Annals of Internal Medicine
COMMENTS AND RESPONSES arrest simulation was identical between the 2 groups. Face-to-face
Improving the Efficiency of Advanced Life Support Training
TO THE EDITOR: We read the article by Perkins and colleagues (1)
with interest. They studied advanced life support (ALS) education
provided to 3732 health care professionals at 31 centers in the
United Kingdom and Australia. We commend the authors for con-
ducting such a large trial but are not surprised by the finding that
learners assigned to the e-learning group performed worse on the
cardiac arrest simulation test. Deliberate practice with feedback from
a skilled instructor is a critical component of mastery. This has been
shown by K. Anders Ericsson in many areas, including development
of expertise in medicine and related domains (2). Therefore, we
believe that removing deliberate practice from ALS education and
replacing it with e-learning led to the decrease in performance on the
simulation test. Current training in ALS has already been shown to
be deficient because skills deteriorate rapidly after training (3). In
contrast, simulation-based training that features deliberate practice
has been shown to boost ALS skills, with improvement lasting up to
14 months (4). These skills have also been shown to transfer to the
clinical setting, resulting in improved quality of care (5).
We commend Perkins and colleagues for their sophisticated
study that shows how costs can be reduced through e-learning. How-
ever, the ultimate goal is to design ALS courses that result in highly
qualified ALS providers. We believe that more, not less, deliberate
practice of simulated scenarios is required to achieve this aim.
Diane B. Wayne, MD
Aashish K. Didwania, MD
William C. McGaghie, PhD
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
Potential Conflicts of Interest: None disclosed.
References
1. Perkins GD, Kimani PK, Bullock I, Clutton-Brock T, Davies RP, Gale M, et al;
Electronic Advanced Life Support Collaborators. Improving the efficiency of advanced
life support training: a randomized, controlled trial. Ann Intern Med. 2012;157:19-28.
[PMID: 22751757]
2. Ericsson KA. Deliberate practice and the acquisition and maintenance of expert
performance in medicine and related domains. Acad Med. 2004;79:S70-81. [PMID:
15383395]
3. Smith KK, Gilcreast D, Pierce K. Evaluation of staff ’s retention of ACLS and BLS
skills. Resuscitation. 2008;78:59-65. [PMID: 18406037]
4. Wayne DB, Siddall VJ, Butter J, Fudala MJ, Wade LD, Feinglass J, et al. A longi-
tudinal study of internal medicine residents’ retention of advanced cardiac life support
skills. Acad Med. 2006;81:S9-S12. [PMID: 17001145]
5. Wayne DB, Didwania A, Feinglass J, Fudala MJ, Barsuk JH, McGaghie WC.
Simulation-based education improves quality of care during cardiac arrest team re-
sponses at an academic teaching hospital: a case-control study. Chest. 2008;133:56-61.
[PMID: 17573509]
IN RESPONSE: We thank Dr. Wayne and coworkers for their com-
ments on our article. We agree that simulation is central to successful
ALS training, which is consistent with international ALS guidelines
(1). In our blended learning trial, the number of sessions of cardiac
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/25476/ by a University of California San Diego User on 01/06/2017
Letters
content, such as lectures and small-group teaching from the 2-day
course, was replaced with e-learning material; skill-focused simula-
tion teaching was not. Improving efficiency and reducing the overall
cost of ALS training present an opportunity to save money that can
be reinvested in further simulation and deliberate self-practice to
reduce the effect of skill decay, which is known to occur within
months after initial training (2).
Gavin D. Perkins, MD
University of Warwick, Warwick Medical School
Coventry CV4 7AL, United Kingdom
Andrew Lockey, MMEd
Calderdale Royal Hospital
Halifax HX3 0PW, United Kingdom
Ian Bullock, PhD
National Clinical Guideline Centre, Royal College of Physicians
London NW1 4LE, United Kingdom
Potential Conflicts of Interest: Disclosures can be viewed at www
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽M11
-3019.
References
1. Soar J, Monsieurs KG, Ballance JH, Barelli A, Biarent D, Greif R, et al. European
Resuscitation Council Guidelines for Resuscitation 2010 Section 9. Principles of edu-
cation in resuscitation. Resuscitation. 2010;81:1434-44. [PMID: 20956044]
2. Soar J, Mancini ME, Bhanji F, Billi JE, Dennett J, Finn J, et al; Education, Imple-
mentation, and Teams Chapter Collaborators. Part 12: Education, implementation,
and teams: 2010 International Consensus on Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care Science with Treatment Recommendations. Resusci-
tation. 2010;81 Suppl 1:e288-330. [PMID: 20956038]
Red Blood Cell Transfusion
TO THE EDITOR: Carson and colleagues’ guideline (1) for the AABB
of adhering to a “restrictive” transfusion threshold that relies on a
hemoglobin level of 7 to 8 g/dL or less for hemodynamically stable
patients is well-intentioned but problematic. We are not surprised
that the editorial (2) accompanying this proposed guideline arrives at
a different conclusion— one that we agree with. We also believe that
transfusion thresholds should be titrated on the basis of many im-
portant individual patient laboratory and physiologic variables. Why
the disparity after considering the same decade of clinical experience
and trial data? The weaknesses of the most influential trial are well-
described in the editorial.
Because this and other trials on which the AABB guideline
committee based its recommendations never tested routine titrated
care (the standard at the time), it was not determined whether either
treatment—2 arbitrarily selected hemoglobin levels defined as “re-
strictive” or “liberal”—improved outcome or saved blood (3). The
trial design only determines which of these 2 strategies should not be
used. The less harmful treatment could still be worse than usual
titrated care. Patients had a risk for death of approximately 2 per
1000, or 0.2% per unit of transfused red blood cells (RBCs), a rate
some 20 times greater than that estimated by the U.S. General
© 2012 American College of Physicians 753
 Letters
Accounting Office for usual transfusion practice (0.01%, or 1 death
for every 10 000 units of transfused blood) (4). Differences in pa-
tient mix and follow-up seem unlikely to explain this enormous
discrepancy.
There is a real possibility that the new AABB guideline has
come to the wrong conclusion. We recognize that Carson and col-
leagues have softened their recommendation by acknowledging that
“clinical judgment is critical in the decision to transfuse . . . transfus-
ing RBCs above or below the specified hemoglobin threshold may be
dictated by the clinical context.” We hope that this statement is not
overlooked by those seeking a simple, protocol-driven care approach.
We do not believe that Carson and colleagues provide sufficient
direct evidence to change previous recommendations by the AABB
and others regarding titrated transfusion practice, but we agree with
their observation that “clinical trials are needed in other patient pop-
ulations.” However, randomized, controlled trials with the addition
of a titrated care group in each condition they describe are neither
practical nor affordable. Because expert clinicians now seem to rec-
ognize more than one “standard of care” for RBCs transfusions, the
time is ripe to do comparative effectiveness trials using real-world
data and large populations to help resolve this conundrum (5).
Harvey G. Klein, MD
Charles Natanson, MD
National Institutes of Health
Bethesda, MD 20892
Potential Conflicts of Interest: None disclosed.
References
1. Carson JL, Grossman BJ, Kleinman S, Tinmouth AT, Marques MB, Fung MK, et
al; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion:
a clinical practice guideline from the AABB. Ann Intern Med. 2012;157:49-58.
[PMID: 22751760]
2. Vincent JL. Indications for blood transfusions: too complex to base on a single
number? [Editorial]. Ann Intern Med. 2012;157:71-2. [PMID: 22751765]
3. Deans KJ, Minneci PC, Suffredini AF, Danner RL, Hoffman WD, Ciu X, et al.
Randomization in clinical trials of titrated therapies: unintended consequences of using
fixed treatment protocols. Crit Care Med. 2007;35:1509-16. [PMID: 17440420]
4. Blood Supply: Transfusion-Associated Risks. Report to the Ranking Minority Mem-
ber Committee on Commerce, House of Representatives. GAO/PEMD-97-2. Wash-
ington DC: U.S. General Accounting Office; 1997.
5. Klein HG. Comparative effectiveness research: welcome to the real world [Editorial].
Transfusion. 2012;52:1162-4. [PMID: 22686529]
IN RESPONSE: We appreciate the opportunity to reiterate that our
guideline states that transfusion should be considered in specific pa-
tient subgroups when the nadir hemoglobin reaches 7 to 8 g/dL. In
addition, the decision to transfuse should be influenced by signs and
symptoms. We based our recommendations on the best available
evidence: 19 randomized clinical trials in 6264 patients. However,
clinical trials provide an average effect in the population studied.
Thus, it is likely that some patients need more or less blood to
improve outcomes.
The “conundrum” is what clinical factors should influence the
“routine titrated” transfusion decision. The largest trial evaluating
754 20 November 2012 Annals of Internal Medicine Volume 157 • Number 10
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/25476/ by a University of California San Diego User on 01/06/2017
transfusion thresholds used prespecified symptoms (such as chest
pain, orthostatic hypotension, or tachycardia unresponsive to fluid
resuscitation) (1), which we included in our guideline. Although this
approach is based on a randomized trial, these symptoms will not
apply to all clinical settings. We agree with the accompanying edito-
rial (2) that other variables (such as fatigue, dyspnea, mechanical
ventilation, or the use of low SvO2) are unproven. Unfortunately,
there is no evidence to support other “important individual patient
laboratory and physiologic variables” as the basis for transfusion
decisions.
Drs. Klein and Natanson suggest that clinical trials evaluating
transfusion thresholds should include a group of patients managed
using the standard of care, which, in their opinion, is individually
titrated transfusions. Although this approach is often recommended,
the evidence strongly suggests that clinicians do not follow this rec-
ommendation and have not adopted this approach as standard of
care. For example, a recent study (3) in orthopedic surgery docu-
ments that transfusion decisions were mostly based on hemoglobin
levels. A similar study (4) conducted in patients having percutaneous
coronary intervention showed that most transfusions were given
when the hemoglobin level decreased to a certain threshold rather
than for individual clinical circumstances. This is also consistent with
anecdotal observations at our own hospitals. Given that most clini-
cians do not individually titrate transfusions, the proposed design
would be difficult to implement and would not reflect real-world
practice. A more clinically applicable trial design incorporates pre-
specified symptoms for transfusion along with hemoglobin
thresholds.
We stand by our recommendations: In prespecified groups of
patients, randomized, clinical trials have shown that restrictive trans-
fusion with a 7- to 8-g/dL threshold reduces blood use without
harm. When this hemoglobin level is reached, we recommend con-
sidering transfusion, but only after evaluating the patient’s clinical
status.
Jeffrey L. Carson, MD
UMDNJ–Robert Wood Johnson Medical School
New Brunswick, NJ 08903
Sunil V. Rao, MD
The Duke Clinical Research Institute
Durham, NC 27705
Louis M. Katz, MD
Americas Blood Centers
Washington, DC 20005
Potential Conflicts of Interest: Disclosures can be viewed at www
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽M11
-3065.
References
1. Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, et al;
FOCUS Investigators. Liberal or restrictive transfusion in high-risk patients after hip
surgery. N Engl J Med. 2011;365:2453-62. [PMID: 22168590]
2. Vincent JL. Indications for blood transfusions: too complex to base on a single
number? [Editorial]. Ann Intern Med. 2012;157:71-2. [PMID: 22751765]
www.annals.org

3. Vuille-Lessard E, Boudreault D, Girard F, Ruel M, Chagnon M, Hardy JF. Red
blood cell transfusion practice in elective orthopedic surgery: a multicenter cohort
study. Transfusion. 2010;50:2117-24. [PMID: 20492612]
4. Moscucci M, Ricciardi M, Eagle KA, Kline E, Bates ER, Werns SW, et al. Fre-
quency, predictors, and appropriateness of blood transfusion after percutaneous coro-
nary interventions. Am J Cardiol. 1998;81:702-7. [PMID: 9527078]
OBSERVATIONS
Sinus Arrest From Mad Honey Disease
Background: Global travel presents physicians with diseases they
have never encountered.
Objective: To describe the introduction of an old disease from 1
part of the world to another.
Case Report: We encountered a 69-year-old man in our outpa-
tient clinic in Munich, Germany, who requested that his pacemaker
be removed.
Six months earlier, he had been admitted to another hospital
with a history of syncope and had sinus arrest with a junctional
escape rhythm of 32 beats/min, which led to implantation of the
pacemaker. The patient told us that the syncope and heart rhythm
disturbances were associated with eating honey. He had bought local
honey during a trip to the Black Sea region of Turkey, and every
time he ate about 3 teaspoons of honey, he developed bradycardia
and had an episode of fainting. After becoming aware of this associ-
ation, he abstained from honey and was free of any symptoms for
several weeks. He then ate the rest of the honey and developed
recurrent symptoms. He presented to the hospital, where a pace-
maker was implanted on an emergency basis.
We arranged for the pacemaker to be removed, and he has been
free of symptoms during a year of follow-up.
Figure. Global distribution of grayanotoxin-producing plants.
Plants rich in grayanotoxin, which is responsible for honey poisoning, are not unique to the Black Sea region of Turkey. They also are found in North
America, Europe, and Asia, as indicated by the green shaded areas.
www.annals.org
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/25476/ by a University of California San Diego User on 01/06/2017
Letters
Discussion: Mad honey disease is an unusual form of food poi-
soning caused by the grayanotoxins in honey produced from the
nectar of Rhododendron ponticum or R. luteum, which grows in the
Turkish Black Sea region. This “bitter honey” is commonly used as a
household remedy for gastric pain, bowel disorders, diabetes, and
hypertension and is believed to be a sexual stimulant (1). The de-
scription of mad honey disease dates back to 401 BCE in Greek
literature, but grayanotoxin ingestion remains one of the most com-
mon forms of food poisoning in Turkey today (2). The major symp-
toms generally last no more than 24 hours and include hypotension
(100%), bradycardia (95%), nausea and vomiting (91%), sweating
(74%), dizziness (74%), impaired consciousness (67%), blurred vi-
sion or diplopia (32%), and fainting (30%) (3, 4). Sinus bradycardia
is the most frequent dysrhythmia, but heart block has also been
reported. Grayonotoxin binds to voltage-gated sodium channels in
their open state, which prevents inactivation of the channels and
maintains excitable cells in a state of depolarization. When this effect
occurs in afferent cardiac branches of the vagus nerve, sympathetic
activity decreases, allowing grayanotoxin to activate the Bezold–
Jarisch reflex to inhibit the heart rate (5). Although the symptoms of
mad honey intoxication can be alarming, close monitoring of vital
signs and symptomatic treatment with fluids supplemented with in-
travenous atropine when needed are usually sufficient for recovery.
Deaths are rare.
Although mad honey disease is regarded as a particularity of the
Black Sea region of Turkey, plants that produce grayanotoxin are
found on several continents (Figure). However, 4.5 million Turkish
migrants are presently living in the European Union, and more
than 26 million tourists visit Turkey annually, so more cases are
expected.
Conclusion: Grayanotoxin intoxication should be kept in mind
in cases of unexplained bradycardia or syncope, particularly in pa-
tients with a relevant travel or migration history.
20 November 2012 Annals of Internal Medicine Volume 157 • Number 10 755
 Letters
Carsten Lennerz, MD
Clemens Jilek, MD
Verena Semmler, MD
Isabel Deisenhofer, PhD
Christof Kolb, PhD
Deutsches Herzzentrum München, Klinik für Herz- und Kreislaufer-
krankungen, TU München
80636 Munich, Germany
Potential Conflicts of Interest: Dr. Lennerz: Travel/accommodations/
meeting expenses unrelated to activities listed: attendance at the annual
meeting of the German Cardiac Society paid by Sorin. Dr. Kolb: Board
membership: Sorin; Consultancy: Biotronik; Grants/grants pending (money
to institution): Biotronik, Medtronic, Sorin, St. Jude Medical, Stereo-
taxis; Payment for lectures including service on speakers bureaus: Biotronik,
Boston Scientific, Medtronic, Sorin; Travel/accommodations/meeting ex-
penses unrelated to activities listed: Biotronik, Medtronic, Sorin, St. Jude
Medical.
References
1. Choo YK, Kang HY, Lim SH. Cardiac problems in mad-honey intoxication. Circ J.
2008;72:1210-1. [PMID: 18577838]
2. Gunduz A, Meriçé ES, Baydin A, Topbas M, Uzun H, Türedi S, et al. Does mad
honey poisoning require hospital admission? Am J Emerg Med. 2009;27:424-7.
[PMID: 19555612]
3. Yavuz H, Ozel A, Akkus I, Erkul I. Honey poisoning in Turkey [Letter]. Lancet.
1991;337:789-90. [PMID: 1672407]
4. Koca I, Koca AF. Poisoning by mad honey: a brief review. Food Chem Toxicol.
2007;45:1315-8. [PMID: 17540490]
5. Eller P, Hochegger K. Honey intoxication and the Bezold-Jarisch reflex [Letter]. Int
J Cardiol. 2010;144:251. [PMID: 19176253]
Fatal Laughter
Background: In the 5th century BCE, the Greek painter Zeuxis
reportedly died while laughing at his painting of Aphrodite, which
was commissioned by a woman who demanded that she be the
model. In the 3rd century BCE, the Greek philosopher Chrysippus
reportedly died laughing after giving his donkey wine and watching
it try to eat figs (1). Although the expression “died laughing” is a
common colloquialism, we are not aware of any contemporary re-
ports of laughter-induced death, although there are reports of
laughter-induced seizures (2) and laughter-induced syncope (3).
Objective: To describe a case of laughter-induced death.
Case Report: Physicians referred a 50-year-old woman with a
prolonged rate-corrected QT (QTc) interval of 570 ms and an iso-
lated incident of polymorphic ventricular tachycardia (torsade de
pointes) after starting ziprasidone therapy for schizophrenia. She did
not report syncope but did report occasional palpitations for 20 years
that had been diagnosed as isolated, unifocal, premature ventricular
contractions. Her medical history included hepatitis C, but she had
no history of hypertension, diabetes, hyperlipidemia, or cardiovascu-
lar disease. Additional medications prescribed included clonazepam,
risperidone, and zolpidem. Her blood pressure was 118/86 mm Hg,
and resting heart rate was 60 beats/min. Cardiovascular auscultation
was unremarkable. Echocardiography showed normal ventricular di-
mensions, wall thickness, and systolic function without valvular le-
sions. Exercise myocardial perfusion scintigraphy revealed normal
regional wall motion without inducible ischemia. Laboratory testing
756 20 November 2012 Annals of Internal Medicine Volume 157 • Number 10
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/25476/ by a University of California San Diego User on 01/06/2017
found normal levels of serum glucose, potassium, magnesium, and
calcium. We diagnosed ventricular ectopy with the acquired long
QT syndrome and strongly recommended discontinuation of anti-
psychotic therapy. She declined, stating that her emotional well-
being was more important than any risk from life-threatening ar-
rhythmia because she became “crazy” without the medications. One
month later, she was relaxing in the breakroom at work with col-
leagues when someone told a joke. She had intense, sustained laugh-
ter that continued for approximately 2 to 3 minutes until she sud-
denly collapsed. Coworkers tried to revive her. Paramedics found
fine ventricular fibrillation followed by asystole and eventually
discontinued resuscitation. A postmortem examination was not
performed.
Discussion: Laughter-induced syncope is analogous to cough-
induced syncope, which results from marked, transient elevation in
intrathoracic pressure from repetitive bursts of forced expiration that
decrease venous return and cardiac output (the Valsalva phenome-
non) and lead to cerebral hypoperfusion and syncope. We postulate
that our patient’s laughter provoked a Valsalva phenomenon leading
to enhanced vagal tone and bradycardia, which is known to trigger
early after-depolarization and incite torsade de pointes in the setting
of a prolonged QTc interval (4). For example, another case report
recently described torsade de pointes induced by the Valsalva ma-
neuver in the setting of QTc interval prolongation (5). We believe
that ziprasidone and risperidone prolonged the QTc interval in our
patient and created the setting in which bradycardia could trigger
torsade de pointes. It is less plausible yet possible that a central
nervous system lesion was the trigger instead of bradycardia, but this
possibility cannot be excluded without autopsy. Although humor
and laughter can reduce emotional stress and protect the heart (6),
our report describes 1 example when laughter was not the best med-
icine and the expression “died laughing” had a literal meaning.
Rajendra Kadari, MD, MPH
University of Colorado
Aurora CO 80045
Michael A. Sarche, MD
Mori J. Krantz, MD, MPH
Denver Health Medical Center
Denver, CO 80204
Potential Conflicts of Interest: None disclosed.
References
1. Bowler P, Green J. What a Way to Go: Some of the Strangest Deaths on Record.
London: Chancellor Pr; 1983.
2. Cheung CS, Parrent AG, Burneo JG. Gelastic seizures: not always hypothalamic
hamartoma. Epileptic Disord. 2007;9:453-8. [PMID: 18077234]
3. Bloomfield D, Jazrawi S. Shear hilarity leading to laugh syncope in a healthy man
[Letter]. JAMA. 2005;293:2863-4. [PMID: 15956630]
4. Wesley RC Jr, Turnquest P. Torsades de pointe after intravenous adenosine in
the presence of prolonged QT syndrome. Am Heart J. 1992;123:794-6. [PMID:
1539535]
5. De Mattia L, Brieda M, Del Bianco F, Dametto E, Nicolosi GL. Polymorphic
ventricular tachycardia induced by Valsalva manoeuvre in a patient with paroxysmal
supraventricular tachycardia. Europace. 2012;14:767-8. [PMID: 22117036]
6. Miller M, Fry WF. The effect of mirthful laughter on the human cardiovascular
system. Med Hypotheses. 2009;73:636-9. [PMID: 19477604]
www.annals.org