Acetaminophen: Where is it Found? And How to Handle Too Much of It!

INTRODUCTORY CASE

A 14-year-old girl with a history of suicidal behavior presents to a pediatric emergency department with polysubstance ingestion.  Over the last two days she has ingested variable amounts of lorazepam, alcohol, and DayQuil™ (acetaminophen, dextromethorphan, and phenylephrine).  She drank an unknown quantity of DayQuil™ the day prior and admits to drinking an entire bottle on the day of presentation.  The patient denies any current symptoms.

Vital signs:  T 97.9 F, BP 133/83, HR 114, RR 20, SpO2 100%

On examination, she is in no acute distress.  Her neurologic examination is non-focal with a Glasgow Coma Scale of 15.  Her abdomen is benign.  She has linear scars to the left forearm from self-injurious behavior.  She is cooperative, nonchalant about her ingestion, describes her mood as “numb”, and has a flat affect. 

Her laboratory analyses reveal an acetaminophen level of 65 mcg/mL.  Liver function tests are unremarkable, INR is 1.0, and ethanol is zero.  All other diagnostics are unremarkable.  Treatment is initiated, and she is admitted to Pediatrics for acetaminophen overdose.  

DISCUSSION

Acetaminophen, commonly referred to internationally as paracetamol, is one of the most widely used analgesics and antipyretics.  It is a major component of many over-the-counter and prescription medications (Table 1).  Each year, approximately 30,000 patients are hospitalized in the United States for acetaminophen toxicity, with half of overdoses thought to be intentional. (1)  Intentional pediatric ingestions typically occur in adolescents while unintentional ingestions are more common among younger children. (2)  The therapeutic dose in children is 15 mg/kg  every four to six hours.  The minimum toxic dose for an acute ingestion is 150 mg/kg. (3,4)  In chronic overdose, the minimum toxic threshold is 150-175 mg/kg over two to four days. (3,5)  

Table 1: Common Medications Containing Acetaminophen
Alka-Seltzer Plus ® NORCO® Sudafed®
Dayquil® Nyquil® Theraflu®
Excedrin® Paracetamol Tylenol® Brand Products
Hydrocet® Percocet® Vicks®
Lortab® Robitussin® Vicodin®
Mucinex® Singlet®

The clinical manifestations of acute acetaminophen poisoning in children are nonspecific.  Initially, patients may be asymptomatic or have mild symptoms such as nausea and vomiting.  Liver injury can occur after approximately 24 hours and manifest as right upper quadrant pain or tenderness, vomiting, jaundice, and elevations in transaminases and prothrombin time.  At peak liver injury, patients can present with signs of fulminant liver failure such as hepatic encephalopathy, systemic inflammatory response system, hypotension, and death. (6)

All patients in whom acetaminophen toxicity is suspected should have a serum acetaminophen concentration drawn.  In patient with a single acute ingestion, the time of ingestion should be established, as a serum acetaminophen concentration at four hours post-ingestion will determine the need for antidotal therapy with N-acetylcysteine (NAC).  The four-hour concentration should be plotted against the treatment nomogram, and concentrations in the probable hepatic toxicity range should be treated with NAC. (4,6,7)

 Figure        SEQ Figure \* ARABIC     1      . Treatment Nomogram for Acetaminophen Toxicity, Reproduced from Rumack et. al 1975 (      ADDIN EN.CITE
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Figure 1. Treatment Nomogram for Acetaminophen Toxicity, Reproduced from Rumack et. al 1975 (7)

In chronic ingestions, the treatment nomogram cannot be used.  Laboratory testing for serum acetaminophen concentration and liver function should be obtained for any at-risk patient.  Patients with evidence of liver injury (AST greater than two times normal or greater than 120 IUL or those with serum acetaminophen levels greater than 30 mcg/mL should have antidotal therapy initiated. (5,6)

Gastric decontamination with activated charcoal is recommended in all pediatric patients who present within four hours of acetaminophen ingestion.  Contraindications include gastrointestinal obstruction or any altered mental status in which airway protection is a concern.  Endotracheal intubation should not be performed solely for the purpose of giving activated charcoal.  Activated charcoal has not been shown to reduce acetaminophen absorption when given greater than four hours after ingestion and is not recommended in this time frame.  Activated charcoal is given as a single dose of 1 g/kg by mouth (maximum 50 g). (8,9) 

Once the need for N-acetylcysteine antidotal therapy is determined, it should be given as soon as possible.  When given within 8 hours of ingestion, the mortality rate approaches 0; however, NAC may be beneficial up to 24 hours after ingestion.  NAC should be given intravenously (IV) if available; however, providers should be aware that IV NAC can cause severe anaphylactoid reactions.  Preparations should be made for immediate interventions if anaphylaxis occurs, and patients should be monitored closely during the initial 30 minutes of the infusion. (6,10)  Providers should also be aware that prothrombin time and INR can be artificially elevated by NAC, which can obscure signs of worsening liver function. (11) 

A well-established protocol for IV NAC dosing involves a 21-hour administration procedure detailed below.  Repeat acetaminophen levels, liver function tests, and INR should be repeated 9 hours into the protocol. (12,13)

Loading dose of 150 mg/kg IV (maximum 15,000 mg) in 200 mL dextrose 5% in water (D5W) infused over 60 minutes

Followed by

First maintenance dose of 50 mg/kg IV (maximum 5,000 mg) in 500 ml D5W infused over 4 hours

Followed by

Second maintenance dose of 100 mg/kg IV (maximum 10,000 mg) in 1000 mL D5W infused over 16 hours

Poor prognostic indicators for liver function include the King’s College Criteria.  Patients with acidosis with pH < 7.3 or patients with the combination of prothrombin time > 100 seconds and creatinine > 3.3 mg/dL and hepatic encephalopathy grade III – IV (marked confusion or coma) are considered high risk for fulminant liver failure and should be transferred to a liver transplant center. (14)

CASE CONCLUSION

Given that the patient had an elevated acetaminophen level greater than 30 mcg/mL with multiple ingestions over the last 48 hours, she was treated with N-acetylcysteine.   Labs were rechecked at 19 hours after initiation of NAC.  Liver function tests and INR were stable.  Repeat acetaminophen level was < 10 mcg/mL.  She was ultimately discharged after Psychiatric evaluation with a home safety plan and outpatient Psychiatry follow up.

Faculty Reviewer: Dr. Jane Preotle

REFERENCES

1.         Blieden M, Paramore LC, Shah D, Ben-Joseph R. A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States. Expert Rev Clin Pharmacol. 2014;7(3):341-348.

2.            Myers WC, Otto TA, Harris E, Diaco D, Moreno A. Acetaminophen overdose as a suicidal gesture: a survey of adolescents' knowledge of its potential for toxicity. J Am Acad Child Adolesc Psychiatry. 1992;31(4):686-690.

3.            Kanabar DJ. A clinical and safety review of paracetamol and ibuprofen in children. Inflammopharmacology. 2017;25(1):1-9.

4.            Lewis RK, Paloucek FP. Assessment and treatment of acetaminophen overdose. Clin Pharm. 1991;10(10):765-774.

5.            Sztajnkrycer MJ, Bond GR. Chronic acetaminophen overdosing in children: risk assessment and management. Curr Opin Pediatr. 2001;13(2):177-182.

6.            Walls RM, Hockberger RS, Gausche-Hill M. Rosen's emergency medicine : concepts and clinical practice. In: Ninth edition. ed. Philadelphia, PA: Elsevier,; 2018: https://login.revproxy.brown.edu/login?url=https://www.clinicalkey.com/dura/browse/bookChapter/3-s2.0-C20141019850 Full text available from ClinicalKey Flex.

7.            Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6):871-876.

8.            Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018;2:CD003328.

9.            Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ. A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Ann Emerg Med. 1994;23(3):519-523.

10.          Bateman DN, Dear JW, Thanacoody HK, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet. 2014;383(9918):697-704.

11.          Pizon AF, Jang DH, Wang HE. The in vitro effect of N-acetylcysteine on prothrombin time in plasma samples from healthy subjects. Acad Emerg Med. 2011;18(4):351-354.

12.          Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet. 1977;2(8035):432-434.

13.          Yarema MC, Johnson DW, Berlin RJ, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2009;54(4):606-614.

14.          O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-445.

An Interview with Dr. Kathy Boutis

Interviewed and edited by Kristina McAteer, MD

Brown Emergency Medicine is pleased to welcome Dr. Kathy Boutis as our next Grand Rounds speaker. Dr. Boutis spoke with us in depth about how she found her unique path to a combined pediatric emergency medicine training with a focus on adolescent trauma as well as the immeasurable benefit of having an engaged mentor. Her insight into taking the 'big picture' look from the front end of a career in medicine as well as establishment of core values early on combine for very powerful words of wisdom for those just starting on the long journey. Thank you to Dr. Boutis for taking the time to speak with us. Take a listen...

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About Dr. Boutis:

Dr. Kathy Boutis graduated from the University of Toronto medical school in 1991. She completed a residency in pediatrics in 1998 and a fellowship in pediatric emergency medicine in 2001 at the Children's Hospital in Boston, Harvard University. In 2008 she completed a Master’s degree in Health Research Methodology at McMaster University. Dr. Boutis is currently a staff physician in the emergency department at The Hospital for Sick Children (SickKids), a Senior Associate Scientist in the Child Health Evaluative Sciences Program at SickKids Research Institute, and an Associate Professor with the University of Toronto. In 2009, she developed and became director of the emergency department-based student volunteer program. In 2012, she was appointed Research Director in Pediatric Emergency Medicine and in 2015 she was appointed as Vice-Chair of the Research Ethics Board.

Dr. Boutis' clinical practice spans both patient care and educational responsibilities in pediatric emergency medicine. Although she practices and teaches on any problem that relates to pediatric emergency medicine, her area of specialty is in the emergency diagnosis and management of pediatric musculoskeletal injuries.

Uric Acid Mayhem and Other Cancer Derived Shenanigans

A brief overview of common pediatric hematologic malignancy emergencies

Case

An 8-year-old girl with past medical history of obesity presents with three weeks of intermittent fevers, joint aches, URI symptoms, abdominal pain, and decreased appetite. She had been treated for strep throat twice and had several visits with her primary care doctor to follow up. She was referred to the ED for blood work and evaluation because she developed a petechial rash on her torso and extremities. She had not had significant weight loss, night sweats, mucosal bleeding, or lymphadenopathy. She has been limping with ambulation, but her gait returned to normal with ibuprofen. On exam, she had no other focal findings other than scant petechial involving her entire body. The differential for this patient was broad and included recurrent viral illnesses, toxic synovitis, Henoch-Schonlein purpura, osteomyeltitis and occult malignancy. Unfortunately, shortly after her CBC was sent, the lab called and reported that her WBC count was 49,000 and abnormal cells were present; a hematologist confirmed that her peripheral blood contained 47% blasts.

Recognizing pediatric malignancies in the Emergency Department can be challenging as the presentations can be quite subtle. Once you diagnose a cancer, often other studies are required to ensure that there are not any other metabolic or physiologic complications resulting from the malignancy. In this blog post, we will focus on the oncologic emergencies in the pediatric patients that are not mechanical or mass related.

Tumor Lysis Syndrome

Description

Rapid cell destruction releases large amounts of intracellular contents. When the amount of material released overwhelms the ability of the kidneys to excrete it, this leads to metabolic derangements known as tumor lysis syndrome (TLS). Risk factors include chemotherapy induction, untreated acute leukemias (particularly ALL and high-grade non-Hodgkin lymphoma), chronic leukemia with blast crisis, or hyperleukocytosis, and hyponatremia. Malignant cells often contain a higher concentration of phosphorus than normal cells; the release of phosphorus causes the precipitation of calcium. Hyponatremia is often from SIADH. The hyperkalemia can be worsened by the development of acute kidney injury from the circulating uric acid [1].

Presentation

A high index of suspicion should be maintained to look for TLS as symptoms can be subtle (nausea, loss of appetite, muscle cramps, tetany, decreased urine output, altered mental status, convulsions, and arrhythmias). There is significant risk of morbidity and mortality if this diagnosis is not recognized and treated early (Howard et al.). Typical lab abnormalities include elevated uric acid (>8 mg/dl), hyperphosphatemia (>6.5 mg/dL), hypocalcemia (<7 mg/dL), hyperkalemia (>6 mEq/L). Typical treatment for hyperkalemia should be initiated to shift and eliminate excess potassium if there are EKG changes or the potassium is >7 mEq/L [1, 2].

Treatment

On all patients that are at risk for TLS, a uric acid level, BMP, ionized calcium, magnesium, phosphorus, and LDH level should be sent frequently to monitor for metabolic derangements. If TLS is present, then IV hydration at 2 – 4 times maintenance rate should be started. Agents to help decrease the uric acid level should also be initiated. Typical choices are IV allopurinol and rasburicase [1]. Allopurinol is a xanthine oxidase inhibitor which stops production of uric acid; it usually is used prophylactically during chemotherapy induction more than for TLS as it does not directly decrease uric acid level. Rasburicase is recombinant urate oxidase which converts uric acid into a metabolite that can be excreted; it usually decreases uric acid levels within hours [3]. While effective, this drug is relatively expensive (approximately $640 per mg of drug), which means it is often reserved for severe cases of tumor lysis syndrome [4]. Hypocalcemia should not be treated if it is asymptomatic as this can cause precipitation of calcium phosphate worsening renal injury. Fluid restriction for SIADH treatment is challenging given the insensible losses typical for patients undergoing chemotherapy and IV fluid requirements to treat other components of TLS. Hyperphosphatemia can be treated with aluminum hydroxide.  If treatment is refractory to the above, then dialysis may be required to treat severe symptoms [1].

Neutropenic Fever

Description

Many patients on chemotherapy become neutropenic and some with active hematologic malignancies are functionally neutropenic as the abnormal cells prevent the formation of normal neutrophils. Patients with a lack of functional neutrophils are more susceptible to serious bacterial infections from all organisms but are particularly vulnerable to the following organisms: S. aureus, Enterococcus, S. viridens, S. pneumoniae, S. pyogenes, Coagulase-negative Staphylococcus, E. coli, Klebsiella, Enterobacter, Pseudomonas, Citrobacter, Acinetobacter, and Stenotrophomonas. Up to 80% of the time, bacterial infections are caused by normal flora organisms [5]. Also, they are at risk of typhlitis, which is a necrotizing colitis caused by invasive behavior by bacteria or fungi from the GI tract. Given this, a fever in this pediatric population must be reacted to aggressively [1].

Presentation and work-up

Often, these immunocompromised patients might not have associated symptoms with severe bacterial infections. Given this, patients require pan cultures (peripheral blood cultures, port cultures, urine culture, and an LP if headache or other neurologic symptoms are present) and chest X-ray. If there is any abdominal pain or tenderness, a CT scan of the abdomen should be considered. Any skin irritation or pain should be evaluated closely as surrounding erythema is often not present over abscesses [1, 5].

Treatment

In the pediatric population, both ceftriaxone and cefepime are acceptable choices for empiric treatment for antibiotic coverage. If patients are already on broad spectrum antibiotics, sometimes this coverage needs to be expanded to meropenem. The goal time for antibiotics is 30 – 60 minutes after arrival; it is recommended that you cover patients prior to the return of the CBC differential if there is a high suspicion that the patient is neutropenic [1].

Hyperviscosity Syndrome

Description

A variety of different processes related to different malignancies can result in an increase in the viscosity of the serum. In the adult population, the most common cause in from circulating proteins from paraproteinemias. However, in the pediatric population, this is more commonly caused by hematologic malignancies leading to hyperleukocytosis (WBC count greater than 100,000/mL) or polycythemia. It is more common in AML was myeloid blasts are larger than the lymphoid blasts in ALL, and thus more likely to “clog” arteries. The increase in viscosity leads to microvascular hypoperfusion from sluggish flow and prolonged bleeding time as platelet aggregation is disrupted. Hyperleukocytosis is a feature of approximately 20% of all pediatric leukemias and can trigger DIC due to a factor consumption and fibrinolytic proteases excreted by blasts [1, 6].

Presentation

The classic triad for hyperviscosity syndrome (HVS) is mucous membrane or skin bleeding, visual disturbance, and focal neurologic deficits. In addition to these symptoms, patients could also present with a variety of other symptoms including: altered mental status, focal neurologic deficits, priapism, pulmonary edema, and acute kidney injury. These end organ effects are caused by micro or macrovascular occlusion from the large white blood cell aggregates. On physical exam, the fundus can have dilated “sausage-like” retinal veins from the slowing of blood flow. Laboratory testing can confirm hyperviscosity; those with HVS have viscosity measurements greater than 3 times the upper limit of normal [6].

Treatment

Treatment begins with supportive measures such as intravenous fluids and can escalate to phlebotomy, plasmapheresis or leukopheresis in the case of leukemia, plasma exchange, and exchange transfusions as needed. Often, urgent chemotherapy can be initiated to help alleviate symptoms as well.  Hydroxyurea can be used to help curb the production of WBCs [1, 6].

Case Resolution

After it was clear that her presentation was consistent with acute leukemia, screening labs for DIC and tumor lysis syndrome were sent. Her LDH was >3,600 IU/L and her uric acid was 13.5 mg/dl. Given this, she was started on aggressive hydration and given a dose of rasburicase. Her final pathology showed that she had Burkitt’s leukemia. She is now doing well and is in remission after several rounds of chemotherapy. Her course was complicated by epistaxis requiring transfusions from thrombocytopenia, hypertension, acute kidney injury, and several episodes of neutropenic fever. Luckily, the cure rate for Burkitt leukemia is very high (>90%) and the course of chemotherapy is usually 2 – 6 months. If remission is not achieved with this first round of treatment, then additional chemotherapy agents can be trialed followed by a stem cell transplant [7].

While the above does not provide a comprehensive list or description of all of emergencies that can occur in the pediatric patient with a hematologic malignancy, it can provide a starting point to make sure that key metabolic and infectious work-up and treatment occurs in a timely fashion in the emergency department.

Faculty Reviewer: Dr. Jane Preotle

References

  1. Prusakowski, MK and Cannon D. (2014). Pediatric Oncologic Emergencies. Emergency Medicine Clinics of North America; 32(3): 527-548.
  2. Howard SC, Jones DP, Pui CH. (2011). The tumor lysis syndrome. New England Journal of Medicine; 364:1844–54.
  3. Wagner, J and Arora, S. (2014). Oncologic Metabolic Emergencies. Emergency Medicine Clinics of North America; 32(3): 509-525.
  4. Rasburicase: drug information. (2018). Retrieved on April 20, 2018 from www.uptodate.com/contents/rasburicase-drug-information
  5. White, L and Ybarra, M. (2014). Neutropenic Fever. Emergency Medicine Clinics of North America; 32(3): 549-561.
  6. Khan, UA, Shanholtz, CB, and McCurdy, MT. (2014). Oncologic Mechanical Emergencies. Emergency Medicine Clinics of North America; 32(3), 495-508.
  7. Burkitt Lymphoma (2018). Dana-Farber Boston Children’s cancer and blood disorders center. Retrieved on April 20, 2018 from http://www.danafarberbostonchildrens.org/conditions/leukemia-and-lymphoma/burkitts-lymphoma.aspx