Haemadsorption therapy for calcium channel blocker overdose

doi:10.21203/rs.3.rs-1983949/v1

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Case Report

Haemadsorption therapy for calcium channel blocker overdose

https://doi.org/10.21203/rs.3.rs-1983949/v1

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A male patient in his twenties was admitted into the Intensive Care Unit (ICU), following an overdose with an unknown quantity of risperidone (atypical antipsychotic) and a dihydropyridine calcium channel blocker (amlodipine). Resuscitation and supportive care were administered, but hypotension did not resolve despite the administration of intravenous fluids, infusions of calcium, adrenaline, and hyperinsulinemic-euglycemic therapy (HIE). Methylene blue was then administered to maintain the mean arterial pressures. However, the haemodynamic effect was short-lived and did not allow the weaning of the adrenaline. Drug clearance using hemoperfusion/haemadsorption with a styrene resin filter was attempted next. During the two hemoperfusion sessions, each of 6 hours duration, and 24 hours apart, the patient was successfully weaned off all supportive measures and later discharged home. Significant amlodipine concentrations were detected in blood aspirated from both haemadsorption filters at the end of each session.

Critical Care & Emergency Medicine

Haemadsorption

hemoperfusion

toxicology

critically ill

Amlodipine

Calcium channel blocker overdose

Calcium channel blockers (CCB) account for 35% of cardiovascular drug overdoses in the USA and are lethal in large amounts (1,2). Dihydropyridine CCBs have a greater affinity for smooth muscle L-type calcium channels while non-dihydropyridine CCBs have an affinity for both cardiac and smooth muscle channels. Specific affinity is lost at high doses. (3)

CCB overdose results in peripheral vasodilation, reduced cardiac contractility, and possibly bradycardia leading to circulatory compromise (3). These drugs are protein bound with a large volume of distribution and not amenable to removal by haemodiafiltration (4). Extracorporeal albumin dialysis has been attempted. (5)

Current management of CCB overdose is focused on supportive measures including vasoactive agents, calcium administration, and HIE therapy. (6) Atropine is indicated for bradycardia. (7) The use of methylene blue has been suggested for refractory hypotension due to its inhibitory effect on guanylate cyclase. (8)

Rescue therapy includes lipid emulsion, pacing, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and hemoperfusion. (7)

Admission day

On arrival in the ICU, the patient tested negative for paracetamol, salicylates, and tricyclic antidepressants. The history revealed consumption of a large unknown quantity of amlodipine (dihydropyridine CCB) in addition to risperidone. His full blood count, platelets and renal function were within reference limits. An electrocardiogram (ECG) did not show any acute changes whilst the chest X-ray was unremarkable.

Treatment

In the ICU, the patient required further increases in adrenaline infusion and fluid challenges. See Figure 1. High-Dose Insulin Euglycaemic Therapy (HIE) was initiated and titrated to 2U/kg/hour, maintaining euglycaemia with 50% dextrose water. A 10% calcium chloride bolus over 10 minutes and subsequent infusion (0.2ml/kg/hour) was also initiated. Despite this, his mean arterial pressures persistently fell below 60mmHg.

Methylene blue 2mg/kg, followed by an intravenous infusion of 1mg/kg/h was initiated with little success. Haemoperfusion therapy was then commenced using a continuous renal replacement therapy (CRRT) circuit with the adsorbent filter connected in series to the CRRT filter. Using a bicarbonate solution, we set the predilution to 500ml/hour and the blood-flow rate to 180ml/minute. Heparin was administered into the circuit according to our CRRT protocol. We performed two six-hour cycles of HA therapy separated by an 18-hour redistribution period.

Outcome and follow-up

During the first 6- hour cycle of Haemoperfusion therapy, the MAP increased from 60mmHg to 70mmHg, and the methylene blue, insulin, and calcium infusions were stopped. Adrenaline was weaned to 0.9 ug/kg/hour and blood lactate decreased to 3mmol/l.

During the second 6-hour cycle of haemoperfusion, adrenaline was weaned to 0.6ug/kg/min and stopped a further 8 hours later. The lactate decreased to 0.9mmol/l while a MAP of 70mmHg was maintained. The patient was extubated 48 hours later and then discharged home after a psychiatric referral.

Amlodipine measurement estimates using liquid chromatography-mass spectrometry on blood from the first and second haemoperfusion filters yielded concentrations of 80mg/l and 40mg/l respectively.

We describe a temporal relationship between the application of haemoperfusion therapy and haemodynamic recovery due to amlodipine overdose. We found one case in the literature that utilized charcoal haemoperfusion for a CCB over-dose. (4) Roberts et al found no clinical improvement during or immediately after haemoperfusion. (4) In contrast, our findings showed both haemodynamic and shock improvement during, and immediately after therapy.

Two important differences included both the type of CCB and filter. Amlodipine (T_1/2 = 50 hours) was the CCB vs. diltiazem in the case by Roberts et al. Diltiazem is a non-dihydropyridine CCB with a T_1/2 6–9 hours and may cause bradycardia as opposed a reflex tachycardia caused by amlodipine. (1) Roberts et al used a single application of a charcoal filter for 3 hours. (4) We applied a multicycle approach using a resin filter composed of styrene and interrupted the two 6- hour cycles with an eighteen-hour interval. Charcoal binds by creating Van der Waals forces with substances and although non-specific, binding is weak. (9) Resins are useful for protein-bound and lipid soluble substances and have superior adsorbent properties. (9, 10) The volume of distribution of both drugs are greater than the ideal of < 1L/kg for effective haemoperfusion. (11) It is possible that the interval between cycles was important to allow intercompartmental transfer and increased the effectiveness of haemoperfusion.

The combined adrenaline and noradrenaline dose was 40ug/min (Roberts et al) compared to 69ug/min of adrenaline in our case. We had had no access to vasopressin.

Although our case illustrates a temporal relationship between the therapy and clinical improvement, beyond determining that there was a significant concentration of amlodipine retained in the filter we did not have sufficient information to calculate the clearance. It is worth noting that the shock resolution after initiation of haemoperfusion in our case occurred in less than one elimination half-life of amlodipine.

Learning points

Knowledge of the type of calcium channel blocker implicated is important for planning appropriate treatment strategies and anticipating the duration of and possible delayed decompensation.
First-line therapies include correcting fluid depletion, intravenous calcium chloride, vasopressors (noradrenaline and adrenaline), high-dose insulin euglycemic therapy, and atropine/pacing for bradycardia or conduction disturbances.
Rescue therapies are used when haemodynamic stability is refractory to first-line therapies.
Consideration of the possible utility of haemoperfusion/haemadsorption therapy can be made at this stage.

1. Stephen VS, Pluymers NA, Gauton SJ. Emergency management of calcium channel blocker overdose. South African Medical Journal. 2019 Aug 28;109(9):635–8

2. Watson WA, Litowitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers toxic exposure surveillance system. Am J Emerg Med 2004;22(5):335-404.

3. Chakraborty R, Hamilton R. Calcium Channel Blocker Toxicity. StatPearls [Internet]. 2022 Apr 30 [cited 2022 Jul 12]; Available from: https://www.statpearls.com/ArticleLibrary/viewarticle/30315

4. Roberts DM, Roberts JA, Boots RJ, Mason R, Lipman J. Lessons learnt in the pharmacokinetic analysis of the effect of haemoperfusion for acute overdose with sustained-release diltiazem. Anaesthesia. 2008;63(7):714-718. doi:10.1111/j.1365-2044.2008.05477.x

5. Pichon N, Dugard A, Clavel M, Amiel JB, François B, Vignon P. Extracorporeal albumin dialysis in three cases of acute calcium channel blocker poisoning with life-threatening refractory cardiogenic shock. Ann Emerg Med. 2012;59(6):540-544. doi:10.1016/j.annemergmed.2011.07.029

6. St-Onge M, Anseeuw K, Cantrell FL, Gilchrist IC, Hantson P, Bailey B, et al. Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults. Crit Care Med. 2017 Mar;45(3):e306–15.

7. St-Onge M, Dubé PA, Gosselin S, et al. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila). 2014;52(9):926-944.2.5643

8. Fisher J, Taori G, Braitberg G, Graudins A. Methylene blue used in the treatment of refractory shock resulting from drug poisoning. Clin Toxicol (Phila). 2014;52(1):63-65. doi:10.3109/15563650.2013.870343

9. Ankawi G, Fan W, Pomarè Montin D, Lorenzin A, Neri M, Caprara C, et al. A New Series of Sorbent Devices for Multiple Clinical Purposes: Current Evidence and Future Directions. Blood Purif. 2019;47(1–3):94–100.

10. Ghannoum M, Bouchard J, Nolin TD, Ouellet G, Roberts DM. Hemoperfusion for the treatment of poisoning: technology, determinants of poison clearance, and application in clinical practice. Semin Dial. 2014 Aug;27(4):350–61.

11. Mirrakhimov AE, Barbaryan A, Gray A, Ayach T. The Role of Renal Replacement Therapy in the Management of Pharmacologic Poisonings. Int J Nephrol. 2016;2016:3047329.

Ethics approval and consent to participate

Study approval statement: This study protocol was reviewed and approved by the following Ethical review board: Human Research Ethics Committee (Medical) [HREC] affiliated to the University of Witwatersrand, approval number [M210988]. The approval date was the 14 October 2021

Consent to participate statement: Written informed consent was obtained from the patient.

Consent for publication

Written informed consent specifically for a Case Report was obtained from the patient.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

Shahed Omar received honoraria from Jafron Biomedical to the value of ZAR 26 000 (approximately USD 1 700) for Webinars during 2020 and 2021.

All other authors have no conflicts of interest to declare.

Funding

Due to the nature of the Case Report no funding has been requested. For the purposes of publication, we will apply for a waiver (South Africa) or contribute individually or apply for University funding if available (unlikely)

Authors' contributions

SO and CG were responsible for the write up of the manuscript.

SO was responsible for the creation of the Figure.

PP was responsible for the data collection, integrity check and formatting prior to analysis.

All authors approved the final manuscript.

Acknowledgements – Not applicable
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Haemadsorption therapy for calcium channel blocker overdose

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