Anesthesia and Perioperative Multimodal Therapy

Review of Pain Pathways

Acute pain usually is nociceptive pain that is caused by noxious stimulation due to injury, disease process, or abnormal function of muscle or viscera. Tissue damage leads to activation of the small nerve endings of nociceptive cells, as well as local inflammatory cells such as mast cells, macrophages, lymphocytes, and platelets. Numerous inflammatory mediators are released that cause pain via nociceptive stimulation and increased excitability of nerve endings. Similar to primary nerve fibers, dorsal horn neurons have many excitatory and inhibitory transmitters and various pain receptors. Although this is a very simplified explanation of a very complicated system, this quick review is meant to illustrate that a variety of pain receptors and mediators can be manipulated and controlled via pharmacologic intervention.

The four levels of pain processing are transduction, transmission, modulation, and perception. Transduction occurs at the tissue level with the release of local inflammatory mediators and stimulation of nociceptive neurons. Drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), antihistamines, local anesthetic creams, local anesthetic skin injections, and opioids work at this level. The process of transmission occurs along the neuron itself. Local anesthetics work here at the level of transmission in the form of peripheral nerve blocks, plexus blocks, and neuraxial blocks, such as a spinal or an epidural. Modulation is seen at the level of the spinal cord, primarily in the dorsal horn. Spinal opioids, alpha-2 agonists, N-methyl-d-aspartate (NMDA) receptor antagonists, and NSAIDs bind to receptors in the dorsal horn. Last, the brain’s perception of pain is affected by general anesthetics, systemic opioids, and alpha-2 agonists.

Although preemptive analgesia has received mixed reviews in the human medical arena, ample evidence suggests that if it is used adequately, some benefit is derived. Several key techniques make preemptive analgesia more successful. First, the entire surgical field should be covered. Second, onset of action of medications must be taken into account and preemptive medications must be given far enough in advance of the surgical stimulus. Next, the analgesia must be adequate enough and deep enough to block transmission of pain pathways. And last, the analgesia must last long enough into the postoperative period to give adequate pain control (Macres et al, 2009). The efficacy of preemptive analgesia depends on its ability to blunt the “windup” of pain (the volley of afferent impulses in the spinal cord that result from stimulation of a nociceptor). A single preemptive intervention may adequately control initial operative pain responses. However, unless this is followed by adequate and occasionally prolonged postoperative pain control, central sensitization to pain can still occur. This underscores the necessity of adequate follow-up of pain control therapy. It is important to realize that one regimen will not work for all situations or all patients. A customized, multimodal approach is one of the best techniques for providing optimal analgesia for surgical patients in the operating room and during the postoperative period.

Pain Assessment

Multimodal analgesia is the natural extension of a balanced anesthetic technique. It is the attempt to manage pain at different receptor sites by using a variety of different drugs and techniques, thereby increasing the efficacy of the analgesic therapy and oftentimes lowering the doses of the individual drugs needed. By using smaller doses of several medications instead of a large bolus of one drug, side effects such as apnea and hypotension can be reduced in both severity and duration. Thus, a broad knowledge base of the different anesthetic drugs—their onset and duration of action as well as their side effects—is extremely helpful in managing the surgical patient.

Before any discussion of different modalities of pain control is presented, how to assess the level of pain in our animal patients should be discussed (Table 12-1). Numerous types of assessment techniques are available, and none is perfect. In the human patient, the visual analog scale is one of the most common pain scales currently in use because it allows the patient to assess his or her own pain and assign a number to that pain. However, this can be problematic even with patients who speak the same language as the caregiver. Patients have different tolerances and expectations of the surgical experience, and a 5 out of 10 pain level often has different implications for different people. These same assessment problems are magnified 10-fold with any attempt to assess pain in our veterinary patients. Therefore an understanding of how animals exhibit pain is very helpful in knowing when and how to treat the surgical patient.

TABLE 12-1

Behavioral and Physiologic Responses to Pain

Modified from Carroll GL: Small animal pain management, Lakewood, Colo., 1998, American Animal Hospital Association Press.

First and foremost, it is important for the veterinarian to find a pain scale that the staff may be able to utilize quickly, easily, and consistently. The role of a pain scale is to guide analgesic therapy, not to deny it (Mich and Hellyer, 2009). It can be helpful in providing timely and adequate pain management and in guiding the tapering of analgesic therapy. When choosing a pain scale guide, one needs to recognize each scale’s strengths and limitations.

Two behavior-based pain scales stand out in being easy to use and having less bias. The Glasgow Composite Measure Pain Score (GLCMPS)–Short Form was developed for use in dogs in acute pain (Reid et al, 2005). Numbers from 0 to 4 or 5 are assigned to differing behaviors and are tabulated to create a score on which analgesic therapy can be based (Fig. 12-1). The two parts consist of initial observation followed by a leash walk and a hands-on portion. Potential advantages that make it more accurate than many scales include limited bias from the observer, ease of use, and specific behaviors identified as being present or absent. One significant disadvantage is that it was developed for dogs, but not for cats. Additionally, it has limited value in the immediate postoperative period because postanesthetic sedation is not part of the evaluation (Mich and Hellyer, 2009). A modified form of the Glasgow Pain Scale has been studied and was found to be effective in assessing acute pain in dogs (Murrell et al, 2008). In this study, sedation was incorporated into the evaluation. The second behavior-based pain scale that deserves mention is the Colorado State University Veterinary Medical Center Acute Pain Scale (Fig. 12-2). It was designed to be a user-friendly scale with verbal and visual descriptions. Similar to the GLCMPS–Short Form, it assigns numbers from 0 to 4 and has both observational and hands-on sections. A section for evaluating body tension is also included. This is the first scale designed to address the feline population (Fig. 12-3).

FIG 12-1 Glasgow Composite Measure Pain Score–Short Form. (From Reid J, Scott M, Nolan A: Development of a short form of the Glasgow Composite Measure Pain Scale [CMPS] as a measure of acute pain in the dog, Vet Anaesth Analg 32:7, 2005.)

FIG 12-2 CSU Acute Pain Scale for the Dog (Modified from Colorado State University Veterinary Medical Center Canine Acute Pain Scale). (Courtesy Peter Hellyer, Samantha Uhrig, Narda Robinson.)

FIG 12-3 CSU Acute Pain Scale for the Cat (Modified from Colorado State University Veterinary Medical Center Canine Acute Pain Scale). (Courtesy Peter Hellyer, Samantha Uhrig, Narda Robinson.)

Be aware that when one uses preconceived ideas regarding how painful a procedure should be (or how an animal should respond to that disease, trauma, or procedure) to guide therapy, personal bias may result in denial of appropriate analgesic therapy for the patient. Individual variation greatly impacts patient response and should always be considered. Behavioral response, a subjective determination, is relied on more than any other single variable when the presence of pain is determined. Pain behaviors are not very adaptive, so these signs may come late in the progression of disease, once all coping mechanisms have been exhausted. Regardless of the scoring system chosen, it is helpful to do in-house training with staff, so that variation from one staff member to another can be minimized. If on examination the patient is determined to have pain, treatment and reevaluation should be undertaken.

NOTE • Do not spend much time convincing yourself that a patient is in pain. Treat the patient early for pain, and if there is no improvement or if unwanted side effects occur, discontinue or change the therapy.

Monitoring

Monitoring in the perioperative period is extremely important. Once sedatives and analgesics have been given, it is important to visually monitor the patient. Depending on the medications utilized, changes in blood pressure, heart rate, mentation, temperature, and respiration should be expected and monitored. Although monitoring begins with visual assessment of the patient, sicker patients may need additional monitoring of oxygen saturation, pulse rate, and blood pressure once sedatives have been given. After induction, other means of monitoring such as end-tidal CO₂ (EtCO₂), electrocardiograph (ECG), and temperature should be added. The arsenal of anesthetic medications available today allows us to perform many surgeries and procedures, but these same medications come with a variety of side effects. There is no better way to prevent and treat these side effects than to continuously monitor the patient throughout the perioperative period.

Nursing Care

Good perioperative nursing care is imperative. To promote well-being, keep patients dry and warm, avoid clipper burns, remove dried blood, check bandages for tightness, position patients so that pressure is not placed on surgical sites, and turn those that are unable to turn themselves. A dry, warm, quiet environment should be provided both for induction of anesthesia and for recovery from surgery. The mouth should be handled carefully during induction and extubation to prevent oral, lingual, tracheal, or dental injury. Use adequate intraoperative and postoperative padding and careful positioning of patients to assist in preventing trauma to nonsurgical sites. Lubrication of the eyes helps to prevent corneal drying. Before extubation, empty the bladder to prevent postoperative discomfort, especially if the surgery is longer than 1 to 2 hours, if large volumes of fluid are given, or if the patient is unable to ambulate shortly after recovery from anesthesia.

Pain is intensified in anxious and sleep-deprived patients. Preventing sleeplessness and anxiety in the perioperative period enhances postoperative pain management. Tranquilizers or sedatives may reduce perioperative anxiety and make the experience less distressing. Sedation may be necessary to curtail activity in rambunctious patients, but this needs to be done with care. Is the patient feeling well enough to potentially overextend activity, and does movement need to be restricted with sedation? Or is the patient restless and uncomfortable? If so, analgesia, not sedation, is warranted. To prevent masking signs of pain, do not use acepromazine or benzodiazepines alone in patients with pain. Usually the pain should be treated first, then the sedative administered if still warranted.

Premedications

Numerous choices are available for premedication of the veterinary patient. Before deciding which premedication to use, one first must decide what it is that needs to be accomplished with the premedication. Is it restraint of the aggressive animal? Is it part of the pain protocol in painful surgeries? Or is it necessary for calming an anxious patient? Once the goal of the premedication has been determined, then choosing one or more appropriate drugs is the next task. Fortunately, there are many premedications from which to choose, each with desirable and undesirable attributes (Box 12-1).

Box 12-1 Premedication for Dogs and Cats *

Give:

• Acepromazine ^† (0.02-0.05 mg/kg IV, IM, SC), or

• Dexmedetomidine ^† (2.5 µg/kg IV or 5 µg/kg IM), or

• Medetomidine ^† (5 µg/kg IV or 10 µg/kg IM), plus

• Diazepam (0.2 mg/kg IV), or

• Midazolam (0.2 mg/kg IV, IM), plus

• Morphine (0.1-0.2 mg/kg IV or 0.2-0.4 mg/kg IM), or

• Hydromorphone (0.1-0.2 mg/kg IV, IM), or

• Buprenorphine (0.005-0.02 mg/kg IV, IM) if only moderate pain anticipated, or

• Butorphanol (0.2-0.4 mg/kg IV, IM) if only mild pain anticipated

^*These medications have synergistic sedative effects. Monitor closely after administration. If unsure of dosage, give lower end of dose range and repeat if necessary. Remember, these drugs should be titrated to effect.

^†Should not be used in older or sicker patients.

Benzodiazepines

Benzodiazepines have five main pharmacologic effects: anxiolysis, sedation, anticonvulsant activity, spinal cord–mediated muscle relaxation, and amnesia. Except for amnesia, which can be neither proven nor disproven, all of these effects can be appreciated in our small animal species. It is the anxiety-reducing and sedative qualities that are most desirable for their use as premeds. Benzodiazepines have their mechanism of action at gamma-aminobutyric acid (GABA) receptors, the primary inhibitory neurotransmitters of the central nervous system (CNS). Because the benzodiazepines cause patients to become disinhibited, the behavioral response can vary from patient to patient and from species to species. Some animals become quiet and sedate. Others, when losing their inhibitions, can become more vocal, excited, dysphoric, and even aggressive. Dysphoria and aggressive behavior limit the use of benzodiazepines, especially when given alone in cats. These unwanted side effects can persist postoperatively when longer-acting drugs, such as diazepam, are used. Diazepam and midazolam provide more predictable sedation when administered with an opioid or sedative. Although numerous benzodiazepines are available, only three are widely used in veterinary anesthesia. All benzodiazepines are reversible with flumazenil. When used, flumazenil should be titrated to effect.

Diazepam

Diazepam is a highly lipid-soluble benzodiazepine with a prolonged duration of action. Because of its lipid solubility, it is rapidly taken up by the brain and redistributed to fatty tissues. It binds quickly to serum proteins, such as albumin, and is metabolized in the liver to active metabolites. These metabolites have prolonged half-lives and eventually are excreted by the kidneys. In dogs, the elimination half-lives of metabolites with high doses of diazepam can be as long as 6 hours. In cats, these half-lives are even longer—approximately 21 hours. These metabolites may have prolonged durations of action in elderly patients, especially those with compromised liver or kidney function.

Combining diazepam with opioids as a premedication attenuates the potential for excitability and produces more reliable sedation in many patients, especially dogs (see Box 12-1). Diazepam is often given at induction with ketamine, barbiturates, propofol, etomidate, or opioids. Its use in this combination takes advantage of the sedative and relaxation properties and allows reduced dosing of the other induction medications. As with other benzodiazepines, diazepam has minimal effect on the cardiovascular system. Additionally, very little respiratory depression occurs at lower doses. Tidal volumes will decrease with small increases in partial pressure of arterial carbon dioxide (PaCO₂). These changes are more pronounced when other respiratory depressants are given with diazepam.

Because of its insolubility, diazepam is dissolved in organic solvents. This makes intramuscular (IM) injection a poor route of administration because of pain of injection and variable absorption. Diazepam should be given as an intravenous (IV) injection and should be given slowly, preferably diluted with crystalloid carrier solution to decrease the potential for irritation and pain with injection.

Alpha-2 Agonists

In small animal veterinary medicine, the alpha-2 agonists most commonly used are medetomidine and dexmedetomidine. Historically, xylazine was used for many years, but it does not have selectivity for alpha-2 versus alpha-1 receptors, as do medetomidine and dexmedetomidine. Medetomidine is a racemic mixture, with dexmedetomidine being the active isomer. Therefore dexmedetomidine is twice as potent as medetomidine. Selective alpha-2 agonists may be used as premedication in healthy small animals for their sedative, analgesic, and muscle relaxant properties (Lemke and Creighton, 2010) (Table 12-2; see also Box 12-1). Even in low doses, they can augment the analgesic and anesthetic effects of other drugs. Both medetomidine and dexmedetomidine dosages are calculated using body surface area. This helps to reduce variations in sedative response from one type of body conformation to another. Premedication with 125 µg/m² or 0.5-1 µg/kg has been shown to reduce the quantity of induction drugs required, as well as the inhalant agent needed for maintenance of anesthesia. Constant rate infusion (CRI) and microdoses of medetomidine and dexmedetomidine have been used with success as part of balanced anesthetic protocols to reduce isoflurane requirements (see Box 12-2). A comparison of 1, 2, and 3 µg/kg/hr determined that a CRI of 1 µg/kg/hr, after a 2.5-5-mg/kg loading dose, had the most stable hemodynamics (Uilenreef et al, 2008).

Box 12-2 Low Dose and CRI Dosing for Select Drugs

Low Dose for Multimodal Approach to Analgesia

• Induction adjuvants

• Dexmedetomidine (0.5-1 µg/kg IV) or

• Medetomidine (1-2 µg/kg IV) plus

• Ketamine (0.5-1 mg/kg IV) plus

• Fentanyl (2-10 µg/kg IV PRN)*

Continuous Rate Infusion (CRI)

• Intraoperative and postoperative infusions

• Hydromorphone (0.025-0.1 mg/kg/hr IV) or

• Fentanyl (1-10 µg/kg/hr loading dose), then 10-30 µg/kg/hr intraoperatively and 2-20 µg/kg/hr IV postoperatively or

• Dexmedetomidine (2.5-5 µg/kg IV loading dose), then 0.5-1 µg/kg/hr or

• Ketamine (0.5 mg/kg IV loading dose), then 10 µg/kg/min IV CRI intraoperatively and 2 µg/kg/min IV CRI postoperatively

• FLK †

Fentanyl (1-5 µg/kg/hr IV) plus

Lidocaine (25-50 µg/kg/min IV) plus

Ketamine (2-5 µg/kg/min IV)

• MLK †

Morphine (3.3 µg/kg/min IV) plus

Lidocaine (50 µg/kg/min IV) plus

Ketamine (10 µg/kg/min IV)

^*For short-term pain relief.

^†Not recommended for use in cats.

TABLE 12-2

Dexmedetomidine-Butorphanol-Ketamine Combination in Healthy Cats *

^*Based on a 4.5 kg (10 lb) cat. All drugs (except atipamezole) can be mixed in one syringe and administered as a single IM injection. If given IV, the drug doses in this combination should be halved; however, if a deeper plane of anesthesia is desired, the full IM dose can be given IV.

^†If reversal is necessary.

^‡More invasive procedures should have a stronger opioid chosen for postoperative analgesia.

From Ko JC, Knesl O, Weil AB, et al: FAQs: analgesia, sedation, and anesthesia: making the switch from medetomidine to dexmedetomidine, Compend Contin Educ Vet 31(Suppl 1A):1, 2009.

The cardiovascular effects of dexmedetomidine and medetomidine are dose dependent and biphasic, with the initial phase of hypertension and reflex bradycardia lasting approximately 15 to 20 minutes after administration. This is followed by a decrease in sympathetic tone, resulting in vasodilation, hypotension, and bradycardia. Monitoring of blood pressure and heart rate is recommended. Before bradycardia is treated, blood pressure should be taken. If necessary, an anticholinergic (e.g., atropine, glycopyrrolate) may be used to treat the second phase of bradycardia when hypotension is also present. It has been shown that a marked hypertensive response occurs when atropine is given before dexmedetomidine (Alvaides et al, 2008). Because of this marked hypertension, anticholinergics are not recommended before alpha-2 agonists are administered or during the hypertensive phase (Ko et al, 2009). Because of blood pressure changes associated with these drugs, they are best used in healthy dogs and cats. Alpha-2 agonists are best avoided in hypotensive, hypertensive, hypovolemic, elderly, or critically ill patients. Respiratory function is maintained, but urine output and blood glucose are increased with both medetomidine and dexmedetomidine.

The alpha-2 agonists are reversible with yohimbine and atipamezole. Both reverse the sedative and analgesic effects. Atipamezole as an IM injection has been used to treat the bradycardia associated with alpha-2 agonists and probably is the drug of choice in hypertension-induced bradycardia. Once given, the sedative and analgesic effects are gone as well, which may interrupt or complicate the procedure. With life-threatening bradycardia and hypertension, atipamezole can be given as a single slow IV bolus (off-label) at a rate of 5 to 20 µg/kg IV over several minutes (Ko et al, 2009). This should be done only in an emergent situation.

Anticholinergics

Atropine and glycopyrrolate are anticholinergic medications often added to the premedication arsenal. With an increase in monitoring abilities, the routine addition of this class of drug to the premedication regimen is often unnecessary. Both atropine and glycopyrrolate act at parasympathetic cholinergic sites to increase heart rate and decrease salivation. Atropine has a greater effect on heart rate as compared with glycopyrrolate. However, glycopyrrolate has a slightly greater effect on decreasing oral secretions compared with atropine. Atropine and/or glycopyrrolate should be easily available for intravenous treatment of bradycardia in the anesthetized patient. At very low doses, a paradoxical decrease in heart rate can occur after administration. This occurs because of inhibition of presynaptic cholinergic receptors that are part of the sympathetic pathways (Stoelting and Hillier, 2006). This is more likely to occur with atropine than with glycopyrrolate because of the greater anticholinergic effects of atropine on the heart and because of its rapid onset of action. Usually this paradoxical bradycardia quickly resolves, but if necessary the dose can be repeated to cover more cholinergic receptors and obtain the desired cardiac effect. Glycopyrrolate and atropine are used with the anticholinesterases in reversing muscle paralysis from nondepolarizing muscle relaxants. The anticholinesterases can cause severe bradycardia that can lead to sinus arrest. Therefore an anticholinergic is given intravenously right before the anticholesterase or is mixed in the same syringe to be given together. Glycopyrrolate has a similar onset of action as neostigmine, whereas atropine has a similar onset of action as edrophonium.

These actions are not the only actions of this drug class. Most notably, they decrease gastrointestinal, bronchial, and genitourinary tone. It is the decrease in gastrointestinal tone and mobility that can cause more complications postoperatively. In addition, anticholinergics should be used with caution in patients with acute glaucoma.

Induction Medications

Propofol

Propofol is an insoluble drug that requires a lipid emulsification. Soybean oil is used for the oil phase, and egg lecithin as the emulsifying agent (Stoelting and Hillier, 2006). Because this solution can support bacterial growth, it is recommended to discard unused portions after 6 hours. Propofol quickly crosses the blood-brain barrier and exerts its action centrally on GABA receptors. Propofol causes rapid hypnosis, but no analgesia, when given as an intravenous bolus. It is metabolized in part by the liver and is excreted in the urine. However, propofol clearance exceeds hepatic blood flow, emphasizing redistribution of propofol into other tissues, including the lungs. Neither liver nor kidney disease appears to affect the clearance rate of propofol.

With a rapid intravenous bolus, propofol causes unconsciousness and apnea. Dose-dependent drops in blood pressure are due to vasodilation and decreased cardiac contractility. Propofol should be titrated to produce unconsciousness. The patient’s age and other associated sedatives should be taken into account. The propofol dose is reduced when other sedatives are given as premedication or at the time of induction. As a general rule, younger, healthy patients need higher doses than the elderly or those who are critically ill.

Although propofol is used most commonly as a rapid induction agent for intubation and general anesthesia, it can also be used as a maintenance anesthetic with repeated boluses or continuous rate infusion. Using propofol as the general anesthetic is helpful with procedures such as magnetic resonance imaging (MRI), for which appropriate anesthetic machines may often be unavailable. Also, intermittent boluses can be given with very short oral cavity procedures or laryngeal examinations, for which the endotracheal tube may need to be temporarily removed. If the procedure time is very short, oxygen by face mask may be adequate. However, endotracheal reintubation is warranted if the patient is unconscious for an extended period.

Other properties of propofol include decreased cerebral metabolic rate, cerebral blood flow, and intracranial pressure. It also has anticonvulsant and excellent antiemetic properties. Intravenous injection of propofol can be painful; this can be attenuated with a small bolus of lidocaine or opioid before its injection. This appears to be a much bigger problem in humans than in animals, probably because of differences in the IV catheter location. Propofol is by far the most widely used induction drug in human medicine. It is predictable and reliable. In human medicine, hypotension is anticipated and most commonly is treated with phenylephrine or ephedrine. Hypotension should also be anticipated and treated in our small animal species, especially in the sick or elderly patient. The patient population in which propofol is less commonly utilized consists of cardiac compromised patients. Propofol should be avoided and other drugs utilized for patients with subaortic stenosis, moderate to severe cardiomyopathy, or pericardial effusion because of decreased preload associated with propofol administration.

Because propofol has no analgesic properties, opioids given as premedication or with induction help attenuate the sympathetic response to endotracheal intubation and surgical stimulation. By combining propofol with opioids, benzodiazepines, ketamine, and/or alpha-2 agonists, the dose of each drug can be reduced, thereby reducing the severity of complications. Depending on the combination of drugs chosen and the comorbidities of the patient, apnea and hypotension associated with propofol can be lessened. Apnea can also be reduced by giving propofol slowly over 20 to 30 seconds. This slow technique should be balanced against the need to rapidly secure an airway with endotracheal intubation. In animals at risk for aspiration or marked drops in oxygen saturation, a rapid bolus technique with immediate intubation and ventilation should be considered.