TIVA

Total intravenous anaesthesia (TIVA) has been suggested as an alternative to inhalational anaesthesia due to the expense of anaesthetic machines and inhalation agents. The equipment required for TIVA is usually inexpensive and readily available in most veterinary practices. TIVA plays an important part in the maintenance of anaesthesia in patients that react adversely to inhalational anaesthetic agents (malignant hyperthermia) or when inhalational anaesthesia is undesirable (laryngeal and pharyngeal surgery). In the clinical practice of TIVA, an understanding of the pharmacokinetics and dynamics of the agents used is required to ensure that patient safety is maintained.

Pharmacokinetics

After the administration of a rapid bolus dose of an intravenous anaesthetic agent, plasma concentrations rise rapidly. Part of the anaesthetic agent is usually bound to plasma proteins (albumin and alpha glycoproteins). The unbound portion of the anaesthetic agents is available for transfer between compartments in the body. Due to the highly lipophilic nature of most intravenous anaesthetics and high proportion of blood flow received by the brain, brain concentration rises rapidly until unconsciousness and anaesthesia result. The intravenous anaesthetic agent diffuses into other well-perfused organ systems (muscles) rapidly. This results in a decline of plasma concentration and diffusion of the anaesthetic agent out of the brain. At this stage, the less well-perfused organ systems (fat) start to take up anaesthetic agent slowly resulting in a further decline of plasma concentration and redistribution of the anaesthetic agent from the brain and muscle groups. Recovery of consciousness occurs as a result of redistribution of the anaesthetic agent from the brain. The changes in concentration found in various organ systems are represented.

Figure 1. Changes in concentration of anaesthetic agent following the induction of anaesthesia with an intravenous agent

The role perfusion plays in the pharmacokinetics of anaesthetic agents cannot be underestimated. A dynamic perfusion results in greater redistribution of anaesthetic agents and hence a more rapid recovery and slower induction. A sluggish perfusion results in a more rapid induction and slower redistribution and a longer anaesthetic period. This may seem paradoxical, as a patient with a poor perfusion appears to take longer to be affected by the anaesthetic agent. The anaesthetic agent has to travel from the cephalic vein to the heart to the lungs back to the heart and finally up the aorta and carotid artery to the brain. Caution should be exercised in patients with poor perfusion, as one is familiar with the 30 seconds or so that it takes from administration until a marked clinical effect is seen, and therefore one tends to overdose the patient as result. When selecting a suitable agent for TIVA a number of pharmacokinetic parameters should be evaluated. The concentration at steady state is used to determine the initial bolus dose required to induce anaesthesia prior to the commencement of continuous rate infusion. The elimination half-life determines the rate at which an agent is permanently removed from the body.

In a one-compartment model, this rate can be used calculate the continuous infusion rate. Almost none of the anaesthetic agents used for TIVA follow a single compartment model. In a multicompartment model, the elimination half-life life gives us a poor indication of the expected time of recovery following the termination of an infusion. The redistribution rates between different compartments, as well as the elimination half-life determines the plasma concentration and hence the rate at which plasma concentrations decline and the rate of recovery. In order for an agent to redistribute, space must be available within the body for the agent to redistribute to. The volume of distribution gives us an indication of the quantity of agent required to saturate the peripheral compartments before recovery becomes solely dependent on the elimination half-life. This gave rise to the concept of the context sensitive half-life, which can be described as the time required after the discontinuation of an infusion for the plasma half-life to decrease by a predetermined percentage.

Thiopentone

Thiopentone is classified as a short-acting thiobarbiturate and is widely used as an induction agent in veterinary medicine. Thiopentone has a volume of distribution of 843 ± 194 ml/kg and an elimination half-life of 419.4 ± 130.8 minutes. The long elimination half-life indicates that sub-anaesthetic concentrations of thiopentone are present in the body for a considerable period after the discontinuation of the infusion. Both a 2 and 3 compartmental model have been described for thiopentone. The short initial redistribution/elimination half-life of 14.9 ± 3.3 minutes explains the rapid recovery of consciousness following a single bolus dose of thiopentone.

Propofol

Propofol has a volume of distribution of 4,863 ± 800 ml/kg and elimination half-life of approximately 100 minutes after a bolus dose. After induction and a 60 minute infusion of propofol, a volume of distribution of 6,510 ± 524 ml and elimination half-life of 322 ± 27 minutes was recorded. Propofol has an initial redistribution/elimination half-life of 2.2–18.7 minutes. The volume of distribution was shown to be smaller in greyhounds than in mixed breeds. In man, after a 3-day infusion of propofol, the elimination half-life has been recorded as 1,704 ± 660 minutes. It has been proposed that the slow return of propofol from poorly perfused compartments is responsible for the extension of half-life and presence of sub-anaesthetic concentration of propofol in the body.

A context-sensitive half-life has been used to describe the time required for a predetermined decrease in plasma concentration following the infusion of an anaesthetic agent. As peripheral compartments are saturated with an anaesthetic agent, recovery becomes more prolonged, as the body is more dependent on metabolism than redistribution. This results in an extension of the recovery time. In man, it was shown that after a 60-minute infusion of thiopentone the context sensitive half-life to 50% decrease in plasma concentration is approximately 80 minutes while that of propofol is less than 15 minutes. Similarly the context sensitive half-life of thiopentone after an 8 h infusion is approximately 200 minutes while propofol is approximately 50 minutes. From this data, it can be seen that propofol is more suited for TIVA than thiopentone. Thiopentone should not be administered for more than 60 minutes to maintain anaesthesia as recovery can be considerably delayed.

The Use of Propofol for TIVA

The clinical use of propofol for TIVA has been described since 1987. In this study, 0.3 to 0.5 mg/kg/min of propofol was infused to maintain anaesthesia. During this study, three dogs in the 0.5 mg/kg/min group developed marked arterial hypotension, and this group was discontinued. The mean induction dose of propofol was 4.89 mg/kg following premedication with acetylpromazine and atropine. In the lower infusion groups (0.3, 0.35 mg/kg/min), additional bolus doses were required to attenuate response to surgical stimuli. The depth and rate of respiration were well maintained, but hypercapnia was evident on blood gas analysis. Blood pressure was maintained. A propofol infusion (0.15 mg/kg/min) following premedication with medetomidine (0.04 mg/kg) has been shown to be an acceptable technique in beagles, with clinically acceptable changes in blood pressure, heart rate, respiratory rate and arterial partial pressure of carbon dioxide. In a surgical model, a planned propofol infusion (0.4 mg/kg/min) following premedication with acetylpromazine and papaveretum, showed acceptable changes in blood pressure, heart rate and respiratory rate. Carbon dioxide did accumulate but remained within acceptable limits.

It is recommended that propofol be administered between 0.2 to 0.4 mg/kg/min to maintain anaesthesia after adequate premedication. Acetylpromazine or a benzodiazepine in combination with an opioid is recommended. Effective premedication reduces anaesthetic requirements and results in a smoother induction and recovery from anaesthesia. In most trials the patient has been induced with propofol (4 – 6 mg/kg), and the infusion is started 60 seconds later.

The dose rate for the patient can be calculated as follows:

Dose (mg/kg/min) x body weight (kg) = dose rate (mg/min)

The quantity of propofol required for the procedure can be calculated from the formulae below:²

Dose rate (mg/min) x time (minutes) = ml of propofol 10 mg/ml

The quantity of propofol calculated is placed into a buretrol. The propofol is then diluted with a 5% dextrose water solution. Only dextrose water should be used, as it has the least effect on the emulsion formulation. This is done to ensure that the concentration of propofol does not decrease to less than 2 mg/ml, as the emulsion becomes unstable at this point in time. The concentration of propofol in the buretrol is calculated as follows:

ml of propofol x 10 mg/ml = concentration of propofol (mg/ml) final volume (Table 3)

The administration rate of propofol is calculated as follows:

Dose rate (mg/min) = drip rate (ml/min) concentration of propofol (mg/ml)

The final drip rate is then calculated by dividing the drip rate (ml/min) by 4 to obtain the drops per second for a 15 drop/ml drip set or in the case of 60 drop/ml drip set, it represents the drops/second.

The Safe Practice of TIVA

Propofol is formulated in a glycerol, egg lecithin and soybean oil as an emulsion. This formulation supports the growth of microorganisms. Propofol should always be handled aseptically to prevent contamination. Propofol should not be placed in a refrigerator to prevent bacterial growth, as the temperature destroys the emulsion. Propofol has recently been reformulated with EDTA as a preservative to prevent bacterial growth. This formulation is preferable to other formulations for this reason.

TIVA does not exonerate the anaesthetist from protecting the airway and the placement of an endotracheal tube is always advisable. Oxygen can be supplemented and ventilation assisted if required. An intravenous catheter should always be placed and left in position until the patient is fully recovered. Anaesthetic monitoring is vital, and a record of the anaesthetic and all events should be kept.

The Clinical Effects of Propofol

Propofol is renowned for causing induction apnoea. The incidence of apnoea associated with propofol is greater than that associated with thiopentone. Induction apnoea has traditionally been considered a dose-dependent phenomena. Evidence suggests that respiratory depression is dose rate dependant, with lower dose rates producing less depression. This was recently challenged.⁷

Propofol has been shown to initially increase heart rate. Blood pressure increases at low doses, but it decreases at higher doses of propofol. The changes induced by propofol in cardiovascular parameters are essentially similar to that of thiopentone.

Conclusion

Propofol can be safely used for the induction and maintenance of anaesthesia. An infusion rate of between 0.2 – 0.4 mg/kg/min is required. Recovery times are not clinically prolonged after an infusion of propofol. Cardiovascular and respiratory effects are similar to that seen with thiopentone, although induction apnoea may be more marked with propofol. The use of an infusion pump greatly aids TIVA, but satisfactory results can be obtained with a buretrol and 60 drop/ml infusion set. Caution should be exercised to prevent bacterial contamination of the propofol.

MLK Infusions

Similarly, analgesia can be provided by constant rate infusion of analgesic drugs. The MLK infusion system has become well known. In this protocol morphine, lidocaine and ketamine are infused at a constant rate. This provides excellent analgesia. The above discussion on pharmacology is relevant to the infusion of any drugs, as accumulation of these drugs can happen and result in side effects.

Ketamine is an NMDA (N-methyl-D-aspartate) antagonist. NMDA receptors are present in the dorsal horn of the spinal cord and certain areas within the brain. Intense and/or chronic noxious input to the dorsal horn cells (mediated principally by C-fibers) results in the removal of magnesium from the NMDA receptors and their activation by glutamate. This causes prolonged depolarization of spinal neurons (an increase in the magnitude and duration of neuron firing), which leads to an "amplification" of the pain response. This is a significant part of the process of central sensitization (an increase in the excitability of spinal neurons) and may result in hyperalgesia (an excessive response to a painful stimulus) and allodynia (a painful response to a normally nonpainful stimulus). It is readily apparent that blocking (antagonizing) the NMDA receptors will help to minimize excessively painful responses. Additionally, studies suggest that antagonizing these receptors improves opioid receptor sensitivity, reduces opioid tolerance and minimizes the development of rebound hyperalgesia (the phenomenon of markedly increased pain when opioids are withdrawn). Ketamine is the most commonly used antagonist of NMDA receptors in veterinary medicine. While its effects as a dissociative anesthetic at standard doses are well known, a new realm of activity occurs when it is delivered at sub-anesthetic doses. At constant rate infusion doses, ketamine blocks receptor activity without causing any dissociative or other adverse effects. It should be noted that a microdose of ketamine CRI should not be used as a sole means of analgesia. It is intended to augment other pain relievers, and should always be used in conjunction with opioids or other analgesics.

Morphine is a mu opioid agonist. A constant rate infusion results in significant analgesia. The steady-state levels of morphine help to avoid some of the "peak and valley" effects seen with intermittent administration of opioids. Additionally, its use intraoperatively serves to reduce the amount of anesthetic gas required, which can be useful in decreasing the risk of hypotension. Other opioids can be substituted for morphine, including fentanyl and buprenorphine.

Lidocaine is a local anaesthetic agents and exerts effects on sodium and calcium channels in the central nervous system. The addition of lidocaine has several benefits. For intractable/very severe pain, it adds to the analgesia and sedation. Various dosage rates of lidocaine have been advocated. In dogs, rates as low as 10 µg/kg/min (0.6 mg/kg/h) provide analgesia, though it may take up to 50 µg/kg/min (3 mg/kg/h) for the full cytoprotective and anti-ileus effects. Until further data is available, lidocaine's use in cats cannot be recommended due to the potential for toxicity, usually manifested as seizures and severe bradycardia.

CRI Dosing Information

Ketamine (100 mg/ml) - 2 to 20 µg/kg/min (0.12 to 1.2 mg/kg/h)

 An initial 0.25 to 0.50 mg/kg IV bolus is given to rapidly achieve initial therapeutic blood levels of the drug (while the CRI is intended to maintain, or very slowly, increase blood levels). Failure to administer this "loading" dose will result in an excessive delay in the drug reaching therapeutic levels.

 Ket/val inductions and Telazol inductions both provide adequate loading doses (tiletamine provides the same NMDA antagonism as ketamine).

 2 to 20 µg/kg/min = 0.002 to 0.020 mg/kg/min

Morphine (15 mg/ml) - 2 to 6 µg/kg/min (0.12 to 0.36 mg/kg/hr)

 If no previous mu agonist has been given, administer 0.5 mg/kg of morphine IM (or very slowly IV) to rapidly achieve initial therapeutic blood levels.

 Morphine is light sensitive. Make sure the syringe or IV bag is covered to protect the morphine from light when using long-term morphine CRIs.

 2 to 6 µg/kg/min = 0.002 to 0.006 mg/kg/min; Lidocaine (20 mg/ml) – 10 to 50 µg/kg/min (0.6 to 3.0 mg/kg/hr)

 An initial 1 mg/kg IV bolus is given to rapidly achieve initial therapeutic blood levels.

 Given the volume of 2% lidocaine this is, a similar volume of the diluent should be removed before any other drugs are added.

 Lidocaine is light sensitive, too. Make sure the syringe or IV bag is covered to protect the lidocaine from light when using long-term lidocaine CRIs.

 10 to 50 µg/kg/min = 0.010 to 0.050 mg/kg/min

General Information

 All three drugs are used routinely in dogs and in any combination.

 Cats - the routine use of morphine CRIs in cats is not common, but it can be an effective option if the feline patient is monitored closely for dysphoric trends. Always start at the low end of the opioid CRI dose range.

 Cats - until more data is obtained, lidocaine's use in cats cannot be recommended due to potential toxicity issues. If it is used in cats, do not exceed 10 µg/kg/min, and monitor carefully for seizure activity and cardiac abnormalities (bradycardia). 10 µg/kg/min = 0.010 mg/kg/min

 It is common to use a ketamine-only CRI bag over several patients, switching IV extension lines between patients. When morphine is added to the CRI, the bag is dedicated to that single patient. The amount of morphine drawn up and the amount unused is carefully recorded in the controlled drug logs.

 Ketamine/morphine/saline solutions have been shown to be stable for at least 4 days.

 D5W as well as other fluids are acceptable diluents.

References

References are available upon request.