Constant rate infusion Analgesia (Proceedings)

Constant rate infusion (CRI) analgesia is a way of providing pain control by ensuring that the blood levels of the drugs are held constant. In practice, it entails maintaining a venous access. This technique can be used during anesthesia as part of balancing the anesthetic technique and continued to the postoperative period. It can also be started right after the end of anesthesia for patients that are known to have painful surgeries. For patients with primary disease, e.g., acute pancreatitis, with pain as one of the signs, CRI analgesia can also be used.

The focus of this presentation will be on the use and techniques of CRI for pain control in small animal patients.

When using CRI, a stable plasma or tissue concentration of the drug in the body should be achieved. It is important to remember that once a drug is administered, part of it is also eliminated. The technique involves maintaining a stable drug concentration in the central component. If this drug concentration is maintained, a steady state is considered to be achieved. This indicates that the rate of infusion matches the rate of elimination. The concentration of the drug at steady state depends on the infusion rate and the body clearance of the drug (see formula below).

Concentration at steady state (Cp ss) = Infusion rate/Body clearance of the drug (β•Vd')

In practice, this steady state can be achieved in an efficient manner by giving an IV bolus dose and then the drug is administered as a CRI. A delay between the start of an infusion and the establishment of a steady state is expected. The longer the half-life of the drug, the longer it takes to reach a steady state or plateau. By 5 half-lives, it is noted that the amount of drug in the body provided by the infusion will reach 97 percent of the steady state value.

Advantages

There are advantages of administering analgesic drug(s) as CRI compared with intermittent IV or IM injections. CRI prevents the sudden peaks and valleys associated with intermittent IV boluses. With IV boluses, there is a fast rise in plasma concentration that may result in adverse effects. It is also possible that drugs with rapid elimination given as IV boluses rapidly fall below the therapeutic concentration. Even with IM and subcutaneous injections, the blood level can go below the therapeutic range. In painful patients, this will lead to breakthrough pain making the pain control more difficult. Because of the constant plasma drug concentration in CRI, the control of pain will be uniform and consistent. Based on our clinical experience, CRI appears to be a very effective technique in patients that are in severe pain. Depending upon the condition and response of the patient, the rate of infusion can also be changed to produce the desired effect. It was shown in a study that CRI of analgesic agent will result in less total amount of drug used to provide pain control compared with intermittent boluses. This results in savings with the cost of the drugs. CRI has also been shown to result in faster recovery from the drug effect. This finding can be useful in patients that have worsening hemodynamic condition. Terminating the CRI will result in quicker lowering of the plasma drug concentration. Overall, it is easier to adjust the amount of drug(s) being administered in relation to the severity of pain.

Disadvantages

Despite the many positive features of CRI technique, it is not as widely used as the other methods of administering analgesic drugs. In a busy practice, it may be less efficient because the solution has to be prepared especially if more than one drug will be used. There is also a need for constant supervision by a staff member since the IV lines can be disconnected or kinked. To administer drugs accurately with CRI, the use of syringe pump is helpful. Unfortunately, syringe pumps are still relatively expensive. Some drugs used in CRIs are not extensively studied. The best infusion rates for different conditions need to be determined. In general, we administer these drugs to effect. These drugs can accumulate in the body if given for a long time resulting in adverse effects. Further studies are needed to determine the best protocol for prolonged administration (greater than 24 hours). Different drugs may be used simultaneously as a multimodal approach to providing analgesia. This presents additional question as to the stability and compatibility of these drugs when mixed together. When adverse effect occurs, it may be more difficult to pinpoint the drug causing the problem because of the multiple drugs used.

Drugs

Opioids

Opioids bind with opioid receptors in the CNS and periphery providing analgesia. This group of drugs is considered to be the most effective analgesic. An opioid can be administered as the sole agent for CRI or it can be given with other analgesic drugs like ketamine and lidocaine. The opioids that are commonly used for CRI are morphine, hydromorphone, and fentanyl. For severe pain, the pure agonists (morphine, hydromorphone or fentanyl) are preferred because they are more efficacious. Efficacy signifies the amount of drug that will produce the maximum effect. The maximum effect for analgesic drug will be relief of severe pain. As the dosage of these drugs is increased, the effect produced also increases. This is in contrast to the agonist-antagonist (butorphanol) that has a ceiling effect on analgesia.

There are adverse effects associated with the use of opioids. The most common ones are sinus bradycardia, vomiting, defecation, dysphoria, panting, respiratory depression, and urinary retention. Critical patients with head trauma, seizures, depressed or debilitated should be monitored very closely when an opioid is being administered as respiratory depression can become profound in these patients. The dose should be adjusted based on the mental state of the patient and oxygen be provided to minimize hypoxemia secondary to hypoventilation. Clinically, the degree of hypoventilation caused by opioids is related to the degree of CNS depression. The danger of hypoventilation remains very low in patients that are conscious and responsive.

Dysphoria is a another side effect of opioids. It has been reported in 30% of dogs that received CRI morphine. In this study, all dogs showing dysphoria were Greyhounds. In practice, other breeds have shown dysphoria and it can easily be managed using anxiolytic or sedatives like diazepam or acepromazine. If a sedative is given, the lowest dose possible should be tried first. Opioid overdose will lead to higher blood concentration and possible dysphoria. The best way to manage it is to give diluted naloxone very slowly until the undesired signs disappear.

Vomiting appears to be less common with fentanyl, hydromorphone, and butorphanol compared with morphine. In general, IM injection of opioid is associated with more vomiting when compared with IV. However, in a limited number of dogs comparing IM and CRI morphine, both groups had the same frequency of vomiting (2/10 dogs). In addition to vomiting, opioids also increase the duodenal, biliary, esophageal, and anal sphincter tone. It is best to avoid opioids in patients with obstructed biliary tract or biliary neoplasm.

For opioids, the bolus dose is necessary and then followed by CRI. All pure agonists mentioned above are suitable for patients in severe pain. Opioid should be part of a multimodal approach to pain management in small animal patients. The factors affecting the decision of clinicians include cost and familiarity with the certain drugs. The duration of the infusion will depend mostly on the course of the clinical disease and the presence of adverse effects.

Lidocaine

Lidocaine is a local anesthetic that has been used as a CRI for providing analgesia. It is the only local anesthetic given IV to provide analgesia. The analgesia produced by lidocaine has been attributed to sodium ion channel blockade in neuronal cells and membrane stabilization. IV lidocaine has been shown to be analgesic in different animal models. Lidocaine has been shown to reduce the anesthetic requirement for inhalant anesthetic, decrease the amount of opioids needed for postoperative pain, and minimize neuropathic pain. The postoperative effect of lidocaine still exists even when it has already been eliminated from the body partially because its metabolites have also analgesic properties. In addition to analgesia, lidocaine also has antiarrhythmic, anti-inflammatory, antishock, free radical scavenging and gastrointestinal promotility properties. It is a good choice for animals with nerve injury, burn, and gastrointestinal problems. When administered at a higher rate of infusion by mistake, patients will exhibit signs characteristic of CNS stimulation. The signs will include nervousness, agitation, excitement, and seizure. Further signs of toxicity will be manifested as cardiovascular depression: hypotension, cardiac output reduction, and bradyarrhythmias. These effects may become worse in really sick patients because of their dependence on the sympathetic nervous system activity for survival. It is advisable not to use lidocaine in patients with high grade 2nd or 3rd degree atrioventricular block because it will suppress the ventricular escape beats. Any sign of agitation and excitement in a patient receiving CRI lidocaine should signal the possibility of toxicity and the infusion should be stopped. It is prudent to investigate the rate of infusion and ensure that the correct infusion rate is being used before the CRI lidocaine is started again. IV lidocaine is not recommended in cats because of the profound depression of the cardiovascular function.

Lidocaine can be infused by itself or in combination with an opioid and ketamine. The analgesic efficacy of the three drugs together cannot be measured simply by the reduction in MAC of the inhalant. The effects of lidocaine and ketamine extend beyond the intraoperative stage. As indicated above, by giving IV lidocaine intraoperatively the amount of opioid needed to provide analgesia in human postoperatively decreased.

Ketamine

The role of ketamine in analgesia stems from its antagonistic effect on the N-methyl-D-aspartate (NMDA) receptors. Stimulation of NMDA receptors is associated with CNS sensitization. To antagonize the NMDA receptors, microdose of ketamine is used. It is important to remember that ketamine by itself will not provide adequate analgesia and should be used with an opioid. Tolerance to an opioid also decreases with the addition of ketamine to the combination.

A study showed that by using CRI of ketamine in dogs that underwent forelimb amputation, the pain scores were lower 12-18 hours postoperatively. The dogs were also observed to be more active 3 days postoperatively.

During anesthesia, the ketamine dose is 0.6 mg/kg/hour. The lower doses of 0.12-0.2 mg/kg/hour are used postoperatively.

Dexmedetomidine

Dexmedetomidine produces analgesia by stimulating the alpha2-adrenergic receptors in the brain and spinal cord. These receptors are located at various sites in the pain pathway. The activation of alpha2-adrenergic receptors in the dorsal horn of the spinal results in the release of substance P. CRI of dexmedetomidine can be used intraoperatively and postoperatively. Dexmedetomidine reduces the requirement for inhalant anesthetic. Postoperatively, dexmedetomidine is given in patients that continue to vocalize and show signs of restlessness and agitation despite repeated administration of opioid and acepromazine. When given for this condition, it is difficult to determine if the dexmedetomidine has significant analgesic property.

Method of Administration and Calculation

In severe pain, a combination of an opioid, ketamine, and lidocaine is recommended. With more than one drug involved, administering the correct dosages becomes a challenge. There are two main methods of administering the infusions: (1) use of syringe pump and 2) "bag" technique which involves adding the drug(s) to the bag of crystalloid and administering it as maintenance fluid in most cases.

Syringe pumps are big-ticket items for veterinary clinics. However, their main advantages are accurate drug dosing, less dilution required, and less drug waste. If different drugs are to be given simultaneously, one syringe pump per drug is an option. If only one syringe pump is used, the three drugs will be mixed in one syringe and the syringe pump will be set to deliver at milliliters per hour. The author prefers this technique during anesthesia.

The "bag" technique can be utilized and the rate of administration will be the maintenance fluid rate. This rate can be more accurately administered using a volumetric infusion pump. The question then is how much of the drugs are to be added to the fluid bag. Using the following equation, the amount of the drug in milligrams will be known:

Drug (mg) = [Infusion rate of the drug (mg/kg/hour) ÷ Fluid infusion rate (ml/kg/hour)] × diluent volume (ml)

To apply this formula, 20-kg dog that needs maintenance fluid and a CRI of morphine, lidocaine and ketamine will be used as an example.

These are the rates that will be used in this example:

     • Maintenance fluid rate - 2.0 ml/kg/hour

     • Morphine CRI dose - 0.1 mg/kg/hour

     • Lidocaine CRI dose - 3.0 mg/kg/hour (50 µg/kg/min)

     • Ketamine CRI dose - 0.18 mg/kg/hour

     • Drugs to be added to the maintenance fluid (e.g. 1000 ml of Normosol)

     • Morphine to be added in mg = (0.1 mg/kg/hour ÷ 2.0 ml/kg/hour) × 1000 ml = 50 mg

     • Lidocaine to be added in mg = (3.0 mg/kg/hour ÷ 2.0 ml/kg/hour) × 1000 ml = 1500 mg

     • Ketamine to be added in mg = (0.18 mg/kg/hour ÷ 2.0 ml/kg/hour) × 1000 ml = 90 mg

The volume of each drug to be added to the maintenance fluid given the concentration of the drugs (morphine-10 mg/ml, lidocaine-20 mg/ml, and ketamine-100 mg/ml) will be: morphine - 5 ml, lidocaine - 75 ml, and ketamine - 0.9 ml.

The total volume of the drugs to be added to the bag of fluid will be 80.9 ml. Before adding the drugs, 80.9 ml of fluid has to be discarded for more accurate dosing.

The dog weighs 20 kg in this example. This means that the fluid should be delivered at the rate of 40 ml/hour (2.0 ml/kg/hour × 20 kg). This preparation can also be used in dogs of different body weights. If you have another dog in the clinic that needs CRI analgesia and maintenance fluid that weighs 30 kg, you simply change the infusion rate to 60 ml/hour (30 kg × 2.0 ml/kg/hour). CRI dose rate for the analgesic drugs will be the same.

It is important to remember that this formula will work if the CRI dose of the drug is in mg/kg/hour! (See table below.)

Table 1: Dosages for Drugs Used in CRI for Pain Control.

For the syringe pump technique, the total volume of the solution (saline and the drugs) is determined by the approximate duration of surgery and body weight of the animal. The size of the largest syringe in the clinic will be the maximum volume that can be prepared. This is usually 60 ml. The rate of fluid infusion should be ≤ 1.0 ml/kg/hour. The bigger the patient, the lower the fluid rate should be used to reduce the number of times a syringe is refilled with drugs and diluent during the surgical procedure. For example, if 1.0 ml/kg/hour is used as fluid rate for a 40-kg dog, 40 ml/hour is needed. If the procedure lasts for 3 hours, total volume needed will be 120 ml; this means that a 60-ml syringe has to be refilled once. The solution for this is to reduce the fluid rate until the total volume for 3 hours will be equal or less than 60 ml or simply use this formula to determine the fluid rate:

     • Fluid rate = [Maximum volume in the syringe ÷ body weight (kg)] ÷ hours of procedure

     • Calculation of the fluid rate for a 40-kg dog that will have approximately 3 hours of surgery is shown below:

     • Fluid rate = [60 ml ÷ 40 kg] ÷ 3 hours = 0.5 ml/kg/hour

     • Drugs needed for this preparation will be calculated given the formula above.

     • Morphine to be added in mg = (0.1 mg/kg/hour ÷ 0.5 ml/kg/hour) × 60 ml = 12 mg (1.2 ml)

     • Lidocaine to be added in mg = (3.0 mg/kg/hour ÷ 0.5 ml/kg/hour) × 60 ml = 360 mg (18 ml)

     • Ketamine to be added in mg = (0.6 mg/kg/hour ÷ 0.5 ml/kg/hour) × 60 ml = 72 mg (0.72 ml)

     • These drugs will be put in a 60-ml syringe and then saline is added to make a total volume of 60 ml. The syringe pump is set at 20 ml/hour (40 kg × 0.5 ml/kg/hour).