Hemoadsorption therapy for calcium channel blocker (CCB) overdose at a tertiary-level Intensive care unit in South Africa. A retrospective study

doi:10.21203/rs.3.rs-5256785/v1

In this retrospective study, we describe the admission frequency, outcomes and management of adult participants with clinically confirmed CCB overdose admitted to the ICU from 2020 to 2022. Of 1719 ICU admissions over the study period, 24 (1,4%) had CCB overdose with a case fatality rate of 12.5% (3/24). Interventions included mechanical ventilation (MV) (71%), vasopressors (92%), high-dose euglycemic therapy (HIET) (71%), calcium (42%), methylene blue (4%) and fluid therapy (100%). Thirteen patients (54%) received hemoadsorption therapy (HA), and eleven received standard care (SoC) based on current guidelines. The HA group had a higher SAPS II score (p=0.002), and a greater total maximal vasopressor dose (p=0.001) compared to SoC. The HA group also had a lower admission mean arterial pressure (MAP), (p=0.014), a greater MAP increase at 48 hours (p=0.044) and a longer ICU length of stay (LOS) (p=0.004) vs. SoC. There was one death in the HA group (7.7%) and two in the SoC group (18.2%). CCB overdose is a life-threatening contributor to toxicology admissions in the ICU. Hemoadsorption therapy may provide a safe and important rescue therapy in cases with refractory shock. Well-designed studies are required to confirm its role in enhancing drug clearance and clinical outcomes.

Hemoadsorption

toxicology

critically ill

calcium channel blocker overdose

extracorporeal blood purification

hypotension

Essential hypertension is common with an estimated prevalence of 38% and 48% in South Africa and on the African continent, respectively, with calcium channel blockers (CCB) prescribed as a first-line agent for many patient groups. [1, 2, 3] Accessibility to medications accounts for a large proportion of overdoses in adults, [4] with CCBs accounting for over 35% of cardiac drug overdoses and an increased risk of death in the USA. [5]

Amlodipine, a dihydropyridine CCB, is one of the three most commonly prescribed antihypertensives in the South African public healthcare setting. [6, 7]. It has a higher affinity for smooth muscle L-type calcium channels than non-dihydropyridine CCBs. This specific affinity is lost at high doses, leading to peripheral vasodilation, reduced cardiac contractility, bradycardia or tachycardia, and shock. [8] These drugs are lipid-soluble, protein-bound, have a large volume of distribution, and cannot be removed by hemodiafiltration or charcoal hemoperfusion. [8, 9] Further, CCB overdose may saturate the hepatic enzymes responsible for its metabolism and reduce the first-pass effects, increasing systemic concentrations of the active drug.[8]

Anecdotal evidence suggests that CCB overdose is a common cause of hospitalization and ICU stays, but recent data on its prevalence and outcomes in South Africa is lacking. [1, 10, 11] Since clinical outcomes depend on treatment strategies, detailing the therapies used in our setting would provide context to current ICU outcomes. Most of the evidence however is based on animal data outcomes, human case series and observational studies with physiological endpoints. [12] There are currently no clinical studies on the effects of modern resin hemoadsorption therapy in ICU patients with calcium channel blocker overdose, especially concerning its impact on platelet counts. [13] Therefore, in this retrospective study, we describe the admission frequency, and outcomes and explore management strategies, including HA therapy in patients admitted to our ICU for CCB overdose over a three-year study period.

Study design and setting

We performed a retrospective observational study to describe the admission frequency, management strategies employed, and ICU outcomes of calcium channel blocker overdose (CCB) admissions to a tertiary-level academic adult ICU from 1st January 2020 to 31st December 2022 at the Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa. This hospital serves 1.5 million people in Soweto and acts as the tertiary referral centre for much of Gauteng, North West, parts of the Northern Cape, and informally to most of South Africa. We followed the STROBE guidelines/checklist for observational studies.

Inclusion criteria

Clinical features of CCB overdose (hypotension, bradycardia/compensatory tachycardia, signs of heart failure, hyperglycemia) and confirmation by family members of the drugs ingested (amlodipine) by providing empty packaging of the ingested drug which in our setting is done with suicidal intent.

Exclusion criteria

Polypharmacy patients with a predominant other toxidrome e.g. cholinergic, adrenergic etc. Family confirmation of the CCB was not recorded.

Data collection

Clinical data, laboratory information, and blood gas lactate levels from the first 48 hours were extracted from patient records into an electronic database. ICU management information and ICU survival were documented.

ICU management strategies for CCB overdose

Standard of Care (SoC)

Standard of care (SoC) comprised fluid optimisation, intravenous calcium (Ca), vasopressor therapy (noradrenaline and/or adrenaline), and high-dose insulin euglycaemic therapy (HIET), while rescue therapies included methylene blue. [1, 4] Supportive management was applied as per usual care.

Hemoadsorption therapy (HA)

Modern resin hemoadsorption therapy is available for toxicology cases in our ICU and is being increasingly utilised. HA therapy was defined as the standard of care plus modern resin hemoadsorption therapy. HA therapy was applied using the HA-230 Jafron filter, Zhuhai City, China. It consisted of two therapies each of six hours duration using an extracorporeal renal circuit with 500ml of predilution therapy. The 2 cycles were performed on separate consecutive days, beginning during the first 48 hours. A continuous renal replacement circuit and hemofilter (ST-150 set) were used with the Prismaflex system (Baxter). Our selected mode was continuous veno-venous hemofiltration (CVVH) with predilution and no postdilution. The HA-230 filter was positioned in series between the access limb of the circuit and the hemofilter. The blood pump speed was set between 150 and 180 ml/minute. Heparin 20 units/kg body weight was administered into the circuit as a bolus and then continued at 15ml/kg/hour for the 6-hour hemoadsorption duration. Figure 1 illustrates the circuit setup used. The predilution rate of 500ml/hour was intended to enhance circuit patency. Amlodipine is almost completely protein-bound and there was no expectation of drug removal using convection/hemofiltration. This decision to initiate HA therapy was made by the on-call Intensivist based on severe disease not responding to all available first and second-line therapies as described in the available standard care.

Sample size and statistical analysis

The primary outcome was to describe the admission frequency, management strategies and outcomes (length of ICU stay (LOS) and ICU mortality) of suspected CCB overdose. The management strategies included a description of the utilised in the ICU, clinical evolution (haemodynamic and lactate profiles during the first 48 hours, maximum and minimum platelet counts, durations of vasopressor therapy, mechanical ventilation (MV), and high-dose insulin euglycaemic therapy (HIET).

Descriptive statistics on baseline characteristics assumed a non-normal distribution (small sample size). Admission frequency was calculated as the proportion of CCB ICU admissions of all ICU admissions during the study period. Independent medians were compared using the Mann-Whitney U test. Proportions were compared using the Chi-square test/ Fisher exact test. Logistic regression was used to determine independent predictors of HA therapy. Statistical analysis was conducted using Statistica version 13.3 (TIBCO, USA). A 0.05 level of significance was assumed for all analyses.

Of the 1719 ICU admissions over the study period, 292 (17%) had toxin ingestion and 28 admissions were referred with CCB overdose (Fig. 2). Four participants did not meet the clinical criteria of CCB overdose and were excluded from the analysis. The admission frequency of CCB overdose was 1,4% (95% Confidence interval 0-3.8%) of all admissions. The median age was 19 (IQR: 18-26.6) and 23 (95.8% were female (Table 1). The median length of stay in the ICU was 8 days (5–10) and 3 of the 24 (12.5%) demised.

Management strategies in the ICU

The frequency of different interventions is provided in Table 2. All patients required intravenous fluid therapy administered based on volume responsiveness. Although not always statistically significant, the HA group had greater utilization of mechanical ventilation, vasopressor support, and HIET therapy. See Table 2. The duration of cardiovascular and ventilatory support is provided in Table 3. The median length of stay in the ICU was significantly longer in the HA group 9 days (IQR 8–12) compared to 5 days (IQR 4–8) in the SoC group, p = 0.004. Although mortality in the ICU was lower in the HA group (1/13, 7.7%) compared to the SoC group (2/11, 18.2%); this did not reach statistical significance, p = 0.44. Platelet counts were not significantly different between the HA and SoC groups. See Table 1.

Table 1: Baseline data

Variable	All (n=24)	HA (n=13)	SoC (n=11)	P
Age years, Median (IQR)	19 (18-26.6)	18 (18-26)	25 (19-28)	0.28
Weight kg, Median (IQR)	68.4 (60-74.5)	60 (60-70)	71 (62-90)	0.07
Female Gender n (%)	23/24 (95.8%)	11/12 (91.7%)	11/11 (100%)	1.0
Co-morbidities present, n (%)	6/24 (25%)	5/12 (41.7%)	1/11 (9.1%)	0.15
SAPS II, Median (IQR)	30 (24-32)	32 (30-35)	24 (18-27)	0.002*
Maximum total pressor dose ug/kg/min	1.18 (0.81-2.25)	2 (1.25-2.9)	0.75 (0-1.1)	0.001*
Insulin dose ≥100U/h	8/24 (33.4%)	8/13 (61.5%)	0/11	0.002*
Time to peak total pressor (h)	22.5 (5.5-37)	28 (11-37)	3 (0-37), n=7	0.12
Acute kidney injury	10/24 (41.7%)	7/13 (53.8%)	3/11 (27.3%)	0.19
Renal replacement therapy	8/24 (33.4%)	7/13 (53.8%)	1/11 (9%)	0.03*
Platelet count high (cells x 10⁹/l)	286 (234-362)	297 (238-384)	279 (230-319)	0.6
Platelet count low (cells x 10⁹/l)	156 (90-180)	121 (69-158)	173 (153-252)	0.06

*Significant p<0.05

Table 2: Frequency of interventions

Variable, Median (IQR)	All (n=24)	HA (n=13)	SC (n=11)	P
MV, n (%)	17/24 (71%)	13/13 (100%)	5/11 (45%)	0,003*
Vasopressor, n (%)	22/24 (92%)	13/13 100%)	9/11 (82%)	0.1
Adrenaline, n (%)	22/24 (92%)	13/13 100%)	9/11 (82%)	0.1
Noradrenaline, n (%)	11/24 (46%)	7/13 (54%)	4/11 (36%)	0.39
Calcium, n (%)	10/24 (42%)	6/13 (46%)	4/11 (36%)	0.68
HIET, n (%)	17/24 (71%)	11/13 (85%)	6/11 (55%)	0.1
Methylene blue n (%)	1/24 (4%)	1/12 (8%)	0/11 (0%)	0.34

*Significant p<0.05, MV= mechanical ventilation

Table 3: Duration of Organ support

Variable, Median (IQR)	All	HA (n=11)	SC (n=11)	p
Vasopressor duration, Median (IQR)	4.5 (3-6)	6 (4-10)	3 (2-5)	0.008*
MV duration, Median (IQR)	5 (0-7)	7 (5-11) n=10	0 (0-5)	0.006*
HIET days, Median (IQR)	1.25 (0-4)	1.25 (0-3)	3 (0-5) n=10	0.76

*Significant p<0.05

Clinical evolution: Haemodynamic profile over the first 48 hours of admission

There was a significantly lower admission mean arterial pressure (MAP1) and a significantly greater increase at 48h in the HA group. Maximum total vasopressor dose (Noradrenaline + Adrenaline) was significantly higher in the HA group compared to the SoC group and the time to peak vasopressor dose trended later in the HA group (28h vs 3 h). See Tables 1 and 4.

Table 4: Mean arterial pressure (MAP)

Variable, Median (IQR)	All (n=21)	HA (n=12)	SoC (n=9)	p
MAP 1 h, mmHg	63 (62-70)	62 (57.5-65)	72 (63-74)	0.014*
MAP 48 h, mmHg	73 (68-82)	73 (67-82) n=13	74.5 (70-84) n=8	0.65
MAP change at 48h, mmHg	14 (5-16)	16 (12-20) n=13	7 (-2-14) n=8	0.044*

h=hours, *Significant p<0.05

Clinical evolution: Changes in lactate (mmol/l) over the first day of ICU admission

There were no significant differences in lactate levels on admission to ICU (p = 0.93). The median lactate in the HA group peaked at 14 hours post-admission and was significantly higher than the SoC lactate (p = 0.028). Lactate levels in the SoC group peaked at 3 hours and reached a nadir at 14 hours, while levels in both groups were similar again at 22 hours (p = 0.11). See Fig. 3.

* Significant difference between median HA and SC groups. Median lactate levels were similar at admission (T = 0 hours, p = 0.93) and at all time points during the first 24 hours except for T = 14 hours, p = 0.028. Median lactate levels in the SoC group peaked at T = 3 hours, while in the HA group, they peaked at T = 14 hours. Peak lactate in the SoC group decreased over the next 11 hours to reach a nadir, while in the HA group, it decreased over the next 6 hours to reach its lowest at T = 20 hours. At this point, there was no significant difference between the 2 groups, p = 0.66

Predictors of use of HA therapy

We selected three variables (8 events per variable to avoid overfitting) that were significantly associated with HA therapy on univariate analysis (p < 0.05) and entered them into a logistic regression model. These were SAPS II score (severity of illness at baseline), initial mean arterial pressure and the use of RRT. SAPS II score independently predicted HA utilization, OR = 1.43 (95% CI 1.03–1.99).

The most important finding of this observational study was that amlodipine (CCB) accounts for 1.4% of ICU admissions, coupled with a high mortality rate. A recent review indicated a lack of data on the frequency of CCB in South Africa. [1] Outside of case reports, we could not find any specific local ICU data in the literature, and our data provides the first published estimate of the burden of amlodipine overdose in an ICU setting. Data from the Danish Poison Information Center (DPIC) indicated that amlodipine accounted for 71% of all CCB enquiries, supporting the significance of our finding. [14] Furthermore, the American Association of Poison Control Centers’ National Poison Data System reported 6132 cases of calcium channel blocker overdose in the United States of America. [5] This 2020 report detailed a 2.4% major adverse event rate including death. According to the DPIC data from a 5-year period in the past decade, the 30-day hospital mortality rate from intentional CCB overdose was 2% and amlodipine was involved in 29% of fatalities. [14] The mortality rate in our study was about 6-fold higher (12.5%) likely reflecting the mortality in a critically ill population requiring ICU care.

Another striking finding from our data was the female preponderance (95% female gender). The DPIC data also reflected a majority of female cases (61%). [14] The gender paradox in suicidology has been well described with a greater frequency of nonfatal suicide attempts in females compared to males. In addition, drug or toxin use in females has been reported to be more common than violent methods [15).

The frequency of interventions in the ICU used to treat CCB overdose reflects current guidelines. [12, 16, 17, 18] All patients required fluid therapy (IV), over 90% required vasopressor support with noradrenaline, adrenaline, or both, about 70% required high-dose insulin euglycaemic therapy (HIET), and 42% required ongoing calcium in ICU. These measures are indicative of first-line treatment published in consensus guidelines. [17] Rescue therapy availability is limited in our setting. Methylene blue is intermittently available, intralipid therapy and extracorporeal membrane oxygenation (veno-arterial) are unavailable. Lipid therapy has been noted to be ineffective in CCB overdose involving dihydropyridines [19]

In addition to standard of care, hemoadsorption therapy (HA) is available and used for protein and lipid-bound toxins in severe poisoning. Based on the physical characteristics of CCBs modern resin hemoadsorption devices could be useful to enhance the elimination of these drugs. [20] Data from an ex-vivo model demonstrated the effective removal of amlodipine using a modern resin adsorption filter similar to the one available in our setting. [21] Removal of amlodipine in a clinical setting, using a styrene resin adsorption filter with associated shock resolution and good clinical outcome has also been suggested. [22] Current EXTRIP guidelines recommend against the use of extra-corporeal therapy for CCB overdose. [23] However, this guideline is based on hemodiafiltration and older charcoal adsorption filter technology. [24] Consideration of the affinity for protein-bound substances that modern resin adsorption filters possess may have been overlooked. [20]

Patients receiving HA therapy had a significantly higher SAPS II score indicating greater severity of illness and higher predicted mortality compared to standard care (SoC). The total maximum vasopressor dose (adrenaline and noradrenaline) was also significantly higher. This reflects the use of HA therapy in patients who were refractory to standard care. Despite a significantly lower mean arterial pressure (MAP), there was a greater recovery in the HA group's 48-hour mean arterial pressure profile. It is plausible that HA therapy may have contributed to the haemodynamic recovery.

Due to the greater haemodynamic instability, initiation of HIET therapy was more frequent in the HA group (85% vs 55%) and significantly higher doses were administered. Despite this, we noted a trend toward a shorter duration of HIET in the HA group compared to the SC group (about 1 day vs. 3 days). There is scarce data on modern hemoadsorption therapy and amlodipine overdose. We postulate that hemoadsorption therapy enhanced the clearance of amlodipine, potentially contributing to a shorter duration of HIET therapy and improved hemodynamic stability, despite initially higher vasopressor doses. [21, 22] We further speculate that additional potential benefits of less HIET therapy could be due to the limitation of adverse effects of this therapy. These are hypoglycemia, hypokalemia, hypomagnesemia, hypophosphatemia and volume overload related to glucose and electrolyte replacement. [25, 26, 27]

Important data from our study reinforces the greater severity of disease in the HA group compared to the SC group with longer durations of vasopressors, mechanical ventilation, and length ICU of stay. Despite this greater severity of disease and the higher predicted mortality in the HA group, there was only one death in the HA group (1/13) 7.7% and two in the SoC group (2/11) 18.2%. This possible mortality benefit of HA therapy needs further exploration.

Our study provides important detail regarding the changes in lactate during the first day of shock from CCB overdose. Median lactate levels were similar at ICU admission. Median lactate levels in the SoC group peaked early, at 3 hours, and cleared slowly over the next 11 hours to reach a low at 14 hours, coinciding with the peak of the HA group. The HA peak lactate decreased to its 24-hour nadir within the next 6 hours, corresponding to approximately half the time of the SoC group. If the reduction of lactate over time is an estimate of lactate clearance this may indicate a faster resolution of a global oxygen delivery deficit (shock) in the HA group. [28] Improved lactate clearance has also been shown to affect mortality independent of its effect on organ support. [29] The potential higher lactate clearance in the HA group needs to be further explored as it may indicate faster shock resolution, increased extracorporeal lactate removal or both.

The lactate peak was significantly greater in the HA group vs. the SoC group and occurred later. This is in keeping with ongoing slower amlodipine absorption from the gastrointestinal tract, possibly with higher doses and associated delayed peak hemodynamic effects as supported by the longer time to peak vasopressor dose in the HA group. Additionally, saturation of the hepatic enzymes may reduce the first pass effect and contribute to ongoing shock from an apparent prolonged T_1/2 and toxic effects with a delayed peak lactate. [8]

Lastly, an important complication of hemoadsorption/hemoperfusion therapy is thrombocytopenia. We found no significant difference in the maximum and minimum platelet counts between the HA and SC groups during the ICU stay. Previous utilisation of this hemoadsorption filter also demonstrated no significant changes in platelet counts or transfusion requirements.[30] This finding provides much-needed safety information regarding HA therapy.

Limitations

This was an observational study with a small sample size. However, it is notable that current guidelines suggest first-line treatment strategies with low levels of evidence. Being retrospective, the study is open to bias and confounding. However, we have described both groups of patients in terms of their predicted risk using underlying physiology and organ function and support. We have also used detailed chronological changes in important clinical parameters to improve characterization of the groups. Finally, the study data was from a single centre limiting the validity of findings even though it represents the only ICU description of CCB overdose that we are aware of.

Calcium channel blocker overdose is an important and life-threatening cause of toxicology admissions in the ICU. Hemoadsorption therapy may contribute to improved haemodynamic stability providing a safe and important rescue therapy in cases with refractory shock. Well-designed studies are required to confirm its role in enhancing drug clearance thereby improving the haemodynamic state and clinical outcomes.

Acknowledgement (optional)

None

Statement of Ethics

Study approval statement: This study protocol was reviewed and approved by the following Ethical review board: Human Research Ethics Committee (Medical) [HREC] affiliated with the University of Witwatersrand, approval number [M220276]. The approval date was the 14^th of March 2022.

Consent to participate statement: Due to the retrospective and observational nature of the study, the requirement for informed consent was waived by the Ethics committee.

Conflict of Interest Statement

Shahed Omar received honoraria from Jafron Biomedical to the value of ZAR 38 000 (approximately USD 2200) for Webinars during 2020 and 2021,2022.

Funding Sources

Due to the retrospective nature of the study, the costs of the study were limited and funded by the investigators. The largest cost will be the publication cost. This will be covered by the authors if there is no University agreement with the publishers.

This study was not supported by any sponsor or funder.

Author Contributions

SOconceived the idea, designed the protocol and was involved in the analysis and interpretation of the work, created the first draft, approved the final version and agreed to be accountable for all aspects of the work.

VS contributed to the development of the protocol, designed the data collection sheets, collected the data, checked the integrity of the data, and contributed to the manuscript and its revision, approved the final draft and agreed to be accountable for all aspects of the work.

AK contributed to the manuscript and its revision, approved the final draft and agreed to be accountable for all aspects of the work.

ZD was instrumental in planning the manuscript and its revision, approved the final draft and agreed to be accountable for all aspects of the work.

Data Availability Statement

An electronic copy of de-identified data is available on request from the corresponding author. The data that support the findings of this study are not publicly available to avoid compromising the privacy of research participants, however, de-identified data are available from the corresponding author [SO] [[email protected]] upon reasonable request.

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Competing interest reported. Shahed Omar received honoraria from Jafron Biomedical to the value of ZAR 38 000 (approximately USD 2200) for Webinars on hemoadsorption therapy during 2020 and 2021,2022 and 2023. All other authors have no conflicts of interest to declare.

Hemoadsorption therapy for calcium channel blocker (CCB) overdose at a tertiary-level Intensive care unit in South Africa. A retrospective study

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