724 improvement after combination therapy J Am Acad Dermatol 2006;54(5) 914–6 102 Jan F, Segal JM, Dyer J, LeBoit P, Siegfried E, Frieden IJ Nephrogenic fibrosing dermopathy two pediatric cases J Pedi[.]
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Frieden IJ. Nephrogenic fibrosing dermopathy: two
pediatric cases J Pediatr 2003;143(5):678–81.
103 Nardone B, Saddleton E, Laumann AE, Edwards
BJ, Raisch DW, McKoy JM, Belknap SM, Bull
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DP. Pediatric nephrogenic systemic fibrosis is
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2014;44(2):173–80.
104 Karcaaltincaba M, Oguz B, Haliloglu M. Current
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MJ Jr, Smith TP, Kim CY. Postintervention patency rates and predictors of patency after percutaneous interventions on intragraft stenoses within failing prosthetic arteriovenous grafts J Vasc Interv Radiol 2015;26(11):1673–9.
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V R Dharnidharka and D C Rivard
Trang 2© Springer Nature Switzerland AG 2021
B A Warady et al (eds.), Pediatric Dialysis, https://doi.org/10.1007/978-3-030-66861-7_38
Extracorporeal Therapy for Drug Overdose and Poisoning
Vimal Chadha
Introduction
Poisoning continues to be a significant cause of
morbidity and mortality The 2018 Annual Report
of the American Association of Poison Control
Centers National Poison Data System (NPDS):
36th Annual Report published information on
2,099,751 human exposure cases of poisoning of
which more than half (59%) were children and
adolescents <20 years old, with majority (75%)
occurring in children ≤5 years [1] A male
pre-dominance was found among cases involving
children ≤12 years, but this gender distribution
was reversed in teenagers and adults, with
females comprising the majority of reported
exposures [1] Prescription drugs, over-the-
counter medications, illicit drugs, and common
household substances can all be responsible for
poisoning The top five most frequently involved
substances in all human exposures were
analge-sics (10.9%), household cleaning substances
(7.3%), cosmetics/personal care products (6.5%),
sedatives/hypnotics/antipsychotics (5.5%), and
antidepressants (5.2%) In children ≤5 years, analgesics (9%) were surpassed by cosmetics/ personal care products (12.1%) and household cleaning substances (10.7%) [1]
Of note, there has been a steady decline (15.7% since 2008) in the number of poisoning cases, but this has been accompanied by an increase (4.45% per year since 2000) in the num-ber of cases with serious outcomes The most rapidly increasing substance categories resulting
in more serious outcomes for the past 10 years have been antidepressants, stimulants/street drugs, antihistamines, and anticonvulsants [1] While most (76.7%) poison exposures are still unintentional, suicide attempts by adolescents are becoming an important emerging trend; sui-cidal intent was suspected in 19.1% (almost dou-ble since 2008) of cases It is noteworthy that in 13% of exposures (273,581 cases), poisoning resulted due to therapeutic errors such as inadver-tent double dosing, incorrect dosing, wrong med-ication taken or given, and inadvertent exposure
to someone else’s medication
The management of poisoning continues to be
a significant burden on the healthcare system In
2018, approximately one-third (31%) of all cases received treatment in a healthcare facility While half of them were treated and released without hospital admission, 97,963 (15%) had to be admitted for critical care management, and 78,401 (12%) were admitted to a non-critical
V Chadha (*)
Department of Pediatrics, University of
Missouri-Kansas City School of Medicine, Acute Kidney
Injury Program, Children’s Mercy Kansas City,
Kansas City, MO, USA
e-mail: vchadha@cmh.edu
38
Trang 3care unit Despite being the most common age
group with poisonings, only 12.5% of children
≤5 years and 18.4% of children between 6 and
12 years were managed in a healthcare facility
compared to 66% of teenagers (13–19 years) and
50% of adults Similarly, children younger than
6 years also experienced the least (<2%) of the
exposure-related fatalities [1]
Poison Characteristics
In the discipline of clinic toxicology, poison
gen-erally refers to any agent (drug or toxin) that can
kill, injure, or impair normal physiologic
func-tion A poison is often referred to as a xenobiotic,
a chemical substance found within an organism
that is not naturally produced or expected to be
present within the organism The term also
includes any naturally existing substances in an
organism that are present in abnormally higher
concentrations
For practical purposes, the poisons can be
divided into two broad categories: those that
cause tissue damage and those that do not
Tissue damage is defined as irreversible or
slowly reversible structural or functional
changes in one or more organ systems that occur
as a direct result of the poison (or its toxic
metabolite) in the body Poisons such as
salicy-lates, acetaminophen, and methanol fall in this
category, and they can cause direct tissue
dam-age despite provision of intensive supportive
care [2 5] Thus, in patients poisoned with this
group of chemicals, use of a specific antidote (if
available) and/or active removal of the poison
by extracorporeal therapies (ECTs) is necessary
to prevent irreversible tissue damage The
sec-ond group of poisons such as barbiturates and
other common sedative/hypnotic drugs does not
have any direct tissue-damaging effect but
causes indirect harm due to respiratory
compro-mise or hypotension These patients can be
treated with specific antidotes (if available) and
supportive care, provided they will metabolize
and/or excrete the poison in a reasonable time
Management of the Poisoned Patient
The general approach to the management of an acute poisoning includes:
1 Patient stabilization (maintenance of the air-way, ventilation, and hemodynamic status)
2 Establishing accurate diagnosis by clinical evaluation which in many cases is aided by identification and determination of blood con-centration of the toxic substance Recognition
of toxidromes (constellation of symptoms and signs associated with certain class of poisons) can be valuable in expediting diagnosis
3 Decontamination (removal of poison from site
of absorption such as GI tract or skin)
4 Administration of antidotes, if available
5 Supportive care (treatment of hypotension, arrhythmias, respiratory failure, electrolyte imbalance, and seizures)
6 Enhancing elimination of poison by manipu-lation of urinary pH
7 Removal of poison by ECTs
Fortunately, the vast majority of patients with poisoning recover with appropriate supportive care and/or timely usage of specific antidote ther-apy As a result, a very limited number of patients require ECTs, but they are also the most critically sick patients where a judicious usage of ECT can determine their outcome According to the NPDS 36th Annual Report, ECTs were utilized in 2817 (2.9%) of 97,963 patients admitted for critical care management [1]
Since poisons achieve their toxic effects on target organs via the bloodstream, it seems logi-cal that their elimination from the blood should result in amelioration of the patient’s condition Accordingly, changes in the serum poison levels are the most frequently used parameters of response to extracorporeal therapy in intoxica-tion; however, this pretext can be misleading and provides false assurance of dialysis efficacy (vide infra) To better understand these perplexi-ties, the nephrologist ought to be well versed
V Chadha
Trang 4with the basic concepts of pharmacokinetics and
principles of detoxification when dealing with
the management of an acutely poisoned patient
These concepts also help in determining the
usefulness of extracorporeal therapy as well as
selection of the optimum modality for drug
removal
Extracorporeal therapies are typically reserved
for a small subset of patients that can be divided
into the following five subgroups:
(a) Patients intoxicated with poisons that cause
direct tissue damage and are life-threatening
(e.g., salicylate overdose)
(b) Patients intoxicated with poisons that can
cause permanent disability (e.g., blindness
with methanol overdose)
(c) Patients intoxicated with poisons that do not
cause direct tissue damage, but the patient’s
ability to metabolize or excrete the toxic
sub-stance is compromised (e.g., metformin
overdose with renal impairment)
(d) Patients intoxicated with poisons in which
active poison removal is considered to
avoid prolonged supportive care and its
associated complications (e.g., barbiturate
overdose with coma requiring mechanical
ventilation)
(e) Patients intoxicated with poisons who
develop signs of toxicity despite provision of
standard supportive measures
Pharmacokinetic Concepts
The extracorporeal removal (dialyzability) of a
substance is determined by various
physico-chemical and pharmacokinetic properties
These properties predict the extent to which
ECT enhances the total body clearance, thereby
lowering the total body poison load faster than
without treatment By far, the primary
determi-nants of poison removal by ECT are the
molec-ular weight (MW), volume of distribution (Vd),
and protein binding; additional factors such as
hydro- and lipophilicity, ionization, and rate of
intercompartmental transfer also play a
signifi-cant role
Molecular Weight
The lower the MW, the more likely that a poison
is dialyzable While older cuprophane dialyzers were able to clear substances with MW up to
500 Da, contemporary high-efficiency high-flux dialyzers with diffusive modalities are capable of clearing poisons in the middle MW range (≤15,000 Da) In contrast, convective modalities such as hemofiltration and hemodiafiltration can permit clearance of solutes approaching 25,000 Da
Volume of Distribution
Volume of distribution (Vd) is an imaginary space that represents the volume of fluid in which a known amount of drug would have to be diluted
to yield the measured serum concentration Theoretically, if the body is presumed to be a single compartment and a substance is homoge-nously distributed in body water without binding
to protein or accumulating in tissues, it would have an apparent Vd equal to the total body water
V Litersd 0 6 L kg body weight kg/ (38.1)
For some substances such as methanol that dis-tribute in body water without significant binding
to tissue or plasma protein and without signifi-cant accumulation in adipose tissue, the apparent
Vd corresponds to a physiologic space: in this case equivalent to total body water However, most substances are not homogeneously distrib-uted but rather vary in their concentration throughout the body as a result of lipid solubility, protein binding, active cellular transport, and pH gradients, and as a result Vd can vary over a wide range of values (0.2 L/kg for valproic acid to
20 L/kg for imipramine) A Vd significantly larger than actual body water reflects a high degree of tissue concentration, while a small Vd suggests concentration within the intravascular space Volume of distribution is clinically important in two ways First, knowing the Vd and plasma con-centration of a particular drug allows calculation
of the total amount of the drug in the body, as:
Trang 5X mg V Ld C mg Lp / (38.2)
where X is the total amount of the drug in
milli-grams (mg) and Cp is the plasma concentration in
mg/L. Second, Vd is one of the factors that
deter-mine accessibility of a drug to removal by
extracorporeal therapy A large Vd implies that
the amount of drug present in blood represents
only a small fraction of the total body load;
there-fore, as the Vd increases, the usefulness of any
ECT decreases substantially Thus, even if a
hemodialysis session extracts most of the drug
present in blood passing through the circuit, the
amount of drug removed represents a small
per-centage of the total body drug burden Although
there is no precise cut-off, a Vd > 1–2 L/kg
usu-ally limits usefulness of ECT [6] On the
con-trary, poisons with a smaller Vd (< 1 L/kg) are
more amenable to removal by ECT. Volume of
distribution of some of the common substances
involved in poisoning is listed in Table 38.1 It is
important to note that these values for Vd are
derived from the general population under
nor-mal dosing conditions and may not apply in the situation of a substantial drug overdose In addi-tion, the presence of renal and/or hepatic dys-function in a poisoned patient can further alter the value of Vd (see section on toxicokinetics, vide infra)
Protein Binding
Many substances bind with varying affinity to plasma proteins, such as albumin, or to intracel-lular proteins in the tissues Thus, in addition to dissolving in fat, substances can accumulate in tissues according to their degree of protein bind-ing A poison-protein complex may exceed 65,000 Da and is too large to be filtered Highly protein-bound (>80%) substances are therefore not amenable to therapy with extracorporeal modalities However, at toxic levels the protein binding sites are usually saturated, thus increas-ing the proportion of free fraction which poten-tially increases poisoning severity because the
Table 38.1 Pharmacokinetic properties of some of the drugs frequently involved in poisoning
Drug
Molecular weight (Da)
Volume of distribution (L/kg)
Protein binding (%)
Preferred extracorporeal modality
Tricyclic
antidepressant
IHD intermittent hemodialysis
a Relatively limited effect, used in select patients with severe toxicity
b Protein binding decreases to 30% with toxic levels
c Protein binding decreases to 15% with toxic levels
d Use high-efficiency high-flux dialyzer
V Chadha
Trang 6free fraction exerts toxicity, but this also
facili-tates removal by the ECT. This explains the high
removal rate of protein-bound drugs such as
val-proate and salicylates, both of which exhibit
satu-rable binding at toxic levels [7 8] Of note, when
the protein binding is <80%, there is little
differ-ence between the removal of a substance that is,
for example, 20% protein-bound and one that is
70% protein-bound because of the logarithmic
nature of extracorporeal solute removal
(Fig. 38.1) [9] It is also important to note that
most drug-protein bonds are weak and easily
reversible, and protein binding can be altered by
a number of variables such as pH and drug
com-petition for the binding sites
Hydro- and Lipophilicity
Hydrophilic poisons distribute primarily in total
body water, have a smaller Vd, and are more
readily removed by ECT. Lipid solubility affects
the accumulation of drug in lipid-rich tissues
such as adipose tissue and the brain The degree
of lipid solubility of a substance is expressed by
its partition coefficient, which is an in vitro measurement of the ratio of lipid (non-polar) phase to aqueous (polar) phase concentration of its non-ionized form Lipid-soluble drugs can accumulate extensively in the adipose tissue and act as a reservoir with poor accessibility due to decreased vascular perfusion
Ionization
Non-ionized substances are more lipid soluble and, therefore, more easily transported across cellular membranes in the body than their ionized form The pK of the substance is the pH at which it is half ionized and half non-ionized An acid is increas-ingly ionized as the pH rises above its pK, and a base is increasingly ionized as pH falls below its
pK. Therefore, pH gradients across the cell mem-branes can affect the extent of diffusion by trapping the ionized form on one side In the stomach and kidney, where large pH gradients exist (or can be induced) with respect to plasma, this phenomenon can have therapeutic implications to prevent absorption and enhance clearance
100%
80%
60%
40%
20%
0%
13% protein bound
73% protein bound
95% protein bound
Time (minutes)
Fig 38.1 Removal of toxins via HD decreases with
greater degrees of protein binding Comparison of removal
of three uremic toxins (p-cresyl glucuronide, 13% protein
bound; indole-3-acetic acid, 73% protein bound; and
p-cre-syl sulfate, 95% protein bound) during a single HD session averaged over 10 patients Blood flow rates were 300 mL/ min, dialysate flow rates were 700 mL/min, and dialyzer urea clearances varied (Modified from King et al [ 9 ])