Severe Toxic Damage to the Rabbit Spinal Cord after Intrathecal Administration of Preservative-free <i>S</i>  (+)-Ketamine

Vranken, Jan; Troost, Dirk; Haan, Peter; Pennings, Fritz A.; Vegt, Marinus H. van der; Dijkgraaf, Marcel G. W.; Hollmann, Markus W.

doi:10.1097/00000542-200610000-00028

Cited by 100 publications

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“…It has been reported that ketamine HCl administered via IT provides sensory and motor blockage both by its antagonist effect on NMDA receptors and by blocking calcium channels (7,12,13,(15)(16)(17)19). The purpose of this study was to use these characteristics of IT administration of ketamine and evaluate its efficacy on calves.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that it provides sensory and motor blockage when administered via IT (7,17). Its action is based on two mechanisms: ketamine is an antagonist of the N methyl-D aspartate (NMDA) receptors located in the dorsal root of the spinal cord (15,16,17,19), and it reduces depolarisation by blocking the sodium channels similarly to local anaesthetics (7,12,13,15,17,18). In addition, it is claimed that ketamine is beneficial for the respiratory system due to its bronchodilator effect (10,12,16).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Intrathecal Administration of Ketamine HCl in Young Calves: A Clinical Trial

Kiliç

Yayla

Kamiloğlu

et al. 2015

Bulletin of the Veterinary Institute in Pulawy

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The purpose of the study was to investigate the clinical, biochemical, and cardiovascular effects of intrathecal (IT) administration of ketamine HCl in calves. The study was performed on seven Simmental and three Montofon calves, 1.70 ± 1.16 weeks old, weighing approximately 37 kg, undergoing surgical procedures including femur fracture repair (one case), atresia anus (five cases), prolapsed rectum (one case), suturing on rear limbs (two cases), and urethrostomy (one case). After administering IT ketamine HCl at a dose of 3 mg/kg to all calves, the level and depth of the anaesthesia was checked with a pinprick test. Each animal was monitored by recording heart rate, arterial blood pressure, respiratory rates, and rectal temperature. Furthermore, certain biochemical parameters, blood gases, oxygen-total haemoglobin, and electrolyte levels were measured. All data were statistically evaluated using Minitab 16 software. Anaesthesia occurred in all calves at an average of 5.00 ± 1.41 min (range: 3-7) and continued for an average of 61.4 ± 40 min (range: 55-70). Sufficient anaesthesia was achieved in all animals for the required operations, and no complications occurred with regard to clinical and haemodynamic measurements. We concluded that in calves, which are not deemed suitable for administration of local anaesthetic via IT due to certain side effects, sufficient anaesthesia can be provided with ketamine by the same method for operations performed in the perineal area and hind extremities, and that this could be a good alternative for anaesthesia under field conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Intrathecal Administration of Ketamine HCl in Young Calves: A Clinical Trial

Kiliç

Yayla

Kamiloğlu

et al. 2015

Bulletin of the Veterinary Institute in Pulawy

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“…In a study by Vranken et al, preservative-free ketamine applied intrathecally in rabbits for 7 days resulted in no significant changes among motor functions, although axonal swelling and chromatolysis were high, suggesting a toxic damage. 21 When Gomes et al applied preser-…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic Effects of Ketamine and Different Doses of Ropivacaine Administered Intrathecally in Rabbits

Sezen¹,

Demiraran²,

Güven³

et al. 2013

Turkiye Klinikleri J Med Sci

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A AB BS S T TR RA AC CT T O Ob b j je ec c t ti i v ve e: : Although a variety of anesthetic medicines are used intrathecally, experimental neurotoxic studies on these drugs are not sufficient. In our study, we used immunocytochemical examination to assess the neurotoxic potential of ketamine and different doses of ropivacaine administered intrathecally. M Ma a t te e r ri i a al l a an nd d M Me et t h ho od ds s: : Thirty rabbits were divided into five groups which were inserted spinal catheters under anesthesia. Each group received in a volume of 0.3 ml, as follows: the R0.2 group received 0.2% ropivacaine, the R0.75 group received 0.75% ropivacaine, the R1 group received 1.0% ropivacaine, the K group received preservative-free S (+) ketamine and the C group received 0.9% NaCl. The onset and duration of action were recorded by using Motor Dysfunction Index (MDI). Rabbits were observed for five days and then euthanasized. After catheters were removed, brains and spinal tissue samples were evaluated by light microscopy and immunocytochemical examination. R Re e s su ul lt ts s: : The longest onset of action was observed in the K group. Among the ropivacaine groups, the onset of action diminished and the duration of action extended with an increase in dose significantly. There was axonal degeneration in the R1 group, but this finding not reach significance. In the ketamine group, significant neuronal degeneration and reduction in number of neurons in the brain sections were observed . In the 1% ropivacaine group, a relative increase in neurofilament intensity was detected using immunocytochemical assessments in the medulla spinalis and brain sections. C Co on nc c l lu u s si i o on n: : The intrathecal applications of 1% ropivacaine and ketamine can induce neurotoxic damage, despite a lack of observed functional neurologic deficits.K Ke ey y W Wo or rd ds s: : Ro pi va ca i ne; ke ta mi ne; in jec ti ons, spi nal Ö ÖZ ZE ET T A Am ma aç ç: : İntratekal olarak uygulanan anestezik ilaçların çeşitliliğine karşın, bu ilaçların deneysel nörotoksik çalışmaları yeterli değildir. Çalışmamızda, intratekal olarak verilen ketamin ve farklı dozlardaki ropivakainin nörotoksik potansiyelini immunohistokimyasal olarak değerlendir-meyi amaçladık. G Ge e r re eç ç v ve e Y Yö ön n t te em m l le er r: : Anestetize edilerek spinal kateter yerleştirilmiş 30 tavşan 5 gruba ayrıldı. Grup R0.2'de ropivakain %0,2, grup R0.75'de ropivakain %0,75, grup R1'de ropivakain %1,0, grup K'de preservative-free S (+) ketamin ve grup C'de %0,9 NaCl 0,3 ml volümde spinal kateterden uygulandı. Etki başlangıç zamanı ve etki süreleri Motor Dysfunction Index (MDI) kullanılarak kaydedildi. Tavşanlar 5 gün gözlendikten sonra ötenazi uygulandı. Kateterler çıkar-ılarak beyin ve spinal doku örnekleri ışık mikroskopisi ve immunohistokimyasal metodla değer-lendirildi. B Bu ul l g gu u l la ar r: : En uzun etki başlangıcı grup K'de gözlemlendi. Ropivakain grupları içinde doz artışı ile birlikte etki başlangıç süreleri kısalarak, etki süreleri uzamış olarak t...

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“…After repeated intrathecal delivery in rabbits [197] or continuous infusion in dogs [198], Ketamine and a number of other NMDA channelblocking antagonists including MK-801, dextrorphan, dextromethorphan and memantine and the nonopiate agent D-methadone, and to a lesser degree the glutamate antagonist 2AP5,resulted in prominent spinal pathology reflecting parenchymal necrosis in dogs and/or sheep [198,199]. These spinal effects, where examined, appear to be concentrationdependent and, with the exception of the neonatal model, the therapeutic ratio (e.g., therapeutic dose/minimum toxicity dose-concentration) has not been defined.…”

Section: Adverse Eventsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Severe Toxic Damage to the Rabbit Spinal Cord after Intrathecal Administration of Preservative-free S (+)-Ketamine

Abstract: The authors conclude that repeated intrathecal administration of preservative-free S(+)-ketamine in a clinically relevant concentration and dosage has, considering the extent and severity of the lesions, a toxic effect on the central nervous system of rabbits.

Cited by 100 publications

References 0 publications

Effects of Intrathecal Administration of Ketamine HCl in Young Calves: A Clinical Trial

Effects of Intrathecal Administration of Ketamine HCl in Young Calves: A Clinical Trial

Neurotoxic Effects of Ketamine and Different Doses of Ropivacaine Administered Intrathecally in Rabbits

Current and Future Issues in the development of spinal agents for the management of pain

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