Sepsis remains a leading cause of mortality in critically ill patients, particularly those with intra-abdominal infections, which account for up to two-thirds of surgical sepsis cases. Despite extensive research, treatment has been limited to infectious source control, antibiotics, and supportive care. Excessive immune activation, particularly from splenic cytokine production, drives systemic inflammation and organ failure in sepsis. Emerging evidence suggests oral sodium bicarbonate (NaHCO3) may induce a splenic anti-inflammatory phenotype. The present study postulated that direct topical splenic application of NaHCO3 during source control laparotomy may attenuate splenic proinflammatory signaling and improve survival in rats with feculent peritonitis.
Methods:
Male Sprague-Dawley rats underwent cecal ligation and incision (CLI) to induce sepsis. Two hours post-CLI, animals underwent peritoneal washout with either physiologic saline (0.5 mL/g, PS, control), 0.1 mEq/mL NaHCO3 (bicarbonate peritoneal washout group), PS washout plus topical splenic NaHCO3 application (1 mEq/mL, 1 µL/g), or PS washout with osmolality-matched 5.8% hypertonic saline (HTS) topical splenic application (osmolality control, 1 µL/g). Survival was monitored for 10 days.
Results:
Peritoneal NaHCO3 washout prolonged survival (median 13.5 vs. 9.0 h, p = 0.01); however, all animals died within 36 h. In contrast, topical splenic NaHCO3 resulted in 60% survival at 10 days, an effect not replicated with HTS. Splenic NaHCO3 application inhibited the Caspase-1/NLRP3/IL-1β axis, neutrophil extracellular traps and promoted an anti-inflammatory M2 phenotype.
Conclusion:
Topical splenic NaHCO3 application was associated with improved survival in severe intra-abdominal sepsis by modulating splenic immune function. This novel tactic holds translational potential as a targeted immunomodulatory adjunct during surgical source control.
FleischmannC, ScheragA, AdhikariNK, et al.; International Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis. current estimates and limitations. Am J Respir Crit Care Med, 2016; 193(3):259–272; doi: 10.1164/rccm.201504-0781OC
2.
SingerM, DeutschmanCS, SeymourCW, et al.The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 2016; 315(8):801–810; doi: 10.1001/jama.2016.0287
3.
AngusDC, van der PollT. Severe sepsis and septic shock. N Engl J Med, 2013; 369(9):840–851; doi: 10.1056/NEJMra1208623
4.
RheeC, DantesR, EpsteinL, et al.; CDC Prevention Epicenter Program. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA, 2017; 318(13):1241–1249; doi: 10.1001/jama.2017.13836
5.
BariePS, WilliamsMD, McCollamJS, et al.; PROWESS Surgical Evaluation Committee. Benefit/risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis. Am J Surg, 2004; 188(3):212–220; doi: 10.1016/j.amjsurg.2004.06.008
6.
HotchkissRS, MoldawerLL, OpalSM, et al.Sepsis and septic shock. Nat Rev Dis Primers, 2016; 2:16045; doi: 10.1038/nrdp.2016.45
7.
ShahAD, MacCallumNS, HarrisS, et al.Descriptors of sepsis using the sepsis-3 criteria: A cohort study in critical care units within the U.K. national institute for health research critical care health informatics collaborative. Crit Care Med, 2021; 49(11):1883–1894; doi: 10.1097/CCM.0000000000005169
8.
DoganyigitZ, ErogluE, AkyuzE. Inflammatory mediators of cytokines and chemokines in sepsis: From bench to bedside. Hum Exp Toxicol, 2022; 41:9603271221078871; doi: 10.1177/09603271221078871
9.
van der PollT, van de VeerdonkFL, SciclunaBP, et al.The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol, 2017; 17(7):407–420; doi: 10.1038/nri.2017.36
10.
WillisRNJr, CharlesEJ, GuidryCA, et al.Effect of hypothermia on splenic leukocyte modulation and survival duration in severely septic rats. J Surg Res, 2017; 215:196–203; doi: 10.1016/j.jss.2017.03.060
11.
TianY, PanD, ChordiaMD, et al.The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE. Basic Res Cardiol, 2016; 111(6):62; doi: 10.1007/s00395-016-0583-0
12.
TianY, FrenchBA, KronIL, et al.Splenic leukocytes mediate the hyperglycemic exacerbation of myocardial infarct size in mice. Basic Res Cardiol, 2015; 110(4):39; doi: 10.1007/s00395-015-0496-3
13.
ZhangAY, MarshKM, RastogiR, et al.Topical neck cooling prolongs survival of rats with intra-abdominal feculent sepsis by activation of the Vagus nerve. Int J Mol Sci, 2021; 22(18):9828; doi: 10.3390/ijms22189828
14.
ZhangA, CharlesEJ, XingJ, et al.Pulsed ultrasound of the spleen prolongs survival of rats with severe intra-abdominal sepsis. J Surg Res, 2021; 259:97–105; doi: 10.1016/j.jss.2020.11.005
15.
MaoJY, ZhangJH, ChengW, et al.Effects of neutrophil extracellular traps in patients with septic coagulopathy and their interaction with autophagy. Front Immunol, 2021; 12:757041; doi: 10.3389/fimmu.2021.757041
16.
TianY, RussoRM, LiY, et al.Serum citrullinated histone H3 concentrations differentiate patients with septic verses non-septic shock and correlate with disease severity. Infection, 2021; 49(1):83–93; doi: 10.1007/s15010-020-01528-y
17.
DengQ, PanB, AlamHB, et al.Citrullinated histone H3 as a therapeutic target for endotoxic shock in mice. Front Immunol, 2019; 10:2957; doi: 10.3389/fimmu.2019.02957
18.
HustonJM, OchaniM, Rosas-BallinaM, et al.Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med, 2006; 203(7):1623–1628; doi: 10.1084/jem.20052362
19.
Rosas-BallinaM, OchaniM, ParrishWR, et al.Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A, 2008; 105(31):11008–11013; doi: 10.1073/pnas.0803237105
20.
KohoutovaM, HorakJ, JarkovskaD, et al.Vagus nerve stimulation attenuates multiple organ dysfunction in resuscitated porcine progressive sepsis. Crit Care Med, 2019; 47(6):e461–e469; doi: 10.1097/ccm.0000000000003714
21.
McMastersKM, CheadleWG. Regulation of macrophage TNF alpha, IL-1 beta, and Ia (I-A alpha) mRNA expression during peritonitis is site dependent. J Surg Res, 1993; 54(5):426–430; doi: 10.1006/jsre.1993.1067
22.
VelissarisD, KaramouzosV, KtenopoulosN, et al.The use of sodium bicarbonate in the treatment of acidosis in sepsis: A literature update on a long term debate. Crit Care Res Pract, 2015; 2015:605830; doi: 10.1155/2015/605830
23.
RaySC, BabanB, TuckerMA, et al.Oral NaHCO(3) activates a splenic anti-inflammatory pathway: Evidence that cholinergic signals are transmitted via mesothelial cells. J Immunol, 2018; 200(10):3568–3586; doi: 10.4049/jimmunol.1701605
24.
AlvarezMR, AlkaissiH, RiegerAM, et al.The immunomodulatory effect of oral NaHCO(3) is mediated by the splenic nerve: Multivariate impact revealed by artificial neural networks. J Neuroinflammation, 2024; 21(1):79; doi: 10.1186/s12974-024-03067-x
25.
MannonEC, SunJ, WilsonK, et al.A basic solution to activate the cholinergic anti-inflammatory pathway via the mesothelium? Pharmacol Res, 2019; 141:236–248; doi: 10.1016/j.phrs.2019.01.007
26.
ZhangZ, ZhuC, MoL, et al.Effectiveness of sodium bicarbonate infusion on mortality in septic patients with metabolic acidosis. Intensive Care Med, 2018; 44(11):1888–1895; doi: 10.1007/s00134-018-5379-2
27.
HuangS, PengY, WangL, et al.Effectiveness of sodium bicarbonate infusion on mortality for elderly septic patients with acute metabolic acidosis. Front Pharmacol, 2022; 13:974271; doi: 10.3389/fphar.2022.974271
28.
BlankSP, BlankRM, LauplandKB, et al.; Queensland Critical Care Research Network (QCCRN). Sodium bicarbonate administration for metabolic acidosis in the intensive care unit: A target trial emulation. Intensive Care Med, 2025; 51(6):1078–1086; doi: 10.1007/s00134-025-07979-x
29.
KrautJA, MadiasNE. Intravenous sodium bicarbonate in treating patients with severe metabolic acidemia. Am J Kidney Dis, 2019; 73(4):572–575; doi: 10.1053/j.ajkd.2018.08.011
30.
SlimMA, van MourikN, DionneJC, et al.Personalised immunotherapy in sepsis: A scoping review protocol. BMJ Open, 2022; 12(5):e060411; doi: 10.1136/bmjopen-2021-060411
31.
RizoliSB, RhindSG, ShekPN, et al.The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: A randomized, controlled, double-blinded trial. Ann Surg, 2006; 243(1):47–57; doi: 10.1097/01.sla.0000193608.93127.b1
32.
PascualJL, FerriLE, SeelyAJ, et al.Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil rolling and adherence to endothelium and reduces in vivo vascular leakage. Ann Surg, 2002; 236(5):634–642; doi: 10.1097/00000658-200211000-00014
33.
OuyangW, ChenY, TanT, et al.A citrullinated histone H3 monoclonal antibody for immune modulation in sepsis. Nat Commun, 2025; 16(1):7435; doi: 10.1038/s41467-025-62788-6
34.
RhodesA, EvansLE, AlhazzaniW, et al.Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med, 2017; 45(3):486–552; doi: 10.1097/CCM.0000000000002255
35.
LiaoF, FanJ, WangR, et al.Neutrophil extracellular traps in sepsis: Trade-off between pros and cons. Burns Trauma, 2025; 13:tkaf046; doi: 10.1093/burnst/tkaf046
36.
ChenY, TetzZA, ZengX, et al.CitH3, a druggable biomarker for human diseases associated with acute NETosis and chronic immune dysfunction. Pharmaceutics, 2025; 17(7):809; doi: 10.3390/pharmaceutics17070809
37.
WeberM, ChenY, ZhouX, et al.Humanized Monoclonal Antibody Against Citrullinated Histone H3 Attenuates Myocardial Injury and Prevents Heart Failure in Rodent Models. 2025.
38.
de BontCM, KoopmanWJH, BoelensWC, et al.Stimulus-dependent chromatin dynamics, citrullination, calcium signalling and ROS production during NET formation. Biochim Biophys Acta Mol Cell Res, 2018; 1865(11 Pt A):1621–1629; doi: 10.1016/j.bbamcr.2018.08.014
39.
SmithJW, Neal GarrisonR, MathesonPJ, et al.Adjunctive treatment of abdominal catastrophes and sepsis with direct peritoneal resuscitation: Indications for use in acute care surgery. J Trauma Acute Care Surg, 2014; 77(3):393–398; discussion 398-9; doi: 10.1097/ta.0000000000000393
40.
LichtensternC, ZimmermannJB, RahbariNN, et al.Patients suffering due to complicated peritonitis may not benefit from splenectomy: Clinical data from a retrospective study. J Surg Res, 2011; 167(2):e345–e355; doi: 10.1016/j.jss.2010.10.021
41.
ZellwegerR, WichmannMW, AyalaA, et al.Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med, 1997; 25(1):106–110; doi: 10.1097/00003246-199701000-00021
42.
El-LakanyMA, FoudaMA, El-GowelliHM, et al.Gonadal hormone receptors underlie the resistance of female rats to inflammatory and cardiovascular complications of endotoxemia. Eur J Pharmacol, 2018; 823:41–48; doi: 10.1016/j.ejphar.2018.01.051
SharawyN, PavlovicD, WendtM, et al.Evaluation of the effects of gender and estradiol treatment on the intestinal microcirculation during experimental sepsis. Microvasc Res, 2011; 82(3):397–403; doi: 10.1016/j.mvr.2011.06.010
