Negative Anion Gap in Critically Ill Patients: A Case Study of Metabolic Alkalosis and Clinical Strategies

Introduction

Patients admitted to the intensive care unit (ICU) are characterized by critical conditions, complex and changeable conditions, multiple system involvement, and unstable vital signs. Arterial blood gas analysis is a routine detection method for ICU patients, which can quickly reflect the patient’s respiratory function, acid-base balance, oxygenation status, and other parameters, among which the anion gap is an important clinical parameter for assessing acid-base imbalances, with a normal reference range of approximately 8 to 16 mmol/L. A negative anion gap is rare in clinical practice and has been reported in cases of salicylate poisoning. However, to date, there have been no documented reports of severe metabolic alkalosis associated with a negative anion gap. Recently, our hospital successfully applied critical care dialectical thinking in the diagnosis and treatment of a patient with mixed acid-base imbalance, presenting with a negative anion gap.

Case Report

A 73-year-old married woman, a farmer by occupation and weighing 55 kg, had a history of interstitial lung fibrosis for over 4 years, for which she had been treated with pirfenidone and prednisone. She also had a 1-year history of coronary artery disease and was receiving treatment with nicorandil and spironolactone (20 mg, twice/day). She was admitted to the hospital on December 23, 2024 due to “dyspnea and chest distress after activity for more than 10 days, and aggravation for 5 days”.

Physical Examination: At admission, the patient’s temperature was 37.8°C, pulse 77 beats/min, respiratory rate 24 breaths/min, and blood pressure 130/74 mmHg. The patient was alert, but with a poor mental state. Her lung auscultation revealed symmetric breath sounds, with crackles audible in both lower lung fields, and mild edema was noted in both lower limbs. The results of other physical examinations were normal.

Auxiliary examinations revealed the following values. (1) Blood biochemistry: alanine aminotransferase 72 U/L, aspartate aminotransferase 85 U/L, albumin 33 g/L, potassium level 2.73 mmol/L, sodium level 134.6 mmol/L, chloride level 81.4 mmol/L, urea nitrogen 16.96 mmol/L, creatinine 55.2 μmol/L, uric acid 334 μmol/L. (2) Cardiac indicators: cardiac troponin I 0.659 ng/mL, N-terminal pro B-type natriuretic peptide 20 501 pg/mL. (3) Inflammatory markers: white blood cells 6.40×109/L, lymphocyte count 0.58×109/L, c-reactive protein 6.06 mg/L, procalcitonin 0.20 ng/mL. (4) Immunological markers: CD4 T lymphocyte count 195 cells/μL, CD8 T lymphocyte count143 cells/μL, NK cell count 142 cells/μL, B cell count 78 cells/μL. (5) Arterial blood gas analysis (radiometer, detection via electrochemical method): pH 7.54, partial pressure of carbon dioxide 72 mmHg, partial pressure of oxygen 152 mmHg, fraction of inspired oxygen 60%, sodium 134 mmol/L, potassium 2.5 mmol/L, calcium 0.84 mmol/L, magnesium 0.71 mmol/L, chloride 84 mmol/L, glucose concentration 7.1 mmol/L, lactate 1.00 mmol/L, anion gap −9.30, actual bicarbonate 61.6 mmol/L, extracellular base excess 39.1 mmol/L. (6) Hypertension-related triple tests: renin activity 0.76 ng/(mL·h), angiotensin II 35 pg/mL, aldosterone 12 ng/dL. (7) Imaging examination: Chest computed tomography (CT) showed interstitial pneumonia, pulmonary fibrosis, pulmonary consolidation, and pleural effusion (Figure 1). (8) On December 25, the t-NGS results of the bronchoalveolar lavage fluid showed that influenza A virus was 188 053×106 copies/mL, Aspergillus flavus was 128 880×105 copies/mL, Aspergillus fumigatus was 64 762×105 copies/mL, and Pseudomonas aeruginosa was 13 810×105 copies/mL; sputum culture results indicated the growth of P. aeruginosa, and the galactomannan assay result was 6.25 μg/L.

Treatment and prognosis: The patient was admitted with the following diagnoses: (1) pulmonary interstitial fibrosis with infection; (2) respiratory failure (type II respiratory failure); (3) coronary atherosclerotic heart disease, moderate pulmonary hypertension, and cardiac insufficiency; (4) electrolyte metabolism disorders (hypokalemia, hyponatremia); (5) hepatic insufficiency; (6) pleural effusion. After admission, the patient was first provided with mechanical ventilation via endotracheal intubation, and empirical antimicrobial therapy with piperacillin-tazobactam was initiated. At the same time, pirfenidone was administered for antifibrotic therapy, corticosteroids for the treatment of interstitial pneumonia, and antispasmodic drugs to relieve bronchospasm and facilitate sputum clearance. Bronchoalveolar lavage fluid was collected to search for pathogenic evidence. Furthermore, the patient underwent a comprehensive therapeutic regimen encompassing percutaneous coronary intervention, optimization of cardiac function, correction of electrolyte disturbances, and management of acid-base imbalances. Following an 8-day intensive treatment period, the patient achieved successful ventilator weaning and transitioned to high-flow nasal cannula oxygen therapy. On January 3, 2025, the patient was successfully transferred to the Department of Respiratory Medicine and discharged 4 days later (with diuretics having been discontinued at the time of transfer). At a 2-week follow-up, there was no recurrence of metabolic alkalosis.

Discussion

Arterial blood gas analysis is one of the rapid bedside detection protocols for critically ill patients. It enables quick assessment of respiratory function and metabolic status, playing a vital role in guiding early clinical decision-making for critically ill individuals. In critically ill patients, disturbances of the internal environment often result in mixed acid-base disorders. In the patient’s first arterial blood gas analysis after admission, an anion gap of −9.3 mmol/L and a bicarbonate concentration as high as 61.6 mmol/L were observed, which is a rare finding in clinical practice. After laboratory re-evaluation excluded both analytical errors and bromide poisoning, the albumin-corrected anion gap (ACAG) [1], calculated using the standard formula, was −6.35 mmol/L. The anion gap is an important parameter for assessing acid-base imbalances. While normal or elevated anion gap values in acid-base disorders are commonly encountered and aid in differentiating types of metabolic acidosis and diagnosing mixed acid-base disturbances, reports of decreased or even negative anion gap values are relatively rare. Kashani [2] reported a retrospective study of 12 cases where salicylate toxicity caused pseudo-hyperchloremia, resulting in negative anion gap values. Yohei Komaru [3] reported a case of lithium toxicity leading to a negative anion gap value. Additionally, according to published literature, causes of a negative anion gap include laboratory errors, specimen contamination or interference, hypoalbuminemia, severe hyperkalemia [4], bromine poisoning, and [5] paraproteins associated with multiple myeloma or similar pathological processes.

According to Professor Dubin’s 6-step arterial blood gas analysis method, we first confirmed that the hydrogen ion concentration corresponded to the actual pH value, indicating that the specimen was valid and suitable for further analysis. We hypothesized that the patient had primary metabolic alkalosis. According to the compensation formula for metabolic alkalosis (PaCO2=40+0.9×(HCO3−-24)±5 mmHg, with a compensation limit of 55 mmHg), the actual measured PaCO2 exceeded the compensation limit, suggesting the presence of primary metabolic alkalosis combined with respiratory acidosis (both secondary and primary). While traditional approaches, such as the Henderson-Hasselbalch equation and bicarbonate-based analysis, are helpful in identifying alkalosis, they fail to explain the underlying mechanisms of a negative anion gap or elevated bicarbonate levels. Therefore, we employed the Stewart approach [6], based on the concept of Strong Ion Difference (SID), to further evaluate the acid-base disturbance. The SID was calculated as (134+2.5+0.84+0.71)-84=138.05-84=54.05 mmol/L. The normal SID is approximately 40 mmol/L; thus, a value of 54.05 mmol/L indicates a significantly elevated SID, which typically reflects a loss of chloride relative to sodium and potassium, or an excess of unmeasured cations, while implying the presence of metabolic alkalosis in the patient.

The patient still presented with hypokalemia despite taking potassium-sparing diuretics. Could she be using other diuretics concurrently? Upon further inquiry into the patient’s medical history, it was found that the patient had started taking torasemide (10 mg, 4 times/day) for diuresis, edema reduction, and improvement of cardiac function 6 months ago. Metabolic alkalosis can be broadly classified into 2 categories based on chloride responsiveness: chloride-responsive and chloride-unresponsive. This classification provides a clinically useful approach to understanding the pathophysiology and directing management. In the present case, the patient exhibited persistent hypokalemia, hypochloremia, and had a documented history of long-term torasemide (loop diuretic) use, which is a classic trigger for chloride-responsive metabolic alkalosis. Loop diuretics impair chloride reabsorption in the thick ascending limb, leading to volume contraction and enhanced bicarbonate reabsorption. Although the patient was also on potassium-sparing diuretics, the persistent hypokalemia suggests inadequate counterbalance. Furthermore, chronic glucocorticoid therapy may contribute indirectly to alkalosis by promoting renal potassium loss and enhancing mineralocorticoid effects, although it is rarely the sole cause of severe alkalosis. The possibility of primary hyperaldosteronism was also considered and ruled out by normal plasma renin, aldosterone levels, and absence of refractory hypertension, thus excluding a chloride-unresponsive etiology. Taken together, the metabolic alkalosis in this case is best explained as chloride-responsive, driven primarily by chronic loop diuretic use and compounded by glucocorticoid-associated hypokalemia. Discontinuation of the offending agent and appropriate volume and electrolyte repletion led to correction of the alkalosis within 3 days. Arterial blood gas parameters were closely monitored throughout the therapeutic course (Figure 2).

When assessing and managing critically ill patients, intensivists should recognize that the clinical condition is inherently dynamic and may evolve rapidly over time. The patient’s condition rapidly progressed to respiratory failure in a short period. Was this due to the gradual worsening of interstitial lung disease leading to decompensation, or did some factor (such as infection) exacerbate the condition? The patient had been receiving long-term glucocorticoid therapy, and lymphocyte count and functional assays at admission revealed combined deficiencies in both cellular and humoral immunity. The patient presented with moderate fever and dyspnea, and chest imaging at admission revealed interstitial pneumonia complicated by infection. The causative pathogen was identified based on t-NGS testing, and the antimicrobial regimen was promptly adjusted. Ultimately, the patient’s condition stabilized, acid-base disturbances were corrected, and the patient was discharged in good condition.

This case provides a valuable opportunity to clarify the clinical meaning of a negative AG, a phenomenon that is often misunderstood. In this context, the negative anion gap does not represent a disease entity but arises as a mathematical artifact resulting from markedly elevated bicarbonate and profound hypochloremia in the setting of chloride–depletion metabolic alkalosis. Notably, in metabolic alkalosis, the diagnostic utility of anion gap is limited; its primary function in this setting is to exclude analytical error and detect coexisting high–AG metabolic acidosis that may be masked by alkalosis. Furthermore, this case illustrates the utility of the Stewart approach – specifically, the concept of SID – in elucidating acid-base disturbances not fully explained by traditional bicarbonate-based models. Finally, it underscores the importance of recognizing loop diuretic–induced, chloride-responsive alkalosis, particularly when compounded by concurrent glucocorticoid therapy. These considerations may help clinicians avoid diagnostic error and apply a more physiologically grounded framework for acid-base interpretation in critically ill patients.

Conclusions

Acid-base disturbances are frequently encountered in critical care, but severe imbalances may present atypically and pose diagnostic challenges. Among these, metabolic alkalosis with a negative anion gap is exceptionally rare and often under-recognized. Clinicians must maintain high vigilance for atypical acid-base presentations and apply mechanistic reasoning when interpreting laboratory results. Moreover, the case illustrates the diagnostic and educational value of recognizing negative anion gap as a rare but predictable mathematical consequence of severe chloride–depletion alkalosis – an insight that may prevent misinterpretation of routine blood gas parameters.