- Email: [email protected]
Evaluation of Cardiovascular Function During S(+)-Ketamine Constant Rate Infusion in Dorsally Recumbent Halothane-Anesthetized Horses
Accepted Manuscript Evaluation of cardiovascular function during S(+)-ketamine constant rate infusion in dorsally recumbent, halothane-anesthetized horses Paulo A. Canola , DVM, PhD, Carlos A.A. Valadão , DVM, PhD, José Henrique S. Borges , DVM, PhD, Júlio C. Canola , DVM, PhD PII:
S0737-0806(14)00457-2
DOI:
10.1016/j.jevs.2014.11.005
Reference:
YJEVS 1801
To appear in:
Journal of Equine Veterinary Science
Received Date: 24 February 2014 Revised Date:
30 September 2014
Accepted Date: 25 November 2014
Please cite this article as: Canola PA, Valadão CAA, Borges JHS, Canola JC, Evaluation of cardiovascular function during S(+)-ketamine constant rate infusion in dorsally recumbent, halothaneanesthetized horses, Journal of Equine Veterinary Science (2014), doi: 10.1016/j.jevs.2014.11.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Evaluation of cardiovascular function during S(+)-ketamine constant rate infusion in
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dorsally recumbent, halothane-anesthetized horses Paulo A. Canola DVM, PhD1; Carlos A. A. Valadão DVM, PhD1; José Henrique S.Borges
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DVM, PhD2; Júlio C. Canola DVM, PhD1
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1
- São Paulo State University. School of Agrarian Sciences and Veterinary Medicine.
Department of Veterinary Clinics and Surgery, Jaboticabal, SP 14884-900, Brazil. 2
- Centro Universitário da Grande Dourados. Dourados, MS 79824-900, Brazil.
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Institution where this work was done: São Paulo State University. School of Agrarian
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Sciences and Veterinary Medicine. Department of Veterinary Clinics and Surgery, Brazil.
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Disclaimers: None.
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Address correspondence and reprint requests: Júlio Canola, FCAV/UNESP - Campus
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of Jaboticabal. Via de Acesso Prof.Paulo Donato Castellane, Km 5; 14884-900 -
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Jaboticabal, SP. Phone: +55 16 3209-2626 Email: [email protected].
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Source of support: CNPq (PQ-1C; 306940/2008-6)
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Conflicts of Interest: None.
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Results / partial results have not been presented in any scientific meeting.
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Running title: Evaluation of cardiovascular function during S(+) ketamine CRI in dorsally
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recumbent, halothane-anesthetized horses
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Abstract
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The cardiovascular effects of constant rate infusion (CRI) of S(+)-ketamine in
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dorsally recumbent, halothane-anesthetized horses were assessed. Six mixed-breed, adult,
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male horses, weighting 350 to 450 kg were used. The animals were randomly distributed
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into two (treatments) groups, with each horse receiving both treatments. Sedation with
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xylazine (1mg/kg, IV), infusion of 10% guaifenesine (100 mg/kg in 5% glucose), induction
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with S(+)-ketamine (1 mg/kg, IV), and maintenance with halothane (end-tidal concentration
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of 1.5 MAC) was standardized for both groups. When halothane end-tidal concentration
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stabilized at 1.5 MAC, CRI with S(+)-ketamine (GrKet) at 0.01 mg/kg/min (diluted in 250 ml
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of 0.9% saline solution) or the same volume of 0.9% saline solution (GrSal) was initiated
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(M0). CRI was maintained for 50 minutes (M50). Cardiac output (CO), fractional shortening
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(FS) and ejection fraction (EF), heart rate (HR), respiratory rate (ƒR), systolic (SAP), mean
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(MAP) and diastolic (DAP) arterial pressures were recorded at: B - baseline; Rec – lateral
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recumbency; PI – two minutes post-anesthetic induction; M0 – beginning of CRI; M10 to
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M50 – CRI elapsed time. Only MAP differed between groups (M20). ƒR decreased (p ≤
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0.05) PI in GrKet and during CR in GrSal. CO, SF, EF, SAP, MAP and DAP decreased (p ≤
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0.05) in both groups during CRI. CRI with S(+)-ketamine at 0.01 mg/kg/min was ineffective
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in improving cardiocirculatory depression commonly observed in halothane-anesthetized
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horses. Despite possible limitations, transcutaneous echocardiographic assessment of left
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ventricular activity in dorsally-recumbent horses seemed applicable. Further studies are
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encouraged to validate its reliability.
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Key words: equine; cardiac output; general anesthesia; left ventricular activity; ultrasound.
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Abreviation
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B – baseline values
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bpm – beats per minute (heart rate) or breaths per minute (respiratory rate)
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MAC – minimal alveolar concentration
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CNS – central nervous system
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CO – cardiac output
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DAP – diastolic arterial pressure
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ECG – electrocardiography
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HR – heart rate
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EF – ejection fraction
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ETHal – end-tidal halothane
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ƒR – respiratory rate
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FS – fractional shortening
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GrSal – saline infusion group
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GrKet – ketamine S(+) infusion group
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LV - left ventricular
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LVIDd - left ventricular internal diameter end diastole
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LVIDs - left ventricular internal diameter end systole
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L/min – liters per minute
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MAP – mean arterial pressure
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ml/kg/min – milliliters per kilogram per minute
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PaCO2 - partial pressure of carbon dioxide in arterial blood
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PAM – pre-anesthetic medication
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PI – post-induction
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PRec – post-recumbence
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SAP – systolic arterial pressure
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SV - stroke volume
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TIVA - total intravenous anesthesia
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PaO2 - partial pressure of oxygen in arterial blood
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1. Introduction Horses are more likely to suffer morbidities and mortality during anesthetic
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procedures when compared with people, dogs, and cats. Therefore, anesthesia in the horse
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is inherently risky. Normally, when cardiovascular factors are recorded as the primary
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cause of death in anesthetized horses, failure of the cardiovascular system is considered
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the primary or initial cause of death. Anesthetic-related deaths in horses attributed to
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cardiovascular causes correspond to 20% to 50% of cases. However, some anesthetic-
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related deaths are surely misclassified as being caused by cardiovascular factors in the
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absence of any other probable cause of death [1].
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Respiratory causes of anesthetic-related death in horses contribute to only 4% to
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25% of cases. Fractures on recovery contributed to death in 12.5% to 38% of cases, and
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postanesthetic myopathy in 7% to 44% of cases. Abdominal complications, such as colitis
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or peritonitis, are reported as causing 13% of anesthetic-related deaths in noncolic cases
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[1-3].
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In order to minimize anesthetic-related death, the concept of balanced anesthesia
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was created. The term “balanced anesthesia” is currently mostly used for an inhalational
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anesthetic-based technique as opposed to techniques that exclude all inhalational
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anesthetics, which have been termed total intravenous anesthesia (TIVA) [4]. Balanced
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anesthesia consists of administering a combination of anesthetic drugs to provide the
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patient with the desired effects of these drugs while minimizing their adverse side effects,
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such that analgesia, hypnosis, and stable cardiorespiratory function are enhanced. In face
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of critical cases, balanced techniques are more likely to be selected than total volatile or
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intravenous techniques to meet patients’ requirements for analgesia, support of
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cardiorespiratory function, and anesthetic depth. In these circumstances, anesthesia time
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tend to be longer when compared to elective cases. Balanced anesthesia preserves
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cardiovascular function but has the potential to depress respiratory function to a greater
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extent than TIVA or volatile anesthesia [4, 5].
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Most balanced anesthesia techniques include the use of alpha2-adrenergic agonists
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mainly because of their potent sedative and analgesic effects [4-7]. Alpha2-adrenergic
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agonists were the first reported class of drugs that reduced inhalation anesthetic
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requirements in horses [7]. Alpha2-adrenergic agonists have been shown to decrease the
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MAC of halothane by approximately 20% to 35% in a dose-dependent and time-dependent
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fashion [6]. The main concern is their impact on cardiovascular function. In that matter,
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alpha2-adrenergic
agonists
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bradyarrhythmias
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(characterized by first, second or third degree atrioventricular [AV] blocks) with decreased
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cardiac output. Increased systemic vascular resistance and increased blood pressure are
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further transient signs observed with alpha2-adrenergic agonists’ administration. Initial
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hypertension is followed by more enduring hypotension [5, 8, 9]. Transient hypertension
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associated with xylazine administration is caused by drug interaction with adrenergic
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receptors, subsequently leading to moderate but prolonged hypotension. The reflex
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bradycardia is caused by response of parasympathetic tonus to the increased systemic
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vascular resistance [10,11].
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In a recent review on the use of injectable anesthetics and analgesics by the
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American Association of Equine Practitioners, the use of xylazine followed by ketamine and
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diazepam was the preferred induction protocol for anesthesia procedures of 20 minutes’
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duration, whereas anesthesia procedures over 30 minutes’ duration were most commonly
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performed with a mixture of guaifenesin, xylazine and ketamine or isoflurane [5, 7].
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Ketamine is a dissociative agent which, in systemically healthy horses, induces
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analgesia, amnesia, and immobility without depressing cardiovascular function. These
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properties make ketamine an ideal agent for balanced anesthesia in the horse [4]. This drug
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has been advocated for induction of general anesthesia in patients with circulatory
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disturbances due to its effects on (enhancing) sympathetic tonus. Drug interaction with
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alpha1-adrenergic agonists results in increased heart rate, cardiac output, mean arterial
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pressure, pulmonary arterial pressure as well as central venous pressure [12, 13].
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Similarly to any other drug, ketamine is composed by racemic mixture of two
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enantiomers: dextrogyre [R(-)] and levogyre [S(+)] isomers. Racemic ketamine can provoke
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emergence reactions during anesthetic recovery that can turn into a fatal event in horses.
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Muscle tremor and rigidity, mydriasis, oculogyric movements, sweating, excitation, ataxia,
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and schizophrenia-like behavior observed during anesthetic recovery of horses have been
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attributed to ketamine’s dextrogyre isomer [4]. To that matter, ketamine’s levogyre isomer
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was more effective in producing analgesia during and following surgery, with fewer
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incidences of hallucinogenic effects, when compared to racemic ketamine [14]. In ponies,
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levogyre ketamine provided an identical degree of immobility after a single injection of half
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the dose of racemic ketamine with a more rapid recovery [4].
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Ketamine produces beneficial hemodynamic effects during halothane anesthesia.
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Increased anesthetic stability and decreased need for dobutamine infusion were observed
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with combination of ketamine and guaifenesin during halothane anesthesia, when
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compared with halothane alone. Moreover, ketamine infusion increases anesthetic and
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hemodynamic stability and decreases hypotension. Its sympathomimetic action minimizes
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bradycardia and hypotensive effects of sedatives such as alpha2-adrenergic agonists and
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inhaled anesthetics [4, 15]. Guaifenesin, a centrally acting muscle relaxant, is used routinely in association with
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xylazine and ketamine as part of anesthetic protocols in large animal species. At
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therapeutic doses (35-100 mg/kg) it promotes skeletal muscle relaxation. However, it does
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not provide analgesia or produce unconsciousness. When guaifenesin is given alone, heart
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rate, respiratory rate, and cardiac output are unchanged. Still, arterial pressures are
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decreased [16, 17]. When administered prior to guaifenesin, xylazine reduced the dose
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necessary to achieve lateral recumbence compared with guaifenesin alone. Addition of
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xylazine typically decreases heart rate, respiratory rate, cardiac output, and partial pressure
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of oxygen in arterial blood (Pa02) [16]. Completing the induction of anesthesia with
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halothane often produces marked arterial hypotension but the pressure recovers slowly
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over the next 20 to 30 min [17].
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Inhalant anesthetics such as halothane are frequently used in horses during surgical
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procedures requiring general anesthesia. With a blood/gas solubility coefficient of 2.3, a
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minimal alveolar concentration (MAC) of 0.88% is required for halothane to induce general
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anesthesia in horses. It does not react with soda-lime; however, it decomposes into
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halogenated gases when exposed to light. Halothane biotransformation occurs primarily in
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the liver where it is converted into trifluoroacetic acid by the cytochrome P-450 system in
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the endoplasmic reticulum of the hepatocytes. However, about 60-80% is eliminated
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unchanged during exhalation [18].
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Halothane depresses circulatory and central nervous systems function in a dose-
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dependent fashion until respiratory and cardiovascular collapse and death. Breathing rate
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decreases with anesthetic depth until complete respiratory arrest at 2.6 MAC. A reduction in
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cardiac output, stroke volume and arterial pressure in humans and animal models has been
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demonstrated during halothane anesthesia, when compared to awaken individuals [18].
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Peripheral vasodilation is not considered the primary cause of hypotension since total
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peripheral resistance changes very little during halothane anesthesia [18, 19].
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Halothane activity on myocardial muscle results in depression of myocardial
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contractility. Most likely, depression of myocardial contractility is offset during spontaneous
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ventilation by increased sympathetic nervous system activity, secondary to increased partial
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pressure of carbon dioxide in arterial blood (PaCO2) [20]. This results in decrease in stroke
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volume which leads to reduction in cardiac output [18].
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Furthermore, halothane predisposes the heart to premature ventricular extrasystoles
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in the presence of catecholamines and also depresses the sensitivity of baroreceptor reflex
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[21-23]. The cardiovascular effects of halothane have been shown to change with duration
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of anesthesia. A time-related increase in arterial blood pressure, stroke volume and cardiac
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output has been observed in horses following long term anesthesia (over 120 minutes) [18,
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20].
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The invasive nature of techniques used to measure cardiac function has prevented
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the study of the effects of different anesthetics and mode of ventilation in clinical equine
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subjects undergoing surgical procedures. The recent development of non-invasive
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techniques currently allows measurement of cardiac function in clinical subjects [19].
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Ultrasonography is a non-invasive and well-tolerated method of accessing left
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ventricular function in horses. Left ventricular systolic function, ejection fraction (EF),
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fractional shortening (FS) are the most common measurements used in equine
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echocardiography [24, 25]. However, echocardiographic assessment of left ventricular
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activity in horses is mainly performed with the patient in upright position.
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Reports of transcutaneous echocardiographic assessment in horses during general
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anesthesia, with the patient kept in dorsal recumbency are sparse [26-28]. A previous study
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demonstrated the applicability of the methodology, with acquisition of similar images as if
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the patient was in upright position [26]. Therefore, we evaluated the effects of constant rate
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infusion of S(+)-ketamine on cardiovascular parameters of dorsally recumbent, halothane-
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anesthetized horses by transcutaneous echocardiographic assessment of left ventricular
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activity.
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2. Material and Methods
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2.1 Animals
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This study was approved and supervised by the institutional animal care and use
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committee. Six adults, mixed-breed geldings, weighting between 350 and 450 kg, and
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considered healthy based on results of physical examination and hematology were
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submitted to the study. During trials, the animals were housed individually, fed hay and
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commercial ration twice daily (1% body weight/day). The animals were also allowed free
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access to water and mineral salt.
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The horses were randomly distributed (randomized crossover design) into two
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groups, with each horse receiving one of two treatments, with a minimum of 15 days
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separating experiments. One group received constant rate infusion (CRI) of S(+)-ketaminea
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(GrKet), and the other CRI infusion of salineb (GrSal).
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2.2. Instrumentation of animals The animals were fastened for 6 hours prior to experimentation. Subsequently, the
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animals (one at time) were accommodated in stocks and a 15x15 cm area comprising the
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4th and 5th right intercostal spaces (parasternal region), located dorsally to the olecranon,
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was clipped to serve as an acoustic window for transcutaneous echocardiographic
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assessment of the left ventricular activity [29-31]. Another 15x10 cm area on the mid-third
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left cervical region was also clipped for purposes of transcutaneous catheterization of the
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left common carotid artery (previously transposed) as well as the left jugular vein. Using
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aseptic technique, an 18-gauge and a 14-gauge catheterc were inserted into the left
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common carotid artery and jugular vein, respectively.
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2.3. Experimental trials
Only one subject and one out of the two groups were tested at time. The animal and
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the group to be tested were selected by randomization (drawing). Anesthetic induction
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protocol was standardized for both groups. The animals were pre-medicated with xylazined
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(1mg/kg), given intravenously (IV). Five minutes following xylazine administration, a 10%
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guaifenesine solution (100 mg/kg dosage diluted in 5% glucose solutionb) was infused under
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pressure into the catheter placed in the left jugular vein. A three-minute infusion period was
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stablished for gauifenesin infusion. As the animal assumed lateral recumbency, anesthetic
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induction was accomplished with intravenous administration of S(+)-ketamine (1 mg/kg).
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As follow, tracheal intubation was performed with a Magillf tube and the subject was
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kept in pure oxygen (20 ml/kg/min) for 10 minutes. Oxygen delivery was provided by
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anesthetic circuitg. Following 10 minutes period, oxygen delivery was readjusted to 10
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ml/kg/min and halothane was introduced into the circuit. Halothane delivery was provided
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by halothane vaporizerg attached to the anesthetic circuit. Patient stabilization was
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achieved when measuredh end-tidal halothane (ETHal) concentration stabilized at 1.5 MAC.
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Immediately following patient stabilization [measured end-tidal halothane (ET Hal)
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concentration stabilized at 1.5 MAC], constant rate infusion with either 0.01 mg/kg/min of
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S(+)-ketamine (diluted in 250 ml of 0.9% saline solution) (GrKet) or the same volume of
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0.9% saline solution (GrSal) was initiated (M0). Constant rate infusion with either S(+)-
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ketamine (GrKet) or 0.9% saline solution (GrSal) was maintained for 50 minutes. Following
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last data acquisition at M50, CRI was discontinued and the animal allowed anesthetic
226
recovery. Heart rate (HR), respiratory rate (ƒR), left ventricular activity (echocardiography),
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systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressures were recorded as follow:
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B – baseline; Rec – animal assumed lateral recumbency following infusion of guaifenesin;
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PI – two minutes post-anesthetic induction with intravenous administration of 1 mg/kg of
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S(+)-ketamine; M0 – beginning of CRI following patient stabilization with end-tidal halothane
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concentration at 1.5 MAC; M10 to M50 – S(+)-ketamine (GrKet) or saline (GrSal) CRI
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elapsed time.
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2.4. Data recording
Heart rate was obtained by computerized electrocardiographyi, utilizing a base-apex
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lead configuration. Respiratory rate was measured by counting thoracic excursions over 1
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minute. Arterial pressures were obtained invasivelyk with a multiparametric monitor,
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connected to the 18-gauge catheter previously inserted into the left common carotid artery
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through extension tubing filled with heparin solution. Cardiac left ventricular activity was
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assessed echocardiographicallyj, using a 3.5 MHz sectorial transducer placed at the right
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parasternal region, dorsally to the olecranon, corresponding to the fourth or fifth intercostal
243
space (acoustic window) [29-31]. For the echocardiographic examination with the patient in
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dorsal recumbency, it was tried to fulfill the same criteria as if the animal was in upright
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position [26] by using recommended measurement techniques [32-34].
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2.5. Transcutaneous Echocardiography A low frequency sectorial transducer (3.5 MHz) was positioned in the right fourth
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intercostal space midway between the point of the shoulder and the point of the elbow. The
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transducer was positioned at 6 o’clock (12 o’clock position with the patient in upright
251
position) and directed caudally to image the four cardiac chambers. The long axis view was
252
obtained with the beam tilted slightly cranially or clockwise to the 7 o’clock position (1
253
o’clock position with the patient in upright position). Two-dimensional (2-D) or B-mode
254
image was primarily used to access the heart in its longitudinal and transversal axis to
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observe all four chambers and to locate papillary muscles and chordae tendineae,
256
respectively. The transducer was rotated clockwise to the 10 o’clock position (4 o’clock
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position with the patient in upright position) at the level of the papillary muscles and chordae
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tendineae in order to obtain the right parasternal short axis view. The M-mode trace was
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used to measure cardiac dimensions of the left ventricle such as interventricular septal
260
thickness, left ventricular (LV) internal diameter in systole (LVIDs) and diastole (LVIDd).
261
These measures were used by the software program to automatically calculate the
262
ventricular function and cardiac output (CO) with the Teicholz formula: SV = [7 x (LVIDd)3 /
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(LVIDd + 2.4)] -[7 x (LVIDs)3 / (LVIDs + 2.4] where SV = stroke volume, LVIDd = left
264
ventricular internal diameter end diastole, LVIDs = left ventricular internal diameter end
265
systole [24]. To avoid variations between individuals, each measurement was performed by
266
the same investigator.
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2.6. Statistical analysis
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Data were analyzed employing SAS® softwarel. Analysis of variance with repeated
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measures followed by Student-Newman-Keuls was used to evaluate data along time within
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each group. T-test was used for purposes of data comparison in between groups. Data
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were expressed as means ± s.d. and the level of significance was p ≤ 0.05.
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3. Results
Results (mean ± s.d.) are expressed in Table 1. Heart rate did not vary (p > 0.05) in
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comparison to baseline values of each group, as well as between groups. Respiratory rate
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(ƒR) did not vary between groups. However, ƒR values at PI and during CRI (M0 to M50) in
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GrKet decreased (p ≤ 0.05) in comparison to B and Rec. Similarly, ƒR values during CRI
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(M0 to M50) in GrSal decreased (p ≤ 0.05) in comparison to B and Rec.
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There was no variation (p > 0.05) in CO, EF and SF between groups. However,
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cardiac output and SF decreased (p ≤ 0.05) over time (from Rec until M50) in comparison
283
to baseline values, in both groups. In GrSal, ejection fraction lowered significantly during
284
CRI (from M0 to M50). Similarly, EF was below baseline values in GrKet during evaluation
285
period, except for M0.
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There were no differences in SAP and DAP in between groups. At M20, MAP was
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significantly higher in GrSal, when compared to GrKet. Systolic and diastolic arterial
288
pressures decreased (p ≤ 0.05) over time, when compared to baseline values, in both
289
groups. Mean arterial pressure decreased (p ≤ 0.05) during CRI (from M0 to M50) in both
290
groups, when compared to baseline values.
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4. Discussion
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The most popular combinations of drugs selected for equine anesthesia are
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combinations of alpha2-adrenergic agonists administered with dissociative anesthetics.
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Centrally acting muscle relaxants are frequently administered in conjunction with ketamine
296
to ensure smooth induction to anesthesia. Cardiovascular depression with this protocol is
297
minimal during anesthesia [35]. Therefore, the (standardized) anesthetic pre-medication
298
(xylazine and guaifenesin) and induction [S(+)-ketamine] used in both groups was chosen
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based on its cardiovascular stability.
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However, alpha2-adrenergic agonists may decrease arterial blood pressure beyond
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what might be expected by halothane solely. Conversely, when administration of alpha2-
302
adrenergic agonists is followed by intravenous bolus of ketamine, heart rate tends to return
303
to acceptable levels, and rhythm disturbances resolve [36]. Guaifenesin may also
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accentuate cardiovascular depression [37].
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The most commonly acknowledged cardiovascular effects of alpha2-adrenergic
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agonists are bradycardia, peripheral vasoconstriction which leads to increased systemic
307
vascular resistance resulting in hypertension and increased blood pressure followed by a
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decrease, an initial decrease in cardiac output and respiratory rate followed by recovery to
309
baseline, and transient decreases in PaO2. Alpha2-adrenergic agonists produce their
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effects by binding to and stimulating alpha-2 adrenergic receptors located in the central
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nervous system and periphery [7, 39].
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The biphasic effects on blood pressure are caused by initial increases in vascular
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resistance from postsynaptic alpha-2B receptor stimulation that induces hypertension,
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followed by decreased sympathetic discharge from presynaptic alpha-2A receptor
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stimulation that decreases norepinephrine release and presynaptic alpha-2C receptor
316
stimulation that decreases epinephrine release from the adrenal glands, resulting in a
317
decrease in vascular resistance and blood pressure. The use of higher doses of alpha2-
318
adrenergic agonists results in a more prolonged increase in vascular resistance. As a result
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cardiac output can be more adversely affected, resulting in hypotension despite the
320
increased vascular resistance [7, 9]. The cardiovascular depression caused by these drugs
321
is enhanced by administration of inhalant anesthetic agents, such as halothane, which
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cause further myocardial depression and reduction in cardiac output [7, 39].
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It has been reported that larger doses of xylazine (i.e., 1.0 mg/kg) produce a
324
decrease in cardiac contractility in horses, most likely due to decrease in sympathetic tone.
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Similarly, increased peripheral vascular resistance has been associated with larger doses
326
of alpha2-adrenergic agonists. The increase in peripheral vascular resistance (an indirect
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indicator of afterload) is thought to be the result of peripheral arterial vascular constriction
328
induced by stimulation of alpha2-adrenergic receptors in vascular smooth muscles.
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Therefore, the decrease in stroke volume is caused by depression of ventricular contractility
330
and increased afterload [40]. Both sedative and physiologic effects of alpha2-adrenergic agonists have been
332
correlated with plasma concentrations [9]. Anesthesia seems to affect the pharmacokinetics
333
of xylazine, because in halothane-anesthetized horses an intravenous bolus of 0.5 mg/kg
334
increased the terminal half-life to 118 minutes and decreased the clearance to 6 mL/kg/min
335
[5]. Therefore, residual xylazine was certainly present during anesthesia and surely
336
influenced cardiovascular parameters.
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The dose-dependent cardiorespiratory effects of guaifenesin include a decrease in
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blood pressure and partial pressure of arterial oxygen, and no changes in other variables
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including diaphragmatic function, heart rate, respiratory rate, arterial pH, and partial
340
pressure of arterial carbon dioxide, arterial blood pressure, and cardiac output. The use of
341
guaifenesin in combination with other injectable anesthetics has also resulted in significant
342
MAC reduction [4, 5]. This reduction in MAC was attributed to the anesthetic sparing effects
343
and to the analgesic properties of the drug combination [4]. Horses receiving guaifenesin
344
following premedication with xylazine and being kept under general anesthesia with
345
halothane usually present marked arterial hypotension which recovers slowly over the next
346
20 or 30 minutes [17].
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337
Several studies have shown that S(+)-ketamine has anesthetic potency up to 2 to 3
348
times higher than racemic ketamine, depending on the species, suggesting that lower
349
doses of the isomer would be sufficient for induction of anesthesia [36]. The dosage of S(+)-
350
ketamine used during anesthetic induction was chosen based on previous studies in horses
351
[41, 42]. In humans and mice, with only half of the necessary racemic dose, S(+)-ketamine
352
was able to propitiate identical depths of anesthesia [5].
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EP
347
353
Although ketamine exerts direct myocardial depression (more pronounced with R(-)-
354
ketamine), clinically administered doses of racemic and S(+)-ketamine (bolus or CRI) were
355
associated with better cardiovascular performance, seen as increases in heart rate, arterial
356
pressure, and cardiac output [38]. These positive effects have been attributed to the
357
sympathomimetic
358
norepinephrine re-uptake at noradrenergic nerve endings, and direct vasodilation of
359
vascular smooth muscle [4]. When ketamine is administered with other agents as part of a
360
balanced anesthetic technique, there is a reduced requirement for other anesthetic agents
interactions
within
the
central
nervous
system,
inhibition
of
12
ACCEPTED MANUSCRIPT 361
with known cardiovascular depressant effects (i.e., inhaled anesthetics), which in turn
362
contributes to the overall improvement of cardiovascular function [35, 38]. A positive correlation between racemic ketamine plasma concentration and a
364
halothane MAC reduction (up to 37%) has also been observed in horses [4, 5, 38]. The use
365
of the S(+)-ketamine has been recommended for CRI in horses over the racemic mixture,
366
because the enantiomer is eliminated faster than the racemic mixture [5]. Increased
367
anesthetic stability was observed with combination of guaifenesin and ketamine with
368
halothane when compared with halothane alone [43].
RI PT
363
The decision to initiate CRI [saline (GrSal) or S(+)-ketamine (GrKet)] following
370
patient stabilization, with measured end-tidal halothane concentration at 1.5 MAC, was
371
based on previous study that demonstrated the effects of S(+)-ketamine on halothane MAC
372
in horses [38]. Constant rate infusion of S(+)-ketamine did not interfere with HR in our
373
study. Similar finding was obtained in a previous study [44]. It has been demonstrated that
374
ketamine has sympathomimetic properties [45]. Therefore, heart rate and arterial pressure
375
would likely increase during S(+)-ketamine CRI. However, our results show that S(+)-
376
ketamine, at the proposed dose, was unable to change heart rate and arterial pressure of
377
horses kept under general anesthesia, with end-tidal halothane concentration at 1.5 MAC.
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SC
369
Mean arterial pressure reduced (p ≤ 0.05) during anesthetic induction and stabilized
379
but maintained under reference (physiological) interval for the species during S(+)-ketamine
380
(M0 to M50). Previous studies verified when ketamine is administered at anesthetic doses,
381
cardiovascular function including blood pressure, heart rate, and cardiac output are usually
382
preserved [5]. In a previous study, decrease in heart rate and mean arterial blood pressure
383
was registered following long term CRI of low-doses of racemic ketamine in awake horses
384
[46]. According to the authors, this was an unexpected result which could supposedly be
385
attributed to the action of a persistent metabolite. Since our S(+)-ketamine CRI dose was
386
similar to the one used on the previous study, the supposed action of a persistent
387
metabolite could explain the lowered MAP values observed in GrKet when compared to
388
GrSal. Alternatively, these effects could also represent a compensatory response following
389
the termination of the sympathomimetic effects of the drug [46].
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378
390
Furthermore, halothane is known to reduce MAP in a dose-dependent manner [37,
391
39]. This effect of halothane on arterial pressure could be observed in our study by
392
comparing MAP values at PI with those recorded following patient stabilization, with end-
393
tidal halothane concentration at 1.5 MAC (M0), in both groups. The association of alpha2-
394
adrenergic agonists, guaifenesin and ketamine is known to reduce the MAC of inhaled
13
ACCEPTED MANUSCRIPT 395
anesthetic agents [7, 35, 38]. Since end-tidal halothane concentration was maintained
396
throughout anesthesia at 1.5 MAC, likely the animals were receiving halothane in excessive
397
amounts. Therefore, the animals were possible under influence of the (sparing) depressant
398
effect of halothane which might be considered the main cause of arterial pressure reduction
399
observed following patient anesthetic stabilization in both groups. Since total peripheral resistance changes very little during halothane anesthesia,
401
peripheral vasodilation cannot be considered the primary cause of hypotension. Therefore,
402
reduction in CO might also be considered a determinant factor for the development of
403
hypotension during halothane anesthesia [18, 19].
RI PT
400
Additionally, the depression of baroreceptor reflex by halothane certainly contributed
405
to maintain arterial pressures below baseline values. The baroreceptor reflex is a short-term
406
central mechanism for systemic arterial blood pressure homeostasis. An acute decrease or
407
increase in arterial blood pressure is detected by the baroreceptors and tends to cause a
408
reflex increase or decrease, respectively, in heart rate. The baroreceptor reflex is
409
particularly sensitive to inhalant anesthesia in adult horses. However, it is markedly
410
depressed in the horse by halothane [21-23, 37].
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SC
404
In daily practice, cardiovascular monitoring in anesthetized horses is usually limited
412
to clinical assessment, electrocardiography, pulse-oximetry, and arterial blood pressure
413
monitoring [47]. Differently, CO is routinely measured in human medicine during general
414
anesthesia and in critical care units and to study exercise physiology. However, with the
415
advent of new technologies, this is also becoming reality in veterinary medicine. Cardiac
416
output not only is one of the most important factors to assess cardiovascular function but
417
also allows for calculation of many other cardiovascular parameters for more complete
418
assessment of function. With knowledge of CO and heart rate (HR), stroke volume (SV) can
419
be determined [48].
EP
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420
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411
All anesthetic agents significantly affect the cardiovascular system. Most anesthetic
421
agents
can
422
vasoconstriction or vasodilatation makes arterial pressure an unreliable indicator of
423
worsening cardiac performance. To that matter, CO monitoring can be a much earlier
424
indicator
425
cardiovascular variables. There are 4 basic methods of measuring CO: (1) indicator
426
methods (i.e., lithium dilution), (2) a derivation of the Fick principle, (3) arterial pulse wave
427
analysis, and (4) imaging diagnostic techniques [48].
of
cause
direct
deteriorating
change
in
cardiovascular
systemic
status
vascular
than
resistance.
other commonly
Excessive
monitored
14
ACCEPTED MANUSCRIPT
Cardiac output was obtained echocardiographically in accordance to previous (and
429
validated) descriptions of transcutaneous echocardiographic assessment of CO in standing
430
horses [34, 49, 50]. Recorded values for CO were inferior to ones previously obtained by
431
thermodilution. However, percentage of variation in CO observed in our study was similar to
432
those reported previously for the species [49, 50]. Acquisition of left ventricular activity by
433
Teicholz formula could be considered a limitation of our study. The use of transesophageal
434
echocardiography, thermodilution, or CO estimation by Simpson rule disk summation
435
method could have been used as alternatives.
RI PT
428
Cardiac output decreased considerably (p ≤ 0.05) following anesthetic induction and
437
remained under baseline values throughout the evaluation period in both groups. Halothane
438
is known to cause dose-dependent reduction in CO during anesthesia [17, 18, 37, 39].
439
Reduction in CO during halothane anesthesia is caused by decrease in stroke volume and
440
reduction in contractility of cardiac muscles (negative inotropic effect), both induced by the
441
inhalant agent [18, 20, 37]. However, cardiac output of horses anesthetized with halothane
442
and kept under spontaneous ventilation might be maintained because there is less
443
reduction of venous return [20].
444
halothane anesthesia, in similarity to CO.
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SC
436
Fractional shortening and EF also diminished during
In other study, the authors demonstrated a progressive decrease in cardiac index
446
over the course of anesthesia in dorsally recumbent horses undergoing surgery. Since
447
heart rate did not change significantly over time (and velocity time integral decreased over
448
time), the authors concluded that the decreased cardiac index was the result of decreased
449
stroke volume [28]. The same authors attributed the CO variations observed at the baseline
450
and subsequent data points to the higher vaporizer settings used to ensure constant end-
451
tidal values. Since our end-tidal halothane concentration was kept at 1.5 MAC throughout
452
anesthesia, halothane concentration surely influenced left ventricular function values (CO,
453
EF, and FS) as well. Reduction in left ventricular function associated with decrease in MAP,
454
following patient stabilization during general anesthesia reinforce the sparing (depressant)
455
effects of halothane overcame the effects of S(+)-ketamine CRI.
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445
456
The body position of the horses during echocardiographic examination throughout
457
anesthesia (dorsal recumbency) could have also been responsible for the differences in CO
458
values obtained in both groups, when compared to baseline values. During transcutaneous
459
echocardiography in dorsal recumbency, the same criteria was tried (with acquisition of
460
similar view) as if the animals were in standing position. However, the measurements could
461
not have been as accurate as if the horses were in upright position, in similarity to previous
15
ACCEPTED MANUSCRIPT 462
descriptions of echocardiographic assessment of cardiac function in laterally-recumbent
463
horses [27]. Respiratory rate also decreased following anesthetic induction and persisted during
465
anesthesia (evaluation period). Infusions of racemic ketamine generally cause minimal
466
respiratory depression with only mild hypercapnia [4]. Thus, changes in ƒR most likely
467
occurred by halothane direct action on respiratory system.
RI PT
464
Halothane and other inhaled anesthetics cause a dose-related depression in
469
respiratory system function that is characterized by an increase in the partial pressure of
470
CO2 in arterial blood and a decreased ability to oxygenate arterial blood. The magnitude of
471
this depression for a given dose of halothane is considerably greater in horses than other
472
species, including humans [37].
SC
468
Since increased terminal half-life and decreased clearance of xylazine were
474
observed in halothane-anesthetized horses, and alpha2-adrenergic agonists are known to
475
decrease respiratory rate, residual xylazine might have also affected ƒR. Respiratory rate
476
alone should not be used as a predictor of respiratory function due to its great variability.
477
This also could be considered a limitation of our study. In that matter, ventilometry would be
478
more suitable protocol for evaluating respiratory dynamics.
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473
480
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479
5. Conclusions
Constant rate infusion of 0.01mg/kg/min of S(+)-ketamine was ineffective in
482
improving cardiocirculatory depression commonly observed in halothane-anesthetized
483
horses. Despite possible limitations (i.e., use of Teicholz formula to calculate left ventricular
484
activity), transcutaneous echocardiographic assessment of left ventricular activity in
485
dorsally-recumbent horses seemed applicable. This maneuver could be employed in other
486
anesthetic models or even in equine anesthetic daily routine for assessment of
487
cardiovascular parameters, during surgical procedures in which the patient is kept in dorsal
488
recumbence, such as celiotomies. However, further studies are encouraged to validate its
489
reliability.
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481
490 491 492 493 494 495
Acknowledgements This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - PQ-1C) for financial assistance.
16
ACCEPTED MANUSCRIPT
502 503 504 505 506 507 508
Abbott Laboratorios, Sao Paulo, Brazil.
d
König, São Paulo, Brazil.
e
Henrifarma, São Paulo, Brazil.
f
Cirúrgica Fernandes, São Paulo, Brazil
g
HB, São Paulo, Brazil.
h
Ohmeda, Louisville – CO, USA.
i
TEB, São Paulo, Brazil.
j
Pie Medical Imaging, Genova, Italy.
k
Digicare Animal Health, Boynton Beach - FL, Brazil.
l
SAS Institute Inc., Cary – NC, USA.
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501
Laboratório Farmacêutico, Ceará, Brazil.
c
SC
500
b
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499
Cristália, São Paulo, Brazil.
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498
a
EP
497
Footnotes
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ACCEPTED MANUSCRIPT References
1. Senior JM. Morbidity, mortality, and risk of general anesthesia in horses. Vet Clin North Am Equine Pract 2013; 29: 1–18. 2. Bidwell LA, Bramlage LR, Rood WA. Equine perioperative fatalities associated
Anaesth Analg 2007; 34:23–30.
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with general anaesthesia at a private practice: a retrospective case series. Vet
3. Johnston GM, Eastment JK, Wood JL, Taylor PM. The confidential enquiry into
Anaesth Analg 2002; 29:159–70.
SC
perioperative equine fatalities (CEPEF): mortality results of Phases 1 and 2. Vet
4. Bettschart-Wolfensberger R, Larenza MP. Balanced anesthesia in the equine. Clin
M AN U
Tech Equine Pract 2007; 6: 104-10.
5. Valverde A. Balanced anesthesia and constant-rate infusions in horses. Vet Clin North Am Equine Pract 2013; 29: 89–122.
6. Bennett RC, Steffey EP, Kollias-Baker C, et al. Influence of morphine sulfate on the halothane sparing effect of xylazine hydrochloride in horses. Am J Vet Res
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2004; 65(4): 519–26.
7. Daunt DA, Steffey EP. Alpha-2 adrenergic agonists as analgesics in horses. Vet Clin North Am Equine Pract 2002; 18: 39–46.
EP
8. Hubbell JA, Saville WJ, Bednarski RM. The use of sedatives, analgesic and anaesthetic drugs in the horse: an electronic survey of members of the American
AC C
Association of Equine Practitioners (AAEP). Equine Vet J 2010; 42(6): 487–93. 9. Valverde A. Alpha2-adrenergic agonists for pain therapy in horses. Vet Clin North Am Equine Pract 2010; 26(3): 515–32.
10. Tranquilli WJ, Thurmon JC, Corbin JE, Benson GJ, Davis LE. Halothane-sparing effect of xylazine in dogs and subsequent reversal with tolazoline. J Vet Pharmacol Therap 1984; 7: 23-28. 11. Wagner AE, Muir WW, Hinchcliff KW. Cardiovascular effects of xylazine and detomidine in horses. Am J Vet Res 1991; 52(5): 651-657.
18
ACCEPTED MANUSCRIPT
12. Guedes AGP, Natalini CC. Anestesia em equinos com síndrome cólica – análise de 48 casos e revisão de literatura. Cienc Rural 2002; 32(3):535-42. 13. Bevan RK, Rose MA, Duggan KA. Evidence for direct interaction of ketamine with α1- and - α2 adrenoceptors. Clin Exp Pharm Physiol 1997; 24: 923-6. 14. Lauretti GR, Lima ICPR, Buscatti RY, Reis MP. Clinical evaluation of
RI PT
hemodynamic, analgesic, psychedelic and neuromuscular block effects of racemic ketamine versus S(+) ketamine. Rev Bras Anest 2000; 50: 357-62.
15. Krugera K, Stegmanna GF. Partial intravenous anaesthesia in 5 horses using ketamine, lidocaine, medetomidine and halothane. Jl S Afr Vet Ass 2009; 80(4):
SC
233–6.
16. Martinez EA, Keegan RD. Muscle relaxants and neuromuscular blockade. In:
M AN U
Tranquilli WJ, Thurmon JC, Grimm KA, editors. Lumb & Jones' Veterinary Anesthesia and Analgesia, 4th ed. Ames: Blackwell Publishing; 2007: 419-37. 17. Hall LW, Clarke KW, Trim CM. Veterinary anaesthesia, 10th ed. London: WB Saunders; 2001: 149-78.
18. Steffey EP. Inhalation anesthetics. In: Riviere JE, Papich MG, editors. Veterinary
TE D
Pharmacology and therapeutics, 9th ed. Hoboken: Wiley-Blackwell; 2009: 229263.
19. Ingwersen W, Allen DG, Dyson D H, Pascoe PJ, O'grady MR. Cardiopulmonary
EP
effects of a halothane/oxygen combination in healthy cats. Can J Vet Res 1988; 52(3): 386-391.
AC C
20. Raisis AL, Blissitt KJ, Henley W, Rogers K, Adams V, Young LE. The effects of halothane and isoflurane on cardiovascular function in laterally recumbent horses. Br J Anaesth 2005; 95: 317–25.
21. Patel PM, Drummond JC. Cerebral physiology and the effects of anesthetics and techniques. In: Miller RD, editor. Miller’s anesthesia. Philadelphia: Elsevier Churchill Livingstone; 2005: 813-57. 22. Pavlin EG, Su JY. Cardiopulmonary pharmacology. In:
Miller RD, editor.
Anesthesia, 4th ed. New York: Churchill Livingstone; 1994: 125-156.
19
ACCEPTED MANUSCRIPT
23. Purchase IF. Cardiac arrhythmias occurring during halothane anaesthesia in cats. Br J Anaesth. 1966; 38: 13-22. 24. Nyland TG, Mattoon JS, editors. Veterinary diagnostic ultrasound. Philadelphia: W.B. Saunders; 1995: 357p. 25. Patteson MW, Gibbs C, Wotton PR, Cripps PJ. Effects of sedation with detomidine
RI PT
hydrochloride on echocardiographic measurements of cardiac dimensions and indices of cardiac function in horses. Equine Vet J 1995; 19: 33-7.
26. Spadavecchia C, Trachsel D, Tschudi P, Schatzmann U. Combined general anaesthesia in a horse with tricuspidal regurgitation and transthoracic sonographic
SC
monitoring of the cardiac function. Pferdeheilkunde 2006; 22 (3): 250-3. 27. Vitale V, Sgorbini M, Briganti A, Corazza M, Breghi G, Staffieri F. Evaluation of
M AN U
echocardiographic parameters during increasing infusion rates of dobutamine in isoflurane-anesthetized horses. J Equine Vet Sci 2013; 33: 1110-4. 28. Blissitt KJ, Raisis AL, Adams VJ, Rogers KH, Henley WE, Young LE. The effects of halothane and isoflurane on cardiovascular function in dorsally recumbent horses undergoing surgery. Vet Anaesth Analg 2008; 35: 208–19.
TE D
29. Canola JC, Cardenas JJ, Canola PA. Efeito da romifidina sobre as dimensões ecocardiográficas e sobre índices da função cardíaca em equinos. Ars Vet 2002; 18(3): 231-237.
EP
30. Canola JC, Valadão CAA, Portugal ES, Canola PA. Avaliação ecocardiográfica de equinos pré-medicados com n-butilbrometo de hioscina e sedados com
AC C
romifidina. Ciênc Anim Bras 2007; 8(4): 833-839. 31. Linardi RL, Canola JC, Valadão CAA. Cardiovascular assessment in horses sedated with xylazine or amitraz. Arq Bras Med Vet Zootec 2008; 60(2): 329-334.
32. Marr CM, Patteson M. Echocardiography. In: Marr CM, Bowen IM, editors. Cardiology of the horse. Edinburgh: Saunders Elsevier; 2010: 105-26.
33. Brown DJ, Rush JE, MacGregor J, Ross Jr JN, Brewer B, Rand WM. M-mode echocardiographic ratio indices in normal dogs, cats, and horses: a novel quantitative method. J Vet Intern Med 2003; 17: 653–62.
20
ACCEPTED MANUSCRIPT
34. Reef VB, Whittier M, Allam LG. Echocardiography. Clin Tech Equine Pract 2004; 3: 274-83. 35. Yamashita K, Muir WW. Intravenous anesthetic and analgesic adjuncts to inhalation anesthesia. In: Muir WW, Hubbell JAE, editors. Equine Anesthesia Monitoring and Emergency Therapy, 2nd ed. St. Louis: Saunders Elsevier; 2009:
RI PT
260-76.
36. Rossetti RB, Cortopassi SRG, Intelizano T, Machado TSL, Ferreira da Cruz RS. Comparison of ketamine and S(+)-ketamine, with romifidine and diazepam, for total intravenous anesthesia in horses. Vet Anaesth Analg 2008; 35: 30-7.
SC
37. Steffey EP. Inhalation anesthetics and gases. In: Muir WW, Hubbell JAE, editors. Equine Anesthesia Monitoring and Emergency Therapy, 2nd ed. St. Louis:
M AN U
Saunders Elsevier; 2009: 288-314.
38. Muir WW, Sams R. Effects of ketamine infusion on halothane minimal alveolar concentration in horses. Am J Vet Res 1992; 53(10):1802-6. 39. Steffey EP, Howland Jr.: Cardiovascular effects of halothane in the horses. Am J Vet Res 1978; 39(4): 611-5.
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40. Yamashita K, Tsubakishita S, Futaoka S, Ueda I, Hamaguchi H, Seno T, Katoh S, Izumisawa Y, Kotani T, Muir W. Cardiovascular effects of medetomidine, detomidine and xylazine in horses. J Vet Med Sci 2000; 62: 1025-32.
EP
41. Larenza MP, Ringer SK, Kutter APN, Conrot A, Theurillat R, Kummer M, Thormann W, Bettschart-Wolfensberger R. Evaluation of anesthesia recovery
AC C
quality after low-dose racemic or S-ketamine infusions during anesthesia with isoflurane in horses Am J Vet Res 2009; 70: 710–8.
42. Larenza MP, Knobloch M, Landoni MF, Levionnois OL, Kronen PW, Theurillat R, Schatzmann U, Thormann W. Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration in Shetland ponies sedated with xylazine. Vet J 2008; 177: 432–5. 43. Spadavecchia C, Stucki F, Moens Y, Schatzmann U. Anaesthesia in horses using halothane and intravenous ketamine guaiphenesin: a clinical study. Vet Anaesth Analg 2002; 29: 20–8.
21
ACCEPTED MANUSCRIPT
44. Flaherty D, Nolan A, Reid J, Monteiro AM. The pharmacokinetics of ketamine after a continuous infusion under halothane anaesthesia in horses. J Vet Anaesth 1998; 25(1): 31-36. 45. Bevan RK, Rose MA, Duggan K A. Evidence for direct interaction of ketamine with α1- and - α2 adrenoceptors. Clin Exp Pharm Physiol 1997; 24: 923-926. CL,
Brumbaugh
GW,
Matthews
NS,
Peck
KE,
Roussel
RI PT
46. Fielding
AJ.
Pharmacokinetics and clinical effects of a subanesthetic continuous rate infusion of ketamine in awake horses. Am J Vet Res 2006; 67: 1484–90.
47. Schauvliege S, Gasthuys F. Drugs for cardiovascular support in anesthetized
SC
horses. Vet Clin North Am Equine Pract 2013; 29: 19–49.
48. Shih A. Cardiac output monitoring in horses. Vet Clin North Am Equine Pract
M AN U
2013; 29: 155-67.
49. Mizuno Y, Ainda H, Hara H, Fujinaga T, Hagio M. Comparison of methods of cardiac output measurements determined by dye dilution, pulsed Doppler echocardiography and thermodilution in horses. J Vet Med Sci 1994; 56(1): 1-5. 50. Blissitt KJ, Young LE, Jones RS, Darke PG, Utting J. Measurement of cardiac
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output in standing horses by Doppler echocardiography and thermodilution.
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Equine Vet J 1997; 29(1): 18-25.
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Table 1. Results of measured variables (mean ± s.d.) obtained from 6 horses anesthetized with halothane and given CRI infusion of either S(+)ketamine (GrKet) or saline (GrSal) VARIABLES GROUPS MOMENTS CRI
FS (%)
SAP (mmHg)
MAP (mmHg)
DAP (mmHg)
M20
M30
M40
M50
RI PT
M10
35±6
40±8
39±3
35±3
34±2
32±3
32±3
31±3
GrSal
35±6
30±4
40±8
38±3
34±11
33±5
32±5
32±5
31±3
GrKet
16±6a
15±7a
11±4ab
8±1b
8±1b
8±2b
8±3b
8±2b
8±2b
GrSal
13±4a
12±2a
9±3b
8±2b
8±1b
9±1b
9±2b
7±2b
9±2b
GrKet
10.6±4a
5.3±2b
6±1b
5.1±1b
4.4±1b
4±2b
4.5±2b
4.6±1b
4.4±1b
GrSal
10.1±1a
5.8±1b
GrKet
59±12a
49.7±13ab
GrSal
63.5±4a
45.8±5b
GrKet
33±7a
25±6b
GrSal
36±3a
24±3b
GrKet
150±12a
GrSal
158±33a
GrKet
121±16a
GrSal
128±21a
GrKet GrSal
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EF (%)
M0
41±21
6.5±1b
5.6±2b
5.7±2b
5.8±3b
4.2±1b
4.8±1b
4.2±1b
47.7±9ab
41.3±9b
42±9b
43.2±14b
34.8±8b
38.8±6b
34.8±7b
42±21b
52.8±16ab
46.3±8b
41.2±9b
33.2±9b
35±6b
41±11b
25±6b
21±6b
22±6b
23±8b
17±4b
20±3b
18±4b
29±5b
29±11b
24±4b
21±5b
17±5b
18±3b
21±6b
103±7b
102±8b
57±10c
60±11c
60±11c
60±11c
61±13c
59±11c
98±11b
106±10b
57±10c
67±7c
70±11c
64±11c
62±12c
68±16c
73±13b
83±8b
40±8c
44±9c
43±8cA
44±9c
44±0c
46±11c
68±30b
86±7c
41±7d
50±7cd
54±7cdB
51±10cd
48±11cd
46±11cd
95±11a
56±15b
68±8c
30±6d
33±8d
33±6d
36±8d
33±9d
39±12d
107±16a
67±7b
70±8b
39±6c
38±7c
41±10c
39±10c
36±9c
35±10c
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CO (L/min)
PI
GrKet
EP
ƒR (bpm)
Rec
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RR (bpm)
B
SC
(n = 6)
B - baseline; Rec – animal assumed lateral recumbency following infusion of guaifenesin; PI – two minutes post-anesthetic induction with S(+)ketamine; M0 – beginning of CRI following patient stabilization with measured end-tidal halothane concentration at 1.5 MAC; M10 to M50 – parameters recorded during S(+)-ketamine (GrKet) or saline (GrSal) CRI elapsed time. Lowercase letters in the same line express significant (p ≤ 0.05) variations along time within each group. Capital letters in the same column express significant (p ≤ 0.05) variation in between groups (Student-Newman-Keuls).
ACCEPTED MANUSCRIPT Highlights •
Constant rate infusion of S(+)-ketamine at 0.01mg/kg/min is ineffective in improving cardiocirculatory function of halothane-anesthetized horses.
Transcutaneous echocardiographic assessment of left ventricular activity in dorsallyrecumbent horses seems applicable.
There is a need for more studies to validate transcutaneous echocardiography in
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dorsally-recumbent horses
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•
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•
S0737-0806(14)00457-2
DOI:
10.1016/j.jevs.2014.11.005
Reference:
YJEVS 1801
To appear in:
Journal of Equine Veterinary Science
Received Date: 24 February 2014 Revised Date:
30 September 2014
Accepted Date: 25 November 2014
Please cite this article as: Canola PA, Valadão CAA, Borges JHS, Canola JC, Evaluation of cardiovascular function during S(+)-ketamine constant rate infusion in dorsally recumbent, halothaneanesthetized horses, Journal of Equine Veterinary Science (2014), doi: 10.1016/j.jevs.2014.11.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Evaluation of cardiovascular function during S(+)-ketamine constant rate infusion in
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dorsally recumbent, halothane-anesthetized horses Paulo A. Canola DVM, PhD1; Carlos A. A. Valadão DVM, PhD1; José Henrique S.Borges
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DVM, PhD2; Júlio C. Canola DVM, PhD1
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- São Paulo State University. School of Agrarian Sciences and Veterinary Medicine.
Department of Veterinary Clinics and Surgery, Jaboticabal, SP 14884-900, Brazil. 2
- Centro Universitário da Grande Dourados. Dourados, MS 79824-900, Brazil.
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Institution where this work was done: São Paulo State University. School of Agrarian
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Sciences and Veterinary Medicine. Department of Veterinary Clinics and Surgery, Brazil.
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Disclaimers: None.
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Address correspondence and reprint requests: Júlio Canola, FCAV/UNESP - Campus
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of Jaboticabal. Via de Acesso Prof.Paulo Donato Castellane, Km 5; 14884-900 -
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Jaboticabal, SP. Phone: +55 16 3209-2626 Email: [email protected].
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Source of support: CNPq (PQ-1C; 306940/2008-6)
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Conflicts of Interest: None.
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Results / partial results have not been presented in any scientific meeting.
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Running title: Evaluation of cardiovascular function during S(+) ketamine CRI in dorsally
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recumbent, halothane-anesthetized horses
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Abstract
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The cardiovascular effects of constant rate infusion (CRI) of S(+)-ketamine in
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dorsally recumbent, halothane-anesthetized horses were assessed. Six mixed-breed, adult,
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male horses, weighting 350 to 450 kg were used. The animals were randomly distributed
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into two (treatments) groups, with each horse receiving both treatments. Sedation with
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xylazine (1mg/kg, IV), infusion of 10% guaifenesine (100 mg/kg in 5% glucose), induction
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with S(+)-ketamine (1 mg/kg, IV), and maintenance with halothane (end-tidal concentration
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of 1.5 MAC) was standardized for both groups. When halothane end-tidal concentration
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stabilized at 1.5 MAC, CRI with S(+)-ketamine (GrKet) at 0.01 mg/kg/min (diluted in 250 ml
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of 0.9% saline solution) or the same volume of 0.9% saline solution (GrSal) was initiated
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(M0). CRI was maintained for 50 minutes (M50). Cardiac output (CO), fractional shortening
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(FS) and ejection fraction (EF), heart rate (HR), respiratory rate (ƒR), systolic (SAP), mean
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(MAP) and diastolic (DAP) arterial pressures were recorded at: B - baseline; Rec – lateral
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recumbency; PI – two minutes post-anesthetic induction; M0 – beginning of CRI; M10 to
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M50 – CRI elapsed time. Only MAP differed between groups (M20). ƒR decreased (p ≤
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0.05) PI in GrKet and during CR in GrSal. CO, SF, EF, SAP, MAP and DAP decreased (p ≤
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0.05) in both groups during CRI. CRI with S(+)-ketamine at 0.01 mg/kg/min was ineffective
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in improving cardiocirculatory depression commonly observed in halothane-anesthetized
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horses. Despite possible limitations, transcutaneous echocardiographic assessment of left
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ventricular activity in dorsally-recumbent horses seemed applicable. Further studies are
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encouraged to validate its reliability.
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Key words: equine; cardiac output; general anesthesia; left ventricular activity; ultrasound.
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Abreviation
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B – baseline values
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bpm – beats per minute (heart rate) or breaths per minute (respiratory rate)
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MAC – minimal alveolar concentration
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CNS – central nervous system
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CO – cardiac output
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DAP – diastolic arterial pressure
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ECG – electrocardiography
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HR – heart rate
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EF – ejection fraction
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ETHal – end-tidal halothane
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ƒR – respiratory rate
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FS – fractional shortening
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GrSal – saline infusion group
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GrKet – ketamine S(+) infusion group
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LV - left ventricular
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LVIDd - left ventricular internal diameter end diastole
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LVIDs - left ventricular internal diameter end systole
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L/min – liters per minute
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MAP – mean arterial pressure
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ml/kg/min – milliliters per kilogram per minute
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PaCO2 - partial pressure of carbon dioxide in arterial blood
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PAM – pre-anesthetic medication
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PI – post-induction
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PRec – post-recumbence
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SAP – systolic arterial pressure
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SV - stroke volume
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TIVA - total intravenous anesthesia
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PaO2 - partial pressure of oxygen in arterial blood
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1. Introduction Horses are more likely to suffer morbidities and mortality during anesthetic
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procedures when compared with people, dogs, and cats. Therefore, anesthesia in the horse
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is inherently risky. Normally, when cardiovascular factors are recorded as the primary
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cause of death in anesthetized horses, failure of the cardiovascular system is considered
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the primary or initial cause of death. Anesthetic-related deaths in horses attributed to
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cardiovascular causes correspond to 20% to 50% of cases. However, some anesthetic-
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related deaths are surely misclassified as being caused by cardiovascular factors in the
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absence of any other probable cause of death [1].
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Respiratory causes of anesthetic-related death in horses contribute to only 4% to
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25% of cases. Fractures on recovery contributed to death in 12.5% to 38% of cases, and
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postanesthetic myopathy in 7% to 44% of cases. Abdominal complications, such as colitis
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or peritonitis, are reported as causing 13% of anesthetic-related deaths in noncolic cases
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[1-3].
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In order to minimize anesthetic-related death, the concept of balanced anesthesia
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was created. The term “balanced anesthesia” is currently mostly used for an inhalational
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anesthetic-based technique as opposed to techniques that exclude all inhalational
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anesthetics, which have been termed total intravenous anesthesia (TIVA) [4]. Balanced
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anesthesia consists of administering a combination of anesthetic drugs to provide the
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patient with the desired effects of these drugs while minimizing their adverse side effects,
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such that analgesia, hypnosis, and stable cardiorespiratory function are enhanced. In face
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of critical cases, balanced techniques are more likely to be selected than total volatile or
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intravenous techniques to meet patients’ requirements for analgesia, support of
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cardiorespiratory function, and anesthetic depth. In these circumstances, anesthesia time
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tend to be longer when compared to elective cases. Balanced anesthesia preserves
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cardiovascular function but has the potential to depress respiratory function to a greater
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extent than TIVA or volatile anesthesia [4, 5].
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Most balanced anesthesia techniques include the use of alpha2-adrenergic agonists
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mainly because of their potent sedative and analgesic effects [4-7]. Alpha2-adrenergic
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agonists were the first reported class of drugs that reduced inhalation anesthetic
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requirements in horses [7]. Alpha2-adrenergic agonists have been shown to decrease the
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MAC of halothane by approximately 20% to 35% in a dose-dependent and time-dependent
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fashion [6]. The main concern is their impact on cardiovascular function. In that matter,
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alpha2-adrenergic
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bradyarrhythmias
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(characterized by first, second or third degree atrioventricular [AV] blocks) with decreased
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cardiac output. Increased systemic vascular resistance and increased blood pressure are
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further transient signs observed with alpha2-adrenergic agonists’ administration. Initial
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hypertension is followed by more enduring hypotension [5, 8, 9]. Transient hypertension
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associated with xylazine administration is caused by drug interaction with adrenergic
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receptors, subsequently leading to moderate but prolonged hypotension. The reflex
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bradycardia is caused by response of parasympathetic tonus to the increased systemic
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vascular resistance [10,11].
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In a recent review on the use of injectable anesthetics and analgesics by the
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American Association of Equine Practitioners, the use of xylazine followed by ketamine and
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diazepam was the preferred induction protocol for anesthesia procedures of 20 minutes’
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duration, whereas anesthesia procedures over 30 minutes’ duration were most commonly
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performed with a mixture of guaifenesin, xylazine and ketamine or isoflurane [5, 7].
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Ketamine is a dissociative agent which, in systemically healthy horses, induces
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analgesia, amnesia, and immobility without depressing cardiovascular function. These
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properties make ketamine an ideal agent for balanced anesthesia in the horse [4]. This drug
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has been advocated for induction of general anesthesia in patients with circulatory
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disturbances due to its effects on (enhancing) sympathetic tonus. Drug interaction with
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alpha1-adrenergic agonists results in increased heart rate, cardiac output, mean arterial
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pressure, pulmonary arterial pressure as well as central venous pressure [12, 13].
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Similarly to any other drug, ketamine is composed by racemic mixture of two
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enantiomers: dextrogyre [R(-)] and levogyre [S(+)] isomers. Racemic ketamine can provoke
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emergence reactions during anesthetic recovery that can turn into a fatal event in horses.
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Muscle tremor and rigidity, mydriasis, oculogyric movements, sweating, excitation, ataxia,
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and schizophrenia-like behavior observed during anesthetic recovery of horses have been
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attributed to ketamine’s dextrogyre isomer [4]. To that matter, ketamine’s levogyre isomer
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was more effective in producing analgesia during and following surgery, with fewer
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incidences of hallucinogenic effects, when compared to racemic ketamine [14]. In ponies,
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levogyre ketamine provided an identical degree of immobility after a single injection of half
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the dose of racemic ketamine with a more rapid recovery [4].
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Ketamine produces beneficial hemodynamic effects during halothane anesthesia.
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Increased anesthetic stability and decreased need for dobutamine infusion were observed
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with combination of ketamine and guaifenesin during halothane anesthesia, when
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compared with halothane alone. Moreover, ketamine infusion increases anesthetic and
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hemodynamic stability and decreases hypotension. Its sympathomimetic action minimizes
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bradycardia and hypotensive effects of sedatives such as alpha2-adrenergic agonists and
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inhaled anesthetics [4, 15]. Guaifenesin, a centrally acting muscle relaxant, is used routinely in association with
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xylazine and ketamine as part of anesthetic protocols in large animal species. At
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therapeutic doses (35-100 mg/kg) it promotes skeletal muscle relaxation. However, it does
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not provide analgesia or produce unconsciousness. When guaifenesin is given alone, heart
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rate, respiratory rate, and cardiac output are unchanged. Still, arterial pressures are
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decreased [16, 17]. When administered prior to guaifenesin, xylazine reduced the dose
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necessary to achieve lateral recumbence compared with guaifenesin alone. Addition of
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xylazine typically decreases heart rate, respiratory rate, cardiac output, and partial pressure
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of oxygen in arterial blood (Pa02) [16]. Completing the induction of anesthesia with
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halothane often produces marked arterial hypotension but the pressure recovers slowly
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over the next 20 to 30 min [17].
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Inhalant anesthetics such as halothane are frequently used in horses during surgical
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procedures requiring general anesthesia. With a blood/gas solubility coefficient of 2.3, a
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minimal alveolar concentration (MAC) of 0.88% is required for halothane to induce general
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anesthesia in horses. It does not react with soda-lime; however, it decomposes into
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halogenated gases when exposed to light. Halothane biotransformation occurs primarily in
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the liver where it is converted into trifluoroacetic acid by the cytochrome P-450 system in
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the endoplasmic reticulum of the hepatocytes. However, about 60-80% is eliminated
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unchanged during exhalation [18].
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Halothane depresses circulatory and central nervous systems function in a dose-
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dependent fashion until respiratory and cardiovascular collapse and death. Breathing rate
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decreases with anesthetic depth until complete respiratory arrest at 2.6 MAC. A reduction in
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cardiac output, stroke volume and arterial pressure in humans and animal models has been
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demonstrated during halothane anesthesia, when compared to awaken individuals [18].
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Peripheral vasodilation is not considered the primary cause of hypotension since total
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peripheral resistance changes very little during halothane anesthesia [18, 19].
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Halothane activity on myocardial muscle results in depression of myocardial
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contractility. Most likely, depression of myocardial contractility is offset during spontaneous
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ventilation by increased sympathetic nervous system activity, secondary to increased partial
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pressure of carbon dioxide in arterial blood (PaCO2) [20]. This results in decrease in stroke
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volume which leads to reduction in cardiac output [18].
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Furthermore, halothane predisposes the heart to premature ventricular extrasystoles
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in the presence of catecholamines and also depresses the sensitivity of baroreceptor reflex
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[21-23]. The cardiovascular effects of halothane have been shown to change with duration
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of anesthesia. A time-related increase in arterial blood pressure, stroke volume and cardiac
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output has been observed in horses following long term anesthesia (over 120 minutes) [18,
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20].
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The invasive nature of techniques used to measure cardiac function has prevented
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the study of the effects of different anesthetics and mode of ventilation in clinical equine
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subjects undergoing surgical procedures. The recent development of non-invasive
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techniques currently allows measurement of cardiac function in clinical subjects [19].
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Ultrasonography is a non-invasive and well-tolerated method of accessing left
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ventricular function in horses. Left ventricular systolic function, ejection fraction (EF),
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fractional shortening (FS) are the most common measurements used in equine
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echocardiography [24, 25]. However, echocardiographic assessment of left ventricular
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activity in horses is mainly performed with the patient in upright position.
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Reports of transcutaneous echocardiographic assessment in horses during general
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anesthesia, with the patient kept in dorsal recumbency are sparse [26-28]. A previous study
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demonstrated the applicability of the methodology, with acquisition of similar images as if
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the patient was in upright position [26]. Therefore, we evaluated the effects of constant rate
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infusion of S(+)-ketamine on cardiovascular parameters of dorsally recumbent, halothane-
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anesthetized horses by transcutaneous echocardiographic assessment of left ventricular
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activity.
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2. Material and Methods
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2.1 Animals
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This study was approved and supervised by the institutional animal care and use
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committee. Six adults, mixed-breed geldings, weighting between 350 and 450 kg, and
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considered healthy based on results of physical examination and hematology were
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submitted to the study. During trials, the animals were housed individually, fed hay and
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commercial ration twice daily (1% body weight/day). The animals were also allowed free
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access to water and mineral salt.
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The horses were randomly distributed (randomized crossover design) into two
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groups, with each horse receiving one of two treatments, with a minimum of 15 days
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separating experiments. One group received constant rate infusion (CRI) of S(+)-ketaminea
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(GrKet), and the other CRI infusion of salineb (GrSal).
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2.2. Instrumentation of animals The animals were fastened for 6 hours prior to experimentation. Subsequently, the
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animals (one at time) were accommodated in stocks and a 15x15 cm area comprising the
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4th and 5th right intercostal spaces (parasternal region), located dorsally to the olecranon,
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was clipped to serve as an acoustic window for transcutaneous echocardiographic
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assessment of the left ventricular activity [29-31]. Another 15x10 cm area on the mid-third
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left cervical region was also clipped for purposes of transcutaneous catheterization of the
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left common carotid artery (previously transposed) as well as the left jugular vein. Using
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aseptic technique, an 18-gauge and a 14-gauge catheterc were inserted into the left
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common carotid artery and jugular vein, respectively.
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2.3. Experimental trials
Only one subject and one out of the two groups were tested at time. The animal and
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the group to be tested were selected by randomization (drawing). Anesthetic induction
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protocol was standardized for both groups. The animals were pre-medicated with xylazined
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(1mg/kg), given intravenously (IV). Five minutes following xylazine administration, a 10%
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guaifenesine solution (100 mg/kg dosage diluted in 5% glucose solutionb) was infused under
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pressure into the catheter placed in the left jugular vein. A three-minute infusion period was
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stablished for gauifenesin infusion. As the animal assumed lateral recumbency, anesthetic
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induction was accomplished with intravenous administration of S(+)-ketamine (1 mg/kg).
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As follow, tracheal intubation was performed with a Magillf tube and the subject was
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kept in pure oxygen (20 ml/kg/min) for 10 minutes. Oxygen delivery was provided by
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anesthetic circuitg. Following 10 minutes period, oxygen delivery was readjusted to 10
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ml/kg/min and halothane was introduced into the circuit. Halothane delivery was provided
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by halothane vaporizerg attached to the anesthetic circuit. Patient stabilization was
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achieved when measuredh end-tidal halothane (ETHal) concentration stabilized at 1.5 MAC.
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Immediately following patient stabilization [measured end-tidal halothane (ET Hal)
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concentration stabilized at 1.5 MAC], constant rate infusion with either 0.01 mg/kg/min of
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S(+)-ketamine (diluted in 250 ml of 0.9% saline solution) (GrKet) or the same volume of
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0.9% saline solution (GrSal) was initiated (M0). Constant rate infusion with either S(+)-
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ketamine (GrKet) or 0.9% saline solution (GrSal) was maintained for 50 minutes. Following
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last data acquisition at M50, CRI was discontinued and the animal allowed anesthetic
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recovery. Heart rate (HR), respiratory rate (ƒR), left ventricular activity (echocardiography),
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systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressures were recorded as follow:
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B – baseline; Rec – animal assumed lateral recumbency following infusion of guaifenesin;
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PI – two minutes post-anesthetic induction with intravenous administration of 1 mg/kg of
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S(+)-ketamine; M0 – beginning of CRI following patient stabilization with end-tidal halothane
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concentration at 1.5 MAC; M10 to M50 – S(+)-ketamine (GrKet) or saline (GrSal) CRI
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elapsed time.
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2.4. Data recording
Heart rate was obtained by computerized electrocardiographyi, utilizing a base-apex
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lead configuration. Respiratory rate was measured by counting thoracic excursions over 1
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minute. Arterial pressures were obtained invasivelyk with a multiparametric monitor,
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connected to the 18-gauge catheter previously inserted into the left common carotid artery
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through extension tubing filled with heparin solution. Cardiac left ventricular activity was
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assessed echocardiographicallyj, using a 3.5 MHz sectorial transducer placed at the right
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parasternal region, dorsally to the olecranon, corresponding to the fourth or fifth intercostal
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space (acoustic window) [29-31]. For the echocardiographic examination with the patient in
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dorsal recumbency, it was tried to fulfill the same criteria as if the animal was in upright
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position [26] by using recommended measurement techniques [32-34].
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2.5. Transcutaneous Echocardiography A low frequency sectorial transducer (3.5 MHz) was positioned in the right fourth
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intercostal space midway between the point of the shoulder and the point of the elbow. The
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transducer was positioned at 6 o’clock (12 o’clock position with the patient in upright
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position) and directed caudally to image the four cardiac chambers. The long axis view was
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obtained with the beam tilted slightly cranially or clockwise to the 7 o’clock position (1
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o’clock position with the patient in upright position). Two-dimensional (2-D) or B-mode
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image was primarily used to access the heart in its longitudinal and transversal axis to
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observe all four chambers and to locate papillary muscles and chordae tendineae,
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respectively. The transducer was rotated clockwise to the 10 o’clock position (4 o’clock
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position with the patient in upright position) at the level of the papillary muscles and chordae
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tendineae in order to obtain the right parasternal short axis view. The M-mode trace was
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used to measure cardiac dimensions of the left ventricle such as interventricular septal
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thickness, left ventricular (LV) internal diameter in systole (LVIDs) and diastole (LVIDd).
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These measures were used by the software program to automatically calculate the
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ventricular function and cardiac output (CO) with the Teicholz formula: SV = [7 x (LVIDd)3 /
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(LVIDd + 2.4)] -[7 x (LVIDs)3 / (LVIDs + 2.4] where SV = stroke volume, LVIDd = left
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ventricular internal diameter end diastole, LVIDs = left ventricular internal diameter end
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systole [24]. To avoid variations between individuals, each measurement was performed by
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the same investigator.
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2.6. Statistical analysis
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Data were analyzed employing SAS® softwarel. Analysis of variance with repeated
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measures followed by Student-Newman-Keuls was used to evaluate data along time within
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each group. T-test was used for purposes of data comparison in between groups. Data
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were expressed as means ± s.d. and the level of significance was p ≤ 0.05.
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3. Results
Results (mean ± s.d.) are expressed in Table 1. Heart rate did not vary (p > 0.05) in
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comparison to baseline values of each group, as well as between groups. Respiratory rate
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(ƒR) did not vary between groups. However, ƒR values at PI and during CRI (M0 to M50) in
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GrKet decreased (p ≤ 0.05) in comparison to B and Rec. Similarly, ƒR values during CRI
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(M0 to M50) in GrSal decreased (p ≤ 0.05) in comparison to B and Rec.
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There was no variation (p > 0.05) in CO, EF and SF between groups. However,
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cardiac output and SF decreased (p ≤ 0.05) over time (from Rec until M50) in comparison
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to baseline values, in both groups. In GrSal, ejection fraction lowered significantly during
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CRI (from M0 to M50). Similarly, EF was below baseline values in GrKet during evaluation
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period, except for M0.
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There were no differences in SAP and DAP in between groups. At M20, MAP was
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significantly higher in GrSal, when compared to GrKet. Systolic and diastolic arterial
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pressures decreased (p ≤ 0.05) over time, when compared to baseline values, in both
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groups. Mean arterial pressure decreased (p ≤ 0.05) during CRI (from M0 to M50) in both
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groups, when compared to baseline values.
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4. Discussion
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The most popular combinations of drugs selected for equine anesthesia are
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combinations of alpha2-adrenergic agonists administered with dissociative anesthetics.
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Centrally acting muscle relaxants are frequently administered in conjunction with ketamine
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to ensure smooth induction to anesthesia. Cardiovascular depression with this protocol is
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minimal during anesthesia [35]. Therefore, the (standardized) anesthetic pre-medication
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(xylazine and guaifenesin) and induction [S(+)-ketamine] used in both groups was chosen
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based on its cardiovascular stability.
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However, alpha2-adrenergic agonists may decrease arterial blood pressure beyond
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what might be expected by halothane solely. Conversely, when administration of alpha2-
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adrenergic agonists is followed by intravenous bolus of ketamine, heart rate tends to return
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to acceptable levels, and rhythm disturbances resolve [36]. Guaifenesin may also
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accentuate cardiovascular depression [37].
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The most commonly acknowledged cardiovascular effects of alpha2-adrenergic
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agonists are bradycardia, peripheral vasoconstriction which leads to increased systemic
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vascular resistance resulting in hypertension and increased blood pressure followed by a
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decrease, an initial decrease in cardiac output and respiratory rate followed by recovery to
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baseline, and transient decreases in PaO2. Alpha2-adrenergic agonists produce their
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effects by binding to and stimulating alpha-2 adrenergic receptors located in the central
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nervous system and periphery [7, 39].
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The biphasic effects on blood pressure are caused by initial increases in vascular
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resistance from postsynaptic alpha-2B receptor stimulation that induces hypertension,
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followed by decreased sympathetic discharge from presynaptic alpha-2A receptor
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stimulation that decreases norepinephrine release and presynaptic alpha-2C receptor
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stimulation that decreases epinephrine release from the adrenal glands, resulting in a
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decrease in vascular resistance and blood pressure. The use of higher doses of alpha2-
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adrenergic agonists results in a more prolonged increase in vascular resistance. As a result
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cardiac output can be more adversely affected, resulting in hypotension despite the
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increased vascular resistance [7, 9]. The cardiovascular depression caused by these drugs
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is enhanced by administration of inhalant anesthetic agents, such as halothane, which
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cause further myocardial depression and reduction in cardiac output [7, 39].
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It has been reported that larger doses of xylazine (i.e., 1.0 mg/kg) produce a
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decrease in cardiac contractility in horses, most likely due to decrease in sympathetic tone.
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Similarly, increased peripheral vascular resistance has been associated with larger doses
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of alpha2-adrenergic agonists. The increase in peripheral vascular resistance (an indirect
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indicator of afterload) is thought to be the result of peripheral arterial vascular constriction
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induced by stimulation of alpha2-adrenergic receptors in vascular smooth muscles.
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Therefore, the decrease in stroke volume is caused by depression of ventricular contractility
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and increased afterload [40]. Both sedative and physiologic effects of alpha2-adrenergic agonists have been
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correlated with plasma concentrations [9]. Anesthesia seems to affect the pharmacokinetics
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of xylazine, because in halothane-anesthetized horses an intravenous bolus of 0.5 mg/kg
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increased the terminal half-life to 118 minutes and decreased the clearance to 6 mL/kg/min
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[5]. Therefore, residual xylazine was certainly present during anesthesia and surely
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influenced cardiovascular parameters.
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The dose-dependent cardiorespiratory effects of guaifenesin include a decrease in
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blood pressure and partial pressure of arterial oxygen, and no changes in other variables
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including diaphragmatic function, heart rate, respiratory rate, arterial pH, and partial
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pressure of arterial carbon dioxide, arterial blood pressure, and cardiac output. The use of
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guaifenesin in combination with other injectable anesthetics has also resulted in significant
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MAC reduction [4, 5]. This reduction in MAC was attributed to the anesthetic sparing effects
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and to the analgesic properties of the drug combination [4]. Horses receiving guaifenesin
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following premedication with xylazine and being kept under general anesthesia with
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halothane usually present marked arterial hypotension which recovers slowly over the next
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20 or 30 minutes [17].
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Several studies have shown that S(+)-ketamine has anesthetic potency up to 2 to 3
348
times higher than racemic ketamine, depending on the species, suggesting that lower
349
doses of the isomer would be sufficient for induction of anesthesia [36]. The dosage of S(+)-
350
ketamine used during anesthetic induction was chosen based on previous studies in horses
351
[41, 42]. In humans and mice, with only half of the necessary racemic dose, S(+)-ketamine
352
was able to propitiate identical depths of anesthesia [5].
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EP
347
353
Although ketamine exerts direct myocardial depression (more pronounced with R(-)-
354
ketamine), clinically administered doses of racemic and S(+)-ketamine (bolus or CRI) were
355
associated with better cardiovascular performance, seen as increases in heart rate, arterial
356
pressure, and cardiac output [38]. These positive effects have been attributed to the
357
sympathomimetic
358
norepinephrine re-uptake at noradrenergic nerve endings, and direct vasodilation of
359
vascular smooth muscle [4]. When ketamine is administered with other agents as part of a
360
balanced anesthetic technique, there is a reduced requirement for other anesthetic agents
interactions
within
the
central
nervous
system,
inhibition
of
12
ACCEPTED MANUSCRIPT 361
with known cardiovascular depressant effects (i.e., inhaled anesthetics), which in turn
362
contributes to the overall improvement of cardiovascular function [35, 38]. A positive correlation between racemic ketamine plasma concentration and a
364
halothane MAC reduction (up to 37%) has also been observed in horses [4, 5, 38]. The use
365
of the S(+)-ketamine has been recommended for CRI in horses over the racemic mixture,
366
because the enantiomer is eliminated faster than the racemic mixture [5]. Increased
367
anesthetic stability was observed with combination of guaifenesin and ketamine with
368
halothane when compared with halothane alone [43].
RI PT
363
The decision to initiate CRI [saline (GrSal) or S(+)-ketamine (GrKet)] following
370
patient stabilization, with measured end-tidal halothane concentration at 1.5 MAC, was
371
based on previous study that demonstrated the effects of S(+)-ketamine on halothane MAC
372
in horses [38]. Constant rate infusion of S(+)-ketamine did not interfere with HR in our
373
study. Similar finding was obtained in a previous study [44]. It has been demonstrated that
374
ketamine has sympathomimetic properties [45]. Therefore, heart rate and arterial pressure
375
would likely increase during S(+)-ketamine CRI. However, our results show that S(+)-
376
ketamine, at the proposed dose, was unable to change heart rate and arterial pressure of
377
horses kept under general anesthesia, with end-tidal halothane concentration at 1.5 MAC.
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SC
369
Mean arterial pressure reduced (p ≤ 0.05) during anesthetic induction and stabilized
379
but maintained under reference (physiological) interval for the species during S(+)-ketamine
380
(M0 to M50). Previous studies verified when ketamine is administered at anesthetic doses,
381
cardiovascular function including blood pressure, heart rate, and cardiac output are usually
382
preserved [5]. In a previous study, decrease in heart rate and mean arterial blood pressure
383
was registered following long term CRI of low-doses of racemic ketamine in awake horses
384
[46]. According to the authors, this was an unexpected result which could supposedly be
385
attributed to the action of a persistent metabolite. Since our S(+)-ketamine CRI dose was
386
similar to the one used on the previous study, the supposed action of a persistent
387
metabolite could explain the lowered MAP values observed in GrKet when compared to
388
GrSal. Alternatively, these effects could also represent a compensatory response following
389
the termination of the sympathomimetic effects of the drug [46].
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378
390
Furthermore, halothane is known to reduce MAP in a dose-dependent manner [37,
391
39]. This effect of halothane on arterial pressure could be observed in our study by
392
comparing MAP values at PI with those recorded following patient stabilization, with end-
393
tidal halothane concentration at 1.5 MAC (M0), in both groups. The association of alpha2-
394
adrenergic agonists, guaifenesin and ketamine is known to reduce the MAC of inhaled
13
ACCEPTED MANUSCRIPT 395
anesthetic agents [7, 35, 38]. Since end-tidal halothane concentration was maintained
396
throughout anesthesia at 1.5 MAC, likely the animals were receiving halothane in excessive
397
amounts. Therefore, the animals were possible under influence of the (sparing) depressant
398
effect of halothane which might be considered the main cause of arterial pressure reduction
399
observed following patient anesthetic stabilization in both groups. Since total peripheral resistance changes very little during halothane anesthesia,
401
peripheral vasodilation cannot be considered the primary cause of hypotension. Therefore,
402
reduction in CO might also be considered a determinant factor for the development of
403
hypotension during halothane anesthesia [18, 19].
RI PT
400
Additionally, the depression of baroreceptor reflex by halothane certainly contributed
405
to maintain arterial pressures below baseline values. The baroreceptor reflex is a short-term
406
central mechanism for systemic arterial blood pressure homeostasis. An acute decrease or
407
increase in arterial blood pressure is detected by the baroreceptors and tends to cause a
408
reflex increase or decrease, respectively, in heart rate. The baroreceptor reflex is
409
particularly sensitive to inhalant anesthesia in adult horses. However, it is markedly
410
depressed in the horse by halothane [21-23, 37].
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404
In daily practice, cardiovascular monitoring in anesthetized horses is usually limited
412
to clinical assessment, electrocardiography, pulse-oximetry, and arterial blood pressure
413
monitoring [47]. Differently, CO is routinely measured in human medicine during general
414
anesthesia and in critical care units and to study exercise physiology. However, with the
415
advent of new technologies, this is also becoming reality in veterinary medicine. Cardiac
416
output not only is one of the most important factors to assess cardiovascular function but
417
also allows for calculation of many other cardiovascular parameters for more complete
418
assessment of function. With knowledge of CO and heart rate (HR), stroke volume (SV) can
419
be determined [48].
EP
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420
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411
All anesthetic agents significantly affect the cardiovascular system. Most anesthetic
421
agents
can
422
vasoconstriction or vasodilatation makes arterial pressure an unreliable indicator of
423
worsening cardiac performance. To that matter, CO monitoring can be a much earlier
424
indicator
425
cardiovascular variables. There are 4 basic methods of measuring CO: (1) indicator
426
methods (i.e., lithium dilution), (2) a derivation of the Fick principle, (3) arterial pulse wave
427
analysis, and (4) imaging diagnostic techniques [48].
of
cause
direct
deteriorating
change
in
cardiovascular
systemic
status
vascular
than
resistance.
other commonly
Excessive
monitored
14
ACCEPTED MANUSCRIPT
Cardiac output was obtained echocardiographically in accordance to previous (and
429
validated) descriptions of transcutaneous echocardiographic assessment of CO in standing
430
horses [34, 49, 50]. Recorded values for CO were inferior to ones previously obtained by
431
thermodilution. However, percentage of variation in CO observed in our study was similar to
432
those reported previously for the species [49, 50]. Acquisition of left ventricular activity by
433
Teicholz formula could be considered a limitation of our study. The use of transesophageal
434
echocardiography, thermodilution, or CO estimation by Simpson rule disk summation
435
method could have been used as alternatives.
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428
Cardiac output decreased considerably (p ≤ 0.05) following anesthetic induction and
437
remained under baseline values throughout the evaluation period in both groups. Halothane
438
is known to cause dose-dependent reduction in CO during anesthesia [17, 18, 37, 39].
439
Reduction in CO during halothane anesthesia is caused by decrease in stroke volume and
440
reduction in contractility of cardiac muscles (negative inotropic effect), both induced by the
441
inhalant agent [18, 20, 37]. However, cardiac output of horses anesthetized with halothane
442
and kept under spontaneous ventilation might be maintained because there is less
443
reduction of venous return [20].
444
halothane anesthesia, in similarity to CO.
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SC
436
Fractional shortening and EF also diminished during
In other study, the authors demonstrated a progressive decrease in cardiac index
446
over the course of anesthesia in dorsally recumbent horses undergoing surgery. Since
447
heart rate did not change significantly over time (and velocity time integral decreased over
448
time), the authors concluded that the decreased cardiac index was the result of decreased
449
stroke volume [28]. The same authors attributed the CO variations observed at the baseline
450
and subsequent data points to the higher vaporizer settings used to ensure constant end-
451
tidal values. Since our end-tidal halothane concentration was kept at 1.5 MAC throughout
452
anesthesia, halothane concentration surely influenced left ventricular function values (CO,
453
EF, and FS) as well. Reduction in left ventricular function associated with decrease in MAP,
454
following patient stabilization during general anesthesia reinforce the sparing (depressant)
455
effects of halothane overcame the effects of S(+)-ketamine CRI.
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445
456
The body position of the horses during echocardiographic examination throughout
457
anesthesia (dorsal recumbency) could have also been responsible for the differences in CO
458
values obtained in both groups, when compared to baseline values. During transcutaneous
459
echocardiography in dorsal recumbency, the same criteria was tried (with acquisition of
460
similar view) as if the animals were in standing position. However, the measurements could
461
not have been as accurate as if the horses were in upright position, in similarity to previous
15
ACCEPTED MANUSCRIPT 462
descriptions of echocardiographic assessment of cardiac function in laterally-recumbent
463
horses [27]. Respiratory rate also decreased following anesthetic induction and persisted during
465
anesthesia (evaluation period). Infusions of racemic ketamine generally cause minimal
466
respiratory depression with only mild hypercapnia [4]. Thus, changes in ƒR most likely
467
occurred by halothane direct action on respiratory system.
RI PT
464
Halothane and other inhaled anesthetics cause a dose-related depression in
469
respiratory system function that is characterized by an increase in the partial pressure of
470
CO2 in arterial blood and a decreased ability to oxygenate arterial blood. The magnitude of
471
this depression for a given dose of halothane is considerably greater in horses than other
472
species, including humans [37].
SC
468
Since increased terminal half-life and decreased clearance of xylazine were
474
observed in halothane-anesthetized horses, and alpha2-adrenergic agonists are known to
475
decrease respiratory rate, residual xylazine might have also affected ƒR. Respiratory rate
476
alone should not be used as a predictor of respiratory function due to its great variability.
477
This also could be considered a limitation of our study. In that matter, ventilometry would be
478
more suitable protocol for evaluating respiratory dynamics.
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473
480
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479
5. Conclusions
Constant rate infusion of 0.01mg/kg/min of S(+)-ketamine was ineffective in
482
improving cardiocirculatory depression commonly observed in halothane-anesthetized
483
horses. Despite possible limitations (i.e., use of Teicholz formula to calculate left ventricular
484
activity), transcutaneous echocardiographic assessment of left ventricular activity in
485
dorsally-recumbent horses seemed applicable. This maneuver could be employed in other
486
anesthetic models or even in equine anesthetic daily routine for assessment of
487
cardiovascular parameters, during surgical procedures in which the patient is kept in dorsal
488
recumbence, such as celiotomies. However, further studies are encouraged to validate its
489
reliability.
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481
490 491 492 493 494 495
Acknowledgements This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - PQ-1C) for financial assistance.
16
ACCEPTED MANUSCRIPT
502 503 504 505 506 507 508
Abbott Laboratorios, Sao Paulo, Brazil.
d
König, São Paulo, Brazil.
e
Henrifarma, São Paulo, Brazil.
f
Cirúrgica Fernandes, São Paulo, Brazil
g
HB, São Paulo, Brazil.
h
Ohmeda, Louisville – CO, USA.
i
TEB, São Paulo, Brazil.
j
Pie Medical Imaging, Genova, Italy.
k
Digicare Animal Health, Boynton Beach - FL, Brazil.
l
SAS Institute Inc., Cary – NC, USA.
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501
Laboratório Farmacêutico, Ceará, Brazil.
c
SC
500
b
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499
Cristália, São Paulo, Brazil.
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498
a
EP
497
Footnotes
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ACCEPTED MANUSCRIPT References
1. Senior JM. Morbidity, mortality, and risk of general anesthesia in horses. Vet Clin North Am Equine Pract 2013; 29: 1–18. 2. Bidwell LA, Bramlage LR, Rood WA. Equine perioperative fatalities associated
Anaesth Analg 2007; 34:23–30.
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with general anaesthesia at a private practice: a retrospective case series. Vet
3. Johnston GM, Eastment JK, Wood JL, Taylor PM. The confidential enquiry into
Anaesth Analg 2002; 29:159–70.
SC
perioperative equine fatalities (CEPEF): mortality results of Phases 1 and 2. Vet
4. Bettschart-Wolfensberger R, Larenza MP. Balanced anesthesia in the equine. Clin
M AN U
Tech Equine Pract 2007; 6: 104-10.
5. Valverde A. Balanced anesthesia and constant-rate infusions in horses. Vet Clin North Am Equine Pract 2013; 29: 89–122.
6. Bennett RC, Steffey EP, Kollias-Baker C, et al. Influence of morphine sulfate on the halothane sparing effect of xylazine hydrochloride in horses. Am J Vet Res
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2004; 65(4): 519–26.
7. Daunt DA, Steffey EP. Alpha-2 adrenergic agonists as analgesics in horses. Vet Clin North Am Equine Pract 2002; 18: 39–46.
EP
8. Hubbell JA, Saville WJ, Bednarski RM. The use of sedatives, analgesic and anaesthetic drugs in the horse: an electronic survey of members of the American
AC C
Association of Equine Practitioners (AAEP). Equine Vet J 2010; 42(6): 487–93. 9. Valverde A. Alpha2-adrenergic agonists for pain therapy in horses. Vet Clin North Am Equine Pract 2010; 26(3): 515–32.
10. Tranquilli WJ, Thurmon JC, Corbin JE, Benson GJ, Davis LE. Halothane-sparing effect of xylazine in dogs and subsequent reversal with tolazoline. J Vet Pharmacol Therap 1984; 7: 23-28. 11. Wagner AE, Muir WW, Hinchcliff KW. Cardiovascular effects of xylazine and detomidine in horses. Am J Vet Res 1991; 52(5): 651-657.
18
ACCEPTED MANUSCRIPT
12. Guedes AGP, Natalini CC. Anestesia em equinos com síndrome cólica – análise de 48 casos e revisão de literatura. Cienc Rural 2002; 32(3):535-42. 13. Bevan RK, Rose MA, Duggan KA. Evidence for direct interaction of ketamine with α1- and - α2 adrenoceptors. Clin Exp Pharm Physiol 1997; 24: 923-6. 14. Lauretti GR, Lima ICPR, Buscatti RY, Reis MP. Clinical evaluation of
RI PT
hemodynamic, analgesic, psychedelic and neuromuscular block effects of racemic ketamine versus S(+) ketamine. Rev Bras Anest 2000; 50: 357-62.
15. Krugera K, Stegmanna GF. Partial intravenous anaesthesia in 5 horses using ketamine, lidocaine, medetomidine and halothane. Jl S Afr Vet Ass 2009; 80(4):
SC
233–6.
16. Martinez EA, Keegan RD. Muscle relaxants and neuromuscular blockade. In:
M AN U
Tranquilli WJ, Thurmon JC, Grimm KA, editors. Lumb & Jones' Veterinary Anesthesia and Analgesia, 4th ed. Ames: Blackwell Publishing; 2007: 419-37. 17. Hall LW, Clarke KW, Trim CM. Veterinary anaesthesia, 10th ed. London: WB Saunders; 2001: 149-78.
18. Steffey EP. Inhalation anesthetics. In: Riviere JE, Papich MG, editors. Veterinary
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Pharmacology and therapeutics, 9th ed. Hoboken: Wiley-Blackwell; 2009: 229263.
19. Ingwersen W, Allen DG, Dyson D H, Pascoe PJ, O'grady MR. Cardiopulmonary
EP
effects of a halothane/oxygen combination in healthy cats. Can J Vet Res 1988; 52(3): 386-391.
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20. Raisis AL, Blissitt KJ, Henley W, Rogers K, Adams V, Young LE. The effects of halothane and isoflurane on cardiovascular function in laterally recumbent horses. Br J Anaesth 2005; 95: 317–25.
21. Patel PM, Drummond JC. Cerebral physiology and the effects of anesthetics and techniques. In: Miller RD, editor. Miller’s anesthesia. Philadelphia: Elsevier Churchill Livingstone; 2005: 813-57. 22. Pavlin EG, Su JY. Cardiopulmonary pharmacology. In:
Miller RD, editor.
Anesthesia, 4th ed. New York: Churchill Livingstone; 1994: 125-156.
19
ACCEPTED MANUSCRIPT
23. Purchase IF. Cardiac arrhythmias occurring during halothane anaesthesia in cats. Br J Anaesth. 1966; 38: 13-22. 24. Nyland TG, Mattoon JS, editors. Veterinary diagnostic ultrasound. Philadelphia: W.B. Saunders; 1995: 357p. 25. Patteson MW, Gibbs C, Wotton PR, Cripps PJ. Effects of sedation with detomidine
RI PT
hydrochloride on echocardiographic measurements of cardiac dimensions and indices of cardiac function in horses. Equine Vet J 1995; 19: 33-7.
26. Spadavecchia C, Trachsel D, Tschudi P, Schatzmann U. Combined general anaesthesia in a horse with tricuspidal regurgitation and transthoracic sonographic
SC
monitoring of the cardiac function. Pferdeheilkunde 2006; 22 (3): 250-3. 27. Vitale V, Sgorbini M, Briganti A, Corazza M, Breghi G, Staffieri F. Evaluation of
M AN U
echocardiographic parameters during increasing infusion rates of dobutamine in isoflurane-anesthetized horses. J Equine Vet Sci 2013; 33: 1110-4. 28. Blissitt KJ, Raisis AL, Adams VJ, Rogers KH, Henley WE, Young LE. The effects of halothane and isoflurane on cardiovascular function in dorsally recumbent horses undergoing surgery. Vet Anaesth Analg 2008; 35: 208–19.
TE D
29. Canola JC, Cardenas JJ, Canola PA. Efeito da romifidina sobre as dimensões ecocardiográficas e sobre índices da função cardíaca em equinos. Ars Vet 2002; 18(3): 231-237.
EP
30. Canola JC, Valadão CAA, Portugal ES, Canola PA. Avaliação ecocardiográfica de equinos pré-medicados com n-butilbrometo de hioscina e sedados com
AC C
romifidina. Ciênc Anim Bras 2007; 8(4): 833-839. 31. Linardi RL, Canola JC, Valadão CAA. Cardiovascular assessment in horses sedated with xylazine or amitraz. Arq Bras Med Vet Zootec 2008; 60(2): 329-334.
32. Marr CM, Patteson M. Echocardiography. In: Marr CM, Bowen IM, editors. Cardiology of the horse. Edinburgh: Saunders Elsevier; 2010: 105-26.
33. Brown DJ, Rush JE, MacGregor J, Ross Jr JN, Brewer B, Rand WM. M-mode echocardiographic ratio indices in normal dogs, cats, and horses: a novel quantitative method. J Vet Intern Med 2003; 17: 653–62.
20
ACCEPTED MANUSCRIPT
34. Reef VB, Whittier M, Allam LG. Echocardiography. Clin Tech Equine Pract 2004; 3: 274-83. 35. Yamashita K, Muir WW. Intravenous anesthetic and analgesic adjuncts to inhalation anesthesia. In: Muir WW, Hubbell JAE, editors. Equine Anesthesia Monitoring and Emergency Therapy, 2nd ed. St. Louis: Saunders Elsevier; 2009:
RI PT
260-76.
36. Rossetti RB, Cortopassi SRG, Intelizano T, Machado TSL, Ferreira da Cruz RS. Comparison of ketamine and S(+)-ketamine, with romifidine and diazepam, for total intravenous anesthesia in horses. Vet Anaesth Analg 2008; 35: 30-7.
SC
37. Steffey EP. Inhalation anesthetics and gases. In: Muir WW, Hubbell JAE, editors. Equine Anesthesia Monitoring and Emergency Therapy, 2nd ed. St. Louis:
M AN U
Saunders Elsevier; 2009: 288-314.
38. Muir WW, Sams R. Effects of ketamine infusion on halothane minimal alveolar concentration in horses. Am J Vet Res 1992; 53(10):1802-6. 39. Steffey EP, Howland Jr.: Cardiovascular effects of halothane in the horses. Am J Vet Res 1978; 39(4): 611-5.
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40. Yamashita K, Tsubakishita S, Futaoka S, Ueda I, Hamaguchi H, Seno T, Katoh S, Izumisawa Y, Kotani T, Muir W. Cardiovascular effects of medetomidine, detomidine and xylazine in horses. J Vet Med Sci 2000; 62: 1025-32.
EP
41. Larenza MP, Ringer SK, Kutter APN, Conrot A, Theurillat R, Kummer M, Thormann W, Bettschart-Wolfensberger R. Evaluation of anesthesia recovery
AC C
quality after low-dose racemic or S-ketamine infusions during anesthesia with isoflurane in horses Am J Vet Res 2009; 70: 710–8.
42. Larenza MP, Knobloch M, Landoni MF, Levionnois OL, Kronen PW, Theurillat R, Schatzmann U, Thormann W. Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration in Shetland ponies sedated with xylazine. Vet J 2008; 177: 432–5. 43. Spadavecchia C, Stucki F, Moens Y, Schatzmann U. Anaesthesia in horses using halothane and intravenous ketamine guaiphenesin: a clinical study. Vet Anaesth Analg 2002; 29: 20–8.
21
ACCEPTED MANUSCRIPT
44. Flaherty D, Nolan A, Reid J, Monteiro AM. The pharmacokinetics of ketamine after a continuous infusion under halothane anaesthesia in horses. J Vet Anaesth 1998; 25(1): 31-36. 45. Bevan RK, Rose MA, Duggan K A. Evidence for direct interaction of ketamine with α1- and - α2 adrenoceptors. Clin Exp Pharm Physiol 1997; 24: 923-926. CL,
Brumbaugh
GW,
Matthews
NS,
Peck
KE,
Roussel
RI PT
46. Fielding
AJ.
Pharmacokinetics and clinical effects of a subanesthetic continuous rate infusion of ketamine in awake horses. Am J Vet Res 2006; 67: 1484–90.
47. Schauvliege S, Gasthuys F. Drugs for cardiovascular support in anesthetized
SC
horses. Vet Clin North Am Equine Pract 2013; 29: 19–49.
48. Shih A. Cardiac output monitoring in horses. Vet Clin North Am Equine Pract
M AN U
2013; 29: 155-67.
49. Mizuno Y, Ainda H, Hara H, Fujinaga T, Hagio M. Comparison of methods of cardiac output measurements determined by dye dilution, pulsed Doppler echocardiography and thermodilution in horses. J Vet Med Sci 1994; 56(1): 1-5. 50. Blissitt KJ, Young LE, Jones RS, Darke PG, Utting J. Measurement of cardiac
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output in standing horses by Doppler echocardiography and thermodilution.
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Equine Vet J 1997; 29(1): 18-25.
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Table 1. Results of measured variables (mean ± s.d.) obtained from 6 horses anesthetized with halothane and given CRI infusion of either S(+)ketamine (GrKet) or saline (GrSal) VARIABLES GROUPS MOMENTS CRI
FS (%)
SAP (mmHg)
MAP (mmHg)
DAP (mmHg)
M20
M30
M40
M50
RI PT
M10
35±6
40±8
39±3
35±3
34±2
32±3
32±3
31±3
GrSal
35±6
30±4
40±8
38±3
34±11
33±5
32±5
32±5
31±3
GrKet
16±6a
15±7a
11±4ab
8±1b
8±1b
8±2b
8±3b
8±2b
8±2b
GrSal
13±4a
12±2a
9±3b
8±2b
8±1b
9±1b
9±2b
7±2b
9±2b
GrKet
10.6±4a
5.3±2b
6±1b
5.1±1b
4.4±1b
4±2b
4.5±2b
4.6±1b
4.4±1b
GrSal
10.1±1a
5.8±1b
GrKet
59±12a
49.7±13ab
GrSal
63.5±4a
45.8±5b
GrKet
33±7a
25±6b
GrSal
36±3a
24±3b
GrKet
150±12a
GrSal
158±33a
GrKet
121±16a
GrSal
128±21a
GrKet GrSal
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EF (%)
M0
41±21
6.5±1b
5.6±2b
5.7±2b
5.8±3b
4.2±1b
4.8±1b
4.2±1b
47.7±9ab
41.3±9b
42±9b
43.2±14b
34.8±8b
38.8±6b
34.8±7b
42±21b
52.8±16ab
46.3±8b
41.2±9b
33.2±9b
35±6b
41±11b
25±6b
21±6b
22±6b
23±8b
17±4b
20±3b
18±4b
29±5b
29±11b
24±4b
21±5b
17±5b
18±3b
21±6b
103±7b
102±8b
57±10c
60±11c
60±11c
60±11c
61±13c
59±11c
98±11b
106±10b
57±10c
67±7c
70±11c
64±11c
62±12c
68±16c
73±13b
83±8b
40±8c
44±9c
43±8cA
44±9c
44±0c
46±11c
68±30b
86±7c
41±7d
50±7cd
54±7cdB
51±10cd
48±11cd
46±11cd
95±11a
56±15b
68±8c
30±6d
33±8d
33±6d
36±8d
33±9d
39±12d
107±16a
67±7b
70±8b
39±6c
38±7c
41±10c
39±10c
36±9c
35±10c
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CO (L/min)
PI
GrKet
EP
ƒR (bpm)
Rec
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RR (bpm)
B
SC
(n = 6)
B - baseline; Rec – animal assumed lateral recumbency following infusion of guaifenesin; PI – two minutes post-anesthetic induction with S(+)ketamine; M0 – beginning of CRI following patient stabilization with measured end-tidal halothane concentration at 1.5 MAC; M10 to M50 – parameters recorded during S(+)-ketamine (GrKet) or saline (GrSal) CRI elapsed time. Lowercase letters in the same line express significant (p ≤ 0.05) variations along time within each group. Capital letters in the same column express significant (p ≤ 0.05) variation in between groups (Student-Newman-Keuls).
ACCEPTED MANUSCRIPT Highlights •
Constant rate infusion of S(+)-ketamine at 0.01mg/kg/min is ineffective in improving cardiocirculatory function of halothane-anesthetized horses.
Transcutaneous echocardiographic assessment of left ventricular activity in dorsallyrecumbent horses seems applicable.
There is a need for more studies to validate transcutaneous echocardiography in
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dorsally-recumbent horses
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•
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•