Introduction

Continuous rate infusion (CRI) is being more widely used to provide analgesia both intraoperatively and perioperatively for both small and large animal patients. This lecture will cover the basic pharmacokinetics of CRIs, and also the scenarios you should consider them in. Some of the most commonly used drugs in analgesia for small animal patients will then be discussed and examples given as to how to work out infusion rates.

Drugs can be infused continuously for a variety of reasons; they may be for analgesia, for sedation or for other therapeutic uses. The reason we choose to give some drugs continuously is to avoid the peaks and troughs in the plasma levels, which you would see if you gave repeated bolus injections of the drugs. This is especially important if the drug you are administering has a narrow therapeutic window, as the up-swings and down-swings associated with this bolus dosing may produce toxic levels (at the peak of the up-swings) or non-therapeutic levels (at the trough of the down-swing). So the aim of the infusion is to maintain the plasma level of the drug within the therapeutic range.

Clinically, when it comes to analgesia, CRIs are useful because the nurse doesn't have to wait to see signs of pain returning (as the previous dose is wearing off) before administering the next dose. The well-being of the patient is also improved because the drugs are administered through an indwelling intravenous catheter, instead of disturbing the patient every 4 hours to repeat an intravenous injection, or even worse to repeatedly inject drugs into the muscle.

Pharmacokinetics

Before we can understand how infusion rates are designed, we must become familiar with some basic pharmacokinetic concepts.

Pharmacokinetics is the process which describes the way in which the body handles drugs after we have administered them, i.e., how it absorbs them, redistributes them around the body, and how it eliminates them from the body.

Often, before we start a CRI we will give a loading dose of that drug. This is so that the plasma levels of the drug are already closer to the therapeutic levels. If we rely on giving just the infusion to the animal, we often have to wait approximately 5 half-lives of the drug before we reach therapeutic levels.

Half-life is the time taken for the plasma concentration to fall to 50% of its initial value.

Loading Dose

To calculate a loading dose, we need to know two pieces of information; the volume of distribution of the drug and the required plasma concentration.

Loading dose = volume of distribution x plasma concentration
The volume of distribution is the apparent volume into which a drug disperses.

Rate of Infusion

If we want to maintain that plasma level we need to start infusing the drug to establish a steady state. A steady state is where the rate of the drug administration is equal to the rate of drug elimination, so the levels in the blood do not accumulate or drop too low. So to know how fast to administer the drug we need to work out how quickly the body is eliminating the drug, so we can match it.

Rate of elimination = clearance x plasma concentration

Clearance is the volume of plasma from which a drug is completely removed per unit time.

Equipment Needed

When we use the term CRI, we usually assume that the infusion is being given intravenously. This certainly is the case in the vast majority of situations. However, we cannot discount infusions of drugs to provide continuous local anaesthetic blockade, i.e., through an indwelling epidural catheter or a local anaesthetic infusion catheter. In these cases, additional equipment will be needed.

For intravenous infusions, obviously we need to have a well secured intravenous catheter placed after aseptic preparation. A peripheral vein is usually appropriate for an analgesic CRI, although some CRIs of other drugs, e.g., high glucose content or total parenteral nutrition, require a larger-bore central venous catheter.

The drug to be administered is usually dissolved in a crystalloid solution, either 0.9% sodium chloride or Hartmann's solution. The dose rate (Figure 1) must be carefully controlled and therefore an infusion pump or a syringe driver is needed to ensure accurate administration. Finally the drug in question needs to be drawn up after first checking the concentration of the solution and ensuring the solution's sterility.

Most importantly, a suitably qualified member of staff should be monitoring these animals, either under anaesthesia, or in the ward situation. Infusions of these drugs will alter the way your patient responds to anaesthesia; the drugs may alter its heart rate, or its ability to ventilate. When the animal is conscious, attention needs to be paid to the catheter, to make sure that the animal is receiving the analgesics, and that the rate is not too low (and the animal is still in pain) or too high (and the animal is experiencing side effects).

The opioids, especially fentanyl, alfentanil and remifentanil, are renowned for causing respiratory depression and bradycardia. The author prefers to use these drugs for patients under anaesthesia, when their lungs can be ventilated, if necessary. Medetomidine's profound cardiovascular effects may be well tolerated by relatively fit, healthy animals, but it should be used with caution in sicker patients.

Figure 1. CRI doses for dogs (N.B. There are 1000 µg (micrograms) in 1 mg (milligram)).

Calculations

Many rates suggested in books will be on a ml per kilogram basis, with instructions provided of how to make your bag up. Sometimes this may be a wasteful approach, if, say for example, you only require an infusion for a couple of hours.

To calculate a rate from scratch, you need the following pieces of information:

 Animal's weight

 The infusion rate

 The drug concentration

 Duration of infusion

 Whether or not the fluids you will be making up the infusion with also constitute the animal's intravenous fluid therapy

1.  First we need to work out our rate for our animal's weight:
Weight (kg) x infusion rate (mg/kg/minute) = mg/min

2.  Next we need to convert from milligrams per minute to milligrams per hour (as this is what most syringe drivers or infusion pumps work in):
Dose rate (mg/min) x 60 = dose rate (mg/hour)

3.  Then decide how long you want your infusion to continue for:
Dose rate (mg/hour) x number of hours = dose (mg)
It is this dose that you will be adding into your bag of fluids or syringe of fluids

4.  To calculate the volume of drug you need:
Dose x concentration = volume

So we now know how much drug we want to add. If this infusion is just piggybacking your animal's fluid therapy, i.e., via a separate line, then add your drug to a known volume (e.g., 500 ml bag or a 20 ml syringe of crystalloid). If your drug volume is a large volume you need to withdraw the equivalent volume of fluid from the bag or the syringe before adding your drug.

To calculate the infusion rate to dial up on your syringe driver or fluid pump:
Volume of bag/syringe (ml) ÷ number of hours (hr) = Infusion rate (ml/hr)

If, however, we wanted to make this infusion also your animal's fluid therapy, you need to first calculate your animal's fluid therapy rate:
Fluid therapy rate (ml/kg/hr) x weight (ml/hr) = Fluid therapy rate (ml/hr)

To find out how many hours worth of infusion that bag will supply:
Volume of bag (ml) ÷ fluid rate (ml/hr) = Number of hours of infusion (hours)

Now insert this number of hours into equation (3) to calculate the total dose you will need for that bag, and then equation (4) for the volume. You can then inject this volume of drug into the bag and administer the fluid at the animal's chosen fluid therapy rate.

All infusions should be fully and clearly labelled once made up, including drug added, amount of drug added, infusion rate, patient's name, date drawn up and by whom.

If for any reason, the animal's fluid therapy demands change, then you should discontinue the infusion and swap for another fresh bag of crystalloids, whilst you sort out its deficit (e.g., it may need a bolus of fluids). If the overall rate changes, you will need to recalculate and redraw up your infusion.