Part 29 (2/2)

2.3.

a272 attempted suicides; 177 excluded for complicating factors (e.g., carbon monoxide), 43 of 122 were suicide gestures during pregnancy; the remainder were suicide attempts in the months preconception.

Compiled from Flint et al., 2002.

256.

Drug overdoses during pregnancy still conscious she will likely provide the most accurate information on what drugs were taken because drug overdoses are largely premeditated. The patient will usually recall approximately how much she took of which substances. If family members or significant others are present, they may be able to provide corroborative information, such as presence of medicine bottles, known prescriptions, etc. Toxicology screens with samples every hour or two (for serial evaluation) should be ordered as soon as possible to determine exactly what substances are involved and whether or not levels are rising or falling, or toxic or approaching toxic. However, a generalized treatment plan may be undertaken before toxicology results are available.

CLINICAL MANAGEMENT.

Blood and/or urine samples are obtained for toxicological a.n.a.lysis as soon as possible.

If the patient still has a gag reflex, orogastric lavage with normal saline should be begun.

Following lavage, administer an activated charcoal slurry regimen (the nonspecific antidote regimen). Whole-bowel irrigation has been used successfully in some cases of drug overdose and has a clinically significant effect on lowering serum drug levels.

Evaluation of the fetal heart rate should begin as soon as possible, especially in cases in which the fetus is viable. Supportive therapy should begin immediately. When toxicological screens are available to doc.u.ment what drugs and/or chemicals have been ingested and may be in potentially toxic doses, information on antidote regimens for given substances may be obtained from several sources. The authoritative source consulted by certified poison control centers (listed in the Physician's Desk Reference Physician's Desk Reference) is PoisIndex, which includes specific data on pregnancy from Teratogen Information System (TERIS). PoisIndex contains a detailed specific management plan for each sub-Box 14.1 Management plan for the pregnant patient with an acute overdose overdose Acute stabilization Medical history Establishment of an open airway This suicide gesture a.s.sisted ventilation, if needed Past history of suicide gestures Circulatory a.s.sistance, if needed Other medical history Fetal monitoring Physical examination Fetal heart rate Special attention to central nervous system Ultrasound of target organs function Supportive care Special attention to cardiac function As needed to maintain stabilization Nonspecific antidote therapy Prevent absorption Obtaining toxicological samples (serial Orogastric lavage measurements) Whole-bowel irrigation Blood, once per hour Activated charcoal PO Urine, once per hour Enhance elimination Amniotic fluid. twice in 48 h Increase liquid intake Increase plasma volume Balance electrolytes Nonnarcotic a.n.a.lgesic overdoses 257.

Table 14.3 Selected antidotes available (see Appendix) Antidote Selected antidotes available (see Appendix) Antidote Overdose of drug/toxin Acetylcysteine Acetaminophen Activated charcoal Nonspecific substance(s) Amyl nitrate Cyanide Cholestyramine Specific for negatively charged medications Cholinesterase inhibitors Atropine Deferoxamine Iron Edrophonium Curare Fab antidigoxin antibody fragments (Digoxin immune Fab) Digoxin/digitalis Flumazenil Benzodiazepines Glucagon Beta-blockers Hyoscyamine Cholinesterase inhibitors Leucororin Folic acid antagonists (methotrexate, pyrimethamine, others) Muscarine Organophosphate poisoning Naloxone: Nalmefene Opioids Neostigmine Curare Penicillamine Heavy metals (except iron) Physostigmine Anticholinergics Prazosina Ergot alkaloids Protamine Heparin Pyridostigmine Curare Pyridoxine Cycloserine Pyridoxine Isoniazid Quinidine None aNitroprusside is another antidote to ergot alkaloid overdoses, but it conjugates to cyanide in fetal liver and should not be used in pregnancy.

stance. A general plan for the management of the drug-overdosed gravida includes stabilization, monitoring, supportive care, and toxicology screens (Box 14.1).

Specific management plans should be formulated in consultation with the regional certified poison control center, which is available 24 h per day, and handles international calls.

Maternal and fetal sequelae for specific antidote regimens are provided below for the 14 drug cla.s.ses most frequently taken in suicide gestures by pregnant women (Table 14.3).

NONNARCOTIC a.n.a.lGESIC OVERDOSES.

Acetaminophen Acetaminophen is the most frequently used drug in suicide gestures during pregnancy (Czeizel et al et al., 1984; Rayburn et al et al., 1984). Sixty-nine cases of acetaminophen overdose in suicide gestures during pregnancy have been reported (Table 14.4). The salient clinical features of these cases are that early administration of the specific antidote ( N N-acetylcysteine) can prevent maternal hepatotoxicity if the antidote is tolerated and fetal hepatotoxicity is uncommon.

258.

Drug overdoses during pregnancy Table 14.4 Case reports of acetaminophen overdose during pregnancy Amount Case reports of acetaminophen overdose during pregnancy Amount EGA (weeks) Treatment Outcome Maternal Fetal Authors Ingested (g) <>

Nonspecific Hepatotoxicity Elective abortiona Silverman and Carithess, 1978 32.5.

36.N-acetylcysteine Uncomplicated Normal Byer et al., 1982 32.5.

29.Nonspecific Hepatotoxicity Normalb Lederman et al., 1983 26.38.N-acetylcysteine Uncomplicated Normal Ruthnum and Goel, 1984 25.18.N-acetylcysteine Hepatotoxicity Normal Stokes, 1984 20.36.N-acetylcysteine Uncomplicated Normal Roberts et al., 1984 29.5.

28.N-acetylcysteined Hepatotoxicityc Fetal death Haibach et al., 1984 36.16.N-acetylcysteine Uncomplicated Normal Robertson et al., 1986 64.15.N-acetylcysteine Hepatotoxicity Normal Ludmir et al., 1986 50.32.N-acetylcysteine Uncomplicated Normal Rosevear and Hope, 1989 35.31.None Hepatorenal failure Death Death w.a.n.g et al., 1997 19.40.N-acetylcysteine Uncomplicated Normal Normal Sancewicz-Pach et al., 1999 EGA, estimated gestation age.

aNot autopsied.

bHyaline membrane disease pursuant to preterm delivery.

cMaternal outcomes were not listed.

dAntidote not tolerated.

Nonnarcotic a.n.a.lgesic overdoses 259.

Table 14.5 Outcome of 300 acetaminophen overdoses during pregnancy n Outcome of 300 acetaminophen overdoses during pregnancy n Outcome Authors Toxic 33 (11%).

N-acetylcysteine 24 normal, 1 malformed, McElhatton et al., 3 sp ab, 5 el ab 1997.

Toxic 16 ( 5%).

Methionine 11 normal, 5 el ab Toxic 52 (17%).

Ipecacuanha 42 normal, 1 malformed, 2 sp ab, 7 el ab Toxic 16 ( 5%).

Charcoal 13 normal, 1 sp ab, 2 el ab Toxic 42 (14%).

Gastric lavage 28 normal, 4 malformed, 2 sp ab, 8 el ab Toxic 3 ( 1%).

Miscellaneous 1 normal, 1 malformed, 1 el ab Subtoxic 81 (27%).

No treatment 62 normal, 1 malformed, 5 sp ab, 14 el ab Unknown 59 (20%).

Treatment not 40 normal, 3 malformed, recommended 5 sp ab, 12 el ab sp ab, spontaneous abortion; el ab, elective abortion.

In a case series of 60 acetaminophen overdoses during pregnancy from a multicenter study in which 24 mothers had serum acetaminophen levels in the toxic range (Riggs et et al al., 1989), only one case of fetal hepatotoxicity and maternal death occurred. In addition, there were four spontaneous abortions. The distribution of these cases across trimesters of pregnancy is given in Table 14.4. No evidence of teratogenicity of acetylcysteine (or paracetan) was found in one study (Janes and Routledge, 1992). However, the investigators concluded that delays in the administration of the antidotal treatment might increase the risk of spontaneous abortions, fetal death, and serious maternal liver damage.

Published case reports (Table 14.4) suggest that treatment of acetaminophen overdose during pregnancy has the best outcome when the antidote is given as early as possible.

Of the available antidote regimens, N N-acetylcysteine is the most effective (Table 14.5).

Acetaminophen overdose during pregnancy should be treated with either oral or intravenous N N-acetylcysteine without delay according to the protocols provided in the manufacturer's insert. Delay in administering the antidote increases the risk of maternal and fetal toxicity, hepatorenal failure, and death (Kozer and Koren, 2001).

Measured levels of acetaminophen at time postingestion can broadly predict whether or not hepatotoxicity should be expected (Fig. 14.1). However, acetaminophen per se per se is not the toxic agent in overdoses. Acetaminophen's metabolic pathways (sulfation and glucuronidation) become saturated, causing an increased metabolic load to cytochrome P-450 oxidases. The P-450 system oxidizes the drug and produces a highly reactive intracellular metabolite that complexes with hepatic glutathione. The P-450-produced metabolite binds to hepatocellular macromolecules when glutathione is depleted and hepatotoxicity ensues (Andrews is not the toxic agent in overdoses. Acetaminophen's metabolic pathways (sulfation and glucuronidation) become saturated, causing an increased metabolic load to cytochrome P-450 oxidases. The P-450 system oxidizes the drug and produces a highly reactive intracellular metabolite that complexes with hepatic glutathione. The P-450-produced metabolite binds to hepatocellular macromolecules when glutathione is depleted and hepatotoxicity ensues (Andrews et al et al., 1976; Davis et al et al., 1976). Fetal P-450 has 10 percent or less of adult activity and produces negligible amounts of the toxic metabolite.

Some authorities speculate that the increased risk of maternal hepatotoxicity compared to fetal hepatotoxicity may be related to the largely inactive fetal enzyme complement, i.e., a protective effect of not being able to metabolize the drug to toxic intermediate. It was also speculated that fetuses of more advanced gestational age may be at greater risk 260 260 Drug overdoses during pregnancy 300.

Toxic 200.

Possible 100.g/mL) 45.Levels ( 45.30.Unlikely 30.0.

4.8.12.16.Hours after intake Figure 14.1 Acetaminophen levels plotted against hours after intake and likelihood of liver damage. (Adapted from Zimmerman HJ. Clin Liver Dis 1998; Acetaminophen levels plotted against hours after intake and likelihood of liver damage. (Adapted from Zimmerman HJ. Clin Liver Dis 1998; 2 2: 529, with permission.) for acetaminophen toxicity than fetuses early in gestation. However, in the largest series studied, this relations.h.i.+p was not readily apparent (Table 14.6). The critical determinant of maternalfetal outcome following acetaminophen overdose is the expediency in administering the antidote.

The most critical aspect of treating acetaminophen overdoses is administering the antidote as early as possible. Those gravidas given N N-acetylcysteine within 10 h of ingesting large doses of acetaminophen have the best pregnancy outcomes (Table 14.6).

Aspirin Aspirin is the second most frequently used drug in attempted suicide or gestures among pregnant women (Rayburn et al et al., 1984). Clinical details have been reported of several cases of aspirin overdose during pregnancy as part of a suicide gesture (Table 14.7). The mean salicylate half-life has been shown to be approximately 20 h, and disappearance of salicylate from the circulation in the post-absorptive period (approximately 6 h after ingestion) is a first-order reaction (Done, 1968). Unfortunately, there is no specific antidote to aspirin, and nonspecific antidote treatment (i.e., activated charcoal) and supportive therapy are the mainstays of management. Alkalinization of the urine by intravenous administration of bicarbonate greatly increases the renal excretion of salicylic acid, as well as enhancing ionization of salicylate in plasma, which facilitates movement of the drug out of the central nervous system (Done, 1968). Both of these factors may contribute to shortening the duration of toxicity.

The risk of congenital anomalies does not seem to be higher among children of women who used aspirin during pregnancy. Among 41 infants born to women who had taken significant amounts of aspirin at various times during pregnancy, one infant was born with congenital anomalies (McElhatton et al et al., 1991b). One fetal death was reported in the study. Notably, aspirin overdose during pregnancy poses a greater risk for fetal death than acetaminophen. Aspirin is the toxic agent, and not a metabolite; it is transferred across the placenta and reaches concentrations in the fetus that are higher than those in the mother (Garrettson et al et al., 1975; Levy et al et al., 1975). The cases of salicylate poisoning in pregnancy that have been reported support the same basic Table 14.6 Table 14.6 Acetaminophen toxicity in one large series Time of treatment Acetaminophen toxicity in one large series Time of treatment n Maternal Maternal Infant/fetal Stillbirths/ Elective Viable Viable deaths hepatotoxic hepatotoxic spontaneous abortions infants preterm abortion Less than 10 h after overdose 10.0.

<script>