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Anaesthetics in Ageing Mice

The effects of ageing on the anaesthetic risk in mice:

Chris Trower is the NVS at MRC Harwell and a member of the ShARM welfare group. In this article, Chris provides ShARM with a summary of the effects of ageing on the anaesthetic risks in mice.

Background

Aging is a universal process which involves degenerative changes in all organ systems and tissues. Under laboratory conditions, the house mouse (Mus musculus), has a life-span of approximately 2-3 years. In this article, the term “aged” refers to laboratory mice over 18 months of age.

General anaesthetic agents are neuro-toxic drugs that produce unconsciousness in man and animals. Their toxic effects act primarily on the central nervous system, but they also produce adverse effects in other tissues and organs, as well as affecting a number of enzyme systems.

The adverse effects of general anaesthesia in young animals are usually temporary, but in older animals, where there may be some loss of functional capacity of organs and tissues, this can affect the animal’s ability to de-toxify and eliminate the anaesthetic agent, resulting in prolonged recovery times, or even death.

Looking at the adverse effects of anaesthetic agents on:

  1. Central nervous system

The central nervous system is the target organ for all general anaesthetics, so any changes in the tissues of the CNS may directly affect the animal’s response to these agents.

Aging produces a gradual decline in the overall mass of the brain, as well as a decrease in the density of neurones and the effectiveness of neuro-transmitters. In general terms, aged mice will require less anesthetic agent than younger mice of the same bodyweight.

General anaesthetics will also increase the rate of neuronal apoptosis, which can result in post-operative cognitive impairment and lasting effects on spatial learning and memory. This effect is particularly seen in older mice if anaesthesia lasts for over 1 hour.

Recommendation: The total anaesthetic dose should always be reduced in older mice to avoid high plasma concentrations of the agent, which may cause sharp falls in blood pressure and respiratory rate (see below).

  1. Respiratory system

All anaesthetic agents depress the depth and rate of respiration. In any given period of time, this means that less air enters the lungs, and so less oxygen is available for exchange, which can lead to low oxygen saturation levels (hypoxia). In older animals, there will also be a loss of elasticity of the interstitial tissues of the lung, which can lead to the collapse of bronchioles and alveoli, further reducing the ability of the animal to exchange oxygen.

Volatile agents: These are nearly always administered using medical oxygen as a carrier gas, so mice anaesthetised using an inhalation system should remain well oxygenated throughout the procedure. However, it is strongly advised that older mice are kept on oxygen alone once the anaesthetic vapouriser has been turned off, until they recover consciousness.

Injectable agents: Mice anaesthetised using an injectable agent may well become hypoxic if they breathe only room air, which contains approximately 20% oxygen. Supplementary oxygen delivered via a nose cone is advisable to all mice under injectable anaesthesia, but is essential in older mice if hypoxia is to be avoided.

  1. Cardiovascular system

Nearly all anaesthetic agents will depress the heart rate and the cardiac output (volume pumped/minute). This decreases the speed of oxygen delivery to the tissues, which can contribute to hypoxia. Although the effects on the cardio-vasular system may not be particularly significant in young animals, they become more important with increasing age. Blood vessels also become less elastic with age, which can result in an increase in resistance and raised blood pressure.

Volatile agents: The total dose of anaesthetic agent required will be lower in older mice, but this is easily controlled when using in an inhalation system with a vapouriser.

Injectable agents: The induction of anaesthesia by intravenous or intraperitoneal injection will be slower in older mice, due to reduced cardiac output, and the total dose of anaesthetic agent required will generally be lower than in younger animals. With both methods of anaesthesia, there is an increased chance of adverse cardiac events, such as heart block, ectopic beats, arrhythmias and atrial fibrillation. All older mice should be considered at increased risk of adverse effects on the cardiovascular system.

It is advisable to use a pulse oximeter to measure the degree of oxygenation of the blood. Pulse oximeters are non-invasive, but be careful when purchasing, as many are not sensitive enough to work reliably with mice.

  1. Renal System

As ageing occurs, the kidneys become less efficient due to a loss of glomeruli from the renal cortex. In addition, the reduced cardiac output in the aged mouse will lead to a reduction in renal perfusion, which can affect the ability of the mouse to conserve fluids. This can lead to increased urination and the potential for dehydration. Because injectable anaesthetic agents are normally excreted via the kidneys, the rate of elimination may be impaired in the older mouse, leading to prolonged recovery times.

Dehydration is of particular significance when using alpha-2 agonists, such as medetomidine or xylazine, which are powerful diuretics. Fluid replacement therapy should be given as part of the peri-operative care for all older mice undergoing anaesthesia.

  1. Temperature regulation

Anaesthesia abolishes thermo-regulatory mechanisms, and this will lead to a gradual loss of core body temperature. This can be particularly important in older mice, which usually have lower basal metabolic rates and a reduced muscle mass, compared to younger animals. Body temperatures below 350C in mice are life-threatening and require urgent correction if the mouse is to survive. It is essential to monitor body temperature throughout any period of anaesthesia lasting beyond 5 minutes.

Post-anaesthesia, low body temperature may show as pilo-erection and vasoconstriction, but it will also have many other effects on blood chemistry and the cardio-vascular system, resulting in delayed recovery. Keeping mice warm is probably the single biggest factor in speeding recovery from anaesthesia.

  1. The effects of increased weight

As mice age, there is usually an increase in body mass, due to the accumulation of adipose tissue. This can have effects on many of the organ systems, but particularly the respiratory and cardiovascular systems. Obese mice will have smaller lung volumes than their size would suggest. In addition, many of the anaesthetic agents are fat-soluble, and so are taken up by the fat from the circulation. The agent may then be released back into the circulation slowly over a period of time, which can delay recovery of consciousness, and lead to very sleepy mice post-operatively. Calculation of the anaesthetic dose in obese mice can be very difficult.

Conclusions

In general, aged mice are more sensitive to anesthetic agents than younger mice. Less agent is needed to achieve the required depth of anaesthesia, and the effects are often prolonged. The two most important factors to control when anaesthetising aged mice are:

  1. The core body temperature
  2. The oxygenation of tissues

These two parameters should be maintained not only during the period of unconsciousness, but in the pre and post anaesthetic periods as well. The use of monitoring equipment, such as a digital thermometer and a pulse oximeter, will help to make sure that the aged mouse has the best chance of survival and rapid recovery from general anaesthesia.