🧭 REBEL Rundown
📌 Key Points
- 📉 Diltiazem can drop BP: Up to 13% of patients experience hypotension after IV diltiazem, which is especially risky in those with limited reserve.
- 💉 Calcium pretreatment helps stabilize BP: Giving calcium before diltiazem reduced systolic BP drops, with the 180 mg dose showing the most stability.
- ⚖️ Trade-off with rate control: Higher calcium doses may blunt heart rate reduction.
- 🤔 Use selectively, not routinely: More evidence is needed before calcium pretreatment becomes standard practice.
🤕 Case
A 68-year-old man with hypertension and heart failure with preserved EF presents to the ED with palpitations and lightheadedness. His vital signs: HR 146, BP 101/64, SpO₂ 96% RA. ECG shows atrial fibrillation with rapid ventricular response. He is afebrile and without chest pain or dyspnea. The ED team plans to administer IV diltiazem but is concerned about hypotension given his borderline blood pressure and cardiac history. A senior resident asks whether giving IV calcium first might protect against the HR drop without blunting rate control.
📝 Introduction
Atrial fibrillation with rapid ventricular response (AF with RVR) is one of the most common dysrhythmias encountered in the emergency department and often requires prompt rate control. Diltiazem remains a go-to agent due to its rapid onset, AV nodal selectivity, and reliable heart rate reduction. However, hypotension occurs in up to 13% of patients, occasionally symptomatic in 4% of patients, and particularly concerning in those with limited reserve (Ellenbogen 1995).
One proposed strategy to mitigate hypotention—IV calcium pretreatment—dates back to the verapamil era. Studies by Haft et al. (1986) and Salerno et al. (1987) demonstrated that calcium given before verapamil could prevent hypotension without diminishing anti-dysrhythmic efficacy. The presumed mechanism is an increase in extracellular calcium, which helps preserve vascular tone and myocardial contractility, offsetting the smooth muscle vasodilation and negative inotropy caused by calcium channel blockers. Because verapamil is a more potent myocardial depressant than diltiazem, its hemodynamic effects may be more amenable to calcium rescue.
Attempts to apply this strategy to diltiazem have shown mixed results. Kolkebeck et al. (2004) found no significant change in blood pressure or heart rate with 90 mg calcium chloride before IV diltiazem in AF with RVR, likely due to the low dose. Similarly, Rossi et al. (2022) reported no meaningful reduction in hypotension using variable calcium formulations and non-standardized dosing (~93 mg elemental calcium). Hypotension was seen, possibly due to inconsistent dosing and study design limitations. So can a calcium bolus prevent the dreaded diltiazem drop in blood pressure?
🧾 Paper
Az A, Sogut O, Dogan Y, et al. Reducing diltiazem-related hypotension in atrial fibrillation: Role of pretreatment intravenous calcium. Am J Emerg Med. 2025;88:23–28. PMID: 39577214
⚙️ What They Did
📈 Results
- Initial enrollment: 421 consecutive adult ED patients with AF/AFL and RVR.
- Exclusions:
- 5 patients excluded due to pregnancy
- 28 patients excluded for hemodynamic instability requiring electrocardioversion
- 129 patients declined to participate
- 21 patients excluded for concurrent use of other oral rate control agents (beta-blockers, amiodarone, digoxin)
- 21 patients excluded due to spontaneous rate control after pretreatment (8 in C90D, 13 in C180D)
- Final study population: 217 patients
- Placebo group (PD): 73
- Calcium 90 mg group (C90D): 71
- Calcium 180 mg group (C180D): 73
- Baseline Characteristics
- Age: No significant differences between groups (p = 0.377)
- Sex distribution: Similar across groups (p = 0.981)
- Initial vital signs:
- HR at admission: No significant difference (p = 0.607)
- SBP at admission: No significant difference (p = 0.485)
- Laboratory values:
- Albumin: No significant difference (p = 0.089)
- Calcium: No significant difference (p = 0.583)
💥 Critical Results
- Heart Rate (ΔHR):
- All groups experienced significant HR reduction at each time point (p < 0.001).
- The magnitude of reduction was greatest in the placebo group and smallest in the 180 mg calcium group.
- Systolic BP (ΔSBP):
- Placebo group showed the most significant SBP drops.
- 180 mg calcium group maintained stable SBP with no significant change from baseline.
- 90 mg calcium group had intermediate results — a modest drop but less than placebo.
💪 Strengths
- Prospective, randomized, double-blind design: minimizes bias and strengthens causal inference.
- Pre-registration of the trial: supports transparency and methodological rigor.
- Placebo control group: enables clear attribution of effects to the intervention.
- Consecutive patient enrollment: reduces selection bias and enhances generalizability.
- Computer-generated randomization: improves allocation concealment and internal validity.
- Stratified calcium dosing (90 mg vs. 180 mg): allows for dose-response analysis.
- Standardized administration protocols: consistent timing, rate, and dosage for both calcium and diltiazem.
- Clinically relevant primary outcome (SBP change): directly linked to the intervention’s intended benefit.
⚠️ Limitations
- Single-center study: limits generalizability.
- Short follow-up window (only 15 minutes): no data on longer-term BP trends, sustained rate control, or ED outcomes (e.g., disposition, recurrence).
- Potential for unblinding: C90D group received 3.33 mL and C180D group 6.66 mL, which could have hinted at group assignment.
- Exclusion of patients on chronic rate-control agents (e.g., beta-blockers, amiodarone, digoxin): limits applicability to the AF population, where these medications are common.
- No reporting of IV fluid or other supportive measures: could influence hemodynamic outcomes and confound the effect attributed to calcium pretreatment.
- Exclusion of unstable patients: yet in real-world practice, borderline hypotensive patients are often the ones where a strategy like this would be most useful.
- Disease-oriented primary outcome (change in SBP): not a patient-oriented outcome.
🗣️ Discussion
Applicability to Practice
Before even considering rate control, clinicians should remember that the first step in managing AF with RVR is assessing and addressing the underlying trigger (e.g., infection, PE, thyrotoxicosis). Once that’s accounted for, the question becomes how best to manage rate control — and that’s where this trial offers some insight. This trial used calcium chloride, whereas calcium gluconate is more commonly administered in U.S. EDs. A 1-gram amp of calcium chloride (~273 mg elemental calcium) contains about three times more elemental calcium than an equivalent amp of calcium gluconate (~93 mg). Thus, the study’s 90 mg and 180 mg doses are roughly equivalent to one and two amps of calcium gluconate, respectively. Additionally, many hospitals restrict calcium chloride use through peripheral IVs due to the risk of tissue injury with extravasation, favoring calcium gluconate instead. Furthermore, many EDs administer diltiazem as a bolus followed by a drip, whereas this trial only evaluated single bolus administration with outcomes measured over 15 minutes. While the physiologic effects are likely similar, these differences in calcium formulation and diltiazem administration limit direct applicability to some U.S. practice settings.
Inside The Numbers
While the study found statistically significant differences in systolic blood pressure between groups, it’s not clear these translate into clinical relevance. For example, a drop from 132 mmHg to 115 mmHg in the placebo arm versus 125 mmHg in the calcium arm may be statistically different, but both pressures are still adequate for organ perfusion. More importantly, the trial did not report patient-centered outcomes such as the need for IV fluids, vasopressors, ICU admission, or ED disposition—interventions that would clarify whether these BP differences matter at the bedside.
Heart rate reduction was also achieved in all groups, but the 180 mg calcium arm showed higher HRs at 10 and 15 minutes. This didn’t increase the need for rescue diltiazem, but it raises the possibility that higher extracellular calcium could blunt AV nodal effects. Whether this tradeoff impacts longer-term outcomes isn’t known.
One additional nuance: 21 patients were excluded because they spontaneously achieved rate control after calcium or placebo pretreatment (8 in the 90 mg group, 13 in the 180 mg group). While reasonable for study consistency, this exclusion further decreases the sample size of an already small study which can magnify differences between treatments due to chance alone.
Taken together, the numbers show modest physiologic differences, but without evidence of downstream impact on patient care, the clinical significance remains uncertain.
Potential Role in Gray-Zone Patients
From a clinical standpoint, these results open the door to a possible adjunctive strategy, particularly for patients in that gray zone — not hypotensive enough to rule out AV nodal blockade, but not stable enough to ignore the risks. While the study excluded unstable patients, it’s the in-between group —soft-BP patients — where calcium pretreatment might offer the most utility. This trial doesn’t answer that question, but future research could explore whether the therapy is worthwhile in that subset of patients.
📘 Author's Conclusion
“IV calcium pretreatment effectively prevents diltiazem-induced hypotension in patients with Atrial fibrillation/ flutter with RVR without compromising the efficacy of diltiazem in achieving and maintaining ventricular rate control.”
💬 Our Conclusion
This study offers a feasible, low-cost intervention that might provide value in select patients. However, until more data is available, calcium pretreatment shouldn’t be routine practice, but it may be reasonable to consider on a case-by-case basis, particularly when the risk of hypotension outweighs the downside of potentially dampened rate control.
🚨 Clinical Bottom Line
Calcium pretreatment may blunt diltiazem hypotension, but higher doses may also modestly dampen early rate control. Clinicians should be cautious and selective before adopting calcium pretreatment as standard practice.
📚 References
- Ellenbogen KA, Dias VC, Cardello FP, et al. Safety and efficacy of intravenous diltiazem in atrial fibrillation or flutter. Am J Cardiol. 1995;75(1):45–49. PMID: 7801862
- Haft JI, Habbab MA. Treatment of atrial arrhythmias: effectiveness of verapamil when preceded by calcium infusion. Arch Intern Med. 1986;146(6):1085–1089. PMID: 3718093
- Salerno DM, Anderson B, Sharkey PJ, Iber C. Immediate control and conversion with intravenously administered verapamil: the use of calcium gluconate prior to verapamil. Ann Intern Med. 1987;107(5):623–628. PMID: 3662276
- Kolkebeck T, Abbrescia K, Pfaff J, Glynn T, Ward JA. Calcium chloride before IV diltiazem in the management of atrial fibrillation. J Emerg Med. 2004;26(4):395–400. doi:10.1016/j.jemermed.2003.12.020. PMID: 15093843
- Rossi N, Allen B, Hailu K, Kamataris K, Ryan C. Impact of intravenous calcium with diltiazem for atrial fibrillation/flutter in the emergency department. Am J Emerg Med. 2023;64:57–61. doi:10.1016/j.ajem.2022.11.018. PMID: 36442264
Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Marco Propersi, DO (X: @Marco_Propersi)
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