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ICU DIRECTOR
vol. X ■ no. X
Prolonged Refractory Hypotension Secondary to
Amlodipine Overdose
A Therapeutic Challenge
Shrinivas Kambali, MD, Raed Alalawi, MD, FACP, and Kenneth Nugent,[AQ: 1] MD, FACP
Abstract: Calcium channel blocker overdose is one of the
leading causes of overdose death among cardiovascular medications. We present a patient with the highest reported dose
of amlodipine ingestion in combination pill. She was asymptomatic initially and soon became hypotensive and obtunded.
She was intubated for airway protection, gastric lavage was
done, and activated charcoal was given. She was resuscitated
with 4L 0.9% normal saline, calcium chloride, glucagon, insulin, and glucose infusions. Her hypotension worsened necessitating use of norepinephrine 200 µg/min, phenylephrine 200 µg/min, dopamine 50 µg/kg/min, and
vasopressin 0.06 U/min concurrently. She continued
to improve and was weaned off vasopressors and
mechanical ventilation. Few cases of extremely highdose ingestion have been reported. Patients may be
normotensive but rapidly progress to shock depending on ingested dose. High doses are associated with
shock, bradycardia, pulmonary edema, renal failure, and heart failure. The primary goal is to maintain adequate circulation. Therapy includes intravenous fluids, insulin, glucagon, vasopressors, calcium
infusion, and atropine. Based on our patient and a
review of literature, we conclude that patients with
near-fatal calcium channel blocker ingestion usually
have good outcomes with appropriate use of highdose vasopressors, glucagon, and insulin.
11.5% of the cardiovascular drug overdoses, they account for
34% of deaths in 2011. These drugs are widely used and may
cause more complicated overdoses because they have long
half-life and come in sustained release preparations. CCBs can
be divided into 2 major categories: the dihydropyridines, which
preferentially block the L-type calcium channels in the vasculature, and the nondihydropyridines, which selectively block
L-type calcium channels in the myocardium. The calcium influx
through the channels causes myocardial and vascular smooth
muscle contractility and
also affects conducting
and pacemaker cells.1,3,4
We present a unique
case of acute intentional
overdose of the combination pill Tribenzor
(olmesartan 40 mg +
amlodipine 10 mg +
hydrochlorothiazide
[HCTZ] 12.5 mg) who
had prolonged hypotension and acute respiratory failure.
“
calcium
channel
blocker (CCB)
overdose is one of
the leading causes of
overdose death by
cardiovascular
medications.”
Keywords: calcium channel blocker overdose, hypotension
management
C
alcium channel blocker (CCB) overdose is one of the
leading causes of overdose death by cardiovascular
medications. There were 11 764 cases of documented
overdose cases by CCBs in the United States in a 2011 report
by poison control centers.1,2 Although they constituted only
Case
A 25-year-old
woman presented to the emergency room
by Emergency Medical Services 2 hours after ingestion. Her
parents called Emergency Medical Services after intentional
overdose with 90 pills of Tribenzor. She had ingested 900 mg
of amlodipine, 3600 mg of olmesartan, and 1125 mg of HCTZ.
The source of medications was from a family relative who was
taking those medications for hypertension. She did not have
any significant past medical or surgical history. On evaluation
DOI: 10.1177/1944451613481383. From Pulmonary and Critical Care Department, Texas Tech University Health Science Center, Lubbock, Texas. Conflict of Interest: The authors declare no
potential conflicts of interest with respect to the authorship and/or publication of this article. Address correspondence to: Shrinivas Kambali, MD, Pulmonary and Critical Care Department, Texas
Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430; e-mail: [email protected].
For reprints and permissions queries, please visit SAGE’s Web site at http://www.sagepub.com/journalsPermission.nav.
Copyright © 2013 The Author(s)
1
ICU DIRECTOR
Mon XXXX
Figure 1. Blood pressure changes.
Figure 2. Calcium level.
in emergency room, she was awake and had a blood pressure
(BP) of 100/50 mm Hg, a heart rate (HR) of 113 beats per minute, a respiration rate of 18 breaths per minute, and oxygen saturation of 96% on 4 L of oxygen. Her initial labs revealed a
normal complete blood count, anion gap metabolic acidosis, a
blood sugar level of 160 mg/dL, and a calcium level of
10 mg/dL.
While she was being evaluated in the emergency room, she
became hypotensive and less responsive. She was intubated
2
for airway protection and started on assist-control mechanical
ventilation. Her repeat blood sugar was elevated at 600 mg/dL.
Gastric lavage was done and 100 g of activated charcoal–sorbitol were given through an orogastric tube. She received 4 L of
normal saline bolus and was started on norepinephrine infusion drip and on dopamine infusion for hypotension (Figure 1).
Despite being on norepinephrine at 180 µg/min and dopamine
at 50 µg/kg/min, her blood pressure was still low with a mean
arterial pressure (MAP) of 45 mm Hg. She was then started on
vol. X ■ no. X
ICU DIRECTOR
Figure 3. Insulin infusion.
Figure 4. Blood sugar monitoring.
3
ICU DIRECTOR
vasopressin 0.06 U/min, phenylephrine 200 µg/min, and glucagon 6.6 mg intravenously (IV). Her cardiac output (CO), stroke
volume (SV), stroke volume variation (SVV), and systemic vascular resistance (SVR) were closely monitored. She was started
on calcium chloride infusion and serum calcium was checked
hourly (Figure 2). She was also started on insulin infusion drip
with 8 U/h, and this was increased to 30 to 40 U/h (Figure 3).
Dextrose infusion was started to maintain euglycemia (Figure 4).
She required high positive end-expiratory and later she was
started on high-frequency oscillator ventilation (HFOV). Despite
being on HFOV her oxygen saturations were around 78%. She
had no urine output with a central venous pressure of 19 cm of
water and was stared on diuretics, initially bumetidine and later
lasix. She started having good urine output, her oxygenation
improved, and she required less vasopressors. She became
more responsive and was slowly weaned off the vasopressors
and extubated on day 6. She recovered completely.
Discussion
Amlodipine is a Food and Drug Administration–approved
(1992) dihydopyridine CCB with potent vasodilator but little
negative chronotropic effect. It is highly protein bound, has a
large volume of distribution, and is metabolized in the liver.
Amlodipine has a peak effect at 6 to 12 hours and has a terminal half-life of 30 to 50 hours. As the dose is increased,
the rate of CCB clearance decreases, prolonging the half-life.
Amlodipine is commonly used in a combination medication
along with angiotensin inhibitors and hydrochlorothiazide. The
combination of amlodipine, olmesartan, and hydrochlorothiazide was approved by the Food and Drug Administration in
2010.5 Olmesartan is a angiotensin II receptor blocker (ARB),
which displaces the angiotensin II from the AT1 receptor and
lowers the blood pressure by antagonizing AT1 induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic
response.5 HCTZ inhibits the sodium reabsorption in the distal
tubules causing increased excretion of sodium and water along
with potassium and hydrogen ions.5
The presence of these other medications may make overdose management more complex. In a report of 2011 poison control data there were 11 766 cases of amlodipine overdose, of which 6620 involved combination medications and
5140 involved amlodipine only. There were 6535 cases of ARB
overdose, of which 3366 were in combination medications and
3169 as single medication. There were 44 fatal cases reported
involving amlodipine, and it was the primary cause of death in
26 cases. Of these 26 cases, 17 had taken combination medication and 9 had taken amlodipine only. It was the second commonest cardiovascular medication causing more fatal cases
after verapamil (32 cases).2 Although there were 6535 cases of
ARB overdose, there were no cases in which it was the primary
cause of death. There was only one case in which an angiotensin-converting enzyme inhibitor (lisinopril) was the primary
cause of death. Other common cardiovascular medications that
caused fatality were cardiac glycosides (16), diltiazem extended
4
Mon XXXX
release (12), metoprolol (11), atenolol (9), diltiazem (8), and
propranolol (7).2
Smith et al6 reported a case of profound toxicity due to coingestion of high doses of amlodipine with valsartan refractory
to crystalloids and colloids, calcium gluconate, epinephrine,
norepinephrine, phenyl epinephrine, and vasopressin infusion.
They reported improvement with high-dose euglycemia therapy
with glucagon and naloxone.6 Plumb et al7 reported a case of
severe hypotension secondary to amlodipine and losartan
overdose that was refractory to conventional treatment with
vasopressors and high-dose euglycemia but responded to a
metarminol infusion.
Diagnosis
Hypotension and bradycardia with sinus arrest or atrioventricular block in the absence of QRS interval prolongation suggest CCB intoxication. Symptoms of toxicity depend on the
type and dose of the CCB and the presence of other medications. Hypotension can develop within 60 minutes of ingestion
with regular release preparations and is delayed with sustainedrelease preparations. Mild toxicity presents with hypotension,
weakness, and lightheadedness. Ingestion of 5 to 10 times the
normal dose can cause severe hypotension along with bradycardia, pulmonary edema, renal failure, and other signs of
heart failure. The electrocardiogram (ECG) may show bradycardia, arrhythmia, and complete heart block.8,9 As in our case,
patients may be normotensive initially but rapidly progress to
shock depending on ingested dose. Hyperglycemia is common
in CCB overdose and it helps in distinguishing between CCB
overdose and beta-blocker overdose. Our patient was euglycemic (160 mg/dL) on initial presentation, but subsequent labs
showed blood sugar levels of 600 mg/dL. This could be attributed to early arrival to the emergency room.
Management
Many patients with CCB overdose are asymptomatic at
the time of presentation. These patients have to be monitored
closely with ECGs for at least 6 hours for the immediate release
medications and much longer for sustained release medications
like amlodipine or verapamil.8,9 All symptomatic patients should
be admitted for at least 24 hours.10 Emergency and supportive therapy to maintain the airway by intubation and assisted
ventilation may be necessary in severe cases. Initial resuscitation in symptomatic patients includes IV fluids and atropine for
bradycardia. The role of gastric decontamination depends on
the time of ingestion if known. It can be useful if given within
60 minutes of ingestion. Only a small fraction of the medication is removed by decontamination. Syrup of ipecac is no longer indicated for any decontamination unless the arrival of the
patient is expected to be delayed by more than 60 minutes and
the patient is awake.11 Gastric lavage is also indicated in asymptomatic patients. Vagal stimulation from lavage may exacerbate
CCB-induced hypotension and bradycardia.12 Activated charcoal
should be administered a single dose of 1 g/kg for children up
ICU DIRECTOR
vol. X ■ no. X
to the adult dose of 60 to 100 g.11 Repeated doses of activated
charcoal may be needed to achieve the desired 10:1 of charcoal to poison.11 Repeated dosing has been shown to reduce
blood concentration by interrupting enterohepatic or enteroenteric recirculation of the drug. It may cause serious fluid and
electrolyte abnormalities and should not be used in patients
with ileus or obstruction.11 Whole bowel irrigation has become
an accepted approach, especially for patients with sustained
release or large dose of enteric-coated tablets, but this has limited supporting quality clinical data. In case reports with CCB
overdose in which whole bowel irrigation was not used, there
was an increase in the drug level and also higher mortality
because of drug reabsorption.
In patients with severe bradycardia or cardiac arrest, emergency cardiopulmonary bypass/extracorporeal membrane oxygenation (ECMO) has been shown to be useful.13-15 Holzer et al13
reported a case of successful resuscitation from pulseless electrical activity secondary to verapamil-intoxicated patient with
ECMO and theophylline therapy. Hendren et al16 reported a
similar case of CCB overdose where ECMO was used to allow
time for liver detoxification. Serum levels of the drug fell during and after the procedure; however, continued absorption
of the drug after bypass resulted in persistent elevation of the
serum levels and lead to unresponsive circulatory failure.16
ECMO leads to reliable tissue perfusion and improved outcome
after cardiac arrest resuscitating patients with refractory cardiac
arrest or other forms of circulatory collapse except trauma.17,18
Sufficient liver perfusion is especially critical for the elimination of verapamil because no specific detoxification treatment
exists.13
Intravenous Calcium
Calcium channel blocker overdose causes hypocalcemia
and intravenous calcium is often needed in patients with moderate to severe CCB toxicity. Calcium infusion is one of the initial treatments but produces variable results.19 Calcium chloride
is preferred over calcium gluconate because of higher percentage of calcium availability (13.6 mEq vs 4.5 mEq in 10 mL of
10% solution).20 Hariman et al21 reported that in a canine model
administration of calcium chloride reversed the verapamil
induced reduction of BP. Similar animal studies have demonstrated that high-dose calcium reverses the negative effects of
CCB toxicity on BP and CO but had no effect on heart rate or
SVR.22-25 Isbister20 reported a case successful treatment of refractory hypotension, bradycardia, and asystole secondary to diltiazem and isosorbide nitrate with high dose (13.5 g) of IV calcium, adrenaline, and temporary pacing. Lam et al26 reported
improved hemodynamic status by maintaining sustained
increases serum ionic calcium level (approximately 2 mmol/L)
with prolonged high-dose IV calcium infusion. Stimulation of
the alpha- and beta-adrenergic receptors is believed to increase
intracellular levels of calcium and to help reduce CCB toxicity.27
A panel review recommended calcium infusions in patients
with CCB-induced hypotension that is refractory to conventional vasopressor therapy.27 There have been many case
reports and case series that showed benefit of high-dose
calcium infusion.20,26,27 Close monitoring of the serum or
ionized calcium concentration (measurements every
2 hours) and serial ECGs are necessary to avoid clinically
significant hypercalcemia.
Vasopressors
After adequate IV fluid administration, vasopressors are
indicated for direct positive inotropy, positive chronotrophy, and vasoconstrictor effects, and norepinephrine is commonly used as the initial pressor. Patients with CCB toxicity
may require very high doses of vasopressors, which can cause
arrhythmias. Our patient had sinus tachycardia with frequent
premature ventricular contractions while on the vasopressors.
Monitoring the CO, SVR, SV, and SVV using minimally invasive hemodynamic monitoring devices is very helpful in guiding the fluid and vasopressor management. They may require
high positive end-expiratory pressure because of the pulmonary edema during fluid resuscitation. Our patient had to be
started on HFOV to maintain her oxygenation. Some studies
have shown that phosphodiesterase inhibitors may also be useful in CCB overdose because increasing intracellular cAMP may
recruit nonantagonized channels.28-30 Phosphodiesterase inhibitors should be used with other vasopressors and never used
alone, as these drugs can increase the risk of hypotension.30
Glucagon
Glucagon raises intracellular levels of cAMP. A systematic
review of 6 studies with CCB overdose reported that glucagon
appeared to increase the HR and CO and transiently reverse
second- and third-degree heart blocks.31 It had no effect on
MAP and had no effect on survival rate. Mahr et al32 reported a
case of successful treatment of diltiazem overdose using intravenous glucagon. Walter et al33 reported a similar case of use
of intravenous glucagon in nifedipine overdose.33 Similar results
were seen in many human cases.34 There is no standard regimen for treatment with glucagon. An initial IV bolus of 5 mg is
a reasonable start and can be repeated twice at 10-minute intervals. A glucagon infusion can be started at the total dose at
which a response is noted.
Insulin and Glucose
A review by Engebretsen et al35 showed that in animal
models, high-dose dose insulin was superior to calcium salts,
glucagon, epinephrine, and vasopressin and improved survival.
Kline et al36 used high-dose insulin (HDI) in verapamil poisoning in dogs. They found that dogs treated with HDI had significantly improved maximum elastance at end systole, left ventricular end diastolic pressure, and coronary blood flow.36 They
did not find any significant improvement in MAP or HR. This
review reported similar results in other animal models.37-39
There are no published controlled clinical trials in humans, but
review of case reports and case series supports use of HDI as
initial therapy.35 Boyer and Shannon40 reported 2 cases of CCB
5
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Mon XXXX
overdose in which conventional treatment with calcium infusion and vasopressors did improve the hemodynamic status of
both. Both were treated with insulin at 0.5 U/kg/h, which rapidly reversed cardiovascular collapse. One patient required dextrose infusion to maintain euglycemia.40 Yuan et al41 reported a
case series of 5 CCB overdose patients; hemodynamic improvement occurred after insulin-euglycemia treatment, but other
therapies were used concomitantly. In a prospective observational study reported by Greene HDI was shown to be safe and
effective in treatment of CCB toxicity along with other conventional therapies.42 Engebretsen et al35 reported that the bolus
dose ranged from 0.1 to 10 U/kg and the continuous insulin infusion ranged from 0.015 to 22 U/kg/h with most patients
receiving between 0.5 and 2 U/kg/h. They found one report
of treatment failure in amlodipine overdose despite HDI and
vasopressor therapy. The mechanism of action of insulin is not
clear. Proposed mechanisms include increased
inotropy, increased intracellular transport, and vascular dilatation.35 Studies have shown that insulin in high concentrations
affects several intracellular mechanisms that contribute to the
inotropic effects, many of which involve calcium handling and
the PI3K pathway.35,43,44 Hypoglycemia and hypokalemia must
be corrected prior to initiating HDI therapy. HDI therapy with
a bolus of 1 U/kg of regular, short-acting insulin given IV followed by continuous infusion at 0.5 to 1 U/kg/h IV is recommended. Insulin should be titrated upward by 2 U/kg/h until
hypotension is corrected or a maximum dose of 10 U/kg/h is
reached.35,40,45-49 Dextrose may be needed to maintain euglycemia in patients who have hypoglycemia with insulin infusion. Insulin and dextrose infusion can cause hypokalemia, and
serum potassium concentration should be measured every
30 minutes until it is stable and then every 1 to 2 hours. A
hemodynamic response to HDI therapy is often delayed for
30 to 60 minutes; therefore, simultaneous implementation of
other therapies to support the patient’s pulse and blood pressure are generally required. There are currently no studies
illustrating the best way to decrease HDI therapy after cardiac
function has improved. After hemodynamic parameters have
stabilized, the insulin infusion may be gradually tapered and
discontinued.
nifedipine overdose that failed to show any hemodynamic or
survival benefit of LET over placebo.
Albumin dialyses with molecular adsorbents recirculating system therapy and levosimendan (calcium sensitizer)
have been used in patients with CCB toxicity with favorable
outcomes.52 Levosimendan acts as a calcium sensitizer and
increases the association rate of myosin actin cross-bridges. It
slows down their dissociation rate by binding to troponin C.
It also exhibits systemic and coronary vasodilatation via ATPsensitive potassium channels in vascular smooth muscle cells
and in mitochondria. Varpula et al53 reported 2 cases of cardiovascular collapse secondary to CCB overdose treated with levosimendan along with other conventional treatment.
Other Treatment Modalities
7. Plumb JOM, Stewart C, Eddleston M, de Beer T. Case report: prolonged refractory hypotension following combined amlodipine
and losartan ingestion responsive to metaraminol. Case Rep Med.
2011;2011:283672.
Wilson et al reported a case of refractory hypotension secondary to sustained release diltiazem poisoning that responded
to lipid emulsion therapy (LET) along with other conventional
therapy. Two mechanisms possibly account for the effectiveness of LET. The first is that the emulsion acts as a “lipid sink,”
surrounding a lipophilic drug molecule and rendering it ineffective. The second is that the fatty acids from the LET provide
the myocardium with a ready energy source, thereby improving cardiac function. A recent systematic review of the LET for
acute poisoning found the overall quality of the studies to be
weak.51 They were beneficial in patients with overdose with
verapamil and beta blockers.51 There was one animal trial with
50
6
Conclusion
Calcium channel blockers are being increasingly used
for treatment of hypertension and are very often combined
with other antihypertensive medication in a combination pill.
Overdose with these drug combination medications can result
in refractory hypotension. Based on our patient and the review
of literature, we conclude that patients with near fatal CCB
ingestion usually have a good outcome with appropriate use of
high-dose vasopressors, glucagon, and insulin.
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