It is widely accepted that inhalant anaesthetics cause cardiopulmonary depression. In order to reduce the concentrations of inhalant administered to an anaesthetised horse, and thereby reduce the side effects, supplemental drugs can be administered by bolus or infusion. This article describes the techniques of using additional drugs with inhalants (partial intravenous anaesthesia [PIVA]) and also covers the techniques and recipes for total intravenous anaesthesia (TIVA).
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Kate White qualified from the University of Cambridge in 1995. She is currently professor of veterinary anaesthesia and analgesia at the University of Nottingham's veterinary school and is head of the division of medicine. She holds the RCVS diploma in anaesthesia and is a diplomate of the European College of Veterinary Anaesthesia and Analgesia. She is president of the Association of Veterinary Anaesthetists.
AT the end of the last century, Johnston and others undertook a large multicentre inquiry looking at fatalities in horses in the seven days after anaesthesia (Confidential Enquiry into Perioperative Equine Fatalities [CEPEF] 1 and 2 [Johnston and others 2002]). One of the outcomes was a statistically significant reduction in risk when horses were anaesthetised with total intravenous anaesthesia (TIVA) protocols. This study demonstrated that even when procedures of similar duration were compared, TIVA procedures were associated with a better outcome compared with volatile anaesthesia, suggesting that TIVA may well be safer. Now, more than a decade on, it is interesting to reflect on the changes that might have been implemented as a result of this study and consider where clinical equine anaesthesia is heading and whether we can make it safer still in practice.
TIVA describes maintaining anaesthesia with intravenous agents alone (with or without oxygen).
PIVA (partial intravenous anaesthesia) describes maintaining anaesthesia with intravenous agents and volatile agents (sometimes also termed ‘balanced anaesthesia’).
SIVA (supplemental intravenous anaesthesia/analgesia) is an alternative terminology referring to the additional use of analgesic or anaesthetic agents with an inhalant.
What place does TIVA have in practice?
TIVA remains the easiest and most efficacious method of providing ‘field anaesthesia’ and anaesthesia for short procedures in the practice setting. The advantages of TIVA compared to using inhalational agents include less cardiopulmonary depression and, consequently, better maintained blood pressure and little need for an anaesthetic machine and associated equipment. However, TIVA can still cause respiratory depression and oxygen supplementation should be available. Most of the drugs used for TIVA are cumulative, so the duration of anaes-thesia is limited by this fact, and it is not recommended to exceed 1.5 hours of anaesthesia. Longer infusions result in poor recoveries.
Ketamine is the most commonly used intravenous anaesthetic in horses in the UK and, in the short term, anaesthesia can be prolonged with boluses (0.2 mg/kg). To optimise recovery, increments should not exceed 2 mg/kg in total, and sufficient time should elapse following the final dose and end of anaesthesia (eg, 15 to 20 minutes). Where repeated boluses are anticipated, adding an alpha-2-agonist increment can improve anaesthesia. For example, a quarter dose of xylazine (eg, 0.25 mg/kg xylazine plus 0.1 to 0.2 mg/kg ketamine) improves muscle relaxation and can provide a degree of sedation for recovery. Recovery to standing might typically be prolonged from 15 to 25 minutes following no increments to more than 50 minutes following two or more increments of ketamine and xylazine.
Ketamine combinations (‘triple drip’ recipes)
Ketamine is also one of the three ingredients of the ‘triple drip’ combination that can be used to maintain anaesthesia. The other ingredients include the centrally acting muscle relaxant guaifenesin (Myorelax; Dechra) (Fig 1) and an alpha-2-agonist (usually detomidine or xylazine). Although all these drugs are cumulative, ‘triple drip’ can be used to prolong anaesthesia for procedures under 1.5 hours, and has been widely used for field anaesthesia. Guaifenesin is an irritant if administered extravascularly, so a long (80 mm) 12 g or 14 g catheter should be used. Guaifenesin can also be combined with ketamine and medetomidine (Yamashita and others 2002) or ketamine and romifidine (McMurphy and others 2002).
Alternatively, recipes using midazolam plus ketamine and medetomidine have been used (Yamashita and others 2007), resulting in stable anaesthesia and good recoveries. One recipe involves combining 8 ml of midazolam (5 mg/ml) with 20 ml ketamine (100 mg/ml) and 5 ml medetomidine (1 mg/ml) and adding 17 ml saline. The resulting mixture is then infused at a rate of approximately 0.1 ml/kg/hr. It is advised to supplement inspired air with oxygen to prevent hypoxaemia. Neither medetomidine nor midazolam are licensed for use in horses. See Box 1 for 'triple drip' recipes.
'Triple drip' recipes
The most commonly used combination is to add 1 g ketamine and 10 mg detomidine (or 500 mg xylazine) to 500 ml 10 per cent guaifenesin. The resulting solution is then infused at approximately 1 to 2 ml/kg/hr (to effect) and the rate reduced after 30 minutes.
Alternatively, remove 500 ml from 1 litre of 5 per cent dextrose saline or 0.9 per cent NaCl, replace with 500 ml 10 per cent guaifenesin, add 500 mg xylazine (or 10 mg detomidine) and 1 g ketamine. This solution can then be infused at 2 to 4 ml/kg/hr.
Both of these infusions can easily be administered without an infusion pump, simply using a standard giving set and counting the drops per second. It is prudent not to incorporate guaifenesin into the induction protocol, thereby reducing the total dose that is administered.
For example, a 300 kg horse requiring 2 ml/kg/hr of ‘triple drip’ using a standard giving set (20 drops/ml) will require approximately three drops per second of triple drip.
To calculate drops per minute if an infusion pump is not available, the following formula is useful:
Drops/min=(ml/kg/hr) x (kg bodyweight) x (infusion set drops/ml)
Monitoring anaesthesia during TIVA
Monitoring depth of anaesthesia is somewhat different in horses maintained with ‘triple drip’ compared to inhalation anaesthesia; the horse will appear lightly anaesthetised, often with a brisk palpebral reflex, occasional nystagmus, swallowing, and lacrimation, good muscle tone, and yet little response to surgery. It is still important to administer additional analgesics such as NSAIDs, opioids and local anaesthetics where indicated. TIVA may not be appropriate for airway surgery, as swallowing can occur throughout surgery.
Monitoring of the pulse should be performed at regular intervals (Fig 2), and the respiration rate should be observed so that obstruction, apnoea or an increase in rate is identified immediately.
Despite respiration being well maintained during ‘triple drip’ anaesthesia, it is prudent to have a device to allow the horse to breathe oxygen-enriched air if necessary, and demand valves (Fig 3) are a useful tool to support respiration should apnoea occur; for example, following a bolus of intravenous ‘top up’.
A response to surgery or ’lightening of the plane of anaesthesia’ is usually signalled by an increased tone or slow movement of the forelimbs. In response to this, surgery should cease, the rate of infusion can be in-creased for a short time (approximately 30 seconds to a minute) and then the depth of anaesthesia is re-evaluated and surgery can recommence. Alternatively, a ketamine bolus (0.1 mg/kg) can be given intravenously. Some practitioners prefer to administer a bolus of thiopental (1 mg/kg) in these instances, as the speed of onset is quicker. Thiopental is no longer licensed for horses and is increasingly difficult to source. Anaesthesia that is becoming ‘too deep’ is signalled by rapid, shallow breathing that progresses to apnoea (or Cheyne-Stokes breathing), a weak pulse, a centrally positioned eye, absent palpebral reflex, and an absent corneal reflex.
As surgery comes to an end, the infusion can be slowed and stopped in the same way the inhalant is turned down and switched off. Recovery is usually smooth and controlled.
Propofol-based combinations for TIVA have also been investigated clinically and in research, but lack significant advantages over the ‘triple drip’ combinations other than that they can be infused for a longer period of time with less accumulation. Propofol and ketamine, or propofol, ketamine and medetomidine have been combined to maintain anaesthesia in clinical cases, in some instances for up to four hours (Bettschart-Wolfensberger and others 2003).
Cardiovascular function is usually well maintained with propofol infusions and inotropic support is rarely needed, but oxygen is strongly recommended and positive pres-sure ventilation may be required, making it impractical in field situations. These combinations tend to result in good, smooth recoveries, but it is unlikely that these combinations will prove popular for field anaesthesia, and propofol is not licensed for use in the horse. Propofol alone is unsuitable for induction of anaesthesia in the horse; however, when combined with guaifenesin or ketamine, the quality of induction is improved. In most cases, anaesthesia is induced with ketamine and an alpha-2-agonist and then TIVA is commenced with propofol or propofol combinations (Bettschart-Wolfensberger and others 2005).
Alfaxalone has been used for induction of anaesthesia in horses (Leece and others 2009, Klöppel and Leece 2011) and it compares similarly to ketamine. Anaesthesia can be induced with alfaxalone (1 mg/kg) combined with diazepam (0.02 mg/kg) following a standard premedication, and anaesthesia is maintained with increments of alfaxalone (0.2 mg/kg) in response to movement or lightening of the plane of anaesthesia. Alfaxalone has also been co-administered with medetomidine to maintain anaesthesia in colts undergoing castration, providing adequate surgical conditions and good to excellent recoveries (Goodwin and others 2013). All colts in the study were intubated and insufflated with oxygen. Alfaxalone is not currently licensed for horses.
Nowadays, it is still the case that the more complicated or prolonged equine surgeries are performed under inhalation anaesthesia (Fig 4). With advancements in laparoscopy and laser techniques, some hospitals and practices are performing more standing surgeries, thereby reducing the numbers of general anaesthesias. However, in most equine practices there is still an enormous reliance on inhalation anaesthesia. One of the major disadvantages of using the inhalants is the profound cardiopulmonary depression that is caused, and in many cases reliance on an inhalant alone fails to provide sufficient analgesia and prevent intraoperative nociception (Fig 5). This problem can be addressed by using combination anaesthesia where increments of intravenous agents are administered or infusions are given. The aim of this is to minimise respiratory depression and hypotension, and improve the analgesia by obtunding some of the nociceptive impulses. Ultimately, the goal is more ‘balanced anaesthesia’, less pain and hopefully more coordinated recoveries from anaesthesia.
PIVA describes the use of both an inhalation agent plus intravenous drugs and volatile agents to produce the desired level of anaesthesia/analgesia. PIVA or ‘balanced anaesthesia’ are terms often used interchangeably.
PIVA has a number of advantages, as listed in Box 2. However, it has not enjoyed widespread acceptance. There must be reasons for this and for why little has changed. Many will be familiar with the adage ‘if it ain't broke don't fix it’, and there is a general consensus that something needs to be seriously wrong before change is adopted, and instigating change is uncomfortable for people as there may be a learning curve to cope with in the face of new drugs and protocols. Other reasons limiting PIVA popularity could be a potential increase in cost, the issue of additional equipment (eg, syringe drivers/infusion pumps that are not always necessary), the fact that cardiopulmonary depression will still occur, and that most drugs are cumulative over time. However, despite these disadvantages, there is much to commend PIVA protocols (Fig 5).
Advantages of PIVA
Using additional agents during the anaesthesia offers the following benefits:
▪ Reduced cardiopulmonary depression because less inhalant can be used;
▪ Provision of additional analgesia;
▪ Improved outcome? In theory, PIVA may provide superior recoveries with fewer complications, but this is still to be proven;
▪ Less environmental pollution and organ toxicity;
▪ Improved intraoperative conditions.
What drugs can be used?
In addition to the aforementioned advantages of PIVA, the drugs used should reduce minimum alveolar concentration (MAC) and ideally exhibit short context sensitive half lives (Box 3). These drugs should be compatible with other drugs for administering as a constant rate infusion (CRI). Unfortunately, no single drug meets all these requirements and it is often necessary to administer combinations.
Minimum alveolar concentration and context sensitive half life
Minimum alveolar concentration
Minimum alveolar concentration (MAC) is a concept used to compare the strengths, or potency, of inhalants. It is defined as the concentration of the vapour in the lungs that is needed to prevent movement in 50 per cent of subjects in response to surgical stimulus.
Context sensitive half life
Context sensitive half life (or context sensitive half time) is defined as the time taken for the blood plasma concentration of a drug to decline by 50 per cent after an infusion designed to maintain a steady state (ie, a constant plasma concentration) has been stopped. The word context refers to the duration of infusion.
The drugs that are most commonly used in equine anaesthesia for PIVA include ketamine, lidocaine, opioids and alpha-2-agonists.
All of these drugs (except possibly the opioids) have the ability to reduce the MAC of the inhalant and allow the setting on the vaporiser to be reduced. A syringe driver attached to an anaesthetic machine can make setting up infusions easier (Fig 6).
Lidocaine provides a dose-dependent MAC reduction (Doherty and Frazier 1998). A loading dose of 1 to 2 mg/kg can be given over 10 to 15 minutes during anaesthesia, followed by an infusion of 0.05 mg/kg/min (Fig 7). This rate will reduce MAC by approximately 25 per cent. Higher infusions (0.1 mg/kg/min) will reduce MAC further (by approximately 50 per cent). It is common practice to switch off the lidocaine 30 minutes before the end of surgery in order to reduce the ataxia on recovery that may be associated with infusing the drug (Valverde and others 2005). Lidocaine can also be combined with other drugs (eg, ketamine, opioids and alpha-2-agonists). Lidocaine's prokinetic effect may be of benefit in protecting the gut from ileus postoperatively. Whether this effect is direct or indirect (ie, through providing analgesia and reducing inflammation thereby encouraging healing and gut movement) has still to be proven. In people, intravenous lidocaine speeds the return of bowel function, decreases postoperative pain and shortens hospital stay (Groudine and others 1998). It must be noted that lidocaine plus adrenaline formulations must not be used for infusions. In cases where this mistake has been made, the horse begins to exhibit tachycardia, sweating and is increasingly difficult to keep anaesthetised. A number or equine practices are using lidocaine infusions during colic surgeries, and others use lidocaine in other types of surgeries too, in respect of the MAC reduction and analgesia provision.
Ketamine can also be given as a CRI during anaesthesia. As for all CRIs, the use of laminated charts with the dosages clearly calculated contributes to safety during anaesthesia, since performing complicated calculations during anaesthesia may be off-putting for many clinicians and may increase the chance of errors (Box 4).
To convert mg/kg/hr to mcg/kg/min:
1 (mg/kg)/hr=16.67 (mcg/kg)/min
To convert mcg/kg/hr to mcg/kg/min
1 (mcg/kg)/hr=0.0167 (mcg/kg)/min
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that can provide analgesia and inhibit central sensitisation (‘windup’) which can prolong and increase pain sensitivity. Ketamine will allow the vaporiser setting to be decreased, but may also support the cardiac function via its sympathomimetic effect. There is also evidence that ketamine administered in vitro to harvested red blood cells possesses cytokine-modulating activity, suggesting a possible anti-inflammatory role, but despite this being the case in rodents and people it has yet to be proven to have an in vivo anti-inflammatory action in horses.
The author uses a ketamine infusion during prolonged inhalation anaesthesia where the horse is requiring multiple ‘top-ups’ of ketamine to improve surgical conditions, and typically where increasing the inhalation agent results in significant cardiopulmonary depression. It may also be the case that the plane of anaesthesia could be improved by also adding an opioid intramuscularly in these circumstances. The dose range for ketamine CRI is 0.4 to 1 mg/kg/hr and titrated to effect. There are reports in the literature of higher doses, up to 3 mg/kg/hr; however, the author has only used the higher doses in TIVA recipes (eg, with propofol). High doses of ketamine will contribute to poorer recoveries (Fig 8).
Xylazine, detomidine, medetomidine and dexmedeto-midine can be given as very small boluses, but have also been infused to anaesthetised horses. Currently, xylazine and detomidine are licensed in the horse, but no alpha-2-agonist is licensed to be infused as a CRI. In view of the fact that these drugs cause increased urine production, attention must be paid to bladder catheterisation and fluid administration during anaesthesia. At the end of anaesthesia it is advisable to empty the bladder so that the horse is not returned to the recovery room with a full bladder that may compromise its recovery.
With many of the studies published in the literature using alpha-2-agonist CRIs, the blood pressure is higher than the values obtained under inhalant alone; however, it must be borne in mind that the increased blood pressure is in part due to increased systemic vascular resistance, and this reminds us that increased pressure does not necessarily result in increased perfusion.
Xylazine is relatively short-acting and is usually combined with other drugs (eg, with ketamine for ‘top ups’ in TIVA), but an infusion of 0.016 mg/kg/min will reduce MAC by approximately 25 per cent, although very little data exists supporting its use as such in clinical cases.
Detomidine has been infused during general anaesthesia (0.18 mcg/kg/min) and markedly reduces MAC in experimental studies; however, a clinical study failed to find significant MAC-sparing effects of a detomidine CRI during isoflurane anaesthesia (Schauvliege and others 2011). Detomidine is also frequently used for standing surgical anaesthesia.
Medetomidine has also been infused (3.5 mcg/kg/hour) and again markedly reduces MAC. For prolonged procedures, attention must be paid to bladder catheterisation and fluid replacement. Ringer and others (2007) concluded that maintenance of a stable anaesthetic ‘depth’ was easier and that lower fractional expired isoflurane concentrations were required to maintain a surgical plane of anaesthesia in horses receiving a medetomidine infusion (3.5 mcg/kg/hr) compared to a lidocaine infusion (50 mcg/kg/min). Recoveries were longer, but of better quality in the medetomidine group, too. The cardiac index was higher in the lidocaine group, but cardiovascular function was generally well maintained in both groups. The medetomidine CRI is becoming popular in some centres around the world. Currently, medetomidine is not licensed for use in the horse in the UK.
Dexmedetomidine has also been infused as a component of balanced anaesthesia in research and clinical settings. This drug has a shorter half-life than medetomidine. Typically, a 50 per cent reduction in the medetomidine dose is used and infusions of 1 to 1.75 mcg/kg/hr offer MAC reduction and improved recoveries (Marcilla and others 2012).
Ideally, the loading dose and CRI should consist of the same alpha-2-agonist, as long as the terminal half-life of the drug used for the loading dose is not exceeded before the start of the CRI with the second alpha-2-agonist. Some studies have used xylazine or romifidine, followed by a CRI of medetomidine on the assumption that clinical effects are maintained by the alpha-2-agonist because of the interaction of an agonist with a specific receptor.
Opioid analgesics provide analgesia and may cause a degree of mild euphoria in the unsedated horse. This propensity for causing agitation/excitement and sympathetic activation may explain why some studies found opioid administration to actually increase MAC in horses (specifically when no other agents were administered). However, despite this, opioids remain a pivotal part of equine anaesthesia and administration in conjunction with sedative drugs usually masks any excitement.
Opioids can be given as boluses or infusions during anaesthesia. Currently, butorphanol is the most commonly used opioid in equine practice; however, recent licensing of buprenorphine for horses may challenge this position. Morphine or methadone, although currently not licensed for horses, can be used for more painful conditions, but their controlled drug status often limits their use. Pethidine is licensed for pain associated with spasmodic colic in horses. Methadone has recently received a licence for use in dogs and cats in the UK (Comfortan; Dechra).
Butorphanol given intraoperatively as a bolus can augment the plane of anaesthesia with little effect on the cardiovascular system (Hofmeister and others 2008), and some limited data exists about the use of butorphanol as an infusion intraoperatively, although it is unlicensed for this indication. Other studies showed butorphanol had a variable effect on MAC of halothane (Matthews and Lindsay 1990). Postoperative butorphanol infusions have been shown to improve behaviour scores and reduce plasma cortisol concentrations in horses that have undergone laparotomy (Sellon and others 2004). Other researchers have shown no benefit from a butorphanol CRI in horses undergoing balanced anaesthesia with isoflurane and medetomidine CRI (Bettschart-Wolfensberger and others 2011). It is unlikely that butorphanol infusions will gain popularity, as their beneficial effect is relatively limited and the volumes required to achieve therapeutic plasma concentrations are high and potentially cost prohibitive.
Some studies have shown variable effects of morphine on the MAC of anaesthetised horses. However, morphine given preoperatively and as an infusion has a positive outcome on the recovery, with fewer attempts to stand/get sternal and a shorter time to standing from first movement (Clark and others 2008). The recommended dose of morphine is 0.1 mg/kg/hr following a loading dose of 0.15 mg/kg. Fentanyl has also been used as an infusion (Thomasy and others 2006), but requires further evaluation. It would seem we still have some way to go to refine the use of opioids in anaesthetised horses.
Propofol can be used during inhalant anaesthesia, but has quite a profound cardiopulmonary depressant effect and lacks any intrinsic analgesic activity. Propofol can be combined with other drugs, such as opioids and ketamine to reduce the dose and side effects. Propofol has been widely trialled as a component of TIVA in research and clinical cases but is unlicensed in horses.
Centrally acting muscle relaxants
As mentioned earlier, the use of guaifenesin as a component of TIVA is well recognised. Guaifenesin cannot induce unconsciousness and lacks any intrinsic analgesic properties. Workers have infused guaifenesin and ketamine and medetomidine during sevoflurane anaesthesia and produced stable anaesthesia, minimal cardiovascular depression and good recoveries (Yamashita and others 2002). Another study demonstrated advantages of infusing ketamine and guaifenesin to ponies receiving halothane compared to maintaining anaesthesia with halothane alone. Patients had good recoveries and stable anaesthesia (Spadavecchia and others 2002).
Midazolam has also been infused to horses during anaesthesia with inhalants. It has been combined with other drugs such as medetomidine and ketamine during sevoflurane anaesthesia with minimal cardiovascular depressant effects and good recoveries, representing another possible PIVA recipe (Kushiro and others 2005). The aim of using drugs such as these is to improve the surgical conditions and be able to rely less heavily on the inhalants alone. Midazolam is not licensed for use in horses.
Many different drug combinations have been tested and more are still to be tried. Ketamine and lidocaine CRIs during anaesthesia have been widely used and results support the use of lidocaine and ketamine to improve anaesthetic and cardiovascular stability during isoflurane anaesthesia (Enderle and others 2008). Ketamine with lidocaine and an alpha-2-agonist have also been evaluated and MAC reductions to a magnitude of 80 to 90 per cent have been reported. Medetomidine combinations have also been evaluated and offer promise. In theory, it is often said to treat every horse as an individual and tailor the administration of drugs to the horse's size, status and physiology, but actually it may be prudent to adopt a couple of predetermined anaesthetic protocols to reduce the chance of error, especially if anaesthesia is not being performed regularly.
The future of equine anaesthesia may well involve PIVA and TIVA protocols, and we must keep an open mind about these incorporations. There are many possible indications and drug combinations, but it is imperative to insist on evidence-based medicine and well-designed trials when new ideas and recommendations are suggested.
With the demise of the use of halothane in horses in the UK and the widespread adoption of isoflurane as the sole agent for equine anaesthesia, plus more advanced monitoring during anaesthesia, it will be interesting to see results of a current study – CEPEF 4 evaluating risk associated with anaesthesia in 2015. Twenty-two years after CEPEF 1 and 2 were started, the questions ‘Are we doing any better? If so, why?’ and ‘Has PIVA or TIVA made any difference?’ are yet to be answered. What is known is that there is still enormous variation in equine anaesthesia (Wohlfender and others 2015), making the evaluation of safety and risk a very difficult task.
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