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ANALGESIC CONSTANT RATE INFUSIONS

Bob Stein, Dave Thompson, and the VIN Gang

October 2005 (edited 11-11)

 

A constant rate infusion/manually controlled infusion (CRI/MCI) of analgesic drugs is a simple and effective means of improving patient comfort. Various formulations can be used as a constant rate infusion; the protocol chosen depends on the patient and the degree of pain experienced or anticipated. Some of the commonly used drugs include the following:

KETAMINE -- NMDA (N-methyl-D-aspartate) receptors are present in the dorsal horn of the spinal cord and certain areas within the brain. Intense and/or chronic noxious input to the dorsal horn cells (mediated principally by C-fibers) results in the removal of magnesium from the NMDA receptors and their activation by glutamate. This causes prolonged depolarization of spinal neurons (an increase in the magnitude and duration of neuron firing), which leads to an “amplification” of the pain response. This is a significant part of the process of central sensitization (an increase in the excitability of spinal neurons) and may result in hyperalgesia (an excessive response to a painful stimulus) and allodynia (a painful response to a normally non-painful stimulus).

It is readily apparent that blocking (antagonizing) the NMDA receptors will help to minimize excessively painful responses. Additionally, studies suggest that antagonizing these receptors improves opioid receptor sensitivity, reduces opioid tolerance and minimizes the development of rebound hyperalgesia (the phenomenon of markedly increased pain when opioids are withdrawn).

Ketamine is the most commonly used antagonist of NMDA receptors in veterinary medicine. While its effects as a dissociative anesthetic at standard doses are well known, a new realm of activity occurs when it is delivered at sub-anesthetic doses. At constant rate infusion doses, ketamine blocks receptor activity without causing any dissociative or other adverse effects.

It should be noted that a microdose ketamine CRI should not be used as a sole means of analgesia. It is intended to augment other pain relievers, and should always be used in conjunction with opioids or other analgesics.

MORPHINE -- When combined with ketamine in a constant rate infusion, significant analgesia is achieved. The steady-state levels of morphine help to avoid some of the “peak and valley” effects seen with prn administration of opioids. Additionally, its use intraoperatively (as a “piggyback” onto anesthetic maintenance fluids) serves to reduce the amount of anesthetic gas required, which can be useful in decreasing the risk of hypotension.

It can be used in cats at the low end of the dosing spectrum (higher rates may induce significant dysphoria and excitation).

While other opiods can be substituted for morphine, we have elected to only include information for one other mu agonist, fentanyl, in the dosing information section. This reference is not intended to be an exhaustive review of all CRI options but to serve as a solid but basic reference for those adding CRI analgesia to their practice.

LIDOCAINE -- The addition of lidocaine has several benefits. For intractable/very severe pain, it adds to the analgesia and sedation. Lidocaine is reported to have some cytoprotective effects, such as weak calcium channel inhibition (which may be helpful in preventing reperfusion injury), and reduced neutrophil chemotaxis and platelet aggregation (which could help significantly in cases with the potential for DIC or SIRS, including GDV’s and splenectomies). Also, lidocaine has some activity in preventing ileus (potentially useful for abdominal procedures).

Various dosage rates of lidocaine have been advocated. Rates as low as 10 ug/kg/minute (0.6 mg/kg/hour) may provide analgesia, though it may take up to 50 ug/kg/minute (3 mg/kg/hour) for the full cytoprotective and anti-ileus effects. For feline patients, high dose rate CRIs should be limited to 2 hours duration after which dose rates should be reduced to between 10 to 25 ug/kg/min (0.6 to 1.5 mg/kg/hour) for up to an additional 4 hours duration.

CRIs can be delivered through the IV fluid bag route or directly through a syringe pump. The IV fluid bag route is attractive because it allows for precise delivery rates using equipment already available at most practices. The simplest method involves a single fluid bag providing both the drug delivery as well as the patient’s fluid needs. The downside to this method is the inability to adjust the fluid rate without changing the drug delivery rate. To maximize the flexibility of this method you generally need to pick a midrange dose rate so that adjustments in patient fluid need don’t take you outside of the preferred drug dose rates.

You can expand your flexibility by running two separate fluid lines through two different IV fluid pumps. In the two-pump model, the CRI drugs would be delivered at a very low rate (ex. 1 ml/kg/hr) while the patient’s additional fluid needs are separately managed through the second line. This allows for total flexibility of drug and fluid delivery but requires two pumps and double IV access.

While the calculations of the various CRI delivery options may seem daunting, this headache has been eliminated by easy to use calculators directly available online at: VASG Drug Delivery Calculators. This calculator allows you to vary the IV fluid bag size, fluid delivery rate, and drug dose rates to satisfy any conceivable combination.

Although the authors do not generally recommend using gravity administration for analgesic CRIs this is an option that may be considered. The more current VASG calculators allow for the determination of gravity delivered drip rates. Working through a buretrol, you maximize control over drug delivery while also setting a limit to the maximum amount of drug delivered.

Syringe pumps may be the most ideal way to deliver CRI drugs as it separates the drugs from any fluid related concerns. Programmable syringe pumps like the Medfusion 2001 and 2010i may be found on the secondary market for $500.00 to $1,000.00. The Razel Scientific Company makes very solid volume delivery based syringe pumps that cost $100.00 to $200.00 used and $550.00 to $800.00 new (http://www.razelscientific.com).

When starting to explore CRI use, running a single agent ketamine CRI at 0.6 mg/kg/hr dose rate is a good start point. This should enhance the preanesthetic opioid analgesia without having too dramatic an effect on the overall patient appearance or inhalant agent needs. After the staff has developed an initial comfort zone with ketamine only CRIs consider adding lidocaine and morphine at the lower end of their dose rate range. Gradually work up to midrange combinations of the three drugs as the staff’s comfort zone expands, allowing the staff to see how the inhalant needs of the average patient decline as the CRI drug effects increase. The final step involves upper dose rate deliveries for the more painful procedure expecting significant reductions in the patient’s inhalant requirements.

Loading doses, which may well be included in the preanesthetic and induction medications, should precede CRIs. Loading doses are needed prior to the initiation of the CRI in order to achieve initial therapeutic blood levels. Otherwise, it would take 3 to 5 half-lives of each drug to reach steady state drug levels.

CRIs are inexpensive tools. An 8 hour mid-dose rate morphine/lidocaine/ketamine CRI for a 20 kg patient costs the practice less than $1.50 (drug costs). As with any drug use, the suitability of a given drug infusion should be based on a sound understanding of that drug’s use in a patient of that given health status. It is beyond the scope of this review to discuss detailed drug suitability issues. 

 

CRI Dosing Information

KETAMINE (100 mg/ml) - 2 to 20 ug/kg/minute (0.12 to 1.2 mg/kg/hr).

  • An initial 0.25 to 0.50 mg/kg IV bolus is given to rapidly achieve initial therapeutic blood levels of the drug (while the CRI is intended to maintain, or very slowly, increase blood levels). Failure to administer this "loading" dose will result in an excessive delay in the drug reaching therapeutic levels.
  • Ket/val inductions and telazol inductions both provide adequate loading doses (tiletamine provides the same NMDA antagonism as ketamine).
  • 2 to 20 ug/kg/min = 0.002 to 0.020 mg/kg/min.

 

MORPHINE (15 mg/ml) - 2 to 6 ug/kg/minute (0.12 to 0.36 mg/kg/hr).

  • If no previous mu agonist has been given, administer 0.5 mg/kg of Morphine IM (or very slowly IV) to rapidly achieve initial therapeutic blood levels.
  • Morphine is light sensitive.  Make sure the syringe or IV bag is covered to protect the morphine from light when using long-term morphine CRIs.
  • 2 to 6 ug/kg/min = 0.002 to 0.006 mg/kg/min.

LIDOCAINE (20 mg/ml) - 10 to 50 ug/kg/minute (0.6 to 3.0 mg/kg/hr).

  • An initial 0.5 to 1 mg/kg IV bolus is given to rapidly achieve initial therapeutic blood levels. Typically the lower dose is used for feline patients.
  • Given the volume of 2% lidocaine this is, a similar volume of the diluent should be removed from the IV bag BEFORE any other drugs are added.
  • Lidocaine is light sensitive too. Make sure the syringe or IV bag is covered to protect the lidocaine from light when using long-term lidocaine CRIs.
  • 10 to 50 ug/kg/min = 0.010 to 0.050 mg/kg/min.

GENERAL INFORMATION

  • All three drugs are used routinely in dogs and in any combination.
  • Cats - the routine use of morphine CRIs in cats is not common. But it can be an effective option if the feline patient is monitored closely for dysphoric trends. Always start at the low end of the opiod CRI dose range.
  • Cats - lidocaine CRIs have been used extensively by the two main authors over a 7+ year timeframe without any clinically relevant adverse patient events. When used in cats, limit high dose rate (50 ug/kg/min) infusions to 2 hours duration or less then reduce dose rate to 10 to 25 ug/kg/min for up to an additional 4 hours duration. As with any patient, monitor carefully for seizure activity and cardiac abnormalities (myocardial depression). 10 ug/kg/min = 0.010 mg/kg/min = 0.6 mg/kg hr.
    • Still curious about lidocaine CRI use in cats? Take a look at a short set of PPT slides that demonstrate data from published lidocaine CRI studies with clear distinction between standard CRI dose rates in use in practice today versus the point at which statistically significant adverse patient effects were noted. Once the file is downloaded and opened, press F5 to start slideshow.
    • Need a free PPT viewer?
    • Want to access the slides as webpages? Click here
  • It is not uncommon to use a ketamine only or lidocaine/ketamine CRI bag over several patients, switching IV extension lines between patients. When morphine is added to the CRI, the bag is dedicated to that single patient. The amount of morphine drawn up and the amount unused is carefully recorded in the controlled drug logs.
  • Ketamine/morphine/saline solutions have been shown to be stable for at least 4 days.
  • D5W as well as other fluids are acceptable diluents.

 

EXAMPLE KETAMINE RECIPE

This simple recipe is based on routine supportive fluid rates of 10 to 20 ml/kg/hr.
This is the recommended starting recipe for those new to CRI analgesics.
The following recipe can be used in dogs and cats.

KETAMINE: Add 60 mg ketamine (0.6 ml) to 1000 ml fluids

  • Deliver at normal anesthesia supportive fluid rate of 10 ml/kg/hr = 10 ug/kg/min or 0.6 mg/kg/hr.

GENERAL INFORMATION

  • Rate can be doubled to 20 ml/kg/hr to deliver 20 ug/kg/min.
  • If higher fluid rates are needed, add a second fluid line to meet the patient’s need.
  • Remember the loading dose requirement detailed above.
  • This recipe assumes that the ketamine concentration is 100 mg/ml.

 

EXAMPLE MK RECIPE

This simple recipe is based on a 1 ml of the final dilution/kg/hr fluid rate.
The following recipe can be used in dogs and cats.

KETAMINE: 60 mg/500 ml = 0.6 ml/500 ml diluent = 1.2 ml/1000 ml diluent

  • Deliver at 1ml/kg/hr fluid rate = 2 ug/kg/min or 0.12 mg/kg/hr
  • This recipe assumes that the ketamine concentration is 100 mg/ml.

MORPHINE: 60 mg/500 ml = 4 ml/500ml = 8 ml/1000 ml

  • Deliver at 1ml/kg/hr fluid rate = 2 ug/kg/min or 0.12 mg/kg/hr
  • This recipe assumes that the morphine concentration is 15 mg/ml.

GENERAL INFORMATION

  • It’s easy then to just enter the patient's wt (in kg) in the infusion pump for the proper initial fluid rate.
  • Dogs – fluid rates can be increased up to 3 ml/kg/hr without exceeding the dosage guidelines for either of the drugs.
  • Cats – fluid rates can be increased up to 3 ml/kg/hr but may cause unwanted dysphoria in awake feline patients. Monitor closely and reduce rate if dysphoria occurs.
  • To substitute fentanyl for morphine at a dose equipotent to the morphine dose above add:
    • FENTANYL (0.05 mg/ml): 0.6 mg/500 ml = 12 ml/500 ml diluent = 24 ml/1000 ml diluent.
      • Deliver at 1ml/kg/hr fluid rate = 0.02 ug/kg/min or 0.0012 mg/kg/hr
    • Given the volume of fentanyl this is, a similar volume of the diluent should be removed before any other drugs are added.
    • For dogs, the fluid rate can be increased up to 3 ml/kg/hr as noted above.
  • Remember the loading dose requirements detailed above.

 

EXAMPLE MLK RECIPE

This simple recipe is based on a 1 ml of the final dilution/kg/hr fluid rate.
The following three drugs can be used in any combination for dogs.

KETAMINE: 60 mg/500 ml = 0.6 ml/500 ml diluent = 1.2 ml/1000 ml diluent

  • Deliver at 1ml/kg/hr fluid rate = 2 ug/kg/min or 0.12 mg/kg/hr
  • This recipe assumes that the ketamine concentration is 100 mg/ml.

MORPHINE: 60 mg/500 ml = 4 ml/500ml diluent = 8 ml/1000 ml diluent

  • Deliver at 1ml/kg/hr fluid rate = 2 ug/kg/min or 0.12 mg/kg/hr
  • This recipe assumes that the morphine concentration is 15 mg/ml.

LIDOCAINE: 500 mg/500 ml = 25 ml/500 ml diluent = 50 ml/1000 ml diluent

  • Deliver at 1ml/kg/hr fluid rate = 17 ug/kg/min or 1.0 mg/kg/hr
  • This recipe assumes that the lidocaine concentration is 20 mg/ml.

GENERAL INFORMATION

  • Just enter the patient's weight (in kg) in the infusion pump for the proper initial fluid rate.
  • Don’t forget to remove a volume equal to the lidocaine volume from the diluent bag before adding any of the drugs planned for the CRI.
  • Remember the loading dose requirements detailed above.
  • Dogs – fluid rates can be increased up to 3 ml/kg/hr without exceeding the dosage guidelines for any of the drugs (irrespective of the drug combinations).
  • Cats - lidocaine CRIs have been used extensively by the two main authors over a 7+ year timeframe without any clinically relevant adverse patient events. When used in cats, limit high dose rate (50 ug/kg/min) infusions to 2 hours duration or less then reduce dose rate to 10 to 25 ug/kg/min for up to an additional 4 hours duration if needed. As with any patient, monitor carefully for seizure activity and cardiac abnormalities (myocardial depression).
    • Optional LIDOCAINE recipe for cats (20 mg/ml): 300 mg/500 ml diluent = 15 ml/500 ml diluent = 30 ml/1000 ml diluent
      • Deliver at 1ml/kg/hr fluid rate = 10 ug/kg/min or 0.6 mg/kg/hr lidocaine
  • To substitute fentanyl for morphine at a dose equipotent to the morphine dose above add:
    • FENTANYL (0.05 mg/ml): 0.6 mg/500 ml = 12 ml/500 ml diluent = 24 ml/1000 ml diluent.
      • Deliver at 1ml/kg/hr fluid rate = 0.02 ug/kg/min or 0.0012 mg/kg/hr
    • Given the volume of fentanyl this is, a similar volume of the diluent should be removed before any other drugs are added.
    • The fluid rate can be increased up to 3 ml/kg/hr as noted above.

ADDITIONAL CRI DRUGS AND DOSES

FENTANYL – 0.02 to 0.06 ug/kg/minute (0.0012 to 0.0036 mg/kg/hr).

  • Fentanyl’s  duration of effect  is only about 30 minutes. Undesirable effects will not linger as long as when morphine, hydromorphone, or oxymorphone are used
  • If no previous mu agonist has been given, administer 0.003 mg/kg of Fentanyl IM or IV to rapidly achieve initial therapeutic blood levels.
  • Given the volume of fentanyl this is, a similar volume of the diluent should be removed before any other drugs are added.
  • 0.02 to 0. 06 ug/kg/min = 0.00002 to 0.00006 mg/kg/min.
     
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Last modified: November 11, 2011 .