humane endpoints and use of score sheets timo nevalainen university of eastern finland

Humane endpoints and use Humane endpoints and use of score sheetsof score sheets

Timo NevalainenTimo Nevalainen

University of Eastern FinlandUniversity of Eastern Finland

Humane endpoint?Humane endpoint?

The The earliest indicatorearliest indicator in an animal experiment of in an animal experiment of severe pain, severe pain, severesevere distress, suffering, or impending distress, suffering, or impending death. death. The ultimate purpose of the application of humane The ultimate purpose of the application of humane endpoints is to be able to endpoints is to be able to accurately predict severe severe pain, severe distress, suffering, or impending death, pain, severe distress, suffering, or impending death, before the animal experiences these effects. before the animal experiences these effects. These adverse conditions, once identified should be These adverse conditions, once identified should be minimised or eliminatedminimised or eliminated, either by humanely killing the , either by humanely killing the animal or, in long-term studies by (temporary) animal or, in long-term studies by (temporary) termination of exposure, or by reduction of the test termination of exposure, or by reduction of the test substance dose. substance dose.

DeathDeath

Predictable DeathPredictable Death presence of clinical signs indicative of deathpresence of clinical signs indicative of death before before

the planned end of the experiment; for example: the planned end of the experiment; for example: inability to reach water or food (CD 22)inability to reach water or food (CD 22)

Impending DeathImpending Death when when moribund state or death is expected prior to the moribund state or death is expected prior to the

next planned time of observationnext planned time of observation. Signs indicative of . Signs indicative of this state in rodents could include convulsions (CD27), this state in rodents could include convulsions (CD27), recumbency, and tremor (CD 26)recumbency, and tremor (CD 26)

MoribundMoribund being in being in state of dying or inability to survivestate of dying or inability to survive, even if , even if

treatedtreated

PainPainAcute nociceptive painAcute nociceptive pain: pain response evoked by a brief : pain response evoked by a brief noxious stimulus which produces no tissue damage. noxious stimulus which produces no tissue damage. This form of pain is not regarded as severeThis form of pain is not regarded as severe. .

Example: pedal reflexExample: pedal reflex

Persistent (chronic) inflammatory painPersistent (chronic) inflammatory pain: the pain resulting : the pain resulting from tissue damage lasting for the duration of the from tissue damage lasting for the duration of the damage or the ensuing inflammatory process, and may damage or the ensuing inflammatory process, and may persist after the local tissue damage has healed. persist after the local tissue damage has healed. This This type of pain may be severe or distressing, particularly if type of pain may be severe or distressing, particularly if long lasting or permanent. long lasting or permanent.

Example: self mutilation, localised infectionExample: self mutilation, localised infection

Neuropathic painNeuropathic pain: pain as a result of compromised : pain as a result of compromised function or abnormal activation of the peripheral or function or abnormal activation of the peripheral or central nervous system. central nervous system. Neuropathic pain is always Neuropathic pain is always considered as severe and distressing painconsidered as severe and distressing pain. .

Example: the presence of a large internal tumour that Example: the presence of a large internal tumour that compresses nerves.compresses nerves.

DistressDistress

An aversive state resulting from maladaption or inability to An aversive state resulting from maladaption or inability to adapt to stressorsadapt to stressors

Physical or behavioural alterations may be signs of stress. Acute Physical or behavioural alterations may be signs of stress. Acute stress is not regarded as a cause of distress; it may be necessary stress is not regarded as a cause of distress; it may be necessary to optimise vigilance and to reduce the risk of boredom. Distress is to optimise vigilance and to reduce the risk of boredom. Distress is usually associated with a change in motility or locomotion, and can usually associated with a change in motility or locomotion, and can result in stereotype behaviour (DC23). result in stereotype behaviour (DC23).

The major stressors associated with distress are situations The major stressors associated with distress are situations that may give rise to marked pain, fear, or anxietythat may give rise to marked pain, fear, or anxiety

Retreat to the corner of the cage or excessive struggling or Retreat to the corner of the cage or excessive struggling or vocalising on dosing are examples of distress in anticipation of an vocalising on dosing are examples of distress in anticipation of an experimental procedure.experimental procedure.

SufferingSuffering

A negative emotional state that A negative emotional state that in human beingsin human beings is produced by persistent pain and /or distress is produced by persistent pain and /or distress

It should be assumed that It should be assumed that persistent pain or persistent pain or distress in animals leads to sufferingdistress in animals leads to suffering of animals of animals

If something is known to cause suffering in If something is known to cause suffering in humans, humans, it should be assumed to cause suffering it should be assumed to cause suffering in animalsin animals

‘‘Absence of evidence is not evidence of absence’Absence of evidence is not evidence of absence’

PrinciplesPrinciples

Severe pain, suffering, or death are to be avoided as Severe pain, suffering, or death are to be avoided as endpointsendpoints

Studies must be designed to Studies must be designed to minimise any pain, distress or minimise any pain, distress or sufferingsuffering experienced by the animals, consistent with the experienced by the animals, consistent with the scientific objective of the studyscientific objective of the study

The The earliest possible endpointsearliest possible endpoints that are indicators of distress, that are indicators of distress, severe pain, or impending death that should be used as severe pain, or impending death that should be used as indications for humanely killing the animals should be indications for humanely killing the animals should be determined prior to the animals’ reaching a moribund state determined prior to the animals’ reaching a moribund state

Studies should be terminated prior to their anticipated Studies should be terminated prior to their anticipated termination time if termination time if the objectives of the study have been the objectives of the study have been satisfied, or if it is obvious that they will not be achievedsatisfied, or if it is obvious that they will not be achieved

Humane endpoints for toxicity Humane endpoints for toxicity studiesstudies

Deviations from an animal’s “Deviations from an animal’s “normal statenormal state” -> ” -> correlation of these changes with the correlation of these changes with the possibility and severity of pain and distresspossibility and severity of pain and distress

observations to detect abnormal signs and observations to detect abnormal signs and conditions (behaviour, physiology, etc.), and other conditions (behaviour, physiology, etc.), and other indicators of welfare problems indicators of welfare problems

whether such observations are indicators of pain whether such observations are indicators of pain and distress, and whether pain and distress are and distress, and whether pain and distress are severesevere

whether abnormal conditions not necessarily whether abnormal conditions not necessarily considered to be indicative of severe pain and/or considered to be indicative of severe pain and/or distress, are indicative of an irreversible condition distress, are indicative of an irreversible condition likely to lead to further deterioration (e.g., moribund likely to lead to further deterioration (e.g., moribund condition; impending death; inability to eat or drink) condition; impending death; inability to eat or drink)

Signs for impending deathSigns for impending death

prolonged, impaired ambulation prolonged, impaired ambulation preventing the animal from preventing the animal from reaching food or water, or reaching food or water, or prolonged anorexiaprolonged anorexiaexcessive weight loss and/or excessive weight loss and/or extreme emaciation and/or extreme emaciation and/or severe dehydrationsevere dehydrationsignificant blood losssignificant blood lossevidence to suggest irreversible evidence to suggest irreversible organ failureorgan failureprolonged absence of voluntary prolonged absence of voluntary responses to external stimuliresponses to external stimuli

persistent, difficult laboured persistent, difficult laboured breathing (CD13)breathing (CD13)prolonged inability to remain prolonged inability to remain uprightuprightpersistent convulsions (CD28)persistent convulsions (CD28)self-mutilationself-mutilationprolonged diarrhoeaprolonged diarrhoeasignificant and sustained significant and sustained decrease in body temperature decrease in body temperature substantial tumourssubstantial tumoursother treatment-related effects other treatment-related effects judged to be indicative of judged to be indicative of impending deathimpending death

Signs for pain and distressSigns for pain and distressLook for changes in Look for changes in

physical appearancephysical appearance (e.g., coat texture; hair soiled (e.g., coat texture; hair soiled with urine or faeces, CD 11)with urine or faeces, CD 11)

clinical signsclinical signs (e.g., respiration rate; posture) (e.g., respiration rate; posture) unprovoked behaviourunprovoked behaviour (e.g., self mutilation; (e.g., self mutilation;

compulsive behaviour)compulsive behaviour) response to external stimuliresponse to external stimuli (e.g., excitability; (e.g., excitability;

righting reflex, CD24)righting reflex, CD24) body weightbody weight, and related changes in food and water , and related changes in food and water

consumptionconsumption clinical parametersclinical parameters (e.g., body temperature; heart (e.g., body temperature; heart

and respiration rate; clinical chemistry and and respiration rate; clinical chemistry and haematology)haematology)

Signs for Signs for severesevere pain and distress pain and distress

abnormal vocalisationabnormal vocalisationabnormal abnormal aggressiveness aggressiveness abnormal postureabnormal postureabnormal reaction to abnormal reaction to handling handling abnormal movements abnormal movements self-induced traumaself-induced traumaopen wounds or skin open wounds or skin ulceration ulceration difficulties in respiration difficulties in respiration

corneal ulceration corneal ulceration bone fractures bone fractures reluctance to move reluctance to move abnormal external abnormal external appearance appearance rapid weight loss or rapid weight loss or emaciation or severe emaciation or severe dehydrationdehydrationsignificant bleeding significant bleeding or any other factor that or any other factor that suggests that the animal suggests that the animal may be in pain or distressmay be in pain or distress

Scoring systemsScoring systems

Impossible to have general scoring sheetImpossible to have general scoring sheet Predicable outcomes are differentPredicable outcomes are different

Sheets must beSheets must be Procedure specificProcedure specific Species/strain specificSpecies/strain specific

Pilot studies needed toPilot studies needed to Identify cardinal signsIdentify cardinal signs

measurable (analogue)measurable (analogue)

qualitative (binary)qualitative (binary)

Jones et al. 1999

CD14

Jones et al. 1999

Example: Rabies vaccine trialExample: Rabies vaccine trial

Cussler et al. 1999

Cussler et al. 1999

Rabies trial conclusionsRabies trial conclusions

Animals scoring 2 never recoveredAnimals scoring 2 never recoveredBody weight Body weight showed an early decrease before clinical showed an early decrease before clinical

signssigns up to 30-40% by time of deathup to 30-40% by time of death

Establishment of humane endpointEstablishment of humane endpoint A decrease of body weight > 15% withA decrease of body weight > 15% with Clinical signs of neurological disorderClinical signs of neurological disorder -> shortened the experiment by 3 days-> shortened the experiment by 3 days

humane endpoints and use of score sheets timo nevalainen university of eastern finland

Documents

pain acute nociceptive

distressing pain

severe distress

pain response

type of pain

form of pain

impending death

treated slide