Transcript Cyclic Antidepressants

Cyclic Antidepressants:
it’s all good.
Toxicology Core Rounds
Jan 15, 2004
Rob Hall PGY4
Randall Berlin (toxicologist extrodinare!)
Objectives
Walk through a case………………
 We need to know the presentation,
diagnosis, disposition, and general
management of TCA overdoses INSIDE
and OUT!
 Specifically, we will focus on the
complications of TCA overdoses

Case of the day!
EMS patches in ………
 ETA 10 min
 42yo female
 Amitriptyline overdose
 Decreased LOC, hypotensive, tachycardic

Case of the day!


How would you
prepare?
List four
complications of TCA
overdose that you
should be prepared
for?


Resusc room, be ready
to intubate, have ECG
there, approach will be
ABCs/monitor/iv/etc
Four predictable
complications
–
–
–
–
Hypotension
Wide complex tach
Seizures
Decreased LOC
Case of the day!

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

EMS arrives
Story = 42yo female, previous overdoses, found
on floor in bathroom, amitriptyline bottle empty,
estimated time since ingestion is 1.5 hours ago, no
coingestants known
T 38.1, HR 120, BP 85/60, C/S normal, sat 95%
NRB, RR 15, GCS E1V2M4, dry red skin, no
bowel sounds, motor X 4, pupils 5mm,
hyporeflexic, no clonus, no rigidity, no signs of
trauma
What’s your management?
Case of the day!

How would you
intubate?

PEARLS of intubating the
TCA overdose
– Preoxygenate
– Hyperventilate before you
push drugs
– AVOID resp acidosis
– Give a bolus dose of bicarb
with your pretreatment
– Best intubator!
Case of the day:
What is the role of gastric lavage?

Evidence against lavage
– Pond 1995: Gastric lavage can be omitted from the treatment
protocol for acute overdoses
– Merigan 1990: No benefit of gastric lavage
– Kulig 1985: No benefit of gastric lavage unless performed < 1hr


All three studies either excluded the critically ill or were
underpowered to evaluate that subgroup
This patient SHOULD be lavaged, why?
– Potentially lethal overdose, no good antidote, delayed gastric
emptying b/c of anticholinergic effect
Case of the day:
When do you expect toxicity?

TCA overdoses will develop toxicity within
6 hours
– Rapidly absorbed
– Peak levels 6-8hrs
– Highly lipophilic thus rapid delivery to
heart, brain
– Has relevance to when patient is
“medically cleared”
TCA mechanisms of Toxicity

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Anti-cholinergic

Na+ channel blockade 
K+ channel blockade 
Alpha 1 antagonism 
Serotonin and NE

reuptake inhibition

GABA antagonism, etc
Anticholinergic toxidrome
Wide QRS
Prolonged QT
Hypotension
Seritonin syndrome
Seizures
Case of the day!
After you intubate, patient has a generalized
seizure
 Why?

–
–
–
–
Anticholinergic effect
Gaba antagonism
Hypotension
Exact mechanism unknown!
Why are seizures so bad?
 Management?

TCA overdoses and seizures
Acidosis
Seizure
DEATH
Shock
Cardiac
toxicity
TCA toxicity and Seizures

Management
– First line: benzodiazepines
– Second line: phenobarbital
– Third line agents: propofol
– Avoid dilantin (Na+ channel blockade)

Should you give bicarb? Yes
Flumazenil


Why is flumazenil contraindicated in a patient
with BZD + TCA overdose?
Will precipitate seizures ----> acidosis, cardiac toxicity,
death, call CMPA

Flumazenil is generally not indicated in the
overdose setting for this reason
– One exception may be a pediatric ingestion of BZD
with absolutely no suspicion of coingestant
– OK with therapeutic use
Any role for physostigmine in
TCA overdoses??

Theory
– Block acetylcholinesterase, increases Ach at
synapse, initially used to treat agitated delirium

Results
– Brady, asystolic arrests
– Do not use
Case of the day!
HR 120, BP 80/50
 What is your management?
 Why?

TCAs and Hypotension
Fluids, go early to pressors
 Norepinephrine is the pressor of choice
 If you are going to use dopamine, titrate up
to alpha range (15 - 20 ug/kg/min) quickly
 Why is norepinephrine better theoretically
than dopamine?

TCAs and Hypotension

How does dopamine
work?
– Dopamine is a
precursor to
norepinephrine
– Dopamine stimulates
the release of stored
norepinephrine
– Dopamine stimulates
adrenergic receptors
TCAs and Hypotension
TCAs
block
alpha
receptors
TCAs and Hypotension
NO controlled human studies comparing
pressors for hypotension
 Animal studies are conflicting
 Teba. Am J Emerg Med 1988
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Best human data
Retrospective review
26 hypotensive TCA overdoses
Better response rates to norepi than dopamine
TCAs and Hypotension

Extreme options!
– ECMO
– Cardiac bypass
– IABP
Case of the day!
Interpretation?
Will she have a bad outcome?
TCA toxicity and the ECG
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Sinus tachycardia
Prolonged QT
Wide QRS
Wide complex tachycardia
– SVT with aberrancy
– Vtach
– Vfib
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Right BBB
Tall R wave in aVR
R/S ratio in aVR >
Terminal 40 msec right axis
TCA toxicity and the ECG

Tall R in aVR, R/S ratio in aVR > 0.7
TCA toxicity and the ECG

Terminal 40 msec right axis: what does that
mean????
TCA toxicity and the ECG

Terminal 40 msec
right axis
– What does a normal
aVR look like?
– Why a right axis?
TCA toxicity and the ECG
 Terminal
40
msec right axis:
the poor man’s
way
– S in lead I
– R in aVR
TCA toxicity and the ECG

What ECG features are predictive of TCA
toxicity?
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–
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–
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QRS width
Tall R in aVR
R/S ratio in aVR
Terminal 40 msec right axis
Which are the most sensitive/specific for
TCA toxicity?
QRS width

Boehnert. NEJM 1985
– QRS > 100msec predictive of complications
– 33% had seizures
– 14% had ventricular dysrhythmias
QRS Width

Liebelt. Ann Emerg Med 1995.
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–
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Prospective cohort of 79 TCA overdoses
Used outcomes of seizures or arrythmias
Sensitivity Specificity
QRS > 100 msec 82%
58%
QRS > 120 msec 59%
87%
Tall R and R/S ratio in aVR

Liebelt. Ann Emerg Med 1995.
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–
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–
–
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Tall R wave and R/S ratio > 0.7 in aVR was
Used outcomes of seizures or arrythmias
Sensitivity Specificity
QRS > 100 msec 82%
58%
QRS > 120 msec 59%
87%
R > 3mm in aVR 81%
72%
R/S > 0.7 in aVR 75%
77%
Terminal 40 msec right axis
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Wolfe. Ann Emerg Med 1995
– Retrospective chart review
– Only looked at symptomatic TCA overdoses
– Outcome: seizure, arrythmia, vital sign
changes, respiratory or level of consciousnous
changes ------------------pretty vague!!
– Terminal 40 msec right axis
» Sensitivity 83%
» Specificity 63%
ICU resident called to psych ward STAT (this isn’t going
to be good!): What is the differential dx of wide QRS in
toxicology?
ECG and Toxicology

Wide QRS (Na+
channel blockade)
– TCAs
– Antihistamines (gravol,
benadryl)
– Amphetamines
– Cocaine
– Carbemazepine
– Chloroquine
– Procainamide
– Propoxyphene
– Propranolol
– Disopiramide
– Quinine, quinidine

Prolonged QTc
–
–
–
–
–
–
–
TCA
Haldol, Mellaril, etc
Ia: pdq
Ic: flec, ec
III: amio, sotalol
Celexa
Erythromycin,
Terfenidine, astemizole
– Lytes: Ca, Mg, K
Case of the day!
What do you want to do now?
TCA and Sodium Bicarbonate
Sodium Bicarbonate is the treatment of
choice for cardiac toxicity
 Dose = 1-2 mEq/kg iv bolus q10 min prn
 End points = no indication, pH 7.50 - 7.55
 Monitor response with repeat ECGs and
ABGs

TCA and Sodium Bicarbonate:
How does it work?
 Increases
protein binding
– TCAs are albumin bound which is pH sensitive; minor
role b/c large Vd and lipophilic thus most TCA is in
tissue not serum
 Alkalosis
– TCA binding to the voltage gated sodium channel is pH
dependent thus elevating the pH decreases the binding
of the TCA molecule to the Na+ channel
 Sodium
loading
– Na load with bicarb creates a larger gradient across the
Na+ channel
TCA and Sodium Bicarbonate:
How does it work?
TCA and Sodium Bicarbonate:
What are the indications?
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Hypotension
Wide complex tachycardia
Conduction blocks
– New/unexplained RBBB
– R in aVR > 3mm, R/S ratio > 0.7, or terminal 40 msec right
axis
– QRS > 100 msec (or > 120 msec)
» Recommendations vary with source
» QRS width related to time from ingestion important

? Seizures
– Makes sense to me but isn’t classically listed as an
indication for bicarb
TCA and Sodium Bicarbonate:
Bolus versus infusion?
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Boluses are preferred for initial indications: Why?
– Studies showing effect of bicarb have used a bolus
– NOTE: bolus = Na+ load, bicarb drip will increase your
pH but is not a large Na+ load
– Probably better b/c big Na load with bolus overcomes
Na blockade; Na load likely more important than pH
change
NO controlled human studies to compare repeat boluses vs
infusion
Bicarb infusion resonable for patient requiring repeat
boluses
Controversies in the management
of wide complex tachycardia
with
TCA toxicity:
bicarb and then what??
You have given 3 amps bicarb and the ECG
still looks like this. Management?
Controversy
What
if there is no
response to the bicarb
boluses despite pH being
in target 7.50 – 7.55?
Controversy
 Is
there any role for Hypertonic
Saline, Phenytoin, or Lidocaine,
Magnesium, Amiodarone, or
Propranolol in the management
of wide complex tach in TCA
overdoses?
Hypertonic Saline

Theory
– Na+ load to overcome Na+ channel blockade
by the TCA
– Na+ load without the adverse effects of
alkalosis as seen with sodium bicarbonate
– Able to give a lot more Na+ than with normal
saline
» Normal Saline: 0.9% NaCl
» Hypertonic Saline: 7.5% NaCl
Hypertonic Saline

Goldfrank 2003
– Theoretical benefit but not adequately studied

Ford 2001
– Not mentioned
Hypertonic Saline

Hoegholm. Clinical Toxicology. 1991
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Case Report of TCA overdose
Hypotensive, wide QRS, recurrent VT and VF
Intubated, lavaged
Sodium bicarb, lidocaine, dopamine, and
hyperventilation (how much of each???)
– Sodium chloride 170 mEq given over 5 min
» Immediate narrowing of the QRS, increased BP, no further VT
or VF

One case report, not much for details, amount of
bicarb could have been more important
Hypertonic Saline

McCabe. Acad Emerg Med. 1994
– Swine model of TCA toxicity
– Nortiptyline until SBP 50% of baseline and
QRS > 120 msec
– Randomized groups
» 10 ml/kg of 7.5% hypertonic saline + 6% dextran
» 10 ml/kg of 0.9% normal saline
– NO bicarbonate treatment arm
Hypertonic Saline:
McCabe. Acad Emerg Med. 1994
BP 10 min
after tx
QRS 10
Survival at
min after tx one hour
Hypertonic 115 +/- 12
Saline
88 +/- 13
4/5
Normal
Saline
180 +/- 8
0/5
45 +/- 8
Hypertonic Saline

McKinney. Ann Emerg Med. 2003
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Case Report
29 yo female ingested 8 gm of nortryptylline
Coma, BP 80/40, QRS 124 msec
Intubated, lavaged, hyperventilation, 3L normal saline,
dopamine 20 ug/kg/min, norepinephrine 22 ug/min, 4
amps bolus sodium bicarb, pH 7.54
– QRS 135 msec
– Given 200 ml of hypertonic saline (7.5%)
Hypertonic Saline

McKinney. Ann Emerg Med. 2003
– BP
0

78/42
3
5
85/50
104/60 112/68 115/68
– QRS

136 msec 120msec
10
30 min
Hypertonic Saline

McCabe. Ann Emerg Med 1998
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–
–
–
–
–
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Swine model (N=24)
Nortyptyline until SBP < 50 and QRS > 120 msec
Group 1 = D5W 10 ml/kg
Group 2 = Hypertonic Saline 7.5% 10 ml/kg
Group 3 = Sodium Bicarb 8.4% 3mEq/kg
Group 4 = Hyperventilation to target pH 7.5-7.6 and
D5W 10 ml/kg
Hypertonic saline looked pretty good!!
Hypertonic Saline:
McCabe. Ann Emerg Med 1998
QRS
Before
tx
QRS
After tx
SBP
Before
tx
SBP
After
tx
Survival
D5W
N=6
HTS
N=6
148
144
56
54
1/6
158
80
57
134
5/6
Bicarb
N=6
HyperV
N=6
156
105
52
85
2/6
146
125
50
60
1/6
Hypertonic Saline: Conclusions


There is animal evidence to support the use of
hypertonic saline after other therapies have been
maximized
Human evidence is limited to case reports
 Consider
Hypertonic Saline for
TCA toxicity if sodium bicarbonate
ineffective and pH of 7.50-7.55 has
been reached
Hypertonic Saline: Conclusions
 Should
Hypertonic Saline be used
instead of sodium bicarbonate?
NO
– Lots of evidence for sodium bicarb and not
much for hypertonic saline
– Needs more study
What about
phenytoin?
Phenytoin
Theory: increases AV conduction thus
enhances delivery of supraventricular
impulses and suppresses ventricular
rhythms; also decreases re-entry
 BUT isn’t phenytoin a Na+ channel
blocker?

– Different Na+ binding site than TCA
– Thought to increase conduction rather than
block it although QRS prolongation can occur
Phenytoin

Goldfranks 2003
– Not recommended

Ford 2001
– Not even discussed

So what evidence is there?
Phenytoin

Callaham. J Pharmacol Exp Ther. 1988
– Dog model
– Control group: amitriptyline infusion
– Experimental group: phenytoin loading before
amitriptyline infusion
– Results
» No differences in physiologic parameters
» Ventricular tachycardia dramatically increased in
phenytoin group
Phenytoin

Kulig. Vet Hum Toxicol 1984 (abstract)
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–
–
–
–
Canine model
Amitiptyline until QRS 160 msec
Phenytoin pretreatment and rescue
No bicarb, no pressors
Phenytoin prevented ventricular arrythmias
only when given as pretreatment
– Details not provided
Phenytoin

Mayron. Ann Emerg Med 1986.
– Rabbit model
– Amitripyline
– Looked at “prophylaxis” and “rescue” treatment with
phenytoin
– Outcome measure was dose of amitriptyline necessary
to cause wide QRS/arrythmia or death
– NO BP data
– Specifics of QRS width not presented
Phenytoin

Mayron. Ann Emerg Med 1986.
– Phenytoin had NO effect on the amitriptyline dose
required to cause “toxicity”
» No pretreatment: mean 11.4 mg/kg (2 – 39range)
» Phenytoin pretx: mean 10.0 mg/kg (2.8-23.3 range)
– Phenytoin had NO effect on the amitriptyline dose
required for lethality
– Phenytoin rescue dose after toxicity had an effect in
2/12 (narrowed the QRS) and no effect in 10/12

Concluded: no effect with pretreatment or rescue
Phenytoin

Cantrill. J Emerg Med. 1983
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–
–
–
–
–
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Case Report
33yo female with amitripyline overdose
BP 70, QRS 170 msec, comatose
Intubated, lavaged, charcoal, bicarb drip
Phenytoin given
QRS narrowed to 90 msec on an ECG 30 minutes later
Concluded: Phenytoin is the drug of choice for
TCA toxicity
Phenytoin

Several other case reports exist in the
literature
Phenytoin

Hagerman. Ann Emerg Med. 1981
– 10 patients with TCA poisoning
– 9/10 had wide QRS, 1/10 had normal QRS but
wide PR interval
– Phenytoin dose was 5 – 7 mg/kg
– Don’t mention the use of bicarb,
hyperventilation, normal or hypertonic saline
– Note: there is NO control group
Phenytoin

Hagerman. Ann Emerg Med. 1981
–
Pre Treatment
– Mean QRS 130 +/-7
– Range QRS 100 – 160
– Mean PR
204 +/- 12

Post Treatment
106 +/-6
80 – 140
175 +/- 5
Concluded that phenytoin was useful
Phenytoin:
Conclusions
Animal Data is conflicting
 Human data limited to case reports and case
series
 No controlled human data exists
 Bicarbonate is the treatment of choice for
QRS conduction abnormalities
 Effect of phenytoin in cases refractory to
bicarb essentially unknown

– Hypertonic saline seems like a better choice
Lidocaine
Most commonly recommended
antiarrythmic if refractory to bicarb
 Doesn’t make sense because it is a Na+
channel blocker thus has the potential to
worsen the problem
 Case reports are the “best” evidence
 NO controlled human trials
 Could try it if you are in a bind

Magnesium

Case Reports
– Citak. Eur J
Emerg Med.
2002.

Rat Model
–
–
–
–
–
–
–
–
Knudsen. CCM 1994.
Norepinephrine pretreatment
Amitriptyline infusion
Waited for Vtach to develop
Got Mg, Lidocaine, or Glucose
Mg: 9/10 converted to sinus tach
Lido: 1/10 converted to sinus tach
Glucose: 1/10 converted to sinus
tach
What other options
are there?
Propranolol: few case reports of success,
case series of crash and burn hypotension (Foulke.
Am J Emerg Med 1986)
Amiodarone: not studied
Could Fab fragments be the cure
for the TCA overdose??
Watch for Fab fragments
in the future.
PEARL!

Anything unique about AMOXAPINE and
MAPROTILINE?
– Bad, refractory seizures
– Less cardiotoxicity
Case of the day!

ICU resident order serum TCA level and
urine TCA screen ------> what do you say?
TCA and lab testing

Urine TCA screen
– Dip stick screen,
immunoassay
– HORRIBLE
specificity thus the
lab doesn’t even
do it

Serum TCA levels
– Do NOT correlate with
toxicity
– False +ves
»
»
»
»
»
»
Benadryl
Gravol
Flexeril
Carbemazepine
Seroquel
Clozapine
TCA overdose and disposition


Toxicity develops within 6 hrs
Monitored for 6hrs: NO seizures, hypotension,
arrythmias, no bicarb Rx
– Can d/c home or to psych



ICU for seizures, hypotension, arrythmias,
decreased LOC
Telemetry for prolonged QTc
Duration of cardiac monitoring
– 24hrs after normalization of BP, off
alkalinization/antidysrhythmics/pressors
ADORA Criteria
AntiDepressant Overdose Risk Assessment
 Foulke. Am J Emerg Med. 1995
 High risk = any of QRS > 100 ms,
arrythmia, conduction defect, altered LOC,
seizures, resp depression, hypotension
 Prospective study of 67 patients
 Any high risk feature predicted the
development of complications (surprise!)

Key Points


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
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
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We need to know more about TCA overdoses than
anybody (except toxicologist!!)
Aggressive decontamination
Expect complications
Be able to manage complications appropriately
Know how, why, when, and how much bicarb to
give
Be aware of ECG features of TCA overdose and
their predictive value
Have a good approach to monitoring and
disposition
The end.
Questions?
Comments?