During the last 20 years, the pharmacologic treatment of hypertension has become more effective and easy to obtain because of the availability of newer antihypertensive agents acting on the different physiopathologic mechanisms and with long duration profiles that allow their once-daily use (1). Transdermal administration of drugs has been developed to bypass the first-pass metabolism through the liver undergone by the orally administered drugs, thus reducing the total dose administered, and to achieve better patient compliance. Moreover, the therapeutic plasma levels of orally administered drugs depend on several variable factors such as the transit time through the small intestine and the presence of food and liquid in the gastrointestinal tract. The resulting kinetic profile gives rise to peaks and troughs in plasma and tissue concentrations avoided with transdermal administration, in which the drugs are absorbed through the skin at a constant rate (2). The advantages of transdermal administration are particularly significant with antihypertensive drugs, as it avoids the "sawtooth" pattern of peaks and troughs in plasma concentrations, resulting in steadier blood pressure (BP) control (3). Transdermal clonidine (TTSC) is a preparation of clonidine hydrochloride that can be released and absorbed transdermally over a 7-day period (4,5). This is believed to be a potentially valuable feature that may reduce the complexity of antihypertensive treatment and increase its acceptance by the patient (6).
The prevalence of hypertension in patients undergoing surgical procedures amounts to ≤61%, and the antihypertensive strategy is frequently characterized by the need of substituting the oral therapy with a parenterally administered drug, which could expose the patient to inadequate BP control and could result in further complexity in patient management (7). In hypertensive patients undergoing surgery, clonidine may be useful because of its α2-adrenoceptor agonistic action, which has been demonstrated to be effective in stabilizing the hemodynamic parameters during anesthetic induction and in reducing the need of sedation and analgesia after surgical procedures (8-11). Our study was undertaken to assess the practical and clinical benefits of TTSC treatment in the perioperative management of mild to moderate hypertension in patients undergoing minor surgical procedures.
PATIENTS AND METHODS
Our study included 29 consecutive patients of either sex (18 men, 11 women) aged 26-74 years, with uncomplicated mild to moderate essential hypertension. The general characteristics of the hypertensive patients studied are reported in Table 1. All patients were receiving long-term treatment with orally administered drugs that provided adequate antihypertensive control and were scheduled for an elective minor surgical operation that required general anesthesia (Table 2). All patients gave written informed consent to participate in the investigation, as approved by the institutional review boards at each center.
Criteria for exclusion included evidence of secondary hypertension or target-organ damage, acute myocardial infarction within the last 6 months, unstable angina, cerebrovascular accident within the last 2 years, transient ischemia within the last 6 months, cardiac insufficiency or arrhythmia, Raynaud's disease, renal insufficiency (serum creatinine >1.8 mg/dl), serious hepatic, autoimmune, hematologic, endocrine, neurologic, or psychic disease, cutaneous disease in the area of patch application, a history of skin allergy, hypersensitivity to clonidine, pregnancy, or lactation.
Concomitant treatment with other antihypertensive agents, barbiturates, or antipsychotics was not allowed. Although concomitant administration of tricyclic antidepressants was not allowed, one patient receiving clomipramine, 25 mg twice daily, when enrolled was maintained on this drug during the study period.
All patients underwent baseline evaluation (visit 0, 15 days before the scheduled surgical procedure) while taking an orally administered antihypertensive treatment. Clinical evaluation included an objective examination and both sitting and standing BP and heart rate (HR) measurements performed after 15 min rest by means of a standard sphygmomanometer. Standard 12-lead electrocardiogram (ECG), 2D and M-mode echocardiography, and fundus oculi examination also were performed to evaluate the presence of target-organ damage. Laboratory examinations included hemoglobin, erythrocyte, leukocyte, and platelet counts, as well as blood urea, plasma creatinine, AST, ALT, Na, K, Cl, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, uric acid, and triglycerides levels. Baseline 24-h ambulatory blood pressure monitoring (ABPM) was then performed to evaluate the efficacy of the standard oral antihypertensive treatments. The 24-h ABPM was performed by means of portable devices (Accutracker II; Suntech Medical Instruments, Raleigh, SC, U.S.A.; Profilomat; Disertronic Medical System, Burgdorf, Switzerland) programmed to record BP and HR at 30-min intervals during the daytime (from 6 a.m. to 10 p.m.) and at 60-min intervals during nighttime (from 10 p.m. to 6 a.m.).
On the next day (visit 1, 2 weeks before the scheduled surgical procedure), oral antihypertensive medication was discontinued and substituted with TTSC, 0.1 mg/day (as 3.5-cm2 self-adhesive skin patches applied once weekly to upper chest or outer arm; Adesipress TTS-1; Pharmacia-Upjohn, Milan, Italy). After 6 days of TTSC treatment (visit 2, 1 week before the scheduled surgical procedure), BP and HR were clinically measured to evaluate the efficacy of therapy, and if necessary, the dose was increased to 0.2 mg/day (as 7-cm2 skin patches; Adesipress TTS-2). The 24-h ABPM was then repeated at visit 3 (2 days before the scheduled surgical procedure) and visit 4 (2 days after the surgical procedure). Clinical evaluation including ECG and laboratory examinations was also repeated at visits 3 and 4.
Quantitative data are reported as arithmetic mean ± standard deviation (SD). The 24-h BP and HR profiles were smoothed by fitting to individual data the first three harmonics of Fourier series (12) by using a time-weighted least-square method. For each subject at each of the three periods (i.e., baseline, presurgery, and postsurgery), 24-h, daytime (6:00 to 22:00), nighttime (22:00 to 06:00), and hourly means were computed as the integral of the smoothing function between the limits of the time interval, divided by the length of the interval. Arithmetic means of all patients were then computed from individual averages. Two-way (subjects and periods) and three-way (subjects, periods, and day/night or hourly intervals) analysis of variance was performed, and pairwise comparisons between period means were carried out, with p values adjusted according to Sidak's inequality to control the overall type-1 error rate. Statistical significance was set to p < 0.05 for each preplanned contrast or set of contrasts (before surgery versus baseline and after versus before surgery).
Laboratory data were compared by using Student's t test for paired data; p values for individual tests were adjusted according to Sidak's inequality, having set statistical significance to p < 0.05 for each preplanned set of contrasts (before surgery versus baseline and after versus before surgery).
Twenty-nine hypertensive patients were enrolled from October 1994 to January 1996. Four patients did not complete the study treatment: three discontinued because of adverse events before the presurgical visit and one because of treatment inefficacy immediately after the presurgical visit. Additionally, two patients who completed treatment lacked a valid 24-h ABPM recording after surgery, one because of refusal to undergo this procedure and one because of a technical problem. Thus 25 hypertensive patients completed the study treatment as planned, and 23 had a full set of baseline, presurgical, and postsurgical 24-h ABPM recordings.
Because of unpredictable changes in the date of surgical procedure, the presurgical evaluation including 24-h ABPM was performed >3 days after the scheduled date in two patients.
Clinical blood pressure, heart rate, and dose adjustment
At baseline visit, during oral antihypertensive treatment, sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 145 ± 10 and 87 ± 8 mm Hg, respectively. At visit 1, after the first week of treatment with TTSC, the initial dose of clonidine (0.1 mg/day) was maintained in 11 (38%) of 29 patients with clinostatic BP 140 ± 9/85 ± 5 mm Hg, and was increased to 0.2 mg/day in 18 (62%) of 29 patients with clinostatic BP 155 ± 14/96 ± 4 mm Hg. Twenty-six patients (all those enrolled, but three dropped out because of adverse events), 10 receiving treatment with TTSC, 0.1 mg/day, and 16 with TTSC, 0.2 mg/day, underwent visit 2 (presurgical). In these patients, clinostatic SBP decreased from 144 ± 11 mm Hg at baseline to 134 ± 13 mm Hg at visit 2, and clinostatic DPB from 86 ± 8 mm Hg at baseline to 80 ± 10 mm Hg at visit 2. A patient already switched to TTSC, 0.2 mg/day, was withdrawn for treatment inefficacy, and adequate BP control was achieved in the remaining 25 patients. All these 25 patients who were receiving treatment with TTSC at the time of surgery still showed adequate BP control at visit 3 (postsurgical). Clinostatic BP in these patients was 134 ± 9/80 ± 8 mm Hg at visit 2 and 134 ± 12/81 ± 9 mm Hg at visit 3. Thus on an intent-to-treat basis, therefore taking into account the three patients withdrawn because of adverse events in addition to the one dropped out for inadequate BP control, the TTSC antihypertensive treatment may be estimated to have been effective in 25 (85%) of 29 patients.
Clinostatic HR in all patients enrolled was 78 ± 10 beats/min at baseline visit. In patients who completed treatment, it was 78 ± 11 beats/min at baseline, 74 ± 11 beats/min at visit 2, and 75 ± 9 beats/min at visit 3.
The mean values of BP and HR measured in the standing position did not differ substantially from those obtained in the sitting position.
Ambulatory blood pressure and heart rate monitoring
The curves of the Fourier functions best fitting to the 24-h ABPM measurements of SBP, DBP, mean BP (MBP = 2/3 DBP + 1/3 SBP), and HR in the 23 patients who completed all study procedures and measurements are shown in Figs. 1-4. Average 24-h, daytime, and night-time values smoothed by the Fourier function are reported in Table 3.
Average 24-h SBP and DBP recorded before surgical procedures were only slightly reduced as compared with baseline values; the difference was statistically not significant and did not exceed 4 mm Hg for DBP or 5 mm Hg for SBP at any point. BP changes after surgical procedures were also negligible and did not reach statistical significance, with differences never exceeding 3 mm Hg for DBP or 5 mm Hg for SBP at any point.
Average 24-h HR before surgery was only slightly reduced as compared with baseline values. The difference was statistically not significant and did not exceed 4 beats/min at any point. A moderate, statistically significant increase in average 24-h HR was observed between presurgical and postsurgical evaluations (p = 0.0067). This difference was more evident for the nighttime average (p = 0.0018) than for the daytime average (p = 0.023). Statistically significant differences in hourly averages varying from 5.4 to 6.2 beats/min were observed from 17:00 through 03:00, with the maximal difference occurring between 18:00 and 19:00.
Ambulatory versus clinical blood pressure
Compared with average daytime ambulatory BP, clinical BP (measured in the same group of 23 patients who completed all study procedures and measurements) was 9/4 mm Hg higher for SBP and DBP at the baseline visit, respectively, whereas differences at visit 2 (−1/0 mm Hg) and at visit 3 (+3/+1 mm Hg) were negligible.
No clinically relevant change was found between the standard 12-lead ECG performed at baseline and during TTSC treatment.
No statistically significant differences or clinically relevant alterations were found concerning the laboratory indices of renal or hepatic function, electrolyte balance, and plasma glucose or lipid concentrations.
Adverse events were reported in four (14%) of 29 patients and were of moderate severity and transient in duration.
Dermatologic reactions occurred in two (7%) patients, 3 and 5 days, respectively, after the start of treatment, and consisted of moderate local erythema and itching in the area where TTSC, 3.5 cm2 (0.1 mg/day), was applied. Both events were considered definitely related to the study treatment, which was therefore discontinued, and regressed completely within 8 days from their onset. In one case, topical steroid treatment of the lesion was needed.
Psychic disturbances of moderate degree, including depression, disorientation, and nightmares, occurred in one patient receiving TTSC, 0.2 mg/day, 9 days after treatment start and led to treatment discontinuation. Relation to the study medication was considered possible, as the disturbances regressed a few days after the treatment was discontinued.
Moderate headache, uncertainly related to the study drug, was reported by a patient receiving TTSC, 0.1 mg/day, 11 days after treatment start and did not require treatment discontinuation, as it regressed spontaneously.
Previous clinical studies demonstrated that TTSC, administered by self-adhesive skin patches applied once a week, is an adequate therapy in mild to moderate essential hypertension (3,6,13-16). The aim of this study was to evaluate the efficacy and the usefulness of substituting traditional oral antihypertensive treatment with TTSC in patients with mild to moderate hypertension undergoing minor surgical procedures that need the discontinuation of any oral treatment. The choice of clonidine was supported by the positive effects reported in stabilizing the hemodynamic parameters during anesthesia and in improving the postoperative analgesia, and by the pharmacokinetic and pharmacodynamic profiles related to transdermal administration.
Our results suggest that TTSC treatment affords an adequate BP control after discontinuation of the orally administered antihypertensive therapy, as demonstrated by both clinical measurements and 24-h ABPM. ABPM profiles over 24 h did not show any interference with physiological circadian rhythm of BP or HR. No episodes of arterial hypotension or hypertensive crises were reported during anesthesiologic procedures or immediately after surgery.
A postsurgical increase in HR was already documented by previous studies and was related to a catecholamine response to surgical stress (17-19). HR increased significantly during the postoperative period, although this increase was limited in extent and clinically negligible. On the other hand, clonidine is known to possess a negative chronotropic effect mediated by a reduced sympathetic nervous system activity, and this could be an advantage during the postoperative period, as previously reported (19,20). In fact, in our study a slight reduction in HR was observed before surgery as compared with baseline values.
In this study BP and HR were measured both clinically and by 24-h ambulatory monitoring. Over the past few years, 24-h ABPM has gained wide acceptance as a method to obtain a more accurate and reliable BP measurement than the traditional clinical measurement. In our study, however, clinical BP measurement was used as an approximate method to obtain a rapid assessment of antihypertensive efficacy to decide for continuation or interruption of therapy and dose adjustment. Mean values of clinical BP were generally in agreement with average daytime ambulatory BP, except for baseline measures, which were higher by 9 mm Hg for SBP and 4 mm Hg for DBP. This finding may reflect a "white-coat effect," which may have been present initially when most patients were not yet or had just been hospitalized, and was no longer present when patients had been hospitalized for several days.
No variations of the ECG examinations or laboratory tests were observed between baseline and the transdermal clonidine treatment.
Adverse events occurred in four (14%) of 29 patients, and all were of moderate severity and transient. A peculiar problem related to transdermally administered clonidine is the possibility of dermatologic reactions, which in our study occurred in two (7%) of 29 patients, compared with a 15% incidence reported by other authors (21).
Transdermal clonidine administration was previously shown to be well accepted in an outpatient setting, thereby improving compliance to therapy. As reported by Hollifield (22) in a large-scale study, as many as 87% of the patients who switched from oral antihypertensive treatment to transdermal clonidine thought this therapy more convenient than previous drugs, and nearly two thirds of these patients were thought to comply better with the transdermal regimen. In our study, TTSC was found to be convenient for administration to surgical patients, resulting in a simplification of therapeutic assistance during the perioperative period. A clear limitation of this study is the relatively small number of patients evaluated and the kinds of surgical procedures, which did not include major or complex operations. However, our results indicate that transdermal clonidine may be a useful alternative treatment of patients with hypertension undergoing surgical procedures that require discontinuation of orally administered treatments.
1. Messerli FH. Cardiovascular drug therapy.
Philadelphia: WB Saunders, 1996:7-12.
2. Breimer DD. Rationale for rate-controlled drug delivery of cardiovascular drugs by the transdermal route. Am Heart J
3. De Leonardis V, De Scalzi M, Becucci A, et al. New indices in the evaluation of clonidine transdermal therapy of hypertension. Int J Clin Pharmacol Res
4. Arndts D, Arndts K. Pharmacokinetics and pharmacodynamics of transdermally administered clonidine. Eur J Clin Pharmacol
5. MacGregor TR, Matzek KM, Keirns JJ, et al. Pharmacokinetics of transdermally delivered clonidine. Clin Pharmacol Ther
6. Mancia G, Parati G, Pomidossi G, et al. Evaluation of the antihypertensive effects of TTS clonidine by multiple 24-hour automatic blood pressure monitoring. J Cardiovasc Pharmacol
7. Mangano DT, Browner WS, Hollenberg M, et al. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med
8. Flacke JW, Bloor BC, Flacke WE. Reduced narcotic requirement by clonidine with improved haemodynamic and adrenergic stability in patients undergoing coronary bypass surgery. Anesthesiology
9. Ghignone N, Calvillo O, Quintin L. Anesthesia and hypertension: the effect of clonidine on preoperative haemodynamics and isoflurane requirements. Anesthesiology
10. Quintin L, Builloc X, Butin E, et al. Clonidine for major vascular surgery in hypertensive patients: a double blind, controlled, randomized study. Anesth Analg
11. Goyagi T, Nashikawa T. Oral clonidine premedication enhances quality of postoperative analgesia by intrathecal morphine. Anesth Analg
12. Streitberg B, Meyer-Sabellek W. Smoothing twenty-four-hour ambulatory blood pressure profiles: a comparison of alternative methods. J Hypertens
13. Fillingim JM, Matzek KM, Hughes EM, et al. Long-term treatment with transdermal clonidine in mild hypertension. Clin Ther
14. McMahon FG, Jain AK, Vargas R, et al. A double-blind comparison of transdermal clonidine and oral captopril in essential hypertension. Clin Ther
15. Burris JF, Papademetriou V, Wallin JD, et al. Therapeutic adherence in the elderly: transdermal clonidine compared to oral verapamil for hypertension. Am J Med
16. Lowenthal DT, Saris S, Paran E, et al. Efficacy of clonidine, a transdermal therapeutic system: the international clinical trial experience. Am Heart J
17. Rosenberg J, Dirkes WE, Kehlet H, et al. Episodic arterial oxygen desaturation and heart rate variations following major abdominal surgery. Br J Anaesth
18. Latson TW, O'Flaherty D. Effects of surgical stimulation on autonomic reflex function: assessment by changes in heart rate variability. Br J Anaesth
19. Dorman T, Clarkson K, Rosenfeld BA, et al. Effects of clonidine on prolonged postoperative sympathetic response. Crit Care Med
20. Segal I, Jarvis DJ, Duncan SR, et al. Clinical efficacy of oral-transdermal clonidine in combination during the perioperative period. Anesthesiology
21. Frishman WK, Sherman D. Transcutaneous clonidine: a new long-acting formulation for the treatment of hypertension. Cardiovasc Rev Rep
22. Hollifield J. Clinical acceptability of transdermal clonidine: a large-scale evaluation by practitioners. Am Heart J