Deaths Associated With Hypocalcemia From Chelation Therapy—Texas, Pennsylvania,

[Guest guest]

Deaths Associated With Hypocalcemia From Chelation Therapy—Texas,

Pennsylvania, and Oregon, 2003-2005

JAMA. 2006;295:2131-2133.

MMWR. 2006;55:204-207

Chelating agents bind lead in soft tissues and are used in the

treatment of lead poisoning to enhance urinary and biliary excretion

of lead, thus decreasing total lead levels in the body.1 During the

past 30 years, environmental and dietary exposures to lead have

decreased substantially, resulting in a considerable decrease in

population blood lead levels (BLLs)2 and a corresponding decrease in

the number of patients requiring che! lation therapy. Chelating

agents also increase excretion of other heavy metals and minerals,

such as zinc and, in certain cases, calcium.1 This report describes

three deaths associated with chelation-therapy–related hypocalcemia

that resulted in cardiac arrest. Several drugs are used in the

treatment of lead poisoning, including edetate disodium calcium

(CaEDTA), dimercaperol (British anti-ite), D-penicillamine, and

meso-2,3-dimercaptosuccinic acid (succimer). Health-care providers

who are unfamiliar with chelating agents and are considering this

treatment for lead poisoning should consult an expert in the

chemotherapy of lead poisoning. Hospital pharmacies should evaluate

whether continued stocking of Na2EDTA is necessary, given the

established risk for hypocalcemia, the availability of less toxic

alternatives, and an ongoing safety review by the Food and Drug

Administration (FDA). Health-care providers and pharmacists should

ensure that Na2EDTA is not administe! red to children during

chelation therapy.

Chelating agents, especially those intended for use in children,

should be effective in reducing lead and other heavy metals from the

body without producing substantial adverse effects on levels of

critical serum electrolytes, such as calcium. The only agent

recommended for intravenous (IV) chelation therapy for children is

CaEDTA.1 However, hospital formularies usually stock multiple

chelation agents. One such agent, Na2EDTA, was formerly used for

treatment of hypercalcemia, but its use has become infrequent because

of concerns regarding nephrotoxicity and because of the availability

of less toxic alternatives.3 Furthermore, Na2EDTA contains a warning

stating, " The use of this drug in any particular patient is

recommended only when the severity of the clinical condition

justifies the aggressive measures associated with this type of

therapy. " According to the package insert, Na2EDTA is " indicated in

selected patients for the emergency treatment of hypercalcemia and

for the con! trol of ventricular arrhythmias associated with

digitalis toxicity. " According to FDA and CDC, the safety and

effectiveness of Na2EDTA in pediatric patients has not been

established, and its use is not recommended because it induces

hypocalcemia and possibly fatal tetany.1

In 2005, the Texas Department of Health childhood lead poisoning

surveillance program reported a death attributable to chelation-

associated hypocalcemia to CDC. Subsequently, CDC queried state and

local lead-surveillance programs regarding chelation-related

fatalities; additional deaths were identified in Pennsylvania and

Oregon.

Case Reports

Texas. In February 2005, a girl aged 2 years who was tested for blood

lead during routine health surveillance had a capillary BLL of 47

µg/dL. A venous BLL of 48 µg/dL obtained 12 days later confirmed the

elevated BLL. A complete blood count and iron study conducted

concurrently revealed low s! erum iron levels and borderline anemia.

On February 28, 2005, the girl was admitted to a local medical center

for combined oral and IV chelation therapy.

The patient's blood electrolytes at admission were within normal

limits. Initial medication orders included IV Na2EDTA and oral

succimer (an agent primarily used for treatment of lead poisoning).

The medication order subsequently was corrected by the pediatric

resident to IV CaEDTA. At 4:00 p.m. on the day of admission, the

patient received her first dose of IV CaEDTA (300 mg in 100 mL normal

saline at 25 mL/hr). At 4:35 p.m., she was administered 200 mg of

oral succimer. Her vital signs remained normal throughout the night.

At 4:00 a.m. the next day, a dose of IV Na2EDTA (instead of IV

CaEDTA) was administered. An hour later, the patient's serum calcium

had decreased to 5.2 mg/dL (normal value for pediatric patients: 8.5-

10.5 mg/dL). At 7:05 a.m., the child's mother noticed that the child

was limp and not breathing. Bedside procedures did not restore a

normal cardiac rhythm, and a! cardiac resuscitation code was called

at 7:25 a.m. The child had no palpable pulse or audible heartbeat.

Repeat laboratory values for serum drawn at 7:55 a.m. indicated that

the serum calcium level was <5.0 mg/dL despite repeated doses of

calcium chloride. All attempts at resuscitation failed, and the girl

was pronounced dead at 8:12 a.m.

An autopsy revealed no results of toxicologic significance. A

postmortem radiologic bone survey indicated areas of sclerosis at the

metaphyses (growth arrest and recovery lines compatible with lead

exposure). The cause of death was recorded as sudden cardiac arrest

resulting from hypocalcemia associated with chelation therapy. The

hospital's child mortality review board findings indicated that a

dose of IV Na2EDTA was unintentionally administered to the child.

Pennsylvania. In August 2005, a boy aged 5 years with autism died

while receiving IV chelation therapy with Na2EDTA in a physician's

office. During the chel! ation procedure, the mother noted that the

child was limp. The physici an initiated resuscitation, and an

emergency services team transported the child to the hospital. At the

emergency department (ED), further resuscitation was attempted,

including administration of at least 1 and possibly 2 doses of IV

calcium chloride. Subsequently, the boy's blood calcium level was

recorded in the ED as 6.9 mg/dL. The child did not regain

consciousness. The coroner examination indicated cause of death as

diffuse, acute cerebral hypoxic-ischemic injury, secondary to diffuse

subendocardial necrosis. The myocardial necrosis resulted from

hypocalcemia associated with administration of Na2EDTA. The case is

under investigation by the Pennsylvania State Board of Medicine.

Oregon. In August 2003, a woman aged 53 years with no evidence of

coronary artery disease, intracranial disease, or injury was treated

with 700 mg IV EDTA in a naturopathic practitioner's clinic. The EDTA

was provided by a compounding laboratory (Creative Compounding,

ville, Oreg! on) and was administered by the practitioner to

remove heavy metals from the body. The practitioner had provided a

similar treatment to the patient on three previous occasions, once in

June 2003 and twice in July 2003. Approximately 10-15 minutes after

treatment began, the patient became unconscious. Cardiopulmonary

resuscitation was initiated, and an emergency services team was

contacted. Attempts to revive the patient en route to and in the ED

were unsuccessful. The medical examiner determined the cause of death

to be cardiac arrhythmia resulting from hypocalcemia associated with

EDTA infusion and vascuolar cardiomyopathy. The patient's ionized

calcium level during code was 3.8 mg/dL (normal value for adult

patients: 4.5-5.3 mg/dL) after one IV injection of calcium gluconate

administered by emergency medical technicians en route to the

hospital and another IV injection of calcium chloride in the ED. The

Oregon State Naturopath Licensing Board is conducting an

investigatio! n to determine whether Na2EDTA or CaEDTA was

administered to this pati ent.

The cases described in this report have been reported to FDA. FDA is

performing a safety assessment of Na2EDTA, including a review of the

adverse event reporting system to determine whether other deaths

related to use of chelating agents have been reported.

Reported by:

RA Beauchamp, MD, TM Willis, TG Betz, MD, J Villanacci, PhD, Texas

Dept of State Health Svcs. RD Leiker, Oregon Childhood Lead Poisoning

Prevention Program. L Rozin, MD, Allegheny County, Pennsylvania

Office of the Coroner. MJ Brown, ScD, DM Homa, PhD, TA Dignam, MPH, T

Morta, Div of Emergency and Environmental Health Svcs, National

Center for Environmental Health, CDC.

CDC Editorial Note:

Both children and adults are subject to potentially lethal

prescription errors involving " look-alike, sound-alike " substitutions

(i.e., confusion of drugs with similar names). In a 1-year study of

errors in a tertiary care teaching hospital, 11.4% of medi! cation

errors were found to have resulted from use of the wrong drug name,

dosage form, or abbreviation.4 A review of medical records in the

Texas case described in this report revealed that the brand names for

the Na2EDTA product, Endrate® (Hospira, Inc., Lake Forest, Illinois),

and the CaEDTA product, Calcium Disodium Versenate® (3M

Pharmaceuticals, St. , Minnesota), were used interchangeably;

this improper use of drug names likely resulted in the inappropriate

administration of Na2EDTA.

Although CaEDTA and succimer were ordered for one patient and the

form of EDTA administered to another remains under investigation,

these drugs singly or in combination probably were not responsible

for the low calcium levels. Hypercalcemia as a result of IV

administration of CaEDTA has been reported.5 Succimer by itself is a

weak calcium binder but is not associated with a drop in essential

minerals such as calcium.6 Moreover, the reported doses of CaEDTA and

succi! mer in the Texas case were appropriate and within established

safety l imits.

Medical center records and coroner reports indicate that Na2EDTA was

administered in at least two of the cases. Na2EDTA is often part of a

standard hospital formulary; however, it should never be used for

treating lead or other heavy metal poisoning in children because it

induces hypocalcemia, which can lead to tetany and death.7 The error

that caused the death in Texas most likely resulted from

miscommunication between the pharmacy and the pediatric unit.

Chelation therapy with CaEDTA, dimercaperol, or succimer has been the

mainstay of medical management for children with BLLs & #8805;45 µg/dL.1 The

effectiveness of chelation therapy in improving renal or nervous

system symptoms of chronic mercury toxicity has not been established.

Nonetheless, certain health-care practitioners have used chelation

therapy for autism in the belief that mercury or other heavy metals

are producing the symptoms.8 Other practitioners have recommended

chelation ther! apy for treatment of coronary artery disease, hoping

to eliminate calcified atherosclerotic plaques that can lead to

coronary artery occlusions and myocardial infarctions. These off-

label uses of chelation therapy are not supported by accepted

scientific evidence. The Institute of Medicine found no scientific

evidence that chelation is an effective therapy for autism spectrum

disorder.8 Because limited consistent data exist on the use of

chelation therapy to treat coronary artery disease, a clinical trial

to assess the safety and effectiveness of chelation therapy is being

conducted by the National Institutes of Health.*

Deaths associated with lead poisoning are rare,9 and childhood deaths

caused by cardiac arrest associated with chelation therapy have not

been documented previously.9 As BLLs among children in the United

States continue to decline,2 fewer children require chelation

therapy. Primary care providers should consult experts in the

chemotherapy of lead! before using chelation drug therapy. If such an

expert is not availab le, primary care providers should contact state

or local childhood lead poisoning prevention programs or the Lead

Poisoning Prevention Branch of the National Center for Environmental

Health, CDC.

CDC and its state and local partners will continue to educate health-

care providers and pharmacists to ensure that Na2EDTA is never

administered to children during chelation therapy. CDC recommends

that hospital pharmacies evaluate the need to keep Na2EDTA in their

formularies. Case reports of cardiac arrest or symptoms of

hypocalcemia during chelation therapy should be reported to the CDC

Lead Poisoning Prevention Branch (770-488-3300) or to MedWatch, the

FDA adverse event reporting system, at http://www.fda.gov/medwatch.

[Guest guest]

I hope people realize that EDTA chelation with the correct medication (CaEDTA)

has an impressive safety record with no deaths!

-

elyse14 <elyse-g@...> wrote:

Deaths Associated With Hypocalcemia From Chelation Therapy—Texas,

Pennsylvania, and Oregon, 2003-2005

JAMA. 2006;295:2131-2133.

MMWR. 2006;55:204-207

Chelating agents bind lead in soft tissues and are used in the

treatment of lead poisoning to enhance urinary and biliary excretion

of lead, thus decreasing total lead levels in the body.1 During the

past 30 years, environmental and dietary exposures to lead have

decreased substantially, resulting in a considerable decrease in

population blood lead levels (BLLs)2 and a corresponding decrease in

the number of patients requiring che! lation therapy. Chelating

agents also increase excretion of other heavy metals and minerals,

such as zinc and, in certain cases, calcium.1 This report describes

three deaths associated with chelation-therapy–related hypocalcemia

that resulted in cardiac arrest. Several drugs are used in the

treatment of lead poisoning, including edetate disodium calcium

(CaEDTA), dimercaperol (British anti-ite), D-penicillamine, and

meso-2,3-dimercaptosuccinic acid (succimer). Health-care providers

who are unfamiliar with chelating agents and are considering this

treatment for lead poisoning should consult an expert in the

chemotherapy of lead poisoning. Hospital pharmacies should evaluate

whether continued stocking of Na2EDTA is necessary, given the

established risk for hypocalcemia, the availability of less toxic

alternatives, and an ongoing safety review by the Food and Drug

Administration (FDA). Health-care providers and pharmacists should

ensure that Na2EDTA is not administe! red to children during

chelation therapy.

Chelating agents, especially those intended for use in children,

should be effective in reducing lead and other heavy metals from the

body without producing substantial adverse effects on levels of

critical serum electrolytes, such as calcium. The only agent

recommended for intravenous (IV) chelation therapy for children is

CaEDTA.1 However, hospital formularies usually stock multiple

chelation agents. One such agent, Na2EDTA, was formerly used for

treatment of hypercalcemia, but its use has become infrequent because

of concerns regarding nephrotoxicity and because of the availability

of less toxic alternatives.3 Furthermore, Na2EDTA contains a warning

stating, " The use of this drug in any particular patient is

recommended only when the severity of the clinical condition

justifies the aggressive measures associated with this type of

therapy. " According to the package insert, Na2EDTA is " indicated in

selected patients for the emergency treatment of hypercalcemia and

for the con! trol of ventricular arrhythmias associated with

digitalis toxicity. " According to FDA and CDC, the safety and

effectiveness of Na2EDTA in pediatric patients has not been

established, and its use is not recommended because it induces

hypocalcemia and possibly fatal tetany.1

In 2005, the Texas Department of Health childhood lead poisoning

surveillance program reported a death attributable to chelation-

associated hypocalcemia to CDC. Subsequently, CDC queried state and

local lead-surveillance programs regarding chelation-related

fatalities; additional deaths were identified in Pennsylvania and

Oregon.

Case Reports

Texas. In February 2005, a girl aged 2 years who was tested for blood

lead during routine health surveillance had a capillary BLL of 47

µg/dL. A venous BLL of 48 µg/dL obtained 12 days later confirmed the

elevated BLL. A complete blood count and iron study conducted

concurrently revealed low s! erum iron levels and borderline anemia.

On February 28, 2005, the girl was admitted to a local medical center

for combined oral and IV chelation therapy.

The patient's blood electrolytes at admission were within normal

limits. Initial medication orders included IV Na2EDTA and oral

succimer (an agent primarily used for treatment of lead poisoning).

The medication order subsequently was corrected by the pediatric

resident to IV CaEDTA. At 4:00 p.m. on the day of admission, the

patient received her first dose of IV CaEDTA (300 mg in 100 mL normal

saline at 25 mL/hr). At 4:35 p.m., she was administered 200 mg of

oral succimer. Her vital signs remained normal throughout the night.

At 4:00 a.m. the next day, a dose of IV Na2EDTA (instead of IV

CaEDTA) was administered. An hour later, the patient's serum calcium

had decreased to 5.2 mg/dL (normal value for pediatric patients: 8.5-

10.5 mg/dL). At 7:05 a.m., the child's mother noticed that the child

was limp and not breathing. Bedside procedures did not restore a

normal cardiac rhythm, and a! cardiac resuscitation code was called

at 7:25 a.m. The child had no palpable pulse or audible heartbeat.

Repeat laboratory values for serum drawn at 7:55 a.m. indicated that

the serum calcium level was <5.0 mg/dL despite repeated doses of

calcium chloride. All attempts at resuscitation failed, and the girl

was pronounced dead at 8:12 a.m.

An autopsy revealed no results of toxicologic significance. A

postmortem radiologic bone survey indicated areas of sclerosis at the

metaphyses (growth arrest and recovery lines compatible with lead

exposure). The cause of death was recorded as sudden cardiac arrest

resulting from hypocalcemia associated with chelation therapy. The

hospital's child mortality review board findings indicated that a

dose of IV Na2EDTA was unintentionally administered to the child.

Pennsylvania. In August 2005, a boy aged 5 years with autism died

while receiving IV chelation therapy with Na2EDTA in a physician's

office. During the chel! ation procedure, the mother noted that the

child was limp. The physici an initiated resuscitation, and an

emergency services team transported the child to the hospital. At the

emergency department (ED), further resuscitation was attempted,

including administration of at least 1 and possibly 2 doses of IV

calcium chloride. Subsequently, the boy's blood calcium level was

recorded in the ED as 6.9 mg/dL. The child did not regain

consciousness. The coroner examination indicated cause of death as

diffuse, acute cerebral hypoxic-ischemic injury, secondary to diffuse

subendocardial necrosis. The myocardial necrosis resulted from

hypocalcemia associated with administration of Na2EDTA. The case is

under investigation by the Pennsylvania State Board of Medicine.

Oregon. In August 2003, a woman aged 53 years with no evidence of

coronary artery disease, intracranial disease, or injury was treated

with 700 mg IV EDTA in a naturopathic practitioner's clinic. The EDTA

was provided by a compounding laboratory (Creative Compounding,

ville, Oreg! on) and was administered by the practitioner to

remove heavy metals from the body. The practitioner had provided a

similar treatment to the patient on three previous occasions, once in

June 2003 and twice in July 2003. Approximately 10-15 minutes after

treatment began, the patient became unconscious. Cardiopulmonary

resuscitation was initiated, and an emergency services team was

contacted. Attempts to revive the patient en route to and in the ED

were unsuccessful. The medical examiner determined the cause of death

to be cardiac arrhythmia resulting from hypocalcemia associated with

EDTA infusion and vascuolar cardiomyopathy. The patient's ionized

calcium level during code was 3.8 mg/dL (normal value for adult

patients: 4.5-5.3 mg/dL) after one IV injection of calcium gluconate

administered by emergency medical technicians en route to the

hospital and another IV injection of calcium chloride in the ED. The

Oregon State Naturopath Licensing Board is conducting an

investigatio! n to determine whether Na2EDTA or CaEDTA was

administered to this pati ent.

The cases described in this report have been reported to FDA. FDA is

performing a safety assessment of Na2EDTA, including a review of the

adverse event reporting system to determine whether other deaths

related to use of chelating agents have been reported.

Reported by:

RA Beauchamp, MD, TM Willis, TG Betz, MD, J Villanacci, PhD, Texas

Dept of State Health Svcs. RD Leiker, Oregon Childhood Lead Poisoning

Prevention Program. L Rozin, MD, Allegheny County, Pennsylvania

Office of the Coroner. MJ Brown, ScD, DM Homa, PhD, TA Dignam, MPH, T

Morta, Div of Emergency and Environmental Health Svcs, National

Center for Environmental Health, CDC.

CDC Editorial Note:

Both children and adults are subject to potentially lethal

prescription errors involving " look-alike, sound-alike " substitutions

(i.e., confusion of drugs with similar names). In a 1-year study of

errors in a tertiary care teaching hospital, 11.4% of medi! cation

errors were found to have resulted from use of the wrong drug name,

dosage form, or abbreviation.4 A review of medical records in the

Texas case described in this report revealed that the brand names for

the Na2EDTA product, Endrate® (Hospira, Inc., Lake Forest, Illinois),

and the CaEDTA product, Calcium Disodium Versenate® (3M

Pharmaceuticals, St. , Minnesota), were used interchangeably;

this improper use of drug names likely resulted in the inappropriate

administration of Na2EDTA.

Although CaEDTA and succimer were ordered for one patient and the

form of EDTA administered to another remains under investigation,

these drugs singly or in combination probably were not responsible

for the low calcium levels. Hypercalcemia as a result of IV

administration of CaEDTA has been reported.5 Succimer by itself is a

weak calcium binder but is not associated with a drop in essential

minerals such as calcium.6 Moreover, the reported doses of CaEDTA and

succi! mer in the Texas case were appropriate and within established

safety l imits.

Medical center records and coroner reports indicate that Na2EDTA was

administered in at least two of the cases. Na2EDTA is often part of a

standard hospital formulary; however, it should never be used for

treating lead or other heavy metal poisoning in children because it

induces hypocalcemia, which can lead to tetany and death.7 The error

that caused the death in Texas most likely resulted from

miscommunication between the pharmacy and the pediatric unit.

Chelation therapy with CaEDTA, dimercaperol, or succimer has been the

mainstay of medical management for children with BLLs & #8805;45 µg/dL.1 The

effectiveness of chelation therapy in improving renal or nervous

system symptoms of chronic mercury toxicity has not been established.

Nonetheless, certain health-care practitioners have used chelation

therapy for autism in the belief that mercury or other heavy metals

are producing the symptoms.8 Other practitioners have recommended

chelation ther! apy for treatment of coronary artery disease, hoping

to eliminate calcified atherosclerotic plaques that can lead to

coronary artery occlusions and myocardial infarctions. These off-

label uses of chelation therapy are not supported by accepted

scientific evidence. The Institute of Medicine found no scientific

evidence that chelation is an effective therapy for autism spectrum

disorder.8 Because limited consistent data exist on the use of

chelation therapy to treat coronary artery disease, a clinical trial

to assess the safety and effectiveness of chelation therapy is being

conducted by the National Institutes of Health.*

Deaths associated with lead poisoning are rare,9 and childhood deaths

caused by cardiac arrest associated with chelation therapy have not

been documented previously.9 As BLLs among children in the United

States continue to decline,2 fewer children require chelation

therapy. Primary care providers should consult experts in the

chemotherapy of lead! before using chelation drug therapy. If such an

expert is not availab le, primary care providers should contact state

or local childhood lead poisoning prevention programs or the Lead

Poisoning Prevention Branch of the National Center for Environmental

Health, CDC.

CDC and its state and local partners will continue to educate health-

care providers and pharmacists to ensure that Na2EDTA is never

administered to children during chelation therapy. CDC recommends

that hospital pharmacies evaluate the need to keep Na2EDTA in their

formularies. Case reports of cardiac arrest or symptoms of

hypocalcemia during chelation therapy should be reported to the CDC

Lead Poisoning Prevention Branch (770-488-3300) or to MedWatch, the

FDA adverse event reporting system, at http://www.fda.gov/medwatch.

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