Transcript New Antidotes in Clinical Toxicology

New Antidotes in Clinical Toxicology
William Darko, B.Pharm(Hons), Pharm.D.
Director, Post Graduate Year – 1 Pharmacy Residency Program
Clinical Pharmacist, Cardiovascular/Critical Care Services
Associate Professor of Pharmacy Practice
Assistant Professor of Medicine, Section of Clinical
Pharmacology
University Hospital, SUNY Upstate Medical University
Syracuse, New York
Objectives
List the indication(s) for each antidote
 Explain the clinical pharmacology of each
antidote
 Demonstrate understanding of clinical evidence
supporting the choice of each antidote
 Identify the side effects and monitoring
parameters associated with each antidote
 Understand the process of compounding or
preparing each antidote for administration
 Apply acquired knowledge to sampled questions

Background

2007: 25th annual report of the AAPCC
◦ Information reported by 61 centers

Reported 4,224,157 total cases
◦ 2,482,041 human exposure cases

NYS updated list of antidotes – June 2009
◦ About 42 antidotes listed
Hydroxocobalamin
N -Acetylcysteine
Road Map
Lipid Emulsion
A 22 year old male was admitted to our institution after intentional
overdose of an unknown quantity of acetaminophen tablets. He then
called EMS and states that “I overdosed because I wanted attention
from my girlfriend who is seeing another guy, please save me. I don’t
want to die”. He was conscious on arrival to our emergency
department but did complain of abdominal pain and nausea.
A stat APAP level, BMP, and liver panel 6.5 hours post ingestion was
reported as;
APAP160 mcg/mL, AST 1554 U/L, Scr 0.9 mg/dL, BUN 15.9 mg/dL
INR 1.20, PT 59 sec.
The PCC was consulted and the recommendation was to start N –
acetyl cysteine
1.What is the dose of NAC required for this patient? IV or oral?
duration??
2. What is the evidence for each route in this patient?
3.How should NAC be prepared for administration?
4.What adverse drug effects should you monitor?
Fatalities from APAP overdose
are common but preventable by
timely administration of NAC
Rumack – Matthew Nomogram
Risk Factors for the Development of Hepatotoxicity
Frequency of acetaminophen dosing
Prolong duration of excessive acetaminophen dosing
Increase capacity for CYP2E1 activation to NAPQI
Decreased glutathione (GSH) availability ( < 30% of baseline)
Decreased capacity of glucuronidation and sulfation
Balance in the activity of GSH and CYP2E1***
Mechanism of Action of NAC
Preserve
multi-organ
function
Increase
capacity to
detoxify
NAPQI
Limit
availability of
free NAPQI
3 Roles
of NAC
NAC serve as a
glutathione precursor
NAC may lead to
increase substrate for
non – toxic sulfation
NAC serve as a GSH
Substitute
Each of these preventive mechanisms must be in place early. None is of benefit after
NAPQI has initiated cell injury. There is an 8 hours window of opportunity
N - Acetlycysteine
Intravenous (Acetadote®)
Oral (Mucomyst®)
Vd
0.47L/Kg
0.417L/Kg
Protein Binding
83%
83%
5.6
11.0
5.6
11.0
Dose
150 mg/Kg LD, then 50 mg /Kg
over 4 hours, followed by 100
mg/kg for 16 hours
Use caution in asthmatics
140 mg/Kg LD, then 70 mg /Kg
every 4 hours x 17 doses
Any NAC dose vomited within 1 hr
should be repeated
Adverse Reaction
17% anaphylactoid reaction :Rash, Nausea and vomiting
flushing, vomiting, hypotension, and
death. Occur during loading dose
Indication
Acetaminophen toxicity within 8 to 10 hours post ingestion. preferably
within 8 hours
Preparation
Loading dose in 200 mL D5W.
Second dose in 500 mL DW and
remaining in 1000 mL D5W
Half Life
Adults
New Born
Mix with enough juice in a drinking
cup. Cover to mask smell of NAC
Difference Between Intravenous and Oral N - acetylcysteine
Item
Intravenous NAC
Oral NAC
Safety
- 17% rate of anaphylatoid reaction of
which 1% serve: this include rash, flushing,
vomiting, and bronchospasm , hypotension
and death – these reactions are dose and
concentration depended
- Higher risk of dosing errors
- Risk of infusion large volume of free
water to pediatric patients if standard dose
is used and in some instances leading to
hyponatremic seizures
Nausea and vomiting present
prior to oral NAC ( ~~50% of
patients) may be worsen with
oral NAC
Diarrhea
Rare skin rash and other
complications
Administration
1. Higher serum concentration , hence
preferred in cerebral edema or in
pregnancy
1.May cause delay in therapy due
to higher rate of vomiting. This
delay is correlated with increase
risk of hepatotoxicity
2.Absorption may be delayed by
up to 1 hour
3.Difficult to administer in
patients with altered mental
status due to the risk of
aspiration
4.Circulation concentration 20 –
30 fold lower than IV
Difference Between Intravenous and Oral N - acetylcysteine
Item
Intravenous NAC
Oral NAC
Duration of Therapy/
Treatment protocol
20 – 21 hours of therapy
(loading dose over 1 hour)
72 hours of therapy
Total Cost
IV – 20% (30 mL) = $137.79
Decreased overall cost of
Increase cost of care due to
care due to shorter duration longer duration of therapy
of therapy , decreased length
of hospital stay leading to
reduction in inpatient cost
and decrease overall hospital
cost
Oral- 20% (30 mL) = $3.53
Specific Indication
1. Fulminant hepatic failure
2. Inability to tolerate oral
NAC after antiemetic
3. Acetaminophen poisoning
in pregnancy
4. Patients with high
[APAP]or approaching the 8
hour mark from the time of
ingestion
1.Oral NAC may prove
effective but has not yet been
demonstrated
3.Placental transfer of oral
NAC may be limited (not
studied)
Less incidence for ADE –
preferred agent for asthmatic
patients unless circumstances
preclude use
Summary of Published Studies on Intravenous and Oral N – acytylcysteine
References
Study
Population
Study Design
Prescott et al
BMJ 1979(2):
1097 - 1100
100 cases with Pts were treated with
sever APAP
IV NAC within 24 hrs
poisoning
300 mg/kg over 20
hrs ( 150mg /kg in
200 mL D5W over
15 min, 50 mg/kg in
500 ml D5W over 4
hrs, and 100 mg/Kg in
one liter D5W over
the next 16 hrs. The
efficacy of NAC was
assessed by
comparing with 57 pt
receiving supportive
treatment
Results
Conclusions
NAC within 10 hrs:
Only 1/62 pts
(1.6%) developed
liver damage vs
33/57 pt (56%)
given supportive
care. Pt who
received NAC
within 8 hrs had
almost complete
resolution
NAC within10 –
24 hrs; 53% liver
toxicity =
supportive tx
< 8 hrs complete
protection
10 – 12 hrs: 7%
12 – 15 hrs 56%
> 15 hrs: Tx was
ineffective
IV NAC is
indicated for the
treatment of
[APAP] above
treatment line if
started <15 hrs
of ingestion.
Treatment
between15 – 24 is
ineffective but
should not be
withheld if time of
ingestion is in
doubt
Summary of Published Studies on Intravenous and Oral N – acytylcysteine
References
Study
Population
Study Design
Results
Conclusions
Smilkstein et
al 1988
NEJM;319:15
57 – 1562
Reported
cases of
suspected
APAP
overdose(197
6 – 1985)
Prospective, national,
multicenter, open label study of oral
NAC (LD : 140
mg/kg, then after 4hrs
70 mg/kg q4 hrs x 17
doses
AST/ALT activity was
reviewed for
hepatotoxicity (>
1000 IU/L). Risk of
hepatotoxic was
compared to study by
Prescott et al
11,195 cases
reported to Rocky
Mountain Poison
and Drug Center.
2540 included.
Serious
hepatotoxicity was
uncommon if NAC
was started within
8 hrs of APAP
ingestion
Tx delay; 8 – 16
resulted in increase
ALT/AST >1000
72 hr oral NAC
regimen is at least
as effective as 20
hour IV when
started within 8
hours from time
of APAP ingestion
Summary of Published Studies on Intravenous and Oral
N – acytylcysteine
References
Study Population
Study Design
Results
Conclusions
Buckley et al
1999;Clin
Toxicology;37(
6):759 - 767
APAP poisoning
patients
Retrospective analysis
of a series of APAP
poisoning patients
treated with a IV NAC
protocol + AC. The
outcome was
incorporated into a
meta-analysis of
previous studies to
compare IV and oral
NAC
341 IV and 1462
oral NAC
Rate of
hepatotoxicity:
< 10 hrs (3% IV and
6% oral)
Late 10 – 24 hrs(30
and 26%)
Overall 0 – 24 hrs
(16 and 19% ) were
all similar.
The difference
between IV and
oral NAC is
artifactual. The
authors
recommended
treating patients
with IV NAC due
to shorter
hospital stay,
convenience,
nausea with oral
NAC, and
concern over
reduced
bioavailability
with AC.
Intravenous Vs Oral NAC
The choice of oral vs IV NAC is complex
 Each has advantages and disadvantages
 IV and oral NAC are equally efficacious in
treating APAP toxicity

◦ Except established liver failure and pregnancy
Efficacy of oral NAC and IV NAC protocols
are equivalent when started within 8 hours
post ingestion
 Decision on route should be based on ADE,
safety, and ease of use but NOT efficacy

Conclusion
NAC is indicated for the treatment of APAP
toxicity
 IV NAC = oral NAC in efficacy
 Best results when NAC is initiated within 8
hours post APAP ingestion
 Preparation and delivery should be timely
 Anaphylactoid reactions are rare with oral
but occur with IV NAC

Intravenous Fat Emulsion (IFE)

Traditionally, IFE is used to provide nutrition
in the form of free fatty acids to patients
requiring Total Perenteral Infusion (TPN)

IFE is currently used in the treatment of
toxicity due to local anesthetics and other
lipid – soluble drugs
◦ This therapy is currently investigational and not
FDA approved in the United States
A 25 year old female with history of drug overdose, was admitted
after ingesting an unknown quantity of her fathers amlodipine and
acetaminophen tablets. At the time of presentation by the EMS her
blood pressure was 80/49 mmHg, HR was 90 bpm. She was receiving
normal saline at 150 mL/hour after a bolus of 1000 mL. She was
lethargic at presentation with cold extremities. Norepinephrine
infusion was started. Her laboratory values were as follows:
Scr 2.7 mg/dL, BUN 37 mg/dL, APAP level <10 mcg/mL, HCO3 17
mmol/L. LFT’s wnl.
PCC was consulted. 20% Fat emulsion was recommended.
1.
2.
3.
4.
5.
What is the dose of IFE
How do you prepare a 20% IFE for the treatment of drug toxicity
What is the duration of therapy?
What side effects should you monitor?
Where is the evidence?
Intravenous Fat Emulsion and drug Toxicity
Mechanism of IFE appears to create an intravascular “lipid Sink”
Action
and have the capacity to bind and sequestrate
lipophilic drugs present in toxic concentrations from
target sites
The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Serves Local Anesthetic
Toxicity. http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on June 27th 2009
Intravenous Fat Emulsion in Local Anesthetic Toxicity
Guidelines
for the
Treatment
of Cardiac
Arrest with
IFE
•Give an intravenous bolus injection of 20% IFE at 1.5 ml/kg
over 1 min (based on a 70kg weight)
o Give a bolus of 100 ml
• Continue CPR
• Start an intravenous infusion of 20% IFE at 0.25 ml/kg/min
o Give at a rate of 400 ml over 20 min
• Repeat the bolus injection twice at 5 min intervals if an
adequate circulation has not been restored
o Give two further boluses of 100 ml at 5 min intervals
• After another 5 min, increase the rate to 0.5 ml/kg/min if
an adequate circulation has not been restored
o Give at a rate of 400 ml over 10 min
• Continue infusion until a stable and adequate circulation
has been restored
The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Severe Local Anesthetic
Toxicity. http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on July 27th 2009
Intravenous Fat Emulsion in Local Anesthetic Toxicity
Adverse
Events
Associated
with the
Use of IFE
Incidence of less than 1%:
a) Dyspnea, cyanosis, allergic reactions, hyperlipemia,
hypercoagulability, nausea, vomiting, headache, flushing,
increase in temperature, sweating, sleepiness, pain in the
chest and back, slight pressure over the eyes, dizziness, and
irritation at the site of infusion, and, rarely,
thrombocytopenia in neonates;
b) Delayed adverse reactions such as hepatomegaly,
jaundice due to central lobular cholestasis, splenomegaly,
thrombocytopenia, leukopenia, transient increases in liver
function tests, and overloading syndrome (focal seizures,
fever, leukocytosis, hepatomegaly. splenomegaly and shock).
The deposition of a brown pigmentation in the
reticuloendothelial system, the so-called “intravenous fat
pigment
The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Serves Local Anesthetic
Toxicity. http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on June 27th 2009
Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid
Soluble Toxins in animal Models
Reference
Model
Toxin
IFE Protocol
Weinberg GL et al.
Anesthesiology
1998;88:1071- 75
Rat
Bupivacaine Pretreatment: 15
mL/kg of 10%, 20%, or
30%
Outcome
Increase mean lethal
dose
Weinberg G et al.
Dog
Reg Anesth Pain
Med 2003;105:217 218
Bupivacaine Rescue: 4mL/kg bolus Increase survival time;
of 20% followed by 0.5 improved
mL/kg over 10 min
hemodynamics, PO2
and pH
Cave G et al. J Med
Toxicol 2006;2:4 –
7
Propranolol Pretreatment: 16
mL/kg of 20%
Trend towards
improved survival
time; improved HR;
decrease QRS
prolongation
Thiopental
Trend toward
decrease respiratory
depression
Rat
Cave G et al. Emerg Rat
Med Australas
2005;17:180 – 181
Rescue: 8 mL/kg of
20%
Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid
Soluble Toxins in animal Models
Reference
Model
Toxin
IFE Protocol
Outcome
Bania TC et al.
Acad Emerg Med
2007;14:105 – 111
Dog
Verapamil
Rescue: 7 mL/kg
of 20%
Improved MAP; increase
survival
Tebbutt S et al.
Acad Emerg Med
2006;13:134 – 139
Rat
Verapamil
Rescue: 12.4
mL/kg of 20%
Increase survival time
and LD50; slower
development of
bradycardia
Goor Y et al Vet
an Human Tox
2002;44:30
Rat
Clomipramine
Simultaneous; 2.5
mL of 10%
Improved survival time
Harvey M et al Ann Robbit Clomipramine
Emerg Med
2007;49:178 – 185
Rescue: 12 and 8
mL/kg of 20%
compared to
sodium
bicarbonate
Improved MAP and
cardiovascular collapse
Bunia TC et al
Acad Emerg Med
2005;12:S12 – Ref
abstract
Pretreatment: 15
mL/kg of 20%
No change in the LD50
Mouse Organophosphate
Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in
the Treatment of Lipid soluble toxins
Reference
Case
Rosenblatt AM et
al. Anesthesiology
2006;105:217 – 8
Toxin
IFE Protocol
Outcome
58 Yr – old 82 kg
Bupivacaine
male with prolong
cardiac arrest after
interscalene block .
Developed cardiac
arrest characterized
by seizure, asystole,
no pulse, and no
blood pressure
100 ml of 20%
Intralipid®, then
0.5 mL/kg/min
over 2 hours
Patient recovered
with no neurologic
sequelae. There was
no complication
from Intralipid®
administration
Litz JR et al
84 – yr – old 50 kg Ropivacaine
Anaesthesia
female , s/p axillary
2006;61:800 – 801 brachial plexus
block with 40 mL of
1% (instead of 0.5%)
ropivacaine.
Developed cardiac
arrest, failed normal
cardiopulmonary
resuscitation
100 mL of 20%
Intralipid®, then
10 mL/min.
Total of 200 mL
at 4 mL/kg
Patients recovered
completely and was
discharged home in 4
days
Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in
the Treatment of Lipid soluble toxins
Reference
Case
Toxin
IFE Protocol
Outcome
Warren AJ et al.
Anesth Analg
2008;106:1578 –
80
60 yr – old 83 kg male
, s/p supraclavicular
brachial plexus block.
Developed respiratory
and cardiac arrest but
failed normal
cardiopulmonary
resuscitation protocol
Bupivacaine
250 mL IV
infusion of
Liposyn® III
20% over 30
minutes
without bolus
He recovered and
was discharged 3
days later
Sirianni JA et al.
17 year – old, 55kg girl,
Ann Emerg Med.
found unresponsive at
2008;51:412 – 415 home with possible
intentional ingestion of
her medications as per
pill count. Developed
seizures and cardiac
arrest 10 hours post
ingestion. She
decompensated after a
brief cardiac
resuscitation
Bupriopion
(7.95 gms)
and
Lamotrigine
(4 gms)
Intralipid®
started 52 min
into a second
ACLS , a single
IV bolus of 100
mL bolus of
Intralipid® 20%
Patients was
discharged from
the PICU after 24
days stay with slight
tremor
Summary of Human Case Reports of the Benefit of Intravenous Fat
Emulsion in the Treatment of Lipid Soluble Toxins
References
Case
Toxin
IFE Protocol
Outcome
Litz JR et al
Anesth Analg
2008;106:1575 –
7
91 yr – old 57 kg male
developed incomplete
block. He developed
central nervous system
and cardiac toxicity
(supraventricular
extrasystoles with
intermittent bigeminy)
Mepivacaine
and plain
Prilocaine
Intralipid® 20% IV
bolus of 1 mL/kg and
repeated after 3
minutes (total 100
mL), then 0.25
mL/kg/min (14
mL/min) to a total of
200 mL
Patient recovered
and later surgery was
performed
uneventfully.
Young CA et al.
Resuscitation
2009;80: S91 93
32 yr – old male
Verapamil
overdosed on sustained –
released verapamil 13.44
gms, levothyroxine,
bupropion, zolpidem CR,
quetiapine, clonazepam,
and benazepril. He failed
glucagon and calcium
gluconate therapy BP.
Was found to be in
junctional bradycardia
and hypotensive despite
pressors
Intralipid® 20%;100
mL over 20 min, then
0.5 mL/kg/h for 23
hours
Patient recovered
and was discharged
home on day 5
without any
neurological deficit
Summary of Human Case Reports of the Benefit of Intravenous Fat
Emulsion in the Treatment of Lipid Soluble Toxins
after
References
Case
Toxin
Finn HDS et al
Anaesthesia.
2009;64:191 –
194
61 yr – old 67 kg
Sertraline
unresponsive after
and
overdosed on 4.3 g quetiapine
of quetiapine, 3.1gm
of sertraline and
possibly
benzodiazepines.
IFE Protocol
Outcome
Intralipid® 20% was
started 4 hours post
ingestion.
1.5 mL/kg (100 mL)
bolus, then infusion
of 6 mL/kg (400 mL)
over next 1 hour
Recovered and
was discharged
without any
neurological
deficit
Conclusion
IFE is not FDA approved for the treatment of drug
toxicity.
 Current success with IFE use is limited to animal
studies and case reports.

◦ Dose not well defined. Especially infusion after bolus dose
◦ Administer undiluted as 20% fat emulsion
More experience with local anesthetic toxicity
 IFE is effective in the management of lipid soluble drug
toxicity

◦ Potential antidote of choice for lipid soluble toxins/drugs

Control studies warranted
Hydroxocobalamin
A 54 – year old woman brought to the hospital from an
apartment fire. She had altered mental status, hypotension
and evidence of inhalation injury, but no burns. Her
carboxyhemoglobin level was 29% and her lactate was 16
mmol/L. She was treated with supplemental and hyperbaric
oxygen for CO intoxication. Hydroxocobalamin 5 gm was
administered intravenously for presumed cyanide poisoning.
1. How will you prepare hydroxycobalamin for Intravenous
administration in this patient
2. What precaution will you take prior to administration of
hydoxocobalamin to this patient?
3. What adverse effects will you expect? How will you
monitor?
2005 AAPCC report: Cyanide poisoning account for 220
of 2.4 million cases of human poisoning reported to
poison centers
•The most common source of CN toxicity is smoke
inhalation
•Estimated to cause 5,000 – 10,000 deaths annually in
the US
•Mortality from smoke inhalation is about 24 – 31%
Smith Dl et al J Trauma 1994;37:655 – 659
Baud FJ et al N Eng J Med 1991;325:1761 – 1766
Silverman SH et al J Trauma 1988;28:171 – 176
Source of
Cyanide
Poisoning
Smoke inhalation, acrylic nail polish(acetonitrile),
electroplating, jewelers, occupational (industries that
produce, solvents, plastics, herbicides, pesticides,),
industries that polish metal, certain nuts, fruit pits
(apricot, cherry), seeds (apple seeds), almond husks,
and certain plants,
Mechanism of
Cyanide Poisoning
Causes toxicity at the cellular level resulting in multisystem
failure.
Ideal Cyanide
Antidote
1.Relatively harmless if given to patients who are not cyanide
toxic, 2. Should be readily available, 3.Scientifically proven to
be effective, 4.Have rapid onset of action, 5. Have
bioavailability in body tissue and 6. Be relatively inexpensive
Cyanokit®
Cobalt containing compound, that is a precursor of
(Hydroxocobalamin) cyanocobalamin. FDA approval in December 2006 ( has been
used in Europe since the 1970s)
Indication
Treatment of known or suspected cyanide poisoning
Dose and
Administration
Initial dose: 5.0 gm(2 vials) IV, a second dose may be given to a
max dose of 10 gm. Administer by IV infusion over 15 – 30 minutes
via a dedicated IV line. Pediatrics: 70 mg/kg followed by a 35 mg/kg
if needed
Clinical Pharmacology
Binds cyanide to form cyanocobalamin and excreted renally. It has a rapid
onset of action and crosses the blood – brain barrier in 1 – 3 minutes
Preparation
Available as 2 vials of 2.5 gm lyophilized powder. Each vial should be
reconstituted with 100 mL of 0.9% normal saline prior to
administration(forms a clear red liquid when reconstituted). Reconstitution
solution not included in kit
Adverse drug effects
Discoloration of skin and urine (can interfere with
spectrophotometric tests), slight elevation in blood pressure, injection
site reaction, decrease lymphocyte count, nausea, chest discomfort,
pustular/papular rash, headache, dysphagia and relative bradycardia
Standard three – part
cyanide antidote Kit
Amyl nitrite, Sodium nitrite, and Sodium thiosulfate : Induce methemoglobin
and nitrite causes hypotension
Has been used since 1950s
Controversy over 3 part
CN antidote Kit
Academic controversy: Evidence is based on animal data, safety studies in
healthy volunteers, and uncontrolled efficacy studies in humans
Adopted from Shepherd G and Velez IL. Ann Pharmacother 2008;42:661 – 669
Chromaturia and skin redness:
Cescon WD and Juurlink ND. CMAJ. 2009;180(2):180
$185.00
$715.00
Adopted from The Ann Pharmacotherapy 2008;42:664 with modification
Clinical Evidence: Hydroxocobalamin for the Treatment of Cyanide
Poisoning
References
Study Population
Study Design
Results
Conclusion
Barron SW et al
Am J Emerg. Med.
2007; 25:551 –
558
Retrospective
chart review.
Excluded patients
with smoking
inhalation
Hydroxocobala
min 5 gm - 20
gm was given to
14 pts (12 were
suicide attempts
+ standard
supportive care
10 (71%) survived
to discharge. 11
pts had cyanide
conc. <100 µmol/L;
7 of these
survived; 8 (57%)
developed ADR
(mostly
discoloration of
skin). Mean
antidote adm time
from ingestion was
3.1 hrs
Study shows that
hydoxocobalamin
could be used
safely with
benefit in
patients with
acute cyanide
poisoning .
However, this did
not address
cyanide poisoning
associated with
smoke inhalation.
Clinical Evidence: Hydroxocobalamin for the Treatment of Cyanide
Poisoning
References
Study Population
Study Design
Results
Conclusion
Fortin JL et al
Clin. Toxicol
2006; 44(1):37 –
44
Respective review of
pre-hospital use of
hydroxocobalamin for
smoke inhalation
Charts of 101
patients reviewed.
Blood cyanide
concentration not
measured
30 patients
survived (41.7%),
42 died. 29 pts
with no data on
survival outcome.
38 pts were in
cardiac arrest
when found. 12
patients were HD
unstable – 9 (75%)
recovered 30 min
after Tx.
Pts with Glasgow
score <13
benefited most
This study support
previous safety
findings of
hydroxocobalamin.
Survival was lower
than expected. This
suggest that
hydroxocobalamin
could be beneficial
in patients with
smoke inhalation
and with
neurologic
impairment. Since
symptoms were
not correlated
with CN
concentration,
benefit cannot be
considered
conclusive.
Clinical Evidence: Hydroxocobalamin for the Treatment of Cyanide
Poisoning
References
Study Population
Study Design
Results
Conclusion
Barron SW et al
Ann Emerg. Med
2007;49(6):794 –
801 e1 – e2
Prehospital use of
hydoxocobalamin
for smoke –
induced cyanide
poisoning
Prospective
uncontrolled open
– label study.
Patients > 15 yrs
(mean 49.6 yrs),
had soot in
mouth/nose/expect
- oration and had
altered neurologic
status
CN concentration
and CO were
measured. Pt
received 5gm of IV
hydroxocobalamin
over 15 – 30 min.
max 15 gm
Enrolled 69 pts (63
had pre – antidote
blood conc.) CN
was present
(>39µmol/L ) in 42
patients, 67%
survived. Median
CN conc. of 52
µmol/L. Overall
Survival rate was
72% (n=50)
CN conc. > 100
µmol/L, survival
was 58% (11/19).
The median dose of
hydroxocobalamin
was 5 gm. 19 pts
developed ADR.
Most commonly
chromaturia and
skin discoloration
(10). HTN (3)
This study
demonstrated that
empiric adm of
hydroxocobalamin
was associated with
survival benefit
irrespective of
presence of CN
poisoning.
Hydroxocobalamin
appears to be safe
and well tolerated
for the treatment
of out – of –
hospital of
presumptive CN
poisoning from
smoke inhalation
Administration Protocol
Hydroxocobalamin has gain acceptance for the
treatment of presumed cyanide poisoning in
fire victims in the pre – hospital setting
 FDNY – EMS in July 2009 adopted a protocol
Patients exposed to smoke:

◦ Hypotension, altered mental status, Coma, seizures
◦ Respiratory arrest, or cardiac arrest

3 tubes of blood will be drawn before
hydroxocobalamin administration
Formulary Consideration


Hydroxocobalamin is an FDA approved cyanide
antidote with alternative mechanism
Offers straightforward administration with
safety profile in patients with smoke inhalation
◦ No methemoglobenemia and hypotension



Offers a more rapid onset of action
Though has higher drug cost, would likely have
little impact on hospital’s drug budget
At minimum, stock enough cyanide antidote to
treat one patient for up to 24 hours
Dart RC et al Ann Emerg. Med 2000;36:126 - 132
Conclusions
Hydroxocobalamin has demonstrated
efficacy and safety profile in the treatment of
patients with cyanide poisoning
 Lack of comparative data to support
superiority over the 3 – part cyanide
antidote
 Hydroxocobalamin may be beneficial choice
in cases:

◦ Where diagnosis of CN poisoning is uncertain
◦ Where induction of metHb may be detrimental
QUESTIONS??