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This project proposes to compare epidural versus spinal anesthesia in patients having liver resection surgery. The investigators hypothesize that spinal anesthesia will result in improved blood pressure control postoperatively and reduce the amount of intravenous fluids required after surgery. Spinal anesthesia is expected to provide the same pain control benefits as epidurals, with faster recovery of function. Spinal anesthesia may be a simple and effective way to improve and enhance the recovery in the increasing number of patients requiring liver resection.
Hepatic resection surgery (hepatectomy) for primary or metastatic malignancy is a major operation involving large, painful upper abdominal incisions, as well as considerable postoperative physiological derangements.
Uncontrolled postoperative incisional pain results in significant respiratory impairment, delayed mobilization, and augmentation of the surgically-induced stress response, placing patients at increased risk of postoperative complications and chronic post-surgical pain. Acute pain management with high-dose parenteral opioids further compounds this risk. Multimodal opioid-sparing therapy, and regional anesthesia in particular, is therefore an essential component of enhanced recovery after surgery (ERAS) pathways and patient-centred care.
Regional anesthesia using neuraxial block (intraoperative spinal anesthesia or thoracic epidural anesthesia) followed by postoperative continuous thoracic epidural analgesia (CTEA; postoperative administration of epidural local anesthetic and/or opioid) is the best method for treating pain following large abdominal surgeries, including liver resection, and has been shown to improve postoperative respiratory function and decrease respiratory complications in other surgeries.
However, the effects of intraoperative neuraxial block and postoperative CTEA on fluid balance, systemic hemodynamics, and functional recovery after hepatic resection surgery remain controversial. CTEA is frequently associated with postoperative hypotension, resulting in increased perioperative intravenous (IV) fluid administration, red blood cell transfusion, and vasopressor use in liver resection patients. For major hepatectomies, CTEA may also be an independent risk factor for postoperative acute kidney injury (AKI), presumably due to impairment of renal autoregulation. Excessive IV fluid administration in the postoperative period is associated with significant weight gain, often necessitating diuretic therapy; delayed return of gastrointestinal function; increased need for packed red blood cell (pRBC) transfusion due to hemodilution; increased infective complications due to this increased pRBC transfusion rate; and increased length of hospital stay.
In addition, concerns remain about the use of CTEA following liver resection surgery due to the potentially increased risk of epidural hematoma formation in the setting of postoperative coagulopathy. This concern has resulted in unplanned delays in epidural catheter removal postoperatively, due to persistent coagulation abnormalities, prolonging hospitalization by 1-3 d in up to 15% of patients.
These concerns about the consequences of excess fluid administration and the safety of CTEA for liver resection surgery have prompted the use of alternative and/or ancillary analgesic techniques, particularly for major resections and in patients with preoperative liver dysfunction, for whom a prolonged period of postoperative coagulopathy is anticipated.
Intraoperative spinal anesthesia (SA) using local anesthetic (LA) and/or opioid (most commonly intrathecal morphine [ITM]) for neuraxial block without CTEA is frequently used as postoperative analgesia for various surgeries. Spinal anesthesia using ITM without LA has been reported in four randomized and three non-randomized studies of patients undergoing liver resections. ITM has provided superior analgesia to IV patient-controlled analgesia (IV-PCA) with opioids, and equivalent analgesia to epidural infusions. Compared with CTEA and/or IV-PCA, ITM was associated with reduced IV fluid administration; earlier mobilization, and resumption of normal dietary intake; decreased incidence of respiratory complications; and decreased hospital length of stay.
Spinal anesthesia using both LA and ITM may provide an additional benefit by providing a degree of preemptive analgesia, as well as by decreasing the stress and inflammatory response, thereby possibly decreasing the incidence of surgical stress-related complications such as postoperative delirium. High-spinal anesthesia (HSA) uses larger doses of LA to achieve a "high" block for this purpose. HSA combined with ITM has been used in cardiac surgery, and decreases the stress and inflammatory response to surgery; facilitates early extubation; improves postoperative analgesia; decreases the incidence of postoperative delirium; and decreases intensive care unit (ICU) readmissions. Neither the use of HSA (with or without ITM) for analgesia following non-cardiac surgical procedures, nor the effectiveness of SA with ITM versus CTEA following hepatic resection surgery has been investigated to date.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intrathecal morphine | Experimental | Spinal anesthesia with intrathecal morphine Bolus (pre-induction): High-spinal anesthesia with 0.25 mg⋅kg-¹ hyperbaric bupivacaine 0.75% plus 3 mcg⋅kg-¹ intrathecal morphine (preservative-free) Postoperative analgesia: IV-PCA hydromorphone (bolus: 0.2 mg [range: 0.1-0.4 mg]; 5 min lockout; no infusion) |
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| Thoracic epidural analgesia | Active Comparator | Continuous thoracic epidural analgesia Bolus (pre-induction): 0.25 mg⋅kg-¹ bupivacaine 0.25% plus 1 mcg⋅kg-¹ hydromorphone (0.1 mL⋅kg-¹) Infusion (initial): 0.25 mg⋅kg-¹⋅h-¹ bupivacaine 0.25% plus 1 mcg⋅kg-¹⋅h-¹ hydromorphone (0.1 mL⋅kg-¹⋅h-¹) Infusion (range): 0.19-0. 3 mg⋅kg-¹⋅h-¹ bupivacaine 0.25% plus 0.75-1.25 mcg⋅kg-¹⋅h-¹ hydromorphone (0.075-0.125 mL⋅kg-¹⋅h-¹) (3-10 mL⋅h-¹) Postoperative analgesia: (1) Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range as above (0.075-0.125 mL⋅kg-¹⋅h-¹) (3-10 mL⋅h-¹), continued for a maximum of 72 h postoperatively; (2) IV-PCA hydromorphone (bolus: 0.2 mg [range: 0.1-0.4 mg]; 5 min lockout; no infusion). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Continuous thoracic epidural analgesia | Procedure | Needle/catheter: 17 Ga. × 80 mm Tuohy epidural needle (Perican®, B. Braun Medical Inc., Bethlehem, PA, USA); Arrow FlexTip Plus® 19 Ga. epidural catheter (Arrow International Inc., Reading, PA, USA) Level of insertion and patient positioning: T6-T8, upright sitting position for insertion of needle and catheter (to 5 cm beyond loss-of-resistance point) and for injection of test dose (3 mL 2% lidocaine with epinephrine 1:200,000); supine for injection of bolus dose Confirmation of correct placement: Loss of resistance to air or saline; negative aspiration of the epidural catheter; negative test dose; and ease of injection of an initial bolus dose |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative 72-hour volume of intravenous fluids and blood products administered | Intraoperative plus cumulative postoperative intravenous (IV) fluid volume administered, total (mL) = sum of volumes of IV crystalloid, IV colloid, and non-albumin blood products (packed red blood cells [pRBC], fresh-frozen plasma [FFP], and platelets) administered | Intraoperatively and during the first 72 hours postoperatively or until hospital discharge, whichever occurs earlier |
| Area under the curve over 72 hours of the summed pain intensity difference scores at rest (AUC-SPID-PAR_0-72h) | Numerical Rating Scale (NRS) Summed Pain Intensity Difference at rest (SPID-PAR) (calculated as Area Under the Curve [AUC] using the trapezoidal rule) over 0 to 72 hours (AUC-SPID-PAR_0-72h) after surgery. Pain intensity (PI) is assessed preoperatively and at 2, 6-12, 24, 36, 48, 60, and 72 hours after surgery or until hospital discharge, whichever came first, using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is the "worst possible pain". Pain intensity difference (PID_t) is calculated as the difference in pain intensity from time 0 to each time point t. SPID_t is calculated using the trapezoidal rule as the area under the curve (AUC) for Pain Intensity Difference over the time interval 0 to t hours, respectively, divided by the length of the time interval (t hours). A positive value is a decrease (improvement) of the pain. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Cumulative 72-hour opioid consumption (OC_0-72h) | Total perioperative epidural, intravenous, and oral opioid requirements measured in oral morphine equivalents (OME, mg). | Intraoperatively and during the first 72 hours postoperatively or until hospital discharge, whichever occurs earlier |
| Measure | Description | Time Frame |
|---|---|---|
| Vasopressor-free days to day 30 | Vasopressor-free days to 30 days after surgery will be defined as the number of days alive and not on vasopressors before 30 days. If the patient is on vasopressors at day 30 or dies prior to day 30, vasopressor-free days will be 0. | During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively) |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative 24-hour volume of intravenous fluids and blood products administered | Intraoperative plus cumulative postoperative intravenous (IV) fluid volume administered, total (mL) = sum of volumes of IV crystalloid, IV colloid, and non-albumin blood products (packed red blood cells [pRBC], fresh-frozen plasma [FFP], and platelets) administered | Intraoperatively and during the first 24 hours postoperatively |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Alex Grunfeld, MD | Contact | 204-787-1125 | alexander.grunfeld@umanitoba.ca |
| Name | Affiliation | Role |
|---|---|---|
| Alex Grunfeld, MD | University of Manitoba | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Manitoba | Recruiting | Winnipeg | Manitoba | R3E 0Z2 | Canada |
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| Spinal anesthesia with intrathecal morphine | Procedure | Needle/catheter: 25 Ga. × 90 mm high-flow Whitacre spinal needle (Becton-Dickinson, Franklin Lakes, NJ, USA) Level of insertion and patient positioning: L2-L3, lateral decubitus position during injection; immediately post-injection, patient is placed supine in <5% degree of Trendelenburg Confirmation of correct placement: Aspiration of cerebrospinal fluid |
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| Bupivacaine 0.75% in Dextrose Inj 8.25% | Drug | 0.25 mg⋅kg-¹ hyperbaric bupivacaine 0.75% |
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| Morphine | Drug | 3 mcg⋅kg-¹ intrathecal morphine (preservative-free) |
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| Bupivacaine 0.25% Preservative-Free Injectable Solution | Drug | 0.25 mg⋅kg-¹ bupivacaine 0.25% |
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| Bupicavaine 0.125% epidural solution | Drug | Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range 0.075-0.125 mL⋅kg-¹⋅h-¹ |
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| Hydromorphone 10 mcg/mL epidural solution | Drug | Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range 0.075-0.125 mL⋅kg-¹⋅h-¹ |
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| Cumulative intraoperative vasopressor and/or inotrope consumption | Cumulative norepinephrine (NE)-equivalent time-weighted dose (mcg·kg-¹·min-¹ of anesthesia time) of vasopressors and/or inotropes (phenylephrine, norepinephrine, dopamine, and/or epinephrine). | Intraoperatively (from anesthesia start time to anesthesia end time) |
| Cumulative perioperative vasopressor and/or inotrope consumption | Cumulative norepinephrine (NE)-equivalent time-weighted dose (mcg·kg-¹·min-¹ of vasopressor and/or inotrope infusion duration) of vasopressors and/or inotropes (phenylephrine, norepinephrine, dopamine, and/or epinephrine). | Intraoperatively and during the first 7 days after surgery or until hospital discharge, whichever occurs earlier |
| Cumulative 72-hour volume of intravenous fluids administered | Intraoperative plus cumulative postoperative intravenous (IV) fluid volume administered, excluding non-albumin blood products, total (mL) = sum of volumes of IV crystalloid and IV colloid administered | Intraoperatively and during the first 72 hours postoperatively |
| Area under the curve over 72 hours of the summed pain intensity difference scores of movement-evoked pain (MEP) (AUC-SPID-MEP_0-72h) | Numerical Rating Scale (NRS) Summed Pain Intensity Difference of movement-evoked pain (SPID-MEP) (calculated as Area Under the Curve [AUC] using the trapezoidal rule) over 0 to 72 hours after surgery (AUC-SPID-MEP_0-72h) | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Cumulative incidence (proportion) of rescue analgesia (parenteral opioid) use (%) | Rescue analgesia (parenteral opioid) use is defined as receipt of supplemental (i.e., in addition to that defined by the intervention protocols) doses of fentanyl, morphine, and/or hydromorphone via the intravenous (IV) route, either via patient-controlled analgesia (PCA) or nurse/physician administration. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Cumulative fluid balance (CFB) at 72 hours | Cumulative fluid balance (CFB) is defined as the sum of current daily fluid balance (DFB) and the sum of DFB from all preceding days. DFB (mL) = (total daily fluid input - total daily fluid output). Daily fluid input includes: (1) resuscitation fluids (isotonic crystalloid [at a rate >1 L/6 h]; colloids [albumin, hydroxyethyl starch]); (2) blood products (packed red blood cells; frozen plasma; platelets; cryoprecipitate); (3) maintenance and replacement fluids (dextrose-containing crystalloid; isotonic crystalloid [at a rate ≤1 L/6 h]); (4) nutrition (enteral nutrition [i.e., tube feeds]; parenteral nutrition; oral fluid intake); and (5) fluid creep (volume due to concentrated electrolytes; volume used to keep venous access open; intermittent and continuous medication). Daily fluid output includes: (1) blood loss; (2) urine output; (3) dialysis ultrafiltrate (if applicable); (4) losses through drains; and (5) losses through enteric (e.g., nasogastric) tubes. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Percentage fluid overload (% FO) at 72 hours | Percentage fluid overload (% FO) is defined as the ratio between cumulative fluid balance and the initial body weight, in percentage: % FO = [(total fluid in (L) - total fluid out (L)) / admission body weight (kg) × 100]. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Volume-related weight gain (VRWG) at 72 hours | Volume-related weight gain at time t (VRWG_t) is defined as the percentage body weight gain at time t, calculated as the difference between the baseline body weight and body weight at time t divided by baseline body weight (t = 0): VRWG_t (%) = [(body weight [kg]_t - body weight [kg]_0) / body weight [kg]_0 × 100%]. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Quality of recovery, as measured by the change from baseline 15-item Quality of Recovery (QoR-15) scale score over the first 72 hours postoperatively | Patient-reported quality of recovery (QoR), as assessed using the 15-item Quality of Recovery (QoR-15) scale, with the change from baseline in the total QoR-15 score (range 0-150) at 72 hours postoperatively defining the analysis endpoint. The QoR-15 is a 15-item patient-completed questionnaire including items measuring pain, physical comfort, psychological support, emotional state, and independence in activities of daily living over the preceding 24 hours. Items are rated on a 10-point scale, with higher subscale (item) and total scale values indicating a better outcome. The scale's validity (content, criterion, and construct), reliability (test-retest and internal consistency [inter-item and split-half coefficients]), responsiveness (minimal clinically important difference [MCID] = 8.0), acceptability, and feasibility properties have been well-established. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Time to mobilization (h) | Defined as time to first out-of-bed mobilization (sitting out of bed, standing or walking). | 7 days after surgery or until hospital discharge, whichever occurs earlier |
| Time to gastrointestinal (GI) recovery (h) | Defined as the later of (1) time to solid diet tolerance (recovery of upper GI function), and (2) time to first flatus or bowel movement. | 7 days after surgery or until hospital discharge, whichever occurs earlier |
| Time to removal of urinary catheter (h) | 7 days after surgery or until hospital discharge, whichever occurs earlier |
| Time to adequate pain control with PO medications (h) | 7 days after surgery or until hospital discharge, whichever occurs earlier |
| Sleep disturbance, as measured by the change from baseline Patient-Reported Outcomes Measurement Information System (PROMIS®) Short Form v1.0 - Sleep Disturbance 8a scale T-score over the first 7 days postoperatively | The Patient-Reported Outcomes Measurement Information System (PROMIS®) Short Form v1.0 - Sleep Disturbance (SD) 8a scale assesses self-reported perceptions of sleep quality, sleep depth, and restoration associated with sleep. The 8-item self-report version (Short Form [SF]) of the PROMIS® SD 8a scale included in this study queries sleep disturbance symptomatology based on the past 7 days, with each item rated on a 5-point Likert scale ranging from 1 (never) to 5 (almost always). All item scores are summed to calculate a total raw score where higher scores indicate more severe sleep disturbance symptomatology. Psychometric evaluations of the 8-item PROMIS® SF SD 8a in a wide range of patient populations have provided support for its high reliability (test-retest, internal consistency) and validity (convergent, divergent, face, construct). A smaller between-group increase from baseline (preoperative) to 7-day postoperative PROMIS® SF SD 8a T-scores indicates a better outcome. | 7 days after surgery or until hospital discharge, whichever occurs earlier |
| Overall Benefit of Analgesia Score (OBAS) at 72 hours | The Overall Benefit of Analgesia Score (OBAS) is a patient-reported outcome measure of seven pain-related quality-of-life indicators: (1) pain intensity at rest (scored 0-4, 0 = minimal pain, to 4 = maximum imaginable pain); patient-reported distress with respect to five opioid-related adverse effects (each scored 0-4, 0 = not at all, to 4 = very much): (2) vomiting, (3) itching, (4) sweating, (5) freezing, and (6) dizziness; and (7) patient satisfaction with pain treatment (scored 0-4, 0 = not at all, to 4 = very much). To calculate the OBAS score, the scores for items 1-6 and 4 minus the score for item 7 are summed for a total scale score range of 0 to 28, with lower values indicating a better outcome. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Index hospitalization length of stay | Duration (days) of index hospitalization from date of index operation to date of hospital discharge (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively). | During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively) |
| Analgesic-related adverse events: incidence rate ratio of severe respiratory depression | Severe respiratory depression is defined as respiratory rate (RR) < 8 and/or hypoxemia (Spo2 < 90%) related to excessive somnolence and/or alveolar hypoventilation. | During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively) |
| Analgesic-related adverse events: incidence rate ratio of sedation | Severe opioid-induced sedation, as defined by Pasero-McCaffery Opioid-induced Sedation Scale (POSS) score of 3 or 4. The POSS is graded on a 5-point scale (S = sleep, easy to arouse; 1 = awake and alert; 2 = slightly drowsy, easily aroused; 3 = frequently drowsy, arousable, drifts off to sleep during conversation; 4 = somnolent, minimal or no response to verbal or physical stimulation), with scores of S, 1, and 2 considered acceptable levels of sedation, and scores of 3 or 4 considered unacceptable levels of sedation. | During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively) |
| Analgesic-related adverse events: cumulative incidence (proportion) of postoperative delirium | Delirium will be evaluated via trained nursing assessments using the 3-min Confusion Assessment Method (3D-CAM). The diagnosis of delirium by 3D-CAM requires a positive response to (1) acute onset or fluctuating course; and (2) inattention; and either (3) disorganized thinking or (4) altered level of consciousness. To reduce the likelihood of fluctuations or temporal changes, all assessments were completed between 11:00 AM and 2:00 PM and for each participant, within a 2-hour time period. | During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively) |
| Number (count) of surgical complications with Clavien-Dindo grade ≥ III | Postoperative surgical complications are assessed using the Clavien-Dindo classification (none, I, II, III, IV, or V) and classified by system. | During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively) |
| Number (count) of non-surgical complications based on the Postoperative Morbidity Survey (POMS) | Postoperative non-surgical complications are assessed using the Postoperative Morbidity Survey (POMS) based on retrospective review of medical charts and patient telephone follow-up at 30 days. | Postoperative non-surgical complications are assessed using the Postoperative Morbidity Survey (POMS) based on retrospective review of medical charts and patient telephone follow-up at 30 days. |
| Comprehensive Complication Index (CCI) score Comprehensive Complication Index (CCI) score Comprehensive Complication Index (CCI) score | Postoperative surgical and non-surgical complications are graded using the Comprehensive Complication Index (CCI), a continuous scale ranking the severity of any combination of postoperative complications from 0 to 100 in each patient. | During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively) |
| Area under the curve (AUC) over 24 hours of the summed pain intensity difference (SPID) scores at rest (AUC-SPID-PAR_0-24h) | Numerical Rating Scale (NRS) Summed Pain Intensity Difference at rest (SPID-PAR) (calculated as Area Under the Curve [AUC] using the trapezoidal rule) over 0 to 24 hours (AUC-SPID-PAR_0-24h) after surgery | 24 hours after surgery |
| Cumulative 24-hour (IV) opioid consumption (OC_0-24h) | Total perioperative epidural, intravenous, and oral opioid requirements measured in oral morphine equivalents (OME, mg). | Intraoperatively and during the first 24 hours postoperatively or until hospital discharge, whichever occurs earlier |
| Time to first parenteral opioid dose administration (min) | Parenteral opioid administration is defined as receipt of fentanyl, morphine, and/or hydromorphone via the intravenous (IV) route, either via patient-controlled analgesia (PCA) or nurse/physician administration. | 72 hours after surgery or until hospital discharge, whichever occurs earlier |
| Cumulative incidence (proportion) of patient-controlled analgesia (PCA) utilization postoperatively (%) | Patient-controlled analgesia (PCA) utilization is defined as use of PCA with intravenous opioids (morphine, fentanyl, and/or hydromorphone). | 7 days after surgery or until hospital discharge, whichever occurs earlier |
| Cumulative incidence (proportion) of postoperative vasopressor and/or inotrope dependency (%) | Requirement for postoperative vasopressor and/or inotrope therapy (phenylephrine, norepinephrine, dopamine, and/or epinephrine) to maintain mean arterial pressure (MAP) ≥ 65 mm Hg and/or to treat signs and/or symptoms of systemic hypoperfusion. | 7 days after surgery or until hospital discharge, whichever occurs earlier |
| ID | Term |
|---|---|
| D010149 | Pain, Postoperative |
| D008113 | Liver Neoplasms |
| D000377 | Agnosia |
| ID | Term |
|---|---|
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
| D010468 | Perceptual Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000775 | Anesthesia, Spinal |
| D002045 | Bupivacaine |
| D009020 | Morphine |
| D004091 | Hydromorphone |
| ID | Term |
|---|---|
| D000765 | Anesthesia, Conduction |
| D000758 | Anesthesia |
| D000760 | Anesthesia and Analgesia |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
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