ARTICLE IN PRESS

THE JOURNAL OF PEDIATRICS • www.jpeds.com ORIGINAL

ARTICLES
Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A
Matched Retrospective Cohort Study
Scott L. Weiss, MD, MSCE1, Luke Keele, PhD2, Fran Balamuth, MD, PhD, MSCE3,4, Neika Vendetti, MPH3, Rachael Ross, MPH3,
Julie C. Fitzgerald, MD, PhD1, and Jeffrey S. Gerber, MD, PhD3,5

Objective To test the hypothesis that resuscitation with balanced fluids (lactated Ringer [LR]) is associated with
improved outcomes compared with normal saline (NS) in pediatric sepsis.
Study design We performed matched analyses using data from 12 529 patients <18 years of age with severe
sepsis/septic shock at 382 US hospitals between 2000 and 2013 to compare outcomes with vs without LR as part
of initial resuscitation. Patients receiving LR were matched 1:1 to patients receiving only NS (NS group), including
separate matches for any (LR-any group) or exclusive (LR-only group) LR use. Outcomes included 30-day hos-
pital mortality, acute kidney injury, new dialysis, and length of stay.
Results The LR-any group was older, received larger crystalloid volumes, and was less likely to have malignan-
cies than the NS group. After matching, mortality was not different between LR-any (7.2%) and NS (7.9%) groups
(risk ratio 0.99, 95% CI 0.98, 1.01; P = .20). There were no differences in secondary outcomes except longer hos-
pital length of stay in LR-any group (absolute difference 2.4, 95% CI 1.4, 5.0 days; P < .001). Although LR was
preferentially used as adjunctive fluid with large-volume resuscitation or first-line fluid in patients with lower illness
severity, outcomes were not different after matching stratified by volume and proportionate LR utilization, including
for patients in the LR-only group.
Conclusions Balanced fluid resuscitation with LR was not associated with improved outcomes compared with NS
in pediatric sepsis. Although the current practice of NS resuscitation is justified, selective LR use necessitates a pro-
spective trial to definitively determine comparative effectiveness among crystalloids. (J Pediatr 2016;■■:■■-■■).

F
luid resuscitation is the cornerstone of acute management for hypovolemia and shock, but there remains uncertainty as
to the most appropriate fluid to restore blood volume and optimize organ perfusion.1-3 Isotonic crystalloid fluids are
generally preferred, except in cases of hemorrhage, as they are inexpensive, easy to store, and available in a wide variety
of settings.4,5 Sepsis guidelines for adults and pediatrics recommend initial crystalloid fluid resuscitation.6,7
Crystalloid fluids can be categorized as either nonbuffered/nonbalanced (eg, 0.9% normal saline [NS]) or balanced (eg, lac-
tated Ringer [LR], Hartmann, Plasma-Lyte, Baxter, Deerfield, Illinois) solutions. Although balanced fluid have a more physi-
ologic electrolyte composition and strong ion difference closer to plasma than NS, these fluids have not been preferentially used
for sepsis resuscitation.4,5,8 However, large amounts of NS can induce a hyperchloremic metabolic acidosis and have been as-
sociated with adverse effects on kidney injury, coagulation, and death.9-12 Alternatively, balanced crystalloids have been associ-
ated with improved outcomes and decreased renal replacement therapy compared with NS in adult sepsis.11,13
In pediatric sepsis, there are limited data comparing clinical outcomes follow-
ing LR vs NS resuscitation. Although Carcillo et al14 demonstrated the impor-
tance of early fluid resuscitation in pediatric septic shock, there was no differentiation
between use of NS or LR. In a randomized trial of 4 fluid regimens in children
with dengue fever, patients receiving LR were slower to recover from shock com- From the 1Division of Critical Care Medicine, Department
of Anesthesiology and Critical Care, The Children’s
pared with NS, but the study was not powered for morbidity or mortality Hospital of Philadelphia, University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA; 2McCourt
outcomes.15 The largest study of fluid resuscitation in children with severe infec- School of Public Policy and Department of Government,
Georgetown University, Washington, DC; 3Center for
tions restricted crystalloid fluids to NS.16 Consequently, guidelines for pediatric Pediatric Clinical Effectiveness, The Children’s Hospital of
sepsis are unable to provide evidence-based recommendations to choose among Philadelphia, Philadelphia, PA; 4Division of Emergency
Medicine; and 5Division of Infectious Diseases,
available crystalloid solutions even despite emerging data questioning the rela- Department of Pediatrics, The Children’s Hospital of
Philadelphia, University of Pennsylvania Perelman School
tive safety of NS in adults.6 Because crystalloid fluids are so commonly used, even of Medicine, Philadelphia, PA
Supported by the Department of Anesthesiology and
Critical Care, Division of Emergency Medicine, and
Center for Pediatric Clinical Effectiveness at The
Children’s Hospital of Philadelphia. S.W. receives support
from National Institute of General Medical Sciences
AKI Acute kidney injury (K23GM110496). F.B. receives support from the Eunice
ICD-9-CM International Classification of Diseases, Ninth Edition, Clinical Modification Kennedy Shriver National Institute of Child Health and
LOS Length of stay Human Development (K23HD082368). The authors
declare no conflicts of interest.
LR Lactated Ringer
NS Normal saline 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights
PICU Pediatric intensive care unit reserved.
http://dx.doi.org10.1016/j.jpeds.2016.11.075

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

a small benefit attributable to type of fluid resuscitation could Demographics, month/site of admission, comorbid condi-
provide a substantial public health impact with only a minor tions, and intensive care therapies were obtained from the
shift in practice. We, therefore, sought to test the hypothesis Premier Healthcare Database. Comorbid conditions were
that balanced fluid resuscitation is associated with improved defined using pediatric complex chronic conditions.19 Thera-
outcomes in pediatric sepsis. pies included use of the following on hospitals days 1, 2, or
3: noninvasive and invasive mechanical ventilation, vasoac-
tive infusions, albumin, blood products, furosemide, cortico-
Methods steroids, use of a central venous catheter, arterial line, or bladder
catheter, and extracorporeal membrane oxygenation. Because
We conducted a matched retrospective cohort study of pedi- doses of vasoactive infusions were not available, we summa-
atric patients <18 years of age with severe sepsis or septic shock rized this variable as the total number of vasoactive infu-
across 382 geographically diverse US hospitals between January sions. Blood products were defined as any combination of red
2000 and December 2013. Patients were identified from the blood cells, platelets, fresh frozen plasma, or cryoprecipitate.
Premier Healthcare Database, an administrative database es-
tablished by the Premier healthcare alliance that contains item- Outcomes
ized daily logs of all patient charges. The Premier Healthcare The primary outcome was all-cause 30-day hospital mortal-
Database is the largest acute care database in the US with a ity in the NS vs LR-any groups. To increase the likelihood that
complete census of all inpatients from more than 600 hospi- death was related to the initial sepsis episode requiring fluid
tals, of which approximately three-quarters are nonteaching resuscitation, we censored the primary outcome at 30 days after
hospitals. Pediatric data is contributed through a combina- admission. Secondary outcomes included uncensored hospi-
tion of community-based and specialty children’s hospitals. tal mortality, hospital mortality plus hospice, acute kidney injury
The study was considered exempt from human subjects re- (AKI) with and without dialysis, and pediatric intensive care
search oversight by The Children’s Hospital of Philadelphia unit (PICU) and hospital length of stay (LOS). AKI was defined
Institutional Review Board because only deidentified data were by the ICD-9-CM code 584.x and AKI with dialysis was defined
used. as an ICD-9-CM code for AKI (584.x) with either (a) a pro-
Eligible patients were <18 years of age, diagnosed with severe cedure charge for a dialysis catheter (38.95) with a charge for
sepsis or septic shock, received initial treatment at the Premier dialysis (39.95) or (b) charge codes for dialysis supplies.13 Pa-
hospital, were not admitted to a neonatal intensive care unit tients with an ICD-9-CM code for end-stage renal disease
(based on all patient refined-diagnosis related group codes), already undergoing dialysis (ICD-9-CM 585.6) were ex-
and were ordered to receive any combination of NS or LR fluid cluded from the analysis of AKI with or without dialysis. All
boluses during the first 3 days of hospital admission. To iden- outcomes were also analyzed separately for patients in the LR-
tify severe sepsis and septic shock, we used previously pub- only group.
lished combinations of International Classification of Diseases,
Ninth Edition, Clinical Modification (ICD-9-CM) codes for Statistical Analyses
either an invasive infection plus acute organ dysfunction Analyses were performed using R 2.13.1 (R Foundation) with
(Tables I and II; available at www.jpeds.com) or the ICD-9- mipmatch package20 and Stata v 12.1 (StataCorp, College
CM codes for severe sepsis (785.52) or septic shock (995.92).17,18 Station, Texas). Data are presented as medians (IQR) or pro-
To increase the likelihood that initial fluid resuscitation was portions. We used mixed integer programming 1:1 matching
related to sepsis, we restricted inclusion to patients with blood to minimize the within-pair Mahalanobis distance for key
cultures and broad-spectrum antibiotics (Table III; available covariates that were both available within Premier and had a
at www.jpeds.com) ordered within the first 3 hospital days. We biologically plausible or previously demonstrated associa-
excluded patients with unknown hospital disposition at day tion, including demographics, comorbidities, and therapies, with
30. risk of death. The Mahalanobis distance is the difference in
Exposure to LR or NS was defined by type and amount of covariate values for patients in the LR vs NS groups divided
fluid recorded over the first three hospital days. Only LR or by the covariates’ SD.21 Unlike propensity scores that can
NS ordered as bolus therapy was considered. Because bal- produce stochastic balance, integer matching ensures a more
anced fluids other than LR (eg, Plasma-Lyte) were rare predictable and precise balance on specific covariates.20 The
(0.3%), we limited our analysis to LR and NS. Fluid volumes specific patient-level covariates used for matching are listed in
were billed as 250, 500, or 1000 mL units. Although some Tables IV and V (Table IV; available at www.jpeds.com). In
patients likely received only a portion of a unit because of addition, because LR use was likely to cluster by hospital, we
weight-based fluid dosing in pediatrics, we considered the also matched within site exactly except for hospitals that had
entire unit to have been administered. Patients were catego- ≤10 patients for which we allowed matching across sites. We
rized as exposure to only NS (NS group) or to varying also repeated the analysis excluding hospitals with ≤10 pa-
amounts LR and NS (LR-any group), similar to the method- tients to ensure matching across low-volume hospitals did not
ology published by Raghunathan et al.13 We also performed impact our findings. Because prior studies have demon-
a separate analysis of patients who received only NS vs only strated differences in mortality for patients identified with spe-
LR (LR-only group). cific severe sepsis/septic shock ICD-9-CM codes compared with
2 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

for the LR-only group. Stratifying by volume before match-

Table V. Patient characteristics in matched cohort
ing ensured that matched pairs did not consist of patients who
LR-any group† NS group‡ received substantially different total volumes of fluid. Finally,
Variables* N = 2117 N = 2117 P value§
one last match was conducted using only those covariates un-
Age (y), median (IQR) 8 (1-15) 7 (1-14) .01 likely to mediate the effect of fluid type on outcome, includ-
Male sex 1119 (53) 1149 (54) .37
Race/ethnicity .31 ing age, sex, race/ethnicity, comorbidities, site, season, year, and
White 983 (46) 1021 (48) sepsis identification strategy. For this final analysis, therapies
Black 451 (21) 466 (22) that may have occurred following fluid resuscitation were not
Hispanic 249 (12) 218 (10)
Other 434 (21) 412 (19) used in the match.
Comorbid conditions¶ We tested for differences in outcomes using McNemar or
Cardiovascular 362 (17) 312 (15) .04 Wilcoxon sign rank tests for matched pairs. To assess for po-
Respiratory 78 (4) 51 (2) .02
Renal 42 (2) 29 (1) .15 tential confounding because of residual statistical differences
Gastrointestinal 62 (3) 50 (2) .29 in matching variables between groups, we used conditional logit
Malignancy 187 (9) 186 (9) 1.0 regression to adjust for any covariates that differed between
Hematologic/immunologic 116 (5) 97 (5) .21
Metabolic 120 (6) 105 (5) .34 groups at P < .01.25 For 30-day mortality, we also performed
Neuromuscular 394 (19) 377 (18) .52 a Kaplan-Meier analysis to determine if time-to-death dif-
Congenital disorders 203 (10) 164 (8) .04 fered between groups. For LOS, we used the Huber M esti-
PICU admission 1729 (82) 1664 (79) .01
Sepsis-related therapies** mate because of long tails and permutation distribution to test
Vasoactive infusion 880 (42) 824 (39) .08 for statistical significance.22 Because LOS may be influenced
Maximum number of 2 (1-3) 2 (1-3) .09 by survival, we conducted 2 analyses to determine if LOS was
concurrent vasoactives††
Noninvasive mechanical 181 (9) 157 (7) .19 sensitive to vital status. First, we set LOS to the sample
ventilation maximum for all nonsurvivors, and, second, we set LOS to 30
Invasive mechanical ventilation 1389 (66) 1347 (64) .19 days for all nonsurvivors.26 To account for the potential pref-
Corticosteroids 551 (26) 488 (23) .02
Hydrocortisone 230 (11) 203 (10) .19 erence of LR utilization in surgical patients, the primary match
Methylprednisolone 390 (18) 347 (16) .09 and analyses were repeated after excluding all patients who un-
Albumin 5% 446 (21) 409 (19) .16 derwent any surgery based on diagnosis related group codes.
Albumin 25% 609 (29) 552 (26) .05
Blood transfusion‡‡ 995 (47) 933 (44) .06 Statistical significance was defined as P < .05.
Furosemide 947 (45) 910 (43) .25
ECMO 12 (<1) 8 (<1) .50 Results
ECMO, extracorporeal membrane oxygenation.
*Data presented as n (%), unless noted. An initial cohort of 12 529 patients met all inclusion/exclusion
†LR group included patients who received any amount of LR fluid resuscitation.
‡NS group included patients who received only NS fluid resuscitation. criteria, including 10 379 ordered for only NS fluid (NS group)
§Statistical comparison using Wilcoxon signed rank and McNemar test for matched pairs, as and 2150 patients ordered for at least 1 LR fluid bolus (LR-
appropriate.
¶Comorbid conditions were categorized using ICD-9-CM codes defining pediatric complex chronic any group) (Figure 1; available at www.jpeds.com). Only 459
conditions.19 patients received exclusive LR resuscitation (LR-only group).
**Includes therapies administered through hospital day 3.
††Includes only patients who received at least 1 vasoactive infusion. Use of LR decreased slightly between 2000 and 2005 (31% to
‡‡Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryo- 16%) but remained between 14% and 16% through 2013. The
precipitate.
median (IQR) volume of total fluid resuscitation was 1000 mL
(500-2000 mL) and by estimated weight-for-age was 24 mL/
codes for infection plus organ dysfunction,17,18 we used fine kg (13-45 mL/kg). Before matching, the LR-any group was older
balance to match patients by sepsis identification strategy. Fine (median 8 vs 5 years, P < .001), received larger crystalloid
balance ensures matching on one variable without restrict- volumes (median 2000 vs 1000 mL [40 vs 22 mL/kg], P < .001),
ing matching on other variables.22 A similar approach matched was less likely to have malignancies, and more likely to receive
patients by year and season. intensive care therapies (Table IV). Unadjusted 30-day hos-
To assess match quality, we calculated standardized differ- pital mortality was not different between the LR-any (7.4%)
ences for each variable by dividing the mean difference between and NS (6.9%) groups (P = .33). However, unadjusted 30-
matched patients by the pooled SD before matching. We used day mortality varied significantly for patients who received only
the benchmark of <0.10, or less than one-tenth of a SD, as the LR (5.0%), a combination of LR and NS (8.1%), and only NS
maximum acceptable standardized difference.23,24 (6.9%) fluid (P = .04).
Matching was repeated within quartiles of total crystalloid A total of 2117 patients who received any LR were matched
volume, such that patients in the LR-any group were matched 1:1 with patients that received only NS on the variables listed
only to patients in the NS group who received a similar total in Table V, as well as site, season, and sepsis identification strat-
volume of crystalloid fluid. We used sex-specific 50th percen- egy. Patient characteristics, comorbidities, and nonfluid thera-
tile weight-for-age (Table VI; available at www.jpeds.com) to pies were similar after matching (Table V). For several
estimate age-related differences in volume administration. Next, covariates, P values remained <.05 reflecting the large sample,
matching was again repeated after stratifying patients by pro- but standardized differences were all <.10 in the matched cohort
portion of total fluid given as LR, including a separate match (Figure 2; available at www.jpeds.com). The majority of pa-
Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 3

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Table VII. Outcomes in matched cohorts for LR-any and LR-only groups
LR-any group† NS group‡ Risk ratio/difference
Outcomes* (n = 2117) (n = 2117) (95% CI) P value§
Mortality, 30-d 153 (7.2) 168 (7.9) 0.99 (0.9, 1.09) .20
Mortality, hospital 194 (9.2) 199 (9.4) 1.0 (0.98, 1.02) .41
Mortality, including hospice 200 (9.4) 211 (10.0) 0.99 (0.98, 1.01) .29
AKI 334 (15.8) 337 (15.9) 1.0 (0.97, 1.02) .41
New dialysis 27 (1.3) 33 (1.6) 1.0 (0.99, 1.00) .21
PICU LOS¶, median (IQR) 7.8 (1.0, 13.0) 7.3 (1.0, 12.0) 0.5 (0.2, 0.8) .01
Hospital LOS¶, median (IQR) 15.5 (6.0, 22.0) 13.1 (4.0, 20.0) 2.4 (1.4, 5.0) <.001

LR-only group** NS group‡ Risk ratio/difference

Outcomes* (n = 459) (n = 459) (95% CI) P value§
Mortality, 30-d 23 (5.0) 21 (4.6) 1.01 (0.98, 1.03) .69
Mortality, hospital 29 (6.3) 28 (6.1) 1.0 (0.97, 1.03) .62
Mortality, including hospice 30 (6.5) 29 (6.3) 1.0 (0.97, 1.03) .62
AKI 45 (9.8) 49 (10.7) 0.99 (0.95, 1.03) .32
New dialysis 5 (1.1) 5 (1.1) 1.0 (0.99, 1.01) .50
PICU LOS¶, median (IQR) 5.8 (1.0, 10.0) 5.5 (1.0, 9.0) 0.33 (-0.1, 0.7) .27
Hospital LOS¶, median (IQR) 11.9 (5.0, 18.0) 10.5 (4.0, 14.0) 1.35 (0.5, 2.2) .01

*Data presented as median (IQR).

†LR-any group included patients who received any amount of LR fluid resuscitation.
‡NS group included patients who received only NS fluid resuscitation.
§Statistical comparison using McNemar test for matched pairs or Wilcoxon sign rank test, as appropriate.
¶LOS is reported in days.
**LR-only group included patients who only received LR fluid resuscitation.

tients included in the matched analysis were identified with Volume-Stratified Analysis
severe sepsis using ICD-9-CM codes for infection plus organ Although mortality rose with increasing weight-adjusted crys-
dysfunction (80.4%) vs specific severe sepsis/septic shock codes talloid fluid volume, 30-day hospital mortality did not differ
(19.6%). between the LR-any and NS groups after matching within
volume quartiles (Figure 4). However, only 142 patients re-
LR-Any Matched Analysis ceived LR in the first quartile of total crystalloid fluid volume,
In the matched cohort of 4234 patients, 30-day hospital mor- and there was an increase in LR utilization with successive
tality was 7.2% in the LR-any group and 7.9% in the NS group
(risk ratio 0.99, 95% CI 0.98, 1.01; P = .20). There were no sig-
nificant differences in overall hospital mortality, hospital mor-
tality plus hospice, or AKI with and without dialysis (Table VII).
There remained no differences in these outcomes after further
adjusting for imperfectly balanced covariates in multivari-
able analyses, after repeating the match using only those
covariates unlikely to mediate the effect of fluid type on
outcome, or after excluding surgical patients (data not shown).
Hospital LOS was longer for the LR-any group compared with
the NS group (absolute difference 2.4, 95% CI 1.4, 5.0 days;
P < .001). Analyses setting LOS to the sample maximum or to
30 days for all nonsurvivors did not impact these findings
(Table VIII; available at www.jpeds.com), nor did excluding
234 matched pairs from hospitals with ≤10 patients (data not
shown). The Kaplan-Meier analysis demonstrated no differ- Figure 4. Hospital mortality for LR-any and NS groups matched
ence in time-to-death between matched groups (log-rank within quartile of total crystalloid fluid volume. The x-axis cat-
P = .11) (Figure 3; available at www.jpeds.com). egorizes patients based on quartile of total fluid crystalloid
Patients with specific ICD-9-CM codes for severe sepsis/ volume received after correcting by estimated weight for age
septic shock had higher 30-day hospital mortality than pa- (median total volume in Q1 = 8 mL/kg, Q2 = 17 mL/kg,
tients identified by infection plus organ dysfunction codes Q3 = 32 mL/kg, and Q4 = 68 mL/kg). The y-axis shows the ad-
(15.0% vs 5.8%, P < .001). However, there were no differ- justed 30-day mortality rate. Patients in the LR-any group were
ences in outcomes between the matched LR-any and NS groups matched within volume quartile to patients who received only
stratified by sepsis identification strategy except for longer PICU NS. There were no significant differences in mortality between
the LR-any and NS groups within any of the total volume
and hospital LOS for the LR group identified by combina-
quartiles.
tion codes (Table IX; available at www.jpeds.com).
4 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

quartiles of total volume administration (Q1: 5.0%; Q2: 11.5%; rich solutions can also cause a hyperchloremic metabolic
Q3: 20.6%; Q4: 30.2%), supporting the preferential use of LR acidosis, which has been shown to be proinflammatory.30
in patients who required larger total fluid volumes. In addi- Our work builds on previous clinical studies that have over-
tion, PICU admission and the use of nonfluid intensive thera- whelmingly focused on adult populations. Most studies have
pies were more common in each successive quartile (Table X; demonstrated either no difference31-34 or a benefit of at least
available at www.jpeds.com) making it difficult to disen- some proportion of resuscitation fluids given as balanced
tangle proportionate LR use, volume of fluid resuscitation, and solutions.11-13 For example, Raghunathan et a13 found that receipt
illness severity. Finally, matching performed least effectively in of at least some balanced fluids during initial resuscitation was
the fourth quartile of patients who received the largest total associated with lower hospital mortality in adults with
fluid volumes and with the most severe illness severity (Figure 5; vasopressor-dependent septic shock. This contrast with our
available at www.jpeds.com). results may be attributable to age-related biological differ-
ences, such as a lower rate of baseline subclinical cardiac and
Dose-Response Analysis renal disease in children, or methodological differences, such
To account for variability in the proportionate use of LR, pa- as limiting the adult study to vasopressor-dependent shock.
tients were separately matched after stratifying by propor- Unfortunately, insufficient sample size precluded limiting our
tion of total crystalloid volume ordered as LR. Patients with pediatric analysis to vasopressor-dependent shock. Moreover,
an increasing proportionate LR use received fewer intensive even though Premier offers a geographically diverse sample,
therapies and had a lower rate of adverse outcomes (Tables XI the relatively low median fluid volume resuscitation and mor-
and XII; available at www.jpeds.com). However, there were no tality <8% suggests an overall moderate illness severity that may
differences in 30-day hospital mortality or AKI (Figure 6; avail- not reflect more severe pediatric sepsis cases that tend to con-
able at www.jpeds.com) or dialysis (data not shown) between centrate at specialty children’s hospitals. It is also possible that
the LR groups stratified by proportionate LR utilization and potential detrimental effects of LR, including microvascular
the NS group. thromboses (because of calcium activating the clotting cascade)9
or cerebral edema (because of mild fluid hypotonicity),35 may
LR-Only Matched Analysis be more problematic in children. For example, in Vietnamese
In the separate matched cohort of 918 patients receiving either children with Dengue shock, patients randomized to resusci-
exclusive LR or NS fluid, 30-day hospital mortality was 5% in tation with LR had a longer time to recovery than patients re-
the LR-only group and 4.6% in the NS group (risk ratio 1.01, suscitated with NS.15 As with other critical therapies, benefits
95% CI 0.98, 1.03; P = .69). There were no significant differ- seen in adult populations may not translate to children.
ences in secondary outcomes, except a longer hospital LOS in Prior studies suggest that potential adverse effects associ-
the LR-only group (Table VII). ated with NS are dose-related such that LR may only be ben-
eficial for patients requiring large-volume fluid resuscitation.1-3
Discussion In our study, mortality increased with larger fluid volumes and
decreased with a greater proportion of fluid given as LR, but
In this large matched cohort study of pediatric severe sepsis there were no differences between LR and NS groups after
and septic shock, balanced fluid resuscitation with LR was not matching within volume quartiles, by proportionate LR uti-
associated with improved mortality, AKI, or dialysis, even when lization, or in the separate matched analysis of LR-only pa-
matched by fluid volume and proportionate LR utilization. tients. However, the preference for LR as first-line fluid in
However, LR was preferentially used either as first-line fluid patients with low illness severity or as an adjunctive fluid in
in patients with lower illness severity or as an adjunctive fluid patients who received a large amount of total fluid could have
in patients who received large amounts of fluid resuscita- masked a true benefit of LR.
tion, and the matching algorithm was least effective in the most There are several limitations. First, claims-based data may
severely ill patients who received the largest total fluid volumes. lead to misclassification bias if ordered and administered thera-
Consequently, the results of our study are best interpreted as pies are discrepant, although this is unlikely to produce dif-
establishing the need for and the equipoise to conduct a pro- ferential bias between groups. Also, we were not able to account
spective randomized trial to definitely address the compara- for prehospital fluid administration, partial administration of
tive effectiveness of balanced fluids and NS in pediatric sepsis. fluid units (which is common in pediatrics because of weight-
Prior data suggest that the supraphysiologic chloride content based fluid administration), or account for deviations in weight
of NS may be detrimental to renal function and acid-base from published growth curves. Even though this may have over-
balance.1-3,9-11 Infusion of chloride-rich fluids reduced renal or underestimated fluid administration, these are unlikely to
blood flow in dogs and healthy human volunteers to a greater have been sources of differential bias between LR and NS.
extent than more balanced fluids.27,28 NS also induced ab- However, the younger age of the NS-only group (before and
dominal discomfort, drowsiness, and impaired cognition, com- after matching) could have introduced slightly more error in
pared with LR and other balanced fluids, in a human study.29 estimated total fluid volumes than in the LR-group because
In a sequential period study of critically ill adults, use of younger patients are more likely to receive partial adminis-
chloride-restrictive fluids reduced the odds of AKI and dialy- tration of a fluid bag and rounding to median weight repre-
sis by almost 50%.11 Infusion of large volumes of chloride- sents a larger proportional change relative to true weight.
Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 5

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Second, using ICD-9-CM codes for infection plus organ dys- 6. Brierley J, Carcillo JA, Choong K, Cornell T, Decaen A, Deymann A, et al.
function to identify pediatric sepsis is controversial.17,18,36 Clinical practice parameters for hemodynamic support of pediatric and
neonatal septic shock: 2007 update from the American College of Criti-
Notably, patients with more specific ICD-9-CM sepsis codes cal Care Medicine. Crit Care Med 2009;37:666-88.
had a trend toward decreased mortality and less dialysis in the 7. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al.
LR group. Moreover, because identification and timing of sur- Surviving sepsis campaign: international guidelines for management of
gical interventions is limited using administrative codes, it was severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580-
difficult to fully account for a possible surgical preference to 637.
8. Ventura AM, Shieh HH, Bousso A, Goes PF, de Cassia FOFI, de Souza
use LR. Third, differences in demographics, comorbidities, and DC, et al. Double-blind prospective randomized controlled trial of do-
intensive therapies indicate nonrandom selective use of LR over pamine versus epinephrine as first-line vasoactive drugs in pediatric septic
NS. Although statistical matching was able to remove much shock. Crit Care Med 2015;43:2292-302.
of these baseline differences, we cannot rule out residual con- 9. Kiraly LN, Differding JA, Enomoto TM, Sawai RS, Muller PJ, Diggs B,
founding within unmeasured covariates. In addition, in the et al. Resuscitation with normal saline (NS) vs. lactated ringers (LR) modu-
lates hypercoagulability and leads to increased blood loss in an uncon-
absence of physiologic and laboratory data, we used inten- trolled hemorrhagic shock swine model. J Trauma 2006;61:57-64, discussion
sive care therapies for illness severity but could not deter- -5.
mine if these therapies occurred after—or as a result 10. Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of
of—differential use of LR vs NS. Because excluding these vari- fluid resuscitation with 0.9% saline versus a balanced electrolyte solution
ables from the match posed risk for increased confounding, on acute kidney injury in a rat model of sepsis. Crit Care Med 2014;42:e270-
8.
we chose a conservative approach similar to Raghunathan et al13 11. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association
fluid study in adult sepsis despite the possibility that match- between a chloride-liberal vs chloride-restrictive intravenous fluid ad-
ing on these covariates could have masked outcome differ- ministration strategy and kidney injury in critically ill adults. JAMA
ences. However, secondary analyses using patients matched only 2012;308:1566-72.
on covariates unlikely to mediate the effect of fluid type on 12. Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR,
et al. Major complications, mortality, and resource utilization after open
outcome also showed no differential effect of LR vs NS. Finally, abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg
because LR was the predominant balanced fluid used, our data 2012;255:821-9.
may not be generalizable to other balanced fluids. 13. Raghunathan K, Shaw A, Nathanson B, Sturmer T, Brookhart A, Stefan
In this large matched observational study, use of LR (alone MS, et al. Association between the choice of IV crystalloid and in-
or in combination with NS) was not associated with im- hospital mortality among critically ill adults with sepsis. Crit Care Med
2014;42:1585-91.
proved outcomes compared with exclusive NS resuscitation in 14. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid resuscitation in pe-
pediatric septic shock. These findings support the current prac- diatric septic shock. JAMA 1991;266:1242-5.
tice of using NS as the first choice for crystalloid fluid resus- 15. Ngo NT, Cao XT, Kneen R, Wills B, Nguyen VM, Nguyen TQ, et al. Acute
citation in pediatric sepsis. However, given the limitations of management of dengue shock syndrome: a randomized double-blind com-
matching within a retrospective observational study to fully parison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis
2001;32:204-13.
account for the nonrandom selective use of LR, our findings 16. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO,
also emphasize the need for a large-scale prospective random- et al. Mortality after fluid bolus in African children with severe infection.
ized trial to definitely determine the comparative effective- N Engl J Med 2011;364:2483-95.
ness of balanced fluids and NS in pediatric sepsis. ■ 17. Balamuth F, Weiss SL, Neuman MI, Scott H, Brady PW, Paul R, et al. Pe-
diatric severe sepsis in U.S. children’s hospitals. Pediatr Crit Care Med
2014;15:798-805.
Submitted for publication Jul 21, 2016; last revision received Sep 28, 2016;
18. Weiss SL, Parker B, Bullock ME, Swartz S, Price C, Wainwright MS, et al.
accepted Nov 29, 2016
Defining pediatric sepsis by different criteria: discrepancies in popula-
Reprint requests: Scott L. Weiss, MD, MSCE, Department of Anesthesiology tions and implications for clinical practice. Pediatr Crit Care Med
and Critical Care, The Children’s Hospital of Philadelphia, University of
2012;13:e219-26.
Pennsylvania Perelman School of Medicine, 3401 Civic Center Blvd, 7 South
Tower, Room 7C04, Philadelphia, PA 19104. E-mail: [email protected] 19. Feudtner C, Hays RM, Haynes G, Geyer JR, Neff JM, Koepsell TD. Deaths
attributed to pediatric complex chronic conditions: national trends
and implications for supportive care services. Pediatrics 2001;107:
References E99.
20. Zubizarreta JR. Using mixed integer programming for matching in an ob-
1. Karakala N, Raghunathan K, Shaw AD. Intravenous fluids in sepsis: what servational study of kidney failure after surgery. J Am Stat Assoc
to use and what to avoid. Curr Opin Crit Care 2013;19:537-43. 2012;107:1360-71.
2. Santi M, Lava SA, Camozzi P, Giannini O, Milani GP, Simonetti GD, et al. 21. Rubin DB. Bias reduction using Mahalanobis-metric matching. Biomet-
The great fluid debate: saline or so-called “balanced” salt solutions? Ital rics 1980;36:293-8.
J Pediatr 2015;41:47. 22. Rosenbaum PR. Sensitivity analysis for m-estimates, tests, and confi-
3. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med dence intervals in matched observational studies. Biometrics 2007;63:456-
2013;369:1243-51. 64.
4. Boulain T, Boisrame-Helms J, Ehrmann S, Lascarrou JB, Bougle A, Chiche 23. Neuman MD, Rosenbaum PR, Ludwig JM, Zubizarreta JR, Silber JH. An-
A, et al. Volume expansion in the first 4 days of shock: a prospective esthesia technique, mortality, and length of stay after hip fracture surgery.
multicentre study in 19 French intensive care units. Intensive Care Med JAMA 2014;311:2508-17.
2015;41:248-56. 24. Silber JH, Rosenbaum PR, Trudeau ME, Even-Shoshan O, Chen W, Zhang
5. Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, et al. X, et al. Multivariate matching and bias reduction in the surgical out-
Fluid challenges in intensive care: the FENICE study: a global inception comes study. Med Care 2001;39:1048-64.
cohort study. Intensive Care Med 2015;41:1529-37. 25. Pearce N. Analysis of matched case-control studies. BMJ 2016;352:i969.

6 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

26. Lin W, Halpern SD, Prasad Kerlin M, Small DS. A “placement of death” critically ill patients presenting with hypovolemic shock: the CRISTAL
approach for studies of treatment effects on ICU length of stay. Stat Methods randomized trial. JAMA 2013;310:1809-17.
Med Res 2014 Aug 1; pii: 0962280214545121. [Epub ahead of print]. 32. Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell
27. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, con- D, et al. Fluid type and the use of renal replacement therapy in sepsis: a
trolled, double-blind crossover study on the effects of 2-L infusions of systematic review and network meta-analysis. Intensive Care Med
0.9% saline and plasma-lyte(R) 148 on renal blood flow velocity and renal 2015;41:1561-71.
cortical tissue perfusion in healthy volunteers. Ann Surg 2012;256:18- 33. Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-
24. Robichaud A, et al. Fluid resuscitation in sepsis: a systematic review and
28. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest network meta-analysis. Ann Intern Med 2014;161:347-55.
1983;71:726-35. 34. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al.
29. Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of in- Effect of a buffered crystalloid solution vs saline on acute kidney injury
travenous lactated Ringer’s solution versus 0.9% sodium chloride solu- among patients in the intensive care unit: the SPLIT randomized clinical
tion on serum osmolality in human volunteers. Anesth Analg 1999;88:999- trial. JAMA 2015;314:1701-10.
1003. 35. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hypona-
30. Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different tremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Renal Physiol
patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. 2008;295:F619-24.
Am J Physiol Regul Integr Comp Physiol 2004;286:R686-92. 36. Balamuth F, Weiss SL, Hall M, Neuman MI, Scott H, Brady PW, et al.
31. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declere AD, et al. Effects Identifying pediatric severe sepsis and septic shock: accuracy of diagno-
of fluid resuscitation with colloids vs crystalloids on mortality in sis codes. J Pediatr 2015;167:1295-300.

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 7

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Figure 1. Patient selection and matching. Patients receiving any LR (LR-any group) and patients receiving only LR (LR-only
group) were separately matched to patients receiving only NS (NS group). A suitable match from the NS group was identified
for 98.5% of patients who received any LR and 100% of patients who received only LR. DRG, diagnosis related group; NICU,
neonatal intensive care unit.

7.e1 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

Figure 2. Summary of A, P values and B, standardized differences in unmatched and matched cohorts. The standardized dif-
ference is computed dividing the mean difference between matched patients by the pooled SD before matching, with values
<.10 considered an acceptable level of discrepancy within a matched pair. Before matching, there were statistically significant
differences in more than one-half of the covariates, and the standardized differences exceeded 0.10 in nearly one-quarter of
covariates. After matching, the median P value across covariates increased to >.25, and the standardized differences were <.10
for all covariates.

Figure 3. Kaplan-Meier survival to hospital discharge through

day 30 for LR-any and NS groups. Patients were censored at
either hospital discharge or death, whichever came first. Time
to death was not different between matched patients in the LR-
any and NS groups, log-rank P = .11.

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 7.e2

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Figure 5. Summary of A, P values and B, standardized differences across matched LR-any and NS patients within quartile of
total crystalloid volume. The standardized differences were <.10 for nearly all covariates in each quartile, reflecting an accept-
able maximum discrepancy within matched pairs in each volume quartile. However, the distribution of P values decreased with
each successive volume quartile, suggesting that the matching algorithm performed least effectively for those patients who re-
ceived the large total crystalloid fluid volumes.

Figure 6. Hospital mortality and AKI for patients matched after first stratifying LR-any group by proportion of total crystalloid
volume ordered as LR. Patients in the LR-any group were matched within each stratum to patients who received only NS. Each
set of bars is grouped by total crystalloid volume given as LR, including patients who only received NS but who were matched
to LR-any patients in those strata. Although both 30-day hospital mortality and AKI occurred less frequently as the proportion
of total fluids given as LR increased, there were no significant differences between the matched LR and NS groups within each
strata with the exception of significantly lower 30-day hospital mortality in the LR group within the 26% to ≤50% strata (*P = .03).

7.e3 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

Table I. ICD-9-CM codes used to identify bacterial or Table I. Continued

fungal infection
ICD-9-CM ICD-9-CM
codes* Description codes* Description
001 Cholera 462 Acute pharyngitis
002 Typhoid/paratyphoid fever 463 Acute tonsillitis
003 Other salmonella infection 464 Acute laryngitis/tracheitis
004 Shigellosis 465 Acute upper respiratory infection of multiple sites/not otherwise
005 Other food poisoning specified
008 Intestinal infection not otherwise classified 481 Pneumococcal pneumonia
009 Ill-defined intestinal infection 482 Other bacterial pneumonia
010 Primary tuberculosis infection 485 Bronchopneumonia with organism not otherwise specified
011 Pulmonary tuberculosis 486 Pneumonia, organism not otherwise specified
012 Other respiratory tuberculosis 491.21 Acute exacerbation of obstructive chronic bronchitis
013 Central nervous system tuberculosis 494 Bronchiectasis
014 Intestinal tuberculosis 510 Empyema
015 Tuberculosis of bone and joint 513 Lung/mediastinum abscess
016 Genitourinary tuberculosis 540 Acute appendicitis
017 Tuberculosis not otherwise classified 541 Appendicitis not otherwise specified
018 Miliary tuberculosis 542 Other appendicitis
020 Plague 562.01 Diverticulitis of small intestine without hemorrhage
021 Tularemia 562.03 Diverticulitis of small intestine with hemorrhage
022 Anthrax 562.11 Diverticulitis of colon without hemorrhage
023 Brucellosis 562.13 Diverticulitis of colon with hemorrhage
024 Glanders 556 Anal and rectal abscess
025 Melioidosis 567 Peritonitis
026 Rat-bite fever 569.5 Intestinal abscess
027 Other bacterial zoonoses 569.83 Perforation of intestine
030 Leprosy 572 Abscess of liver
031 Other mycobacterial disease 572.1 Portal pyemia
032 Diphtheria 575.0 Acute cholecystitis
033 Whooping cough 590 Kidney infection
034 Streptococcal throat/scarlet fever 597 Urethritis/urethral syndrome
035 Erysipelas 599.0 Urinary tract infection not otherwise specified
036 Meningococcal infection 601 Prostatic inflammation
037 Tetanus 614 Female pelvic inflammation disease
038 Septicemia 615 Uterine inflammatory disease
039 Actinomycotic infections 616 Other female genital inflammation
040 Other bacterial diseases 681 Cellulitis, finger/toe
041 Bacterial infection in other diseases not otherwise specified 682 Other cellulitis or abscess
090 Congenital syphilis 683 Acute lymphadenitis
091 Early symptomatic syphilis 686 Other local skin infection
092 Early syphilis latent 711.0 Pyogenic arthritis
093 Cardiovascular syphilis 730 Osteomyelitis
094 Neurosyphilis 790.7 Bacteremia
095 Other late symptomatic syphilis 996.6 Infection or inflammation of device/graft
096 Late syphilis latent 998.5 Postoperative infection
097 Other and unspecified syphilis 999.3 Infectious complication of medical care not otherwise classified
098 Gonococcal infections
100 Leptospirosis *Where 3- or 4-digit codes are listed, all associated subcodes were included.
101 Vincent's angina
102 Yaws
103 Pinta
104 Other spirochetal infection
110 Dermatophytosis Table II. ICD-9-CM codes used to identify acute organ
111 Dermatomycosis not otherwise classified or specified dysfunction
112 Candidiasis
114 Coccidioidomycosis ICD-9-CM codes* Description
115 Histoplasmosis 785.5 Shock without trauma
116 Blastomycotic infection 458 Hypotension
117 Other mycoses 96.7 Mechanical ventilation
118 Opportunistic mycoses 348.3 Encephalopathy
320 Bacterial meningitis 293 Transient organic psychosis
322 Meningitis, unspecified 348.1 Anoxic brain damage
324 Central nervous system abscess 287.4 Secondary thrombocytopenia
325 Phlebitis of intracranial sinus 287.5 Thrombocytopenia, unspecified
420 Acute pericarditis 286.9 Other/unspecified coagulation defect
421 Acute or subacute endocarditis 286.6 Defibrination syndrome
451 Thrombophlebitis 570 Acute and subacute necrosis of liver
461 Acute sinusitis 573.4 Hepatic infarction
(continued) 584 Acute renal failure

*Where 3- or 4-digit codes are listed, all associated subcodes were included.

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 7.e4

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Table III. Premier codes for broad-spectrum antibiotics Table III. Continued
Premier standard Premier standard
Premier antibiotic names charge codes Premier antibiotic names charge codes

Amikacin, Amikin 1 g 250250002200000 Cefoperazone, Cefobid 2 g 250250010490000

Amikacin, Amikin 500 mg 250250002210000 Cefotaxime, Claforan Adv 1 g 250250010500000
Amikacin, Amikin 250 mg/mL 1 mL 250250002420000 Cefotaxime, Claforan Adv 2 g 250250010510000
Amikacin, Amikin 250 mg/mL 2 mL 250250002430000 Cefotaxime, Claforan 1 g 250250010520000
Amikacin, Amikin 250 mg/mL 4 mL 250250002440000 Cefotaxime, Claforan 2 g 250250010530000
Amikacin, Amikin 50 mg/mL 2 mL 250250002450000 Cefotaxime, Claforan 10 g 250250010540000
Amp/Sulbac, Unasyn Adv 1.5 g 250250003320000 Cefotaxime, Claforan 1 g 250250010550000
Amp/Sulbac, Unasyn Adv 3 g 250250003330000 Cefotaxime, Claforan 2 g 250250010560000
Amp/Sulbac, Unasyn 1.5 g 250250003340000 Cefotaxime, Claforan 500 mg 250250010570000
Amp/Sulbac, Unasyn 3 g 250250003350000 Cefotetan, Cefotan 1 g 250250010580000
Amp/Sulbac, Unasyn 1.5 g 250250003360000 Cefotetan, Cefotan 2 g 250250010590000
Amp/Sulbac, Unasyn 3 g 250250003370000 Cefotetan, Cefotan 10 g 250250010600000
Ampicillin, Omnipen-N Adv 1 g 250250003470000 Cefotetan, Cefotan 1 g 250250010610000
Ampicillin, Omnipen-N Adv 2 g 250250003480000 Cefotetan, Cefotan 2 g 250250010620000
Ampicillin, Omnipen-N Adv 500 mg 250250003490000 Cefoxitin, Mefoxin Adv 1 g 250250010630000
Ampicillin, Omnipen-N 125 mg 250250003500000 Cefoxitin, Mefoxin Adv 2 g 250250010640000
Ampicillin, Omnipen-N 1 g 250250003510000 Cefoxitin, Mefoxin Intravenous Premix 1 g 250250010650000
Ampicillin, Omnipen-N 250 mg 250250003520000 Cefoxitin, Mefoxin Intravenous Premix 2 g 250250010660000
Ampicillin, Omnipen-N 2 g 250250003530000 Cefoxitin, Mefoxin 1 g 250250010670000
Ampicillin, Omnipen-N 500 mg 250250003540000 Cefoxitin, Mefoxin 2 g 250250010680000
Ampicillin, Omnipen-N 10 g 250250003550000 Cefoxitin, Mefoxin 10 g 250250010690000
Ampicillin, Omnipen-N 125 mg 250250003560000 Cefoxitin, Mefoxin 1 g 250250010700000
Ampicillin, Omnipen-N 1 g 250250003570000 Cefoxitin, Mefoxin 2 g 250250010710000
Ampicillin, Omnipen-N 250 mg 250250003580000 Ceftazidime, Fortaz Intravenous Premix 1 g 250250010880000
Ampicillin, Omnipen-N 2 g 250250003590000 Ceftazidime, Fortaz Intravenous Premix 2 g 250250010890000
Ampicillin, Omnipen-N 500 mg 250250003600000 Ceftazidime, Fortaz 1 g 250250010900000
Azithromycin, Zithromax 500 mg 250250005110000 Ceftazidime, Fortaz 2 g 250250010910000
Aztreonam, Azactam 1 g 250250005250000 Ceftazidime, Fortaz 3 g 250250010920000
Aztreonam, Azactam 2 g 250250005260000 Ceftazidime, Fortaz 10 g 250250010930000
Aztreonam, Azactam 500 mg 250250005270000 Ceftazidime, Fortaz 1 g 250250010940000
Aztreonam, Azactam 1 g 250250005280000 Ceftazidime, Fortaz 2 g 250250010950000
Aztreonam, Azactam 2 g 250250005290000 Ceftazidime, Fortaz 500 mg 250250010960000
Aztreonam, Azactam 500 mg 250250005300000 Ceftazidime, Fortaz 6 g 250250010970000
Azithromycin, Zithromax 500 mg 250250005310000 Ceftizoxime, Cefizox Intravenous Premix 1 g 250250011070000
Cefamandole, Mandol Adv 1 g 250250010010000 Ceftizoxime, Cefizox Intravenous Premix 2 g 250250011080000
Cefamandole, Mandol Adv 2 g 250250010020000 Ceftizoxime, Cefizox 1 g 250250011090000
Cefamandole, Mandol Intravenous Premix 1 g 250250010030000 Ceftizoxime, Cefizox 2 g 250250011100000
Cefamandole, Mandol Intravenous Premix 2 g 250250010040000 Ceftizoxime, Cefizox 1 g 250250011110000
Cefamandole, Mandol 1 g 250250010050000 Ceftizoxime, Cefizox 2 g 250250011120000
Cefamandole, Mandol 2 g 250250010060000 Ceftizoxime, Cefizox 500 mg 250250011130000
Cefamandole, Mandol 10 g 250250010070000 Ceftriaxone, Rocephin Adv 1 g 250250011140000
Cefamandole, Mandol 1 g 250250010080000 Ceftriaxone, Rocephin Adv 2 g 250250011150000
Cefamandole, Mandol 2 g 250250010090000 Ceftriaxone, Rocephin Intravenous Premix 1 g 250250011160000
Cefamandole, Mandol 500 mg 250250010100000 Ceftriaxone, Rocephin Intravenous Premix 2 g 250250011170000
Cefazolin, Ancef Adv 1 g 250250010110000 Ceftriaxone, Rocephin 1 g 250250011180000
Cefazolin, Ancef Adv 500 mg 250250010120000 Ceftriaxone, Rocephin 2 g 250250011190000
Cefazolin, Ancef 1 g 250250010130000 Ceftriaxone, Rocephin 10 g 250250011200000
Cefazolin, Ancef 250 mg 250250010140000 Ceftriaxone, Rocephin 1 g 250250011210000
Cefazolin, Ancef 2 g 250250010150000 Ceftriaxone, Rocephin 250 mg 250250011220000
Cefazolin, Ancef 500 mg 250250010160000 Ceftriaxone, Rocephin 2 g 250250011230000
Cefazolin, Ancef 10 g 250250010170000 Ceftriaxone, Rocephin 500 mg 250250011240000
Cefazolin, Ancef 1 g 250250010180000 Cefuroxime, Zinacef Adv 1.5 g 250250011320000
Cefazolin, Ancef 20 g 250250010190000 Cefuroxime, Zinacef Adv 750 mg 250250011330000
Cefazolin, Ancef 250 mg 250250010200000 Cefuroxime, Zinacef 1.5 g 250250011340000
Cefazolin, Ancef 2 g 250250010210000 Cefuroxime, Zinacef 750 mg 250250011350000
Cefazolin, Ancef 500 mg 250250010220000 Cefuroxime, Zinacef 1.5 g 250250011360000
Cefepime, Maxipime 1 g 250250010270000 Cefuroxime, Zinacef 750 mg 250250011370000
Cefepime, Maxipime 2 g 250250010280000 Cephalothin, Keflin Intravenous Premix 1 g 250250011490000
Cefepime, Maxipime 500 mg 250250010290000 Cephalothin, Keflin Intravenous Premix 2 g 250250011500000
Cefepime, Maxipime 1 g 250250010300000 Cephalothin, Keflin 1 g 250250011510000
Cefepime, Maxipime 2 g 250250010310000 Cephalothin, Keflin 2 g 250250011520000
Cefepime, Maxipime 500 mg 250250010320000 Cephalothin, Keflin 1 g 250250011530000
Cefonicid, Monocid 1 g 250250010390000 Cephalothin, Keflin 20 g 250250011540000
Cefonicid, Monocid 10 g 250250010400000 Cephalothin, Keflin 2 g 250250011550000
Cefonicid, Monocid 1 g 250250010410000 Cephapirin, Cefadyl 1 g 250250011560000
Cefonicid, Monocid 500 mg 250250010420000 Cephapirin, Cefadyl 20 g 250250011570000
Cefoperazone, Cefobid Intravenous Premix 1 g 250250010430000 Cephapirin, Cefadyl 2 g 250250011580000
Cefoperazone, Cefobid Intravenous Premix 2 g 250250010440000 Cephapirin, Cefadyl 4 g 250250011590000
Cefoperazone, Cefobid 1 g 250250010450000 Cephapirin, Cefadyl 500 mg 250250011600000
Cefoperazone, Cefobid 2 g 250250010460000 Cephapirin, Cefadyl 10 g 250250011610000
Cefoperazone, Cefobid 3 g 250250010470000 Cephapirin, Cefadyl 1 g 250250011620000
Cefoperazone, Cefobid 1 g 250250010480000 Cephapirin, Cefadyl 20 g 250250011630000
(continued) (continued)

7.e5 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

Table III. Continued Table III. Continued

Premier standard Premier standard
Premier antibiotic names charge codes Premier antibiotic names charge codes

Cephapirin, Cefadyl 2 g 250250011640000 Mezlocillin, Mezlin 1 g 250250042900000

Cephapirin, Cefadyl 4 g 250250011650000 Mezlocillin, Mezlin 20 g 250250042910000
Cephapirin, Cefadyl 500 mg 250250011660000 Mezlocillin, Mezlin 2 g 250250042920000
Cephradine, Velosef 2 g 250250011690000 Mezlocillin, Mezlin 3 g 250250042930000
Cephradine, Velosef 1 g 250250011760000 Mezlocillin, Mezlin 4 g 250250042940000
Cephradine, Velosef 250 mg 250250011770000 Minocycline, Minocin 100 mg 250250043430000
Cephradine, Velosef 500 mg 250250011780000 Nafcillin, Nallpen 1 g 250250045320000
Chloramphen, Chloromycetin 1 g 250250012290000 Nafcillin, Nallpen 2 g 250250045330000
Ciprofloxacin, Cipro Intravenous Premix 200 mg 250250013620000 Nafcillin, Nallpen 500 mg 250250045340000
Ciprofloxacin, Cipro Intravenous Premix 400 mg 250250013630000 Nafcillin, Nallpen 10 g 250250045360000
Ciprofloxacin, Cipro 200 mg 20 mL 250250013680000 Nafcillin, Nallpen 1 g 250250045370000
Ciprofloxacin, Cipro 400 mg 40 mL 250250013690000 Nafcillin, Nallpen 2 g 250250045380000
Clindamycin, Cleocin 150 mg 250250014050000 Nafcillin, Nallpen 500 mg 250250045390000
Clindamycin, Cleocin 300 mg 250250014060000 Neomycin Inj 500 mg 250250046380000
Clindamycin, Cleocin 600 mg 250250014070000 Netilmicin, Netromycin 100 mg/mL 1.5 mL 250250046630000
Clindamycin, Cleocin 900 mg 250250014080000 Ofloxacin, Floxin Intravenous Premix 200 mg 250250048320000
Clindamycin, Cleocin 150 mg/mL 2 mL 250250014170000 Ofloxacin, Floxin Intravenous Premix 400 mg 250250048330000
Clindamycin, Cleocin 150 mg/mL 4 mL 250250014180000 Ofloxacin, Floxin 200 mg 250250048370000
Clindamycin, Cleocin 150 mg/mL 60 mL 250250014190000 Ofloxacin, Floxin 400 mg 250250048380000
Clindamycin, Cleocin 150 mg/mL 6 mL 250250014200000 Oxacillin, Bactocill Adv 1 g 250250048710000
Colistimethate Na, Coly-Mycin M 150 mg 250250015320000 Oxacillin, Bactocill Adv 2 g 250250048720000
Doxycycline, Vibramycin 200 mg 250250020760000 Oxacillin, Bactocill 1 g 250250048750000
Doxycycline, Vibramycin 100 mg 250250020840000 Oxacillin, Bactocill 2 g 250250048760000
Doxycycline, Vibramycin 100 mg 250250020910000 Oxacillin, Bactocill 10 g 250250048790000
Doxycycline, Vibramycin 200 mg 250250020920000 Oxacillin, Bactocill 1 g 250250048800000
Gentamicin, Garamycin Inj 100 mg 250250028490000 Oxacillin, Bactocill 250 mg 250250048810000
Gentamicin, Garamycin Inj 60 mg 250250028500000 Oxacillin, Bactocill 2 g 250250048820000
Gentamicin, Garamycin Inj 80 mg 250250028510000 Oxacillin, Bactocill 4 g 250250048830000
Gentamicin, Garamycin Intrathecal 4 mg 250250028520000 Oxacillin, Bactocill 500 mg 250250048840000
Gentamicin, Garamycin 100 mg 250250028530000 Oxytetracycline, Terramycin 100 mg 250250049250000
Gentamicin, Garamycin 120 mg 250250028540000 Oxytetracycline, Terramycin 250 mg 250250049260000
Gentamicin, Garamycin 20 mg 250250028550000 Pcn G Benz, Bicillin La Inj 1.2 mU 2 mL 250250049750000
Gentamicin, Garamycin 40 mg 250250028560000 Pcn G Benz, Bicillin La Inj 2.4 mU 4 mL 250250049760000
Gentamicin, Garamycin 60 mg 250250028570000 Pcn G Benz, Bicillin La Inj 600 000 units 1 mL 250250049770000
Gentamicin, Garamycin 80 mg 250250028580000 Pcn G Benz, Bicillin La 300 000 units/mL 10 mL 250250049780000
Gentamicin, Garamycin 90 mg 250250028590000 Pcn G Benz/Proc, Bicillin Cr Inj 1.2 mU 2 mL 250250049790000
Gentamicin, Garamycin Ped 10 mg/mL 2 mL 250250028600000 Pcn G Benz/Proc, Bicillin Cr Inj 2.4 mU 4 mL 250250049800000
Gentamicin, Garamycin 40 mg/mL 1 mL 250250028610000 Pcn G Benz/Proc, Bicillin Cr Inj 600 000 units 1 mL 250250049810000
Gentamicin, Garamycin 40 mg/mL 20 mL 250250028620000 Pcn G Benz/Proc, Bicillin Cr Inj 900 000 units/300 000 units 250250049820000
Gentamicin, Garamycin 40 mg/mL 2 mL 250250028630000 Pcn G Benz/Proc, Bicillin Cr 300 000 units/mL 250250049830000
Gatifloxacin, Tequin 200 mg 250250028790000 Pcn G Na 5 mU 250250049840000
Gatifloxacin, Tequin 400 mg 250250029230000 Pcn G Pot 1 mU 250250049920000
Gatifloxacin, Tequin Intravenous Premix 400 mg 250250029240000 Pcn G Pot 2 mU 250250049930000
Gatifloxacin, Tequin Intravenous Premix 200 mg 250250029260000 Pcn G Pot 3 mU 250250049940000
Imipenem, Primaxin 1 g 250250032840000 Pcn G Pot 10 mU 250250049950000
Imipenem, Primaxin 250 mg 250250032990000 Pcn G Pot 1 mU 250250049960000
Imipenem, Primaxin 500 mg 250250033000000 Pcn G Pot 2.5 mU 250250049970000
Imipenem, Primaxin 1 g 250250033010000 Pcn G Pot 20 mU 250250049980000
Imipenem, Primaxin 250 mg 250250033020000 Pcn G Pot 2 mU 250250049990000
Imipenem, Primaxin 500 mg 250250033030000 Pcn G Pot 3 mU 250250050000000
Imipenem, Primaxin 750 mg 250250033040000 Pcn G Pot 5 mU 250250050010000
Levofloxacin, Levaquin 250 mg 250250037000000 Pcn G Proc, Wycillin Inj 1.2 mU 2 mL 250250050020000
Levofloxacin, Levaquin 500 mg 250250037010000 Pcn G Proc, Wycillin Inj 2.4 mU 4 mL 250250050030000
Levofloxacin, Levaquin 500 mg 250250037040000 Pcn G Proc, Wycillin Inj 600 000 units/mL 1 mL 250250050040000
Meropenem, Merrem 1 g 250250040800000 Pcn G Proc, Wycillin 300 000 units/mL 10 mL 250250050050000
Meropenem, Merrem 500 mg 250250040810000 Pcn G Proc, Wycillin 500 000 units/mL 12 mL 250250050060000
Meropenem, Merrem 1 g 250250040820000 Pcn G Proc, Wycillin/Prob Pkt 2.4 mU/500 mg 250250050070000
Meropenem, Merrem 500 mg 250250040830000 Pcn G Pot 5 mU 250250050280000
Methicillin, Staphcillin 1 g 250250041470000 Pentamidine, Pentam 300 mg 250250050300000
Methicillin, Staphcillin 10 g 250250041480000 Piperacillin/Tazo, Zosyn 36/4.5 g 250250051310000
Methicillin, Staphcillin 1 g 250250041490000 Piperacillin/Tazo, Zosyn 36/4.5 g 250250051320000
Methicillin, Staphcillin 4 g 250250041500000 Piperacillin, Pipracil Adv 2 g 250250052520000
Methicillin, Staphcillin 6 g 250250041510000 Piperacillin, Pipracil Adv 3 g 250250052530000
Metronidazole, Flagyl 1 g 250250042720000 Piperacillin, Pipracil Adv 4 g 250250052540000
Metronidazole, Flagyl 500 mg 250250042730000 Piperacillin, Pipracil 2 g 250250052550000
Metronidazole, Flagyl 500 mg 250250042740000 Piperacillin, Pipracil 3 g 250250052560000
Metronidazole, Flagyl Rtu 500 mg 100 mL 250250042750000 Piperacillin, Pipracil 4 g 250250052570000
Mezlocillin, Mezlin Adv 3 g 250250042850000 Piperacillin, Pipracil 2 g 250250052580000
Mezlocillin, Mezlin Adv 4 g 250250042860000 Piperacillin, Pipracil 3 g 250250052590000
Mezlocillin, Mezlin 2 g 250250042870000 Piperacillin, Pipracil 40 g 250250052600000
Mezlocillin, Mezlin 3 g 250250042880000 Piperacillin, Pipracil 4 g 250250052610000
Mezlocillin, Mezlin 4 g 250250042890000 Piperacillin/Tazo, Zosyn 2/0.25 g 250250052620000
(continued) (continued)

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 7.e6

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Table III. Continued Table IV. Patient characteristics in full cohort before
Premier standard matching
Premier antibiotic names charge codes
LR group† NS group‡
Piperacillin/Tazo, Zosyn 3/0.375 g 250250052630000 Variables* n = 2150 n = 10 379 P value§
Piperacillin/Tazo, Zosyn 4/0.5 g 250250052640000
Piperacillin/Tazo, Zosyn 4/0.5 g 250250052860000 Age (y), median (IQR) 8 (1-15) 5 (1-13) <.001
Piperacillin/Tazo, Zosyn 3/0.375 g 250250052870000 Male sex 1136 (53) 5521 (53) .78
Piperacillin/Tazo, Zosyn 2/0.25 g 250250052890000 Race/Ethnicity .09
Quinupristin/Dalfopristin, Synercid 500 mg 10 mL 250250056410000 White 1004 (47) 4991 (48)
Ticar/Clav Pot, Timentin Adv 3.1 g 250250062680000 Black 456 (21) 2245 (22)
Ticar/Clav Pot, Timentin Intravenous Premix 3.1 g 250250062690000 Hispanic 252 (12) 1028 (10)
Ticar/Clav Pot, Timentin 3.1 g 250250062700000 Other 438 (20) 2115 (20)
Ticar/Clav Pot, Timentin 3.1 g 250250062710000 Comorbid conditions¶
Ticarcillin, Ticar Adv 3 g 250250062720000 Cardiovascular 371 (17) 1568 (15) .01
Ticarcillin, Ticar 3 g 250250062730000 Respiratory 79 (4) 505 (5) .02
Ticarcillin, Ticar 1 g 250250062740000 Renal 44 (2) 185 (2) .43
Ticarcillin, Ticar 20 g 250250062750000 Gastrointestinal 63 (3) 251 (2) .17
Ticarcillin, Ticar 30 g 250250062760000 Malignancy 191 (9) 1144 (11) <.001
Ticarcillin, Ticar 3 g 250250062770000 Hematologic/immunologic 121 (6) 671 (6) .16
Ticarcillin, Ticar 6 g 250250062780000
Metabolic 121 (6) 603 (6) .01
Tmp-Smz, Bactrim 10 mL 250250063080000
Neuromuscular 406 (19) 1366 (23) .08
Tmp-Smz, Bactrim 20 mL 250250063090000
Tmp-Smz, Bactrim 30 mL 250250063100000
Congenital disorders 211 (10) 923 (9) <.001
Tmp-Smz, Bactrim 50 mL 250250063110000 PICU admission 1761 (82) 7594 (73) <.001
Tmp-Smz, Bactrim 5 mL 250250063120000 Sepsis-related therapies**
Tmp-Smz, Bactrim Adv 10 mL 250250063130000 Vasoactive infusion 904 (42) 3416 (33) <.001
Tmp-Smz, Bactrim Adv 5 mL 250250063140000 Maximum number of 2 (1-3) 2 (1-2) .05
Tobramycin, Nebcin Inj 40 mg/mL 1.5 mL 250250063150000 concurrent vasoactives††
Tobramycin, Nebcin Inj 40 mg/mL 2 mL 250250063160000 Noninvasive mechanical 189 (9) 816 (8) .15
Tobramycin, Nebcin 100 mg 250250063170000 ventilation
Tobramycin, Nebcin 120 mg 250250063180000 Invasive mechanical ventilation 1419 (66) 5902 (57) <.001
Tobramycin, Nebcin 20 mg 250250063190000 Corticosteroids 567 (26) 2617 (25) .26
Tobramycin, Nebcin 40 mg 250250063200000 Hydrocortisone 235 (11) 1075 (10) .44
Tobramycin, Nebcin 60 mg 250250063210000 Methylprednisolone 404 (19) 1792 (17) .09
Tobramycin, Nebcin 80 mg 250250063220000 Albumin 5% 461 (21) 1690 (16) <.001
Tobramycin, Nebcin Pwdr 1.2 g 250250063230000 Albumin 25% 627 (29) 1981 (19) <.001
Tobramycin, Nebcin 10 mg/mL 2 mL 250250063240000 Blood transfusion‡‡ 1020 (47) 3653 (35) <.001
Tobramycin, Nebcin 10 mg/mL 6 mL 250250063250000
Furosemide 975 (45) 3846 (37) <.001
Tobramycin, Nebcin 10 mg/mL 8 mL 250250063260000
ECMO 12 (<1) 37 (<1) .18
Tobramycin, Nebcin 40 mg/mL 1 mL 250250063270000
Tobramycin, Nebcin 40 mg/mL 2 mL 250250063280000
ECMO, extracorporeal membrane oxygenation.
Tobramycin, Nebcin 40 mg/mL 30 mL 250250063290000 *Data presented as n (%), unless noted.
Trimetrexate, Neutrexin 25 mg 5 mL 250250065010000 †LR group included all patients who received any amount of LR fluid resuscitation.
Trovafloxacin, Trovan 5 mg/mL 40 mL 250250065370000 ‡NS group included patients who received only NS fluid resuscitation.
Trovafloxacin, Trovan 5 mg/mL 60 mL 250250065380000 §Statistical comparison using Wilcoxon signed rank and McNemar test for matched pairs, as
Trovafloxacin, Trovan 200 mg 250250065410000 appropriate.
Trovafloxacin, Trovan 300 mg 250250065420000 ¶Comorbid conditions were categorized using ICD-9-CM codes defining pediatric complex chronic
Vancomycin, Vancocin Adv 1 g 250250065800000 conditions.19
Vancomycin, Vancocin Adv 500 mg 250250065810000 **Includes therapies administered through hospital day 3.
Vancomycin, Vancocin 1 g 250250065840000 ††Includes only patients who received at least one vasoactive infusion.
Vancomycin, Vancocin 250 mg 250250065850000 ‡‡Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryo-
Vancomycin, Vancocin 500 mg 250250065860000 precipitate.
Vancomycin, Vancocin 750 mg 250250065870000
Vancomycin, Vancocin 10 g 250250065930000
Vancomycin, Vancocin 1 g 250250065940000
Vancomycin, Vancocin 500 mg 250250065950000
Vancomycin, Vancocin 5 g 250250065960000
Linezolid, Zyvox 200 mg 250250073350000
Linezolid, Zyvox 400 mg 250250073360000
Linezolid, Zyvox 600 mg 250250073370000
Moxifloxacin, Avelox 400 mg 250250100010000
Ertapenem, Invanz 1 g 250250100400000
Daptomycin, Cubicin 250 mg 250250103650000
Daptomycin, Cubicin 500 mg 250250103660000
Levofloxacin, Levaquin 750 mg 250250103790000
Levofloxacin, Levaquin 750 mg 250250104050000
Levofloxacin, Levaquin 250 mg 250250108380000
Doripenem, Doribax 500 mg 250250108640000
Ceftaroline, Teflaro 400 mg 250250110450000
Ceftaroline, Teflaro 600 mg 250250110460000
Telavancin, Vibativ 250 mg 250250111670000
Telavancin, Vibativ 750 mg 250250111680000

7.e7 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

Table VI. Estimated 50th percentile weight for age

50th percentile weight (kg)
Ages (y) Male Female
0 to <1 8 7.5
1 to <2 11.5 11
2 to <3 13 12.5
3 to <4 15 14
4 to <5 17 16
5 to <6 19 19
6 to <7 21 21
7 to <8 23 24
8 to <9 26 27
9 to <10 29 31
10 to <11 34 35
11 to <12 38 39
12 to <13 42 43
13 to <14 48 48
14 to <15 53 51
15 to <16 58 53
16 to <17 62 55
17 to 18 66 56

Source: http://www.cdc.gov/growthcharts.

Table VIII. Sensitivity analyses for LOS in matched cohort

LR-any group† NS group‡ Risk ratio/difference
Outcomes* (n = 2117) (n = 2117) (95% CI) P value§
¶
PICU LOS, death recorded as maximum 9.6 (2.0, 16.0) 9.3 (1.0, 16.0) 0.3 (−0.1, 0.7) .25
PICU LOS, death recorded as 30 d** 9.6 (2.0, 16.0) 9.3 (1.0, 16.0) 0.3 (−0.1, 0.6) .18
Hospital LOS, death recorded as maximum¶ 17.8 (7.0, 27.0) 16.1 (5.0, 25.0) 1.7 (1.1, 2.3) <.001
Hospital LOS, death recorded as 30 d** 15.9 (7.0, 27.0) 14.4 (5.0, 25.0) 1.5 (1.0, 2.0) <.001

*Data presented as median days (IQR).

†LR group included patients who received any amount of LR fluid resuscitation.
‡NS group included patients who received only NS fluid resuscitation.
§Statistical comparison using Wilcoxon sign rank test.
¶LOS was set to the sample maximum for all nonsurvivors.
**LOS was set to 30 days for all nonsurvivors.

Table IX. Outcomes in matched cohort stratified by criteria used to identify severe sepsis/septic shock
Risk ratio/difference
Outcomes* LR-any group† NS group‡ (95% CI) P-value§
All patients with ICD-9-CM codes for severe sepsis or septic shock¶
Mortality, 30-d 57 (13.8) 68 (16.4) 0.97 (0.92, 1.03) .16
Mortality, hospital 66 (15.9) 78 (18.8) 0.97 (0.91, 1.03) .15
Mortality, including hospice 68 (16.4) 82 (19.8) 0.96 (0.90, 1.02) .12
AKI 125 (30.1) 122 (29.4) 1.0 (0.92, 1.10) .60
New dialysis 8 (1.9) 16 (3.9) 0.98 (0.96, 1.00) .07
PICU LOS**, median (IQR) 8.5 (2.0, 14.5) 8.6 (2.0,15.0) −0.05 (−1.2, 1.1) .95
Hospital LOS**, median (IQR) 14.8 (6.0, 22.0) 13.9 (5.0, 22.0) 0.88 (−0.6, 2.4) .34
Only patients with ICD-9-CM codes for infection and organ dysfunction
Mortality, 30-d 96 (5.6) 100 (5.9) 1.0 (1.47, 2.81) .41
Mortality, hospital 128 (7.5) 121 (7.1) 1.0 (0.99, 1.02) .71
Mortality, including hospice 132 (7.8) 129 (7.6) 1.0 (0.98, 1.02) .61
AKI 209 (12) 215 (13) 1.0 (0.97, 1.02) .40
New dialysis 19 (1.1) 17 (1.0) 1.0 (0.99, 1.01) .75
PICU LOS**, median (IQR) 7.5 (1.0, 13.0) 6.9 (1.0, 12.0) 0.6 (0.1, 1.1) .04
Hospital LOS**, median (IQR) 14.9 (6.0, 22.0) 12.8 (4.0, 20.0) 2.1 (1.5, 2.8) <.001

*Data presented as median (IQR).

†LR group included patients who received any amount of LR fluid resuscitation.
‡NS group included patients who received only NS fluid resuscitation.
§Statistical comparison using McNemar test for matched pairs or Wilcoxon sign rank test, as appropriate.
¶Includes all patients with had ICD-9-CM codes for severe sepsis/septic shock with or without concurrent combination codes for infection and organ dysfunction.
**LOS is reported in days.

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 7.e8

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Table X. Patient characteristics by quartile of total crystalloid volume corrected for estimated weight
Quartile 1 Quartile 2 Quartile 3 Quartile 4
Variables* (n = 2816) (n = 3300) (n = 3212) (n = 3201) P-value†
Total crystalloid volume range, mL/kg 2 to 13 13.1 to 23.5 23.6 to 45.5 45.6 to 550
Age (y), median (IQR) 13 (8-16) 7 (1-14) 5 (1-13) 1 (0-4) <.001
Male sex 1434 (51) 1761 (53) 1740 (54) 1722 (54) .06
Race/ethnicity <.001
White 1470 (52) 1604 (49) 1490 (46) 1432 (45)
Black 587 (21) 68 (21) 691 (22) 735 (23)
Hispanic 249 (9) 348 (11) 354 (11) 329 (10)
Other 510 (18) 660 (20) 329 (10) 706 (22)
Comorbid conditions‡
Cardiovascular 272 (10) 430 (13) 496 (15) 741 (23) <.001
Respiratory 79 (3) 148 (4) 144 (4) 213 (7) <.001
Renal 49 (2) 59 (2) 65 (2) 56 (2) .81
Gastrointestinal 80 (3) 74 (2) 60 (2) 100 (3) .006
Malignancy 375 (13) 391 (12) 336 (10) 233 (7) <.001
Hematologic/Immunologic 237 (8) 218 (7) 194 (6) 143 (4) <.001
Metabolic 173 (6) 166 (5) 177 (6) 208 (7) .06
Neuromuscular 747 (27) 761 (23) 640 (20) 624 (19) <.001
Congenital disorders 300 (11) 286 (9) 276 (9) 272 (9) .01
PICU admission 1764 (63) 2322 (70) 2470 (77) 2799 (87) <.001
Sepsis-related therapies§
Vasoactive infusion 687 (24) 958 (29) 1115 (35) 1560 (48) <.001
Max number of concurrent vasoactives¶ 1 (1-2) 1 (1-2) 2 (1-2) 2 (1-3) <.001
Noninvasive mechanical ventilation 227 (8) 275 (8) 263 (8) 240 (8) .63
Invasive mechanical ventilation 1212 (43) 1721 (52) 1902 (59) 2486 (78) <.001
Corticosteroids 624 (22) 792 (24) 839 (26) 929 (29) <.001
Hydrocortisone 245 (9) 303 (9) 332 (10) 430 (13) <.001
Methylprednisolone 431 (15) 566 (17) 598 (19) 601 (19) .001
Albumin 5% 289 (10) 466 (14) 584 (19) 812 (25) <.001
Albumin 25% 335 (12) 542 (16) 676 (21) 1055 (33) <.001
Blood transfusion** 827 (29) 1089 (33) 1192 (37) 1565 (49) <.001
Furosemide 731 (26) 1096 (33) 1298 (40) 1696 (53) <.001
ECMO 7 (<1) 5 (<1) 10 (<1) 27 (<1) <.001

*Data presented as n (%), unless noted.

†Statistical comparison using Kruskal-Wallis and chi-square tests, as appropriate.
‡Comorbid conditions were categorized using ICD-9-CM codes defining pediatric complex chronic conditions.19
§Includes therapies administered through hospital day three.
¶Includes only patients who received at least one vasoactive infusion.
**Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryoprecipitate.

7.e9 Weiss et al

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

2016 ORIGINAL ARTICLES

Table XI. Patient characteristics in LR-any group by proportion of total crystalloid fluids received as LR
1% to ≤25% LR 26% to ≤50% LR 51% to ≤75% LR 76% to <100% LR 100% LR
Variables* (n = 300) (n = 872) (n = 383) (n = 136) (n = 459) P-value†
Age (y), median (IQR) 11 (3-15) 10 (2-15) 8 (1-15) 5 (0-13) 5 (1-13) <.001
Male sex 168 (56) 463 (53) 192 (50) 82 (60) 231 (50) .16
Race/ethnicity .02
White 147 (49) 403 (46) 157 (41) 62 (46) 235 (51)
Black 58 (19) 186 (21) 82 (22) 31 (23) 98 (21)
Hispanic 21 (7) 102 (12) 56 (15) 19 (14) 54 (12)
Other 74 (25) 181 (21) 87 (23) 24 (18) 72 (16)
Comorbid conditions‡
Cardiovascular 56 (19) 156 (18) 61 (16) 26 (19) 72 (16) .69
Respiratory 7 (2) 31 (4) 10 (3) 8 (6) 23 (5) .14
Renal 6 (2) 14 (2) 10 (3) 3 (2) 11 (2) .78
Gastrointestinal 13 (4) 24 (3) 12 (3) 2 (1) 12 (3) .49
Malignancy 26 (9) 80 (9) 46 (12) 8 (6) 31 (7) .07
Hematologic/Immunologic 17 (6) 40 (5) 32 (8) 10 (7) 23 (5) .12
Metabolic 28 (9) 42 (5) 20 (5) 12 (9) 19 (4) .009
Neuromuscular 68 (23) 159 (18) 69 (18) 25 (18) 85 (19) .51
Congenital disorders 32 (11) 94 (11) 32 (8) 18 (13) 35 (8) .17
PICU admission 270 (90) 744 (85) 319 (83) 110 (81) 318 (69) <.001
Sepsis-related therapies§
Vasoactive infusion 166 (55) 417 (48) 164 (43) 53 (39) 104 (23) <.001
Max number of concurrent vasoactives¶ 2 (1-3) 2 (1-3) 1 (1-2) 1 (1-2) 1 (1-2) .004
Noninvasive mechanical ventilation 31 (10) 85 (10) 32 (8) 5 (4) 36 (8) .14
Invasive mechanical ventilation 232 (77) 606 (70) 247 (64) 87 (64) 247 (54) <.001
Corticosteroids 100 (33) 235 (27) 100 (26) 42 (31) 90 (20) .001
Hydrocortisone 54 918) 99 (11) 34 (9) 17 (13) 31 (7) <.001
Methylprednisolone 62 (21) 164 (19) 74 (19) 33 (24) 71 (15) .15
Albumin 5% 77 (26) 235 (27) 80 (21) 25 (18) 44 (10) <.001
Albumin 25% 89 (30) 279 (32) 133 (35) 40 (29) 86 (19) <.001
Blood transfusion** 160 (53) 459 (53) 208 (54) 65 (48) 128 (28) <.001
Furosemide 159 (53) 438 (50) 176 (46) 55 (40) 147 (32) <.001
ECMO 4 (1) 5 (1) 1 (<1) 0 2 (<1) .31

*Data presented as n (%), unless noted.

†Statistical comparison using Kruskal-Wallis and chi-square tests, as appropriate.
‡Comorbid conditions were categorized using ICD-9-CM codes defining pediatric complex chronic conditions.19
§Includes therapies administered through hospital day three.
¶Includes only patients who received at least one vasoactive infusion.
**Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryoprecipitate.

Table XII. Outcomes in LR-any group by proportion of total crystalloid fluids received as LR
Outcomes* 1% to ≤25% LR 26% to ≤50% LR 51% to ≤75% LR 76% to <100% LR 100% LR
n 300 872 383 136 459
Mortality, 30-d 38 (12.7) 67 (7.7) 20 (5.2) 12 (8.8) 23 (5.0)
Mortality, hospital 43 (14.3) 87 (10) 27 (7.0) 16 (11.8) 29 (6.3)
Mortality, including hospice 44 (14.7) 90 (10.3) 28 (7.3) 16 (11.8) 30 (6.5)
AKI 75 (25.0) 145 (16.7) 57 (14.9) 18 (13.2) 45 (9.8)
New dialysis 9 (2.5) 9 (1.0) 3 (<1) 2 (1.5) 5 (1.1)
PICU LOS†, median (IQR) 9.7 (0, 7.0) 8.2 (1.0, 12.0) 7.1 (1, 11.0) 7.7 (3.0, 16.0) 5.8 (0, 9.0)
Hospital LOS†, median (IQR) 15.6 (4.0, 14.0) 16.1 (5.0, 21.0) 16.0 (5.0, 19.0) 14.9 (7.0, 23.0) 11.8 (4, 17)

*Data presented as median (IQR).

†LOS is reported in days.

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study 7.e10

FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017