“Fluid resuscitation with lactated Ringer’s solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial“
E de-Madaria, I Herrera-Marante, V Gonza´lez-Camacho, et al.
United European Gastroenterol J. 2018 Feb;6(1):63-72. doi: 10.1177/2050640617707864. Epub 2017 Apr 27. [Full Text]
The treatment of acute pancreatitis is purely supportive with one of the mainstays of that support being intravenous hydration. There seems to be a general belief that LR is “better” for pancreatitis than NS. This is an example of the importance of understanding the evidence behind a treatment strategy and how sometimes what becomes common practice has deviated from the primary source outcomes.
Indeed LR has been shown to improve pancreatitis surrogate “outcomes”. The key is knowing what those outcome measures were. It is then up to the clinician to determine that outcome’s clinical meaningfulness. A close review may have one reconsidering if IV hydration, type or quantity, remains a “mainstay” in acute pancreatitis management.
Adults 18 ≥yo (n = 676) admitted with acute pancreatitis (AP) at a single center in Spain were eligible. AP required 2 of 3 to be true: (1) typical pancreatitis abdominal pain, an (2) Amylase or Lipase ≥3x ULN, or (3) consistent cross sectional imaging. AP had to be the final discharge diagnosis as well (few patients were mis diagnosed and excluded)
Exclusion criteria included the following (of note 64% during the study period were not eligible):
- Baseline Cr > 2mg/dL, on iHD
- NHYA ≥2
- Chronic Lung dz on O2
- Na <135 or >145 mEq/L
- Acute infection
- Chronic infection (i.e., HIV, TB)
Methods and Protocol
The study was triple blided, in that researchers, treating team and statistical analyses were blided to assignments. The primary outcomes were related to surrogates of systemic inflammation: ≥2 SIRS Criteria at 24, 48, and 72 hr as well as median CRP at 48 and 72 hr. The authors also had secondary outcomes looking at the in-vitro cytokine response of macrophages from patients in each group.
ALL pts received 1L of D10% with no justification given for this by the authors. Then the groups received LR or NS based on group assignment in the following planned protocols:
- 10 mL/kg over 60 min (70 kg ~ 700 mL), then
- 1 mL/kg/hr x3 days (70 kg = ~1.7 L/d = ~5 L total)
The exception was for those needing more aggressive fluid resuscitation, defined by either a HCT >44%, BUN >20 mg/dL, ≥2 SIRS criteria, or signs of dehydration. In that case the fluid protocol was as follow
- 15 mL/kg over 60 min (70 kg ~1 L), then
- 1.2 mL/kg/hr over 3 days (70 kg = ~2 L/d = ~6 L total)
A total of 40 patients were enrolled – based on the assumption this number of patients could show a difference in 100 mg/dL change in CRP between LR and NS. In the LR there were 19 and in NS group 21.
The groups were statistically similar at baseline but the NS group had more patients with ≥2 SIRS (66%) compared to LR (47%). Additionally, in the end the NS group received about 1 more L of fluid compared to the LR group (5.9L LR vs. 6.9L NS, P=0.045) because of the predefined hydration protocols.
There were no differences at any timepoint in the proportion of ≥2 SIRS criteria. The CRP did not rise as high in the LR group, either at 48 hr – 28 vs. 168 mg/DL (P=0.037), or at 72 hr – 25 vs. 217 mg/DL (P=0.043)
An interesting but secondary outcome was that more IL-1B and TNFa RNA expression occurred in the LR group, with more suppression of MRC-1. These differences are shown shown in the article Figure 4.
In a small study the authors did show a difference in CRP between LR and NS, proposed to be either from the hyperchloremia induced by NS or a direct LR immune effect. The authors state “Lactated Ringer’s is associated with an anti-inflammatory effect in patients with acute pancreatitis” and do not make further reaching claims about superiority, but rather recommend a definitive RCT (that they estimate will require >600 patients).
This study and an earlier, similarly small study of 40 pts (which showed no CRP difference but did show a SIRS difference) , along with trials including both LR and NS but not distinguishing between each  have since become the basis for LR “superiority” in AP. But a review of the evidence by Vege et al. for the AGA found the existing evidence to be of “very low quality” and that LR has not been shown to effect any meaningful clinical outcomes, such as mortality or multiple organ failure .
There may not be harm in utilizing LR instead of NS for AP, and guidelines favor LR based on this limited evidence. The bigger context is that fluid resuscitation for AP, long thought of key importance for preventing or limiting complications such as necrosis, has a similarly “paltry” evidence base that is of poor quality. So much so that fluids in general for AP are “anybody’s guess” .
- Wu BU, Hwang JQ, Gardner TH, et al., Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011 Aug;9(8):710-717.e1. doi: 10.1016/j.cgh.2011.04.026. Epub 2011 May 12. PMID: 21645639.
- Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial Medical Treatment of Acute Pancreatitis: American Gastroenterological Association Institute Technical Review. Gastroenterology. 2018 Mar;154(4):1103-1139. doi: 10.1053/j.gastro.2018.01.031. Epub 2018 Feb 6.
- Haydock MD, Mittal A, Wilms HR, Phillips A, Petrov MS, Windsor JA. Fluid therapy in acute pancreatitis: anybody’s guess. Ann Surg. 2013 Feb;257(2):182-8. doi: 10.1097/SLA.0b013e31827773ff. PMID: 23207241.