Calcium Channel Blockers in Acute Care: The Links and Missing Links Between Hemodynamic Effects and Outcome Evidence

Abstract

Calcium channel blockers (CCBs) exert profound hemodynamic effects via blockage of calcium flux through voltage-gated calcium channels. CCBs are widely used in acute care to treat concerning, debilitating, or life-threatening hemodynamic changes in many patients. The overall literature suggests that, for systemic hemodynamics, although CCBs decrease blood pressure, they normally increase cardiac output; for regional hemodynamics, although they impair pressure autoregulation, they normally increase organ blood flow and tissue oxygenation. In acute care, CCBs exert therapeutic efficacy or improve outcomes in patients with aneurysmal subarachnoid hemorrhage, acute myocardial infarction and unstable angina, hypertensive crisis, perioperative hypertension, and atrial tachyarrhythmia. However, despite the clear links, there are missing links between the known hemodynamic effects and the reported outcome evidence, suggesting that further studies are needed for clarification. In this narrative review, we aim to discuss the hemodynamic effects and outcome evidence for CCBs, the links and missing links between these two domains, and the directions that merit future investigations.

FormalPara Key Points
Despite some clear links, there are many missing links between the hemodynamic effects exerted by calcium channel blockers and the outcome evidence associated with their clinical use.
These missing links suggest future research directions.

Introduction

Since the discovery of calcium channel blockers (CCBs) in the mid-1960s [1], they have been widely used or investigated for the treatment of hypertension, angina pectoris, cardiac arrhythmias, left ventricular diastolic dysfunction, Raynaud’s phenomenon, migraine, esophageal spasm, and bipolar disorder [2]. These medical conditions are characterized by a chronic course and are typically managed by doctors specializing in a non-acute care setting. In contrast, CCBs are also widely used in emergency departments, intensive critical units, and perioperative environments, all of which are distinguished by the rapidity of disease onset, the severity of the patient’s condition, and the intensity of the care needed.

The scenarios in acute care in which CCBs are typically used include aneurysmal subarachnoid hemorrhage (aSAH), intracerebral hemorrhage, acute myocardial infarction, hypertensive crises, and surgery under general anesthesia. These conditions frequently involve drastic systemic or regional hemodynamic changes. Hemodynamics is the magnitude and efficiency of blood circulation in the cardiovascular system and through different tissue beds. Its management is a crucial task in acute care. Although a complicated concept, hemodynamics can be pragmatically viewed as a ladder involving seven essential steps: intravascular volume, preload, cardiac output (CO), blood pressure (BP), organ perfusion, oxygen delivery, and tissue oxygen consumption–supply balance (Fig. 1) [3]. Although the effects of CCBs on BP are well-known, their effects on other hemodynamic aspects are less familiar to most physicians or care providers. Arguably, the effects of CCBs on organ perfusion and tissue oxygenation may be more essential than those on BP since the purpose of BP is to drive blood flow for organ perfusion and tissue oxygen supply. Therefore, it is apposite to specifically and comprehensively review the hemodynamic effects of CCBs in acute care.

Fig. 1
figure1

The common effects of CCBs on hemodynamics and the cardiovascular system. The hemodynamics is conceptualized as a ladder construct [3]. CCBs calcium channel blockers, CO cardiac output, HR heart rate, PA pressure autoregulation, SV stroke volume, SVR systemic vascular resistance, ↑ denotes increase, ↓ denotes decrease, ↔ denotes inconsistent results

On the other hand, we cannot overlook the endpoint of medicine when talking about science and applying it in medicine. The endpoint of medicine is a favorable patient outcome. No matter how rational an intervention appears scientifically, it must be judged by its impact on patient outcomes. The same principle applies to the use of CCBs in acute care. No matter how desirable a hemodynamic effect exerted by a CCB appears, the appropriateness of its administration needs to be appraised by the outcome evidence.

The aims of this narrative review are to (1) review the hemodynamic effects of CCBs, (2) summarize the outcome evidence related to their use in acute care, and (3) discuss the links and missing links between the hemodynamic effects and outcome evidence for CCBs. This review does not review the discovery, development, and clinical use of CCBs in chronic settings as they have already been discussed [1, 2, 4,5,6].

Two Pharmacologic Classes of CCBs

The CCBs are divided pharmacologically into dihydropyridines and non-dihydropyridines:

  • The dihydropyridines are primarily vasodilators and differ in their time to onset and duration. Clevidipine is a rapid-onset, short-acting intravenous drug, making it highly titratable [7]. Nicardipine is also intravenous but longer acting and less rapidly titratable as a result. Nifedipine, nimodipine, isradipine, and amlodipine are longer acting, predominantly enteral dihydropyridines.

  • The non-dihydropyridines are less vasodilatory and predominantly atrioventricular (AV) nodal blockers. The predominant drugs are diltiazem and verapamil. Both are available in parenteral and enteral formulations.

Hemodynamic Effects of Calcium Channel Blockers (CCBs)

In this discussion, we differentiate hemodynamics and the cardiovascular system because these two concepts are related but different. Hemodynamics, defined as the magnitude and efficiency of blood circulation in the cardiovascular system and through different tissue beds, is the result of the work by the cardiovascular system. Before the discussion on the hemodynamic effects of CCBs, we first briefly review their effects on the cardiovascular system.

Effects of CCBs on the Cardiovascular System

CCBs exert direct, drug- and dose-dependent, mostly negative inotropic, mostly negative dromotropic (AV node conduction speed) and mostly positive chronotropic effects in humans (Table 1 in the Electronic Supplementary Material [ESM]) and animals (Table 2 in the ESM) [8,9,10]. For example, verapamil and diltiazem but not nifedipine prolong AV conduction [9, 11, 12]. The depressive effect on cardiac performance is more profound for nifedipine than for nicardipine [13]. Different CCBs have different heart rate (HR)-accelerating effects (e.g., nifedipine > verapamil > diltiazem) [9].

Table 1 The links and missing links between the hemodynamic effect of calcium channel blockers and outcome evidence

The use of CCBs does not normally increase myocardial oxygen consumption [14,15,16,17,18,19,20]. Nifedipine is three to ten times more potent for inhibiting coronary artery smooth muscle contraction than myocardial contraction [21, 22], a property that allows CCBs to dilate coronary arteries at doses that do not significantly suppress myocardial performance. Both properties appear advantageous during the treatment of acute myocardial infarction or unstable angina.

The direct effects of CCBs on the cardiovascular system are modulated, in a drug-dependent fashion, by the vasodilation-induced and baroreceptor-mediated autonomic reflex responses [9, 10, 21, 23, 24]. In conscious dogs, nifedipine causes tachycardia primarily via sympathetic activation, and verapamil causes tachycardia primarily via vagal withdrawal, whereas diltiazem causes tachycardia via the interplay between sympathetic activation and vagal withdrawal [9]. This is supported by the observation that nifedipine, but not verapamil, causes a transient increase in plasma renin activity and a tendency to increase plasma catecholamines in human subjects [25]. When chronically administered, verapamil may suppress sympathetic activity, as suggested by decreases in resting HR and plasma norepinephrine levels [26].

In summary, the cardiovascular effects of CCBs are diverse; varying; dependent on drug, dose, course, and condition; and the result of complex interplays between direct and indirect effects.

Effects of CCBs on Systemic Hemodynamics

Systemic hemodynamics refers to the global and overall magnitude and efficiency of blood circulation and is typically measured by parameters including BP, CO, and systemic vascular resistance (SVR) (Fig. 1).

CCBs decrease SVR as a result of arteriolar vasodilation; however, they normally maintain or increase CO in humans (Table 1 in the ESM) and animals (Table 2 in the ESM). These facts imply that the effects of CCBs on SVR prevail over their effects on CO, otherwise, CCBs would not be able to decrease BP because BP is proportional to CO and SVR (BP ~ CO × SVR). CO is the product of stroke volume (SV) and HR; therefore, to understand the effect of a CCB on CO, we need to first understand its effect on SV and HR. However, this may vary among patients. For example, in a healthy patient with laparoscopic hysterectomy, the use of intravenous nicardipine led to a significant increase in HR without significantly affecting SV, and—as a result—CO increased (Fig. 2). Of note, this patient’s BP had a significant drop following nicardipine administration, as a result of the much more significant decrease in SVR compared with the increase in CO, otherwise, BP would not significantly drop (also refer to the video in the ESM).

Fig. 2
figure2

Effects of nicardipine on hemodynamics in an otherwise healthy anesthetized 47-year-old woman undergoing laparoscopic hysterectomy. The timing of nicardipine administration is indicated by the red and yellow arrows. The recorded hemodynamic parameters include a BP (black belt with the upper and lower edges as systolic and diastolic BP and the red line within as the mean BP) and SVR (green belt), b CO (red belt), c SVV (blue tracing), d HR (pink tracing) and SV (blue belt), and e SmtO2 monitored on the flank (light blue tracing) and forearm (light green tracing). Systemic hemodynamics were continuously monitored using a LiDCO monitor (LiDCO Group, London, UK), whereas SmtO2 was continuously monitored using a FORE-SIGHT Elite tissue oximeter (CAS Medical Systems Inc., Branford, CT, USA). Nicardipine infusion (3 mg/h) led to an evident decrease in BP and SVR, an increase in HR and CO, and a minimal effect on SVV and SV. Its administration caused an evident increase in forearm SmtO2, which was most likely secondary to an increase in forearm blood flow. The increase in forearm blood blow was likely due to the prevailing decrease in SVR over BP, which can be alternatively explained as a result of an increased CO leading to an increased share of CO by the forearm (consent for presenting this information was obtained from this patient). BP blood pressure, CO cardiac output, HR heart rate, SmtO2 muscular tissue oxygen saturation, SV stroke volume, SVR systemic vascular resistance, SVV stroke volume variation

However, it is important to emphasize that the effects of CCBs on systemic hemodynamics are dependent on drug, disease, and anesthetic. For example, diltiazem reduces CO in normotensive humans, an effect that is likely secondary to a decrease in SV without a significant increase in HR [27], and this differs from the effects observed for most CCBs (i.e., a rare exception). The doses of verapamil and nifedipine that decrease BP in hypertensive humans have minimal effect on BP in normotensive humans [25]. The effect of verapamil on CO differs between conscious [28] and anesthetized dogs [29].

Effects of CCBs on Regional Hemodynamics

Regional hemodynamics refers to the magnitude and efficiency of blood circulation through different organs and tissue beds (Fig. 1). The overall evidence suggests that the blood flow for most organs, including the brain [30], heart [31], kidney [32], gut [33], and skeletal muscle [34], is augmented following the administration of CCBs (Tables 1 and 2 in the ESM). This is corroborated by the increased muscular tissue oxygenation following intravenous nicardipine administration in anesthetized surgical patients (Fig. 2).

Regional hemodynamics share a close analogy with Ohm’s law, i.e., blood flow is proportional to perfusion pressure and inversely proportional to flow resistance. It can be inferred that, although CCBs decrease both perfusion pressure and flow resistance, the decrease in flow resistance prevails over the decrease in perfusion pressure, and blood flow is increased as a result. An alternative perspective is that regional blood flow accounts for a percentage or share of CO, so because CO normally increases following the administration of CCBs, the blood flow to most organs is accordingly increased.

The effects of CCBs on regional hemodynamics are dependent on drug [9], organ [35], disease [36], and anesthesia [37]. For example, different CCBs increase coronary blood flow differently: nifedipine > diltiazem = verapamil [9]. Additionally, nicardipine increases cerebral blood flow, whereas diltiazem does not [38].

Effects of CCBs on Pressure Autoregulation

Perfusion pressure is one of the factors that determines organ blood flow. However, due to the corresponding change in flow resistance, a change in perfusion pressure may not always lead to a change in blood flow. This phenomenon is embodied in pressure autoregulation (PA), a mechanism that upholds stable organ blood flow despite changes in perfusion pressure [39]. Impaired PA renders organ blood flow pressure-passive and less tolerant to perfusion pressure fluctuations. Multiple factors related to the patient, disease, physiology and medications affect PA [39,40,41]. Before discussing the effects of CCBs on PA, it is prudent to first briefly review the mechanism underlying PA, although it is complicated and remains to be fully elucidated.

Among different theories, the myogenic response of arteriolar smooth muscle to intravascular pressure changes is likely to be principally responsible for PA [42,43,44,45,46]. The core of the myogenic response revolves around calcium flux and function (Fig. 3), and the following are key events in arteriolar constriction: (1) an increase in intravascular pressure depolarizes arteriolar smooth muscle cells via mechanisms that are incompletely understood; (2) this depolarization opens voltage-gated calcium channels, leading to calcium influx; (3) the calcium residing in sarcoplasmic reticulum is subsequently mobilized; (4) calcium and calmodulin combine and activate myosin light chain kinase; (5) myosin light chain kinase phosphorylates myosin light chains; and (6) the interaction between myosin and actin results in vasoconstriction [42, 43, 47,48,49,50].

Fig. 3
figure3

Illustration of Ca2+ dynamics in a vascular smooth muscle cell. An extracellular supply of Ca2+ is required for the maintenance of arteriolar vasomotor tone and myogenic response. An increase in intraluminal pressure or a stretch causes vascular smooth muscle cell membrane depolarization and Ca2+ influx via VGCCs. How a stretch is sensed by vascular smooth muscle cells and coupled to the events that ultimately lead to contraction is incompletely understood. It may involve the activation of mechanosensitive ion channels, the activation of membrane-bound enzymes, or the modulation of the cytoskeleton [135]. Mechanical forces may be transmitted from the extracellular matrix to the cytoskeleton via cell surface receptors such as integrins to regulate ion channels and other signaling pathways [136]. It is likely that several underlying mechanosensitive mechanisms are operative and contribute to myogenic responses in an integrated manner. The negative feedback is exemplified by K+ currents, which act to attenuate stretch-induced changes in membrane potential [137]. Intraluminal pressure and smooth muscle cell membrane potential are closely related. The release of Ca2+ from internal stores (e.g., SR) also contributes to the increase in free intracellular Ca2+. The free Ca2+ binds to calmodulin, and Ca2+-calmodulin complexes activate MLCK, an enzyme that phosphorylates MLCs in the presence of ATP. MLC phosphorylation leads to cross-bridging between myosin heads and actin filaments and subsequent smooth muscle contraction. Additional regulatory mechanisms participate in controlling smooth muscle contraction. Such mechanisms include the modulation of Ca2+ sensitivity, the Ca2+-mediated regulation of ion channels, the refilling of intracellular Ca2+ stores, and the regulation of Ca2+ sequestration and extrusion. The degree of MLC phosphorylation is regulated by G-protein-coupled signal transduction pathways and the nitric oxide-mediated activation of guanylyl cyclase and cGMP formation. Gq-protein activation by norepinephrine (α1-adrenoceptors), angiotensin II (AT1 receptors), endothelin-1 (ETA receptors), or vasopressin (V1 receptors) stimulates the release of calcium (IP3-mediated) from SR and activates Rho-kinase, which inhibits MLC phosphatase. Both of these mechanisms enhance contraction. Gs-protein activation by epinephrine (β2-adrenoceptors), adenosine (A2 purinergic receptors), or prostacyclin (IP receptors) increases cAMP, which inhibits MLCK, reducing MLC phosphorylation and leading to relaxation. Gi-protein activation by norepinephrine elicits contraction by reducing cAMP, which increases the activity of MLCK. (Referenced to the figure published by Richard E. Klabunde, PhD at https://cvphysiology.com/Blood%20Pressure/BP026 with permission and revision). ATP adenosine triphosphatase, Ca2+ calcium, cAMP cyclic adenosine monophosphate, cGMP cyclic guanosine monophosphate, MLC myosin light chains, MLCK myosin light chain kinase, SR sarcoplasmic reticulum, VGCC voltage-gated calcium channel

Given the pivotal role played by calcium in the myogenic response, it is intuitive to infer that CCBs can disrupt PA. Indeed, this adverse effect has been substantiated by multiple studies performed in rats [51, 52], dogs [53, 54], baboons [55], and humans [56, 57]. Most studies focused on renal PA, which is significantly impaired in dogs by verapamil [54], diltiazem [58, 59], nifedipine [54], and amlodipine [60] (both dihydropyridines and non-dihydropyridines). The afferent glomerular arteriole is likely the vessel principally targeted by CCBs [61, 62]. It is worth noting that CCBs appear to be the only class of antihypertensives that impair renal PA [61]. Diltiazem and nimodipine impair cerebral PA in dogs [63] and baboons [55], respectively. Nicardipine impairs cerebral PA in conscious [46, 56] and anesthetized [57] adult patients. Diltiazem impairs coronary PA in pigs [64].

It is possible that organ blood flow could be critically reduced after the administration of a CCB because of the coincidental occurrence of BP decrement and PA impairment. However, the majority of the evidence suggests that CCBs increase organ blood flow. These extrapolations seem conflicting. It is possible that, following CCB administration, the plateau of PA tilts but also shifts upwards to a level with increased organ blood flow; as a result, organ blood flow following CCB administration is greater than that before CCB administration despite decreased BP and impaired PA (Fig. 4).

Fig. 4
figure4

Effects of CCBs on PA. CCBs impair PA, with the lower limit shifted leftward and the plateau elevated, sloped, and shortened [58, 59, 64, 138, 139], The green and red lines are the autoregulatory plots before and after CCB administration, respectively. The green and red circles illustrate the OPP and OBF before and after CCB administration, respectively. CCB administration leads to a decrease in OPP but an increase in OBF. CCB calcium channel blocker, OBF organ blood flow, OPP organ perfusion pressure, PA pressure autoregulation

The Outcome Evidence Related to CCB Application in Acute Care

CCBs have been used in various settings in acute care. In this section, we review the outcome evidence related to the application of CCBs in these settings (Table 3 in the ESM).

Aneurysmal Subarachnoid Hemorrhage

Vasospasm, delayed cerebral ischemia, and rebleeding are serious complications after aSAH [65,66,67]. Although the pathogenesis of vasospasm, a grave complication, remains incompletely understood, it is probably a contributing factor to secondary cerebral ischemia [67]. Theoretically, CCBs are ideal treatments both early and later after aSAH. Early on, they decrease BP, an effect that may reduce the frequency and severity of rebleeding prior to open or endovascular obliteration of the aneurysm; later on (days after the ictus of the hemorrhage), they augment cerebral blood flow, an effect that may counter secondary ischemia in the setting of cerebral vasospasm.

Indeed, it is suggested by multiple randomized controlled trials that the use of CCBs, and oral nimodipine in particular, improves post-aSAH outcome (Table 3 in the ESM). A meta-analysis based on 3361 patients from 16 trials showed that CCBs reduced the risk of the within-6-month poor outcomes, defined as death or dependence on help for activities of daily life (relative risk 0.81; 95% confidence interval [CI] 0.72–0.92) [67]. This benefit was drug and route dependent, i.e., it was oral nimodipine and not intravenous nimodipine or other CCBs that were outcome favorable [67]. American Heart Association (AHA)/American Stroke association (ASA) guidelines recommend that oral nimodipine should be given to all patients with aSAH (class I recommendation), although the evidence for this recommendation is not incontrovertible [68].

Although oral nimodipine improves neurological outcome, there is a “mysterious” lack of robust evidence for its efficacy in reversing cerebral vasospasm and augmenting cerebral blood flow [69, 70]. One study showed that although 3-month outcomes were improved, oral nimodipine actually mildly lowered cerebral blood flow in patients with aSAH [71, 72]. This is in contrast to the results of studies performed in patients with acute ischemic stroke, in whom intravenous nimodipine therapy caused a dose-dependent increase in hemispheric cerebral blood flow [73]. One prospective study suggested that some patients with acute ischemic stroke may benefit from oral nimodipine treatment [74]. However, the VENUS (Very Early Nimodipine Use in Stroke) trial, performed primarily in patients with ischemic stroke, was terminated early because an interim analysis showed a nil effect on survival and functional outcomes [75]. This trial highlights that outcome evidence rather than hemodynamic effect must guide clinical practice.

Cerebral PA is frequently impaired after aSAH [76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]. How impaired cerebral PA is affected by CCBs (i.e., worsened vs. improved vs. no effect) remains controversial. After aSAH, nimodipine improved cerebral PA in rats [92], exerted minimal effect on cerebral PA in baboons [93, 94], and did not affect cerebral PA in patients [95]. Abundant evidence shows a close association between impaired cerebral PA and unfavorable outcomes after aSAH [78,79,80,81,82,83,84,85,86,87,88,89,90,91]. However, at this time, whether clinical outcomes in patients with aSAH can be improved by interventions that improve cerebral PA remains unknown [96].

Oral nimodipine improves clinical outcome after aSAH. However, there are missing links between what we have learned about the hemodynamic effects of CCBs and the outcome evidence in this patient population.

Acute Myocardial Infarction or Unstable Angina

Physiologically, CCBs that lack a prominent HR-accelerating effect (verapamil and diltiazem) are more suitable in treating acute myocardial infarction or unstable angina than CCBs that have prominent HR-accelerating effects (dihydropyridines). However, diltiazem and verapamil have not been found to have a beneficial effect on long-term major events although they provide symptomatic relief [97]. The aggregation of data from 19,000 patients included in 28 randomized trials concluded that, when given routinely for unstable angina or after acute myocardial infarction, CCBs did not reduce the risk of initial or recurrent infarction or death [98].

Oral non-dihydropyridine CCBs are reasonable choices after β-blockers and nitrates have been fully used in patients with recurrent ischemia and without contraindications [99]. When combining a β-blocker and a CCB for refractory ischemic symptoms, greater caution is needed because they synergistically depress pump function and prolong sinus and AV node conduction [100, 101]. American College of Cardiology (ACC)/AHA guidelines recommend using verapamil or diltiazem in patients with unstable angina and the closely related condition, non–ST-segment elevation myocardial infarction, under the following circumstances: (1) ischemia continues or frequently recurs; (2) β-blockers are not successful, are contraindicated, or cause unacceptable side effects; and (3) there is an absence of clinically significant left ventricular dysfunction, increased risk for cardiogenic shock, PR interval > 0.24 s, or second- or third-degree AV block without a cardiac pacemaker (class I recommendation) [99].

In summary, verapamil and diltiazem (non-dihydropyridines) can be used to treat unstable angina or non–ST-segment elevation myocardial infarction; however, their use should be carefully considered, and the therapeutic effect is limited to symptom control. Their favorable hemodynamic effects, i.e., dilating stenotic coronary segments and lacking prominent HR-accelerating and myocardial oxygen consumption-increasing effects [102, 103], do not translate into an outcome benefit in this patient population, another example of the missing links between the hemodynamic effects of CCBs and outcome evidence.

Hypertensive Crisis in Nonsurgical Patients

Hypertensive crisis encompasses a heterogeneous group of acute hypertensive disorders that mandate prompt recognition and treatment to prevent or limit end-organ damage. This condition is further classified as hypertensive emergency or hypertensive urgency depending on the presence/absence of acute hypertensive end-organ injury [104,105,106]. Approximately 1% of patients with essential hypertension will develop a hypertensive crisis at some point [107]. A variety of parenteral and oral antihypertensive drugs are available for the treatment of hypertensive crisis. Although these agents are tolerated reasonably well, their efficacy and safety have not been substantially compared with one another [108]. As a result, the drug of choice is often dictated by the type of hypertensive emergency and the local hospital formulary.

Hypertensive emergency requires immediate BP reduction using short-acting, titratable, intravenous agents in an acute care setting in which patients can be closely monitored [107]. Based on ten studies performed in patients with hypertensive crisis across an array of settings (stroke, the emergency department, critical care, surgery, pediatrics, and pregnancy), intravenous nicardipine and labetalol appear to have comparable efficacy and safety profiles, although nicardipine provides more predictable and consistent BP control than labetalol [109]. In the emergency department, patients with hypertensive crises are more likely to reach the physician-specified BP target range within 30 min when treated with intravenous nicardipine than with intravenous labetalol [110], and this pattern is not affected by the presence of renal dysfunction [111] or suspected end-organ damage [112]. In the intensive care unit, intravenous nicardipine, compared with intravenous labetalol, appears more effective and results in less hypotension and bradycardia or AV block in unselected patients with acute hypertension [113].

Hypertensive urgency is often treated with oral agents. Oral nifedipine retard (a slow-release formulation) is recommended as a first-line therapy for hypertensive urgencies based on its more gradual and predictable BP-lowering property [105]. Although oral nimodipine is a practical alternative [114], it is labetalol that is recommended for the treatment of hypertension in patients with preeclampsia [105]. The most recent study showed that, although oral nifedipine retard, labetalol, and methyldopa reduced BP to the reference range in most pregnant women, the use of nifedipine retard as single drug resulted in a greater frequency of primary outcome attainment than the use of labetalol or methyldopa [115]. Newer agents, such as clevidipine (a short-acting dihydropyridine CCB), may hold considerable advantages over other agents in the management of hypertensive crisis; however, it should be used cautiously given the lack of robust outcome evidence [107, 116].

In summary, certain CCBs are among the choices of drugs for the treatment of hypertensive crisis; intravenous nicardipine can effectively and safely lower BP in patients with hypertensive emergency, whereas oral nifedipine retard is recommended as a first-line therapy for hypertensive urgency, especially for pregnant women. The long-term outcomes associated with the type of pharmacologic treatment of hypertensive crisis have not been reported.

Hemodynamic Management in Perioperative Care

Hemodynamic management is an essential task in perioperative care because anesthesia and surgery can adversely affect hemodynamics, and there appears to be a close association between suboptimally managed hemodynamics and adverse outcomes in surgical patients [3, 117]. CCBs are of particular relevance in this setting because of their profound impacts on systemic and regional hemodynamics.

Hypertension frequently complicates the perioperative course. Following coronary artery bypass grafting, BP is frequently unfavorably high and should be lowered; however, this should be done without compromising myocardial perfusion. Nicardipine and isradipine are the antihypertensive agents of choice in this setting because, compared with sodium nitroprusside, they augment CO and coronary blood flow without adversely increasing myocardial oxygen consumption [118,119,120]. In patients undergoing craniotomy, nicardipine is superior to esmolol [121] but has efficacy comparable to that of labetalol [122] in the treatment of hypertension during the emergence of anesthesia. Dissimilar from nitroprusside [123] and urapidil [124], nicardipine and labetalol do not normally raise intracranial pressure (ICP) [122], a property favorable to neurosurgical patients. These desirable effects on ICP stem from the fact that the dihydropyridines are selective arterial vasodilators, not venodilators, unlike the nitrates [125, 126].

Atrial tachyarrhythmia, a common complication after thoracic surgery, is associated with significant morbidity, longer hospitalization, and higher costs [127]. CCBs, particularly the non-dihydropyridines verapamil and diltiazem, reduce the risk of atrial tachyarrhythmia based on aggregate data from four trials (relative risk 0.50; 95% CI 0.34–0.73) [127].

It is common to encounter patients with heart failure, a complex clinical syndrome resulting from structural or functional impairments of ventricular filling or pumping, in the perioperative setting [128]. Heart failure is classified as systolic heart failure (i.e., heart failure with a reduced ejection fraction [EF < 40%]) or diastolic heart failure (i.e., heart failure with a preserved EF [> 50%]) [129]. CCBs are not recommended as routine treatment in patients with systolic heart failure since they provide no functional or mortality benefit and some first-generation agents may worsen outcomes [129]. In contrast, in patients with diastolic heart failure, CCBs may be useful in the perioperative management of hypertension by maintaining filling pressure and avoiding tachycardia [128]; however, there is currently a lack of robust evidence attesting to this speculated application.

CCBs clearly play an important role in the management of perioperative hemodynamics. However, their effects should also be tested with regard to long-term outcomes and not just BP control and atrial tachyarrhythmia reduction limited to the immediate perioperative period. It needs to be noted that when BP is decreased following intravenous nicardipine administration, tissue oxygenation is increased in anesthetized surgical patients (Fig. 2); whether this hemodynamic effect can be translated into an outcome benefit remains to be tested, another example of the missing links between the hemodynamic effects of CCBs and outcome evidence.

Safety Profile and Side Effects Associated with CCBs

As with all drugs, CCBs have both therapeutic effects and side effects. The dihydropyridine CCBs may lead to tachycardia, headache, lightheadedness, flushing, and dose-dependent peripheral edema in as many as 20–30% of patients [130]. The non-dihydropyridines can cause dose-dependent constipation, which may occur in as many as 25% of patients, as well as bradycardia and worsening CO [2]. In terms of mortality and major cardiovascular events, previous studies present somewhat conflictive findings associated with the chronic use of CCBs for hypertension treatment [5, 6, 131,132,133]; however, the evidence based on chronic care may not be generalizable to patients requiring acute care. Nonetheless, safety concerns have been raised regarding the use of CCBs in acute care. For example, the once popular use of oral (sublingual) nifedipine in the treatment of hypertensive emergencies was put on moratorium because of the seriousness of reported adverse events (such as stroke, acute myocardial infarction, and death) and a lack of clinical documentation attesting to a benefit [134].

The Links and Missing Links Between the Hemodynamic Effects of and Outcome Evidence for CCBs

CCBs have distinct hemodynamic properties. Systemically, they normally decrease BP while increasing CO; regionally, they normally increase organ blood flow and tissue oxygenation but decrease perfusion pressure and impair PA. Although CCBs impair PA of organ blood flow, they may not worsen or may actually improve the impaired cerebral PA in patients with aSAH. Overall, the hemodynamic profile of CCBs is diverse but appears advantageous in situations where CO and tissue perfusion are in jeopardy.

Indeed, CCBs are widely used in acute care involving drastic changes in hemodynamics or the cardiovascular system. Highlighted uses include the use of oral nimodipine in aSAH, the conditional use of verapamil and diltiazem for symptom control in acute myocardial infarction or unstable angina, the use of intravenous nicardipine for hypertensive emergency and perioperative hypertension, the use of oral nifedipine retard for hypertensive urgency, and the use of verapamil and diltiazem for the prevention or treatment of atrial tachyarrhythmia after thoracic surgery.

However, there are missing links between what we know about the hemodynamic effects of CCBs and what we have learned about their outcome evidence (Table 1). For example, although oral nimodipine improves post-aSAH outcomes, there is no evidence showing improved cerebral blood flow following its administration. Although verapamil and diltiazem appear to have advantageous coronary circulation profiles, their use in acute myocardial infarction or unstable angina is limited to symptom control if there are no contraindications and β-blockers and nitrates have been fully used but ineffective. Although intravenous nicardipine is effective in controlling BP in patients with hypertensive emergency or perioperative hypertension, there is a lack of evidence showing its long-term benefit.

The potential causes for these missing links are multifold. First, pure hemodynamic research has limitations because, being normally conducted in small homogeneous samples and under strictly controlled conditions, pure hemodynamic research tends to be explanatory only, i.e., not pragmatic and reflective of the complicated real-world patient care. Second, the wellbeing of hemodynamics is important; however, the outcome is not all about hemodynamics. Third, hemodynamics is far more complicated than most people think. Using BP for hemodynamic management in every patient is likely an oversimplified and inadequate approach. We need to be cautious in that our knowledge about hemodynamics may still be too superficial or the knowledge may have been inadequately disseminated or applied. Fourth, we have neither a means to reliably and practically monitor hemodynamics (not just BP but also CO and tissue perfusion) nor to routinely or selectively use a hemodynamic monitor that provides valuable information in a particular patient. Fifth, we may have set incorrect hemodynamic goals, including the parameters to be prioritized and the thresholds beyond which intervention should be instituted. Sixth, we may be overlooking important side effects associated with the CCBs used to achieve the therapeutic goals.

Future efforts should focus on improving the technology used for hemodynamic measurement. Hemodynamics is not only BP and HR (the “vital signs”); we also need to pay due attention to flow-oriented parameters, including CO, organ perfusion, and tissue oxygenation. This requires a hemodynamic monitor that is accurate, precise, cost sensitive, non- or minimally invasive, and provides continuous bedside measurement. It is intriguing to see improved CO and tissue oxygenation in the face of decreased BP following nicardipine administration in anesthetized patients (Fig. 2). The question is whether this hemodynamic effect can be translated into outcome benefits. The use of a CCB based on favorable hemodynamic properties should be tested by outcome evidence. Future trials are needed to determine when improved organ perfusion equals improved patient outcome.

Conclusions

CCBs are a class of heterogeneous pharmacological agents that exert profound impacts on both systemic and regional hemodynamics. Although CCBs decrease BP and impair PA, they commonly increase CO, organ perfusion, and tissue oxygenation. There exists promising evidence attesting to the therapeutic efficacy and outcome benefits following CCB administration in acute care, including aSAH, acute myocardial infarction, unstable angina, hypertensive crisis, perioperative hypertension, and atrial tachyarrhythmias. There are physiological rationales supporting the use of CCBs in acute care; however, there are certain missing links between the known hemodynamic effects exerted by CCBs and the outcome benefits related to their clinical use. Future efforts should further explore the appropriate use of CCBs in acute care, in a drug-, disease-, and anesthetic-dependent context, with a focus on hemodynamic optimization and outcome improvement.

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The authors would like to acknowledge the support received from institutional and departmental sources.

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JW helped conduct literature search, analyze the data, write the manuscript, and approve the final manuscript. DLM helped write and edit the manuscript and approved the final manuscript. LM helped conceptualize the topic, provided the observational data, wrote and edited the manuscript, and approved the final manuscript.

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Correspondence to Lingzhong Meng.

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Jin Wang, David L. McDonagh, and Lingzhong Meng have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Supplementary file2 Supplementary video An intravenous bolus of nicardipine 0.4 mg was administered to a patient undergoing laparoscopic hysterectomy. It led to a quick decrease in BP (black belt with the upper and lower edges as systolic and diastolic BP and the red line within as the mean BP) and SVR (green belt). HR (pink tracing and pink numbers) and SV (blue numbers) are both mildly increased. As a result, cardiac output increased (not shown). Hemodynamics were monitored using a LiDCO monitor (LiDCO Group, London, UK). BP blood pressure, HR heart rate, SV stroke volume, SVR systemic vascular resistance (MOV 67126 kb)

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Wang, J., McDonagh, D.L. & Meng, L. Calcium Channel Blockers in Acute Care: The Links and Missing Links Between Hemodynamic Effects and Outcome Evidence. Am J Cardiovasc Drugs 21, 35–49 (2021). https://doi.org/10.1007/s40256-020-00410-4

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