Use of Lactated Ringers Solution Compared to Normal Saline is Associated With Shorter Length of Stay in Pediatric Acute Pancreatitis

Abstract

Objective:

To evaluate Lactated Ringers (LR) versus Normal Saline (NS) in pediatric acute pancreatitis (AP).

Methods:

Retrospective study utilizing Pediatric Health Information System database of primary AP patients, 2013 to 2017.

Results:

The study included 1581 first time AP patients with exclusive use of a single fluid (111 LR, 1470 NS) for the first 48 hours. The LR cohort had a significantly shorter length of stay (P < 0.001) compared to NS. A multivariable logistic regression analysis suggests use of NS in the first 48 hours (after controlling for total parenteral nutrition, operation, and infection during the admission) had a significantly increased likelihood of requiring a hospitalization for ≥4 days compared to the LR group (odds Ratio, 3.31; 95% confidence interval, 1.95–5.62). The overall cost was significantly less in the LR group. There was no statistical difference observed in risk factors for AP, intensive care transfer, organ dysfunction or mortality.

Conclusion:

This represents the first large dataset analysis of LR versus NS in pediatric AP. The use of LR was associated with a shorter length of stay and reduced cost compared to NS. Future randomized trials will help determine the ideal fluid choice for pediatric AP.

Introduction

Acute pancreatitis (AP) represents a significant cause of morbidity across the globe; the absolute incidence in all ages has increased from 10 million cases in 1990 to more than 17 million in 2013.¹ Recently, there has been increased awareness of pediatric AP, which has an incidence of about 13/100,000 persons per year, representing a significant pediatric disease burden.^2,3 There is also a significant financial burden. A study which examined pediatric AP from 2004–2014 determined that the median cost of admission for pediatric AP (not requiring an intensive care unit [ICU] admission) was $2257 per hospital day and that the cost further increased if an ICU stay was part of the admission as well.⁴

In all ages, AP is associated with reversible inflammation of the pancreas with varying degrees of local pancreatic complications as well as systemic disease.⁵ In 2012, the International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE) group published diagnostic criteria for pediatric AP, subsequently endorsed by the Pancreas Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN).^6,7 Diagnosis of AP requires at least two of the following: 1. Characteristic abdominal pain, 2. Amylase and/or lipase ≥3 times the age adjusted upper limit of normal, and 3. Imaging findings consistent with AP.^6,7 In 2017, a new severity classification schema subdivided pediatric AP patients into mild, moderately severe, or severe disease based on the presence or absence of local pancreatic complications or transient versus persistent systemic organ dysfunction.⁸

Management has, until very recently, relied heavily on the extrapolation of adult data to the pediatric population, although AP in children is distinct from AP in adults.⁶ In contrast to the adult patient population, where the etiology is overwhelmingly associated with alcohol or gallstones, pediatric AP encompasses multiple distinct etiologies.^5,9 Pediatric AP etiologies include biliary causes, medications, traumatic, infectious, autoimmune, metabolic disorders, or systemic disease.⁵

Several adult studies have suggested that the choice of fluid for management of AP should be LR.^10–12 In 2013, the International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) released guidelines for the management of AP, which recommended the use of LR as the fluid of choice for the initial resuscitation in adult patients.¹³ The 2018 American Gastroenterological Association (AGA) guidelines do not recommend a specific fluid, although it acknowledges that LR may be beneficial.¹⁴

Pediatric AP management is emerging as a field. Two guidelines were recently published that provide guidance for the overall management of pediatric AP.^6,15 The mainstay of AP management consists of enteral nutrition, appropriate analgesia and antiemetics.^6,15–17 In terms of fluid support, it is recommended to use “aggressive” fluids without specifying the type of fluid.⁶ The 2018 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition report recommends using isotonic fluid (and suggests that LR may be a more favorable fluid) at a rate of 1.5–2 times the maintenance intravenous (IV) fluid rate as calculated by the Holiday-Seger method for the first 24–48 hours, but acknowledges that there is limited pediatric data.⁶ The use of LR in pediatric AP has not been investigated in prior studies.

This study compares the outcomes associated with two of the most commonly used fluids for resuscitation in pediatric AP by measuring length of stay (LOS) and other proxies of severity. By examining LR and NS use in patients from a national database, our goal is to identify opportunities to improve our current understanding of fluid management in pediatric AP.

MATERIALS AND METHODS

The Pediatric Health Information System (PHIS) is a comprehensive database that contains clinical and financial data from more than 45 freestanding pediatric hospitals across the United States. Admission and cost data were extracted from PHIS for patients who had a primary AP admission between January 2013 and December 2017 and who were less than 19 years of age. Primary AP cases were identified by principle discharge diagnosis based on International Classification of Diseases, Ninth Revision (ICD-9) code 577.0 or Tenth Revision (ICD-10) code K85.xx. The PHIS system contains encrypted medical record numbers and discharge IDs allowing for admissions from the same patient to be tracked within a hospital. We extracted demographic information (age, sex, race) as well as information on LOS, admission to the ICU, mortality, care team, region of the country, transfer from outside facilities, emergency department (ED) presentation, and admission cost data. Additionally, we queried PHIS for ICD-9 and ICD-10 codes associated with etiologic risk factors for AP, management codes associated with AP disease severity, and organ dysfunction information (Supplemental Table 1). The costs were adjusted using the cost-to-charge ratios for each hospital as well as adjusted for regional differences by using the Centers for Medicare and Medicaid Services wage/price index for the hospital’s location. In an attempt to eliminate confounding comorbidities, admissions where patients were flagged as having a pediatric complex chronic condition, as previously defined, were excluded.^18,19

The isotonic IV fluids used to group the patients were pulled from PHIS using clinical transaction classification codes. Patients were categorized in the NS group if they received either IV sodium chloride 0.9% or D5 0.9% sodium chloride. Patients were categorized as part of the LR group if they received IV ringers solution or lactated ringers. Patients who received both LR and NS during the first 48 hours were excluded. The study was reviewed by the local Institutional Review Board (IRB) and was granted a non-human research exemption per institutional IRB policy.

Statistical Analysis

Data were analyzed using SAS®, version 9.4 (SAS Institute, Cary, NC). The first primary AP admission for a patient between 2013 and 2017 was used for analysis purposes. Due to the distribution of variables, continuous data were summarized as medians with interquartile range (IQR: 25^th–75^th percentiles) while categorical data were summarized as frequency counts with percentages. Chi-square tests and Fisher exact tests were used as appropriate for the group comparisons of categorical variables. For continuous data, non-parametric Wilcoxon-Mann-Whitney tests were used to compare characteristics between the LR and NS groups. A linear regression model was used to assess fluid choice percentage over time. A multivariable logistic regression analysis was performed in order to identify the patients at highest risk of requiring hospitalization for ≥4 days. P < 0.05 was considered statistically significant.

RESULTS

The PHIS cohort identified a total of 1581 unique patients from 38 separate hospitals (36 university affiliated) who had a primary AP admission and exclusive use of a single fluid type for the first 48 hours of the hospitalization, including the ED. The overwhelming majority (93%) of patients (n = 1470) received NS; 111 patients received LR. Demographics and risk factors of the patients are presented in Table 1. There was no statistical difference in age, sex, race, urban/rural residence, median income, primary payment source or risk factors between the groups. There was a statistical difference in the regional distribution of the centers (P = 0.007) based on fluid choice (Table 1).

TABLE 1.

Demographics and Risk Factors of Patients Suffering First Episode With Primary Diagnosis of AP From 2013–2017

	LR n = 111	NS n = 1470	P
Admission age, y	13.6 (10.5–15.7)	13.7 (10.0–16.1)	0.54
Sex, female	60 (54)	832 (57)	0.60
Race			0.56
White	78 (70)	1038 (71)
Black	12 (11)	160 (11)
Asian	0 (0)	24 (2)
Other	21 (19)	248 (17)
US region			0.007
Northeast	9 (8)	62 (4)
Midwest	34 (31)	399 (27)
South	54 (49)	627 (43)
West	14 (13)	382 (26)
Urban			0.22
Urban/suburban	87/110 (79)	1196/1430 (84)
Not urban	23/110 (21)	234/1430 (16)
Median household income, $*	39,750 (33,605–49,875)	40,250.5 (32,779–53,152)	0.56
Primary payment source			0.86
Private/commercial	51 (46)	622 (42)
Public/government	57 (51)	787 (54)
Self-pay/charity	1 (1)	30 (2)
Other payer/unknown	2 (2)	31 (2)
Risk factors
Gallstone/biliary	18 (16.2)	232 (15.8)	0.90
Triglyceridemia/lipidemia	0 (0)	0 (0)	–
Trauma	0 (0)	4 (0.3)	1.00
Divisum/anomalies	0 (0)	0 (0)	–
Obesity/overweight	12 (10.8)	248 (16.9)	0.10
Alcohol abuse	1 (0.9)	12 (0.8)	0.61

Data presented as median (IQR) or n (%).

^*Based on calendar year 2010.

The percentage of patients who received LR significantly increased annually from 2013 to 2017 (from 2.7% to 11.8%, P = 0.02) (Fig. 1, Supplemental Table 2).

FIGURE 1.

Percentage distribution of fluid choice by year, 2013–2017. The percentage of patients who received LR significantly increased annually from 2013 to 2017 (from 2.7% to 11.8%, P = 0.02).

Details of the inpatient admission including LOS, ICU admissions, mortality, care team, ED presentation, Total Parenteral Nutrition (TPN) use, operating room visit, presence of infection, transfer from outside institutions, overall cost of the admission and management strategies were analyzed between the two treatment arms (Table 2). Overall, patients who received LR had a significantly shorter LOS (median 2 days with IQR, 1–3 days) compared to those who received NS (median 3 days with IQR, 2–5 days; P < 0.001, Table 2, Fig. 2). There was no statistical difference between the groups in ICU transfer, mortality or transfer from outside institutions, or in any of the available management choices (Table 2). The patients who received LR were more likely to have been cared for on a surgical service line (P < 0.001) compared to a medical service line, and to not have received care in the ED (P < 0.001, Table 2). For patients on the medical service line, the LR group had a significantly shorter LOS with a median of 2 days (IQR, 1–3 days) compared to the NS group which had a median of 3 days (IQR, 2–4 days; P < 0.001, Table 2). For patients on the surgical service line, the LR group had a significantly shorter LOS with a median of 2 days (IQR, 1–3 days) compared to the NS group which had a median of 4 days (IQR, 3–6 days; P < 0.001, Table 2). The median admission cost was significantly higher in the NS group, costing $7875 for NS versus $5784 for the LR group (P < 0.001, Table 2).

TABLE 2.

Hospitalization and Management Details

	LR n = 111	NS n = 1470	P
Medical	86 (77)	1314 (89)	<0.001
Surgical	25 (23)	156 (11)
LOS, d	2.0 (1.0–3.0)	3.0 (2.0–5.0)	<0.001
Medical LOS	2.0 (1.0–3.0)	3.0 (2.0–4.0)	<0.001
Surgical LOS	2.0 (1.0–3.0)	4.0 (3.0–6.0)	<0.001
ICU during admit	2 (1.8)	29 (2.0)	1.00
Mortality	0 (0)	0 (0)	–
ED during admit	36 (32)	1081 (74)	<0.001
TPN during admit	1 (0.9)	89 (6)	0.02
Operating room charge during admit	24 (22)	180 (12)	0.005
Infection during admit	72 (65)	1192 (81)	<0.001
Transfer from another hospital/healthcare facility	27/92 (29)	320/1360 (24)	0.21
Admission cost, $	5784 (3073–10,017)	7875 (5063–12,742)	<0.001
Management
ERCP	8 (7.2)	47 (3.2)	0.052
Cholecystectomy	4 (3.6)	83 (5.7)	0.52
Surgery to pancreas	1 (0.9)	13 (0.9)	1.00

Data presented as median (IQR) or n (%).

ERCP indicates endoscopic retrograde cholangiopancreatography.

FIGURE 2.

Comparison of LOS in days between LR and NS*. AP Patients that received LR (median 2 days with IQR 1–3 days) had a significantly shorter LOS (P < 0.001) compared to those who received NS (median 3 days with IQR, 2–5 days) using a Wilcoxon-Mann-Whitney test for analysis. *Outliers greater than 10 days were excluded for graphical purposes but were included in the analysis.

To examine the factors associated with longer LOS, admissions were divided into LOS <4 days or ≥4 days. There were a total of 606 patients (38%) with a LOS ≥4 days (Table 3). Based on a multivariable logistic regression analysis, the exclusive use of NS in the first 48 hours, after controlling for TPN, operation, and infection, had a significantly increased likelihood of requiring hospitalization for ≥4 days compared to the LR group (odds ratio, 3.31; 95% confidence interval, 1.95–5.62) (Table 3).

TABLE 3.

Multivariable Logistic Regression Model Predicting a Longer LOS

	Odds Ratio (95% CI)	P
Fluid group
NS	3.31 (1.95–5.62)	<0.001
LR	Ref	N/A
TPN during admit
Yes	23.09 (9.94–53.62)	<0.001
No	Ref	N/A
Operating room charge during admit
Yes	4.30 (3.08–6.01)	<0.001
No	Ref	N/A
Infection during admit
Yes	1.50 (1.13–1.99)	0.005
No	Ref	N/A

Longer LOS was defined as ≥4 days. There were a total of 606 patients (38%) with a LOS ≥4 days.

N/A indicates not applicable

Geographic regions were examined individually, and in all regions except the Northeast, the group that received LR had a statistically significant shorter LOS compared to the group that received NS (Supplemental Table 3). There were no statistical differences between the two groups in terms of AP complications, neither in organ dysfunction during the admission, Systemic Inflammatory Response Syndrome (SIRS), acute kidney injury (AKI), shock, hypotension, respiratory failure, respiratory dysfunction, or cardiac dysfunction (Supplemental Table 4).

DISCUSSION

This novel study represents the first large data analysis of the use of LR versus NS in hospitalized pediatric AP patients. Based on this analysis of 5 years of data from pediatric patients with AP we found a significantly shorter LOS for patients who exclusively received LR when compared to NS, even when correcting for other variables that may increase length of stay or indicate a more severe disease course such as the use of TPN, or the occurrence of operation, and/or infection as part of the hospital course. It corroborates recent adult literature and suggests that LR may be beneficial in management of AP.^10–13 We found that the exclusive use of LR in the first 48 hours of an admission remains rare compared to NS, but its use has been trending up over the past several years, following the 2013 publication of the IAP/APA guidelines.¹³

It is interesting to note that while the LOS was reduced, there was no significant difference in organ dysfunction, one of the indicators of severity of AP. This may be due to the smaller sample size in the LR group. In the adult literature, many theories have been advanced regarding why LR may be more beneficial than NS, from reduction of hyperchloremia to decreased activation of macrophages, to reduction in acidosis.^11,20–22

Wu et al demonstrated in a small randomized controlled trial involving 40 adult patients with AP that the patients randomized to the LR arm of the study had significantly lower levels of C-Reactive Protein (CRP) and SIRS compared with the NS group.¹² In 2013, the IAP and APA guidelines recommended the use of LR as the fluid of choice for the initial resuscitation in adult patients.¹³ In 2018, de-Madaria et al showed in a randomized controlled trial of 40 adults a reduction in CRP in the arm that received LR at 48 and 72 hours.¹¹ A decreased activation of macrophages was appreciated in the LR group, suggesting this may be the mechanism of the anti-inflammatory nature of LR.¹¹ Unfortunately, none of these proposed mechanisms have been thoroughly investigated in the pediatric population. Regardless of the mechanism, the findings of decreased LOS in patients who receive LR represent a significant and unique contribution to the pediatric AP literature.

In addition to decreased LOS in those receiving LR, there is a significant healthcare cost reduction in patients who receive LR when compared to NS. The total median cost for the admission in the LR group is $5784 versus $7875 in the NS group, with a substantial potential overall savings. Based on the CDC’s 2017 population estimate, there are approximately 73.6 million children under the age of 18 in the US.²³ If the annual incidence of pediatric AP is 13/100,000, there would be approximately 9500 cases of AP each year. If each of those admissions saved $2000, this would be a total direct annual savings of $19.1 million of healthcare spending simply by using LR as the fluid therapy in pediatric AP. In addition to the healthcare savings, there are other benefits as well in terms of societal impact (e.g. in fewer missed days at work by caregivers or days of school by patients). Therefore, this data suggests that the use of exclusive LR may lead to shorter LOS and an overall lower cost to the patient and the healthcare system without demonstrating significant differences in disease complications.

We examined various factors that might provide an explanation for the noted differences outside of the fluid choice alone and attempted to control for factors that may increase LOS, as this was the primary outcome that we could examine in the PHIS database that is most closely associated with AP severity. We excluded patients with complex conditions from our analysis as their underlying conditions may have led to longer LOS at baseline. We also controlled for the use of TPN, the presence of a bacterial or viral infection, or an operating room charge when we created our multivariable model, as all of these factors are associated with an increased LOS. Our multivariable logistic regression analysis was built to identify the patients at highest risk of requiring hospitalization for ≥4 days, as hospitalization for less than 4 days has been associated with a more mild AP course for pediatric patients in previous studies.^4,6,8,24,25 In particular, Szabo et al showed that in patients who received early aggressive fluid resuscitation as well as early enteral nutrition, the average LOS in mild AP cases was less than 4 days, which led to us using hospitalizations for greater than or equal to 4 days as a presumptive indicator for the development of severe disease.²⁶ Patients who received exclusive NS in the first 48 hours, even after controlling for TPN, operation, and infection, had a significantly increased likelihood of requiring hospitalization for ≥4 days compared to the LR group.

The PHIS database is a tremendous resource for large database analysis, but it is not without its limitations. The database relies on billing code data. The regional difference in the use of LR is an interesting observation as well which cannot be fully explained from this dataset. Additionally, this database does not allow us to identify the volume of fluid that the patients received, or the rate at which it was administered, which is why we chose to look only at patients who exclusively received either LR or NS during the first 48 hours. Only 7% of the study patients with AP exclusively used LR, which may have led to a sampling bias. Finally, our multivariable model is built on the cutoff of 4 days, which while well founded in the literature, it remains speculative that patients who are hospitalized for longer than 4 days represent a more severe disease state cohort.

In conclusion, our data shows that the use of LR was associated with a decreased length of hospital stay and admission cost. Furthermore, the use of LR in pediatric AP is on the rise, albeit with some variation based on geographic location and service line. More investigation is warranted to answer questions regarding the benefits of LR in AP, mechanism of action, and the exact volume needed amongst other related questions. Prospective randomized control trials are needed in the future in order to evaluate the potential benefit of LR in the pediatric AP population.

Abbreviations:

AP

Acute Pancreatitis

NS

Normal Saline

LR

Lactated Ringers

PHIS

Pediatric Health Information System

CRP

C-Reactive Protein

SIRS

Systemic Inflammatory Response Syndrome

IAP

International Association of Pancreatology

APA

American Pancreatic Association

ICU

Intensive Care Unit

ED

Emergency Department

LOS

Length of Stay

ICD-9

International Classification of Diseases, Ninth Revision

ICD-10

International Classification of Diseases, Tenth Revision

IRB

Institutional Review Board

TPN

Total Parenteral Nutrition