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Benzodiazepines - can they help reduce anaesthesia related side effects?

BACKGROUND 

Benzodiazepines (BDZ) have been used regularly since the 1960s as anticonvulsants and as part of a balanced approach to anaesthesia.  The group of drugs are particularly useful in the more critical cases, and have several advantages over the more commonly used sedatives for this group of patients.

BDZ all have a similar basic chemical structure: a benzene ring joined with a diazepine ring.  Minor changes to the basic structure can have significant effects on the pharmacokinetics of the individual drug1


MODE OF ACTION 

BDZ act mainly at the post-synaptic gamma amino butyric acid-A (GABAA) receptors of the cerebral cortex, with some activity in the cerebellar cortex, hypothalamus, thalamus & limbic system1

The BDZ augment the effects of GABA at the GABAA receptor2 by increasing the influx of chloride ions, with resultant hyperpolarisation and depression of neuronal transmission2,3,4,5.  This mainly results in anxiolysis, sedation and hypnosis, although in the healthy animal disinhibition (excitement, aggression) is frequently seen, and this class of drugs is not routinely used in such patients1,2,5,6.  

BDZ act at a different location on the GABAA receptor to other CNS depressants e.g. alfaxalone, propofol, ethanol3

All BDZ are highly lipid soluble and readily cross the blood-brain barrier. The highly lipophilic nature of the BDZ can result in redistribution to fatty tissues and a short duration of action1.  This is of relevance in obese patients where there is a higher volume of distribution, and shorter duration of action, than in lean animals4.  Midazolam is more lipid soluble than diazepam and has a duration of action of 1-4 hours in dogs, compared to 4-12 hours for diazepam6

BDZ are highly protein bound2,3,6,7


METABOLISM

Both midazolam and diazepam undergo initial oxidation followed by conjugation via the cytochrome P450 system in the liver1

Diazepam is metabolised to N-desmethyldiazepam1,2,4, oxazepam & temazepam. All have some degree of clinical activity. Conjugation (glucuronidation) and subsequent excretion occur via urine and bile2,6. The active metabolites of diazepam have the potential for entero-hepatic recycling and accumulation6

Midazolam is hydroxylated to 4-hydroxymidazolam which has minimal clinical activity1.

Accumulation of BDZ metabolites can also occur in animals experiencing renal failure4, and juveniles, geriatrics and liver disease patients may experience increases in elimination half-life with resultant prolonged activity1


GENERAL CLINICAL EFFECTS 

Anxiolysis1,3,4,5
Sedation1,3,4
Hypnosis1,3,4
Retrograde amnesia1,3,4
Anticonvulsant1,4,5
Muscle relaxation1,3,4,5
Minimal cardiovascular effects (at clinical doses)5
Minimal respiratory effects (at clinical doses)5
Appetite stimulation in cats7
Not analgesic7

Cardiovascular effects 

At clinical doses and when administered intravenously (IV) BDZ have only minor effects on the cardiovascular system. Slight reductions in systemic vascular resistance, preload, cardiac output and blood pressure may be occasionally observed, but are well tolerated in healthy patients1.   

Respiratory effects 

At clinical doses BDZ usually have minimal effects on the respiratory system. Minor reductions in tidal volume and a mild increase in respiratory rate may be observed. However, if combined with other CNS depressants, and/or used at doses >0.2mg/kg (for both midazolam and diazepam), there may be an exacerbation of respiratory depression with a reduced ventilatory response to carbon dioxide and a slight relaxation of the intercostal muscles1,6

Muscle tone 

Muscle tone is reduced via the effects of the BDZ on dorsal horn of the spinal cord1


BENZODIAZEPINES IN THE HEALTHY PATIENT 

There is a marked difference in individual sensitivity to BDZs, particularly in healthy patients, and maximum effects may not be seen for several minutes following IV administration3

In healthy patients disinhibition, or paradoxical excitement, is commonly observed rather than anxiolysis/sedation3,8, and previously calm animals can become aggressive5,6.  Although these effects may be masked by administering BDZ together with an opioid, they are not fully eliminated and excitement can still occur5.  For this reason, BDZ are not routinely used in healthy patients for premedication or sedation5,6

Animals with a higher American Society of Anaesthesiaologists (ASA) Physical Status Classification (III or above) are more likely to be sedated following BDZ administration, with excitement being rarely seen3,5.  BDZ are useful for critically ill patients as there is minimal cardiovascular or respiratory depression at clinical doses5.  


MIDAZOLAM 

The structure of midazolam, and its water solubility, are pH dependent: at a low pH the diazepine ring in midazolam is ionised and open producing a water-soluble formulation1,2,6.  If the surrounding pH exceeds 4 the diazepine ring closes, is no longer ionised, and the midazolam becomes lipid soluble and hydrophobic2,3,4,5.  Therefore, when administered intravenously in its water soluble, open ring, form the midazolam is subjected to a plasma pH of approximately 7.4 and the ring closes.  This produces the lipid soluble structure allowing it to cross the blood-brain barrier1. Midazolam is 95% protein bound1

As midazolam is water soluble it causes minimal pain on injection2,3,5, and is not associated with thrombophlebitis. It may be administered intramuscularly5.  

The elimination half-life of midazolam is 77-98 mins in the dog3.  It is more rapidly acting, more potent and more readily redistributed than diazepam1,4,5. Additionally, it has a shorter duration of action than diazepam (1-4 hours for midazolam compared to 4-12 hours for diazepam).   The less active metabolites of midazolam make it more suitable for infusions6

Midazolam is commonly used in animals assessed to be ASA Physical Status III or greater, or as a co-induction agent with alfaxalone, opioids, ketamine or propofol3

At doses > 0.2mg/kg midazolam may produce peripheral vasoconstriction and negative inotropy with resultant hypotension and a slight increase in heart rate6

Midazolam has powerful amnesic properties2

The only formulation registered in the United Kingdom is licenced for use in horses. 


DIAZEPAM

Diazepam is hydrophobic with a high lipid solubility1,2,7 and is 95% protein bound2.  Commercial formulations of diazepam are either solubilised in propylene glycol plus ethanol1,5, or in a soya bean lipid emulsion1.  Both formulations of diazepam are poorly absorbed when given intramuscularly (IM), and are painful, therefore use should be restricted to intravenous administration5,6,7

Intravenous administration of the aqueous formulation of diazepam can cause pain and thrombophlebitis3,5 and, additionally, the propylene glycol in the aqueous formulation has been implicated in the development of cardiac arrhythmias, hypotension and heamolysis6. In cats, prolonged or repeated intravenous administration of propylene glycol has been reported to cause cardiovascular depression, and therefore midazolam is the BDZ of choice for cats7

Intravenous administration of the lipid emulsion formulation of diazepam is non-irritant and less painful than the aqueous product, therefore, in the majority of patients the emulsion is the preferred product5

Diazepam has a slower onset of action than midazolam and a longer duration of action (4-12 hours for diazepam compared to 1-4 hours for midazolam)6.  The plasma elimination half-life of diazepam is 3.2 hours in the dog3, with an even longer half-life for the active metabolite desmethyldiazepam3,4

In cats diazepam inhibits bile acid efflux resulting in bile acid accumulation in the hepatocytes. Repeated or prolonged administration may therefore contribute to feline liver injury7

Diazepam adheres to some plastics, possibly including syringes & giving sets, so injections should be prepared & immediately administered6

2 formulations are registered in the UK for cats and dogs, both 5mg/ml. 


FLUMAZENIL (antagonist)

Like midazolam, flumazenil is an imidazobenzodiazepine. Flumazenil is a competitive, potent and selective BDZ receptor antagonist1,3,4. It is 40-50% protein bound and is readily redistributed1. Flumazenil is rapidly acting, demonstrating clinical effects within 2 minutes of administration2, although the duration of action is shorter than either diazepam or midazolam. Therefore, close observation of the patient is required as the clinical effects of midazolam or diazepam can re-emerge, and supplementary doses of flumazenil may be required1,2


USES OF BENZODIAZEPINES

Sedation & anaesthesia 

BDZ are commonly used in anaesthesia for sedation, premedication2, and co-induction. The aim of co-induction is to reduce the dose of other CNS depressants, therefore minimising the potentially unwanted side-effects of the induction and maintenance agents3,4.  However, it should be remembered that in fit, healthy animals BDZ alone may not result in sedation and may in fact, cause disinhibition and excitement or aggression.  BDZ alone cannot induce anaesthesia in healthy animals and should be used in combination with other CNS depressants e.g. alfaxalone9,10

The main use of BDZ is part of a multimodal approach to anaesthesia3

a. Sedation/premedication 

BDZ may be used as a sole anxiolytic agent for severely debilitated, paediatric or geriatric patients6. The dose of either midazolam of diazepam for these patients is 0.1-0.25mg/kg IV6 starting with the lowest dose.

BDZ, in combination with an opioid, are suitable for premedication of debilitated patients in the ASA III and above category or for paediatric/geriatric animals5,6,11.

Several techniques are described: 

  • Premedication with opioid followed by BDZ co-induction of anaesthesia

Premedication with an opioid administered intramuscularly and allow a suitable period of time to reach peak effect.

The BDZ, midazolam or diazepam, is administered by slow intravenous injection immediately followed by the IV induction agent, to effect.  This will allow a reduced dose of induction agent.

The induction agent should be administered immediately following the BDZ as, if too much time is allowed to elapse, excitement may occur.

This protocol is not ideally suited to difficult patients as the opioid premedicant may not provide a suitable degree of sedation5.

Suggested BDZ doses are 0.2-0.5mg/kg5,7.

  • Opioid + BDZ premedication followed by induction agent

Premedication with an opioid plus BDZ and sufficient time allowed for the drugs to reach peak effect.

Induction as normal with a the same degree of dose sparing as one would expect from the use of acepromazine as a premedicant.

In healthy patients this protocol produces unpredictable results: the level of sedation following opioid + BDZ premedication ranging from none to profound5.

In the sicker patient sedation tends to be more reliable and predictable5.

Suggested BDZ doses vary:

Midazolam IM 0.2mg/kg from plus an opioid IM5
BDZ 0.1-0.25mg/kg IV plus an opioid6;
Midazolam 0.3-0.4mg/kg plus opioid IM or IV12.

  • BDZ plus opioid co-administration for induction

In poor anaesthetic risk patients it may be possible to induce anaesthesia with a co-administered opioid and BDZ.

This type of protocol results in good cardiovascular stability, but should be reserved for the sicker patient3,5,13.

If the BDZ/opioid combination fails to achieve stage III anaesthesia it will still have produced a significant dose sparing effect on the actual induction agent with a resultant reduction in cardiorespiratory side-effects5.

BDZ are not induction agents and the opioid/BDZ combination is rarely effective for induction of anaesthesia in the healthy patient5.

  • Severely debilitated animals 

 BDZ alone may be sufficient to provide anxiolysis/sedation in these patients6.

b. BDZ with ketamine 

BDZ may reduce hallucinations when used prior to, or in combination with, dissociative anaesthetics e.g. ketamine3. Midazolam (usually) may also be used in combo with ketamine to offset muscle rigidity produced by the ketamine and to improve CNS depression5.

Suggested BDZ doses are: 0.1-0.25mg/kg IV6

c. Reducing restlessness during anaesthetic recovery or for intensive care patients 

Midazolam or diazepam are useful for reducing restlessness during anaesthetic recovery (0.25-0.4mg/kg IV) but respiratory depression can occur6

Midazolam is the preferred drug of many anaesthetists for the critical care patient: It is water soluble, has a short duration of action and a short elimination half-life11

Midazolam may be administered to reduce anxiety and restlessness in intensive care patients: Provided adequate analgesia has been administered and the patient checked to ensure the bladder is empty 6, small doses of BDZ (0.1-0.2mg/kg5) will assist in calming distressed patients. Midazolam infusions can be titrated to effect8 and will provide longer term sedation (0.2mg/kg/hour IV5).  It should be noted however, that long-term infusions may result in dysphoria although this can be treated with the antagonist flumazenil 


Appetite stimulation 

In cats small doses of intravenous diazepam (0.4mg/kg) administered every 24 hours have been used for the management of anorexia. Although the mode of action is unclear5 it may be related to increased attraction to tastes11. If used for this indication food should be readily available following administration as the response will occur in seconds8. Cats treated with diazepam should be closely observed and the food/water removed immediately sedation occurs to avoid aspiration. 


Blocked cats 

Urethral relaxation following intravenous BDZ may be useful for “blocked cats” (0.5-1mg/kg IV)6


Treatment of convulsions/status epilepticus. 

For the initial treatment of convulsions up to 0.5mg/kg of midazolam or diazepam may be administered IV and repeated every 10 mins for up to 3 doses. If an infusion is necessary midazolam is the better choice as it does not adhere to plastics (diazepam in both aqueous & emulsion version can adhere to plastics), is less cumulative, and has a low risk of thrombophlebitis6.  Suggested midazolam infusion rate: 0.4µg/kg/min IV6.


Get your copy of the downloadable Benzodiazepines Summary & Suggested Dose Table here

Article by
Dr. Karen Heskin
BVSc CertSAO MRCVS

Veterinary Technical Manager, Jurox UK

Originally published: Thursday, 29th November 2018

References

  1. Smith T, Pinnock C, Lin T & Jones R (2009). Fundamental of anaesthesia, 3rd edition. Cambridge University Press.
  2. Peck T, Hills S & Williams M (2008). Pharmacology and Anaesthesia for Intensive Care, 3rd edition. Cambridge University Press.
  3. Clarke KW, Trim CM, Hall LW (2014). Veterinary Anaesthesia, 11th edition. Saunders Elsevier.
  4. Hemmings HC & Hopkins PM (2005). Foundations of Anaesthesia. Basic Sciences for Clinical Practice. Elsevier
  5. Welsh L (2009). Anaesthesia for Veterinary Nurses. Wiley & Sons
  6. Dugdale A (2010). Veterinary Anaesthesia: Principles to Practice. Blackwell Publishing Ltd.
  7. Steagal P, Robertson S & Taylor P (2018). Feline Anaesthesia and Pain Management. Wiley Blackwell.
  8. Covey-Crump GL & Murrison PJ (2008). Fentanyl or midazolam for co-induction of anaesthesia with propofol in dogs. Veterinary Anaesthesia and Analgesia, 35, 463-472
  9. Italiano M & Robinson R (2018). Effect of benzodiazepines on the dose of alfaxalone needed for endotracheal intubation in healthy dogs. Veterinary anaesthesia and Analgesia, 45, 720-728
  10. Zapata A, Laredo FG, Escobar M, Agut A, Soler M & Belda E (2018). Effects of midazolam before or after alfaxalone for co-induction of anaesthesia in healthy dogs. Veterinary Anaesthesia and Analgesia, 45, 609-617
  11. Silverstein DC & Hopper K (2015). Small Animal Critical Care Medicine, Saunders Elsevier
  12. Duke-Novakovski T, de Vries M & Seymour C (2016). BSAVA Manual of Canine and Feline Anaesthesia and Analgesia.
  13. Psatha E, Alibhai HIK, Jiminez-Lozano A, Armitage-Chan E & Broadbelt DC (2011). Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are poor anaesthetic risk. Veterinary Anesthesia and Analgesia, 38, 24-36

 

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