Tachypnea and Antipyresis in Febrile Horses after Sedation with α2-Agonists
2010; Wiley; Volume: 24; Issue: 4 Linguagem: Inglês
10.1111/j.1939-1676.2010.0528.x
ISSN1939-1676
AutoresAnna Kendall, Cornelia Mosley, Johan Bröjer,
Tópico(s)Essential Oils and Antimicrobial Activity
ResumoJournal of Veterinary Internal MedicineVolume 24, Issue 4 p. 1008-1011 Brief CommunicationOpen Access Tachypnea and Antipyresis in Febrile Horses after Sedation with α2-Agonists A. Kendall, A. Kendall Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenSearch for more papers by this authorC. Mosley, C. Mosley Canada West Veterinary Specialists & Critical Care Hospital, Vancouver, BC, CanadaSearch for more papers by this authorJ. Bröjer, J. Bröjer Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenSearch for more papers by this author A. Kendall, A. Kendall Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenSearch for more papers by this authorC. Mosley, C. Mosley Canada West Veterinary Specialists & Critical Care Hospital, Vancouver, BC, CanadaSearch for more papers by this authorJ. Bröjer, J. Bröjer Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenSearch for more papers by this author First published: 01 July 2010 https://doi.org/10.1111/j.1939-1676.2010.0528.xCitations: 15 Corresponding author: Anna Kendall, Department of Clinical Sciences, Swedish University of Agricultural Sciences, P.O. Box 7054, SE-750 07 Uppsala, Sweden; e-mail: anna.kendall@kv.slu.se. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Background: Signs of tachypnea after sedation of febrile horses with α2-agonists have been noted previously but have not been further investigated. Objectives: To examine the effects of xylazine and detomidine on respiratory rate and rectal temperature in febrile horses and to investigate if either drug would be less likely than the other to cause changes in these variables. Animals: Nine febrile horses and 9 healthy horses were included in the study. Methods: Horses were randomly assigned to sedation with xylazine 0.5 mg/kg or detomidine 0.01 mg/kg. Heart rate and respiratory rate were recorded before sedation and at 1, 3, and 5 minutes after injection. Hourly measurements of rectal temperature were performed starting before sedation. Results: All febrile horses experienced an episode of tachypnea and antipyresis after sedation. Rectal temperature in the febrile group was significantly lower at 1, 2, and 3 hours after sedation. In several measurements, the decrease was >1°C. Respiratory rate in the febrile group was significantly increased after sedation. All febrile horses were breathing >40 breaths/min and 3 horses >100 breaths/min 5 minutes after sedation. No differences were noted between the 2 treatments. No significant changes in respiratory rate or temperature were noted in the reference group. Conclusions and Clinical Importance: Febrile horses can become tachypneic after sedation with detomidine or xylazine. The antipyretic properties of α2-agonists need consideration when evaluating patients that have been sedated several hours before examination. α2-Agonists were first developed to treat hypertension in humans.1 They are used in horses for sedation, analgesia, and muscle relaxation. α2-Receptors exist pre- and postsynaptically in neuronal and nonneuronal tissues, and extrasynaptically in vasculature and platelets.1 The α2-agonists have inhibitory effects on the release of noradrenaline in the synaptic cleft via G-protein that causes decreased cAMP formation. In addition to this mode of action, α2-agonists utilize other signaling pathways including regulation of ion channel activities.1 The receptor specificity for α2-adrenoceptor agonists is not absolute, and high doses can influence the α1-receptor. Different α2-agonists also have different α2/α1 specificity. Xylazine has an α2 : α1 receptor selectivity ratio of 160 : 1, detomidine of 260 : 1, and romifidine of 340 : 1.1 The α2-agonists have dose-dependent effects and duration of action2 that need to be considered when comparing results among studies. Differences in receptor specificity as well as variable dose regimens may account for the slightly different clinical effects reported for various α2-agonists. The role of noradrenaline in thermoregulation and fever has been studied in other species. Both agonists and antagonists of the α2-receptors have been shown to attenuate lipopolysaccharide-induced fever.3-5 Although somewhat contradictory, these results indicate that the α-adrenoceptor has a functional role in thermoregulatory processes. The release of noradrenaline in the preoptic area of rats after systemic injection of lipopolysaccharide has been documented,6 and noradrenaline microdialyzed in the preoptic area of guinea pigs evokes a rise in core temperature.7 Accordingly, noradrenergic terminals in the central nervous system (CNS) could mediate the febrile response. Among previously reported adverse effects of α2-agonists are decreased heart rate, ataxia, and increased sensitivity to touch.8 Focal sweating, diuresis, and initial hypertension because of peripheral vasoconstriction followed by a longer period of hypotension also have been reported.2 Although anecdotally reported and relatively well known by practicing veterinarians, signs of tachypnea after sedation of febrile horses have not been reported previously in the veterinary literature. Changes in respiration in normothermic horses are inconsistent among studies with decreases, increases, and unchanged respiratory rate described.2, 9 The purpose of this study was to examine the effects of xylazine and detomidine on respiratory rate and rectal temperature in febrile horses. Equipotent doses of xylazine and detomidine8 were used to investigate if either drug would be less likely than the other to cause changes in these variables. Materials and Methods Animals The study was conducted in patients admitted to the University Equine Clinic of the Swedish University of Agricultural Sciences. In order to be included in the febrile group, the horse had to have a rectal temperature of ≥39°C and no treatments could have been administered on the day of admission. The need for sedation was decided by the treating veterinarian, and owner's consent was obtained before inclusion in the study. Nine horses (3 geldings, 3 mares, and 3 stallions) were included in the febrile group. Rectal temperature ranged from 39.1 to 40.7°C (mean, 39.7°C). Age ranged from 1 to 19 years (mean, 9 years), weight ranged from 323 to 530 kg (mean, 458 kg) and breeds represented were Swedish Warmblood (2), Thoroughbred (1), Standardbred (4), Knabstrup (1), and Pura Raza Española (1). Final diagnoses were neoplastic disease (2), pleuritis (2), strangles (1), granulomatous enteritis (1), and anaplasmosis (1). For 2 horses, a final diagnosis for the cause of fever was not determined. The reference group consisted of 9 Standardbreds (3 geldings, 2 mares, and 4 stallions) admitted for dental examination. Age ranged from 3 to 7 years (mean, 4 years) and weight ranged from 400 to 565 kg (mean, 499 kg). In order to be included, the horses had to be normothermic (rectal temperature ranged from 37.4 to 38.1°C; mean, 37.6°C), have no abnormal findings on general clinical examination and have a normal CBC and plasma fibrinogen concentration. Study Design Horses were randomly assigned to 1 of 2 treatments. Five horses were sedated with xylazinea (0.5 mg/kg) and 4 horses received detomidineb (0.01 mg/kg) in both the febrile and reference groups. The drugs were injected IV by venipuncture or through a preplaced IV catheter in the jugular vein. Before sedation, blood was submitted for CBC as well as total serum protein, serum albumin, and plasma fibrinogen concentration. Heart rate and respiratory rate were recorded before sedation and at 1, 3, and 5 minutes after injection. Because of clinical considerations, the monitoring of respiration without other interventions could only be done for 5 minutes, and the end point with return to presedation respiratory rate could not be determined. Rectal temperature was measured before sedation and hourly for 4 hours after sedation in febrile horses, and for 3 hours in the reference group. Blood for arterial blood gas analysis was collected in preheparinized self-filling syringesc from the transverse facial artery before sedation and after the last recording of respiratory rate. Samples were analyzed immediately on a hand-held analyzer.d No additional treatments were given during the time of data collection. The study was approved by the Ethical Committee for Animal Experiments, Uppsala, Sweden. Statistical Analyses Data were compared by 2-way analysis of variance for repeated measures. Values were log-transformed in order to normalize data before analysis and P-values <.05 were considered significant. Significant differences between means were identified by use of Tukey's test. All statistical evaluations were performed by a statistical software program.e Results All febrile horses experienced an episode of marked tachypnea and antipyresis after sedation. No differences in respiratory rate (P= .817) or rectal temperature (P= .586) were recorded between the 2 α2-agonist treatments. Neither decreased temperature nor tachypnea was noted in the reference group. Rectal temperature was not monitored in 1 febrile horse because it received metamizol because of colic within 1 hour after sedation with xylazine. Consequently, 8/9 febrile horses were included in the measurements of rectal temperature. Rectal temperature in the febrile group was significantly lower at 1, 2, and 3 hours after sedation compared with presedation values (P < .001, P < .001, and P= .004, respectively). Mean temperature decrease was 1.1°C at 1 and 2 hours, and 1.0°C at 3 hours after sedation (Fig 1). There were no significant differences in respiratory rates between febrile and normothermic horses before sedation (P > .1). In the febrile group, the respiratory rate was significantly higher from 1 to 5 minutes after sedation compared with presedation values (P < .001, P= .016, and P < .001, respectively, at 1, 3, and 5 minutes). All febrile horses were breathing >40 breaths/min and 3/9 horses >100 breaths/min at 5 minutes after sedation (Fig 2). The tachypnea was in some cases accompanied by pale mucous membranes (personal observation, data not recorded). Heart rate was significantly higher in the febrile group (42–81 bpm; mean, 56 bpm) compared with normothermic horses (24–42 bpm; mean, 32 bpm) before sedation (P < .001). All horses in the normothermic group had significantly lower heart rates at 1 and 3 minutes after sedation compared with heart rate before sedation (P < .001 and P= .027, respectively). No significant decreases in heart rate were noted in the febrile group (P > .05). Figure 1Open in figure viewerPowerPoint Rectal temperatures presented as mean values before (0) and hourly after sedation in 8 febrile (♦) and 9 reference (▴) horses. Error bars show standard deviation. *Significantly decreased rectal temperature in the febrile group compared with presedation values. Figure 2Open in figure viewerPowerPoint Respiratory rate in all horses before (0) and 1, 3, and 5 minutes after sedation. Dotted lines represent febrile horses sedated with detomidine and solid lines represent febrile horses sedated with xylazine. Respiratory rates of the reference horses (both treatments) are indicated as dashed lines. Total white blood cell counts in the febrile group ranged from 3.8 to 14.6 × 109/L (mean, 9.8 × 109/L). Four horses had band neutrophils noted in the CBC. Plasma fibrinogen concentration ranged from 3.2 to 10.3 g/L (mean, 6.9 g/L), total serum protein concentration ranged from 41 to 78 g/L (mean, 62 g/L), and serum albumin concentration ranged from 22 to 35 g/L (mean, 27 g/L) in the febrile group. Arterial blood gases were obtained both before sedation and after the last recording of respiratory rate and heart rate from 6/9 febrile horses and from 7/9 horses in the reference group. Results are presented in Table 1. Because of problems with sampling, the 2nd arterial samples were not taken at a consistent time interval after sedation. In the febrile group, samples were obtained between 1 and 10 minutes after the last recording of respiratory rate and heart rate. All of the 2nd samples were obtained while the horses were still tachypneic. In the reference group, the 2nd sample was obtained between 1 and 5 minutes after the last recording of respiratory rate and heart rate. Because of the inconsistency in sampling times and the low numbers of sampled individuals, no statistical analysis of the arterial blood gas data was included. The febrile horses were mildly alkalemic because of a mild respiratory alkalosis. Although all febrile horses were very tachypneic after sedation, only 3/6 horses showed further decreases in arterial Pco2 in the 2nd blood gas sample. The decrease in Pco2 ranged between 6 and 6.5 mmHg in these horses. In the reference group, 3/7 horses showed decreases in arterial Pco2 ranging from 3.3 to 12.5 mmHg. None of the reference horses was noted to be tachypneic and there were no significant changes in respiratory rate in this group compared with before sedation (P > .8). Table 1. Arterial blood gas values in 6 febrile and 7 reference horses before and after sedation. Group pH Pco2 (mmHg) Po2 (mmHg) HCO3− (mmol/L) Before sedation Febrile 7.49 (7.46–7.52) 31.4 (26.4–35.5) 90.5 (82.5–105.8) 24.0 (19.8–26.2) Reference 7.43 (7.42–7.45) 45.8 (42.7–47.7) 100.6 (83.3–107.3) 30.6 (28.5–32.0) After sedation Febrile 7.53 (7.47–7.61) 28.7 (21.4–38.0) 97 (87–117) 24.0 (20.6–27.8) Reference 7.44 (7.39–7.52) 43.9 (34.5–51.7) 90.8 (69–111.8) 30.0 (27.8–32.6) Values are expressed as mean (ranges). Discussion In the present prospective clinical case study, we report 2 adverse effects of sedation of febrile horses with α2-agonists that to the authors' knowledge have not been described previously—tachypnea and antipyresis. The mechanisms for fever are complex and in part still not fully elucidated.10 Endogenous pyrogens (such as interleukin-1, interleukin-6, and tumor necrosis factor) cause increase of prostaglandins in the CNS. A direct effect of exogenous pyrogens on prostaglandin production also is discussed as a possible mechanism for fever.10 The thermoregulatory set point in the preoptic anterior hypothalamus changes and mechanisms of heat conservation such as shivering, heat-seeking behavior, and vasoconstriction are coupled with increased heat production because of increased metabolic rate.11 There is a growing body of evidence that noradrenaline in the preoptic area is involved as a transmitter substance in thermoregulation.3-7 It has been shown that the α2-agonist clonidine causes an initial decrease of prostaglandin E2 in the hypothalamus of guinea pigs,3 and it can be hypothesized that a similar mechanism is responsible for antipyresis in the febrile horse after sedation with xylazine or detomidine. However, the results of fever research are inconsistent, and extrapolating data from studies in small animals such as guinea pigs and rabbits that easily become hypothermic may not be accurate for the horse. A previous study in healthy horses has shown alterations in rectal temperature in horses after sedation with detomidine,12 indicating that α2-agonist sedation influences thermoregulation in horses. When using a dosage of approximately 0.01 mg/kg of detomidine, horses had significantly lower rectal temperatures compared with starting values 2 hours after sedation12 but the decrease was small, approximately 0.2°C. A similar decrease in temperature was not noted in the normothermic reference group of the present study where no differences in rectal temperature over time were found. Sweating has been recorded as a common adverse effect of sedation with α2-agonists.2 This may have caused some of the temperature decrease noted; however, the same decrease in temperature was not recorded in the normothermic reference group, making this explanation less likely. If an α2-agonist induced decrease in prostaglandins changes the thermoregulatory set point, the tachypnea could be a way to decrease core temperature by increased heat loss (ie, the set point for temperature is lowered and the horse suddenly perceives itself to be too warm and starts panting). It is unlikely that the increased respiratory rate in itself would cause the decrease in temperature, because it lasted a relatively short time and the decrease in temperature was still significant after 3 hours (exact time of tachypnea was not noted for all the horses, but the horse with the most forceful reaction had a normal respiratory rate 30 minutes after sedation). However, the authors have observed horses treated with nonsteroidal anti-inflammatory drugs for febrile conditions that have started to breathe with markedly increased respiratory rate after sedation despite being normothermic at the time (unpublished data), indicating that the tachypnea may be a separate response. Another possible explanation for the tachypnea could be direct effects of the α2-receptors in the pneumotactic center.13 Why this reaction would mainly occur in febrile horses is unclear. Only 3/6 febrile horses increased their alveolar ventilation after sedation as shown by an additional decrease in arterial Pco2. The maximum decrease in arterial Pco2 after sedation in the febrile group was 6.5 mmHg. A more pronounced and consistent decrease in Pco2 was expected in the febrile group considering the clinical signs with severely increased respiratory rate. The tachypnea noted after sedation in this study is more likely to be increased ventilation of dead space than hyperventilation. Respiratory alkalosis was noted before sedation in the febrile group. The duration of the changes in acid-base balance was not known and therefore it cannot be excluded that some individuals may have had mixed acid-base disorders. However, considering duration of illness and final diagnosis it is most likely that the horses had chronic metabolic compensation (data not shown). No statistical difference was found in respiratory rate between the febrile and reference group before sedation, and the respiratory alkalosis present in the febrile group may have been because of an increase in tidal volume in these horses. This could not be determined because tidal volume was not evaluated in the present study. It would have been interesting to follow the signs of tachypnea for the full extent of the reaction. Because the study was carried out on acute patients that received sedation before other procedures in the diagnostic evaluation, this was not an option, because (for example) the use of a twitch or an endoscopy procedure would potentially have influenced respiratory rate. Recording clinical variables for >5 minutes would have interfered with the diagnostic evaluation and may have resulted in the need for additional sedation. Performing the study on patients also limited the possibilities for core temperature measurements although rectal temperature is a reasonable estimate of core temperature.14 One febrile horse experienced forceful tachypnea immediately after sedation and had a decrease in rectal temperature, but the fever did not return. This horse had received tetracycline on the day before admission, and subsequently was diagnosed with acute anaplasmosis. The reference group is not optimal because it only consists of 1 breed (Standardbreds). Also, because of constraints in availability, the rectal temperature in the reference group could not be followed for more than 3 hours after sedation in most of the horses. These factors are unlikely to have influenced the results of the study. The present study includes too few horses to make any definite recommendations, but no horse needed reversal of the α2-agonist because of the tachypnea despite some having rather marked changes in breathing. The tachypnea was sometimes accompanied by appearance of pale mucous membranes, but this was attributed to the fact that it was immediately after sedation in the time frame of peripheral vasoconstriction.2 No differences in tachypnea or rectal temperature decrease were found between the 2 α2-agonist treatments. Although not studied here, using a lower dose for sedation or combining the α2-agonist with an opioid may alleviate the signs of tachypnea in febrile horses (personal observation). It is not within the scope of this study to determine the mechanism of the reactions described above, and further research is warranted. From a clinical point of view, the antipyretic properties of α2-agonists need consideration when evaluating patients that have been sedated within a few hours before examination. Footnotes aNarcoxyl vet, Intervet Schering Plough Animal Health, Stockholm, Sweden bDomosedan vet, Orion Pharma Animal Health, Sollentuna, Sweden cPico 70, Radiometer, Copenhagen, Denmark di-STAT 1 Analyzer, Abbott Scandinavia AB, Solna, Sweden eSigmaPlot 11, Systat Software UK Limited, London, UK Acknowledgment This study was funded by Intervet Schering Plough Animal Health, Sweden. The authors also thank Dr Susanne Demmers for assistance with the reference cases. References 1 Tranquilli WJ, Thurmon JC, Grimm KA. Lumb and Jones' Veterinary Anesthesia and Analgesia, 4th ed. Iowa, USA: Blackwell Publishing; 2007: 210– 212. Google Scholar 2 Vainio O. 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