A constant rate infusion (CRI) allows for a continuous low-dose delivery of analgesic drug. This method of administration targets a steady state effective plasma concentration of the drug and should avoid any peaks and troughs in both drug concentration and clinical analgesia, which can occur with intermittent bolus dosing. In veterinary medicine the most common route of administration of analgesic drugs via CRI is intravenously, whilst in human medicine the epidural route is also commonly used, especially during child birth.
Certain drugs suit administration via CRI, and these include ketamine, lidocaine, (dex-)medetomidine, fentanyl and less commonly methadone. The drugs listed can be given alone or are frequently used in combination.
A basic level of pharmacology knowledge is needed when considering when and how to use drugs via CRI. The aim of the CRI is to maintain a steady state plasma concentration of the analgesic drug, which should therefore give a continuous level of analgesia (Figure 1). When given by intermittent bolus doses, the plasma concentration gradually rises but contains multiple “peaks and troughs”. These begin to fluctuate around a steady concentration after five half-lives, or dosing intervals (Hill, 2004). These fluctuations risk encroaching on levels where side effects may be seen, or plasma concentrations exceed that of the therapeutic range. When given by CRI, the aim is to target a steady plasma concentration that is both clinically effective and does not exceed safe levels. The time taken to reach this steady level is the same as when given by intermittent bolus, five half-lives (Figure 1). This time to reach a steady state plasma concentration can be reduced if a bolus is given at the start of the infusion. A bolus gives an immediate elevation in plasma concentration that is then maintained as the CRI continues.
Whether to give a bolus or not really depends on the drug being infused and the clinical reason for the CRI. As an example, if a fentanyl CRI is started shortly after induction of anaesthesia to provide intraoperative analgesic for orthopaedic surgery, a bolus may not be required as the plasma concentration will increase during the time taken to clip and prep for surgery. However, if the same CRI is started in theatre just prior to starting surgery, a bolus would be required as the time taken to achieve a therapeutic plasma concentration would be longer than the time to the noxious stimuli. As a general rule of thumb for analgesics, if the infusion is given at a rate of Xmg/kg per minute then a bolus should not be required, whereas if the rate is Xmg/kg per hour then a bolus would be beneficial to reach therapeutic plasma concentrations quicker.
Context-sensitive half times
The second pharmacological idea is that of context-sensitive half times, which become applicable at the end of a longer infusion. The context-sensitive half time is the time taken for the plasma concentration to halve once the CRI finishes. For some drugs this may be the same as the half-life after bolus injection, but for others it can become prolonged (Figure 2). This is due to deposition of the drug in tissue outside of the circulating plasma concentration. This has clinical relevance as it will dictate when interval dosing should begin after cessation of a CRI (eg how long you should wait before starting methadone boluses after stopping a fentanyl CRI). For most of our analgesics, if used during surgery or in the immediate post-operative period, this will not be applicable. However, if a patient is on a CRI for an extended duration after surgery some thought must be given to this concept, otherwise signs of overdose may be seen if a drug of the same class is to be given or a false sense of clinical analgesia could be due to prolonged action of the drug used for the infusion. This will most commonly be seen when switching from opioid CRI to set interval dosing. In this context the use of pain scores can be useful as the set dosing interval can be started once the pain score initially begins to increase following the end of the CRI. This point marks the start of the set dosing interval, and ensures that side effects such as sedation, hypoventilation, hypothermia and dysphoria are not seen.
Practically CRIs can be done by either dilution of the drug into a saline fluid bag (Figure 3) or by use of a precision infusion pump (Figure 4). A precision infusion pump gives the advantage of providing a second line of safety against accidental incorrect infusion rates being given, along with the ability to give a set bolus over a given time period and very accurate infusion rates. The downside is that the equipment needed comes at extra cost, whilst using a fluid bag and standard fluid pumps utilises equipment that is already available. When using fluid bags, it can be useful to make dilutions that result in a rate of 1ml/kg/hr, as then increasing or decreasing the infusion is a simple and easy process. It is common to use infusions that mix multiple drugs, with morphine-lidocaine-ketamine being common historically, but now largely replaced by combinations of fentanyl-lidocaine-ketamine. If multiple drugs are to be mixed in the same fluid bag then careful consideration must be given that any increase or decrease in the fluid rate must not exceed the safe limits, or fall below the therapeutic range for any of the individual drugs used. The bag should also be clearly labelled with the contents and the resultant concentration of each drug used.