Yale University Policy & Guidelines for the Use of Neuromuscular Blocking Agents

Background:

• The Guide for the Care and Use of Laboratory Animals (Guide) states that neuromuscular blocking drugs do not provide relief from pain. It is recommended that prior to the use of paralytic agents, the appropriate amount of anesthetic be established for the procedure using the anesthetic of choice without a blocking agent.
• According to the U.S. Government Principles, procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia or anesthesia. Surgical or other painful procedures should not be performed on un-anesthetized animals paralyzed by chemical agents.
• Animal Welfare Regulations states that procedures that may cause more than momentary or slight pain or distress to the animals will not include the use of neuromuscular blocking agents without anesthesia.

Policy:

• Neuromuscular blocking drugs paralyze skeletal muscles but they do not produce analgesia or loss of consciousness. Procedures that may cause more than momentary or slight pain or distress to the animals may not include the use of paralytics without anesthesia. Due to the inherent difficulties in assessing the level of surgical anesthesia in paralyzed animals, the use of these drugs will be approved only if it is clearly established that:
1. neuromuscular blockers are essential for the proposed research, and
2. that the investigator is able to monitor the animals appropriate for signs of pain and distress and prepare to take the necessary steps to ensure the animal remains unconscious during the period of paralysis.
• The use of neuromuscular blocking agents may be approved for research procedures where scientific justification is provided for paralysis of the animal. Proposed use will be reviewed by the IACUC on a case-by-case basis.

Guidelines: The following requirements are necessary during procedures using neuromuscular blocking agents:

1. A surgical plane of anesthesia must be established and verified and the animal intubated prior to administration of the neuromuscular blocking drug. A fixed anesthetic level, with the animal not exhibiting any changes in physiological state, must be well established prior to beginning the administration of paralytic drugs, to ensure that the animal is at a stable plane of anesthesia. This period should also be used to establish and validate the physiological signs that will be monitored under paralysis to document that the animal is being maintained in a suitable condition.
2. A surgical plane of anesthesia must be maintained during the entire time that the neuromuscular blocking drug is present and effective.
3. Use of neuromuscular blocking agents should be confined solely to that phase of the procedure for which they are indicated.
4. Controlled ventilation must be initiated prior to the administration of the neuromuscular blocking drug.
5. During the period of paralysis, multiple physiologic indicators of pain and stress must be monitored at a minimum every 15 minutes as appropriate to the species and recorded on the intra-operative record (e.g., heart rate, blood pressure). An increase of >20% in any one or combination of monitored parameters without other explanations, indicates a pain/stress response. If noted, anesthetic levels should be deepened.
6. Monitoring of electroencephalography (EEG) may also be helpful. However, the normal EEG appearance differs with different types of anesthetics, and confirmation of an anesthetized state may not always be possible based on the EEG. Therefore, the investigator should be thoroughly familiar with the expected EEG pattern for the particular anesthetic used.
7. Core temperature and fluid balance must be maintained within normal levels during the period of paralysis. If animals will be paralyzed for long periods of time (e.g. greater than 4 hours) provision must be made for periodic voiding of the urinary bladder.
8. The details on the specific physiologic measures to be monitored and the frequency and means of documentation will be determined on a case-by-case basis. The use of automated monitoring devices cannot substitute for direct monitoring of the animal by a human observer, and a human observer should be present at all times any procedures using neuromuscular blocking agents, as the clinical status of the animal can change quickly and require intervention.
9. Care should be taken to ensure that the animal has recovered control of respiration and locomotion before it is returned to the home cage.
10. Monitoring data should be filed by experiment and animal and kept for at least the duration of the overall protocol.
11. Prior to using neuromuscular blocking drugs in a procedure, investigators may be requested by the IACUC to demonstrate to a VCS veterinarian that the proposed procedure may be performed in the absence of the paralyzing drug. This will assure that the anesthetic technique is sufficient to prevent pain and distress associated with the procedure, and to confirm that escape behavior does not occur in the absence of the neuromuscular blocking agent.

References:

1. NRC. (1996) Guide for the Care and Use of Laboratory Animals, Washington, DC: National Academy Press.
2. Appendix D: PHS Policy and Government Principles Regarding the Care and Use of Animals. Animal Welfare Regulations: USDA 9CFR, 2.31 Section D:IV:C; NRC 1992.
3. NRC. (2003). Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research. Washington, DC: National Academy Press.
4. NIH (1991) Preparation and Maintenance of Higher Mammal During Neuroscience Experiments: Report of a National Institutes of Health Workshop. Bethesda, MD: NIH/National Eye Institute.
5. Drummond JC, Todd MM, Saidman LJ. (1996) Use of neuromuscular blocking drugs in scientific investigations involving animal subjects: The benefit of the doubt goes to the animal. Anesthesiology. 85: 697-699.
6. Marsch SCU, Studer W. (1999) Guidelines for the use of laboratory animals: what about neuromuscular blocking agents? Cardiovascular Research 42: 565-566.
7. Mason DE and Brown MI. (1997) Monitoring of anesthesia. D.F.Kohn, S.K. Wixson, WJ White, GJ Benson (eds), Anesthesia and Analgesia in Laboratory Animals. San Diego: Academic Press.

APPROVED BY THE IACUC: 5/19/04

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Last Modified: May 19, 2004

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