Influence of intravenous fentanyl or dexmedetomidine infusions, combined with lidocaine and ketamine, on cardiovascular response, sevoflurane requirement and postoperative pain in dogs anesthetized for unilateral mastectomy.

OBJECTIVE: To compare the effects of constant rate infusions (CRI) of fentanyl or dexmedetomidine, combined with lidocaine and ketamine, on cardiovascular response during surgery, sevoflurane requirement and postoperative pain in dogs undergoing mastectomy. STUDY DESIGN: Prospective, randomized, blinded, clinical trial. ANIMALS: A total of 29 female dogs with mammary tumors. METHODS: Premedication consisted of intramuscular acepromazine and morphine. General anesthesia was induced with intravenous propofol and maintained with sevoflurane. Dogs were randomized to be administered intravenous DLK [dexmedetomidine 1 µg kg-1 loading dose (LD) and 1 µg kg-1 hour-1; lidocaine 2 mg kg-1 LD and 3 mg kg-1 hour-1; ketamine 1 mg kg-1 LD and 0.6 mg kg-1 hour-1; n = 14] or FLK (fentanyl 5 µg kg-1 LD and 9 µg kg-1 hour-1; same doses of lidocaine and ketamine; n = 15) during anesthesia. Cardiorespiratory variables and end-tidal sevoflurane (Fe'Sevo) were recorded during surgery. The number of dogs administered ephedrine to treat arterial hypotension [mean arterial pressure (MAP) < 60 mmHg] was recorded. Meloxicam was administered to both groups. Postoperative pain and rescue analgesia requirement were assessed for 24 hours using the short form of the Glasgow Composite Measure Pain Scale. Data were compared using a mixed effects model or a Mann-Whitney test. RESULTS: More dogs required ephedrine in FLK than in DLK (67% versus 7%). Heart rate was not significantly different between groups, whereas lower values of MAP (p ≤ 0.01) and Fe'Sevo (p = 0.018) were observed in FLK than in DLK. Rescue analgesia was administered to 2/15 dogs in FLK and 0/14 dogs in DLK. CONCLUSIONS AND CLINICAL RELEVANCE: Based on the cardiovascular response during surgery, intraoperative infusions of FLK and DLK provided adequate antinociception. Infusion of DLK provided greater stability of blood pressure. Both protocols resulted in minimal need for additional analgesia within 24 hours postoperatively.

Systems-level analysis of local field potentials reveals differential effects of lysergic acid diethylamide and ketamine on neuronal activity and functional connectivity.

Psychedelic substances have in recent years attracted considerable interest as potential treatments for several psychiatric conditions, including depression, anxiety, and addiction. Imaging studies in humans point to a number of possible mechanisms underlying the acute effects of psychedelics, including changes in neuronal firing rates and excitability as well as alterations in functional connectivity between various brain nodes. In addition, animal studies using invasive recordings, have suggested synchronous high-frequency oscillations involving several brain regions as another key feature of the psychedelic brain state. To better understand how the imaging data might be related to high-resolution electrophysiological measurements, we have here analyzed the aperiodic part of the local field potential (LFP) in rodents treated with a classic psychedelic (LSD) or a dissociative anesthetic (ketamine). In addition, functional connectivity, as quantified by mutual information measures in the LFP time series, has been assessed with in and between different structures. Our data suggest that the altered brain states of LSD and ketamine are caused by different underlying mechanisms, where LFP power shifts indicate increased neuronal activity but reduced connectivity following ketamine, while LSD also leads to reduced connectivity but without an accompanying change in LFP broadband power.

Overdoses and deaths related to the use of ketamine and its analogues: a systematic review.

Background: Although the misuse of ketamine constitutes a worldwide issue, ketamine is quickly taking its place as a therapeutic option in the management of several mental disorders. However, the use of ketamine and/or its analogues, as well as combinations with other drugs, can be fatal.Objective: To outline the cases of overdoses and deaths related to the use of ketamine and/or its analogues, as reported in the scientific literature. To investigate if ketamine is safe in a therapeutic context, particularly in its use as an antidepressant.Methods: Electronic searches were performed on three medical databases. Articles describing cases of overdose and/or death associated with ketamine and/or its analogues were included. After the removal of duplicates, title analysis and full-text analysis, 34 articles were included in this review.Results: Eighteen articles described fatal cases and sixteen described overdoses. Poly-substance use was mentioned in 53% of the selected articles. Most cases were males and the ages varied from two to 65 years old. A total of 312 overdose cases and 138 deaths were reported. In both death reports and overdose cases, ketamine was preponderant: 89.1% and 79%, respectively. No cases of overdose or death related to the use of ketamine as an antidepressant in a therapeutic setting were found; most of the deaths occurred in the circumstances of polydrug use and overdoses left no sequelae.Conclusion: There is legitimate concern about the risks involving the use of ketamine and its analogues, especially in recreational settings. On the other hand, ketamine as medicine is considered safe and it is listed as an essential medicine by the World Health Organization. Although clinicians must remain vigilant, this should not deter appropriate prescription.

Efficacy of ketamine for comorbid depression and acute or chronic pain: A systematic review.

Pain and depression frequently co-occur. Due to its antidepressant and analgesic properties, ketamine has been used for the management of treatment-resistant depression and pain. This systematic review examined the literature on the efficacy of sub-anesthetic doses of ketamine in individuals experiencing comorbid depression and chronic pain (CDCP), as well as comorbid depression and acute pain (CDAP). A secondary objective was to provide an assessment of dosage, route, and adverse effects of ketamine treatment for CDCP and CDAP. A literature search was conducted on MEDLINE, PsycINFO, and Embase databases, coupled with a manual screening of the bibliography sections of included articles. In addition, registered ongoing and planned trials were searched on Clinicaltrials.gov. The end date of the search was April 9th, 2022. Included studies assessed changes in depression and pain in patients receiving at least one sub-anesthetic dose of ketamine. Assessment of quality was conducted using the GRADE checklist. Of the 7 CDCP clinical trials, 3 reported a reduction in depression and pain, 3 reported a reduction in depression or pain only, and 1 reported no improvement in either comorbidity. Among the 7 CDAP clinical trials, 4 studies found improvements in depression and pain while the remaining 3 reported improvements in only one parameter. Ten of the 12 case studies and 2 of the 3 observational studies assessing CDCP and CDAP found improvements in pain and depression scores post-treatment with effects of variable duration. The planned methodologies of the registered clinical trials are in line with those of the published research. Preliminary evidence supports the efficacy of ketamine in treating CDCP and CDAP. However, the current review identified a small number of heterogeneous studies with mixed results, preventing comprehensive conclusions. More longitudinal placebo-controlled studies are needed to identify the effects of ketamine for patients with CDCP and CDAP.

Effects of ketamine constant rate infusions on cardiac biomarkers and cardiac function in dogs.

OBJECTIVE: To evaluate the effects of ketamine continuous rate infusions (CRI) at two dose rates on cardiovascular function and serum creatine kinase MB isoenzyme (CK-MB) and troponin I in healthy conscious dogs. STUDY DESIGN: Experimental, prospective, crossover, randomized, blinded study. ANIMALS: Eight adult mixed-breed dogs, aged 6±1 years and weighing 19±8.6 kg (mean±standard deviation). METHODS: Dogs were administered an intravenous bolus of ketamine (0.5 mg kg-1) followed by a ketamine CRI for 12 hours (20 µg kg-1 minute-1; treatment TC20 or 40 µg kg-1 minute-1; treatment TC40). Sedation, heart rate (HR), mean arterial pressure (MAP), electrocardiographic and echocardiographic parameters were evaluated at baseline (T0) and 1 (T1), 2 (T2), 4 (T4), 8 (T8), 12 (T12) and 24 (T24) hours after ketamine infusion started. Serum concentrations of CK-MB and troponin I were measured at baseline and 12, 24 and 48 hours after infusion started. RESULTS: HR increased over the first 4 hours, significantly at T1 in TC20 and at T4 in TC40 when compared with T0 (p < 0.05). MAP was significantly increased at T2 in TC40 when compared with TC20. Behavioral changes, such as stereotypical head movements and twitches, occurred within 4 hours in TC40. There were no significant changes in echocardiographic examinations in any dog when compared with baseline. There were no temporal changes in serum CK-MB activity either within or between treatments (p > 0.05). No troponin I was detected in any sample. CONCLUSIONS AND CLINICAL RELEVANCE: No indication of myocardial injury resulting from ketamine infusion was detected in this study in healthy dogs. Further studies are needed to assess the ketamine infusion effects on antinociception and other organ function not evaluated in the present study.

Syntheses, analytical and pharmacological characterizations of the 'legal high' 4-[1-(3-methoxyphenyl)cyclohexyl]morpholine (3-MeO-PCMo) and analogues.

New psychoactive substances (NPS) are commonly referred to as 'research chemicals', 'designer drugs' or 'legal highs'. One NPS class is represented by dissociative anesthetics, which include analogues of the arylcyclohexylamine phencyclidine (PCP), ketamine and diphenidine. A recent addition to the NPS market was 4-[1-(3-methoxyphenyl)cyclohexyl]morpholine (3-MeO-PCMo), a morpholine analogue of 3-MeO-PCP. Although suspected to have dissociative effects in users, information about its pharmacological profile is not available. From clinical and forensic perspectives, detailed analytical data are needed for identification, especially when facing the presence of positional isomers, as these are frequently unavailable commercially. This study presents the analytical and pharmacological characterization of 3-MeO-PCMo along with five additional analogues, namely the 2- and 4-MeO-PCMo isomers, 3,4-methylenedioxy-PCMo (3,4-MD-PCMo), 3-Me-PCMo and PCMo. All six arylcyclohexylmorpholines were synthesized and characterized using chromatographic, mass spectrometric and spectroscopic techniques. The three positional isomers could be differentiated and the identity of 3-MeO-PCMo obtained from an internet vendor was verified. All six compounds were also evaluated for affinity at 46 central nervous system receptors including the N-methyl-d-aspartate receptor (NMDAR), an important target for dissociative anesthetics such as PCP and ketamine. In vitro binding studies using (+)-[3-3 H]-MK-801 in rat forebrain preparations revealed moderate affinity for NMDAR in the rank order of 3-Me >3-MeO > PCMo >3,4-MD > 2-MeO > 4-MeO-PCMo. 3-MeO-PCMo was found to have moderate affinity for NMDAR comparable to that of ketamine, and had an approximate 12-fold lower affinity than PCP. These results support the anecdotal reports of dissociative effects from 3-MeO-PCMo in humans.

Effects of esketamine sedation compared to morphine analgesia on hydrostatic reduction of intussusception: A case-cohort comparison study.

BACKGROUND: Hydrostatic or pneumatic reduction of intussusception is an invasive procedure that is stressful and may be painful for a child. Resistance of the child may increase the duration of the procedure and decrease success rate of reduction. Analgesia can help to reduce pain, but not necessarily resistance. General anesthesia increases success rate of reduction. However, it requires the presence of an anesthesiologist, and may lead to anesthesia-related complications. Procedural sedation with esketamine could be a safe alternative. AIM: The aim of this study was to compare hydrostatic reduction using morphine analgesia compared to procedural sedation with esketamine in terms of success rate, adverse events, and duration of reduction. METHODS: A retrospective case-cohort comparison study was performed with two groups of patients who had undergone hydrostatic reduction for ileocolic intussusception and received morphine analgesia (n = 37) or esketamine sedation (n = 20). Until July 2013, reduction was performed after intravenously administered morphine. Hereafter, a new protocol for procedural sedation was implemented and reduction was performed after administration of esketamine. Cases were matched for age and duration of symptoms. RESULTS: No adverse events requiring intervention other than administration of oxygen were reported for either group. Success rate of reduction using esketamine sedation was 90% vs 70% using morphine analgesia, risk ratio (RR) 1.29, 95% CI[0.93-1.77]. Recurrence rate using esketamine sedation was 10% vs 15% using morphine analgesia, RR 0.67, 95% CI[0.12-3.57]. Reduction time was shorter using esketamine sedation (Median 5 minutes, IQR 9 minutes) vs morphine analgesia (Median 8 minutes, IQR 16 minutes, P = .04, Median difference 3, 95% CI[-1.50-8.75]). Median hospital stay in the esketamine group was 1.5 days (IQR 1.8) vs 2 days (IQR 5.3) in the morphine group. CONCLUSION: No serious adverse events were recorded. In comparison to morphine analgesia, with esketamine there was weak evidence for a higher success rate, lower recurrence rate, shorter duration, and shorter length of hospital stay.

Selected ophthalmic and physiologic parameters in rabbits (Oryctolagus cuniculus) submitted to retrobulbar block with lidocaine, morphine or ketamine / Avaliação de parâmetros oftálmicos e fisiológicos em coelhos (Oryctolagus cuniculus) submetidos a bloqueio retrobulbar com lidocaína, morfina ou cetamina

The aim of the present study was to evaluate selected ophthalmic and physiologic parameters in rabbits submitted to retrobulbar blockade with lidocaine, morphine or ketamine. Eighteen adult rabbits, seven males and eleven females, New Zealand White breed, weighing 3.9 ± 0.7 kg were randomly assigned to perform the retrobulbar block according to the groups: LID (2% lidocaine without a vasoconstrictor - 7 mg kg-1); MOR (1% morphine - 1 mg kg-1) or KET (10% Ketamine - 5 mg kg-1). Ophthalmic and physiologic parameters were assessed, including lacrimal production using Schirmer tear test (STT), corneal touch threshold (CTT), pupillary diameter, intraocular pressure (IOP), pulse rate (PR), respiratory rate (RR), oxyhemoglobin saturation (SpO2), rectal temperature (RT) and systolic, mean and diastolic blood pressures (SAP, MAP and DAP) and were evaluated every 10 minutes for 70 minutes. All drugs used in the present study promoted central positioning of the eyeball for up to one minute later the retrobulbar administration in all cases. There was a significant increase of STT values in MOR and LID, when compared to baseline, while the CTT values had a significant decrease in all groups. KET kept the IOP values unaltered at the time points and there was a significant decrease of pupillary diameter in MOR. There was no significant change in PR, RR and SpO2; however, LID presented significantly lower values of SAP. MOR had increased values for RT when compared to the other two groups. The established parameters may help in ophthalmic procedures using retrobulbar nerve blocks.

Objetivou-se com o presente estudo estabelecer parâmetros oftálmicos e hemodinâmicos em coelhos submetidos ao bloqueio retrobulbar com lidocaína, morfina ou cetamina. Dezoito coelhos da raça Nova Zelândia, adultos, sete machos e onze fêmeas, com peso de 3,9 ± 0,7 kg foram aleatoriamente distribuídos para realização de bloqueio retrobulbar de acordo com os seguintes grupos: LID (lidocaína 2% sem vasoconstrictor ­ 7 mg/kg); MOR (morfina 1% - 1 mg/kg) ou KET (cetamina 10% ­ 5 mg/kg). Os seguintes parâmetros oftálmicos e hemodinâmicos foram avaliados: produção lacrimal através do teste lacrimal de Schirmer (TLS), limiar de sensibilidade corneana ao toque, diâmetro pupilar, pressão intraocular (PIO), frequência de pulso (FP) e respiratória (FR), saturação da oxihemoglobina (SpO2), temperatura retal (TR) e pressão arterial sistólica, diastólica e média (PAS, PAD e PAM). Todos os fármacos utilizados no presente estudo promoveram centralização do bulbo do olho em até um minuto após a sua administração retrobulbar em todos os casos. Houve um aumento significativo do TLS no grupo MOR e LID, quando comparados aos valores basais, enquanto o limiar de sensibilidade corneana reduziu significativamente em todos os grupos. O grupo KET manteve os valores da PIO inalterados em todos os tempos e houve uma redução significativa do diâmetro pupilar no grupo MOR. Não houve alteração significativa dos valores de FP, FR e SpO2. No entanto, o grupo LID apresentou valores significativamente menores de PAS. O grupo MOR apresentou maiores valores de TR quando comparado aos demais grupos. Os parâmetros estabelecidos no presente estudo podem servir como base para a realização de procedimentos oftálmicos que requerem o uso de bloqueio retrobulbar.

Comparação da contenção farmacológica com cetamina e xilazina, administradas pela via intramuscular no membro torácico ou pélvico, em jacarés-do-papo-amarelo juvenis / Comparison of pharmacological restraint with ketamine and xylazine, administered intramuscularly in the forelimb or hindlimb, in broad-snouted caiman juveniles

Os répteis possuem um sistema porta-renal, o qual pode desviar parte do sangue proveniente das porções caudais do corpo aos rins antes que a mesma atinja a circulação sistêmica. Em vista disto, vem sendo aconselhada a administração de medicamentos injetáveis nos membros torácicos, para que se evite a filtração imediata pelo parênquima renal, causando redução do efeito esperado. O objetivo do presente estudo foi comparar aspectos qualitativos e quantitativos da associação de cetamina (30 mg/kg) e xilazina (1 mg/kg), injetada no membro torácico ou pélvico, em jacarés-do-papo-amarelo (Caiman latirostris) juvenis. Oito animais machos com peso médio (±DP) de 1,3 (±0,3) kg e, aproximadamente, dois anos de idade foram anestesiados em duas ocasiões distintas com intervalo de sete dias. Em cada ocasião, os animais receberam, de forma aleatória, a associação anestésica por via intramuscular em membro torácico (tratamento MT) ou pélvico (tratamento MP). Foram avaliados os intervalos de tempo entre a administração do tratamento e a perda do reflexo de endireitamento (período de indução), entre a perda e o retorno desse reflexo (duração do efeito clínico importante) e entre o retorno do reflexo de endireitamento e os primeiros movimentos de deambulação (duração do efeito residual), as frequências cardíaca e respiratória e as temperaturas ambiental e cloacal. Os escores de sedação/anestesia foram avaliados através de uma escala com variação de 0 (alerta/consciente) a 10 (anestesia profunda/sobredosagem). No tratamento MP, dois animais não apresentaram perda de reflexo de endireitamento. Considerando somente aqueles que apresentaram a perda desse reflexo, o tempo de indução (21±9 e 17±5 minutos) e a duração do efeito clínico importante (35±19 e 43±21 minutos) e residual (28±31 e 12±11 minutos) foram similares entre os tratamentos MT e MP (média±desvio padrão)...

Reptiles possess a renal portal system which can divert part of the blood from the caudal portions of the body to the kidney before it reaches the systemic circulation. In view of this, it has been recommended the administration of injectable medications in the forelimbs, in order to avoid immediate glomerular filtration, which might result in a reduction of the expected effect. The aim of this study was to compare qualitative and quantitative aspects of the pharmacological restraint provided by the combination of ketamine (30mg/kg) and xylazine (1mg/kg), injected into the forelimb or hindlimb, in broad-snouted caiman juveniles (Caiman latirostris). Eight male animals, with a mean weight (±SD) of 1.3 (±0.3) kg, and aged about 2 years old, were anesthetized on two separate occasions with an interval of 7 days. On each occasion, the animals were randomly assigned to receive the anesthetic combination intramuscularly into the forelimb (FL treatment) or hindlimb (HL treatment). The time intervals between administration of treatment and loss of the righting reflex (induction time), between the loss and return of this reflex (duration of important clinical effect), and between the return of the righting reflex and first movements of ambulation (duration of residual effect) were measured as well as heart and respiratory rates and cloacal and environmental temperatures. Sedation/anesthesia scores were evaluated using a scale ranging from 0 (alert/conscious) to 10 (deep anesthesia/overdose). In the HL treatment, loss of righting reflex was not observed in two animals. Considering only those animals whose loss of righting reflex was observed, the induction time (21±9 and 17±5 minutes), the duration of important clinical effect (35±19 and 43±21 minutes), and the duration of residual effect (28±31 and 12±11 minutes) were similar between the FL and HL treatments, respectively (mean±SD). Sedation/anesthesia scores were significantly higher than at baseline...