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BACKGROUND Providing pain relief for patients with neuropathic pain syndrome (NPS) is difficult, as sodium-channel blockers pose serious adverse events (AEs). Intravenous (i.v.) lidocaine infusion responses may identify patients likely to benefit from oral sodium channel blockers. We evaluated i.v. lidocaine responses to predict oral oxcarbazepine (OXC) efficacy in patients with NPS. MATERIAL AND METHODS This prospective cohort study administered one-time 3 mg/kg i.v. lidocaine infusion to patients with NPS. Numeric rating scale (NRS) pain scores and AEs were observed. Next, OXC 150 mg was prescribed; dosages were increased by 150 mg every 3 days until ≥50% pain reduction or the maximum tolerable dose or 1800 mg/day was reached. NRS, rescue drug requirements, and AEs were evaluated by phone at 1, 3, and 5 weeks and clinic visits at 2, 4, and 6 weeks. Depression, Anxiety & Stress Scales 21 (DASS-21), and EuroQol-Five Dimensions-Five Levels (EQ-5D-5L) questionnaires were assessed at baseline and in week 6. RESULTS Of 46 patients, 14 discontinued due to intolerable AEs, and 32 were in the final analysis. Average post-intervention NRS significantly decreased from 6.8±1.7 (baseline) to 3.8±2.0 (lidocaine) and 4.1±2.3 (OXC); P<0.001. Negative and positive predictive values for OXC efficacy were 76.2% (95% CI: 61.6-86.5%) and 54.5% (95% CI: 32-75.4%), respectively. Six weeks after OXC treatment, 20 and 11 patients achieved ≥30% pain reduction and ≥50% pain relief, respectively. EQ-5D-5L (P=0.018) and DASS-21 stress dimension (P<0.001) significantly improved. CONCLUSIONS Negative responses to i.v. lidocaine predicted a lack of oral OXC response. AEs of OXC may have obscured an analgesic effect.
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Lidocaína , Neuralgia , Oxcarbazepina , Humanos , Lidocaína/uso terapêutico , Lidocaína/farmacologia , Lidocaína/administração & dosagem , Masculino , Neuralgia/tratamento farmacológico , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Oxcarbazepina/farmacologia , Oxcarbazepina/uso terapêutico , Administração Oral , Adulto , Idoso , Administração Intravenosa , Resultado do Tratamento , Medição da Dor/métodos , Carbamazepina/análogos & derivados , Carbamazepina/uso terapêutico , Carbamazepina/farmacologia , Carbamazepina/administração & dosagemRESUMO
BACKGROUND: Chronic pain is a disabling condition that adversely affects patient quality of life. The dorsal root entry zone lesioning procedure (DREZotomy) is a modality used to treat intractable pain caused by insults to neural structures. This study aimed to investigate the efficacy of and the factors that determine the outcome of microsurgical DREZotomy (MDT). METHOD: All consecutive patients who underwent MDT for treatment of intractable pain during September 2008 to December 2016 were enrolled. Demographic data, clinical characteristics, intraoperative findings, and postoperative outcomes were analyzed. RESULTS: The 40 included patients underwent MDT for relief of intractable pain caused by 27 brachial plexus injuries (BPIs), 6 spinal cord injuries, 3 neoplasms, and 4 other causes. A significant reduction in pain was observed post-MDT for both average (p < 0.001) and maximal pain (p < 0.001). Favorable outcome (≥50% pain reduction) was observed in 67.5% of patients, with the best outcome in BPI-related pain. In multivariate analysis, injury of the spinal nerve root (root avulsion or injury) was significantly associated with good average pain relief (OR, 5.8; 95% CI, 1.2-27.5; p = 0.026) and pain freedom (OR, 5.0; 95% CI, 1.12-22.30; p = 0.035). Electrical pain (OR, 6.49; 95% CI, 1.20-35.19; p = 0.030) and lower number of painful dermatomes (OR, 1.30; 95% CI, 1.01-1.67; p = 0.039) were significantly associated with good maximal pain relief. CONCLUSIONS: MDT is an effective procedure for treatment of intractable pain in well-selected patients, particularly in cases with brachial plexus avulsion pain. Injury of the spinal nerve root (brachial plexus avulsion and cauda equina injury) was associated with good average pain relief and pain freedom, and electrical pain and lower number of painful dermatomes were associated with good maximal pain relief. The results are useful in the selection of candidates for DREZotomy and prediction of surgical outcome.
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Complicações Pós-Operatórias/epidemiologia , Rizotomia/métodos , Raízes Nervosas Espinhais/cirurgia , Adulto , Idoso , Neuropatias do Plexo Braquial/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Intratável/cirurgia , Complicações Pós-Operatórias/etiologia , Radiculopatia/cirurgia , Rizotomia/efeitos adversos , Traumatismos da Medula Espinal/cirurgiaRESUMO
BACKGROUND: Posterior cranial fossa surgery is commonly performed under sitting and horizontal position in our institution. Venous air embolism is a potentially serious complication of neurosurgery especially in the sitting position. OBJECTIVE: We aim to compare the incidence of severe venous air embolism and other complications of both positions. MATERIAL AND METHOD: A retrospective analysis of medical record was performed in 192 patients undergoing posterior cranial fossa craniotomy from January 2010 to December 2013. Data collected from the records included demographic profile, patient position, hemodynamic changes, venous air embolism (VAE), blood loss/transfusion, duration of surgery, postoperative complications, duration of ICU stay, and postoperative discharge status. The definition of severe air embolism was identified as suspected VAE with decreased systolic blood pressure greater than 20%. RESULTS: There were 92 patients in sitting position (SP) group and 100 patients in horizontal position (HP) group. The incidence of severe venous air embolism was signficantly higher in SP group compared with HP group (41.3% vs. 11.0%, p<0. 001). SP group had more complications than HP group in both central nervous system (71% vs. 34.0%, p = 0.001), and cardiovascular system (17% vs. 6%, p = 0.001). Although postoperative ventilator time in SP group was less than HP group (1.24 vs. 1.60 days, p = 0.029), ICU and hospital stay were not different in either group. CONCLUSION: The incidence of severe venous air embolism detected by end tidal CO2 was significantly higher in SP group. However, 11% of HP group were suspected of severe air embolism.
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Fossa Craniana Posterior/cirurgia , Embolia Aérea/etiologia , Complicações Intraoperatórias/etiologia , Posicionamento do Paciente , Adulto , Idoso , Craniotomia/efeitos adversos , Embolia Aérea/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Previous studies have shown ultrasound guidance (USG)for arterial cannulation being advantageous compared to palpation technique, but little is known about its performance by novices. OBJECTIVE: This study was to compare the utility of USG radial artery cannulation with palpation technique in terms of success rate, real-time to placement, number of attempts and complications. MATERIAL AND METHOD: After IRB approval, a randomized prospective study was performed November 2009-October 2010. Ten third-year residents, having performed USG vascular catheterization as yet less than 3 times, were coached on the pork-phantom during a workshop for real time ultrasound-guided vascular access. For the study patients were randomized to US-guided technique (US-group) and palpation (P-group); ten patients for each resident. RESULTS: One hundred adult patients undergoing neurosurgery were enrolled. There were no statistically significant differences between US-group vs. P-group in success rate (78% vs. 82%; p = 0.62), time to success (60 (12.8, 547.0) vs. 52 (6.9, 639.0) sec; p = 0.22), and number of attempts (1 (1, 4) vs. 1 (1, 3); p = 0.79). Most common complication was puncture hematoma (US-group 26% vs. P-group 24%; p = 0.82). Success was defined as no change in catheterization site, performer and technique. CONCLUSION: Regarding success rate, attended time, or number of attempts for radial arterial cannulation, we did not find any benefit of ultrasound guidance compared to palpation technique. Our findings were not in accordance to other trials. However, we have to consider operators in our study being in experienced in ultrasound-guided procedures but not in palpation techniques.
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Cateterismo Periférico/métodos , Palpação/métodos , Artéria Radial , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Estudos ProspectivosRESUMO
OBJECTIVE: The aim of this study was to evaluate validity and reliability of the Thai version of the Neuropathic Pain Symptom Inventory (NPSI-T) in Thai patients with neuropathic pain. Although the Thai version of Neuropathic Pain Symptom Inventory (NPSI-T) has been linguistically validated, the tool has to be psychometrically validated before applying to neuropathic pain patients in daily practice. MATERIAL AND METHOD: Forty Thai patients with diagnosis of neuropathic pain were enrolled to the study and were evaluated by visual analog scale (VAS), the Thai version of Neuropathic Pain Diagnostic Questionnaire (DN4-T) and NPSI-T questionnaires. Four hours later the patients were asked to perform retest NPSI-T and to evaluate the understanding of each NPSI-T question. RESULTS: The total score of NPSI-T questionnaire was statistically correlated to visual analog scale (VAS) (Spearman's correlation coefficient = 0.599, p < 0.001) and neuropathic pain diagnostic questionnaire (DN4-T) (Spearman's correlation coefficient = 0.695, p < 0.001). The reliability was determined by Intraclass correlation coefficient (ICC), an excellent interobserver agreement (ICC > 0.8) and good agreement (ICC 0.6-0.8) were presented in 30% and 70% of the questionnaire, respectively. CONCLUSION: The study demonstrated validity and reliability of the NPSI-T for assessing the neuropathic pain in Thai patients.
Assuntos
Neuralgia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/psicologia , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários , Tailândia , Escala Visual AnalógicaRESUMO
BACKGROUND: Hypertension and tachycardia during emergence from anesthesia for craniotomy could increase risks of cerebral complications. Several anesthetic, sedative, and antihypertensive drugs have been suggested that may be successful at suppressing these unwanted hemodynamic consequences. OBJECTIVE: To study the equivalent efficacy and side effects of two antihypertensive drugs, diltiazem and labetalol. MATERIAL AND METHOD: A block randomized control trial was performed in 184 patients who developed emergence hypertensive response after craniotomyfor supratentorial tumor removal. Systolic blood pressure (SBP) of each patient was suppressed by 2.5 mg of study drugs and repeated with fix dosage of 2.5 mg every two to three minutes to maintain SBP lower than 140 mmHg with a cumulative dose within 20 mg. Data regarding demographic, successful rate in controlling hypertension, drug dosage, and incidence of side effects were analyzed. RESULTS: The success rate of treatment of labetalol was equivalent to diltiazem (87.1% and 80.2% respectively) [p = 0.003, 95% CI = 6.88 (-2.06 to 15.8)]. There was no statistical significant difference on dosage of drugs used or incidence ofside effect (hypotension, bradycardia, heart block, and bronchospasm). Median (minimum-maximum) dosage of labetalol and diltiazem were 10 mg (2.5-20 mg) and 10 mg (2.5-20 mg) respectively. The expense for labetalol was 1/6 of diltiazem. CONCLUSION: Labetalol has equivalent efficacy to diltiazem. Both drugs used low median dosage giving low incidence of side-effects. Labetalol is a good alternative drug to control hypertensive response during emergence from anesthesia for post-craniotomy.
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Anti-Hipertensivos/uso terapêutico , Diltiazem/uso terapêutico , Hipertensão/tratamento farmacológico , Labetalol/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Supratentoriais/cirurgia , Tailândia , Adulto JovemRESUMO
BACKGROUND: This study investigated the outcomes up to 12 weeks after serial lidocaine infusion for early-onset peripheral neuropathic pain. METHODS: This pilot double-blind, randomized, 2-arm placebo-controlled trial recruited 50 participants with onset of peripheral neuropathic pain within the past 6 months and randomized them to either receive lidocaine (3 mg/kg) in normal saline (50 mL) intravenous infusion over 1 hour (lidocaine group) once a week for 4 weeks or 50 mL of normal saline infusion (placebo group) once a week for 4 weeks. Twenty-nine participants completed the protocol; 15 participants were assigned to the lidocaine group and 14 to the placebo group. The outcomes were pain intensity assessed using a numerical rating scale (NRS), quality of life assessed using EuroQol-Five Dimensions-Five Levels questionnaire (EQ-5D-5L), psychological function using the Thai version of the 21-item Depression Anxiety Stress Scales (DASS-21), pain medication use, and adverse effects, all assessed at baseline (BL) and again at 4, 8, and 12 weeks following randomization. RESULTS: The reported tramadol use at 8 and 12 weeks following the first infusion was significantly lower in the lidocaine group (Pâ =â .023). No other significant between-group differences were observed at any time point or for any other outcome, and no serious adverse events were observed. CONCLUSION: Multiple lidocaine infusions of 3 mg/kg once a week for 4 weeks in participants with recent onset of peripheral neuropathic pain demonstrated no significant benefits in pain intensity, quality of life, or psychological outcomes. At most, this treatment may result in less tramadol use.
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Anestésicos Locais , Lidocaína , Neuralgia , Medição da Dor , Qualidade de Vida , Humanos , Lidocaína/administração & dosagem , Método Duplo-Cego , Feminino , Masculino , Projetos Piloto , Neuralgia/tratamento farmacológico , Anestésicos Locais/administração & dosagem , Anestésicos Locais/uso terapêutico , Pessoa de Meia-Idade , Infusões Intravenosas , Resultado do Tratamento , Adulto , Tramadol/administração & dosagem , Tramadol/uso terapêutico , IdosoRESUMO
The COVID-19 pandemic has affected millions of individuals worldwide. Pain has emerged as a significant post-COVID-19 symptom. This study investigated the incidence, characteristics, and risk factors of post-COVID chronic pain (PCCP) in Thailand. A cross-sectional study was conducted in participants who had been infected, including those hospitalized and monitored at home by SARS-CoV-2 from August to September 2021. Data were collected for screening from medical records, and phone interviews were done between 3 to 6 months post-infection. Participants were classified into 1) no-pain, 2) PCCP, 3) chronic pain that has been aggravated by COVID-19, or 4) chronic pain that has not been aggravated by COVID-19. Pain interference and quality of life were evaluated with the Brief Pain Inventory and EuroQol Five Dimensions Five Levels Questionnaire. From 1,019 participants, 90% of the participants had mild infection, assessed by WHO progression scale. The overall incidence of PCCP was 3.2% (95% CI 2.3-4.5), with 2.8% (95% CI 2.0-4.1) in mild infection, 5.2% (95% CI 1.2-14.1) in moderate infection and 8.5% (95% CI 3.4-19.9) in severe infection. Most participants (83.3%) reported pain in the back and lower extremities and were classified as musculoskeletal pain and headache (8.3%). Risk factors associated with PCCP, included female sex (relative risk [RR] 2.2, 95% CI 1.0-4.9) and greater COVID-19 severity (RR 3.5, 95% CI 1.1-11.7). Participants with COVID-19-related exacerbated chronic pain displayed higher pain interferences and lower utility scores than other groups. In conclusion, this study highlights the incidence, features, and risk factors of post-COVID chronic pain (PCCP) in Thailand. It emphasizes the need to monitor and address PCCP, especially in severe cases, among females, and individuals with a history of chronic pain to improve their quality of life in the context of the ongoing COVID-19 pandemic.
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COVID-19 , Dor Crônica , Feminino , Humanos , Dor Crônica/complicações , Dor Crônica/epidemiologia , Incidência , Estudos Transversais , Tailândia/epidemiologia , Pandemias , Qualidade de Vida , COVID-19/complicações , COVID-19/epidemiologia , SARS-CoV-2 , Fatores de RiscoRESUMO
BACKGROUND: Blue wheals and blue angioedema, the adverse reactions to blue dye injections with or without anaphylaxis, are poorly defined. OBJECTIVE: The objective is to review the characteristics (ie, sex and age at onset, interval between blue dye injection and symptom onset, clinical manifestations, duration of blue wheals or angioedema), natural courses, and treatments of blue dye adverse reactions. METHODS: A review of the articles published through July 2021 was performed per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. RESULTS: Across 523 patients (175 studies) with any adverse reactions to blue dye injections, wheals, angioedema, or both occurred in 193 patients (36.9%). Of these 193 patients, 68 patients (35.2%) developed blue wheals or angioedema, 118 (61.1%) had ordinary wheals or angioedema (nonbluish), and 7 had both (3.6%). We reviewed 169 patients with available data (99 with ordinary lesions and 70 with blue lesions). Patent blue violet had the highest rate of inducing blue wheals or angioedema (odds ratio 4.9). Almost half of the patients with blue wheals or angioedema developed systemic symptoms; and of those with systemic symptoms, all except 1 progressed to anaphylaxis. On-demand treatments with antihistamines, corticosteroids, and epinephrine were commonly used and effective. CONCLUSIONS: Using blue dyes can lead to blue wheals or angioedema and systemic reactions. In patients with a history of a severe allergic reaction to a blue dye, repeat administration of a blue dye should be used only after carefully weighing all the risks and benefits.
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BACKGROUND: Nefopam is a non-opioid, non-nonsteroidal anti-imflammatory drug, analgesic drug that inhibits the reuptake of serotonin, norepinephrine, and dopamine. It is widely used as an adjuvant for pain. This study investigated whether the intraoperative, intravenous infusion of nefopam (20 mg) reduces postoperative morphine consumption, pain scores, and alleviates neuropathic pain in patients undergoing cervical spine surgery. METHODS: A prospective, paralleled design, randomized study was conducted on 50 patients (aged 18-75 years) in a university-based hospital. The patients were assigned to an intervention or a control group (25 patients in each). The intervention group received a 1-hour infusion of nefopam (20 mg) before the end of surgery. The control group received normal saline (NSS). The outcome measures were morphine consumption during the first 24 postoperative hours, numerical rating scale (NRS) pain scores, and scores for the Thai version of the Neuropathic Pain Symptom Inventory (NPSI-T) in patients with neuropathic pain and adverse drug reactions. The NPSI-T scores were assessed on the preoperative day, postoperative day 1, 3, 15, and 30. The outcome assessors were blinded to group allocation. RESULTS: Fifty patients were analyzed. During the first 24 postoperative hours, morphine consumption was 8 mg (nefopam) and 12 mg (NSS; Pâ =â .130). The intervention and control groups demonstrated no significant differences in the median NRS scores or total NPSI-T scores or adverse drug reactions. CONCLUSIONS: A single, intraoperative infusion of 20 mg of nefopam did not significantly reduce postoperative (24 hours) morphine consumption in patients undergoing anterior cervical spine surgery.
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Analgesia , Analgésicos não Narcóticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Nefopam , Neuralgia , Humanos , Nefopam/uso terapêutico , Analgésicos não Narcóticos/uso terapêutico , Estudos Prospectivos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/induzido quimicamente , Morfina/uso terapêutico , Neuralgia/tratamento farmacológico , Vértebras Cervicais/cirurgia , Analgésicos Opioides/uso terapêutico , Método Duplo-CegoRESUMO
Objectives: The objective was to examine the effectiveness of the updated approach. Methods: With IRB approval, outpatients with cancer were enrolled from January to December 2018. Assessments were recorded at baseline and three consecutive visits (BL, FU1, FU2, and FU3), including Numerical Rating Scale (NRS), the Brief Pain Inventory (BPI), the Edmonton Symptom Assessment System (ESAS), side effects, and analgesic use. The primary outcome was a favorable response, defined as an NRS decrease more than 30% or NRS <4. Secondary outcomes included trends over time in BPI, ESAS, side effects, and analgesic use. Pain response predictors at FU3 were analyzed using logistic regression. Results: Among 150 patients, 72 (48%) completed follow-ups. Of these, 61% achieved a favorable response at FU3. Pain interference diminished at all visits relative to baseline (p < 0.05). Median morphine equivalent daily dosage (MEDD) at BL was 20 mg/day, with a statistically significant, but clinically modest increase to 26.4 mg/day at FU3. Radiation therapy during pain care was a predictor of pain responders. Conclusion: The current Siriraj multidisciplinary approach provided effective relief of pain and stabilization of other cancer-related symptoms. Radiation therapy during pain care can be used to predict pain outcomes. Ongoing improvement domains were identified and considered in the context of cultural, economic, and geographic factors.
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Dor do Câncer , Neoplasias , Manejo da Dor , Idoso , Dor do Câncer/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Pacientes Ambulatoriais , Clínicas de Dor , Estudos Prospectivos , Centros de Atenção Terciária , TailândiaRESUMO
STUDY DESIGN: Prospective, double-blinded, randomized controlled study. OBJECTIVE: To determine whether the use of 2 doses of tranexamic acid (TXA) can reduce perioperative blood loss and blood transfusions in low-risk adult patients undergoing complex laminectomy. SUMMARY OF BACKGROUND DATA: Complex laminectomy (multilevel laminectomy or laminectomy and instrumentation) is a procedure with a medium risk of blood loss, which may require allogeneic blood transfusion. Previous studies of TXA showed its inconsistent effectiveness in reducing blood loss during spine surgery. The negative results may stem from ineffective use of a single dose of TXA during long and complex operations. METHODS: 80 adult (18-65 yr old) patients in Siriraj Hospital, Mahidol University, Thailand were enrolled and allocated into 2 groups (40 patients in each group) by computer-generated randomization. Patients with history of thromboembolic diseases were excluded. Anesthesiologists in charge and patients were blinded. Group I received 0.9% NaCl (NSS) or placebo and group II received 2 doses (15 mg/kg) of TXA. The first dose was administered before anesthesia induction and the second dose, after 3 hours. The assessed outcomes were the amount of perioperative blood loss and the incidence of blood transfusions. RESULTS: 78 patients were analyzed (1 patient in each group was excluded) with 39 patients randomized to each group. There were no differences in patient demographics and pre and postoperative hematocrit levels. The total blood loss in the control group (NSS) was higher [900 (160, 4150) mL] than in the TXA group [600 (200, 4750) mL]. Patients in the control group received more crystalloid, colloid, and packed red blood cell transfusions. Within 24 hours, we observed a 64.6% reduction of blood transfusions (43.5% vs.15.4%, P = 0.006). No serious thromboembolic complications occurred. CONCLUSION: 2 effective doses (15 mg/kg) of TXA can reduce blood loss and transfusions in low-risk adults undergoing complex spine surgery. LEVEL OF EVIDENCE: 1.
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Antifibrinolíticos/uso terapêutico , Transfusão de Sangue/estatística & dados numéricos , Procedimentos Ortopédicos/métodos , Coluna Vertebral/cirurgia , Ácido Tranexâmico/uso terapêutico , Adolescente , Adulto , Idoso , Perda Sanguínea Cirúrgica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos/efeitos adversos , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
A randomized controlled trial was conducted to determine the effect of adding epidural ketamine to epidural morphine comparing between giving ketamine at preincisional time and postincisional time on postoperative analgesia in patients undergoing gynecological operations. Eighty patients scheduled for gynecological operation under combined epidural-general anesthesia were randomly divided into 4 groups. Group 1 received epidural morphine 3 mg before skin incision. Group 2 received epidural morphine 3 mg after skin incision. Group 3 received epidural morphine 3 mg and ketamine 30 mg before skin incision. Group 4 received epidural morphine 3 mg and ketamine 30 mg after skin incision. Lidocaine 2 per cent with epinephrine 1:200,000 was used as the main anesthetic agent during the operation in all groups. Postoperative analgesics were pethidine 1 mg/kg intramuscularly or paracetamol 1,000 mg oral. The time to the first analgesic requirement and pain during 48 h were recorded. The amount of pethidine and paracetamol required and the time to the first dose of analgesic requirement were not significantly different among the groups. There were no differences in the incidences of pruritus, nausea, vomiting and nightmare. We concluded that adding ketamine to epidural morphine either by preincisional or postincisional administration did not potentiate the analgesic effect of epidural morphine.