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Many common elective surgeries are associated with moderate-to-severe postoperative pain. These common surgeries include total knee and total hip arthroplasty, thoracotomy, and multilevel lumbar spine surgery. Unfortunately, many patients requiring these surgeries are already in moderate-to-severe pain, necessitating high doses of oral or transdermal opioids preoperatively. This is an established risk factor for difficult-to-control postoperative pain.
Opioid-sparing interventions are important elements in these patients to promote convalescence and reduce common opioid side effects such as constipation, confusion, pruritus, nausea, vomiting, and urinary retention. Potential interventions to reduce postoperative pain can include nonsteroidal anti-inflammatory drugs, acetaminophen, gabapentin, and even invasive therapies such as epidural or peripheral nerve blockade. Ketamine is a well-known anesthetic agent that has opioid-sparing analgesic properties, is noninvasive, and in analgesic doses, has few contraindications. This article will review the basic science behind ketamine, some of the evidence supporting its perioperative use, and the logistics of how the Department of Anesthesia at Mayo Clinic in Jacksonville, Florida rolled out a hospital-wide ketamine infusion protocol.
Originally used for anesthetic induction, ketamine is a phencyclidine derivative and is described as a dissociative hypnotic because of the cataleptic state of involuntary movement, maintenance of spontaneous respirations, profound analgesia, and unresponsiveness to surgical stimulation achieved with induction doses. Ketamine continues to be a commonly used medication for the induction of anesthesia, especially in neonates.
Because of an associated increase in sympathetic activity following a large bolus and consequent lack of vasodilation, ketamine has proven especially useful for anesthetic induction in hemodynamically unstable patients.
Ketamine has several mechanisms of action. The drug primarily induces its analgesic effect through antagonism of the N-methyl-d-aspartate receptor in dorsal horn neurons,
although it has also been described to interact with calcium and sodium channels, dopamine cholinergic receptors, and inhibit noradrenergic and serotoninergic reuptake.
In recent years, the use of ketamine has expanded beyond induction of anesthesia. Studies have shown low-dose intravenous (IV) ketamine infusions to be a helpful adjunct in the treatment of postoperative pain especially in patients with chronic preoperative pain.
Similarly, the drug has been shown to decrease discomfort in several chronic pain syndromes and conditions, such as complex regional pain syndrome, central neuropathic pain, peripheral neuropathic pain, postherpetic neuralgia, fibromyalgia, and cancer-related pain.
Perioperatively, ketamine is primarily given intravenously; however, it is also effective via intramuscular, oral, and rectal routes. General anesthetic induction doses of ketamine are 1 to 2 mg/kg, 4 to 6 mg/kg intramuscular, and 8 to 10 mg/kg per rectum.
The dosing of IV ketamine for chronic pain conditions is not standardized and has been described as doses that range from 150 mcg/kg/hour for 20 minutes to doses of up to 30 mg/hour for as long as 10 days.
A relatively common approach for perioperative ketamine dosing includes an IV bolus of 0.1 to 0.5 mg/kg before surgical incision, followed by an IV infusion of varying duration of 2 to 10 mcg/kg/minute.
Ketamine is known to cause emergence delirium characterized by hallucinations, vivid dreams, and illusions that can result in significant patient dissatisfaction. Concerns about psychotropic side effects have therefore limited its routine use. These side effects can be reduced with lower dosing and the use of benzodiazepines.
The drug produces sedation but does not commonly produce significant respiratory depression.
Evidence for Ketamine as a Perioperative Analgesic
Many clinical trials of ketamine for acute postoperative analgesia have been performed. Unfortunately, heterogeneity of study design (eg, dosing protocols), patient populations (eg, single-level laminectomy vs total knee replacement patients), and primary outcomes (eg, 24-hour morphine equivalents, 48-hour morphine equivalents, and patient-controlled analgesia [PCA] requests) have made it difficult to recommend routine use of ketamine. This article presents a brief review of evidence for the use of perioperative ketamine in patients undergoing spinal fusion or total joint replacement, two surgical categories in which ketamine has been more commonly studied.
investigated an intraoperative ketamine infusion in a prospective, randomized, double-blinded, placebo-controlled trial of 102 patients in the United States who were receiving long-term opioid therapy for chronic pain before lumbar spine surgery. The dose of IV ketamine used was a 0.5 mg/kg bolus before incision and an infusion of 10 mcg/kg/minute for the duration of the case. To put this dosing in context, in a 70 kg person, this would equate to a 35 mg bolus followed by an infusion of 42 mg/hour. The average duration of surgery was roughly 3.5 hours, yielding a total dose of approximately 175 mg of study drug in an average-sized person. The primary outcome of interest was 48-hour morphine consumption. At 48 hours postoperative, the adjusted morphine equivalents were 323 mg in the placebo group and 203 mg in the ketamine group (P = 0.045). On subgroup analysis, patients who had a preoperative opioid intake of greater than 40 mg of oral morphine equivalents were observed to have decreased opioid consumption when exposed to ketamine (241 vs 471 mg; mean, P = 0.031). However, in patients taking less than 40 mg/day of oral morphine equivalents preoperatively, no significant difference was noted. Thus, the authors state that although there appeared to be a subset of patients on long-term opioid therapy that had a large reduction in morphine use postoperatively secondary to their exposure to ketamine, it did not appear to have a treatment effect in patients taking small doses opioids before major spine surgery.
investigated the effect of intraoperative IV ketamine in a much smaller study of 20 patients undergoing multilevel spine instrumentation and fusion in France. Patients received a 0.5 mg/kg bolus before incision and an infusion of 2.5 mcg/kg/minute of either ketamine or saline (placebo) for the duration of surgery, which is approximately 10 mg/hour of study drug in a 70 kg person. The mean duration of surgery was approximately 2 hours, yielding a total exposure of ketamine in the treatment group of about 55 mg in a 70 kg person. In addition, patients in the ketamine treatment group received methadone plus ketamine by IV PCA (0.25 mg of methadone + 0.5 mg of ketamine per PCA bolus). Patients in the placebo group received methadone only by IV PCA (0.5 mg per PCA bolus). Both patient groups were allowed 3 maximum PCA bolus doses/hour and were given a 10-minute lockout interval. Patients also received intraoperative and postoperative dexketoprophen (nonsteroidal anti-inflammatory drug [NSAID]) and paracetamol (acetaminophen). Again, the primary outcome of interest was 48-hour opioid consumption. There was a statistically significant decrease in methadone use at 24 and 48 hours with an absolute methadone reduction of 11 mg at 24 hours (P < 0.001) and 7.5 mg at 48 hours (P = 0.001) in those who received both methadone and ketamine. This study was not designed or powered to look at secondary analyses such as side effects.
studied the effects of a 24-hour ketamine infusion in patients undergoing primary elective total hip arthroplasty in France. In a prospective, randomized, placebo-controlled, double-blind study of 154 patients, the group received an IV bolus of 0.5 mg/kg of study drug (either ketamine or placebo/saline) followed by an IV infusion for 24 hours at a dose of 2 mcg/kg/minute. Using similar calculations as above, this result yielded a total exposure of approximately 239 mg of ketamine over 24 hours in the treatment group. Although a higher cumulative dose was administered than in the previous study by Loftus, it was delivered over a sixfold longer time period. All patients received general anesthesia, acetaminophen, ketoprofen (NSAID), and a morphine/droperidol mixture via IV PCA. The primary outcome of interest was 24-hour morphine consumption. The ketamine treatment group had a mean 24-hour morphine consumption of 14 mg versus 19 mg in the placebo group (P = 0.004). Although statistically significant, the clinical relevance of a 5 mg decrease in IV morphine is unclear. However, on secondary analysis, the ketamine treatment group had statistically significant decreases in (1) the need for two crutches or a walking frame at Postoperative Day 30 (31% vs 56%; P = 0.0035); (2) pain at rest from Postoperative Days 30 to 180 (P = 0.008); and (3) persistent pain in the operative hip at rest at Postoperative Day 180 (8% vs 21%; P = 0.036; relative risk reduction, 67%).
studied 40 patients presenting for elective total knee arthroplasty in a prospective, double-blind, randomized, placebo-controlled trial in France. Surgeries were performed under general anesthesia. Perioperative pain management consisted of a continuous femoral nerve block for 48 hours and postoperative morphine IV PCA. The study drug (either ketamine or placebo/saline) was administered via a 0.5 mg/kg IV bolus and an intraoperative IV infusion of 3 mcg/kg/minute, which was decreased to 2 mcg/kg/minute postoperatively for 48 hours. Using similar calculations as above, the cumulative ketamine dose in the treatment group was approximately 468 mg over the 2-day time period. After 48 hours, the IV PCA, femoral catheter, and study drug were all removed and the patients received oral acetaminophen, dextropropoxyphene (opioid), and naproxen (NSAID) for analgesia with subcutaneous morphine for breakthrough pain. This study was powered to detect a 40% reduction in morphine consumption at 48 hours postoperatively. The ketamine treatment group experienced a significant decrease in morphine (45 vs 69 mg in the placebo group; P < 0.02). Secondary analysis found an increase in maximal active knee flexion and a shorter time in days to reach 90° of active flexion in the ketamine treatment group (P < 0.02 and P < 0.03, respectively). However, there were no differences in side effects such as nausea or vomiting, no difference in overall patient satisfaction, and no differences at 6 weeks or 3 months postoperatively in terms of function.
Although only four studies are presented here, it is worth noting that the studies discussed used different dosing for both preincisional bolus (0.1 to 0.5 mg/kg) and intraoperative infusion (eg, 2 to 10 mcg/kg/minute). Further confusing the issue is the duration of ketamine exposure in each study. Some used the infusion for the intraoperative course only (eg, 1 to 4 hours), whereas others extended the infusion for up to 48 hours postoperatively. Exclusion criteria varied as well. Some studies excluded patients on long-term opioid therapy, whereas others excluded patients with depression or anxiety. These may in fact be the very patients who might benefit the most from ketamine, as suggested by the work of Lapidus et al,
who found that intranasal ketamine produced rapid antidepressant effects with minimal adverse effects in patients with major treatment-resistant depression. Thus, when determining the use of the drug at Mayo Clinic in Florida, the authors decided to follow the study data to the best of their ability while also attempting to minimize the risk of side effects such as dysphoria and hallucinations, which would certainly hinder a patient's recovery from major surgery.
Perioperative Ketamine at Mayo Clinic in Florida
The Acute Pain Service Anesthesiologists at Mayo Clinic in Florida have used IV ketamine infusions to supplement postoperative analgesia since 2012. At the facility, postoperative IV ketamine is reserved for patients who have a high likelihood of requiring large amounts of postoperative opioid, such as those with preoperative opioid consumption exceeding 30 mg oral morphine equivalents per day. To that end, the ketamine infusions are used in primarily three surgical populations:
1.
Total joint reconstruction, namely total knee or hip arthroplasties
2.
Multilevel spine surgery
3.
Thoracotomy or laparotomy
In arthroplasty, thoracotomy, and laparotomy patients, selection criteria includes patients with preoperative opioid consumption greater than 30 mg oral morphine equivalents per day, intolerance of opioids, or previous requirements of large amounts of postoperative opioids despite appropriately functioning perineural or epidural catheters when applicable. IV ketamine infusions are used postoperatively for spine surgery patients who are consuming significant preoperative opioids or who are judged by the attending anesthesiologist to require a greater-than-expected amount of intraoperative or immediate postoperative IV opioid.
Ketamine infusion therapy at Mayo Clinic in Florida is not withheld from patients with a history of depression or anxiety. In fact, it has been noted that patients with clinical depression and long-term opioid use respond very well to ketamine infusion therapy. However, IV ketamine infusions are not administered to patients with a history of schizophrenia. Although there are no “hard stops” for age exclusion, the therapy is rarely used in patients greater than 70 years of age. However, given the increasing prevalence of older adults taking opioids for chronic pain treatment, these patients are carefully and individually evaluated to determine whether ketamine therapy is appropriate. Ketamine infusions are usually reserved for patients undergoing surgical procedures that are typically associated with moderate-to-severe postoperative pain (eg, thoracotomy, total joint replacement, major abdominal surgery, or spine fusion or instrumentation) and require at least a two-night hospital stay. It is not administered postoperatively to patients with a plan for discharge the next morning. IV ketamine is used solely during the intraoperative period in patients who meet the criteria for ketamine therapy but will have a short hospital stay.
Although dosing is individualized and may vary slightly among the anesthesiologists at Mayo Clinic in Florida, the starting dose for IV ketamine infusion is usually 10 mg/hour, titrated to a maximum of 15 mg/hour if needed, based on the attending anesthesiologist's assessment. As an example, 10 mg/hour is essentially equivalent to 2.5 mcg/kg/minute in a 70 kg person, which is a common infusion dose used in clinical trials of perioperative IV ketamine. In a review by Himmelseher and Durieux
, the authors noted that cognitive impairment effects were negligible at doses less than or equal to 10 mg/hour. This is consistent with the experience at Mayo Clinic in Florida as well. There are no restrictions on the drugs the anesthesiologist may administer preoperatively or intraoperatively to patients receiving, or who will receive a ketamine infusion at Mayo Clinic, Jacksonville; these decisions are individualized based on the attending anesthesiologist's assessment.
Protocol: Initiation, Maintenance, and Monitoring
Before the use of ketamine infusions at Mayo Clinic Hospital in Florida, all registered nurses (RNs) were required to complete an education module. The education module explained why and how ketamine would be used, pharmacology and adverse effects of the drug, and nursing responsibilities in accordance with the Florida RN scope of practice. No new policy or procedure was written specifically for ketamine infusions as ketamine fell under the category of high-risk medications for which policies and procedures already existed at the hospital. RNs periodically review the education module and policy for high-risk medications, particularly when there are questions about the drug.
The protocol requires an anesthesiologist to complete an order set for patients who will receive ketamine postoperatively or in the palliative care setting. Because of RN scope of practice in Florida, an anesthesiologist must connect and initiate the ketamine infusion. For surgical patients, this is done preoperatively in the holding room or when the patient arrives in the post anesthesia care unit (PACU). Although some infusions are begun in the preoperative area or operating room, all infusions are established before discharge from the PACU. Patients who receive ketamine are not required to stay in the PACU for any specific time. Similar to other patients, they are discharged to the clinical unit when stable.
The Pharmacy Department prepares the ketamine infusions (1 mg/1 mL concentration), and “smart” pump infusion devices with “guardrail” technology are used to administer the ketamine infusions to reduce the likelihood of programming and dosing errors. The medication is programmed into the drug library in the infusion device with an upper dose limit of 30 mg/hour. The ketamine infusion is secured in a locked box and infused with port-less tubing at the prescribed infusion rate (Figure 1). A separate IV line is used for the infusion; on very rare occasions (ie, when IV access is difficult), the infusion has been hooked up to the port closest to the patient's IV insertion site. Although another RN witnesses, RNs may remove empty ketamine drug reservoirs and add new ketamine reservoirs to the existing infusions, discontinue therapy (with an order), and waste unused ketamine. However, an anesthesiologist must change ketamine infusion rates, if needed, administer bolus doses (which are rarely needed), and order discontinuation of therapy.
Figure 1Ketamine infusion.
Used with permission of CareFusion. This figure is available in color online at www.jopan.org.
Patients are evaluated on a daily basis by the Anesthesia Regional Catheter Service for adequacy of pain control and the development of any side effects, including sedation, respiratory depression, hallucinations, delirium, dysphoria, diplopia, and nystagmus. The postoperative pain management plan is prescribed and monitored by the patient's primary health care team, and the anesthesia service does not impose any restrictions on analgesics that may be administered. Opioids are usually administered postoperatively, and no increase in the incidence of excessive sedation or respiratory depression has been noted with the subanesthetic ketamine doses (10 to 15 mg/hour) that are administered at Mayo Clinic in Florida. Ketamine infusions are administered for 48 hours, unless specifically requested otherwise by the surgical service. The goal is that no patient be discharged within 24 hours of discontinuation of the ketamine infusion to allow for an adequate drug “washout” period.
RNs monitor patients during ketamine therapy, and patients may be admitted to any clinical unit as all the RNs are trained to care for patients receiving ketamine therapy. Blood pressure, heart rate, respiratory rate, and sedation level are obtained every hour for the first 4 hours, then every 2 hours for 4 hours, and then every 4 hours for the duration of therapy. Oxygen saturation is monitored via continuous pulse oximetry during therapy. Pain intensity is assessed at rest and with activity using a 0 to 10 numeric rating scale every hour for the first 2 hours and then every 4 hours for the duration of therapy. This level of monitoring has not necessitated a change in the nurse-to-patient ratio at Mayo Clinic in Florida. However, health care facilities differ in their nurse-to-patient ratios and must consider their unique staffing patterns when establishing a ketamine protocol.
Questions regarding ketamine therapy or changes in patient condition are directed to the anesthesia team. For example, the RNs know to call if any confusion, delirium, or hallucination is detected in patients during therapy. Lorazepam 0.5 mg IV may be given every 4 hours as needed for anxiety or delirium. All patient data and health care team actions are documented in the Medication Administration Record and other areas of the medical record as appropriate. The ketamine orders are summarized in Figure 2 (PowerChart, Cerner Corporation, Kansas City, MO).
Figure 2Ketamine order set.
By permission of Mayo Foundation for Medical Education and Research. All rights reserved. This figure is available in color online at www.jopan.org.
Early experience with ketamine infusions at Mayo Clinic in Florida has led to one anecdotal finding: Ketamine appears to reduce the amount of fibromyalgia-related pain in patients with this condition undergoing joint replacements. The reduction was in overall opioid consumption and could not be attributed specifically to either the fibromyalgia or the acute postoperative pain specifically. However, some patients have volunteered that their fibromyalgia pain was significantly better in the postoperative period.
As reported in abstract form, on review of the medical records of 15 patients with fibromyalgia undergoing joint replacement with a perioperative ketamine infusion and comparing them with 10 patients with fibromyalgia undergoing joint replacement without a ketamine infusion, the dose requirement of oral morphine to control pain in the 48 hours after surgery was 135 mg for patients who received ketamine versus 250 mg for those who did not (P = 0.054).
Perioperative Ketamine Reduces Post-operative Opioid Consumption After Major Orthopedic Surgery in Patients With Fibromyalgia: A Retrospective Chart Review of 26 Cases.
described three studies that showed positive results after IV ketamine infusion in patients with fibromyalgia. Improvements were noted in pain intensity, muscular hyperalgesia, pain tolerance, and muscle pain at rest; however, further research is required to determine if there are long-term analgesic effects after ketamine infusion in individuals with fibromyalgia.
Summary
Ketamine is a drug with potential for analgesia and opioid dose reduction at subanesthetic doses. It has been administered by IV bolus and infusion with varying results in a large number of clinical trials. It is relatively inexpensive, widely available, noninvasive, and does not require any additional laboratory work. Multiple systematic reviews and meta-analyses support the opioid-sparing effects of subanesthetic doses of ketamine.
The Acute Pain Service at Mayo Clinic in Jacksonville, Florida, has incorporated the use of ketamine into practice. Logistically, the development and successful rollout of a perioperative ketamine infusion protocol involves buy-in from physicians, nurses, pharmacists, educators, and administrators throughout the hospital. As of the date of this publication, the Service has experience in treating more than 500 patients with ketamine without any serious adverse events. Perioperative ketamine should be considered in hospitals with an acute pain service that provides 24-hour coverage to its patients.
References
de Leon-Casasola O.A.
Myers D.P.
Donaparhi S.
et al.
A comparison of postoperative epidural analgesia between patients with chronic cancer taking high doses of oral opioids versus opioid-naive patients.
Perioperative Ketamine Reduces Post-operative Opioid Consumption After Major Orthopedic Surgery in Patients With Fibromyalgia: A Retrospective Chart Review of 26 Cases.
AAPM,
2013 (Abstract 113 presented at the 2013 American Academy of Pain Medicine Annual Meeting. Available at)
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