Central Versus Peripheral Blood Pressure in Malignant Hypertension; Effects of Antihypertensive Treatment

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1 American Journal of Hypertension Advance Access published January 10, 2013 Original Article Central Versus Peripheral Blood Pressure in Malignant Hypertension; Effects of Antihypertensive Treatment Bas van den Bogaard 1, Rogier V. Immink 2,3, Berend E. Westerhof 3,4, Gert A. van Montfrans 1, Johannes J. van Lieshout 3,5, and Bert-Jan H. van den Born 1 Background Sodium nitroprusside (SNP) and labetalol are recommended for the immediate treatment of malignant hypertension. Both are intravenous agents but have different effects on systemic hemodynamics, and may have differential effects on pulse-wave reflection and pulse-pressure amplification, with consequences for peripheral versus central blood pressures (BPs). METHODS We conducted a nonrandomized, open-label study of 8 patients treated with sodium nitroprusside (mean age (±SD), 44 ± 14 years; 6 males; diastolic/systolic BP, 225 ± 22/135 ± 8 mm Hg) and 6 patients treated with intravenous labetalol (mean age, 39 ± 15 years; 4 males; systolic/diastolic BP, 232 ± 22/138 ± 17 mm Hg) before and after treatment for malignant hypertension, aiming at a 25% reduction in mean arterial pressure. We measured peripheral pressures with an intra-arterial catheter in the radial artery and derived central pressures with a generalized transfer filter. RESULTS Mean arterial pressure was similarly reduced with sodium nitroprusside and labetalol (by 27% and 30%, respectively; P = 0.76). There was Malignant hypertension is a hypertensive emergency defined by a severe elevation of blood pressure (BP) accompanied by bilateral grade III and IV retinopathy according to the Keith, Wagener, and Barker classification. 1 Patients with malignant hypertension should receive immediate antihypertensive treatment because of the high risk of renal failure, stroke, myocardial infarction, and heart failure created by this condition. However this should be done with caution because in malignant hypertension, cerebral autoregulation, which is the capacity of the cerebral vasculature to maintain a stable cerebral blood flow, is impaired, and the velocity of blood flow through the middle cerebral artery decreases a nonsignificantly greater reduction in peripheral systolic blood pressure (SBP) with labetalol than with sodium nitroprusside (29 ± 11% vs. 18 ± 7%, P = 0.08). The decline in peripheral diastolic blood pressure (DBP) with the two agents was comparable, whereas the reduction in peripheral pulse pressure was 8 ± 16% with SNP and 33 ± 17% with labetalol (P = 0.01). The decline in reflection magnitude was greater with SNP than with labetalol. There were no significant differences in the reduction of central BP with SNP and labetalol. The amplification of PP increased with SNP but did not change with labetalol. Conclusions We found no difference in central SBP or PP in subjects treated with SNP and labetalol, but labetalol produced a greater reduction in peripheral SBP and PP in the immediate treatment of malignant hypertension. Keywords: malignant hypertension; central blood pressure; hemodynamics; wave reflection; blood pressure; hypertension. considerably during an acute reduction of BP. 2, 3 Because immediate reductions in mean arterial pressure (MAP) of more than 50% have been associated with cerebral ischemia, stroke, and death, 4,5 there is a consensus of opinion that to prevent hypoperfusion of the brain, the acute phase of treatment of malignant hypertension should pursue a reduction in MAP of no more than 25%. 6 8 Sodium nitroprusside (SNP) and labetalol are recommended as first-line agents for the immediate treatment of malignant hypertension. Both of these intravenous agents are effective in reducing BP, but have different effects on systemic hemodynamics. Sodium nitroprusside, a nitric oxide donor, Correspondence: Bas van den Bogaard, MD PhD, Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, room F4-142, 1105 AZ, Amsterdam, The Netherlands, tel , fax , (b.vandenbogaard@amc.nl). Initially submitted April 17, 2012; date of first revision November 16, 2012; accepted for publication November 23, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Department of Anesthesiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands; 3 Laboratory for Clinical Cardiovascular Physiology, Center for Heart Failure Research, Academic Medical Center, University of Amsterdam, The Netherlands; 4 BMEYE BV, Amsterdam, The Netherlands; 5 School of Biomedical Sciences, University of Nottingham Medical School, Queen s Medical Centre, United Kingdom. American Journal of Hypertension, Ltd All rights reserved. For Permissions, please journals.permissions@oup.com American Journal of Hypertension 1

2 Bogaard et al. reduces BP mainly by decreasing systemic vascular resistance, with cardiac output (CO) being increased because of an increase in heart rate (HR) without a significant change in stroke volume. With labetalol, a selective alpha-1-adrenergic and nonselective beta-adrenergic receptor antagonist, the reduction in systemic vascular resistance is modest, with a decline in CO produced by a reduction in HR. 2 Clinically, the treatment of malignant hypertension is guided by measurements of BP with an intra-arterial catheter placed in the radial artery. It has been recognized, however, that antihypertensive drugs differ in their capacity to reduce central BP, whereas their effects on peripheral BP may be similar. Vasodilatory antihypertensive drugs such as calcium-channel blockers and angiotensin-converting enzyme inhibitors reduce central BP more than do thiazide diuretics or first- and second-generation beta-blockers, despite producing similar reductions in peripheral BP. 9 These differences are attributed to differential effects on HR and systemic vascular resistance that alter the wave-reflection patterns of pulse waves. To our knowledge, the differential effects of antihypertensive drugs on peripheral and central BPs have not been studied in malignant hypertension. We hypothesized that SNP and labetalol act differently on peripheral and central hemodynamics in malignant hypertension. We therefore assessed the effects of these two antihypertensive agents on peripheral and central systolic and pulse pressures and on pulse-wave reflection and pulse-pressure amplification during the treatment of malignant hypertension, aiming at a 25% reduction in MAP. METHODS Study design and treatment To assess the effects of SNP and labetalol in malignant hypertension, we conducted a study consisting of a retrospective analysis of data for subjects (14) with malignant hypertension. The present study describes 14 patients; all 14 patients had malignant hypertension. Other data for these same subjects have been reported previously. 2,3 One paper reported data for 8 patients with malignant hypertension, who were treated with SNP to study the effects of acute antihypertensive treatment on cerebral autoregulation. 3 A second paper compared these 8 patients treated with SNP with 7 new patients treated with labetalol to study differences in cerebral hemodynamics with the two treatment regimens. 2 Of the 15 patients with malignant hypertension described in these two publications, data for analysis in the present study were available for 14 patients. The patients were recruited from 2002 to All 14 patients fulfilled the World Health Organization (WHO) criteria for malignant hypertension, with severely elevated BP accompanied by grade III or IV hypertensive retinopathy according to the Keith, Wagener, and Barker classification. 1 Patients who had a stroke or transient ischemic attack or both were excluded from the study. All of the patients in the study were admitted to the medium-care unit of the Academic Medical Center, Amsterdam, for intravenous treatment and continuous BP monitoring with a radial-artery catheter. The patients clinical data have been described previously, 2,3 as has also the treatment protocol for the study. 2, 3 According to the protocol, no oral treatment was to be given before the beginning of intravenous treatment, and treatment was to be begun within 1 hour after the diagnosis of malignant hypertension. With the goal of achieving a reduction in MAP of approximately 25% below the presenting value, the first 8 patients were treated with SNP and the latter 6 with labetalol. The infusion of SNP was started at 0.3 μg/kg/min, increased to 0.5 μg/kg/ min after 5 minutes, and then increased by 0.5 μg/kg/min every 5 minutes until the target MAP was reached (with a maximum infusion dosage of 5 μg/kg/min). Labetalol was administered as a bolus of 0.5 mg/kg every 8 minutes, with a maximum infusion dosage of 200 mg. When the desired MAP was reached, a continuous infusion of 20 mg/h was given. The investigators who conducted the study were not blinded to the treatment protocols. All patients gave their written informed consent for participation in the study, and the study was approved by the Medical Ethics Committee of the Academic Medical Center, Amsterdam. Hemodynamic measurements Peripheral systolic blood pressure (psbp), diastolic blood pressure (DBP), peripheral pulse pressure (ppp), and MAP were measured at baseline (at admission) and before and after treatment through the use of an intra-arterial catheter (1.1-mm ID, 20 gauge) placed in the radial artery. We compared a 3-minute interval of hemodynamic data before treatment with the hemodynamic data at the instant when the desired reduction in MAP was reached. Central systolic blood pressure (csbp) and central pulse pressure (cpp) were derived off-line with a generalized pressure-transfer filter as previously described. 10,11 Because peripheral and central values for MAP and DBP are more or less similar, we report only peripheral MAP and DBP. Pulse-pressure amplification (PPA) was defined as ppp/cpp. Waveform separation by dedicated software programmed in Mathematica version 4.0 (Wolfram Research, Champaign, IL) was applied to the calculated central aortic pressure waves to derive forward (Pf) and backward pressure (Pb) waves. Reflection magnitude (RM), 12 as a measure of wave reflection, was calculated as the ratio of the amplitudes of Pb and Pf. Statistical analysis Data are expressed as mean (±SD) for continuous variables and as n (%) for categorical variables. Because of the small sample size in the study, we conservatively used nonparametric tests. Pre- vs. post-treatment differences within each treatment group were calculated with the Wilcoxon matched-pairs signed ranks test. Because BPs before treatment differed in the two treatment groups, we normalized the pretreatment data and compared percent changes in outcome parameters in the two treatment groups. We used the Wilcoxon rank sum test to assess the normalized betweengroup differences in the two treatment groups. We considered a value of P < 0.05 as significant. Data were analyzed with SPSS software version (SPSS, Chicago, IL). 2 American Journal of Hypertension

3 Central Blood Pressure in Malignant Hypertension RESULTS Baseline characteristics Table 1 shows the baseline characteristics and BPs of the study subjects at admission. There were no significant differences in age, sex, body mass index (BMI), or BP in the SNP- and labetalol-treated groups at baseline. Peripheral and central blood pressures Table 2 shows the absolute BPs of the study subjects before and after treatment. The reduction in MAP was similar with SNP and labetalol (27% vs. 30%, P = 0.76). During treatment with SNP and labetalol, all peripheral and central BP parameters decreased significantly from their pretreatment values. Figure 1 shows the percent changes from before treatment in peripheral and central systolic and pulse pressure for both treatment groups. There was a trend toward a greater reduction in psbp with labetalol than with SNP (29 ± 11% vs. 18 ± 7%, P = 0.08). Peripheral pulse pressure declined by 8 ± 16% with SNP and 33 ± 17% with labetalol (P = 0.01). The change in pdbp with SNP did not differ from that with labetalol (25 ± 8% vs. 27 ± 11%, P = 0.76). In the case of central BP there were no significant differences with SNP vs. labetalol. Central SBP decreased by 27 ± 9% in the SNP treatment group as compared with 29 ± 11% in the labetalol treatment group (P = 0.76); the decreases in cpp with SNP and labetalol were 35 ± 11% and 34 ± 18%, respectively (P = 0.85). Pulse-pressure amplification increased by 0.5 ± 0.3 (38%) upon treatment with SNP but did not change with labetalol. In both treatment groups, RM decreased significantly with treatment, with the decrease being larger with SNP than with labetalol, at 0.24 ± 0.1(35%) vs ± 0.1 (10%), P < 0.01, respectively. Discussion The treatment of malignant hypertension calls for immediate reduction of BP. Guidelines for treatment of Table 1. Baseline characteristics of study participants the condition call for a reduction in MAP by 25% because reductions of MAP that exceed this have been associated with symptomatic hypoperfusion of the brain, resulting in cerebral damage and even death. 4,5 A finding in the present study was the absence of differences in central systolic and pulse pressure in the treatment of malignant hypertension with SNP or labetalol with the goal of a 25% reduction in MAP. In contrast, labetalol produced a greater reduction in psbp and ppp than did SNP. Pulse-pressure amplification therefore increased with SNP but not with labetalol. One explanation for this is that wave reflection decreased with SNP but did not change with labetalol. We previously showed that in the treatment of malignant hypertension, SNP decreases systemic vascular resistance by 43%, while for a similar reduction in BP, labetalol decreases systemic vascular resistance by 13% and reduces CO by reducing HR. 2 In the present study we show that these differences in hemodynamics did not lead to differences in the percent changes in csbp and cpp in the treatment of malignant hypertension with the goal of a 25% reduction in MAP. There were, however, differences in peripheral BP, with labetalol producing greater reductions in psbp and ppp than did SNP. Differences in the capacity of different classes of antihypertensive drugs to reduce peripheral and central BPs are attributed to differential effects of these drug classes on HR and systemic vascular resistance, which in turn alter the patterns of pressure-wave reflection in different ways. In the Conduit Artery Function Evaluation (CAFE) study, randomization of subjects to treatment with a beta-blockers and thiazide diuretics or treatment with a calcium-channel blocker and angiotensin-converting enzyme inhibitor showed similar reductions in peripheral BPs, with the latter treatment regimen providing lower central BPs. 9 Moreover, the treatment group receiving the calcium-channel blocker and angiotension-converting enzyme inhibitors showed a significant reduction in major cardiovascular endpoints as compared with the group receiving the beta-blocker and thiazide diuretic-based treatment regimen. 13 Parameters SNP Labetalol P-value n 8 6 Age, y 44 ± ± Male, n (%) 6 (75) 4 (67) 0.73 Smoking, n (%) 2 (25) 1 (13) 0.71 Diabetes mellitus, n (%) 1 (13) 0 (0) 0.37 Statin use, n (%) 0 (0) 0 (0) BMI, kg/m 2 24 ± 2 25 ± psbp, mm Hg 225 ± ± DBP, mm Hg 135 ± ± MAP, mm Hg 162 ± ± Data are means ±SD or otherwise specified, with their values measured at admission. Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; MAP, mean arterial pressure. psbp, peripheral systolic blood pressure; SNP, sodium nitroprusside. American Journal of Hypertension 3

4 Bogaard et al. Table 2. Peripheral and central blood pressures before and after treatment SNP Labetalol Parameters Before After Before After psbp, mm Hg 222 ± ± 15* 233 ± ± 27 ppp, mm Hg 102 ± ± ± ± 21 DBP, mm Hg 121 ± ± 18* 138 ± ± 12 MAP, mm Hg 156 ± ± 16* 169 ± ± 15 HR, bpm 86 ± ± 18* 98 ± ± 13 csbp, mm Hg 204 ± ± 11* 202 ± ± 25 cpp, mm Hg 79 ± ± 7* 66 ± ± 16 PPA 1.3 ± ± 0.2* 1.5 ± ± 0.2 RM 0.69 ± ± 0.1* 0.67 ± ± 0.2 *P = 0.01, P = 0.03 and P = pre- vs. post-treatment. Values are mean (±SD) peripheral and central BPs before and after treatment with sodium nitroprusside (SNP) and labetalol. Abbreviations: cpp, central pulse pressure; csbp, central systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; PPA, pulse pressure amplification; ppp, peripheral pulse pressure; psbp, peripheral systolic blood pressure; RM, reflection magnitude. Figure 1. Pre- to post-treatment percent change (±SD) in peripheral systolic blood pressure (psbp), peripheral pulse pressure (ppp), central systolic blood pressure (csbp), and central pulse pressure (cpp) with sodium nitroprusside (black bars) and (labetalol) grey bars. Evidence is mounting that central BP has better predictive value of organ damage and cardiovascular mortality than does peripheral SBP. 14,15 Ochi et al. showed that central SBP but not peripheral BP was associated with cerebral small-vessel disease. 16 Also, central SBP provided better prediction of white-matter lesions than did peripheral SBP. 17 In malignant hypertension, cerebral autoregulation is impaired and systemic reductions in BP are transferred to cerebral blood flow in an almost one-to-one manner, 3 thus supporting the clinical relevance of effects of antihypertensive agents on arterial pulse-wave reflection. Pulse-pressure amplification as the ratio of ppp to cpp decreased during treatment with SNP but not with labetalol. Because cpp was equally reduced with the two treatment modalities, the difference 4 American Journal of Hypertension

5 Central Blood Pressure in Malignant Hypertension in PPA seems largely attributable to the differential change in ppp. Pulse-pressure amplification is the physiological phenomenon that describes the increase in pulse pressure from central to peripheral arteries, because of regional differences in arterial compliance. Both the increase in PPA and the decrease in RM during treatment with SNP probably reflect the decrease in systemic vascular resistance and/ or the increase in HR with SNP, since it has been shown that PPA and wave reflection are dependent on HR. 18,19 The effect of an antihypertensive agent on peripheral BP does not necessarily correspond to its effect on central BP. In the labetalol treatment group in the present study, the equal reduction in peripheral and central PP can be appreciated from the lack of a change in PPA. This is not the case for SNP, for which a given decrease in psbp would lead to a lower than desired central SBP because of the increase in PPA. However, because treatment in the present study was targeted at MAP, this was not a clinical problem. Besides being impaired in malignant hypertension, cerebral autoregulation is also impaired in ischemic stroke 20 and pre-eclampsia, 21 both of which sometimes require prompt treatment to reduce BP. However, current recommendations for stroke and pre-eclampsia are targeted at reducing psbp. When targeting peripheral BP, central BP, as a surrogate of cerebral perfusion pressure, might unintentionally be reduced even further, depending on the antihypertensive agent used. Under the conditions of impaired cerebrovascular autoregulatory capacity, a reduction in BP may result in cerebral hypoperfusion. The following points merit consideration. Our study was a retrospective analysis of data from a nonrandomized treatment study. To study the effects of acute antihypertensive treatment on cerebral hemodynamics, the first 8 subjects in our study were treated with SNP, which was at the time and in our hospital the treatment of choice for malignant hypertension. In a further study, treatment with SNP was compared with treatment with labetalol, and because the incidence of malignant hypertension is very low, we chose not to randomize the patients in this latter study but to treat consecutive patients with labetalol and compare them with the previous patients treated with SNP. As is inherent in the incidence of malignant hypertension, the patient groups were small, with some differences between the treatment groups in pretreatment BPs, although these were not significant. Importantly, the relative reductions in MAP with labetalol and SNP were of comparable magnitude, permitting us to adequately compare the cardiovascular effects of the two drugs. We did not use a Bonferroni correction for multiple testing, because this would have considerably reduced the power of our hypothesis-generating study with a limited number of patients. Because of the small sample size in our study and the nonrandomized nature of the treatment, the study does not permit definite conclusions to be reached about differential effects of SNP and labetalol on peripheral and central BP in the treatment of malignant hypertension, and larger and prospective randomized studies are needed to confirm our results. During the immediate treatment of malignant hypertension, while aiming at a 25% reduction in MAP, we found no differences in central systolic and pulse pressures with SNP and labetalol. However, with SNP, cpp did not match ppp because of changes in PPA and RM. Therefore, depending on the choice of antihypertensive drug, components of central pulsatile BP may not correspond to peripheral pressures upon BP reduction. This may be relevant when choosing BP targets for antihypertensive therapy, especially in situations in which cerebral autoregulation is impaired. Acknowledgments We gratefully acknowledge the statistical advice of prof. dr. A.H. Zwinderman. DISCLOSURE Berend Westerhof is a full-time employee and holds shares of BMEYE, the manufacturer of the Nexfin device. References 1. Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1974; 268: Immink RV, van den Born BJ,van Montfrans GA, Kim YS, Hollmann MW, van Lieshout JJ. Cerebral hemodynamics during treatment with sodium nitroprusside versus labetalol in malignant hypertension. Hypertension 2008; 52: Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP, Karemaker JM, van Lieshout JJ. Impaired cerebral autoregulation in patients with malignant hypertension. Circulation 2004; 110: Haas DC, Streeten DH, Kim RC, Naalbandian AN, Obeid AI. 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