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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.58 no.4 Campinas July/Aug. 2008
Preoperative intravenous clonidine in the surgical treatment of cataract: evaluation of the clinical benefits*
Clonidina por vía venosa en el preoperatorio del tratamiento quirúrgico de catarata: evaluación del beneficio clínico
Eduardo Tocchetto LemesI; Fábio Van Der FritzI; Paulo Henrique Poti HomrichI; Andressa Prestes StolzII; Julio César Mercador de FreitasI; Elaine A. Felix Fortis, TSAIII
do Serviço de Anestesia do HCPA
IIOftalmologista; Fellow do Serviço de Oftalmologia Setor de Córnea e Doenças Externas do HCPA
IIIProfessora Adjunta de Anestesiologia do Departamento de Cirurgia da Faculdade de Medicina da Universidade Federal do Rio Grande do Sul; Responsável pelo CET/SBA do SAMPE/HCPA
OBJECTIVES: Clonidine has been used in anesthesia for its sedative and analgesic
properties, and to achieve greater hemodynamic stability with reduction in intra-ocular
pressure. This study evaluated the clinical effects of intravenous clonidine
(2.5 µg.kg-1) on the intra-ocular pressure (IOP), hemodynamic
parameters, and post-anesthetic recovery in the surgical treatment of cataract.
METHODS: This is a randomized, double-blind, placebo-controlled study that included patients undergoing cataract surgery under peribulbar block. After placement of monitoring devices, baseline (M0) values of IOP, mean arterial pressure (MAP), heart rate (HR), SpO2, and the degree of sedation (Ramsay) were determined. Afterwards, placebo (Group P) or clonidine (Group C) was administered intravenously. After 30 minutes, at Moment 1 (M1), measurements were repeated, and once again at the end of the surgery, at Moment 2 (M2).
RESULTS: The change in IOP between M0 and M1 was different for both groups, 14.5% in Group C and 5.25% in Group P (p = 0.01), and the means remained reduced until M2. Mean arterial pressure in Group C showed a 17% reduction from M0 to M1 and increased 3.5% in Group P (p < 0.001) and in Group C it showed a recovery at M2 (p = 0.17). The heart rate decreased 6.4% in Group C and 1% in Group P (p = 0.1) from M0 to M1. There was a greater sedation in Group C when compared with Group P (p < 0.001) but there was no cases of respiratory depression. The relative risk of intraoperative hypertension was 0.657 (CI 95% 0.517 to 0.835) in Group C, p < 0.01. Differences in the incidence of tachycardia, hypoxemia, hypotension, and increased hospital staying were not observed between both groups.
CONCLUSIONS: Clonidine, under the conditions of the present study, showed to be a safe drug and decreased IOP and the intraoperative risk of hypertension without delaying hospital discharge.
Key Words: ANALGESICS: clonidine; SEDATION: intravenous; SURGERY, Ophthalmologic: cataracts, fasciectomy, phacoemulsification, intra-ocular pressure.
Y OBJETIVOS: La clonidina ha sido utilizada en la anestesia por añadir
propiedades analgésicas y sedativas, y por proporcionar una mayor estabilidad
hemodinámica con reducción de la presión intraocular. Este
estudio evalúa los efectos clínicos de la clonidina (2,5 µg.kg-1),
por vía venosa, en la presión Intraocular (PIO), en la hemodinámica
y en la recuperación postanestésica del tratamiento quirúrgico
MÉTODOS: Se realizó un ensayo clínico a doble ciego, controlado por placebo y con distribución aleatoria, que incluyó pacientes que fuesen realizar operación de catarata bajo bloqueo peribulbar. Después de la monitorización, Momento 0 (M0), se realizaron las medidas iniciales de PIO, presión arterial media (PAM), frecuencia cardíaca (FC), SpO2 y el grado de sedación (Ramsay), y entonces se administró el placebo (Grupo P) o la clonidina (Grupo C) por vía venosa. Treinta minutos después, Momento 1 (M1), se repetían las medidas y nuevamente al fin de la operación, Momento 2 (M2).
RESULTADOS: Entre M0 y M1, hubo una disminución diferente de la PIO, 14,5% en el Grupo C y 5,25% en el P (p = 0,01), manteniendo sus medias reducidas en M2. La PAM del Grupo C se redujo un 17% de M0 a M1 y subió un 3,5% en el Grupo P (p < 0,001), con una recuperación de la PAM del Grupo C hasta M2 (p = 0,17). La FC disminuyó 6,4% en el Grupo C y 1% en el Grupo P (p = 0,1) de M0 a M1. Se registró un aumento de la sedación en el Grupo C con relación al P (p < 0,001), sin embargo sin que ocurriera depresión respiratoria. El RR de hipertensión arterial en el intraoperatorio del Grupo C fue 0,657 (IC95% 0,517 a 0,835), p < 0,01. No hubo diferencias con relación a la incidencia de la taquicardia, hipoxemia, hipotensión arterial, ni atraso del alta hospitalaria.
CONCLUSIONES: La clonidina, en las condiciones de este estudio, fue un fármaco seguro y redujo la PIO y el riesgo de hipertensión arterial intraoperatoria sin retardar el alta hospitalaria.
Clonidine, a central acting a2-adrenergic receptor agonist, has been used in anesthesiology for its analgesic and sedative properties 1,2, and for providing greater perioperative hemodynamic stability in hypertensive patients 3,6. Its ability to decrease the sympathetic activity reduces the release of norepinephrine, perioperative myocardial ischemia, and postoperative mortality in cardiac patients undergoing non-cardiac surgeries 7,8. It has been used in ophthalmologic procedures as preoperative medication since it leads to a reduction in intra-ocular pressure (IOP) and attenuates the increase in IOP secondary to laryngoscopy and tracheal intubation 9,10. The dose of 5 µg.kg-1 of clonidine reduced the response to atropine in episodes of bradycardia, which was not observed with doses below 2.5 µg.kg-1 11.
It is known that increased intra-ocular pressure hinders the surgical procedure and increases the risk of complications, such as vitreous loss, iris or lens prolapse, and bleeding. Thus, controlled reduction of IOP is recognized as an essential component of a good anesthesia for intra-ocular surgeries.
There are evidence of the reduction of IOP and blood pressure (BP) with oral clonidine; however, there are no data in the medical literature on the intravenous administration of this drug.
The objective of this study was to evaluate the effects of the preoperative administration of intravenous clonidine on IOP and hemodynamic parameters, and determine the repercussions of its sedative property on postoperative recovery and length of stay in the recovery room in patients undergoing cataract surgery.
After approval by the Ethics Commission of the Hospital de Clínicas de Porto Alegre (HCPA), a randomized, double-blind, placebo-controlled study was undertaken, which included 68 patients from the outpatient clinic, older than 18 years, who were admitted for elective cataract surgeries under general anesthesia; all patients signed an informed consent. Exclusion criteria included patients who were using clonidine for any other reason, anti-psychotic medications, tricyclic antidepressants, calcium channel blockers, lithium, MAO inhibitors, or who refused to participate. Patients with AV block or bundle-branch block in the electrocardiogram or patients with preoperative baseline systolic blood pressure < 100 mmHg and/or HR < 50 bpm were also excluded.
Randomization was accomplished by distributing drugs that could not be identified by the researchers. The vials of clonidine and placebo used were identical in shape, size, color, and labeling, differentiated only by a code ranging from 01 to 200 printed on their white labels. This identification procedure was done by the company Cristália®, that commercializes the clonidine available at the HCPA, upon request. The table with the identification of the vials was given to the project manager and opened only after all the data of the study had been recorded. After the identification of the drugs, patients were divided in two groups. Group C received 2 to 2.5 µg.kg-1 of intravenous clonidine, up to a maximum of 150 µg, and group P received placebo.
Hemodynamic monitoring consisted of electrocardiogram (ECG), automatic non-invasive blood pressure (MAP), and pulse oximetry (SpO2), recorded by a 2010 Dixtal® monitor.
After venipuncture, baseline parameters were recorded at the preparation room (Moment 0 - M0): degree of sedation according to the Ramsay scale, MAP, HR, SpO2, and IOP. The coded study drugs were administered by the anesthesiologist who ignored which drug was being used. Thirty minutes after administration of the drug, Moment 1 (M1), the same parameters were recorded again and a peribulbar block was performed with 80 to 100 mg of 1% ropivacaine with 320 IU to 400 IU of hyaluronidase, and prior sedation with 0.5 to 1.5 mg.kg-1 of propofol.
An oxygen tent was used in all patients during the surgery. Intraoperative hemodynamic variables were followed and recorded. At the end of the surgery, Moment 2 (M2), parameters were recorded once again.
Two examiners, who ignored which medication had been administered, measured IOP in both eyes with the patient in dorsal decubitus, using the same Perkins applanation tonometer at MO and M1, and in the non-operated eye at M2.
Respiratory depression was defined as a respiratory rate below 10 bpm, and hypoxemia as SpO2 < 90%. Hypotension was defined as MAP < 60 mmHg or 30% lower than baseline BP and hypertension as MAP > 115 mmHg or 30% above baseline values. Tachycardia was diagnosed when the heart rate was greater than 100 bpm or 30% greater than baseline HR, and bradycardia as HR below 50 bpm or 30% lower than the initial parameters. A score of 3 on the Ramsay scale was considered mild sedation and, from 4 on, moderate to deep sedation.
Discharge from anesthesia was done when the patient showed to be awake and oriented, a revised Aldrete and Kroulik score > 8, a score of 1 or 2 on the Ramsay scale, and absence of postural hypotension, nausea, vomiting, pain, and a negative Romberg sign. All those parameters were evaluated every 15 minutes after the surgery.
The minimal calculated study sample for a power of 90% and a 5% level of significance included 17 patients in each group. The Student t test was used to compare independent parametric means of normal behavior between both groups. Analysis of Variance (ANOVA) for repeated measures was used to analyze IOP, MAP, HR, SpO2, and Ramsay on the three moments of the study. The Chi-square test was used to calculate the relative risk of adverse events. The level of significance adopted was 5% (p < 0.05).
The sample was homogenous regarding baseline characteristics, except for MAP, which was higher in Group C, p = 0.011 (Table I).
The right eye was operated in 19 patients in each group and the left eye in 13 patients in Group C and 15 patients in Group P (p = 0.77). Eleven fasciectomies were performed in each group, 22 phacoemulsifications in Group C and 24 in Group P (p = 0.87). The mean time from M0 to M2 for fasciectomy was 164.6 ± 20.61 minutes in Group C and 149.55 ± 37.11 minutes in Group P (p = 0.19), and the mean time for phacoemulsification was 131.32 ± 25.38 minutes in Group C and 121.9 ± 28.8 minutes in Group P (p = 0.31).
The use of ropivacaine, propofol, mannitol, and NS for anesthesia was similar in both groups (p > 0.27), as well as the preoperative use of b-blockers, ACE inhibitors, benzodiazepines, and diuretics (p > 0.16).
Figure 1 shows the analysis of the behavior of IOP at moments 0, 1, and 2, demonstrating a reduction in IOP in both groups (p time < 0.001). However, the reduction in IOP was more pronounced in Group C when compared with Group P (p interaction = 0.045).
Comparing the variation of IOP between M0 and M1, it was observed that Group C showed a reduction in IOP of 14.2% and 5.17% in Group P (p = 0.01). However, between M0 and M2, IOP showed a 16% reduction in Group C and 7.55% in Group P, but with a p = 0.064.
Similar analyses were done for the hemodynamic parameters in both groups. The behavior of MAP at moments 0, 1, and 2 can be seen in Figure 2, which shows that the variation of MAP along the study was significant in each group (p time = 0.001). Once more, the reduction in MAP was more pronounced in Group C when compared with Group P (p interaction < 0.001) and both groups were homogenous (p = 0.93). Between M0 and M1, it was observed a 16.9% reduction in MAP in Group C and a 2.8% increase in Group P (p < 0.001), and between M0 and M2 there was a partial recovery of MAP in Group C, but it still showed a 8.55% reduction in Group C and 3.5% increase in Group P (p = 0.004).
The heart rate was reduced throughout the study in both groups (p time < 0.001); however, it demonstrated a different behavior between both groups, with a more pronounced decrease in Group C (p interaction = 0.02), but both groups were homogenous regarding HR (p group = 0.62) (Figure 3). Between M0 and M1 there was a 6.4% reduction in HR in Group C and 1.11% in Group P, p = 0.016, and between M0 and M2 Group C showed a 9% reduction while Group P showed a 1.7% reduction (p = 0.016).
All patients maintained normal oxygen saturation. Both groups presented discrete and similar variations in SpO2 (p interaction = 0.07), which was not clinically significant. Mean SpO2 at M0 was 96.9 ± 1.7 in Group C and 96.21 ± 1.7 in Group P. At M1, it was 96.1 ± 2.15 in Group C and 96.48 ± 1.5 in Group P. At M2, it was 97.58 ± 1.5 in Group C and 97.3 ± 1.4 in Group P.
The Ramsay sedation scale (Figure 4) showed different variations throughout the study (p time < 0.001) and between both groups (p interaction < 0.001), with a small increase in the degree of sedation in Group C at M1 (mean 2.6 ± 0.81) when compared with Group P (mean 1.84 ± 0.37), p < 0.0001
Differences in the incidence of hypotension, bradycardia, tachycardia, ventilatory depression, or hypoxemia between both groups were not statistically significant. However, 12 patients in the placebo group developed intraoperative hypertension (Table II).
All patients in both groups fulfilled the criteria for anesthesia discharge immediately after the end of the surgery, except for one patient in Group P, who needed anti-hypertensive treatment in the postoperative period, delaying his discharge from the hospital.
The mean degree of satisfaction of patients in Group C was 9.8 ± 0.56 on a scale from 0 to 10, and 9.79 ± 0.43 in Group P, with p = 0.94.
This study compared the use of intravenous clonidine with placebo in ophthalmological surgeries. Clonidine reduced IOP, maintained hemodynamic stability, and light sedation (Ramsay 2 and 3) intraoperatively.
The reduction in blood pressure provided by the sympatholytic activity of clonidine demonstrated to be a protective factor for the development of intraoperative hypertension (RR 0.657).
In general, phacoemulsification does not last more than 30 minutes. In this study, the longer duration of the surgery might have contributed for a reduction in the effects of clonidine on the reduction of IOP at the end of the surgery. Surgeries in the present study lasted longer since they were performed at a teaching hospital. Although the reduction in IOP in the Clonidine Group had been greater at the end of the surgeries, this reduction was not significant.
In the immediate postoperative period, the state of consciousness did not differ between both groups. Clonidine had the advantage of maintaining patients more sedated, in a state of mild sedation without losing consciousness or developing hypoxemia. The length of stay in the recovery room was similar in both groups and all patients, who presented discharge criteria immediately after the end of the surgeries, but for one patient in the Placebo Group. This patient had a longer stay in the recovery room due to a treatment of hypertension.
The use of the intravenous route and the possibility to administer clonidine at the pre-anesthetic preparation room made for a safe administration, which can be done in all outpatients. When it is administered by mouth, it cannot be controlled by the physician, depends on patient compliance, and is associated with an irregular absorption. The intravenous administration of clonidine has a peak of action after 30 minutes and, therefore, can be administered closer to the time of surgery than oral clonidine, whose peak of action is around 2 and 4 hours. Thus, the possible adverse effects would be monitored more safely intraoperatively.
The determination of IOP during the procedure demonstrated a clear benefit of clonidine in the surgical treatment of cataract. However, measurement of IOP after peribulbar block and the use of the Honan intraocular pressure reducer, when one should observe the greatest benefit of clonidine, were not possible due to operational reasons. Besides, data recording ended the moment the patient fulfilled the post-anesthetic discharge criteria, and only patients who developed any intercurrence were followed-up postoperatively.
The safety of clonidine was evaluated through its potential adverse effects. The side effects of clonidine, a non-selective a2-agonist, are secondary to sympatholytic responses. On the doses used in the present study, mild to moderate decrease in blood pressure and heart rate, sedation, anxiolysis, and analgesic synergism were expected 13. Clonidine resulted in a reduction in the concentration of catecholamines and, consequently, reduced heart rate and blood pressure, decreasing perioperative tachycardia and hypertension, especially in hypertensive patients who present greater variations in cardiac rhythm and blood pressure than the general population 12. On the studies quoted by Ghignone3 and Filos10, a 5% incidence of mean arterial pressure < 70 mmHg and 5% to 10% incidence of heart rate < 55 bpm were observed without cardiac arrest or mortality. In the present study, clonidine did not increase the risk of bradycardia (RR 1.06) and hypotension. All those intraoperative sympatholytic effects are expected and desired in this type of surgery, since they promote greater hemodynamic stability in those patients, who are usually elderly with some comorbidities, especially cardiovascular. However, it has been demonstrated that 5 µg.kg-1 of oral clonidine attenuates the parasympatholytic response to atropine, requiring greater doses of this drug to treat episodes of bradycardia secondary to surgery, represented by the ocular-cardiac reflex, or even by the direct action of clonidine, although rare, as a sympatholytic agent 11.
In conclusion, the use of intravenous clonidine as a pre-anesthetic medication, administered 30 minutes before ophthalmologic procedures, demonstrated to be effective in reducing IOP and maintaining hemodynamic stability besides protecting against the development of hypertension. Sedation levels varied from light to moderate without influencing the length of stay in the recovery room.
Thus, under the conditions of the present study, intravenous clonidine demonstrated clinical benefits in patients undergoing surgical treatment of cataract.
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Correspondence to: Submitted em 4
de maio de 2007 *
Received from Serviço de Anestesia e Medicina Perioperatória (SAMPE)
do Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS
Dr. Eduardo Tocchetto Lemes
Rua Machado de Assis, 855/1.302 - Jardim Botânico
90620-260 Porto Alegre, RS
Accepted para publicação em 18 de março de 2008
Submitted em 4
de maio de 2007
* Received from Serviço de Anestesia e Medicina Perioperatória (SAMPE) do Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS