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Anesth Analg 1999;88:1239
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Effects of Clonidine on Sensitivity to Phenylephrine and Nitroprusside in Patients with Essential Hypertension Recovering from Surgery

Joel L. Parlow, MD, FRCP(C)*, Pierre Sagnard, MD{dagger}, Gérard Begou, MD{dagger}, Jean-Paul Viale, MD, PhD{dagger}, and Luc Quintin, MD, PhD{ddagger},{ddagger}

{ddagger}Department of Anesthesia, CHU Nord, St Etienne; {dagger}Department of Anesthesia, Hôpital Edouard Herriot; {ddagger}Department of Physiology, School of Medicine, Lyon, France; and *Department of Anesthesiology, Queen's University, Kingston, Ontario, Canada

Address correspondence and reprint requests to L. Quintin, Department of Physiology, School of Medicine, 69373 Lyon 08, France. Address e-mail to quintin{at}univ-lyon1.fr


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Clonidine reduces postoperative circulatory instability in patients with essential hypertension. It also increases the sensitivity to vasopressors before and during anesthesia. We investigated blood pressure responses to phenylephrine and nitroprusside pre- vs postoperatively and the effect of clonidine on these responses in patients with essential hypertension. Twenty patients received clonidine 6 µg/kg orally 120 min before anesthesia and 3 µg/kg IV over the final hour of surgery or an identical placebo. During increasing bolus doses of phenylephrine and nitroprusside (30–300 µg), the maximal systolic pressure responses were recorded at baseline on the day before surgery, before the induction of anesthesia, and 1 and 3 h postoperatively. Sensitivity to phenylephrine and nitroprusside was interpolated from linear regression of the data. There was no difference between preoperative and postoperative sensitivity to phenylephrine or nitroprusside in either group. Clonidine increased sensitivity to phenylephrine versus placebo before and after surgery (response to dose of 1.5 µg/kg: 42 ± 14 vs 27 ± 8 mm Hg preinduction, 37 ± 10 vs 26 ± 8 mm Hg 3 h postoperatively; both P < 0.01), but not to nitroprusside (38 ± 6 vs 37 ± 10 mm Hg preinduction and 40 ± 6 vs 39 ± 8 mm Hg postoperatively). Clonidine increases the sensitivity to phenylephrine but not nitroprusside at baseline and postoperatively in hypertensive patients.

Implications: Clonidine increases the sensitivity to bolus injections of the vasoconstrictor phenylephrine, but not the vasodilator sodium nitroprusside, before and after surgery in patients with preexisting hypertension. The doses of vasopressors should be reduced accordingly in hypertensive patients receiving perioperative clonidine.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Patients with preexisting essential hypertension exhibit increased lability of arterial blood pressure (1,2) and a surge in plasma catecholamines (3) during the postoperative period. Perioperative administration of {alpha}2-adrenergic agonists such as clonidine reduces this blood pressure lability and increased catecholamine concentration (3–5). These drugs may thus present their highest benefit to risk ratio when administered at therapeutic levels in the postoperative period in hypertensive/coronary patients. During the early postoperative period, vasodilators may be required to treat a hyperdynamic circulatory syndrome, or vasoconstrictors may be required to treat hypotension from a variety of causes. Clonidine interacts with a number of vasoactive drugs, augmenting the pressor effects of phenylephrine and ephedrine in normotensive patients before and immediately after the induction of anesthesia (6,7). The objectives of the present study were to determine, in patients with essential hypertension undergoing surgery, whether the blood pressure response to phenylephrine or nitroprusside is altered in the early postoperative period with respect to preoperative values and the effect of perioperative clonidine administration on these responses.


   Methods
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 Abstract
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 Methods
Results
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We used a randomized, double-blinded, placebo-controlled, prospective study design. Institutional ethics approval and signed informed consent were obtained. Twenty patients who were participating in a separate study (8) and who were scheduled for elective abdominal intestinal or orthopedic surgery with an expected surgical time of at least 2 h were included. All patients were >50 yr of age and had essential hypertension, as defined by a systolic blood pressure (SBP) >160 mm Hg or diastolic blood pressure >95 mm Hg on at least three occasions for >1 yr. All patients were chronically treated preoperatively for hypertension by their usual physicians. Patients were excluded if they had a history of diabetes mellitus or other conditions causing autonomic impairment, stroke, congestive heart failure, or abnormal cardiac rhythms. ß-adrenergic blockers and centrally acting antihypertensive drugs were withdrawn gradually and replaced with nifedipine during the week before surgery. All such medications, except nifedipine, were stopped at least 48 h preoperatively. Patients were randomized by the hospital pharmacy to receive either clonidine or an identical placebo drug in a double-blinded manner, with the randomization code held by the pharmacist until the end of data collection. Patients received clonidine 6 µg/kg (or placebo) orally 120 min before arrival in the operating suite, and clonidine 3 µg/kg (or placebo) was infused IV over 60 min during the final hour of surgery.

Central venous pressure, intraarterial pressure, electrocardiogram, oxygen saturation, end-tidal carbon dioxide, and nasopharyngeal temperature were monitored perioperatively. Fluid deficits, maintenance, and losses were replaced with an infusion of lactated Ringer's solution or packed red blood cells to maintain central venous pressure and blood pressure within 20% of baseline and a hemoglobin of at least 100 g/L. Using a protocol described previously (3,8), anesthesia was induced with midazolam 75 µg/kg, alfentanil 20 µg/kg, and lidocaine 1.5 mg/kg, and muscle relaxation was achieved with atracurium 500 µg/kg. Anesthesia was maintained with nitrous oxide 70% in oxygen adjusted to maintain oxygen saturation >95%, isoflurane as required for control of pressure, and an infusion of atracurium 500 µg · kg-1 · h-1 and alfentanil 0.25 µg · kg-1 · min-1 until wound closure. At skin closure, morphine 150 µg/kg was administered subcutaneously. End-tidal carbon dioxide tension was maintained at 30–35 mm Hg, and temperature was maintained >36°C. Patients were tracheally extubated in the recovery area when they were awake and able to maintain adequate oxygen saturation and end-tidal carbon dioxide without reversal of neuromuscular blockade. Circulatory derangements were treated according to a standard protocol (3,8). Nicardipine was infused postoperatively to treat hypertension, defined as SBP >170 mm Hg for >=5 min. Fluids were administered to maintain adequate central venous pressure and diuresis.

The magnitude of blood pressure responses to vasoactive drug injections was assessed at four intervals: at baseline (BL) on the day before surgery, 90 min after the administration of the study drug before the induction of anesthesia (PI), and 1 (R1) and 3 (R3) h into the recovery period. To avoid an extra day of arterial cannulation, blood pressure at BL was obtained noninvasively on a beat-by-beat basis using a Finapres 2300 (Ohmeda, Madison, WI), which reliably tracks intraarterial pressures during a variety of tests of autonomic function (9,10). At each study interval, bolus injections of phenylephrine and sodium nitroprusside were alternately administered in increasing doses (30–300 µg) to elicit an increase or decrease in SBP of at least 30 mm Hg, with the maximal dose of each drug being repeated twice. Each drug bolus was diluted in isotonic sodium chloride solution to a total of 5 mL and injected over approximately 5 s. The catheter was rinsed with 20 mL of saline. A minimum of 5 min elapsed between injections to allow circulatory values to return to within 5% of preinjection levels. During these injections, the arterial blood pressure waveforms were recorded using a calibrated paper recorder (DASH-8; Astromed, West Warwick, RI). The maximal change in blood pressure induced by each injection was identified and plotted against the logarithm of the respective dose for each drug. Log dose-response curves were thereby generated for each study session. Linear regression of each curve allowed the interpolation of the phenylephrine dose leading to an absolute increase in SBP of 25 mm Hg (PE25) and of the nitroprusside dose leading to an absolute decrease in SBP of 25 mm Hg (NP25). In addition, interpolation of the linear regressions was used to calculate the absolute change in SBP resulting from an arbitrary dose of 1.5 µg/kg of both drugs. This dose was chosen to approximate clinically used bolus doses of these drugs (approximately 100 µg) and to evoke significant, but not excessive, blood pressure excursions.

Data are expressed as mean ± SD unless otherwise stated. Data were analyzed using two-way repeated measures analysis of variance for continuous variables. Where significance was determined (P < 0.05), a post hoc Tukey's test was performed.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Ten patients were randomized to each group. Patient demographics were similar between groups (Table 1). One subject in the clonidine group exhibited persistent ventricular extrasystoles, which made blood pressure changes difficult to calculate with sufficient precision. Thus, blood pressure data from 19 patients are presented (placebo n = 10, clonidine n = 9). Six patients in the placebo group and one patient in the clonidine group received nicardipine for postoperative hypertension (P < 0.05) (Table 1).


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  		Table 1. Perioperative Characteristics in Treated Hypertensive Patients Presenting for Surgery
 
Preinjection SBP was decreased after clonidine administration at all intervals (Fig. 1). Figure 2 illustrates the dose-response curves in response to serial injections of phenylephrine in one placebo and one clonidine patient. Pressure responses to vasoactive drugs (PE25 and NP25) were similar between groups at BL, and within each group over time (Fig. 3). Clonidine was associated with lower PE25 at all intervals after its administration, compared with placebo (P < 0.05) (Fig. 3A). Accordingly, the calculated increase in SBP in response to an arbitrary clinically relevant dose of phenylephrine 1.5 µg/kg was greater in the clonidine group both before induction and after surgery (P < 0.001) (Fig. 4A). By contrast, nitroprusside requirements (NP25) were similar between groups at all intervals (Fig. 3B). There was no difference in the calculated response to a dose of nitroprusside 1.5 µg/kg (Fig. 4B).



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  		Figure 1. Preinjection systolic blood pressure (SBP) at baseline (BL; day before surgery), before anesthetic induction (PI), and 1 (R1) and 3 (R3) h after discontinuation of anesthesia. Patients with essential hypertension received placebo ({circ}) or clonidine (•; 6 µg/kg orally 120 min before arrival in the operating suite and 3 µg/kg IV over the last 60 min of anesthesia). Data (mean ± SEM) represent mean of SBP recorded immediately before injections of vasoactive agents at each study period. *P < 0.05 between groups at the time point. {dagger}P < 0.05 versus respective baseline values within the group.

 


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  		Figure 2. Dose-response curves illustrating the change in systolic blood pressure ({Delta}SBP) in response to serial injections of phenylephrine (logarithmic scale) in one placebo patient ({circ}; r = 0.80) and one clonidine patient (•; r = 0.88) before the induction of anesthesia. Lines represent linear regressions obtained from data.

 


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  		Figure 3. Doses of (A) phenylephrine and (B) nitroprusside required to produce a systolic blood pressure change of 25 mm Hg at baseline (BL; day before surgery), before anesthetic induction (PI), and 1 (R1) and 3 (R3) h after discontinuation of anesthesia. Overall analysis of variance for systolic blood pressure: P < 0.001 between groups. *P < 0.05 between groups at the time point. Values are mean ± SD. {circ} = placebo, • = clonidine.

 


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  		Figure 4. Calculated change in systolic blood pressure ({Delta}SBP) in response to an arbitrary dose of 1.5 µg/kg phenylephrine (A) or nitroprusside (B) in placebo ({circ}) or clonidine (•) patients at baseline (BL; day before surgery), before anesthetic induction (PI), and 1 (R1) and 3 (R3) h after discontinuation of anesthesia. Overall analysis of variance: P < 0.01 between groups. Data interpolated from raw data (as illustrated in Figure 2) to represent the response to doses of vasoactive agents often used in clinical practice. Values are mean ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In hypertensive patients recovering from surgery and anesthesia, the sensitivity to vasoactive drugs is unchanged when the postoperative period is compared with BL measurements. Clonidine increases the sensitivity to phenylephrine, but not to nitroprusside, both before anesthetic induction and after surgery.

A number of methodological issues merit discussion. First, the change in the technique of measurement of pressure between BL (Finapres) and preinduction (intraarterial) periods (9,10) is likely not a confounding factor, as the responses to phenylephrine were unchanged in the placebo group, but not in the clonidine group. Second, the double-blinded design allowed comparison of the sensitivity to vasoactive drugs, regardless of any effects of residual anesthetics in the early postoperative period. Indeed, similar alfentanil concentrations were measured between groups (3,8). There may have been differences in residual isoflurane concentrations, because intraoperative concentrations of halogenated anesthetics have been reported to be lower in clonidine-treated patients (3,5); however, these differences would be minimal 1 and 3 h after emergence. Third, only IV bolus administration of the vasoactive drugs was studied. Continuous IV infusion of nitroprusside, such as during controlled hypotension, may have unmasked differences not seen in our study (11). Finally, ethical consideration necessitated treatment of postoperative hypertension, thus precluding the determination of vasoactive drug sensitivity in the absence of nicardipine.

Phenylephrine Responses
First, given the background nicardipine administered to 60% of the placebo patients, the level of pressure was similar pre- and postoperatively in the placebo group. Thus, a shift of the pressure-dose curve to a higher pressure did not likely influence the results. Second, comparing the pre- and postoperative period (Fig. 3A) in placebo patients, identical responses to phenylephrine are obtained in the presence of increased endogenous catecholamines postoperatively (8). This implies that simple competition between endogenous and exogenous amines at the {alpha}1-receptor cannot be the major contributor to possible changes in the sensitivity to phenylephrine in the placebo group or, equally, in the clonidine group.

Using the current protocol, stable clonidine concentrations were obtained in the clonidine group and were associated with a major suppression of the postoperative increase in plasma catecholamine concentrations, heart rate, and pressure otherwise seen in hypertensive patients recovering from surgery (3,8). After clonidine, increased sensitivity to phenylephrine and ephedrine has been documented in normotensive patients both before and after the induction of anesthesia (6,7). Similar increased sensitivity has also been observed in relation to noradrenaline during recovery from liver transplantation (12) and to isoproterenol in hypertensive patients recovering from aortic surgery (3). The present study extends the finding of increased vasoactive drug sensitivity induced by clonidine to phenylephrine administered during the early postoperative period to patients with essential hypertension.

The first explanation for the enhanced sensitivity to phenylephrine could relate to a larger diameter induced by clonidine (13,14), leading to a modified pressor response after an identical phenylephrine bolus. In addition, in the current protocol (8), clonidine was measured to be at therapeutic concentrations for {alpha}2 receptors (15), excluding an {alpha}1-agonist action for clonidine itself. Thus, the most likely explanation is a putative upregulation of {alpha}1 receptor after clonidine administration. Such an upregulation was reported for {alpha}1 receptors after the administration of another centrally acting antihypertensive, {alpha}-methyldopa, to spontaneously hypertensive rats for 3 days (16).

Nitroprusside Responses
As previously observed outside the perioperative setting (17), no change in sensitivity to nitroprusside was observed postoperatively in clonidine-treated patients. One explanation lies in the fact that nitroprusside does not act on the {alpha}1 receptor, but via other nonspecific mechanisms, because nitroprusside is a direct-acting vasodilator that generates nitric oxide in vascular endothelial cells (18).

Taking into account the increased postoperative nicardipine administration in the placebo patients, the requirement for nitroprusside seems identical between groups. This contrasts with the need to reduce the dose of phenylephrine to treat hypotension after the administration of clonidine. It is likely that clonidine leaves the catecholamine stores intact at sympathetic nerves endings. Furthermore, {alpha}2-agonists lower baseline sympathetic activity while leaving intact reflex circulatory responses (17,19–24). The reduction in requirements for phenylephrine and other vasopressors (3,6,7,12) after an {alpha}2-agonist contrasts with responses seen with first-generation sympatholytics. Large doses of reserpine lead to a depletion of catecholamine stores and circulatory collapse in the presence of anesthesia (25). Phenoxybenzamine is associated with a prolonged blockade of {alpha}1 receptors (25), whereas the effects of the {alpha}-antagonist phentolamine can be overcome with larger doses of {alpha} agonists (25), as opposed to what has been observed with clonidine.

Given similar nociceptive or environmental stimuli during the recovery period and the greater sensitivity to vasopressors after clonidine administration, it may be postulated that an identical release of peripheral noradrenaline would lead to greater pressure increases than in the absence of clonidine. In fact, the reverse is observed: in hypertensive clonidine-treated patients, circulatory stability seems to be improved, both over time (3,5) and on a beat-by-beat basis (8). Thus, stability is not the result of dampened peripheral responsiveness, but of more efficient buffering (8) of postoperative circulatory surges after clonidine administration.

In hypertensive patients undergoing uncomplicated surgery, responsiveness to phenylephrine and nitroprusside bolus doses is unchanged during the recovery period, compared with their preoperative responses. Clonidine increases the pressor response to phenylephrine pre- and postoperatively, whereas the response to nitroprusside is unchanged. Accordingly, phenylephrine doses should be reduced in hypertensive patients receiving perioperative clonidine.


   Acknowledgments
 
This work was supported by Fondation de France, INSERM CN 91 48, MESR 1896, CNRS 5578, and the Canadian Anaesthetists' Society.

We thank Professors Tissot, Fischer, Barth, and Bejui for referral of patients. We also thank Professor Petit for his support. Dr. Nageotte monitored the study. We acknowledge the assistance of the nurse anesthetists of Pavillon D and T, Hôpital E. Herriot.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 12, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press