READERS’ COMMENTS
Initial Downward Deflection in Lead
aVR in Cyclic Antidepressant
Poisoning—S or Q Wave?
Electrocardiography is a convenient
bedside tool that can provide important
diagnostic information in assessing pa-
tients after cyclic antidepressant (CA)
overdose. Many researchers have been
interested in predicting seizures, ven-
tricular dysrhythmias, or death after CA
overdose using electrocardiographic pa-
rameters,1–5 including the amplitude of
the R wave and the R wave/S wave ratio
in lead aVR. R-wave amplitude ⱖ3 mm
and R wave/S wave ratio ⱖ0.7 were the
most sensitive predictors of seizures or
dysrhythmias in a series of patients who
overdosed on CAs (sensitivity 81% and
75%, respectively).6 Also, it has been
suggested that decreases in the ampli-
tude of the R wave and R wave/S wave
ratio in lead aVR may be related to the
level of consciousness and be informa-
tive in predicting recovery from toxicity
after CA overdose.7 With regard to the
significance of lead aVR in the assess-
ment of patients after CA overdose, it
seems that the identification of the R
and S waves in this lead is among the
basic principles for all physicians and
nurses involved in the care of patients
with CA poisoning.
I have recently read the chapter on
CAs by Liebelt8 in the most recent edi-
tion of Goldfrank’s Toxicologic Emer-
gencies. Surprisingly, the author incor-
rectly illustrated the Q wave (instead of
the S wave) in the description of the
measurement of the R wave in lead aVR
in significant CA poisoning (Figure
73-3, p. 1053). The correct S wave in
lead aVR, from 1 of my patients with
CA poisoning, is illustrated in Figure 1.
In this lead, the R wave is a terminal R
wave, and downward deflection before
that is essentially an S wave. Therefore,
the S wave is measured in millimeters
as the depth of the initial downward
deflection.6,7
Hossein Sanaei-Zadeh, MD
Tehran
University of Medical Sciences, Iran
15 June 2011
1. Boehnert MT, Lovejoy FH Jr. Value of the
QRS duration versus the serum drug level in
predicting seizures and ventricular arrhyth-
Am J Cardiol 2011;108:899 –903
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Figure 1. An abnormal QRS interval (120 ms) as it appeared in a patient with severe tricyclic
antidepressant poisoning. The S and R waves are 4.5 and 2.5 mm, respectively and R wave/S wave ratio
is 0.55.
mias after an acute overdose of tricyclic
antidepressants. N Engl J Med 1985;313:
474 – 479.
2. Caravati EM, Bossart PJ. Demographic and
electrocardiographic factors associated with
severe tricyclic antidepressant toxicity. J Toxi-
col Clin Toxicol 1991;29:31– 43.
3. Harrigan RA, Brady WJ. ECG abnormalities
in tricyclic antidepressant ingestion. Am J
Emerg Med 1999;17:387–393.
4. Singh N, Singh HK, Khan IA. Serial elec-
trocardiographic changes as a predictor of
cardiovascular toxicity in acute tricyclic an-
tidepressant overdose. Am J Ther 2002;9:
75–79.
5. Bailey B, Buckley NA, Amre DK. A meta-
analysis of prognostic indicators to predict sei-
zures, arrhythmias or death after tricyclic an-
tidepressant overdose. J Toxicol Clin Toxicol
2004;42:877– 888.
6. Liebelt EL, Francis PD, Woolf AD. ECG lead
aVR versus QRS interval in predicting sei-
zures and arrhythmias in acute tricyclic anti-
depressant toxicity. Ann Emerg Med 1995;26:
195–201.
7. Choi KH, Lee KU. Serial monitoring of lead
aVR in patients with prolonged unconscious-
ness following tricyclic antidepressant over-
dose. Psychiatry Invest 2008;5:247–250.
8. Liebelt EL. Cyclic antidepressants. In: Nel-
son LS, Lewin NA, Howland MA, Hoffman
RS, Goldfrank LR, Flomenbaum NE, eds.
Goldfrank’s Toxicologic Emergencies. 9th
ed. New York, New York: McGraw-Hill,
2011:1049 –1059.
doi:10.1016/j.amjcard.2011.06.026
Should We Focus on Hematocrit or
Hemoglobin in Patients With
Eisenmenger Syndrome?
We read with great interest the re-
port by Broberg et al1 on seeking an
optimal relation between oxygen sat-
uration at rest and hemoglobin (Hb).
In patients with Eisenmenger syn-
drome (ES), chronic hypoxia due to
right-to-left shunting results in in-
creased erythropoiesis with secondary
erythrocytosis. This is a physiologic
response to maintain arterial oxygen
content and therefore oxygen delivery
to the peripheral tissues.2 Iron re-
placement therapy in iron-deficient
cyanotic congenital heart disease pa-
tients caused an increase in Hb, which
resulted in a significant improvement
in exercise tolerance.3 In contrast, an
increase in whole-blood viscosity
(WBV) is an unavoidable result of an
increased erythropoiesis and, by in-
creasing peripheral resistance, will in-
crease the afterload in patients with
ES. Broberg et al1 showed earlier that
hematocrit (Hct) is the main determi-
nant of WBV, independent of red cell
size, red cell shape, or iron stores.4
www.ajconline.org
900
Figure 1. The relation between WBV and Hct is similar in patients with or without iron deficiency.
However, it has also been shown that
for a certain Hb concentration, WBV
may be higher in iron-deficient pa-
tients.5,6 Should we focus on Hct or
Hb in patients with ES?
In this study, 74 patients with ES
included in the Belgian Congenital
Heart Disease registry were evaluated.
Laboratory measurements were per-
formed at the different centers using
the same techniques. Hct, Hb concen-
tration, mean corpuscular volume, and
mean corpuscular Hb were obtained
with automated electronic particle
counters. The laboratory test also in-
cluded ferritin and transferrin saturation.
Iron deficiency was defined as ferritin ⬍30
ng/ml or ferritin 30 to 100 ng/ml and a
transferring saturation ⬍20%. WBV was
estimated using the formula proposed by
Hutton et al5: ln(WBV) ⫽ [Hb concentra-
tion (g/dl)/ln(mean corpuscular Hb) (pg)] ⫻
[0.5696 ⫺ 0.0542 ln(shear rate ⫹ 0.3214)].
For the purposes of the study, a shear
rate of 2.3 seconds⫺1 was considered.
Oxygen-carrying capacity was esti-
mated as 1.39 ml oxygen/g Hb ⫻ Hb
(g/dl) ⫻ saturation (%). The small pro-
portion of oxygen dissolved in the
blood was not considered (0.003 ⫻ ar-
terial oxygen pressure).7
A linear regression was performed to
assess the relation between Hct, Hb and
oxygen-carrying capacity with WBV. To
assess whether the relation was signifi-
cantly different between iron-replete and
iron-deficient patients, the interaction be-
tween the 2 groups was evaluated. All
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The American Journal of Cardiology (www.ajconline.org)
tests were 2 sided, and p values ⬍0.05
were considered statistically significant.
Patients’ mean age was 36 ⫾14
years, and 28% were men. Forty-six
percent of patients had Down syn-
drome. Thirty-eight percent of patients
were in New York Heart Association
class ⱖIII, and 57% were receiving spe-
cific pulmonary arterial hypertension
treatment. Thirty-nine percent (n ⫽ 29)
were iron deficient.
The Hct of iron-deficient patients was
not statistically different (56 ⫾ 9% vs 59
⫾ 7%, p ⫽ 0.093), whereas Hb was sig-
nificantly lower (18 ⫾ 3 vs 20 ⫾ 2 g/dl, p
⬍0.0001) compared to iron-replete pa-
tients. There was a linear relation between
Hct and WBV in iron-replete (R2 ⫽
0.834, p ⬍0.0001) and iron-deficient (R2
⫽ 0.866, p ⬍0.0001) patients. Moreover,
there was no significant interaction be-
tween the 2 groups (p ⫽ 0.808; Figure 1).
There was a linear relation between Hb
and WBV in iron-replete (R2 ⫽ 0.923, p
⬍0.0001) and iron-deficient (R2 ⫽ 0.854,
p ⬍0.0001) patients. The relation be-
tween the 2 groups was significantly dif-
ferent (interaction p ⬍0.0001; Figure 2).
Finally, there was a weaker relation be-
tween oxygen-carrying capacity and
WBV in iron-replete (R2 ⫽ 0.507, p
⬍0.0001) and iron-deficient (R2 ⫽ 0.349,
p ⫽ 0.001) patients. The relation differed
significantly between the 2 groups (inter-
action p ⫽ 0.037; Figure 3).
These results are consistent with the
findings of Broberg et al4 indicating that
for any Hct, WBV is similar between
iron-replete and iron-deficient patients.
However, at a certain Hb concentration,
patients who are iron deficient have
higher WBV than iron-replete patients,
confirming earlier reports.5,6 This can
be explained by higher Hct for the same
Hb and supports earlier findings that
intrinsic red cell changes do not neces-
sarily contribute to WBV in iron-de-
pleted patients.4,8
Because Hb is the main determi-
nant of oxygen-carrying capacity and
Hct the main determinant of viscosity,
these results suggest that iron-defi-
cient patients have higher viscosity
for a certain Hb concentration because
of higher Hct. This indicates that the 2
parameters are not interchangeable in
patients with ES and that iron-defi-
cient patients not only have subopti-
mal oxygen-carrying capacity but also
a higher viscosity for the same-oxy-
gen carrying capacity.
Two questions arise from this study.
First, although iron therapy could theo-
retically lower WBV at a certain Hb
concentration, in practice, iron replace-
ment will also increase Hct. Is the in-
crease in Hb higher relative to the in-
crease in Hct in case of iron
supplementation? Second, Broberg et
al1 described an ideal relation between
oxygen saturation at rest and Hb. How-
ever, patients with very low oxygen sat-
urations fail to achieve this optimal re-
lation, possibly because of a too high
“optimal Hb.” Should we look at both
Hct and Hb to optimize Hb (and oxy-
 Readers’ Comments 901

Figure 2. Patients with iron deficiency have higher WBV at a given Hb concentration compared to iron-replete patients.

Figure 3. Patients with iron deficiency have higher WBV at a given arterial oxygen content compared to iron-replete patients.

gen-carrying capacity) for the lowest
Hct (and WBV) achievable by gentle
iron supplementation in these patients?
Alexander Van De Bruaene, MD
Marion Delcroix, MD, PhD
Werner Budts, MD, PhD
Leuven, Belgium
16 May 2011
1. Broberg CS, Jayaweera AR, Diller GP,
Prasad SK, Thein SL, Bax BE, Burman J,
Gatzoulis MA. Seeking optimal relation be-
tween oxygen saturation and hemoglobin
concentration in adults with cyanosis from
congenital heart disease. Am J Cardiol 2011;
107:595–599.
2. Van De Bruaene A, Delcroix M, Pasquet A,
De Backer J, De Pauw M, Naeije R,
Vachiéry JL, Paelinck B, Morissens M,
Budts W. Iron deficiency is associated with
adverse outcome in Eisenmenger patients.
Eur Heart J. In press.
3. Tay EL, Peset A, Papaphylactou M, Inuzuka R,
Alonso-Gonzalez R, Giannakoulas G, Tzifa A,
Goletto S, Broberg C, Dimopoulos K, Gatzoulis
MA. Replacement therapy for iron deficiency
improves exercise capacity and quality of life in
patients with cyanotic congenital heart disease
and/or the Eisenmenger syndrome. Int J Cardiol.
In press.
4. Broberg CS, Bax BE, Okonko DO, Rampling
MW, Bayne S, Harries C, Davidson SJ, Ue-
bing A, Khan AA, Thein S, Gibbs JS, Burman
J, Gatzoulis MA. Blood viscosity and its rela-
tionship to iron deficiency, symptoms, and ex-
ercise capacity in adults with cyanotic congen-
ital heart disease. J Am Coll Cardiol 2006;48:
356 –365.
5. Hutton RD. The effect of iron deficiency on
whole blood viscosity in polycythaemic pa-
tients. Br J Haematol 1979;43:191–199.
6. Van de Pette JE, Guthrie DL, Pearson TC.
Whole blood viscosity in polycythaemia: the

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902
effect of iron deficiency at a range of
haemoglobin and packed cell volumes. Br J
Haematol 1986;63:369 –375.
7. Heusser F, Fahey JT, Lister G. Effect of he-
moglobin concentration on critical cardiac out-
put and oxygen transport. Am J Physiol 1989;
256:H527–H532.
8. Pearson TC, Grimes AJ, Slater NG, Wether-
ley-Mein G. Viscosity and iron deficiency in
treated polycythaemia. Br J Haematol 1981;
49:123–127.
doi:10.1016/j.amjcard.2011.06.027
Adherence to Medications in
Revascularized Patients
I read with great interest the recent
report of Kulik et al1 on adherence to
statin therapy in elderly patients after
hospitalization for coronary revascu-
larization. The investigators con-
cluded that in patients receiving inva-
sive coronary treatment, despite
strong evidence supporting their use,
statin adherence remains suboptimal.
In another recent study addressing the
adherence to medications,2 only 27%
of patients who underwent coronary
artery bypass grafting were treated
with clopidogrel after hospital dis-
charge, although the guidelines since
2004 have suggested that post–myocar-
dial infarction patients take clopidogrel
for 9 to 12 months after coronary artery
bypass grafting.3–5 This had an impact on
outcomes, as the clopidogrel-treated pa-
tients had a lower risk for the combined
end point of death or recurrent myocardial
infarction.2 In the study by Kulik et al,1
the prehospital use of clopidogrel in the
coronary artery bypass grafting group
was 19.5%, and postdischarge use was
9.3% (vs 22.1% in the medical therapy
group after discharge). It is important to
highlight this finding to focus on dis-
charge medications of patients who un-
dergo revascularization.
Wassef Karrowni, MD
Iowa City, Iowa
1. Kulik A, Shrank WH, Levin R, Choudhry
NK. Adherence to statin therapy in elderly
patients after hospitalization for coronary re-
vascularization. Am J Cardiol 2011;107:
1409 –1414.
2. Sørensen R, Abildstrøm SZ, Hansen PR,
Hvelplund A, Andersson C, Charlot M, Fos-
bøl EL, Køber L, Madsen JK, Gislason GH,
Torp-Pedersen C. Efficacy of post-operative
clopidogrel treatment in patients revascu-
larized with coronary artery bypass grafting
after myocardial infarction. J Am Coll Cardiol
2011;57:1202–1209.
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The American Journal of Cardiology (www.ajconline.org)
3. Stein PD, Schunemann HJ, Dalen JE, Gut-
terman D. Antithrombotic therapy in pa-
tients with saphenous vein and internal
mammary artery bypass grafts: the Seventh
ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004;
126(suppl):600 – 608.
4. Dunning J, Versteegh M, Fabbri A, Pavie A,
Kolh P, Lockowandt U, Nashef SA; EACTS
Audit and Guidelines Committee. Guideline
on antiplatelet and anticoagulation manage-
ment in cardiac surgery. Eur J Cardiothorac
Surg 2008;34:73–92.
5. Becker RC, Meade TW, Berger PB, Eze-
kowitz M, O’Connor CM, Vorchheimer DA,
Guyatt GH, Mark DB, Harrington RA;
American College of Chest Physicians. The
primary and secondary prevention of coronary
artery disease: American College of Chest Phy-
sicians evidence-based clinical practice guide-
lines (8th edition). Chest 2008;133(suppl):
776 – 814.
doi:10.1016/j.amjcard.2011.06.028
Authors’ Reply
We appreciate Van De Bruaene et al’s
interest in this topic and our report. The
multiple relations that govern red cell pro-
duction in cyanotic congenital heart disease
are not well characterized in our opinion.
Our own data are congruous with Van De
Bruaene et al’s in showing that hematocrit is
maintained in iron deficiency, whereas he-
moglobin decreases. In other words, iron
deficiency invokes production of smaller,
hypochromatic cells, but red cell mass is
unchanged, as are hematocrit and thus vis-
cosity.
We appreciate the authors’ point that
because of this shift, theoretical viscosity
for a given hemoglobin will be higher,
although in practical terms, the same he-
moglobin cannot be maintained if iron
stores are low, and hence viscosity will
likely be unchanged. The observation
made by Van De Bruaene et al highlights
the fact that cyanosis invokes a relative
macrocytosis, as also shown by others.1
We fully agree with the authors’ point
that hemoglobin and hematocrit have po-
tential clinical impact, for different rea-
sons, and should be considered sepa-
rately.
Craig S. Broberg, MD
Portland, Oregon
25 June 2011
1. Kaemmerer H, Fratz S, Braun SL, Koelling K,
Eicken A, Brodherr-Heberlein S, Pietrzik K,
Hess J. Erythrocyte indexes, iron metabolism,
and hyperhomocysteinemia in adults with cy-
anotic congenital cardiac disease. Am J Car-
diol 2004;94:825– 828.
doi:10.1016/j.amjcard.2011.06.030
Immortal Person Time Bias in
Pharmacoepidemiological Studies of
Antihypertensive Drugs
We read with interest the study of
Huang et al1 examining the risk for can-
cer associated with the use of angioten-
sin II receptor blockers (ARBs) in a
large observational cohort of Taiwanese
subjects with incident hypertension.
The study was motivated by a highly
publicized meta-analysis of clinical tri-
als that found a small but nominally
significant increased risk for cancer in
patients randomized to ARBs compared
to those not randomized to ARBs (risk
ratio 1.08, 95% confidence interval [CI]
1.01 to 1.15), driven largely by an ex-
cess risk for lung cancer (risk ratio 1.25,
95% CI 1.05 to 1.49).2 Contrary to this
clinical trial meta-analysis, Huang et al1
report an impressive approximate 34%
reduction in cancer risk associated with
the use of ARBs. The reduction in risk
was uniform across several co-morbid
conditions and all major cancer sites,
including lung cancer. The protective
effect was substantially more pro-
nounced in patients with ⬎1 year of
exposure to ARBs (hazard ratio 0.50,
95% CI 0.46 to 0.53) compared to those
with ⱕ1 year of exposure (hazard ratio
0.79, 95% CI 0.75 to 0.83). The strong
duration-response relation suggests a
causal association.
Reports of an elevated cancer risk
attributed to the use of various classes
of antihypertensive drugs have tran-
siently received widespread attention in
the past. However, initial concerning re-
ports have invariably been refuted
through additional studies.3 ARBs ap-
pear to be following a similar course,
with more recent expanded meta-analy-
ses of clinical trials conducted by the
United States Food and Drug Adminis-
tration and others showing no excess
risk for cancer in ARB users.4 – 6 Fur-
thermore, a large Danish observational
cohort study also detected no increased
risk for cancer in ARB users.7
How then does one explain the ex-
traordinary protective effects of ARBs
on cancer risk observed by Huang et al1
in light of the totality of evidence com-
ing from other studies? On the basis of
the investigators’ declared analytic ap-
proach, we strongly suspect that the
protective effect observed is merely a
consequence of immortal person-time
bias.8