Case 12: A 84-Year-Old Man With Decreased Consciousness and Hyperpnea

Dr. Seung-Hwan Lee: An 84-year-old man with a body weight of 54 kg and a history of stroke 20 years ago, presented at the emergency department with general weakness. He was taking acetylsalicylic acid 100 mg once a day for prevention of secondary stroke. He denied other comorbidities or past medical history besides stroke and smoking history of 60 pack-years. Since initial laboratory tests showed elevated serum creatinine to 2.68 mg/dL, he was referred to the Nephrology Department.

On initial presentation, he was alert, and his vital signs were stable with a body temperature of 37.4°C, blood pressure of 111/67 mmHg, heart rate of 72 beats per minute (bpm), and respiratory rate of 16 bpm. However, he began to show hyperpnea and decreased consciousness in emergency room. He had decreased skin turgor and a dry tongue, which suggested a hypovolemic status. Lung sounds were clear during auscultation.

The laboratory work-up showed a white blood cell count of 8,060 /mm³, a C-reactive protein level of 2.53 mg/dL, serum creatinine level of 2.68 mg/dL, serum albumin level of 4.1 g/dL and serum sodium, potassium, and chloride levels of 140, 4.7 and 110 mmol/L, respectively. In the arterial blood gas panel, pH was 7.395, PCO2 was 19.3 mmHg and HCO3 was measured 11.5 mmol/L (Table 1). Anion gap was calculated at 18.5 mmol/L. Coagulation profile showed the prolongation of international normalized ratio (INR) and activated partial thromboplastin time (PTT). Further analysis of urine chemistry revealed urine sodium of 57 mEq/L, urine chloride of 33 mEq/L and the fractional excretion of sodium was calculated as 0.8%.

Table 1
Laboratory data of the patient

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Chest radiography revealed flattened diaphragm, which suggested hyperinflation of the lungs. Microbiological screening did not reveal any infective organism.

Dr. Seung-Hwan Lee: High anion gap metabolic acidosis with respiratory alkalosis.

Dr. Changyong Shin: Arterial blood gas analysis (ABGA) is a simple yet essential test that provides valuable information about the patient's metabolic and oxygenation status in a timely manner. When interpreting ABGA in patients with metabolic acidosis, anion gap and expected compensatory respiratory response should be calculated first to obtain additional diagnostic information.

The most common causes of high anion gap metabolic acidosis are arranged in the mnemonic “GOLDMARK,” which stands for glycols (ethylene, propylene and diethylene), 5-oxoproline (acetaminophen), L-lactic acid, D-lactic acid, methanol, aspirin, renal failure, and ketoacidosis.1 Keeping ‘GOLDMARK’ in mind, initial examination of high anion-gap acidosis should first include a thorough history taking of inappropriate drug ingestion. Next, the medical history of diabetes mellitus and chronic alcohol use disorder must be determined due to the possibility of diabetic or alcoholic ketoacidosis. Accumulation of multiple inorganic and organic acids in renal failure can cause uremic acidosis, which presents as high anion gap metabolic acidosis. The presence of calcium oxalate crystals in the urine is a typical finding of ethylene glycol poisoning.

Among the above causes of high anion gap metabolic acidosis, patients with salicylate intoxication typically present with mixed respiratory alkalosis and increased anion gap metabolic acidosis. Therefore, it is important to suspect salicylate toxicity in patients who present to the hospital with this mixed acid-base disorder. Such mixed acid-base disorder can also be seen in critically ill patients with metabolic acidosis caused by lactic acidosis or severe kidney injury, in combination with hyperventilation resulting from fever, sepsis, hypoxia, and/or mechanical hyperventilation.

Dr. Seung-Hwan Lee: On further questioning, we found that he had taken excessive amount of acetylsalicylic acid. He was prescribed regular acetylsalicylic acid, which is 180 tablets of 100 mg, for a six-month supply three days ago. However, his daughter found that strips for more than 60 days were already empty. Since he had recently run out of his daily acetylsalicylic acid pills, he said that he took missed pills at once. It was suspected that he consumed more than 100 mg/kg of acetylsalicylic acid for only 2 days.

Dr. Hanbi Lee: According to further history taking, he is suspected to have a salicylate induced mixed acid-base disorder. Symptoms got worse on the day of visit, which was followed by decreased consciousness and hyperpnea. Because of progressive neurological symptoms and accompanying renal insufficiency, intermittent hemodialysis was started according to EXTRIP guideline.2

Hemodialysis treatment was performed using high flux dialysis filter with surface area 2.0 m² at a blood flow rate of 250 mL/min and a dialysate flow of 600 mL/min. During 4 daily treatments of hemodialysis, breathing pattern and consciousness recovered. The patient was discharged in a stable clinical condition.

The blood salicylate levels measured before and during hemodialysis were reported. The results confirmed the suspected ingestion of overdose acetylsalicylic acid, with a salicylate level of 49.45 mg/dL (therapeutic range 3–30 mg/dL, toxic > 30 mg/dL) at initial presentation (Fig. 1). The salicylate level fell to 25.61 mg/dL directly after the first treatment of hemodialysis, and after 4 daily treatments of hemodialysis, the salicylate level fell to < 0.30 mg/dL.

Fig. 1
Salicylate measurement before and during HD treatment.
HD = hemodialysis.

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Dr. Hanbi Lee: Salicylate induced high anion gap metabolic acidosis with respiratory alkalosis.

Dr. Injoon Hwang: Fortunately, the patient has recovered well through prompt diagnosis and appropriate treatment of hemodialysis. Are there any other options for treating aspirin overdose besides hemodialysis?

Dr. Hanbi Lee: Since there is no antidote for salicylate, supportive management for eliminating salicylate from the body is important. The cornerstone of the supportive management is aggressive volume resuscitation with alkalinization.3 Especially, in patients with hypotension and decreased extracellular fluid volume, lactated Ringer’s solution or isotonic saline infusion is required to maintain euvolemia and urinary flow. Intravenous sodium bicarbonate is used for alkalinization of the urine, which accelerates the renal clearance of salicylate (pKa 2.97). An increase in urine pH from 6.1 to 8.1 increases the clearance by a factor of 18.4 Additionally, alkalinization of the blood promotes the movement of salicylate out of tissues, including the central nervous system. However, since raising the gastrointestinal (GI) luminal pH can enhance the absorption of salicylate, oral bicarbonate is not recommended. The target urine pH is above 7.5.

Oral activated charcoal may reduce further salicylate absorption in GI tract even more than 2 hours after ingestion. This is because ingestion of large quantities of aspirin slows gastric emptying, and enteric-coated tablets remain in the GI tract for a long time.4

However, in severe intoxication including change in mental status, new hypoxemia requiring oxygen therapy, accompanying renal insufficiency or a salicylate blood concentration of more than 100 mg/dL regardless of coexisting symptoms, emergent hemodialysis may be the most effective solution for eliminating salicylate from the body.2

Dr. Hanbi Lee: Salicylate, commonly prescribed as “aspirin,” is one of the most widely used drugs globally. Derived from the bark of the willow tree, salicylates have been used for thousands of years due to their analgesic and antipyretic properties. However, because the drug is easily available, salicylate intoxication is a common and dangerous problem. Acute salicylate intoxication occurs after the ingestion of ≥ 100 to 150 mg/kg salicylate. This typically occurs in young adults attempting suicide or in children after unintentional exposure.

The most characteristic acid-base disorder presented by salicylate intoxication is a mixed high anion gap metabolic acidosis and respiratory alkalosis. At toxic levels, salicylates directly stimulate the respiratory center of the medulla, leading to respiratory alkalosis. Additionally, salicylates uncouple oxidative phosphorylation and inhibit citric acid cycle dehydrogenases, resulting in a shift from aerobic to anaerobic production of ATP. This process increases the production of lactic acid and ketoacids, contributing to the high anion gap metabolic acidosis. Salicylate itself plays a small role in the high anion gap.

Furthermore, in vitro studies have demonstrated that salicylate can inhibit the activation of coagulation factors 2, 7, 9, and 10 at salicylate concentrations ranging from 30 to 50 mg/dL. In an 11-year retrospective study, 12% of patients with elevated salicylate concentrations had an elevated INR (> 1.5).5 This effect can be reversed by administering vitamin K.

Dr. Hyunglae Kim: This case highlights the important role of Nephrologists in poisoning and drug intoxication. However, it should be noted that not all drugs can be eliminated through hemodialysis. Are there any characteristics of drugs that need to be considered when deciding the mode of extracorporeal removal for drug intoxication?

Dr. Hanbi Lee: In the choice of extracorporeal removal modality, four characteristics of drugs which affect “dialyzability” should be taken into account: volume of distribution, protein binding affinity, molecular weight, and redistribution from tissue to plasma.6

The volume of distribution is related to whether the substance is present in sufficient amounts in the intravascular space. For a substance to be cleared from the body, it must be present in appreciable quantities in the intravascular space. Lipophilic toxins tend to have high volumes of distribution, which makes them difficult to remove by dialysis. If volume of distribution exceeds 1–1.5 L/kg, extracorporeal removal is ineffective.7

In plasma, almost all solutes are bound to proteins to varying degrees. When solutes are protein-bound in the plasma, they become difficult to remove by dialysis because of their large size. Therefore, for them to be dialyzable, protein binding must be less than 80%.6 When protein binding exceeds 80%, dialysis clearance rates drop sharply.

The molecular mass of substances is also one of the important properties that determines dialyzability. Conventional dialyzers used in hemodialysis can clear substances up to 15,000 Dalton in size, while high-cutoff dialyzers can clear substances up to 50,000 Dalton in size.6 On the other hand, plasmapheresis can clear substances of any size.

For effective extracorporeal treatment, a substance must rapidly distribute from tissue to plasma. During dialysis, the substance is redistributed from tissue to plasma based on their concentration gradient. Some substances, like lithium, have a slow transit, leading to the “rebound” phenomenon, where plasma levels rise hours after dialysis and requires continuous renal replacement therapy.7

Salicylate has a molecular weight of only 180 Dalton, a volume of distribution of 0.5L/kg and a 30% protein binding in overdose.2 These physicochemical properties make salicylate easily removable from the body by hemodialysis.

Dr. Eun Jeong Ko: Herein, we presented a case of acute salicylate intoxication in a patient with mixed high anion gap metabolic acidosis and respiratory alkalosis. This case emphasizes the importance of proper interpretation of ABGA and thorough history taking for prompt diagnosis and treatment. Furthermore, when choosing an extracorporeal modality for drug intoxication, four characteristics of drugs should be taken into consideration.