Constant rate infusions: Indications, calculations and applications in pain management (Proceedings)

Systemic administration of analgesic agents is the most common route of delivery during the perioperative period. These routes would include delivery by transdermal, subcutaneous, intramuscular, intra-articular and intravenous. Intravenous administration of analgesic agents may be timed to be given intermittently or by constant rate infusion. It is often most desirable for patient management to achieve and maintain a steady rate of delivery to prevent the "roller coaster" effect of intermittent bolus administration as well as maintain a therapeutic concentration. Ideally, all CRIs should be administered via a syringe pump to ensure accurate dosing.

Some disadvantages of CRI analgesic management would include the very obvious reason that any agent being given intravenously must be under constant supervision of an attending veterinary nurse as the IV lines might become kinked, disconnected or the IV catheter may lose patency due to patient interference. Further study is ongoing for dome of the agents used in CRIs to determine the best protocol for prolonged use (over 24 hrs of administration). Syringe pumps at this time are still fairly expensive.

Constant rate infusions may include multiple agents for a multimodal approach to analgesia or a single analgesic agent.

Metric system:

The majority of drug dosages are calculated in either milligram (mg) or microgram (mcg) per kilogram (kg) of body weight. This information provides concentration of the drug.

     1000mg = 1 gram (gm)

     1000mcg = 1 mg

     Ergo there are 1,000,000 mcg per gram

Volume Equivalents

     Liter (L) = 1,000 milliliters (ml)

     500ml (0.5L) = 1 pint (473ml) = 2 cups = 16 ounces

     (Weight = 1 pound)

     15 ml = 1 tablespoon

      5 ml = 1 teaspoon

     30 ml = 1 ounce

     240 ml= 1 cup = 8 ounces

Percentages

Agents with doses written as % concentration represent grams per 100ml

     For example: Furosemide = 5% solution =50 mg/ml

                              Lidocaine = 2% solution = 20mg/ml

                              Dextrose 50% = 500mg/ml

Calculating agent based on body weight

Lidocaine 2% to be given at a one time 2mg/kg dosage.

     Body wt (kg) x dose of agent concentration =

     lidocaine = 20mg/ml

               dose = 2mg/kg

               body weight = 10kg

     Dose x BW (kg) = 20mg

     Dose/concentration = 20mg/mg = 1 ml

Calculating fluid drip rate (gravity flow)

There are three standard IV administration sets available for use with gravity flow vs. the specialty administration tubing required for some fluid pumps.

     Microdrip sets are calibrated to equal 60 drops per ml

     Standard drips sets (called by some macrodrip) are calibrated to equal 15 drops per ml

     Flashball drip sets (again called macrodrip by some) are calibrated to equal 10 drops per ml.

To calculate the desired volume to be delivered over a set time period:

     Volume (to be infused) x drip set rate

     Divide by length of time in minutes

     Equals drops per minute

For example:

     Class I patient for IV administration during surgery

     LRS to be given at 10ml/kg/hr for the first hour of anesthesia

     Patient weighs 12 kg

     Standard drip set is available for use (15 drops/ml)

     10 (ml) x 12 (kg) = 120ml divided by 60 (minutes) = 8 ml per minute

To obtain drops per minute:

     Divide mls/minute by drops/ml of drip used

     8 (ml) divided by 15 = 0.53 drops per second

KEEP IT SIMPLE SWEETHEART RULE:

Desired mls to be delivered over 1 hour x #drops/ml (drip set dependant) divided by 3600 (60 minutes x 60 seconds)

     Class I patient for IV administration during surgery

     LRS to be given at 10ml/kg/hr for the first hour of anesthesia

     Patient weighs 12 kg

     120mls x 15drops (standard drips set) = 1800 drops

     divided by 3600 = 0.5 drops per second

     120mls x 60drops (microdrip set) = 7200 drops

     Divided by 3600 = 2 drops per second

I find this formula to be an easier method to calculate fluid administration. For the second or subsequent hours if the rate is to be cut by half simply divide by 2 to determine hourly rate as well as drops per second.

CRI Calculations

Example if delivered via a syringe pump:

     Fentanyl CRI following a Fentanyl bolus at 2 mcg/kg/hour

     Mcg (dose) per kg (patient body weight) per hour

     2mcg/kg = mcg/hour divided by concentration = mls/hour

     2mcg x 12kg = 24 mcg/hour divided by 50 mcg/ml = 0.48 ml/hour

     Lidocaine CRI following a Lidocaine bolus at 25 mcg/kg/min

     25mcg x 12kg = 300mcg/minute x 60 minutes =18,000 mcg/hour

     18,000mcg. (18mg.) divided by 20mg = 0.9ml/hour

     Example if delivered via gravity flow administration set:

     Hourly dose (dose x weight/kg)

     Drug concentration

     Desired fluid rate (LRS, etc.) volume of bag divided by mls/hour.

     Multiply hours x patient's dose (number of mgs to be added to the volume)

     Divide the total dose by the drug concentration

     Fentanyl at 2mcg/kg/hour – 2mcg x 12 kg = 24mcg.

     Divided by 50 mcg = 0.48ml Fentanyl/ hour

     15mls LRS/hour divided by 250mls =16.6 hours

Sample dosages for single agent analgesic CRIs

The following listed multimodal combinations may be added to IV crystalloid fluids and delivered at either 10ml/kg/hr or 5ml/kg/hr using the following table adapted from Dr. W. Muir, Chapter 9, Small Animal Anesthesia and Analgesia, Dr. G. L. Carroll, editor, Blackwell publishing, 2008

Alpha 2 agonists

     Used in veterinary medicine to produce:

     sedation, analgesia, anxiolysis

Dexmedatomadine

     Alpha 2 agonist

     Profound sedation and analgesia

Significant cardiovascular effects

     Increase in total peripheral resistance due to vasoconstriction

     Bradycardia

     Decreased cardiac output (due primarily to bradycardia)

     Reversal: Antisedan

Current thinking for CRI dosage administration:

Loading dose of 1 mcg/kg with a CRI of 1 mcg/kg/hr

This agent should be used cautiously in the canine patient and I would not recommend it for any patient with existing cardiovascular disease or the trauma patient that would be susceptible to traumatic myocarditis and its potential for arrhythmic activity.

Mu opioids

Fentanyl

Pure mu agonist

Causes dose dependant bradycardia (increase in vagal tone)

Bradycardia is responsive to anticholinergics – atropine/glycopyrrolate

Single dose IV is very short acting – up to 20 minute duration.

Loading dose for CRI administration – 2-5 mcg/kg IV and a management rate of 2-6 mcg/kg/hr.

This CRI can be utilized with several other agents for the management of moderate to severe pain management as well in combination with a benzodiazepine for MAC reduction for critical or cardiac anesthetic management as it can reduce MAC settings when used in combination with an inhalant anesthetic agent. Anesthetic adjunctive dosages for intra-operative administration may range from 10-48 mcg/kg/hr as these patients have airway and ventilatory support provided. Higher rates of administration of fentanyl will cause a dose related permissive hypercapnea. It is recommended that at the intra-operative dose rates of fentanyl CRIs that respiratory monitoring include the use of a capnograph to prevent inadvertent hypoventilation/hypercapnea.

Hydromorphone:

morphine-like agonist, primary activity at the mu receptors.

Cardiovascular effects:

bradycardia due to central vagal stimulation,

alpha-adrenergic depression causing peripheral vasodilaiton, decreased peripheral resistance

Baroreceptor inhibition.

A loading dose of 0.05mg/kg given IV and followed by a CRI dosed at 0.01-0.04 mg/kg/hour may be administered for intra as well as post-operative analgesic management.

Oxymorphone

Similar effects to hydromorphone

Case management of side effects the same

Morphine

No direct myocardial effect

Dose dependent bradycardia – responsive to anticholinergics. Regardless of the route of administration whether IM or IV as a CRI, morphine can result in hypothermia and panting.

To avoid histamine release, which may have a profound effect of systemic blood pressure causing hypotension, morphine when intended as a CRI should have a loading dose calculated at 0.15-0.5 mg/kg diluted with saline and given over a minimum of 5 -10 minutes. CRI management when used in combination with other agents, the dosage is typically 3.3 mcg/kg/minute.

Mixed agonist/antagonists

Butorphanol

Partial agonist/antagonist. Similar to buprenorphine in cardiovascular/respiratory effects.

Loading dose of 0.1-0.2 mg/kg followed by a CRI management dose of 0.1-0.2 mg/kg/hour. Good management of mild to moderate pain in post-operative cats if a CRI is indicated.

Dissassociative agents

At accepted dosage for restraint or anesthetic induction, these agents will indirectly stimulate the cardiovascular system by increasing sympathetic tone thereby causing an increase in heart rate, cardiac output, mean arterial pressure, pulmonary arterial pressure and central venous pressure.

Additionally, due to the increase in heart rate, they will cause an increase in myocardial work and oxygen demand/consumption.

Ketamine

Does not produce a true anesthetic state – dissociation from the environment with analgesia and sensory loss. NMDA antagonists are useful to prevent "wind up" (central hyper sensitization) of the NMDA receptors found in the dorsal horns of the spinal cord. Chronic pain, surgery or trauma can stimulate these receptors to the point where the response threshold is decreased and neural transmission to the brain causes an increase in pain perception. Ketamine is an excellent addition for management of chronic diseases leading to surgical repair both intra-opearative and for post-operative analgesic management.

By decreasing the dosage for CRI administration, undesirable side effects such as dysphoria/hallucinations do not seem to occur.

Dosage for CRI administration:

Loading dose of 0.5 mg/kg IV followed by a CRI of 10 mcg/kg/minute is an excellent choice intra-operatively for patients with chronic pain experiencing the "wind up" phenomenon.

Post –operative CRI dosing is reduced to 2 mcg/kg/minute.

Lidocaine without epinephrine

Lidocaine without epinephrine may be administered as a CRI both intra-operatively as an adjunctive agent to provide a MAC (mean alveolar concentration) sparing effect on inhalants anesthetic agents, provide a free radical scavenging benefit, protection against cytokines during reperfusion events as well as provide some control of ventricular arrhythmias. Consider this addition for management of the acute abdomen patient or those withlumbar sacral disease. The lower dosage used in typical analgesia management ranges from 25-50 mcg/kg/minute. A loading dose of 1-2 mg/kg IV should be given over a 2 minute period to avoid transient hypotensive effects. This should not be used in patients that are shocky, hypovolemic or those having SA or AV nodal disease. Not recommended for use in feline patients due to the lower toxic dose.