved with a given infusion rate is highly variable providing another impetus to increase the infusion rate if the desired goal is not achieved within a reasonable time period. Although the improvement in CI and SVI associated with dopamine administration at 10 lg kg)1 minute)1 was not different from that produced by ephedrine, the lack of change in TPR resulted in a better BP response. Although it might be suggested that a reduction in TPR is preferential for perfusion and reduces cardiac workload, this must be considered in light of the fact that both Iso and acepromazine cause some vasodilation and thus, there may be little advantage to a further reduction in TPR. Unfortunately, without the measurement of CO there may be little evidence during anesthesia of a drug effect on this parameter unless a change in BP is produced. The improvement in BP with dopamine administration is evidence of its effect and a reflection of the increase in CO. Maintenance of adequate systemic BP influences perfusion pressure and organ blood flow (Guyton & Hall 2000) and thus, the ability of dopamine to increase MAP above 60 mmHg in all our dogs while ephedrine was only effective in one animal provided some evidence for the preferred use of dopamine in clinical cases. Only two dogs in the dopamine group received epidural bupivacaine compared with five in the ephedrine group. This may reduce the comparability of the groups, but both the dogs in the dopamine group responded well to dopamine at 10 lg kg)1 minute)1. If epidural administration of bupivacaine contributed to the poorer BP response of ephedrine boluses in this study, dopamine, at 10 lg kg)1 minute)1 may be preferable in such situations.
Variation in the actual activity of the dopamine solution used in this study cannot be ruled out, it was not diluted immediately before each use. The dopamine was pre-diluted and stored in the refrigerator. Commercial availability of pre-diluted dopamine (DOPamine HCl and 5% Dextrose injection, 800 lg mL)1, 250 mL bags; Baxter Corp.) provided some evidence that our preparation was likely to be effective. We have obtained good results with our pre-diluted dopamine in clinical cases and are confident in the efficacy of the dopamine. Despite this shortcoming, an expected dose–response was shown in the present study. Individual variation was apparent in the cardiovascular responses to the treatment in this study. This variability could be the result of differences in age, sex, cardiac condition, volume status, ETIso, PE¢CO2, residual effects of prior administered drugs, degree of physical stimulation, differences in the sensitivity of specific receptor types, existing endogenous catecholamine, and variation in the pharmacokinetics, and thus, plasma concentrations of the drugs used (MacGregor et al. 2000). Although all data were collected prior to surgery, maneuvers such as extending and hanging of the limb for surgical preparation, and changes in position may have produced stimulation of the dogs, as anesthesia was maintained at a light plane. All the dogs in this study hypoventilated, with PE¢CO2 values higher than 45 mmHg. Hypercapnia augments BP and CO through stimulation of the sympathetic nervous system and release of catecholamines (Cullen & Eger 1974; Wagner et al. 1990). The degree of hypercapnia was unlikely to have influenced the cardiovascular values significantly. In addition, it was similar over the assessment time, between dogs and between groups. Ideally all variables would have been controlled. However, the intention of this study was to apply the treatments in the face of the variation that occurs in clinical cases. In conclusion, the results of this study suggest that ephedrine (0.2 mg kg)1, IV), repeated at a 10minute interval was less effective than a dopamine infusion to augment BP pre-surgically in hypotensive dogs during routine anesthetic management. However, the degree of improvement in CI, SVI, and DO2I was not different between the two treatments and hence perfusion may be increased with either. A dopamine infusion may be more useful clinically, as the rate can be adjusted according to individual BP responses.
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Acknowledgements This study was supported by the Pet Trust Fund, Ontario Veterinary College. Statistical consultation was provided by William C Sears, MS (Zoology), MSc (Statistics), Department of Population Medicine, University of Guelph, Guelph, Canada. References Abdul-Rasool IH, Chamberlain JH, Swan PC et al. (1987) Cardiorespiratory and metabolic effects of dopamine and dobutamine infusions in dogs. Crit Care Med 15, 1044– 1050. Bernards CM (1996) Epidural and spinal anesthesia. In: Clinical Anesthesia (3rd edn). Barash PG, Cullen BR, Stoelting SK (eds). Lippincott-Raven Publishers, Philadelphia, PA, USA, pp. 645–668. Boyd CJ, McDonell WN, Valliant A (1991) Comparative hemodynamic effects of halothane and halothane-acepromazine at equipotent doses in dogs. Can J Vet Res 55, 107–112. Butterworth JF, Piccione W Jr, Berrizbeitia LD et al. (1986) Augmentation of venous return by adrenergic agonists during spinal anesthesia. Anesth Analg 65, 612–616. Chan WS, Irwin MG, Tong WN et al. (1997) Prevention of hypotension during spinal anaesthesia for caesarean section: ephedrine infusion versus fluid preload. Anaesthesia 52, 908–913. Coulter DB, Whelan SC, Wilson RC et al. (1980) Determination of blood pressure by indirect methods in dogs given acetylpromazine maleate. Cornell Vet 71, 76–84. Critchley LA, Stuart JC, Conway F et al. (1995) Hypotension during subarachnoid anaesthesia: haemodynamic effects of ephedrine. Br J Anaesth 74, 373–378. Cullen DJ, Eger EI 2nd (1974) Cardiovascular effects of carbon dioxide in man. Anesthesiology 41, 345–349. Franquelo C, Toledo A, Manubens J et al. (1995) Bupivacaine disposition and pharmacologic effects after intravenous and epidural administration in dogs. Am J Vet R 56, 1087–1091. Gajraj NM, Victory RA, Pace NA et al. (1993) Comparison of an ephedrine infusion with crystalloid administration for prevention of hypotension during spinal anesthesia. Anesth Analg 76, 1023–1026. Gaynor JS, Dunlop CI, Wagner AE et al. (1999) Complications and mortality associated with anesthesia in dogs and cats. J Am Anim Hosp Assoc 35, 13–17. Grandy JL, Hodgson DS, Dunlop CI et al. (1989) Cardiopulmonary effects of ephedrine in halothane-anesthetized horses. J Vet Pharmacol Ther 12, 389–396. Guyton AC, Hall JE (2000) Textbook of Medical Physiology (10th edn). WB Saunders, Philadelphia, PA, USA, pp. 210–710. Haskins SC (1996) Monitoring the anesthetized patients. In: Lumb and Jones’ Veterinary Anesthesia (3rd edn).
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Pascoe PJ, Ilkiw JE, Pypendop BH (2006) Effects of increasing infusion rates of dopamine, dobutamine, epinephrine, and phenylephrine in healthy anesthetized cats. Am J Vet 67, 1491–1499. Raner C, Biber B, Henriksson BA et al. (1995) Are the cardiovascular actions of dopamine altered by isoflurane? Acta Anaesthesiol Scand 39, 678–684. Robie NW, Goldberg LI (1975) Comparative systemic and regional hemodynamic effects of dopamine and dobutamine. Am Heart J 90, 340–345. Steffey EP, Howland D (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833–1836. Stoelting RK (1999) Pharmacology & Physiology in Anesthetic Practice (3rd edn) Lippincott Williams & Wilkins, Philadelphia, PA, USA, pp. 259–276. Torske KE, Dyson DH, Conlon PD (1999) Cardiovascular effects of epidurally administered oxymorphone and oxymorphone-bupivacaine combination in halothaneanesthetized dogs. Am J Vet Res 60, 194–200.
Wagner AE (2000) Focused supportive care: blood pressure and blood flow during equine anesthesia. In: Recent Advances in Anesthetic Management of Large Domestic Animals. Steffey EP (ed.). International Veterinary Information Service (http://www.ivis.org). Wagner AE, Brodbelt DC (1997) Arterial blood pressure monitoring in anesthetized animals. J Am Vet Med Assoc 210, 1279–1285. Wagner AE, Bednarski RM, Muir WW 3rd (1990) Hemodynamic effects of carbon dioxide during intermittent positive-pressure ventilation in horses. Am J Vet Res 51, 1922–1929. Wagner AE, Dunlop CI, Chapman PL (1993) Effects of ephedrine on cardiovascular function and oxygen delivery in isoflurane-anesthetized dogs. Am J Vet Res 54, 1917–1922. Received 27 July 2004; accepted 15 December 2005.
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