Besitzerfragebogen zur Schmerzbeurteilung
Fragebogen Schmerzverhalten Hund
Um die Schmerzhaftigkeit ihres Hundes im Heilungsverlauf besser erfassen zu können, bitten wir Sie Ihr Tier zu beobachten und den folgenden Fragebogen auszufüllen.
Bitte wählen Sie jeweils nur die eine Antwort aus, die Ihren Hund am besten beschreibt.
3. Wie oft äußert Ihr Hund Schmerzen (Winseln, Heulen, Jaulen, Stöhnen)?
nie fast nie manchmal oft sehr oft
4. Wie oft beachtet der Hunde den Wundbereich (Lecken, Kratzen, Kopfhinwendung)?
nie fast nie manchmal oft sehr oft
5. Wie ist die Futteraufnahme des Hundes?
sehr gut gut leicht reduziert schlecht sehr schlecht
6. Wie ist die Körperhaltung Ihres Tieres?
Für Patienten mit Operationen an den Gliedmaßen 7. Wie läuft Ihr Hund?
uneingeschränkt schont sich lahmt leicht lahmt stark läuft gar nicht
Bitte bewerten Sie noch Ihren Gesamteindruck des Tieres von 0 (schmerzfrei, Verhalten wie vor der Operation) bis 10 (extrem schmerzhaft, stark verändertes Verhalten)
Sonstige Beobachtungen:
Mussten zusätzliche Schmerzmittel gegeben werden? Wenn ja, welche, wann und wie oft?
Besitzereinverständniserklärung
Besitzererlaubnis
Bei operativen Eingriffen an Hunden mit ungestörtem oder nur leicht eingeschränktem Allgemeinbefinden ist es üblich, vor der Operation ein Antibiotikum zusammen mit einem schmerz- und entzündungshemmenden Mittel (nichtsteroidales Antiphlogistikum = NSAID) zu verabreichen.
Marbofloxacin ist ein für den Hund zugelassenes Breitspektrum-Antibiotikum, das häufig bei schweren Infektionen eingesetzt wird. Carprofen und Cimicoxib sind für den Hund zugelassene NSAIDs, die routinemäßig vor Operationen an der Kleintierklinik der Tierärztlichen Hochschule eingesetzt werden.
In der Studie soll Marbofloxacin mit Carprofen (intravenös) oder Cimicoxib (oral) kombiniert werden und dabei eventuelle Vor- oder Nachteile der angewendeten Verabreichungsform festzustellen. Zusätzlich zur Routineanästhesieüberwachung soll ein Elektroenzephalogramm geschrieben werden, das die Hirnströme aufzeichnet und somit eventuell vorkommende Veränderungen registriert werden können, wie es zum Teil in der Humanmedizin zur Anästhesieüberwachung schon Standard ist.
Außerdem werden vor, während und nach dem Eingriff verschiedene Parameter, wie Herzfrequenz und Blutdruck bestimmt, sowie die Menge der benötigten Anästhetika und die Erforderlichkeit weiterer analgetischer Maßnahmen ausgewertet, um die Qualität der Schmerzausschaltung während der Operation zu überprüfen. Die Qualität der Aufwachphase wird anhand von Körperhaltung und Verhalten des Einzeltieres, Grad der Beweglichkeit, Aufmerksamkeit auf den Wundbereich, Reaktionsdruckmessung und Notwendigkeit der Applikation zusätzlicher Analgetika, über 24 Stunden beurteilt. Dies bedeutet konkret eine optimale und besonders engmaschige Überwachung, die ihrem Tier sowohl während als auch nach dem Eingriff zugute kommt.
Zusätzlich werden Ihnen als Dank für die Teilnahme ihres Hundes an der Studie die verwendeten Medikamente nicht berechnet, so dass die Operation insgesamt günstiger wird.
Nach 10 Tagen post OP würden wir Sie bitten, Ihren Hund zu einer abschließenden kostenlosen Kontrolle noch einmal vorzustellen.
Bei weiteren Fragen zu der Untersuchung stehen wir Ihnen gerne zur Verfügung.
Hiermit bestätige ich, dass ich mir die oben genannten Informationen in Ruhe durchgelesen und verstanden habe. Weiterhin bestätige ich, dass ich damit einverstanden bin, dass mein Tier an der beschriebenen Studie teilnimmt und dass die erhobenen Daten veröffentlicht werden dürfen.
(Datum & Unterschrift Besitzer)
Short-form of the Glasgow Composite Measure Pain Scale
Observers Assessment of Alertness/Sedation (OAA/S) Scale
Manuskript
Effects of concurrent perioperative use of marbofloxacin and cimicoxib or carprofen in dogs
Clarissa Weil 1), Julia Tünsmeyer 1), Andrea Tipold 2), Sonja Hoppe 3), Martin Beyerbach 4), Wolf-Rüdiger Pankow 5), Sabine B. Kästner 1)
1) Department of anaesthesia, Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation
2) Department of neurology, Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation
3) Department of internal medicine, Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation
4) Department of biometry, epidemiology and information processing, University of Veterinary Medicine Hannover, Foundation
5) Vétoquinol GmbH, Germany
Address corresponding author:
Clarissa Weil Small Animal Clinic
University of Veterinary Medicine Hannover, Foundation Bünteweg 9
30159 Hannover Germany
Clarissa.Weil@tiho-hannover.de Tel.: 0511-9536276
Fax: 0511-9536204
Abstract
OBJECTIVES: To investigate possible interactions visible on electroencephalogram recordings caused by concomitant administration of marbofloxacin and carprofen or cimicoxib in dogs without central nervous system (CNS) disease. Second aim was to compare postoperative analgesia of cimicoxib and carprofen given preoperatively by the oral and intravenous route, respectively.
METHODS: Twenty-one client-owned dogs undergoing different surgeries were included in a randomized, blinded, clinical study. Dogs were assigned to two groups treated with either carprofen (CAR) or cimicoxib (CIM) pre- and postoperatively. After anaesthetic induction both groups received marbofloxacin intravenously while recording an electroencephalogram. Offline electroencephalogram analysis included qualitative evaluation and Fast Fourier Transformation. Postoperative analgesia was evaluated for 24 hours and after 10 days with the short-form Glasgow Composite Measure Pain Scale and an owner questionnaire was completed. Statistical analysis included Wilcoxon signed rank test, Mann-Whitney U test and Student´s t- test with α set at 5%.
RESULTS: Marbofloxacin injection caused no effects on quantitative and qualitative electroencephalogram parameters. No differences in postoperative pain scoring were found between treatment groups.
CLINICAL SIGNIFICANCE: Concurrent use of marbofloxacin with either cimicoxib or carprofen did not induce neuroexcitatory activities in dogs without CNS disease directly after administration. Postoperative pain scores did not differ between groups.
Keywords
EEG, marbofloxacin, cimicoxib, carprofen, seizures
Introduction
Marbofloxacin is a fluoroquinolone which was developed for veterinary medicine. It has a wide spectrum encompassing gram-positive, gram-negative, and mycoplasma bacteria. Different side effects have been reported for fluoroquinolones including a decrease in seizure thresholds in both animals and humans (Traeger et al. 1995, Zhang et al. 2003). The proposed mechanism is an antagonism at the GABAA
receptor (Tsuji et al. 1988). This proconvulsive effect might be enhanced by concurrent administration of nonsteroidal anti-inflammatory drugs (NSAIDs) (Hori et al. 2003) leading to some controversy about the concomitant administration of these groups of drugs, even in neurologically healthy patients.
However, differences exist regarding proconvulsive activity among fluoroquinolones and in potentiation of fluoroquinolone-induced convulsions among NSAIDs (Kim et al.
2009). Several drug combinations have been investigated (Hori et al. 2003), but to the author’s knowledge no information is available about the combination of marbofloxacin with either carprofen or cimicoxib in dogs. Carprofen is a well-established NSAID in dogs which provides analgesic, antipyretic and anti-inflammatory effects by inhibition of cyclooxygenases (Kamali et al. 1998), with a preference for COX-2 (Kay-Mugford et al. 2000). Formulations are available for intravenous, subcutaneous or oral administration. In contrast, cimicoxib is the newest member of highly selective COX-2 inhibitors (coxib) and is registered as oral formulation for management of osteoarthritic and perioperative pain in dogs (Ema 2011).
Therefore, the aim of this study was to investigate if marbofloxacin in combination with these NSAIDs induces neuroexcitatory activity in dogs without central nervous system (CNS) disease.
Second aim of the study was to compare postoperative analgesia between carprofen and cimicoxib when given preoperatively by the intravenous (IV) and oral (PO) route, respectively.
Materials and Methods
Animals
Twenty-one client-owned dogs undergoing soft tissue or orthopaedic surgeries were included in this study (table 1). Inclusion criteria were American Society of Anesthesiologists status I or II, minimum age of 12 months and bodyweight (BW) between 10 kg and 40 kg. Dogs with a history of seizures or any abnormalities during neurological examination were excluded.
Study design
A prospective randomized clinical trial with blinded observer was conducted. The study received approval by the local ethical review committee and informed written owner consent was obtained prior to enrolment.
Dogs were randomly assigned to two groups. Group CIM received 2 mg/kg BW cimicoxib (Cimalgex; Vétoquinol GmbH) orally two to four hours before induction of anaesthesia by an independent person. Group CAR received 4 mg/kg BW carprofen (Rimadyl; Zoetis GmbH) intravenously at induction of anaesthesia; group CIM
received an appropriate volume of isotonic saline instead. Syringes were non-transparent and prepared by an independent person.
Anaesthesia
Dogs were sedated with 0.02 mg/kg BW acepromazine (Vetranquil; Ceva Tiergesundheit GmbH) intramuscularly 30 minutes prior to anaesthesia induction. A venous catheter (VasoVet; B. Braun Melsungen AG) was placed in a cephalic vein and dogs received either carprofen or saline in groups CAR and CIM, respectively.
Anaesthesia was induced with a 0.6 mg/kg BW levomethadone / 0.03 mg/kg BW fenpipramide combination (L-Polamivet; Intervet Deutschland GmbH) and 2 mg/kg BW alfaxalone (Alfaxan; Vétoquinol GmbH). After orotracheal intubation volume-controlled intermittent positive pressure ventilation was initiated to maintain an end-tidal carbon dioxide (ETCO2) of 4.6 - 6.0 kPa. During EEG recording anaesthesia was maintained with alfaxalone dosed to effect. Following EEG recording, isoflurane (Isofluran CP; CP-Pharma GmbH) in an 1:1 oxygen/air mixture was used for maintenance. Ventilation and oxygenation were monitored by side stream capnography and peripheral pulse oximetry (Infinity Delta monitor; Drägerwerk AG).
Electroencephalogram
Dogs were instrumented with five sub-dermal stainless steel electroencephalogram (EEG) electrodes in a 5-electrode-montage (left frontal F3, right frontal F4, middle Cz, left occipital O1 and right occipital O2) (Brauer et al. 2011, Redding 1978). The reference electrode was placed on the nose and the ground electrode caudal to the occipital protuberance. EEGs (NicoletOne nEEG; Viasys Healthcare) were recorded
with sensitivity = 70 µV/cm; time constant = 0.3 s; Hf = 70 Hz; notch filter inserted;
impedance of all electrodes < 10 kΩ.
Two sub-dermal needle electrocardiogram (ECG) electrodes were placed at the lateral thoracic wall for continuous recording of a bipolar lead ECG.
After a ten minute instrumentation period baseline EEG and ECG were recorded for five minutes (time BL) followed by intravenous injection of 2 mg/kg BW marbofloxacin (Marbocyl FD 1%; Vétoquinol GmbH) over a period of one minute (time M). Heart rate and rhythm during marbofloxacin injection and during the subsequent five minute period (time PM) were compared to individual baseline ECGs. For oscillometric arterial blood pressure (ABP) measurement (petMAP; Ramsey Medical Inc.) an appropriately sized cuff was attached to a front limb at heart level. Each time before, during and after injection of marbofloxacin three measurements were performed and the arithmetic mean of mean arterial pressure (MAP) was calculated for further analysis. Electroencephalogram recordings were analysed offline by a board certified neurologist by visual examination to detect paroxysmal epileptic activities and by quantitative analysis using Fast Fourier Transformation.
Routine anaesthetic monitoring via ECG, pulse oximetry, capnography, inspiratory and end-expiratory gas analysis and oscillometric blood pressure measurement (Infinity Delta monitor; Drägerwerk AG) was continued during surgical preparation and surgery.
End-tidal isoflurane (ETIso) concentration was titrated to maintain loss of palpebral reflex and jaw tone. Intraoperatively a fentanyl (Fentanyl-Janssen; Janssen-Cilag GmbH) bolus of 1 μg/kg BW IV was scheduled as rescue analgesia if HR and MAP
Postoperative pain assessment
Prior to any medication a baseline pain evaluation with the short-form of the Glasgow Composite Measure Pain Scale (CMPS-SF) (Reid et al. 2007) was performed and baseline respiratory rate (fR), MAP and HR were evaluated in all dogs. After surgery the blinded and trained investigator assessed pain behaviour by CMPS-SF at the following time points: 2 hours (h), 6 h, 12 h, 24 h and 10 days (d) after extubation.
The CMPS-SF ranges from 0 (minimal pain) to 24 points (maximal pain). A CMPS-SF
> 5 was considered as cut-off for rescue analgesia with 0.2 mg/kg BW methadone (Comfortan; Albrecht GmbH) IV. Sedation was evaluated at 2 h, 6 h and 12 h after extubation by the Observer’s Assessment of Alertness/Sedation (OAA/S) Scale (Chernik et al. 1990). Prior to pain scoring, HR, fR and ABP were measured at the same times by auscultation, chest movements and oscillometry, respectively.
Owners were supplied with a questionnaire (appendix 1) to assess their dogs between time of discharge and 10 d follow-up.
Side effects
During the hospital stay dogs were closely monitored for any side effects. After discharge owners were asked to monitor their pets carefully for any adverse reactions and were encouraged to inform the investigator if problems occurred. At the 10 d control they were personally interviewed by the blinded investigator.
Blood samples for white blood cell counts (WBC), haematocrit, haemoglobin, creatinine and urea were obtained before anaesthesia and 24 h and 10 d after surgery.
Statistical analysis
For statistical analysis SAS statistical software enterprise guide version 5.1 was used. Normal distribution was tested with Shapiro Wilk test and by stem and leaf plots. Wilcoxon signed rank test and Mann-Whitney U test were used for non-parametric data, student’s t-test and paired t-test for non-parametric data. Friedman test was used to test for equality of location parameters, followed by Dunn’s multiple comparison. Correlation was tested with Spearman’s Rank Correlation. Alpha was set at 5%.
Results
Demographic data are presented in table 1.
Duration of analgesic treatment varied, but was statistically not different between groups (6.1 ± 3.0 d group CIM, 7.2 ± 3.0 d group CAR).
Neurotoxic effects
None of the dogs showed clinical signs of seizures during the study period. Four dogs (2 CIM, 2 CAR) had to be excluded from EEG analysis because of superimposed electromyogram activity. Qualitative analysis revealed different patterns like spikes, sharp-waves, spike-slow-wave-complexes and polyspikes in all recorded EEGs. The occurrence of these patterns differed between the individual dogs but no significant effect of marbofloxacin was observed and no difference between groups was found (figure 1). Relative power was not significantly different
between group CIM and CAR, therefore, data were pooled for further analysis.
Quantitative EEG analysis revealed no effect of marbofloxacin on power in the different frequency bands in any of the five leads (figure 2).
Cardiovascular effects
A physiologic sinus rhythm was observed in both groups during the entire anaesthetic period. Marbofloxacin injection did not alter HR in comparison to BL in group CIM. In group CAR, HR decreased significantly during marbofloxacin injection (p = 0.0047) and at minutes 4 (p = 0.0361) and 5 (p = 0.0067) post marbofloxacin injection compared to BL (table 3). In both groups no significant effect on MAP of marbofloxacin injection was observed (table 3).
Anaesthesia
During the entire anaesthetic period HR, ABP, peripheral oxygen saturation (SpO2) and ETCO2 were in physiologic ranges for anaesthetized dogs in both groups.
Overall there was no significant difference in HR or MAP between groups at any time.
Required ETIso concentration did not differ significantly between NSAID-groups. No rescue analgesia was required intraoperatively.
Postoperative analgesia
The postoperative CMPS-SF revealed no significant differences between groups. In group CAR, CMPS-SF was significantly increased at 2 h (p = 0.0078) and 12 h (p =
changes from baseline were detected. One dog in group CIM required rescue analgesia three times (2 h, 4 h and 19 h postoperatively) (figure 3).
The sedation score was significantly increased in both groups at extubation (CIM p <
0.001, CAR p < 0.001) and at 2 h (CIM p = 0.0078, CAR p = 0.002) compared to baseline. At 6 h post extubation all dogs were awake and OAA/S scale did not differ from baseline. There was no significant correlation between OAA/S scale and CMPS-SF. No difference was seen between CAR and CIM in OAA/S scale at any time (figure 4).
The owner evaluation score did not differ between groups (figure 5).
There was no significant difference in HR, fR and MAP in both groups at any time compared to the preoperative baseline value and no significant difference between groups.
Blood analysis
Results of blood analysis are presented in table 2.
Adverse reactions
No major adverse effects were observed in both groups.
Discussion
None of the dogs in this study showed clinical or electroencephalographic signs of paroxysmal activity after receiving marbofloxacin concurrently with either carprofen or cimicoxib. The identified EEG patterns in this study (spikes, sharp-waves, spike-slow-wave-complexes and polyspikes) can be observed in healthy dogs under general
anaesthesia (Kearse et al. 1993) but might also have been a sign of paroxysmal activity (Holliday and Williams 1998). However, these patterns were observed to the same extent pre, during and post injection of marbofloxacin and no increase in their occurrence was induced by the fluoroquinolone. Several studies have proven that different fluoroquinolones decrease the seizure threshold by antagonising the GABAA
receptor (Tsuji et al. 1988). It is hypothesized that structural differences at position 7 of the quinolone nucleus influence an agent´s binding activity with GABAA receptors in the brain (Rubinstein 2001). At that position, an unsubstituted piperazine group or an unsubstituted pyrrolidone group were associated with an increased risk of seizures (Akahane et al. 1989, Mehlhorn and Brown 2007). The incidence of convulsive brain activity after administration of fluoroquinolones at approved dosages in healthy patients is low but may increase with coadministration of NSAIDs because of their synergistic inhibition of GABAA receptors (Akahane et al. 1994). In addition, neuroexcitatory risk seems to be particularly increased in patients with predispositions like epilepsy (Mehlhorn and Brown 2007). In our study only patients without any history of neurological disorders were included and no evidence of harmful interactions was found. This result may be explained by the specific molecule structure of marbofloxacin (methyl piperazine group at position 7) or the missing predisposition of animals tested.
Very little information about the neurological effects of marbofloxacin exists in the literature. In this study an EEG was recorded because it is an established tool to detect seizure activity in dogs (Berendt et al. 1999). A disadvantage of EEG monitoring in dogs is the need to sedate or anaesthetize the animal to avoid muscle artifacts (Tepper and Shores 2014). Various anaesthetics dose dependently dampen
the EEG (Ambrisko et al. 2011, Bergamasco et al. 2003) and anaesthesia probably had an impact on the baseline EEG monitoring in our study. The anaesthetic protocol used in the study purposefully avoided using drugs known to exert anticonvulsive properties (such as benzodiazepines). Acepromazine was used instead for premedication, which might even lower the seizure threshold in epileptic patients like the structurally related phenothiazine chlorpromazine (Hedges et al. 2003, Holliday and Williams 1998). However, controversy about this effect exists (Tobias et al.
2006). In EEGs of epileptic patients paroxysmal discharges were observed after sedation with acepromazine and meperidine (Holliday and Williams, 1998). Isoflurane was avoided during EEG recordings because it can cause burst suppressions and isoelectricity even at clinically relevant doses (Dworacek and De Vlieger 1984). Some depression of EEG activity by alfaxalone, however, cannot be excluded in this study (Ambrisko et al., 2011).
The second aim of our study was to compare postoperative analgesia in dogs treated with preoperative cimicoxib PO or carprofen IV. Neither the CMPS-SF nor the unvalidated owner evaluation score differed between treatment groups. In CAR, CMPS-SF increased from baseline at 2 h and 12 h after extubation. This increase was not accompanied by concurrent increases in HR or MAP, but was most likely due to postoperative pain. However, the CMPS-SF increase was in a clinically acceptable range and none of the dogs in group CAR needed rescue analgesia. In group CIM one outlier needed three times rescue analgesia. This dog was very nervous and anxious; and high CMPS-SF might have been influenced by excitation and anxiety. In the early postoperative phase CMPS-SF, HR, fR and MAP may have
half-life of racemic methadone varies in different dog breeds (Ingvast-Larsson et al.
2010, Kukanich and Borum 2008) and duration of action can be unpredictable to some extent, but both groups received levomethadone at the same dose. Therefore, influence on pain scales is similar in both groups. Two hours post extubation, OAA/S scale indicated that dogs were still sedated. This might be secondary to premedication but sedation did not differ between groups.
A recent multicenter study in dogs, comparing preoperative cimicoxib PO to carprofen given by the SC route, found similar results with no difference in postoperative pain scoring between groups (Grandemange et al. 2012, Grandemange et al. 2013). Methods and interpretation of that study have recently been criticized (Kropf et al. 2014) and due to slow subcutaneous absorption of carprofen (Clark et al. 2003), it is unclear if comparable carprofen concentrations are achieved in the early postoperative period by SC and IV injection. In addition, the pain scoring systems used were different from our study; therefore, comparability of the results is limited. Both studies, however, demonstrated no difference in efficacy between IV or SC carprofen and oral cimicoxib in the preoperative phase.
Limitations of our study are the small number of patients and that only one pain scale was used. The CMPS-SF is a validated pain scale to measure acute pain in dogs in a hospital setting (Reid et al. 2007) and results were supported by the owner evaluation score. However, value of owner evaluation was limited because it was a non-validated, unblinded score.
Another limitation is, that duration of NSAID therapy differed between individual dogs,
Another limitation is, that duration of NSAID therapy differed between individual dogs,