One approach to altering the pharmacokinetics of a xenobiotic is to administer a gastrointestinal (GI) evacuant. Selected patients benefit from minimizing systemic exposure by decreasing GI transit time and increasing rectal evacuation. The most effective process of evacuating the GI tract in poisoned patients is referred to as whole-bowel irrigation (WBI). Whole-bowel irrigation is typically accomplished using polyethylene glycol with a balanced electrolyte lavage solution (PEG-ELS). Unless stated otherwise, WBI will mean WBI with PEG-ELS. A detailed discussion of the merits of WBI in the context of various decontamination strategies is provided in Chap. 5.
In 1625 while endeavoring to recover from the febrile “Hungarian disease,” Johann Glauber drank from a well from which he later isolated sal mirabile, now known as sodium sulfate, Na2SO4.54 He advocated its use as a purgative and determined a synthetic production method.54 In 1675, Nehemiah Grew first observed the presence of the eponymous purgative salt in the springs at Epsom, later determined to be magnesium sulfate.125 Phosphate of soda, called “tasteless purging salt,” was found in the urine by Hellot in 1737 and introduced into clinical practice as a purgative by George Pearson some 50 years later.119 In 1882 and 1883, Hay reported a series of experiments that provided the foundational understanding of the mechanism of action of the saline cathartics. He identified the viscus as the main source of bowel fluid, which was secretory in nature, and established the dose–response principle of decreased time to stool as salt concentrations were increased.50,51 Polyethylene glycol was initially introduced in 1957 as a nonabsorbable marker for the study of human fat, carbohydrate, and protein absorption.20 Experimental studies of intestinal lavage in normal human subjects appeared in 1968.89 In 1973, Hewitt and colleagues reported on WBI in clinical practice using their method of “whole-gut irrigation” with a solution of sodium chloride, potassium chloride, and sodium bicarbonate in distilled water to prepare the large bowel for surgery.53 In 1976, WBI was used therapeutically for poisoning in a patient ingesting 300 lead air-gun pellets who was unresponsive to oral magnesium sulfate purgation.159
Xenobiotics that promote intestinal evacuation are referred to as laxatives, cathartics, purgatives, promotility agents, and evacuants. Depending on the dose, the same xenobiotic might accomplish some or all of these tasks, with differing side effect profiles. Laxatives promote a soft-formed or semifluid stool within 6 hours to 3 days. Cathartics promote a rapid, watery evacuation within 1 to 3 hours.131 The term purgative relates the force associated with bowel evacuation. Evacuants are commonly used for preprocedural bowel cleansing, with an onset of action of as little as 30 to 60 minutes, but typically require 4 hours for a more complete effect. Promotility xenobiotics stimulate GI motor function via the enteric nervous system through a variety of acetylcholine, dopamine, guanylate cyclase-C, motilin, opioid, and serotonin receptor and intestinal chloride channel interactions.
Laxatives are further classified into categories of bulk-forming, softener or emollient, lubricant, stimulant or irritant, saline, hyperosmotic, and evacuant. Bulk-forming laxatives include high-fiber products such as methylcellulose, polycarbophil, and psyllium; softeners or emollients include docusate calcium. Mineral oil is the sole lubricant. These cathartics are not used therapeutically in medical toxicology because their onset of action is delayed. Stimulant or irritant laxatives include anthraquinones (sennosides, aloe, and casanthranol), diphenylmethane (bisacodyl), and castor oil. Saline (meaning salt) cathartics, which include magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium phosphate, and sodium sulfate, are used infrequently. Hyperosmotic xenobiotics, generally nonabsorbable sugars and alcohols, including sorbitol and lactulose, are occasionally used in poisoned patients. The most common process of evacuating the intestinal tract in poisoned patients is WBI.
Magnesium citrate and magnesium sulfate (“Epsom salt”) are water-soluble salts of magnesium; magnesium hydroxide (“milk of magnesia”) is insoluble.64 Sodium sulfate is prepared either through purification of naturally occurring brine deposits or other manufacturing processes. Sodium phosphate is supplied as a combination of the monobasic monohydrate and dibasic anhydrous forms. D-Sorbitol, an isomer of mannitol, is a hexitol naturally occurring in many fruits and is produced commercially by the reduction of glucose. Lactulose is a water-soluble, synthetic disaccharide, 4-O-β-D-galactopyranosyl-D-fructofuranose. Sodium picosulfate is a monohydrate, disodium salt prodrug.
The addition reaction of ethylene oxide to an ethylene glycol equivalent polymerizes ethylene oxide into PEG. The “n” in the molecular structure of PEG, H-(OCH2CH2)n-OH refers to the average number of repeating oxyethylene groups.69 The number after PEG represents its average molecular weight (MW). Also known as macrogol, PEG has numerous medicinal applications. It can be conjugated to pharmaceuticals to delay vascular clearance or preclude blood–brain barrier transit (“PEGylation”), serve as a solvent in oral liquids and soft capsules, function as a nonalcohol solubilizer and diluent for liquid oral-dose medications, provide a base for medical ointment and cosmetics, and act as a base liquid for producing vapor in electronic cigarettes.1 Low-molecular-weight PEG (eg, 300 or 400 Da), because of its advantageous solvent properties, is used to decontaminate phenol burns, although animal studies demonstrated the equal efficacy of copious (ie, deluge) quantities of water.59 Higher-molecular-weight variants are used to promote laxation. Although PEG’s physical properties (eg, water solubility, hygroscopicity, vapor pressure, melting or freezing range, and viscosity) vary with MW and blending because of chain-length effects, the chemical properties are similar.145 Polyethylene glycol 3350 used in pharmaceutical, personal care, and food applications is water soluble. It has a MW range of 3,015 to 3,685 Da, an average number of 75.7 repeating oxyethylene units, a pH of a 5% aqueous solution of 4.5 to 7.5 at 25°C, a density of 1.09 g/cm3 at 60°C, a melting or freezing range between 53° and 57°C, a water solubility of 67% by weight at 20°C, and a viscosity of 90.8 centistokes at 100°C.144 Polyethylene glycol 3350 without electrolytes is sold for nonprescription use for short-term treatment of constipation. Whole-bowel irrigation used in poison management is typically accomplished using PEG 3350 added to a balanced electrolyte lavage solution (PEG-ELS), which contains an isotonic mixture of sodium sulfate, sodium bicarbonate, sodium chloride, and potassium chloride.131
The effects of saline cathartics are largely attributed to their relatively nonabsorbable ions that establish an osmotic gradient and draw water into the gut.116 The increased water leads to increased intestinal pressure and a subsequent increase in intestinal motility. Magnesium ions also lead to the release of cholecystokinin from the duodenal mucosa, which stimulates intestinal motor activity and alters fluid movement, contributing to catharsis.19,131,138 A lack of endogenous hydrolytic enzymes allows sorbitol, lactulose, and sodium picosulfate to reach the colon unchanged. Colonic bacteria metabolize sorbitol into acetic and short-chain fatty acids and lactulose into lactic acid and small amounts of formic and acetic acids. This results in a slight acidification of colonic contents, an increase in osmotic pressure that draws water into the lumen, and stimulation of colonic propulsive motility.131 Colonic bacteria hydrolyze sodium picosulfate, marketed in the United States for bowel preparation in combination with magnesium oxide and citric acid, which create magnesium citrate in solution, to active 4,4’-dihydroxydiphenyl-(2-pyridiyl)methane, a stimulant laxative.4,72
Long-chain PEGs (eg, MW ~3,350 Da) are nonabsorbable, isoosmotic, indigestible molecules that remain in the colon together with the water diluent, resulting in WBI primarily by the mechanical effect of large-volume lavage. As assessed in controlled clinical trials in patients undergoing colonoscopy, the added balanced electrolyte solution practically eliminates electrolyte abnormalities and helps preclude fluid shifts across the GI mucosa.16,83 Sodium sulfate in many preparations reduces sodium absorption in the small intestine because of the absence of chloride, which is the accompanying anion necessary for active absorption against the electrochemical gradient.94
Promotility xenobiotics such as metoclopramide and erythromycin stimulate gut motor function. Metoclopramide mediates GI 5-hydroxy tryptamine (5HT4) receptor agonist and dopamine (D2) receptor antagonist activity, which both result in increased acetylcholine release and GI motility. Erythromycin stimulates gut motor function via direct stimulation of GI motilin receptors.151 Prucalopride (approved outside of the United States) and tegaserod (withdrawn from the US market because of adverse cardiovascular effects but supplied in emergency situations) are selective, 5-HT4 receptor agonists. Tegaserod and WBI were combined together in an attempt to improve colonoscopy preparations but not in poisoned patients.3 Lubiprostone activates chloride channel protein 2 to induce chloride secretion and to enhance the contraction of gastric and colonic musculature.70 Lubiprostone is sometimes used with WBI to treat constipation but not in poisoned patients. Linaclotide and plecanatide are guanylate cyclase-C agonists that increase intracellular and extracellular cGMP concentrations to stimulate secretion of chloride and bicarbonate and water into the intestinal lumen primarily through activation of the cystic fibrosis transmembrane conductance regulator ion channel.140 Use in poisoning is unstudied. Nonselective μ-opioid antagonists (naloxone and naltrexone), although primarily used to reverse central nervous system–associated effects, also mitigate acute and chronic opioid-associated constipation; they are used in combination with WBI in certain opioid poisonings (eg, enteral concealment of drug packets and transdermal fentanyl patch ingestion).43,147 Use of peripherally acting μ-opioid antagonists (methylnaltrexone, naloxegol, and alvimopan) in poisoning is not yet reported.
Absorption of magnesium, phosphate, and other electrolytes contained in hypertonic products is well described.34,110,116 In one prospective, nonrandomized study, 9 of 14 patients developed elevated magnesium concentrations (2.2–5.0 mEq/L) after multiple doses of magnesium-containing cathartics were administered for suspected drug overdose despite normal blood urea nitrogen and creatinine concentrations.135 During the 24 hours after administration of oral sodium phosphate solution in seven healthy volunteers, serum phosphorus reached a mean peak concentration of 7.6 mg/dL (range, 3.6–12.4 mg/dL), and ionized calcium reached a mean nadir concentration of 4.6 mg/dL (range,4.4–5.2 mg/dL).34
By virtue of its high osmotic nature, long-chain PEG is poorly absorbed, is retained in the lumen, and does not distribute. Polyethylene glycol is therefore eliminated unmetabolized in rectal effluent. A lack of absorption presents sorbitol, lactulose, and sodium picosulfate to endogenous bacteria for metabolism within the gut lumen.
Patients who ingested 45 mL of an aqueous sodium phosphate preparation taken the evening before and the morning of a procedure had stool production within 1.7 hours of the first dose and within 0.7 hours of the second dose, with a mean duration of activity of 4.6 and 2.9 hours, respectively, and termination of increased stool production within 4 to 5 hours.85 In six volunteers, saline cathartics decreased activated charcoal (AC) mean GI transit time from 29.3 ± 1.2 hours to 24.4 ± 1.2 hours, 15.4 ± 3.0 hours, 17.3 ± 1.9 hours, and 17.5 ± 2.3 hours with sodium chloride, sodium sulfate, magnesium sulfate, and a proprietary cathartic “salt” (36.7% anhydrous citric acid, 17.65% magnesium sulfate, and 45.6% sodium bicarbonate), respectively.117 When different cathartics were compared with respect to time to first stool and number of stools,62,78,108,109,139 sorbitol produced 10 to 15 watery stools and the most abdominal cramping before catharsis. Sorbitol produced stools in the shortest amount of time, which also was associated with the highest incidence of nausea, vomiting, generated gas, and flatus.71,74,111 In one systematic review, the mean transit times after administration of sorbitol, magnesium citrate, magnesium sulfate, and sodium sulfate were 0.9 to 8.5 hours, 3 to 14 hours, 9.3 hours, and 4.2 to 15.4 hours, respectively.9 In comparison, the first bowel movement typically occurs relatively quickly after the initiation of WBI. Patients ingesting PEG-ELS (1.2–1.8 L/h until the rectal effluent was clear) completed their colonic preparation goals within 1.5 to 3 hours after averaging a total of 5.5 L per patient (range, 3–8 L).46 As assessed by magnetic resonance imaging in 24 healthy volunteers, ingesting either a split dose (1 L the evening before and 1 L on the study day) or single dose (2 L) of WBI rapidly increased small bowel water content by fourfold over baseline, increased total colonic volume by 35 ± 8% (split dose) and 102 ± 27% (single dose), and dramatically increased the ascending colon motility index.97
ROLE OF GASTROINTESTINAL EVACUATION IN POISONING MANAGEMENT
Cathartics should not be used in the routine management of overdosed patients.9 Intuitively, the advantages of cathartics appear to result from their ability to decrease the potential for constipation or obstruction from AC and hasten the delivery of AC to the small intestine. However, these theoretical advantages were never demonstrated clinically.
Studies demonstrate that when administered alone, cathartics such as sorbitol or sodium sulfate decrease peak or total absorption of some xenobiotics, but no study of cathartics alone has achieved pharmacokinetic results comparable to that of AC alone.6,30,100,120,153 When comparing the efficacy of a single dose of AC alone with that of AC plus a single dose of cathartic, studies suggest the combination to be equal to,6,105,114,134 slightly better than,30,71 or even slightly worse than AC alone.100,153 We currently advocate WBI to hasten the elimination of poorly absorbed xenobiotics or sustained-release medications before they can be absorbed. This approach is theoretically sound and does not produce the fluid and electrolyte complications associated with cathartics. Unfortunately, evidence of efficacy is limited to anecdotal case reports and volunteer studies.
Many studies of WBI demonstrate patient acceptance, effectiveness, and safety when used for bowel preparation, its labeled indication.8,17,21,22,35,38,39,121,146,149 Animal models suggest that WBI enhances systemic clearance via GI dialysis, similar to multiple-dose AC (MDAC).84 In actuality, low flow rates, the typical delay in administering WBI in actual clinical situations, and the inconvenience of this procedure make it highly unlikely that enhanced systemic clearance can be achieved in humans. In human volunteer studies, WBI was more effective than AC with sorbitol for enteric-coated acetylsalicylic acid (ASA) when administered 4 hours after ingestion,74 decreased peak lithium concentrations, and lithium area under the plasma drug concentration versus time curve (AUC) compared with control participants;136 decreased the bioavailability of two sustained-release medications;26,81 and propelled radiopaque markers through the gut more efficiently than control participants.91 In a retrospective analysis of 59 acute-on-chronic lithium overdoses, those decontaminated at an early stage with sodium polystyrene sulfonate, WBI, or both achieved statistically significant and clinically relevant decreases in peak serum lithium concentrations compared with those with delayed (>12 hours) or no decontamination (2.39 versus 4.08 mEq/L).23 A retrospective chart review of 176 pediatric cases documented WBI use in 72 cases involving sustained- and delayed-release medications, such as nifedipine, bupropion, verapamil, diltiazem, and felodipine.86 Abdominal radiographs were performed in 36 patients, of whom 16 had demonstrable radiopaque pills. Four of these individuals had repeat abdominal radiographs, all of which demonstrated a decrease in opacities.
As expected, WBI was inferior to AC with regard to prevention of absorption when administered after 650 mg of immediate-release aspirin.124 Additionally, after the aspirin was absorbed, WBI was unable to enhance systemic clearance.99 Likewise, only a small, statistically insignificant effect of WBI could be demonstrated on the absorption of extended-release acetaminophen (APAP) in a human volunteer study.91 These findings highlight the limited utility of WBI to assist in the prevention of absorption of relatively rapidly absorbed xenobiotics. Reports suggest successful WBI use in the management of overdoses of iron,40,68,96,141,142 sustained-release theophylline,63 sustained-release verapamil,24 modified-release fenfluramine,107 zinc sulfate,25lead,104,106,128,159 arsenic trioxide,61 arsenic-containing herbicide,82 mercuric oxide powder,92 strontium,73 potassium chloride capsules,49,58 clonidine and fentanyl transdermal patches43,60 and in body packers.57,147 Whole-bowel irrigation for 5 hours after ingestion of 10 fluorescent coffee beans by each of seven volunteers removed an average of only four beans (range, 1–8).126 Similar failures are reported with jequirity beans (Abrus precatorium),25 iron,29,154 and button batteries.141 It can be argued that because of physical characteristics (eg, density, solubility, size, or pharmacobezoar formation), these cases might not be representative of xenobiotics amenable to WBI. The American Academy of Clinical Toxicology/European Association of Poisons Centres and Clinical Toxicologists (AACT/EAPCCT) 2015 WBI position paper recapitulates the 2004 guidelines that WBI “can be considered for potentially toxic ingestions of sustained-release or enteric-coated drugs, drugs not adsorbed by activated charcoal (eg, lithium, potassium, and iron) and for removal of illicit drugs in body ‘packers’ or ‘stuffers,’” but there was no evidence to demonstrate improved outcomes.143 Whole-bowel irrigation is recommended for evacuation of highly toxic xenobiotics with a slow absorption phase and not adsorbed to AC (eg iron, lead, lithium, potassium). When AC is expected to be of benefit, it is recommended that it be administered prior to WBI to achieve its greatest effect.
The approach to patients with internal concealment and enteral transport of illicit substances (eg, cocaine, heroin, amphetamines, and hashish) is comprehensively reviewed in Special Considerations: SC5. In uncontrolled poison control center studies, these patients, along with incarcerated patients, had a higher utilization of WBI and presented a high risk for major adverse events, including death.27 Close coordination with surgical services is advised because of the risks of obstruction, intestinal retention, or rupture. Because mineral oil rapidly degrades latex condoms,156 its use in evacuating drug packets, which can be constructed in this fashion, risks fatal rupture155 and is therefore contraindicated. In a retrospective descriptive case series of 16 body packers, management with WBI was successful in 14; a ruptured cocaine packet produced mild toxicity in 1 patient, and packets were retained in 1 heroin body packer.42 In another retrospective analysis of 34 cocaine body stuffers who were asymptomatic on presentation, 14 received AC (2 left against medical advice before 24 hours), 1 received WBI alone, and 19 received AC plus WBI and remained asymptomatic and were discharged after 24 hours.66 A review of 1,250 confirmed body packers found the success rate of WBI to be 98%.95 All WBI-managed patients passed all of their packets within 5 days. WBI occasionally fails to evacuate all of the drug packets because of inadequate dosing, partial obstruction, or the nature of the procedure. In one case, prolonged WBI failed to clear packets from a methamphetamine body stuffer who engaged in “parachuting (swallowing powdered or crushed drugs by rolling or folding in toilet paper or other paper).”52 As a result of these failures, promotility xenobiotics were added to WBI and presumably successfully enhanced bowel evacuation in two body packers suspected of having ingested well-constructed drug packets.148
ADVERSE EFFECTS AND SAFETY ISSUES
Potential adverse effects associated with various cathartics and promotility xenobiotics include salt and water depletion, hypernatremia, hypermagnesemia, hyperphosphatemia, hypokalemia, and metabolic (contraction) alkalosis, absorption of magnesium or other absorbable electrolytes, activation of the renin–angiotensin–aldosterone system, phosphate-induced nephropathy, and colonic fermentation of digestible sugars.28,44,133 Cathartic-induced rectal prolapse is reported in geriatric patients.76 The use of repetitive doses of cathartics, either by design or unintentionally, has led to hypermagnesemia, altered mental status, and death.65,110,135,158 Hypocalcemia, hyperphosphatemia, and hypokalemia have accompanied the use of hypertonic phosphate enemas and oral sodium phosphate despite adherence to recommended dosing.36,44,48,88,98,122,137 Frail elderly patients, children, and those with decreased kidney function are most susceptible to adverse effects.15,18 On January 8, 2014, the US Food and Drug Administration issued a safety warning that using more than one dose of nonprescription sodium phosphate–containing drugs in 24 hours to treat constipation risked rare but serious severe salt and water depletion, electrolyte abnormalities, acute kidney injury, dysrhythmias, and death.5