The concept of “balanced anaesthesia” has been known for a long time. It consists of a single drug or a combination of drugs providing the different parts of anaesthesia, such as hypnosis, analgesia and muscle relaxation¹. The best anaesthetic protocol reduces the risk to the patient and achieves the end points required to complete the proposed procedure.

Total IV anaesthesia (TIVA) is the administration of combinations of IV anaesthetic and analgesic drugs to maintain anaesthesia. The first TIVA was documented in dogs in 1656².

Partial IV anaesthesia (PIVA) allows use of lower dose of the primary general anaesthetic and limits potentially harmful side effects, yet still provides good-quality anaesthesia³.

Infusion of drugs can also reduce the inspired concentration of inhaled agents. These techniques are applied to many veterinary and medical situations¹, and drug choice must be matched to patient health status to allow completion of the procedure, and maintain patient safety.

Why should we consider introducing these techniques in our daily practice?

Good analgesia and stable anaesthesia

Meeting all criteria of general anaesthesia by using a single anaesthetic may expose the patient to additional risks associated with the adverse effects of that drug. For example, increasing an inhalant agent concentration will result in physiologic changes in a dose-dependent manner¹.

They are characterised as myocardial depression, vasodilation, hypotension and hypoventilation. Isoflurane and sevoflurane have vasodilatory properties, negatively impact cardiac contractility and result in hypotension, and may result in harm¹.

On the other hand, the anaesthetic-sparing effects of the anaesthetic/analgesic infusions can reduce the inspired concentration of the volatile agent and, therefore, reduce its detrimental haemodynamic effects⁴. Therefore, PIVA and TIVA techniques provide superior haemodynamic stability^5,6 and potent volatile anaesthetic-sparing capability.

Many drugs can be chosen, and their benefits change depending on the species: studies have shown that morphine, lidocaine and ketamine infusions reduce isoflurane requirements by 48%, 29% and 25%, respectively, in dogs⁷. Moreover, in highly debilitated patients or those with a severely painful condition, PIVA/TIVA can be used for more marked anaesthetic-sparing effects¹.

These techniques provide a more stable plasma concentration, and an accurate level of anaesthesia and analgesia throughout the procedure. Adding supplemental analgesia to inhalant anaesthesia results in a better quality of pain control and improves safety by reducing inhalation drug dose¹.

The infusion can be stopped at the end of the anaesthetic period or even continued into the recovery phase.

Smoother recovery

Recovery may be smoother. Drugs can be continued and gradually decreased into the postoperative phase for both sedation and analgesia, allowing more control and a quieter emergence from general anaesthesia into recovery¹.

No facilities

Where no facilities exist for inhalational anaesthesia (in some rural spay/neuter programmes or critical care patients under ventilator support), TIVA is commonly used for anaesthesia^8,9.

Avoid accidental overdose of volatile agent

An unnecessary increase in volatile agent concentration may occur and enhance the risk of overdosage when the clinician is uncomfortable with reducing vaporiser settings from more familiar levels¹.

Greenhouse gas impact

When TIVA is used, personnel exposure and environmental pollution risks from the inhalant agent are reduced to zero. Isoflurane, sevoflurane and desflurane are substituted halogenated hydrocarbons, which are environmentally harmful and potentially dangerous to personnel.

By decreasing patient, veterinary personnel and environmental exposure, anaesthesia is successfully administered with a greener outcome¹⁰.

Human medicine

Over the past two decades, changes in human anaesthesia practice have occurred to improve the quality of anaesthesia and patient experience¹⁰. The first objective is to decrease anaesthesia recovery time and speed discharge. The second is to decrease post-anaesthesia nausea and vomiting, and the last is to decrease postoperative opioid use due to addiction concerns.

Human research has shown that anaesthesia associated with PIVA/TIVA has equivalent or better recovery time post-anaesthesia analgesia, and reduces the incidence of post-anaesthesia nausea and vomiting^11,12.

What are their disadvantages?

As with other anaesthesia techniques, disadvantages may exist to using PIVA or TIVA in daily practice¹⁰. Respiratory depression can be noticeable with TIVA and even exacerbated by the additional use of inhalant agents (PIVA)¹. Therefore, ventilatory support may be required.

Close patient monitoring is required during the postoperative phase to identify potential loss of airway reflexes and excessive sedation. During TIVA administration, a breathing system and anaesthetic machine should be used for patient respiratory support, oxygen delivery and carbon dioxide removal¹⁰.

Other potential disadvantages of TIVA/PIVA are personal training to assess patient responses, concern regarding complexity versus inhalation agents and familiarity with equipment. An initial barrier may also exist in requiring a comfort level with drug calculations and infusion rates^1,10. In addition, using PIVA alongside inhalational anaesthesia may be more costly and challenging than potential benefits^1,10.

Application of TIVA/PIVA

To maintain an effective receptor occupation and a desired effect, an infusion needs to reach the drug’s plasma concentration.

Although it seems simple, it may be challenging to achieve this because the compartmental redistribution, the biotransformation and the drug clearance are different, and specified for each drug. The best match is to achieve the steady-state plasma concentration of a drug – with its redistribution, biotransformation and clearance – for the duration of the general anaesthesia^10,13.

The time it takes to achieve peak effect is called “effect-site equilibrium”. An IV bolus of the drugs increases the plasma concentration and allows rapid delivery to the site of action.

In human medicine, advanced techniques and algorithms have been studied and developed into delivery systems (computers, syringe pumps) for controlling drug delivery, and achieving a faster and steady state¹⁴. In veterinary medicine, this discovery of information is only just the beginning^15,16.

A fundamental strategic goal in formulating TIVA/PIVA protocols is to combine drugs for an effect greater than each alone – this is called “synergism”¹⁰.

One to three drugs are usually selected along with a volatile agent: mu-opioid agonists are always chosen for their analgesia properties with haemodynamic stability; alpha-2 adrenergic agonists for sedation and analgesia, lidocaine for its anti-inflammatory effects, ketamine for its sound analgesic effects with modulation of central sensitisation processes, benzodiazepines for haemodynamic stability, and injectable anaesthetic drugs for haemodynamic stability and anaesthetic-sparing effects¹.

Drugs used for PIVA/TIVA

Propofol

Propofol has been widely studied as part of TIVA and suggested for PIVA techniques^17,18. A sub-anaesthetic infusion rate can also be used alongside inhalant anaesthetic.

Its flexibility in dosage produces a range of responses ranging from light to profound sedation with good muscle relaxation. It is rapidly and consistently metabolised, resulting in a short in vivo half-life after a single dose or a prolonged constant rate infusion (CRI) administration, still resulting in a rapid recovery after drug discontinuation.

The evaluation of anaesthetic depth by eye reflexes and position changes are similar between propofol and the inhalant agent. For these reasons, propofol is a human and veterinary foundation drug^19,20, and is an “ideal TIVA/PIVA drug”. However, it can accumulate in cats because propofol glucuronidation occurs slower. Therefore, prolonged recoveries might occur in cats and a gradual decrease in propofol rate is required²¹.

Alfaxalone

Alfaxalone is a steroid-based injectable anaesthetic for use in cats and dogs, and has the same mechanism of action as propofol and thiopental. It shares many qualities described for propofol and has similar pharmacokinetics.

Reports of the use of alfaxalone have been published for TIVA^22-24. Delayed recovery has been observed in cats when alfaxalone TIVA is used; although, this might have been due to concurrently administered drugs²⁵. Nevertheless, alfaxalone shows promise for TIVA, and its safe use for PIVA requires thorough evaluation in cats.

Opioids

Opioids are often given in combinations at premedication, and are ideal for intraoperative analgesia and complementary inhalational anaesthesia. Their activity is prolonged intraoperatively by infusions.

Opioids with high activity at the mu-opioid receptor have an anaesthetic-sparing effect. In dogs, mu-opioid agonists can decrease the concentration of inhaled agents required, by as much as 50% to 60%, for maintaining a surgical plane of anaesthesia^1,7,26.

“The opioids commonly used for infusions in veterinary anaesthesia include morphine, hydromorphone, fentanyl, sufentanil, and remifentanil”¹. After an initial loading dose, they share the characteristic of producing a rapid effect and maintaining a steady-state plasma level.

The most commonly used opioid in veterinary TIVA is fentanyl. However, a time delay in developing a steady-state plasma concentration has been observed in studies evaluating in vivo pharmacokinetic-pharmacodynamic (PK-PD) characteristics, after CRI administration of up to 180 to 240 minutes. It is, therefore, necessary to administer a loading dose to reach the steady state faster^1,10.

A “ceiling effect” also exists where higher-dose rates do not decrease volatile agent requirement further²⁷.

In cats, the anaesthetic-sparing effect, with the same mu-opioid agonists, is less pronounced: a 15% to 20% reduction in inhaled anaesthetic requirement is observed²⁸.

Mu-opioid agonist infusions provide good haemodynamic stability, but may induce bradycardia, resulting from the increased vagal tone, and may require anticholinergics to correct. Mu-opioid agonists also have respiratory depressant effects, and ventilation support may be required.

Ketamine

Ketamine is a dissociative anaesthetic drug, and its use is widespread both intraoperatively and postoperatively for its analgesic properties²⁹. Its analgesic property is due to inhibition of the N-methyl D-aspartate (NMDA) receptor, which enhances pain transmission, activated by central sensitisation (continuous noxious stimulation).

The NMDA receptor is especially important in painful long-term conditions. It is used as an adjunct to improve sedation and inhibit pain signal upregulation (wind-up) in the CNS. It produces minimum psychoactive or physiologic consequence at low doses, and may delay recovery when higher doses are administered, although this does not seem to be a concern clinically when adjunct doses are administered²⁹.

Intraoperatively, ketamine infusions can be anaesthetic-sparing of around 25% at the same infusion rates used for postoperative analgesia (0.3mg/kg/h to 0.6mg/kg/h), but higher infusion rates (3.0mg/kg/h to 6.0mg/kg/h) can have a powerful anaesthetic-sparing ability of 40% to 45%^30,31.

Increased systemic blood pressure and body temperature, mydriasis, regurgitation, cardiac arrhythmias such as ventricular premature complexes, and dysphoria in conscious patients may occur. Unwanted effects may subside as the dose is reduced.

Dexmedetomidine

Dexmedetomidine, an alpha-2 adrenoreceptor agonist, produces deep sedation in many species and provides good analgesia³². The combined sedative and analgesic qualities produce a strong anaesthetic-sparing effect of up to 60%^32-34. Moreover, combining these with opioids produces a superior quality of analgesia in dogs.

However, all alpha-2 adrenergic agonists cause vasoconstriction, bradycardia, decreased cardiac contractility, and lowered cardiac output^34,35. Hyperglycaemia and increased urine production are also reported. Fluid therapy may be required to compensate for fluid losses. Ventilatory support may be required – especially when these agonists are used with opioids.

Dexmedetomidine is used in PIVA and TIVA protocols owing to its profound sedation and analgesic qualities. The lower dose of dexmedetomidine can achieve moderate sedation and analgesia with less marked haemodynamic changes. Dexmedetomidine has residual analgesia and a short recovery after CRI discontinuation, which is attractive. It also has a specific antagonist if needed^36-38.

Benzodiazepine tranquilisers

With their excellent sedative and haemodynamic stability properties, benzodiazepines are helpful for PIVA/TIVA techniques³⁹. They are often used in combination with mu-opioid agonists in critically ill patients^39,40. These drugs are no analgesics, but provide increased centrally mediated muscle relaxation for some procedures. High infusion rates have been shown to reduce enflurane requirements by 55% in dogs⁴⁰.

Diazepam and midazolam both produce dose-dependent sedation and muscle relaxation. They have complex and extended biotransformation. Due to the biological activity of first-generation and second-generation metabolites, the duration of action is prolonged^41,42. This factor makes them less enticing, unless a benzodiazepine-specific antagonist, like flumazenil, is available⁴³. Therefore, as a slow recovery can occur, flumazenil may help to antagonise it.

Neuromuscular blocking drugs

If complete skeletal muscle relaxation is required, neuromuscular blocking drugs can be helpful.

Newer neuromuscular blocking agents produce good neuromuscular relaxation following the loading dose. They are also predictable and have a short duration of action following single-dose administration. Cisatracurium is a popular choice owing to its relatively rapid onset (1 to 2 minutes) and predictable duration (30 to 35 minutes) of effect⁴⁴.

Lidocaine

Lidocaine has a predictable duration of action and analgesic effects at a low-dose CRI, which may be useful for inflammatory conditions. It provides effective analgesia for visceral pain for soft tissue procedures (including intra-abdominal and intrathoracic techniques). In conscious dogs, lidocaine has sedative actions at high infusion rates (50mcg/kg/minute)⁴⁵ and produces an anaesthetic-sparing effect between 20% to 40% in dogs.

However, in a feline study, a bolus dose of lidocaine was shown to be haemodynamically depressant. Therefore, its use in cats is not recommended⁴⁶. Further studies may clarify whether lidocaine infusion techniques are a valuable tool in feline anaesthetic management.

Because of their cardiotoxic properties, long-duration local anaesthetics, such as bupivacaine, are not suitable substitutes for IV infusions.

Delivery systems

To deliver a drug at a constant rate, a devoted delivery device is required. The calculated drug doses may be mixed into a fluid such as 0.9% saline, and infused using a standard fluid pump or gravity dripped using a drip controller.

Although infusions from fluid bags are less expensive, they may result in inaccurate delivery and difficulty in changing infusion rates if more than one drug is mixed in a single bag. Syringe drivers or syringe pumps are programmed to give a precise and desired rate, and changes may easily be made^1,10.

In human medicine, target-controlled infusion pumps are set up with pre-programmed PK-PD data for each drug. The patient information is entered by the operator, and the infusion pump automatically calculates and delivers the drug dose to maintain a target plasma concentration. Several articles have been written regarding this approach in veterinary anaesthesia^1,10.

Long microbore tubing extension sets are available with low priming volumes and are useful for attaching the drug syringe to the patient fluid therapy line, and avoiding excessive drug waste.

Summary

To produce safe anaesthesia and avoid unwanted effects associated with agents, TIVA and PIVA are further options that may be used. In many hospital-based centres, they are used to meet the needs for safer anaesthesia. Although veterinary TIVA/PIVA knowledge is still sparse compared with human medicine, research on the pharmacokinetics of injectable anaesthetic drugs continues to expand and the literature is still constantly evolving.

In small animal veterinary medicine, future objectives must include the availability of delivery devices (target-controlled infusion) and the development of pharmacokinetic profiles for parenteral anaesthetic drugs.

Development of equipment, drugs and patient monitoring techniques will make more options available for clinical use in the future.

• Use of some of the drugs mentioned in this article is under the veterinary medicine cascade.