{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T08:05:54Z","timestamp":1784880354145,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Albumin administration in sepsis and septic shock remains controversial because of uncertain clinical benefits and complex acid\u2013base effects. Unlike crystalloids, albumin influences acid\u2013base equilibrium through effects on chloride balance, strong ion difference (SID), buffering systems, and weak acid concentration. These effects may be interpreted differently by the traditional bicarbonate-centered framework and Stewart\u2019s physicochemical approach. In the traditional paradigm, albumin acts mainly as a non-bicarbonate plasma buffer influencing base excess and anion gap interpretation. In the Stewart framework, albumin is a weak non-volatile acid contributing to total weak acids (Atot), thereby influencing hydrogen ion dissociation and pH regulation. This narrative review compares these two approaches to albumin-related acid\u2013base physiology in sepsis, with emphasis on chloride balance, strong ion difference, hypoalbuminemia, dilutional effects, and cardiorespiratory interactions during mechanical ventilation and septic shock. We also contextualize these mechanisms within major randomized trials of albumin and resuscitation fluids and present illustrative conceptual simulations illustrating the directional acid\u2013base effects of different fluid compositions. The narrative review focuses on masked acidosis in hypoalbuminemic patients and on the interpretation of pH changes after albumin administration. Finally, we propose an integrated bedside framework combining traditional, physicochemical, respiratory, and hemodynamic variables for acid\u2013base interpretation during fluid resuscitation.<\/jats:p>","DOI":"10.3390\/jcm15155789","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:36:13Z","timestamp":1784878573000},"page":"5789","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Acid\u2013Base Effects of Albumin in Sepsis: Reconciling the Stewart Physicochemical Approach with the Traditional Buffer\u2013Base Paradigm"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7136-0343","authenticated-orcid":false,"given":"Daniele","family":"Orso","sequence":"first","affiliation":[{"name":"Department of Anesthesia and Intensive Care Medicine, \u201cSanta Maria della Misericordia\u201d Udine University Hospital, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Saro","sequence":"additional","affiliation":[{"name":"Department of Medicine (DMED), University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Della Rocca","sequence":"additional","affiliation":[{"name":"Department of Medicine (DMED), University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1097\/CCM.0000000000007089","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026","volume":"54","author":"Prescott","year":"2026","journal-title":"Crit. Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1056\/NEJMoa2202707","article-title":"Restriction of Intravenous Fluid in ICU Patients with Septic Shock","volume":"386","author":"Meyhoff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Shapiro, N.I., Douglas, I.S., Brower, R.G., Brown, S.M., Exline, M.C., Ginde, A.A., Gong, M.N., Grissom, C.K., and Hayden, D. (2023). Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N. Engl. J. Med., 388, 499\u2013510.","DOI":"10.1056\/NEJMoa2212663"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1056\/NEJMoa040232","article-title":"A comparison of albumin and saline for fluid resuscitation in the intensive care unit","volume":"350","author":"Finfer","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1056\/NEJMoa1305727","article-title":"Albumin replacement in patients with severe sepsis or septic shock","volume":"370","author":"Caironi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2559297","DOI":"10.1001\/jamanetworkopen.2025.59297","article-title":"Albumin Replacement Therapy in Septic Shock: A Randomized Clinical Trial","volume":"9","author":"Sakr","year":"2026","journal-title":"JAMA Netw. Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jcrc.2016.04.019","article-title":"Fluid management in sepsis: The potential beneficial effects of albumin","volume":"35","author":"Vincent","year":"2016","journal-title":"J. Crit. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1002\/hep.20720","article-title":"Albumin: Biochemical properties and therapeutic potential","volume":"41","author":"Quinlan","year":"2005","journal-title":"Hepatology"},{"key":"ref_9","first-page":"259","article-title":"The clinical use of albumin: The point of view of a specialist in intensive care","volume":"7","author":"Caironi","year":"2009","journal-title":"Blood Transfus."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1152\/ajplegacy.1908.21.4.427","article-title":"The theory of neutrality regulation in the animal organism","volume":"21","author":"Henderson","year":"1908","journal-title":"Am. J. Physiol. -Leg. Content"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1007\/s00134-026-08416-3","article-title":"A pragmatic approach to complex acid base disturbances of critical illness: The \u201cStewart light\u201d","volume":"52","author":"Krbec","year":"2026","journal-title":"Intensive Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ciabattoni, A., Chiumello, D., Mancusi, S., Pozzi, T., Monte, A., Rocco, C., and Coppola, S. (2025). Acid-Base Status in Critically Ill Patients: Physicochemical vs. Traditional Approach. J. Clin. Med., 14.","DOI":"10.3390\/jcm14093227"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1152\/japplphysiol.00042.2021","article-title":"Stewart\u2019s approach to quantitative acid-base physiology should replace traditional bicarbonate-centered models","volume":"130","author":"Rubin","year":"2021","journal-title":"J. Appl. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A scale for the quality assessment of narrative review articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_15","unstructured":"Hasselbalch, K.A. (1916). Die Berechnung der Wasserstoffzahl des Blutes aus der Freien und Gebundenen Kohlens\u00e4ure Desselben, und die Sauerstoffbindung des Blutes als Funktion der Wasserstoffzahl, Springer."},{"key":"ref_16","first-page":"103","article-title":"Acidosis and Alkalosis","volume":"10","year":"1934","journal-title":"Bull. N. Y. Acad. Med."},{"key":"ref_17","first-page":"1","article-title":"The Acid-base Status of the Blood","volume":"15","year":"1963","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/S0140-6736(60)90930-2","article-title":"The acid-base metabolism. A new approach","volume":"1","author":"Astrup","year":"1960","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/0002-9343(78)90227-9","article-title":"The nature of the renal response to chronic disorders of acid-base equilibrium","volume":"64","author":"Schwartz","year":"1978","journal-title":"Am. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1139\/y83-207","article-title":"Modern Quantitative Acid-Base Chemistry","volume":"61","author":"Stewart","year":"1983","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1164\/ajrccm.162.6.9904099","article-title":"Diagnosis of metabolic acid-base disturbances in critically ill patients","volume":"162","author":"Fencl","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","first-page":"453","article-title":"The Role of Serum Proteins in Acid-Based Equilibria","volume":"117","author":"Figge","year":"1991","journal-title":"J. Lab. Clin. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1097\/00003246-199811000-00019","article-title":"Anion gap and hypoalbuminemia","volume":"26","author":"Figge","year":"1998","journal-title":"Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/bja\/aen148","article-title":"Physiological effects of hyperchloraemia and acidosis","volume":"101","author":"Handy","year":"2008","journal-title":"Br. J. Anaesth."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"162","DOI":"10.2215\/CJN.03020906","article-title":"Serum anion gap: Its uses and limitations in clinical medicine","volume":"2","author":"Kraut","year":"2007","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.lab.2005.07.008","article-title":"Influence of hypoalbuminemia or hyperalbuminemia on the serum anion gap","volume":"146","author":"Feldman","year":"2005","journal-title":"J. Lab. Clin. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/cc2189","article-title":"Closing the gap on unmeasured anions","volume":"7","author":"Kellum","year":"2003","journal-title":"Crit. Care"},{"key":"ref_28","first-page":"1151","article-title":"Hypoalbuminemi som \u00e5rsak til metabolsk alkalose [Hypoalbuminemia as a cause of metabolic alkalosis]","volume":"102","author":"Ystgaard","year":"1982","journal-title":"Tidsskr. Nor. Laegeforen."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1186\/cc3789","article-title":"Clinical review: Reunification of acid-base physiology","volume":"9","author":"Kellum","year":"2005","journal-title":"Crit. Care"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1093\/bja\/41.3.196","article-title":"Acid-base balance in blood","volume":"41","author":"Morgan","year":"1969","journal-title":"Br. J. Anaesth."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0883-9441(93)90001-2","article-title":"A physical chemical approach to the analysis of acid-base balance in the clinical setting","volume":"8","author":"Gilfix","year":"1993","journal-title":"J. Crit. Care"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/cc2985","article-title":"Bench-to-bedside review: Fundamental principles of acid-base physiology","volume":"9","author":"Corey","year":"2005","journal-title":"Crit. Care"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1001\/jama.2012.13356","article-title":"Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults","volume":"308","author":"Yunos","year":"2012","journal-title":"JAMA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1001\/jama.2015.12334","article-title":"Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial","volume":"314","author":"Young","year":"2015","journal-title":"JAMA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1056\/NEJMoa1711584","article-title":"Balanced Crystalloids versus Saline in Critically Ill Adults","volume":"378","author":"Semler","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa1711586","article-title":"Balanced Crystalloids versus Saline in Noncritically Ill Adults","volume":"378","author":"Self","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1001\/jama.2021.11684","article-title":"Effect of Intravenous Fluid Treatment with a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial","volume":"326","author":"Zampieri","year":"2021","journal-title":"JAMA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1056\/NEJMoa2114464","article-title":"Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults","volume":"386","author":"Finfer","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1172\/JCI110820","article-title":"Regulation of renal blood flow by plasma chloride","volume":"71","author":"Wilcox","year":"1983","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s00134-005-2683-4","article-title":"Changes in acid-base balance following bolus infusion of 20% albumin solution in humans","volume":"31","author":"Bruegger","year":"2005","journal-title":"Intensive Care Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1136\/adc.87.6.526","article-title":"Correction of the anion gap for albumin in order to detect occult tissue anions in shock","volume":"87","author":"Hatherill","year":"2002","journal-title":"Arch. Dis. Child."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ejim.2023.07.003","article-title":"Albumin administration in internal medicine: A journey between effectiveness and futility","volume":"117","author":"Pompili","year":"2023","journal-title":"Eur. J. Intern. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.annemergmed.2024.12.016","article-title":"Intervention with Concentrated Albumin for Undifferentiated Sepsis in the Emergency Department (ICARUS-ED): A Pilot Randomized Controlled Trial","volume":"86","author":"Williams","year":"2025","journal-title":"Ann. Emerg. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1513\/AnnalsATS.201409-426OI","article-title":"Practical approach to physical-chemical acid-base management. Stewart at the bedside","volume":"12","author":"Magder","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_45","first-page":"257","article-title":"Albumin as a drug: Its biological effects beyond volume expansion","volume":"22","author":"Bihari","year":"2020","journal-title":"Crit. Care Resusc."},{"key":"ref_46","first-page":"624","article-title":"Albumin is an interface between blood plasma and cell membrane, and not just a sponge","volume":"15","author":"Joles","year":"2021","journal-title":"Clin. Kidney J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.bjae.2023.03.002","article-title":"The respiratory system and acid-base disorders","volume":"23","author":"Pippalapalli","year":"2023","journal-title":"BJA Educ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1186\/cc9238","article-title":"Bench-to-bedside review: Hypercapnic acidosis in lung injury\u2014From \u2018permissive\u2019 to \u2018therapeutic\u2019","volume":"14","author":"Ijland","year":"2010","journal-title":"Crit. Care"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/cc7116","article-title":"Bench-to-bedside review: Ventilatory abnormalities in sepsis","volume":"13","author":"Magder","year":"2009","journal-title":"Crit. Care"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lee, T.H., Kuo, G., Chang, C.H., Huang, Y.T., Yen, C.L., Lee, C.C., Fan, P.C., and Chen, J.J. (2021). Diuretic effect of co-administration of furosemide and albumin in comparison to furosemide therapy alone: An updated systematic review and meta-analysis. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0260312"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2110-5820-1-16","article-title":"Fluid management in acute lung injury and ards","volume":"1","author":"Roch","year":"2011","journal-title":"Ann. Intensive Care"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"R169","DOI":"10.1186\/cc9264","article-title":"Pulmonary vascular and right ventricular dysfunction in adult critical care: Current and emerging options for management: A systematic literature review","volume":"14","author":"Price","year":"2010","journal-title":"Crit. Care"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/j.1365-2044.2007.04941.x","article-title":"The short-term effect of hyperoncotic albumin, given alone or with furosemide, on oxygenation in sepsis-induced acute respiratory distress syndrome","volume":"62","author":"Kuper","year":"2007","journal-title":"Anaesthesia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40635-020-00319-x","article-title":"Fluids in ARDS: More pros than cons","volume":"8","author":"Mendes","year":"2020","journal-title":"Intensive Care Med. Exp."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Sinatra, N., Cuttone, G., Testa, T.S., Via, L., Rubulotta, F.M., Abrignani, M.G., Zumbino, C., Mul\u00e8, G., Geraci, G., and Carollo, C. (2026). Chloremia Disturbances in Critical Care: A Narrative Review of Pathophysiology, Clinical Impact and Management Strategies. Life, 16.","DOI":"10.3390\/life16010151"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1001\/jama.2013.280502","article-title":"Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: The CRISTAL randomized trial","volume":"310","author":"Annane","year":"2013","journal-title":"JAMA"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/15\/5789\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:56:56Z","timestamp":1784879816000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/15\/5789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":56,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jcm15155789"],"URL":"https:\/\/doi.org\/10.3390\/jcm15155789","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}