Perioperative Ketamine Infusion

Ketamine infusions have been used for decades to treat acute pain, but a recent surge in usage has made the infusions a mainstay of treatment in emergency departments, in the perioperative period in individuals with refractory pain, and in opioid-tolerant patients. The widespread variability in patient selection, treatment parameters, and monitoring indicates a need for the creation of consensus guidelines. The development of acute pain ketamine guidelines grew as a corollary from the genesis of chronic pain ketamine guidelines. The charge for the development of acute pain ketamine guidelines was provided by the Boards of Directors of both the American Society of Regional Anesthesia and Pain Medicine and the American Academy of Pain Medicine, who approved the document along with the American Society of Anesthesiologists' Committees on Pain Medicine and Standards and Practice Parameters. The committee chair developed questions based on input from the committee during conference calls, which the committee then refined. Groups of 3 to 5 panel members and the committee chair were responsible for answering individual questions. After preliminary consensus was achieved, the entire committee made further revisions via e-mail and conference calls. Consensus guidelines were prepared in the following areas: indications, contraindications for acute pain and whether they differ from those for chronic pain, the evidence for the use of ketamine as an adjunct to opioid-based therapy, the evidence supporting patient-controlled ketamine analgesia, the use of nonparenteral forms of ketamine, and the subanesthetic dosage range and whether the evidence supports those dosages for acute pain. The group was able to reach consensus on the answers to all questions. Evidence supports the use of ketamine for acute pain in a variety of contexts, including as a stand-alone treatment, as an adjunct to opioids, and, to a lesser extent, as an intranasal formulation. Contraindications for acute pain are similar to those for chronic pain, partly based on the observation that the dosage ranges are similar. Larger studies evaluating different acute pain conditions are needed to enhance patient selection, determine the effectiveness of nonparenteral ketamine alternatives, define optimal treatment parameters, and develop protocols optimizing safety and access to care.

Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may enhance conventional analgesics in the acute postoperative setting. To evaluate the efficacy and safety of perioperative intravenous ketamine in adult patients when used for the treatment or prevention of acute pain following general anaesthesia. We searched CENTRAL, MEDLINE and Embase to July 2018 and three trials registers (metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)) together with reference checking, citation searching and contact with study authors to identify additional studies. We sought randomised, double-blind, controlled trials of adults undergoing surgery under general anaesthesia and being treated with perioperative intravenous ketamine. Studies compared ketamine with placebo, or compared ketamine plus a basic analgesic, such as morphine or non-steroidal anti-inflammatory drug (NSAID), with a basic analgesic alone. Two review authors searched for studies, extracted efficacy and adverse event data, examined issues of study quality and potential bias, and performed analyses. Primary outcomes were opioid consumption and pain intensity at rest and during movement at 24 and 48 hours postoperatively. Secondary outcomes were time to first analgesic request, assessment of postoperative hyperalgesia, central nervous system (CNS) adverse effects, and postoperative nausea and vomiting. We assessed the evidence using GRADE and created a 'Summary of findings' table. We included 130 studies with 8341 participants. Ketamine was given to 4588 participants and 3753 participants served as controls. Types of surgery included ear, nose or throat surgery, wisdom tooth extraction, thoracotomy, lumbar fusion surgery, microdiscectomy, hip joint replacement surgery, knee joint replacement surgery, anterior cruciate ligament repair, knee arthroscopy, mastectomy, haemorrhoidectomy, abdominal surgery, radical prostatectomy, thyroid surgery, elective caesarean section, and laparoscopic surgery. Racemic ketamine bolus doses were predominantly 0.25 mg to 1 mg, and infusions 2 to 5 µg/kg/minute; 10 studies used only S-ketamine and one only R-ketamine. Risk of bias was generally low or uncertain, except for study size; most had fewer than 50 participants per treatment arm, resulting in high heterogeneity, as expected, for most analyses. We did not stratify the main analysis by type of surgery or any other factor, such as dose or timing of ketamine administration, and used a non-stratified analysis.Perioperative intravenous ketamine reduced postoperative opioid consumption over 24 hours by 8 mg morphine equivalents (95% CI 6 to 9; 19% from 42 mg consumed by participants given placebo, moderate-quality evidence; 65 studies, 4004 participants). Over 48 hours, opioid consumption was 13 mg lower (95% CI 10 to 15; 19% from 67 mg with placebo, moderate-quality evidence; 37 studies, 2449 participants).Perioperative intravenous ketamine reduced pain at rest at 24 hours by 5/100 mm on a visual analogue scale (95% CI 4 to 7; 19% lower from 26/100 mm with placebo, high-quality evidence; 82 studies, 5004 participants), and at 48 hours by 5/100 mm (95% CI 3 to 7; 22% lower from 23/100 mm, high-quality evidence; 49 studies, 2962 participants). Pain during movement was reduced at 24 hours (6/100 mm, 14% lower from 42/100 mm, moderate-quality evidence; 29 studies, 1806 participants), and 48 hours (6/100 mm, 16% lower from 37 mm, low-quality evidence; 23 studies, 1353 participants).Results for primary outcomes were consistent when analysed by pain at rest or on movement, operation type, and timing of administration, or sensitivity to study size and pain intensity. No analysis by dose was possible. There was no difference when nitrous oxide was used. We downgraded the quality of the evidence once if numbers of participants were large but small-study effects were present, or twice if numbers were small and small-study effects likely but testing not possible.Ketamine increased the time for the first postoperative analgesic request by 54 minutes (95% CI 37 to 71 minutes), from a mean of 39 minutes with placebo (moderate-quality evidence; 31 studies, 1678 participants). Ketamine reduced the area of postoperative hyperalgesia by 7 cm² (95% CI -11.9 to -2.2), compared with placebo (very low-quality evidence; 7 studies 333 participants). We downgraded the quality of evidence because of small-study effects or because the number of participants was below 400.CNS adverse events occurred in 52 studies, while 53 studies reported of absence of CNS adverse events. Overall, 187/3614 (5%) participants receiving ketamine and 122/2924 (4%) receiving control treatment experienced an adverse event (RR 1.2, 95% CI 0.95 to 1.4; high-quality evidence; 105 studies, 6538 participants). Ketamine reduced postoperative nausea and vomiting from 27% with placebo to 23% with ketamine (RR 0.88, 95% CI 0.81 to 0.96; the number needed to treat to prevent one episode of postoperative nausea and vomiting with perioperative intravenous ketamine administration was 24 (95% CI 16 to 54; high-quality evidence; 95 studies, 5965 participants). Perioperative intravenous ketamine probably reduces postoperative analgesic consumption and pain intensity. Results were consistent in different operation types or timing of ketamine administration, with larger and smaller studies, and by higher and lower pain intensity. CNS adverse events were little different with ketamine or control. Perioperative intravenous ketamine probably reduces postoperative nausea and vomiting by a small extent, of arguable clinical relevance.

Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI -6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. National Institutes of Health and Cancer Center Support.

Ketamine is used frequently as an adjunct for general anaesthesia, exerting analgesic and opioid-sparing properties at lower doses and psychotomimetic effects at higher doses. All dose ranges may have effects on the incidence of postoperative delirium, but clinical trials have been equivocal. We hypothesised that intra-operative low-dose ketamine is associated with a lower risk of postoperative delirium. A total of 106,982 adult patients undergoing general anaesthesia for non-cardiac, non-neurosurgical and non-transplant procedures between 2008 and 2024 were included. Primary exposure was the intra-operative cumulative ketamine dose (mg.kg-1 body weight) dichotomised into high vs. low-dose, based on the median of the cohort. Primary outcome was postoperative delirium within 7 days, based on keyword-based search strategy, manual chart review, Confusion Assessment Method recordings and International Classification of Diseases diagnostic codes. Multivariable logistic regression and fractional polynomial regression analyses to assess a potential nonlinear dose-response relationship were performed. Postoperative delirium occurred in 2837 (2.7%) patients. In total, 12,199 (11.4%) patients received ketamine, with a median (IQR [range]) intra-operative dose of 0.35 (0.25-0.52 [0.01-3.86]) mg.kg-1. Compared with patients not receiving ketamine, a low dose (≤ 0.35 mg.kg-1, 6109 patients) was associated with lower risks of postoperative delirium (adjusted odds ratio 0.74 (95%CI 0.59-0.89), adjusted risk difference -0.7% (95%CI -1.0 to -0.3%); p = 0.003). Higher doses of ketamine (> 0.35 mg.kg-1, 6090 patients) did not affect the risk of postoperative delirium (adjusted odds ratio 1.00 (95%CI 0.85-1.18); p = 0.96). Fractional polynomial regression analyses indicated a U-shaped dose-response relationship, with a minimum postoperative delirium risk at a cumulative ketamine dose of 0.25-0.34 mg.kg-1. Intra-operative low-dose ketamine was associated with a lower risk of postoperative delirium, while high doses did not influence the risk. Ketamine is a medicine often used during surgery to help with pain. Small amounts can help reduce pain and the need for strong painkillers. Large amounts can cause strange thoughts or feelings. Doctors aren't sure if ketamine changes the chance of patients feeling confused after surgery, which is called delirium. This study looked at whether giving a low dose of ketamine during surgery makes delirium less likely. The study looked at 106,982 adults who had surgery (not heart, brain or transplant surgery) between 2008 and 2024. It compared patients who got high or low doses of ketamine during surgery. The researchers checked if the patients had delirium in the week after surgery using hospital records, doctor notes and special tests. Out of all the patients, 2.7% had delirium after surgery. About 11% of patients received ketamine. The middle dose given was about 0.35 mg for each kilogram of body weight. Patients who got a low dose (0.35 mg per kg or less) had a lower chance of delirium. Patients who got a higher dose (more than 0.35 mg per kg) had no change in their chance of getting delirium. The safest dose seemed to be between 0.25 mg per kg and 0.34 mg per kg. Giving a small amount of ketamine during surgery may help lower the chance of confusion afterwards. Higher doses didn't make a difference.

Postoperative pain management in opioid users remains challenging. The perioperative administration of ketamine might lead to favourable pain outcomes in these patients. A systematic review of randomised controlled trials (RCT) with meta-analysis and assessment of the quality of evidence by GRADE was performed. Perioperative pain treatment. Adult opioid users undergoing surgery. Perioperative administration of ketamine. Primary outcomes were postoperative acute pain at rest/during movement after 24 h and number of patients with ketamine-related adverse events. Nine RCTs (802 patients with at least two weeks opioid-intake) were included. There is low-quality evidence that ketamine may slightly reduce postoperative pain during movement after 24 h (mean difference: -0.79; 95% confidence interval (CI): -1.22 to -0.36). Based on a very low-quality of evidence, we are uncertain on any effect of ketamine on pain at rest after 24 h and incidences of adverse events like hallucinations and confusion within 48 h. However, perioperative ketamine reduced cumulative mean opioid consumption by 97.3 mg (95%CI: -164.8 to -29.7) after 24 h and 186.4 mg (95%CI: -347.6 to -25.2) after 48 h. The relative risks (RR) for opioid-related adverse events were significantly different for sedation within 24 h (RR: 0.54; 95%CI 0.37 to 0.78). There is currently limited evidence for a reduced postoperative pain intensity using perioperative ketamine in preoperative opioid-consuming patients. However, a clinically relevant opioid-sparing effect was evident associated with a reduced risk for postoperative sedation and without increased harm. Therefore, ketamine might be a useful anti-hyperalgesic adjuvant in these patients. Nevertheless, with clinical heterogeneity being considerable, it's too premature to suggest any specific ketamine protocol. Furthermore, many questions (like ideal dosing, treatment duration and more favourable patient-related outcome measures including long-term effects) remain open and need to be addressed in future studies. Prospero CRD42020185497.

Perioperative handling of surgical patients with opioid dependency represents an important clinical problem. Animal studies suggest that ketamine attenuates central sensitization and hyperalgesia and thereby reduces postoperative opioid tolerance. We hypothesized that intraoperative ketamine would reduce immediate postoperative opioid consumption compared with placebo in chronic pain patients with opioid dependency undergoing lumbar spinal fusion surgery. Primary outcome was morphine consumption 0 to 24 hours postoperatively. Secondary outcomes were acute pain at rest and during mobilization 2 to 24 hours postoperatively (visual analogue scale), adverse events, and persistent pain 6 months postoperatively. One hundred fifty patients were randomly assigned to intraoperative S-ketamine bolus 0.5 mg/kg and infusion 0.25 mg&#xb7;kg&#xb7;h or placebo. Postoperatively, patients received their usual opioids, paracetamol and IV patient-controlled analgesia with morphine. In the final analyses, 147 patients were included. Patient-controlled analgesia IV morphine consumption 0 to 24 hours postoperatively was significantly reduced in the ketamine group compared with the placebo group: 79 (47) vs 121 (53) mg IV, mean difference 42 mg (95% confidence interval -59 to -25), P < 0.001. Sedation was significantly reduced in the ketamine group 6 and 24 hours postoperatively. There were no significant differences regarding acute pain, nausea, vomiting, hallucinations, or nightmares. Back pain at 6 months postoperatively compared with preoperative pain was significantly more improved in the ketamine group compared with the placebo group, P = 0.005. In conclusion, intraoperative ketamine significantly reduced morphine consumption 0 to 24 hours after lumbar fusion surgery in opioid-dependent patients. The trend regarding less persistent pain 6 months postoperatively needs further investigation.