730 Intercompartmental Transfer In a single compartment model, a change in plasma level would reflect a similar change in levels throughout the body Unfortunately, most substances in the body are dist[.]
V Chadha 730 Intercompartmental Transfer In a single-compartment model, a change in plasma level would reflect a similar change in levels throughout the body Unfortunately, most substances in the body are distributed in multiple compartments, and movement across these compartments is variable and dependent on several factors as listed above Knowledge of these parameters is crucial in understanding the relationship between blood level and drug removal during extracorporeal therapies [10] Rebound The increase in plasma poison concentration following a session of intermittent ECT is commonly seen with poisons that have a large Vd This phenomenon of rebound happens when the rate of poison redistribution within the body is slower than the rate of removal by an ECT. Except in situations where the rebound is caused by ongoing absorption of the poison from the gastrointestinal tract, when supplementary treatments may be required, it is uncertain if rebound by itself is concerning For example, in lithium poisoning, the rebound after a session of dialysis actually moves the lithium away from the site of toxicity (CNS) to a relatively more benign compartment (the vascular space) [11] Endogenous Clearance To be worthwhile, the rate of poison removal by an extracorporeal method should be a significant addition to the endogenous (systemic) clearance (sum of renal and non-renal clearance) If endogenous clearance is high, then an ECT is unlikely to significantly increase total clearance enough to justify its use [12, 13] For example, endogenous metformin clearance in the presence of normal kidney function is 600 mL/min and far exceeds the clearance achieved by HD (240 mL/min) In this situation, ECT will usually not be recommended for metformin overdose unless the endogenous clearance is impaired due to con- comitant decreased kidney function, and ECT is the only means of providing useful clearance It is commonly suggested that ECT can be considered worthwhile if the endogenous clearance of the poison is below 4 mL/kg/min [6] It has also been recommended that extracorporeal clearance must represent at least 30% of total clearance to be a significant contributor to drug removal in vivo [14], but the utility of this parameter is questionable under certain situations [15] Toxicokinetics The reported pharmacokinetic characteristics of the drugs are normally evaluated in the context of therapeutic levels One should be cognizant of the fact that many of these properties for the same drug can change with toxic levels (toxicokinetics) Some of the highly protein-bound drugs such as valproate and salicylates can have significant free fraction at toxic levels as the protein binding sites become saturated For example, the protein binding of salicylate falls from 90% at therapeutic concentrations to 50% when it reaches 800 mg/dL; valproic acid’s protein binding decreases markedly from 94% at therapeutic levels to 15% at drug levels >1000 mg/L. In contrast, carbamazepine (protein binding 75%) and phenytoin (protein binding 90%) show little to no saturable binding in overdose conditions The Vd for several drugs (e.g., salicylates) can also change with higher doses, especially in the presence of renal and/or hepatic impairment Furthermore, the drug elimination kinetics for certain drugs can change from first order to zero order, thus extending the elimination half-life pecific Issues in Neonates and Young S Infants The implications and management of poisoning in newborns and young infants require understanding of their unique physiology Primarily, the organs that play an important role in susceptibility to and moderation of toxic reactions such as the liver and kidney are immature in their 38 Extracorporeal Therapy for Drug Overdose and Poisoning function Their gastric emptying is slower, and gastric pH is higher which can enhance absorption of certain drugs, thus increasing their susceptibility to toxicity Once absorbed, the drug distribution varies considerably during the neonatal period and infancy largely due to age-related variations in protein binding, body fat, and total body water [16] Overall, protein binding of drugs is reduced, and body fat and total body water are increased in the neonate This may result in an increase in the apparent Vd and consequent increase in the elimination half-life of the drug Furthermore, the reduction in protein binding may result in an increased concentration of free (unbound) drug with a potentially augmented pharmacological response for a given drug concentration in the plasma As mentioned before, due to the immaturity of their liver function, this group of patients has a decreased capacity to metabolize drugs in the liver due to significantly lower activity of cytochrome P450- dependent mixed-function oxidases In addition, the renal clearance of drugs is reduced, and various tubular functions are suboptimal Finally, successful usage of extracorporeal techniques in infants and young children is technically complex and can be carried out only in few specialized centers Obtaining a suitable vascular access can also become very challenging In these situations, exchange transfusion that can be easily performed in neonates may be used successfully for eliminating certain toxins that have a low Vd Extracorporeal Clearance The efficacy of any extracorporeal therapy is assessed by the accurate determination of the amount of drug removed from the body Several parameters such as dialysance or clearance, efficiency ratio, extraction ratio, and mass removal are commonly utilized to scientifically assess drug removal from the body in an attempt to determine the success or failure of the intervention Dialysance (D) is a measure of solute removal by dialysate and in most modern systems is tech- 731 nically same as clearance (C), as concentration of the toxic substance in the dialysate is minimal in single-pass dialysis with high dialysate flow rates Clearance (C) for hemodialysis is expressed as: C Q b A V / A (38.3) where Qb is the blood flow rate, A is the arterial or inlet concentration, and V is the venous or outlet blood concentration of the toxic substance Note that (A – V)/A is termed the extraction ratio (Ex) that represents the solute removed as a fraction of the maximum it is theoretically possible to remove For continuous renal replacement therapy, clearance (C) is expressed as: C E / P Qe (38.4) where E is the effluent concentration, P is the plasma concentration of the toxic substance, and Qe is the effluent flow rate which can be Quf (ultrafiltrate), or Qd (dialysate), or Quf + Qd The term E/P is also known as sieving coefficient that is equivalent to extraction ratio (Ex) As is apparent, these clearance calculations are based on plasma concentration of the substance, and the results can be misleading in terms of effectiveness of dialysis therapy unless drug distribution and inter-compartmental kinetics (vide supra) are also taken into account To understand this better, consider a drug “x” with a large volume of distribution of 20 L/kg One gram of this drug when given to a 30 kg child will yield a plasma concentration of 0.0016 mg/mL (eq 2) With maximal extraction at a blood flow rate of 200 mL/min, clearance could theoretically be 200 mL/min, which is equivalent to drug removal of 0.32 mg/ or 76.8 mg in 4 hours, which is less than 10% of the total given dose As illustrated by this example, the dialysis is highly efficient, but it is not very effective as the reduction in drug burden is minimal However, it is conceivable but unproven that early pre-emptive initiation of ECT during the absorption and distribution phase may promote the removal of a significant amount of poison with a large Vd For clinical efficacy, one can compare the drug half-lives or their clearance rates from the V Chadha 732 body with and without treatment; this is also known as efficacy ratio Half-life is calculated as: Half - life t ½ 0.693 / K e (38.5) K e log Cpeak log C trough / t interval where Ke is the elimination rate constant and Cpeak and Ctrough are two plasma levels separated by time interval “t” (these levels need not be “true” peak and trough as long as they are separated in time and realizing that the longer the interval, the better the estimate) Drug clearance is calculated as: C 0.693 Vd / t ‰ (38.6) where Vd is the volume of distribution of drug in question Efficacy ratio can then be calculated as t’½/t½ or C′/C, where t’½ and C′ are half-life and clearance with treatment and t½ and C are half-life and clearance without treatment, respectively Half-life calculation based on serial plasma concentrations obtained during ECT can help in estimating the duration of ECT to achieve a safe target concentration for the poison being removed lyzable because of high Vd [20] With these kinds of clinical situations, in addition to a better understanding of pharmacokinetic/toxicokinetic principles (vide supra), improvement in supportive care, availability of effective antidotes, and lack of any well-designed trials to test the efficacy of ECTs, the overall usefulness of ECTs became controversial and marred with uncertainty [21] Nonetheless, the introduction of better (high-efficiency, high-flux) dialysis membranes that can remove poisons once considered undialyzable has permitted newer opportunities for their application In summary, ECTs can play a crucial, if not essential, role in a subset of intoxications as discussed before Intermittent Hemodialysis (IHD) Intermittent hemodialysis is the most widely available, least expensive, and the quickest to implement ECT modality [22] For these reasons, IHD remains the preferred modality for the majority of poisonings According to the NPDS 36th Annual Report, IHD was the most common (90%) of 2817 ECTs used for the management of poisoning [1] During IHD, the poison diffuses down the concentration gradient from the plasma Extracorporeal Modalities through a semipermeable membrane to dialysate flowing in a countercurrent direction In contrast Intermittent hemodialysis (IHD) that is one of the to other ECTs, HD removes the poison rapidly most common ECT was in fact utilized over more due to the high blood and dialysate flow rates than 100 years ago (much before it became a Because poisoned patients are at low risk of dialwell-recognized therapy for patients with end- ysis disequilibrium, IHD can be initiated with stage kidney disease) for salicylate removal from higher clearance, and the dialysis duration can be poisoned animals [17] By the 1970s, most poi- prolonged depending on the clinical context As sonings were considered amenable to treatment the metabolic derangements seen in patients with by dialysis based on two intuitive assumptions: poisoning can be very different from patients (1) ECTs can remove poison, and (2) removal of with ESKD, dialysate composition should be taipoison enhances survival [18] This dichotomy lored for the patient; in addition, high clearance is, however, well exemplified by paraquat toxic- and longer duration of IHD can cause hypokaleity; while paraquat has all the physical character- mia and hypophosphatemia requiring replaceistics associated with high ECT clearance (i.e., ment of both electrolytes low molecular weight, low protein binding, and While hemodialysis has a long track record low Vd), dialysis will generally not alter the for safety, it is associated with many potential dreadful clinical course unless it is initiated early complications that are outlined elsewhere in the after ingestion [19] Conversely, dialysis seems text (see Chapters 24 and 25) In particular, one to improve outcome of metformin poisoning, must be aware that the dialysis process may although metformin does not seem to be very dia- remove other drugs, such as antibiotics and 38 Extracorporeal Therapy for Drug Overdose and Poisoning v asopressor agents Thus, these drugs must be delivered distal to the dialyzer and will perhaps require higher doses to be effective Nonetheless, currently IHD has supplanted all other ECT modalities and is the preferred ECT modality for removal of the majority of poisons ontinuous Renal Replacement C Therapy (CRRT) Continuous renal replacement therapies provide clearance through both convection and diffusion mechanisms, either alone or in combination For larger molecules, convection can provide better clearance than that achieved by diffusion However, the total clearance with CRRT per unit time is 50% to 80% less than that obtained with IHD because of the lower effluent flow rates This can be disadvantageous in a patient with acute poisoning and manifestations of cellular toxicity who requires rapid and immediately effective therapy Nonetheless, CRRT has been historically favored for the removal of drugs that distribute in multiple compartments with slow equilibration In these situations, CRRT has been considered beneficial as continuous removal of the drug from the vascular compartment maintains a favorable gradient and facilitates its release from the inaccessible compartments into the vascular compartment As a result, the typical rebound phenomenon resulting in high serum levels due to redistribution seen after HD is not seen with CRRT modalities The advantages of avoiding this rebound phenomenon are debatable [23] Currently, CRRT usage is reserved only for patients who cannot tolerate HD due to hemodynamic instability It should also be noted that, while receiving CRRT, the patients must remain immobile for prolonged times to ensure proper machine function ustained Low-Efficiency Dialysis S (SLED) SLED is a hybrid technique usually provided as a prolonged treatment using both reduced dialysate and blood flow rates (QD and QB, respectively) 733 Often times, SLED is reserved for hemodynamically unstable patients who would alternatively be candidates for CRRT [24] SLED differs from CRRT in the following three key areas: SLED is still an intermittent therapy with usual runs of to 12 hours The dialysate flow rate (QD) is higher than that used during CRRT SLED can be administered using the standard HD equipment Even though SLED uses a higher QD than CRRT, small solute clearance between these two modalities is reportedly similar [25] On the other hand, the modeled clearance of middle and large solutes during CRRT is greater than during SLED, likely due to the extended duration and additional convective clearance provided by CRRT [25] Although SLED and CRRT may limit hemodynamic instability in patients requiring fluid removal, it is questionable if this would be the case in poisoned patients when no net ultrafiltration is required When poison removal is urgent, SLED and CRRT are not the treatments of choice unless no other method is available or ultrafiltration is needed in an unstable patient [23, 26] Therapeutic Plasma Exchange (TPE) TPE is the extracorporeal blood purification technique used for removal of large molecular weight substances from plasma such as pathogenic autoantibodies, immune complexes, and endotoxins (see also Chap 48) In general, a single exchange of plasma volume (3 L for a 70 kg patient) removes approximately 63% of all solutes in the plasma, and an exchange of 1.5 plasma volume removes about 78% [27], which under normal conditions corresponds to removal of 40–60 ml of plasma/kg over 2–3 hours [28] TPE’s role in the treatment of acute poisoning is only considered for tightly and/or highly (>95%) protein- bound poisons with very low VD (0.2 L/kg) and poisons with MW over 50,000 Da such as monoclonal antibodies [29, 30] As most commonly encountered poisons are small or middle sized, there are no well-established clinical 734 indications for the use of TPE in the treatment of the poisoned patient Nonetheless, there are reports that support its usage in patients with mushroom (Amanita Phalloides) [31], vincristine [32], and cisplatin [33] poisoning Exchange Transfusion Exchange transfusion is rarely used for management of poisonings It has been successfully used in management of toxicity with drugs that are highly bound to erythrocytes, like cyclosporine [34, 35] or tacrolimus [36] Exchange transfusion has the advantage of being simpler to use in infants and has been tried in that population for poisonings with salicylates [37], theophylline [38], and barbiturates [39] Hemoperfusion During hemoperfusion, blood is percolated through a cartridge coated with activated charcoal (resin-coated cartridges are no longer used in many countries); poisons are adsorbed irrespective of their MW and protein binding, making this modality a better choice for highly protein-bound poisons [15] These cartridges can also absorb lipid-soluble substances Substances with molecular weight up to 40,000 Da are effectively removed by this technique A standard hemodialysis machine can generally be used for hemoperfusion with a cartridge inserted in place of the dialyzer There are certain well-documented complications with hemoperfusion such as platelet depletion, drop in white blood cells, and clotting in the cartridge It can also cause hypoglycemia and hypocalcemia and, as with any extracorporeal therapy, results in undesirable removal of other therapeutic drugs from the patient The cartridges usually get saturated and must be changed every 4–6 hr Finally, hemoperfusion does not correct acid-base or electrolyte abnormalities, nor volume overload Thus, it may be necessary to perform hemodialysis in addition to hemoperfusion Despite the theoretical appeal of hemoperfusion for the treatment of intoxications, its use V Chadha remains quite limited and decreasing over time According to the NPDS 36th Annual Report, hemoperfusion was used for only 43 poisoning cases [1] The cartridges are not freely available in all hospitals, and modern high-efficiency high- flux dialyzers may give clearance rates for certain poisons that approach those achieved with hemoperfusion olecular Adsorbent Recirculating M System (MARS) The molecular adsorbent recirculating system (MARS) (see also Chap 46) employs dialysis across a membrane impregnated with albumin and a 20% albumin dialysate, thus attracting highly protein-bound substances In addition, charcoal and anion exchange resin cartridges are employed to filter the dialysate, regenerating it for continued use [40] MARS may be of interest in the setting of poisons that have a predilection for liver toxicity, as the system is reportedly capable of removing certain hepatotoxins, restoring hemodynamics, diminishing hepatic encephalopathy, and improving renal function [40] MARS is not available in many medical centers, and its role as ECT for poison removal is very limited Single-Pass Albumin Dialysis (SPAD) In the absence of MARS availability, SPAD has been used with similar efficacy Albumin can be added to the dialysate bag during CVVHD where it acts as a “sink” to bind any free toxin that crosses the dialyzer membrane with a concentration gradient from the blood to the dialysate side [41, 42] 400 mL of 25% albumin (100 gm) is added to a 5 L bag of dialysate resulting in final albumin concentration of 1.85% [43] Most of the clearance during CVVHD is then provided as diffusive clearance, but with very high dialysate flows, the running cost increases as albumin is not being regenerated for further use This technique has been used with success in enhancing the clearance of valproic acid and carbamazepine [43, 44] 38 Extracorporeal Therapy for Drug Overdose and Poisoning Peritoneal Dialysis In peritoneal dialysis, the clearance kinetics is dependent on intrinsic characteristics of the membrane and the mesenteric circulation, and not amenable to significant external adjustments (see also Chap 13) In cases with intoxication, peritoneal dialysis is only 10–25% as effective as hemodialysis Thus, the role of peritoneal dialysis in detoxification is limited to situations where other modalities are not available, contraindicated, or not possible due to lack of vascular access The efficacy (in terms of time) of various ECTs in achieving a safe concentration in a patient poisoned with methanol is graphically illustrated in Fig. 38.2 [45] The superiority of the IHD over other ECTs is clearly apparent Therapeutic Decisions When confronted with a case of poisoning, the physician must consider many parameters in choosing the appropriate therapeutic modality A 735 simplified decision-making approach is provided in the algorithm (Fig. 38.3) The list of toxic substances that have been subjected to extracorporeal therapies is quite long, and information is available on more than 200 substances However, the ability to remove a toxic substance by extracorporeal therapy is not equivalent to an indication for these procedures One must take into account the patient’s underlying health (including any comorbidities), the toxicity of the absorbed substance, the presence of or likelihood of advancing to severe illness, the availability of extracorporeal therapies, and the availability of acceptable alternatives (good supportive care, antidotes) While the availability of antidotes such as N-acetylcysteine, flumazenil, fomepizole, and Fab have significantly changed some clinical management plans, it is often impossible to identify the small group of patients who will fail to respond to intensive supportive care alone Thus, the decision to institute extracorporeal therapy is based on clinical judgment Some of the broad criteria as suggested by Winchester et al [46] and Rosenbaum et al [47] for initiating extracorporeal therapy are provided in Table 38.2 Methanol concentration (mmol/l) 100 No ECTR PD TPE CVVHD HD 80 60 40 T = 211h T = 69h 20 T = 9h T = 35h T = 23h Safe zone 0 10 20 30 40 Time (hours) Fig 38.2 Simulation of the effect of different extracorporeal treatments for methanol poisoning Theoretical model of a methanol-poisoned patient with an initial concentration of 100 mmol/L (320 mg/dL) treated with fomepizole and either nothing, hemodialysis (HD), continuous venovenous hemodialysis (CVVHD), therapeutic plasma exchange (TPE), or peritoneal dialysis (PD) The 50 60 70 time (T) to achieve a safe plasma concentration is shown Assumptions are Vd = 0.6 L/kg, weight = 70 kg, endogenous body clearance of methanol with fomepizole = 10 ml/ min, HD methanol clearance = 240 mL/min, CVVHD methanol clearance = 80 mL/min, TPE methanol clearance = 50 ml/min, and PD methanol clearance = 20 mL/ (Modified from Ghannoum et al [45]) ... supra) are also taken into account To understand this better, consider a drug “x” with a large volume of distribution of 20 L/kg One gram of this drug when given to a 30 kg child will yield a... concentration in the plasma As mentioned before, due to the immaturity of their liver function, this group of patients has a decreased capacity to metabolize drugs in the liver due to significantly... protein binding of drugs is reduced, and body fat and total body water are increased in the neonate This may result in an increase in the apparent Vd and consequent increase in the elimination half-life