Hemodynamic Effects Of Clonidine Research Articles

The use of clonidine in elderly patients with delirium; pharmacokinetics and hemodynamic responses

BackgroundThe Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is an RCT investigating the effect of clonidine in medical patients > 65 years with delirium. To assess the dosage regimen and safety measures of this study protocol, we measured the plasma concentrations and hemodynamic effects of clonidine in the first 20 patients.MethodsPatients were randomised to clonidine (n = 10) or placebo (n = 10). The treatment group was given a loading dose (75μg every 3rd hour up to a maximum of 4 doses) to reach steady state, and further 75μg twice daily until delirium free for 2 days, discharge or a maximum of 7 days. Blood pressure (BP) and heart rate (HR) were measured just before every dose. If the systolic BP was < 100 mmHg or HR < 50 beats per minute the next dose was omitted. Plasma concentrations of clonidine were measured 3 h after each drug intake on day 1, just before intake (day 2 and at steady state day 4–6) and 3 h after intake at steady state (Cmax). Our estimated pre-specified plasma concentration target range was 0.3–0.7μg/L.Results3 h after the first dose of 75μg clonidine, plasma concentration levels rose to median 0.35 (range 0.24–0.40)μg/L. Median trough concentration (C0) at day 2 was 0.70 (0.47–0.96)μg/L. At steady state, median C0 was 0.47 (0.36–0.76)μg/L, rising to Cmax 0.74 (0.56–0.95)μg/L 3 h post dose. A significant haemodynamic change from baseline was only found at a few time-points during the loading doses within the clonidine group. There was however extensive individual BP and HR variation in both the clonidine and placebo groups, and when comparing the change scores (delta values) between the clonidine and the placebo groups, there were no significant differences.ConclusionsThe plasma concentration of clonidine was at the higher end of the estimated therapeutic range. Hemodynamic changes during clonidine treatment were as expected, with trends towards lower blood pressure and heart rate in patients treated with clonidine, but with dose adjustments based on SBP this protocol appears safe.Trial registrationClinicalTrials.gov NCT01956604, 09.25.2013. EudraCT Number: 2013–000815-26, 03.18.2013. Enrolment of first participant: 04.24.2014.

Haemodynamic effects of clonidine in an ovine model of severe sepsis with septic acute kidney injury

In sepsis, sympathetic nerve activity is increased, which helps maintain arterial pressure in the face of nitric oxide-induced vasodilatation. Accordingly, we investigated the haemodynamic effects of the centrally acting α-adrenoceptor agonist clonidine in an ovine model of severe sepsis.

Respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome

To investigate the respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome after sedation interruption. Prospective, interventional, single-center study in 30 ventilated ICU patients. Metabolic [oxygen consumption (VO(2)), CO(2) production (VCO(2)), resting energy expenditure (REE)], respiratory [minute ventilation (V (E)), tidal volume (V (T)), respiratory rate (RR)] and hemodynamic (HR, SAP, MAP) parameters were measured in 30 ventilated ICU patients. Measurements were performed first under sedation with remifentanil-propofol, then after sedation interruption, and finally after clonidine administration (0.9-1.8 mg of clonidine in two doses of 10 min interval). Sedation interruption produced significant increases in the hemodynamic parameters (SAP and MAP by 33%, HR by 37%), and metabolic rate (increase in VO(2) by 70%, VCO(2) by 88% and REE by 74%), leading to high respiratory demands (increase in V (E) from 9 to 15 l/min). The V (E) was increased due to a twofold increase in the RR; V (T) remained constant. In 25 out of 30 patients, clonidine administration decreased the hemodynamic (SAP, MAP and HR), metabolic (VO(2), VCO(2), REE) and respiratory parameters to values close to those observed with sedation. Clonidine induced mild sedation and patients became more cooperative with the ventilator. All patients responding to clonidine were weaned from the ventilator in 2 days (median, range 1-18 days). Patients with withdrawal syndrome had significantly elevated hemodynamic, metabolic and respiratory demands. Clonidine significantly decreased these demands, induced mild sedation and facilitated patient cooperation with the ventilator, enabling ventilator weaning.

Hemodynamic effects of clonidine in two contrasting models of autonomic failure: Multiple system atrophy and pure autonomic failure

We assessed the effects of clonidine on blood pressure (BP) and heart rate (HR) in multiple system atrophy (MSA), where the autonomic nervous system lesion site is preganglionic, and in pure autonomic failure (PAF), where it is postganglionic. In normal subjects, intravenous infusion of the selective alpha2-adrenoceptor agonist clonidine reduces BP and plasma noradrenaline (NA) levels by means of central alpha2-adrenoceptor action, as well as inducing growth hormone (GH) release. Clonidine-induced GH release is impaired in MSA but spared in PAF. However, the hemodynamic effects of clonidine have not been studied extensively in these disorders. We examined intravenous clonidine test results (performed in our autonomic laboratories using the London Autonomic Units protocol) in 58 patients: 39 with probable MSA and 19 with PAF. Systolic BP (SBP), diastolic BP (DBP), HR, and NA levels were measured supine at baseline and for up to 60 minutes after clonidine. Clonidine resulted in a significant BP fall in MSA patients, which occurred earlier (within 15 minutes of clonidine) and to a greater extent than seen in PAF patients. MSA and PAF patients showed reduction in HR after clonidine administration, although this finding was significantly greater in MSA than in PAF patients. NA levels decreased significantly after clonidine administration in both groups. Although basal NA levels were lower in PAF than in MSA patients, there was no difference in NA reduction relative to baseline between groups. MSA patients showed significant negative correlation between basal NA levels and BP response to clonidine. Clonidine infusion reduces BP and HR in both MSA and PAF groups but to a greater extent in MSA patients. The greater vasodepressor action of clonidine in MSA patients suggests that there is partial preservation of brainstem sympathetic outflow pathways in MSA and may reflect its action at sites in the brainstem and spinal cord that were in part functionally preserved in MSA. Despite similar degrees of NA reduction after clonidine administration, the vasodepressor effect of clonidine was attenuated in PAF compared with MSA patients. This attenuation in PAF patients may reflect greater peripheral alpha2-adrenoceptor denervation supersensitivity due to the postganglionic lesion site. These BP differences, thus, may reflect the underlying lesion site in MSA and PAF, and the hemodynamic data after clonidine infusion may help differentiate these conditions.

Effects of chronic ethanol feeding on clonidine-evoked reductions in blood pressure, heart rate, and their variability: time-domain analyses.

The effects of chronic ethanol administration on the acute hemodynamic effects of clonidine were investigated in conscious radiotelemetered spontaneously hypertensive rats (SHRs). Changes evoked by clonidine (30 micro g/kg i.p.) in blood pressure, heart rate, and their variability were evaluated in ethanol [2.5 or 5% (w/v), 12 weeks] and pair-fed control rats. The blood pressure variability was determined as the standard deviation of the mean arterial pressure (SDMAP). Two heart rate variability indices were used, the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive beat-to-beat differences in R-R interval durations (rMSSD). Compared with control rats, ethanol (2.5 and 5%)-fed rats exhibited concentration-related reductions in mean arterial pressure (MAP) and SDMAP versus no change in heart rate variability. In control rats, clonidine caused a significant reduction in MAP that continued for at least 5 h and was associated with significant reductions in SDMAP, SDRR, and rMSSD, responses that are consistent with the inhibition of central sympathetic tone. The hypotensive effect of clonidine was attenuated by ethanol in a concentration-related manner. The maximum reductions in MAP elicited by clonidine in ethanol (2.5 and 5%)-fed rats amounted to -23.4 +/- 2.8 and -15.1 +/- 1.5 mm Hg, respectively, compared with -35.4 +/- 1.2 mm Hg in control rats. The clonidine-induced reductions in SDMAP, SDRR, and rMSSD were also significantly attenuated by ethanol. These findings suggest that the attenuation of MAP and heart rate variability responses elicited by clonidine in ethanol-fed SHRs reflects alterations in the sympathovagal balance, which may be implicated in the antagonistic hemodynamic interaction between the two drugs.

Intraoperative clonidine modulates sympathetic tone in the early postoperative period after remifentanil. A double blind, placebo-controlled study

Abstract Aim of the study : Severe pain following major surgery can impair the control of the cardiovascular system (CVS) by causing sympathetic stimulation, possibly leading to myocardial ischaemia. In this study we examine the influence of intraoperative intravenous (i.v.) clonidine infusion on postoperative analgesia and blood concentrations of noradrenaline and adrenaline after major gynaecological surgery. Methods : All patients underwent an abdominal hysterectomy under balanced general anaesthesia using the new opioid remifentanil. The patients were randomised to receive either 5 μg kg −1 of i.v. clonidine intraoperatively ( n =20), or placebo ( n =20). Over a period of 240 minutes postoperatively we assessed pain intensity, consumption of the opioid piritramide (a μ-receptor agonist) via an i.v. patient controlled analgesia device, together with blood pressure, heart rate, shivering, nausea, vomiting and sedation. Blood concentrations of adrenaline and noradrenaline in both groups were analysed using HPLC. Results : Postoperative pain intensity and opioid consumption were not influenced by intraoperative clonidine. Clonidine, however, did modulate the postoperative sympathetic tone, and the steep rise of plasma catecholamine concentrations, as part of the postoperative stress response, was clearly diminished. The haemodynamic effects of clonidine in the form of a significant reduction in mean arterial pressure and heart rate, were only seen in the first 15 minutes postoperatively. Conclusion : Intraoperative infusion of clonidine 5 μg kg −1 modulates the postoperative sympathetic tone after abdominal hysterectomy under anaesthesia with remifentanil, resulting in a decreased haemodynamic stress response. Surprisingly, a clonidine dose of 5 μg kg −1 had no influence on postoperative pain or opioid consumption.

Clonidine Improves Recovery from Myocardial Stunning in Conscious Chronically Instrumented Dogs

Clonidine, an alpha2-adrenergic agonist, has been widely used in anesthesia because of its sedative, analgesic, sympatholytic, and specific hemodynamic effects. The use of clonidine in myocardial ischemia is controversial because of its bradycardic and hypotensive effects. In the present study, we tested the hypothesis that clonidine improves recovery from myocardial stunning in conscious dogs. Seven dogs were chronically instrumented to allow measurement of left atrial pressure (LAP), aortic blood pressure (ABP), left ventricular pressure (LVP), maximal rate of increase of LVP (LVdP/dtmax), and myocardial wall thickening fraction (WTF). The myocardial blood flow was measured using colored microspheres. To compensate for any potential interaction between the two ischemic episodes, experiments were performed on separate days in a cross-over fashion (four animals underwent Condition 1, and three underwent Condition 2 as their first experiment). The ischemic episodes involved 1) 10 min of ischemia of the left anterior descending (LAD) coronary artery without any intervention, and 2) 10 min of LAD ischemia 30 min after 10 microg/kg iv clonidine. WTF was measured before the induction of ischemia or the application of clonidine (baseline) and at predetermined time points until complete recovery of myocardial function. WTF recovered faster during the first 2 h of reperfusion when clonidine was administered. The increase in plasma epinephrine was attenuated by clonidine during ischemia, but there was no change during reperfusion. The increase of plasma norepinephrine levels was attenuated during ischemia and reperfusion. The hemodynamic effects of clonidine did not depress myocardial perfusion or impair myocardial function. In this study, we investigated the effects of IV clonidine on myocardial stunning in chronically instrumented dogs. Clonidine improved the recovery from myocardial stunning and attenuated increases in catecholamine plasma levels.

Alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995).

alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995).

Effects of clonidine and dihydralazine on atrial natriuretic factor and cGMP in humans

The effects of a 1-wk treatment with clonidine (75 micrograms/day twice a day) and dihydralazine (25 mg/day twice a day) on base-line levels of plasma atrial natriuretic factor (ANF) and plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and their changes by acute saline infusion (2 liters) in eight normal subjects were evaluated. Basal ANF was decreased to 65% in the clonidine group compared with both the control and dihydralazine groups. Volume loading increased plasma ANF levels by 30-40% of base-line values in the control and the dihydralazine groups and by 15% in the clonidine group. Basal plasma and urinary cGMP levels were raised by 30 and 90% in the dihydralazine group compared with both other groups. Volume loading increased plasma cGMP levels by 40% in the control and clonidine-treated groups and by 25% in the dihydralazine-treated group. It is concluded that ANF may contribute to hemodynamic effects of clonidine but not to those of dihydralazine. Dihydralazine increases plasma and urinary cGMP, supposedly by direct activation of the soluble guanylate cyclase.

The Haemodynamic Effects of Clonidine in Patients with Grade III to IV Hypertension

In 10 patients (aged 46 to 72 years) with essential hypertension (grade III to IV), the acute effects on the haemodynamics in the systemic and pulmonary circulation were analysed following intravenous administration of clonidine. Pressure measurements in the right atrium (RA), right ventricle (RV), and the pulmonary artery (PA) were taken using cardiac catheterisation. Cardiac output was calculated according to the Fick principle. After determination of the initial values, 150 micrograms clonidine was administered intravenously and the haemodynamic parameters measured up to the 90th minute. Cardiac output and the peripheral vascular resistance were determined before and 15 and 30 min after clonidine administration. Heart rate decreased on average from 87 +/- 18 to 78 +/- 20 beats/min (p less than 0.01) 30 min after clonidine. Systolic blood pressure dropped from 215 +/- 33 to 164 +/- 26 mm Hg (p less than 0.01); the diastolic value from 117 +/- 15 to 98 +/- 14 mm Hg (p less than 0.01). At the same time, the systolic PA pressure decreased from 40 +/- 13 to 32 +/- 11 mm Hg (p less than 0.01) and the diastolic pressure decreased from 20 +/- 8 to 15 +/- 8 mm Hg (p less than 0.01). The mean PA pressure dropped from 29 +/- 11 to 23 +/- 10 mm Hg (p less than 0.05). Likewise, the mean RA value decreased from 8 +/- 1.6 to 5.3 +/- 1 (p less than 0.01) following clonidine administration. Cardiac output was not changed significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic Effects of Clonidine in Patients with Acute Myocardial Infarction Complicated by Hypertension

Arterial hypertension complicating acute myocardial infarction (AMI) may aggravate myocardial damage, possibly through an increase in myocardial oxygen demand. This study reports the effects of clonidine in patients with hypertension complicating acute myocardial infarction. Forty patients (37 men and three women, average age 53 years) with acute myocardial infarction, admitted to the coronary care unit not more than 24 h after the onset of symptoms, were studied. Thirty-four had anterior myocardial infarction and six had inferior myocardial infarction. All patients were in Forrester I [WP less than 18 mm Hg, cardiac index (CI) greater than 2.21 L/min/m2] or II (WP greater than 18 mm Hg, CI greater than 2.21 L/min/m2) hemodynamic subset. Blood pressure limits were systolic blood pressure greater than or equal to 150 mm Hg and diastolic blood pressure greater than or equal to 95 mm Hg. Clonidine was administered intravenously in a dose of 5 micrograms/kg over a 5-min period. Hemodynamic parameters (Swan-Ganz thermodilution catheter), systolic time intervals (Weissler), and calculated hemodynamic indexes were measured both before and 60 min after cessation of intravenous injection. Blood pressure fell from 161 +/- 20 to 126 +/- 19 mm Hg (systolic) and from 105 +/- 7.6 to 84.7 +/- 9 mm Hg diastolic. Overall, clonidine produced a decrease in total systemic resistance (-21%). Cardiac index did not change significantly (-3%). Left ventricular stroke work index was significantly reduced (-21%, p less than 0.001), as was the triple product, suggesting a favorable effect of clonidine on myocardial oxygen supply/demand ratio. This may result in a reduction in infarct size.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional hemodynamic effects of clonidine in congestive heart failure.

Regional and central hemodynamic variables were ascertained in 10 patients with congestive heart failure before and after the oral administration of clonidine. Following the 0.2 mg dose, renal, hepatic, and limb blood flow remained unaltered, whereas a reduction was noted in heart rate (10%), mean systemic (14%), and pulmonary capillary wedge pressures (27%). Cardiac index and systemic vascular resistance fell slightly, however the changes were not statistically significant. Higher dose clonidine (0.4 mg) elicited similar regional hemodynamic effects whereas systemic vascular resistance significantly diminished (21%) and cardiac index remained unchanged. In congestive heart failure, the central antihypertensive agent, clonidine, effects a significant reduction in preload (left ventricular filling pressure) and afterload (systemic blood pressure) without markedly altering other central and regional hemodynamic variables.

Clonidine raises blood pressure in severe idiopathic orthostatic hypotension

The hemodynamic effects of clonidine were studied in four patients with severe idiopathic Orthostatic hypotension and one patient with baroreceptor dysfunction. No depressor response to clonidine was observed in any patient with idiopathic Orthostatic hypotension at any dosage. Rather, two patients responded to 0.4 mg of oral clonidine with a 40 mm Hg increment In systolic blood pressure lasting several hours. Each has been receiving clonidine, 0.4 mg twice daily, for one year with greatly increased functional capacity. The other two patients with idiopathic Orthostatic hypotension had an even greater pressor response to 0.8 mg of oral clonidine, but adverse effects prevented continued therapeutic use. In marked contrast, the patient with baroreceptor dysfunction had a profound depressor response to 0.2 mg of clonidine. In the treatment of idiopathic orthostatic hypotension, the major advantage of clonidine over other pressor agents is its longer duration of action. The major adverse effects of the drug in these patients are sedation, dry mouth, altered mentation, and excessive hypertension. The drug should not be given to patients with mild idiopathic Orthostatic hypotension or selective baroreceptor dysfunction, since severe hypotension may result.

Clonidine Monotherapy in Mild Hypertension

Elsewhere in this symposium, we have reported on the hormonal and hemodynamic effects of clonidine used as a sole therapeutic agent, 1 Golub MS Thananopavarn C Eggena P Barrett JD Sambhi MP Hormonal and hemodynamic effects of acute and chronic clonidine therapy in patients with mild to moderate hypertension. Chest. 1983; 83: 377-379 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar as well as the role of clonidine monotherapy in treatment of hypertension in the elderly. 2 Thananopavarn C Golub MS Sambhi MP Clonidine in the elderly hypertensive: monotherapy and with a diuretic. Chest. 1983; 83: 410-411 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar This article presents a synthesis and review of the evolution of the concepts in favor of the use of clonidine monotherapy in patients with mild hypertension.

Clonidine, a New Potent Antihypertensive Agent.

Excerpt Clonidine (Catapres⌖) is a new imidazoline derivative with potent antihypertensive effect. The acute hemodynamic effects of Clonidine were evaluated in seven hypertensive patients. Two dist...