736 Is the poison toxic to the tissue? No No No No No Yes Yes Yes Yes Yes Are there co morbidities, renal failure/hepatic failure? Is the exposure likely to cause serious morbidity or mortality? Suppo[.]
V Chadha 736 Is the poison toxic to the tissue? Yes No Are there co-morbidities, renal failure/hepatic failure? Yes No Is the exposure likely to cause serious morbidity or mortality? Yes No Supportive therapy* Is supportive therapy prolonged? No Yes Continue supportive therapy IHD Supportive therapy* Is poison dialyzable based on MW, Vd, and protein binding? Yes Consider extracorporeal therapy$ CRRT Hemoperfusion No Supportive therapy* MARS TPE *Specific antidote to be used when available; $ Choice of particular extracoporeal therapy is based on the type of poison and patient’s hemodynamic staus IHD: Intermittent hemodialysis; CRRT: Continuous renal replacement therapies; MARS: Molecular adsorbents recirculating system; TPE: Therapeutic plasma exchange Fig 38.3 Simplified approach to a patient with poisoning 38 Extracorporeal Therapy for Drug Overdose and Poisoning Table 38.2 Criteria for extracorporeal therapy (Modified from Refs [46, 47]) Potentially lethal plasma concentration of intoxicant known to be cleared effectively from blood by extracorporeal therapy Significant quantity of circulating toxin that is metabolized to a more noxious substance (e.g., methanol, ethylene glycol) Ingestion and probable absorption of a potentially lethal dose Severe clinical intoxication with abnormal vital signs Impairment of normal route of excretion Progressive clinical deterioration despite carful medical management Prolonged coma with its potential hazards (e.g., aspiration pneumonia, septicemia) Need for prolonged assisted ventilation Persistent hypotension or need for vasoactive therapy Poisoning by agents with delayed toxicity (e.g., paraquat) 737 management are included below, with most of the information derived from the EXTRIP recommendations [48–60] Acetaminophen Worldwide, acetaminophen is the most common analgesic used and, therefore, one of the most commonly overdosed medications; it is also the leading cause of drug-induced liver failure in many countries The MW is 151 Da with Vd of 0.8 to 1 L/kg; the protein binding is low at 10–30% and does not change much with toxic levels A single acute ingestion of >150 mg/kg in adults and >200 mg/kg in children is considered toxic with a lethal dose of >500 mg/kg Although acetaminophen is readily dialyzable, ECT is not warranted in most cases, because of the effectiveFinally, although several studies have shown ness of N-acetylcysteine (NAC) especially with enhanced drug elimination using several tech- early and less severe presentations The EXTRIP niques, the data regarding how these methods workgroup suggests ECT for severe acetaminoaffect morbidity and mortality are often lacking phen poisoning when patients manifest signs of In 2011, a multidisciplinary and multinational mitochondrial dysfunction (altered mental status collaborative known as EXTRIP (Extracorporeal and severe metabolic acidosis) prior to the onset Treatment In Poisoning) was established to clarify of hepatic failure Many patients with severe the role of ECTs in clinical practice through the acetaminophen poisoning also develop AKI with development of evidence- and expert opinion- or without associated hepatotoxicity which might based recommendations [13] Since inception, the be another indication for utilizing an group has published treatment recommendations ECT. Acetaminophen concentrations are typifor 13 poisons that include acetaminophen, barbi- cally obtained when absorption is thought to be turates, carbamazepine, digoxin, lithium, metfor- complete at 4 hr post ingestion or as soon as posmin, methanol, phenytoin, salicylates, thallium, sible thereafter Subsequent treatment decisions theophylline, tricyclic antidepressants, and val- are guided by plotting the acetaminophen conproic acid [48–60] The executive summaries of all centration on the Rumack-Matthew nomogram EXTRIP recommendations are available at http:// [48] ECT is suggested if acetaminophen levels www.extrip-workgroup.org/recommendations are more than 1000 mg/L (>700 mg/L with signs More recently, the Pediatric Continuous Renal of mitochondrial dysfunction) and NAC has not Replacement Therapy (PCRRT) workgroup have been administered ECT is suggested even after also published their recommendations on renal NAC has been administered when the levels are replacement therapy in the management of intox- >900 mg/L and patient has signs of mitochonications in children [61] drial dysfunction NAC should be continued As detailed management of individual poi- during ECT, and the dose increased based on sonings with ECTs and antidotes is beyond the ECT (25% with CRRT and 50% with IHD) as scope of this chapter, the reader is referred to NAC is dialyzable IHD is the preferred modality recently published recommendations from the for acetaminophen poisoning, but CRRT can be EXTRIP and PCRRT workgroups Summaries used as support for AKI or hepatic failure of some of the common poisonings and their Exchange transfusion can be used in neonates V Chadha 738 Continuation of ECT is recommended until sustained clinical improvement is apparent [48] Salicylates Salicylate (MW 180 Da) has low Vd of 0.2 L/kg (up to 0.5 L/kg in overdose); it is highly protein bound (90%), but the binding decreases to 30% with toxic levels Salicylate toxicity primarily results from uncoupling of mitochondrial oxidative phosphorylation The clinical manifestations range from tinnitus, vomiting, metabolic acidosis, primary respiratory alkalosis, agitated delirium, and/or somnolence; severe toxicity is associated with acute respiratory distress syndrome, AKI, hyperthermia, seizures, and shock Most fatalities are due to cerebral edema Events that lower blood pH can lead to rapid shifts of salicylate across the blood-brain barrier with worsening toxicity manifestations Early consideration of ECT is critical in severe salicylate poisoning regardless of the salicylate blood concentration Most sources acknowledge that clinical status is a more important factor than the salicylate concentration in the decision to initiate ECT. Nonetheless, high salicylate concentrations (>100 mg/dL and 90 mg/dL in the presence of impaired kidney function) are indications of ECT regardless of signs and symptoms ECT is also suggested for severe acidosis (pH 50 mg/L can induce coma, and concentrations >80 mg/L can be fatal IHD is the preferred ECT; MDAC should be continued during ECT. Cessation of ECT is indicated when clinical improvement is apparent [49] Carbamazepine Carbamazepine has a narrow therapeutic index Its structure is similar to tricyclic antidepressants The MW is 236 Da with Vd of 0.8–1.4 L/kg; it is highly protein bound (70–80%), and the binding does not change with overdose It is therefore only moderately dialyzable MDAC is useful, but ECT is recommended in cases of multiple seizures that are refractory to treatment, life- threatening dysrhythmias, and prolonged coma or respiratory depression requiring mechanical ventilation IHD is the preferred ECT modality and should be continued until clinical improvement is apparent [50] Albumin-enhanced CVVHD has also been successfully used in a pediatric patient with severe carbamazepine overdose [44] Valproic Acid (VPA) VPA (MW 144 Da) has a low Vd (0.1–0.5 L/Kg) and exhibits saturable plasma protein binding with 94% bound at therapeutic concentrations (50–100 mg/L) and 15% when concentration exceeds 1000 mg/L. The increase in the free fraction (active drug) at higher total VPA concentrations likely leads to greater clinical toxicity The drug is primarily metabolized in the liver and 1300 mg/L or patients with features of cerebral edema or shock ECT is suggested for serum VPA concentration >900 mg/L, or patients with coma or respiratory depression requiring mechanical ventilation, or acute hyperammonemia or severe acidosis (pH 4 mEq/L in the presence of renal impairment or in the presence of altered consciousness, seizures, or life-threatening dysrhythmias irrespective of the lithium level ECT should be continued for a minimum of 6 hours if the lithium cannot be readily measured Unlike most toxins, lithium travels from cells to plasma via sodium channels and thus equilibrates more slowly than nearly all other dialyzable toxins As a result, repeat HD sessions are commonly needed as rebound of plasma levels is seen several hours after HD. IHD is the preferred initial ECT modality for rapid resolution of life- threatening symptoms This can be followed by repeated IHD sessions or a prolonged (~6 hr) HD session CRRT remains a good alternative modality Cessation of ECT is recommended when the lithium level is 70 mg/dL after fomepizole therapy; in the absence of fomepizole therapy, ECT is indicated for levels >50 mg/dL. IHD is the ECT modality of choice; CRRT is an alternative Fomepizole (if available) should be continued during ECT. ECT can be discontinued when the methanol concentration is 500 mL/min but decreases proportionately with decreasing renal function Metformin-associated lactic acidosis (MALA) is uncommon but associated with a high mortality of 30% Although MALA usually occurs in the presence of impaired kidney function, rarely a large acute overdose can also produce severe toxicity characterized by lactic acidosis, shock, and multi-organ failure Metformin is moderately dialyzable, with an average t½ of 4 hours with HD and 16 hours with CRRT. The EXTRIP workgroup recommends HD for severe acidemia and lactate levels >20 mmol/L and suggests consideration of HD at lower levels with concomitant organ failure [53] Conclusion The field of toxicology continues to expand with the introduction of newer drugs and chemicals Basic understanding of pharmacokinetic and toxicokinetic principles helps guide the management of patients with overdose and poisoning While improvement in supportive care and the availability of antidotes have improved the outcome of several poisonings, ECTs continue to play an important but limited role The background information provided in this chapter should help guide the nephrologist in making the right choices References Gummin DD, Mowry JB, Spyker DA, Brooks DE, Beuhler MC, Rivers LJ, Hashem HA, Ryan ML 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 36th Annual Report Clin Toxicol 2019;57:1220–413 Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose Ed: Shannon MW, Borron SW, Burns M 4th edition, Philadelphia, W. 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Theophylline toxicity in a premature neonate – elimination kinetics of exchange transfusion J Toxicol Clin Toxicol 1993;31:639–44 ... dysrhythmias irrespective of the lithium level ECT should be continued for a minimum of 6 hours if the lithium cannot be readily measured Unlike most toxins, lithium travels from cells to plasma... coma It is noteworthy that clinical presentation does not correlate well with lithium levels ECT is recommended if lithium level is >4 mEq/L in the presence of renal impairment or in the presence... IHD is the preferred ECT modality with intermittent hemoperfusion as an alternative [55] Lithium Lithium is a small molecule (MW 7 Da) and has low Vd (0.7–0.9 L/Kg) and no protein binding; therefore,