Intravenous Ketamine Infusion

Ketamine is a noncompetitive N-methyl- d -aspartate (NMDA) glutamate receptor antagonist and a sodium channel blocker. The drug is available as racemic ketamine, which contains the S (+) and R (−) stereoisomers. The S (+) ketamine has 4 times greater affinity for the NMDA receptor than the R (−) ketamine. Ketamine has a half-life of 80–180 minutes. Its metabolite norketamine has a longer half-life and is one-third as potent as the parent compound. Early studies have shown ketamine to have analgesic properties at low, subanesthetic doses. The analgesic effects of ketamine occur at plasma concentrations of 100–150 ng/mL.

Ketamine has many qualities as an analgesic and does not have the same side-effect profile as opioids do. Ketamine does not suppress cardiovascular function in the presence of an intact nervous system, does not depress the laryngeal protective reflexes and causes less depression of ventilation compared with opioids, and may even stimulate respiration. However, ketamine does have undesirable characteristics, including postoperative malaise, accumulation of metabolites, development of tolerance, cardiovascular excitation, and the occurrence of psychotomimetic side effects. Psychotomimetic effects are the most common feared complication by clinical practitioners, but few studies have formally evaluated these side effects.

Randomized controlled clinical studies on perioperative IV ketamine showed beneficial effect. In a study in patients who underwent cervical and lumbar spine surgery, ketamine (1 mg/kg bolus followed by 83 μg.kg ⁻¹ .h ⁻¹ ) resulted in less analgesic requirements, lower pain scores, and better satisfaction than patients who had saline infusion or those who had lower dose of ketamine infusion (same 1 mg/kg bolus but at an infusion rate of 42 μg.kg ⁻¹ .h ⁻¹ ). The same beneficial effects were seen in patients who had major abdominal surgery. Perioperative ketamine infusion (0.5 mg/kg bolus followed by 2 μg.kg ⁻¹ .min ⁻¹ ) for 48 hours after surgery resulted in lower pain scores and less morphine consumption than patients who had saline infusion or those who had the same infusion given intraoperatively. To better evaluate the effect of a ketamine bolus on the infusion, a group of investigators compared ketamine bolus followed by an infusion, versus ketamine bolus alone given either before the surgical incision or at wound closure in patients undergoing gynecologic laparotomy. They noted that the patients who had the ketamine bolus and infusion had lower morphine consumption and lower pain scores. Ketamine infusion also reduced postoperative opioid consumption in subjects who had spinal anesthesia for cesarean section.

In patients who had total intravenous (IV) anesthesia with remifentanil and propofol infusions, no beneficial effect of ketamine infusion was noted. The lack of benefit may be related to the investigators’ generous use of intraoperative opioids. A review that evaluated more than 4700 patients demonstrated the efficacy of ketamine in reducing pain and postoperative opioid consumption, especially for upper abdominal, thoracic, and major orthopedic surgical procedures. Despite less opioid use, 25 out of 32 treatment groups (78%) experienced less pain than the placebo groups at some point postoperatively.

Perioperative IV ketamine infusion may not prevent postamputation pain. Ketamine 0.5 mg/kg bolus followed by an infusion of 0.5 mg.kg ⁻¹ .h ⁻¹ for 72 hours was not effective in reducing morphine consumption or in decreasing the incidence of stump allodynia. At 6-month follow-up, the incidences of phantom pain and stump pain were 47% in the ketamine group compared with 71% and 35% in the control (saline) group. There was no statistical difference in the incidences, so the investigators concluded that IV ketamine did not significantly reduce acute central sensitization or the incidence and severity of postamputation pain.

The addition of an IV ketamine infusion to epidural analgesia in patients who underwent colorectal surgery resulted in less patient-controlled analgesia (PCA) morphine requirements and reduced areas of hyperalgesia. Another group of investigators noted the salutary effect of adding low-dose IV ketamine (0.05 mg.kg ⁻¹ .h ⁻¹ , approximately 3 mg/h) to epidural analgesia after thoracotomy. In this study, the patients with a ketamine infusion had less pain and took less analgesics at 3 months after surgery. Ketamine infusion therefore appears to have a beneficial effect on epidural analgesia. This beneficial effect of ketamine in preventing chronic pain after surgery was not confirmed in other studies. In one study, a ketamine infusion (1 mg/kg at induction, 1 mg.kg ⁻¹ .h ⁻¹ during surgery, and then 1 mg/kg for 24 hours) in addition to intrapleural ropivacaine, improved immediate postoperative pain compared with saline. However, at 4 months after surgery, the analgesic intake and neuropathic pain scores were similar in both groups. In another study, the incidences of moderate and severe postthoracotomy pain syndrome at 3 and 6 months were similar in the ketamine and control groups.

The addition of ketamine infusion appears to be beneficial in opioid tolerant patients. An earlier study by Loftus et al. showed reduced opioid consumption in the first 48 hours after back surgery in patients who had a ketamine bolus ([0.5 mg/kg] and intraoperative infusion [10 μg.kg ⁻¹ .min ⁻¹ ]). A later study showed that the addition of ketamine infusion (0.2 mg.kg ⁻¹ .h ⁻¹ ) to hydromorphone IV PCA resulted in a statistically significant reduction of “average” pain scores in opioid-dependent patients. It should be noted that the “least” and “worst” pain scores and postoperative opioid use did not differ between the ketamine and control groups.

Most of the studies showed no increased side effects when low-dose ketamine infusions are used. Zakine et al. did not observe nightmares, delusions, sleep, or psychiatric disorders in their study. Sleep disturbance and psychomotor performances were similar between the ketamine infusion group and control group. In a quantitative systematic review, Laskowski and colleagues detected that hallucinations and nightmares were more common with ketamine, but sedation was not. They noted that when ketamine was efficacious for pain, postoperative nausea and vomiting were diminished.

Studies on ketamine infusion involved a small number of patients, different ketamine regimens, different routes of administration, and large variations in clinical settings. Most of the randomized controlled studies showed some beneficial effects of a low-dose ketamine infusion. A recent review and meta-analysis by Wang et al. that looked at 36 randomized controlled trials encompassing 2502 eligible patients determined that the addition of ketamine to a morphine or hydromorphine PCA decreased postoperative pain intensity at 6–72 hours postoperatively, morphine consumption at 24–72 hours postoperatively, as well as postoperative nausea and vomiting. There was not enough data to determine any significant adverse events such as hallucinations.

In summary, ketamine infusion appears to improve the efficacy of epidural analgesia. It does not seem to have any effect when the anesthetic technique is total IV anesthesia where moderate or substantial amounts of intraoperative opioid are used. Ketamine also has a beneficial effect when added to PCA postoperatively by decreasing pain intensity, opioid consumption, and side effects. IV ketamine may find its use as an adjunct in opioid-tolerant patients, or in patients with a higher incidence of chronic postsurgical pain such as thoracotomy, inguinal herniorraphies, or mastectomies.

Intravenous Lidocaine Infusion

Lidocaine has peripheral and central properties that are suitable for pain relief. It decreases albumin extravasation in animal models of chemical peritonitis and inhibits leukocyte migration and metabolic activation. Lidocaine modifies the neuronal responses in the dorsal horn and suppresses synaptic spinal transmission by decreasing C-fiber evoked activity in the spinal cord. Clinically, local anesthetic infusions have been used in the treatment of neuropathic pain and pain from burns.

Studies showed the beneficial effects of IV lidocaine in abdominal surgery. In a randomized, double-blind, placebo-controlled study, Cassuto et al. showed the analgesic efficacy of a low-dose lidocaine infusion in patients who underwent cholecystectomy. After an IV bolus of 100 mg of lidocaine, the investigators infused lidocaine at 2 mg/min, starting at 30 minutes before the surgery, and continued for 24 hours after the surgery. Compared with the group who had saline infusions, the patients with lidocaine infusions had significantly lower pain scores during the first day of surgery, and required significantly less meperidine during the first two postoperative days. Other randomized controlled studies showed the technique to result in lower postoperative pain scores, less opioid consumption, faster return of bowel function, and reduced hospital stay. Groudine et al. compared lidocaine with saline in patients who had radical retropubic prostatectomy. In the lidocaine group, the patients had 1.5 mg/kg bolus of lidocaine before induction, an intraoperative infusion of either 3 mg/min or 2 mg/min (for patients with weights <70 kg) that was continued until 1 hour postoperatively. The analgesic consumption between the patients in the two groups was the same. However, the patients who had lidocaine infusions had lower pain scores, a shorter return of bowel movement (62 ± 13 hours vs. 74 ± 16 hours), and a shorter hospital stay (4 vs. 5 days). In patients who underwent major abdominal surgery, Koppert et al. gave a 1.5 mg/kg bolus over 10 minutes, followed by 1.5 mg.kg ⁻¹ .h ⁻¹ 30 minutes before surgical incision and continued up to 1 hour after the end of surgery. The lidocaine infusion group had lower pain scores, less morphine requirement (130 vs. 159 mg) over a 72-hour period, and bowel movements sooner compared with the control. The opioid-sparing effect was noted to be most pronounced on the third postoperative day. These prompted the investigators to consider that the lidocaine infusion may have a true preventive analgesic effect. In another study in patients who underwent laparoscopic colectomy, patients were given a lidocaine bolus injection of 1.5 mg/kg at the induction of anesthesia followed by a continuous infusion of 2 mg.kg ⁻¹ .h ⁻¹ intraoperatively and 1.33 mg.kg ⁻¹ .h ⁻¹ postoperatively for 24 hours. The times to first flatus (17 vs. 28 hours), defecation (28 vs. 51 hours), and hospital discharge (2 vs. 3 days) were significantly shorter in the patients who had the lidocaine infusion compared with control. In addition, the lidocaine infusion also significantly reduced postoperative pain and fatigue scores and opioid consumption.

A recent trial by Peng et al. demonstrated a beneficial effect of IV lidocaine in craniotomy procedures. Looking at 94 patients undergoing supratentorial craniotomy, patients received either a lidocaine bolus (1.5 mg/kg) followed by an infusion of 2 mg.kg ⁻¹ .h ⁻¹ for the duration of surgery or placebo (normal saline). The incidence of mild pain was lower in the lidocaine group compared with control, and the number of patients leaving the postanesthesia care unit (PACU) with a numerical rating scale (NRS) pain score of 0 was greater in the lidocaine group. They also noted that there were no differences in blood pressure, heart rate, and bispectral index scores, intraoperatively. These data were, however, a secondary finding from a clinical trial whose primary outcome was actually neuropsychological outcome (which interestingly was found to not be different between the two groups). Furthermore, pain scores were only assessed in the PACU and not any further during their hospital stay.

Two studies looked at pain relief and also the effect of the lidocaine infusion on markers of inflammation and immune response. A randomized study in patients who underwent open hysterectomy showed less severe postoperative pain in the first 8 hours after surgery, both at rest and during coughing. However, there was no difference in pain scores for the 12–72 hours after surgery between IV lidocaine and IV saline. The authors noted less ex vivo production of IL-1ra and IL-6, and better maintenance of the lymphocyte proliferation response to phytohemagglutinin-M in the IV saline group, signifying the ability of lidocaine to reduce surgery-induced immune changes. Another study did not notice better pain scores but showed other beneficial effects when lidocaine infusion was employed in patients undergoing colorectal surgery. Another group of investigators gave an IV bolus of lidocaine, 1.5 mg/kg, followed by a continuous infusion of 2 mg/min until 4 hours postoperatively. The pain ratings were the same in the lidocaine and saline control groups. However, the return of bowel function was shorter, and the length of hospital stay was decreased by 1 day in the lidocaine group. The authors also noted significant reduction of the plasma levels of IL6, IL8, complement C3a, and IL-1ra, as well as expression of CD11b, P-selectin, and platelet-leukocyte aggregates. The findings showed the ability of IV lidocaine to modify surgery-induced inflammatory activity.

The beneficial effects of IV lidocaine infusion were not duplicated in patients who had a total hip replacement or coronary artery bypass graft surgery. In a randomized, double-blind, placebo-controlled study, 1.5 mg/kg lidocaine bolus was given over 10 minutes at 30 minutes before surgical incision, followed by an infusion of 1.5 mg.kg ⁻¹ .h ⁻¹ until 1 hour after the end of the surgery. There was no difference between the lidocaine and control groups in terms of postoperative pain scores and opioid consumption (17 vs. 15 mg morphine over 24 hours), and no difference in hip flexion. In patients who underwent coronary artery bypass surgery, low-dose lidocaine infusion was also noted to be ineffective in reducing the supplemental fentanyl, midazolam, or propanolol postoperative requirements. In this study, the lidocaine infusion did not reduce the time to extubation, ICU stay, or hospital length of stay. In view of the minimal studies done so far, additional studies are needed to determine if lidocaine infusion is truly ineffective in these surgical settings.

Initial studies on lidocaine infusion (1.5 mg/kg bolus followed by an infusion of 2 mg.kg ⁻¹ .h ⁻¹ ) in patients undergoing ambulatory surgery noted that the infusion resulted in less intraoperative opioid use and less pain scores. De Oliveira et al. determined that perioperative lidocaine not only reduced postoperative pain and opioid consumption but also improved overall quality of postsurgical recovery in patients undergoing outpatient laparoscopic gynecologic surgery. Patients who received lidocaine met discharge criteria faster than the group who received saline.

IV lidocaine infusion is not as effective as perioperative epidural analgesia. IV lidocaine was inferior to thoracic epidural analgesia in terms of pain relief and attenuation of cytokine “surge” in patients who underwent colonic surgery. This was shown by Kuo et al., who demonstrated that thoracic epidural analgesia resulted in better pain relief, lower opioid consumption, earlier return of bowel function, and lesser production of cytokines than IV lidocaine during the 72-hour observation study period. The patients who received IV lidocaine did experience better pain relief and less cytokine release compared with the control group.

A randomized, unblinded study compared IV lidocaine infusion with epidural analgesia in patients who had open colon resection. The IV lidocaine group had infusions of 1–2 mg/min (1 mg/min in <70 kg patients and 2 mg/min in ≥70 kg patients), while the epidural analgesia group had 10 mL/h of 0.125% bupivacaine and hydromorphone 6 μg/mL. The infusions were started within 1 hour of the end of surgery and continued until return of bowel function or by the fifth day. There were no statistical differences in the average pain scores (VAS of 2.2 in the epidural group vs. 3.1 in the IV lidocaine group) and a trend toward greater opioid consumption in the IV lidocaine group. The return of bowel function or the length of hospital stay was not statistically different between the groups. It is interesting to note that two chronic pain patients in the IV lidocaine group were excluded and an epidural had to be subsequently placed in one of the patients for “further pain treatment.”

Two meta-analyses publications showed beneficial effects of a perioperative lidocaine infusion. An earlier meta-analysis of eight trials noted improved rehabilitation and shortened hospital stay when a lidocaine infusion was used. The improved recovery was supported by decreased postoperative pain at 24 hours after surgery, lower incidence of nausea and vomiting, and shorter duration of ileus. The ability of IV lidocaine to shorten the duration of ileus was shown not only clinically (e.g., first passage of gas and feces), but also through radiopaque markers and serial abdominal radiographs. The other meta-analysis evaluated over 1700 patients and showed that at 6 hours postoperatively, IV lidocaine infusion reduced pain at rest (weighted mean difference [WMD] −8.70, 95% confidence intervals [CI] −16.19 to −1.21), during cough (WMD −11.19, 95% CI −17.73 to −4.65), and during movement (WMD −9.56, 95% CI −17.31 to −1.80). IV lidocaine infusion also reduced morphine requirement (WMD −8.44 mg, 95% CI −11.32 to −5.56), time to first flatus (WMD −7.62 hours, 95% CI −10.78 to −4.45), time to first feces (WMD −10.71 hours, 95% CI −16.14 to −5.28), nausea/vomiting (risk ratios = 0.71, 95% CI 0.57–0.90), and hospital length of stay (WMD −0.17 days, 95% CI −0.41 to 0.07). The authors concluded that lidocaine infusions are beneficial in abdominal surgery.

The beneficial effects of a perioperative lidocaine infusion in abdominal surgery may be related to its ability to suppress inflammatory processes from the surgery. IV lidocaine attenuates increased levels of proinflammatory cytokines, preventing the development of peripheral and central nervous system sensitization that leads to clinical hyperalgesia.

Systemic perioperative lidocaine has been shown to reduce the development of postsurgical pain syndrome after mastectomies. The effect was very large, but the study sample size was small (36 subjects). Larger randomized trials are needed to refute or confirm the role of lidocaine as an effective intervention in reducing chronic postsurgical pain.

The comparative effects of perioperative IV ketamine and lidocaine infusions are shown in Table 12.1 . It can be seen that infusion of either drug is beneficial in abdominal surgery. Ketamine infusion is effective in spine surgery but showed no added benefit when the technique of general anesthesia was total IV anesthesia. Lidocaine infusion appears to have no benefit in patients who undergo total hip replacement or coronary artery bypass surgery. As noted, a randomized blinded study showed less efficacy of IV lidocaine infusion when compared with epidural analgesia.

Intravenous Naloxone Infusion

Naloxone is a pure mu-receptor antagonist. Naloxone infusions have been used to decrease the incidence of nausea, vomiting, respiratory depression, and urinary retention after epidural and intrathecal opioids. Its use comes with the possibility of reversing analgesia from the opioid. Naloxone infusion at 10 μg.kg ⁻¹ .h ⁻¹ reduced the duration and quality of analgesia from epidural morphine or fentanyl. The infusion of naloxone at 1 μg.kg ⁻¹ .h ⁻¹ attenuated the pain relief in patients who had intrathecal diamorphine after lumbar laminectomy. In a retrospective study patients who had radical prostatectomy and given 0.8–1.7 mg intrathecal morphine, an IV infusion of naloxone at 5 μg.kg ⁻¹ .h ⁻¹ provided excellent analgesia with infrequent and minor side effects.

The efficacy of naloxone infusion in decreasing the incidence of side effects from neuraxial opioids led a group of investigators to look at the effect of naloxone infusion on PCA morphine. In a randomized, double-blind study, 60 patients who underwent hysterectomy were assigned into three groups: (1) PCA morphine, 1 mg/mL, with saline infusion; (2) PCA morphine with low-dose naloxone infusion (0.25 μg.kg ⁻¹ .h ⁻¹ ); and (3) PCA morphine with high-dose naloxone infusion (1 μg.kg ⁻¹ .h ⁻¹ ). They noted that both naloxone doses were equally effective in reducing the incidence of nausea and vomiting, and pruritus compared with placebo. There was no difference in the pain scores between the three groups, even though the cumulative morphine usage was significantly lower in the low-dose group (42.3 ± 24.1 mg) compared with the placebo (59.1 ± 27.4 mg) or the high-dose group (64.7 ± 33 mg). There was no respiratory depression and no difference in sedation scores, respiratory rate, hemodynamic parameters, or antiemetic use among the three groups. Another group of investigators examined the effect of a 24-hour low-dose naloxone infusion in 90 patients who had hysterectomies. They showed that naloxone significantly reduced morphine consumption over the first 24 postoperative hours compared with the control group (saline). Morphine consumption was also lower, 19.5 (standard deviation [SD] 3.4 mg vs. 27.5 [SD 5.9] mg). In addition, the incidence and severity of nausea and vomiting was significantly reduced in the naloxone group, similar to what was observed in a previous study.

Naloxone’s dose-dependent effect on pain leads to its ability to improve postoperative analgesia. Small doses of naloxone produced analgesia in rats, while large doses resulted in hyperalgesia. Naloxone was shown to initially produce analgesia in a dose-dependent manner and then caused hyperalgesia. Other investigators noted this biphasic or dual modulatory effect of naloxone. The mechanisms of analgesic effect of naloxone may be related to the release of endorphins or displacement of endorphins from receptor sites not related to analgesia. Augmentation of the activity of opioid receptors is another possibility, although this upregulation phenomenon has been demonstrated after prolonged naloxone infusion (7 days) and in animals. At higher doses, naloxone blocks the action of the released or displaced endorphin at the postsynaptic receptor.

There is no added benefit when naloxone is administered via IV PCA. The different pharmacokinetics of the drug when given intermittently compared with when given as infusion explain the lack of added benefit. Naloxone has an alpha half-life of 4 minutes and a beta half-life of 55–60 minutes ; a continuous infusion of the drug therefore results in constant plasma levels resulting in a more consistent effect.

The present indication for IV naloxone infusion is to control the side effects of neuraxial opioids. Few studies such as the one by Gan et al. and the one from Movafegh et al. showed the efficacy of a low-dose naloxone infusion in reducing opioid consumption. Its increased clinical use for postoperative analgesia should await additional controlled studies in different surgical procedures.