Description of postoperative complications and bacterial contamination of wound soaker catheters used to administer postoperative local analgesia after mastectomy in 11 dogs: case series.

Mastectomy is a common and painful procedure in dogs. Wound soaker catheters (WSC) are frequently used to reduce postoperative pain, including pain after mastectomy. The objectives of this case series were to describe the use of WSC for owner administration of postoperative local analgesia in dogs with mammary tumors treated surgically, to identify complications associated with WSC and to determine the frequency of bacterial colonization of the catheters. Twelve WSC were placed in 11 dogs during mastectomy surgery, left in place for three days, protected by a dressing and successfully managed by owners at home. No postoperative antibiotics were administered. No complications were identified in any cases. No bacterial growth was identified on bacteriological analysis of the twelve WSC. These results suggest that the use of WSC is a safe alternative for postoperative analgesia administration following mastectomy in dogs. Future studies comparing dogs with or without WSC with a larger number of dogs are needed to further evaluate efficacy and complications.

Intraoperative effect of low doses of ketamine or dexmedetomidine continuous rate infusions in healthy dogs receiving propofol total intravenous anaesthesia and epidural anaesthesia: A prospective, randomised clinical study.

The present study aimed to determine the effect of either ketamine or dexmedetomidine constant rate infusion (CRI) on intraoperative propofol anaesthetic requirements during total intravenous anaesthesia (TIVA) in healthy dogs undergoing hindlimbs orthopaedic procedures receiving epidural anaesthesia. In this randomised, blinded clinical study, thirty-nine healthy client-owned dogs were premedicated intramuscularly (dexmedetomidine 4 µg/kg and methadone 0.3 mg/kg). General anaesthesia was induced to effect with propofol administered as intravenous bolus, and maintained with propofol TIVA (18 mg/kg/h), adjusted to meet the suitable clinical anaesthetic depth (indicatively±20%) based on clinical judgement. Lumbosacral epidural anaesthesia was performed using bupivacaine (1 mg/kg) and morphine preservative free (0.1 mg/kg). Dogs randomly received either saline (SP; loading dose 1 mL/kg, CRI 1 mL/kg/h), or ketamine (KP; loading dose 1.5 mg/kg, CRI 1.5 mg/kg/h), or dexmedetomidine (DP; loading dose 1 µg/kg/, CRI 1 µg/kg/h). Physiological variables were recorded intraoperatively at 5-min intervals using standard-of-care monitoring. Recovery quality and duration were recorded. Treatment groups were compared with parametric and non-parametric tests as appropriate, p < 0.05. Propofol rates and recovery scores were similar between groups. Overall mean and diastolic blood pressures were higher in group DP compared to group KP (12-14 mmHg, p = 0.016 and p = 0.015, respectively). More dogs required mechanical ventilation in group KP (12 dogs) than in either group SP or DP (7 dogs per group, p = 0.037). Ketamine or dexmedetomidine CRIs, at the studied rates, did not reduce propofol TIVA requirements in dogs undergoing orthopaedic surgery with epidural anaesthesia.

Individualized positive end-expiratory pressure following alveolar recruitment manoeuvres in lung-healthy anaesthetized dogs: a randomized clinical trial on early postoperative arterial oxygenation.

OBJECTIVE: To assess and compare the effect of intraoperative stepwise alveolar recruitment manoeuvres (ARMs), followed by individualized positive end-expiratory pressure (PEEP), defined as PEEP at maximal respiratory system compliance + 2 cmH2O (PEEPmaxCrs+2), with that of spontaneous ventilation (SV) and controlled mechanical ventilation (CMV) without ARM or PEEP on early postoperative arterial oxygenation in anaesthetized healthy dogs. STUDY DESIGN: Prospective, randomized, nonblinded clinical study. ANIMALS: A total of 32 healthy client-owned dogs undergoing surgery in dorsal recumbency. METHODS: Dogs were ventilated intraoperatively (inspired oxygen fraction: 0.5) with one of the following strategies: SV, CMV alone, and CMV with PEEPmaxCrs+2 following a single ARM (ARM1) or two ARMs (ARM2, the second ARM at the end of surgery). Arterial blood gas analyses were performed before starting the ventilatory strategy, at the end of surgery, and at 5, 10, 15, 30 and 60 minutes after extubation while breathing room air. Data were analysed using Kruskal-Wallis and Friedman tests (p < 0.050). RESULTS: At any time point after extubation, PaO2 was not significantly different between groups. At 5 minutes after extubation, PaO2 was 95.1 (78.1-104.0), 93.8 (88.3-104.0), 96.9 (86.6-115.0) and 89.1 (87.6-102.0) mmHg in the SV, CMV, ARM1 and ARM2 groups, respectively. PaO2 decreased at 30 minutes after extubation in the CMV, ARM1 and ARM2 groups (p < 0.050), but it did not decrease after 30 minutes in the SV group. Moderate hypoxaemia (PaO2, 60-80 mmHg) was observed in one dog in the ARM1 group and two dogs each in the SV and ARM2 groups. CONCLUSIONS AND CLINICAL RELEVANCE: Intraoperative ARMs, followed by PEEPmaxCrs+2, did not improve early postoperative arterial oxygenation compared with SV or CMV alone in healthy anaesthetized dogs. Therefore, this ventilatory strategy might not be clinically advantageous for improving postoperative arterial oxygenation in healthy dogs undergoing surgery when positioned in dorsal recumbency.

Sedative and analgesic effects of two subanaesthetic doses of ketamine in combination with methadone and a low dose of dexmedetomidine in healthy dogs.

OBJECTIVE: To evaluate the sedative, analgesic and recovery characteristics of two subanaesthetic ketamine doses in combination with dexmedetomidine and methadone for intramuscular sedation in healthy Beagles. STUDY DESIGN: Randomized, blinded, crossover, experimental study. ANIMALS: Six healthy adult Beagles. METHODS: Dogs were randomly given three treatments: dexmedetomidine (3 µg kg-1) and methadone (0.3 mg kg-1) combined with ketamine at 1 and 2 mg kg-1 (K1 and K2, respectively) or saline (K0), intramuscularly. Sedation score, response to tail clamping and rectal temperature were recorded at baseline, 5, 15, 25, 35, and 45 minutes posttreatment. Pulse rate (PR), respiratory rate, oxygen haemoglobin saturation and noninvasive blood pressure were also recorded at baseline and every 5 minutes until 45 minutes posttreatment. Onset and duration of recumbency, response to venous catheterization and recovery quality were also assessed. Sedation and physiological variables were compared between treatments and within treatments compared to baseline (analysis of variance). Nonparametric data were analysed with the Friedman and Cochran's Q tests; p < 0.050. RESULTS: Increased sedation was found at 15 (K0 and K1), 25 (all treatments) and 35 (K1) minutes compared with baseline. Sedation score, onset (3-12 minutes) and duration of recumbency (29-51 minutes) were similar between treatments. Recovery quality was considered acceptable in all cases. Response to tail clamping was inconsistent within treatments with no differences between them. None of the dogs responded to venous catheterization. There were no differences between treatments in physiological variables, except for PR which was higher in K2 than in K0. Oxygen supplementation was required in five and three dogs administered saline and ketamine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The addition of 1 or 2 mg kg-1 of ketamine to methadone and dexmedetomidine combination did not enhance sedation or antinociception in healthy dogs. Recovery quality was unaffected.

Attitudes of Spanish-speaking veterinarians interested in anaesthesia towards use of total intravenous anaesthesia in dogs: a survey study.

OBJECTIVES: To describe Spanish-speaking veterinary anaesthetists' attitudes towards use of total intravenous anaesthesia (TIVA) in dogs. STUDY DESIGN: Prospective online voluntary survey. POPULATION: Data from 300 answered surveys. METHODS: An anonymous questionnaire was sent via e-mail to representatives of the four largest Spanish-speaking veterinary anaesthesia and analgesia associations. It was distributed through mailing lists (Spain, Argentina, Mexico) or social media (Spain, Chile) to gather information on the use, opinions and perceived advantages of TIVA, as well as on preferred alternatives to isoflurane for providing general anaesthesia. Logistic regression was used to test for response associations. RESULTS: A total of 275 (92%) respondents had used TIVA (24% rarely, 36% sometimes, 40% very often or always). There was an association between a higher rate of TIVA usage and a low specialization level, less clinical experience and unavailability of anaesthetic gas scavenging systems. The main reasons for not using TIVA were lack of familiarity with the technique (92%), unavailability of infusion pumps (32%), established institutional anaesthetic protocol (32%), and technical difficulty (20%). Among frequent TIVA users, a higher proportion reported the greater ease of TIVA use (52%) compared to those that did not perceive such benefit (17%) [odds ratio (OR) = 5.2; 95% confidence interval (CI95), 1.7-16.6; p = 0.004). More respondents did not consider TIVA more expensive (60%) (OR = 2.1; CI95, 1.0-4.3; p = 0.034), more difficult to perform (59%) (OR = 2.5; CI95, 1.3-4.9; p = 0.006) or to manage the equipment (53%) (OR = 3.3; CI95, 1.4-7.8; p = 0.008), than inhalational anaesthetics. During isoflurane shortages, respondents reportedly preferred using an alternative inhalational agent (59%) rather than TIVA (47%). CONCLUSIONS AND CLINICAL RELEVANCE: TIVA use is widespread among veterinarians within the surveyed associations. Frequent TIVA users reported greater perceived advantages. In situations of isoflurane shortage, an alternative inhalational anaesthetic was preferred over TIVA.

Sedative effects of two doses of alfaxalone in combination with methadone and a low dose of dexmedetomidine in healthy Beagles.

OBJECTIVE: To evaluate the sedative effects of two doses of alfaxalone when added to a combination of dexmedetomidine and methadone injected intramuscularly (IM) in healthy Beagles. STUDY DESIGN: Randomized, blinded, crossover, experimental study. ANIMALS: A group of six adult Beagles. METHODS: Dogs were sedated on three different occasions with IM dexmedetomidine (3 µg kg-1) and methadone (0.3 mg kg-1) combined with two doses of alfaxalone (0.5 and 1 mg kg-1; A0.5 and A1, respectively) or saline (A0). Quality of sedation, response to tail clamping and rectal temperature were recorded at baseline, 5, 15, 25, 35 and 45 minutes. Pulse and respiratory rates, oxygen saturation of haemoglobin (SpO2) and noninvasive blood pressure (NIBP) were recorded every 5 minutes. Onset of sedation and duration of recumbency, response to venous catheterization and recovery quality were assessed. Physiological variables (analysis of variance) were analysed between treatments and within treatments compared with baseline (Student t test). Nonparametric data were analysed using Friedman and Cochran's Q tests. Significance was p < 0.05. RESULTS: Sedation scores were significantly higher when alfaxalone was co-administered (area under the curve; p = 0.024, A0.5; p = 0.019, A1), with no differences between doses. Onset of sedation was similar, but duration of recumbency was longer in A0.5 than in A0 [median (minimum-maximum), 43 (35-54) versus 30 (20-47) minutes, p = 0.018], but not in A1. Response to venous catheterization and tail clamping, and quality of recovery (acceptable) presented no differences between treatments. A decrease in all physiological variables (compared with baseline) was observed, except for NIBP, with no differences between treatments. All dogs required oxygen supplementation due to reduced SpO2. CONCLUSIONS AND CLINICAL RELEVANCE: Adding alfaxalone to methadone and dexmedetomidine enhanced sedation and duration of recumbency. Although cardiopulmonary depression was limited, oxygen supplementation is advisable.

Effect of recumbency and body condition score on open-lung positive end-expiratory pressure and respiratory system compliance following a stepwise lung recruitment manoeuvre in healthy dogs during general anaesthesia.

The aim was to assess the effects of recumbency and body condition score (BCS) on open-lung positive end-expiratory pressure (OL-PEEP) and quasistatic respiratory system compliance (Crs) following stepwise lung recruitment manoeuvre (RM) in healthy dogs under general anaesthesia. Thirty-four dogs were anaesthetised and mechanically ventilated (tidal volume of 10 mL/kg) without PEEP for 1 min (baseline). A stepwise RM was then performed and the individual OL-PEEP was subsequently applied. The Crs was registered at baseline and every 10-min for 50 min after RM. Dogs were classified into either dorsal or lateral recumbency groups, and as normal (score 4-5/9) or high (≥6/9) BCS groups. The OL-PEEP was higher in lateral than in dorsal recumbency (P = .002), but differences were not observed between normal and high BCS (P = .865). The Crs was increased from baseline at all time points after RM in all groups. The Crs did not differ between dorsally and laterally recumbent dogs at any time point. However, the baseline Crs was significantly lower in dogs with a high BCS than in those with a normal BCS (P < .001); therefore, the absolute change from baseline was considered when comparing Crs after the RM and it was similar in both BCS groups. In conclusion, in anaesthetised healthy dogs the OL-PEEP following RM was lower when dogs were positioned in dorsal than in lateral recumbency. The Crs after RM remained unchanged regardless of the dogs' recumbency. A stepwise RM followed by OL-PEEP could compensate for the potential negative impact of moderately increased BCS on Crs.

Effects of ketamine or midazolam continuous rate infusions on alfaxalone total intravenous anaesthesia requirements and recovery quality in healthy dogs: a randomized clinical trial.

OBJECTIVE: To determine the alfaxalone dose reduction during total intravenous anaesthesia (TIVA) when combined with ketamine or midazolam constant rate infusions and to assess recovery quality in healthy dogs. STUDY DESIGN: Prospective, blinded clinical study. ANIMALS: A group of 33 healthy, client-owned dogs subjected to dental procedures. METHODS: After premedication with intramuscular acepromazine 0.05 mg kg-1 and methadone 0.3 mg kg-1, anaesthetic induction started with intravenous alfaxalone 0.5 mg kg-1 followed by either lactated Ringer's solution (0.04 mL kg-1, group A), ketamine (2 mg kg-1, group AK) or midazolam (0.2 mg kg-1, group AM) and completed with alfaxalone until endotracheal intubation was achieved. Anaesthesia was maintained with alfaxalone (6 mg kg-1 hour-1), adjusted (±20%) every 5 minutes to maintain a suitable level of anaesthesia. Ketamine (0.6 mg kg-1 hour-1) or midazolam (0.4 mg kg-1 hour-1) were employed for anaesthetic maintenance in groups AK and AM, respectively. Physiological variables were monitored during anaesthesia. Times from alfaxalone discontinuation to extubation, sternal recumbency and standing position were calculated. Recovery quality and incidence of adverse events were recorded. Groups were compared using parametric analysis of variance and nonparametric (Kruskal-Wallis, Chi-square, Fisher's exact) tests as appropriate, p < 0.05. RESULTS: Midazolam significantly reduced alfaxalone induction and maintenance doses (46%; p = 0.034 and 32%, p = 0.012, respectively), whereas ketamine only reduced the alfaxalone induction dose (30%; p = 0.010). Recovery quality was unacceptable in nine dogs in group A, three dogs in group AK and three dogs in group AM. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam, but not ketamine, reduced the alfaxalone infusion rate, and both co-adjuvant drugs reduced the alfaxalone induction dose. Alfaxalone TIVA allowed anaesthetic maintenance for dental procedures in dogs, but the quality of anaesthetic recovery remained unacceptable irrespective of its combination with ketamine or midazolam.

Effects of a single paracetamol injection on the sevoflurane minimum alveolar concentration in dogs.

This study aimed to determine the effect of a single injection of paracetamol on the sevoflurane minimum alveolar concentration (MAC) response to noxious mechanical stimulation. Seven healthy adult beagles were enrolled in a prospective, randomized, blinded, crossover experimental study. Anesthesia was induced with propofol [11.6 ± 2.4 mg/kg body weight (BW)] and maintained with sevoflurane. The MAC was determined before (MAC-1) and after (MAC-2) treatment with 15 mg/kg BW of intravenous (IV) paracetamol or saline over 15 minutes. Samples for plasma paracetamol determination were collected immediately after IV treatment administration and following MAC-2 determination (123 ± 27 minutes after starting paracetamol administration). The MAC-1 was similar between treatments (1.7% ± 0.4%). There were no differences between control and paracetamol groups at MAC-2 (2.0% ± 0.4% and 1.7% ± 0.5%, respectively; P = 0.285). Paracetamol plasma concentrations after paracetamol administration were 34.5 ± 9.9 µg/mL, decreasing at the end of the procedure (8.5 ± 4.2 µg/mL). In conclusion, 15 mg/kg BW of IV paracetamol did not significantly reduce sevoflurane MAC in healthy dogs.

La présente étude visait à déterminer l'effet d'une injection unique de paracétamol sur la réponse de la concentration alvéolaire minimale (MAC) de sévoflurane à une stimulation mécanique nocive. Sept chiens adultes en santé de race Beagle participèrent à une étude croisée prospective, randomisée, et à l'aveugle. L'anesthésie fut induite avec du propofol [11,6 ± 2,4 mg/kg de poids corporel (BW)] et maintenue avec du sévoflurane. La MAC fut déterminée avant (MAC-1) et après (MAC-2) traitement par voie intraveineuse (IV) avec 15 mg/kg BW de paracétamol ou de saline sur une période de 15 minutes. Des échantillons pour déterminer le paracétamol plasmatique furent prélevés immédiatement après l'administration IV du traitement et suivant la détermination de MAC-2 (123 ± 27 minutes après le début de l'administration de paracétamol). La valeur de MAC-1 était similaire entre les traitements (1,7 % ± 0,4 %). Il n'y avait pas de différence entre les groupes témoins et paracétamol à MAC-2 (2,0 % ± 0,4 % et 1,7 % ± 0,5 %, respectivement; P = 0,285). Les concentrations plasmatiques de paracétamol après l'administration de paracétamol étaient de 34,5 ± 9,9 µg/mL, et diminuaient à la fin de la procédure (8,5 ± 4,2 µg/mL). En conclusion, 15 mg/kg de BW de paracétamol par voie IV n'a pas réduit de manière significative la MAC de sévoflurane chez des chiens en santé.(Traduit par Docteur Serge Messier).

Efficacy of the Parasympathetic Tone Activity monitor to assess nociception in healthy dogs anaesthetized with propofol and sevoflurane.

OBJECTIVE: To compare a Parasympathetic Tone Activity (PTA) monitor with cardiovascular changes in invasive mean arterial pressure (IMAP) and heart rate (HR) when evaluating the response to nociceptive stimuli in anaesthetized dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: A group of nine (seven male and two female) adult Beagle dogs weighing 13.4 ± 1.5 kg (mean ± standard deviation). METHODS: Anaesthesia was induced with propofol and maintained with sevoflurane in oxygen. Electrical stimuli of different nociceptive intensities were applied for 30 seconds. Stimuli were classified in each patient according to the response obtained (relevant change ≥ 20%) as low (no response), medium (PTA only) or high (PTA and IMAP/HR). Immediate and averaged values of PTA, IMAP and HR were recorded every second from 60 seconds before to 120 seconds after application of the nociceptive stimulus. Time to nociceptive response and peak response were evaluated with analysis of variance and t test. RESULTS: Immediate PTA baseline values did not differ significantly before application of the low, medium and high stimuli (73 ± 15, p = 0.966). Immediate PTA response was observed with the medium stimulus at 33 ± 7 seconds with a maximum decrease of 57 ± 13% at 69 ± 5 seconds. With the high stimulus, the immediate PTA response was of a similar magnitude to the medium stimulus with a response at 28 ± 7 seconds (p = 0.221) and a maximum decrease of 68 ± 15% (p = 0.115) at 72 ± 7 seconds (p = 0.436). The cardiovascular change occurred (22 ± 8 seconds) prior to the immediate PTA response (p = 0.032). CONCLUSIONS AND CLINICAL RELEVANCE: The PTA monitor detected nociceptive stimuli at lower intensities than those eliciting cardiovascular changes. However, nociceptive stimuli of higher intensities provoked cardiovascular changes that occurred before a PTA response was observed.

Comparative effects of open-lung positive end-expiratory pressure (PEEP) and fixed PEEP on respiratory system compliance in the isoflurane anaesthetised healthy dog.

This study was performed to assess the effects of open-lung positive end-expiratory pressure (OL-PEEP) following stepwise recruitment manoeuvre (RM) and those of a fixed PEEP of 5 cm H2O without previous RM on respiratory system compliance (Crs) and selected cardiovascular variables in healthy dogs under general anaesthesia. Forty-five healthy client-owned dogs undergoing surgery were anaesthetised and mechanically ventilated (tidal volume, VT = 10-12 mL/kg; PEEP = 0 cm H2O) for 1 min (baseline) and randomly allocated into zero positive end-expiratory pressure (ZEEP), PEEP (5 cm H2O) and OL-PEEP treatment groups. In the OL-PEEP group, a stepwise RM was performed and the individual OL-PEEP was subsequently applied. The Crs, heart rate (HR) and non-invasive mean arterial pressure (NIMAP) were registered at baseline and then every 10 min during 60 min. In the ZEEP group, Crs decreased from baseline. In the PEEP group, Crs was not different from either baseline or ZEEP group values. In the OL-PEEP group, Crs was higher than both baseline and ZEEP group values at all time points as well as of those in the PEEP group during at least 20 min after RM. There were no differences for HR and NIMAP between groups. A clinically relevant hypotension following RM was observed in 40% of dogs. Therefore, an individually set OL-PEEP following stepwise RM improved Crs in anaesthetised healthy dogs, although transient but clinically relevant hypotension was observed during RM in some dogs. Fixed PEEP of 5 cm H2O without previous RM did not improve Crs, although it prevented it from decreasing.

Toll-like receptor 4 deficient mice do not develop remifentanil-induced mechanical hyperalgesia: An experimental randomised animal study.

BACKGROUND: Drugs with antagonistic actions on the Toll-like receptor 4 (Tlr4), such as naloxone at ultra low doses, have been used to inhibit opioid-induced hyperalgesia in rodents suggesting the involvement of this receptor and pathway on opioid-induced hyperalgesia. OBJECTIVE: The aim of this study was to determine whether mice without the Tlr4 gene (Tlr4) would not develop remifentanil-induced hyperalgesia. DESIGN: An experimental randomised animal study. SETTING: Experimental Unit, Complutense University of Madrid, Madrid, Spain. ANIMALS: Twelve adult female wild-type mice and 12 adult Tlr4 mice. INTERVENTIONS: Under sevoflurane anaesthesia, a 1-h, constant rate subcutaneous infusion of remifentanil (4 µg kg min) or 0.9% saline. MAIN OUTCOME MEASURES: Mechanical nociceptive thresholds were evaluated using a von Frey hair test before (baseline) and on days 5, 6 and 7 after treatment. Hyperalgesia was considered to be a decrease in the mechanical nociceptive threshold. Changes in mechanical nociceptive thresholds in the different groups were compared with one-sided paired t tests. RESULTS: Baseline mechanical nociceptive thresholds were similar in all groups (2.2 ±â€Š0.1 g). Remifentanil produced a 24% decrease in mechanical nociceptive thresholds in the wild-type mice (1.7 ±â€Š0.0 g, averaged over 3 days, P = 0.00021), whereas the nociceptive thresholds were not changed in Tlr4 mice (2.2 ±â€Š0.1 g, P = 0.857) or in mice receiving 0.9% saline (Tlr4, 2.2 ±â€Š0.1 g, P = 0.807; wild-type, 2.2 ±â€Š0.1 g, P = 0.962). CONCLUSION: Tlr4 receptor involvement is suggested in the development of remifentanil-induced hyperalgesia in mice. TRIAL REGISTRATION: CEA-UCM 107/2012.

The Effects of the Toll-Like Receptor 4 Antagonist, Ibudilast, on Sevoflurane's Minimum Alveolar Concentration and the Delayed Remifentanil-Induced Increase in the Minimum Alveolar Concentration in Rats.

BACKGROUND: Ultralow doses of naloxone, an opioid and toll-like receptor 4 antagonist, blocked remifentanil-induced hyperalgesia and the associated increase in the minimum alveolar concentration (MAC), but not tolerance. The aim was to determine the effects of the toll-like receptor 4 antagonist, ibudilast, on the MAC in the rat and how it might prevent the effects of remifentanil. METHODS: Male Wistar rats were randomly allocated to 5 treatment groups (n = 7 per group): 10 mg/kg ibudilast intraperitoneally, 240 µg/kg/h remifentanil IV, ibudilast plus remifentanil, remifentanil plus naloxone IV, or saline. The sevoflurane MAC was determined 3 times in every rat and every day (days 0, 2, and 4): baseline (MAC-A) and 2 further determinations were made after treatments, 1.5 hours apart (MAC-B and MAC-C). RESULTS: A reduction in baseline MAC was produced on day 0 by ibudilast, remifentanil, remifentanil plus ibudilast, remifentanil plus naloxone (P < 0.01), but not saline. Similar effects were found on days 2 and 4. A tolerance to remifentanil was found on days 0, 2, and 4, which neither ibudilast nor naloxone prevented. The MAC increase produced by remifentanil on day 4 (P = 0.001) was prevented by either ibudilast or naloxone. CONCLUSIONS: Ibudilast, besides reducing the MAC, prevented the delayed increase in baseline MAC produced by remifentanil but not the increase in MAC caused by tolerance to remifentanil.

Tramadol-induced hyperalgesia and its prevention by ketamine in rats: A randomised experimental study.

BACKGROUND: Opioid analgesia not only reduces inhalational anaesthetic requirements but may also induce delayed hyperalgesia, with potential effects on the minimum alveolar concentration (MAC) of inhalational anaesthetics. OBJECTIVES: The objective of this study was to evaluate the development of tramadol-induced hyperalgesia and the associated changes in MAC, and whether ketamine prevents both processes. DESIGN: A randomised, experimental study. SETTING: Experimental Surgery Unit, La Paz University Hospital, Madrid, Spain. ANIMALS: Thirty-nine adult male Wistar rats. INTERVENTIONS: Mechanical nociceptive thresholds (MNT) were determined up to 21 days after the intraperitoneal administration of a single dose of tramadol (50 mg kg) with or without ketamine (10 mg kg), or 0.9% saline. The MNT and the MAC of sevoflurane were also assessed in a second experiment before, early (30 min) and 7 days after drug administration with the same treatments. MAIN OUTCOME MEASURES: The MAC and MNT were evaluated. The analysis of variance (ANOVA) test was employed to determine differences between treatments and times on MAC and MNT. RESULTS: Tramadol, alone or combined with ketamine, produced an early increase in MNT. However, tramadol given alone decreased MNT from day 1 up to 3 weeks, which was associated with an increase in the MAC of sevoflurane (P < 0.05; day 7). Ketamine administration prevented both the reduction in MNT and the increase in MAC (P > 0.05). CONCLUSION: Tramadol-induced hyperalgesia in the rat lasted for several weeks and was associated with an increase in the MAC of sevoflurane. Prior administration of ketamine blocked both phenomena.

Amitriptyline, minocycline and maropitant reduce the sevoflurane minimum alveolar concentration and potentiate remifentanil but do not prevent acute opioid tolerance and hyperalgesia in the rat: a randomised laboratory study.

BACKGROUND: The antidepressant amitriptyline, the inhibitor of microglia activation minocycline, and the neurokinin-1 antagonist maropitant have all been used to prevent or treat hyperalgesia and opioid tolerance. OBJECTIVES: To determine the effect of amitriptyline, minocycline, maropitant, independently or with remifentanil, on the sevoflurane minimum alveolar concentration in rats and whether these drugs may block opioid-induced hyperalgesia and acute opioid tolerance under inhalational anaesthesia. DESIGN: A randomised, laboratory study. SETTING: Experimental Unit, La Paz University Hospital, Madrid, Spain. ANIMALS: One hundred and fourteen adult male Wistar rats. INTERVENTIONS: Intraperitoneal administration of amitriptyline (10 and 50  mg  kg-1), minocycline (30 and 100  mg  kg-1), maropitant (10 and 30 mg  kg-1) or isotonic saline, combined with a constant rate intravenous infusion of remifentanil (240 µg  kg-1  h-1) or saline. MAIN OUTCOME MEASURES: Sevoflurane minimum alveolar concentration was determined before and after administration of the drugs; acute opioid tolerance was defined as a decreased ability of remifentanil to reduce the minimum alveolar concentration in the short term. In addition, mechanical nociceptive thresholds were determined before and after these treatments. Opioid-induced hyperalgesia was defined as an increase in mechanical nociceptive thresholds after opioid administration. RESULTS: Amitriptyline, minocycline and maropitant reduced minimum alveolar concentration up to 24 (8)%, 23 (6)% and 15 (5)%, respectively (P <0.001). Remifentanil alone reduced minimum alveolar concentration by 36 (6)% (P <0.001), and in combination with amitriptyline, minocycline and maropitant, the reduction was 76 (9)%, 75 (16)% and 59 (5)%, respectively (P <0.001). An acute tolerance effect (P < 0.01) and a decrease in the mechanical nociceptive thresholds were observed with remifentanil in all groups. CONCLUSION: Amitriptyline, minocycline and maropitant reduced the minimum alveolar concentration and potentiated the remifentanil minimum alveolar concentration reduction but failed to block opioid-induced hyperalgesia and acute opioid tolerance.

Hyperalgesia and increased sevoflurane minimum alveolar concentration induced by opioids in the rat: a randomised experimental study.

BACKGROUND: Perioperative opioids reduce inhalational anaesthetic requirements. The initial hypoalgesia may, however, be followed by a rebound hyperalgesia. OBJECTIVES: To determine whether prior opioid administration influences inhalational anaesthetic requirements, which might be associated with opioid-induced hyperalgesia. DESIGN: A prospective, randomised, experimental study. SETTING: Experimental Surgery, La Paz University Hospital, Madrid, Spain. ANIMALS: Seventy-nine adult male Wistar rats. INTERVENTIONS: Sevoflurane minimum alveolar concentration (MAC) and mechanical nociceptive thresholds (MNTs) were assessed at baseline and 7 days later following opioid treatment with remifentanil 120 µg  kg-1  h-1, buprenorphine 150 µg kg-1, methadone 8 mg  kg-1 or morphine 10 mg  kg-1 The duration of the effect of remifentanil on MAC and MNT was evaluated in addition to the preventive effect of ketamine 10 mg  kg-1 on remifentanil-induced hyperalgesia. MAIN OUTCOME MEASURES: The effect of different opioid treatments on MAC and MNT was evaluated using analysis of variance (ANOVA). RESULTS: All studied opioids produced an immediate reduction in sevoflurane MAC, followed by an increase (16%) in baseline MAC 7 days later (P < 0.05), although the immediate MAC reduction produced by these opioids at that time was not different. Remifentanil produced a decrease in MNT (P < 0.05), which was associated with an increase in the MAC (P < 0.05) that persisted at 21 days. The effect of remifentanil on MNT and MAC was blocked by ketamine. CONCLUSION: Opioid-induced hyperalgesia was associated with an increase in the MAC in normal rats who had not undergone surgery. Both effects lasted 21 days and were prevented by ketamine.

Pressure safety range of barotrauma with lung recruitment manoeuvres: a randomised experimental study in a healthy animal model.

CONTEXT: Recruitment manoeuvres aim at reversing atelectasis during general anaesthesia but are associated with potential risks such as barotrauma. OBJECTIVE: To explore the range of pressures that can be used safely to fully recruit the lung without causing barotrauma in an ex-vivo healthy lung rabbit model. DESIGN: Prospective, randomised, experimental study. SETTING: Experimental Unit, La Paz University Hospital, Madrid, Spain. ANIMALS: Fourteen healthy young New Zealand rabbits of 12 weeks of age. INTERVENTIONS: Animals were euthanised, the thorax and both pleural spaces were opened and the animals were allocated randomly into one of two groups submitted to two distinct recruitment manoeuvre strategies: PEEP-20 group, in which positive end-expiratory pressure (PEEP) was increased in 5-cmH2O steps from 0 to 20 cmH2O and PEEP-50 group, in which PEEP was increased in 5-cmH2O steps from 0 to 50 cmH2O. In both groups, a driving pressure of 15 cmH2O was maintained until maximal PEEP and its corresponding maximal inspiratory pressures (MIPs) were reached. From there on, driving pressure was progressively increased in 5-cmH2O steps until detectable barotrauma occurred. Two macroscopic conditions were defined: anatomically open lung and barotrauma. MAIN OUTCOME MEASURES: We measured open lung and barotrauma MIP, PEEP and driving pressure obtained using each strategy. A pressure safety range, defined as the difference between barotrauma MIP and anatomically open lung MIP, was also determined in both groups. RESULTS: Open lung MIP was similar in both groups: 23.6 ±â€Š3.8 and 23.3 ±â€Š4.1 cmH2O in the PEEP-50 and PEEP-20 groups, respectively (P = 0.91). However, barotrauma MIP in the PEEP-50 group was higher (65.7 ±â€Š3.4 cmH2O) than in the PEEP-20 group (56.7 ±â€Š5 0.2 cmH2O) (P = 0.003) resulting in a safety range of pressures of respectively 33.3 ±â€Š8.7 and 42.1 ±â€Š3.9 cmH2O (P = 0.035). CONCLUSION: In this ex-vivo model, we found a substantial difference between recruitment and barotrauma pressures using both recruitment strategies. However, a higher margin of safety was obtained when a higher PEEP and lower driving pressure strategy was used for recruiting the lung.

Effects of naloxone on opioid-induced hyperalgesia and tolerance to remifentanil under sevoflurane anesthesia in rats.

BACKGROUND: Opioid antagonists at ultra-low doses have been used with opioid agonists to prevent or limit opioid tolerance. The aim of this study was to evaluate whether an ultra-low dose of naloxone combined with remifentanil could block opioid-induced hyperalgesia and tolerance under sevoflurane anesthesia in rats. METHODS: Male adult Wistar rats were allocated into one of four treatment groups (n = 7), receiving remifentanil (4 µg·kg·min) combined with naloxone (0.17 ng·kg·min), remifentanil alone, naloxone alone, or saline. Animals were evaluated for mechanical nociceptive thresholds (von Frey) and subsequently anesthetized with sevoflurane to determine the baseline minimum alveolar concentration (MAC). Next, treatments were administered, and the MAC was redetermined twice during the infusion. The experiment was performed three times on nonconsecutive days (0, 2, and 4). Hyperalgesia was considered to be a decrease in mechanical thresholds, whereas opioid tolerance was considered to be a decrease in sevoflurane MAC reduction by remifentanil. RESULTS: Remifentanil produced a significant decrease in mechanical thresholds compared with baseline values at days 2 and 4 (mean ± SD, 30.7 ± 5.5, 22.1 ± 6.4, and 20.7 ± 3.7g at days 0, 2, and 4, respectively) and an increase in MAC baseline values (2.5 ± 0.3, 3.0 ± 0.3, and 3.1 ± 0.3 vol% at days 0, 2, and 4, respectively). Both effects were blocked by naloxone coadministration. However, both remifentanil-treated groups (with or without naloxone) developed opioid tolerance determined by their decrease in MAC reduction. CONCLUSIONS: An ultra-low dose of naloxone blocked remifentanil-induced hyperalgesia but did not change opioid tolerance under inhalant anesthesia. Moreover, the MAC increase associated with hyperalgesia was also blocked by naloxone.

Reduction of the sevoflurane minimum alveolar concentration induced by methadone, tramadol, butorphanol and morphine in rats.

This study aimed to estimate the reduction in the minimum alveolar concentration (MAC) of sevoflurane induced by low and high doses of methadone (5 and 10 mg/kg), tramadol (25 and 50 mg/kg), butorphanol (5 and 10 mg/kg) or morphine (5 and 10 mg/kg) in the rat. A control group received normal saline. Sixty-three adult male Sprague-Dawley rats were anaesthetized with sevoflurane (n = 7 per group). Sevoflurane MAC was then determined before and after intraperitoneal administration of the opioids or saline. The duration of the sevoflurane MAC reduction and basic cardiovascular and respiratory measurements were also recorded. The baseline MAC was 2.5 (0.3) vol%. Methadone, tramadol and morphine reduced the sevoflurane MAC (low dose: 31 ± 10, 38 ± 15 and 30 ± 13% respectively; high dose: 100 ± 0, 83 ± 17 and 77 ± 25%, respectively) in a dose-dependent manner. The low and high doses of butorphanol reduced the sevoflurane MAC to a similar extent (33 ± 7 and 31 ± 4%, low and high doses, respectively). Two rats developed apnoea following administration of high-dose butorphanol and methadone. These anaesthetic-sparing effects are clinically relevant and may reduce the adverse effects associated with higher doses of inhalational anaesthetics.

The effects of gabapentin on acute opioid tolerance to remifentanil under sevoflurane anesthesia in rats.

BACKGROUND: Tolerance to remifentanil during sevoflurane anesthesia may blunt the ability of this drug to reduce anesthetic requirements. Gabapentin has been shown to be effective in reducing postoperative narcotic usage, a reduction that may be associated with a reduction in opioid-induced tolerance and hyperalgesia. We sought to determine whether gabapentin might prevent the observed acute opioid tolerance (AOT) produced by remifentanil in sevoflurane minimum alveolar concentration (MAC). METHODS: Wistar rats were anesthetized with sevoflurane and the effects of gabapentin alone on sevoflurane MAC were determined at doses of 150 and 300 mg · kg(-1). In a second experiment, gabapentin 300 mg · kg(-1) was administered before remifentanil (120 and 240 µg · kg(-1) · h(-1)). The MAC was determined before gabapentin administration and 3 more times at 1.5-hour intervals after drug administration to assess AOT. MAC was determined from intratracheal gas samples using a sidestream gas analyzer; tail clamping was used as a supramaximal stimulus. Statistical analysis was performed with the 1-way analysis of variance test. RESULTS: Remifentanil reduced MAC (2.5 ± 0.2%) by 16% ± 5% and 36% ± 6% (120 and 240 µg · kg(-1) · h(-1), respectively, P < 0.01) with a further reduction produced by coadministration with gabapentin 300 mg · kg(-1) to 39% ± 12% and 62% ± 14%, respectively (P < 0.01 versus remifentanil alone). Gabapentin given alone at 150 and 300 mg · kg(-1) reduced MAC by 26% (both doses, P < 0.01). AOT was observed with remifentanil and characterized by a lower degree of MAC reduction, approximately 1.5 hours later (P < 0.05). However, when remifentanil was administered with gabapentin, the AOT to remifentanil was not observed (P > 0.05). CONCLUSIONS: Gabapentin reduced the sevoflurane MAC and enhanced the MAC reduction produced by remifentanil. This enhancement may limit AOT in rats.