Toxicology of childhood differs from adult toxicology on several key issues. In both scenarios, the patient is frequently uncooperative and history is often cluded, leading to empirical decisionmaking. In children, the situation is complicated by their tendency to compensate readily up to a certain cliff's edge, and then to collapse in a spectacular manner.

Most of the routine toxicological primary survey is valid in the paediatric setting. In fact, expert writers on the topic comment that very little adjustment is required for routine adult toxicological approaches, and refer to adult literature for details so as not to duplicate effort. In spite of this, Question 28 from the first paper of 2016 asked the candidates to compare assessment and management of poisoning in a two-year-old to the same issues in an adult, as if these issues were dramatically different.  Other groups needing to be compared were pregnant women in the third trimester and elderly people with renal impairment, in which case there are genuine differebces.  Of these three, the paediatric population would have been the least familiar to the general intensivist who has spent their whole period of training looking after adults, and the group requiring the most subtle changes to practice.

The primary resource for an answer to this question would have to be Chapter 112 from Oh's Manual, (pp. 1148), "Paediatric  poisoning"  by James  Tibballs. For all its merits, it still does not address a series of key issues. For pharmacokinetic changes in infancy and childhood, my most useful source was Kearns et al (NEJM, 2003). For the specialised approach to the poisoned child, I referred mainly to the excellent 2014 article by Callelo and Henretig. Another good (short-form) source was the Toxicology Handbook by Murray et al  (2015), as according to previous exam experiences this is the favourite college source for SAQs. The influence of extremely young age on pharmacokinetics and pharmacodynamics is also explored in the required reading section on Variability in Drug Response for the CICM Part I exam. 

Major differences in pharmacokinetics

Exposure

  • Frequently accidental and small in scale:  the inquisitive toddler will not continue eating the foul-tasting tablets. Ergo, doses consumed by toddlers are frequently well below the doses normally seen in adult overdoses (who start with a litre of vodka and take the whole packet of whatever)
  • Occasionally, several children are involved: in which case, assume each child took all the pills: i.e. treat as if the maximal exposure has occurred.

Absorption:

  • Gastric pH is elevated in neonates (~ 4.0) which leads to increased bioavailability of acid-labile compounds (eg. phenoxymethylpenicillin) and decreased bioavailability of weak acids (eg. phenobarbital). Lipid-soluble drug absorption will also be altered unpredictably.
  • Gastric emptying is poor during the first week of life, but normalises quickly.
  • Active and passive intenstinal molecule transport is slow in the first four months of life, but transport mechanisms mature around the time you are supposed to be starting solids. Villous formation completes its maturation process around the 20th week of gestation.
  • Intestinal microflora changes throughout infancy, influencing the degradation of drugs like digoxin
  • Cutaneous  absorption is more rapid, because babies and small children have a thinner stratum corneum. One ends up with more corticosteroids absorbed systemically than one might expect from the sparse application of creams and ointments. Toxicity may result from increased systemic absorption of usually benign antiinflammatory NSAID creams used for nappy rash.
  • Intramuscular depot absorption is less rapid in neonates because skeletal muscles in a neonate receive a decreased blood supply, and because skeletal muscle contractions which usually disperse the drug are inefficient. On the other hand:
  • Intramuscular depot absorption is more rapid in toddlers because skeletal muscles in a toddler receive an increased blood supply with a higher than average capillary density.
  • Increased absorption by inhalation increases susceptibility to volatile toxins; children have a higher baseline respiratory rate and minute volume (in terms of ml/kg/min) than adults. A classical exmaple of this is carbon monoxide toxicity: among exposed groups from the same fire, the most severe symptoms are usually in the youngest child.

Distribution

  • Volume of distribution is greater for water soluble drugs: neonates and infants have relatively larger extracellular and total-body water spaces.
  • Volume of distribution is smaller for fat-soluble drugs: neonates and infants have a higher water-to fat ratio in their adipose tissue; drugs which rely on lipid redistribution for their offset effect will linger.
  • Albumin and α1-acid glycoprotein levels are lower in neonates and infants, increasing the free fraction of highly protein bound drugs. Also foetal albumin is quite unlike adult albumin, and has a decreased capacity to bind acidic drugs
  • The blood brain barrier is immature, apparently with larger pore sizes. This results in an enhanced penetration of drug into the CNS.

Metabolism

  • Increased expression of Phase I metabolic enzymes results in rates of drug clearance which exceed thse of adults, for example in the case of caffeine and theophylline, or phenytoin.
  • Generally, hepatic metabolism of drugs is increased,with relatively higher weight-based dose requirements. By age 10, adult metabolic rates develop. Some of this is likely due to the high ratio of liver mass to total body mass, which reaches its maximum at around the age of 3.

Renal elimination

  • Glomerular filtration rate is reduced in pre-term neonates, with associated decreases in drug clearance. It reaches adult values by around 12 months of age.
  • Active tubular secretion is immature at birth, but achieves an adult-lke level of function by the end of the first year.

Major differences in pharmacodynamics

  • This is poorly understood. According to Kearney et al (2003), "little information exists about the effect of human ontogeny on interactions between drugs and receptors and the consequence of these interactions".
  • Most of the adjustments to age-relate drug dosing are made because of differences in pharmacokinetics, particularly clearance.
  • However, there are probably a few true age-dependent differences in the interaction between a drug and its specific receptor. Thus, there are age-related differences in the relationship between the plasma level and pharmacologic effect. This is seen in warfarin, cyclosporine, midazolam, and valproate.

Specific drug effects

  • Respiratory depression occurs more readily in children, as their susceptibility to respiratory failure is increased (this includes both opiate effects and the effects of aspiration)
  • Hypoglycaemia occurs more readily because of decreased glycogen stores.
  • Cardiovascular collapse occurs more precipitously: cardiac output is more heavily reliant on heart rate, and adrenergictone is nicreased. Tachycardia will be the solitary vital sign abnormality until everything falls in a heap.
  • QT prolongation occurs more readily in infants
  • Paradoxical reaction to benzodiazepines and sedating antihistamines has been obsered in the under-2s

Major issues in management of a paediatric toxicologic emergency:

Even though Question 28 from the first paper of 2016  insists on comparing adult toxicology to paediatric toxicology, various non CICM experts such as Callelo and Henretig (2014) actually refer heavily to adult literature for their approach to toxicologic assessment and management, insisting that "little modification is necessary in expanding these overviews to focus on the pediatric situation".

Differences in approach to assessment:

  • Diagnosis of poisoning is frequently obvious from the parents.
  • When it is not obvious, poisoning needs to be excluded in "any child who presents with unexplained obtundation, fitting, hypoventilation,hypotension or has a metabolic derangement"
  • Most "exploratory" overdoses occur in the group of 1-5 year olds.
  • "Pica-prone" children tend to be intellectually impaired or syndromic
  • Routine screening for unreported acetaminophen ingestion is not usually indicated in small children.

Differences in approach to management

  • Most overdoses in childhood recover with little or no management
  • Aspiration is more serious than the actual poisoning.
  • Intubation should be considered early, considering especially the childhood propensity to  airway failure and respiratory compromise
  • The decision to decontaminate (eg. using charcoal or gastric lavage) is thefore based on the risk of aspiration, and on whether or not the patient is intubated
  • The incompletely conscious child should not be given NG charcoal: it may cause a fatal bronchiolitis obliterans. Nor should they have gastric lavage, because of aspiration risk.
  • In any case activated charcoal loses much of its effect at 2 hours port ingestion
  • Gastric lavage and activated charcoal are reserved for the child who presents very soon after their poisoning.
  • The charcoal will need to be disguised by a fruity flavouring, and presented in a popper or other closed-lid container so that the child is not horrified by the black sludge appearance.

Empirical therapy of critical importance in the peri-arrest poisoned child

  • Naloxone 1-2mg IV - i.e. around 0.1mg/kg, a high dose in comparison to the adult. You are not concenrned about precipitating acute withdrawal in the chronic addict (Shieh-Czaja et al, 2005)
  • Dextrose 50% -  children are more susceptible to hypoglycaemia, and more so in β-blocker overdose

Overdoses which are trivial in adults but lethal in children:

  • This is a list from Tibballs's chapter:
  • Methadone
  • Buprenorphine
  • Diphenoxylate with atropine (Lomotil)
  • Camphor
  • Quinine derivatives
  • Cyclic antidepressants
  • Clonidine
  • Sulfonylureas
  • Salicylates,
  • Calcium channel blockers
  • Colchicine
  • Lead (it is absorbed better by children)

Specific overdoses which are (almost) unique to children:

  • Button batteries: major issue is corrosive injuries to the oesophagus, resulting in oesophageal perforation and mediastinitis. By electrolysis, strong alkali is produced at the cathode and strong acid is produced at the anode. Urgent endoscopic removal is the only option
  • Small magnets: by clamping together across a section of mucosa, these may cause bowel perforation.
  • Petrochemicals: petrol, kerosene, lighter fluid, etc. Pneumonitis and a decreased level of consciousness are the usual presenting features. Fatal arrhythmias may occur because the hydrocarbons tend to sensitise catecholamine receptors.
  • Essential oils, eg. eucalyptus or turpentine (which cause pneumonitis and a decreased level of consciousness, as well as a high anion gap high osmolar gap metabolic acidosis)
  • Others:  automatic dishwasher tablets, drain cleaners

Major non-ICU issues to consider:

  • Advice to parents regarding securing the medicines in an inaccessible place
  • Psychosocial help for children who had an intentional overdose
  • One needs to consider non-accidental overdose, i.e. child abuse by poisoning. This typically presents as unusual drugs with repeated incidents of exposure.
  • Accidental "exploratory" overdose may raise the suspicion of neglect, particularly if the child had ingested illict drugs belonging to the parents (although this could be described as a judgement call, and it is not inconceivable that one might have dutiful and doting parents who pays meticulous attention to securing their meth crystals in a toddler-inaccessible cupboard).
  • Steps to be taken to prevent any further iatrogenic overdoses (eg. education or drug labelling). A not uncommon household or in-hospital overdose is a ten-fold overdose arisng from the error of calculating a mg/kg dose.

References

Kearns, Gregory L., et al. "Developmental pharmacology—drug disposition, action, and therapy in infants and children." New England Journal of Medicine 349.12 (2003): 1157-1167.

Barry, J. Dave. "Diagnosis and management of the poisoned child." Pediatric annals 34.12 (2005): 937-946.

Reid, David HS. "Treatment of the poisoned child." Archives of disease in childhood 45.241 (1970): 428.

Henretig, Fred M. "Special considerations in the poisoned pediatric patient." Emergency medicine clinics of North America 12.2 (1994): 549-567.

Calello, Diane P., and Fred M. Henretig. "Pediatric toxicology: specialized approach to the poisoned child." Emergency medicine clinics of North America 32.1 (2014): 29-52.

Shieh-Czaja, Angela, Diane P. Calello, and Kevin C. Osterhoudt. "Sick sisters." Pediatric emergency care 21.6 (2005): 400-402.