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

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 hospital 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 malignancies 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 hospital 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 prospective 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, 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 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 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 importance 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 From the 1Division of Critical Care Medicine, Department with dengue fever, patients receiving LR were slower to recover from shock comof Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia, University of Pennsylvania pared with NS, but the study was not powered for morbidity or mortality Perelman School of Medicine, Philadelphia, PA; 2McCourt outcomes.15 The largest study of fluid resuscitation in children with severe infecSchool 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 Philadelphia, Philadelphia, PA; 4Division of Emergency sepsis are unable to provide evidence-based recommendations to choose among Medicine; and 5Division of Infectious Diseases, available crystalloid solutions even despite emerging data questioning the relaDepartment 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

AKI ICD-9-CM LOS LR NS PICU

Acute kidney injury International Classification of Diseases, Ninth Edition, Clinical Modification Length of stay Lactated Ringer Normal saline Pediatric intensive care unit

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 (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

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THE JOURNAL OF PEDIATRICS • www.jpeds.com a small benefit attributable to type of fluid 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 established by the Premier healthcare alliance that contains itemized 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 children’s hospitals. The study was considered exempt from human subjects research oversight by The Children’s Hospital of Philadelphia Institutional Review Board because only deidentified 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 first 3 days of hospital admission. To identify severe sepsis and septic shock, we used previously published combinations of International Classification of Diseases, Ninth Edition, Clinical Modification (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-9CM 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 first 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 methodology published by Raghunathan et al.13 We also performed a separate analysis of patients who received only NS vs only LR (LR-only group).

Volume ■■ 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 Therapies 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 summarized this variable as the total number of vasoactive infusions. Blood products were defined 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 defined by the ICD-9-CM code 584.x and AKI with dialysis was defined as an ICD-9-CM code for AKI (584.x) with either (a) a procedure charge for a dialysis catheter (38.95) with a charge for dialysis (39.95) or (b) charge codes for dialysis supplies.13 Patients 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 LRonly group. Statistical Analyses Analyses were performed using R 2.13.1 (R Foundation) with mipmatch package20 and Stata v 12.1 (StataCorp, College Station, Texas). Data are presented as medians (IQR) or proportions. 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 specific 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 findings. Because prior studies have demonstrated differences in mortality for patients identified with specific severe sepsis/septic shock ICD-9-CM codes compared with

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2016

Table V. Patient characteristics in matched cohort Variables* Age (y), median (IQR) Male sex Race/ethnicity White Black Hispanic Other Comorbid conditions¶ Cardiovascular Respiratory Renal Gastrointestinal Malignancy Hematologic/immunologic Metabolic Neuromuscular Congenital disorders PICU admission Sepsis-related therapies** Vasoactive infusion Maximum number of concurrent vasoactives†† Noninvasive mechanical ventilation Invasive mechanical ventilation Corticosteroids Hydrocortisone Methylprednisolone Albumin 5% Albumin 25% Blood transfusion‡‡ Furosemide ECMO

LR-any group† N = 2117

NS group‡ N = 2117

8 (1-15) 1119 (53)

7 (1-14) 1149 (54)

983 451 249 434

(46) (21) (12) (21)

1021 466 218 412

(48) (22) (10) (19)

362 78 42 62 187 116 120 394 203 1729

(17) (4) (2) (3) (9) (5) (6) (19) (10) (82)

312 51 29 50 186 97 105 377 164 1664

(15) (2) (1) (2) (9) (5) (5) (18) (8) (79)

P value§ .01 .37 .31

.04 .02 .15 .29 1.0 .21 .34 .52 .04 .01

880 (42) 2 (1-3)

824 (39) 2 (1-3)

.08 .09

181 (9)

157 (7)

.19

1389 551 230 390 446 609 995 947 12

(66) (26) (11) (18) (21) (29) (47) (45) (<1)

1347 488 203 347 409 552 933 910 8

(64) (23) (10) (16) (19) (26) (44) (43) (<1)

.19 .02 .19 .09 .16 .05 .06 .25 .50

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 identification strategy. Fine balance ensures matching on one variable without restricting 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 fluid. We used sex-specific 50th percentile 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

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 fluid 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 underwent any surgery based on diagnosis related group codes. Statistical significance was defined as P < .05.

Results An initial cohort of 12 529 patients met all inclusion/exclusion criteria, including 10 379 ordered for only NS fluid (NS group) and 2150 patients ordered for at least 1 LR fluid bolus (LRany 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 fluid 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 30day mortality varied significantly 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 identification strategy. Patient characteristics, comorbidities, and nonfluid therapies were similar after matching (Table V). For several covariates, P values remained <.05 reflecting the large sample, but standardized differences were all <.10 in the matched cohort (Figure 2; available at www.jpeds.com). The majority of pa-

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Volume ■■

Table VII. Outcomes in matched cohorts for LR-any and LR-only groups Outcomes*

LR-any group† (n = 2117)

Mortality, 30-d Mortality, hospital Mortality, including hospice AKI New dialysis PICU LOS¶, median (IQR) Hospital LOS¶, median (IQR)

153 194 200 334 27 7.8 15.5

Outcomes*

LR-only group** (n = 459)

Mortality, 30-d Mortality, hospital Mortality, including hospice AKI New dialysis PICU LOS¶, median (IQR) Hospital LOS¶, median (IQR)

23 29 30 45 5 5.8 11.9

(7.2) (9.2) (9.4) (15.8) (1.3) (1.0, 13.0) (6.0, 22.0)

(5.0) (6.3) (6.5) (9.8) (1.1) (1.0, 10.0) (5.0, 18.0)

NS group‡ (n = 2117) 168 199 211 337 33 7.3 13.1

(7.9) (9.4) (10.0) (15.9) (1.6) (1.0, 12.0) (4.0, 20.0)

NS group‡ (n = 459) 21 28 29 49 5 5.5 10.5

(4.6) (6.1) (6.3) (10.7) (1.1) (1.0, 9.0) (4.0, 14.0)

Risk ratio/difference (95% CI) 0.99 1.0 0.99 1.0 1.0 0.5 2.4

(0.9, 1.09) (0.98, 1.02) (0.98, 1.01) (0.97, 1.02) (0.99, 1.00) (0.2, 0.8) (1.4, 5.0)

Risk ratio/difference (95% CI) 1.01 1.0 1.0 0.99 1.0 0.33 1.35

(0.98, 1.03) (0.97, 1.03) (0.97, 1.03) (0.95, 1.03) (0.99, 1.01) (-0.1, 0.7) (0.5, 2.2)

P value§ .20 .41 .29 .41 .21 .01 <.001 P value§ .69 .62 .62 .32 .50 .27 .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 severe sepsis using ICD-9-CM codes for infection plus organ dysfunction (80.4%) vs specific 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 significant 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 multivariable 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 difference in time-to-death between matched groups (log-rank P = .11) (Figure 3; available at www.jpeds.com). Patients with specific ICD-9-CM codes for severe sepsis/ septic shock had higher 30-day hospital mortality than patients identified 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 stratified by sepsis identification strategy except for longer PICU and hospital LOS for the LR group identified by combination codes (Table IX; available at www.jpeds.com).

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 first quartile of total crystalloid fluid volume, and there was an increase in LR utilization with successive

Figure 4. Hospital mortality for LR-any and NS groups matched within quartile of total crystalloid fluid volume. The x-axis categorizes patients based on quartile of total fluid 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 adjusted 30-day mortality rate. Patients in the LR-any group were matched within volume quartile to patients who received only NS. There were no significant differences in mortality between the LR-any and NS groups within any of the total volume quartiles.

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2016 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 nonfluid intensive therapies were more common in each successive quartile (Table X; available at www.jpeds.com) making it difficult to disentangle proportionate LR use, volume of fluid resuscitation, and illness severity. Finally, matching performed least effectively in the fourth quartile of patients who received the largest total fluid 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 fluid, 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 fluid resuscitation with LR was not associated with improved mortality, AKI, or dialysis, even when matched by fluid 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 fluid in patients who received large amounts of fluid resuscitation, and the matching algorithm was least effective in the most severely ill patients who received the largest total fluid 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 fluids 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 fluids reduced renal blood flow in dogs and healthy human volunteers to a greater extent than more balanced fluids.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 dialysis by almost 50%.11 Infusion of large volumes of chloride-

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 overwhelmingly focused on adult populations. Most studies have demonstrated either no difference31-34 or a benefit of at least some proportion of resuscitation fluids given as balanced solutions.11-13 For example, Raghunathan et a13 found that receipt of at least some balanced fluids 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 concentrate at specialty children’s 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 resuscitated 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 beneficial for patients requiring large-volume fluid resuscitation.1-3 In our study, mortality increased with larger fluid 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 first-line fluid in patients with low illness severity or as an adjunctive fluid in patients who received a large amount of total fluid could have masked a true benefit of LR. There are several limitations. First, claims-based data may lead to misclassification 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 fluid administration, partial administration of fluid units (which is common in pediatrics because of weightbased fluid administration), or account for deviations in weight from published growth curves. Even though this may have overor 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 represents a larger proportional change relative to true weight.

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THE JOURNAL OF PEDIATRICS • www.jpeds.com 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 identification 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 after—or 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 fluid 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 findings support the current practice of using NS as the first choice for crystalloid fluid resuscitation 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 definitely 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 Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3401 Civic Center Blvd, 7 South Tower, Room 7C04, Philadelphia, PA 19104. E-mail: [email protected]

References 1. Karakala N, Raghunathan K, Shaw AD. Intravenous fluids in sepsis: what to use and what to avoid. Curr Opin Crit Care 2013;19:537-43. 2. Santi M, Lava SA, Camozzi P, Giannini O, Milani GP, Simonetti GD, et al. The great fluid debate: saline or so-called “balanced” salt solutions? Ital J Pediatr 2015;41:47. 3. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med 2013;369:1243-51. 4. Boulain T, Boisrame-Helms J, Ehrmann S, Lascarrou JB, Bougle A, Chiche A, et al. Volume expansion in the first 4 days of shock: a prospective multicentre study in 19 French intensive care units. Intensive Care Med 2015;41:248-56. 5. Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, et al. Fluid challenges in intensive care: the FENICE study: a global inception cohort study. Intensive Care Med 2015;41:1529-37.

Volume ■■ 6. Brierley J, Carcillo JA, Choong K, Cornell T, Decaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009;37:666-88. 7. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580637. 8. Ventura AM, Shieh HH, Bousso A, Goes PF, de Cassia FOFI, de Souza DC, et al. Double-blind prospective randomized controlled trial of dopamine versus epinephrine as first-line vasoactive drugs in pediatric septic shock. Crit Care Med 2015;43:2292-302. 9. Kiraly LN, Differding JA, Enomoto TM, Sawai RS, Muller PJ, Diggs B, et al. Resuscitation with normal saline (NS) vs. lactated ringers (LR) modulates hypercoagulability and leads to increased blood loss in an uncontrolled hemorrhagic shock swine model. J Trauma 2006;61:57-64, discussion -5. 10. Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Crit Care Med 2014;42:e2708. 11. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566-72. 12. Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg 2012;255:821-9. 13. Raghunathan K, Shaw A, Nathanson B, Sturmer T, Brookhart A, Stefan MS, et al. Association between the choice of IV crystalloid and inhospital mortality among critically ill adults with sepsis. Crit Care Med 2014;42:1585-91. 14. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid resuscitation in pediatric septic shock. JAMA 1991;266:1242-5. 15. Ngo NT, Cao XT, Kneen R, Wills B, Nguyen VM, Nguyen TQ, et al. Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001;32:204-13. 16. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483-95. 17. Balamuth F, Weiss SL, Neuman MI, Scott H, Brady PW, Paul R, et al. Pediatric severe sepsis in U.S. children’s hospitals. Pediatr Crit Care Med 2014;15:798-805. 18. Weiss SL, Parker B, Bullock ME, Swartz S, Price C, Wainwright MS, et al. Defining pediatric sepsis by different criteria: discrepancies in populations and implications for clinical practice. Pediatr Crit Care Med 2012;13:e219-26. 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: E99. 20. Zubizarreta JR. Using mixed integer programming for matching in an observational study of kidney failure after surgery. J Am Stat Assoc 2012;107:1360-71. 21. Rubin DB. Bias reduction using Mahalanobis-metric matching. Biometrics 1980;36:293-8. 22. Rosenbaum PR. Sensitivity analysis for m-estimates, tests, and confidence intervals in matched observational studies. Biometrics 2007;63:45664. 23. Neuman MD, Rosenbaum PR, Ludwig JM, Zubizarreta JR, Silber JH. Anesthesia 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.

6

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2016 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 flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012;256:1824. 28. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983;71:726-35. 29. Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg 1999;88:9991003. 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 fluid resuscitation with colloids vs crystalloids on mortality in

32.

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36.

critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA 2013;310:1809-17. 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. Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, FoxRobichaud A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med 2014;161:347-55. 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. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Renal Physiol 2008;295:F619-24. 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 difference 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 LRany and NS groups, log-rank P = .11. Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

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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 acceptable 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 received 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

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

Table I. Continued

ICD-9-CM codes*

ICD-9-CM codes*

001 002 003 004 005 008 009 010 011 012 013 014 015 016 017 018 020 021 022 023 024 025 026 027 030 031 032 033 034 035 036 037 038 039 040 041 090 091 092 093 094 095 096 097 098 100 101 102 103 104 110 111 112 114 115 116 117 118 320 322 324 325 420 421 451 461

Description Cholera Typhoid/paratyphoid fever Other salmonella infection Shigellosis Other food poisoning Intestinal infection not otherwise classified Ill-defined intestinal infection Primary tuberculosis infection Pulmonary tuberculosis Other respiratory tuberculosis Central nervous system tuberculosis Intestinal tuberculosis Tuberculosis of bone and joint Genitourinary tuberculosis Tuberculosis not otherwise classified Miliary tuberculosis Plague Tularemia Anthrax Brucellosis Glanders Melioidosis Rat-bite fever Other bacterial zoonoses Leprosy Other mycobacterial disease Diphtheria Whooping cough Streptococcal throat/scarlet fever Erysipelas Meningococcal infection Tetanus Septicemia Actinomycotic infections Other bacterial diseases Bacterial infection in other diseases not otherwise specified Congenital syphilis Early symptomatic syphilis Early syphilis latent Cardiovascular syphilis Neurosyphilis Other late symptomatic syphilis Late syphilis latent Other and unspecified syphilis Gonococcal infections Leptospirosis Vincent's angina Yaws Pinta Other spirochetal infection Dermatophytosis Dermatomycosis not otherwise classified or specified Candidiasis Coccidioidomycosis Histoplasmosis Blastomycotic infection Other mycoses Opportunistic mycoses Bacterial meningitis Meningitis, unspecified Central nervous system abscess Phlebitis of intracranial sinus Acute pericarditis Acute or subacute endocarditis Thrombophlebitis Acute sinusitis (continued)

462 463 464 465 481 482 485 486 491.21 494 510 513 540 541 542 562.01 562.03 562.11 562.13 556 567 569.5 569.83 572 572.1 575.0 590 597 599.0 601 614 615 616 681 682 683 686 711.0 730 790.7 996.6 998.5 999.3

Description Acute pharyngitis Acute tonsillitis Acute laryngitis/tracheitis Acute upper respiratory infection of multiple sites/not otherwise specified Pneumococcal pneumonia Other bacterial pneumonia Bronchopneumonia with organism not otherwise specified Pneumonia, organism not otherwise specified Acute exacerbation of obstructive chronic bronchitis Bronchiectasis Empyema Lung/mediastinum abscess Acute appendicitis Appendicitis not otherwise specified Other appendicitis Diverticulitis of small intestine without hemorrhage Diverticulitis of small intestine with hemorrhage Diverticulitis of colon without hemorrhage Diverticulitis of colon with hemorrhage Anal and rectal abscess Peritonitis Intestinal abscess Perforation of intestine Abscess of liver Portal pyemia Acute cholecystitis Kidney infection Urethritis/urethral syndrome Urinary tract infection not otherwise specified Prostatic inflammation Female pelvic inflammation disease Uterine inflammatory disease Other female genital inflammation Cellulitis, finger/toe Other cellulitis or abscess Acute lymphadenitis Other local skin infection Pyogenic arthritis Osteomyelitis Bacteremia Infection or inflammation of device/graft Postoperative infection Infectious complication of medical care not otherwise classified

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

Table II. ICD-9-CM codes used to identify acute organ dysfunction ICD-9-CM codes* 785.5 458 96.7 348.3 293 348.1 287.4 287.5 286.9 286.6 570 573.4 584

Description Shock without trauma Hypotension Mechanical ventilation Encephalopathy Transient organic psychosis Anoxic brain damage Secondary thrombocytopenia Thrombocytopenia, unspecified Other/unspecified coagulation defect Defibrination syndrome Acute and subacute necrosis of liver Hepatic infarction Acute renal failure

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

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THE JOURNAL OF PEDIATRICS • www.jpeds.com Table III. Premier codes for broad-spectrum antibiotics

Volume ■■

Table III. Continued

Premier antibiotic names

Premier standard charge codes

Premier antibiotic names

Premier standard charge codes

Amikacin, Amikin 1 g Amikacin, Amikin 500 mg Amikacin, Amikin 250 mg/mL 1 mL Amikacin, Amikin 250 mg/mL 2 mL Amikacin, Amikin 250 mg/mL 4 mL Amikacin, Amikin 50 mg/mL 2 mL Amp/Sulbac, Unasyn Adv 1.5 g Amp/Sulbac, Unasyn Adv 3 g Amp/Sulbac, Unasyn 1.5 g Amp/Sulbac, Unasyn 3 g Amp/Sulbac, Unasyn 1.5 g Amp/Sulbac, Unasyn 3 g Ampicillin, Omnipen-N Adv 1 g Ampicillin, Omnipen-N Adv 2 g Ampicillin, Omnipen-N Adv 500 mg Ampicillin, Omnipen-N 125 mg Ampicillin, Omnipen-N 1 g Ampicillin, Omnipen-N 250 mg Ampicillin, Omnipen-N 2 g Ampicillin, Omnipen-N 500 mg Ampicillin, Omnipen-N 10 g Ampicillin, Omnipen-N 125 mg Ampicillin, Omnipen-N 1 g Ampicillin, Omnipen-N 250 mg Ampicillin, Omnipen-N 2 g Ampicillin, Omnipen-N 500 mg Azithromycin, Zithromax 500 mg Aztreonam, Azactam 1 g Aztreonam, Azactam 2 g Aztreonam, Azactam 500 mg Aztreonam, Azactam 1 g Aztreonam, Azactam 2 g Aztreonam, Azactam 500 mg Azithromycin, Zithromax 500 mg Cefamandole, Mandol Adv 1 g Cefamandole, Mandol Adv 2 g Cefamandole, Mandol Intravenous Premix 1 g Cefamandole, Mandol Intravenous Premix 2 g Cefamandole, Mandol 1 g Cefamandole, Mandol 2 g Cefamandole, Mandol 10 g Cefamandole, Mandol 1 g Cefamandole, Mandol 2 g Cefamandole, Mandol 500 mg Cefazolin, Ancef Adv 1 g Cefazolin, Ancef Adv 500 mg Cefazolin, Ancef 1 g Cefazolin, Ancef 250 mg Cefazolin, Ancef 2 g Cefazolin, Ancef 500 mg Cefazolin, Ancef 10 g Cefazolin, Ancef 1 g Cefazolin, Ancef 20 g Cefazolin, Ancef 250 mg Cefazolin, Ancef 2 g Cefazolin, Ancef 500 mg Cefepime, Maxipime 1 g Cefepime, Maxipime 2 g Cefepime, Maxipime 500 mg Cefepime, Maxipime 1 g Cefepime, Maxipime 2 g Cefepime, Maxipime 500 mg Cefonicid, Monocid 1 g Cefonicid, Monocid 10 g Cefonicid, Monocid 1 g Cefonicid, Monocid 500 mg Cefoperazone, Cefobid Intravenous Premix 1 g Cefoperazone, Cefobid Intravenous Premix 2 g Cefoperazone, Cefobid 1 g Cefoperazone, Cefobid 2 g Cefoperazone, Cefobid 3 g Cefoperazone, Cefobid 1 g

250250002200000 250250002210000 250250002420000 250250002430000 250250002440000 250250002450000 250250003320000 250250003330000 250250003340000 250250003350000 250250003360000 250250003370000 250250003470000 250250003480000 250250003490000 250250003500000 250250003510000 250250003520000 250250003530000 250250003540000 250250003550000 250250003560000 250250003570000 250250003580000 250250003590000 250250003600000 250250005110000 250250005250000 250250005260000 250250005270000 250250005280000 250250005290000 250250005300000 250250005310000 250250010010000 250250010020000 250250010030000 250250010040000 250250010050000 250250010060000 250250010070000 250250010080000 250250010090000 250250010100000 250250010110000 250250010120000 250250010130000 250250010140000 250250010150000 250250010160000 250250010170000 250250010180000 250250010190000 250250010200000 250250010210000 250250010220000 250250010270000 250250010280000 250250010290000 250250010300000 250250010310000 250250010320000 250250010390000 250250010400000 250250010410000 250250010420000 250250010430000 250250010440000 250250010450000 250250010460000 250250010470000 250250010480000

Cefoperazone, Cefobid 2 g Cefotaxime, Claforan Adv 1 g Cefotaxime, Claforan Adv 2 g Cefotaxime, Claforan 1 g Cefotaxime, Claforan 2 g Cefotaxime, Claforan 10 g Cefotaxime, Claforan 1 g Cefotaxime, Claforan 2 g Cefotaxime, Claforan 500 mg Cefotetan, Cefotan 1 g Cefotetan, Cefotan 2 g Cefotetan, Cefotan 10 g Cefotetan, Cefotan 1 g Cefotetan, Cefotan 2 g Cefoxitin, Mefoxin Adv 1 g Cefoxitin, Mefoxin Adv 2 g Cefoxitin, Mefoxin Intravenous Premix 1 g Cefoxitin, Mefoxin Intravenous Premix 2 g Cefoxitin, Mefoxin 1 g Cefoxitin, Mefoxin 2 g Cefoxitin, Mefoxin 10 g Cefoxitin, Mefoxin 1 g Cefoxitin, Mefoxin 2 g Ceftazidime, Fortaz Intravenous Premix 1 g Ceftazidime, Fortaz Intravenous Premix 2 g Ceftazidime, Fortaz 1 g Ceftazidime, Fortaz 2 g Ceftazidime, Fortaz 3 g Ceftazidime, Fortaz 10 g Ceftazidime, Fortaz 1 g Ceftazidime, Fortaz 2 g Ceftazidime, Fortaz 500 mg Ceftazidime, Fortaz 6 g Ceftizoxime, Cefizox Intravenous Premix 1 g Ceftizoxime, Cefizox Intravenous Premix 2 g Ceftizoxime, Cefizox 1 g Ceftizoxime, Cefizox 2 g Ceftizoxime, Cefizox 1 g Ceftizoxime, Cefizox 2 g Ceftizoxime, Cefizox 500 mg Ceftriaxone, Rocephin Adv 1 g Ceftriaxone, Rocephin Adv 2 g Ceftriaxone, Rocephin Intravenous Premix 1 g Ceftriaxone, Rocephin Intravenous Premix 2 g Ceftriaxone, Rocephin 1 g Ceftriaxone, Rocephin 2 g Ceftriaxone, Rocephin 10 g Ceftriaxone, Rocephin 1 g Ceftriaxone, Rocephin 250 mg Ceftriaxone, Rocephin 2 g Ceftriaxone, Rocephin 500 mg Cefuroxime, Zinacef Adv 1.5 g Cefuroxime, Zinacef Adv 750 mg Cefuroxime, Zinacef 1.5 g Cefuroxime, Zinacef 750 mg Cefuroxime, Zinacef 1.5 g Cefuroxime, Zinacef 750 mg Cephalothin, Keflin Intravenous Premix 1 g Cephalothin, Keflin Intravenous Premix 2 g Cephalothin, Keflin 1 g Cephalothin, Keflin 2 g Cephalothin, Keflin 1 g Cephalothin, Keflin 20 g Cephalothin, Keflin 2 g Cephapirin, Cefadyl 1 g Cephapirin, Cefadyl 20 g Cephapirin, Cefadyl 2 g Cephapirin, Cefadyl 4 g Cephapirin, Cefadyl 500 mg Cephapirin, Cefadyl 10 g Cephapirin, Cefadyl 1 g Cephapirin, Cefadyl 20 g

250250010490000 250250010500000 250250010510000 250250010520000 250250010530000 250250010540000 250250010550000 250250010560000 250250010570000 250250010580000 250250010590000 250250010600000 250250010610000 250250010620000 250250010630000 250250010640000 250250010650000 250250010660000 250250010670000 250250010680000 250250010690000 250250010700000 250250010710000 250250010880000 250250010890000 250250010900000 250250010910000 250250010920000 250250010930000 250250010940000 250250010950000 250250010960000 250250010970000 250250011070000 250250011080000 250250011090000 250250011100000 250250011110000 250250011120000 250250011130000 250250011140000 250250011150000 250250011160000 250250011170000 250250011180000 250250011190000 250250011200000 250250011210000 250250011220000 250250011230000 250250011240000 250250011320000 250250011330000 250250011340000 250250011350000 250250011360000 250250011370000 250250011490000 250250011500000 250250011510000 250250011520000 250250011530000 250250011540000 250250011550000 250250011560000 250250011570000 250250011580000 250250011590000 250250011600000 250250011610000 250250011620000 250250011630000

(continued)

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(continued)

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Table III. Continued

Table III. Continued

Premier antibiotic names

Premier standard charge codes

Premier antibiotic names

Premier standard charge codes

Cephapirin, Cefadyl 2 g Cephapirin, Cefadyl 4 g Cephapirin, Cefadyl 500 mg Cephradine, Velosef 2 g Cephradine, Velosef 1 g Cephradine, Velosef 250 mg Cephradine, Velosef 500 mg Chloramphen, Chloromycetin 1 g Ciprofloxacin, Cipro Intravenous Premix 200 mg Ciprofloxacin, Cipro Intravenous Premix 400 mg Ciprofloxacin, Cipro 200 mg 20 mL Ciprofloxacin, Cipro 400 mg 40 mL Clindamycin, Cleocin 150 mg Clindamycin, Cleocin 300 mg Clindamycin, Cleocin 600 mg Clindamycin, Cleocin 900 mg Clindamycin, Cleocin 150 mg/mL 2 mL Clindamycin, Cleocin 150 mg/mL 4 mL Clindamycin, Cleocin 150 mg/mL 60 mL Clindamycin, Cleocin 150 mg/mL 6 mL Colistimethate Na, Coly-Mycin M 150 mg Doxycycline, Vibramycin 200 mg Doxycycline, Vibramycin 100 mg Doxycycline, Vibramycin 100 mg Doxycycline, Vibramycin 200 mg Gentamicin, Garamycin Inj 100 mg Gentamicin, Garamycin Inj 60 mg Gentamicin, Garamycin Inj 80 mg Gentamicin, Garamycin Intrathecal 4 mg Gentamicin, Garamycin 100 mg Gentamicin, Garamycin 120 mg Gentamicin, Garamycin 20 mg Gentamicin, Garamycin 40 mg Gentamicin, Garamycin 60 mg Gentamicin, Garamycin 80 mg Gentamicin, Garamycin 90 mg Gentamicin, Garamycin Ped 10 mg/mL 2 mL Gentamicin, Garamycin 40 mg/mL 1 mL Gentamicin, Garamycin 40 mg/mL 20 mL Gentamicin, Garamycin 40 mg/mL 2 mL Gatifloxacin, Tequin 200 mg Gatifloxacin, Tequin 400 mg Gatifloxacin, Tequin Intravenous Premix 400 mg Gatifloxacin, Tequin Intravenous Premix 200 mg Imipenem, Primaxin 1 g Imipenem, Primaxin 250 mg Imipenem, Primaxin 500 mg Imipenem, Primaxin 1 g Imipenem, Primaxin 250 mg Imipenem, Primaxin 500 mg Imipenem, Primaxin 750 mg Levofloxacin, Levaquin 250 mg Levofloxacin, Levaquin 500 mg Levofloxacin, Levaquin 500 mg Meropenem, Merrem 1 g Meropenem, Merrem 500 mg Meropenem, Merrem 1 g Meropenem, Merrem 500 mg Methicillin, Staphcillin 1 g Methicillin, Staphcillin 10 g Methicillin, Staphcillin 1 g Methicillin, Staphcillin 4 g Methicillin, Staphcillin 6 g Metronidazole, Flagyl 1 g Metronidazole, Flagyl 500 mg Metronidazole, Flagyl 500 mg Metronidazole, Flagyl Rtu 500 mg 100 mL Mezlocillin, Mezlin Adv 3 g Mezlocillin, Mezlin Adv 4 g Mezlocillin, Mezlin 2 g Mezlocillin, Mezlin 3 g Mezlocillin, Mezlin 4 g

250250011640000 250250011650000 250250011660000 250250011690000 250250011760000 250250011770000 250250011780000 250250012290000 250250013620000 250250013630000 250250013680000 250250013690000 250250014050000 250250014060000 250250014070000 250250014080000 250250014170000 250250014180000 250250014190000 250250014200000 250250015320000 250250020760000 250250020840000 250250020910000 250250020920000 250250028490000 250250028500000 250250028510000 250250028520000 250250028530000 250250028540000 250250028550000 250250028560000 250250028570000 250250028580000 250250028590000 250250028600000 250250028610000 250250028620000 250250028630000 250250028790000 250250029230000 250250029240000 250250029260000 250250032840000 250250032990000 250250033000000 250250033010000 250250033020000 250250033030000 250250033040000 250250037000000 250250037010000 250250037040000 250250040800000 250250040810000 250250040820000 250250040830000 250250041470000 250250041480000 250250041490000 250250041500000 250250041510000 250250042720000 250250042730000 250250042740000 250250042750000 250250042850000 250250042860000 250250042870000 250250042880000 250250042890000

Mezlocillin, Mezlin 1 g Mezlocillin, Mezlin 20 g Mezlocillin, Mezlin 2 g Mezlocillin, Mezlin 3 g Mezlocillin, Mezlin 4 g Minocycline, Minocin 100 mg Nafcillin, Nallpen 1 g Nafcillin, Nallpen 2 g Nafcillin, Nallpen 500 mg Nafcillin, Nallpen 10 g Nafcillin, Nallpen 1 g Nafcillin, Nallpen 2 g Nafcillin, Nallpen 500 mg Neomycin Inj 500 mg Netilmicin, Netromycin 100 mg/mL 1.5 mL Ofloxacin, Floxin Intravenous Premix 200 mg Ofloxacin, Floxin Intravenous Premix 400 mg Ofloxacin, Floxin 200 mg Ofloxacin, Floxin 400 mg Oxacillin, Bactocill Adv 1 g Oxacillin, Bactocill Adv 2 g Oxacillin, Bactocill 1 g Oxacillin, Bactocill 2 g Oxacillin, Bactocill 10 g Oxacillin, Bactocill 1 g Oxacillin, Bactocill 250 mg Oxacillin, Bactocill 2 g Oxacillin, Bactocill 4 g Oxacillin, Bactocill 500 mg Oxytetracycline, Terramycin 100 mg Oxytetracycline, Terramycin 250 mg Pcn G Benz, Bicillin La Inj 1.2 mU 2 mL Pcn G Benz, Bicillin La Inj 2.4 mU 4 mL Pcn G Benz, Bicillin La Inj 600 000 units 1 mL Pcn G Benz, Bicillin La 300 000 units/mL 10 mL Pcn G Benz/Proc, Bicillin Cr Inj 1.2 mU 2 mL Pcn G Benz/Proc, Bicillin Cr Inj 2.4 mU 4 mL Pcn G Benz/Proc, Bicillin Cr Inj 600 000 units 1 mL Pcn G Benz/Proc, Bicillin Cr Inj 900 000 units/300 000 units Pcn G Benz/Proc, Bicillin Cr 300 000 units/mL Pcn G Na 5 mU Pcn G Pot 1 mU Pcn G Pot 2 mU Pcn G Pot 3 mU Pcn G Pot 10 mU Pcn G Pot 1 mU Pcn G Pot 2.5 mU Pcn G Pot 20 mU Pcn G Pot 2 mU Pcn G Pot 3 mU Pcn G Pot 5 mU Pcn G Proc, Wycillin Inj 1.2 mU 2 mL Pcn G Proc, Wycillin Inj 2.4 mU 4 mL Pcn G Proc, Wycillin Inj 600 000 units/mL 1 mL Pcn G Proc, Wycillin 300 000 units/mL 10 mL Pcn G Proc, Wycillin 500 000 units/mL 12 mL Pcn G Proc, Wycillin/Prob Pkt 2.4 mU/500 mg Pcn G Pot 5 mU Pentamidine, Pentam 300 mg Piperacillin/Tazo, Zosyn 36/4.5 g Piperacillin/Tazo, Zosyn 36/4.5 g Piperacillin, Pipracil Adv 2 g Piperacillin, Pipracil Adv 3 g Piperacillin, Pipracil Adv 4 g Piperacillin, Pipracil 2 g Piperacillin, Pipracil 3 g Piperacillin, Pipracil 4 g Piperacillin, Pipracil 2 g Piperacillin, Pipracil 3 g Piperacillin, Pipracil 40 g Piperacillin, Pipracil 4 g Piperacillin/Tazo, Zosyn 2/0.25 g

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(continued)

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

(continued)

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THE JOURNAL OF PEDIATRICS • www.jpeds.com Table III. Continued Premier antibiotic names

Premier standard charge codes

Piperacillin/Tazo, Zosyn 3/0.375 g Piperacillin/Tazo, Zosyn 4/0.5 g Piperacillin/Tazo, Zosyn 4/0.5 g Piperacillin/Tazo, Zosyn 3/0.375 g Piperacillin/Tazo, Zosyn 2/0.25 g Quinupristin/Dalfopristin, Synercid 500 mg 10 mL Ticar/Clav Pot, Timentin Adv 3.1 g Ticar/Clav Pot, Timentin Intravenous Premix 3.1 g Ticar/Clav Pot, Timentin 3.1 g Ticar/Clav Pot, Timentin 3.1 g Ticarcillin, Ticar Adv 3 g Ticarcillin, Ticar 3 g Ticarcillin, Ticar 1 g Ticarcillin, Ticar 20 g Ticarcillin, Ticar 30 g Ticarcillin, Ticar 3 g Ticarcillin, Ticar 6 g Tmp-Smz, Bactrim 10 mL Tmp-Smz, Bactrim 20 mL Tmp-Smz, Bactrim 30 mL Tmp-Smz, Bactrim 50 mL Tmp-Smz, Bactrim 5 mL Tmp-Smz, Bactrim Adv 10 mL Tmp-Smz, Bactrim Adv 5 mL Tobramycin, Nebcin Inj 40 mg/mL 1.5 mL Tobramycin, Nebcin Inj 40 mg/mL 2 mL Tobramycin, Nebcin 100 mg Tobramycin, Nebcin 120 mg Tobramycin, Nebcin 20 mg Tobramycin, Nebcin 40 mg Tobramycin, Nebcin 60 mg Tobramycin, Nebcin 80 mg Tobramycin, Nebcin Pwdr 1.2 g Tobramycin, Nebcin 10 mg/mL 2 mL Tobramycin, Nebcin 10 mg/mL 6 mL Tobramycin, Nebcin 10 mg/mL 8 mL Tobramycin, Nebcin 40 mg/mL 1 mL Tobramycin, Nebcin 40 mg/mL 2 mL Tobramycin, Nebcin 40 mg/mL 30 mL Trimetrexate, Neutrexin 25 mg 5 mL Trovafloxacin, Trovan 5 mg/mL 40 mL Trovafloxacin, Trovan 5 mg/mL 60 mL Trovafloxacin, Trovan 200 mg Trovafloxacin, Trovan 300 mg Vancomycin, Vancocin Adv 1 g Vancomycin, Vancocin Adv 500 mg Vancomycin, Vancocin 1 g Vancomycin, Vancocin 250 mg Vancomycin, Vancocin 500 mg Vancomycin, Vancocin 750 mg Vancomycin, Vancocin 10 g Vancomycin, Vancocin 1 g Vancomycin, Vancocin 500 mg Vancomycin, Vancocin 5 g Linezolid, Zyvox 200 mg Linezolid, Zyvox 400 mg Linezolid, Zyvox 600 mg Moxifloxacin, Avelox 400 mg Ertapenem, Invanz 1 g Daptomycin, Cubicin 250 mg Daptomycin, Cubicin 500 mg Levofloxacin, Levaquin 750 mg Levofloxacin, Levaquin 750 mg Levofloxacin, Levaquin 250 mg Doripenem, Doribax 500 mg Ceftaroline, Teflaro 400 mg Ceftaroline, Teflaro 600 mg Telavancin, Vibativ 250 mg Telavancin, Vibativ 750 mg

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Volume ■■

Table IV. Patient characteristics in full cohort before matching Variables* Age (y), median (IQR) Male sex Race/Ethnicity White Black Hispanic Other Comorbid conditions¶ Cardiovascular Respiratory Renal Gastrointestinal Malignancy Hematologic/immunologic Metabolic Neuromuscular Congenital disorders PICU admission Sepsis-related therapies** Vasoactive infusion Maximum number of concurrent vasoactives†† Noninvasive mechanical ventilation Invasive mechanical ventilation Corticosteroids Hydrocortisone Methylprednisolone Albumin 5% Albumin 25% Blood transfusion‡‡ Furosemide ECMO

LR group† n = 2150

NS group‡ n = 10 379

P value§

8 (1-15) 1136 (53)

5 (1-13) 5521 (53)

<.001 .78 .09

1004 456 252 438

(47) (21) (12) (20)

4991 2245 1028 2115

(48) (22) (10) (20)

371 79 44 63 191 121 121 406 211 1761

(17) (4) (2) (3) (9) (6) (6) (19) (10) (82)

1568 505 185 251 1144 671 603 1366 923 7594

(15) (5) (2) (2) (11) (6) (6) (23) (9) (73)

904 (42) 2 (1-3) 189 (9) 1419 567 235 404 461 627 1020 975 12

(66) (26) (11) (19) (21) (29) (47) (45) (<1)

.01 .02 .43 .17 <.001 .16 .01 .08 <.001 <.001

3416 (33) 2 (1-2)

<.001 .05

816 (8)

.15

5902 2617 1075 1792 1690 1981 3653 3846 37

(57) (25) (10) (17) (16) (19) (35) (37) (<1)

<.001 .26 .44 .09 <.001 <.001 <.001 <.001 .18

ECMO, extracorporeal membrane oxygenation. *Data presented as n (%), unless noted. †LR group included all 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 one vasoactive infusion. ‡‡Includes administration of whole blood, packed red blood cells, platelets, plasma, and cryoprecipitate.

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Table VI. Estimated 50th percentile weight for age 50th percentile weight (kg) Ages (y)

Male

Female

0 to <1 1 to <2 2 to <3 3 to <4 4 to <5 5 to <6 6 to <7 7 to <8 8 to <9 9 to <10 10 to <11 11 to <12 12 to <13 13 to <14 14 to <15 15 to <16 16 to <17 17 to 18

8 11.5 13 15 17 19 21 23 26 29 34 38 42 48 53 58 62 66

7.5 11 12.5 14 16 19 21 24 27 31 35 39 43 48 51 53 55 56

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

Table VIII. Sensitivity analyses for LOS in matched cohort LR-any group† (n = 2117)

Outcomes* ¶

PICU LOS, death recorded as maximum PICU LOS, death recorded as 30 d** Hospital LOS, death recorded as maximum¶ Hospital LOS, death recorded as 30 d**

9.6 9.6 17.8 15.9

(2.0, (2.0, (7.0, (7.0,

NS group‡ (n = 2117)

16.0) 16.0) 27.0) 27.0)

9.3 9.3 16.1 14.4

(1.0, (1.0, (5.0, (5.0,

Risk ratio/difference (95% CI)

16.0) 16.0) 25.0) 25.0)

0.3 0.3 1.7 1.5

(−0.1, 0.7) (−0.1, 0.6) (1.1, 2.3) (1.0, 2.0)

P value§ .25 .18 <.001 <.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 LR-any group†

Outcomes* All patients with ICD-9-CM codes for severe sepsis or septic shock¶ Mortality, 30-d Mortality, hospital Mortality, including hospice AKI New dialysis PICU LOS**, median (IQR) Hospital LOS**, median (IQR) Only patients with ICD-9-CM codes for infection and organ dysfunction Mortality, 30-d Mortality, hospital Mortality, including hospice AKI New dialysis PICU LOS**, median (IQR) Hospital LOS**, median (IQR)

NS group‡

Risk ratio/difference (95% CI)

P-value§

57 66 68 125 8 8.5 14.8

(13.8) (15.9) (16.4) (30.1) (1.9) (2.0, 14.5) (6.0, 22.0)

68 78 82 122 16 8.6 13.9

(16.4) (18.8) (19.8) (29.4) (3.9) (2.0,15.0) (5.0, 22.0)

0.97 0.97 0.96 1.0 0.98 −0.05 0.88

(0.92, 1.03) (0.91, 1.03) (0.90, 1.02) (0.92, 1.10) (0.96, 1.00) (−1.2, 1.1) (−0.6, 2.4)

.16 .15 .12 .60 .07 .95 .34

96 128 132 209 19 7.5 14.9

(5.6) (7.5) (7.8) (12) (1.1) (1.0, 13.0) (6.0, 22.0)

100 121 129 215 17 6.9 12.8

(5.9) (7.1) (7.6) (13) (1.0) (1.0, 12.0) (4.0, 20.0)

1.0 1.0 1.0 1.0 1.0 0.6 2.1

(1.47, 2.81) (0.99, 1.02) (0.98, 1.02) (0.97, 1.02) (0.99, 1.01) (0.1, 1.1) (1.5, 2.8)

.41 .71 .61 .40 .75 .04 <.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 FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

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THE JOURNAL OF PEDIATRICS • www.jpeds.com

Volume ■■

Table X. Patient characteristics by quartile of total crystalloid volume corrected for estimated weight Variables* Total crystalloid volume range, mL/kg Age (y), median (IQR) Male sex Race/ethnicity White Black Hispanic Other Comorbid conditions‡ Cardiovascular Respiratory Renal Gastrointestinal Malignancy Hematologic/Immunologic Metabolic Neuromuscular Congenital disorders PICU admission Sepsis-related therapies§ Vasoactive infusion Max number of concurrent vasoactives¶ Noninvasive mechanical ventilation Invasive mechanical ventilation Corticosteroids Hydrocortisone Methylprednisolone Albumin 5% Albumin 25% Blood transfusion** Furosemide ECMO

Quartile 1 (n = 2816)

Quartile 2 (n = 3300)

Quartile 3 (n = 3212)

Quartile 4 (n = 3201)

2 to 13 13 (8-16) 1434 (51)

13.1 to 23.5 7 (1-14) 1761 (53)

23.6 to 45.5 5 (1-13) 1740 (54)

45.6 to 550 1 (0-4) 1722 (54)

1470 587 249 510

(52) (21) (9) (18)

1604 68 348 660

(49) (21) (11) (20)

1490 691 354 329

(46) (22) (11) (10)

1432 735 329 706

(45) (23) (10) (22)

272 79 49 80 375 237 173 747 300 1764

(10) (3) (2) (3) (13) (8) (6) (27) (11) (63)

430 148 59 74 391 218 166 761 286 2322

(13) (4) (2) (2) (12) (7) (5) (23) (9) (70)

496 144 65 60 336 194 177 640 276 2470

(15) (4) (2) (2) (10) (6) (6) (20) (9) (77)

741 213 56 100 233 143 208 624 272 2799

(23) (7) (2) (3) (7) (4) (7) (19) (9) (87)

<.001 <.001 .81 .006 <.001 <.001 .06 <.001 .01 <.001

687 1 227 1212 624 245 431 289 335 827 731 7

(24) (1-2) (8) (43) (22) (9) (15) (10) (12) (29) (26) (<1)

958 1 275 1721 792 303 566 466 542 1089 1096 5

(29) (1-2) (8) (52) (24) (9) (17) (14) (16) (33) (33) (<1)

1115 2 263 1902 839 332 598 584 676 1192 1298 10

(35) (1-2) (8) (59) (26) (10) (19) (19) (21) (37) (40) (<1)

1560 2 240 2486 929 430 601 812 1055 1565 1696 27

(48) (1-3) (8) (78) (29) (13) (19) (25) (33) (49) (53) (<1)

<.001 <.001 .63 <.001 <.001 <.001 .001 <.001 <.001 <.001 <.001 <.001

P-value† <.001 .06 <.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.

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Table XI. Patient characteristics in LR-any group by proportion of total crystalloid fluids received as LR Variables* Age (y), median (IQR) Male sex Race/ethnicity White Black Hispanic Other Comorbid conditions‡ Cardiovascular Respiratory Renal Gastrointestinal Malignancy Hematologic/Immunologic Metabolic Neuromuscular Congenital disorders PICU admission Sepsis-related therapies§ Vasoactive infusion Max number of concurrent vasoactives¶ Noninvasive mechanical ventilation Invasive mechanical ventilation Corticosteroids Hydrocortisone Methylprednisolone Albumin 5% Albumin 25% Blood transfusion** Furosemide ECMO

1% to ≤25% LR (n = 300)

26% to ≤50% LR (n = 872)

51% to ≤75% LR (n = 383)

76% to <100% LR (n = 136)

100% LR (n = 459)

P-value†

11 (3-15) 168 (56)

10 (2-15) 463 (53)

8 (1-15) 192 (50)

5 (0-13) 82 (60)

5 (1-13) 231 (50)

<.001 .16 .02

147 58 21 74

(49) (19) (7) (25)

403 186 102 181

(46) (21) (12) (21)

157 82 56 87

(41) (22) (15) (23)

62 31 19 24

(46) (23) (14) (18)

235 98 54 72

(51) (21) (12) (16)

56 7 6 13 26 17 28 68 32 270

(19) (2) (2) (4) (9) (6) (9) (23) (11) (90)

156 31 14 24 80 40 42 159 94 744

(18) (4) (2) (3) (9) (5) (5) (18) (11) (85)

61 10 10 12 46 32 20 69 32 319

(16) (3) (3) (3) (12) (8) (5) (18) (8) (83)

26 8 3 2 8 10 12 25 18 110

(19) (6) (2) (1) (6) (7) (9) (18) (13) (81)

72 23 11 12 31 23 19 85 35 318

(16) (5) (2) (3) (7) (5) (4) (19) (8) (69)

.69 .14 .78 .49 .07 .12 .009 .51 .17 <.001

166 2 31 232 100 54 62 77 89 160 159 4

(55) (1-3) (10) (77) (33) 918) (21) (26) (30) (53) (53) (1)

417 2 85 606 235 99 164 235 279 459 438 5

(48) (1-3) (10) (70) (27) (11) (19) (27) (32) (53) (50) (1)

164 1 32 247 100 34 74 80 133 208 176 1

(43) (1-2) (8) (64) (26) (9) (19) (21) (35) (54) (46) (<1)

53 1 5 87 42 17 33 25 40 65 55 0

(39) (1-2) (4) (64) (31) (13) (24) (18) (29) (48) (40)

104 1 36 247 90 31 71 44 86 128 147 2

(23) (1-2) (8) (54) (20) (7) (15) (10) (19) (28) (32) (<1)

<.001 .004 .14 <.001 .001 <.001 .15 <.001 <.001 <.001 <.001 .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

n Mortality, 30-d Mortality, hospital Mortality, including hospice AKI New dialysis PICU LOS†, median (IQR) Hospital LOS†, median (IQR)

38 43 44 75 9 9.7 15.6

300 (12.7) (14.3) (14.7) (25.0) (2.5) (0, 7.0) (4.0, 14.0)

26% to ≤50% LR 67 87 90 145 9 8.2 16.1

872 (7.7) (10) (10.3) (16.7) (1.0) (1.0, 12.0) (5.0, 21.0)

51% to ≤75% LR 20 27 28 57 3 7.1 16.0

383 (5.2) (7.0) (7.3) (14.9) (<1) (1, 11.0) (5.0, 19.0)

76% to <100% LR 12 16 16 18 2 7.7 14.9

136 (8.8) (11.8) (11.8) (13.2) (1.5) (3.0, 16.0) (7.0, 23.0)

100% LR 459 23 (5.0) 29 (6.3) 30 (6.5) 45 (9.8) 5 (1.1) 5.8 (0, 9.0) 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 FLA 5.4.0 DTD ■ YMPD8860_proof ■ January 4, 2017

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