CME: Intoxication by PCM, Side effects of Phenytoin, Infant withdrawal syndrome

Posted: December 23, 2010 by gerardloh in Paediatrics

Intoxication by Paracetamol in peds
Definition: Poisioning by ingestion of > 150mg/kg Paracetamol ( fatality >205mg/kg)

Incidence: Rare in infants (100ml usually contains only 2.4mg), mostly in teenage child seeking attention (psychiatric evaluation required)

Dossage of PCM:

  • · < 12 years and/or <50 kg in weight, the max dose: 80 mg/kg/day (not to exceed a cumulative daily dose of 2.6 g).
  • · Max daily adult dose of PCM: 4 g (recommended 352-650 mg every 4-6 hours or 1 g every 6 hours)
  • Therapeutic weight-based oral dosing for children younger than 12 years is 10-15 mg/kg every 4-6 hours with a maximum of 5 doses per 24-hour period.
  • In adults, the minimum toxic dose of acetaminophen for a single ingestion is 7.5-10 g. Single ingestions of 12 g or higher have high potential for hepatotoxicity.

Pathophysiology:

- PCM is rapidly absorbed by GIT (0.5-2 hrs), serum peak levels after 4 hours

- Half life of PCM = 2-4hrs

- Metabolism of acetaminophen is primarily hepatic, hence hepatotoxicity can occur with misuse and overdoses

- hepatic glutathione stores are depleted (by 70-80%) in PCM overdose, NAPQI cannot be detoxified and covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis

Metabolism of PCM

- Sulfation is the primary metabolic pathway in children aged 12 years and younger.
– Glucuronidation predominates in adolescents and adults.

Clinical

Patients with acetaminophen-induced hepatotoxicity present in 4 clinical stages.

  • Stage 1 (0.5-24 h postingestion)
    • The first stage lasts for 24 hours.
    • Patients have anorexia, nausea, vomiting, malaise, and diaphoresis (non-specific)
    • Some patients remain asymptomatic but still have risk to develop clinically significant toxicity.
    • Neurologic, respiratory, and cardiac symptoms are rare in stage 1.
  • Stage 2 (24-72 h postingestion)
    • The second stage begins 24 hours after ingestion and lasts for another 48 hours.
    • Stage 1 symptoms become less evident than before and/or resolve.
    • Patients present with pain and tenderness in the right upper quadrant. Liver enlargement (hepatomegaly) can be present.
    • Acute pancreatitis (in alcoholics)
    • elevated ALT and AST levels, prothrombin (PT) times, and bilirubin values.
    • Renal function abnormalities (eg, BUN, creatinine) may be present (nephrotoxicity)
  • Stage 3 (72-120 h postingestion)
    • Stage 3 develops 3-5 days after ingestion.
    • Symptoms in stage 1 reappear
    • + signs of hepatic failure: jaundice, hypoglycemia, bleeding (coagulopathies), encephalopathy, and/or sepsis.
    • Renal failure and cardiomyopathy may occur.
    • Lactic acidosis, prolonged PT or international normalized ratio (INR), markedly elevated ALT and AST (≥ 10,000 IU/L), elevated total bilirubin level of more than 4 mg/dL (primarily indirect) and hyperammonemia are reported.
  • Stage 4 (5-14 d postingestion) Recovery Phase
    • Stage 4 occurs 5-14 days after ingestion. This stage can last as long as 21 days.
    • Patients either have a complete recovery of liver function or they die.

Management

-Emergency (Within 1hr of ingestion): give Activated charcoal

-Measure plasma paracetamol (4 hrs after ingestion, then 4 hourly)

-RBS/LFT/PT/PTT/RFT daily for 3 days

Once confirmed 4 hour plasma PCM <150 microg/ml (if test unavailable, base on clinical hx)

- Initiate N-Acetylcysteine (effective if given <24hrs): IV NAC if 4 hour plasma PCM <150 microg/ml
Dossage: 150mg in 200ml D5 over 15 mins

50mg/kg  in 500ml D5 over 4 hours

100mg/kg in 500ml D5 over 16 hours

Rumack-Matthew nomogram


Phenytoin Side effects

Phenytoin is a commonly prescribed anticonvulsant used to treat most types of seizure disorders and status epilepticus, with the exception of absence seizures.

MOA: suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels.

Route: PO/IV/IM *The route of administration is the most important determinant of toxicity.

Indications: Seizure, epilepsy

Pathophysiology

-Phenytoin toxicity depends on the route of administration, duration, exposure, and dosage.

PO: Oral exposures are associated predominantly with CNS symptoms

IV/IM: Extravasation of the solution may cause skin irritation or phlebitis. Phenytoin administered intravenously at a rate higher than 50 mg/min may cause hypotension and arrhythmias.

Duration: Peak blood levels occur 3-12 hours following single dose ingestion, but absorption can be extended up to 2 weeks, especially in massive overdose.

-Individuals with impaired metabolic or excretory pathways may exhibit early signs of toxicity.

Dose-related side effects
The most common side effects are neurotoxic and dose-related. They include:

  • sedation
  • impaired memory
  • slurred speech
  • nystagmus
  • decreased coordination
  • confusion
  • dizziness
  • headache


Clinical

History

Establish if the toxicity is acute or chronic.


  • Intentional overdose
    • Important historical elements
      • Time of ingestion
      • Co-ingestants
      • Motivation for ingestion
      • Medications available in the household


  • Chronic toxicity
    • Important historical elements
      • Duration of administration
      • Dosing
      • Frequency
      • Compliance (last dose and missed dose)
      • Recent changes to their pharmacotherapy
    • Important elements for patient query
      • When symptoms began
      • Severity of symptoms
      • Exacerbating factors
      • Associated problems
      • Relieving factors


Physical

  • Phenytoin may cause a febrile reaction, hypotension (during intravenous infusion), or bradycardia.
  • Mouth -Gingival hyperplasia (chronic use), the most common adverse effect (20%)
  • Neurologic
    • Hyperreflexia or hyporeflexia
    • Abnormal gait (bradykinesia, truncal ataxia - Ataxia is very typical presentation for patients with elevated phenytoin levels.
    • Respiratory distress
    • Encephalopathy
    • Meningeal irritation with pleocytosis
    • Tremor (intention)
    • Irritability or agitation
    • Confusion
    • Hallucinations
    • Mental status varies from completely normal to the extremes of stupor and coma, particularly if co-ingestants are present
    • Peripheral neuropathy (chronic use)
    • Priapism
    • Urinary incontinence
    • Choreoathetoid movements
    • Dysarthria
    • Dysphagia
    • Seizures (rare)
    • Death (rare)


  • Eyes
    • Nystagmus (horizontal, vertical)
    • Ophthalmoplegia
    • Diplopia
    • Miosis or mydriasis


  • Hypersensitivity reactions (usually 1-4 wk after exposure)
  • Cardiovascular
    • Hypotension, bradycardia , myocardial depression, ventricular fibrillation, asystole, and tissue necrosis all have been associated with the IV formulation.
    • Phlebitis, necrosis, even gangrene
    • “Purple glove syndrome”
      • Distal limb edema, discoloration, and pain after IV administration
      • Usually in elderly and after massive/multiple doses


  • Skin
  • GI/abdomen
    • Right upper quadrant tenderness
    • Hepatomegaly
    • Splenomegaly
    • Nausea
    • Vomiting
    • Hepatitis


Investigations

-Obtain a serum phenytoin level.

  • Lower than 10 – Rare
  • Between 10 and 20 – Occasional mild nystagmus
  • Between 20 and 30 – Nystagmus
  • Between 30 and 40 – Ataxia, slurred speech, nausea, and vomiting
  • Between 40 and 50 – Lethargy and confusion
  • Higher than 50 – Coma and seizures

-For acute toxicity:

  • Measure ethanol level for multiple ingestions or altered mental status.
  • Measure electrolyte levels
  • LFT for suspected hepatotoxicity

-For chronic toxicity:

  • Obtain a complete blood count (CBC) to rule out anemia, eosinophilia, atypical lymphocytosis, and pancytopenia.
  • Measure electrolytes to rule out hyperglycemia and hyperosmolar nonketotic coma.


Other: ECG, Brain CT

Management
-The usual measures of airway maintenance, breathing assessment, and circulatory support are indicated.
-Administer multiple dose activated charcoal7 every 2-6 hours until passage of charcoal stool, loss of bowel sounds, or improved clinical condition is observed.
-The treatment of hypotension secondary to IV infusion includes decreasing the rate of infusion, intravenous fluids, and, possibly, vasopressors.

Neonatal Drug Withdrawal

A withdrawal syndrome/discontinuation syndrome, occurs when a person suddenly stops taking or reduces the dosage of some types of medications. The risk of a discontinuation syndrome occurring increases with dosage and length of use.

Neonatal withdrawal or neonatal abstinence syndrome (NAS) is a withdrawal syndrome of infants, caused by administration of drugs. Tolerance, dependence and withdrawal may occur as a result of repeated administration of drugs, or even after short-term high dose use for example during mechanical ventilation in intensive care units.

There are two types of NAS: prenatal and postnatal. Prenatal NAS is caused by substance abuse by the pregnant mother, while postnatal NAS is caused by discontinuation of drugs directly to the infant.

Causes

Through multiple mechanisms, all drugs of abuse can cause molecular and cellular changes that ultimately lead to changes in neural migration, cell structure, neurotransmitter dynamics, and overall brain formation. These alterations are likely associated with a whole range of behavioral and cognitive changes. Maternal polydrug use is likely to be far more damaging than use of any single drug.

Laboratory Studies

The following studies are indicated when assessing perinatal drug abuse and neonatal drug withdrawal:

  • Obtain a serum glucose level.
  • Obtain a serum calcium level.
  • Perform a CBC count with differential and platelets.
  • Consider blood culture and other cultures to rule out newborn sepsis.
  • Confirm maternal hepatitis status and treat accordingly.
  • Confirm human immunodeficiency virus (HIV) status.
  • A urine toxicological screen may be helpful in determining drug use. A urine screen only signifies recent use or heavy use of drugs. In general, the length of time that a drug is present in urine after use is as follows:
    • Marijuana: 7 days to 1 month in an adult, perhaps even longer in an infant
    • Cocaine: 24-28 hours in an adult, 72-96 hours in an infant
    • Heroin: 24 hours in an adult, 24-48 hours in an infant
    • Methadone: Up to 10 days in an infant
  • Neonatal toxicology screening should also include algorithms using meconium testing.[21
  • ]Meconium testing provides higher sensitivity than urine testing and is comparable to umbilical cord tissue samples.
  • Neonatal hair analysis may prove useful in confirming fetal drug exposure and possibly predicting neonatal withdrawal severity. Hair analysis should be used in conjunction with urine and meconium analysis.

Severity of newborn withdrawal from substances depends on the drugs and the frequency of use by the mother during pregnancy.

Signs

  • Alcohol withdrawal: hyperactivity, crying, irritability, poor sucking, tremors, seizures, poor sleeping patterns, hyperphagia, and diaphoresis. Signs usually appear at birth and may continue until age 18 months. Withdrawal typically appears within 3-12 hours after delivery.
  • Barbiturate withdrawal: irritability, severe tremors, hyperacusis, excessive crying, vasomotor instability, diarrhea, restlessness, increased tone, hyperphagia, vomiting, and disturbed sleep.
  • Marijuana withdrawal : fine tremors, hyperacusis, and a prominent Moro reflex; however, these symptoms rarely require treatment.
  • Nicotine withdrawal: Mild signs are observed, including fine tremors and variations in tone; recent data have shown that maternal smoking was associated with subtle neonatal behaviors, such as poor self-regulation and an increased need for handling.[17 ]These behaviors are suggestive that neonatal withdrawal is possible for nicotine exposure in utero.
  • Acute narcotic withdrawal: This withdrawal usually begins 24-48 hours after birth, depending on the time of last dose. However, signs may not appear in the infant until 3-4 days after birth.
  • Methadone withdrawal: Symptoms typically appear within 48-72 hours but may not start until the infant is aged 3 weeks. This is particularly true for infants whose mothers took excessively higher doses. Conflicting data have emerged concerning withdrawal severity and higher in-utero methadone doses. Data have shown that coexposure with nicotine increases the severity and duration of the neonatal withdrawal.
  • Buprenorphine withdrawal: Symptoms typically occur within the first 72 hours. 10% of infants exposed to buprenorphine are delivered prematurely
  • Opiate withdrawal: hyperirritability, gastrointestinal dysfunction, respiratory distress, and vague autonomic symptoms (eg, yawning, sneezing, mottling, fever). Tremors and jittery movements, high-pitched cries, increased muscle tone, and irritability are common. Normal reflexes may be exaggerated. Loose stools are common, leading to possible electrolyte imbalances and diaper dermatitis.
    • Long-term symptoms have been difficult to study, but evidence supports that these children show hyperphagia, increased oral drive, sweating, hyperacusis, irregular sleep patterns, poor tolerance to environmental changes, and continued loose stools.
    • NAS appears to be less severe if the mother has used opiates longer than one week prior to delivery.
  • Cocaine: Acute signs such as tremors, high-pitched cry, irritability, excess suck, hyperalertness, apnea, and tachycardia can be seen with the first 72 hours of life
  • Antidepressants: show jitteriness, respiratory distress, and other neonatal complications. They are more commonly observed in newborns whose mothers were taking a short-acting SSRI such paroxetine (Paxil).

Management

-The mainstays of treatment include opioids (especially if specific prenatal opioid use was known) and phenobarbital.
– Until the child has been weaned off medication, or until the symptoms have abated (as confirmed by the Neonatal Abstinence Scoring System), the patient should be constantly monitored by newborn nursery staff. Vital signs should be checked, the Neonatal Abstinence Scoring System score should be obtained, seizure precautions should be taken, and frequent weight checks should be performed.
– 40% of all withdrawing newborns can be treated symptomatically (without medication). Specific methods include the following:

  • Loose swaddling, as well as holding and slow rocking the infant, may be helpful.
  • Perform environmental controls emphasizing quiet zones, low lighting, and gentle handling.
  • Use a pacifier for excessive sucking.
  • Frequent diaper changes are necessary. Diaper dermatitis is common in infants who are withdrawing from narcotics and have loose stools. Proper skin care can minimize skin breakdown and associated discomfort.
  • Position the newborn to reduce aspiration. Some recent evidence suggests that placing babies in the left lateral position is more useful to decrease gastroesophageal reflux than placing babies in the right lateral or supine position.

Opiods
Opiate substitutes and phenobarbital are the mainstays of treatment. Other sedatives such as diazepam have not been shown to be effective. Many studies have compared opiates with phenobarbital alone. In general, opiates have been most effective. However, considerable data have shown that a combination treatment of opiates and phenobarbital significantly decreases hospital stay and decreases withdrawal severity. The drawback is that total duration of treatment (mostly as an outpatient on phenobarbital) is increased.

Opium, deodorized tincture 1:25 dilution
Starting dose: 0.05-0.1 mL/kg PO q4-6h
Maintenance dose: 0.05 mL/kg q4-6h; increase by 0.05 mL/kg at the end of every 4-h period until desired response is achieved; then, maintain dose for 3-5 d; then begin taper of 10% (of peak dose) every 2-3 d; rare to exceed 0.7 mL/dose; not to exceed 1-2 mL/kg/24h

Barbiturates

Although barbiturates also are available for neonatal withdrawal syndrome, their optimal use is limited to several clinical situations, including the following:

  1. The newborn with a nonopiate withdrawal
  2. The newborn with a known polydrug withdrawal
  3. The newborn with abstinence-related seizures
  4. The newborn who has already received the maximum safe level of deodorized tincture of opium (DTO)

Phenobarbital (Luminal)

    • Loading dose: 20 mg/kg PO
      If continued Neonatal Abstinence Scoring System scores are >8 for 3 consecutive periods or if scores are >12 for 2 consecutive periods, then administer another 10 mg/kg q12h until a serum level of 40 mcg/mL is achieved
      Maintenance dose: 2-5 mg/kg/d PO divided q8-12h, provided serum phenobarbital level is therapeutic; with good control, continue maintenance phenobarbital dose for another 72h
      Weaning: The goal is to lower the serum level by 15% q24h; lower maintenance dose to 2 mg/kg/d; if serum level falls by >20% q24h, increase to 3 mg/kg/d; if serum level falls by only 10% q24h, decrease dose to 1 mg/kg/d; discontinue phenobarbital once serum level is <10 mcg/mL and the patient is clinically in good control

Neonatal abstinence scoring form.


This system is currently used as a diagnostic tool and as a monitor for the response of a newborn with withdrawal to pharmacotherapy.

  • Each of the 21 different symptoms is scored depending on severity. All scores are then added. Scoring is performed in 4-hour intervals. If the newborn receives a score of 8 or greater, then scoring should occur every 2 hours. If the scores in the first 96 hours of life are consistently 8 or less, then scoring can be discontinued and pharmacotherapy is typically not needed.
  • If the maternal urine screen or history is positive for drug use, first assess the infant at 2 hours after birth. Scores should reflect the symptoms observed during the entire interval, not just at a single point. Scores involving sleep and behavior should reflect any changes during the test period. For instance, if the child was awakened for the examination, do not score against the child for diminished sleep.
  • A higher total score implies a more severe withdrawal syndrome. Likewise, as the child responds to treatment, use the scores to titrate the amount of pharmacotherapy needed.

Reference: http://emedicine.medscape.com/article/978492-print

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Comments
  1. Deepaneswari Kamala Kannan says:

    Dear doctors,

    Im a final year student from Volgograd , Russia. I have been going through this blog since the day i was told bout it. I would like to express my heartfelt gratitude to all of you , for being so kind and considerate, sharing with us, all the information that you all have learned in Malaysia. Being 2 months away from my finals and just a few more months away from my working life, i have to say, the fear towards housemanship is tearing me apart. But at least i have this website to focus on the things that i actually need to learn rather than just blindly reading everything and getting confused at the end :)

    im writting this email, to ask bout paeds.. In Volgo, we start with normal basic physiology of a kid ( the information and the calculation bout their weight, height, head circumferance and so on, and then each systems development). Later we are thought bout the diseases in children.

    My question is, how is it during the working time??
    Do we need to know the norms for the normal growth as well?
    And the diseases we learn in Volgo – Rickets
    Anaemia ( everything)
    Haemotological disorders
    Pneumonia, BA
    Kidney diseases
    Leukaemia

    is this the same diseases i need to revise the working life in Malaysia aswell… or the diseases that we see in Malaysia are different.

    Please guide me the right way to get prepared for the paeds posting in future :)

    thank you so much for kindness. Hats off to all you for this great job :)

    Truly,
    Deepa Kannan

    • kiamseong says:

      Dear Deepa,

      Thanks for your kind support. We are actually also final year students from Crimea, Ukraine. As for the paediatrics topic, the most important topics are the following (of course there are a lot more that we couldn’t mention here):-
      -febrile fits
      -hypoglycaemic child/ infant of diabetic mother
      -neonatal jaundice
      -AGE (fluid management)
      -asthma and bronchiolitis etc

      We will update in our blog once we get any new information. If you have any information would like to share with us, kindly send to csmuhow@gmail.com

      Thanks. Good luck in your finals =)

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