Rapid Blood Pressure Reduction Research Articles

Clevidipine Rapidly and Safely Reduces Blood Pressure in Acute Intracerebral Hemorrhage: The ACCELERATE Trial

Background: Intracerebral hemorrhage (ICH) causes 10-15% of primary strokes, with mortality related to hematoma volume. Blood pressure (BP) reduction may attenuate hematoma expansion. ACCELERATE (the Evaluation of Patients with Acute Hypertension and Intracerebral Hemorrhage with Intravenous Clevidipine Treatment) is a pilot study representing the first evaluation of safety and efficacy of intravenous clevidipine for the rapid treatment of hypertension in ICH patients. Methods: ICH patients with a systolic BP (SBP) >160 mm Hg who present within 6 h (n = 27) or 12 h (n = 10) of symptoms were prospectively enrolled, treated with open-label clevidipine until SBP ≤160 mm Hg was achieved and then titrated to keep target SBP between 140-160 mm Hg. Results: A total of 35 patients with baseline median Glasgow Coma Scale score of 12, median NIH Stroke Scale score of 14, mean SBP of 186 mm Hg and a mean time from onset of symptoms of 5.5 h received clevidipine. Median time to achieve SBP target range was 5.5 min. All patients achieved target SBP within 30 min; 96.9% achieved target SBP with clevidipine monotherapy. CT scans showed minimal hematoma volume change for the overall population (median change 0.01 ml, -2.9%). Mild/moderate hypotension was reported in 3 patients and resolved with dose reduction or drug discontinuation. Conclusion: Clevidipine monotherapy was effective and safe for rapid BP reduction in this cohort of critically ill ICH patients. Overall, patients showed minimal hematoma expansion with BP reduction, suggesting that rapid BP control with clevidipine may have a beneficial impact on hematoma expansion and warrants further investigation.

303 High dose Intravenous Melatonin for Augmentation of Hypothermic Neuroprotection Leads to Hypotension

BackgroundTherapeutic hypothermia provides neuroprotection in infants with moderate to severe neonatal encephalopathy, however further treatments are necessary as hypothermic neuroprotection is not absolute.AimTo assess the effect on mean arterial blood...

Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety

BackgroundHepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule.MethodsPotential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days.ResultsWe established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF.ConclusionsIntravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

The Intracerebral Haemorrhage Acutely Decreasing Arterial Pressure Trial: ICH ADAPT

The majority of intracerebral haemorrhage patients present with markedly elevated blood pressure immediately after symptom onset. Management of blood pressure in the first 24 h is extremely controversial and lends itself to two competing rationales. There is some evidence that early treatment may improve outcome, potentially by reducing the rate of haematoma expansion. It is also possible that this will reduce cerebral blood flow and therefore exacerbate the cerebral injury, particularly in the region surrounding the haematoma. Only a trial that includes both randomisation of patients to two different blood pressure management strategies and actual measurement of cerebral blood flow can effectively address this pressing debate. This is the only unequivocal way to demonstrate the haemodynamic effects of rapid blood pressure reduction. The Intracerebral Haemorrhage Acutely Decreasing Arterial Pressure Trial is designed to test the hypothesis that blood pressure reduction does not result in significant or harmful changes in cerebral blood flow in acute intracerebral haemorrhage. Two hours after randomisation to a systolic blood pressure target of <150 or <180 mmHg, cerebral blood flow is measured using computed tomography perfusion, which is the primary end-point of the trial. A study of this type is critical to establishing the safety of early blood pressure treatment and is necessary for planning larger efficacy trials in a rational manner. This trial is registered with clinicaltrials.gov (NCT00963976).

Beating the clock: reducing cardiovascular risk by rapid blood pressure reduction with olmesartan

Importance of the field: Hypertension is a major cardiovascular risk factor, and treatment guidelines acknowledge the value not only of reducing elevated blood pressure (BP) to target levels (< 140/90 mmHg and < 130/80 mmHg in patients with diabetes or those at high cardiovascular risk) but also of doing this rapidly.Areas covered in this review: The importance of rapid BP control has been demonstrated by trials like the Valsartan Antihypertensive Long-term Use Evaluation trial. Combination therapy provides greater efficacy than monotherapy and reduces BP more rapidly. Combining angiotensin receptor blockers (ARBs) with agents from other classes, like calcium channel blockers or diuretics, is an established way to provide effective, rapid and well-tolerated BP reduction.What the reader will gain: Although ARBs are widely used as mono- and combination therapy, it is not widely appreciated that there are differences between these drugs in efficacy and speed of action. The ARB olmesartan medoxomil provides rapid reductions in BP as monotherapy and combination therapy, with large BP reductions observed within the first few weeks of treatment.Take home message: In addition to controlling BP, speed of onset of action is an important factor in the management of hypertensive patients and treatments that lower BP rapidly should help to reduce cardiovascular risk.

Angiotensin II-Receptor Blockers: their Relevance in Clinical Practice

The implication of the renin angiotensin system (RAS) and specifically angiotensin II in the pathogenesis of essential hypertension, cardiac, cerebrovascular and renal disease is well established. Among the different categories of drugs that manage hypertension, angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are notably effective in the downregulation of RAS. Whereas ACEIs achieve RAS inhibition by constraining the conversion of angiotensin I to angiotensin II, they can display adverse effects, such as cough and angioedema that result from the increased production of bradykinin and prostaglandin. The direct antagonistic action of ARBs on angiotensin II receptors has proved to be very well tolerated. Achieving rapid blood pressure reduction and twenty-four hour hypertension control, they are superior to other antihypertensive agents in the regression of left ventricular hypertrophy, new onset diabetes and stroke and in the delay of renal dysfunction. The combination of ARBs with other drug categories, such as diuretics or calcium channel blockers, can provide additive effects, favouring their recommendation and use for the clinical management of hypertension and cardiovascular diseases. Meta-analyses of clinical trials have provided evidence that ARBs are comparable with other drugs against cardiovascular and all-cause mortality.

Severe hypertension in children and adolescents: pathophysiology and treatment

Severe, symptomatic hypertension occurs uncommonly in children, usually only in those with underlying congenital or acquired renal disease. If such hypertension has been long-standing, then rapid blood pressure reduction may be risky due to altered cerebral hemodynamics. While many drugs are available for the treatment of severe hypertension in adults, few have been studied in children. Despite the lack of scientific studies, some agents, particularly continuous intravenous infusions of nicardipine and labetalol, are preferred in many centers. These agents generally provide the ability to control the magnitude and rapidity of blood pressure reduction and should--in conjunction with careful patient monitoring--allow the safe reduction of blood pressure and the avoidance of complications. This review provides a summary of the underlying causes and pathophysiology of acute severe hypertension in childhood as well as a detailed discussion of drug treatment and the optimal clinical approach to managing children and adolescents with acute severe hypertension.

Cerebral Vasomotor Reactivity Before and After Blood Pressure Reduction in Hypertensive Patients

Hypertension is associated with cerebrovascular remodeling and endothelial dysfunction, which may reduce cerebral vasomotor reactivity to CO2. Treatment combining blood pressure (BP) reduction with inhibition of vascular effects of angiotensin II may reverse these changes. However, the reduction in BP at the onset of treatment can compromise cerebral perfusion and exhaust vasomotor reserve, leading to impaired CO2 reactivity. Eleven patients (nine men, two women) with newly diagnosed, untreated mild-to-moderate hypertension aged (mean (s.d.)) 52 (9) years, and eight controls (seven men, one woman) aged 46 (10) years were studied. Patients received losartan/hydrochlorothiazide (50/12.5 or 100/25 mg) to reduce BP to <140/<90 mm Hg within 1-2 weeks. BP (Finapres), heart rate (HR), CBFV (cerebral blood flow velocity, transcranial Doppler), cerebrovascular resistance, and CO2 reactivity were measured at baseline, after the rapid BP reduction, and after long-term treatment (3-4 months). At baseline, hypertension was not associated with reduced CO2 reactivity. Treatment effectively lowered BP from 148 (12)/89 (7) to 130 (15)/80 (9) after 1-2 weeks and 125 (10)/77 (7) mm Hg after 3-4 months (P = 0.003). CO2 reactivity was not affected by the reduction in BP within 2 weeks, and long-term treatment did not augment reactivity. In hypertension without diabetes or advanced cerebrovascular disease, CO2 reactivity is not reduced, and rapid normalization (within 2 weeks) of BP does not exhaust vasomotor reserve. CO2 reactivity did not change between 2 and 12 weeks of treatment, which argues against a direct vascular effect of angiotensin II inhibition within this period.

Not only the effective, but a rapid blood pressure reduction as a novel aim in hypertension treatment. The role of combination therapy

введениероль артериальной гипертензии (Аг), как важ-нейшего, независимого, но корригируемого фактора риска в развитии различного ряда сердечно-сосудис-тых осложнений хорошо известна. В клинических исследованиях показана принципиальная возмож-ность достижения целевых значений артериального давления (АД) у подавляющего большинства больных с Аг, однако реальная эпидемиологическая ситуация свидетельствует о незначительной доле пациентов с удовлетворительным контролем АД [1–5]. Во многих странах, включая россию, уже в течение нескольких десятков лет предпринимаются попытки улучшить эпидемиологическую ситуацию в отношении Аг и ее осложнений, разрабатываются специальные программы по выявлению Аг, повышению информированности на-селения и т.д. проводимые медицинские и социальные мероприятия привели к определенным успехам в этой сфере [6–7], однако эксперты считают, что доля боль-ных с недостаточным контролем АД будет продолжать расти с течением времени [8]. Это связано с тем, что среди больных с артериальной гипертензией постоянно растет число пациентов, относящихся к группам высо-кого риска, — больных с ожирением и метаболическим синдромом (мС), с сахарным диабетом (СД), пожилых пациентов, больных с органными поражениями. так, согласно мировым статистическим данным число боль-ных с Аг в мире на 2000 год составило 972 миллиона человек, а к 2025 прогнозируемое число таких пациентов при сохраняющихся темпах прироста, составит уже 1.56 биллиона [9]. при этом число жителей земли старше 60 лет к 2025 году увеличится примерно на 5%, тогда как распространенность Аг в этой категории составляет по-рядка 60%. трудность успешного контроля АД, особенно систолического, в этой подгруппе хорошо известна, тог-да как негативная роль изолированной систолической Аг также не подлежит сомнению. Уже один возрастной аспект проблемы дает основание предполагать, что число больных с Аг, требующих более агрессивной тактики антигипертензивной терапии с применением комбинированной терапии, будет существенно нарас-тать. повышение распространенности ожирения и са-

Rapid Blood Pressure Reduction in Acute Intracerebral Hemorrhage: Feasibility and Safety

The optimal blood pressure (BP) for treating acute intracerebral hemorrhage remains (ICH) uncertain. High BP may contribute to hematoma growth while excessive BP reduction might precipitate peri-hemorrhage ischemia. We examine here the feasibility and safety of reducing BP to lower than presently recommended levels in patients with acute ICH. Patients with ICH were prospectively randomized to standard BP treatment (mean arterial BP [MAP] 110-130 mmHg) or aggressive BP lowering (MAP < 110 mmHg) within 8 h of symptom onset. MAP was managed during the 48 h treatment period. NIHSS was obtained at baseline, 24, and 48 h. Brain CT was done 24 h after symptoms. A modified Rankin Scale (mRs) was obtained at 90 days. A clinical decline (NIHSS drop > or = 2 points) within the first 48 h was the primary endpoint. Hematoma enlargement at 24 h was a secondary endpoint. We enrolled 21 patients into each group. Mean age was 60.6 +/- 12.3 years and MAP on presentation was 147.6 +/- 18.2 mmHg. Treatment was started on average 3.2 +/- 2.2 h after symptom onset. Baseline clinical variables were identical between the 2 treatment groups. Target blood pressure was achieved within 87.1 +/- 59.6 min in the standard group and 163.5 +/- 163.8 min in the aggressive BP treatment group. There were no significant differences in early neurological deterioration, hematoma and edema growth, and clinical outcome at 90 days. A more aggressive reduction of acute hypertension after ICH does not increase the rate of neurological deterioration even when treatment is initiated within hours of symptom onset. Lowering BP aggressively did not affect hematoma and edema expansion but this possibility deserves further study.

Management of Uncontrollable Hypertension With a Carotid Sinus Stimulation Device

Hypertensive crisis is a serious condition that results in target-organ damage, such as stroke, heart attack, or renal failure, if left untreated.1 Causes of acute increases in blood pressure in patients with primary essential hypertension include medication noncompliance and poorly controlled chronic hypertension. Treatment of a hypertensive crisis should be tailored to each individual based on the extent of target-organ injury and comorbid conditions. Prompt and rapid reduction of blood pressure under continuous surveillance is essential. We encountered a patient with target-organ damage and poor response to accepted antihypertensive regimens. Many terms are used to describe this degree of hypertension; the term “uncontrollable” will be used here. After an 8-drug regimen was not successful, we elected a radical, controversial, but novel therapy. Only long-term clinical trials, perhaps above-and-beyond the trial in which we currently participate, will be necessary to answer the hypothesis that a device-based treatment can triumph over tablets alone. A 58-year-old woman with known primary hypertension for 40 years was referred to our clinic because of difficult-to-control “resistant or uncontrollable” hypertension. She did not have diabetes or known renal disease. However, she did have modest proteinuria at ≈500 mg/d. Her left ventricle wall thickness was moderately enlarged by echocardiography. Five or more different concomitantly prescribed medications failed to result in adequate blood pressure control. She had been diagnosed earlier with accelerated (malignant) hypertension on the basis of severe headaches, retinal hemorrhages, and macular edema. Secondary causes of hypertension were sought but not identified. Her medication consisted of furosemide, minoxidil, atenolol, metolazone irbesartan, amiloride, and glyceryl trinitrate. Amlodipine was added; however, an outpatient visit disclosed a blood pressure of 240/140 mm Hg (these and subsequent values are in the presented supine position). The drug doses were commensurate with the maximum-recommended doses given in the package inserts. Therefore, the …

Reversible posterior leukoencephalopathy associated with postpartum HELLP syndrome

We describe a case of a severe, immediate postpartum HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count) with reversible posterior leukoencephalopathy (RPLS) characterized by generalized seizure, altered mental status, and visual loss in a 37-year-old primigravid woman. Magnetic resonance brain imaging showed diffuse subcortical edema, which resolved completely after 2 weeks along with complete symptom regression. The pathogenesis of RPLS is discussed and the importance of a prompt diagnosis is emphasized, as is the crucial role of rapid blood pressure reduction.

Ventricular arrhythmia following short-acting nifedipine administration

Short-acting nifedipine is still advocated for use in children with severe hypertension, but is no longer recommended for use in adults because of adverse effects from rapid blood pressure reduction. A 19 year-old adolescent with symptomatic, severe hypertension (blood pressure 180/120) received 10 mg of short-acting nifedipine sublingually for blood pressure reduction. Within minutes after the dose, the patient complained of palpitations. Tachycardia (heart rate 100 beats per minute) and bigeminy were noted on the cardiac monitor. The bigeminy resolved but premature ventricular contractions were noted for the duration of her hospital stay. We hypothesize that reflex sympathetic activation following an abrupt drop in blood pressure may cause arrhythmias because of elevated catecholamine levels. Given this, it may be more appropriate to treat severe hypertension in children with intravenous antihypertensive agents that can be titrated to produce controlled reductions in blood pressure.

Impaired cerebral autoregulation in patients with malignant hypertension.

In patients with a malignant hypertension, immediate parenteral treatment with blood pressure-lowering agents such as intravenous sodium nitroprusside (SNP) is indicated. In this study, we evaluated static and dynamic cerebral autoregulation (CA) during acute blood pressure lowering with SNP in these patients. In 8 patients with mean arterial pressure (MAP) >140 mm Hg and grade III or IV hypertensive retinopathy at hospital admission, middle cerebral artery blood velocity (MCA V) and blood pressure were monitored. Dynamic CA was expressed as the 0.1-Hz MCA V(mean) to MAP phase lead and static CA as the MCA V(mean) to MAP relationship during SNP treatment. Eight normotensive subjects served as a reference group. In the patients, the MCA V(mean) to MAP phase lead was lower (30+/-8 degrees versus 58+/-5 degrees , mean+/-SEM; P<0.05), whereas the transfer gain tended to be higher. During SNP treatment, target MAP was reached within 90 minutes in all patients. The MCA V(mean) decrease was 22+/-4%, along with a 27+/-3% reduction in MAP (from 166+/-4 to 121+/-6 mm Hg; P<0.05) in a linear fashion (averaged slope, 0.82+/-0.15% cm x s(-1) . % mm Hg(-1); r=0.70+/-0.07). In patients with malignant hypertension, dynamic CA is impaired. An MCA V(mean) plateau was not detected during the whole SNP treatment, indicating loss of static CA as well. This study showed that during the whole rapid reduction in blood pressure with SNP, MCA V(mean) decreases almost one on one with MAP.

Sudden Sensorineural Hearing Loss after Rapid Reduction of Blood Pressure in Malignant Hypertension

Although circulatory impairment of the cochlea would be intuitively a possible cause of sudden sensorineural hearing loss (SSHL), definite proof is lacking. A 46-year-old man developed bilateral SSHL immediately after rapid reduction of the blood pressure in malignant hypertension. Vertigo and left-sided hearing impairment and tinnitus resolved spontaneously a few hours after onset. The right-sided hearing loss and tinnitus persisted, and the hearing loss improved only 17 dB after 3 months of treatment. This case may provide an in vivo human model of SSHL caused by ischemia. Bilateral involvement is possible in SSHL if the circulatory disturbance is systemic. In addition, a poorer prognosis is anticipated on the side with the more severe initial attack.

A method for determining whether hypotension caused by novel compounds in preclinical development results from histamine release

Introduction: Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive compound, SC-372. Methods: In Inactin anesthetized rats, after intravenous administration of SC-372 (0.3-7 mg/kg), the 2 and 7 mg/kg resulted in a dose-dependent decrease in blood pressure. Histamine (0.1 and 1 mg/kg) was injected intravenously to establish whether histamine release was the mechanism of action for the hypotension induced by SC-372. Compound 48/80 (0.1 mg/kg, promotes histamine release) and Cromolyn (1 mg/kg/min, [5 min], prevents histamine release from mast cells) were characterized and used intravenously in combination with/or compared to SC-372. Results: Histamine resulted in a decrease in blood pressure that was unaffected by Cromolyn (1 mg/kg). Administration of Compound 48/80 resulted in a rapid reduction of systemic blood pressure. Intravenous infusion of Cromolyn prior to the injection of Compound 48/80 significantly attentuated the hypotensive response and the increase in histamine levels in the plasma. Intravenous administration of SC-372 resulted in a rapid reduction in blood pressure with a profile similar to that of Compound 48/80. When the rats were treated with Cromolyn prior to the administration of SC-372, both the blood pressure and plasma histamine levels were maintained at their pretreatment control levels. Discussion: These data indicate that Compound 48/80 and Cromolyn can be used in rats to screen for histamine release-dependent drug-induced hypotension and suggest that the rapid decrease in blood pressure caused by SC-372 may result from histamine release from mast cells.

Renal dopamine receptor function in hypertension.

Dopamine plays an important role in the regulation of renal sodium excretion. The synthesis of dopamine and the presence of dopamine receptor subtypes (D1A, D1B, as D1-like and D2, and D3 as D2-like) have been shown within the kidney. The activation of D1-like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D1-like receptors are linked to the multiple cellular signaling systems (namely, adenylyl cyclase, phospholipase C, and phospholipase A2) in the different regions of the nephron. Defective renal dopamine production and/or dopamine receptor function have been reported in human primary hypertension as well as in genetic models of animal hypertension. There may be a primary defect in D1-like receptors and an altered signaling system in the proximal tubules that lead to reduced dopamine-mediated effects on renal sodium excretion in hypertension. Recently, it has been shown in animal models that the disruption of either D1A or D3 receptors at the gene level causes hypertension in mice. Dopamine and dopamine receptor agonists also provide therapeutic potential in treatment of various cardiovascular pathological conditions, including hypertension. However, because of the poor bioavailability of the currently available compounds, the use of D1-like agonists is limited to the management of patients with severe hypertension when a rapid reduction of blood pressure is clinically indicated and in acute management of patients with heart failure. In conclusion, there is convincing evidence that dopamine and dopamine receptors play an important role in regulation of renal function, suggesting that a defective dopamine receptor/signaling system may contribute to the development and maintenance of hypertension. Further studies need to be directed toward establishing a direct correlation between defective dopamine receptor gene in the kidney and development of hypertension. Subsequently, it may be possible to use a therapeutic approach to correct the defect in dopamine receptor gene causing the hypertension.

Guidelines for the drug treatment of hypertensive crises.

Hypertensive crises are a group of clinicopathological entities in which rapid reduction of hypertension is necessary to prevent serious end-organ damage. The diagnosis and treatment plan depends on the identification of specific end-organ dysfunction. The goal of treatment is to limit the progression of end-organ damage in patients with hypertensive crises. Several potent antihypertensive drugs, such as sodium nitroprusside, labetalol and urapidil, are available to produce an immediate fall in blood pressure. The choice of the drug should be made on the basis of its pharmacodynamic properties, clinical effects, advantages and contraindications. Additionally, rapid reduction of blood pressure carries a considerable risk, if it is performed in an uncontrolled manner, leading to further end-organ damage. The aim of the treatment is not just to reduce blood pressure, but to do so with minimal adverse effects while preserving organ function.

Nitric oxide: physiology and pharmacology.

Nitric oxide: physiology and pharmacology.

Nitric Oxide

Nitric Oxide