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Departments of *Anesthesiology and Otorhinolaryngology, Universitätsklinik Regensburg; and Department of Anesthesiology, Universitätsklinik Ulm, Germany
Address correspondence to Michael T. Pawlik, MD, DEAA, Department of Anesthesiology, University of Regensburg, Franz-Josef-Strauss-Allee 6, D-93046 Regensburg, Germany. Address e-mail to michael.pawlik{at}klinik.uni-regensburg.de.
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Introduction |
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Hypertension, arrhythmia, and coronary artery disease are frequently associated with OSAS and influence the clinical course of the disease (2). Because of the frequent incidence of an obstructed airway, a high risk of respiratory depression, and the incidence of coexisting cardiopulmonary disorders, OSAS patients are at increased risk during general anesthesia (3). Analgesics and sedatives aggravate OSAS by decreasing pharyngeal tone, and depressing ventilatory responses to hypoxia and hypercapnia (4). For these reasons, drugs that cause sedation and respiratory depression should be avoided for premedication (5). Therefore, current opinion does not recommend premedication for sleep apnea patients, although oral premedication is common practice in general anesthesia (6). The 
2-agonist clonidine possesses rapid eye movement (REM)-suppressant activity and improves the level of nocturnal hypoxemia in patients with OSAS (7). Clonidine has been used for some years in supplementing general anesthesia. It is beneficial when used for preoperative medication before general anesthesia by enhancing the effects of anesthetics (8). Several studies have shown reduced changes in heart rate and mean arterial blood pressure (MAP) in patients receiving premedication with clonidine without having adverse effects on respiratory rate (9). We hypothesize that oral administration of 2 µg/kg clonidine given the night before and 2 h before surgery reduces changes in heart rate, MAP, and the requirement for perioperative anesthetics and analgesics without adverse effects on the apnea/hypopnea index (AHI) of OSAS patients.
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Methods |
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= 0.05 and ß = 0.95.
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All patients underwent polysomnography (Eden Trace; Edentec Monitoring System, Eden Prairie, MN) from 08:00 pm to 08:00 am on the preoperative day, and on the day of surgery until 08:00 am on the first postoperative morning. Respiratory events were assessed by measuring oronasal airflow using a dual thermistor. Chest wall movements were measured using an inductive respiratory plethysmograph, oxyhemoglobin saturation was analyzed by finger oximetry in the Edentec® recorder, sound was recorded using a microphone placed at the level of the larynx, body position was monitored through a sensor positioned on the chest, and cardiac rhythm was monitored by electrocardiogram (ECG). The sleep variables used in this study were AHI, desaturation index, and minimum oxygen saturation (MSAT). The AHI index was calculated as the number of apnea/hypopnea episodes/hour of sleep. An apnea episode was defined as a cessation of airflow lasting >10 s, whereas a hypopnea episode was defined as a 
50% reduction in combined oral and nasal airflow lasting >10 s. A desaturation event was defined as a saturation <90% and a duration >10 s; the index was calculated as the number of desaturation episodes/hour. MSAT was defined as the lowest arterial oxygen saturation level detected during the observation period. An oxygen desaturation <90% was considered abnormal. To minimize the possibility of misinterpretation, signal strength and data were monitored off-line by a physician trained in sleep medicine (TSK).
On arrival in the operating room, monitoring consisted of three-lead ECG, pulse oximetry, capnography, heart rate, MAP (9000C®; Siemens, Erlangen, Germany). Bispectral index (BIS®; Aspect Medical Systems Inc., Natick, MA) electrodes were applied and BIS® A 2000 monitoring commenced. MAP and heart rate were recorded at intervals of 1 min during anesthetic induction until tracheal intubation and after cessation of anesthetics at emergence from anesthesia. During surgery and recovery, measurement was performed in 5-min intervals and hourly intervals on the ward for 8 h after surgery on the first postoperative day. All patients had an induction technique commencing with a bolus of remifentanil 1 µg/kg, followed by propofol 1.5 mg/kg until loss of the eyelash reflex and a BIS® target value of 40. Increased BIS® values (>40) were treated by repeated bolus of 0.5 mg/kg propofol. Muscle relaxation and tracheal intubation followed 2.5 min after IV mivacurium 0.2 mg/kg. Anesthesia was maintained during surgery with remifentanil infusion immediately commenced at 0.2 µg · kg–1 · min–1 and increased to 0.5 µg · kg–1 · min–1 to keep heart rate between 60–80 bpm. A decrease of heart rate to <40 bpm was treated by injection of 0.5 mg of atropine. Further propofol dosage adjustments were standardized by protocol, according to adverse hemodynamic responses and BIS® measurements. In general, this consisted of 1. a bolus of propofol and increased propofol rates if signs of "light" anesthesia (systolic blood pressure >15% compared with values before induction, or BIS® >45) were present, or 2. reduced propofol infusion rates if signs of "deep" anesthesia (systolic blood pressure <15% compared with values before induction or BIS® <35) were present.
At the time of surgical dressing, all anesthetic infusions were stopped, and time until opening of eyes on command was recorded. The total amount of intraoperative propofol and remifentanil was recorded. Tracheal extubation occurred when the patient was fully awake and cooperative, with a respiratory rate between 10 and 20 breaths/min, and had satisfactory pulse oximetry.
Postoperative analgesia was assessed by using a visual analog scale (VAS) score. Standard analgesia consisted of rectal diclofenac 1.5 mg/kg immediately after induction of anesthesia. Piritramide 0.1 mg/kg was administered IV at the patient's request by nurses or if the VAS score was >3. Patient pain scores were obtained after tracheal extubation, at 10-min intervals in the first 2 h after surgery, and then every hour for 8 h after completion of the procedure. Patients received oxygen during the first 2 h after tracheal extubation, if oxygen saturation was constantly <92%. Because of nasal tamponades nCPAP (nasal continuous positive airway pressure), patients were not able to use their nCPAP device postoperatively.
Statistical analysis was performed using the SPSS 12.0 software package (SPSS® Inc., Chicago, IL). The Student's t-test was used to compare normally distributed continuous variables between the two groups, and the nonparametric Mann-Whitney U-test was used for nonparametric or not normally distributed data. Hemodynamic values were analyzed by comparing corresponding time points during induction and emergence of anesthesia between the groups. Hemodynamic data during surgery, recovery room, and on the postoperative ward, as well as BIS values and VAS pain scores were added, averaged, and analyzed using Student's t-test. A paired t-test with Bonferroni adjustment for multiple comparisons was used for possible changes of AHI, desaturation index, and MSAT within the groups. Data are presented as means and their standard deviations (sd). Statistical significance was considered at P < 0.05.
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Results |
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On the morning of surgery, the MAP before induction of anesthesia was significantly lower in the clonidine group than in the placebo group, whereas the heart rates showed no difference between groups (Table 2). Only during the first 3 min of induction were MAP values significantly lower in the clonidine group, whereas there was no difference in heart rate between the groups (Fig. 1A and B). MAP and heart rates were significantly lower during the entire surgery in the clonidine-premedicated patients than in placebo (P < 0.001, t-test; Table 2). During emergence from anesthesia, MAPs, but not heart rates, were significantly lower in the clonidine group (Fig. 2A and B). After emergence, differences in MAP were significant (P < 0.001). Additionally, we found significant differences of MAP and heart rates (P < 0.001) in the recovery room; significant differences in heart rate and MAP were also observed between the groups on the ward (Table 2).
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The induction dose of propofol required to reach a target BIS® value of 40 was significantly smaller in clonidine-premedicated patients (Table 3). Patients receiving clonidine required a significantly smaller average dosage of propofol during the entire surgery than the placebo group (Table 3). The consumption of remifentanil showed no significant differences between the groups (Table 3). There was no difference in the administered basic analgesic regimen of diclofenac (118 ± 53.8 mg placebo versus 110 ± 68.6 mg clonidine) and the consumption of piritramide in the first postoperative hour in the recovery room, but clonidine-premedicated patients required significantly less piritramide in the 24 postoperative hours than placebo patients (Table 3). Time until eye opening on command after cessation of total IV anesthesia (TIVA) was significantly shorter in the clonidine group (Table 3). The overall quality of analgesia was excellent in both groups throughout the observation according to psychometric evaluation (VAS <3). Mean VAS was significantly lower in the clonidine group after tracheal extubation in the recovery room and significantly lower in the clonidine group than in the placebo group after 24 h (P < 0.001; Table 3).
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There were no airway difficulties during anesthesia in any of the 30 patients. Hypertensive events that required treatment postoperatively with additional antihypertensive medication occurred in 8 of 15 (53.3%) patients only in the placebo group (Table 2). The majority of hypertensive events occurred in the first 6 h after surgery on the ward. One patient in the placebo group had angina pectoris in the recovery room and needed aspirin, heparin, and nitroglycerin. Two patients in the clonidine group required atropine because of bradycardia (<40 bpm) during the operation; none of the patients in the placebo group required atropine. No adverse respiratory events were observed. The baseline AHI and oxygen desaturation index were comparable in both groups indicating that all patients had comparably severe OSAS. There were no significant differences between the groups at any time and no significant differences within the groups at different time points (Fig. 3A). Desaturation indices showed no significant differences between the groups at all time points. There was a significant decrease on the preoperative night, the day of surgery, and the postoperative night compared with baseline values within both groups (Fig. 3B). The recorded MSAT of placebo and clonidine patients showed no changes from baseline within the groups. However, on the day of surgery, MSAT was significantly less in placebo-treated patients than in those receiving clonidine. (Fig. 3C)
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Discussion |
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In the present study, we found a perioperative incidence of 53% of hypertensive patients in the control group. One of the sequelae of OSAS is a constantly increased sympathetic tone as a consequence of repetitive hypoxia and arousal during sleep (14). Oral clonidine has been shown to reduce sympathetic hyperactivity and suppress the increase in sympathetic activity after tracheal intubation (15). We found a significant reduction in heart rate and MAP after clonidine premedication during anesthesia and 24 hours postoperatively. Importantly, none of our patients used his or her nCPAP, although there are reports that the use of nCPAP reduces postoperative complications such as cardiac events (16). Even if desirable, there may be situations in which patients cannot use their nCPAP because of nasal packing after having undergone nose and throat surgery.
There was a significant reduction in both the amount of propofol required during induction (15%) and total propofol consumption (15%) in our patients given clonidine, which is in accordance with other reports on non-OSAS patients (17). In OSAS patients, short-acting anesthetic drugs such as propofol and remifentanil are considered advantageous, and, from a pharmacokinetic point of view, they are useful to achieve a rapid awakening after surgery. In fact, all patients in our study were fully awake shortly after cessation of the anesthetics and could easily be tracheally extubated. It has been reported that clonidine is associated with a prolonged recovery from propofol anesthesia (18). However, we were surprised to find a significantly faster awakening after the use of clonidine premedication in the OSAS patient, probably because of significantly less propofol consumption throughout the operation. Studies on the analgesic potency of clonidine show inconsistent results, ranging from significant opioid-sparing effects to minor analgesic effects (19,20). Importantly, we found a significant postoperative opioid-sparing effect with a better quality of analgesia, when clonidine was given preoperatively. Non-opioids have been shown to ensure safe pain relief in OSAS patients in the majority of cases, but sufficient pain control in some cases may be achieved only with opioids, especially after oropharyngeal surgery (21).
There are several case reports of deleterious outcomes in OSAS patients who received opioids in the postoperative course and who were not monitored adequately (22), thus we considered the reduction of opioid administration as an important step in both patient comfort and safety. Although pain scores were statistically different between the groups, the finding is not of clinical significance, because the low pain score values in both groups indicated an excellent pain reduction in all study patients. The most interesting finding is that clonidine-premedicated patients required about half the dose of opioids compared with placebo patients. One possible explanation of reduced opioid requirement and increased effect of opioids in OSAS patients could be upregulation of µ-opioid receptors in the brainstem caused by continuous hypoxemia as shown by Moss and Laferriere (23) in a hypoxic animal model. There is evidence of an interaction between clonidine and µ receptors, which is probably responsible for the significant opioid-sparing effect we found in our study (24). However, despite a decreased requirement for opioids, we found no improvement of respiratory function, which could have been for two reasons. First, the severity of the underlying OSAS probably has a greater role than the reduction of respiratory-depressing opioids. Second, the effects of clonidine on patients with OSAS in a perioperative setting are still unknown. There may be potentially depressing effects of clonidine itself which are not antagonized by a decreased requirement of opioids, on the ventilatory pattern of those patients. Roberge et al. (25) reported one case of severe respiratory acidosis, hypotension, and associated central nervous system depression in an OSAS patient taking continuous clonidine medication.
Another important aspect of OSAS is that hypopnea/apnea is mainly associated with REM sleep stages, which facilitates muscle relaxation and leads to upper airway obstruction in the OSAS patient. Issa (7) had already shown in 1992 that clonidine is able to suppress REM sleep and thus improve nocturnal hypoxemia. Preoperative anxiety over the anticipated surgery leads to interruption of normal sleep cycles in the OSAS patient, which is aggravated by the administration of clonidine premedication. This could be a possible explanation for our finding of a marked decrease in AHI and desaturation index in both groups on the morning before operation. We speculate that the return of the AHI to baseline values on the day of surgery in both groups was related to postoperative pain medication. All AHI of the first postoperative night showed neither a significant difference between the clonidine and placebo group nor differences within the groups compared with baseline values. Interestingly, minimum desaturation was comparable in both groups except for the day of surgery. This could be explained by the decreased amount of propofol and piritramide required in the clonidine-premedicated patients. In our study, protocol polysomnography follow-up was restricted to the postoperative night. Thus, further studies are needed to examine whether profound REM rebounds occur after clonidine premedication during the first week after anesthesia.
There are some limitations to this study. First, the study was technically difficult to perform. The signal quality of oronasal flow sensors was intermittently poor because of patient movement and saliva or blood running over the oronasal sensor. All analyzed recorded events were manually reevaluated by a specialist, which led to a marked reduction of originally recorded apnea/hypopnea events. Second, there was a high interindividual scatter in both groups representing mild to severe OSAS with an AHI range of 10/hour to 84/hour. However, our results do show that patients receiving clonidine premedication had fewer changes in their perioperative hemodynamic patterns than controls. We demonstrated that 2 µg/kg oral clonidine was able to reduce the postoperative piritramide consumption significantly without deterioration of the respiratory pattern. We therefore conclude that premedication with 2 µg/kg oral clonidine is helpful in reducing perioperative changes in heart rate, MAP, and the amount of intraoperative propofol. We also found quicker recovery at the end of anesthesia and improved postoperative pain management without adverse effects on respiratory pattern of the OSAS patient.
The authors thank David Tracey, PhD (Department of Anatomy, University of New South Wales, Sydney, Australia), for his help in preparing the manuscript.
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Footnotes |
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Accepted for publication April 20, 2005.
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This article has been cited by other articles:
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  S. A. Chung, H. Yuan, and F. Chung A Systemic Review of Obstructive Sleep Apnea and Its Implications for Anesthesiologists Anesth. Analg., November 1, 2008; 107(5): 1543 - 1563. [Abstract] [Full Text] [PDF]
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C. B. E. S. Hennig and A. R. Heller What Is the Definite Merit of Clonidine Premedication in Patients with Sleep Apnea? Anesth. Analg., December 1, 2006; 103(6): 1590 - 1591. [Full Text] [PDF]
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M. T. Pawlik, E. Hansen, and T. Kuehnel What Is the Definite Merit of Clonidine Premedication in Patients with Sleep Apnea? Anesth. Analg., December 1, 2006; 103(6): 1591 - 1591. [Full Text] [PDF]
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