IACUC Guideline LARGE ANIMAL FORMULARY

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1 The intention behind the development of a University of Pennsylvania IACUC-endorsed drug formulary for the larger species used in biomedical research was to provide guidance for anesthetic and analgesic regimens from the ULAR and SVM veterinarians. This formulary provides current species-specific IACUCapproved drug regimens, as well as additional options based on contemporary standards in veterinary practice and refinements in pharmaceutical choices. ULAR veterinary-recommended regimens for particular species are provided at the beginning of each relevant section. This guideline will cover the following topics: Definitions Sheep (p. 2) Swine (p. 6) Nonhuman primates (p. 9) Dogs (p. 11) DEFINITIONS Anesthetic Premedication: premedication refers to a drug treatment given to a patient before a surgical or invasive medical procedure. These drugs are sedative or analgesic in nature, and are usually given intramuscularly or subcutaneously to sedate the animal for handling. Induction: the administration of a drug or combination of drugs at the beginning of an anesthetic that results in a state of general anesthesia. These drugs are typically given intravenously. General Anesthesia: a state of unconsciousness with the absence of pain sensation over the entire body, through the administration of anesthetic drugs. Maintenance: ongoing state of general anesthesia. Inhaled anesthetics are preferred for maintenance of anesthesia because they allow a more precise control of the anesthetic state and do so at low cost. However, intravenous drugs can also be used to maintain a surgical level of general anesthesia. Analgesic: a drug used to achieve relief from pain. They are distinct from anesthetics, (defined above) which only reversibly eliminate conscious sensation. Analgesic drugs act in various ways on the peripheral and central nervous systems, and include non-steroidal anti-inflammatory drugs (NSAIDs), and opioids (such as morphine and buprenorphine). Typically, several analgesics are chosen for one patient that each work on different pain pathways to create a multi-modal approach to managing pain. Local Anesthetics: anesthesia of a small part of the body such as a tooth or an area of skin. Common techniques include topical anesthesia (surface), and local injectable infiltration. Local anesthesia differs from general anesthesia in that it only affects a specific part of the body. Prior to selection of any drug regimen for a surgical research model, a ULAR laboratory animal veterinarian should be consulted to provide assistance and input into the final animal protocol. APPROVED 1 12/09/2014

2 SHEEP Recommended regimens For major survival surgery Place fentanyl patch at least 12 hours prior to surgical incision. Sedate in cage with 0.5 mg/kg midazolam (IM or SC) for light sedation. If heavy sedation is needed, ketamine 4 mg/kg IM can be added to midazolam. Once sedation has taken effect (about 30 minutes) move sheep to induction area. Induce with Propofol 2-6 mg/kg IV, adding ketamine 2-6 mg/kg IV if Propofol alone is inadequate. Place endotracheal tube and maintain on isoflurane 1-2.5% Place rumen tube. Infiltrate 0.25% Bupivacaine at 1-2 mg/kg into surgical site. (Do not apply into pericardium or near phrenic nerves.) Flunixin 2 mg/kg IV slowly prior to incision Continue flunixin once daily at 1 mg/kg SC for 3-4 days. Remove fentanyl patch 72 hours after placement. For very painful procedures, consider adding mu opioid agonist immediately post op, alpha 2 agonist, ketamine/lidocaine CRI or an epidural. For mild sedation for non-painful short procedure (e.g. stomach tubing, chest x-ray) mg/kg midazolam IM or IV Sedation/Anesthetic Premedication Sedation in cage may decrease stress, and is recommended prior to induction Light sedation Midazolam mg/kg SC, IM, or IV Very low doses of benzodiazepines (generally lower than the ranges listed) can cause excitement when given IV. Diazepam mg/kg IV REVERSAL for diazepam or midazolam can be accomplished with flumazenil (0.02 mg/kg IV or IM); if needed, reversal can be performed after short sedations with larger doses of benzodiazepines. 2

3 Moderate sedation Midazolam + Buprenorphine Midazolam + Butorphanol mg/kg mg/kg SC or IM mg/kg mg/kg SC or IM Not recommended when mu opioid agonist (such as fentanyl, morphine) will also be used Xylazine 0.1 mg/kg IM Alpha 2 agonists such as xylazine may cause adverse pulmonary changes and hypoxemia in sheep, especially when given at high dose or IV. Yohimbine for xylazine reversal: mg/kg IV. Atipamezole may also be used for reversal: mg/kg IV or IM. Dexmedetomidine mg/kg IM Alpha 2 agonists such as dexmedetomidine may cause adverse pulmonary changes and hypoxemia in sheep, especially when given at high dose or IV. Atipamezole for dexmedetomidine reversal: mg/kg IV or IM. Heavy sedation Midazolam + Diazepam + Dexmedetomidine mg/kg + 4 mg/kg SC or IM mg/kg + 3 mg/kg IV to effect mg/kg + 1 mg/kg IM Alpha-2 agonists such as dexmedetomidine may cause adverse pulmonary changes and hypoxemia in sheep, especially when given at high dose or IV. Atipamezole for dexmedetomidine reversal: mg/kg IV or IM. 3

4 Anticholinergics NOT recommended as routine premedications in sheep due to potential adverse effects on GI function. If used, sheep may require high doses and/or frequent administration Induction Propofol 2-8 mg/kg IV to effect 4-10 mg/kg to effect + Diazepam mg/kg IV 4-10 mg/kg to effect + Midazolam mg/kg IV Propofol mg/kg mg/kg IV to effect Maintenance Place rumen tube to avoid ruminal tympany. During recovery from anesthesia, after rumen tube and endotracheal tube are removed, recover sheep in a sternal position. Isoflurane 0.5-3% inhaled to effect Fentanyl 5 mcg/kg IV then 5-10 mcg/kg/h (+ isoflurane to effect) CRI Propofol 5-7 mg/kg/h CRI after bolus induction Can add fentanyl CRI. Add isoflurane to effect, but may be minimized amount of isoflurane needed. Analgesics For major surgery, recommend opioid + NSAID + local anesthetic. Begin analgesia before surgical stimulus, if possible. Opioid Analgesics DRUG DOSE NOTES Buprenorphine mg/kg SC, IM, IV q 4-12 h Fentanyl patch 2-3 mcg/kg/h transdermal Place on shaved limb at least 2 hours before pain control needed. Replace at 72 hours. Do not expose to warming devices (may increase release of fentanyl from patch). NSAID Analgesics Flunixin 1-2 mg/kg SC or IV once daily, or 1 mg/kg SC or IV BID 4

5 Local Analgesics/Anesthetics NOTE: Bladder and rumen function should be monitored continuously during and after epidural procedures. PROCEDURE DRUG DOSE NOTES Bupivacaine up to 1-2 mg/kg 0.5% Bupivacaine (+/- epinephrine 5 mcg/ml) over 1-2 min Intrapleural via chest tube Intercostal 2 spaces cranial and caudal to thoracotomy site Infiltration of surgical site Bupivacaine total up to 1-2 mg/kg % Bupivacaine (+ /- epinephrine 5 mcg/ml) Bupivacaine up to 1-2 mg/kg % Bupivacaine (+/- epinephrine 5 mcg/ml) Flush with 2 ml saline; lasts 3-12 h. (If animal is conscious, intrapleural Bupivacaine can be painful and should be preceded by intrapleural lidocaine at 1 mg/kg.) 5

6 SWINE Recommended regimens For survival surgery Short Procedures with minimal potential for pain: Place fentanyl patch the night before surgery (See table for proper dosing regimen). Sedate in cage with 0.5 mg/kg midazolam and 20 mg/kg IM/SQ. Once sedation has taken effect move pig to induction area and intubate. Masking with isoflurane briefly may be necessary for intubation. Give hydromorphone ( mg/kg IV) after intubation. Maintain on isoflurane (around 2%). Use local Bupivacaine at surgical site. Meloxicam 0.2 mg/kg IV prior to incision Post op analgesia-fentanyl patch can remain in place for hours. Give meloxicam mg/kg SQ SID for 2-3 days post-op. For very painful procedures, consider adding mu opioid agonist immediately post-op, an alpha-2 agonist, ketamine/lidocaine CRI or an epidural. Sedate in cage with 0.5 mg/kg midazolam and 20 mg/kg IM/SQ. Or Midazolam 0.3 mg/kg, Dexmedetomidine 0.04 mg/kg and buprenorphine mg/kg IM/SQ. Sedation/Anesthetic Premedication Rarely used alone, alone or in combinations usually do not get pigs sedated deeply enough for intubation without supplemental anesthesia, i.e. masking with isoflurane. DRUG DOSE NOTES + Xylazine mg/kg + 2 mg/kg SQ or IM + Xylazine + Acepromazine mg/kg + 2 mg/kg mg/kg SQ or IM + Acepromazine mg/kg mg/kg SQ or IM + Midazolam mg/kg mg/kg SQ or IM + Dexmedetomidine 10 mg/kg mg/kg SQ or IM + Dexmedetomidine + Butorphanol 4-6 mg/kg SQ or IM mg/kg mg/kg 6

7 Midazolam + Dexmedetomidine + Butorphanol mg/kg SQ or IM mg/kg mg/kg May be able to intubate with this combination alone; Reversible with Atipamezole 0.1 mg/kg SQ or IM; Flumazenil 0.02 mg/kg IV or IM Midazolam mg/kg SQ or IM Dexmedetomidine mg/kg SQ or IM Telazol mg/kg SQ or IM Sedation of healthy animals only REVERSAL for midazolam can be accomplished with flumazenil (0.02 mg/kg IV or IM); if needed, reversal can be performed after short sedations with larger doses of benzodiazepines. Anticholinergics Atropine Glycopyrrolate Induction DRUG DOSE mg/kg SQ or IM mg/kg SQ or IM Isoflurane** 3-5% Propofol mg/kg IV to effect + Midazolam + Midazolam + Butorphanol 1-5 mg/kg mg/kg IV 2-5 mg/kg SQ or IM mg/kg SQ or IM mg/kg SQ or IM Subsequent to + Midazolam given as premedication For compromised CV patients prior to masking with isoflurane Sevoflurane 2.5-3% Sufentanil 7 mcg/kg IV May have effect on cardiovascular (CV) system **preferred Maintenance Isoflurane 1-3% inhaled to effect Sevoflurane 2.5-3% to effect Isoflurane + Nitrous oxide:oxygen 0.5-1% + 2:1 Compromised CV, supplement with Isoflurane 0.5% to effect; Sufentanil + Midazolam mcg/kg/hr CRI 8.3 mg/kg/hr mg/kg/hr CRI Subsequent to + Midazolam given as induction 7

8 Analgesics For major surgery, recommend opioid + NSAID + local anesthetic. Begin analgesia before surgical stimulus if possible. Fentanyl Patch <30 kg use 25 mcg patch; kg use 50 mcg patch; >50 kg use 75 mcg patch Variable absorption and efficacy; higher dosing may be necessary with age of pigs and strain differences. Apply patch day prior to surgery (ideally 24 hours prior), patch should remain in place up to 72 hours. Buprenorphine mg/kg BID SQ or IM Buprenorphine SR (Sustained Release) Zoopharm product mg/kg SQ Provides up to 3 days of moderate pain relief Hydromorphone mg/kg IV, IM, SQ Dose every 2-4 hours Dexmedetomidine mcg/kg IV Use as adjunctive analgesic if animal still painful despite opioids and NSAID Carprofen 2-3 mg/kg BID PO/SQ or IM Meloxicam mg/kg SID PO/SQ or IM Once or twice daily dosing Flunixin meglumine 1-4 mg/kg SID/BID SQ or IM Local Analgesics/Epidurals PROCEDURE DRUG DOSE NOTES Epidurals: morphine 0.1 mg/kg Lidocaine + epinephrine 4 mg/kg + 5 mcg/ml Locals: Lidocaine ± epinephrine 0.5-2% 2-5 mg/kg ± 5 mcg/ml Infiltration of surgical site: 1-2 mg/kg (± epinephrine 5 mcg/ml) Interpleural via chest tube Intercostal 2 spaces cranial and caudal to thoracotomy site Bupivacaine Bupivacaine ± epinephrine Bupivacaine ± epinephrine % 1-2 mg/kg 1-2 mg/kg 0.5% ±5 mcg/ml over 1-2 min 1-2 mg/kg 0.5% ±5 mcg/ml over 1-2 min flush with 2 ml saline; lasts 3-12 hours 8

9 NON-HUMAN PRIMATES RHESUS MACAQUES Recommended regimens For major surgery Sedate pre-operatively with Telazol. Buprenorphine mg/kg should be administered pre-operatively after intubation if buprenorphine SR is going to be used. Maintain on isoflurane throughout surgical procedure. Provide analgesia with buprenorphine SR given SQ once the animal is extubated and sternal. Meloxicam is provided for 3 to 4 days post operatively. Sedation/Anesthetic Premedication PROCEDURE DRUG DOSE NOTES Short to medium length 4mg/kg For restraint sedation: + Dexmedetomidine mg/kg IM mg/kg IM Medium length sedation: Telazol 3-5 mg/kg IM If additional time needed then dose with ketamine at 5-10 mg/kg Maintenance Isoflurane % to effect Analgesics For major surgery, recommend opioid + NSAID. Begin analgesia before surgical stimulus if possible. Opioid Analgesics DRUG DOSE NOTES Buprenorphine mg/kg BID to QID IM or SQ Buprenorphine SR mg/kg Q72 hours SQ Give once the animal is extubated and sternal. If given for a surgical procedure, a preop dose of buprenorphine mg/kg IM or SQ must be given. NSAID Analgesics Meloxicam Ketoprofen Acetaminophen 0.2mg/kg loading, 0.1mg/kg maintenance SID PO or SQ 2mg/kg SID to BID IM 6 mg/kg BID PO 9

10 MARMOSETS For major surgery Sedate pre-operatively with ketamine. Buprenorphine mg/kg should be administered close to recovery. Maintain on isoflurane throughout surgical procedure. Meloxicam is provided for 3 to 4 days post operatively and be given pre-operatively. Anesthetics Sedation/Anesthetic Premedication PROCEDURE DRUG DOSE NOTES Short to medium length sedation + Midazolam 8-10 mg/kg + 1 mg/kg IM mg/kg IM Maximum dose 25 mg per animal due to myotoxicity Maintenance Isoflurane 1-3.0% To effect Analgesics For major surgery, recommend opioid + NSAID. Begin analgesia before surgical stimulus if possible. Opioid Analgesics DRUG DOSE NOTES Buprenorphine mg/kg BID to TID IM or SQ Marmosets can be sensitive to opioids, start at the lower end of the dose range Butorphanol mg/kg IM or SQ QID May cause respiratory depression NSAID Analgesics Meloxicam: Acetaminophen 0.1mg/kg BID PO or SQ 5-10mg/kg BID to QID PO 10

11 DOGS Recommended regimens Brief sedation for non-painful procedures (e.g. stomach tubing, chest x-ray) Minor surgery or prolonged imaging procedure (e.g. MRI, wound repair, vascular access cut-down) Sedate with Dexmedetomidine 5-15 mcg/kg IM with Butorphanol mg/kg IM OR Buprenorphine mg/kg IM. Dexmedetomidine may be reversed with Atipamezole (always give by IM route; use the same volume of Atipamezole as the previously dosed Dexmedetomidine. For example: if 0.5 ml of Dexmedetomidine was given, use 0.5 ml of Atipamezole to reverse) Pre-medicate with Dexmedetomidine 5-15 mcg/kg IM AND Buprenorphine mg/kg IM. Once sedation has taken effect, induce with propofol 3-4 mg/kg, give slowly IV, only to effect. Place endotracheal tube and maintain on isoflurane (1-3% as needed to maintain anesthetic plane). Use local anesthetic Bupivicaine and/or lidocaine at surgical or vascular access site, if applicable. NSAID post-operatively if tissue manipulation or vascular access cut-down performed. Additional doses of Buprenorphine or another analgesic may be required if the animal appears painful or uncomfortable following the procedure. For major survival surgery Place fentanyl patch the evening prior to surgery. Pre-medicate with Dexmedetomidine 5-10 ug/kg IM AND Hydromorphone mg/kg IM OR Morphine mg/kg IM OR Methadone mg/kg IM. Once sedation has taken effect induce with: 5 mg/kg IV and Diazepam 0.20 mg/kg IV. Place endotracheal tube and maintain on isoflurane OR Isoflurane plus Lidocaine CRI. Use local Bupivacaine 1-2 mg/kg at surgical site (e.g. intercostals block). NSAID given intraoperatively and postoperatively. May require additional opioids post-operatively (fentanyl patch may take up to 24 hours to to reach therapeutic levels). For very painful procedures, consider adding mu opiod agonist immediately post op, an alpha-2 agonist, ketamine/lidocaine CRI or an epidural. 11

12 Sedation/Anesthetic Premedication Acepromazine Diazepam DRUG DOSE NOTES mg/kg IM or SQ mg/kg IV Midazolam: mg/kg IV Dexmedetomidine 500 mcg/m 2 IM or SQ Review insert from medication packaging for appropriate dosing Acepromazine +Butorphanol mg/kg IM or SQ mg/kg IM or SQ Acepromazine Plus ONE of the following: +Buprenorphine +Morphine +Hydromorphone +Methadone Dexmedetomidine Butorphanol Dexmedetomidine Plus ONE of the following: +Morphine +Hydromorphone +Methadone Anticholinergics mg/kg IM or SQ mg/kg IM or SQ mg/kg IM or SQ only mg/kg IM, SQ mg/kg IM 5-15 mcg/kg mg/kg IM or SQ 5-15 mcg/kg IM or SQ mg/kg mg/kg mg/kg Ace+Butorphanol preferred if additional analgesia already on board Morphine SHOULD NOT be administered IV For short procedures, imaging For procedures deemed to be more painful Atropine Glycopyrrolate Induction DRUG DOSE 0.01 mg/kg IM or SQ or IV 0.01 mg/kg IM or SQ or IV DRUG DOSE NOTES Propofol 6 mg/kg slow IV to effect (Unpremedicated animal) Propofol 3-4 mg/kg slow IV to effect (Premedicated animal) + Diazepam 5-10 mg/kg mg/kg IV Combine together in one syringe prior to administration; to effect + Midazolam 5-10 mg/kg mg/kg IV Combine together in one syringe prior to administration; to effect Isoflurane 3-5 % to effect 12

13 Maintenance Isoflurane 1-3% to effect Fentanyl 5 mcg/kg IV then 5-10 mcg/kg/h +Isoflurane to effect) CRI Propofol 5-7 mg/kg/h CRI after bolus induction Can add fentanyl CRI. +Isoflurane to effect Lidocaine (for use with isoflurane inhalant) ug/kg/min CRI after a 2.0 mg/kg loading dose When used with isoflurane, can reduce inhalant usage and/or provide analgesia for stimulating (for use with isoflurane inhalant) Dexmedetomidine (for use with isoflurane inhalant) Propofol Fentanyl Lidocaine Fentanyl Lidocaine mg/kg/hr CRI after a mg/kg loading dose ug/kg/hr CRI after a 1.0 ug/kg loading dose GIVEN SLOWLY mg/kg/min ug/kg/min Lidocaine ug/kg/min mg/kg/hr ug/kg/min Lidocaine ug/kg/min procedures When used with isoflurane, can reduce inhalant usage and/or provide analgesia for stimulating procedures; good for somatic analgesia When used with isoflurane, can reduce inhalant usage and/or provide analgesia for stimulating procedures For total intravenous anesthesia (TIVA) for a major surgical procedure For total intravenous anesthesia (TIVA) for a major surgical procedure; Recommended protocol for MRI, brain surgery, thoracotomy; orthopedic procedures Analgesics For major surgery, recommend opioid + NSAID + local anesthetic. Begin analgesia before surgical stimulus Recuvyra (transdermal fentanyl) Buprenorphine 2.7 mg/kg transdermally applied 2-4 hours prior to surgery mg/kg SQ BID-QID An alternative is to give 0.12 mg/kg oral transmuscosal over 10 minutes as premedication. This will provide analgesia for up to 24 hours. Provides 4 days of pain control Prior to induction; mild sedative and may have effect when used in combination with other agents 13

14 Buprenorphine SR (sustained release) by ZooPharm Carprofen mg/kg SQ once Provides up to 72 hours of pain control. Do not use with other opioids. May cause respiratory depression within 1 hour of administration. 4.0 mg/kg PO, SQ or IV SID Or 2.0 mg/kg BID Meloxicam 0.2 mg/kg IM, SQ or PO on first day of procedure (single administration) Ketoprofen 1-2 mg/kg IV or SQ daily for 3 days. Fentanyl patch <7 kg = 25 mcg patch; 7-20 kg = 50 mcg patch; kg= 75 mcg patch; >30 kg= 100 mcg patch Administer minutes prior to the procedure that has potential to induce pain; administer for up to 7 days Dose at 0.1 mg/kg IM, SQ, or PO daily. Place patch 6-12 hours prior to surgery. Patch remains in place for up to 72 hours postoperatively. Deracoxib 1-2mg/kg PO q 24 hrs Dexmedetomidine mcg/kg IV Use as adjunctive analgesic if animal still painful despite opioids and NSAID Local Analgesics/Anesthetics NOTE: Bladder function should be monitored continuously during and after epidural procedures. PROCEDURE DRUG DOSE NOTES Bupivacaine up to 1-2 mg/kg 0.5% (+/- epinephrine 5 mcg/ml) over 1-2 min Intrapleural via chest tube Intercostal 2 spaces cranial and caudal to thoracotomy site Infiltration of surgical site Infiltration of surgical site Epidural-lumbosacral Bupivacaine total up to 1-2 mg/kg % (+ /- epinephrine 5 mcg/ml) Bupivacaine ( %) Lidocaine (0.5-2%) Morphine (preservativefree Duramorph) +Bupivacaine or +Lidocaine up to 1-2 mg/kg (+/- epinephrine 5 mcg/ml) up to 2-5 mg/kg lidocaine (+/- epinephrine 5 mcg/ml) 0.1 mg/kg 0.1 mg/kg of 0.5% solution Flush with 2 ml saline; lasts 3-12 h For hindlimb, abdominal and thoracic surgeries; Total volume of the two drugs should NOT exceed 8-10 mg Lidocaine used for shorter procedures 14