Correspondence
patients with standard-risk hepatoblastoma and
probably in those with other localized cancers.
However, the use of sodium thiosulfate in pa-
tients with disseminated disease may affect sur-
vival, and caution is warranted in that context.
David R. Freyer, D.O.
Children’s Hospital Los Angeles
Los Angeles, CA
dfreyer@​­chla​.­usc​.­edu
A. Lindsay Frazier, M.D.
Dana–Farber/Boston Children’s Cancer and Blood Disorders Center
Boston, MA
Lillian Sung, M.D., Ph.D.
Hospital for Sick Children
Toronto, ON, Canada
Dr. Freyer reports being a scientific advisor for Otonomy and
Sensorion, and Dr. Frazier being on the clinical advisory board
of Decibel Therapeutics. No other potential conflict of interest
relevant to this letter was reported.
1. Brock PR, Maibach R, Childs M, et al. Sodium thiosulfate for
protection from cisplatin-induced hearing loss. N Engl J Med
2018;​378:​2376-85.
2. Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thio-
sulfate versus observation on development of cisplatin-induced
hearing loss in children with cancer (ACCL0431): a multicentre,
randomised, controlled, open-label, phase 3 trial. Lancet Oncol
2017;​18:​63-74.
DOI: 10.1056/NEJMc1809501
The authors reply: We agree with Freyer et al.
that drawing conclusions for clinical practice
from our trial and ACCL04311 would support the
use of sodium thiosulfate for protection from
cisplatin-induced hearing loss in patients with
any localized solid tumor and encourage careful
further clinical assessment in patients with meta-
static disease. No definitive conclusion or thera-
peutic direction should be drawn from any post
hoc analysis, particularly in ACCL0431, in which
children were not randomly assigned according
to disease-specific key prognostic factors that are
important in determining outcome in metastatic
disease.
Evidence-based up-front hearing protection
Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis
To the Editor: In their report on the Pediatric
Emergency Care Applied Research Network trial
of fluid infusion rates in patients with diabetic
ketoacidosis (PECARN DKA FLUID), Kuppermann
et al. (June 14 issue)1 do not provide data on
n engl j med 379;12 nejm.org  September 20, 2018
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
with sodium thiosulfate is preferable to the wide-
ly accepted non–evidence-based clinical practice
of either cisplatin dose reduction or chemother-
apy replacement on development of ototoxic ef-
fects. The latter approach permits permanent
hearing loss to develop and could jeopardize
survival. Treatment protocol amendments incor-
porating sodium thiosulfate for cisplatin-induced
hearing loss require reducing cisplatin infusion
times to a maximum of 6 hours. This allows a
6-hour gap between the end of the cisplatin in-
fusion and the start of the sodium thiosulfate
infusion. Such a gap, which prevents the sodium
thiosulfate from inhibiting the antitumor effect
of the cisplatin, is within the 4-to-8-hour gap
required for effective hearing protection.2-4
Penelope R. Brock, M.D., Ph.D.
Great Ormond Street Hospital
London, United Kingdom
peppybrock@​­gmail​.­com
Rudolf Maibach, Ph.D.
International Breast Cancer Study Group
Bern, Switzerland
Edward A. Neuwelt, M.D.
Oregon Health and Science University
Portland, OR
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thio-
sulfate versus observation on development of cisplatin-induced
hearing loss in children with cancer (ACCL0431): a multicentre,
randomised, controlled, open-label, phase 3 trial. Lancet Oncol
2017;​18:​63-74.
2. Erdlenbruch B, Nier M, Kern W, Hiddemann W, Pekrun A,
Lakomek M. Pharmacokinetics of cisplatin and relation to nephro-
toxicity in paediatric patients. Eur J Clin Pharmacol 2001;​57:​
393-402.
3. Muldoon LL, Pagel MA, Kroll RA, et al. Delayed administra-
tion of sodium thiosulfate in animal models reduces platinum
ototoxicity without reduction of antitumor activity. Clin Cancer
Res 2000;​6:​309-15.
4. Doolittle ND, Muldoon LL, Brummett RE, et al. Delayed
sodium thiosulfate as an otoprotectant against carboplatin-
induced hearing loss in patients with malignant brain tumors.
Clin Cancer Res 2001;​7:​493-500.
DOI: 10.1056/NEJMc1809501
whether there was a correlation between a de-
crease in the effective plasma osmolality and
deterioration in the Glasgow Coma Scale score or
clinically apparent brain injury. Observational
data and physiological analyses of the factors
1181
 The n e w e ng l a n d j o u r na l
that may contribute to development of cerebral
edema suggest that a rapid decline in plasma ef-
fective osmolality (two times the plasma sodium
concentration plus the plasma glucose concen-
tration) may be associated with an increased risk
of cerebral edema in children with diabetic keto-
acidosis. 2,3Hence, it was suggested that fluid
therapy should aim to prevent a decline in effec-
tive plasma osmolality.2-4 Data that can be used to
calculate the effective plasma osmolality are avail-
able only for the patient who had seizures and
died (with details provided in Table S2 in the Sup-
plementary Appendix of the article, available at
NEJM.org). The plasma osmolality was 297.6 mOsm
per kilogram of water on admission, 304.8 at
4 hours, and 288.5 at 12 hours (with an even
lower value of 274.5 if the plasma sodium con-
centration was 131 mmol per liter). Factors other
than administered fluid tonicity may contribute
to a decrease in the effective plasma osmolality
— for example, a rapid decrease in plasma glu-
cose and a gain of electrolyte-free water after ab-
sorption of retained fluids in the stomach.3,5 In
the absence of a demonstrated advantage, we
think that the administration of hypotonic solu-
Table 1. Comparison of Fluid Infusion Rates and Outcomes in the PECARN
Trial and the Dallas Study.*
Infusion Rates and Outcomes PECARN Trial Dallas Study
Volume of fluid bolus — ml of normal saline 600 600
Fluid volume administered during subsequent 3240 3565
23 hr — ml of normal saline
Total fluid volume administered in 24 hr 3840 4165
— ml of normal saline
Total no. of episodes of diabetic ketoacidosis 682† 3712‡
Patients with clinically apparent brain injury 4 (0.6)§ 7 (0.2)¶
— no. (%)
Patients who died from cerebral edema 1 (0.15) 0 showing that slow fluid rates have no benefit and
— no. (%)
* Fluid infusion rates were calculated for a child weighing 30 kg with a body-
surface area of 1 m2 in both the Pediatric Emergency Care Applied Research
Network (PECARN) trial and the Dallas study.1,2 Data from the PECARN trial
are included for the two subgroups that received fast infusion of sodium chlo-
ride solution (0.45% or 0.9%).
† Diabetic ketoacidosis was defined as a pH level of less than 7.25 or a serum
bicarbonate level of less than 15 mmol per liter.
‡ Diabetic ketoacidosis was defined according to the International Classification
of Diseases, Ninth Revision (ICD-9) code of 250.1x.
§ Clinically apparent brain injury was defined as the need for infusion of hyper-
tonic solution or intubation and was adjudicated by committee.
¶ Clinically apparent brain injury was defined as the need for infusion of hyper­
tonic solution or intubation and abnormal results on magnetic resonance
­imaging.
1182 n engl j med 379;12 nejm.org  September 20, 2018
The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
tions should not be recommended, and the effec-
tive plasma osmolality should be monitored dur-
ing therapy.
Kamel S. Kamel, M.D.
St. Michael’s Hospital
Toronto, ON, Canada
kamel​.­kamel@​­utoronto​.­ca
Ana P.C.P. Carlotti, M.D.
Ribeirão Preto Medical School
Ribeirão Preto, Brazil
Mitchell L. Halperin, M.D.
St. Michael’s Hospital
Toronto, ON, Canada
No potential conflict of interest relevant to this letter was re-
ported.
1. Kuppermann N, Ghetti S, Schunk JE, et al. Clinical trial of
fluid infusion rates for pediatric diabetic ketoacidosis. N Engl J
Med 2018;​378:​2275-87.
2. Hoorn EJ, Carlotti AP, Costa LA, et al. Preventing a drop in
effective plasma osmolality to minimize the likelihood of cere-
bral edema during treatment of children with diabetic ketoacido-
sis. J Pediatr 2007;​150:​467-73.
3. Kamel KS, Halperin ML. Acid–base problems in diabetic keto-
acidosis. N Engl J Med 2015;​372:​546-54.
4. Friedman AL. Choosing the right fluid and electrolytes pre-
scription in diabetic ketoacidosis. J Pediatr 2007;​150:​455-6.
5. Carlotti AP, St George-Hyslop C, Guerguerian AM, Bohn D,
Kamel KS, Halperin Ml. Occult risk factor for the development
of cerebral edema in children with diabetic ketoacidosis: possi-
ble role for stomach emptying. Pediatr Diabetes 2009;​10:​522-33.
DOI: 10.1056/NEJMc1810064
To the Editor: Diabetic ketoacidosis is a frequent
adverse event in children with type 1 diabetes
and is associated with rare but potentially devas-
tating complications, including cerebral edema.
Because gross fluid overload may increase the
risk of cerebral edema, many centers impose
stringent limitations on fluid resuscitation rates,
which perhaps increase the duration of severe
dehydration and acidosis. Kuppermann and col-
leagues have rendered a tremendous service by
may be detrimental, especially in more severe
cases. They found no effect of fluid sodium con-
centration on any outcome. However, they did not
include a study group that was treated with iso-
tonic fluids, which might have been most effec-
tive; their 0.9% saline fluid is markedly hypertonic
(399 mOsm per liter) because it includes 20 mmol
of potassium chloride per liter and 20 mmol of
dipotassium phosphate per liter. A protocol that
specifies the administration of isotonic fluids at
a relatively rapid rate is indeed associated with
very low morbidity and mortality (Table 1).1,2
However, there was only one death (0.08%) in the
 Correspondence
entire PECARN trial; commonly cited higher
rates of death3 are probably no longer relevant, at
least in tertiary referral centers.
Perrin C. White, M.D.
UT Southwestern Medical Center
Dallas, TX
perrin​.­white@​­utsouthwestern​.­edu
No potential conflict of interest relevant to this letter was re-
ported.
1. Felner EI, White PC. Improving management of diabetic keto-
acidosis in children. Pediatrics 2001;​108:​735-40.
2. White PC, Dickson BA. Low morbidity and mortality in chil-
dren with diabetic ketoacidosis treated with isotonic fluids.
J Pediatr 2013;​163:​761-6.
3. Wolfsdorf JI, Allgrove J, Craig ME, et al. ISPAD Clinical Prac-
tice Consensus Guidelines 2014: diabetic ketoacidosis and hyper-
glycemic hyperosmolar state. Pediatr Diabetes 2014;​15:​Suppl 20:​
154-79.
DOI: 10.1056/NEJMc1810064
To the Editor: In their trial comparing fast in-
fusion (over 36 hours) and slow infusion (over 48
hours) of 0.9% or 0.45% sodium chloride solu-
tion in children with diabetic ketoacidosis, Kup-
permann et al. compare fast replacement of an
assumed 10% deficit versus slow replacement of
a 5% deficit, regardless of the severity of the clin-
ical presentation. Hence, this trial compares “fast
and more” versus “slow and less.” There were 20
more patients (151 vs. 131) with a pH level of less
than 7.1 in the slow-replacement group (i.e., 5%
deficit) than in the fast-replacement group (i.e.,
10% deficit) (Table S4 in the Supplementary Ap-
pendix of the article). This is important, since two
thirds of patients with clinically apparent brain
injury had an initial pH level of less than 7.1.
There is a temporal relationship between a
decrease in the corrected plasma sodium level
and the development of cerebral edema.1 National
guidelines for pediatric diabetic ketoacidosis rec-
ommend monitoring of corrected sodium levels.2,3
Publication of corrected sodium trends in the
trial population, especially in those with cerebral
edema, would be useful.
Mark J. Russell, B.M., B.S.
Hari‑Krishnan Kanthimathinathan, M.D.
Birmingham Women’s and Children’s NHS Foundation Trust
Birmingham, United Kingdom
markrussell2@​­nhs​.­net
No potential conflict of interest relevant to this letter was re-
ported.
1. Durward A, Ferguson LP, Taylor D, Murdoch IA, Tibby SM.
The temporal relationship between glucose-corrected serum
sodium and neurological status in severe diabetic ketoacidosis.
Arch Dis Child 2011;​96:​50-7
n engl j med 379;12 nejm.org  September 20, 2018
The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
2. Wolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in
infants, children, and adolescents: a consensus statement from
the American Diabetes Association. Diabetes Care 2006;​29:​
1150-9.
3. British Society for Paediatric Endocrinology and Diabetes
guideline for the management of children and young people un-
der the age of 18 years with diabetic ketoacidosis. North Bristol,
United Kingdom:​British Society for Paediatric Endocrinology
and Diabetes, August 2015 (https://www​.bsped​.org​.uk/​media/​
1381/​dkaguideline​.pdf).
DOI: 10.1056/NEJMc1810064
The authors reply: We thank our colleagues
for their comments. Several mentioned the rela-
tionship between changes in glucose-corrected
sodium and in effective osmolality and altera-
tions in mental status and clinically apparent
cerebral injury during treatment of diabetic keto-
acidosis. We collected such data during the trial
and are currently performing analyses. Prelimi-
nary results are available only for the first 4 hours
of treatment, and these results show no asso-
ciations between changes in glucose-corrected
sodium and either altered mental status or clini-
cally apparent cerebral injury.
Kamel et al. mention data regarding the one
death in our study. That patient had an initial
Glasgow Coma Scale score of 14, which declined
to 9 at hour 4. At that time, despite clear abnor-
malities in mental status, the effective osmolal-
ity had not declined but rather increased. It is
also notable that among the most severely ill
patients (as detailed in Table S4 in the Supple-
mentary Appendix of our article), decreases in
the Glasgow Coma Scale score occurred less
frequently in those treated with fast infusion of
0.45% sodium chloride.
Previous retrospective studies, including one
by our group, showed associations between a
lack of increase in serum sodium levels during
treatment and clinically apparent cerebral injury.1,2
However, the duration of abnormal mental status
before a diagnosis of cerebral injury was unclear.
In a prospective study, it is likely that careful
monitoring of mental status results in earlier
detection of cerebral injury. Alterations in the
hormonal regulation of sodium and fluid bal-
ance may result from cerebral injury (rather than
vice versa), and previously documented associa-
tions may reflect the occurrence of these altera-
tions later in the disease course.
Kamel et al. also suggest that changes in osmo-
lality could have resulted from the absorption of
retained fluid from the stomach. However, per-
1183
 The n e w e ng l a n d j o u r na l
sistent vomiting is characteristic of diabetic keto-
acidosis, so this mechanism seems unlikely.
White notes that our trial fluids were either
hypotonic or somewhat hypertonic (taking into
account potassium salts). We did not evaluate
strictly isotonic fluids; however, our data indi-
cate no association between fluid tonicity and
neurologic outcome. Furthermore, in the Dallas
study, the requirement for abnormal results on
magnetic resonance imaging to diagnose cere-
bral injury or edema related to diabetic keto-
acidosis differs from our study definition of this
outcome and may account for the lower fre-
quency reported. 3
Russell and Kanthimathinathan note that,
by random chance, the number of patients with
a low pH in the slow-infusion groups was slight-
ly higher than that in the fast-infusion groups.
However, in our analyses, we compared propor-
tions rather than absolute numbers of patients
Cultured Cells and ROCK Inhibitor for Bullous Keratopathy
To the Editor: The clinical trial on corneal endo-
thelial cell (CEC)–injection therapy by Kinoshita
et al. (March 15 issue)1 is a landmark study in
corneal transplantation. In the trial, seven pa-
tients had Fuchs’s endothelial corneal dystrophy,
characterized by extracellular matrix aggregates
(guttae) that are known to inhibit CEC monolayer
formation.2,3 The authors noted that “a silicone
needle . . . was used to remove the abnormal
extracellular matrix,” yet specular microscopic
images showed guttae at 24 weeks after surgery.
Do there exist data showing the elimination of
guttae after scraping? Furthermore, guttae ap-
pear to have worsened from 24 weeks to 2 years
(i.e., in Patients 3, 7, and 8). Do the authors be-
lieve this is due to new guttae formation or expo-
sure of old guttae, resulting in toxic effects on
overlying injected CECs? Have these patients
worsened clinically during the past 3 years?
Stephen Wahlig, B.Sc.
Duke University Medical Center
Durham, NC
Viridiana Kocaba, M.D.
Edouard Herriot Hospital
Lyon, France
1184 n engl j med 379;12 nejm.org  September 20, 2018
The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
with the outcomes of interest. Therefore, the
small difference in group numbers should not
have had an effect on the results.
Nathan Kuppermann, M.D., M.P.H.
Nicole S. Glaser, M.D.
University of California Davis School of Medicine
Sacramento, CA
nkuppermann@​­ucdavis​.­edu
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Glaser N, Barnett P, McCaslin I, et al. Risk factors for cere-
bral edema in children with diabetic ketoacidosis. N Engl J Med
2001;​344:​264-9.
2. Harris GD, Fiordalisi I, Harris WL, Mosovich LL, Finberg L.
Minimizing the risk of brain herniation during treatment of dia-
betic ketoacidemia: a retrospective and prospective study. J Pediatr
1990;​117:​22-31.
3. Muir AB, Quisling RG, Yang MC, Rosenbloom AL. Cerebral
edema in childhood diabetic ketoacidosis: natural history, radio-
graphic findings, and early identification. Diabetes Care 2004;​
27:​1541-6.
DOI: 10.1056/NEJMc1810064
Jodhbir S. Mehta, M.B., B.S.
Singapore Eye Research Institute
Singapore, Singapore
jodmehta@​­gmail​.­com
No potential conflict of interest relevant to this letter was re-
ported.
1. Kinoshita S, Koizumi N, Ueno M, et al. Injection of cultured
cells with a ROCK inhibitor for bullous keratopathy. N Engl J
Med 2018;​378:​995-1003.
2. Rizwan M, Peh GS, Adnan K, et al. In vitro topographical
model of fuchs dystrophy for evaluation of corneal endothelial
cell monolayer formation. Adv Healthc Mater 2016;​5:​2896-910.
3. Kocaba V, Katikireddy KR, Gipson I, Price MO, Price FW,
Jurkunas UV. Association of the gutta-induced microenvironment
with corneal endothelial cell behavior and demise in Fuchs endo-
thelial corneal dystrophy. JAMA Ophthalmol 2018;​136:​886-92.
DOI: 10.1056/NEJMc1805808
To the Editor: In their article, Kinoshita et al.
described a pioneering cell therapy for bullous
keratopathy. Although this proof-of-concept study
is promising, methodologic discrepancies com-
plicate interpretation.
The study includes two culture protocols, two
methods of removing damaged endothelium, two
different injected suspensions, and five underly-
ing pathologic conditions. Although these limita-
tions are described, the limited cohort and hetero-