452222

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 fl resuscitation with LR was not associated with improved outcomes compared with NS
in pediatric sepsis. Although the current practice of NS resuscitation is justifi selective LR use necessitates a pro-
spective trial to defi determine comparative effectiveness among crystalloids. (J Pediatr 2017;182:304-10).
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, lactated Ringer [LR], Hartmann, Plasma-Lyte, Baxter, Deerfield, Illinois)
solutions. Although balanced fluid have a more physiologic electrolyte composition and strong ion
difference closer to plasma than NS, these fl 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 associated with adverse effects on kidney injury, coagulation, and death.9-12 Alternatively,
balanced crystalloids have been associated 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 following LR vs NS resuscitation. Although Carcillo
et al14 demonstrated the impor- tance of early fl 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 From the 1Division of Critical Care Medicine, Department
of Anesthesiology and Critical Care, The Childrens
with dengue fever, patients receiving LR were slower to recover Hospital of Philadelphia, University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA; 2McCourt
from shock compared with NS, but the study was not School of Public Policy and Department of Government,
powered for morbidity or mortality outcomes.15 The largest Georgetown University, Washington, DC; 3Center for
Pediatric Clinical Effectiveness, The Childrens Hospital of
study of fluid resuscitation in children with severe infections Philadelphia, Philadelphia, PA; 4Division of Emergency
Medicine; and 5Division of Infectious Diseases,
restricted crystalloid fluids to NS. Consequently, guidelines for
16
Department of Pediatrics, The Childrens Hospital of
pediatric sepsis are unable to provide evidence-based Philadelphia, University of Pennsylvania Perelman School
of Medicine, Philadelphia, PA
recommendations to choose among available crystalloid Supported by the Department of Anesthesiology and
solutions even despite emerging data questioning the relative Critical Care, Division of Emergency Medicine, and
Center for Pediatric Clinical Effectiveness at The
safety of NS in adults. Because crystalloid fl
6
are so commonly Childrens Hospital of Philadelphia. S.W. receives support
from National Institute of General Medical Sciences
used, even (K23GM110496). F.B. receives support from the Eunice
Kennedy Shriver National Institute of Child Health and
Human Development (K23HD082368). The authors
declare no conflicts of interest.
0022-3476/$ - see front matter. 2016 Elsevier Inc. All rights

reserved.
http://dx.doi.org10.1016/j.jpeds.2016.11.075
AKI Acute kidney injury
ICD-9-CM International Classification of Diseases, Ninth Edition, Clinical Modification
LOS Length of stay
LR Lactated Ringer
NS Normal saline
PICU Pediatric intensive care unit
304
Volume 182 March
2017
a small benefi attributable to type of fl resuscitation could provide a substantial public health impact
with only a minor shift in practice. We, therefore, sought to test the hypothesis that balanced fluid
resuscitation is associated with improved outcomes in pediatric sepsis.
Methods
We conducted a matched retrospective cohort study of pediatric patients <18 years of age with severe
sepsis or septic shock across 382 geographically diverse US hospitals between January 2000 and December
2013. Patients were identified from the Premier Healthcare Database, an administrative database es-
tablished by the Premier healthcare alliance that contains item- ized daily logs of all patient charges. The
Premier Healthcare Database is the largest acute care database in the US with a complete census of all
inpatients from more than 600 hospitals, of which approximately three-quarters are nonteaching
hospitals. Pediatric data is contributed through a combination of community-based and specialty
childrens hospitals. The study was considered exempt from human subjects re- search oversight by
The Childrens Hospital of Philadelphia Institutional Review Board because only deidentifi data were
used.
Eligible patients were <18 years of age, diagnosed with severe sepsis or septic shock, received initial
treatment at the Premier hospital, were not admitted to a neonatal intensive care unit (based on all
patient refined-diagnosis related group codes), and were ordered to receive any combination of NS or LR
fluid boluses during the fi 3 days of hospital admission. To identify severe sepsis and septic shock, we
used previously published combinations of International Classifi ion of Diseases, Ninth Edition, Clinical Modifi
ion (ICD-9-CM) codes for either an invasive infection plus acute organ dysfunction (Tables I and II;
available at www.jpeds.com) or the ICD-9- CM codes for severe sepsis (785.52) or septic shock (995.92).17,18
To increase the likelihood that initial fluid resuscitation was related to sepsis, we restricted inclusion to
patients with blood cultures and broad-spectrum antibiotics (Table III; available at www.jpeds.com)
ordered within the fi 3 hospital days. We excluded patients with unknown hospital disposition at day 30.
Exposure to LR or NS was defined by type and amount of fluid recorded over the first three hospital
days. Only LR or NS ordered as bolus therapy was considered. Because balanced fluids other than LR
(eg, Plasma-Lyte) were rare (0.3%), we limited our analysis to LR and NS. Fluid volumes were billed as
250, 500, or 1000 mL units. Although some patients likely received only a portion of a unit because of
weight-based fluid dosing in pediatrics, we considered the entire unit to have been administered.
Patients were categorized as exposure to only NS (NS group) or to varying amounts LR and NS
(LR-any group), similar to the method- ology published by Raghunathan et al.13 We also performed a
separate analysis of patients who received only NS vs only LR (LR-only group).
Demographics, month/site of admission, comorbid conditions, and intensive care therapies were
obtained from the Premier Healthcare Database. Comorbid conditions were defined using
pediatric complex chronic conditions.19 Thera- pies included use of the following on hospitals days 1,
2, or 3: noninvasive and invasive mechanical ventilation, vasoactive infusions, albumin, blood
products, furosemide, corticosteroids, use of a central venous catheter, arterial line, or bladder catheter,
and extracorporeal membrane oxygenation. Because doses of vasoactive infusions were not available,
we summa- rized this variable as the total number of vasoactive infusions. Blood products were
defi as any combination of red blood cells, platelets, fresh frozen plasma, or cryoprecipitate.
Outcomes
The primary outcome was all-cause 30-day hospital mortality in the NS vs LR-any groups. To increase
the likelihood that death was related to the initial sepsis episode requiring fluid resuscitation, we
censored the primary outcome at 30 days after admission. Secondary outcomes included uncensored
hospital mortality, hospital mortality plus hospice, acute kidney injury (AKI) with and without dialysis,
and pediatric intensive care unit (PICU) and hospital length of stay (LOS). AKI was defi
by the ICD-9-CM code 584.x and AKI with dialysis was defi
as an ICD-9-CM code for AKI (584.x) with either (a) a pro- cedure charge for a dialysis catheter (38.95)
with a charge for dialysis (39.95) or (b) charge codes for dialysis supplies.13 Pa- tients with an ICD-9-CM
code for end-stage renal disease already undergoing dialysis (ICD-9-CM 585.6) were excluded
from the analysis of AKI with or without dialysis. All outcomes were also analyzed separately for patients
in the LR- only group.
Statistical Analyses
Analyses were performed using R 2.13.1 (R Foundation) with mipmatch package 20 and Stata v 12.1
(StataCorp, College Station, Texas). Data are presented as medians (IQR) or pro- portions. We used
mixed integer programming 1:1 matching to minimize the within-pair Mahalanobis distance for key
covariates that were both available within Premier and had a biologically plausible or previously
demonstrated association, including demographics, comorbidities, and therapies, with risk of death.
The Mahalanobis distance is the difference in covariate values for patients in the LR vs NS groups
divided by the covariates SD.21 Unlike propensity scores that can produce stochastic balance,
integer matching ensures a more predictable and precise balance on specific covariates.20 The specifi
patient-level covariates used for matching are listed in Tables IV and V (Table IV; available at
www.jpeds.com). In addition, because LR use was likely to cluster by hospital, we also matched within
site exactly except for hospitals that had
10 patients for which we allowed matching across sites. We also repeated the analysis excluding
hospitals with 10 patients to ensure matching across low-volume hospitals did not impact our fi s.
Because prior studies have demonstrated differences in mortality for patients identifi with specifi
severe sepsis/septic shock ICD-9-CM codes compared with
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THE JOURNAL OF PEDIATRICS Volume
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om for the LR-only group. Stratifying by volume
before matching ensured that matched pairs did
not consist of patients who received substantially
different total volumes of fluid. Finally, one last
match was conducted using only those covariates
unlikely to mediate the effect of fluid type on
outcome, including age, sex, race/ethnicity,
comorbidities, site, season, year, and sepsis
identification strategy. For this final analysis,
therapies that may have occurred following fl
resuscitation were not used in the match.
We tested for differences in outcomes using
McNemar or Wilcoxon sign rank tests for
matched pairs. To assess for potential
confounding because of residual statistical
differences in matching variables between groups,
we used conditional logit regression to adjust for
any covariates that differed between groups at P
< .01.25 For 30-day mortality, we also performed a
Kaplan-Meier analysis to determine if time-to-
death differed between groups. For LOS, we
used the Huber M estimate because of long
tails and permutation distribution to test for
statistical significance.22 Because LOS may be
influenced by survival, we conducted 2 analyses to
determine if LOS was sensitive to vital status.
First, we set LOS to the sample maximum for all
nonsurvivors, and, second, we set LOS to 30 days
for all nonsurvivors.26 To account for the potential
preference of LR utilization in surgical patients,
the primary match and analyses were repeated
after excluding all patients who un- derwent any
surgery based on diagnosis related group codes.
Statistical significance was defined as P < .05.
Results
ECMO, extracorporeal membrane oxygenation.
*Data presented as n (%), unless noted.
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 signed rank and McNemar test for matched pairs, as appropriate.
Comorbid conditions were categorized using ICD-9-CM codes defining pediatric complex chronic conditions.19
**Includes therapies administered through hospital day 3.
Includes only patients who received at least 1 vasoactive infusion.
Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryoprecipitate.
codes for infection plus organ dysfunction,17,18 we used fine balance to match patients by sepsis identifi
strategy. Fine balance ensures matching on one variable without restrict- ing matching on other
variables.22 A similar approach matched patients by year and season.
To assess match quality, we calculated standardized differences for each variable by dividing the mean
difference between matched patients by the pooled SD before matching. We used the benchmark of
<0.10, or less than one-tenth of a SD, as the maximum acceptable standardized difference.23,24
Matching was repeated within quartiles of total crystalloid volume, such that patients in the LR-any
group were matched only to patients in the NS group who received a similar total volume of crystalloid
fl We used sex-specifi 50th percen- tile weight-for-age (Table VI; available at www.jpeds.com) to
estimate age-related differences in volume administration. Next, matching was again repeated after
stratifying patients by proportion of total fluid given as LR, including a separate match
306 Weiss et al
March ORIGINAL ARTICLES
2017
An initial cohort of 12 529 patients met all inclusion/exclusion criteria, including 10 379 ordered for only NS
fl (NS group) and 2150 patients ordered for at least 1 LR fluid bolus (LR- any group) (Figure 1; available
at www.jpeds.com). Only 459 patients received exclusive LR resuscitation (LR-only group). Use of LR
decreased slightly between 2000 and 2005 (31% to 16%) but remained between 14% and 16% through
2013. The median (IQR) volume of total fl resuscitation was 1000 mL (500-2000 mL) and by estimated
weight-for-age was 24 mL/ kg (13-45 mL/kg). Before matching, the LR-any group was older (median 8 vs 5
years, P < .001), received larger crystalloid volumes (median 2000 vs 1000 mL [40 vs 22 mL/kg], P < .001),
was less likely to have malignancies, and more likely to receive intensive care therapies (Table IV).
Unadjusted 30-day hospital mortality was not different between the LR-any (7.4%) and NS (6.9%)
groups (P = .33). However, unadjusted 30- day mortality varied signifi for patients who received only
LR (5.0%), a combination of LR and NS (8.1%), and only NS (6.9%) fluid (P = .04).
A total of 2117 patients who received any LR were matched 1:1 with patients that received only NS on
the variables listed in Table V, as well as site, season, and sepsis identifi strategy. Patient characteristics,
comorbidities, and nonfl therapies were similar after matching (Table V). For several covariates, P
values remained <.05 refl the large sample, but standardized differences were all <.10 in the matched
cohort (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 307
182
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om included in the matched analysis were identified with severe sepsis using ICD-9-CM codes for
tients
infection plus organ dysfunction (80.4%) vs specifi severe sepsis/septic shock codes (19.6%).
LR-Any Matched Analysis

In the matched cohort of 4234 patients, 30-day hospital mortality 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 signifi differences in overall
hospital mortality, hospital mortality 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 fl 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 fi s (Table VIII; available at www.jpeds.com), nor did excluding
Volume-Stratified Analysis
Although mortality rose with increasing weight-adjusted crystalloid fluid volume, 30-day hospital
mortality did not differ between the LR-any and NS groups after matching within volume quartiles
(Figure 4). However, only 142 patients received LR in the fi quartile of total crystalloid fl volume, and
there was an increase in LR utilization with successive
234 matched pairs from hospitals with 10 patients (data not
shown). The Kaplan-Meier analysis demonstrated no differ-

ence in time-to-death between matched groups (log-rank
P = .11) (Figure 3; available at www.jpeds.com).
Patients with specifi ICD-9-CM codes for severe sepsis/ septic shock had higher 30-day hospital
mortality than patients identifi by infection plus organ dysfunction codes (15.0% vs 5.8%, P < .001).
However, there were no differences in outcomes between the matched LR-any and NS groups stratifi
by sepsis identifi strategy except for longer PICU and hospital LOS for the LR group identifi by
combination codes (Table IX; available at www.jpeds.com).
308 Weiss et al
2017
Figure 4. Hospital mortality for LR-any and NS groups matched within quartile of total crystalloid fluid volume. The x-axis cat-
egorizes patients based on quartile of total fl crystalloid volume received after correcting by estimated weight for age
(median total volume in Q1 = 8 mL/kg, Q2 = 17 mL/kg, Q3 = 32 mL/kg, and Q4 = 68 mL/kg). The y-axis shows the ad-
justed 30-day mortality rate. Patients in the LR-any group were matched within volume quartile to patients who received only NS.
There were no signifi differences in mortality between the LR-any and NS groups within any of the total volume quartiles.
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om
quartiles of total volume administration (Q1: 5.0%; Q2: 11.5%; Q3: 20.6%; Q4: 30.2%), supporting the
preferential use of LR in patients who required larger total fluid volumes. In addition, PICU admission
and the use of nonfl intensive therapies were more common in each successive quartile (Table X;
available at www.jpeds.com) making it diffi to disen- tangle proportionate LR use, volume of fl
resuscitation, and illness severity. Finally, matching performed least effectively in the fourth quartile of
patients who received the largest total fl volumes and with the most severe illness severity (Figure 5;
available at www.jpeds.com).
Dose-Response Analysis
To account for variability in the proportionate use of LR, patients were separately matched after
stratifying by proportion of total crystalloid volume ordered as LR. Patients with an increasing
proportionate LR use received fewer intensive therapies and had a lower rate of adverse outcomes (Tables
XI and XII; available at www.jpeds.com). However, there were no differences in 30-day hospital mortality or
AKI (Figure 6; available at www.jpeds.com) or dialysis (data not shown) between the LR groups stratified
by proportionate LR utilization and the NS group.
LR-Only Matched Analysis

In the separate matched cohort of 918 patients receiving either exclusive LR or NS fl 30-day hospital
mortality was 5% in the LR-only group and 4.6% in the NS group (risk ratio 1.01, 95% CI 0.98, 1.03; P =
.69). There were no significant differences in secondary outcomes, except a longer hospital LOS in the
LR-only group (Table VII).
Discussion
In this large matched cohort study of pediatric severe sepsis and septic shock, balanced fl resuscitation
with LR was not associated with improved mortality, AKI, or dialysis, even when matched by fl volume and
proportionate LR utilization. However, LR was preferentially used either as first-line fluid in patients with
lower illness severity or as an adjunctive fl
in patients who received large amounts of fl resuscitation, and the matching algorithm
was least effective in the most severely ill patients who received the largest total fl volumes.
Consequently, the results of our study are best interpreted as establishing the need for and the
equipoise to conduct a prospective randomized trial to definitely address the comparative
effectiveness of balanced fl and NS in pediatric sepsis. Prior data suggest that the supraphysiologic
chloride content of NS may be detrimental to renal function and acid-base balance.1-3,9-11 Infusion of
chloride-rich fl reduced renal blood fl w in dogs and healthy human volunteers to a
greater extent than more balanced fl 27,28 NS also induced abdominal discomfort, drowsiness, and
impaired cognition, compared with LR and other balanced fluids, in a human study.29 In a sequential
period study of critically ill adults, use of chloride-restrictive fluids reduced the odds of AKI and dialy-
sis by almost 50%.11 Infusion of large volumes of chloride-
310 Weiss et al
2017
rich solutions can also cause a hyperchloremic metabolic acidosis, which has been shown to be
proinflammatory.30
Our work builds on previous clinical studies that have over- whelmingly focused on adult populations.
Most studies have demonstrated either no difference31-34 or a benefit of at least some proportion of
resuscitation fl given as balanced solutions.11-13 For example, Raghunathan et a13 found that receipt of at
least some balanced fl during initial resuscitation was associated with lower hospital mortality in
adults with vasopressor-dependent septic shock. This contrast with our results may be attributable
to age-related biological differences, such as a lower rate of baseline subclinical cardiac and renal
disease in children, or methodological differences, such as limiting the adult study to vasopressor-
dependent shock. Unfortunately, insufficient sample size precluded limiting our pediatric analysis to
vasopressor-dependent shock. Moreover, even though Premier offers a geographically diverse sample,
the relatively low median fluid volume resuscitation and mortality <8% suggests an overall moderate
illness severity that may not reflect more severe pediatric sepsis cases that tend to con- centrate at
specialty childrens hospitals. It is also possible that potential detrimental effects of LR, including
microvascular thromboses (because of calcium activating the clotting cascade)9 or cerebral edema
(because of mild fluid hypotonicity),35 may be more problematic in children. For example, in Vietnamese
children with Dengue shock, patients randomized to resuscitation with LR had a longer time to
recovery than patients re- suscitated with NS.15 As with other critical therapies, benefits seen in adult
populations may not translate to children.
Prior studies suggest that potential adverse effects associated with NS are dose-related such that
LR may only be benefi for patients requiring large-volume fl resuscitation.1-3 In our study, mortality
increased with larger fl volumes and decreased with a greater proportion of fluid given as LR, but there
were no differences between LR and NS groups after matching within volume quartiles, by
proportionate LR utilization, or in the separate matched analysis of LR-only patients. However, the
preference for LR as fi fl in patients with low illness severity or as an adjunctive
fluid in patients who received a large amount of total fl could have masked a true benefit of LR.
There are several limitations. First, claims-based data may lead to misclassifi bias if ordered and
administered therapies are discrepant, although this is unlikely to produce differential bias
between groups. Also, we were not able to account for prehospital fl administration, partial
administration of fl units (which is common in pediatrics because of weight- based fl administration),
or account for deviations in weight from published growth curves. Even though this may have over- or
underestimated fluid administration, these are unlikely to have been sources of differential bias
between LR and NS. However, the younger age of the NS-only group (before and after matching)
could have introduced slightly more error in estimated total fluid volumes than in the LR-group
because younger patients are more likely to receive partial administration of a fluid bag and
rounding to median weight repre- sents a larger proportional change relative to true weight.
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om
Second, using ICD-9-CM codes for infection plus organ dysfunction to identify pediatric sepsis is
controversial.17,18,36 Notably, patients with more specific ICD-9-CM sepsis codes had a trend toward
decreased mortality and less dialysis in the LR group. Moreover, because identifi and timing of surgical
interventions is limited using administrative codes, it was difficult to fully account for a possible surgical
preference to use LR. Third, differences in demographics, comorbidities, and intensive therapies indicate
nonrandom selective use of LR over NS. Although statistical matching was able to remove much of these
baseline differences, we cannot rule out residual confounding within unmeasured covariates. In
addition, in the absence of physiologic and laboratory data, we used intensive care therapies for
illness severity but could not determine if these therapies occurred afteror as a result of
differential use of LR vs NS. Because excluding these variables from the match posed risk for increased
confounding, we chose a conservative approach similar to Raghunathan et al13 fluid study in adult sepsis
despite the possibility that matching on these covariates could have masked outcome differences.
However, secondary analyses using patients matched only on covariates unlikely to mediate the effect of
fluid type on outcome also showed no differential effect of LR vs NS. Finally, because LR was the
predominant balanced fl used, our data may not be generalizable to other balanced fluids.
In this large matched observational study, use of LR (alone or in combination with NS) was not
associated with improved outcomes compared with exclusive NS resuscitation in pediatric septic
shock. These fi s support the current practice of using NS as the first choice for crystalloid fluid resus-
citation in pediatric sepsis. However, given the limitations of matching within a retrospective
observational study to fully account for the nonrandom selective use of LR, our findings also
emphasize the need for a large-scale prospective randomized trial to defi ely determine the
comparative effectiveness of balanced fluids and NS in pediatric sepsis.
Submitted for publication Jul 21, 2016; last revision received Sep 28, 2016;
accepted Nov 29, 2016
Reprint requests: Scott L. Weiss, MD, MSCE, Department of Anesthesiology and Critical Care, The Childrens Hospital of Philadelphia, University of Pennsylvania
Perelman School of Medicine, 3401 Civic Center Blvd, 7 South Tower, Room 7C04, Philadelphia, PA 19104. E-mail: WeissS@email.chop.edu
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22. Rosenbaum PR. Sensitivity analysis for m-estimates, tests, and confi dence intervals in matched observational studies.
Biometrics 2007;63:456- 64.
23. Neuman MD, Rosenbaum PR, Ludwig JM, Zubizarreta JR, Silber JH. An- esthesia technique, mortality, and length of stay after hip
fracture surgery. JAMA 2014;311:2508-17.
24. Silber JH, Rosenbaum PR, Trudeau ME, Even-Shoshan O, Chen W, Zhang X, et al. Multivariate matching and bias reduction in
the surgical outcomes study. Med Care 2001;39:1048-64.
25. Pearce N. Analysis of matched case-control studies. BMJ 2016;352:i969.
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26. Lin W, Halpern SD, Prasad Kerlin M, Small DS. A placement of death approach for studies of treatment effects on ICU length of stay.
Stat Methods Med Res 2014 Aug 1; pii: 0962280214545121. [Epub ahead of print].
27. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L
infusions of 0.9% saline and plasma-lyte(R) 148 on renal blood fl w velocity and renal cortical tissue perfusion in healthy
volunteers. Ann Surg 2012;256:18- 24.
28. Wilcox CS. Regulation of renal blood fl w by plasma chloride. J Clin Invest 1983;71:726-35.
29. Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous lactated Ringers solution versus 0.9% sodium
chloride solution on serum osmolality in human volunteers. Anesth Analg 1999;88:999- 1003.
30. Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW
264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004;286:R686-92.
31. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declere AD, et al. Effects of fl resuscitation with colloids vs crystalloids on
mortality in
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critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA 2013;310:1809-17.
32. Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, et al. Fluid type and the use of renal replacement
therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med 2015;41:1561-71.
33. Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox- Robichaud A, et al. Fluid resuscitation in sepsis: a systematic
review and network meta-analysis. Ann Intern Med 2014;161:347-55.
34. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al. Effect of a buffered crystalloid solution vs saline on acute
kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA 2015;314:1701-10.
35. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hypona- tremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol
Renal Physiol 2008;295:F619-24.
36. Balamuth F, Weiss SL, Hall M, Neuman MI, Scott H, Brady PW, et al. Identifying pediatric severe sepsis and septic shock:
accuracy of diagnosis codes. J Pediatr 2015;167:1295-300.
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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.
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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 fi Time
to death was not different between matched patients in the LR-
any and NS groups, log-rank P = .11.
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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 signifi lower 30-day hospital mortality in the LR group within the 26% to 50% strata (*P = .03).
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Table I. ICD-9-CM codes used to identify bacterial or fungal infection
ICD-9-CM
codes* Description
1 Cholera
2 Typhoid/paratyphoid fever
3 Other salmonella infection
4 Shigellosis
5 Other food poisoning
8 Intestinal infection not otherwise classified
9 Ill-defined intestinal infection
10 Primary tuberculosis infection
11 Pulmonary tuberculosis
12 Other respiratory tuberculosis
13 Central nervous system tuberculosis
14 Intestinal tuberculosis
15 Tuberculosis of bone and joint
16 Genitourinary tuberculosis
17 Tuberculosis not otherwise classified
18 Miliary tuberculosis
20 Plague
21 Tularemia
22 Anthrax
23 Brucellosis
24 Glanders
25 Melioidosis
26 Rat-bite fever
27 Other bacterial zoonoses
30 Leprosy
31 Other mycobacterial disease
32 Diphtheria
33 Whooping cough
34 Streptococcal throat/scarlet fever
35 Erysipelas
36 Meningococcal infection
37 Tetanus
38 Septicemia
39 Actinomycotic infections
40 Other bacterial diseases
41 Bacterial infection in other diseases not otherwise specified
90 Congenital syphilis
91 Early symptomatic syphilis
92 Early syphilis latent
93 Cardiovascular syphilis
94 Neurosyphilis
95 Other late symptomatic syphilis
96 Late syphilis latent
97 Other and unspecified syphilis
98 Gonococcal infections
100 Leptospirosis
101 Vincent's angina
102 Yaws
103 Pinta
104 Other spirochetal infection
110 Dermatophytosis
111 Dermatomycosis not otherwise classified or specified
112 Candidiasis
114 Coccidioidomycosis
115 Histoplasmosis
116 Blastomycotic infection
117 Other mycoses
118 Opportunistic mycoses
320 Bacterial meningitis
322 Meningitis, unspecified
324 Central nervous system abscess
325 Phlebitis of intracranial sinus
420 Acute pericarditis
421 Acute or subacute endocarditis
451 Thrombophlebitis
461 Acute sinusitis
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codes*
dysfunction
Description
*Where 3- or 4-digit codes are listed, all associated subcodes were included.
(continued)
*Where 3- or 4-digit codes are listed, all associated subcodes were included.
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Table III. Premier codes for broad-spectrum antibiotics
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Table III. Continued
Premier antibiotic names
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Premier standard charge codes
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Amikacin, Amikin 1 g 250250002200000
Amikacin, Amikin 500 mg 250250002210000
Amikacin, Amikin 250 mg/mL 1 mL 250250002420000
Amp/Sulbac, Unasyn Adv 1.5 g 250250003320000
Amp/Sulbac, Unasyn Adv 3 g 250250003330000
Amp/Sulbac, Unasyn 1.5 g 250250003340000
Amp/Sulbac, Unasyn 3 g 250250003350000
Amp/Sulbac, Unasyn 1.5 g 250250003360000
Amp/Sulbac, Unasyn 3 g 250250003370000
Ampicillin, Omnipen-N Adv 1 g 250250003470000
Ampicillin, Omnipen-N Adv 2 g 250250003480000
Ampicillin, Omnipen-N Adv 500 mg 250250003490000
Ampicillin, Omnipen-N 125 mg 250250003500000
Ampicillin, Omnipen-N 1 g 250250003510000
Azithromycin, Zithromax 500 mg 250250005110000
Aztreonam, Azactam 1 g 250250005250000
Aztreonam, Azactam 500 mg 250250005270000
Aztreonam, Azactam 500 mg 250250005300000
Azithromycin, Zithromax 500 mg 250250005310000
Cefamandole, Mandol Adv 1 g 250250010010000
Cefamandole, Mandol Adv 2 g 250250010020000
Cefamandole, Mandol Intravenous Premix 1 g 250250010030000
Cefamandole, Mandol Intravenous Premix 2 g 250250010040000
Cefamandole, Mandol 1 g 250250010050000
Cefamandole, Mandol 500 mg 250250010100000
Cefazolin, Ancef Adv 1 g 250250010110000
Cefazolin, Ancef Adv 500 mg 250250010120000
Cefazolin, Ancef 1 g 250250010130000
Cefazolin, Ancef 250 mg 250250010140000
Cefepime, Maxipime 1 g 250250010270000
Cefepime, Maxipime 500 mg 250250010290000
Cefepime, Maxipime 500 mg 250250010320000
Cefonicid, Monocid 1 g 250250010390000
Cefonicid, Monocid 500 mg 250250010420000
Cefoperazone, Cefobid Intravenous Premix 1 g 250250010430000
Cefoperazone, Cefobid Intravenous Premix 2 g 250250010440000
Cefoperazone, Cefobid 1 g 250250010450000
(continued)
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Cefotaxime, Claforan Adv 1 g 250250010500000
Cefotaxime, Claforan Adv 2 g 250250010510000
Cefotaxime, Claforan 1 g 250250010520000
Cefotaxime, Claforan 500 mg 250250010570000
Cefotetan, Cefotan 1 g 250250010580000
Cefoxitin, Mefoxin Adv 1 g 250250010630000
Cefoxitin, Mefoxin Adv 2 g 250250010640000
Cefoxitin, Mefoxin Intravenous Premix 1 g 250250010650000
Cefoxitin, Mefoxin Intravenous Premix 2 g 250250010660000
Cefoxitin, Mefoxin 1 g 250250010670000
Ceftazidime, Fortaz Intravenous Premix 1 g 250250010880000
Ceftazidime, Fortaz Intravenous Premix 2 g 250250010890000
Ceftazidime, Fortaz 1 g 250250010900000
Ceftazidime, Fortaz 500 mg 250250010960000
Ceftizoxime, Cefizox Intravenous Premix 1 g 250250011070000
Ceftizoxime, Cefizox Intravenous Premix 2 g 250250011080000
Ceftizoxime, Cefizox 1 g 250250011090000
Ceftizoxime, Cefizox 500 mg 250250011130000
Ceftriaxone, Rocephin Adv 1 g 250250011140000
Ceftriaxone, Rocephin Adv 2 g 250250011150000
Ceftriaxone, Rocephin Intravenous Premix 1 g 250250011160000
Ceftriaxone, Rocephin Intravenous Premix 2 g 250250011170000
Ceftriaxone, Rocephin 1 g 250250011180000
Ceftriaxone, Rocephin 250 mg 250250011220000
Ceftriaxone, Rocephin 500 mg 250250011240000
Cefuroxime, Zinacef Adv 1.5 g 250250011320000
Cefuroxime, Zinacef Adv 750 mg 250250011330000
Cefuroxime, Zinacef 1.5 g 250250011340000
Cefuroxime, Zinacef 750 mg 250250011350000
Cefuroxime, Zinacef 1.5 g 250250011360000
Cefuroxime, Zinacef 750 mg 250250011370000
Cephalothin, Keflin Intravenous Premix 1 g 250250011490000
Cephalothin, Keflin Intravenous Premix 2 g 250250011500000
Cephalothin, Keflin 1 g 250250011510000
Cephapirin, Cefadyl 1 g 250250011560000
Cephapirin, Cefadyl 500 mg 250250011600000
(continued)
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Cephapirin, Cefadyl 500 mg 250250011660000
Cephradine, Velosef 2 g 250250011690000
Cephradine, Velosef 1 g 250250011760000
Cephradine, Velosef 250 mg 250250011770000
Cephradine, Velosef 500 mg 250250011780000
Chloramphen, Chloromycetin 1 g 250250012290000
Ciprofloxacin, Cipro Intravenous Premix 200 mg 250250013620000
Ciprofloxacin, Cipro Intravenous Premix 400 mg 250250013630000
Ciprofloxacin, Cipro 200 mg 20 mL 250250013680000
Ciprofloxacin, Cipro 400 mg 40 mL 250250013690000
Clindamycin, Cleocin 150 mg 250250014050000
Clindamycin, Cleocin 150 mg/mL 2 mL 250250014170000
Colistimethate Na, Coly-Mycin M 150 mg 250250015320000
Doxycycline, Vibramycin 200 mg 250250020760000
Gentamicin, Garamycin Inj 100 mg 250250028490000
Gentamicin, Garamycin Intrathecal 4 mg 250250028520000
Gentamicin, Garamycin 100 mg 250250028530000
Gentamicin, Garamycin Ped 10 mg/mL 2 mL 250250028600000
Gentamicin, Garamycin 40 mg/mL 1 mL 250250028610000
Gatifloxacin, Tequin 200 mg 250250028790000
Gatifloxacin, Tequin 400 mg 250250029230000
Gatifloxacin, Tequin Intravenous Premix 400 mg 250250029240000
Gatifloxacin, Tequin Intravenous Premix 200 mg 250250029260000
Imipenem, Primaxin 1 g 250250032840000
Imipenem, Primaxin 250 mg 250250032990000
Imipenem, Primaxin 1 g 250250033010000
Levofloxacin, Levaquin 250 mg 250250037000000
Meropenem, Merrem 1 g 250250040800000
Meropenem, Merrem 500 mg 250250040810000
Meropenem, Merrem 1 g 250250040820000
Meropenem, Merrem 500 mg 250250040830000
Methicillin, Staphcillin 1 g 250250041470000
Metronidazole, Flagyl 1 g 250250042720000
Metronidazole, Flagyl 500 mg 250250042730000
Metronidazole, Flagyl 500 mg 250250042740000
Metronidazole, Flagyl Rtu 500 mg 100 mL 250250042750000
Mezlocillin, Mezlin Adv 3 g 250250042850000
Mezlocillin, Mezlin Adv 4 g 250250042860000
Mezlocillin, Mezlin 2 g 250250042870000
(continued)
310.e16 Weiss et al
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Minocycline, Minocin 100 mg 250250043430000
Nafcillin, Nallpen 1 g 250250045320000
Nafcillin, Nallpen 500 mg 250250045340000
Nafcillin, Nallpen 500 mg 250250045390000
Neomycin Inj 500 mg 250250046380000
Netilmicin, Netromycin 100 mg/mL 1.5 mL 250250046630000
Ofloxacin, Floxin Intravenous Premix 200 mg 250250048320000
Ofloxacin, Floxin Intravenous Premix 400 mg 250250048330000
Ofloxacin, Floxin 200 mg 250250048370000
Ofloxacin, Floxin 400 mg 250250048380000
Oxacillin, Bactocill Adv 1 g 250250048710000
Oxacillin, Bactocill Adv 2 g 250250048720000
Oxacillin, Bactocill 1 g 250250048750000
Oxacillin, Bactocill 250 mg 250250048810000
Oxacillin, Bactocill 500 mg 250250048840000
Oxytetracycline, Terramycin 100 mg 250250049250000
Oxytetracycline, Terramycin 250 mg 250250049260000
Pcn G Benz, Bicillin La Inj 1.2 mU 2 mL 250250049750000
Pcn G Benz, Bicillin La Inj 2.4 mU 4 mL 250250049760000
Pcn G Benz, Bicillin La Inj 600 000 units 1 mL 250250049770000
Pcn G Benz, Bicillin La 300 000 units/mL 10 mL 250250049780000
Pcn G Benz/Proc, Bicillin Cr Inj 1.2 mU 2 mL 250250049790000
Pcn G Benz/Proc, Bicillin Cr Inj 2.4 mU 4 mL 250250049800000
Pcn G Benz/Proc, Bicillin Cr Inj 600 000 units 1 mL 250250049810000
Pcn G Benz/Proc, Bicillin Cr Inj 900 000 units/300 000 units 250250049820000
Pcn G Benz/Proc, Bicillin Cr 300 000 units/mL 250250049830000
Pcn G Na 5 mU 250250049840000
Pcn G Pot 1 mU 250250049920000
Pcn G Pot 2 mU 250250049930000
Pcn G Pot 3 mU 250250049940000
Pcn G Pot 10 mU 250250049950000
Pcn G Pot 1 mU 250250049960000
Pcn G Pot 2.5 mU 250250049970000
Pcn G Pot 20 mU 250250049980000
Pcn G Pot 2 mU 250250049990000
Pcn G Pot 3 mU 250250050000000
Pcn G Pot 5 mU 250250050010000
Pcn G Proc, Wycillin Inj 1.2 mU 2 mL 250250050020000
Pcn G Proc, Wycillin Inj 2.4 mU 4 mL 250250050030000
Pcn G Proc, Wycillin Inj 600 000 units/mL 1 mL 250250050040000
Pcn G Proc, Wycillin 300 000 units/mL 10 mL 250250050050000
Pcn G Proc, Wycillin 500 000 units/mL 12 mL 250250050060000
Pcn G Proc, Wycillin/Prob Pkt 2.4 mU/500 mg 250250050070000
Pcn G Pot 5 mU 250250050280000
Pentamidine, Pentam 300 mg 250250050300000
Piperacillin/Tazo, Zosyn 36/4.5 g 250250051310000
Piperacillin, Pipracil Adv 2 g 250250052520000
Piperacillin, Pipracil 2 g 250250052550000
(continued)
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310.e18 Weiss et al
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Premier standard matching

Premier antibiotic names charge codes
Piperacillin/Tazo, Zosyn 3/0.375 g 250250052630000 Variables* n = 10 379

Quinupristin/Dalfopristin, Synercid 500 mg 10 mL 250250056410000
Ticar/Clav Pot, Timentin Adv 3.1 g 250250062680000
Ticar/Clav Pot, Timentin Intravenous Premix 3.1 g 250250062690000
Ticar/Clav Pot, Timentin 3.1 g 250250062700000
Ticar/Clav Pot, Timentin 3.1 g 250250062710000
Ticarcillin, Ticar Adv 3 g 250250062720000
Ticarcillin, Ticar 3 g 250250062730000
Tmp-Smz, Bactrim 10 mL 250250063080000
Tmp-Smz, Bactrim Adv 10 mL 250250063130000
Tmp-Smz, Bactrim Adv 5 mL 250250063140000
Tobramycin, Nebcin Inj 40 mg/mL 1.5 mL 250250063150000
Tobramycin, Nebcin Inj 40 mg/mL 2 mL 250250063160000
Tobramycin, Nebcin 100 mg 250250063170000
Tobramycin, Nebcin Pwdr 1.2 g 250250063230000
Tobramycin, Nebcin 10 mg/mL 2 mL 250250063240000
Trimetrexate, Neutrexin 25 mg 5 mL 250250065010000
Trovafloxacin, Trovan 5 mg/mL 40 mL 250250065370000
Trovafloxacin, Trovan 5 mg/mL 60 mL 250250065380000
Trovafloxacin, Trovan 200 mg 250250065410000
Trovafloxacin, Trovan 300 mg 250250065420000
Vancomycin, Vancocin Adv 1 g 250250065800000
Vancomycin, Vancocin Adv 500 mg 250250065810000
Vancomycin, Vancocin 1 g 250250065840000
Vancomycin, Vancocin 250 mg 250250065850000
Linezolid, Zyvox 200 mg 250250073350000
Moxifloxacin, Avelox 400 mg 250250100010000
Ertapenem, Invanz 1 g 250250100400000
Daptomycin, Cubicin 250 mg 250250103650000
Daptomycin, Cubicin 500 mg 250250103660000
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
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ECMO, extracorporeal membrane oxygenation.

LR group included all patients who received any amount of LR fluid resuscitation.
Statistical comparison using Wilcoxon signed rank and McNemar test for matched pairs, as appropriate.
**Includes therapies administered through hospital day 3.
Includes only patients who received at least one vasoactive infusion.
Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryoprecipitate.
310.e20 Weiss et al
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Source: http://www.cdc.gov/growthcharts.
Table VIII. Sensitivity analyses for LOS in matched cohort

LR-any group
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NS group
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Risk ratio/difference
Outcomes*
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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).
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
All patients with ICD-9-CM codes for severe sepsis or septic shock
310.e26 Weiss et al
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(95% CI) P-value
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).
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.
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Variables*
<.001
<.001
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
Statistical comparison using Kruskal-Wallis and chi-square tests, as appropriate.
Includes therapies administered through hospital day three.
**Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryoprecipitate.
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Variables*
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

Statistical comparison using Kruskal-Wallis and chi-square tests, as appropriate.
Includes therapies administered through hospital day three.
**Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryoprecipitate.
*Data presented as median (IQR).

LOS is reported in days.
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Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A

Matched Retrospective Cohort Study

0022-3476/$ - see front matter. 2016 Elsevier Inc. All rights

LR-Any Matched Analysis

shown). The Kaplan-Meier analysis demonstrated no differ-

LR-Only Matched Analysis

Figure 3. Kaplan-Meier survival to hospital discharge through

Premier antibiotic names

Premier antibiotic names

Premier standard matching

Piperacillin/Tazo, Zosyn 3/0.375 g 250250052630000 Variables* n = 10 379

ECMO, extracorporeal membrane oxygenation.

Table VIII. Sensitivity analyses for LOS in matched cohort

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

*Data presented as median (IQR).

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