Accidental and intentional intoxications occur in about 7.5 million cases per year, resulting in approximately 10,000 deaths per year in the USA [¹]. Data from the Toxic Exposure Surveillance System of the American Association of Poison Centers identify that 65% of these intoxications occur in people less than 20 years of age, yet this age group only accounts for 11% of the fatalities. While the number of children with toxic ingestions is very small, these patients are ill enough to require therapy in the intensive care unit (ICU) due to respiratory, metabolic or cardiac compromise [²]. Holubek et al. reported a trend in the changes of the etiology of intoxications as well as of therapy between the years 1985 and 2005, noting that more than 19,000 cases of intoxication required extracorporeal therapy as a treatment [³]. They also noted that there was a change in both the etiology (an increase in anti-convulsant overdose) and the therapy [a trend away from charcoal hemoperfusion (CH)] for these intoxications.

The management for toxic ingestions has changed over time. In the early mid 1980s and early 1990s, CH was commonly used as a therapy for intoxications [⁴]. New forms of renal replacement therapy (RRT), including high-flux hemodialysis (HD) and continuous renal replacement therapy (CRRT) have, for the most part, replaced the use of CH [⁵]. Additionally, in the last decade, a number of specific rescue therapies have been developed for the treatment of some intoxications, avoiding the need for RRT [⁶]. Examples of these include naloxone for opiate or narcotic overdose, n-acetylcysteine for the treatment of acetaminophen intoxication and fomepizole as the specific treatment for alcohol intoxications [⁷–¹⁰]. Despite these advances in rescue therapy, a significant number of adults and children continue to require RRT as an adjunct to their native renal function for removal of the drug [¹¹].

This review will describe common intoxications in the pediatric age group and their therapeutic intervention with RRT.

When the pediatric patient presents for the care of a toxic ingestion, it is important to determine the natural elimination process, i.e. whether the toxic substance is hepatically or renally excreted. If a medication is excreted via the renal system in the setting of concomitant kidney injury, the half-life of that medication will be prolonged and, therefore, RRT may be indicated [¹, ¹¹].

Currently available data have yet to identify an absolute indication or the best RRT mode to treat intoxications [¹²]. It is suggested that RRT should be used in the case of worsening metabolic consequences, including metabolic acidosis and lactic acidosis, with or without concomitant hypertension. Further respiratory depression related to a direct central nervous system (CNS) effect of the medication or cardiac dysrhythmias may occur secondary to direct cardiac toxicity. RRT should be considered in the setting of impairment with underlying organ dysfunction and in the face of worsening metabolic and respiratory compromise. In addition, the basic level of medical care needs to be done as indicated (e.g. saline diuresis, enteral charcoal placement or gastric lavage if there is an adequate airway protection) [¹, ⁶].

Extracorporeal therapy modalities to support the elimination of intoxications would include RRT, peritoneal dialysis, CH, HD (both standard as well as high flux) as well as CRRT [⁵, ¹¹].

Peritoneal dialysis (PD) has been used in the past as a treatment modality for acute intoxications [¹³]. PD can be performed for acute intoxications as it is used in the settings of acute kidney injury (AKI) or end-stage kidney disease (ESRD). The mechanism of toxic clearance in PD is by diffusion, and the factors that affect clearance include volume and frequency of exchanges of the PD solution and the concentration of the intoxicant present in the serum. The advantages of using PD as a continuous form of RRT are (1) its relative simplicity, (2) availability, (3) avoidance of anticoagulation and (4) lower cost compared to other RRT treatment modalities. The disadvantage (using urea as a marker of clearance) is that compared to HD or CRRT, PD is the least effective model of elimination [¹⁴]. Small molecular weight medications (i.e. lithium) can be eliminated by PD, but due to the greater clearance that HD and CRRT offer in general, PD should be used only when other options for RRT are not available or feasible [¹⁵].

With the diminished availability of CH cartridges as well as a decreasing expertise among health professionals with using these membranes, CH treatment has become less common. CH was commonly used in the past as a way to bind protein-bound intoxicants. The use of CH membranes is associated with hypothermia, hemodynamic compromise, coagulation abnormalities and thrombocytopenia and hypocalcemia [¹⁶]. CH was often coupled with HD in line to negate some of the side effects. The difficulty of performing sequential CH with hemodialysis is the large extracorporeal volume that would be necessary to use these in tandem. It would not be unusual that a 400- to 500-mL extracorporeal circuit would be needed to support both systems in sequence. The cost of keeping a “ready to go” CH cartridge available with a relatively short shelf life and a reduction in the manufacturing of these cartridges have resulted in the decreased use of this method [⁵].

Hemodialysis comes in standard as well as high-efficiency or high-flux modalities, both of which use clearance by diffusion. The major difference is the pore size of the membrane, the type of membrane and the amount of dialysate flow that occurs. Typically, with flux or high-efficiency HD, membranes with a larger pore size (as large as 20 kDa) are available for the clearance of intoxications. With the advent of high-flux or high-efficiency HD membranes, the use of CH has essentially become something of the past [¹⁷].

The use of CRRT has become commonplace in pediatric ICU settings during the last decade and a half [¹⁸]. CRRT either in a convective mode by effecting mass transport of the medication across the membrane or in a diffusive mode is often used in patients with AKI. Studies using sieving coefficients have clearly demonstrated that there is a higher clearance of larger molecular weight molecules and higher protein membrane mediations when convective clearance is used [¹⁹]. Therefore, if CRRT is to be used for intoxications, the focus should be predominantly on a convective modality. A large disadvantage of CRRT for intoxications is that it is less efficient and the patient has less mobility as compared to HD [¹²].

If intoxicants have a large volume of distribution, HD can be used to remove the initial intravascular load of this intoxicant, followed by CRRT, thereby avoiding the rebound that would occur as HD is discontinued.

In the case of poor patient hemodynamics and a patient at extremis, then extracorporeal support with venous arterial extracorporeal membrane oxygenation (ECMO) may be necessary to support the patient hemodynamically [²⁴]. Once stable, RRT can be added to the ECMO circuit for elimination of the intoxicant

Before beginning RRT for a toxic ingestion, the following issues about that intoxication need to be considered:

1. Was it delivered as a short or prolonged release product?
2. What is the volume of distribution?
3. What is the molecular weight?
4. What is it protein binding?

The medication half-life needs to be characterized. If the patient has been overdosed with a sustained release product, there will be an ongoing slow delivery of medications into the plasma space with subsequent complications. This is where the use of gastro-intestinal (GI) elimination in addition to RRT may be necessary.

If RRT is being considered, the molecular weight, protein binding and volume of distribution of the toxin will need to be accounted for. Large molecular weight medications are less well cleared by RRT. Medications that have a high protein binding are also removed less efficiently by RRT. Finally, in medications with a large volume of distribution through multiple compartments of the body, RRT will only clear what is in the plasma space, so the elimination of the intoxicant will be prolonged.

Table 1 identifies common medications that are still causes of intoxication in children together with their molecular weight, volume of distribution and protein-bound percentages.

As opposed to the setting of AKI, if dialysis is needed to treat an acute intoxication, the dialysate or replacement bath needs to have the therapeutic levels of phosphorous and potassium in order to avoid electrolyte disturbances [⁴⁸].

Renal replacement therapy is not commonly utilized for treating intoxications in children, and CH, once a common procedure, has essentially been relegated to the past. Despite the perception of poor clearance, many medications that are highly protein bound can be removed through the use of high-flux or high-efficiency HD membranes. Many medication intoxications have a volume of distribution such that a rebound may occur once RRT is removed. If this is the case, serial HD treatments or the use of sequential HD followed by CRRT may be performed until the medication is naturally eliminated. Peritoneal dialysis has a role in RRT and can be considered if other options are not available.

High-flux or high-efficiency HD should always be considered the first line of treatment if the patient tolerates this therapy. High-flux or high-efficiency HD followed by convective mode of CRRT should be considered in the setting of a large-volume of distribution intoxicant. Convective mode CRRT can be considered in a patient that cannot tolerate HD as initial treatment.

(Answers appear following the reference list)

1. Factor(s) that affect the benefit of RRT for the treatment of drug overdose would include
   1. the volume of distribution
   2. the molecular weight
   3. its protein binding
   4. all of the above
2. If an intoxicant is highly protein bound, which of the following forms of RRT would be best to use for drug removal
   1. standard HD
   2. high-efficiency HD
   3. peritoneal dialysis
   4. diffusive form of CRRT
3. If an intoxicant has low protein binding, a small molecular weight and a low volume of distribution, which of the following forms of RRT could be used for drug removal
   1. standard HD
   2. high-efficiency HD
   3. CRRT
   4. any of the above
4. Comparing the “dialysis bath” in RRT for AKI versus RRT for intoxication in a child without AKI, the bath is
   1. identical
   2. should have physiologic levels of potassium and phosphorous
5. Vancomycin removal is best achieved with either intermittent high-efficiency HD or high-efficiency HD followed by convective CRRT because vancomycin
   1. is highly protein bound
   2. has a large volume of distribution
   3. has a large molecular weight
   4. all of the above

Answers

1. d

2. b

3. d

4. b

5. d