UNRAVELING THE MYSTERY OF ACIDOSIS LIKE A 'BIG BANG'

Introduction:

Metabolic acidosis is a frequently encountered condition in critically ill patients, often resulting from underlying causes such as shock, sepsis, uremia, severe catabolic states, or intoxication. Refractory high anion gap metabolic acidosis (HAGMA), particularly when related to previously unrecognized inborn errors of metabolism (IEM), is challenging to manage due to its serious impact on myocardial contractility, cardiac output, and catecholamine responsiveness. Rapid identification and treatment of the underlying cause are crucial for effective management.

Sodium bicarbonate is commonly administered to correct the acid-base imbalance in severe cases of metabolic acidosis. However, its use, especially in large doses, is associated with complications such as hypernatremia, hypervolemia, and hyperosmolarity, particularly in patients with renal dysfunction. The challenge of managing IEMs is further compounded in resource-limited settings, where such complications and the lack of advanced therapies can hinder treatment. In these cases, peritoneal dialysis (PD) with bicarbonate-buffered dialysate offers a viable life-saving alternative.

We present a unique case of IEM with refractory metabolic acidosis, successfully managed through timely diagnosis, stabilization, and prompt therapy using peritoneal dialysis. Early intervention, appropriate supplementation, and patient compliance contributed to a favorable long-term outcome.

Methods:

A 4-month-old male infant, born to parents in a third-degree consanguineous marriage, was brought to the emergency department with severe respiratory distress. There was no history of fever, cough, changes in feeding patterns, or disturbances in urinary or bowel habits. The infant had not experienced convulsions and was otherwise growing well, with developmental milestones appropriate for his age.

The infant's medical history included a 14-day neonatal intensive care unit stay shortly after birth due to early-onset sepsis, pneumonia, and metabolic acidosis. He was not on any long-term medications other than maintenance vitamin D supplements.

Upon arrival at the hospital, the child was afebrile but pale and in severe respiratory distress, with a respiratory rate of 76 breaths per minute and signs of impaired perfusion. He was drowsy on examination, with a normal anterior fontanelle. His chest was clear, with no murmurs or organomegaly noted.

Initial investigations revealed normocytic anemia (Hb 6.6 g/dL, TLC 12,000/mm³, Platelets 345,000/mm³), acute kidney injury (AKI) stage 2 (BUN 5 mg/dL, Creatinine 0.5 mg/dL, urine output 0.5 mL/kg/hr), and acute liver failure (SGOT 6,900 U/L, SGPT 1,490 U/L, INR 2.8, Total Bilirubin 1.8 mg/dL, Direct Bilirubin 1.6 mg/dL, Serum Albumin 2.4 g/dL, RBS 56 mg/dL). The infant also had HAGMA (pH 6.89, pCO₂ 34 mmHg, HCO₃⁻ 4.2 mmol/L, Anion Gap 32), along with elevated ammonia (240 mmol/L) and lactate (2.46 mmol/L), raising the suspicion of an IEM.

Given the severity of his condition, the patient was promptly intubated and transferred to the pediatric intensive care unit, where he was initiated on mechanical ventilation, fluid resuscitation, packed red blood cell transfusion, hepatic drip, and N-acetylcysteine infusion. Intravenous sodium bicarbonate was administered to correct the metabolic acidosis. Blood cultures, a sepsis workup, and a comprehensive panel for inborn errors of metabolism (including Tandem Mass Spectrometry (TMS) and Gas Chromatography-Mass Spectrometry (GCMS)) were sent for further investigation.

Despite aggressive alkali therapy, the acidosis remained refractory, and the patient developed hypernatremia, with a serum sodium level of 167 mEq/L. At this point, the decision was made to initiate PD. An indigenously manufactured low-sodium, bicarbonate-buffered dialysate was used. Following the initiation of PD, there was marked improvement in the patient’s acid-base balance, correction of hypernatremia, and overall clinical condition, allowing for extubation and the start of enteral feeds.

However, three days later, the patient experienced a sudden clinical deterioration with the recurrence of life-threatening HAGMA. Additionally, there was a recurrence of anemia (Hb 5 g/dL, reticulocyte count 7%, LDH 1037 U/L, negative direct Coombs test), characterized as hemolytic in nature, without any evidence of bleeding. The patient was reintubated, resuscitated, and transfused.

Given the recurrence of HAGMA and the patient’s critical condition, a second session of bicarbonate-buffered peritoneal dialysis was initiated, leading to another improvement in his metabolic status. Following stabilization, the patient was transitioned to enteral feeds and oral alkali therapy.

Results:

During this time, the results of the urine GCMS were received, revealing elevated levels of 5-oxoproline, a metabolite indicative of Glutathione Synthetase Deficiency (GSSD). This finding, in conjunction with the clinical presentation of HAGMA, hemolytic anemia, and acute liver failure, confirmed the diagnosis of GSSD. The patient was subsequently started on high doses of Vitamin C, Vitamin E, and folic acid, while continuing high-dose alkali therapy.During this time, the results of the urine GCMS were received, revealing elevated levels of 5-oxoproline, a metabolite indicative of GSSD. This finding, in conjunction with the clinical presentation of HAGMA, hemolytic anemia, and acute liver failure, confirmed the diagnosis of GSSD. The patient was subsequently started on high doses of Vitamin C, Vitamin E, and folic acid, while continuing high-dose alkali therapy.

To confirm the diagnosis, Whole Exome Sequencing (WES) was performed, which identified a trans compound heterozygous missense mutation in the  Glutathione Synthetase (GSS) gene (c.1349 G>A, c.808T>C), classified as pathogenic according to American College of Medical Genetics and Genomics Guidelines. With the diagnosis of GSSD confirmed, the patient was initiated on high-dose antioxidant therapy, including Vitamin C, Vitamin E, and Selenium. Oral sodium bicarbonate and potassium citrate were also introduced to manage the ongoing metabolic acidosis.

Over the next five days, the patient’s acidosis gradually improved, allowing for the discontinuation of PD. Although the acidosis persisted, it did not reach a severity requiring another session of PD. By the sixth day of antioxidant therapy, the acidosis began improving further, but it remained necessary to continue alkali therapy for its management.

The patient was eventually discharged with detailed instructions for ongoing management, including antioxidant supplements, folic acid, oral alkali agents, and dietary recommendations to increase the intake of antioxidant-rich foods during weaning. The parents were also advised to avoid medications contraindicated in Glucose 6 Phosphatase Deficiency (G6PD) due to the potential risk of triggering hemolysis. The case was closely followed, and the patient demonstrated stable metabolic parameters and appropriate growth during subsequent follow-up visits.

Conclusions:

This case highlights the challenges in managing a child with an IEM who developed severe, refractory HAGMA. The condition was initially stabilized using bicarbonate-buffered PD, demonstrating the critical importance of this intervention in complex metabolic crises. However, when the child experienced a sudden deterioration, a second session of PD was required due to the recurrence of life-threatening acidosis. The logistical hurdles of re-initiating PD, including timely access to dialysis resources and managing fluid overload and electrolyte imbalances, were key to the successful stabilization and recovery.

This case highlights that the combination of hemolytic anemia with HAGMA in an infant can serve as a vital clue to the presence of this disorder. It also emphasizes the pivotal role of bicarbonate-buffered PD in managing metabolic crises in these infants, particularly in settings where continuous renal replacement therapy (CRRT) is unavailable. CRRT requires specialized expertise, which may not always be accessible, making PD a viable and efficient alternative in critical situations.

It is important to note that commercially available dialysates for acute PD typically contain acetate or lactate as buffering agents. In cases of acute liver failure, the conversion of lactate to bicarbonate is often impaired, limiting the effectiveness of these dialysates. We observed that bicarbonate, as a physiological buffer, bypassed the need for metabolic conversion, making it a more logical and effective treatment in our case. The significant diffusion of lactate and bicarbonate during PD, driven by their concentration gradients, ensured efficient lactate removal and bicarbonate delivery without undesirable changes in osmolality or fluid volume.

These findings underscore the importance of considering bicarbonate-buffered peritoneal dialysis in similar clinical scenarios, particularly in patients with metabolic acidosis and impaired lactate metabolism, to optimize treatment outcomes and minimize complications.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.