1999;353(9166):17978. 2018;15(4):1392402. Midazolam (mi daz' oh lam) is a benzodiazepine with particularly potent sedative activity. Status epilepticus and epileptic seizures in dogs. Bateman SW, Parent JM. WebMidazolam or Diazepam 25 0.10.4 Ketamine used alone causes muscle rigidity and could potentially exacerbate some types of seizures and tachyarrhythmias. Epilepsia. Specifically, after IN administration of MDZ (lowest clinically recommended dose of 0.2mg/kg) and DZP (lowest clinically recommended dose of 0.5mg/kg), mean bioavailability was 52% (solution) [155] or 70.4% (gel formulation) [155] for MDZ and 80% (solution) [33] or 42% (solution/atomised formulation) [157] for DZP. Scott RC, Besag FM, Neville BG. BMC Vet Res 17, 103 (2021). 1990;40(5 Suppl 2):1323. Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children. Modern drugs that target the brain are chemically modified to increase their stability and degree of BBB penetration [175]. Vet Clin North Am Small Anim Pract. WebBenzodiazepine drugs used in dogs with seizures include diazepam, midazolam, clorazepate, and clonazepam. Give This effect leads to hyperpolarisation of the cell membrane and inhibition of the transmission of nerve impulses [30, 33]. Epilepsy Curr. Krull DP, Thomovsky SA, Chen AV, Mealey KL, Papich MG. Welch RD, Nicholas K, Durkalski-Mauldin VL, Lowenstein DH, Conwit R, Mahajan PV, et al. 2019;33(6):270917. 2002;7(23):11849. Nair PP, Kalita J, Misra UK. internalization of GABAA receptors -subunits, alterations in GABAA receptor trafficking and conversion of receptors subunits to less BZD-responsive) and changes in chloride homeostasis [34, 35]. Naylor DE, Liu H, Niquet J, Wasterlain CG. Illum L. Nasal drug delivery - recent developments and future prospects. Article 2017;24:87583. Clinical evaluation of intranasal medetomidine-ketamine and medetomidine-S(+)-ketamine for induction of anaesthesia in rabbits in two centres with two different administration techniques. Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus. Zimmermann R, Hulsmeyer V, Sauter-Louis C, Fischer A. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Regarding results from veterinary clinical studies, two recent open-labelled randomised controlled clinical trials demonstrated that IN-MDZ was not only safe and superior to R-DZP but also superior to the gold standard IV route of MDZ administration, especially when the time to place an IV catheter was considered [22, 23]. J Vet Pharmacol Ther. The mean serum concentration was 0.210.02g/mL (solution) [155] or 0.450.09g/mL (gel formulation) [155] for MDZ and 0.440.04g/mL (solution) [33] or 0.31 +/0.17 (solution/atomised formulation) [157] for DZP. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. The mechanism of action for midazolam is mediated via its interaction with the GABA A receptor. Wagner SO, Sams RA, Podell M. Chronic phenobarbital therapy reduces plasma benzodiazepine concentrations after intravenous and rectal administration of diazepam in the dog. Eur J Pharm Biopharm. Liu HT, Mazarati AM, Katsumori H, Sankar R, Waterlain CG. Intranasal treatment of central nervous system dysfunction in humans. McMartin C, Hutchinson LE, Hyde R, Peters GE. Agu RU. Talukdar B, Chakrabarty B. Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: a randomized controlled trial. 2011;57(3):24252. Midazolam Therefore, estimating BZDs therapeutic serum concentration and bioavailability after IN administration might not be an accurate tool for estimating drugs efficacy, as it occurs with other administration routes. The sublingual route is another administration method within the oral cavity similar to buccal. volume17, Articlenumber:103 (2021) BZDs are lipophilic drugs with molecular weight<400Da; therefore, not only can they be absorbed by the nasal mucosa to the systemic blood circulation, but the drugs can also penetrate the BBB and reach the brain [90, 166, 176]. WebA variety of drugs can be used to stop seizures in dogs and cats. 10 minutes after the first dose, a second 5 mg dose may be given if your healthcare provider has instructed you to give a second dose. Lancet. Am J Vet Res. Proc Natl Acad Sci U S A. administration routes that might avoid BBB) with the aim to circumvent the mechanisms that sustain continuous seizure activity is fundamental for the management of SE (Fig. Adjunctive non-anaesthetic (e.g. In dogs, no studies evaluating the sublingual BZDs administration have been performed. Diazepam Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water. Eur J Paediatr Neurol. Treatment of acute seizures: is intranasal midazolam a viable option? 1), which differ in terms of sensitivity to the drugs used, treatment options as well as morbidity and mortality rates [17, 19, 20, 27,28,29,30,31]: Less than 5min of continuous seizure activity. The primary goals of this review are to i) provide an outline about the management of SE at home and in the hospital, with particular focus on first-line pharmacological intervention, ii) discuss the considerations and challenges of the various routes of BZD administration, iii) analyse and evaluate the recently introduced intranasal (IN) drug delivery method for controlling SE in dogs, and iv) provide guidance for primary and specialist clinicians regarding SE management within home and hospital settings. Charalambous, M., Volk, H.A., Van Ham, L. et al. However, in two canine clinical studies [22, 23], various small, medium, and large breed as well as brachycephalic and dolichocephalic dogs were included, but no difference in the efficacy of IN-MDZ was detected among the dogs. J Small Anim Pract. elimination of nasally entering substances by nasal mucosa) regulates the contact time of drugs with the nasal mucosa affecting the degree of their absorption [207]. 2). Antiepileptic Drugs Used to Stop Ongoing Seizure Activity phenobarbital, levetiracetam) or general anaesthetic (e.g. J Control Release. Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation. 1987;76(7):53540. Comparison of plasma benzodiazepine concentrations following intranasal and intravenous administration of diazepam to dogs. Specifically, after R administration of DZP (at the dose of 1mg/kg as solution [52] or 2mg/kg as solution [53] or 2mg/kg as gel formulation/suppository [131]), mean bioavailability was reported to be 52% [52] or 7.4% [53] for the solution but was not detected for suppositories [131]. Lethal Injection 2019;21(12):11817. 2018;1:CD001905. 1989;1(4):51634. Vlerick L, Devreese M, Peremans K, Dockx R, Croubels S, Duchateau L, et al. De Waele L, Boon P, Ceulemans B, Dan B, Jansen A, Legros B, et al. Your privacy choices/Manage cookies we use in the preference centre. J R Soc Interface. Absorption can also be very slow [111]. Regarding R administration of MDZ, studies report erratic bioavailability and serum concentration ranging from undetectable to low [72, 73]. J Vet Intern Med. Induction without Opiate or Sedative Premedication. Brain Res. WebIntravenous Induction Protocols for Dogs and Cats Choosing an ideal IV induction protocol is one of the many decisions required for a smooth anesthetic event. The maximum serum concentrations were achieved within 17min (solution) [155] or 12min (gel formulation) [155] for MDZ and 4.5min (solution) [33] or 8min (solution/atomised formulation) [157] for DZP. Marawar R, Basha M, Mahulikar A, Desai A, Suchdev K, Shah A. Probst CW, Thomas WB, Moyers TD, Martin T, Cox S. Evaluation of plasma diazepam and nordiazepam concentrations following administration of diazepam intravenously or via suppository per rectum in dogs. Information regarding each BZDs recommended dose and target serum concentration as well as reported serum concentrations, time to peak serum concentrations and time to seizure control achieved with each administration route in dogs is provided in Table2. Antiepileptic Drugs Used to Stop Ongoing Seizure Activity 2003;68(3):46976. Harkema JR, Carey SA, Wagner JG. Seigler RS. Seizures WebIn people, midazolam is used for seizure control as well as sedation, but canines experiencing seizures are treated with other drugs. Curr Opin Neurol. Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. J Postgrad Med. 2012;39(5):5119. 2009;50(3):41521. The sublingual route provides a thinner and more permeable layer of absorption compared to buccal and, thus, could potentially provide a faster onset of action [110]. PubMed Central WebRecommended dose in dogs and cats of medetomidine is 520 g (micrograms)/kg i.m. Given the fact that R-DZP in dogs with SE is relatively inconvenient and likely less successful compared to other routes [22, 131], the promising value of alternative delivery methods (i.e. Exp Brain Res. First-line management of canine status epilepticus at home and in hospital-opportunities and limitations of the various administration routes of benzodiazepines, https://doi.org/10.1186/s12917-021-02805-0, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/. Adult: Conscious sedation for procedures; for dental and minor surgical procedures: Initially, 2-2.5 mg given at a rate of 2 mg/minute 5-10 minutes before procedure, with increments of 0.5-1 mg at intervals of at least 2 minutes if required until the desired endpoint is achieved. Epilepsy Behav. 2017;31(4):114958. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. And if your dog suffers from health conditions like epilepsy and seizures, you might be wondering what you can do to make sure hes happy and healthy. Epilepsy Cur. Midazolam Nat Rev Neurosci. First-line management of canine status epilepticus at home and in CAS 2012;73(4):53945. Neuroscience. Seizure PubMed The transdermal route for administering long-term antiseizure drugs, i.e. Striepens N, Kendrick KM, Hanking V, Landgraf R, Wullner U, Maier W, et al. Gabapentin For Dogs: Safe Dosages And Uses Forbes Advisor 2016;237:14759. 1990;8(2):1559. Google Scholar. Usually prescribed as 1 spray into one nostril. Intranasal delivery: an approach to bypass the blood brain barrier. 1995;206(11):17218. Illum L. Is nose-to-brain transport of drugs in man a reality? 2019;295:187200. The 95% confidence interval was used to detect the true population of dogs that were successfully treated. In addition, loss of AMPA receptors GluA2 subunit and overexpression of NMDA receptors occur, which promote glutamate-induced excitation [40, 41]; these changes lead to calcium accumulation within the cells and trigger apoptosis [41]. Bourganis V, Kammona O, Alexopoulos A, Kiparissides C. Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics. Midazolam 2016:5. WebMidazolam must be used only under close medical supervision. Reconstruction and morphometric analysis of the nasal airway of the dog (Canis familiaris) and implications regarding olfactory airflow. 2013;36(5):4717. 1992;9(3):1368. IN-MDZ is also considered a good and successful alternative to other non-IV and IV routes of administration because its efficacy, safety and feasibility has been shown in multiple different species [22, 23, 122, 136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151]. Scheepers M, Comish S, Cordes L, Clough P, Scheepers B. Buccal midazolam and rectal diazepam for epilepsy. Risk factors for development of status epilepticus in dogs with idiopathic epilepsy and effects of status epilepticus on outcome and survival time: 32 cases (1990-1996). Craven BA, Paterson EG, Settles GS. 2011;1(1):2331. Lui CY, Amidon GL, Goldberg A. Intranasal absorption of flurazepam, midazolam, and triazolam in dogs. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Give the second dose in the other nostril. The dog's seizures were classified as either SE or CS and the neurologic examination at presentation to NCVH was recorded as normal or abnormal. Ther Deliv. In veterinary medicine, pharmacokinetic studies showed that IN-MDZ [155, 156], IN-DZP [33, 157] and IN-flurazepam [156] are rapidly and efficiently absorbed by the nasal mucosa and can reach adequate therapeutic serum concentrations. The physical barrier prevents molecules that are hydrophilic and/or have a high molecular weight (>400600Da) to enter the brain [170]. 2009;83(23):14451. Mol Ther. Final distribution of the drug from the point of entry into the brain, i.e. 1990;4(3):2659. 2019;11:3. Seizures and Anticonvulsant Medications No clinical trials to support its efficacy in canine SE exist up to date. The aims of first-line management are i) cessation of seizures, ii) prevention of SE refractory phases, iii) prevention of complications, and iv) avoidance of adjunction of anaesthetic and non-anaesthetic antiseizure medications that could increase the risk of adverse effects [24]. The IN route provides fast and efficient drug delivery to the brain. WebSevere hypotension and seizures have been reported following rapid intravenous administration, Midazolam hydrochloride injection is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection. Rectal administration of BZDs and in particular DZP has been well recommended and widely used as a relatively cheap and potentially effective managing option in human SE, with an onset of action within 1015min [124, 125]. Loscher W, Luna-Tortos C, Romermann K, Fedrowitz M. Do ATP-binding cassette transporters cause pharmacoresistance in epilepsy? Efficacy of nonvenous medications for acute convulsive seizures: a network meta-analysis. In addition, one recent multicenter open-labelled controlled clinical study compared R-DZP to IN-MDZ and showed that R-DZP was successful in terminating SE in only 20% of the dogs (versus 70% in the IN-MDZ group) and was significantly inferior to IN-MDZ [22]. Studies showed that 3240%, 2759%, and 723% of dogs with structural epilepsy, IE, and reactive seizures, respectively, can present with SE [12,13,14, 16]. Another process that occurs during SE is the overexpression of BBB drug transporters, which results in pharmaco-resistance [47]. Drug Deliv. Adv Drug Deliv Rev. Sedation/immobilization protocols Wang X, He H, Leng W, Tang X. Specifically, human studies reported that IN-MDZ (at the minimum clinically recommended dose of 0.2mg/kg) can reach the human brain and cease seizure activity within 25min, as shown on electroencephalography [132]. 2009;14(9):375479. J Vet Pharmacol Ther. Costa C, Moreira JN, Amaral MH, Sousa Lobo JM, Silva AC. Veterans affairs status Epilepticus cooperative study group. Winsnes M, Jeppsson R, Sjoberg B. Diazepam adsorption to infusion sets and plastic syringes. SE is broadly defined clinically as seizures lasting >5min or multiple seizures with incomplete inter-seizure recovery and remains a common neurological emergency [1,2,3]. Versed Do not use more than 2 doses to treat a seizure cluster episode. 1996;38(11):103745. Springer Nature. J Am Vet Med Assoc. Intravenous versus nonintravenous benzodiazepines for the cessation of seizures: a systematic review and meta-analysis of randomized controlled trials. 2013;18(2):7987. 2005;366(9481):20510. Similar limitations exist in dogs, including the risk of caregivers injury due to accidental dog bites, which impair the effect and use of oral BDZs in canine SE. Challenges in the treatment of convulsive status epilepticus. Eur J Neurol. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. BMC Vet Res. R-DZP is unlikely to be as effective as IN-MDZ to terminate SE, based on the current evidence. Kozlovskaya L, Abou-Kaoud M, Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route. MDZ-induced brain and respiratory depression are less severe compared to DZP and LZP [30]. 2014;21(2):7586. Cascade of choices for the first-line management of SE at home and in-hospital, with or without IV access. Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity. For the initial treatment of SE, diazepam should be administered as an intravenous bolus at 0.25-1 mg/kg in the dog and 0.5 mg/kg in the cat. radiotherapy or surgical therapy in case of brain neoplasia, immunosuppressive therapy in case of immune-mediated meningoencephalitis) [5, 26]. Figures from authors personal record modified with microsoft power point. Cochrane Database Syst Rev. IV administration of BZDs has an onset of action approximately within <27min, circumvents first-pass hepatic metabolism (i.e. Benzodiazepines (BZDs) have been exclusively used in veterinary medicine for decadesas first-line drugs based on their high potency and rapid onset of action. Malu CK, Kahamba DM, Walker TD, Mukampunga C, Musalu EM, Kokolomani J, et al. Correspondence to N Engl J Med. Janigro D, Iffland PH 2nd, Marchi N, Granata T. A role for inflammation in status epilepticus is revealed by a review of current therapeutic approaches. Bennett DA, Lal H. Discriminative stimulus properties of the vasodilator, hydralazine: differential generalization with alpha 1 and alpha 2 adrenoreceptor drugs. In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo. J Vet Pharmacol Ther. BZDs effectiveness, though, may gradually decrease with prolonged SE due to reduced synaptic targets (e.g. Ann Neurol. Neuroscience. Falco-Walter JJ, Bleck T. Treatment of Established Status Epilepticus. Lowenstein DH, Cloyd J. Out-of-hospital treatment of status epilepticus and prolonged seizures. Trafficking of GABA(a) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. This is an update of a Cochrane review published in 2016, which aimed to determine the evidence on the effectiveness of midazolam for sedation when administered before a diagnostic or An IV CRI at the dose of 0.20.5mg/kg/h might be advised to sustain good seizure control after the delivery of the initial MDZ bolus dose [5, 25]. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Pharmacological management of seizures and status epilepticus in critically ill patients. BMJ. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. (3 dogs), or both intranasally and IV (2 dogs). Fernandez-Parra R, Pey P, Zilberstein L, Malve M. Use of computational fluid dynamics to compare upper airway pressures and airflow resistance in brachycephalic, mesocephalic, and dolichocephalic dogs. The "perivascular pump" driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. CNS depression/electrolyte disturbances. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. Characteristics of compounds that cross the blood-brain barrier. Third, there are epithelial transporters in nasal epithelium that can cause efflux of drugs from cells and reduce their absorption [200, 208,209,210,211,212]. It might be possible that, due to the above anatomical reasons, trigeminal nerve might not be as significant as the olfactory nerve for transporting drugs into the human brain [90, 202]. Epilepsia. 2012;64(10):9118. Epilepsy Behav. 2010;14(5):4348. Therefore, MDZ is unlikely to be successful, but there are no clinical studies evaluating drugs effect in SE. Dose for anxiolysis and sedation: 0.2 0.3 mg/kg, maximum dose In veterinary medicine, there are not enough clinical trials to allow the conduction of a systematic review/meta-analysis evaluating and comparing different BDZ or IV versus non-IV routes of administration, but it is likely that the experience and evidence derived from human medicine could be translated to veterinary medicine. 2018;5:56. Boddu SHS, Kumari S. A Short Review on the Intranasal Delivery of Diazepam for Treating Acute Repetitive Seizures. 2018;667:8491. Adv Drug Deliv Rev. The median dose associated with seizure control was 0.3 mg/kg/h (range, 0.12.5 mg/kg/h). and of dexmedetomidine is 2.510 g/kg i.m. Koestner A. Neuropathology of canine epilepsy. Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. Article My dog turned 2 in April. CBDfx Rating: 5.0 ORegan ME, Brown JK, Clark M. Nasal rather than rectal benzodiazepines in the management of acute childhood seizures? Loss of orally administered drugs in GI tract. Brigo F, Nardone R, Tezzon F, Trinka E. Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: a systematic review with meta-analysis. Direct access of drugs to the human brain after intranasal drug administration? Neuroscience. When a dog is having a partial seizure, only one limb, side of the body, or just the face will be affected. 2011;17(26):280828. Neurohospitalist. Zaccara G, Giannasi G, Oggioni R, Rosati E, Tramacere L, Palumbo P, et al. Brain and Development. IV. J Pharm Sci. WebThe usual dose of furosemide for healthy dogs is 1 to 5 milligrams per kilogram of your dog's weight, two or three times a day. 1998;29(12):15777. Vidgren MT, Kublik H. Nasal delivery systems and their effect on deposition and absorption. IM BZDs provide onset of action within 15min after administration and have been suggested for at-home and in-hospital SE management in humans [64, 66, 84,85,86,87,88]. Activation of calcineurin underlies altered trafficking of alpha2 subunit containing GABAA receptors during prolonged epileptiform activity. In (super) refractory SE, resistance to most of GABAA-acting drugs may occur due to several factors including phosphorylation and internalization of the potassium-chloride transporter and increased concentration of intracellular chloride [39]. 1996;60(1):1424. 2019;11:10. 1999;93(1):11723. Sisodiya SM, Thom M. Widespread upregulation of drug-resistance proteins in fatal human status epilepticus. Kamata K, Numazawa T, Kasuya Y. Vasodilator effects of clonidine on the mesenteric arterial beds in normotensive and spontaneously hypertensive rats. Eckel R, Szulc B, Walker MC, Kittler JT. i.e. Clin Pharmacol Ther. J Pharm Sci. Pediatr Emerg Care. Experimental: Ketamine and Midazolam. PubMed Nasal-nanotechnology: revolution for efficient therapeutics delivery. Midazolam For Dogs It was suggested that the MDZ serum concentration needed to cease activity is even less compared to sedation in humans (<0.04g/mL) [54]. Harris D, Robinson JR. Drug delivery via the mucous membranes of the oral cavity. The direct pathway has gained attention in recent years as it offers a direct nose-brain axis for drug delivery via specific cranial nerves [164, 177,178,179,180,181,182,183]. Lochhead JJ, Wolak DJ, Pizzo ME, Thorne RG. Bilston LE, Fletcher DF, Brodbelt AR, Stoodley MA. J Vet Pharmacol Ther. Results. Google Scholar. Res Commun Chem Pathol Pharmacol. Oral, in particular, and rectal route undergo first-pass hepatic metabolism, although rectally administered drugs could potentially avoid the first-pass metabolism, if they do not reach more cranial parts of the colon. Serum levetiracetam concentrations after transdermal levetiracetam administration, 3 times daily, to healthy cats. Alshehri A, Abulaban A, Bokhari R, Kojan S, Alsalamah M, Ferwana M, et al. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 1992;15(4):34350. One of the main challenges is the at-home management of emergency seizures as therapeutic options and routes of administration are quite limited and restricted to non-IV routes of administration. Epilepsia. The three main types of seizures are focal, generalized, and focal with secondary generalization. In the two veterinary clinical trials evaluating the effect of IN-MDZ in dogs with SE [22, 23], a human device (i.e. If the seizure cluster continues for at least 10 minutes after the first dose, a second 5 mg dose may be given if your healthcare provider has instructed you to give a second dose. Such a device might provide rapid and convenient delivery as well as enhanced efficacy of MDZ in dogs with SE. Ann Neurol. Buccal-BZD might provide an alternative administration option in humans due to its relatively easy use (no requirement for syringes or injections) and the fact that it is socially acceptable (avoidance of rectal drug administration especially in public) [98]. Fleck notes that most effective and safe dosage will Diazepam | VCA Animal Hospital | VCA Animal Hospitals CNS depressionslow or shallow breathing, shortness of breath, feeling faint, dizziness, confusion, trouble staying awake. Tesoro EP, Brophy GM. Usually prescribed as 1 spray into one nostril. 1998;13(3):14451. The maximum serum concentrations were achieved within 15min [52, 53] for the solution and 80min [131] for the suppository. 3 In general, they are not recommended for chronic administration in dogs due to tolerance and the tendency for the seizures to become refractory. Evaluation of brain-targeting for the nasal delivery of estradiol by the microdialysis method. 2015;56(2):25462. Niquet J, Baldwin R, Suchomelova L, Lumley L, Naylor D, Eavey R, et al. Vet Anaesth Analg. propofol, ketamine, pentobarbital, etomidate, inhalation anaesthetics) antiseizure therapy might be needed. A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation. 2012;20(4):33144. Silbergleit R, Lowenstein D, Durkalski V, Conwit R. Neurological Emergency Treatment Trials I. RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics. Akhtar N, Singh V, Yusuf M, Khan RA. Dogs with SE may benefit from the design of a specific nasal device which would be adapted for small animals (e.g. Acta Anaesthesiol Scand. DZP is not advised to be given IM because of its erratic absorption [30]. Epilepsia. PubMed Repeat DZP bolus leads to accumulation and high concentrations of the drug in the central nervous system (CNS), cerebrospinal fluid (CSF), and serum; although this may result in prolonged antiseizure activity, it can also cause severe CNS depression and cardiorespiratory collapse [59]. However, before therapeutic levels of any drug appear to the systemic circulation, drug crossing and accumulation through the dermal layers is necessary [93, 94]; the latter depends on several factors such as pharmacological characteristics and delivery systems, skin thickness and barrier, and enzymes present in skin that degrade drugs [91,92,93,94]. In dogs, only pharmacokinetic studies have been performed. Treatment of acute seizures and status epilepticus. In one meta-analysis, IN-MDZ was found to terminate >90% of seizures within 510min and sustain seizure freedom for minimum an hour in 80% of people with SE [89]. Based on the fact that animals have remarkable larger olfactory area compared to humans [109, 162, 164, 203], it might be likely that there is similar drug distribution between direct and indirect methods of drug transport in each nasal area, although this assumption has not been proven yet. 2007;30(3):60811. Eur J Clin Pharmacol. Overall, based on the current evidence, IN-MDZ is recommended as a first-choice treatment in dogs with SE at home or in hospital and a proposed cascade is provided by the authors (Fig. Animals: One-hundred six client-owned dogs presenting to a veterinary teaching hospital with CS or SE.
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