It is marketed for small animal practice as 1 mg/mL (1000 µg/mL). Ketamine in combination with medetomidine (MK) has been widely used as an anaesthetic for laboratory rats and mice [1, 7, 21–24]. Dry Mouth Profound sedation and ... Medetomidine is a potent non-narcotic alpha 2-adrenoreceptor agonist which produces sedation and analgesia. Medetomidine can be used on its own as a premedicant or it can be combined with ketamine to provide surgical anaesthesia. In case of accidental eye exposure, flush with water for 15 minutes. Elimination from plasma is rapid, with reported half-lives varying between 0.96 and 1.28 hours (Kuusela et al., 2000; Salonen, 1992). Dexmedetomidine and medetomidine are presently the only α2-agonists used routinely as analgesic adjuvants in dogs and cats, so further clinical discussions will focus on these agents. Blood pressure will initially increase and then return to normal or slightly below. Racemic medetomidine is quickly absorbed after IM administration, with peak plasma levels occurring in approximately 30 minutes. These effects are dose dependent in depth and duration. It can be given by subcutaneous rather than intramuscular injection. Immobilization was reversed with naltrexone, tolazoline, and atipamezole. Peak levels in the brain are five times higher than those in the plasma and are reached in 15–20 minutes. Precaution should be used while handling and using f… Other actions that follow medetomidine use are slowing of gastrointestinal motility, hypothermia, changes to endocrine function and, occasionally, vomiting and muscle twitching. Approximately 85% of the drug in plasma is protein-bound. At the suggested midazolam dose rates, the omission of flumazenil does not significantly change the quality or time to recovery. Many veterinarians use doses that are much less than the doses listed on the label. Due to the large doses used in zoo and wildlife species, this drug must be considered dangerous in case of a significant accidental human exposure. Nasal oxygen supplementation of 3–8 L/min was recommended for animals with respiratory rates <15 breaths/min or SpO2 <90% at sea level; a lower value at higher altitudes. It is a white, or almost white, crystalline, water soluble substance having a molecular weight of 236.7. The sedative effect is increased in senior dogs and frequently half the dose rate will have the same effect as the full dose in a younger dog. Acepromazine provides some protection against histamine release. 3; Dexdomitor is the purified version of medetomidine 3,4 Ketamine/medetomidine produces restraint for minor procedures in mice, such as retroorbital bleeding, which can be reversed rapidly by atipamezole (Cruz et al., 1998; Taylor et al., 2000). The cardiovascular effects of medetomidine, detomidine, and xylazine in horses were studied. Remove contaminated clothing. Hydroxylated products may be subsequently oxidized or conjugated with glucuronic acid. Blood gas analysis revealed hypoxaemia and the authors recommended use of supplemental oxygen with this anaesthetic protocol. It is relatively expensive and rabbits require comparatively larger doses than other species. The atipamezole dose for the reversal of IV dexmedetomidine or medetomidine is 3750 mcg/m 2. This can significantly reduce the amount of time needed for recovery. The molecular formula is C13 H16 N2•HCl and the structural formular is: Each mL of Medeto… Medetomidine causes peripheral vasoconstriction, which gives mucous membranes a slight mauve appearance that may be mistaken for cyanosis. Elimination half-life is 1.6 hours (Salonen, 1989). Medetomidine Hydrochloride (medetomidine hydrochloride) is a synthetic alpha 2-adrenoreceptor agonist with sedative and analgesic properties. Medetomidine should not be used in animals with known hypersensitivity or allergy to the drug. It is an α2 adrenergic agonist that can be administered as an intravenous drug solution with sterile water. zolazepam drug combination tiletamine Medicine & Life Sciences In the rat, absorption of medetomidine following SQ administration is rapid, with peak plasma concentrations reached within 10 minutes. Slowing of the respiratory rate is a frequent effect of medetomidine with some dogs showing signs of cyanosis. Other studies (Mich et al., 2008; Miller et al., 2009) have evaluated in white-tailed deer a combination of butorphanol, azaperone, and medetomidine, at approximate dosages of 0.43 mg/kg, 0.36 mg/kg, 0.14 mg/kg, or 0.34 mg/kg, 0.27 mg/kg, 0.11 mg/kg, or 0.30 mg/kg, 0.16 mg/kg, 0.20 mg/kg, respectively. It has been replaced by dexmedetomidine in domestic dog and cat anesthesia, because medetomidine is currently no longer available in a small animal formulation. Medetomidine is a prescription drug and can only be obtained from a veterinarian or by prescription from a veterinarian. Mule deer and mule deer hybrids were immobilized by medetomidine, 0.1 mg/kg, and ketamine, 2.5 mg/kg, IM for 60 minutes followed by reversal with atipamezole, 0.5 mg/kg, injected half IV and half IM (Caulkett et al., 2000). Use of the combination of ketamine/medetomidine may cause hyperglycemia and polyuria similar to xylazine. Doses above 60 µg/kg may cause swelling of the head; this problem can be prevented by propping the head in a normal position. The vasoconstriction is not dangerous but the poor colour of the mucous membranes could mask a true cyanosis should it occur. The overall level of sedation and cardiorespiratory effects did not differ between MED40, DEX20 and DEX10 during the first hour, apparently due to a ceiling effect. Medetomidine and detomidine are metabolized similarly, by hepatic monooxygenases. Medetomidine, 0.01–0.02 mg/kg (10–20 µg/kg), IV significantly decreases serum insulin concentration but plasma glucose concentration remains within the normal physiological range (Burton et al., 1997). A specific α2-antagonist, atipamezole, was marketed alongside medetomidine and rapidly reverses all sedative, analgesic, and cardiovascular effects associated with medetomidine administration, if desired. Selectivity provides greater predictability and control. Hypoxia occurs during anaesthesia with medetomidine and oxygen should be administered throughout the anaesthetic period (Flecknell, 2000). Ketamine is a centrally acting NMDA-receptor antagonist that rapidly induces dissociative anaesthesia while providing analgesia. Copyright © 2021 Elsevier B.V. or its licensors or contributors. Reverse with atipamezole at a dose of 25-300 mcg/kg (equal to volume of medetomidine used) IM. The chemical name is (±)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. A main advantage to the use of these two combinations is their reversibility with nalbuphine or butorphanol and atipamazole. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. Saunders Handbook of Veterinary Drugs (Fourth Edition), Textbook of Rabbit Medicine (Second Edition), Handbook of Veterinary Pain Management (Second Edition), Handbook of Veterinary Pain Management (Third Edition), Use of Naltrexone and Atipamezole in Emergency Response to Human Exposure to Ultra-Potent Opioids and Alpha-2 Agonists in Zoo and Wildlife Medicine, Fowler's Zoo and Wild Animal Medicine Current Therapy, Volume 9, Pharmacology of Injectable Anesthetics, Sedatives, and Tranquilizers, Anesthesia and Analgesia in Laboratory Animals (Second Edition), http://www.fda.gov/cvm/Green_Book/200702.pdf, Veterinary Anaesthesia (Eleventh Edition), Anesthesia and Analgesia for Laboratory Rodents, Update on Field Anesthesia Protocols for Free-Ranging African Lions, Anaesthesia of sheep, goats, and other herbivores. The side effects of medetomidine were bradycardia, respiratory depression, stasis of the rumen with tympany, salivation and polyuria. Medetomidine is an equal mixture of two optical enantiomers, dexmedetomidine and levomedetomidine. It is often used as the hydrochloride salt, medetomidine hydrochloride, a crystalline white solid. The authors have not observed adverse central nervous system or cardiorespiratory effects following intravenous atipamezole administration in cases of anesthetic emergencies. The product information sheet contains detailed tables on volume of drug to administer for different weights of dogs. Adverse effects of medetomidine include slowed heart rate with partial heart block, low body temperature and slowed breathing rate. With this combination, induction occurred within 1 minute (Hahn et al., 2005). Opposing studies have demonstrated high levels of anesthetic complications and mortality when rats are premedicated with SC buprenorphine 1 hour prior to IP ketamine/medetomidine administration (Roughan et al., 1999). See package insert for full information on side effects, precautions, warnings and contraindications. In mice, very low doses of medetomidine are anxiolytic without obvious signs of sedation (MacDonald et al., 1989). Adverse effects of medetomidine include slowed heart rate with partial heart block, low body temperature and slowed breathing rate. The effects of medetomidine can be reversed with the use of atipamezole. Medetomidine is an equal mixture of two optical enantiomers: dexmedetomidine (see previous discussion) and levomedetomidine. Fifteen horses, whose right carotid arteries had previously been surgically raised to a subcutaneous position during general anesthesia were used. Medetomidine should not be used in the last trimester of pregnancy since it can induce premature labor. Female mice appear to be more resistant to the effects of this anesthetic combination than male mice (Cruz et al., 1998; Taylor et al., 2000). In Veterinary Anaesthesia (Eleventh Edition), 2014. In rats, there is a dose-dependent sedation and loss of righting reflexes, but deep sedation is not produced in mice or rabbits. Medetomidine is a racemic mixture of two stereoisomers, dextro-medetomidine and levo-medetomidine. Side-effects: Due to the mode of action of medetomidine, heart rate and body temperature decrease. Survival surgery requires concurrent preemptive analgesia. The highest dose rate for a 15 kg dog is roughly equivalent to 0.03–0.04 mg/kg (30–40 µg/kg). Results from the third dose rate combination included times to sternal and lateral recumbency on average 8 and 13 minutes, respectively, and an excellent rated quality of induction. If irritation or other adverse reaction occurs (e.g., sedation, hypotension, bradycardia), seek medical attention. From: Saunders Handbook of Veterinary Drugs (Fourth Edition), 2016, Molly Varga BVetMed DZooMed MRCVS, in Textbook of Rabbit Medicine (Second Edition), 2014. Despite its increased use in recent years, scant research has quantified the physiologic responses of immobilized animals or assessed its relative efficacy using different trapping methods. Dexmedetomidine has twice the potency of medetomidine. Usage, warnings, side effects, and community information for the prescription drug Medetomidine Hydrochloride A specific α2-antagonist, atipamezole, was marketed alongside medetomidine and rapidly reverses all sedative, analgesic, and cardiovascular effects associated with medetomidine, dexmedetomidine, and other α2-agonists, if desired. It is a sedative that provides pain relief as well as muscle relaxation. The principal metabolite in rats is hydroxydetomidine glucuronide. We use cookies to help provide and enhance our service and tailor content and ads. Consult with your veterinarian to determine if other drugs your pet is receiving could interact with medetomidine. Vomiting occurs in about 20% of dogs receiving medetomidine, which is less than xylazine. Medetomide alone can be used for deep sedation and analgesia with rapid reversal by its specific antagonist, atipamezole (Antisedan®) (Virtanen, 1989). Antinociceptive actions of medetomidine have been demonstrated in a variety of assays and species (Vainio, 1992), including subcutaneous formalin injection in rats (Pertovaara et al., 1990) and the acetic acid-induced writhing test in mice (Virtanen, 1986). In case of accidental eye exposure, flush with water for 15 minutes. The IM dose rates given to induce profound sedation are up to 750–1000 µg/m2. This drug is registered for use in animals only. The most common effect noted is an initial hypertension (due to peripheral postsynaptic adrenoreceptors causing vasoconstriction), which results in a baroreceptor-mediated reflex bradycardia. Detomidine is an imidazole derivative and α 2-adrenergic agonist, [citation needed] used as a large animal sedative, primarily used in horses.It is usually available as the salt detomidine hydrochloride.It is a prescription medication available to veterinarians sold under the trade name Dormosedan.. Mark G. Papich DVM, MS, DACVCP, in Saunders Handbook of Veterinary Drugs (Fourth Edition), 2016. Medetomidine provides better sedation and analgesia than xylazine and has a longer duration of action (Tyner et al., 1997). The alpha2 agonists may be used for sedation, analgesia, and minor surgical procedures. Specific and selective alpha2-adrenoceptor agonist 1,2 approved for companion animals. Medetomidine combined with an opiate (butorphanol or hydromorphone) has produced a longer duration of sedation and more desirable degree of sedation than medetomidine used alone. Profound sedation and recumbency, with reduced sensitivity to environmental stimuli (sounds, etc. While generally safe and effective when prescribed by a veterinarian, medetomidine can cause side effects in some animals. Dexmedetomidine is the active component, whereas levomedetomidine is considered pharmacologically inactive (though it may play a role in drug interactions).19, Racemic medetomidine is lipophilic, facilitating rapid absorption after intramuscular administration; peak plasma concentrations are reached in approximately ½ hour.21, Elimination of medetomidine from plasma is also rapid, with reported half-lives varying between 0.9619 hour and 1.28 hours.21, Medetomidine/dexmedetomidine are the most specific α2-agonists available clinically with an α2:α1 binding ratio of 1620:1.18. Field experience has shown that BMM-immobilized lions may spontaneously stand up at ≥45 minutes after induction, especially following a loud noise or painful manipulation. Medetomidine is used to produce sedation for short procedures and provides a short period of analgesia. All Rights Reserved. Vomiting can occur following medetomidine administration and may result in aspiration pneumonia. Antinociceptive and sedative actions of medetomidine in rabbits, guinea pigs, and hamsters are inconsistent (Vainio, 1992). It was developed by Orion Pharma. Medetomidine is a synthetic compound used as a surgical anesthetic and analgesic. The condition appears self-limiting and does not require treatment. For sedation in dogs, medetomidine is dosed at 0.75 mg/square meter of body surface area intravenous or 1 mg/square meter body surface area intramuscular. Butorphanol–Azaperone–Medetomidine (BAM) is a relatively new drug mixture compounded for the past decade to immobilize mammals, particularly ungulates. Additional atipamezole doses (10× medetomidine dose, mg) may also be given following prolonged procedures to ensure animals do not become resedated. See package insert for full information on side effects, precautions, warnings and contraindications. Following intramuscular (IM) administration, medetomidine was faster in onset and the magnitude of effect was also greater than that obtained with dexmedetomidine. No analgesic effect was produced by xylazine, however moderate analgesia was obtained by medetomidine. Storage: Store between 20-25°C (68-77°F) with excursion permitted between 15-30°C (59-86°F). Atipamezole is 200 times more selective for α-2 adrenoceptor receptors than yohimbine (Virtanen, 1989). Medetomidine is available in 1 mg/ml concentration in 10 ml vials. ), are seen with medetomidine. Peter Buss, Michele Miller, in Fowler's Zoo and Wild Animal Medicine Current Therapy, Volume 9, 2019, BMM combination (see Table 76.1) provides an effective immobilizing drug combination for lions with a rapid induction (5–10 minutes) and 45 minutes of stable anesthesia.8 Immobilized lions do not react to minor painful procedures but more invasive surgeries require additional analgesia. After intramuscular (IM) injection, the effects of medetomidine are seen within 10 to 15 minutes. Veterinary formulations: Domitor® (Pfizer). Medetomidine causes peripheral vasoconstriction, which gives mucous membranes a slight mauve appearance that may be mistaken for cyanosis. In cats, medetomidine is dosed at 20 to 40 mcg per pound (40 to 80 mcg/kg) intramuscular. Profound sedation and recumbency, with reduced sensitivity to environmental stimuli … There were no marked changes in heart rate and respiratory rate during the observation period in pigs of any groups, however mild hypothermia after the administration of … Such drugs include fentanyl, butorphanol, atropine, propofol and meperidine. Currently, there is little information available regarding the use of medetomidine in cats so caution should be used. Simple hepatic hydroxylation can explain the rapid removal of the drug; metabolism is regulated primarily by hepatic blood flow (Salonen, 1992). The effects of medetomidine can be reversed by injection of atipamezole at a dose rate up to five times the medetomidine dose. Dexmedetomidine has recently been approved by the FDA for use in humans (Precedex) and dogs (Dexdomitor; http://www.fda.gov/cvm/Green_Book/200702.pdf, accessed 24 July 2007). An advantage of this combination is that reversal agents can be administered at any time point following induction.8. Medetomidine belongs to a class of drugs known as alpha 2 adrenergic agonists and is similar to clonidine and xylazine. This combination has also been used for rodents in field studies. Some common side effects like period of surgical anaesthesia (Grant et al, salivation, frequent urination, defaecation, 1996). Excretion of 3H-labeled medetomidine is mainly in the urine: 41% over 72 hours compared with 18% in the feces. Within the first 3 to 5 minutes after IM injection, vomiting can occur. Medetomidine may interact with other medications. It is also used as a preanesthetic before local or general anesthesia. Low Blood Pressure If experienced, these tend to have a Less Severe expression 1. The IHC Group. Atipamezole is the recommended antagonist for medetomidine in veterinary species.19, Robert E. Meyer, Richard E. Fish, in Anesthesia and Analgesia in Laboratory Animals (Second Edition), 2008. Medetomidine (Domitor, Pfizer) is a more specific α2-agonist than xylazine and has a lower incidence of side effects. Must use precision vaporizer Reversal agents (Mice and Rats) Atipamezole 1‐2.5 mg/kg SC, IP, or IV For reversal of Medetomidine or Xylazine effects More specific for medetomidine than for By continuing you agree to the use of cookies. Respiration rates were variable and hypoxaemia was identified using pulse oximetry. Medetomidine is presently the only α2-agonist used routinely as an analgesic adjuvant in dogs and cats, so further clinical discussions will focus on this agent. Decreased Oxygen In The Tissues Or Blood 2. Leigh Lamont, in Handbook of Veterinary Pain Management (Second Edition), 2009. Its side effects include tachycardia, dysphoria, and muscle rigidity. In rats, ketamine/medetomidine anesthesia can be prolonged with the addition of buprenorphine (Hedenqvist et al., 2000). Jeffery R. Zuba, Mark Greenberg, in Fowler's Zoo and Wild Animal Medicine Current Therapy, Volume 9, 2019, Medetomidine is considered the most selective of all the α-2 agonists and is currently prepared only in formulations intended for zoo and wildlife species.6,19 It is available in highly concentrated injectable solutions (20 and 40 mg/mL, Wildlife Pharmaceuticals, Inc.); therefore it may be combined in darts with UPOs and other drugs intended for nondomestic ungulate and megavertebrate species. DEXDOMITOR is also indicated for use as a preanesthetic to general anesthesia in dogs. Medetomidine has some advantages. 1‐3% inhalant to effect (up to 5% for induction). •medetomidine 5 g/kg + methadone 0.5 mg/kg IM •medetomidine 5 g/kg + methadone 0.5 mg/kg + ketamine 0.5 mg/kg IM •medetomidine 10 g/kg + methadone 0.5 mg/kg ketamine 0.5-1 mg/kg IM •or dexmedetomidine at half the above medetomidine doses ketamine … Five percent or less of the urine radioactivity is unchanged medetomidine. Antidote dose rates are calculated on the total immobilizing drug doses administered. Diane J. Gaertner, ... Margaret A. Batchelder, in Anesthesia and Analgesia in Laboratory Animals (Second Edition), 2008. The cardiopulmonary effects of medetomidine are similar to previously described, however, the changes are quantitatively similar for doses ≥5 µg/kg (Pypendop & Verstegen, 1998). It is normally found as its hydrochloride salt, medetomidine hydrochloride.Medetomidine is an intravenously available alpha-2 adrenergic agonist. Side effects occur frequently with alpha-2 agonists. In cats, IM medetomidine had a tendency to produce higher sedation scores and a greater level of analgesia. Medetomidine has a steep dose–response curve and doses should, ideally, be calculated on a body surface area (BSA) rather than on body weight. The analgesia associated with medetomidine only lasts 15 to 30 minutes but sedation can last 1 to 2 hours. Medetomidine can be used on its own as a premedicant or it can be combined with ketamine to provide surgical anaesthesia. Medetomidine hydrochloride can be absorbed and may cause irritation following direct exposure to skin, eyes, or mouth. Extreme caution must be used if medetomidine is given to animals with heart disease, low blood pressure, shock, breathing problems, severe liver or kidney disease, a known seizure disorder or if the animal is severely debilitated. For example, lower doses are sometimes used for short-term sedation and analgesia, particularly when combined with other drugs such as opiates. In practice, this means that large dogs require relatively lower doses than smaller dogs. The atipamezole dose for the reversal of IM dexmedetomidine or medetomidine is 5000 mcg/m 2. Bruno H. Pypendop, in Handbook of Veterinary Pain Management (Third Edition), 2015, Dexmedetomidine is the active component, whereas levomedetomidine is considered pharmacologically inactive (although it may play a role in drug interactions).23, Racemic medetomidine is lipophilic, facilitating rapid absorption after intramuscular administration; peak plasma concentrations are reached in approximately ½ hour.25, Medetomidine and dexmedetomidine are the most specific α2-agonists available clinically, with an α2:α1 binding ratio of 1620:1.22. Other side effects include reduction in gut motility, hyperglycaemia, sweating and an increase in urination. Sedation is achieved at 2 µg/kg IV and increasing the dose rate increases the intensity and duration of sedation, from 60 minutes after 5 µg/kg to 120 minutes after 20 µg/kg. Medetomidine Hydrochloride should be administered at the rate of 750 µg IV or 1,000 µg IM per square meter of body surface. DEXDOMITOR is indicated for use as a sedative and analgesic in dogs and cats to facilitate clinical examinations, clinical procedures, minor surgical procedures, and minor dental procedures. Medetomidine (Domitor®) is an α-2 adrenoceptor agonist with 10 times greater specificity than xylazine and fewer notable side effects (Virtanen, 1989). However, the analgesic effect of DEX20 lasted longer than the effect of the corresponding dose of racemic medetomidine, suggesting greater potency for dexmedetomidine in dogs. Medetomidine, dexmedetomidine, and detomidine are more specific for the alpha2 receptor than xylazine. The use of medetomidine in combination with ketamine is described in Box 4.5. Medetomidine is a potent non-narcotic alpha 2-adrenoreceptor agonist which produces sedation and analgesia. Sedation and analgesia at predictable depths and duration while minimizing unwanted side effects. Analgesic DrugsAutonomic Nervous System Drugs; Anesthetics; Analgesics, ©Copyright 1999 - 2021. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second degree heart block. Medetomidine, 0.06–0.08 mg/kg, IM administered with ketamine, 1–2 mg/kg, IM is a useful combination to sedate deer. Medetomidine is an imidazole derivative more potent than xylazine (Salonen, 1992; Savola et al., 1986), with higher alpha2-adrenoceptor selectivity, greater lipophilicity, and faster elimination (Scheinin and Macdonald, 1989). Medetomidine can cause hypothermia and diuresis. Despite appearing completely sedated, animals can still move, even kick, bite or scratch, in response to sharp auditory stimulation. Treated animals should be kept in a warm and even temperature during the procedure and for 12 hours after sedation. Medetomidine is a commonly used supplemental drug combined with ketamine and other injectable anesthetic agents for use in great apes,22–24 nonhuman primates, and carnivores. There is a dose-dependent decrease in spontaneous activity and prolongation of barbiturate sleep time, more than with either detomidine or xylazine (Virtanen, 1986). Dosage and administration: Administer medetomidine at a dose rate of 40 µg medetomidine/kg and the product at a dose rate of 5.0-7.5 mg ketamine/kg bodyweight (equivalent to 0.5-0.75 ml/10 kg), depending on duration of anaesthesia required, by intramuscular injection. In case of accidental oral exposure or injection, seek medical attention. These effects are dose dependent in depth and duration. The use of blindfolds and hobbles is advocated to limit the possibility of injury to people working with the lions. Vomiting can occur following medetomidine administration and may result in aspiration pneumonia. Medetomidine hydrochloride can be absorbed and may cause irritation following direct exposure to skin, eyes, or mouth. The cut-off weight between higher and lower dose rates is 15 kg, so that dogs <15 kg need a higher dose and dogs >15 kg need less. In Skin analgesia and recumbence were produced ruminants, xylazine has proven to be a safe with xylazine while no analgesia was achieved anesthetic adjunct when administered with after administration of detomidine and ketamine or other anesthetic to induce short medetomidine. After intravenous injection, the effects are seen within 5 minutes. A comprehensive series of articles on the veterinary use of medetomidine and dexmedetomidine have been published (Daunt and Maze, 1992; Lammintausta et al., 1989; Murrell and Hellebrekers, 2005). Medetomidine, commonly known by the brand name Dormitor, is an injectable drug used for sedation in dogs and cats. Immobilized lions should be administered one-third of the initial BMM dose IM at 45 minutes after induction and every subsequent 30 minutes. Mild bradycardia (<50 beats/min), mild metabolic acidosis, normocapnia, and mean PaO2 of 87 mm Hg have been reported in BMM-immobilized lions.8 Complete reversal is achieved with naltrexone-atipamezole-flumazenil administration, with recovery to standing within 4–8 minutes.