Continuous Venovenous Hemofiltration as a Rescue Therapy for Severe Acetaminophen Toxicity in a Toddler

Abstract

Acetaminophen poisoning is one of the common accidental poisoning in children. Accidental administration of mismatched doses of drops for syrups can lead to life-threatening overdose. N-acetylcysteine (NAC) is the specific antidote; however, extracorporeal therapy such as continuous venovenous hemofiltration (CVVH) can be used as a rescue measure when there is no improvement despite adequate NAC therapy and can be lifesaving. We reported an 18-month-old male infant patient who presented with acetaminophen poisoning following accidental ingestion of acetaminophen drops in place of syrup and developed fulminant hepatic failure. Treatment with NAC did not lead to improvement and CVVH was used as a rescue therapy for 24 hours which led to dramatic clinical and biochemical improvement with intact neurological outcome.

Introduction

Acetaminophen is a commonly used analgesicantipyretic and quite safe in therapeutic dose (<90 mg/kg/d). The potentially toxic dose is >150 mg/kg. The ingestion—either intentionally (adolescents and adults) or accidentally (infants and children)—can lead to fulminant liver failure which has high mortality. ^{1 2} Timely diagnosis, prompt administration of specific antidote (N-acetylcysteine, NAC), and supportive care are lifesaving. ² If there is no improvement, extracorporeal therapies such as hemodialysis (HD), sustained low efficiency dialysis (SLED), continuous venovenous hemofiltration (CVVH), high-volume plasma exchange (PLEX), and molecular adsorbent recirculating system (MARS) can be used as rescue measures. ^{3 4 5 6 7 8 9 10 11 12} Here, we present an 18-month-old male infant who had presented with fulminant liver failure following accidental ingestion of acetaminophen. CVVH was used as a rescue therapy, which led to complete recovery. To the best of our knowledge, there is hardly any study evaluating the efficacy, effectiveness, and safety of this type of extracorporeal treatments (CVVH) in severe acetaminophen toxicity in children and hence the importance of this case report.

Case Report

An 18-month-old male infant weighing 10 kg presented to emergency department with fever for 3 days and altered sensorium for 1 day. There was no history of rigors, rash, jaundice, vomiting, bleeding manifestations, seizures, swelling, or decreased urine output. On reviewing history, it was revealed that parents had inadvertently given 5-mL drops of acetaminophen (1 mL =100 mg) instead of 5-mL syrup (5 mL =125 mg) for seven times in last 24 hours (total dose of 350 mg/kg). Examination showed encephalopathy (Glasgow coma scale of 9), pallor, icterus, hepatomegaly, and features of raised intracranial pressure (ICP). The possibility of acute acetaminophen poisoning with fulminant hepatic failure was considered.

Investigations revealed hypoglycemia, high anion gap metabolic acidosis, hyperlactatemia, elevated aspartate aminotransferase and alanine aminotransferase, coagulopathy, and hyperammonemia ( Table 1 ). He was started on mechanical ventilation, first tier measures for raised ICP with osmotherapy (3% saline infusion), glucose infusion rate upto 6 mg/kg/h, sedoanalgesia, NAC infusion (150 mg/kg over 1 hour followed by 50 mg/kg over 4 hours followed by 100 mg/kg over 16 hours), sodium benzoate, rifaximin, lactulose, and frequent bowel enema. Serum acetaminophen level at 6 hours of hospital stay was 432 μg/mL (a serum acetaminophen level of 10–20 μg/mL is considered safe and levels >150 μg/mL at 4 hours after ingestion indicate that there is risk for liver injury) and urinary gas chromatography–mass spectrometry was also suggestive of acetaminophen overdose.

Table 1. Summary of clinical analytical results in index case with massive acetaminophen ingestion.

Analytical parameters	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
Hemoglobin (g/dL)	9.7	7.2	8.6	8.1	8.0	6.9	11.6
Total leucocyte count (per cumm)	10,030	6,450	11,680	11,380	11,330	7,200	15,000
Platelets (per cumm)	258,000	166,000	50,000	105,000	119,000	147,000	188,000
Sodium (mEq/L)	156	147	153	145	146	149	142
Potassium (mEq/L)	5.6	4.5	3.6	4.1	4	4.8	4.2
Urea (mg/dL)	28/0.28	32/0.4	06/0.15	10/0.2	11/0.38	26/0.2	25/0.15
Creatinine (mg/dL)	0.28	0.4	0.15	0.2	0.38	0.2	0.15
AST (IU/L)	10,209	14,050	1,654	851	495	156	86
ALT (IU/L)	4,339	4,654	2,208	1,634	1,389	717	339
Ammonia (µmol/L)	437	698	271	107	98
Lactate (mmol/L)	9.6	10.2	4.1	3.2	1.8	1.4	1.5
INR	4.2	6.4	2.8	1.2
Acetaminophen levels	432 μg/mL

Abbreviations: ALT, alanine aminotransferase; AST, aspartate transaminase; INR, international normalized ratio.

During the first 24 hours of hospital stay, despite above measures, there was no improvement in clinical and laboratory parameters ( Table 1 ). On the basis of clinical and biochemical parameters, the decision was made to start CVVH. Right internal jugular vein was catheterized with 7-Fr double lumen catheter and CVVH was started with blood flow rate of 50 mL/min, hemofiltration of 300 mL/h, and replacement fluid flow rate of 300 mL/h without anticoagulation and it was continued for the next 24 hours. After initialing CVVH, there was gradual improvement in clinical and biochemical parameters and he was extubated on day 6 of hospital stay and discharged on day 10 with intact neurological status at discharge and at 3 months follow-up.

Discussion

Acetaminophen is metabolized in liver, 80% of administered dose (therapeutic dose) undergoglucuronide and sulfate conjugation, and 20% undergo hydroxylation to form a highly reactive oxidative product, N-acetyl-p-benzoquinone imine (NAPQI), which conjugates with glutathione to form mercapturic acid and is eliminated in urine. ^{2 13} In acetaminophen overdose, cellular glutathione (GSH) stores are depleted and hepatotoxicity occurs due to accumulation of NAPQI. The administration of NAC repletes endogenous GSH stores and promotes conjugation of NAPQI to nontoxic metabolites, thereby decreasing the toxic effects of NAPQI. ^{12 13 14}

The signs and symptoms of acetaminophen toxicity occur in the four progressive phases. In phase 1 (lasts for 0.5–24 hours), there is anorexia, nausea, vomiting, diaphoresis, and lethargy. In phase 2 (lasts for 24–72 hours), the features include right upper abdominal pain, liver enlargement, elevation of bilirubin and liver enzymes, and prolongation of prothrombin time. The phase 3 (lasts for 72–96 hours) is characterized by features of hepatic failure including jaundice, hypoglycemia, and encephalopathy, and eventually leading to renal failure, metabolic acidosis, hypothermia, shock, central nervous system depression, and cardiac failure. During phase 4 (lasts for 4–14 days), the patient will either die ofmultiorgan failure or recover from liver failure. ^{12 15}

While managing a child with acetaminophen toxicity, levels are obtained at 4 and 8 hours of ingestion and plotted on Rumack–Matthew nomogram and if levels cross the treatment line, NAC is started. ¹⁶ Sometimes with ingestion of massive doses of acetaminophen, the standard dose of NAC does not lead to improvement because NAC reacts in 1:1 fashion with NAPQI and with larger overdose, there is more NAPQI than NAC. In such scenarios, acute liver injury progresses and can lead to death. The suggested strategies in such scenarios are to increase the dose and duration of NAC, removal of acetaminophen from blood by an extracorporeal therapy (SLED, CVVH, PLEX, or MARS), and in dire circumstances, liver transplantation. ^{3 4 5 6 7 8 9 10 11 13} The Extracorporeal Treatments in Poisoning workgroup recommends extracorporeal therapies such as intermittent HD, CVVH, or PLEX in acetaminophen poisoning, where there is evidence of mitochondrial dysfunction and exceedingly high drug levels. ⁷

The Pediatric Continuous Renal Replacement Therapy workgroup recommended to startrenal replacement therapy (RRT) with HD for severe acetaminophen toxicity. The alternative options include continuous renal replacement therapy (CRRT) or hemoperfusion. HD leads to rapid correction of metabolic acidosis and hasless complications than hemoperfusion. The group suggested to start RRT in acetaminophen toxicity in the presence of declining neurological status (encephalopathy or coma) with depression of autonomic control of circulatory or respiratory systems; severe metabolic acidosis (pH <7.1) refractory to supportive treatment; and acetaminophen blood levels >1,000 mg/L and NAC therapy has not been initiated. ¹²

The index child was started on CRRT (CVVH) as there was no improvement in clinical and biochemical status despite treatment with NAC, presence of severe liver dysfunction, small size (10 kg) of the child, and availability of CRRT. There are only few case reports among adults with massive acetaminophen toxicity where HD or CRRT was used as a rescue measure with a favorable outcome. ^{4 5 6 7} In patients with fulminant liver failure with suspected or proven cerebral edema, CRRT is more beneficial than intermittent HD due to increased risk of worsening cerebral edema with later. ⁵ Also, with HD, there is concern of removal of NAC along with acetaminophen which may require increase in dose of NAC. ⁵ The index case received CVVH as a rescue therapy, after which there was improvement in clinical status (encephalopathy and raised ICP) and biochemical parameters (transaminitis, lactic acidosis, ammonia, and coagulopathy).

Conclusion

Medication error is a common cause of acetaminophen toxicity in children and can lead to increased healthcare expenditure. The standard treatment includes early identification, aggressive treatment, and early administration of NAC. CVVH can be a rescue option in cases with massive ingestion which do not respond to the standard treatment.

Funding Statement

Funding None.