Page 1736 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 124: Toxicology in Adults 1205

ion. Accordingly, bicarbonate administration in the presence of signifi- For example, vancomycin has a molecular weight of 1500 Da, but is
cant hypokalemia will not achieve alkaline urine, yet increases the risk significantly cleared by HD with a high-flux membrane. 87,88
of alkalemia. Since urinary alkalinization can cause hypokalemia by 3. Protein binding: Low protein binding (<90%) facilitates drug
alkalemia-induced intracellular potassium shift and by increased urinary removal by hemodialysis, since only unbound drug is free to cross
potassium losses with alkaline diuresis, addition of potassium chloride to the hemodialysis membrane; for example, for a drug which is 90%
the bicarbonate infusion is commonly required and may be considered protein-bound, hemodialytic removal of 50% of free drug only
prophylactically. We do not recommend the use of acetazolamide to reduces its concentration in blood passing through the dialyzer by 5%.
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induce alkaline diuresis. This therapy causes metabolic acidosis, which
can further complicate management, particularly in the case of salicylate 4. Volume of distribution (Vd): This is the theoretical volume into
intoxication (where acidemia increases CNS entry of the drug). which the intoxicant is distributed. As a general rule, substances with
Urinary acidification to enhance elimination of weak bases, such a Vd of <250 L (approximately 3-4 L/kg) are potentially significantly
as phencyclidine and amphetamines, is not recommended. It is not cleared by hemodialysis. Conversely, hemodialytic removal of sub-
an effective elimination technique and carries with it the real risk of stances with a larger Vd is generally insignificant in comparison to the
increased renal injury and systemic metabolic acidosis. total body load of the substance, which often equilibrates too slowly
with the vascular space to allow significant removal. In fact, most
■ EXTRACORPOREAL REMOVAL OF TOXINS substances substantially removed by HD have a smaller Vd of 1 L/kg.

In some instances, treatment of an intoxicated patient with supportive 5. Intrinsic clearance of the substance: Most drugs have a hemo-
dialysis clearance of 5 to 100 mL/min; if a patient’s clearance of a
measures, decontamination, and acceleration of renal drug elimination substance exceeds 500 to 700 mL/70 kg per minute, hemodialysis
does not alter the course of events to optimize outcome. Application of is unlikely to significantly augment the substance’s clearance. It is
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extracorporeal drug removal (ECR) techniques may be lifesaving for important to note that the clearance of a drug at toxic levels may be
such patients, although clear proof that ECR favorably alters the course significantly less than that reported within the therapeutic range,
of any intoxication is generally lacking. Application of ECR for any because of saturable hepatic metabolism at high drug concentra-
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intoxication is based on critical appraisal of both the clinical status of tions (concentration-dependent kinetics) or intoxication-induced
the patient and of current available data on the prognosis and treat- renal, hepatic, or cardiac dysfunction. Furthermore, there is usually
ment of the intoxication. In general, ECR should be considered when a paucity of information regarding the production and relative clear-
(1) supportive care fails to stabilize the patient’s clinical status; (2) the ance (intrinsic vs extracorporeal) of toxic metabolites.
intoxication is projected to undergo delayed or insufficient clearance
because of renal, hepatic, or cardiac dysfunction; (3) the intoxicating Complications of HD include
agent produces toxic metabolites; or (4) delayed toxicity is characteris- 1. Intravenous access complications: If possible, temporary vascular
tic of the intoxication. 79-81 In addition to these general considerations, access should be placed in the femoral vein to minimize the poten-
specific clinical features or serum drug levels may indicate the necessity tial for serious complications (pneumothorax, central vessel or nerve
for ECR. Finally, physicochemical properties of the intoxicant, and its injury, or catheter-induced arrhythmia). Vascular access should also
pharmacokinetic behavior in overdose (which may differ from the agent’s be removed as soon as possible (but not before the period for poten-
pharmacokinetic properties in the therapeutic range), also dictate the tial development of rebound intoxication has passed) to minimize
feasibility of ECR and the choice of method. Three methods for ECR are the potential for access infection or thrombosis.
generally available: (1) dialysis (usually hemodialysis rather than perito- 2. Hypophosphatemia: In patients without concomitant renal failure
neal dialysis); (2) hemoperfusion; and (3) hemofiltration. Rarely, other
techniques such as plasmapheresis and exchange transfusion are consid- and hyperphosphatemia, the dialysis bath should be supplemented
with phosphorus to prevent severe dialysis-induced hypophospha-
ered for specific intoxications; these will not be further discussed here.
temia. Addition of 1.3 mmol/L of phosphorus to the dialysis bath
Hemodialysis: Hemodialysis (HD) is the treatment of choice for ECR of should prevent hypophosphatemia.
very few intoxicants, because hemoperfusion (HP) provides superior drug 3. Alkalemia: Since the usual dialysis bath bicarbonate (buffer)
extraction in most cases in which ECR is considered. Hemodialysis is still concentration is 35 to 38 mEq/L, severe alkalemia can result from
preferred to HP for removal of substances that are particularly dialyzable hemodialysis against a standard bath in the absence of associated
(see below), especially in the presence of metabolic acidosis, renal failure, acidosis (particularly in the presence of hyperventilation or emesis-
dialyzable toxic metabolites, or other HD indications. Hemodialysis induced metabolic alkalosis). If the predialysis plasma bicarbonate
removes water-soluble unbound (free) solutes that are small enough to concentration is 28 mEq/L or higher, then the bath bicarbonate
pass through the pores of the semipermeable dialysis membrane, which concentration must be lowered to 15 to 28 mEq/L.
separates the patient’s blood from the countercurrent flow of the dialy- 4. Disequilibrium syndrome: Acute neurologic deterioration caused
sis bath fluid (which is discarded as effluent dialysate following passage by large, rapid changes in cerebral tissue osmolality may occur in an
through the dialyzer). Solute transport, including transfer of drugs, acutely uremic patient who receives a prolonged initial session of
toxins, or metabolites, occurs by diffusion down the blood-to-dialysis intensive hemodialysis for drug removal. High-sodium dialysis bath
bath concentration gradient, which is maintained by countercurrent flow and intravenous mannitol may be useful prophylactically in blunt-
of dialysate. In addition to low molecular weight and water solubility, both ing large acute transcellular water shifts caused by HD removal of
low protein binding and a small volume of distribution are necessary char- uremic toxins.
acteristics of a substance that is readily cleared by HD. 82-86
Criteria for potential dialyzability include: 5. System saturation: This is not possible using standard hemodi-
alysis, because of maintenance of the concentration gradient for
1. Water solubility: Water-soluble substances cross dialysis membranes diffusion by countercurrent flow (blood vs dialysate), except when
more readily than lipid-soluble agents (drugs or metabolites). a sorbent dialysis system is used. This system is inappropriate for
2. Low molecular weight: Traditionally, a substance is described as extracorporeal removal of an intoxicant, since the sorbent cartridge
small enough to be significantly removed by hemodialysis when it used to regenerate new dialysis solution from dialysate may become
has a molecular weight of <500 daltons (Da). More recently, high- saturated and cease to function. If such a system is the only available
flux dialysis membranes with increased porosity and surface area option, frequent cartridge changes will be required.
have been introduced. Such membranes are capable of removing 6. Other: Hypotension is a potential adverse effect of HD (or HP),
drugs with weights in the middle-molecule range, up to 5000 Da. particularly if this therapy is instituted in an already unstable

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