Case 24-2006 — A 40-Year-Old Woman with Hypotension after an Overdose of Amlodipine
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《新英格兰医药杂志》
Presentation of Case
Dr. Murray McLachlan (Emergency Medicine): A 40-year-old woman was transferred to the emergency department of this hospital because of hypotension. She had been well until the early afternoon of the day of admission, when she left the physician's office where she worked and went home, saying that she did not feel well. At approximately 4:30 p.m., her husband arrived home and found her pale and groggy. She told him that she had ingested 100 sample tablets of amlodipine (10 mg, not specified as standard or sustained release) at the office at about 12:30 p.m., in a suicide attempt. Her husband rushed her to a local hospital.
On arrival, the patient was awake and conversant. The pulse was 60 beats per minute and the blood pressure 100/60 mm Hg. The skin was cool and dry, and the results of the physical examination were otherwise normal. She vomited shortly after arrival, and ondansetron was given intravenously. The blood pressure fell to 88/76 mm Hg, and she felt light-headed; a dopamine infusion was begun. The bicarbonate level was 20 mmol per liter, the creatinine level was 1.5 mg per deciliter (132.6 μmol per liter), the glucose level was 290 mg per deciliter (16.1 mmol per liter), and the results of an initial toxicology screening were negative. Eighty minutes after her arrival, her blood pressure fell to 58/38 mm Hg and she became somnolent. The trachea was intubated after premedication with 200 mg of succinylcholine, 6 mg of lorazepam, and 100 μg of fentanyl. An orogastric tube was placed, its position was confirmed by radiography, and charcoal (75 g) was administered. A bolus of regular insulin (80 U) was administered intravenously, followed by an intravenous infusion of insulin at a rate of 40 U per hour. The rate of the intravenous infusion of dopamine was increased, and norepinephrine and dextrose solution were added. Calcium chloride (4 g) and calcium gluconate (2 g) were administered. The patient was transferred to this hospital by helicopter less than two hours after arrival at the local hospital.
The patient had no known illnesses or history of psychiatric disorders. She lived with her husband and three children and worked in a clerical position in a physician's office. She did not smoke and rarely consumed alcohol. She had no known drug allergies and took no medications regularly.
On arrival at the emergency department at 7:30 p.m., the temperature was 36.7°C, the heart rate 74 beats per minute, the blood pressure 42/32 mm Hg, and the oxygen saturation 99 percent by pulse oximetry while receiving mechanical ventilation with pure oxygen. Physical examination revealed that she was intubated and sedated, with no evidence of trauma. Her skin was cool to the touch. Her pupils were equal, round, and reactive. An endotracheal tube, 7.5 mm in internal diameter and 22 cm in length (from the patient's lips to the tip), was in place, and an end-tidal carbon dioxide detector showed normal exhalation of carbon dioxide. Her neck was supple. The breath sounds were normal on the right, and coarse rhonchi were present on the left. Her heart rate was regular, with no murmurs. Her abdomen was soft and nondistended, and no masses were palpable. The anal-sphincter tone was normal, and the rectum contained brown stool that was positive for occult blood. There was no cyanosis, edema, or clubbing of the fingers or toes. The results of the neurologic examination were not informative, because the patient was sedated; she did not respond to noxious stimuli.
An electrocardiogram showed a junctional rhythm (Figure 1). The results of blood screening for common toxic substances were negative. The results of additional laboratory tests are shown in Table 1.
Figure 1. Electrocardiogram Obtained on the Patient's Arrival in the Emergency Department.
The ventricular rate is 67 beats per minute, the QRS interval 100 msec, and the QT interval corrected for heart rate 471 mm. There is junctional rhythm, counterclockwise rotation of uncertain clinical significance, and nonspecific ST-segment and T-wave abnormalities.
Table 1. Results of Laboratory Tests.
Central venous catheters were placed in the right femoral and left subclavian veins, and a catheter was placed in the right femoral artery for blood-pressure monitoring. A chest radiograph showed that the tip of the endotracheal tube was 1.5 cm above the carina, a nasogastric tube was coiled in the stomach, and the tip of the left subclavian venous catheter was in the left internal jugular vein. There was volume loss in the left lung, with probable partial collapse of the left lower lobe. No definite pneumothorax was identified. The right lung was clear.
The catheter was removed from the left subclavian vein. The insulin infusion was increased to 80 U per hour. Calcium chloride (4 g) and calcium gluconate (2 g) were administered. An intravenous infusion of calcium gluconate was begun at a rate of 2 g per hour. Glucagon (5 mg) was given intravenously, with no change in the patient's hemodynamic status. The poison-control center was apprised of the management plan. Whole-bowel irrigation was initiated with an oral solution of polyethylene glycol and electrolytes at a rate of 2 liters per hour. A rectal tube was placed. Infusions of dopamine and norepinephrine were continued; the hypotension persisted; after the initiation of an infusion of phenylephrine, the blood pressure rose to 96/46 mm Hg.
During the patient's four hours in the emergency department, she received 2200 ml of fluids intravenously and had a urinary output of approximately 100 ml. She was admitted to the medical intensive care unit.
Management
Dr. N. Stuart Harris: This patient arrived in the emergency department approximately seven hours after reportedly ingesting 1000 mg of the calcium-channel blocker amlodipine in a suicide attempt. The largest ingestion of this drug in which the patient survived was 560 mg. The management of a case in which the poisoned patient is critically ill is a common challenge for the emergency physician. Although most toxicologic exposures are not acutely life-threatening, the five leading causes of death by poisoning in 2004 were (according to substance category) as follows: analgesics; sedatives, hypnotic agents, or antipsychotic agents; antidepressants; stimulants and so-called street drugs; and cardiovascular agents.1 Calcium-channel blockers make up the largest portion of cardiovascular agents. This case presented the specific problem of the proper management of an overdose of a calcium-channel blocker, but first we had to follow the general principles of the emergency care of the poisoned patient.
Emergency Care of the Poisoned Patient
With one important exception, the priorities in the care of a poisoned patient are identical to those in the care of any patient in a hemodynamically unstable condition who presents to the emergency department: the evaluation of the patient's airway, breathing, and circulation — the "ABCs." The important exception is the patient who may have been exposed to (or "contaminated" with) toxins such as organophosphate pesticides or nerve agents. In that circumstance, external decontamination outside the emergency department must precede even the evaluation of the ABCs, to prevent contamination of the caregiver or the hospital. In this case, however, there was no reason to suspect an externally acting toxin.
The patient arrived intubated, sedated, and receiving continuous cardiac monitoring. In any new patient, the prudent emergency physician looks first to the airway. Accordingly, the placement and function of this patient's endotracheal tube were assessed immediately. The tube was securely tied in place, with the tip 22 cm from the lips. Colorimetry was used to measure end-tidal carbon dioxide, pulse oximetry to reveal an oxygen saturation of 99 percent, and auscultation to identify equal breath sounds bilaterally. There was no reason to suspect a cervical-spine injury that could lead to instability of the spine and affect the airway. A chest radiograph was ordered to confirm that the endotracheal tube had been properly positioned and to rule out aspiration or other abnormalities in the chest.
The circulation was assessed next. Initially, the blood pressure was 42/32 mm Hg, with a heart rate of 74 beats per minute. There was no evidence of trauma or bleeding to explain the hypotension. This disparate dyad of vital signs (low blood pressure and normal pulse rate) reflects the specific activity of amlodipine. Immediate steps were taken to support the patient's blood pressure, including the administration of fluid, insulin, calcium, and adrenergic agonists.
Early electrocardiography is critical to identify toxins with specific cardiotoxic effects, most notably tricyclic antidepressants, digoxin, beta-blockers, or calcium-channel blockers. Many of these toxins, if not quickly identified and their effects treated, can rapidly produce fatal arrhythmias. In this patient, an accelerated junctional rhythm was noted, without other important findings; this finding is not unexpected in a case of amlodipine overdose.
With the ABCs addressed and the patient receiving general supportive care, the emergency physician's attention was next focused on determining whether any specific antidote or specific critical early intervention existed for the toxin involved. Anyone who was a potential source of information was interviewed, since emergency-medical-service providers, primary care physicians, or family members may have seen pill fragments or the contents of medicine cabinets that might have provided information critical to constructing a differential diagnosis. A thorough examination of a patient's belongings may reveal a single pill or an empty bottle, which may guide therapy. In this case, although we were not able to determine the pill form (standard vs. sustained release), which could impact the time of onset and consequently, clinical care, we were aided by the report of both the type and quantity of the overdose. Nonetheless, in cases of an intentional overdose, one must rule out the possibility that the patient ingested multiple poisons and is concealing that fact. Broad classes of clinical poisoning toxidromes (Table 2) can provide important clues to common poisonings, including those for which specific antidotes may exist. The finding of typical odors associated with toxic exposures (e.g., the scent of bitter almonds with cyanide, the scent of garlic with organophosphates and some heavy metals, and a fruity scent with acetone and isopropyl alcohol) on the patient's breath or skin may also be helpful. This patient's altered mental status, dry skin, hypotension, and normal heart rate matched none of the common toxidromes.
Table 2. Common Toxidromes.
In a case such as this, standard protocols should be followed to identify and treat readily reversible, potentially fatal causes of altered mental status. Bedside blood-glucose testing, empirical intravenous administration of dextrose and thiamine, and in the appropriate clinical setting, a trial of naloxone can all be helpful. Neurologic examination to identify a focal deficit can provide important clues to specific lesions of the central nervous system caused by trauma, hemorrhage, or ischemia. Emergency computed tomography of the head can help identify these lesions. If an infection of the central nervous system is suspected, it should be treated empirically with antibiotics, pending definitive diagnosis. This patient had multiple reasons for altered mental status — marked hypotension, sedation, and overdose of a toxic substance. She did not have fever, a focal neurologic deficit, or an antecedent trauma.
Directed laboratory evaluation and toxin panels can be helpful. Even in a case in which the toxin is known, one must continue to be vigilant for signs of overdoses of other potentially life-threatening substances, particularly acetaminophen, aspirin, and other readily available over-the-counter medications, as well as alcohol (both ethanol and common toxic alcohols, including isopropyl, methanol, and ethylene glycol). In this case, these possibilities were considered and judged to be unlikely on the basis of the initial evaluation of the patient, and a screening panel for toxic substances was negative.
Although there is no evidence that the administration of activated charcoal improves the clinical outcome and there are clear contraindications to its use, activated charcoal may be administered in cases of recent (less than an hour) or potentially lethal toxic ingestions (1 to 2 g per kilogram of body weight to a maximum of 50 to 60 g).2 Its administration is contraindicated unless the patient has an intact or protected airway. In light of this patient's supralethal dose of amlodipine, activated charcoal was administered by nasogastric tube after endotracheal intubation at the first hospital. Consultation with a regional poison-control center may provide important insights in patients with unusual or severe poisonings or in cases in which there are questions about management.
Management of Overdose of Calcium-Channel Blockers
Basic Principles
Calcium-channel blockers have been used in the United States since the late 1970s for the treatment of conditions including hypertension, dysrhythmias, stable angina, subarachnoid hemorrhage, high-altitude pulmonary edema, migraine, and Raynaud's disease. Reports of fatal poisoning with calcium-channel blockers through the mid-1980s were not common; however, 10,513 toxic exposures were reported by 2004, with 62 deaths.1 Calcium-channel blockers are metabolized by the liver to inactive metabolites and possess widely varying half-lives (from 1 to more than 50 hours).
Calcium-channel antagonists block the movement of calcium into cells by interfering with the action of the voltage-gated slow (L-type) calcium channels (Figure 2).3,4 In general, calcium influx increases the actin–myosin interaction in cardiac and smooth muscle and so tends to increase inotropy and arterial tone. L-type calcium channels are found throughout the body, but the most important clinical effect of calcium-channel blockers is on cardiac myocytes, cardiac conductive tissue, vascular smooth muscle, and pancreatic beta cells; overdoses may result in hypotension, bradycardia, altered mental status, sinus arrest, various cardiac conduction delays, nausea, vomiting, and metabolic acidosis with hyperglycemia.5 Many of these features were seen in this patient.
Figure 2. Role of L-Type Calcium Channels and Amlodipine Activity in Myocytes.
The extracellular concentration of calcium is 10,000 times the intracellular concentration. The gradient is maintained by the impermeability of the cell membrane to calcium and through pumps that excrete intracellular calcium ions into the extracellular space (Ca2+/H+-ATPase and Na+/Ca2+ exchanger), as well as by the active uptake and release of calcium by intracellular organelles (endoplasmic reticulum and mitochondria). Calcium flows into the cell through a voltage-gated calcium channel in response to a variety of stimuli, including -adrenergic receptors. The influx of calcium into the cell and from the endoplasmic reticulum ultimately increases the activity of the actin–myosin–troponin complex. Amlodipine binds the 1c subunit of voltage-gated L-type calcium channels on the myocyte membrane, blocking the flow of calcium and reducing the activity of the actin–myosin–troponin complex.
Chemical Classes of Calcium-Channel Blockers
Three classes of calcium-channel blockers are currently in use in the United States (Table 3).6 Each class acts with varying degrees of selectivity on cardiac myocytes, conductive tissue, and vascular smooth muscle. The differences can lead to widely varying clinical manifestations of overdose. Although verapamil can produce marked bradycardia or asystole because of its affinity for sinoatrial and atrioventricular nodal tissue, this patient, who had a massive overdose of amlodipine, which acts mostly on peripheral arterial smooth muscle, presented with marked hypotension with a normal-to-elevated heart rate.7 Her sinoatrial node was suppressed, but the atrioventricular node functioned, producing the junctional rhythm seen on the electrocardiogram (Figure 1). Calcium-channel blockers typically do not produce ventricular dysrhythmias. The unique exception to this is bepridil (whose use was recently discontinued in the United States), which also acts to antagonize fast sodium channels, leading to prolongation of the QT interval and potential torsade de pointes in patients with an overdose.8
Table 3. Classes of Calcium-Channel Blockers.
Volume Replacement
As was done in this case, appropriate intravascular volume should first be established with the use of intravenous fluids (normal saline). In the setting of primarily peripherally acting calcium-channel blockers such as amlodipine, marked vasodilatation may require many liters of fluid for adequate repletion of intravascular volume. When there is hemodynamic instability, the placement of a pulmonary-artery catheter to monitor central pressures, as was performed in this case, may help guide efforts to replenish intravascular fluids and avoid overzealous administration that can lead to pulmonary edema. At the local hospital, this patient received 3000 ml of fluids intravenously, and while she was in our emergency department, she received an additional 2200 ml of normal saline.
Calcium Therapy
Attempts to overcome calcium-channel antagonism with the use of supratherapeutic doses of calcium salts, although expected to have a limited effect, are physiologically reasonable and clinically indicated.9 In this case, a total of 8 g of calcium chloride and 4 g of calcium gluconate were given over a period of six hours in two emergency departments, and intravenous administration of calcium gluconate at a rate of 2 g per hour was begun. Although either formulation may be used, 10 percent calcium chloride solution yields 27 mg of elemental calcium per milliliter; an identical concentration of calcium gluconate yields a concentration of 9 mg per milliliter. Calcium salts can cause tissue necrosis if extravasation occurs, and they should preferably be given through a central venous catheter. Exact dosing requirements have not been studied adequately, but the intravenous administration of 10 to 20 ml of 10 percent calcium chloride solution or 20 to 60 ml of 10 percent calcium gluconate solution over a period of 5 minutes, with repeated boluses every 15 minutes, for a total of at least three or four doses is a reasonable start; substantially higher doses may be indicated.10 Blood total calcium levels as high as 23.8 mg per deciliter and doses of up to 30 g during a 12-hour period have been reported to have no adverse effects.11 The peak calcium level in this patient was 15.4 mg per deciliter, with an ionized calcium level of 2.34 mg per deciliter.
Suspected cardiac glycoside poisoning is an important contraindication to empirical calcium therapy; in this event, calcium therapy should be withheld until after treatment with digoxin-specific Fab fragments, lest increases in the intracellular calcium levels exacerbate the toxic effects of digoxin.12 This patient had no measurable digoxin level.
Circulatory Support
Atropine is a potentially useful intervention for bradycardia associated with overdose of calcium-channel blockers. Initial treatment with doses of 0.5 to 1 mg of atropine every two to three minutes, up to a total of 3 mg, may be given. Physicians should expect atropine to be only transiently effective and should be prepared to initiate electrical pacing if the drug proves ineffective.13 Given the primary peripheral activity of amlodipine and the absence of bradycardia, atropine was not given to this patient.
Hyperinsulinemia–Euglycemia Therapy
Increasing amounts of data from studies in animals and humans support the administration of insulin while maintaining normal blood glucose levels (hyperinsulinemia–euglycemia therapy) as first-line therapy in poisoning with calcium-channel blockers.14 A number of potential explanations for its action have been suggested, from the inherent activity of insulin as a positive inotrope15 to the hypothesis that it acts by improving carbohydrate metabolism in cardiac myocytes.16 By antagonizing pancreatic L-type calcium channels, calcium-channel blockers restrict insulin secretion by pancreatic beta cells17 and, as in this patient, may produce hyperglycemia.18 In several small case series, the addition of insulin therapy in overdoses of calcium-channel blockers was beneficial.19,20,21 Interestingly, studies of nonpoisoned but critically ill patients in both medical and surgical settings suggest that intensive insulin therapy may reduce the rates of complications and death.22,23 Whether the beneficial effect of insulin therapy is unique to the patient population poisoned by calcium-channel blockers remains an intriguing question. Guidelines for this therapy are outlined in Table 4. Close monitoring of blood glucose must continue throughout treatment. This patient's infusion of regular insulin at a rate of 40 U per hour was increased to 80 U per hour on arrival at this hospital.
Table 4. Hyperinsulinemia–Euglycemia Therapy and Other Options for the Treatment of an Overdose of Calcium-Channel Blockers.
Adrenergic-Receptor Stimulation
Each of the cardiovascular effects of calcium-channel blockers can be addressed with appropriate pharmacologic stimulation of cardiac 1-adrenergic receptors and peripheral vascular 1-adrenergic receptors. Epinephrine, norepinephrine, phenylephrine, isoproterenol, dobutamine, and dopamine have been used in case series, with varied effect.24,25 Although dopamine is typically the first agent used, its action is indirect, and in the critically ill patient, direct-acting adrenergic agonists (e.g., norepinephrine or phenylephrine) should be considered if dopamine does not improve the blood pressure.26 As with calcium levels, the exact dosing for adrenergic agonists in calcium-channel–blocker poisoning has not been firmly established. If hypotension continues, the rate of administration should be increased and additional adrenergic agonists should be considered. In cases in which the patient's mental status cannot be assessed, close monitoring with the use of the Swan–Ganz catheter may help optimize pressor therapy.
In this case, in anticipation of the predilection of amlodipine to produce peripheral vasodilation, the direct-acting 1-adrenergic agonist norepinephrine was used. When the patient remained hypotensive despite an increase in the initial dopamine and norepinephrine infusions, a phenylephrine infusion was initiated. During her subsequent stay in the medical intensive care unit, she received simultaneous infusions of epinephrine, phenylephrine, vasopressin, norepinephrine, isoproterenol, dobutamine, and dopamine.
Glucagon is a first-line agent for the treatment of beta-blocker overdose because it acts independently of the beta-adrenergic receptor to activate adenylate cyclase in the myocardium (Figure 2). Its use in cases of overdoses of calcium-channel blockers should be considered, especially if there is concern about the possibility of associated beta-blocker–induced toxic effects.27 In this patient, an initial bolus of glucagon (5 mg) was administered intravenously but did not alter her hemodynamic status. In the intensive care unit, a glucagon infusion was initiated, without clear effect.
Although some case reports have indicated the successful use of phosphodiesterase inhibitors, in conjunction with other therapies,28 this agent was not used in this patient because peripheral increases in cyclic AMP can result in peripheral vasodilatation.29
Toxin Removal
Once a mainstay of poison management, the use of ipecac has not been found to improve outcomes; it can cause grave complications and is rarely, if ever, indicated.30 Although clinical data are equivocal, whole-bowel irrigation is a reasonable intervention in cases in which large quantities of calcium-channel blockers have been ingested.31,32 As in this case, patients who have ingested lethal doses of calcium-channel blockers may arrive in the emergency department with stable vital signs and normal mental status, only to have a sudden decline. In particular, the effects of the ingestion of delayed-release preparations may not be fully manifested for hours. Patients who have ingested large quantities of toxins should be admitted for observation even if their initial vital signs are stable. Because of this patient's massive ingestion of amlodipine, whole-bowel irrigation was performed. Unlike some toxins (most notably methanol, ethylene glycol, and aspirin), for which hemodialysis is clearly indicated, calcium-channel blockers have large volumes of distribution and are highly protein-bound, making them poor candidates for removal by hemodialysis. Hemodialysis for the removal of the toxin was not indicated in this case. In the intensive care unit, the patient received treatment for transient acute renal failure and metabolic acidosis with the use of continuous venovenous hemofiltration with bicarbonate replacement on the first hospital day.
Mechanical Support
Transthoracic and intravenous cardiac pacing to increase the heart rate has been successful in patients with an overdose of a calcium-channel blocker, but two primary limitations have been noted: the failure to capture and the failure to increase blood pressure, despite successful increases in heart rate.33,34,35 As a last effort in cases in which other treatments have failed, mechanical support with the use of intraaortic balloon counterpulsation or even extracorporeal bypass should be considered.36 Since the inotropic failure resulting from an overdose of calcium-channel blockers is generally transient (lasting less than 72 hours), invasive mechanical support and even extracorporeal bypass can be lifesaving and return a patient to his or her previous level of functioning.37
Follow-up
The patient had severe hypotension for the next two days, with systolic blood pressure in the range of 82 to 104 mm Hg and diastolic blood pressure in the range of 41 to 57 mm Hg while she was receiving supportive measures. A pulmonary-artery catheter was placed to allow optimal titration of vasopressors. The insulin infusion was stopped after two days, and the vasopressors were tapered and discontinued over the next three to seven days as her blood pressure gradually rose. The cardiac rhythm converted from accelerated junctional rhythm to sinus rhythm on the sixth hospital day.
Ventilator-associated pneumonia, the acute respiratory distress syndrome, and an ileus developed and resolved with treatment. The trachea was extubated after two weeks, and the patient was transferred to a medical floor two days later with suicide precautions and a recommendation for a psychiatric evaluation. The patient was discharged to an inpatient psychiatric unit 27 days after admission. One year later, her primary care physician reports that she has returned to her prior level of functioning with no medical or psychiatric problems.
Final Diagnosis
Massive overdose of amlodipine (calcium-channel blocker).
No potential conflict of interest relevant to this article was reported.
I am indebted to Drs. James Takayesu and Michael Shannon for their expertise and assistance.
Source Information
From the Department of Emergency Medicine, Massachusetts General Hospital, and the Department of Surgery, Harvard Medical School.
References
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Dr. Murray McLachlan (Emergency Medicine): A 40-year-old woman was transferred to the emergency department of this hospital because of hypotension. She had been well until the early afternoon of the day of admission, when she left the physician's office where she worked and went home, saying that she did not feel well. At approximately 4:30 p.m., her husband arrived home and found her pale and groggy. She told him that she had ingested 100 sample tablets of amlodipine (10 mg, not specified as standard or sustained release) at the office at about 12:30 p.m., in a suicide attempt. Her husband rushed her to a local hospital.
On arrival, the patient was awake and conversant. The pulse was 60 beats per minute and the blood pressure 100/60 mm Hg. The skin was cool and dry, and the results of the physical examination were otherwise normal. She vomited shortly after arrival, and ondansetron was given intravenously. The blood pressure fell to 88/76 mm Hg, and she felt light-headed; a dopamine infusion was begun. The bicarbonate level was 20 mmol per liter, the creatinine level was 1.5 mg per deciliter (132.6 μmol per liter), the glucose level was 290 mg per deciliter (16.1 mmol per liter), and the results of an initial toxicology screening were negative. Eighty minutes after her arrival, her blood pressure fell to 58/38 mm Hg and she became somnolent. The trachea was intubated after premedication with 200 mg of succinylcholine, 6 mg of lorazepam, and 100 μg of fentanyl. An orogastric tube was placed, its position was confirmed by radiography, and charcoal (75 g) was administered. A bolus of regular insulin (80 U) was administered intravenously, followed by an intravenous infusion of insulin at a rate of 40 U per hour. The rate of the intravenous infusion of dopamine was increased, and norepinephrine and dextrose solution were added. Calcium chloride (4 g) and calcium gluconate (2 g) were administered. The patient was transferred to this hospital by helicopter less than two hours after arrival at the local hospital.
The patient had no known illnesses or history of psychiatric disorders. She lived with her husband and three children and worked in a clerical position in a physician's office. She did not smoke and rarely consumed alcohol. She had no known drug allergies and took no medications regularly.
On arrival at the emergency department at 7:30 p.m., the temperature was 36.7°C, the heart rate 74 beats per minute, the blood pressure 42/32 mm Hg, and the oxygen saturation 99 percent by pulse oximetry while receiving mechanical ventilation with pure oxygen. Physical examination revealed that she was intubated and sedated, with no evidence of trauma. Her skin was cool to the touch. Her pupils were equal, round, and reactive. An endotracheal tube, 7.5 mm in internal diameter and 22 cm in length (from the patient's lips to the tip), was in place, and an end-tidal carbon dioxide detector showed normal exhalation of carbon dioxide. Her neck was supple. The breath sounds were normal on the right, and coarse rhonchi were present on the left. Her heart rate was regular, with no murmurs. Her abdomen was soft and nondistended, and no masses were palpable. The anal-sphincter tone was normal, and the rectum contained brown stool that was positive for occult blood. There was no cyanosis, edema, or clubbing of the fingers or toes. The results of the neurologic examination were not informative, because the patient was sedated; she did not respond to noxious stimuli.
An electrocardiogram showed a junctional rhythm (Figure 1). The results of blood screening for common toxic substances were negative. The results of additional laboratory tests are shown in Table 1.
Figure 1. Electrocardiogram Obtained on the Patient's Arrival in the Emergency Department.
The ventricular rate is 67 beats per minute, the QRS interval 100 msec, and the QT interval corrected for heart rate 471 mm. There is junctional rhythm, counterclockwise rotation of uncertain clinical significance, and nonspecific ST-segment and T-wave abnormalities.
Table 1. Results of Laboratory Tests.
Central venous catheters were placed in the right femoral and left subclavian veins, and a catheter was placed in the right femoral artery for blood-pressure monitoring. A chest radiograph showed that the tip of the endotracheal tube was 1.5 cm above the carina, a nasogastric tube was coiled in the stomach, and the tip of the left subclavian venous catheter was in the left internal jugular vein. There was volume loss in the left lung, with probable partial collapse of the left lower lobe. No definite pneumothorax was identified. The right lung was clear.
The catheter was removed from the left subclavian vein. The insulin infusion was increased to 80 U per hour. Calcium chloride (4 g) and calcium gluconate (2 g) were administered. An intravenous infusion of calcium gluconate was begun at a rate of 2 g per hour. Glucagon (5 mg) was given intravenously, with no change in the patient's hemodynamic status. The poison-control center was apprised of the management plan. Whole-bowel irrigation was initiated with an oral solution of polyethylene glycol and electrolytes at a rate of 2 liters per hour. A rectal tube was placed. Infusions of dopamine and norepinephrine were continued; the hypotension persisted; after the initiation of an infusion of phenylephrine, the blood pressure rose to 96/46 mm Hg.
During the patient's four hours in the emergency department, she received 2200 ml of fluids intravenously and had a urinary output of approximately 100 ml. She was admitted to the medical intensive care unit.
Management
Dr. N. Stuart Harris: This patient arrived in the emergency department approximately seven hours after reportedly ingesting 1000 mg of the calcium-channel blocker amlodipine in a suicide attempt. The largest ingestion of this drug in which the patient survived was 560 mg. The management of a case in which the poisoned patient is critically ill is a common challenge for the emergency physician. Although most toxicologic exposures are not acutely life-threatening, the five leading causes of death by poisoning in 2004 were (according to substance category) as follows: analgesics; sedatives, hypnotic agents, or antipsychotic agents; antidepressants; stimulants and so-called street drugs; and cardiovascular agents.1 Calcium-channel blockers make up the largest portion of cardiovascular agents. This case presented the specific problem of the proper management of an overdose of a calcium-channel blocker, but first we had to follow the general principles of the emergency care of the poisoned patient.
Emergency Care of the Poisoned Patient
With one important exception, the priorities in the care of a poisoned patient are identical to those in the care of any patient in a hemodynamically unstable condition who presents to the emergency department: the evaluation of the patient's airway, breathing, and circulation — the "ABCs." The important exception is the patient who may have been exposed to (or "contaminated" with) toxins such as organophosphate pesticides or nerve agents. In that circumstance, external decontamination outside the emergency department must precede even the evaluation of the ABCs, to prevent contamination of the caregiver or the hospital. In this case, however, there was no reason to suspect an externally acting toxin.
The patient arrived intubated, sedated, and receiving continuous cardiac monitoring. In any new patient, the prudent emergency physician looks first to the airway. Accordingly, the placement and function of this patient's endotracheal tube were assessed immediately. The tube was securely tied in place, with the tip 22 cm from the lips. Colorimetry was used to measure end-tidal carbon dioxide, pulse oximetry to reveal an oxygen saturation of 99 percent, and auscultation to identify equal breath sounds bilaterally. There was no reason to suspect a cervical-spine injury that could lead to instability of the spine and affect the airway. A chest radiograph was ordered to confirm that the endotracheal tube had been properly positioned and to rule out aspiration or other abnormalities in the chest.
The circulation was assessed next. Initially, the blood pressure was 42/32 mm Hg, with a heart rate of 74 beats per minute. There was no evidence of trauma or bleeding to explain the hypotension. This disparate dyad of vital signs (low blood pressure and normal pulse rate) reflects the specific activity of amlodipine. Immediate steps were taken to support the patient's blood pressure, including the administration of fluid, insulin, calcium, and adrenergic agonists.
Early electrocardiography is critical to identify toxins with specific cardiotoxic effects, most notably tricyclic antidepressants, digoxin, beta-blockers, or calcium-channel blockers. Many of these toxins, if not quickly identified and their effects treated, can rapidly produce fatal arrhythmias. In this patient, an accelerated junctional rhythm was noted, without other important findings; this finding is not unexpected in a case of amlodipine overdose.
With the ABCs addressed and the patient receiving general supportive care, the emergency physician's attention was next focused on determining whether any specific antidote or specific critical early intervention existed for the toxin involved. Anyone who was a potential source of information was interviewed, since emergency-medical-service providers, primary care physicians, or family members may have seen pill fragments or the contents of medicine cabinets that might have provided information critical to constructing a differential diagnosis. A thorough examination of a patient's belongings may reveal a single pill or an empty bottle, which may guide therapy. In this case, although we were not able to determine the pill form (standard vs. sustained release), which could impact the time of onset and consequently, clinical care, we were aided by the report of both the type and quantity of the overdose. Nonetheless, in cases of an intentional overdose, one must rule out the possibility that the patient ingested multiple poisons and is concealing that fact. Broad classes of clinical poisoning toxidromes (Table 2) can provide important clues to common poisonings, including those for which specific antidotes may exist. The finding of typical odors associated with toxic exposures (e.g., the scent of bitter almonds with cyanide, the scent of garlic with organophosphates and some heavy metals, and a fruity scent with acetone and isopropyl alcohol) on the patient's breath or skin may also be helpful. This patient's altered mental status, dry skin, hypotension, and normal heart rate matched none of the common toxidromes.
Table 2. Common Toxidromes.
In a case such as this, standard protocols should be followed to identify and treat readily reversible, potentially fatal causes of altered mental status. Bedside blood-glucose testing, empirical intravenous administration of dextrose and thiamine, and in the appropriate clinical setting, a trial of naloxone can all be helpful. Neurologic examination to identify a focal deficit can provide important clues to specific lesions of the central nervous system caused by trauma, hemorrhage, or ischemia. Emergency computed tomography of the head can help identify these lesions. If an infection of the central nervous system is suspected, it should be treated empirically with antibiotics, pending definitive diagnosis. This patient had multiple reasons for altered mental status — marked hypotension, sedation, and overdose of a toxic substance. She did not have fever, a focal neurologic deficit, or an antecedent trauma.
Directed laboratory evaluation and toxin panels can be helpful. Even in a case in which the toxin is known, one must continue to be vigilant for signs of overdoses of other potentially life-threatening substances, particularly acetaminophen, aspirin, and other readily available over-the-counter medications, as well as alcohol (both ethanol and common toxic alcohols, including isopropyl, methanol, and ethylene glycol). In this case, these possibilities were considered and judged to be unlikely on the basis of the initial evaluation of the patient, and a screening panel for toxic substances was negative.
Although there is no evidence that the administration of activated charcoal improves the clinical outcome and there are clear contraindications to its use, activated charcoal may be administered in cases of recent (less than an hour) or potentially lethal toxic ingestions (1 to 2 g per kilogram of body weight to a maximum of 50 to 60 g).2 Its administration is contraindicated unless the patient has an intact or protected airway. In light of this patient's supralethal dose of amlodipine, activated charcoal was administered by nasogastric tube after endotracheal intubation at the first hospital. Consultation with a regional poison-control center may provide important insights in patients with unusual or severe poisonings or in cases in which there are questions about management.
Management of Overdose of Calcium-Channel Blockers
Basic Principles
Calcium-channel blockers have been used in the United States since the late 1970s for the treatment of conditions including hypertension, dysrhythmias, stable angina, subarachnoid hemorrhage, high-altitude pulmonary edema, migraine, and Raynaud's disease. Reports of fatal poisoning with calcium-channel blockers through the mid-1980s were not common; however, 10,513 toxic exposures were reported by 2004, with 62 deaths.1 Calcium-channel blockers are metabolized by the liver to inactive metabolites and possess widely varying half-lives (from 1 to more than 50 hours).
Calcium-channel antagonists block the movement of calcium into cells by interfering with the action of the voltage-gated slow (L-type) calcium channels (Figure 2).3,4 In general, calcium influx increases the actin–myosin interaction in cardiac and smooth muscle and so tends to increase inotropy and arterial tone. L-type calcium channels are found throughout the body, but the most important clinical effect of calcium-channel blockers is on cardiac myocytes, cardiac conductive tissue, vascular smooth muscle, and pancreatic beta cells; overdoses may result in hypotension, bradycardia, altered mental status, sinus arrest, various cardiac conduction delays, nausea, vomiting, and metabolic acidosis with hyperglycemia.5 Many of these features were seen in this patient.
Figure 2. Role of L-Type Calcium Channels and Amlodipine Activity in Myocytes.
The extracellular concentration of calcium is 10,000 times the intracellular concentration. The gradient is maintained by the impermeability of the cell membrane to calcium and through pumps that excrete intracellular calcium ions into the extracellular space (Ca2+/H+-ATPase and Na+/Ca2+ exchanger), as well as by the active uptake and release of calcium by intracellular organelles (endoplasmic reticulum and mitochondria). Calcium flows into the cell through a voltage-gated calcium channel in response to a variety of stimuli, including -adrenergic receptors. The influx of calcium into the cell and from the endoplasmic reticulum ultimately increases the activity of the actin–myosin–troponin complex. Amlodipine binds the 1c subunit of voltage-gated L-type calcium channels on the myocyte membrane, blocking the flow of calcium and reducing the activity of the actin–myosin–troponin complex.
Chemical Classes of Calcium-Channel Blockers
Three classes of calcium-channel blockers are currently in use in the United States (Table 3).6 Each class acts with varying degrees of selectivity on cardiac myocytes, conductive tissue, and vascular smooth muscle. The differences can lead to widely varying clinical manifestations of overdose. Although verapamil can produce marked bradycardia or asystole because of its affinity for sinoatrial and atrioventricular nodal tissue, this patient, who had a massive overdose of amlodipine, which acts mostly on peripheral arterial smooth muscle, presented with marked hypotension with a normal-to-elevated heart rate.7 Her sinoatrial node was suppressed, but the atrioventricular node functioned, producing the junctional rhythm seen on the electrocardiogram (Figure 1). Calcium-channel blockers typically do not produce ventricular dysrhythmias. The unique exception to this is bepridil (whose use was recently discontinued in the United States), which also acts to antagonize fast sodium channels, leading to prolongation of the QT interval and potential torsade de pointes in patients with an overdose.8
Table 3. Classes of Calcium-Channel Blockers.
Volume Replacement
As was done in this case, appropriate intravascular volume should first be established with the use of intravenous fluids (normal saline). In the setting of primarily peripherally acting calcium-channel blockers such as amlodipine, marked vasodilatation may require many liters of fluid for adequate repletion of intravascular volume. When there is hemodynamic instability, the placement of a pulmonary-artery catheter to monitor central pressures, as was performed in this case, may help guide efforts to replenish intravascular fluids and avoid overzealous administration that can lead to pulmonary edema. At the local hospital, this patient received 3000 ml of fluids intravenously, and while she was in our emergency department, she received an additional 2200 ml of normal saline.
Calcium Therapy
Attempts to overcome calcium-channel antagonism with the use of supratherapeutic doses of calcium salts, although expected to have a limited effect, are physiologically reasonable and clinically indicated.9 In this case, a total of 8 g of calcium chloride and 4 g of calcium gluconate were given over a period of six hours in two emergency departments, and intravenous administration of calcium gluconate at a rate of 2 g per hour was begun. Although either formulation may be used, 10 percent calcium chloride solution yields 27 mg of elemental calcium per milliliter; an identical concentration of calcium gluconate yields a concentration of 9 mg per milliliter. Calcium salts can cause tissue necrosis if extravasation occurs, and they should preferably be given through a central venous catheter. Exact dosing requirements have not been studied adequately, but the intravenous administration of 10 to 20 ml of 10 percent calcium chloride solution or 20 to 60 ml of 10 percent calcium gluconate solution over a period of 5 minutes, with repeated boluses every 15 minutes, for a total of at least three or four doses is a reasonable start; substantially higher doses may be indicated.10 Blood total calcium levels as high as 23.8 mg per deciliter and doses of up to 30 g during a 12-hour period have been reported to have no adverse effects.11 The peak calcium level in this patient was 15.4 mg per deciliter, with an ionized calcium level of 2.34 mg per deciliter.
Suspected cardiac glycoside poisoning is an important contraindication to empirical calcium therapy; in this event, calcium therapy should be withheld until after treatment with digoxin-specific Fab fragments, lest increases in the intracellular calcium levels exacerbate the toxic effects of digoxin.12 This patient had no measurable digoxin level.
Circulatory Support
Atropine is a potentially useful intervention for bradycardia associated with overdose of calcium-channel blockers. Initial treatment with doses of 0.5 to 1 mg of atropine every two to three minutes, up to a total of 3 mg, may be given. Physicians should expect atropine to be only transiently effective and should be prepared to initiate electrical pacing if the drug proves ineffective.13 Given the primary peripheral activity of amlodipine and the absence of bradycardia, atropine was not given to this patient.
Hyperinsulinemia–Euglycemia Therapy
Increasing amounts of data from studies in animals and humans support the administration of insulin while maintaining normal blood glucose levels (hyperinsulinemia–euglycemia therapy) as first-line therapy in poisoning with calcium-channel blockers.14 A number of potential explanations for its action have been suggested, from the inherent activity of insulin as a positive inotrope15 to the hypothesis that it acts by improving carbohydrate metabolism in cardiac myocytes.16 By antagonizing pancreatic L-type calcium channels, calcium-channel blockers restrict insulin secretion by pancreatic beta cells17 and, as in this patient, may produce hyperglycemia.18 In several small case series, the addition of insulin therapy in overdoses of calcium-channel blockers was beneficial.19,20,21 Interestingly, studies of nonpoisoned but critically ill patients in both medical and surgical settings suggest that intensive insulin therapy may reduce the rates of complications and death.22,23 Whether the beneficial effect of insulin therapy is unique to the patient population poisoned by calcium-channel blockers remains an intriguing question. Guidelines for this therapy are outlined in Table 4. Close monitoring of blood glucose must continue throughout treatment. This patient's infusion of regular insulin at a rate of 40 U per hour was increased to 80 U per hour on arrival at this hospital.
Table 4. Hyperinsulinemia–Euglycemia Therapy and Other Options for the Treatment of an Overdose of Calcium-Channel Blockers.
Adrenergic-Receptor Stimulation
Each of the cardiovascular effects of calcium-channel blockers can be addressed with appropriate pharmacologic stimulation of cardiac 1-adrenergic receptors and peripheral vascular 1-adrenergic receptors. Epinephrine, norepinephrine, phenylephrine, isoproterenol, dobutamine, and dopamine have been used in case series, with varied effect.24,25 Although dopamine is typically the first agent used, its action is indirect, and in the critically ill patient, direct-acting adrenergic agonists (e.g., norepinephrine or phenylephrine) should be considered if dopamine does not improve the blood pressure.26 As with calcium levels, the exact dosing for adrenergic agonists in calcium-channel–blocker poisoning has not been firmly established. If hypotension continues, the rate of administration should be increased and additional adrenergic agonists should be considered. In cases in which the patient's mental status cannot be assessed, close monitoring with the use of the Swan–Ganz catheter may help optimize pressor therapy.
In this case, in anticipation of the predilection of amlodipine to produce peripheral vasodilation, the direct-acting 1-adrenergic agonist norepinephrine was used. When the patient remained hypotensive despite an increase in the initial dopamine and norepinephrine infusions, a phenylephrine infusion was initiated. During her subsequent stay in the medical intensive care unit, she received simultaneous infusions of epinephrine, phenylephrine, vasopressin, norepinephrine, isoproterenol, dobutamine, and dopamine.
Glucagon is a first-line agent for the treatment of beta-blocker overdose because it acts independently of the beta-adrenergic receptor to activate adenylate cyclase in the myocardium (Figure 2). Its use in cases of overdoses of calcium-channel blockers should be considered, especially if there is concern about the possibility of associated beta-blocker–induced toxic effects.27 In this patient, an initial bolus of glucagon (5 mg) was administered intravenously but did not alter her hemodynamic status. In the intensive care unit, a glucagon infusion was initiated, without clear effect.
Although some case reports have indicated the successful use of phosphodiesterase inhibitors, in conjunction with other therapies,28 this agent was not used in this patient because peripheral increases in cyclic AMP can result in peripheral vasodilatation.29
Toxin Removal
Once a mainstay of poison management, the use of ipecac has not been found to improve outcomes; it can cause grave complications and is rarely, if ever, indicated.30 Although clinical data are equivocal, whole-bowel irrigation is a reasonable intervention in cases in which large quantities of calcium-channel blockers have been ingested.31,32 As in this case, patients who have ingested lethal doses of calcium-channel blockers may arrive in the emergency department with stable vital signs and normal mental status, only to have a sudden decline. In particular, the effects of the ingestion of delayed-release preparations may not be fully manifested for hours. Patients who have ingested large quantities of toxins should be admitted for observation even if their initial vital signs are stable. Because of this patient's massive ingestion of amlodipine, whole-bowel irrigation was performed. Unlike some toxins (most notably methanol, ethylene glycol, and aspirin), for which hemodialysis is clearly indicated, calcium-channel blockers have large volumes of distribution and are highly protein-bound, making them poor candidates for removal by hemodialysis. Hemodialysis for the removal of the toxin was not indicated in this case. In the intensive care unit, the patient received treatment for transient acute renal failure and metabolic acidosis with the use of continuous venovenous hemofiltration with bicarbonate replacement on the first hospital day.
Mechanical Support
Transthoracic and intravenous cardiac pacing to increase the heart rate has been successful in patients with an overdose of a calcium-channel blocker, but two primary limitations have been noted: the failure to capture and the failure to increase blood pressure, despite successful increases in heart rate.33,34,35 As a last effort in cases in which other treatments have failed, mechanical support with the use of intraaortic balloon counterpulsation or even extracorporeal bypass should be considered.36 Since the inotropic failure resulting from an overdose of calcium-channel blockers is generally transient (lasting less than 72 hours), invasive mechanical support and even extracorporeal bypass can be lifesaving and return a patient to his or her previous level of functioning.37
Follow-up
The patient had severe hypotension for the next two days, with systolic blood pressure in the range of 82 to 104 mm Hg and diastolic blood pressure in the range of 41 to 57 mm Hg while she was receiving supportive measures. A pulmonary-artery catheter was placed to allow optimal titration of vasopressors. The insulin infusion was stopped after two days, and the vasopressors were tapered and discontinued over the next three to seven days as her blood pressure gradually rose. The cardiac rhythm converted from accelerated junctional rhythm to sinus rhythm on the sixth hospital day.
Ventilator-associated pneumonia, the acute respiratory distress syndrome, and an ileus developed and resolved with treatment. The trachea was extubated after two weeks, and the patient was transferred to a medical floor two days later with suicide precautions and a recommendation for a psychiatric evaluation. The patient was discharged to an inpatient psychiatric unit 27 days after admission. One year later, her primary care physician reports that she has returned to her prior level of functioning with no medical or psychiatric problems.
Final Diagnosis
Massive overdose of amlodipine (calcium-channel blocker).
No potential conflict of interest relevant to this article was reported.
I am indebted to Drs. James Takayesu and Michael Shannon for their expertise and assistance.
Source Information
From the Department of Emergency Medicine, Massachusetts General Hospital, and the Department of Surgery, Harvard Medical School.
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