Intravenous Calcium Channel Blockers Research Articles

Successful Recovery from Severe Fever with Thrombocytopenia Syndrome and Hemophagocytic Lymphohistiocytosis with Standard Treatment and a Calcium Channel Blocker of Nicardipine Hydrochloride: A Case Report.

A 67-year-old man was admitted to our hospital with a high fever. Laboratory tests revealed leukopenia, thrombocytopenia, liver dysfunction, rhabdomyolysis, and hyperferritinemia. He was diagnosed with severe fever with thrombocytopenia syndrome (SFTS) complicated by hemophagocytic lymphohistiocytosis and treated with steroid therapy, intravenous calcium channel blocker (CCB), and supportive care, without favipiravir. Serum levels of ferritin and soluble interleukin 2 receptor (sIL2R) were markedly elevated on Day 3 after admission and decreased thereafter, while an SFTS viral load of 6.8×104 copies/μL was detected on Day 2, increasing to 2.9×105 copies/μL on Day 6. Serum ferritin and sIL2R levels may be better indicators of mortality than the SFTS viral load, and CCBs may have a therapeutic effect.

JS-NG-2: LONG-TERM EFFICACY AND SAFETY OF ALISKIREN IN FOUR CASES WITH MALIGNANT HYPERTENSION

Objective: Malignant hypertension (MH) is a form of hypertensive emergency defined by a severe increase in blood pressure (BP) with multiple organ injuries. One possible pathophysiology of MH is an acute activation of the renin-angiotensin system (RAS) driven by the intense stimulation of renin secretion in the juxtaglomerulosa cells. Considering this mechanism, aliskiren, a direct renin inhibitor (DRI), can be a treatment option for MH. However, there is little information on the efficacy and safety of DRI in controlling MH. We herein report four cases with MH that have been successfully controlled by DRI for a long term. Case description: All of the four cases (three male and one female; 34 to 57 years of age) developed advanced retinopathy (III or IV grade on Keith-Wagener classification) and severe hypertension (> 200/120 mmHg) at presentation, meeting the criteria for MH according to the 2020 ISH global hypertension practice guideline. Mean systolic/diastolic BP was 215 ± 5/148 ± 8 mmHg. All developed acute kidney injury, with the mean serum creatinine (sCr) of 4.47 ± 1.13 mg/dl on admission. The ranges of plasma renin activity (PRA) and plasma aldosterone concentration (PAC, as measured by RIA) were 11–33 ng/mL/hr and 371–1370 pg/mL, respectively. Followed by initial treatment with an intra-venous calcium channel blocker, these patients were prescribed aliskiren, starting at 150 mg/day once daily, after confirmation of the elevated PRA levels. In general, aliskiren was well tolerated and BP was successfully controlled in all of the four cases (at discharge, mean systolic/diastolic BP was 123/74 mmHg and mean sCr was 3.84 mg/dL). Patients continued to receive aliskiren (at a dose of 150 or 300 mg/day) after the discharge and mean systolic/diastolic BP and sCr were 131 ± 4/84 ± 3 mmHg and 2.02 ± 0.16 mg/dl at two years of follow-up, respectively. The ranges of PRA and PAC of four cases have fallen to 0.2–0.8 ng/mL/hr and 105–203 pg/mL, respectively. Conclusions: In our cases, severe hypertension and target organ damage were fairly controlled with aliskiren on acute and chronic phases of MH. In all of the four cases, PRA declined with anti-hypertensive treatment and was useful in guiding the doses of medications. Although DRI is not a first-line anti-hypertensive drug class, it may be useful in a certain form of MH with high PRA, which merits further study.

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Objectives Elevated diastolic blood pressure (dBP) is related to maternal organ involvement in hypertension in pregnancy. Nicardipine (Nic) is the only available intravenous calcium channel blocker. We used the antihypertensive therapy of Nic as related to dBP. Step-wise protocols were developed starting with low dose Nic for treatment of hypertension in the antepartum/intrapartum period, postpartum period, and eclampsia. In this study, we examined the effect of Nic treatment in eclampsia which is the most hazardous disorder. Methods Eclampsia was diagnosed by MRI image. A group of 9 cases of “progressing disease” (PD) (relapse, prolonged loss of consciousness, brainstem and vasospasm lesions) was compared to 7 cases with no PD. Nic was started in low dose of 0.5 mg/h in the antepartum or intrapartum period, and 1.0 mg/h in the postpartum period. Our stepwise protocol was based upon dBP (not systolic blood pressure (sBP). Changes in blood pressure were studied between the two groups. Results Eclampsia was diagnosed by MRI image. A group of 9 cases of “progressing disease” (PD) (relapse, prolonged loss of consciousness, brainstem and vasospasm lesions) was compared to 7 cases with no PD. Nic was started in low dose of 0.5 mg/h in the antepartum or intrapartum period, and 1.0 mg/h in the postpartum period. Our stepwise protocol was based upon dBP (not systolic blood pressure (sBP). Changes in blood pressure were studied between the two groups. Conclusions Both groups of PD and no PD had severe hypertension. The PD group had significantly higher blood pressure than no PD. By our protocol we achieved below 140/90 mmHg after 6–12 h. We elucidate that the pre-ordered stepwise protocol using dBP and low dose Nic could accomplish the stable and effective antihypertensive treatment even in eclampsia. Disclosures O. Nakamoto: None. I. Mita: None. S. Nishimoto: None. K. Kajitani: None. K. Tanaka: None. H. Nakamura: None. C. Motohisa: None.

Clevidipine in acute heart failure: Results of the A Study of Blood Pressure Control in Acute Heart Failure—A Pilot Study (PRONTO)

Rapid blood pressure (BP) control improves dyspnea in hypertensive acute heart failure (AHF). Although effective antihypertensives, calcium-channel blockers are poorly studied in AHF. Clevidipine is a rapidly acting, arterial selective intravenous calcium-channel blocker. Our purpose was to determine the efficacy and safety of clevidipine vs standard-of-care intravenous antihypertensive therapy (SOC) in hypertensive AHF. This is a randomized, open-label, active control study of clevidipine vs SOC in emergency department patients with AHF having systolic BP ≥160 mm Hg and dyspnea ≥50 on a 100-mm visual analog scale (VAS). Coprimary end points were median time to, and percent attaining, a systolic BP within a prespecified target BP range (TBPR) at 30 minutes. Dyspnea reduction was the main secondary end point. Of 104 patients (mean [SD] age 61 [14.9] years, 52% female, 80% African American), 51 received clevidipine and 53 received SOC. Baseline mean (SD) systolic BP and VAS dyspnea were 186.5 (23.4) mm Hg and 64.8 (19.6) mm. More clevidipine patients (71%) reached TBPR than did those receiving SOC (37%; P = .002), and clevidipine was faster to TBPR (P = .0006). At 45 minutes, clevidipine patients had greater mean (SD) VAS dyspnea improvement than did SOC patients (-37 [20.9] vs -28 mm [21.7], P = .02), a difference that remained significant up to 3 hours. Serious adverse events (24% vs 19%) and 30-day mortality (3 vs 2) were similar between clevedipine and SOC, respectively, and there were no deaths during study drug administration. In hypertensive AHF, clevidipine safely and rapidly reduces BP and improves dyspnea more effectively than SOC.

Unsolved Issues in the Management of High Blood Pressure in Acute Ischemic Stroke

High blood pressure is common in acute stroke patients. Very high as well as very low blood pressure is associated with poor outcome. Spontaneous fall of blood pressure within the first few days after stroke was associated both with neurological improvement and impairment. Several randomized trials investigated the pharmacological reduction of blood pressure versus control. Most trials showed no significant difference in their primary outcome apart from the INWEST trial which found an increase of poor outcome when giving intravenous nimodipine. Nevertheless, useful information can be extracted from the published data to help guide the clinician's decision. Blood pressure should only be lowered when it is clearly elevated, and early after onset, reduction should be moderate but may be achieved rapidly. No clear recommendations can be given on the substances to use; however, care should be taken with intravenous calcium channel blockers and angiotensin receptor antagonists. Two ongoing randomized trials will help to solve the questions on blood pressure management in acute stroke.

Anaesthetic Management of Parturient with Acute Atrial Fibrillation for Emergency Caesarean Section

A 31-year-antenatal lady with critical mitral stenosis presented for emergency caesarean section with fetal distress. She had acute onset atrial fibrillation. She was given a combined spinal epidural (CSE) anaesthesia and her arrhythmia was successfully managed after delivery of the baby with intravenous calcium channel blocker. Mitral stenosis is the most common valvular heart disease complicating pregnancy in developing countries. The physiological changes during pregnancy may exacerbate their cardiac symptoms. They may present with complications like congestive cardiac failure, atrial fibrillation, or pulmonary thromboembolism during the antenatal, intrapartum, or postpartum period. Here we discuss the management of parturient woman with high maternal and fetal risk presenting for emergency caesarean. The merits of regional anaesthesia and the importance of invasive monitoring are also discussed.

Clevidipine: a state-of-the-art antihypertensive drug under the scope

Introduction: Clevidipine butyrate is the first intravenous antihypertensive drug to be approved by the FDA over the last decade. This medication is approved for use in the USA, Australia and New Zealand, but is still pending for approval in Europe. It is a new agent that might change the current management for severe acute hypertension in the critical care, emergency and perioperative areas.Areas covered: This systematic review summarizes the pharmacological and clinical characteristics of this third-generation dihydropyridine intravenous calcium channel blocker, and was done using the literature available from the first publication in 1999 up until now, including the pivotal trials that led to its approval.Expert opinion: This agent is arterially selective, has an ultrashort half-life, with no CYP-mediated interactions with other medications and is easily titratable. These characteristics place it in a unique category compared with other commonly used antihypertensives. Clevidipine butyrate reaches target systolic blood pressure in more than 90% of patients, within 30 min. It has a low incidence of adverse reactions and is generally well tolerated. The main goal of this review is to provide healthcare providers with a comprehensive appraisal of this promising medication.

Atrial Fibrillation with Rapid Ventricular Response following use of Dietary Supplement Containing 1,3 Dimethylamylamine and Caffeine

Our nation?s servicemembers commonly use dietary supplements to enhance their performance. Despite this prolific use, many of these products have detrimental side-effects that compromise servicemembers? health and could, by proxy, compromise a mission. This paper presents the case of a 32-year old Navy Special Operations Forces (SOF) Sailor who, prior to physical training, used a supplement containing 1,3 Dimethylamylamine (DMAA), and then developed atrial fibrillation with rapid ventricular response. He required intravenous calcium channel blocker administration, followed by beta blockers, for rate control. As military providers, we routinely ask our patients about their use of supplements and while the regulation of these products is beyond the scope of practice for most of us, it is our duty to become better educated about the risks and benefits of these supplements. We must educate our patients and our commands on the potential harm that these supplements may pose.

Role of clevidipine butyrate in the treatment of acute hypertension in the critical care setting: a review

Acutely elevated blood pressure in the critical care setting is associated with a higher risk of acute end-organ damage (eg, myocardial ischemia, stroke, and renal failure) and perioperative bleeding. Urgent treatment and careful blood pressure control are crucial to prevent significant morbidity. Clevidipine butyrate (Cleviprex) is an ultrashort-acting, third-generation intravenous calcium channel blocker. It is an arterial-selective vasodilator with no venodilatory or myocardial depressive effects. Clevidipine has an extremely short half-life of approximately 1 minute as it is rapidly metabolized by blood and tissue esterases. These metabolites are then primarily eliminated through urine and fecal pathways. The rapid onset and the short duration of action permit tighter and closer adjustment of the blood pressure than is possible with other intravenous agents.

A New Intravenous Calcium Channel Blocker Option to Treat Acute Elevations in Blood Pressure

Intravenous (IV) agents are needed to treat acute elevations in blood pressure (BP) in a number of different clinical settings including in the emergency department, perioperatively, and during hypertensive crises in the intensive care unit. IV agents are often needed to maintain BP within a narrow target range and many of the existing agents have a prolonged half-life, with overshooting of BP goals occurring frequently. IV agents available up to now have included a number of different agents with various advantages and adverse effects. For more than a decade, only one IV dihydropyridine calcium channel blocker (CCB), nicardipine, has been available for IV use for treatment of hypertension. Issues with IV dihydropyridine CCB delivery in the past include poor water solubility of this class and the reduction of pH in the 3.7 to 4.7 range with IV nicardipine, which may be part of the reason why changing the peripheral IV site every 12 hours is recommended in the package insert. Nicardipine is a second-generation IV dihydropyridine CCB. It is an effective antihypertensive; however, its major limitation is a longer half-life that precludes rapid titration. Its onset of action is within 10 to 15 minutes and its duration of action is 15 to 30 minutes but may exceed 4 hours. Clevidipine is a new third-generation IV dihydropyridine CCB that was recently approved by the US Food and Drug Administration in 2008 for treatment of severe hypertension. It reduces BP without affecting cardiac filling pressures or causing reflex tachycardia.1,2 The main advantage of this drug is that it has an ultra-short half-life of <1 minute.3 It exerts a rapid and titratable arterial BP reduction with fast termination of effect. It is an arterial selective vasodilator that reduces peripheral vascular resistance directly without causing venous capacitance dilation.4 BP reductions occur within 6 to 10 minutes and BP and heart rate return to baseline within 10 to 15 minutes after discontinuation of the drug. Rapid elimination of the drug is maintained after stopping either a long (24-hour) or short infusion.5 Clevidipine incorporates an easily hydrolyzable ester group into its chemical structure and, as a result, clevidipine is rapidly metabolized by the blood and tissue esterases independent of liver and kidney function.6 Esterase-based metabolism may also partially account for the lack of drug toxicity and little to no risk of cytochrome P450–associated drug toxicity.7 Clevidipine does result in a modest increase in heart rate from baseline, as has been shown with other IV CCB agents. Heart rate increases within the first 30 minutes of administration, but this appears to decrease back to baseline.8 The drug has been shown to be well tolerated without an increase in adverse side effects compared with placebo. Initial studies showed a slight increase in atrial fibrillation, but this has not been reproduced in subsequent studies. Clevidipine represents a new IV option for acute reduction in BP with an ultrashort half-life, therefore reducing the risk of overshooting BP targets.9 It has been shown in various studies to be effective in producing acute reductions in BP in the emergency department9 and perioperatively in cardiac surgery where maintenance of a narrow range of BP is required.1,10

Immediate Management of Atrial Fibrillation: State of the Art

During programmed stimulation cardiac arrhythmias are more commonly induced when the applied extrastimulus is near the refractory period. This was illustrated in a study by Wijffels [1] entitled “Atrial Fibrillation Begets Atrial Fibrillation.” In this experiment, a single extrastimulus applied to the right atrium of goats did not induce atrial fibrillation when applied at the atrial refractory period (127 msec). Using pacemaker techniques, atrial fibrillation was induced for 6 hours and an extrastimulus was reapplied. The atrial refractory period was shortened (104 msec) and short runs of atrial fibrillation were induced. With longer inductions of pacemaker induced atrial fibrillation, the atrial refractory period became shorter and induced atrial fibrillation lasted longer. The authors concluded that atrial fibrillation results in electrophysiologic changes of a shorter refractory period which promote the maintenance of atrial fibrillation. The reasons for this electrical remodeling are unclear however they can be reversed. If sinus rhythm is maintained for a week, the electrophysiologic changes return to normal. These results have important implications in the management of patients with acute atrial fibrillation. New onset atrial fibrillation is recognized in three general clinical categories. The first category represents the minority of patients with atrial fibrillation. These are patients who have a rapid ventricular response and hemodynamic compromise. Frequently these patients are brought to the hospital after experiencing dizziness, syncope or some other type of cardiac symptom requiring prompt attention. In these patients the immediate management is direct current cardioversion. In the second clinical setting, atrial fibrillation results in a rapid ventricular response but without hemodynamic compromise. These patients seek medical attention early in the course of symptoms and may complain of dizziness, chest pain, dyspnea, or palpitations. In these patients AV node blocking agents such as digoxin, beta blockers or calcium channel blockers are usually given. Whether oral or intravenous medications are given depends upon the clinical context. For patients with heart rates greater than 120–130 bpm or with patients with severe symptoms, intravenous diltiazem (20–25 mg bolus, 10–15 mg per hour) or intravenous esmolol (0.5 mg/kg over 1 minute followed by 0.05 to 0.1 mg/kg per minute) offer prompt control of the ventricular response in most cases [2,3] and are often preferred over oral agents. IV digoxin could also be considered in these cases but the onset of action is slower. A special case involves the patient with a preexcitation syndrome in which atrial fibrillation occurs with a rapid ventricular response. Direct current countershock is indicated in these patients if hemodynamic instability is present. However, for patients who hemodynamically stable, intravenous procainamide is the drug of choice. This drug slows conduction in the accessory pathway and may convert atrial fibrillation to sinus rhythm. Digoxin and intravenous calcium channel blockers may accelerate conduction across the accessory pathway and should be avoided in this situation. Intravenous procainimide should be given with caution since a main side effect is hypotension. Once the ventricular rate is controlled, the physician needs to determine if the patient should be converted to sinus rhythm. Many patients with atrial fibrillation of less than 48 hours will convert to sinus rhythm spontaneously. Other patients will convert to sinus rhythm while receiving digoxin, calcium blockers, or beta blockers. Although there are data suggesting that intracellular calciumlowering drugs (beta blockers and calcium channel blockers) may prevemt early recurrences of atrial fibrillation after electrical cardioversion [4], these drugs are administered primarily for rate control. Because of the high rate of spontaneous conversion to sinus rhythm, the success rates of antiarrythmic drugs must be evaluated in placebo controlled trials. (Table 1, references 5–9,11–13) Digoxin given in doses of 0.6, 0.4, 0.2 and 0.2 mg at 0, 4, 8, and 14 hours has been shown to convert 50% of patients with new onset atrial fibrillation by 18 hours. However 44% of placebo treated patients converted to sinus rhythm, not a significant difference. The atrial refractory period is shortened by digoxin which may be an undesirable

Part 6: Advanced Cardiovascular Life Support

Part 6: Advanced Cardiovascular Life Support

The use of calcium salts in the prevention and management of verapamil-induced hypotension.

To review the available literature on the use of intravenous calcium salts for the prevention of hypotension associated with intravenous verapamil. A MEDLINE search (1966-June 1999) identified pertinent articles; references from these articles were identified to serve as additional resources. Verapamil is effective in inhibiting atrioventricular nodal conduction, thereby controlling ventricular rate in patients with atrial fibrillation/flutter and terminating paroxysmal supraventricular tachycardia. However, hypotension may be caused by the negative inotropic and vasodilating effects of verapamil. In vitro and animal data suggest that calcium pretreatment may minimize the effects of verapamil on cardiac output and blood pressure. Case reports suggest that intravenous calcium may be useful for both prevention and reversal of the hemodynamic effects of verapamil. A number of small clinical trials have been performed, suggesting that calcium administered prior to intravenous verapamil results in a decreased incidence of hypotension. The most common adverse effect of intravenous calcium is flushing. Calcium pretreatment prior to intravenous calcium-channel blocker administration should be considered in patients in whom further reductions in blood pressure may precipitate hypoperfusion or worsen underlying cardiovascular status. A dose of calcium gluconate 1 g (ionized calcium 90 mg) administered over three minutes is recommended for preventing or lessening the hypotensive effect of verapamil without affecting the antiarrhythmic effects of verapamil.

Elevated transcranial Doppler flow velocities after severe head injury: cerebral vasospasm or hyperemia?

Sixty-seven patients (45 males and 22 females) aged 2 to 70 years (mean 36 years) who had suffered closed head injury were investigated with daily transcranial Doppler (TCD) recordings. A total of 470 TCD recordings (mean 7) were made during Days 1 to 14 after admission. Blood flow velocities were determined in the middle cerebral artery (MCA) and the extracranial internal carotid artery (ICA). Twenty-seven (40%) of the 67 patients demonstrated traumatic subarachnoid hemorrhage (tSAH) on the first computerized tomography (CT) scan after the injury. Flow velocities exceeded 100 cm/second in 22 patients. Eleven (41%) of the 27 patients who showed tSAH on the first CT scan developed velocities greater than 100 cm/second, as compared to 11 (28%) of 40 patients without tSAH on CT. Two patients in whom a thick layer of tSAH was revealed on the first CT scan had MCA flow velocities exceeding 200 cm/second for several days. Measurements of cerebral blood flow (CBF) with single-photon emission CT (SPECT) were performed in six tSAH patients who showed TCD flow velocities exceeding 120 cm/second (uni- or bilaterally) to determine whether the increase in velocity reflected vasospasm or hyperemia. The SPECT studies verified ischemia in five patients but revealed general hyperemia in one. The bilateral increase in MCA flow velocities in the latter case was due to high-volume flow through the MCA secondary to elevated CBF rather than arterial narrowing. In one patient with a thick layer of subarachnoid blood on a CT scan obtained at admission, MCA flow velocities exceeded 220 cm/second bilaterally on Day 8 after the head injury. A SPECT measurement obtained on the same day reflected bilateral ischemia. In this patient flow velocities decreased, with a corresponding normalization of CBF, after 5 days of intravenous nimodipine administration. The MCA/ICA ratio correlated well with the distribution of CBF in the six patients studied using SPECT. This report suggests that vasospasm is an important secondary posttraumatic insult in patients suffering severe head injury and, in some cases, is probably treatable by administration of intravenous calcium channel blockers.

Efficacy and Safety of Intravenous Nicardipine in the Control of Postoperative Hypertension: IV Nicardipine Study Group*

In a double-blind, randomized, multicenter study, the efficacy and safety of intravenous (IV) nicardipine was compared with placebo in the control of postoperative hypertension in cardiac and noncardiac surgical patients. One hundred twenty-two patients (17 cardiac and 105 noncardiac surgery) met the entry criteria (systolic BP greater than or equal to 140 mm Hg or diastolic BP greater than or equal to 95 mm Hg) and were randomized (3:2) to receive IV nicardipine (n = 71) or placebo (n = 51). Therapeutic response (greater than or equal to 15 percent reduction in BP from baseline) was achieved in 94 percent of patients treated with IV nicardipine vs 12 percent with placebo (p less than 0.001). The mean response time and infusion rate for IV nicardipine were 11.5 (+/- 0.8) minutes and 12.8 (+/- 0.3) mg/h, respectively. The magnitude of BP reduction was similar in both cardiac and noncardiac postsurgical patients. Blood pressure control was sustained with minimal dose adjustments of IV nicardipine (3.0 +/- 0.2 mg/h) during a prolonged maintenance infusion period of 6.8 +/- 0.5 h. A reflex mean increase in heart rate of 5 bpm was seen in patients treated with IV nicardipine. Sixteen patients (15 noncardiac and one cardiac surgery) had a sustained heart rate of greater than 100 bpm, with a mean increase of 24 bpm from the baseline. In all these patients except three, tachycardia was resolved while receiving nicardipine. None of these patients who had development of tachycardia during nicardipine therapy had exhibited ST segment changes indicative of ischemia. One patient with tachycardia at baseline had exhibited ST segment depression (3 to 4 mm) during nicardipine treatment, which was resolved following discontinuation of nicardipine therapy and application of nitroglycerin (Nitropaste). Hemodynamic evaluation revealed that IV nicardipine significantly decreased mean arterial pressure, systemic vascular resistance, and significantly increased cardiac index with no change in heart rate. These hemodynamic changes were similar in cardiac and noncardiac surgical patients. Adverse experiences reported with IV nicardipine included hypotension (4.5 percent), tachycardia (2.7 percent), and nausea/vomiting (4.5 percent). In the placebo group, the incidence of adverse experience was 6 percent, with an equal distribution of hypotension (2 percent), nausea/vomiting (2 percent), and headache (2 percent). No clinically important changes in laboratory variables related to IV nicardipine were reported. In conclusion, these findings indicate that nicardipine, a titratable intravenous calcium channel blocker, can rapidly and effectively control postoperative hypertension in cardiac and noncardiac surgical patients.

Effect of intravenous calcium channel blockers on cardiac performance, cardiac metabolism and coronary blood flow following CABG surgery

Effect of intravenous calcium channel blockers on cardiac performance, cardiac metabolism and coronary blood flow following CABG surgery