Abstract
Objective
Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock.
Design
Retrospective analysis of a pediatric septic shock database.
Setting
Twenty-nine pediatric intensive care units in the United States
Patients
Eight hundred and ninety children ≤ 10 years of age with septic shock.
Interventions
None.
Measurements and Main Results
We considered the minimum, maximum, and mean chloride values during the initial seven days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration ≥110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of ≥2 organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 (25%) patients with a complicated course and 93 (10%) mortalities. Seventy patients had a minimum chloride ≥110 mmol/L, 179 had a mean chloride ≥110 mmol/L, and 514 had a maximum chloride ≥110 mmol/L. A minimum chloride ≥110 mmol/L was associated with increased odds of complicated course (O.R. 1.9, 95% C.I. 1.1 – 3.2, p = 0.023) and mortality (O.R. 3.7, 95% C.I. 2.0 – 6.8, p < 0.001). A mean chloride ≥110 mmol/L was also associated with increased odds of mortality (O.R. 2.1, 95% C.I. 1.3 – 3.5, p = 0.002). The secondary analysis yielded similar results.
Conclusion
Hyperchloremia is independently associated with poor outcomes among children with septic shock.
Keywords: Septic Shock, Sepsis, Chloride, Hyperchloremia, Mortality
Introduction
A growing body of evidence shows that hyperchloremia is associated with worse outcomes in the adult critically ill population. [1]. In post-operative patients, hyperchloremia has been associated with increased morbidity and mortality [2, 3]. In addition, hyperchloremia in patients with sepsis is associated with increased acute kidney injury and worsening morbidity and mortality [4–10]. It is currently unknown whether hyperchloremia is also detrimental in critically ill children.
In the pediatric population, septic shock is a major cause of morbidity and mortality [11]. Children with septic shock are at risk for hyperchloremia because standard of care includes aggressive volume resuscitation with crystalloid solutions to expand intravascular volume [12]. The most frequently used crystalloid solution is 0.9% NaCl [13]. Since the amount of chloride in this solution is 154 mEq/L, it is considered supraphysiologic compared to the chloride content of plasma, which is around 100 mEq/L [14]. Resuscitation with unbalanced, chloride-rich solutions, such as 0.9% NaCl, was recently found to be associated with worse outcomes in pediatric patients[15].
The purpose of this study was to test the hypothesis that hyperchloremia is associated with poor outcomes in pediatric patients with septic shock, after taking illness severity into consideration. Secondarily, we sought to determine if the association between hyperchloremia and poor outcomes is dependent on baseline risk of mortality, as determined by the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) [16].
Materials and Methods
Study and Data Collection
Subjects were part of an ongoing, 29 center epidemiologic and genomic study of patients admitted with septic shock (n = 890). This was a retrospective analysis; the ongoing study was approved by Institutional Review Boards at each participating institution. The protocol has been previously described [17–28]. After obtaining informed consent, blood samples were obtained within 24 hours of PICU admission and clinical and laboratory data were collected daily based on each institution’s standard of care. Mortality within 28 days of admission and organ failure were assessed for each subject.
Hyperchloremia variables
Subjects with at least three chloride values during the initial 7 days of PICU admission were included in the analysis. If a subject had more than one value per day, the highest of these values was used in calculations. From these daily values, we extracted the minimum, mean, and maximum chloride values for the initial 7 days of PICU admission. We considered these values for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration ≥110 mmol/L. This cut-off was chosen a priori based on our laboratory’s upper limit of normal. Adult data used this same cut-off when evaluating the effect of hyperchloremia on critically ill septic patients [7]. We also performed a secondary analysis treating chloride as a continuous variable.
Stratification
Subjects were stratified using PERSEVERE, which assesses the baseline risk of 28-day mortality among children with sepsis [16]. The PERSEVERE biomarkers and the method for calculating baseline risk of mortality were previously published. Of the 890 initial subjects, 687 (77%) had PERSEVERE data available. The remaining 203 subjects had no PERSEVERE data available as there was no remaining serum to allow for biomarker testing.
Data Analysis
Statistical analyses were performed using SigmaPlot Software (Systat Software, Inc., San Jose, CA). The clinical characteristics between the study groups are presented as median, frequencies, and percent[29].
We used logistic regression to estimate the odds of poor outcome associated with hyperchloremia. We adjusted for illness severity using the Pediatric Risk of Mortality (PRISM)-III score. In a secondary analysis, we used PERSEVERE to adjust for baseline risk of mortality.
There were two outcomes of interest: 28-day mortality and complicated course. The term “complicated course” has been previously described, and is defined as either death by 28 days or ≥ 2 organ failures at 7 days after meeting criteria for septic shock [30]. A p-value of <0.05 was considered to be statistically significant for all analyses.
Results
Demographics and Clinical Characteristics
There were 890 children included, of which 514 subjects had a maximum chloride ≥ 110 mmol/L, 179 had a mean chloride ≥ 110 mmol/L, and 70 had a minimum chloride ≥ 110 mmol/L. Table 1 compares the subjects with a complicated course (n=226) and subjects without a complicated course (n=664). Patients with a complicated course had a significantly higher PRISM-III score, a higher PERSEVERE-based mortality probability, and a smaller proportion had culture-negative sepsis. No other differences were noted.
Table 1.
Clinical characteristics of patients with and without a complicated course.
| Variable | Complicated Course (n=226) | Non-Complicated Course (n=664) | p-value |
|---|---|---|---|
| Median Age (IQR) | 3.2 (0.8 – 7.6) | 3.9 (1.4 – 8.1) | 0.130 |
| Male, n (%) | 134 (59%) | 360 (54%) | 0.236 |
| PRISM Score (IQR) | 16 (10 – 23) | 11 (6 – 15) | <0.001 |
| Pediatric Sepsis Biomarker Risk Model Probability of Mortality (95% CI) | 0.2 (0.2 – 0.2) | 0.06 (0.05 – 0.07) | <0.0001 |
| Mean Chloride ± S.D. | 105.8 ± 6.4 | 105.7 ± 5.6 | 0.876 |
| No. of patients with Gram-positive infection (%) | 61 (27%) | 143 (21%) | 0.062 |
| No. of patients with gram-negative infection (%) | 57 (25% | 141 (21%) | 0.210 |
| No. of patients with viral infection (%) | 13 (6%) | 31 (5%) | 0.560 |
| No. of patients with fungal infection (%) | 7 (3%) | 13 (2%) | 0.382 |
| No. of patients with mixed infection (%) | 1 (1%) | 4 (1%) | 1 |
| No. of patients with no organism identified (%) | 86 (38%) | 328 (49%) | 0.004 |
Supplemental table 1 shows the difference between minimum chloride values, PRISM-III scores, and PERSEVERE risk of mortality scores based on center.
Table 2 compares the 93 subjects who were non-survivors with the 797 patients who were survivors. Similar to the subjects with complicated course, non-survivors had a significantly higher PRISM-III score, a higher PERSEVERE-based mortality probability, and a smaller proportion had culture-negative sepsis.
Table 2.
Clinical Characteristics of survivors and non-survivors.
| Variable | Non-Survivors (n=93) | Survivors (n=797) | p-value |
|---|---|---|---|
| Median Age (IQR) | 4.2 (0.8 – 8.7) | 3.7 (1.2 – 8.0) | 0.906 |
| Male n (%) | 58 (62%) | 438 (55%) | 0.160 |
| PRISM Score (IQR) | 19 (11 – 28) | 11 (7 – 16) | <0.001 |
| Pediatric Sepsis Biomarker Risk Model Probability of Mortality (95% CI) | 0.3 (0.2 – 0.3) | 0.08 (0.07 – 0.09) | <0.0001 |
| Mean Chloride ± S.D. | 106.8 ± 7.4 | 105.6 ± 5.6 | 0.063 |
| No. of patients with Gram-positive infection (%) | 25 (27%) | 179 (22%) | 0.275 |
| No. of patients with gram-negative infection (%) | 26 (28%) | 172 (22%) | 0.191 |
| No. of patients with viral infection (%) | 5 (5%) | 39 (5%) | 1 |
| No. of patients with fungal infection (%) | 2 (2%) | 18 (2%) | 1 |
| No. of patients with mixed infection (%) | 0 (0%) | 5 (1%) | 0.333 |
| No. of patients with no organism identified (%) | 34 (37%) | 380 (48%) | 0.044 |
Patients with PERSEVERE data were compared to patients without PERSEVERE data. Patients with PERSEVERE data had a significantly higher rate of viral infections (Supplemental Table 2). No other differences were noted.
Association between Hyperchloremia and Outcomes
The three hyperchloremia variables were moderately correlated with each other: maximum versus minimum chloride (r = 0.250, p < 0.001); maximum versus mean chloride (r = 0.429, p < 0.001); and minimum versus mean chloride (R = 0.582, p < 0.001). Because of this co-linearity, we considered the three hyperchloremia variables separately in the logistic regression procedures.
Table 3 shows the results of logistic regression testing for an association between hyperchloremia and complicated course. A minimum chloride ≥ 110 mmol/L was independently associated with increased odds of complicated course (OR 1.9, 95% CI 1.1–3.2). A maximum or mean chloride ≥ 110 mmol/L was not associated with complicated course.
Table 3.
Multivariable logistic regression testing for an association between hyperchloremia and complicated course.
| Variable | O.R. | 95% CI | p-value | |
|---|---|---|---|---|
| Minimum Chloride ≥110 mmol/L | 1.9 | 1.1–3.2 | 0.023 | |
| PRISM | 1.1 | 1.1–1.1 | <0.001 | |
| Maximum Chloride ≥110 mmol/L | 0.9 | 0.7–1.3 | 0.603 | |
| PRISM | 1.1 | 1.1–1.1 | <0.001 | |
| Mean Chloride ≥110 mmol/L | 1.3 | 0.9–1.8 | 0.221 | |
| PRISM | 1.1 | 1.1–1.1 | <0.001 | |
Table 4 shows the results of logistic regression testing for an association between hyperchloremia and mortality. A minimum chloride ≥ 110 mmol/L (OR 3.7, 95% CI 2.0–6.8) and a mean chloride ≥110 mmol/L (OR 2.1, 95% CI 1.3–3.5) were independently associated with increased risk of mortality. A maximum chloride ≥ 110 mmol/L was not associated with increased odds of mortality.
Table 4.
Multivariable logistic regression testing for an association between hyperchloremia and mortality.
| Variable | O.R. | 95% CI | p-value | |
|---|---|---|---|---|
| Minimum Chloride ≥110 mmol/L | 3.7 | 2.0–6.8 | <0.001 | |
| PRISM | 1.1 | 1.1–1.1 | <0.001 | |
| Maximum Chloride ≥110 mmol/L | 1.2 | 0.7–1.9 | 0.483 | |
| PRISM | 1.1 | 1.1–1.1 | <0.001 | |
| Mean Chloride ≥110 mmol/L | 2.1 | 1.3–3.5 | 0.002 | |
| PRISM | 1.1 | 1.1–1.1 | <0.001 | |
Association between Hyperchloremia and Outcomes in PERSEVERE Stratified Patients
There were 687 subjects (77%) with available PERSEVERE data. Table 5 shows the results of logistic regression testing for an association between hyperchloremia and complicated course, and hyperchloremia and mortality, after adjustment for baseline mortality probability, as estimated by PERSEVERE. A minimum chloride ≥110 mmol/L was associated with increased odds of complicated course (OR 1.9, 95% CI 1.0–3.4). A minimum chloride ≥ 110 mmol/L (OR 4.1, 95% CI 2.1–8.1) and mean chloride ≥ 110 mmol/L (OR 2.3, 95% CI 1.3–3.9) were associated with increased risk of mortality.
Table 5.
Multivariable logistic regression testing for an association between hyperchloremia and complicated course (CC) or mortality, after adjusting for PERSEVERE-based risk of mortality.
| Outcome | Variable | OR (95% CI) | P value |
|---|---|---|---|
| Complicated Course | Minimum Chloride ≥110 mmol/L | 1.9 (1.0–3.4) | 0.047 |
| Maximum Chloride ≥110 mmol/L | 0.9 (0.6–1.3) | 0.572 | |
| Mean Chloride ≥110 mmol/L | 1.3 (0.8–2.0) | 0.223 | |
| Mortality | Minimum Chloride ≥110 mmol/L | 4.1 (2.1–8.1) | <0.001 |
| Maximum Chloride ≥110 mmol/L | 1.3 (0.7–2.1) | 0.384 | |
| Mean Chloride ≥110 mmol/L | 2.3 (1.3–3.9) | 0.003 |
Chloride as a Continuous Variable
There was no association with between chloride values and complicated course when treating chloride as a continuous variable. However, there was an association between continuous chloride values and mortality. When adjusting for PRISM-III scores, the minimum chloride had an OR of 1.04 (95% CI 1.01–1.07, p-value 0.022). There was a similar association when using PERSEVERE to stratify baseline mortality risk (OR 1.04, 95% CI 1.01–1.08, p-value 0.026).
Discussion
This analysis explored the association between hyperchloremia and outcomes in a large, heterogeneous cohort of children with septic shock. Hyperchloremia was independently associated with increased risk for mortality and complicated course after adjusting for illness severity (PRISM-III). We saw similar results when adjusting for baseline mortality risk, as estimated by PERSEVERE.
Although mean chloride levels were not significantly different between patients with and without complicated course and between survivors and non-survivors, it appears that persistently elevated chloride levels, reflected by a minimum chloride concentration ≥110 mmol/L during the first 7 days of septic shock, are detrimental. Hyperchloremia may be injurious to a number of organ systems [7, 31–36], and these combined insults are potential contributors to the increased morbidity and mortality seen in these patients.
Adult septic patients with hyperchloremia were more likely to be anemic and require blood transfusions [7], and post-operative patients who received chloride-rich solutions had coagulation abnormalities and were more likely to bleed [34, 37]. Chloride may also affect the kidney by reducing velocity of renal blood flow and reducing renal cortical tissue perfusion [31]. Hyperchloremic acidosis is also associated with impaired cardiac contractility and hypotension[32], as well as reduced gastric blood flow [33].
Of particular interest in the sepsis population may be the effects of chloride on the immune system. Hyperchloremic metabolic acidosis induced an augmented pro-inflammatory response via increased interleukin (IL)-6 to IL-10 ratios in an in vitro cell model [36], as well as in animal models [35]. It is currently unknown whether these inflammatory responses are present in humans with hyperchloremia.
This growing evidence of the detrimental effects of hyperchloremia has led to discussions around the use of 0.9% NaCl for resuscitation, which is the current standard of care. 0.9% NaCl is neither normal nor physiologic and is associated with worse outcomes [38]. In adult trauma patients, the use of sodium acetate instead of 0.9% NaCl led to improvement of hyperchloremia with no ill effect on hemodynamics [39], and clinicians have argued that balanced crystalloid solutions may be superior to 0.9% NaCl for pediatric and adult septic patients [15, 40].
Although the association between outcomes and type of fluid has been examined, our study is the first to examine hyperchloremia itself in the pediatric septic population. It adds to the growing evidence from adult literature that hyperchloremia may be harmful in certain patient populations. The strengths of our study include its large sample size and the ability to control for illness severity in two independent ways: controlling for PRISM-III scores as well as controlling for baseline mortality risk using the PERSEVERE biomarkers.
Our study has limitations. First, our database did not reliably capture the type and amount of fluid used in resuscitation. Second, as an observational study the amount of fluid and the type of fluid used for resuscitation were not standardized. There are therefore multiple confounders that could affect our results. However, given that initial resuscitation with unbalanced crystalloid solution is standard of care, it is likely that this fluid was commonly used for these patients. In addition, we accounted for several confounders by considering illness severity and baseline mortality risk. Finally, this study only included patients ≤10 years of age with septic shock. It is unknown whether these findings will be true for older children and in other forms of critical illness.
Conclusions
In conclusion, hyperchloremia is common in children with septic shock and is independently associated with increased odds of poor outcome. Since the chloride composition in fluid differs, the degree of chloride load is a modifiable factor that may influence patient outcomes. Although we cannot conclude that this association reflects the type of fluid used for resuscitation, the data nonetheless suggest a continuing need for further evaluation of the optimal fluid to use in resuscitation of pediatric patients with septic shock.
Supplementary Material
Acknowledgments
The authors thank the following research coordinators for their effort and dedication in enrolling study participants: Tasha Capozzi, Mary Ann De Liberto, Angela Doucette, Kristin Greathouse, Lauren Hoadley, Katherine Luther, Stephanie Osborne, Amber Hughes-Schalk, Tonia Polanski, Julie Simon, Debra Spear, Lisa Steels, Naresh B. Talathoti, Tiffany Vertican, Monica Weber, Andrew A. Wiles, and Trisha Williams.
Source of Funding: Supported by National Institutes of Health Grants RO1GM099773 and R01GM108025.
Dr. Wong and the Cincinnati Children’s Hospital Research Foundation hold a U.S. patent for PERSEVERE.
Copyright form disclosure: Drs. Stenson, Allen, Fitzgerald, Checchia, and Wong’s institutions received funding from the National Institutes of Health (NIH). Drs. Stenson, Cvijanovich, Allen, Fitzgerald, Checchia, Meyer, Freishtat, Grunwell, and Wong received support for article research from the NIH. Dr. Cvijanovich’s institution received funding from Cincinnati Children’s Medical Center, Boston Children’s Hospital, and the UCLA School of Medicine. Dr. Thomas’ institution received funding from GeneFluidics, and he received funding from Therabron and CareFusion. Dr. Weiss’s institution received funding from National Institute of General Medical Sciences K23GM110496, and he received funding from Bristol-Myers Squibb (member of advisory panel). Dr. Gertz’s institution received funding from Cincinnati Children’s Hospital. Dr. Grunwell’s institution received funding from Cincinnati Children’s Hospital.
Footnotes
Conflicts of Interest: The remaining authors have no competing interests to report.
References
- 1.Sen A, Keener CM, Sileanu FE, Foldes E, Clermont G, Murugan R, Kellum JA. Chloride Content of Fluids Used for Large-Volume Resuscitation Is Associated With Reduced Survival. Crit Care Med. 2017;45(2):e146–e153. doi: 10.1097/CCM.0000000000002063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Scheingraber S, Rehm M, Sehmisch C, et al. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology. 1990;90(5):1265–1270. doi: 10.1097/00000542-199905000-00007. [DOI] [PubMed] [Google Scholar]
- 3.McCluskey SA, Karkouti K, Wijeysundera D, et al. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg. 2013;117(2):412–421. doi: 10.1213/ANE.0b013e318293d81e. [DOI] [PubMed] [Google Scholar]
- 4.Lobo DN, Awad S. Should chloride-rich crystalloids remain the mainstay of fluid resuscitation to prevent ‘pre-renal’ acute kidney injury?: con. Kidney international. 2014;86(6):1096–1105. doi: 10.1038/ki.2014.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Krajewski ML, Raghunathan K, Paluszkiewicz SM, et al. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015;102(1):24–36. doi: 10.1002/bjs.9651. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Noritomi DT, Soriano FG, Kellum JA, et al. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med. 2009;37(10):2733–2739. doi: 10.1097/ccm.0b013e3181a59165. [DOI] [PubMed] [Google Scholar]
- 7.Neyra JA, Canepa-Escaro F, Li X, Manllo J, Adams-Huet B, Yee J, Yessayan L. Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients. Crit Care Med. 2015;43(9):1938–1944. doi: 10.1097/CCM.0000000000001161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Boniatti MM, Cardoso PR, Castilho RK, Vieira SR. Is hyperchloremia associated with mortality in critically ill patients? A prospective cohort study. Journal of critical care. 2011;26(2):175–179. doi: 10.1016/j.jcrc.2010.04.013. [DOI] [PubMed] [Google Scholar]
- 9.Marttinen M, Wilkman E, Petaja L, Suojaranta-Ylinen R, Pettila V, Vaara ST. Association of plasma chloride values with acute kidney injury in the critically ill - a prospective observational study. Acta anaesthesiologica Scandinavica. 2016;60(6):790–799. doi: 10.1111/aas.12694. [DOI] [PubMed] [Google Scholar]
- 10.Suetrong B, Pisitsak C, Boyd JH, Russell JA, Walley KR. Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Critical Care. 2016;20(1):315. doi: 10.1186/s13054-016-1499-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wong HR, Nowak JE, Standage S, de Oliveira CF. Pediatric Critical Care Medicine. 4th. St. Louis: Mosby; 2011. [Google Scholar]
- 12.Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2016;45(3):1–67. doi: 10.1097/CCM.0000000000002255. [DOI] [PubMed] [Google Scholar]
- 13.Powell-Tuck J, Gosling P, Lobo D, et al. British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients (GIFTASUP) The British Association for Parenteral and Enteral Nutrition (BAPEN) 2008 (updated 2011). Available online at http://www.bapen.org.uk/pdfs/bapen_pubs/giftasup.pdf. Accessed February 1, 2017.
- 14.Guidet B, Soni N, Della Rocca G, et al. A balanced view of balanced solutions. Critical Care. 2010;14(5):325. doi: 10.1186/cc9230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Emrath ET, Fortenberry JD, Travers C, McCracken CE, Hebbar KB. Resuscitation With Balanced Fluids Is Associated With Improved Survival in Pediatric Severe Sepsis. Crit Care Med. 2017;45(7):1177–1183. doi: 10.1097/CCM.0000000000002365. [DOI] [PubMed] [Google Scholar]
- 16.Wong HR, Salisbury S, Xiao Q, et al. The pediatric sepsis biomarker risk model. Critical Care. 2012;16(R:174) doi: 10.1186/cc11652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Basu RK, Standage SW, Cvijanovich NZ, et al. Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray. Critical Care. 2011;15:R273. doi: 10.1186/cc10554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Cvijanovich N, Shanley TP, Lin R, et al. Validating the genomic signature of pediatric septic shock. Physiological Genomics. 2008;34:127–134. doi: 10.1152/physiolgenomics.00025.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Shanley TP, Cvijanovich N, Lin R, et al. Genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock. Mol Med. 2007;13:495–508. doi: 10.2119/2007-00065.Shanley. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Wong HR, Cvijanovich N, Allen GL, et al. Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med. 2009;37:1558–1566. doi: 10.1097/CCM.0b013e31819fcc08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Wong HR, Cvijanovich N, Lin R, et al. Identification of pediatric septic shock subclasses based on genome-wide expression profiling. BMC Medicine. 2009;7:34. doi: 10.1186/1741-7015-7-34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Wong HR, Cvijanovich N, Wheeler DS, et al. Interleukin-8 as a stratification tool for interventional trials involving pediatric septic shock. Am J Respir Crit Care Med. 2008;178:276–282. doi: 10.1164/rccm.200801-131OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Wong HR, Cvijanovich N, Allen GL, et al. Validation of a gene expression-based subclassification strategy for pediatric septic shock. Crit Care Med. 2011;39:2511–2517. doi: 10.1097/CCM.0b013e3182257675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Wong HR, Cvijanovich N, Hall M, et al. Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Critical Care. 2012;16:R213. doi: 10.1186/cc11847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Wong HR, Freishtat RJ, Monaco M, Odoms K, Shanley TP. Leukocyte subset-derived genomewide expression profiles in pediatric septic shock. Pediatric critical care medicine. 2010;11:349–355. doi: 10.1097/PCC.0b013e3181c519b4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Wong HR, Shanley TP, Sakthivel B, et al. Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome. Physiological Genomics. 2007;30:146–155. doi: 10.1152/physiolgenomics.00024.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Wong HR, Wheeler DS, Tegtmeyer K. Toward a clinically feasible gene expression-based subclassification strategy for septic shock: Proof of concept. Crit Care Med. 2010;38:1955–1961. doi: 10.1097/CCM.0b013e3181eb924f. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Wynn JL, Cvijanovich NZ, Allen GL, et al. The influence of developmental age on the early transcriptomic response of children with septic shock. Mol Med. 2011;17:1146–1156. doi: 10.2119/molmed.2011.00169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.MedCalc for Windows, version 16.8.4 (MedCalc Software, Ostend, Belgium) https://www.medcalc.org/calc/comparison_of_means.php
- 30.Wong HR, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT. Developing a Clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med. 2015;191(3):309–315. doi: 10.1164/rccm.201410-1864OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.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. Annals of surgery. 2012;256(1):18–24. doi: 10.1097/SLA.0b013e318256be72. [DOI] [PubMed] [Google Scholar]
- 32.Levy B, Collin S, Sennoun N, et al. Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med. 2010;36(12):2019–2029. doi: 10.1007/s00134-010-2045-8. [DOI] [PubMed] [Google Scholar]
- 33.Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesthesia and analgesia. 2001;93(4):811–816. doi: 10.1097/00000539-200110000-00003. [DOI] [PubMed] [Google Scholar]
- 34.Martin G, Bennett-Guerrero E, Wakeling H, et al. A prospective, randomized comparison of thromboelastographic coagulation profile in patients receiving lactated Ringer’s solution, 6% hetastarch in a balanced-saline vehicle, or 6% hetastarch in saline during major surgery. J Cardiothorac Vasc Anesth. 2002;16(4):441–446. doi: 10.1053/jcan.2002.125146. [DOI] [PubMed] [Google Scholar]
- 35.Kellum JA, Song M, Almasri E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest. 2006;130(4):962–967. doi: 10.1378/chest.130.4.962. [DOI] [PubMed] [Google Scholar]
- 36.Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. American Journal of Physiology Regulatory, Integrative and Comparative Physiology. 2004;286(4):R686–692. doi: 10.1152/ajpregu.00564.2003. [DOI] [PubMed] [Google Scholar]
- 37.Waters JH, Gottlieb A, Schoenwald P, et al. Normal saline versus lactated Ringer’s solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesthesia and analgesia. 2001;93(4):817–822. doi: 10.1097/00000539-200110000-00004. [DOI] [PubMed] [Google Scholar]
- 38.Li H, Sun SR, Yap JQ, Chen JH, Qian Q. 0.9% saline is neither normal nor physiological. Journal of Zhejiang University Science B. 2016;17(3):181–187. doi: 10.1631/jzus.B1500201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.McCague A, Dermendjieva M, Hutchinson R, Wong DT, Dao N. Sodium acetate infusion in critically ill trauma patients for hyperchloremic acidosis. Scandinavian journal of trauma, resuscitation and emergency medicine. 2011;19:24. doi: 10.1186/1757-7241-19-24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Loflin R, Winters ME. Fluid Resuscitation in Severe Sepsis. Emergency medicine clinics of North America. 2017;35(1):59–74. doi: 10.1016/j.emc.2016.08.001. [DOI] [PubMed] [Google Scholar]
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