Analgesic efficacy of dexmedetomidine as compared to sufentanil in intraperitoneal surgeries: comparative study

Abstracts

BACKGROUND AND OBJECTIVES: Dexmedetomidine, alpha2-adrenergic agonist with alpha1:alpha2 specificity of 1:1620, does not promote respiratory depression and is intraoperatively used for sedation and analgesia. It has been used associated to opioids in anesthesia for procedures with high painful stimulation, such as intraperitoneal surgeries, and there are no references to its use as single agent. Dexmedetomidine was compared to sufentanil during intraperitoneal procedures in patients above 60 years of age. METHODS: Participated in this study 41 patients randomly distributed in two groups: GS (n = 21), receiving sufentanil, and GD (n = 20) receiving dexmedetomidine for anesthetic induction and maintenance. Patients were given etomidate (GS and GD) with midazolam (GD) for induction and isoflurane and nitrous oxide for maintenance. Hemodynamic attributes (mean blood pressure and heart rate), emergence and extubation times, extubation site (OR or PACU), PACU stay, need for additional analgesia and antiemetics in PACU, OR and PACU complications, Aldrete-Kroulik index at PACU discharge and the need for oxygen mask at PACU discharge were evaluated. RESULTS: There were no differences in hemodynamic stability. GD group has remained for a shorter time in PACU with lower need for oxygen mask at PACU discharge. CONCLUSIONS: Dexmedetomidine may be used as single analgesic for intraperitoneal procedures in patients above 60 years of age, promoting hemodynamic stability similar to sufentanil, with better recovery profile.

ANALGESICS; ANALGESICS; ANESTHESIA; ANESTHETIC TECHNIQUES

JUSTIFICATIVA E OBJETIVOS: A dexmedetomidina, agonista alfa2-adrenérgico com especificidade alfa1:alfa2 1:1620, não determina depressão respiratória, sendo utilizada no intra-operatório como sedativo e analgésico. Esse fármaco tem sido empregado com os opióides em anestesia de procedimentos com elevado estímulo doloroso, como os abdominais intraperitoneais, não havendo referências sobre seu uso como analgésico único. Comparou-se a dexmedetomidina ao sufentanil em procedimentos intraperitoneais, de pacientes com mais de 60 anos de idade. MÉTODO: Foram estudados 41 pacientes divididos aleatoriamente em dois grupos: GS (n = 21), que recebeu sufentanil, e GD (n = 20), dexmedetomidina, ambos na indução e manutenção da anestesia. Os pacientes receberam etomidato (GS e GD) com midazolam (GD) na indução, isoflurano e óxido nitroso na manutenção da anestesia. Foram avaliados os atributos hemodinâmicos (pressão arterial média e freqüência cardíaca), tempos de despertar e de extubação ao final da anestesia, locais onde os pacientes foram extubados - sala de operação (SO) ou sala de recuperação pós-anestésica (SRPA), tempo de permanência na SRPA, necessidade de analgesia suplementar e antiemético na SRPA, complicações apresentadas na SO e SRPA, índice de Aldrete-Kroulik na alta da SRPA e a necessidade de máscara de oxigênio na alta da SRPA. RESULTADOS: Não houve diferença quanto à estabilidade hemodinâmica e GD apresentou menor tempo de permanência na SRPA e menor necessidade de máscara de oxigênio na alta da SRPA. CONCLUSÕES: A dexmedetomidina pode ser utilizada como analgésico isolado em operações intraperitoneais em pacientes com mais de 60 anos, determinando estabilidade hemodinâmica semelhante à do sufentanil, com melhores características de recuperação.

ANALGÉSICOS; ANALGÉSICOS; ANESTESIA; TÉCNICAS ANESTÉSICAS

JUSTIFICATIVA Y OBJETIVOS: La dexmedetomidina, agonista alfa2-adrenérgico con especificidad alfa1:alfa2 1:1620, no determina depresión respiratoria, siendo utilizada en el intra-operatorio como sedante y analgésico. Ese fármaco ha sido empleado con los opioides en anestesia de procedimientos con elevado estímulo doloroso, como los abdominales intraperitoneales, no habiendo informes sobre su uso como único analgésico. Se comparó la dexmedetomidina al sufentanil en procedimientos intraperitoneales, de pacientes con más de 60 años de edad. MÉTODO: Fueron estudiados 41 pacientes divididos aleatoriamente en dos grupos: GS (n = 21), que recibió sufentanil, y GD (n = 20), dexmedetomidina, ambos en la inducción y mantenimiento de la anestesia. Los pacientes recibieron etomidato (GS y GD) con midazolam (GD) en la inducción, isoflurano y óxido nitroso en el mantenimiento de la anestesia. Fueron evaluados los atributos hemodinámicos (presión arterial media y frecuencia cardíaca), tiempos de despertar y de extubación al final de la anestesia, locales donde los pacientes fueron extubados - sala de operación (SO) o sala de recuperación pos-anestésica (SRPA), tiempo de permanencia en la SRPA, necesidad de analgesia suplementar y antiemético en la SRPA, complicaciones presentadas en la SO y SRPA, índice de Aldrete-Kroulik en la alta de la SRPA y la necesidad de máscara de oxígeno en la alta de la SRPA. RESULTADOS: No hubo diferencia en cuanto a la estabilidad hemodinámica y GD presentó menor tiempo de permanencia en la SRPA y menos necesidad de máscara de oxígeno en la alta de la SRPA. CONCLUSIONES: La dexmedetomidina puede ser utilizada como analgésico separado en operaciones intraperitoneales en pacientes con más de 60 años, determinando estabilidad hemodinámica semejante a la del sufentanil, con mejores características de recuperación.

SCIENTIFIC ARTICLE

Analgesic efficacy of dexmedetomidine as compared to sufentanil in intraperitoneal surgeries. Comparative study^*

Eficacia analgésica de la dexmedetomidina comparada al sufentanil en cirugías intraperitoneales. Estudio comparativo

Marco Aurélio Marangoni, M.D.^I; Yara Marcondes Machado Castiglia, TSA, M.D.^II; Tiago Pechutti Medeiros, M.D.^III

^IPós-Graduando do Departamento de Anestesiologia da FMB - UNESP

^IIProfessora Titular do CET/SBA da FMB - UNESP

^IIIME₂ do CET/SBA da FMB - UNESP

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Dexmedetomidine, a₂-adrenergic agonist with a₁:a₂ specificity of 1:1620, does not promote respiratory depression and is intraoperatively used for sedation and analgesia. It has been used associated to opioids in anesthesia for procedures with high painful stimulation, such as intraperitoneal surgeries, and there are no references to its use as single agent. Dexmedetomidine was compared to sufentanil during intraperitoneal procedures in patients above 60 years of age.

METHODS: Participated in this study 41 patients randomly distributed in two groups: GS (n = 21), receiving sufentanil, and GD (n = 20) receiving dexmedetomidine for anesthetic induction and maintenance. Patients were given etomidate (GS and GD) with midazolam (GD) for induction and isoflurane and nitrous oxide for maintenance. Hemodynamic attributes (mean blood pressure and heart rate), emergence and extubation times, extubation site (OR or PACU), PACU stay, need for additional analgesia and antiemetics in PACU, OR and PACU complications, Aldrete-Kroulik index at PACU discharge and the need for oxygen mask at PACU discharge were evaluated.

RESULTS: There were no differences in hemodynamic stability. GD group has remained for a shorter time in PACU with lower need for oxygen mask at PACU discharge.

CONCLUSIONS: Dexmedetomidine may be used as single analgesic for intraperitoneal procedures in patients above 60 years of age, promoting hemodynamic stability similar to sufentanil, with better recovery profile.

Key words: ANALGESICS: dexmedetomidine, sufentanil; ANESTHESIA, Geriatric; ANESTHETIC TECHNIQUES, General

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La dexmedetomidina, agonista a₂-adrenérgico con especificidad a₁:a₂ 1:1620, no determina depresión respiratoria, siendo utilizada en el intra-operatorio como sedante y analgésico. Ese fármaco ha sido empleado con los opioides en anestesia de procedimientos con elevado estímulo doloroso, como los abdominales intraperitoneales, no habiendo informes sobre su uso como único analgésico. Se comparó la dexmedetomidina al sufentanil en procedimientos intraperitoneales, de pacientes con más de 60 años de edad.

MÉTODO: Fueron estudiados 41 pacientes divididos aleatoriamente en dos grupos: GS (n = 21), que recibió sufentanil, y GD (n = 20), dexmedetomidina, ambos en la inducción y mantenimiento de la anestesia. Los pacientes recibieron etomidato (GS y GD) con midazolam (GD) en la inducción, isoflurano y óxido nitroso en el mantenimiento de la anestesia. Fueron evaluados los atributos hemodinámicos (presión arterial media y frecuencia cardíaca), tiempos de despertar y de extubación al final de la anestesia, locales donde los pacientes fueron extubados - sala de operación (SO) o sala de recuperación pos-anestésica (SRPA), tiempo de permanencia en la SRPA, necesidad de analgesia suplementar y antiemético en la SRPA, complicaciones presentadas en la SO y SRPA, índice de Aldrete-Kroulik en la alta de la SRPA y la necesidad de máscara de oxígeno en la alta de la SRPA.

RESULTADOS: No hubo diferencia en cuanto a la estabilidad hemodinámica y GD presentó menor tiempo de permanencia en la SRPA y menos necesidad de máscara de oxígeno en la alta de la SRPA.

CONCLUSIONES: La dexmedetomidina puede ser utilizada como analgésico separado en operaciones intraperitoneales en pacientes con más de 60 años, determinando estabilidad hemodinámica semejante a la del sufentanil, con mejores características de recuperación.

INTRODUCTION

Dexmedetomidine is an a₂-adrenergic agonist with a₁:a₂ selectivity of 1:1620 ¹ not associated to dose-dependent respiratory depression as seen with opioids ² and may decrease intraoperative need for such drugs ^3-5 and for inhalational anesthetics. It is an imidazole compound with chiral core - medetomidine d-enantiomer (potent and widely used veterinary anesthetic). Clinically it has anxiolytic, analgesic and sympatholytic properties which, together, promote a "relaxed" state ⁶. Dexmedetomidine may be safely given to patients at high risk of cardiovascular events ⁷. Dexmedetomidine plasma target concentration of 0,45 ng.mL^-1 has resulted in lower incidence of intraoperative myocardial ischemia in with cardiac disease patients submitted to vascular procedures.

So, dexmedetomidine promotes intraoperative hemodynamic stability by dose-dependently decreasing blood pressure and heart rate, preventing tachycardia and hypertension ⁸, and decreasing myocardial oxygen need, especially in patients with hypertension or tachycardia ⁹, being used with this aim during myocardial revascularization procedures ⁵. However, its rapid intravenous administration triggers brief blood pressure increase as a consequence of vascular smooth muscles a receptors stimulation, in addition to reflex bradycardia ^10,11. Initial dexmedetomidine dose should be administered in approximately 10 minutes.

Sufentanil is the most potent µ opioid receptor agonist available ¹², but do to its pharmacokinetic profile, it slows down emergence when used in continuous infusion. It promotes deep analgesia and lower hormonal response to stress, but may cause respiratory depression, bradycardia, histamine release, muscle stiffness, pruritus, urinary retention, decreased bowel movements, nausea and vomiting ¹³.

This clinical study aimed at comparing dexmedetomidine and sufentanil as analgesics during anesthesia for intraperitoneal procedures in patients above 60 years of age, and at evaluating hemodynamic characteristics, and time for emergence, extubation and PACU discharge.

METHODS

After the Clinical Research Ethics Committee, Faculdade de Medicina, Botucatu - UNESP - approval and their written consent, participated in this study 41 patients physical status ASA I or II, aged 60 to 87 years, 38 to 87 kg, 1.40 to 1.76 m, submitted to general anesthesia for intraperitoneal procedures (cholecystectomy, gastrectomy, hemicolectomy or rectosigmoidectomy).

Patients were not premedicated. At OR arrival and after tracheal intubation and vesical catheter insertion, patients were monitored with ECG (in D_II), pulse oximetry, noninvasive blood pressure and capnography.

Patients were randomly divided in two groups. Sufentanil group (GS) (n = 21) received sufentanil during anesthetic induction and maintenance; dexmedetomidine group (GD) (n = 20) received dexmedetomidine during anesthetic induction and maintenance.

Anesthetic agent for intravenous induction for both groups was etomidate (0.3 mg.kg^-1) which was associated to midazolam (0.1 mg.kg^-1) for the dexmedetomidine group.

Intravenous analgesic doses before etomidate were: sufentanil (1 µg.kg^-1) for GS, and dexmedetomidine (1 µg.kg^-1) in 10-minute continuous infusion for GD.

Neuromuscular blocker was atracurium (0.5 mg.kg^-1), which has promoted adequate relaxation for oxygenation and tracheal intubation.

Anesthesia was maintained with oxygen and nitrous oxide in equal parts, and isoflurane in concentrations necessary for a successful procedure. Total volume of this agent was recorded for further consumption comparison between groups. Total diluent gas volume for both groups was standardized in 1.5 L.min^-1. Analgesia was achieved with sufentanil (0.01 µg.kg^-1.min^-1) for GS, with dose adjusted as needed, and dexmedetomidine (0.4 to 0.8 µg.kg^-1.h^-1) for GD as needed, both in intravenous continuous infusion (Samtronic^® pump).

To help mechanical ventilation and surgical procedure, intermittent doses of neuromuscular blocker, equal to 1/5 of initial dose, were administered at 30-minute intervals. Patients were submitted to controlled mechanical ventilation and respiratory rate and tidal volume were adjusted to maintain P_ETCO₂ between 35 and 45 mmHg.

Sufentanil infusion was withdrawn approximately 80 minutes before surgery completion (whenever abdominal cavity closing was started), while dexmedetomidine was withdrawn approximately 10 minutes before surgery completion. Isoflurane was maintained for both groups even after sufentanil and dexmedetomidine withdrawal.

All patients received intravenous tramadol (100 mg) and dipyrone (1 g) before surgery completion for postoperative analgesia.

Attributes evaluated were: demographics (age, gender, weight, height and physical status), mean blood pressure (MBP) during procedure, ratio between mean MBP and initial MBP, ratio between MBP after tracheal intubation and initial MBP, mean heart rate (HR) during procedure, ratio between mean HR and initial HR, ratio between post-intubation HR and initial HR, surgery length, anesthesia length, sevoflurane consumption, emergence time after anesthesia, extubation time after anesthesia, extubation site (OR or PACU), PACU stay, need for additional analgesia in PACU, need for antiemetics in PACU, need for oxygen mask at PACU discharge, OR and PACU complications, and modified Aldrete-Kroulik index at PACU discharge. Patient would be referred to the ward with oxygen mask when SpO₂ was between 90% and 92% in room air, and when presenting other conditions part of modified Aldrete-Kroulik index with discharge values.

Hemodynamic data (HR and MBP) were observed for statistical analysis in the following moments: before analgesic administration (M1), after TI (M2), 10 minutes after TI (M3), 30 minutes after TI (M4), 60 minutes after tracheal intubation (M5) and 120 minutes after TI (M6). Hypotension was defined as MBP 30% decrease, and bradycardia as heart rate decrease to values below 50 bpm.

MBP was calculated by the following equation: (systolic blood pressure + 2 x diastolic blood pressure) x 3^-1. Values were then comparatively analyzed during moments M1, M2, M3, M4, M5 and M6 between groups to evaluate hemodynamic profiles determined by both drugs. Mean MBP maintained by patients during the procedure was calculated by adding all measured pressures and dividing the result by the number of measurements. Result was again divided by initial MBP resulting in a value representing the ratio between mean MBP and initial MBP. Ratio between MBP after TI and initial MBP was also calculated and the result was treated as an inference of possible protection against hemodynamic changes induced by tracheal manipulation. Same calculations were used for HR.

Patients were considered awaken when they answered to their names by promptly and vigorously opening eyes. When respiratory conditions were adequate patients were extubated - respiratory rate between 16 and 24 movements per minute and capnometry values between 35 and 45 mmHg, in addition to adequate muscle strength (determined by hand grasping or raising and supporting head). Patients with conditions for such up to 20 minutes after surgery were extubated in the OR. If not, they were extubated in the PACU.

Student's t test for independent samples to compare quantitative variables between groups, and Fisher's exact test for categorical variables to compare variance proportions between groups were used for statistical analysis. P < 0.05 was considered statistically significant and p between 0.10 and 0.05 was considered a trend, being p the probability of erroneously determining significance. The minimum number of patients per group was determined to detect (with test power of 0.95 and a of 0.05) a 70-minute difference between groups in extubation time after both analgesics infusion withdrawal.

RESULTS

There were no statistically significant differences in demographics for both groups, determining that samples were homogeneous (Table I).

Brazilian Journal of Anesthesiology, 2005; 55: 1: 19 - 27

Analgesic efficacy of dexmedetomidine as compared to sufentanil in intraperitoneal surgeries. Comparative study

Marco Aurélio Marangoni; Yara Marcondes Machado Castiglia; Tiago Pechutti Medeiros

Surgical and anesthetic lengths (presented as mean ± standard deviation) for GS (respectively 175 ± 58.1 min and 211.9 ± 67.9 min) and GD (respectively, 187.8 ± 77.6 min and 238.5 ± 91.7 min) were statistically equivalent (Table II).

Brazilian Journal of Anesthesiology, 2005; 55: 1: 19 - 27

Analgesic efficacy of dexmedetomidine as compared to sufentanil in intraperitoneal surgeries. Comparative study

Marco Aurélio Marangoni; Yara Marcondes Machado Castiglia; Tiago Pechutti Medeiros

GS patients were awaken 105.5 ± 41.5 min after sufentanil withdrawal and GD patients 40.8 ± 20.7 min after dexmedetomidine withdrawal.

Emergence time after anesthetic procedure was not significantly different (GS = 19.1 ± 23.6 min and GD = 17.9 ± 11.4 min) (Table II).

Time between end of analgesic infusion and extubation was 126.9 ± 51.5 min for GS, and 59.3 ± 29.7 min for GD. Time between end of anesthetic procedure and extubation was statistically similar between groups (GS = 40.8 ± 31.1 min and GD = 47.4 ± 21.4 min) (Table II).

There have been no statistically significant difference in isoflurane consumption in mL.h^-1 per hour between groups (mean ± standard deviation): GS = 7.23 ± 3.13 min, and GD = 6.92 ± 2.45 min.

There were no differences between groups in extubation site, whether OR or PACU (Table II).

There were no significant differences between groups in the need for additional analgesia or oxygen mask at PACU discharge, however GS patients needed more antiemetics.

PACU discharge criterion was patient's evaluation according to modified Aldrete-Kroulik index. GD patients had a trend toward higher scores (10) as compared to GS.

Hemodynamic evaluation within standardized moments has shown correspondence as to MBP and heart rate behavior. There have been no significant differences between groups in ratio between MBP after TI and initial MBP. The same analysis comparing the ratio between mean MBP during procedure and initial MBP has also resulted in correspondence. There have also been no significant differences in comparing initial mean MBP (M1), after TI (M2), and 10 (M3), 30 (M4), 60 (M5) and 120 minutes (M6) after TI for GS and GD (Figure 1). The same analysis were performed for HR values with results similar to MBP (Figure 2).

Brazilian Journal of Anesthesiology, 2005; 55: 1: 19 - 27

Analgesic efficacy of dexmedetomidine as compared to sufentanil in intraperitoneal surgeries. Comparative study

Marco Aurélio Marangoni; Yara Marcondes Machado Castiglia; Tiago Pechutti Medeiros

Brazilian Journal of Anesthesiology, 2005; 55: 1: 19 - 27

Analgesic efficacy of dexmedetomidine as compared to sufentanil in intraperitoneal surgeries. Comparative study

Marco Aurélio Marangoni; Yara Marcondes Machado Castiglia; Tiago Pechutti Medeiros

PACU stay length for GS patients was 174.0 ± 99.2 min and for GD 119.7 ± 55.9 min, being GD stay significantly shorter as compared to GS (Table II).

Adverse effects observed in both environments (OR and PACU) are shown in table III. There have been no statistically significant differences in incidence between groups.

Brazilian Journal of Anesthesiology, 2005; 55: 1: 19 - 27

Analgesic efficacy of dexmedetomidine as compared to sufentanil in intraperitoneal surgeries. Comparative study

Marco Aurélio Marangoni; Yara Marcondes Machado Castiglia; Tiago Pechutti Medeiros

DISCUSSION

Our study has observed hemodynamic stability in both groups, statistically confirmed by heart rate and mean blood pressure values, notwithstanding the expectation that the dexmedetomidine group (GD) would show lower blood pressure values and possibly bradycardia ⁷. This suggests that both drugs were able to block sympathetic cardiovascular responses after peritoneal noxious stimulation.

Considering the results of initial mean blood pressure and mean blood pressure immediately after intubation, which has statistically confirmed similarity between groups, one may state that, for the population evaluated, dexmedetomidine was similar to sufentanil in blocking hemodynamic changes usually observed during endotracheal intubation, and which had already been shown in gynecologic and ophthalmic surgeries ^3,14.

Since dexmedetomidine sedation is more superficial ^15,16 and respiratory depression negligible ², it is easy to understand the trend toward better Aldrete-Kroulik indices at PACU discharge, in addition to shorter extubation time for patients under a₂-agonists (GD) as compared to sufentanil patients (GS). It should be considered that even the association of dexmedetomidine and midazolam has not prevented better recovery conditions for this group as compared to the sufentanil group.

The hypothesis of the analgesic effect of dexmedetomidine associated to propofol has already been shown in young patients submitted to ENT surgeries ¹⁷. Our study has not observed statistically significant differences in isoflurane consumption between groups, confirming such ability, even during surgeries with high painful potential, such as intraperitoneal procedures. It is worth highlighting that a₂-agonist was the single analgesic agent. As a consequence, one may infer the excellent analgesic potential of dexmedetomidine.

The decreased need for inhalational anesthetics and opioids when dexmedetomidine is used as adjuvant therapy has been widely described in the literature and reinforces our analgesic results ^3,18.

Considering our sample of elderly patients, it has been observed that dexmedetomidine may promote intraoperative analgesia with hemodynamic stability statistically comparable to sufentanil.

All patients were given tramadol and dipyrone before surgery completion as preventive analgesia, since studied surgical procedures are very painful in the immediate postoperative period (major procedures). Next, we have observed the need for additional analgesia in both groups. There has been no difference between groups and one may attribute similar residual analgesia efficacy after continuous sufentanil or dexmedetomidine administration, in line with the literature which attributes considerable analgesic efficacy to dexmedetomidine ¹⁷. Fixed tramadol dose, regardless of patients' weight, has not influenced results since there has been no significant difference between them.

There has been no difference in the incidence of nausea and vomiting in the PACU, as well as in number of patients presenting side effects. PACU stay length was significantly shorter for the dexmedetomidine group.

So, one may conclude that, in the conditions of our study, dexmedetomidine associated to isoflurane, nitrous oxide and midazolam was an analgesic alternative to sufentanil for intraperitoneal procedures in patients above 60 years of age.

REFERENCES

Submitted for publication March 3, 2004

Accepted for publication September 21, 2004

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*

Received from Departamento de Anestesiologia da Faculdade de Medicina de Botucatu, FMB UNESP, Botucatu, SP

Publication Dates

• Publication in this collection
  01 Mar 2005
• Date of issue
  Feb 2005

History

• Accepted
  21 Sept 2004
• Received
  03 Mar 2004