8: Techniques Used to Prevent Gastrointestinal Absorption

Gastrointestinal (GI) decontamination is a highly controversial issue in medical toxicology. It can play an essential role in the initial management of orally poisoned patients and frequently is the only treatment available other than routine supportive care. Unfortunately, as is true in most areas of medical toxicology, rigorous studies that demonstrate the effects of GI decontamination on clinically meaningful endpoints are difficult to find. The heterogeneity of poisoned patients demands that very large randomized studies be performed because patients who present to an emergency department (ED) may have an unreliable history and a low-risk exposure.^31,156 These factors, as well as other significant sources of bias, are often hidden in inclusion and exclusion criteria of the available studies. Numerous determinants contribute to the difficulties in designing and completing studies that provide sound evidence for or against a particular therapeutic option. Incontrovertible endpoints, such as complication-specific mortality, also demand exceptionally large studies because the overall morbidity and mortality of poisoned patients are quite low.³¹ Whereas other endpoints, such as the length of stay in the hospital or intensive care unit (ICU), change in xenobiotic concentration, the rate of secondary complications, and the need for specific treatments such as expensive antidotes, must be considered, these surrogate markers are not adequately rigorous and are inadequately precise measures of morbidity. In the science of GI decontamination, we are also faced with the dilemma that randomizing half of a group of potentially ill patients to no decontamination is a significant ethical concern—we rarely omit decontamination unless a minimally toxic exposure has occurred or an effective, safe, readily available, and inexpensive antidote exists. Because acetaminophen (APAP) meets many of these parameters, it has been used both as the xenobiotic of choice in volunteer overdose ­studies^{42,82,94,152,239} and in the evaluation of actually poisoned patients.⁵³ However, despite its widespread use as a model, the applicability of the management approach for APAP poisoning to other ingestions is limited.

As might be suspected, no available study provides adequate guidance for the management of a patient who has definitely ingested an unknown xenobiotic at an unknown time. Fortunately, in most cases, there is some component of the history or clinical presentation, such as vital signs, physical examination, and focused diagnostic studies such as an electrocardiogram and anion gap, that might offer insight into the nature of the ingested xenobiotic (Chap. 3).

For many, the ongoing controversy or debate on GI decontamination culminated in 1997 with the publication of the position statements on activated charcoal, orogastric lavage, syrup of ipecac–induced emesis, and whole-bowel irrigation (WBI) from the American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT),^{43,124,208,224,225} and has evolved from very invasive to a less aggressive approach after subsequent revisions.^{44,125,209,226} Contrary to initial expectations of some, these excellent reviews failed to end the debate; they simply highlighted many shortcomings and ambiguities within this field. A 2000 study concluded that despite having the evidence reviewed and consensus recommendations made, poison specialists at North American poison centers still offered a wide variety of recommendations for GI decontamination.¹¹⁷ The study evaluated decontamination options for a theoretical patient with a serious potentially life-threatening overdose of enteric-coated aspirin. The recommendations made were often inconsistent with the published position statements, and in some cases, were frankly dangerous. Even toxicologists who made substantial contributions to the development of these consensus statements disagreed on certain aspects of the treatment, although to a lesser extent. In a similar study, when an interactive questionnaire was sent to 14 European Poison Centers, significant differences in the protocols for the recommended method of GI decontamination, timing, and intervention doses were found.⁸¹ These differences suggest that there is inadequate evidence available to produce a proper evidence-based answer for many of the decisions in question. In most of the clinical studies that provide evidence to form the basis for the consensus statements, either the proportion of patients with life-threatening ingestions is very small, or these specific patients were excluded from the study. Similarly, there are no studies for most drugs with modified release kinetics, for newly marketed drugs, for patients with mixed overdose, extremes of age, or with significant end-organ dysfunction. Thus, the clinician must often make decisions based on a theoretical approach emphasizing an understanding of basic principles rather than evidence with a substantial level of uncertainty.

More recent studies investigating the trends in GI decontamination in both the advice given by poison centers and the clinical setting demonstrate a considerable decline in the use of all methods of decontamination.^31,44 One study specifically evaluating orogastric lavage found that during the years 1993 to 1997, an average of 18.7% of all poisoned patients received orogastric lavage compared with an average of 10.3% of poisoned patients during the years 1998 to 2003. The decline in the use of GI decontamination after the publication of the position statements is also probably a result of the epidemiologic shift in the developed world away from overdoses of more lethal substances, such as salicylates, theophylline, barbiturates, and tricyclic antidepressants, toward benzodiazepines, prescription opioids, serotonergic reuptake inhibitors, and APAP with a natural resultant decrease in morbidity and mortality or the availability of an excellent antidote. Although true, for the Western world, studies in developing countries indicate a different pattern of poisonings with patients ingesting xenobiotics such as organic phosphorus compounds and other pesticides and herbicides with a more lethal toxicologic profile.⁶²

This chapter does not discuss details with regard to the evaluation of the amount and type of xenobiotic ingested or other strategies for managing a patient with an unknown overdose; these issues are discussed in Chap. 4. Rather, the focus is on determining which decontamination technique or combination of techniques is preferred after an indication for GI decontamination has been established. The literature published since the previously mentioned position papers and previous edition of this book is emphasized, existing evidence is summarized, and areas necessitating further investigation are identified. Detailed discussions of activated charcoal and WBI can be found in the corresponding Antidotes in Depth sections, Activated Charcoal (A1) and Whole-Bowel Irrigation and Other Intestinal Evacuants (A2). A limited discussion on induced emesis is presented here because it is no longer considered an appropriate intervention. In addition, when the ingested xenobiotic is known, readers should also refer to the decontamination sections found in Chaps. 35 through 128, which will offer insight into xenobiotic-specific issues that may alter decontamination strategies.

The principal theory governing gastric emptying is very simple: If a portion of xenobiotic with substantial toxic potential can be removed before absorption, this potential toxicity should be either prevented or minimized. From 1982 to 1995, several important clinical trials attempted to define the role of gastric emptying in poisoned patients.^{6,29,48,103,148,177,223} Although all of these studies were flawed because of the inclusion of a large number of low-risk patients, numerous restrictive exclusion criteria, and a variety of other biases, they clearly demonstrated that many patients can be successfully managed without aggressive gastric emptying. From 1995 until the present, few additional studies on gastric emptying have been published, and the series of updated position papers in 2004 and reviews further emphasized the limited need for aggressive gastric emptying in poisonedpatients.^{7,125,134,226} The studies showed diverging opinions of gastric emptying and no clear evidence to support its clinical effectiveness.^{27,29,63,84,206,207} The clinical parameters listed in Table 8–1 help to identify individuals for whom gastric emptying is usually not indicated based on a risk-to-benefit analysis. In contrast, for a small subset of patients (Table 8–1), gastric emptying may still be indicated. A thorough understanding of this risk analysis is essential when deciding whether gastric emptying is appropriate for a patient who has ingested a xenobiotic.

Time is an important consideration because for gastric emptying to be beneficial, a consequential amount of xenobiotic must still be present in the stomach. Demographic studies have found that very few poisoned patients arrive at the ED within 1 to 2 hours after ingestion. In most studies, the average time from ingestion to presentation was approximately 3 to 4 hours, with significant variations.^{118,125,126,211} This delay diminishes the likelihood of recovering a large percentage of the xenobiotic from the stomach unless the patient has ingested a xenobiotic that slows gastric emptying rates. As is discussed in more depth in the section on orogastric lavage later in this chapter, many authors advise against interventions beyond one hour after ingestion. Actual analysis of the data highlights the arbitrary nature of this limitation. One human volunteer study evaluated the pharmacokinetic effects of diphenhydramine and oxycodone in a simulated APAP overdose.⁹⁰ This model is relevant because of the rapid absorption of APAP and the presence of many such combination products in the marketplace. Whereas diphenhydramine did not delay gastric emptying significantly, oxycodone delayed the time to peak APAP concentration by approximately one hour. Although GI decontamination was not part of the study protocol, it can be inferred that APAP was available for GI decontamination for a longer time than the one-hour guideline suggests. Case reports frequently demonstrate that poisoned patients still have xenobiotics in their stomach (as confirmed by computed tomography or gastroscopy) as residuals or pharmacobezoars, from 5 hours up to several days after ingestion and even on autopsy.^60,121

In fact, markedly prolonged gastric emptying half-lives and gastric hypomotility were demonstrated using gastric scintigraphy in a prospective study of 85 poisoned patients.¹ Remarkably, these findings occurred with ingestions such as APAP, which are not typically expected to prolong gastric emptying. Patients who underwent orogastric lavage did not have significantly different gastric emptying half-lives, suggesting that the procedure itself was not the cause of the gastroparesis, and likewise there was no evidence that activated charcoal affected gastric emptying rates. The authors speculated that stress in an overdosed patient might be part of the etiology of the hypomotility observed and that the management of patients should not be based on the assumption that GI motility is normal.

Assessment of whether or not gastric emptying is appropriate for a patient continues with an evaluation for potential contraindications (Table 8–2). Regardless of the severity of the ingestion and other contributing factors, such as time, there must be no contraindication to gastric emptying procedures. Because the demonstrable benefit of emptying after ingestion of an unidentified xenobiotic is marginal at best, even relative contraindications usually dictate that the procedure should not be attempted. However, the clinical benefit could be sizable if the ingested dose places the patient on the steep portion of the dose–response curve (Chap. 9). Under these circumstances, a small reduction in dose might translate into a significant reduction in toxicity.

Orogastric Lavage

Many authors have adopted the consensus approach that orogastric lavage should not be considered unless a patient has ingested a potentially life-threatening amount of a xenobiotic and the procedure can be undertaken within 60 minutes of ingestion.¹⁸¹ Since the publication of the clinical studies cited in the 9th edition of this book, studies of orogastric lavage have been scarce.^{3,24,39,72,86,91,125,146,156,177,181} The previous studies observed a modest, varied, and unreliable effect of orogastric lavage.^{83,84,129,130,187} Gastric lavage was shown to be effective in the treatment of few specific xenobiotic poisoning (tetramine rodenticides), where fatality rate was lowered in the patient group that received gastric lavage compared to patients not lavaged.²³⁵ Use of combination therapies with administration of activated charcoal before gastric lavage was described by several,^{3,4,11,25,33,69,72,111,114,132,146,172,180,217,227} but the procedure was not more effective than activated charcoal alone^26,42,129 and sometimes resulted in increased xenobiotic concentration and worsened clinical outcome.¹¹ In some cases, gastric lavage delays activated charcoal administration further, and considerations to eliminate gastric lavage and only administer activated charcoal should be made in order to initiate the fastest decontamination procedure. The trend in using gastric lavage continually declines.¹³¹ The frequency of gastric lavage procedure varies from lowest frequency (percent compared with total decontaminations using activated charcoal, gastric lavage, syrup of ipecac, and WBI) in North America (5.7%)³¹ and Scandinavia (7.9%–9%; Denmark and Norway),^137,237 in Mediterranean countries (30%–32%; Spain and Palestine),^11,132,192 to the highest frequency in Asia and South American countries, India (34%–>50%),^24,153 Nepal (43%),³³ and Bolivia (96%).⁷⁰ The frequency tends to ­correlate with the type of xenobiotic ingested, with highest frequency of lavage in regions where insecticides such as organic phosphorus compounds and carbamates are more commonly ingested.^24,33,70

It is important to highlight the differences between volunteer studies using therapeutic doses of drugs and actual patients with clinically significant overdoses. The most important aspect of this comparison is a bias against gastric emptying and toward a benefit with activated charcoal. The drugs used in volunteer studies are typically well adsorbed by activated charcoal, and the doses of activated charcoal are significantly in excess of the activated charcoal:drug ratios that can be achieved in clinically significant overdoses. Larger overdoses, as might occur in patients with clinically important ingestions, are likely to saturate activated charcoal. An additional bias is introduced against gastric emptying because the small amounts of any study drug used are unlikely to alter gastric motility, and thus the drugs may pass through the pylorus before orogastric lavage can occur. A synthesis of available data can be used to develop indications for orogastric lavage (Table 8–2). This procedure should always be performed by trained health care professionals and in health care settings. When deciding whether to actually perform orogastric lavage on a poisoned patient, these indications, contraindications, and potential adverse effects must be considered. Table 8–3 summarizes the technique of orogastric lavage.

Reported adverse effects of orogastric lavage include injury to the esophagus^34,85 and stomach,⁵⁷ as well as significant decreases in serum calcium,⁸⁰ ionized calcium,⁸⁰ and magnesium⁸⁰; severe hypernatremia¹⁴⁹; and leukocytosis.¹¹¹ Hypernatremia resulted from a lavage that was performed using 12 L of hypertonic saline.¹⁴⁹ An observational case series studying 14 consecutive gastric lavages performed in a resource-poor location found three deaths directly related to the procedure, all of which seemed to have resulted from inadequate airway protection.⁶⁴ These cases, as well as other well-known complications such as respiratory events, including need for mechanical ventilation,¹¹² hypoxemia,¹¹² respiratory failure,²³⁴ and higher frequency of aspiration pneumonitis,^{112,224,226,234} demonstrate that orogastric lavage is not risk free and should only be considered based on the rigorous indications for gastric emptying listed in Table 8–1.

Syrup of Ipecac

Syrup of ipecac–induced emesis is no longer a recommended approach for gastric emptying in the treatment of poisoning. Clinical benefit for the use of syrup of ipecac as a gastric emptying technique has never been proven,^{27,86,101,125} and gastric content may be forced beyond the pylorus, increasing the amount of xenobiotic available for absorption.¹⁸⁷ Since the position statement from AAPCC/EAPCCT in 1997,¹²⁴ the frequency of syrup of ipecac use has declined steadily.³¹ Furthermore, as the benefits of activated charcoal are recognized and the time to its administration evaluated, it has become evident that the administration of syrup of ipecac delays the administration of activated charcoal¹²³ and possibly oral antidotes.

Activated Charcoal

Activated charcoal continues to be recognized as an effective method for reducing the systemic absorption of many xenobiotics.^{2,7,16,20,77,86,110,119,160,166} For certain xenobiotics, it also enhances elimination through interruption of either the enterohepatic or enteroenteric cycle.⁴⁹ Its superb adsorptive properties theoretically make it the single most useful management strategy for diverse patients with acute oral overdoses.^{12, 13, and 14,26,42,49,50,79,102,173,174} However, as is true for the other methods of GI decontamination, there is a lack of sound evidence of its benefits as defined by clinically meaningful endpoints. This opinion is reflected both in the consensus statements and reviews and in the overall trend toward not performing decontamination as shown in poison center data^{7,31,44,110,147} (Chap. 136). The consensus opinion concluded that a single dose of activated charcoal should not be administered routinely in the management of poisoned patients and, based on volunteer studies, the effectiveness of activated charcoal decreased with time, providing the greatest benefit in severely poisoned patients if dosed within one hour of ingestion. There was no evidence that the administration of a single dose of activated charcoal improved clinical outcome. These opinions are unfortunately biased by the fact that most “routinely” poisoned patients have low-risk exposures and do well with minimal intervention. Additionally, it is generally accepted that unless either airway protective reflexes are intact (and expected to remain so) or the patient’s airway has been protected, the administration of activated charcoal is contraindicated.⁴⁴ Despite little scientific basis or support from clinical trials, less severely poisoned patients might benefit from activated charcoal in terms of reduced need for life support, monitoring, and antidotes.¹¹⁰

Theoretically, the early administration of activated charcoal to patients presenting with a significant oral overdose of a potentially toxic xenobiotic would lower systemic exposure to that xenobiotic and thus be of benefit to the patient. Surprisingly, this intuitive result has been difficult to demonstrate using clinically relevant endpoints in large unselected populations of poisoned patients, again most likely as a result of inclusion of large numbers of minimally exposed low-risk individuals.

A randomized, controlled clinical trial of all orally overdosed patients (n = 327) presenting to the ED of a large hospital in an urban setting during 16 consecutive months found no difference in clinical endpoints such as length of stay or other outcomes between patients treated with a single dose of activated charcoal compared with no decontamination. The study excluded seven severely poisoned patients who all arrived within one hour of ingestion; the majority of the patients in the trial (nearly 60%) arrived within 2 hours postingestion. The most common xenobiotics ingested were APAP, benzodiazepines, and newer antidepressants all of which have low case-fatality rates.⁵⁴

A larger trial (n = 4629) studying self-poisoned patients from a rural and resource-poor location found no difference in mortality rates between those who received no activated charcoal, single-dose activated charcoal, or multiple-dose activated charcoal (MDAC). The patients primarily ingested pesticides and yellow oleander (Thevetia peruviana) seeds, both xenobiotics having very different kinetic properties compared to pharmaceuticals. It is important to note that the first 1904 patients in the control group actually received orogastric lavage, as was the case for all patients presenting within 2 hours of ingestion of substantial amounts of pesticides or potentially toxic xenobiotics because of pressure from the national doctors’ union. Although the authors claim that logistic regression analysis found no influence of lavage on their results, the data are not presented.⁶⁵ Furthermore, in an article on compliance related to activated charcoal, nested within this randomized, controlled trial, it is stated that a large number of patients included in the trial had undergone gastric emptying in some form before being transferred from peripheral hospitals.¹⁵⁰ The results of this trial are probably valid for the authors’ particular setting and patient profiles but cannot be generalized to developed nations. In contrast with the lack of effect on clinical endpoints such as death, a pharmacokinetic analysis from another subset of patients (n = 104) from this large trial found a significant increase in plasma clearance of the Thevetia peruviana cardenolides in patients administered both single-dose activated charcoal and MDAC. There was no difference between groups in mortality, but given the absolute numbers of two to three deaths per group, this could be related to a lack of power in the study design.¹⁸²

Mechanism.

The entire effect of activated charcoal takes place in the GI tract. Oral activated charcoal is not absorbed through the GI wall but passes straight through the gut unchanged. Administration of xenobiotics may happen by a variety of routes, and these xenobiotics enter or are transported into the GI tract by different mechanisms determined by the specific physical-chemical properties of the individual xenobiotic. To be adsorbed to activated charcoal, the xenobiotic must be dissolved in the GI liquid phase and be in physical contact to the activated charcoal. The surface (internal and external) of activated charcoal is manufactured to possess a chemical nature that attracts certain molecules (xenobiotics). The possible sites of adsorption are indicated in Fig. 8–1. Activated charcoal forms an equilibrium between free xenobiotic and xenobiotic that is adsorbed to it through relatively weak intermolecular forces.

Desorption of the adsorbed xenobiotic may occur, but if sufficient activated charcoal is present (see dosing below), the equilibrium will be shifted toward the xenobiotic–activated charcoal complex. The effect is a low free xenobiotic concentration in the liquid phase and reduced xenobiotic absorption.⁴⁹

Time Factors.

The general statement in the literature is that administration of a single dose of activated charcoal should be considered if a patient has ingested a potentially toxic amount of a xenobiotic that is known to be adsorbed to activated charcoal in the previous hour. This position was chosen based primarily on case reports and volunteer studies using nontoxic doses of xenobiotics because it was believed that there were insufficient data to support or exclude the use of single-dose activated charcoal therapy more than one hour beyond ingestion.^43,44 However, the efficacy of activated charcoal administered more than one hour after xenobiotic ingestion has been evaluated in several studies. These investigations confirm enhanced effect of activated charcoal if dosed as early as possible but also demonstrate a significant effect if dosing is delayed up to 4 hours after the xenobiotic ingestion.^{75,106,109,110,116,152,202} In fact, a few studies suggest efficacy up to 6 hours after ingestion.^116,236 Furthermore, prolonged gastric emptying time caused by massive xenobiotic ingestion or specific properties of an ingested xenobiotic or bezoar formation possibly increase the time frame when activated charcoal might effectively adsorb the xenobiotic.^1,121 The studies below empha­size this concept.

In volunteers, the effect of activated charcoal administered 2 and 4 hours after ingestion of acetaminophen demonstrated no significant difference in plasma acetaminophen concentration compared with control participants. In contrast, when administered one hour after a simulated acetaminophen ingestion, activated charcoal reduced serum acetaminophen concentrations significantly.²³⁹ Likewise, when the effectiveness of activated charcoal administered 1, 2, and 3 hours after xenobiotic ingestion was determined, only the one-hour group had a pharmacokinetic profile that differed from the control group.⁸² Although these data do not support the administration of activated charcoal as a GI strategy more than one hour after an overdose, the applicability of these results to actual overdosed patients has not been adequately evaluated. The method in this volunteer study was an 8-hour fast followed by a small meal 1 hour before the administration of 3 to 4 g of acetaminophen.^82,239 Considering the rapid absorption of acetaminophen, the small 3- to 4-g doses used, and the absence of food in the stomach, it is highly probable that little or no acetaminophen would be left in the GI tract to be adsorbed by activated charcoal, limiting the potential time to benefit from activated charcoal to approximately one hour.

In contrast, activated charcoal given 3 hours after an overdose was investigated in vivo, again using acetaminophen and a larger-than-standard dose (ie, 75 g) of activated charcoal. The results demonstrated some benefit in administering activated charcoal 3 hours after an overdose because there were significantly lower serum acetaminophen concentrations in the activated charcoal group than in the control group, 23% lower at 4 hours and 62% lower at 7 hours after ingestion.¹⁹¹ In a similar study, activated charcoal was effective in reducing the systemic absorption of acetaminophen when administered both 1 and 2 hours after ingestion, although the effect of the 2-hour intervention was substantially less than at one hour, reemphasizing the importance of early intervention.⁴²

The efficacy of activated charcoal was studied in 53 patients following 63 episodes of citalopram overdose.⁷⁵ When activated charcoal was administered between 0.5 and 4 hours to 17 patients who had ingested potentially toxic doses of citalopram, there was a 72% increase in clearance and a 22% decrease in bioavailability. In most patients, the activated charcoal was dosed more than one hour after ingestion. Only one patient received activated charcoal within one hour, nine patients received activated charcoal within 1 to 2 hours, and seven patients received activated charcoal within 2 to 4 hours.

Despite a delay to activated charcoal of 0.5 to 6.0 hours after a quetiapine overdose, a significant benefit for a single dose of activated charcoal was demonstrated. Activated charcoal decreased the fraction absorbed of quetiapine by 35%. No apparent effect on clearance was demonstrated.¹⁰⁷ In a later study by the same investigators, only early use (<2 hours) of activated charcoal was able to reduce the probability of intubation in quetiapine overdose patients. Activated charcoal administered between 2 and 4 hours did not reduce the probability of intubation. The study included 286 patients overdosed with quetiapine alone or in combination with other drugs. However, only a total of 42 patients (15%) received activated charcoal based on unknown criteria, four patients (1%) received activated charcoal within1 hour but were excluded from analysis, 19 patients (7%) received activated charcoal within 2 hours, and 36 patients (13%) received activated charcoal within 4 hours from quetiapine ingestion.¹⁰⁹

A meta-analysis was performed to evaluate the effect of activated charcoal on xenobiotic absorption during the first 6 hours after ingestion. Data were obtained from 64 controlled studies in which activated charcoal was compared with placebo up to 6 hours after drug ingestion in volunteers. Additional considerations were given to assess the influence of physical and pharmacologic properties and the activated charcoal-to-drug ratio. The authors concluded that activated charcoal was most effective when administered immediately after xenobiotic ingestion. However, even with a delay of 4 hours after ingestion, 25% of the participants achieved at least a 32% reduction in absorption, especially when activated charcoal was given with large activated charcoal-to-drug ratios.¹¹⁶

Similarly, when aminotransferase elevations (>1000 IU/L) were measured in patients with acetaminophen overdose who presented more than 4 hours after ingestion, patients who received activated charcoal along with N-acetylcysteine (NAC) had less elevation than those who received NAC alone. Although this study was limited by its observational methodology, the findings are both consistent with studies described earlier and are biologically plausable.²⁰²

Efforts to reduce time to activated charcoal administration have been evaluated using pre-arrival communication between a poison center and both emergency medical services and an ED.^221,222 Both approaches reduced the time from overdose to activated charcoal dosing to less than one hour.

Thus, it should be clear that the use of a one-hour time frame should serve as a guideline rather than an absolute concept. It is only logical that if an intervention is effective at 59 minutes, it will also be beneficial at 61 minutes.Although it is logical that efficacy decreases as time from ingestion increases, in certain cases, some benefit may be derived many hours after ingestion. Because after massive life-threatening ingestions, the absorption of xenobiotics may be prolonged, there is no exact time limit for activated charcoal use.¹⁵⁷ As discussed earlier, good data from patients with actual ingestions demonstrate that a significant amount of xenobiotic can be found in the stomach beyond this arbitrary one-hour time frame. Activated charcoal should therefore be considered to prevent absorption in poisoned patients even when they present late to medical care. Additional benefits on enhanced elimination are discussed below.

Prehospital Use.

Adherence to the recommendation that activated charcoal should be administered within one hour of ingestion limits the potential to treat most poisoned patients. A study over a 6-month period identifying 63 patients who had taken potentially serious overdoses demonstrated a median time of arrival to health care of 136 minutes after the overdose. Only 15 patients presented within 1 hour, and only four of 10 patients who qualified actually received activated charcoal within 1 hour. The results demonstrate not only the difficulty in clinically assessing patients before1 hour but also the difficulty in adhering to the principle of treating patients with activated charcoal when they arrive within 1 hour unless activated charcoal could be safely administered to appropriate patients in the prehospitalization setting.¹¹⁸

Prehospital use of activated charcoal has not gained wide acceptance because of the concern that it would not be administered properly by the untrained lay public and that many children would refuse to drink the charcoal slurry. In fact, an 18 month consecutive case series demonstrated that activated charcoal can be administered successfully in the home by the lay public. Home use of activated charcoal significantly reduced the time to activated charcoal administration after xenobiotic ingestion from a mean of 73 ± 18.1 minutes for ED treatment to a mean of 38 ± 18.3 minutes for home treatment.²⁰¹ However, many authorities still recommend that activated charcoal should not be standard home treatment, but administration should only be carried out by health professionals.^{10,45,141,144,156,195,196}

A prospective follow-up study from Finland evaluated the adherence to a new protocol of administering activated charcoal in the prehospital setting. The protocol was implemented by either the first-response unit or paramedics. Activated charcoal was indicated in 722 of 2047 patients. Of these patients, 555 actually received activated charcoal at a mean of88 minutes after ingestion. There were no adverse effects noted, although 72 patients refused to drink the activated charcoal. This study shows that it is feasible to administer activated charcoal in the prehospital setting, but its clinical implications are unknown.⁵

In reality, many factors, such as the presence of food in the stomach, sustained-release formulations, and co-ingestions that delay gastric emptying, can slow the rate of absorption of a xenobiotic. These factors increase the time frame for possible adsorption to activated charcoal. This increased effect of activated charcoal was demonstrated in a randomized, crossover study in which volunteers were administered acetaminophen in either the presence or absence of the anticholinergic drug atropine and subsequently given a single dose of activated charcoal 1 hour later. Activated charcoal was more effective in reducing acetaminophen bioavailability in the presence of atropine.⁸³

Dosing.

The optimal dose of oral activated charcoal has never been fully established. Since the beginning of its clinical use as a GI decontaminant, various factors have been recommended for determining the optimal dose of activated charcoal. Two factors commonly discussed are the patient’s weight and the quantity of the xenobiotic ingested. The problem in using the quantity of the xenobiotic as a basis for activated charcoal dosing is that the amount is usually unknown, and there is an implication that nothing else in the GI tract will occupy binding sites on activated charcoal. Additionally, the xenobiotic is often unknown, and xenobiotics vary enormously in their toxicities, rate of absorption, and the clinical effects they produce (eg, respiratory depression, convulsions, and effect on gastric emptying rate). Some xenobiotics are well adsorbed to activated charcoal, but others are not.⁴⁹ Because of variables such as the physical properties of the formulation ingested (liquid, solid, or sustained-release tablet), the volume and pH of gastric and intestinal fluids, and the presence of other xenobiotics adsorbed by activated charcoal,^{14,18,92,95,133,162,164} the optimal dose cannot be known with certainty in any given patient.

Information concerning the maximum adsorptive capacity of activated charcoal for the particular xenobiotic ingested permits a theoretical calculation of an adequate dose,^{8,12,17,19,40,50,158,159,162,163,183,184,186,199,214,219} assuming that the amount of xenobiotic ingested is known. However, clinicians must remain cognizant of the risk of approaching or exceeding the adsorptive capacity of the standard dose of approximately 1 g/kg of body weight of activated charcoal. This possibility has been investigated in some studies.^{8,19,36,95,104,155,186,231}

Thus, the idea that a fixed activated charcoal-to-xenobiotic ratio is appropriate for all xenobiotics is clearly imperfect. It is possible, however, to develop a logical approach to dosing based on available data. The effect of the activated charcoal:xenobiotic ratio is such that theoretically increasing the ratio enhances the completeness of adsorption corresponding to a higher percentage of adsorption and total amount of adsorbed xenobiotic (Fig. 8–2).¹⁵⁷ This was confirmed by Jürgens et al., demonstrating an increasing effect of activated charcoal with increasing activated charcoal–xenobiotic dose, up to a 40:1 ratio.¹¹⁶ The optimal activated charcoal dose is theoretically the minimum dose that completely adsorbs the ingested xenobiotic and, if relevant, that maximizes enhanced elimination. The results of in vitro studies show that the ideal activated charcoal:xenobiotic ratio varies widely, but a common recommendation is to deliver an activated charcoal:xenobiotic ratio of 10:1, or 50 to 100 g of activated charcoal to adult patients, whichever is greater. From a theoretical perspective, this amount will adsorb 5 to 10 g of a xenobiotic, which should be adequate for most poisonings.^{12,13,44,49,163} In human volunteers, the acetaminophen clearance was increased with increasing doses of activated charcoal.⁸⁷ Fixed doses of 50, 25, or 5 g activated charcoal were administered 1 hour after 50 mg/kgof acetaminophen was given. The apparent half-life of acetaminophen was significantly reduced from 2.5 hours for the 5 g activated charcoal dose to 1.9 hours and 1.6 hours for the 25 and 50 g doses, respectively.⁸⁷ The effect of larger doses of activated charcoal, adsorbing larger amounts of xenobiotics was supported by the meta-analysis mentioned earlier.¹¹⁶ Based on available data from in vivo and in vitro studies, the actual recommended dosing regimen for activated charcoal is 50 to 100 g in adults (1 g/kg of body weight) and 0.5 to 1.0 g/kg of body weight in children.^44,49 These recommendations are generally based more on activated charcoal tolerance than on efficacy. When calculation of a 10:1 ratio exceeds these recommendations, either gastric emptying or MDAC therapy should be considered.

For example, consider a patient who intentionally overdosed by ingesting 30 (0.25-mg) digoxin tablets (total dose, 7.5 mg). Achieving a 10:1 ratio is quite easy, and a standard dose of 1 g/kg might exceed a 10,000:1 ratio. In comparison, consider a patient who intentionally ingests 30 (325-mg) aspirin tablets (total dose, 9.75 g). In this case, obtaining a 10:1 activated charcoal:xenobiotic ratio is quite difficult and is even less likely if a patient ingests 60 or 100 of the aspirin tablets. Poisoning with a combination of xenobiotics may also approach or exceed the maximum adsorptive capacity for the standard dose of activated charcoal, and increasing the dose to reach a higher activated charcoal:xenobiotic ratio might be necessary to consider in multiple-xenobiotic poisonings.⁹⁵

Methods to Increase the Palatability of Activated Charcoal.

Activated charcoal has a pronounced gritty texture, and it immediately sticks in the throat because it adheres to the mucosal surfaces and begins to cake.⁴⁹ In addition, the black appearance and insipid taste of activated charcoal make it less attractive.

There have been numerous attempts at making activated charcoal more appealing by providing flavors, including jam,⁵⁸ chocolate syrup,^142,154 cherry extract or syrup,^88,168,238 cookie,¹²² juice,¹⁶⁸ sorbitol,^51,55,143 saccharin,⁵² strawberry flavor,¹⁶⁷ orange or peppermint oil,⁴⁹ melted milk chocolate,^66,67 chocolate milk,^39,88,168 soda,^{39,88,168,179} yogurt,⁹⁴ and ice cream.^40,93,210 The general recommendation, however, remains that activated charcoal should be mixed with water.^10,115 Because activated charcoal adsorbs the flavoring agents, the palatable taste from added flavors often disappears within minutes after mixing.^49,51,52,58 However, in cases in which the activated charcoal does not completely adsorb the flavoring agents, they provided a pleasant taste without significantly reducing the adsorptive properties of the activated charcoal.^{49,51,52,93,94}

Effect on Oral Therapeutics.

The nonspecific nature and high adsorptive capacity of activated charcoal raises concerns about the simultaneous use of orally administered therapeutics. It would be expected that therapeutics administered shortly before or simultaneously with activated charcoal would be extensively adsorbed, greatly reducing therapeutic efficacy. Restored utility of a therapeutic would be as complex and would depend on all of the factors that influence the efficacy of activated charcoal. Although there is some concern over activated charcoal limiting the efficacy of common oral antidotes such as NAC and succimer, additional concerns arise regarding the administration of oral maintenance medications. For example, activated charcoal might alter the kinetics of the new oral anticoagulants (dabigatran, apixaban, and rivaroxaban).¹⁹⁷ The issue is described to a limited extent and not in the context of poisoning.^178,203

Contraindications and Complications.

Few clinically significant adverse effects are associated with the use of activated charcoal for poisoned patients.^49,178 Adverse GI effects are most commonly described, but the frequency varies,¹⁷⁸ and it might be difficult to differentiate from adverse effects resulting from the ingested xenobiotic.¹⁹⁰ In a study of 24 volunteers, mild adverse effects such as abdominal fullness or constipation (46%) and nausea (17%) were most common.¹⁹⁰ In a randomized clinical trial, vomiting was not more frequent in patients treated with activated charcoal compared with the control group, which received no activated charcoal.⁵⁴ Similarly, although vomiting was observed in 22% of patients in a randomized controlled trial of 1103 patients with intentional poisoning, a nonsignificant difference in incidence was reported between patients who had or had not received GI emptying procedures.¹⁵⁰ A prospective cohort study estimating the incidence of vomiting subsequent to the therapeutic administration of activated charcoal to poisoned children younger than 18 years of age showed that one of five of these children vomited. Children with previous vomiting or nasogastric tube administration were at highest risk.¹⁶⁹ This incidence of vomiting appears to be greater when activated charcoal is administered with sorbitol²²⁵ and after rapid ingestion of larger doses.¹⁵⁷

Pulmonary aspiration of gastric contents containing activated charcoal and inadvertent direct instillation of activated charcoal into the lungs from a misplaced nasogastric tube are rare but severe incidents^54,74,198 that might lead to airway obstruction, bronchospasm, hypoxemia, aspiration, permanent lung injury, and even death.^161,166 Administration of activated charcoal to already intubated patients is associated with a low incidence of aspiration pneumonia.¹⁵¹ In fact, pulmonary complications associated with activated charcoal aspiration might be primarily related to the aspiration of acidic gastric contents and not directly related to aspiration of activated charcoal.¹⁸⁵ A retrospective study found that only 1.6% of unselected overdose patients aspirated and that administration of activated charcoal was not found to be an associated risk factor.¹⁰⁶ Pulmonary aspiration in overdose patients who have received activated charcoal is more easily documented because activated charcoal is a very identifiable marker.

Although relatively few reports of clinically significant emesis and pulmonary aspiration resulting from the administration of activated charcoal exist, the severity of these complications is clear. Consequently, it is important to evaluate, particularly in patients determined to be at limited risk from their exposures, whether single-dose activated charcoal therapy is likely to be beneficial based on the indications and contraindications listed in Table 8–4. This is especially true in small children, in whom the risks of nasogastric tube use might outweigh the benefits of activated charcoal.

MDAC is typically defined as at least two sequential doses of activatedcharcoal.²²⁵ In many cases, the actual number of doses administered is substantially greater. This technique serves two purposes: (1) to prevent ongoing absorption of a xenobiotic that persists in the GI tract (usually in the form of a modified-release preparation) and (2) to enhance elimination in the postabsorptive phase by either disrupting enterohepatic recirculation or enteroenteric recirculation (“gut dialysis”).

The 1999 position statement of the AACT and the EAPCCT concluded that based on clinical studies, MDAC should be considered only if a patient has ingested a potentially life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. Although data have confirmed enhanced elimination of these drugs, no controlled studies have demonstrated clinical benefit after their ingestion. Volunteer studies demonstrate that MDAC increases the elimination of amitriptyline, dextropropoxyphene, digitoxin, digoxin, disopyramide, nadolol, phenylbutazone, phenytoin, piroxicam, and sotalol, but there are insufficient clinical data to support or exclude the use of MDAC in these patients.²²⁵ A possibly beneficial effect of MDAC has recently been shown in poisonings including Amanita phalloides and other Amanita spp,^{38,79,113,176} amiodarone,²⁰⁵ carbamazepine,²²⁷ dosulepin,¹⁴⁵ duloxetin,⁶⁹ diquat,²¹⁸ lamotrigine,⁶⁹ phenobarbital,⁴⁶ theophylline,³⁷ valproic acid,²²⁹ and verapamil.¹⁹³ Furthermore, MDAC is recommended in severe poisonings, including with colchicine²⁸ and quinine.¹¹¹ Although technically correct, the preceding statements suffer from a lack of high quality evidence. Because the clinical studies used to formulate this opinion all lack sufficient numbers of significantly poisoned patients, they induce a bias against any benefit of MDAC. Additionally, none of the studies included a detailed analysis of sustained- or extended-release formulations, which are widely used today. Finally, it is noteworthy that the definition of “life threatening” is highly subjective. Endpoints such as decreased morbidity or rigorously determined lengths of stay should be considered essential in any study design. Three studies with these clinical endpoints were previously discussed.⁸⁷ Unfortunately, their results were discordant, highlighting the difficulties within this field of study.^30,59,65

Dosing.

Various MDAC regimens were evaluated to optimize the efficacy of activated charcoal.^105,119 Reduced xenobiotic absorption and enhanced elimination were demonstrated compared with either single-dose activated charcoal or control without activated charcoal.¹¹⁹ The effect of MDAC on elimination was studied in volunteers who were dosed with lamotrigine and oxcarbazepine in therapeutic doses.¹¹⁹ The MDAC dose regimen was 25 g activated charcoal at 6, 12, 24, 36, 48, and 72 hours after a 100 mg lamotrigine dose or 20 g activated charcoal at 12, 24, 36, and48 hours after a 300 mg oxcarbazepine dose. Each regimen was compared to control subjects with no activated charcoal and one single dose of 50 g activated charcoal at 30 minutes after lamotrigine or oxcarbazepine ingestion, respectively. Pharmacokinetic parameters were evaluated from the serum concentrations of lamotrigine and oxcarbazepine (by measuring the active metabolite 10-hydroxy-carbazepine). Both activated charcoal regimens significantly reduced the total systemic xenobiotic load compared with control subjects with reductions of 51% for lamotrigine and41% for 10-hydroxy-carbazepine. The elimination half-life for both xenobiotics was significantly shortened with MDAC; 11±3.5 hours (MDAC) versus 25±4.3 hours (control) for lamotrigine, and 9.0±1.5 (MDAC) versus 20±12 hours (control) for 10-hydroxy-carbazepine.¹¹⁹

Intravenous administration of a xenobiotic is an ideal method to evaluate the ability of different MDAC dose regimens to enhance elimination of a xenobiotic in the postabsorptive phase. A total dose of 150 g activated charcoal given as a loading dose of 50 g and the remaining 100 g divided in either 12.5 g every hour, 25.0 g every 2 hours, or 50.0 g every 4 hours during a total time of 8 hours was equally effective in reducing the mean area under the concentration versus time curve (AUC) in volunteers receiving 8 mg/kg of aminophylline intravenously over a period of 60 minutes.¹⁰⁵

Contraindications and Complications.

Similar to single-dose activated charcoal, MDAC can produce emesis, with subsequent pulmonary aspiration of gastric contents containing activated charcoal. It is intuitive that these risks are greater with MDAC than with single-dose therapy. One retrospective study attempted to determine the frequency of complications associated with the use of MDAC.⁶¹ The authors identified nearly 900 patientswho had received MDAC and found that only 0.6% of patients had clinically significant pulmonary aspiration. Although no patients developed GI obstruction, 9% had hypernatremia or hypermagnesemia without any clinical consequences noted. The authors did not specify whether the multiple-dose regimens administered included the use of cathartics, but the profile of the adverse reactions suggests that these electrolyte abnormalities were probably from cathartic use. Despite the obvious limitations, this study demonstrates a reasonably low rate of complications associated with MDAC.

Table 8–5 summarizes the indications and contraindications for MDAC therapy. Because the optimal doses and intervals for MDAC have not been established, recommendations are based more on amounts that can be tolerated than on amounts that might be considered pharmacologically appropriate. Table 8–6 lists typical dosing regimens. Larger doses and shorter intervals should be used for patients with more severe toxicity. It is reasonable to base endpoints either on the patient’s clinical condition or on xenobiotic concentrations when they are easily measured.

Further clinical and toxicokinetic studies concerning MDAC are needed to establish an optimal dosing regimen and to confirm an effect on relevant endpoints. From available data discussed earlier, the dosing and most appropriate dosing intervals should be considered in each individual overdose case including compliance and clinical challenges from complications (eg, emesis and vomiting). Readers are referred to Antidotes in Depth: A1 for a more detailed discussion of single-dose activated charcoal and MDAC therapy.

Whole-bowel irrigation represents a method of purging the GI tract in an attempt to expeditiously achieve gut clearance and prevent further absorption of xenobiotics. This is achieved through the oral or nasogastric administration of large amounts of an osmotically balanced polyethylene glycol electrolyte lavage solution (PEG-ELS). WBI was subjected to a thorough literature review, which was published as a revised position statement in 2004.²⁰⁸ The position statement was unable to establish a clear set of evidence-based indications for the use of WBI because no clinical outcome studies have ever been performed. When experimental, theoretical, and anecdotal human experience is considered, the use of WBI with PEG-ELS can be supported for patients with potentially toxic ingestions of sustained-release pharmaceuticals and substantial amounts of metals. Other indications include the ingestion of large amounts of a xenobiotic with a slow absorptive phase in which morbidity is expected to be high, the ingested xenobiotic is not adsorbed by activated charcoal, and other methods of GI decontamination are unlikely to be either safe or beneficial.²⁰⁸ The removal of packets of xenobiotics from body packers can be considered a unique indication for WBI.^22,215

Whole-bowel irrigation cannot be applied safely if the GI tract is not intact; there is an adynamic or obstructive ileus; in the presence of significant GI hemorrhage; or in patients with inadequate airway protection, uncontrolled vomiting, or consequential hemodynamic instability that compromises GI function or integrity.^56,208 Compliance may be an issue because 1 to 2 L/h of PEG-ELS is required for rapid cleansing. These large volumes can be facilitated when the solution is administered via a nasogastric tube.¹³⁶ Additionally, in vitro, the combination of WBI and activated charcoal decreases the adsorptive capacity of activated charcoal or increases the desorption of xenobiotic from activated charcoal,^17,99,139 especially when the WBI solution is premixed with activated charcoal.¹³⁹ Activated charcoal should therefore be administered immediately after the WBI procedure, rather than simultaneously.

Results from volunteer studies often offer extreme variability in results,^{127, 128, and 129,138} and significant variations are noted when individual subjects are simultaneously given three different sustained release xenobiotics.¹²⁹ In one study, nine volunteers took sustained-release preparations of 200 mg of carbamazepine, 200 mg of theophylline, and 120 mg of verapamil, and1 hour after ingestion, they were assigned to 25 g of activated charcoal followed by WBI, 1 L/h PEG-ELS, 25 g of activated charcoal, or water (200 mL).When the combination therapy was compared with activated charcoal alone, it was not more efficient at reducing pharmacokinetic parameters such as AUC (0–24 hours) and C_max (maximum concentration) for carbamazepine and theophylline, but for verapamil, the combination therapy was more effective than activated charcoal alone.¹²⁹ WBI could not be demonstrated to significantly reduce the AUC for sustained-release acetaminophen (75 mg/kg) compared with control participants in a volunteer study in which WBI was initiated 30 minutes after drug ingestion.¹³⁸ In this study, a capsule containing radiopaque markers, which was given simultaneously with acetaminophen, reached colon more rapidly and in a “collected cluster” on the day of WBI administration compared with the control when the markers were spread throughout the GI tract.

In both of these studies, therapeutic or nontoxic doses of pharmaceuticals were used as marker xenobiotics. In actual overdoses, the pharmacokinetic properties of pharmaceuticals and the effects of decontamination may differ substantially. As mentioned earlier, study designs using activated charcoal and small doses of xenobiotics tend to bias the study toward a benefit of activated charcoal. In an overdose scenario, when the adsorptive capacity of activated charcoal may be exceeded, it is intuitive that the benefits of other modalities would be more evident.

Pharmacokinetic and pharmacodynamic evaluation in venlafaxine-overdosed patients showed that compared with activated charcoal alone, combination therapy of WBI and activated charcoal might be more beneficial based on decreased venlafaxine bioavailability (29% reduction), increased venlafaxine clearance (35% increase), and lower venlafaxine peak concentrations¹²⁸ and resulted in a decreased probability of venlafaxine- induced seizures (odds ratio {OR}, 0.25 for the combination therapy vs 0.48 for activated charcoal alone).¹²⁷

A small, retrospective, descriptive case series of 16 body packers treated with WBI supports the safety of WBI for body packers. Although the complication rate was reported as 12.5% (two of 16), these complications were not serious. One case of mild cocaine toxicity resulted from leakage, and one heroin body packer had to undergo surgery because of retainedpackages. There was no correlation between the dose of PEG-ELS, drug type, or packet quantity and length of hospital stay. Because there was no control group, it is not possible to evaluate whether WBI influenced any clinical outcome.⁷¹ Clearance of cocaine packets was performed using PEG-ELS WBI in 33% of 61 verified body packers judged not to be able to clear the packets from their gut. A dosage regimen of 1.5 L/h PEG-ELS was continued until all packets had passed, and there was no limit on the total volume given.²²

Whole-bowel irrigation has been used to treat overdoses in pregnant women and children. Two such cases involved iron overdoses in women during the second and third trimesters of pregnancy; both women were treated successfully and without complications.^220,228 Pediatric case reports describe combined WBI with succimer therapy⁴⁷ and eventually colonoscopic removal of ingested lead pellets.^47,91 Abdominal radiographs showed two small lead pellets, which WBI failed to remove, therefore requiring endoscopic removal.⁴⁷ Seven days of WBI, however, was ineffective in the removal of approximately 800 ingested lead pellets, which necessitated removal by colonoscopy.⁹¹ Several reports support the use of WBI in children, including an intentional ingestion of mercury,¹⁸⁹ two pediatric body packers,²¹⁶ and a 16 month-old boy who had ingested a significant amount of iron.²³² In the latter case, despite WBI, the iron bezoar was not removed, treatment was eventually stopped, and the bezoar was expelled after a normal diet was resumed.²³²

The current evidence for the clinical efficacy of WBI is divergent, depending on the xenobiotic and its formulation. Additional case reports and series demonstrate the overall safety of WBI as well as some beneficial effects on secondary endpoints, but the benefits remain generally theoretical. The evidence for simultaneous administration of activated charcoal with WBI is contradictory. Although there is little doubt that PEG-ELS reduces the adsorptive capacity of activated charcoal in vitro, it is unclear if this effect has any clinical significance.

The indications for WBI with PEG-ELS are patients with potentially toxic ingestions of sustained-release pharmaceuticals, xenobiotic ingestions with slow absorptive phases when morbidity is expected to be high, and foreign body ingestions. The combination of WBI and activated charcoal should be considered when adsorption of the ingested xenobiotic to activated charcoal is expected to be high. Other uses of WBI remain theoretical because the only support for the efficacy comes from surrogate markers and anecdotal experience. Table 8–7 summarizes the indications and contraindications for WBI.

At present, there is no indication for the routine use of cathartics as a method of either limiting absorption or enhancing elimination. A single dose can be given as an adjunct to activated charcoal therapy when there are no contraindications and constipation or an increased GI transit time is expected. Multiple-dose cathartics should never be used, and magnesium-containing cathartics should be avoided in patients with kidney disease (Antidotes in Depth: A2).

Surgery and endoscopy are occasionally indicated for decontamination of poisoned patients. As might be expected, no controlled studies have been conducted, and potential indications are based largely on case reports and case series. A prospective, uncontrolled series of 50 patients with cocaine packet ingestion was published more than 20 years ago.³⁵ The patients were conservatively managed and only underwent surgery if there were signs of leakage or mechanical bowel obstruction. Bowel obstruction occurred in three patients, who promptly underwent successful emergency laparotomy; another six patients chose elective surgery. The authors concluded that body packers should be treated conservatively and only operated on for xenobiotic leakage or bowel obstruction.³⁵ A similar study performed a 16-year retrospective analysis of all body packers treated in a single center.¹⁹⁴ Of the 2880 body packers who were identified, 63 (2.2%) developed symptoms of severe cocaine toxicity after rupture of a package, 43 of the 63 symptomatic patients (68%) died before surgery could be initiated, and 20 (32%) underwent emergency laparotomy to remove the drug packets and survived. A more recent report described two body packers who successfully underwent surgery to remove drug packets. In one case, the indications were rupture and signs of cocaine toxicity. In the other case, the indication for surgery was bowel obstruction.¹⁶⁵ Because most packages do not spontaneously rupture, mechanical obstruction is probably the most common reason for surgical removal of ingested drug packets.²¹⁵ Leakage from heroin-containing packages can usually be managed by naloxone infusion, but the lack of antidote when cocaine packages rupture necessitates surgery (Special Considerations: SC5).²¹⁵

Over the years, a few case reports have presented mixed results for the endoscopic removal of drug packets or pharmacobezoars from the stomach.^{41,60,200,204,215} At present, this method is not commonly recommended because of concerns about packet rupture. However, under exceptional circumstances, there is certainly a precedent for attempting this procedure in a highly controlled setting such as an ICU or operating room.

In rare cases of massive iron overdoses when emesis, orogastric lavage, and gastroscopy failed or were estimated to result in an insufficient treatment outcome, gastrotomy was performed. The significant clinical improvement and postoperative recovery indicated that surgery in these particular cases was the correct approach.^73,89,171 In a case of zinc toxicity resulting from massive chronic coin ingestion, laparotomy and gastrotomy proved essential to remove the more than 270 coins ingested¹⁷⁰ (Chap. 103).

Other xenobiotics, such as cholecystokinin, have been considered as adjuncts to standard measures for GI decontamination.^68,97 Pharmaceuticals that either speed up GI passage or slow down gastric emptying have been administered in an attempt to minimize the absorption of a xenobiotic. In all cases, the results have been negligible, and the potential risks of administering additional pharmacologically active xenobiotics to an already poisoned patient seem to outweigh any benefit.^9,233 Interventions that reduce the absorption of xenobiotics from the GI tract other than activated charcoal have also been studied, including sodium polystyrene sulphonate for lithium^{23,78,138, 139, and 140,181,213} or thallium overdose.¹⁰⁰ Human studies showed minimal decreased absorption and increased clearance of lithium when sodium polystyrene sulphonate was administered.^78,181 Likewise, case reports describe the use of the lipid-lowering resins cholestyramine and colestipol to interrupt the enterohepatic circulation of digoxin, digitoxin, and chlordane to increase elimination.^{21,76,120,175} With the increased use ofactivated charcoal and availability of digoxin-specific Fab fragments, indications for lipid-lowering resins for cardioactive steroid ingestions seem obsolete. Studies on clay products in vitro have demonstrated a lower efficacy compared with activated charcoal and activated charcoal-kaolin products in the adsorption of Nerium oleander toxins.²¹²

Only a few studies provide guidance based on meaningful clinical endpoints for GI decontamination. Pharmacokinetic and pharmacodynamic parameters were introduced and systematically evaluated in human venlafaxine, citalopram, escitalopram, and quetiapine overdose cases,^{107, 108, and 109,127,128} increasingly popular pharmaceuticals known to cause central nervous system and cardiac toxicity. Cohort studies^{107, 108, and 109,127,128} have recently evaluated the effect of GI decontamination with the aim to predict cardiotoxicity and the effects of the GI decontamination method chosen in real-life situations that are often inconsistent with the recommendations of the positionpapers.^{43,125,209,225,226} In a cohort of 436 venlafaxine overdose occasions, activated charcoal increased venlafaxine clearance and decreased the probability of seizures.^127,128 Similarly, 77 escitalopram patient overdoses were used to develop a pharmacokinetic–pharmacodynamic model that predicted the probability of having abnormal QT as a surrogate for torsade de pointes.²³⁰ In this model, activated charcoal decreased the bioavailability by 31% and reduced the relative risk reduction of prolonged QT interval by 35% after the ingestion of 200 mg of escitalopram or more.²³⁰

The trends in GI decontamination have dramatically shifted toward less intervention over the years. In 2011, of the 2,334,004 human exposure reported to the American Association of Poison Control Centers,³¹ it is remarkable that only 64,866 patients were given single-dose activated charcoal, 1904 were given MDAC, 4126 underwent lavage, and 2040 received WBI. Similar trends are reported elsewhere with no apparent worsening of outcome.¹⁵ These trends in practice noted reflect the overall combined philosophy of the position statements, which are applicable to the vast majority of poisoned patients. They highlight the benign nature of many exposures and the benefits of good supportive care in the typical patient in whom the interventions of decontamination represent more risk than benefit. In contrast, the survey mentioned on the first page of this chapter of recommendations for a theoretical patient with a serious enteric-coated aspirin overdose reveals less consensus in that 36 different courses of action were proposed for the same patient—a situation in which nonintervention may have greater risk to the patient than decontamination. Most of the poison centers and toxicologists did, however, recommend at least one dose of activated charcoal.¹¹⁷ This distinction serves as a reminder that the existing studies and consensus statements cannot be applied to all cases and that a lack of data produces significant uncertainty in choices for GI decontamination in either atypical or severely poisoned patients.⁹⁸

It is essential to note that only one study has ever demonstrated a survival advantage for any form of GI decontamination of poisoned patients.⁵⁹ Its unique design, involving a cohort of patients with life-threatening toxicity, forces a reassessment of all previous and subsequent literature and confirms that the principles of decontamination are sound. It also suggests that the failure of most studies to demonstrate a benefit results not from a failure of the techniques used but from applying decontamination techniques to subsets of patients who were likely to have good outcomes regardless of intervention.

• The approach to GI decontamination needs to be more individualized than previously thought. No decontamination method is completely free of risks. The indications and contraindications for GI decontamination must be well defined for each patient, and the method of choice must depend largely on what was ingested, how much was ingested, who ingested it, and when it was ingested.

• Evidence now points away from the routine GI decontamination of most patients presenting to an ED with an oral pharmaceutical drug overdose.

• A single dose of activated charcoal alone will be sufficient in moderate-risk patients, and only in a small subset of exceptionally high-risk patients will the benefit of orogastric lavage outweigh the risks.

• Orogastric lavage as a single intervention is reserved for cases in which the ingested xenobiotic is not adsorbed by activated charcoal and there is reason to believe that the ingested xenobiotic is both life threatening and still in the stomach.

• MDAC and WBI have narrowly defined indications, which may broaden in the future as more studies focus on subsets of significantly poisoned patients.

• The absolute time frame for when decontamination is indicated depends on many factors, such as the rate of gastric emptying, the rate of xenobiotic absorption, and the possibility of enterohepatic and enteroenteric recirculation. The commonly stated short time frame of up to 1 hour postingestion for intervention is most likely an artificially constructed evidence-free time limitation and the potential benefits associated with GI decontamination after a potentially serious ingestion.

References