Clinical Cases of Refractory Hyperlactatemia in Pediatric Inpatients

Case 1: A 16-year-old male with no prior hospitalizations was admitted for urgent neurosurgical management of a craniopharyngioma, a benign brain tumor that grows adjacent to the pituitary gland. He underwent right transcortical craniotomy for tumor resection with right frontal external ventricular drain insertion. His postoperative course was complicated by central diabetes insipidus, a condition of antidiuretic hormone deficiency and subsequent polyuria, and a fluctuating level of consciousness preventing him from feeding orally. Nasogastric feeds were started four days postoperatively. While alert, he drank to thirst. Gastric absorption was likely impaired due to constipation, ileus, and dependent edema. Due to his central diabetes insipidus, he had polyuria with urine output >5 mL/kg/h while a steady state of vasopressin, then desmopressin, was achieved. In the first 11 days postoperative, he lost 8% of his body weight (4.2 kg), even with fluid replacements to a neutral balance. His lactate began climbing with levels peaking at 7.1 mmol/L (normal for age: 1.2 to 2.5 mmol/L; Fig. 1, A). Vital signs were stable with no evidence of end organ hypoperfusion. Septic workup was negative. An echocardiogram showed normal cardiac function. His fluid status was neutral, with urinary losses replaced. Liver function was normal with no hepatocellular injury. There were no new medication exposures, and no current medications were known to cause hyperlactatemia. Given his poor nutritional intake, absorption and ongoing polyuria, an alternative cause of his hyperlactatemia was considered. Hyperlactatemia and other laboratory markers in two pediatric inpatients. If multiple lab values were taken within a single indicated time period on the x axis, peak value is shown. (A), Case 1: lactate (mmol/L; black. Reference range for 1 to 10 years is 1.4 to 3.2 mmol/L; 10 to 15 years 1.2 to 3.0 mmol/L; >15 years 1.2 to 2.5 mmol/L) and triglycerides (mmol/L; dashed grey. No reported reference range in pediatrics) trend before and after the intervention presented in these cases; timing shown with dashed vertical line; (B), Case 2: lactate trend (mmol/L; black) throughout admission. Initial peak with hypovolemia, corrected with fluid resuscitation, then increase in lactate peaking 18 h post-admission. Initial therapy at low dose shown with dashed vertical line; dose increase shown with second heavier dashed line, continued for 7 day course. Case 2: A 6-year-old female with a history of developmental delay was admitted to hospital following a 1 month history of oral intake refusal and 10 days of emesis. Prior to this, she had been eating a selective diet of almost exclusively processed carbohydrates. At time of admission, she was noted to have dehydration requiring fluid resuscitation. Initial lactate at presentation was 3.5 mmol/L (normal for age: 1.4 to 3.2 mmol/L), which came down after a bolus of isotonic fluid (Fig. 1, B). On the second day of admission, she had hypophosphatemia and hypokalemia suggestive of refeeding syndrome, and was started on standard therapy of careful nutritional rehabilitation, phosphate replacement, and intravenous thiamine. Her lactate again peaked at 6.1 mmol/L (Fig. 1, B). Vital signs were stable with no clinical signs of hypoperfusion requiring further fluid resuscitation. There was no evidence for sepsis, and liver enzymes and abdominal ultrasound were negative. The patient was not on any medication known to cause hyperlactatemia. Given her developmental delay, a congenital inborn error of metabolism was considered, but deemed to be an unlikely cause of her lactic acid accumulation given her consistently normal measurements previously. What is the biochemical pathway of lactate production, and what necessary cofactors may contribute to lactate accumulation? Here, we present cases of hyperlactatemia improved with thiamine supplementation, from suspected thiamine deficiency. Thiamine is a water-soluble essential micronutrient with various functions including energy metabolism, neuronal function, and immune modulation. Thiamine is a cofactor for pyruvate dehydrogenase (PDH), which metabolizes pyruvate to fuel oxidative phosphorylation (1), an essential step in aerobic energy metabolism (Fig. 2). Deficiency of thiamine can cause an acquired mitochondrial dysfunction through functional PDH deficiency (2). Clinically and biochemically, this can mimic end organ dysfunction with a persistently elevated lactate. Each case presents an interesting consideration for risk factors for thiamine deficiency and hyperlactatemia. Energy metabolism and the role of thiamine. Simplified diagram of energy metabolism. Thiamine is a necessary cofactor for pyruvate dehydrogenase to continue to aerobic metabolism. In the absence of thiamine, pyruvate is unable to continue, and anaerobic metabolism produces lactate as a byproduct. What are the causes of refractory hyperlactatemia in the absence of end organ hypoperfusion? What additional laboratory markers may assist in the diagnosis? In case 1, risk factors for thiamine deficiency included poor nutrition and increased renal losses. Given the short half-life and limited storage of thiamine, individuals with poor nutritional intake, absorption abnormalities, high metabolic demand, or increased water-soluble vitamin losses are at risk for deficiency (3). Supportive evidence for thiamine deficiency was a concurrently elevated triglyceride level, both of which corrected with thiamine replacement (Fig. 1, A). Triglycerides accumulate in thiamine deficiency due to peroxisome dysfunction, specifically disrupted phytanic acid catabolism (4). With replacement, both lactate and triglycerides quickly normalized in our patient. This finding may serve as a potential biomarker for thiamine deficiency in the future. Interestingly, although this patient had multifactorial reasons for impaired cognition, symptoms of a fluctuating level of consciousness and motor impairment improved post-thiamine replacement. Sodium levels remained stable throughout the course and were not likely contributory. Post-replacement, he was then able to attend school, albeit with persisting slow speech and short-term memory loss. Oculomotor findings were never described, but fluctuating mental status and motor symptoms, specifically gait changes, improved with supplementation, which may be consistent with Wernicke encephalopathy, a known clinical syndrome related to thiamine deficiency that causes symptoms of confusion, altered cognition, gait instability, and visual symptoms. It is possible that after initial injury from neurosurgery, neurological recovery was further impaired by thiamine deficiency. The primary neurological structure for short-term memory, the hippocampus, was not directly impacted by surgery, but may have been affected by these postoperative nutritional and metabolic consequences. This patient’s subjective improvement in strength, energy, and his ability to attend physiotherapy sessions post-thiamine replacement may be a result of correction of deficiency and improved energy metabolism, and possible underlying Wernicke encephalopathy that improved symptoms of dyscoordination and ataxia. In the second case, the risk factor for thiamine deficiency was similarly poor nutrition. Thiamine is stored in the liver for only 2 weeks (3), and this patient had poor intake for at least 1 month, with clinical and biochemical evidence of malnutrition. It is likely that physiological stores of thiamine had been depleted. The initial elevated lactate on admission was secondary to hypovolemia, corrected with fluid resuscitation. The subsequent rapid rise in lactate may have been due to administration of glucose and substrate accumulation for energy metabolism, with inability to proceed to aerobic respiration with deficiency of thiamine as a necessary cofactor (Fig. 2). Ongoing replacement of thiamine, and an increase in dose, correlated with a rapid correction of lactate (Fig. 1, B). Here, we present a series of cases of refractory hyperlactatemia in pediatric inpatients, corrected with thiamine replacement. In pediatrics, thiamine is gaining global recognition as an important deficiency in low- and middle-income countries (5), however, is still underappreciated in a general pediatric clinical context (6). This suggests an under-recognized cause of hyperlactatemia in pediatric patients, and requires more conversation and consideration given the low-cost, low-harm intervention with the potential to alter clinical care and improve patient outcomes. All patients provided full written, informed consent. Thiamine is a necessary cofactor for pyruvate dehydrogenase in aerobic energy metabolism, and in the absence of thiamine, lactic acid accumulates from anaerobic metabolism. Risk factors for thiamine deficiency include poor intake, increase losses such as polyuria, and increased demand through catabolic demand. Clinical symptoms of thiamine deficiency can be subtle, but unexplained neurological deficits in combination with an elevated lactate should prompt consideration for thiamine supplementation. Triglycerides are a potential adjunct biomarker in addition to hyperlactatemia to suggest thiamine deficiency, but require further study. Thiamine replacement should be considered in patients with refractory hyperlactatemia with no evidence of shock. Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. R. Hay (Conceptualization-Equal, Data curation-Equal, Formal analysis-Equal, Investigation-Equal, Methodology-Equal, Writing—original draft-Equal, Writing—review & editing-Equal), T. F. Wu (Conceptualization-Equal, Formal analysis-Equal, Investigation-Equal, Methodology-Equal, Writing—original draft-Equal, Writing—review & editing-Equal). Authors’ Disclosures or Potential Conflicts of Interest:No authors declared any potential conflicts of interest.

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