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1580
we agree that interstitial lung disease is the most
important severe side effect induced by gefitinib
and that it can appear at any time during the
treatment period. Since we had investigated this
toxicity ever since gefitinib was first used in Ja-
pan,
1,2
we paid very careful attention to this side
effect, including prevention (avoiding use in pa-
tients with risk factors for interstitial lung dis-
ease), early diagnosis (careful observation for
signs of the condition and appropriate examina-
tions), and intensive treatment if the condition
appeared (e.g., immediate glucocorticoid thera-
py). We believe that our heightened awareness,
prevention, and treatment resulted in a lower rate
of death from interstitial lung disease than that
observed in the general population treated with
gefitinib in Japan. Recently, we conducted an-
other clinical trial of first-line gefitinib for elderly
patients (75 years of age or older) who had EGFR-
mutated nonsmall-cell lung cancer in which 1 of
30 patients with interstitial lung disease (3%)
died.
3
Although even this low rate is regrettable,
it is probably an acceptable toxicity risk in the
context of other chemotherapies used in such an
elderly population with advanced nonsmall-cell
lung cancer.
Akira Inoue, M.D., Ph.D.
Tohoku University Hospital
Sendai, Japan
akinoue@idac.tohoku.ac.jp
Kunihiko Kobayashi, M.D., Ph.D.
Saitama Medical University
Saitama, Japan
Toshihiro Nukiwa, M.D., Ph.D.
Tohoku University Hospital
Sendai, Japan
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial
pneumonia and gefitinib. Lancet 2003;361:137-9.
2. Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial lung disease
in Japanese patients with lung cancer: a cohort and nested case-
control study. Am J Respir Crit Care Med 2008;177:1348-57.
3. Minegishi Y, Maemondo M, Okinaga S, et al. First-line gefi-
tinib therapy for elder advanced non-small cell lung cancer
patients with epidermal growth factor receptor mutations: multi-
center phase II trial (NEJ 003 study). J Clin Oncol 2010;28:
Suppl:7561. abstract. (http://meeting.ascopubs.org/cgi/content/
abstract/28/15_suppl/7561.)
Dietary Therapy in Hypertension
To the Editor: Sacks and Campos (June 3 is-
sue)
1
review dietary therapy in hypertension and
recommend the Dietary Approaches to Stop Hy-
pertension (DASH) diet with low sodium intake
(1.5 g per day) for all patients with hypertension.
However, two limitations should be addressed.
First, as an important source of dietary iodine
worldwide, iodized salt accounts for 75% of so-
dium intake.
2
Low intake of salt, which is the most
common approach to reduce sodium intake, may
result in iodine deficiency. Moreover, DASH di-
ets
3
containing reduced amounts of organ meat
may result in deficiency of some essential ele-
ments such as iron and vitamin A. Second, the
composition of the DASH diet (low in fat and
carbohydrate but relatively high in protein) may
be problematic in patients with hypertensive ne-
phropathy or renal dysfunction, because protein
overload may further compromise renal func-
tion and aggravate hypertension.
4
Thus, we rec-
ommend that dietary therapy of hypertension
should take adequate essential nutrient intake
into account, and the appropriateness of the
DASH diet for patients with other diseases
should be assessed before dietary treatment is
recommended.
Di Zeng, M.D.
Qiang-sun Zheng, M.D., Ph.D.
Dong-bo Ou, M.D.
Tangdu Hospital
Xian, China
qiangsunzheng@gmail.com
No potential conflict of interest relevant to this letter was re-
ported.
1. Sacks FM, Campos H. Dietary therapy in hypertension. N Engl
J Med 2010;362:2102-12.
2. Dietary guidelines for Americans 2005. Washington, DC:
Department of Health and Human Services, Department of Agri-
culture. (http://www.healthierus.gov/dietaryguidelines.)
3. Sacks FM, Obarzanek E, Windhauser MM, et al. Rationale
and design of the Dietary Approaches to Stop Hypertension trial
(DASH): a multicenter controlled-feeding study of dietary pat-
terns to lower blood pressure. Ann Epidemiol 1995;5:108-18.
4. Fouque D, Aparicio M. Eleven reasons to control the protein
intake of patients with chronic kidney disease. Nat Clin Pract
Nephrol 2007;3:383-92.
To the Editor: We would like to emphasize that
a significant benefit of the DASH-type diets dis-
cussed by Sacks and Campos is attributable to
the higher potassium content of these diets. Am-
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correspondence
n engl j med 363;16 nejm.org october 14, 2010
1581
ple evidence shows that increased potassium
intake, along with sodium restriction, plays a
critical role in blood pressure reduction. Most
high-sodium diets are also grossly deficient in
potassium, and this deficiency increases sodium
sensitivity in both normotensive and hyperten-
sive persons; in these cases potassium supple-
mentation mitigates this effect.
1
In one study,
increased dietary potassium resulted in a 50%
reduction in the need for antihypertensive medi-
cations.
2
Compliance with DASH-type diets can
be determined by monitoring the ratio of urinary
sodium to potassium, which should be low (<0.01
to 1.78).
3
The Institute of Medicine advises adults to
consume at least 120 mmol of potassium per day.
4
The authors also failed to mention the bene-
fits of potassium-containing salt substitutes in
the treatment of hypertension in patients addicted
to table salt, especially if there is a low risk of
hyperkalemia. A randomized clinical trial showed
that a salt substitute containing 40% potassium
chloride significantly improved blood pressure
in patients with diabetes who had high blood
pressure.
5
Uday S. Nori, M.D.
Anil K. Agarwal, M.D.
Jon R. Von Visger, M.D., Ph.D.
Ohio State University Medical Center
Columbus, OH
uday.nori@osumc.edu
No potential conflict of interest relevant to this letter was re-
ported.
1. Morris RC Jr, Sebastian A, Forman A, Tanaka M, Schmidlin
O. Normotensive salt sensitivity: effects of race and dietary po-
tassium. Hypertension 1999;33:18-23.
2. Siani A, Strazzullo P, Giacco A, Pacioni D, Celantano E,
Mancini M. Increasing the dietary potassium intake reduces the
need for antihypertensive medication. Ann Intern Med 1991;115:
753-9.
3. Intersalt Cooperative Research Group. Intersalt: an interna-
tional study of electrolyte excretion and blood pressure: results
for 24-hour urinary sodium and potassium excretion. BMJ 1988;
297:319-28.
4. Dietary reference intakes for water, potassium, sodium,
chloride, and sulfate. Washington, DC: National Academies
Press, 2005.
5. Gilleran G, OLeary M, Bartlett WA, Vinall H, Jones AF, Dod-
son PM. Effects of dietary sodium substitution with potassium
and magnesium in hypertensive type II diabetics: a randomised
blind controlled parallel study. J Hum Hypertens 1996;10:517-21.
To the Editor: In their article, Sacks and Cam-
pos do not mention two important aspects of
hypertension and diet. The first concerns the
crucial role of the association between salt sensi-
tivity and the reduced decline in nocturnal blood
pressure that precedes microalbuminuria, a very
sensitive marker of vascular inflammation and
endothelial dysfunction in persons with insulin-
resistant states such as essential hypertension
and type 2 diabetes mellitus.
1
The second is re-
lated to the patients treatment. We would not
manage the care of such a patient for 6 months
with dietary treatment alone. Instead, we would
immediately initiate treatment with a small dose
of chlorthalidone and a reninangiotensin sys-
tem blocker such as an angiotensin-converting
enzyme inhibitor, together with diet and exercise,
to achieve the blood pressure target specified in
the Seventh Report of the Joint National Com-
mittee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC7).
2-4
For
busy clinicians, such an approach seems more
practical.
Jose Mario F. de Oliveira, M.D., Ph.D.
Paulo Roberto P. Santana, M.D.
Universidade Federal Fluminense
Niteri, Brazil
jmariofranco@gmail.com
No potential conflict of interest relevant to this letter was re-
ported.
1. Suzuki M, Kimura Y, Tsushima M, Harano Y. Association
of insulin resistance with salt sensitivity and nocturnal fall of
blood pressure. Hypertension 2000;35:864-8.
2. Moser M, Sowers J, Black HR. Microalbuminuria, chronic
renal disease, and the effects of the metabolic syndrome on
cardiovascular events. J Clin Hypertens (Greenwich) 2007;9:551-6.
3. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of
the Joint National Committee on Prevention, Detection, Evalua-
tion, and Treatment of High Blood Pressure. Hypertension 2003;
42:1206-52.
4. Major outcomes in high-risk hypertensive patients random-
ized to angiotensin-converting enzyme inhibitor or calcium
channel blocker vs diuretic: the Antihypertensive and Lipid-Low-
ering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
2002;288:2981-97.
To the Editor: Sacks and Campos write that
Compliance with dietary therapy is better, and
success rates in achieving blood-pressure control
are higher, when accompanied by active guid-
ance or counseling of the patient by clinicians or
ancillary medical personnel with expertise in di-
etary management. Compliance and adherence
to lifestyle modifications, such as diet, physical
activity, and smoking and drinking cessation, are
essential for achieving treatment goals, improv-
ing prognosis, and reducing the risk of death
from conditions such as hypertension, diabetes,
and coronary heart disease.
1
Depressive symp-
toms are common in persons with hypertension
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The new engl and journal o f medicine
n engl j med 363;16 nejm.org october 14, 2010
1582
and other cardiovascular diseases and have been
shown to interfere with patient compliance with
antihypertensive medication regimens and with
recommended changes in health-related behav-
ior.
2,3
In a large, population-based study, we found
that depressive symptoms in patients with hyper-
tension were associated with unhealthy behav-
iors and a higher body-mass index.
4
Health care
professionals involved in hypertension manage-
ment should be aware of the negative effect that
depressive symptoms may have on compliance
and recognize the need for additional active
guidance and counseling of patients with such
symptoms.
Raz Gross, M.D., M.P.H.
Columbia University
New York, NY
rg547@columbia.edu
Aviva Goral, M.Sc.
Sheba Medical Center
Tel Hashomer, Israel
Khitam Muhsen, M.Sc.
Tel Aviv University
Tel Aviv, Israel
No potential conflict of interest relevant to this letter was re-
ported.
1. Stringhini S, Sabia S, Shipley M, et al. Association of socio-
economic position with health behaviors and mortality. JAMA
2010;303:1159-66.
2. Eze-Nliam CM, Thombs BD, Lima BB, Smith CG, Ziegelstein
RC. The association of depression with adherence to antihyper-
tensive medications: a systematic review. J Hypertens 2010;28:
1785-95.
3. Whooley MA, de Jonge P, Vittinghoff E, et al. Depressive
symptoms, health behaviors, and risk of cardiovascular events
in patients with coronary heart disease. JAMA 2008;300:2379-88.
4. Goral A, Muhsen K, Gross R. Chronic hypertension, depres-
sive symptoms, and health related risk behaviors: findings from
the First Israel National Health Interview Survey (2003-2004).
Isr J Psychiatry 2009;46:45-6.
To the Editor: Sacks and Campos reviewed the
use of dietary therapy in hypertension and rec-
ommended that the patient in their vignette
reduce sodium and calorie intake and adopt a
Mediterranean-style diet. A recently published
prospective study (although not based on a ran-
domized, controlled trial) showed that reducing
the consumption of sugar and sugar-sweetened
beverages was associated with reduced blood
pressure.
1
This finding is consistent with the re-
port of a positive association between habitual
consumption of sugar-sweetened beverages and
elevated blood pressure in a previous cross-sec-
tional study.
2
According to the vignette in the
review by Sacks and Campos, the patient drinks
beverages containing sugars and sodium, but she
was not given instructions on how to change her
drinking habits. The authors should have includ-
ed recommendations for reducing the intake of
sugar-sweetened beverages in their dietary in-
structions.
Jaewon Oh, M.D.
Namki Hong, M.D.
Seok-Min Kang, M.D., Ph.D.
Yonsei University College of Medicine
Seoul, Korea
smkang@yuhs.ac
No potential conflict of interest relevant to this letter was re-
ported.
1. Chen L, Caballero B, Mitchell DC, et al. Reducing consump-
tion of sugar-sweetened beverages is associated with reduced
blood pressure: a prospective study among United States adults.
Circulation 2010;121:2398-406. [Erratum, Circulation 2010;
122(4):e408.]
2. Nguyen S, Choi HK, Lustig RH, Hsu CY. Sugar-sweetened
beverages, serum uric acid, and blood pressure in adolescents.
J Pediatr 2009;154:807-13.
The Authors Reply: Sufficient iodine intake can
coexist with low sodium intake by increasing the
content of iodine in salt, by having food manu-
facturers use only iodized salt, and by adding
iodine to other ingredients besides salt.
1
The
amount of protein in the DASH diet and the diets
used in the Optimal Macronutrient Intake Trial
to Prevent Heart Disease (OmniHeart) would not
be detrimental to the vast majority of patients
who have prehypertension or hypertension. Pa-
tients with severe nephropathy who have special
requirements for protein and other nutrients
should have these needs incorporated into the
clinical care provided by nephrologists and dieti-
tians.
We agree with Nori et al. that the effects
fruits and vegetables have in lowering blood
pressure could be caused by their high potassium
content. But potassium cannot account for the
much larger effects on blood pressure observed
in patients following the DASH and OmniHeart
diets. We refer readers to our online Supplemen-
tary Appendix (available with the full text of our
article at NEJM.org), which discusses potassium
extensively.
The sodium sensitivity of blood pressure is
associated with microvascular dysfunction, insu-
lin resistance, and a smaller-than-usual decrease
in blood pressure during the night. However, we
caution clinicians that the sodium sensitivity of
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correspondence
n engl j med 363;16 nejm.org october 14, 2010
1583
blood pressure is not reproducible enough to
have clinical value. Optimal diets improve micro-
vascular dysfunction, and they reduce blood
pressure during the day and at night.
2
Thus, diet
is the treatment of choice for these linked disor-
ders, and low sodium intake would have special
effectiveness in such patients. We cannot agree
with the opinion of de Oliveira and Santana to
prescribe combination antihypertensive drug
treatment for the primary prevention of cardio-
vascular disease in a patient with newly discov-
ered essential hypertension. Such a patient could
avoid drug treatment entirely if she optimizes her
diet. Drug treatment for hypertension, although
unquestionably effective in reducing cardiovas-
cular events, has adverse effects that partially off-
set its benefits, as shown in a recent large trial.
3
We agree with the statement by Oh and col-
leagues concerning sugars, and in our article we
stated that we encourage patients to eat . . .
vegetables and fruit instead of snacks and des-
serts high in sugars, [and] fruit itself rather than
juice. We also recommended that sections of
the market that contain sweetened beverages,
candies, and cookies should be avoided entirely
when shopping for food. We also agree that con-
trolled trials are needed to determine direct ef-
fects that sugar and other carbohydrates have on
blood pressure. We are completing such a trial us-
ing the controlled feeding methods of the DASH
study (Effect of Amount and Type of Dietary Car-
bohydrates on Risk for Cardiovascular Heart Dis-
ease and Diabetes [OmniCarb]; ClinicalTrials.gov
number, NCT00608049).
Frank M. Sacks, M.D.
Hannia Campos, Ph.D.
Harvard School of Public Health
Boston, MA
fsacks@hsph.harvard.edu
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Reducing salt intake in populations: report of a WHO forum
and technical meeting, 5-7 October 2006, Paris, France. Geneva:
World Health Organization, 2007.
2. Uzu T, Kimura G, Yamauchi A, et al. Enhanced sodium sen-
sitivity and disturbed circadian rhythm of blood pressure in es-
sential hypertension. J Hypertens 2006;24:1627-32.
3. The ACCORD Study Group. Effects of intensive blood-pres-
sure control in type 2 diabetes mellitus. N Engl J Med 2010;
362:1575-85.
Poppers-Associated Retinal Toxicity
To the Editor: Poppers (slang for various
forms of alkyl nitrite) are volatile nitric oxide
donors that have been used for decades as recre-
ational drugs. Both the popularity of and legal
tolerance for poppers have led to the perception
that these drugs are relatively innocuous.
1
Here,
we describe four patients who were seen within a
few months of one another and who had pro-
longed visual loss as a result of damage to foveal
photoreceptors shortly after inhaling poppers.
In January 2010, Patient 1, a 27-year-old
woman, presented with an 11-day history of a
reduction in bilateral vision and a central bright
dot in both eyes. The night before the onset of
symptoms, she had attended a party, at which
both she and Patient 2 had inhaled poppers
(brand name, Jungle Juice) and consumed ap-
proximately half a bottle of high-grade alcohol.
Patient 1 was an occasional consumer of other
brands of poppers but reported having had no
previous visual symptoms. Her medical history
was unremarkable.
The visual acuity was 20/50 in the right eye
and 20/40 in the left eye. Anterior segments and
intraocular pressure were normal. The fundus
examination showed a yellow foveal dot in both
eyes (Fig. 1A and 1B, top row). Findings on high-
resolution optical coherence tomography were
consistent with damage to the photoreceptor
outer segment in the fovea of both eyes (Fig. 1A
and 1B, bottom row). Color vision and full-field
electroretinograms were normal. Isopropyl nitrite
was identified by gas chromatographymass
spectrometry in the vapors from the popper vial.
On follow-up examination 1 month later, the vi-
sual symptoms and ophthalmologic examination
were unchanged.
Within a 3-month period, we examined three
other patients who also had visual loss with
central phosphenes after inhaling isopropyl ni-
trite (see the Supplementary Appendix, available
with the full text of this letter at NEJM.org). Two
of these patients showed resolution of symp-
toms over several weeks.
To our knowledge, over the past 10 years,
there have been only two case reports of visual
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