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This study is conducted to evaluate the effectiveness and safety of ketamine infusion for pain relief after knee replacement surgery. Adult patients who have undergone knee arthroplasty will be randomly assigned to one of two groups. The study group will receive standard pain management plus a continuous infusion of ketamine using patient-controlled analgesia (PCA), while the control group will only receive standard pain management. All patients will be monitored for pain intensity using the Numeric Rating Scale (NRS) at several time points the first 24 hours after surgery. The study will compare the total amount of opioid pain medication required, the level of pain experienced, and the frequency and severity of side effects such as nausea, vomiting, and neuropsychiatric reactions. The goal is to determine whether adding ketamine to standard pain management reduces opioid use and improves pain control without increasing side effects. The results improve pain management strategies after knee replacement surgery.
This is a prospective, randomized controlled study evaluating the use of ketamine infusion as part of postoperative pain management for adult patients undergoing knee arthroplasty. The study will enroll patients aged 18 to 90 years who have undergone knee replacement surgery at the N.I. Pirogov National Medical and Surgical Center.
Participants will be randomly assigned to either the study group or the control group. Both groups will receive standardized pain management with ketoprofen and paracetamol in keeping with current guidelines. The study group will receive an additional continuous infusion of ketamine using PCA at a rate of 0.15 mg/kg/h, with 1 mg boluses available in 5-minute lockout intervals and a maximum daily dose of 500 mg. In both groups, opioid analgesics (morphine 10 mg intramuscularly as needed) will be administered if pain control is inadequate. Regional nerve blocks may be repeated under ultrasound guidance if necessary; patients requiring repeated femoral nerve block will be analyzed separately.
Pain intensity will be assessed using the NRS at 0, 2, 4, 6, 10, 14, 18, and 24 hours postoperatively. Data will be collected on the total dose of opioids used, additional analgesic requirements, the number and severity of neuropsychiatric adverse events (graded according to CTCAE), the frequency of postoperative nausea and vomiting, and the total dose and number of ketamine boluses administered.
The primary outcome is the total dose of opioid analgesics (morphine equivalents, mg) administered the first 24 hours after surgery. Secondary outcomes include pain scores at each time point, incidence and severity of neuropsychiatric side effects, frequency of postoperative nausea and vomiting, and total ketamine dose received.
The study is designed to compare the efficacy and safety of ketamine infusion in reducing opioid consumption and improving pain control after knee arthroplasty, while closely monitoring adverse events. The results aim to provide evidence for optimizing multimodal analgesia in orthopedic surgery.This clinical trial was preceded by a pilot study involving patients undergoing knee arthroplasty. The pilot phase aimed to evaluate the variability of key parameters such as pain intensity, opioid requirements, and the incidence of neuropsychiatric side effects. Based on the analysis of the investigators' published data, modifications were made in the main study protocol, including adjustments to the ketamine bolus dose within the PCA regimen to optimize efficacy and safety.
The changes were introduced to enhance pain control and minimize adverse effects in the main study population. The current trial involves these protocol refinements, and the investigators anticipate that the optimized ketamine dosing schedule will lead to improved outcomes compared to the initial regimen.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketamine Plus Standard Analgesia | Experimental | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) plus a continuous intravenous infusion of ketamine using PCA at 0.15 mg/kg/h, with 1 mg boluses available every 5 minutes (maximum daily dose 500 mg), for 24 hours after knee arthroplasty. Morphine 10 mg intramuscularly (IM) may be administered as needed for rescue therapy. |
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| Standard Analgesia Alone | Active Comparator | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) without ketamine infusion. Morphine 10 mg IM may be administered as needed for rescue therapy. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketamine | Drug | Ketamine administered intravenously at 0.15 mg/kg/h via PCA with 1 mg boluses, 5-minute lockout, maximum 500 mg per 24 hours after knee arthroplasty. |
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| Measure | Description | Time Frame |
|---|---|---|
| Total Opioid Consumption in Morphine Equivalents Within 24 Hours After Surgery | The total dose of opioid analgesics (calculated in milligrams of morphine equivalents) administered to each patient during the first 24 hours after knee arthroplasty. | 24 hours postoperatively |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Intensity Assessed by Numeric Rating Scale (NRS) | Pain intensity measured using the 11-point Numeric Rating Scale (NRS), where 0 = no pain and 10 = worst pain imaginable, averaged across two time intervals: 2-10 hours (mean of time points 2, 4, 6, 10h) and 10-24 hours (mean of time points 14, 18, 24h) after surgery. | 2-10 hours and 10-24 hours postoperatively |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Boris Teplykh, MD | Pirogov National Medical and Surgical Center | Study Director |
| Ivan Shcheparev, MD, PhD | Pirogov National Medical and Surgical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pirogov National Medical and Surgical Center | Moscow | 105203 | Russia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21773855 | Background | Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011 Oct;58(10):911-23. doi: 10.1007/s12630-011-9560-0. Epub 2011 Jul 20. | |
| 15271729 | Background | Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004 Aug;99(2):482-95, table of contents. doi: 10.1213/01.ANE.0000118109.12855.07. |
| Label | URL |
|---|---|
| Official website of the Pirogov National Medical and Surgical Center | View source |
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2 months after completion of the study
upon the request
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Patients undergoing knee arthroplasty at Pirogov National Medical and Surgical Center were sequentially recruited and randomly assigned to intervention or control group.
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| ID | Title | Description |
|---|---|---|
| FG000 | Ketamine Plus Standard Analgesia | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) plus a continuous intravenous infusion of ketamine using PCA at 0.15 mg/kg/h, with 1 mg boluses available every 5 minutes (maximum daily dose 500 mg), for 24 hours after knee arthroplasty. Morphine 10 mg intramuscularly (IM) may be administered as needed for rescue therapy. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 21, 2025 |
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Participants will be randomly assigned in a 1:1 ratio to one of two parallel groups:
the intervention group (standardized postoperative analgesia plus ketamine infusion via patient-controlled analgesia),
or the control group (standardized postoperative analgesia without ketamine). Randomization will be performed using permuted blocks of six patients. There will be no crossover or switching between groups; all interventions and assessments will be conducted independently and concurrently for both groups.
The study is single-center and prospective.
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| Standard Analgesia | Drug | Standard analgesia includes ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty; morphine 10 mg IM as needed for rescue therapy. |
|
| Incidence of Postoperative Nausea and Vomiting | The number of patients experiencing any episode of postoperative nausea or vomiting during the first 24 hours after surgery. | 24 hours postoperatively |
| Number of Participants With Neuropsychiatric Adverse Events | Number of participants experiencing neuropsychiatric adverse events during 0-10 hours (NPA 0-10 hours) and 10-24 hours (NPA 10-24 hours) after knee arthroplasty. | 0-10 hours and 10-24 hours postoperatively |
| Severity of Neuropsychiatric Adverse Events | The maximum severity of any neuropsychiatric adverse event experienced by a patient, graded according to the Common Terminology Criteria for Adverse Events (CTCAE). The scale ranges from Grade 1 (Mild) to Grade 5 (Death). Specific conditions and symptoms may have values or descriptive comment for each level, but the general guideline is:
| 24 hours postoperatively |
| Cumulative Ketamine Dose Administered | The total cumulative dose of ketamine (in milligrams) administered during the first 24 hours after surgery, including both the continuous infusion and patient-initiated boluses. | 24 hours postoperatively |
| 12933413 | Background | Guillou N, Tanguy M, Seguin P, Branger B, Campion JP, Malledant Y. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003 Sep;97(3):843-847. doi: 10.1213/01.ANE.0000075837.67275.36. |
| 25530168 | Background | Jouguelet-Lacoste J, La Colla L, Schilling D, Chelly JE. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of the current literature. Pain Med. 2015 Feb;16(2):383-403. doi: 10.1111/pme.12619. Epub 2014 Dec 19. |
| 22227789 | Background | American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012 Feb;116(2):248-73. doi: 10.1097/ALN.0b013e31823c1030. No abstract available. |
| 18627367 | Background | Fischer HB, Simanski CJ, Sharp C, Bonnet F, Camu F, Neugebauer EA, Rawal N, Joshi GP, Schug SA, Kehlet H; PROSPECT Working Group. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Anaesthesia. 2008 Oct;63(10):1105-23. doi: 10.1111/j.1365-2044.2008.05565.x. Epub 2008 Jul 10. |
| 30570761 | Background | Brinck EC, Tiippana E, Heesen M, Bell RF, Straube S, Moore RA, Kontinen V. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018 Dec 20;12(12):CD012033. doi: 10.1002/14651858.CD012033.pub4. |
| 26133677 | Background | Bell RF, Dahl JB, Moore RA, Kalso EA. WITHDRAWN: Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2015 Jul 2;2015(7):CD004603. doi: 10.1002/14651858.CD004603.pub3. |
| 26003764 | Background | Porter SB, McClain RL, Howe BL, Ardon AE, Mazer LS, Knestrick BM, Clendenen AM. Perioperative ketamine for acute postoperative analgesia: the Mayo Clinic-Florida experience. J Perianesth Nurs. 2015 Jun;30(3):189-95. doi: 10.1016/j.jopan.2015.01.010. |
| 36247824 | Background | Pouldar TM, Maher DP, Betz AW, Wiegers JJ, Friedman JA, Zaidi SS, Rejali A, Tran HP, Yumul R, Louy C. Adverse Effects Associated with Patient-Controlled Analgesia with Ketamine Combined with Opioids and Ketamine Infusion with PCA Bolus in Postoperative Spine Patients: A Retrospective Review. J Pain Res. 2022 Oct 10;15:3127-3135. doi: 10.2147/JPR.S358770. eCollection 2022. |
| 34335740 | Background | Seman MT, Malan SH, Buras MR, Butterfield RJ, Harold KL, Madura JA, Rosenfeld DM, Gorlin AW. Low-Dose Ketamine Infusion for Perioperative Pain Management in Patients Undergoing Laparoscopic Gastric Bypass: A Prospective Randomized Controlled Trial. Anesthesiol Res Pract. 2021 Jul 21;2021:5520517. doi: 10.1155/2021/5520517. eCollection 2021. |
| 35897081 | Background | Puzio TJ, Klugh J, Wandling MW, Green C, Balogh J, Prater SJ, Stephens CT, Sergot PB, Wade CE, Kao LS, Harvin JA. Ketamine for acute pain after trauma: the KAPT randomized controlled trial. Trials. 2022 Jul 27;23(1):599. doi: 10.1186/s13063-022-06511-6. |
| 29870457 | Background | Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):456-466. doi: 10.1097/AAP.0000000000000806. |
| FG001 | Standard Analgesia Alone | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) without ketamine infusion. Morphine 10 mg IM may be administered as needed for rescue therapy. |
| COMPLETED |
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| NOT COMPLETED |
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Per-protocol analysis population including participants who completed 24-hour follow-up without major protocol deviations (49 in ketamine group, 46 in control group; total n=95).
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| ID | Title | Description |
|---|---|---|
| BG000 | Ketamine Plus Standard Analgesia | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) plus a continuous intravenous infusion of ketamine using PCA at 0.15 mg/kg/h, with 1 mg boluses available every 5 minutes (maximum daily dose 500 mg), for 24 hours after knee arthroplasty. Morphine 10 mg intramuscularly (IM) may be administered as needed for rescue therapy. |
| BG001 | Standard Analgesia Alone | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) without ketamine infusion. Morphine 10 mg IM may be administered as needed for rescue therapy. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Patient age at enrollment (in years) | Mean | Standard Deviation | years |
| ||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | Participants |
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| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m² |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Opioid Consumption in Morphine Equivalents Within 24 Hours After Surgery | The total dose of opioid analgesics (calculated in milligrams of morphine equivalents) administered to each patient during the first 24 hours after knee arthroplasty. | Of 100 randomized participants, 5 were excluded from analysis due to protocol violations or incomplete follow-up. The final per-protocol analysis included 49 participants in the ketamine group and 46 participants in the control group (total n=95). | Posted | Median | Inter-Quartile Range | mg morphine equivalents (MME) | 24 hours postoperatively |
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| Secondary | Pain Intensity Assessed by Numeric Rating Scale (NRS) | Pain intensity measured using the 11-point Numeric Rating Scale (NRS), where 0 = no pain and 10 = worst pain imaginable, averaged across two time intervals: 2-10 hours (mean of time points 2, 4, 6, 10h) and 10-24 hours (mean of time points 14, 18, 24h) after surgery. | Of 100 randomized participants, 5 were excluded from analysis due to protocol violations or incomplete follow-up. The final per-protocol analysis included 49 participants in the ketamine group and 46 participants in the control group (total n=95). | Posted | Mean | Standard Deviation | points on a scale | 2-10 hours and 10-24 hours postoperatively |
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| Secondary | Incidence of Postoperative Nausea and Vomiting | The number of patients experiencing any episode of postoperative nausea or vomiting during the first 24 hours after surgery. | Of 100 randomized participants, 5 were excluded from analysis due to protocol violations or incomplete follow-up. The final per-protocol analysis included 49 participants in the ketamine group and 46 participants in the control group (total n=95). | Posted | Count of Participants | Participants | 24 hours postoperatively |
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| Secondary | Number of Participants With Neuropsychiatric Adverse Events | Number of participants experiencing neuropsychiatric adverse events during 0-10 hours (NPA 0-10 hours) and 10-24 hours (NPA 10-24 hours) after knee arthroplasty. | Of 100 randomized participants, 5 were excluded from analysis due to protocol violations or incomplete follow-up. The final per-protocol analysis included 49 participants in the ketamine group and 46 participants in the control group (total n=95). | Posted | Count of Participants | Participants | 0-10 hours and 10-24 hours postoperatively |
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| Secondary | Severity of Neuropsychiatric Adverse Events | The maximum severity of any neuropsychiatric adverse event experienced by a patient, graded according to the Common Terminology Criteria for Adverse Events (CTCAE). The scale ranges from Grade 1 (Mild) to Grade 5 (Death). Specific conditions and symptoms may have values or descriptive comment for each level, but the general guideline is:
| Of 100 randomized participants, 5 were excluded from analysis due to protocol violations or incomplete follow-up. The final per-protocol analysis included 49 participants in the ketamine group and 46 participants in the control group (total n=95). | Posted | Count of Participants | Participants | 24 hours postoperatively |
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| Secondary | Cumulative Ketamine Dose Administered | The total cumulative dose of ketamine (in milligrams) administered during the first 24 hours after surgery, including both the continuous infusion and patient-initiated boluses. | Of 100 randomized participants, 5 were excluded from analysis due to protocol violations or incomplete follow-up. The final per-protocol analysis included 49 participants in the ketamine group and 46 participants in the control group (total n=95). | Posted | Median | Inter-Quartile Range | milligrams (mg) | 24 hours postoperatively |
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From randomization until 24 hours post-operative
Neuropsychiatric adverse events including hallucinations and post-traumatic stress reaction (PTSR) were systematically assessed and recorded throughout the study period. Additionally, serious adverse events such as thrombotic complications and inadequate regional anesthesia were documented.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ketamine Plus Standard Analgesia | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) plus a continuous intravenous infusion of ketamine using PCA at 0.15 mg/kg/h, with 1 mg boluses available every 5 minutes (maximum daily dose 500 mg), for 24 hours after knee arthroplasty. Morphine 10 mg intramuscularly (IM) may be administered as needed for rescue therapy. | 0 | 50 | 1 | 50 | 0 | 50 |
| EG001 | Standard Analgesia Alone | Participants in this group will receive standardized postoperative pain management (ketoprofen 100 mg twice daily and paracetamol 1000 mg every 8 hours for 24 hours after knee arthroplasty) without ketamine infusion. Morphine 10 mg IM may be administered as needed for rescue therapy. | 0 | 50 | 1 | 50 | 3 | 50 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hallucinations | Psychiatric disorders | MedDRA 10.0 | Systematic Assessment | Patient experienced severe hallucinations following ketamine administration. Event resulted in study withdrawal. Related to study intervention. |
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| Arterial Thrombosis | Vascular disorders | MedDRA 10.0 | Systematic Assessment | One participant developed acute arterial thrombosis of the operated limb in the immediate postoperative period. Managed surgically. Related to surgical procedure, not to study intervention. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Inadequate Regional Anesthesia | Surgical and medical procedures | MedDRA 10.0 | Systematic Assessment | Inadequate femoral nerve block resulting in insufficient anesthesia and pain control; patients required alternative pain management strategies. |
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Single-center study with small sample size (n=100). Short 24-hour follow-up period limits detection of late adverse events. No long-term outcomes assessed.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ivan Shcheparev, MD, PhD | Pirogov National Medical and Surgical Center | +7 (901) 908-90-88 | is22@list.ru |
| Jan 8, 2026 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D010149 | Pain, Postoperative |
| D000377 | Agnosia |
| D009325 | Nausea |
| D014839 | Vomiting |
| ID | Term |
|---|---|
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D010468 | Perceptual Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009422 | Nervous System Diseases |
| D012817 | Signs and Symptoms, Digestive |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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