Treatment Modalities in Calcium Channel Blocker Overdose: A Systematic Review

Calcium channel blocker poisoning is one of the most common poisonings encountered which presents with life-threatening complications. However, there is no unified approach for treating these patients in the existing literature. This study aimed to assess the effects of different treatment modalities used in calcium channel blocker poisoning, as reported by previous studies. The primary outcomes studied were mortality and hemodynamic parameters after treatment. The secondary outcomes were the length of hospital stay, length of intensive care unit stay, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. A thorough literature search was performed through Ovid, PubMed, Cochrane Library, and Google Scholar from January 2014 to December 31, 2022, to identify all studies analyzing the effects of the treatment of calcium channel blocker poisoning on the desired outcomes. Two reviewers reviewed 607 published articles from January 2014 to December 2022 to identify studies analyzing the effects of the treatment of calcium channel blocker poisoning on desired outcomes. In this review, 18 case reports, one case series, and one cohort study were included. Most patients were treated with an injection of calcium gluconate or calcium chloride. The use of calcium along with dopamine and norepinephrine was found to have lower mortality rates. A few patients were also treated with injection atropine for bradycardia. High-dose insulin therapy was used in 14 patients, of whom two did not survive. In the cohort study, 66 calcium channel blocker toxicity patients were included. These patients were treated with high-dose insulin therapy. A total of 11 patients with calcium channel blocker toxicity succumbed. Although it was found to be associated with improved hemodynamic parameters and lower mortality, side effects such as hypokalemia and hypoglycemia were noted. Intravenous lipid emulsion therapy (administered to eight patients), extracorporeal life support (used in three patients with refractory shock or cardiac arrest), injection glucagon, methylene blue, albumin infusion, and terlipressin were associated with a lower mortality rate as well as improvement in hemodynamic parameters. None of the case reports provided any information on end-organ damage on long-term follow-up.


Introduction And Background
Calcium channel blocker toxicity is reportedly the third fastest-growing substance exposure according to the American Association of Poison Control Centers, followed by beta-blocker overdose [1].Verapamil is one of the most commonly reported calcium channel blocker overdoses [2].As miscellaneous treatment regimens have been reported for calcium channel blocker poisons, formulating protocolized practice guidelines for calcium channel overdose is warranted.
A systematic review by St-Onge et al. [3] published in 2014 summarized the treatment for calcium channel blocker poisoning in the existing literature until December 31, 2013.Our systematic review aims to add to this systematic review by summarizing treatment modalities from January 2014 to December 2022.We have studied the reported effects of various treatment modalities used in calcium channel blocker toxicity on the desired outcomes of the patients managed for calcium channel blocked toxicity.The primary outcomes were mortality and hemodynamic parameters.The secondary outcomes were functional status, length of hospital stay, length of intensive care unit stay, duration of vasopressor use, and serum calcium channel blocker concentrations.This systematic review included all case reports, case series, original articles, and abstracts from scientific and clinical meetings published from January 2014 to December 2022 on the treatment of calcium channel blocker toxicity.We defined a case report as an article that pertained to an individual case, or case series when two or more cases were reported.

Interventions
Studies with defined treatment strategies with an impact on primary or secondary outcomes were included in this systematic review.

Outcomes
The studies were required to study at least one of the primary and secondary outcomes.Primary outcomes included hospital mortality and hemodynamic parameters such as the improvement in blood pressure, stroke volume, heart rate, cardiac output, and peripheral vascular resistance.The secondary outcomes included the length of hospital stay, duration of intensive care unit stay, vasopressor use, and calcium channel blocker concentrations.

Search Strategy
A thorough search was made on Ovid, PubMed, Cochrane Library, Scopus, and Google Scholar from January 2014 to December 2022.Two researchers searched original articles, case series, and case reports using the keywords [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect].Animal studies were excluded from this review.Disagreements on the final articles included were resolved by a third reviewer.For data collection, a single flow sheet was used which included detailed study characteristics such as year of publication; study type; authors; demographic history of the subjects; history of comorbidities; treatment given; type, dose, and route of calcium channel blocker exposure; and primary and secondary outcomes.Quality assessment was done using Strengthening the Reporting of Observational Studies in Epidemiology for the original article.As the studies, interventions, and outcomes were heterogeneous, a planned meta-analysis could not be performed.After a thorough search, a total of 607 articles were identified, of which 20 articles were included.One was an original article, one was a case series, and 18 were case reports (Figure 1).

Results
Table 1 shows the results of individual studies.

Effects of Individual Treatment Modalities Used
Gastrointestinal decontamination: Four case reports utilized this treatment modality [4][5][6][7].All reported cases of calcium channel blocker toxicity survived.In one case report, 70 g of activated charcoal followed by polyethylene glycol was used for gastrointestinal decontamination [4].In the other two cases, gastric lavage with activated charcoal (60 g) was performed [5,6].None of the cases reported cardiac arrests or aspiration after gastric lavage.In one case report, gastrointestinal decontamination was done using magnesium sulfate [7].
Methylene blue: The use of methylene blue at a dose of 1 mg/kg/hour was reported in three cases to improve blood pressure.All three patients survived and reported improvements in hemodynamic parameters [13,15,16].
Intravenous lipid emulsion (ILE) therapy: 20% ILE therapy was utilized at a dose of 0.25 mL/kg/minute for three hours in one case report [20], while a dose of 100 mL bolus followed by 1,200 mL/hour was considered in another [15].ILE was used as a treatment option in six case reports and one case series [8,9,12,13,17,18,20].All except one study showed improvement in blood pressure and heart rate [8].
Single-pass albumin dialysis: It was utilized in two case studies as a treatment measure for calcium channel blocker toxicity [16,20].Both case studies showed benefits to the patient outcome with the use of albumin dialysis.
Extracorporeal membrane oxygenation (ECMO): The use of ECMO was found to be associated with an improvement in survival in patients with calcium channel blocker toxicity.Arterial-venous ECMO was used in five case reports [6,8,13,15,16].Out of these cases, one patient did not survive [8].The use of ECMO was associated with increased chances of survival and improvement in the left ventricular function and blood pressure.

Effects of Interventions on the Outcome of the Patients
Effect on mortality: HIET was associated with improved survival reports.In most case studies, it was given after the injection of calcium gluconate and glucagon therapy.It was utilized in all 20 articles included in the systematic review, including the cohort study.Overall, 20% ILE therapy was also associated with better survival and was used in eight case studies after high-dose insulin therapy.Vasopressors such as noradrenaline and dopamine showed improvement in mortality rate but the results were inconsistent.ECMO was used in patients with refractory shock as the last therapeutic resort.It was also associated with better survival in these patients [6,13,15,16].Two patients survived after receiving albumin dialysis [16,20].
Effects on hemodynamic parameters: Positive effects were reported with glucagon, calcium gluconate, highdose insulin therapy, as well as lipid emulsion.The case studies showed improvement in blood pressure, heart rate, mean arterial blood pressure, and urine output.The case studies also showed the positive effects of methylene blue on blood pressure [13,15,16].This review also highlights the role of vasopressors in the improvement of blood pressure for patients with calcium channel blocker overdose.
Improvement in functional status: One case report documented that the patient was discharged without any lasting organ system damage [20].This case report described two cases of calcium channel blocker poisoning.The patients underwent albumin dialysis apart from the usual treatment given.In another case report, the patient was discharged with an intact mental status and returned to functional independence on day 56.Veno-arterial ECMO was used for the patient for the management of a massive amlodipine overdose [13].Koliastasis et al. reported a case with refractory shock from an amlodipine overdose overcome with hyperinsulinemia.The patient was discharged on day 14 and on follow-up at one month showed no cardiovascular comorbidity [5].Cole et al. conducted a study among 41 patients who experienced cardiac arrest at some point during the treatment [11].Another case report highlighting the efficacy of albumin dialysis in the reversal of refractory vasoplegic shock due to amlodipine toxicity reported that the patient was discharged on day 12 without any lasting organ dysfunction [20].

Study limitations
The major limitation of our study was the heterogeneity of the available data.As most of the studies included in our review were case reports, the risk of bias could not be determined.The lack of any randomized control trials for the individual or all treatment modalities makes it difficult to analyze the exact effects of the same in the management of calcium channel blocker poisoning.

Conclusions
This systematic review focuses on the array of treatment modalities available for calcium channel blocker toxicity and their effects on mortality and other desired functional outcomes.Multiple treatment modalities are available such as calcium, high-dose insulin, lipid emulsion, vasopressors, ECMO, and albumin dialysis.
As controlled trials are lacking, the evidence supporting superiority is inconsistent.Thus, randomized controlled trials supporting their role should be conducted.However, due to ethical concerns, in most toxicological emergencies, conducting randomized controlled trials may not be feasible.
no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

FIGURE 1 :
FIGURE 1: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.
started on fluid boluses and 2 g of intravenous calcium gluconate.Gastric lavage was done with 70 g charcoal, followed by polyethylene glycol.IV dopamine was started and a central venous line was secured.Fluid resuscitation was continued along with vasopressors and calcium gluconate infusion at 0.5 g/hour.He was also given 40 units of insulin along with 50% APTT = activated partial thromboplastin time; CCB = calcium channel blocker; COPD = chronic obstructive pulmonary disease; CRRT = continuous renal replacement therapy; CVVHD = continuous venovenous hemodialysis; CVVHDF = continuous venovenous hemodiafiltration; ECMO = extracorporeal membrane oxygenation; GCS = Glasgow Coma Scale; GI = gastrointestinal; HIET = high-dose insulin euglycemic therapy; IABP = intra-arterial blood pressure; ICU = intensive care unit; ILE = intravenous lipid emulsion; IU = international unit; IV = intravenous; KCl = potassium chloride; MAP = mean arterial pressure; NAC = N-acetylcysteine; PCM = paracetamol; RR = respiratory rate; SBP = systolic blood pressure; SPAD = single-pass albumin dialysis; VAD = ventricular assist device calcium chloride, and ILE.He was then initiated on insulin (90 IU/hour up to a maximum of 180 IU/hour) and dextrose infusion.He was intubated due to large 2023 Baid et al.Cureus 15(8): e42854.DOI 10.7759/cureus.428543 of 12 life-threatening lercanidipine and amlodipine overdose overdose and 50 mg amlodipine overdose dextrose and another 40 units of insulin was repeated after 30 minutes.The patient was started on charcoal hemoperfusion without ultrafiltration, with a 1 U/mL heparinized extracorporeal circuit for over four hours, followed by 6,000 mg/hour which was reduced to 3,000 mg/hour and stopped when the calcium level reached 5.05 mmol/L.rate of 220 units/hour (2 units/kg/hour).Noradrenaline infusion was started and the patient was intubated after 20 minutes due to altered mental state.Dopamine was added approximately 90 minutes later.Over the next 2 hours, the norepinephrine infusion was increased to the institution's maximum rate of 0.3 µg/kg/minute.During this timeframe, he also received two 20% lipid boluses of 150 and 250 mL, respectively.At this point, both epinephrine and vasopressin were started.Over the next 2 hours, he received an additional 2 g of calcium chloride and 250 mL of 20% lipids.Phenylephrine was then started and was titrated to the institution's maximum rate of 5 µg/kg/minute within 20 minutes.Methylene blue was started in an attempt to achieve hemodynamic stability.He received a 100 mg dose of methylene blue that was repeated approximately 1 hour later.He also received 2 hours of plasma exchange therapy after which he was placed on CRRT.Over the next 2 hours, he received an additional 250 mL of 20% lipids and 2 g of calcium chloride.2023 Baid et al.Cureus 15(8): e42854.DOI 10.7759/cureus.42854attempt vasopressin, lipid emulsion, insulin with dextrose infusion, calcium chloride, hydrocortisone, and electrolyte correction.A ventricular assist device (VAD)-Impella CP 4.0 (delivering 4 L of cardiac output (CO) per minute), was placed hemodynamic instability.