The perioperative use of calcium channel blockers (CCBs) has been associated with few cardiovascular side effects. In cases of coronary artery spasm, intravenous bepridil or sublingual nifedipine proved effective in early reports, especially during coronary artery bypass grafting (CABG) surgery. Much of the literature summarized in this lesson dates from the 1980s and should be read as history: bepridil has since been withdrawn because it prolongs the QT interval and causes torsades de pointes, and sublingual or intranasal immediate-release nifedipine is no longer recommended for acute hypertension because its absorption is unpredictable and precipitous falls in pressure have caused stroke and myocardial infarction. The intravenous agents used today are nicardipine and clevidipine for pressure and diltiazem for rate, described later in this lesson. These medications have also been reported to reduce vascular resistance in venous coronary grafts, with sublingual nifedipine 10 mg showing positive results in this regard.
Myocardial Ischemia
The effectiveness of prescribing CCBs to prevent myocardial ischemia during anesthesia remains unclear, in contrast to the well-documented benefits of beta-blockers. Some studies have reported that discontinuing CCBs for 24 hours can lead to recurrent angina pectoris. For instance, patients who continued receiving nifedipine until the day of CABG surgery required more inotropic support but less vasodilation therapy after cardiopulmonary bypass, compared to those who discontinued nifedipine the day before surgery. However, the continuation of diltiazem until anesthesia did not show significant hemodynamic differences compared to a control group.
Despite continuing verapamil and nifedipine therapy until surgery, tachycardia was observed during laryngoscopy in patients with coronary artery disease (CAD). In an attempt to define the role of CCBs in preventing myocardial ischemia during CABG surgery, three prospective studies have been conducted. Slogoff and Keats, in a study involving 444 patients, observed that those who received no treatment or only CCB therapy before surgery experienced more ischemic episodes than patients who received beta-blockers, with or without CCBs. This finding was supported by Chung et al., who studied 92 patients, and Tuman et al., who examined 803 patients. Despite greater left ventricular (LV) dysfunction in the CCB group prior to surgery, patients in the control group had a higher incidence of perioperative myocardial infarction and ischemia than the CCB group, while those receiving beta-blockers had the lowest incidence. However, the mortality rates were similar across all groups.
Although calcium channel blockers (CCBs) appeared less effective in preventing ischemia compared to beta-blockers, the studies mentioned above were not randomized and involved unequal group sizes. Tachycardia has been correlated with ischemic episodes, and the inclusion of patients on different types of CCBs in these studies might have introduced methodological bias. One study by Henling et al. showed that the combination of a beta-blocker with a CCB did not lead to an increased incidence of conduction disturbances.
In two randomized studies, diltiazem (0.15 mg/kg IV) followed by a continuous infusion (3-5 µg/kg/min), started before the induction of anesthesia and continued for 3-12 hours after tracheal extubation in CAD patients undergoing non-cardiac surgery, reduced the incidence of ischemic episodes. This was accompanied by a significant improvement in hypertension management.
Hypertension Management
The ability of CCBs to prevent or manage perioperative hypertensive episodes has been well-documented. Verapamil (0.1 mg/kg IV) and sublingual nifedipine (10 mg) have effectively prevented pressor responses to laryngoscopy without affecting heart rate. CCBs have also been used to induce controlled hypotension during surgery. For example, Zimpfer et al. administered verapamil (0.07 mg/kg IV) during neuroleptanalgesia, resulting in a 10-20% decrease in arterial pressure within the first 10 minutes, primarily due to a reduction in systemic vascular resistance (SVR).
Nicardipine IV was similarly effective in reducing mean arterial pressure to 50-60 mmHg during hip surgery (a deliberate-hypotension target lower than current practice, which keeps mean pressure at or above 60 to 65 mmHg), accompanied by a decrease in SVR and an increase in cardiac output. In vascular surgery, Kishi et al. administered nicardipine (1-2 mg IV) to manage hypertensive episodes, with no change in right and left filling pressures or heart rate. While nifedipine was also effective, its light sensitivity complicated its use. In a study by Van Wezel et al., verapamil, nifedipine, and nitroglycerine were compared for maintaining arterial pressure below 120% of control during CABG surgery. Both nifedipine and nitroglycerine were well-tolerated, but verapamil increased the PQ interval, pulmonary artery pressure, and pulmonary capillary wedge pressure. Nicardipine IV has also been used in the management of pheochromocytoma, where it controls hypertension by blocking norepinephrine-mediated calcium influx into vascular smooth muscle rather than by blocking adrenergic receptors; CCBs may also reduce catecholamine release from the tumor, and they are used as add-on or alternative preoperative therapy when alpha blockade is not tolerated.
Postoperatively, CCBs have been utilized to manage hypertension as well. Intranasal nifedipine (10 mg) effectively controlled hypertension after carotid endarterectomy in most patients, leading to increased cardiac index and mixed venous oxygen saturation, along with decreased pulmonary capillary wedge pressure.
Postoperative Hypertension
In a comparative study, Mullen et al. evaluated the use of IV diltiazem, intranasal nifedipine, and IV sodium nitroprusside for treating hypertension after CABG surgery. The dosages required to achieve equivalent reductions in arterial pressure were 150-300 µg/kg for diltiazem, 20-50 mg for nifedipine, and 1 µg/kg/min for sodium nitroprusside. Heart rate and myocardial oxygen consumption (MVO2) decreased only with diltiazem. Left ventricular systolic function indices were reduced by diltiazem and nifedipine, but not by sodium nitroprusside, which uniquely reduced myocardial lactate uptake.
Intravenous nicardipine was efficient in managing hypertension in the majority of patients, achieving results within 15 minutes and followed by a continuous infusion. Nicardipine appeared easier to administer than sodium nitroprusside and did not induce rebound hypertension, likely due to its longer half-life and stable plasma norepinephrine levels. It effectively reduced blood pressure without affecting preload, resulting in an increase in cardiac index.
| Setting | Agent and dose reported | Reported effect |
|---|---|---|
| Coronary artery spasm during CABG | IV bepridil or sublingual nifedipine (dose not stated) | Effective; sublingual nifedipine 10 mg also reduced vascular resistance in venous coronary grafts |
| Myocardial ischemia, CAD patients undergoing non-cardiac surgery | Diltiazem 0.15 mg/kg IV before induction, then 3–5 µg/kg/min continued 3–12 hours after extubation | Reduced incidence of ischemic episodes with significant improvement in hypertension management |
| Pressor response to laryngoscopy | Verapamil 0.1 mg/kg IV or sublingual nifedipine 10 mg | Prevented the pressor response without affecting heart rate |
| Controlled hypotension under neuroleptanalgesia | Verapamil 0.07 mg/kg IV | 10–20% fall in arterial pressure within 10 minutes, mainly from reduced systemic vascular resistance |
| Controlled hypotension for hip surgery | Nicardipine IV | Mean arterial pressure reduced to 50–60 mmHg (below current deliberate-hypotension floors) with decreased SVR and increased cardiac output |
| Hypertensive episodes in vascular surgery | Nicardipine 1–2 mg IV | Controlled hypertension with no change in right or left filling pressures or heart rate |
| Pheochromocytoma | Nicardipine IV | Controlled hypertension by blocking norepinephrine-mediated calcium influx into vascular smooth muscle (not by receptor blockade); may also reduce catecholamine release from the tumor |
| Hypertension after carotid endarterectomy | Intranasal nifedipine 10 mg | Controlled hypertension in most patients; increased cardiac index and mixed venous oxygen saturation, decreased pulmonary capillary wedge pressure |
| Hypertension after CABG | Diltiazem 150–300 µg/kg or intranasal nifedipine 20–50 mg | Pressure reduction equivalent to sodium nitroprusside 1 µg/kg/min; heart rate and MVO2 fell only with diltiazem |
Current Intravenous Agents and Perioperative Continuation
Three intravenous CCBs are in routine perioperative use today, and their doses are worth knowing. Nicardipine is started at 5 mg/h and increased by 2.5 mg/h every 5 to 15 minutes to a maximum of 15 mg/h; onset takes 5 to 15 minutes, and after a prolonged infusion the effect can persist for hours because the drug accumulates. Clevidipine, an ultra-short-acting dihydropyridine formulated in a 20% lipid emulsion and cleared by blood and tissue esterases (half-life about 1 minute), is started at 1 to 2 mg/h and doubled at 90-second intervals until the pressure approaches target, then titrated in smaller steps; most patients respond at 4 to 6 mg/h, the labeled maximum is 32 mg/h for short periods, and no more than 1,000 mL of emulsion should be given in 24 hours. It is contraindicated in patients allergic to soy or egg products and in those with defective lipid metabolism, and the vial must be discarded within 12 hours of being spiked. Diltiazem is the rate-control agent: 0.25 mg/kg IV over 2 minutes, a second dose of 0.35 mg/kg after 15 minutes if needed, then 5 to 15 mg/h. Verapamil 2.5 to 5 mg IV over 2 minutes, repeated as 5 to 10 mg after 15 to 30 minutes (total about 20 mg), is the alternative but is more negatively inotropic. For the patient who takes a CCB at home, the 2024 AHA/ACC perioperative guideline makes no recommendation to hold it, and the usual practice is to continue it through the morning of surgery, because abrupt withdrawal has been followed by rebound hypertension and angina, while the hypotension that can follow induction is manageable with the approach described in the next lesson.
Malignant Hyperthermia
Malignant hyperthermia (MH) is a potentially life-threatening condition triggered by certain anesthetic agents in genetically susceptible individuals. It results from a dysfunction in calcium regulation in the sarcoplasmic reticulum of skeletal muscle, leading to unregulated calcium release, hypermetabolism, and severe muscle rigidity. CCBs are not MH triggers, and patients with known susceptibility may take them; the problem is giving a CCB while dantrolene, the primary treatment for MH, is on board. In swine, verapamil followed by dantrolene produced hyperkalemia and cardiovascular collapse, the same combination caused life-threatening hyperkalemia in a patient, and diltiazem has been implicated as well. The mechanism is thought to be profound myocardial depression (dantrolene inhibits calcium release from the sarcoplasmic reticulum while the CCB blocks calcium influx) together with potassium efflux from skeletal muscle. Thus, once dantrolene has been given, do not add verapamil or diltiazem for rate control or a dihydropyridine for blood pressure; treat arrhythmias with other agents and watch the potassium closely in a patient already taking a CCB. The CCB is never a reason to withhold dantrolene when MH is genuinely suspected.
