- Email: [email protected]
Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine
Accepted Manuscript Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine Chris J. Kapelios, MD, George Karamanakos, MD, Stavros Liatis, MD, Ph.D, Magda Sarafadi, MD, Marios Polizois, MD, Ioannis Papoutsis, MD, Ph.D, Alexander D. Kokkinos, MD, Ph.D PII:
S1109-9666(16)30336-0
DOI:
10.1016/j.hjc.2016.12.001
Reference:
HJC 99
To appear in:
Hellenic Journal of Cardiology
Received Date: 24 November 2016 Revised Date:
5 December 2016
Accepted Date: 8 December 2016
Please cite this article as: Kapelios CJ, Karamanakos G, Liatis S, Sarafadi M, Polizois M, Papoutsis I, Kokkinos AD, Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2016.12.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine
Chris J. Kapelios [1], MD, George Karamanakos [2], MD, Stavros Liatis [2], MD,
RI PT
Ph.D., Magda Sarafadi [2], MD, Marios Polizois [2], MD, Ioannis Papoutsis [3], MD, Ph.D., Alexander D. Kokkinos [2], MD, Ph.D.
SC
[1] Department of Cardiology, Laiko General Hospital, Athens, Greece
[2] First Department of Propaedeutic Medicine, Medical School, National and
M AN U
Kapodistrian University of Athens, Athens, Greece
[2] Department of Forensic Medicine and Toxicology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Short title: Shock after amlodipine poisoning
TE D
Key words: hypotension; renal failure; overdose Address for correspondence:
EP
Chris J. Kapelios, MD
Department of Cardiology, Laiko General Hospital, Athens, Greece
AC C
67 Mikras Asias Street, 11 527, Athens, Greece Tel: +30 6980 489580
Fax: +30 210 7791839
e-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract Calcium channel blockers (CCBs) have a narrow therapeutic index, and their intake in excess is associated with a critical clinical presentation of sustained
RI PT
hypotension and non-cardiogenic pulmonary edema, which are difficult to treat. Unfortunately, available means of treatment fail to resuscitate a significant number of patients poisoned by CCBs, rendering them the main cardiovascular drugs
SC
involved in deaths due to overdose. Importantly, in all cases reported until now in
M AN U
the literature, CCB intoxication was known at the time of the patients’ presentation and the medical challenge regarded solely the therapeutic approach. In this case report, we describe our experience in treating a 72-year-old patient with recurrent episodes of sustained hypotension refractory to crystalloid and vasoconstrictor Prolonged
pharmacologic
support
and
intermittent
sessions
of
TE D
infusions.
hemofiltration induced stabilization and recovery. An extensive diagnostic workup
EP
to elucidate the cause was unfruitful. The recurrent and paroxysmal nature of clinical presentation along with its incidence after the patient’s leaving the protected
AC C
setting of the hospital led the diagnostic approach towards a possible external factor, which proved to be, after toxicological investigation, unintentional amlodipine intoxication.
2
ACCEPTED MANUSCRIPT To the editor: Calcium channel blockers (CCBs) represent a classic drug in clinician’s armamentarium for treatment of arterial hypertension. [1] Importantly, CCBs
RI PT
constitute the main category of cardiovascular drug involved in intoxication and have been implicated in up to 48% of deaths resulting from overdose. [2,3] CCB poisoning may present with a multitude of clinical features, [4] but typical
SC
presentation includes refractory hypotension, which is unresponsive to intravenous
M AN U
fluids and vasoactive medications, non-cardiogenic pulmonary edema, acute respiratory distress syndrome, and brady- or tachycardia. [4,5] We report the case of a 72-year-old man, with an 18-year history of arterial hypertension presented to the emergency department of our hospital with severe
TE D
sustained systemic hypotension over the past 4 hours.
The patient’s history starts 2 months previously, when he was hospitalized
EP
for a reported syncopal episode, which was attributed to amiodarone overdosing (400 instead of 200 mg). Two weeks later the patient visited the same hospital for a
AC C
reported episode of hypoglycemia, on the basis of known type 2 diabetes mellitus for which he was receiving subcutaneous insulin, and hypotension, which was restored with the intravenous administration of crystalloids. The patient returned home and was admitted to the intensive care unit of another tertiary hospital the day after, due to systemic hypotension (systolic arterial pressure [SAP] <40 mmHg) and hypoxemia. Laboratory panel revealed elevated d-dimer levels (>60 times the upper normal limit) and echocardiogram showed a severely hypokinetic and dilated right 3
ACCEPTED MANUSCRIPT ventricle with suppressed left ventricular contractility (ejection fraction~45%). The patient was administered thrombolysis based on a tentative diagnosis of massive pulmonary embolism. His condition did not improve significantly and he remained
RI PT
on hemodynamic support, while his renal function deteriorated and had to be treated with intermittent hemodialysis due to volume overload.
The patient
underwent a pulmonary perfusion scintigram which was negative for the presence
SC
of pulmonary embolism or chronic thromboembolic disease. After improvement, he
M AN U
was discharged on day 17 with the recommendation to discontinue antihypertensive medication, which consisted of 10 mg amlodipine and 320 mg valsartan.
The following day the patient was admitted to our hospital due to a new
TE D
episode of refractory hypotension (SAP 70mmHg). Despite being afebrile, a culture from his previous hospitalization reported the presence of Klebsiella pneumoniae ESBL
EP
(+) in his urine. He was started on intravenous meropenem and noradrenaline as empiric treatment for presumed septic shock. Due to anuria, acute renal failure and
AC C
dyspnea, he underwent hemodialysis. CT scan precluded the presence of pulmonary embolism and showed diffuse parenchymal infiltrates with bilateral pleural effusions, which proved to be transudates after aspiration. The patient’s renal function gradually improved and the vasoconstrictors were discontinued on day six. During his stay the patient underwent a new echocardiogram which did not reveal significant abnormal findings. The patient was also submitted to testing for orthostatic hypotension, baroreflex sensitivity and heart rate variability, the results 4
ACCEPTED MANUSCRIPT of which were inconsistent with serious cardiac autonomic dysfunction. He was discharged on day 25, in good clinical condition, with an appointment to undergo a tilt-test and a coronary angiogram during the following week.
RI PT
The patient was re-admitted 16 hours later due to sustained hypotension. At presentation, he had a systemic arterial pressure of 70/50mmHg, 76 bpm and normal lung and heart auscultation. His jugular venous pressure was within normal range
SC
and his limbs were cold and dry. The rest of his physical examination was
M AN U
unremarkable apart from bilateral, fine hand tremor and mild weakness of the extremities. From his laboratory findings at presentation anemia (haemoglobin of 10.3gr/dl), severe hyperglycemia (glucose of 342mg/dl), and renal dysfunction (serum creatinine 2.1mg/dl) were notable. The patient was oliguric. Laboratory tests
TE D
revealed serum creatine phosphokinase and troponine levels within normal range. Serum levels of thyroid stimulating hormone, cortisole, adrenocorticotropic
EP
hormone and tryptase were also normal. Multiple urine and blood cultures were negative. The patient’s EKG and chest x-ray were unremarkable.
AC C
The patient was admitted to the hospital and administered high doses of intravenous vasoconstrictors and mineralocorticoids for 3 days. Glycemic control was achieved with an intravenous insulin drip. The patient underwent sessions of ultrafiltration (every other day for 4 sessions in total) with progressive improvement of symptoms and restoration of diuresis. He was weaned from vasoconstrictors on day 7. Thereafter, his clinical and laboratory course improved on a daily basis.
5
ACCEPTED MANUSCRIPT Due to the paroxysmal nature of the episodes, which occurred immediately after discharge from the “safe and protected” environment of the hospital, a urine sample obtained on admission was sent to the toxicology department for analysis.
RI PT
Based on the patient’s symptoms and signs, the diagnostic suspicion was directed towards possible intoxication with cardiovascular medication. Namely, CCB poisoning was most compatible with the patient’s clinical presentation.
SC
Within the frame of the toxicological investigation of the case, screening tests
M AN U
for all groups of drugs of abuse (opiates, cannabinoids, cocaine, amphetamine type stimulants and benzodiazepines) were performed by immunoassay (VIVA-E, Siemens Healthcare Global, Erlangen, Germany) in the patient’s urine sample and results were negative. A general screening of his urine sample for unknown
TE D
medicinal drugs was also carried out using a GC/MS method. The results of the toxicological analysis, which were available ten days after the patient’s admission,
EP
showed the presence of high levels of amlodipine in the patient’s urine sample. The identification of amlodipine in the patient’s urine sample was based on the retention
AC C
time of amlodipine’s peak, as well as on the matching with amlodipine’s mass spectrum.
The patient reported having discontinued the medication 40 days ago, but the
drug was still available at his residence. Psychiatric evaluation did not verify suspicions of self-inflicted illness, due to depression, which has been previously associated with hypertension, [6] and neurological assessment did not reveal signs of dementia. Due to circumstantial evidence of malignant exogenous administration of 6
ACCEPTED MANUSCRIPT the medication, the legal department of the hospital recommended that the patient be informed about the diagnosis in the presence of all involved family members. After discharge from the hospital, the patient moved to a new residence with
RI PT
different cohabitants. Ten months after discharge, no recurrence of hypotensive episodes has been reported.
CCBs directly inhibit the opening of voltage-gated L-type calcium channels
Consequently,
they
interfere
with
sino-atrial
node
M AN U
excitation-contraction.
SC
inside cardiac and vascular smooth muscle cells during the slow inward phase of
depolarization, myocardial electromechanical coupling, and vascular muscle tone. [7] CCBs also inhibit L-type calcium channels in pancreatic islet cells, reducing insulin secretion, and decrease insulin sensitivity and tissue glucose uptake,
TE D
resulting in substantial hyperglycemia and acidosis. [7] Such reductions in tissue glucose uptake may perpetuate decreases in cardiac inotropy and peripheral
EP
vascular resistance. [5] Thus, hypotension from CCB poisoning can be multifactorial and result from a combination of negative myocardial inotropy and chronotropy as
AC C
well as peripheral vasodilation. [7] Amlodipine overdose predominately affects vascular smooth muscle tone, leading to vasoparalysis and subsequent vasodilatory shock [8]. Direct cardiac toxicity with amlodipine, from loss of vascular smooth muscle calcium-channel specificity, has been observed in large overdoses and in children [9]. However, amlodipine is the most benign among dihydropyridines in terms of cardiac contractility depression. [10] Nonetheless, in the case of our patient
7
ACCEPTED MANUSCRIPT a repeated, large amlodipine overdose had led to severely depressed cardiac function, especially of the right ventricle, during prior hospitalization. Initial measures CCB overdose typically include intravenous infusions of
management
or
QRS
widening,
vasopressor
RI PT
crystalloids. Subsequent steps consist of sodium bicarbonate infusions for acidosis administration
for
resistant
hypotension, and intravenous atropine for symptomatic bradycardia. Some patients
SC
may also require cardiac pacing due to severe cardiovascular collapse or
M AN U
endotracheal intubation and mechanical ventilation for ARDS management. [10] Hyperinsulinemia-euglycemia therapy, glucagon, calcium gluconate, adrenergic agonists, intravenous lipid emulsion therapy, phosphodiesterase inhibitors and invasive therapy have been used with inconsistent efficacy.
TE D
In conclusion, CCB overdose is complicated by a serious, though varying, clinical presentation. The lack of a standardized, evidence-based approach for the
EP
management of CCB poisoning leads to divergent strategies in clinical practice and persistently high mortality rates. The absence of a known history of CCB intoxication
AC C
at the time of presentation, as in our patient, renders the case not only a therapeutic but primarily a diagnostic challenge. Conflict of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment,
8
ACCEPTED MANUSCRIPT consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
RI PT
Acknowledgements
AC C
EP
TE D
M AN U
SC
None
9
ACCEPTED MANUSCRIPT References 1. Stefanadis CI. Management of arterial hypertension: from no treatment to renal denervation. Hellenic J Cardiol. 2015;56(3):277-8.
RI PT
2. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 annual report of the American Association Of Poison Control Centers’ National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila). 2012;50(10):911–1164.
SC
3. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual Report
M AN U
of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;52(10):1032-283. 4. Mokhlesi B, Leikin JB, Murray P, Corbridge TC. Adult toxicology in critical care: part II: specific poisonings. Chest. 2003;123(3):897–922.
TE D
5. Siddiqi TA, Hill J, Huckleberry Y, Parthasarathy S. Non-cardiogenic pulmonary edema and life-threatening shock due to calcium channel blocker overdose: a case
EP
report and clinical review. Respir Care. 2014;59(2):e15-21. 6. Mermerelis A, Kyvelou SM, Vellinga A, Papageorgiou C, Stefanadis C, Douzenis
AC C
A. Association between anxiety and depression symptoms with resistant hypertension and central hemodynamics: A pilot study. Hellenic J Cardiol. 2016;57(3):203-204.
7. Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016;81(3):453-61.
10
ACCEPTED MANUSCRIPT 8. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther. 1993;267(2):744–750.
RI PT
9. Benson BE, Spyker DA, Troutman WG, Watson WA, Bakhirev LN. Amlodipine toxicity in children less than 6 years of age: a dose–response analysis using National Poison Data System data. J Emerg Med 2010; 39:186–93.
AC C
EP
TE D
M AN U
overdoses. J Hosp Med. 2014;9(10):663-8.
SC
10. Shenoy S, Lankala S, Adigopula S. Management of calcium channel blocker
11
S1109-9666(16)30336-0
DOI:
10.1016/j.hjc.2016.12.001
Reference:
HJC 99
To appear in:
Hellenic Journal of Cardiology
Received Date: 24 November 2016 Revised Date:
5 December 2016
Accepted Date: 8 December 2016
Please cite this article as: Kapelios CJ, Karamanakos G, Liatis S, Sarafadi M, Polizois M, Papoutsis I, Kokkinos AD, Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2016.12.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine
Chris J. Kapelios [1], MD, George Karamanakos [2], MD, Stavros Liatis [2], MD,
RI PT
Ph.D., Magda Sarafadi [2], MD, Marios Polizois [2], MD, Ioannis Papoutsis [3], MD, Ph.D., Alexander D. Kokkinos [2], MD, Ph.D.
SC
[1] Department of Cardiology, Laiko General Hospital, Athens, Greece
[2] First Department of Propaedeutic Medicine, Medical School, National and
M AN U
Kapodistrian University of Athens, Athens, Greece
[2] Department of Forensic Medicine and Toxicology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Short title: Shock after amlodipine poisoning
TE D
Key words: hypotension; renal failure; overdose Address for correspondence:
EP
Chris J. Kapelios, MD
Department of Cardiology, Laiko General Hospital, Athens, Greece
AC C
67 Mikras Asias Street, 11 527, Athens, Greece Tel: +30 6980 489580
Fax: +30 210 7791839
e-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract Calcium channel blockers (CCBs) have a narrow therapeutic index, and their intake in excess is associated with a critical clinical presentation of sustained
RI PT
hypotension and non-cardiogenic pulmonary edema, which are difficult to treat. Unfortunately, available means of treatment fail to resuscitate a significant number of patients poisoned by CCBs, rendering them the main cardiovascular drugs
SC
involved in deaths due to overdose. Importantly, in all cases reported until now in
M AN U
the literature, CCB intoxication was known at the time of the patients’ presentation and the medical challenge regarded solely the therapeutic approach. In this case report, we describe our experience in treating a 72-year-old patient with recurrent episodes of sustained hypotension refractory to crystalloid and vasoconstrictor Prolonged
pharmacologic
support
and
intermittent
sessions
of
TE D
infusions.
hemofiltration induced stabilization and recovery. An extensive diagnostic workup
EP
to elucidate the cause was unfruitful. The recurrent and paroxysmal nature of clinical presentation along with its incidence after the patient’s leaving the protected
AC C
setting of the hospital led the diagnostic approach towards a possible external factor, which proved to be, after toxicological investigation, unintentional amlodipine intoxication.
2
ACCEPTED MANUSCRIPT To the editor: Calcium channel blockers (CCBs) represent a classic drug in clinician’s armamentarium for treatment of arterial hypertension. [1] Importantly, CCBs
RI PT
constitute the main category of cardiovascular drug involved in intoxication and have been implicated in up to 48% of deaths resulting from overdose. [2,3] CCB poisoning may present with a multitude of clinical features, [4] but typical
SC
presentation includes refractory hypotension, which is unresponsive to intravenous
M AN U
fluids and vasoactive medications, non-cardiogenic pulmonary edema, acute respiratory distress syndrome, and brady- or tachycardia. [4,5] We report the case of a 72-year-old man, with an 18-year history of arterial hypertension presented to the emergency department of our hospital with severe
TE D
sustained systemic hypotension over the past 4 hours.
The patient’s history starts 2 months previously, when he was hospitalized
EP
for a reported syncopal episode, which was attributed to amiodarone overdosing (400 instead of 200 mg). Two weeks later the patient visited the same hospital for a
AC C
reported episode of hypoglycemia, on the basis of known type 2 diabetes mellitus for which he was receiving subcutaneous insulin, and hypotension, which was restored with the intravenous administration of crystalloids. The patient returned home and was admitted to the intensive care unit of another tertiary hospital the day after, due to systemic hypotension (systolic arterial pressure [SAP] <40 mmHg) and hypoxemia. Laboratory panel revealed elevated d-dimer levels (>60 times the upper normal limit) and echocardiogram showed a severely hypokinetic and dilated right 3
ACCEPTED MANUSCRIPT ventricle with suppressed left ventricular contractility (ejection fraction~45%). The patient was administered thrombolysis based on a tentative diagnosis of massive pulmonary embolism. His condition did not improve significantly and he remained
RI PT
on hemodynamic support, while his renal function deteriorated and had to be treated with intermittent hemodialysis due to volume overload.
The patient
underwent a pulmonary perfusion scintigram which was negative for the presence
SC
of pulmonary embolism or chronic thromboembolic disease. After improvement, he
M AN U
was discharged on day 17 with the recommendation to discontinue antihypertensive medication, which consisted of 10 mg amlodipine and 320 mg valsartan.
The following day the patient was admitted to our hospital due to a new
TE D
episode of refractory hypotension (SAP 70mmHg). Despite being afebrile, a culture from his previous hospitalization reported the presence of Klebsiella pneumoniae ESBL
EP
(+) in his urine. He was started on intravenous meropenem and noradrenaline as empiric treatment for presumed septic shock. Due to anuria, acute renal failure and
AC C
dyspnea, he underwent hemodialysis. CT scan precluded the presence of pulmonary embolism and showed diffuse parenchymal infiltrates with bilateral pleural effusions, which proved to be transudates after aspiration. The patient’s renal function gradually improved and the vasoconstrictors were discontinued on day six. During his stay the patient underwent a new echocardiogram which did not reveal significant abnormal findings. The patient was also submitted to testing for orthostatic hypotension, baroreflex sensitivity and heart rate variability, the results 4
ACCEPTED MANUSCRIPT of which were inconsistent with serious cardiac autonomic dysfunction. He was discharged on day 25, in good clinical condition, with an appointment to undergo a tilt-test and a coronary angiogram during the following week.
RI PT
The patient was re-admitted 16 hours later due to sustained hypotension. At presentation, he had a systemic arterial pressure of 70/50mmHg, 76 bpm and normal lung and heart auscultation. His jugular venous pressure was within normal range
SC
and his limbs were cold and dry. The rest of his physical examination was
M AN U
unremarkable apart from bilateral, fine hand tremor and mild weakness of the extremities. From his laboratory findings at presentation anemia (haemoglobin of 10.3gr/dl), severe hyperglycemia (glucose of 342mg/dl), and renal dysfunction (serum creatinine 2.1mg/dl) were notable. The patient was oliguric. Laboratory tests
TE D
revealed serum creatine phosphokinase and troponine levels within normal range. Serum levels of thyroid stimulating hormone, cortisole, adrenocorticotropic
EP
hormone and tryptase were also normal. Multiple urine and blood cultures were negative. The patient’s EKG and chest x-ray were unremarkable.
AC C
The patient was admitted to the hospital and administered high doses of intravenous vasoconstrictors and mineralocorticoids for 3 days. Glycemic control was achieved with an intravenous insulin drip. The patient underwent sessions of ultrafiltration (every other day for 4 sessions in total) with progressive improvement of symptoms and restoration of diuresis. He was weaned from vasoconstrictors on day 7. Thereafter, his clinical and laboratory course improved on a daily basis.
5
ACCEPTED MANUSCRIPT Due to the paroxysmal nature of the episodes, which occurred immediately after discharge from the “safe and protected” environment of the hospital, a urine sample obtained on admission was sent to the toxicology department for analysis.
RI PT
Based on the patient’s symptoms and signs, the diagnostic suspicion was directed towards possible intoxication with cardiovascular medication. Namely, CCB poisoning was most compatible with the patient’s clinical presentation.
SC
Within the frame of the toxicological investigation of the case, screening tests
M AN U
for all groups of drugs of abuse (opiates, cannabinoids, cocaine, amphetamine type stimulants and benzodiazepines) were performed by immunoassay (VIVA-E, Siemens Healthcare Global, Erlangen, Germany) in the patient’s urine sample and results were negative. A general screening of his urine sample for unknown
TE D
medicinal drugs was also carried out using a GC/MS method. The results of the toxicological analysis, which were available ten days after the patient’s admission,
EP
showed the presence of high levels of amlodipine in the patient’s urine sample. The identification of amlodipine in the patient’s urine sample was based on the retention
AC C
time of amlodipine’s peak, as well as on the matching with amlodipine’s mass spectrum.
The patient reported having discontinued the medication 40 days ago, but the
drug was still available at his residence. Psychiatric evaluation did not verify suspicions of self-inflicted illness, due to depression, which has been previously associated with hypertension, [6] and neurological assessment did not reveal signs of dementia. Due to circumstantial evidence of malignant exogenous administration of 6
ACCEPTED MANUSCRIPT the medication, the legal department of the hospital recommended that the patient be informed about the diagnosis in the presence of all involved family members. After discharge from the hospital, the patient moved to a new residence with
RI PT
different cohabitants. Ten months after discharge, no recurrence of hypotensive episodes has been reported.
CCBs directly inhibit the opening of voltage-gated L-type calcium channels
Consequently,
they
interfere
with
sino-atrial
node
M AN U
excitation-contraction.
SC
inside cardiac and vascular smooth muscle cells during the slow inward phase of
depolarization, myocardial electromechanical coupling, and vascular muscle tone. [7] CCBs also inhibit L-type calcium channels in pancreatic islet cells, reducing insulin secretion, and decrease insulin sensitivity and tissue glucose uptake,
TE D
resulting in substantial hyperglycemia and acidosis. [7] Such reductions in tissue glucose uptake may perpetuate decreases in cardiac inotropy and peripheral
EP
vascular resistance. [5] Thus, hypotension from CCB poisoning can be multifactorial and result from a combination of negative myocardial inotropy and chronotropy as
AC C
well as peripheral vasodilation. [7] Amlodipine overdose predominately affects vascular smooth muscle tone, leading to vasoparalysis and subsequent vasodilatory shock [8]. Direct cardiac toxicity with amlodipine, from loss of vascular smooth muscle calcium-channel specificity, has been observed in large overdoses and in children [9]. However, amlodipine is the most benign among dihydropyridines in terms of cardiac contractility depression. [10] Nonetheless, in the case of our patient
7
ACCEPTED MANUSCRIPT a repeated, large amlodipine overdose had led to severely depressed cardiac function, especially of the right ventricle, during prior hospitalization. Initial measures CCB overdose typically include intravenous infusions of
management
or
QRS
widening,
vasopressor
RI PT
crystalloids. Subsequent steps consist of sodium bicarbonate infusions for acidosis administration
for
resistant
hypotension, and intravenous atropine for symptomatic bradycardia. Some patients
SC
may also require cardiac pacing due to severe cardiovascular collapse or
M AN U
endotracheal intubation and mechanical ventilation for ARDS management. [10] Hyperinsulinemia-euglycemia therapy, glucagon, calcium gluconate, adrenergic agonists, intravenous lipid emulsion therapy, phosphodiesterase inhibitors and invasive therapy have been used with inconsistent efficacy.
TE D
In conclusion, CCB overdose is complicated by a serious, though varying, clinical presentation. The lack of a standardized, evidence-based approach for the
EP
management of CCB poisoning leads to divergent strategies in clinical practice and persistently high mortality rates. The absence of a known history of CCB intoxication
AC C
at the time of presentation, as in our patient, renders the case not only a therapeutic but primarily a diagnostic challenge. Conflict of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment,
8
ACCEPTED MANUSCRIPT consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
RI PT
Acknowledgements
AC C
EP
TE D
M AN U
SC
None
9
ACCEPTED MANUSCRIPT References 1. Stefanadis CI. Management of arterial hypertension: from no treatment to renal denervation. Hellenic J Cardiol. 2015;56(3):277-8.
RI PT
2. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 annual report of the American Association Of Poison Control Centers’ National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila). 2012;50(10):911–1164.
SC
3. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual Report
M AN U
of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;52(10):1032-283. 4. Mokhlesi B, Leikin JB, Murray P, Corbridge TC. Adult toxicology in critical care: part II: specific poisonings. Chest. 2003;123(3):897–922.
TE D
5. Siddiqi TA, Hill J, Huckleberry Y, Parthasarathy S. Non-cardiogenic pulmonary edema and life-threatening shock due to calcium channel blocker overdose: a case
EP
report and clinical review. Respir Care. 2014;59(2):e15-21. 6. Mermerelis A, Kyvelou SM, Vellinga A, Papageorgiou C, Stefanadis C, Douzenis
AC C
A. Association between anxiety and depression symptoms with resistant hypertension and central hemodynamics: A pilot study. Hellenic J Cardiol. 2016;57(3):203-204.
7. Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016;81(3):453-61.
10
ACCEPTED MANUSCRIPT 8. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther. 1993;267(2):744–750.
RI PT
9. Benson BE, Spyker DA, Troutman WG, Watson WA, Bakhirev LN. Amlodipine toxicity in children less than 6 years of age: a dose–response analysis using National Poison Data System data. J Emerg Med 2010; 39:186–93.
AC C
EP
TE D
M AN U
overdoses. J Hosp Med. 2014;9(10):663-8.
SC
10. Shenoy S, Lankala S, Adigopula S. Management of calcium channel blocker
11