QT Prolongation Considerations
for IM Hospitalists
Lenny Noronha, MD
UNM Hospital Medicine Best Practices
2/8/12
Outline
• Review cardiac cycle, pathophysiology
• Discuss risk factors for Prolonged QT, TdP
• Analyze medication classes prescribed by
Hospitalists
• Propose “Best Practices”, discuss
Special thanks to:
•
•
•
•
•
•
•
Carlos Macias, MD
Brook Parrish, MD
Davin Quinn, MD
Nicole Klein, MD
Vincent Zummo, PA
Katya Calvo, MD
Shmuel Inbar, MD
Case
44yf adm to Red Med team for GI sx, AMS
Adm to Pres 1 wk prior, ureter stented, on cipro 500 po bid.
1. AMS: “MRI pending”. Attributed to K 2.8 and ketones in
urine.
2. UTI: Order cultures, start zosyn
3. “Prolonged QTc” Will repeat EKG after electrolytes replaced.
4. Lip lac may need to be sutured.
5. Pain control: tylenol and oxycodone
6. Hospital issues
Case cont’d
Pt seen by neuro before IM eval.
“Feeling funny…my heart fluttering like a butterfly”
QTc 600 documented.
Impression:
• LOC c tongue abrasion, split lip, most likely
secondary to seizure
• Low potassium
• Prolonged QT
Initial ED EKG, K 2.8, QTc 602
HD 2, K 3.6, QTc 511
Subsequent course
HD 2 EEG normal.
Cardiology consult HD 3 after several runs of nonsustained
polymorphic VT (8-9 beats).
QTc range 528 – 699 during admission, despite electrolyte
replacement
Outpt EKG from 1yr prior: NSR, QTc 467
ID, Pulm consults for complex infection
Started on Bb, titrated to tolerance
Family all had EKG’s. Daughter’s QTc 462.
Pt dc’d c LifeVest, had ICD placed after 14 d course abx,
ureteral stone/stent removed
ZOLL LifeVest Wearable Defibrillator
http://lifevest.zoll.com/medical-professionals/
What is normal, prolonged?
“Prevention of Torsade de Pointes in Hospital Settings”, Barbara Drew,
et al, JACC Scientific statement, 2010; 55, 9:934-947
“The QT interval: Too long, too short or just right”, Sami Viskin, Heart
Rhythm, May 2009,: 6, 5: 711-715
Next 9 slides adapted from:
Antiarrhythmic Overview
Carlos Macias, MD
Jan 31st 2012
Fellows Conference
Part 1. Basic principals
• Cardiac action potential
– Electrical impulse of the heart is the summation of
thousand of tiny electrical currents generated by
thousands of individual cardiac cells.
– Electrical activity of an individual cardiac cell is
described by the cardiac action potential.
Part 1. Basic principals
• Depolarization
– Phase 0
– Rapid sodium channels in the cell membrane are
stimulated to open.
– Allows positively charged Na ions to rush into the cell.
– Voltage spike – positively directed change the
transmembrane potential
– Na channels are voltage dependent.
– The speed of the slope determined how fast the next
cell will be stimulated to depolarize.
– Anything that causes the causes the slope to change
will affect conduction velocity.
Part 1. Basic principals
• Repolarization corresponds to phases 1-3
• Accounts for most of the action potential
• Time from the end of phase 0 to late in phase
3 is considered refractory period.
• Duration of the action potential determines
the refractory period.
– Anything that increases duration of the action
potential also changes the refractory period.
Part 1. Basic principals
• Repolarization begins rapidly
– Phase 1
– Interrupted by plateau (Phase 2) “slow” Ca
channels
– Most important ionic shift during repol is the
outflow of positive K ions.
– At least six different K “currents” have been
identified.
– At the end of repolarization the transmembrane
voltage returns to baseline.
Part 1. Basic principals
Part 1. Basic principals
Mechanism of cardiac tachyarrhythmias
Most tachyarrhythmias are thought to be due to
one of the following mechanisms:
– Automaticity
– Reentry
– Channelopathy (congenital LQTS)
– Triggered activity (dig tox arryth, CCB-sens VT, TdP)
Prolonged Repol sets up EAP
Molecular mechanisms of inherited arrhythmias, Wolf, Berul, et
al, Curr Genomics. 2008 May; 9(3): 160–168.
Basic principals
Triggered mechanism
Ectopy triggered if
threshold exceeded
Current concepts in the mechanisms and management of drug-induced QT prolongation and
torsade de pointes, Gupta, American Heart Journal, Jue 2007; 153: 891-899
Drug-Induced Prolongation of the QT Interval,Dan M. Roden, M.D.,
N Engl J Med 2004; 350:1013-1022
Notes on TdP
• Usually self-limited
• Typical symptoms: palpitations, syncope,
“seizure-like activity”
• Immediate tx: Mg Sulfate 2g IV bolus, followed
by 2-4g IV infusion over 2 hours
Drugs and the QT Interval — Caveat Doctor
Barbara A. Liu, M.D., and David N. Juurlink, M.D., Ph.D.
N Engl J Med 2004; 351:1053-1056
Patient Factors
•
•
•
•
•
•
Female gender
Age > 65
Electrolyte loss (i.e. Diuretics, Diarrhea)
Cardiac disease
Liver or Renal disease, Hypothyroidism
Congenital LQTS (1:2500 gen population)
– h/o unexplained syncope, FH sudden death < 40
Direct Drug Effects
Most meds that prolong QT thought to block IKR
Psychiatric
• Antipsychotics
• TCA’s
• Lithium
• Citalopram
Antimicrobials
• Macrolides
• Quinolones
•Azoles
•Pentamidine
•Amantadine
Other
• Methadone
•Hydroxyzine
•Loratidine
•Tacrolimus
•Cocaine
Cardiac
• Quinidine, procainamide
• Flecainide
• Amiodarone, Sotalol
Indirect Drug Effects
Common C P450 3A4 Inhibitors
Cardiovasc
• Diltiazem
• Verapamil
Psych
• Fluoxetine
• Midazolam
Antimicrobials
• Macrolides!
• Ketoconazole
• INH
• HIV meds
- Amprenavir, Delavirdine
- Nelfinavir, Ritonavir
Endocrine
•Ethinylestradiol
•Gestodene
•Mifepristone
•Raloxifene
•Tamoxifen
Others
• Grapefruit juice
•Resveratrol
•Irinotecan
FYI :This is the mechanism for patients with liver disease
Clinical Features Associated with risk of TdP
“Cardiac side effects of psychiatric drugs” Mackin,
Human Psychopharmacology 2008; 23: 3-14.
Literature: Antibiotics
“Oral Erythromycin and the Risk of Sudden Death from Cardiac
Causes”, Ray, NEJM 2004
Response to case reports of TdP assoc c IV
erythromycin
Retrospective review of TN Medicaid cohort
investigated from sudden death ‘88-’93.
Compared matched population “person years” of
current and former users of oral erythromycin to
patients using amoxicillin at time of investigation
“Oral Erythromycin and the Risk of Sudden Death from Cardiac
Causes”, Ray, NEJM 2004
Led to numerous letters,
review articles, and…
2006 ACC/AHA/ESC Guideline
Recommend removing of offending agent in patients
with drug-induced LQTS
2010 ACC/AHA Scientific Statement, “Prevention
of Torsades de Pointes in Hospital Settings
Recommend continuous cardiac monitoring for drugs at
risk to cause TdP. If QTc becomes > 500ms or increases
> 60ms, seek alternative therapies, assess for drug
interactions. Patients should not be transported from
the unit for procedures.
Literature: Antipsychotics
1980’s: Dose-dependent risk of QTP, TdP, sudden
death noted with antipsychotics, especially
droperidol, haldol and thioridizine
1990: UK Committee on Safety of Medicines
recc gradual dose increase, EKG before and
periodically in patients receiving high doses
Literature Review cont’d
2007: FDA label warning for QTP/TdP from
Haldol IV in response to adverse events
reports. Recc: continuous tele monitoring
2010 Systematic Review (Meyer-Massetti)
Methods:Cases of QTP/TdP from Pubmed, Embase,
Scopus databases (1823-2009; FDA MedWatch
reports (‘97-’08)
Results:
70 cases, 2 deaths.
42 of 54 cases of TdP preceded by QTP
68 had identified RF
TdP cases had cumulative dose 5-645 mg
Deaths had cumulative doses of 530, 634 mg
2010 Systematic Review (Meyer-Massetti)
Discussion - APA 2004 recc: Haldol dosing
initial IV dosing 1-2mg q 2-4h
Geriatric: 0.25-0.5mg q4, titrate as needed
Key Conclusion/UCSF policy:
- IV haldol can be given in cumulative doses
< 2mg without tele/serial EKG in patients without risk
factors
- Cardiac monitoring if doses greater than 2mg
anticipated or risk factors for TdP
3/17/09
Especially in doses
over 100 mg/d
Recommendation 1 (Disclosure): Clinicians should
inform patients of arrhythmia risk when they
prescribe methadone.
Recommendation 2 (Clinical History): Clinicians
should ask patients about any history of structural
heart disease, arrhythmia, and syncope.
Recommendation 3 (Screening): Obtain a
pretreatment electrocardiogram for all patients to
measure the QTc interval and a follow-up
electrocardiogram within 30 days and annually.
Additional electrocardiography is recommended if
the methadone dosage exceeds 100 mg/d or if
patients have unexplained syncope or seizures.
Recommendation 4 (Risk Stratification): If the QTc
interval is greater than 450 ms but less than 500
ms, discuss the potential risks and benefits with
patients and monitor them more frequently. If the
QTc interval exceeds 500 ms, consider
discontinuing or reducing the methadone dose;
eliminating contributing factors, such as drugs that
promote hypokalemia; or using an alternative
therapy.
Recommendation 5 (Drug Interactions): Clinicians
should be aware of interactions between
methadone and other drugs that possess QT
interval–prolonging properties or slow the
elimination of methadone.
Suggested “Best Practices”
1. Awareness of “Patient Factors” for prolonged QT
– Age > 65
– Female
– ANY cardiac disease
– Hypokalemia
– Hypomagnesemia
– Hypocalcemia
– CKD, Chronic liver disease, hypothyroidism
– FH Sudden death/prolonged QT
Suggested “Best Practices”
2. Awareness of chronic outpatient medications
most likely to prolong QT interval
- Methadone
- Erythromycin (i.e. gastroparesis)
- Amiodarone
- Atypical antipsychotics
- Tricyclic antidepressants
Suggested “Best Practices”
3. Obtain EKG or tele strip measurement of QTc
in patients with Patient Factors/above meds
before starting AND after doses of:
- Antipsychotics
- Macrolides
- Quinolones
- Pentamidine (i.e. PJP)
- CYP 3A4 inhibitors
Suggested “Best Practices”
Do NOT add meds than can prolong QT in
patients with QTc > 500
Discontinue meds that can prolong QT if QTc
increases > 60msec after addition
Suggested “Best Practices”
4. Patient Education
www.qtdrugs.org
www.azcert.com
Suggested “Best Practices”
5. Document QTc in progress note if EKG ordered
to measure
6. Add diagnosis to Powerchart problem list and
Discharge Summary
426.82 – Long QT syndrome (I45.81 in ICD-10)
794.31 – Nonspec Abnormal EKG (R94.31)
Suggested “Best Practices”
For delirious patient with QTc > 500, consider:
• Trazadone
• Depakote
• Seroquel, Abilify (less QT effect)
• Telephone consultation with PES attending
Questions?
What is normal QT?
References
“Antiarrhthmic Overview”, Macias, Carlos, Fellow Conference 1/31/12
“Drugs and the QT Interval — Caveat Doctor”, Barbara A. Liu, M.D., and David N. Juurlink, M.D., Ph.D.N Engl J Med 2004; 351:1053-1056
“Oral Erythromycin and the Risk of Sudden Death from Cardiac Causes”, Wayne A. Ray, Ph.D., Katherine T. Murray, M.D., Sarah Meredith, M.B., B.S.,
Sukumar Suguna Narasimhulu, M.B., B.S., M.P.H., Kathi Hall, M.S., and C. Michael Stein, M.B., Ch.B.N Engl J Med 2004; 351:1089-1096
“Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes”, Gupta, American Heart Journal, Jue
2007; 153: 891-899
“Drug-Induced Prolongation of the QT Interval”, Dan M. Roden, M.D., N Engl J Med 2004; 350:1013-1022
“Cardiac side effects of psychiatric drugs” Mackin, Human Psychopharmacology 2008; 23: 3-14.
“Consensus statement on high-dose antipsychotic medication” Royal College of Psychiatrists, October 2005
“Prevention of Torsade de Pointes in Hospital Settings”, Barbara Drew, et al, JACC Scientific statement, 2010; 55, 9:934-947
“The QT interval: Too long, too short or just right”, Sami Viskin, Heart Rhythm, May 2009,: 6, 5: 711-715