Uncontrolled nausea and vomiting in the pediatric intensive care unit may result in consequences that range from minor patient discomfort to life-threatening infection or electrolyte imbalance. To the patient this can mean wound dehiscence, gastrointestinal (GI) bleeding, malnutrition, dehydration, pulmonary aspiration, and increased anxiety with future medical interventions.¹ Indeed, nausea and vomiting has been referred to as the “big little problem” with the capacity to delay discharge, monopolize nursing care, and impact financial resources.² These costs can be limited with a focus on prophylactic treatment, employing recent drug developments and guideline-driven therapy when possible. The data that drive these guidelines are, particularly in pediatrics, largely based on studies that look at vomiting more specifically than nausea.³ Because nausea is an unpleasant, largely subjective sensation in the epigastrium that may be associated with vomiting, it is more difficult to quantify objectively.^3,⁴ Vomiting, defined as the forceful expulsion of gastric contents from the mouth, can be more easily measured for medication assessment purposes. Although distinct, when vomiting is discussed here, it can be inferred to also pertain to managing nausea (unless otherwise noted).

The causes of nausea and vomiting in intensive care are as diverse as their consequences and include radiation, increased intracranial pressure, meningitis, diabetic ketoacidosis, hypercalcemia, hyponatremia, hepatitis, pancreatitis, bowel obstruction, GI bleeding, and surgery. Common medications that can trigger vomiting include antineoplastics, anesthetics, antibiotics, contrast media, and opiates. This section’s focus, and on which the majority of research has focused, considers chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). Before moving on to these topics specifically, the mechanism mediating nausea and vomiting will be explored.

Pathophysiology

The vomiting center or emetic center or “central pattern generator,” located in the medulla oblongata, is a collection of neurons that may trigger vomiting after receiving input from the chemoreceptor trigger zone, abdominal vagal afferents or cerebral cortex.^1,⁵^–⁷ The chemoreceptor trigger zone, located in the area postrema region near the fourth ventricle, is not fully protected by the blood-brain barrier; and is therefore vulnerable to antineoplastic agents, or other stimuli in the blood or cerebral spinal fluid.⁵^–⁷ The vagus nerve provides important stimuli to both the chemoreceptor trigger zone and vomiting center, and appears to have the largest role in CINV.^5,⁷ This occurs when cells within the GI tract are exposed to chemotherapy and release mediators, including 5-hydroxytryptamine (5-HT), substance P, and cholecystokinin, that stimulate the vagus nerve.^5,⁷ Finally, the role of the cerebral cortex is less well defined, but is thought to play a role in anticipatory nausea and vomiting.¹

The mechanism described is most dependent upon the neurotransmitter receptors for dopamine, serotonin (5-hydroxytryptamine type 3), and substance P.^1,⁵^–⁷ Additional receptors that are thought to play a supporting role include corticosteroid, histamine, cannabinoid, acetylcholine, opiate, neurokinin-1, and gamma-aminobutyric acid.^1,^6,⁸ The intricate cascade briefly described here and multiple neurotransmitter involvement, foreshadow treatment guidelines that will often be rooted in multiple agents that target various pathways.

Chemotherapy-Induced Nausea and Vomiting: Types of Emesis

Emesis that occurs from chemotherapy is divided into three distinct categories. Anticipatory CINV occurs before chemotherapy administration and occurs as a conditioned response in patients that have had significant past CINV. Acute CINV occurs within 24 hours of chemotherapy administration and is the most widely studied. Delayed nausea and vomiting occur after 24 hours and may persist for 7 days. Pediatric patients that have well-controlled acute nausea and vomiting are less likely to have delayed nausea and vomiting.⁸ This highlights the importance of “staying ahead” of symptoms with prophylactic treatment.

Treatment Guidelines

The advent of 5-HT₃ receptor antagonists in the early 1990s provided a new cornerstone in how acute nausea and vomiting is managed in patients receiving highly or moderately emetogenic chemotherapy. The first-generation 5-HT₃ receptor antagonists of dolasetron, granisetron, and ondansetron have been established in pediatrics to be equally effective, and equally toxic, with the most common side effects including headache, constipation, and dizziness.^3,⁹^–¹³ It should be noted that the approved pediatric dose of granisetron of 10 ug/kg once daily is likely ineffective, and a dose of 40 ug/kg once daily is more appropriate.^3,^13,^14,²⁰ The 5-HT₃ receptor antagonists have been established, at the appropriate doses, to be as effective when given orally as when given intravenously, and that single daily dose schedules are as effective as multiple-dose schedules.¹⁵^–²⁰ These agents are most useful for CINV occurring within the first 24 hours after administration of chemotherapy.²¹

In 2003, what may be considered a “second-generation” 5-HT₃ receptor antagonist, palonosetron, gained Food and Drug Administration approval for both acute and delayed CINV. It is unique from other 5-HT₃ antagonists because of its long half-life (21 to 37 hours in children and 40 hours in adults) and greater affinity for 5-HT₃ receptors.^14,²² Three phase III trials have established palonosetron as not inferior to older 5-HT₃ antagonists.²³^–²⁵ A trial comparing palonosetron with ondansetron in pediatric patients found a significant reduction in emesis on the first 3 days after treatment, and in nausea intensity the first 4 days after treatment favoring the palonosetron group.²⁶ Further prospective study is needed before palonosetron can be established as superior to other 5-HT₃ receptor antagonists. To date, CINV guidelines have not stated any one 5-HT₃ receptor antagonist to be superior to another.²⁰

Corticosteroids, most commonly dexamethasone or methylprednisolone, are potent antiemetics and have a critical role in managing acute and delayed CINV in pediatrics. Their exact mechanism of action is unclear, but may involve decreasing 5-HT₃ release in the periphery.²⁷ However, corticosteroids also have the potential to decrease the effect of antineoplastic drugs on brain tumors, osteosarcomas and carcinomas.²⁷ Dexamethasone may augment the ability of a number of carcinomas to resist both radiation and chemotherapy.³ Interferon or interleukin-2 may be less effective when used along with steroids.¹ Corticosteroids may also impact the quality of brain tumor images generated by computed tomography or magnetic resonance imaging by altering the distribution of contrast media.³ In addition to these concerns, the usual side effects of steroids must be kept in mind, including: hyperglycemia, hypokalemia, anxiety, euphoria, and insomnia. It would be prudent to consult a patient’s chemotherapy protocol or an oncologist before initiating corticosteroids in a pediatric patient with a malignancy to verify the appropriateness of this approach.

The neurokinin-1 receptor antagonist is the most recent antiemetic class. These are effective for both acute and delayed nausea and vomiting in moderately and highly emetogenic chemotherapy. Such agents are approved in CINV only when used in conjunction with a 5-HT₃ antagonist and a corticosteroid. Currently the only medications that represent this class on the market are oral aprepitant and intravenous fosaprepitant. They are generally well tolerated with diarrhea, fatigue, headache, and hiccups being common side effects.²⁸^–³⁰ Both aprepitant and fosaprepitant are substrates, inhibitors and inducers of the cytochrome P450 enzymes 3A4 and 2C9.¹⁴ A thorough review of potential interactions for individual patients is merited. Most notable of these cytochrome interactions are: The effect of Coumadin (brand name form of the generic warfarin) on coagulation pathway (altered prothrombin time, International Normalized Ratio) may be reduced, the concentration of corticosteroids will be increased with a dose reduction needed when used for CINV with aprepitant, and a backup contraception method should be used for patients taking oral contraceptives.³⁰ This class of medication does not have approval for patients younger than 18 years, nor are suggested dose modifications available.¹⁴ One study examined aprepitant dosed for young adults in patients ages 11 to 19 years weighing 43 to 105 kg.³¹ Aprepitant containing regimens performed comparably to non-aprepitant-containing regimens, but an increase in the number of cases of febrile neutropenia was noted in the aprepitant patients.³¹ Further prospective study is necessary before neutrokinin-1 receptor antagonists are prescribed in pediatric patients.

Other agents commonly seen in pediatrics for CINV include benzodiazepines, most often lorazepam, which is routinely employed for anticipatory nausea and vomiting at a dose of 0.04 to 0.08 mg/kg/dose (maximum dose, 4 mg).¹⁴ Diphenhydramine is anecdotally used in pediatric patients despite its absence from guidelines and reviews of CINV.^3,²⁰ Dopamine receptor antagonists, including phenothiazines (e.g., prochlorperazine), butyrophenones (e.g., droperidol), and benzamides (e.g., metoclopramide), cause a high incidence of dystonic reactions when used at high doses for several days and potentially oculogyric crisis.^20,³² Cannabinoids (i.e., dronabinol) are limited by their lack of pediatric data, and their side effects, which include euphoria, sedation, depression, and hallucinations.¹⁴ A scopolamine patch may have some utility in patients older than 12 years that are able to wait up to 12 hours for relief.³ Generally speaking, these agents should only be considered for pediatric patients who do not tolerate first-line therapy alone.

Determining appropriate antiemetic therapy requires one to first evaluate the likelihood that a particular chemotherapy regimen will produce nausea or vomiting.^20,³³^–³⁵ This has been accomplished with literature and expert opinion and is summarized in Table 87-1, with subsequent dosing information provided in Table 87-2.^14,^20,³³^–⁴⁰ This categorization is largely based on adult data, so it is vital to take individual patient parameters and CINV history into account. If a chemotherapy regimen is close to the next highest emetic risk category, it is better to be aggressive with antiemetic management.

Table 87–1 Antiemetic Selection for Chemotherapy Based on Emetogenicity of Frequently Encountered Single-Day Pediatric Chemotherapy

Emetic Risk (Incidence of Emesis with no Prophylaxis)	Antineoplastic Agent^∗	Recommended Antiemetic
High (>90%)	Cisplatin Cyclophosphamide >1.5 g/m² Dactinomycin Methotrexate >5 g/m²

Children: day 1: 5-HT₃ antagonist + dexamethasone

Adults:

Day 1: 5-HT₃ antagonist + dexamethasone + NK-1 antagonist

Day 2, 3: dexamethasone + NK-1 antagonist

Day 4: dexamethasone

Moderate (30%-90%)

Carboplatin

Cyclophosphamide <1.5 g/m² or oral

Children: day 1: 5-HT₃ antagonist + dexamethasone

Adults:

For anthracycline and cyclophosphamide combination:

Day 1: 5-HT₃ antagonist + dexamethasone + NK-1 antagonist

Day 2, 3: NK-1 antagonist (dexamethasone if NK-1 antagonist contraindicated)

All other regimens:

Day 1: 5-HT₃ antagonist + dexamethasone

Day 2, 3: dexamethasone or 5-HT₃ antagonist

Low (10%-30%)

Methotrexate >100 to <1000 mg/m²

Topotecan

Children: day 1: 5-HT₃ antagonist or dexamethasone

Adults: day 1: dexamethasone

Minimal (<10%)

6-Thioguanine (oral)

Hydroxyurea (oral)

Methotrexate <100 mg/m² or oral

Rituximab

Vinblastine

Vincristine

Children and adults: 5-HT₃ antagonist or dexamethasone only if needed

5-HT₃, 5-Hydroxytryptamine-3; NK-1, neurokinin-1.

∗ Table focuses on more common pediatric chemotherapy (see references 20 and 33 through 38 for complete list). Medication is parental unless otherwise stated.

Table 87–2 Antiemetic Dosing in Chemotherapy-Induced and Postoperative Nausea and Vomiting ^14,^36,^39,⁴⁰

Table 87-1 includes aprepitant and dexamethasone that may be contraindicated for multiple reasons in children as discussed previously. In such patients, medications that are less-well supported for delayed CINV, such as diphenhydramine or 5HT₃ receptor antagonists, may be employed based on individual practitioner preference. Other areas of future research include breakthrough emesis that occurs despite adequate prophylaxis in a single cycle, and refractory emesis that occurs despite adequate prophylaxis over multiple cycles.⁸ Additional areas that require further investigation in pediatric CINV include multiple-day chemotherapy, high-dose chemotherapy with stem cell rescue, and intractable symptoms in terminal patients.⁴¹^–⁴³ Finally, each institution would be well advised to conduct a pharmacoeconomic review to aid in antiemetic selection of pharmacologically equivalent products.

Postoperative Nausea and Vomiting

Assessing the risk of the pediatric surgical candidate is the first step in determining PONV prophylaxis. Strabismus repair, tonsillectomy, hernia repair, orchiopexy, penile surgery, or any procedure where anesthesia time is 30 minutes or longer have an increased likelihood of PONV.^4,^40,⁴⁴ Children aged 3 years and older continue to increase their risk of PONV until they become pubescent.^40,⁴⁴ Patients who have a history of PONV, motion sickness, or patients with first-degree relatives with such histories are more prone to have PONV.^40,⁴⁴ Prophylaxis is recommended only for children thought to be at moderate or high risk of PONV.⁴ Regional anesthesia is optimal in such patients.⁴ However, if general anesthesia is necessary, the following may reduce the risk of PONV: using intraoperative supplemental oxygen, adequate hydration, minimizing opioid or neostigmine exposure, and avoiding nitrous oxide or volatile anesthetics when possible.⁴⁰

Individual institutions should determine which patients are at moderate or high risk. These patients should receive a combination of two or three agents with distinct mechanisms of action for PONV prophylaxis.^4,⁴⁰ A 5HT₃ receptor antagonist and dexamethasone combination is a reasonable first choice.⁴ Other options include dimenhydrinate, perphenazine, or droperidol.^4,^40,⁴⁴ Because of potential for QT prolongation and torsades des pointes, droperidol should be reserved for patients who have failed first-line therapy and are hospital inpatients.⁴ Droperidol should be dosed once for prophylaxis at 0.05 mg/kg (maximum, 1.25 mg), or at 0.01 to 0.03 mg/kg/dose for PONV treatment.^14,⁴⁰ Finally, NK-1 receptor antagonists have been established as potent agents for PONV in adult patients, but even if approved in pediatrics it seems likely a multiple agent approach to PONV as described above will remain the standard of care.⁴⁵^–⁴⁸

Diarrhea

Introduction and Definition

It is estimated that in the United States, diarrhea-based illnesses result in approximately 200,000 hospital admissions and 400 deaths per year.⁴⁹ The majority of acute diarrhea episodes stem from infections to the GI tract and it is estimated that 20% to 40% of children treated with broad-spectrum antibiotics will develop diarrhea.^50,⁵¹ Infectious causes include viruses (e.g., Rotavirus), bacteria (e.g., Escherichia coli, Shigella, Clostridium difficile), and parasites (e.g., Cryptosporidium parvum, Giardia lamblia). Noninfectious causes include appendicitis, intussusception, food allergies, irritable bowel syndrome, and ulcerative colitis. Diarrhea may be defined for practical purposes as a decrease in stool consistency, along with an increase in frequency to more than three bowel movements in 24 hours.⁴⁹ After diarrhea is identified, rehydration is paramount. Identifying the underlying cause will guide specific treatment.

Treatment

If C. difficile is identified, any potentially contributing broad-spectrum antibiotics should be discontinued, or streamlined to more a specific agent if possible. Oral metronidazole for 10 days is first line therapy in mild to moderate disease.^51,⁵² Cases that require protracted courses of metronidazole should include monitoring for peripheral neuropathy. Oral vancomycin should be considered for patients with severe symptoms, intolerance to metronidazole, or metronidazole failure.⁵¹^–⁵³ Indeed, there is growing evidence in the adult population of superior outcomes when vancomycin is used first line for severe disease.^52,⁵³ Probiotics, bile-acid sequestrants, intravenous immunoglobulin, or tapering doses of vancomycin may be considered for recurrent cases. The impact of C. difficile can be minimized with prevention that includes good hand hygiene, infection control, and appropriate antibiotic usage. It would be prudent to limit acid suppressing agents (e.g., proton pump inhibitors, histamine H₂ antagonists) to legitimate indications, as a positive association has been identified in adult populations between acid suppression and C. difficile disease.^54,⁵⁵

Probiotics are widely defined as live microorganisms that offer health benefits. These agents have been studied in pediatric patients in terms of potential reduction in antibiotic-associated diarrhea. One meta-analysis found that for every seven pediatric patients administered probiotics, one fewer would develop antibiotic-associated diarrhea. Positive risk reduction was identified, in decreasing strength, for those treated with Lactobacillus GG, Saccharomyces boulardii, and the combination of Bifidobacterium lactis and Streptococcus thermophilus.⁵⁶ Significant reductions were not found with L. acidophilus/Bifidobacterium infantis or L. acidophilus/L. bulgaricus.⁵⁶ A second meta-analysis reviewing Lactobacillus GG, L. sporogenes, and Saccharomyces boulardii found a significant decrease in antibiotic-associated diarrhea but nonsignificant overall results in intent-to-treat analysis.⁵⁷ Such agents require further study from an efficacy and pharmacoeconomic standpoint before they become the standard of care. If these agents are used, sufficient live organism content should be verified. These agents should be used cautiously, if at all, in premature infants and in patients with any of the following: short bowel syndrome, central catheters, cardiac valve disease, and immune compromise.^58,⁵⁹

Other important treatments for diarrhea include the antimotility agents loperamide and diphenoxylate. Both inhibit excessive GI peristalsis and increase GI transit time.¹⁴ Neither medication should be used in diarrhea resulting from pseudomembranous enterocolitis or any infectious cause, because it is critical that toxins produced are cleared from the GI tract.^14,⁴⁹ Underlying electrolyte imbalances and dehydration should be addressed before these antimotility agents are initiated, because the potential exists that intestinal fluid retention may exacerbate such underlying conditions. Side effects to be mindful of include: sedation, confusion, ileus, and respiratory depression (with younger children at increased risk).¹⁴

Constipation

Introduction and Definition

Constipation is defined as a reduction in the number of bowel movements. This number varies significantly based on the infant or child’s age and breastfeeding status with exclusively breast-fed infants having an increased frequency of bowel movements.^60,⁶¹ The differential diagnosis underlying constipation in a pediatric intensive care unit is extensive and includes: anatomical (e.g., anal stricture, rectal abscess), metabolic (e.g., hypothyroidism, cystic fibrosis), neurologic (e.g., Hirschsprung disease, cerebral palsy), and connective tissue disorder (e.g., systemic lupus erythematosus).⁶¹ Medications such as opiates, phenobarbital, antacids, antihypertensives, anticholinergics, and antidepressants, and lead may all contribute to a child’s constipation.⁶¹

Treatment

Any underlying disease state or anatomical anomaly should be managed individually. If medication related, the offending agent should be discontinued if possible; or the minimal effective dose should be targeted. Constipation itself is addressed as a two-step process of disimpaction lasting 3 to 5 days, followed by maintenance. The duration of the latter stage is determined by symptom recurrence when treatment is withdrawn.^60,⁶²

Disimpaction may be accomplished with oral or rectal medication administration. The oral route is less invasive and may give a sense of empowerment to the child, but the rectal route is quicker and may be necessary if the child has abdominal pain. Oral options include mineral oil, oral electrolyte solutions, lactulose, sorbitol, magnesium hydroxide, magnesium citrate, senna, and bisacodyl. Mineral oil may result in lipoid pneumonia if aspirated and is not recommended in children younger than 1 year or any patient on aspiration precautions. Options for rectal disimpaction include phosphate soda, saline, or mineral oil enemas followed by a phosphate enema. Also effective are glycerin suppositories in infants, and bisacodyl suppositories in older children. Soapsuds, tap water, and magnesium enemas are discouraged because of their potential toxicity.⁶⁰ Enemas are to be avoided in children younger than 3 years and in young children with severe neurologic deficiencies as they are more likely to be retained with subsequent resulting toxicities.⁶²

Maintenance therapy with polyethylene glycol 3350 without electrolytes (MiraLax) has demonstrated superior palatability in children, and although not yet recommended by guidelines in infants, there is growing evidence of its safe use in this population.^60,⁶² Other maintenance therapies include mineral oil, magnesium hydroxide, lactulose, and sorbitol. Bisacodyl or senna may be necessary as a stimulant laxative as rescue therapy, but should be avoided for extended use.⁶⁰

Gastroesophageal Reflux Disease

Treatment of gastroesophageal reflux disease (GERD) should alleviate symptoms and prevent or heal esophageal damage. Although researchers conducting multiple pediatric studies have used varying doses, multiple drug therapies, and non-pharmacologic therapies, guidelines do exist for the treatment of GERD in infants and children.⁶³ Many patients who may be admitted to the intensive care unit for other conditions are likely to have preexisting gastroesophageal reflux conditions and corresponding surgical and pharmacologic therapies. These populations include patients with reactive airway disease, recurrent pneumonia, neurologic impairment, premature infants, and genetic syndromes including Down syndrome.

Histamine-2 Receptor Antagonists

Histamine-2 (H₂) receptor antagonists inhibit gastric acid secretion by means of competitive inhibition of H₂ receptors of the gastric parietal cells. H₂ receptor antagonists are generally well tolerated. Common adverse effects include nausea and headache. Although thrombocytopenia may occur, it is often difficult to determine the sole cause in critically ill patients. Ranitidine should be avoided in patients with acute porphyria. Tachyphylaxis is well documented for intravenous and oral H₂ receptor blockers in adult and pediatric populations. Infants may suffer from irritability, headache, and somnolence, which when mistaken for GERD symptoms, may lead to an unwarranted increase in dose.⁶³ All of the currently available H₂ receptor blockers require dosage adjustment for renal impairment. Although fewer pediatric studies exist for ranitidine and famotidine, these agents are frequently used and may be preferred over cimetidine because of fewer drug interactions and central nervous system adverse effects. Availability of both oral and intravenous formulations allow for easy continuation of therapy when patients are admitted to the intensive care unit.

Proton Pump Inhibitors

By covalently bonding to the hydrogen-potassium-adenosine triphosphatase (ATP) of parietal cells, proton pump inhibitors (PPIs) suppress gastric acid secretion for the life of the parietal cell. Ideally, therapy should be given 30 minutes before feeding so that peak plasma concentrations coincide with parietal cell stimulation. Administration with food reduces bioavailability by fifty percent. Although their serum half-lives are relatively short; the pharmacological effect persists until new parietal cells are generated.⁶⁴ Omeprazole, esomeprazole, and lansoprazole have been approved for use in pediatrics. Extemporaneously compounded suspensions of omeprazole and lansoprazole are frequently used, even in patients with various types of feeding tubes. Intravenous lansoprazole is no longer available. Neither intravenous pantoprazole nor esomeprazole is Food and Drug Administration (FDA)–approved for use in pediatric patients. Until sufficient pediatric dosing information becomes available, intravenous PPIs are likely to be reserved for patients with active GI bleeding or contraindication to alternative therapies. Although PPIs are generally thought of as well tolerated, both long- and short-term adverse effects are gaining more attention. Reactions include idiosyncratic reactions, drug-drug interactions, drug-induced hypergastrinemia, and drug-induced hypochlorhydria.⁶³ The most common side effects are headache, diarrhea, constipation, and nausea.¹⁴ Case reports of biopsy proven interstitial nephritis associated with PPI use have emerged. Thus far no pediatric cases have been reported.⁶³ The FDA and Health Canada are currently investigating potential links between PPIs and decreased effectiveness of clopidogrel. Although the data are primarily from adult reports, the potential interaction may be relevant in pediatrics as well. PPIs should not be discontinued abruptly because a hypersecretory phase results.^63,⁶⁵ Acid suppression, whether from H₂ receptor antagonists or PPIs, may increase the rates of community-acquired pneumonia, gastroenteritis, candidemia, and necrotizing enterocolitis.^63,⁶⁶^–⁶⁸

Antacids

Both aluminum hydroxide and magnesium hydroxide are effective treatments of GERD. In infants, however, aluminum hydroxide formulations can increase plasma levels of aluminum to those reported to cause osteopenia, microcytic anemia, and neurotoxicity. Aluminum-based antacids should be avoided in patients with renal impairment. Efficacy of calcium carbonate antacids has not been demonstrated in pediatric patients. Depending on the antacid formulation chosen, adverse effects may include electrolyte disturbances, nausea, flatulence, diarrhea, or constipation. Because alternative therapies are available and generally well tolerated, antacids should be reserved for intermittent symptom management rather than chronic treatment of GERD.⁶³

Surface Agents

Sucralfate, an aluminum salt of sulfated sucrose, forms a protective barrier by binding to damaged mucosa in an acidic environment. Although it has demonstrated effectiveness in the treatment of esophagitis, it is not recommended for long-term treatment of GERD in children because of a lack of efficacy data and safety concerns associated with aluminum toxicity.⁶³

Prokinetic Therapy

Prokinetic agents are of interest in GERD because of their ability to enhance esophageal peristalsis and accelerate gastric emptying. Cisapride is a prokinetic agent that at one time was widely used not only for GERD, but also for a variety of adult and pediatric motility disorders, including constipation and gastroparesis. It was prescribed more frequently than metoclopramide in children most likely because of its broader range of action and decreased risk of neurological side effects. Prolongation of the QTc interval with potential life-threatening ventricular arrhythmias was reported when cisapride was used concomitantly with drugs that inhibit the hepatic cytochrome P450-3A4 system. This uncommon, yet potentially fatal, adverse effect led the manufacturer to place it under a limited access protocol requiring close supervision by a pediatric gastroenterologist.

Erythromycin is a macrolide antibiotic and motilin agonist. It increases motility in the proximal GI tract. The most frequent adverse effects include abdominal cramping, nausea, vomiting, diarrhea, cardiac dysrhythmias with interacting medications, and risk of bacterial overgrowth. Metoclopramide promotes gastric emptying by acting as an antagonist to the inhibitory actions of dopamine in the gut. It also sensitizes the gut to acetylcholine and increases lower esophageal sphincter tone.⁶⁹ Metoclopramide blocks dopamine receptors in the chemoreceptor trigger zone and accelerates gastric emptying and intestinal transit time without stimulating gastric, biliary, or pancreatic secretions.¹⁴ Adverse effects are common; are dose dependent; and can include extrapyramidal effects, seizures, and Parkinsonian reactions, which may be irreversible.^14,⁶³ The FDA required the addition of a boxed warning to metoclopramide drug labels regarding the risks of long-term or high-dose use. Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body, even after drug discontinuation. It is noted that these adverse effects are more prevalent in elderly populations.⁷⁰ Extrapyramidal reactions in children and younger adults are more likely after intravenous administration of high doses, particularly within 24 to 48 hours after starting therapy.¹⁴ Prescribers are urged to carefully consider legitimate indications for initiating drug therapy. Current GERD guidelines recommend against use of prokinetic agents.

Gastroesophageal Reflux Disease and Acute Life-Threatening Event

An acute life-threatening event (ALTE) is an episode of combined apnea, color change (cyanosis, pallor, plethora), abnormal muscle tone (limpness and stiffness), choking, and gagging that requires intervention. Some patients have succumbed to sudden infant death syndrome who have had a history of ALTE with documented GER. This combination is rare and assigning the timing and causality of the event is extremely difficult. Neither pharmacotherapy nor surgical intervention has been adequately studied in secondary prevention of ALTE. Those patients who may benefit from pharmacologic intervention may include those whose ALTEs were obviously associated with vomiting, regurgitation, or obstructive apnea.⁶³

Stress-Induced Mucosal Damage: Ulcer Prophylaxis

Prospective studies reveal similar incidence of GI hemorrhage between adult and pediatric intensive care units. Of 1006 patients admitted to a pediatric intensive care unit, 10.2% had upper GI hemorrhage; however, only 1.6% of the admissions were viewed as clinically significant. Respiratory failure, coagulopathy, and a Pediatric Risk of Mortality score greater than or equal to 10 were identified as independent risk factors for GI hemorrhage.^71,⁷² Other studies also identified pneumonia, multitrauma, a surgical operation longer than 3 hours, and circulatory shock in patients as high-risk factors.^73,⁷⁴ One subsequent pediatric study demonstrated mechanical ventilation as the only statistically significant risk factor for clinically significant bleeds after multivariate analysis.⁷⁵ Children ventilated for greater than 48 hours were at additional risk of hemorrhage if thrombocytopenia, coagulopathy, organ failure, high pressure ventilator settings (>25 cm H₂O), or Pediatric Risk of Mortality score greater than 10 were present.⁷⁶ Mechanical ventilation and coagulopathy are recognized as independent risk factors in adult patients.⁷² Because of the low incidence of clinically significant hemorrhage, prophylaxis may only be warranted in those patients with risk factors.⁷⁷

Sucralfate, H₂ receptor antagonists, antacids, and PPIs have been used for prophylaxis of stress-induced mucosal damage in pediatric critical care patients. Individual trials including comparative studies and case series have shown each agent to be effective. With the low incidence of clinically significant bleeds, studies intending to demonstrate superiority of one drug class or agent over another would require an extremely large sample size. Therefore pediatric studies use a surrogate endpoint of gastric pH 4 or greater to evaluate efficacy of various dosing regimens.⁷⁸^–⁸⁰

One study included 165 patients treated with ranitidine, antacid, sucralfate, or placebo. There were no differences among the treatment groups and all treatment groups had a lower incidence of bleeding than the placebo group.⁸¹ Another study compared ranitidine, omeprazole, sucralfate, or placebo for stress ulcer prophylaxis and also compared adverse events. No differences were found among groups with regard to macroscopic stress ulcer bleeding, mortality, or ventilator-associated pneumonia.⁸² Because multiple agents appear to be effective for stress ulcer prophylaxis, selecting an appropriate agent may be patient specific. However, when prescribing prophylaxis to adult patients, the inadequacy of sucralfate it is widely recognized after the landmark trial by Cook et al.⁸³ published in 1998 that demonstrated significantly lower rates of clinically relevant bleeding in the ranitidine treatment group. In addition there was no significant difference in pneumonia rates in this 1200-patient trial. Critical care patients do present challenges with regard to drug administration for antacids and sucralfate. Both agents require multiple doses per day, lack intravenous formulations, and may chelate or inhibit absorption of other drugs. In addition, aluminum toxicity may be of greater concern in critical care patients because of the potential for renal impairment. H₂ receptor antagonists are commonly used because of the availability of intravenous formulations. Adverse effects of the central nervous system, particularly in patients with renal impairment who have not been dose adjusted; thrombocytopenia; and drug interactions remain a concern. Most of these adverse events, however, can be prevented or at least monitored for early detection. PPIs may also be used orally, intravenously, or off-label through feeding tubes.

Stress ulcer prophylaxis is recommended, along with other supportive therapies, for acute lung injury and acute respiratory distress syndrome in children.⁸⁴ Stress ulcer prophylaxis is also recommended as supportive care for patients with sepsis in the 2008 Surviving Sepsis Campaign. H₂ receptor antagonists use was recommended with a stronger level of evidence than PPIs.⁸⁵ Some experts believe that although greater acid suppression is achieved with PPIs over H₂ receptor antagonists, PPIs should be used as second-line agents for stress ulcer prophylaxis because of the greater association with adverse effects such as community-acquired pneumonia, ventilator acquired pneumonia, and C. difficile infection.⁸⁶

Gastrointestinal Hemorrhage

Clinical guidelines for treatment of nonvariceal upper GI bleeding in adults include recommendations for pharmacotherapy.⁸⁷ Unfortunately, this body of evidence does not exist in the pediatric population. H₂ receptor antagonist use is discouraged as primary treatment for patients with acute bleeding. Although octreotide and somatostatin are more effective than H₂ receptor antagonists, these agents are also not recommended for routine management. PPIs are cited as the drugs of choice for treatment of acute nonvariceal upper GI bleeding.⁸⁷ High-dose intravenous proton pump inhibitor therapy (80 mg pantoprazole bolus followed by 8 mg/hr for 72 hours after endoscopic therapy³⁹) is preferred over H₂ receptor antagonists alone, or in combination with octreotide, to prevent rebleeding in adult patients. As more data become available regarding the use of intravenous proton pump inhibitors in pediatric patients, parallels may be seen between the treatments of adult and pediatric nonvariceal upper GI bleeding.

Proton Pump Inhibitors

Multiple oral proton pump inhibitors are approved for pediatric use. Pantoprazole and esomeprazole are available intravenously in the United States; however, neither product’s intravenous formulation has been well studied in children. Doses have been extrapolated from the adult high-dose intravenous pantoprazole recommendations for use in clinical practice in pediatric patients with nonvariceal upper GI bleeding. Although it is not yet specified in the literature, many pediatric sites reportedly use a pantoprazole loading dose of 2 mg/kg IV, followed by 0.2 mg/kg/hr for 72 hours (neither the loading dose nor continuous infusion should exceed the adult dose).

Octreotide and Somatostatin

Octreotide is a somatostatin analogue. Its pharmacologic actions include inhibition of gastric acid secretion and decreased splanchnic blood flow. Although its 1.7-hour half-life is approximately 30 times longer than that of somatostatin, octreotide is usually administered through continuous infusion for GI hemorrhage. Adverse effects include abdominal pain, sinus bradycardia, nausea, pain at the site of injection, elevation of liver enzymes, chest pain, emesis, headache, dizziness, fatigue, flushing, and diarrhea. Long-term use (longer than 1 month) has been associated with changes in thyroid function, gallstone formation, and cholecystitis.⁸⁸

In adults, octreotide has been shown to decrease the duration of hemorrhage and prevent recurrence of peptic disease more so than cimetidine or ranitidine. A Cochrane Review cited improved initial hemostasis and decreased transfusion requirements; however, no change was evident in rebleeding or secondary outcomes when octreotide was used to treat variceal bleeding.⁸⁸ Few researchers have evaluated octreotide for GI hemorrhage in children. In one study, continuous infusion of octreotide in seven patients was evaluated. Bleeding ceased in six of the seven patients. The duration of infusion ranged from 24 to 234 hours. Although bleeding stopped within 24 hours in nearly half of the patients, on average, bleeding stopped after 40 hours. The most notable adverse effect was hyperglycemia.⁸⁹ Subcutaneous octreotide has also been used for severe chronic GI hemorrhage for periods of 24 to 50 months.⁹⁰

Vasopressin

Generally vasopressin has been used for treatment of variceal bleeding more frequently than for nonvariceal upper GI bleeding. In fact, adult guidelines do not address the use of vasopressin for non-variceal bleeding.⁸⁷ Vasopressin acts by mechanisms similar to octreotide; however, its effects on blood pressure make it a less desirable option in many patients.⁹¹ From a medication safety perspective, vasopressin prescribing can be confusing given the wide range of accepted dosing conventions and variety of indications in pediatric patients (e.g., diabetes insipidus, GI hemorrhage, shock). Dosing recommendations that require units per kg per unit time require careful decimal place checks. Intensive care units should decide on the accepted dosing convention and dose range for vasopressin for each indication and use infusion pumps with safety software that can accommodate the predetermined limits to prevent 10-fold dosing errors.

Helicobacter Pylori Infection

Patients who have GI bleeding of unknown etiology should be tested for Helicobacter pylori. At minimum, therapy requires three different medications administered twice daily for 1 to 2 weeks. Three different regimens are recommended for first-line treatment in pediatrics. Each consists of a proton pump inhibitor in combination with amoxicillin and clarithromycin, amoxicillin and metronidazole, or metronidazole and clarithromycin. Second-line options incorporate bismuth subsalicylate or ranitidine, and tetracycline as one of the antibiotic choices.⁹² Tetracycline is contraindicated in patients younger than 8 years because of permanent discoloration of teeth, enamel hypoplasia, and retardation of skeletal development and bone growth.¹⁴ Noncompliance with H. pylori regimens is the most commonly cited reason for treatment failure.⁹² Pediatric H. pylori treatment guidelines are currently under revision.⁹³

Drug-Induced Liver Injury

Cause

Liver injury in children may result from autoimmune disease, metabolic disease, infectious causes, acute hepatitis, ischemia, irradiation damage, and exposure to toxins or medications.^94,⁹⁵ Drug-induced liver injury (DILI) has been noted to account for more than 50% of cases of acute liver failure in adults and approximately 20% in children, with acetaminophen as the agent most cited in the United States.^96,⁹⁷ Most cases of DILI in children are mild, and many correct after the offending medication is discontinued.⁹⁷ However, some still progress to chronic liver injury.^98,⁹⁹ Diagnosis of DILI is largely a diagnosis of exclusion. DILI patients typically present within 12 months of starting the suspected medication.⁹⁸ The Pediatric Acute Liver Failure (PALF) Study Group, a multinational, multisite consortium, was formed to prospectively study acute liver failure in children from birth through 18 years of age.^94,⁹⁷ The 24 sites in the PALF study group hope to improve understanding of the pathogenesis, treatment, and outcomes of acute liver failure in children.⁹⁵ The PALF study group found that of the first 348 children enrolled through 2005, 14% had acute liver failure caused by acetaminophen, 5% caused by a drug or toxin other than acetaminophen, 10% caused by metabolic disease, 6% caused by autoimmune liver disease, 5% was idiosyncratic DILI, and 49% of unknown cause.^95,^97,⁹⁸ Younger children were more likely to develop ascites, require ventilator support, and require red blood cell and plasma infusions than older children.⁹⁵

Various clinical scoring systems, including the Roussel Uclaf Causality Assessment Method (RUCAM) and the Naranjo Probability Scale, have been developed as a means to increase the specificity of diagnosis of drug hepatotoxicity. These scales consider the postexposure interval, biochemical pattern, exclusion of alternative causes, extrahepatic manifestations, rechallenge attempts, and previously reported cases. Their routine use has been limited in pediatrics and is not routinely recommended.⁹⁷ Table 87-3 summarizes the pharmacologic agents most cited as causing DILI in adult and pediatric patients. The corresponding references provide a more thorough discussion of the individual agents and/or case reports.

Table 87–3 Common Agents Cited in Drug-Induced Liver Injury ^94,^{96–99,103,117,145–147}

Drug Class or Group	Specific Agents and Reaction	Comments
Analgesics	Acetaminophen: necrosis
	Aspirin: Reye syndrome, necrosis
	Bromfenac^∗: acute liver failure
	Celecoxib: hepatocellular
	Diclofenac: hepatitis, cholestasis
	Etodolac: fulminant hepatic failure
	Ibuprofen (rare): hepatitis, vanishing bile duct syndrome
	Indomethacin: cholestasis, necrosis
	Meloxicam: hepatitis
	Naproxen: cholestasis
	Oxaprozin: hepatocellular, hepatitis
	Piroxicam: hepatocellular, cholestasis, necrosis
	Sulindac: hepatitis, cholestasis
Cardiovascular agents	Amiodarone: steatohepatitis, acute liver failure
	Angiotensin-converting enzyme inhibitors (captopril, enalapril, fosinopril): hepatitis, cholestasis
	Angiotensin II receptor inhibitors (irbesartan, candesartan, losartan): cholestasis, hepatocellular
	β-Adrenergic receptor blockers (propranolol, metoprolol, acebutolol, atenolol, labetalol): hepatocellular, cholestasis
	Calcium channel antagonists (diltiazem, nifedipine, verapamil): hepatitis, cholestasis
	Hydralazine: hepatitis, necrosis, granulomas, cholestasis
	Labetalol: necrosis, hepatitis	Labetalol: most hepatotoxic β-blocker
	Methyldopa: hepatitis, cholestasis, steatosis, cirrhosis, granulomas
	Thiazide diuretics (hydrochlorothiazide, chlorothiazide, chlorthalidone): cholestasis
Drugs used to treat diabetes mellitus	Glucosidase inhibitors (acarbose): hepatitis, cholestasis	Thiazolidinediones: monitor baseline liver tests and every 2 months after during first year of therapy
	Human insulin: hepatitis
	Metformin: hepatitis, cholestasis
	Sulfonylureas (chlorpropamide, gliclazide, glipizide, glimepiride, tolazamide, tolbutamide): hepatitis, cholestasis, vanishing bile duct syndrome
	Thiazolidinediones (troglitazone,^∗ rosiglitazone, pioglitazone): liver failure, hepatotoxicity, fibrosis
Lipid-lowering agents	Ezetimibe: elevated serum transaminases
	Fibrates (fenofibrate, gemfibrozil, nicotinic acid): hepatitis, acute liver failure, cholestasis, necrosis
	HMG-CoA reductase inhibitors (statins) (atorvastatin, cerivastatin,^∗ fluvastatin, lovastatin, pravastatin, simvastatin): cholestasis, hepatitis, acute liver failure	Statins: monitor liver function at baseline, within 12 weeks, and then every 6 months
Anticonvulsants	Carbamazepine, oxcarbazepine: cholestasis, hepatitis, vanishing bile duct syndrome, acute liver failure
	Felbamate: hepatitis, acute liver failure (reserve use to drug-refractory epilepsy and Lennox-Gastaut syndrome)	Felbamate: discontinue immediately if aminotransferase is elevated
	Lamotrigine: hepatitis
	Phenobarbital: acute hepatitis, cholestasis
	Phenytoin: hepatitis (rare), cholestasis, granulomas, focal necrosis
	Topiramate: acute liver failure, hepatocellular
	Valproic acid: steatosis, necrosis, increase in aminotransferases; greatest risk in first 2 years of life; progression to liver failure most common in patients with underlying mitochondrial disorders
Psychotropic and antidepressant medications	Atomoxetine: hepatobiliary
	Chlorpromazine: cholestasis
	Clozapine: hepatocellular, fulminant hepatic failure
	Haloperidol: cholestasis
	Nefazodone: liver failure
	Olanzapine: hepatitis
	Paroxetine: hepatitis
	Pemoline: hepatitis, acute liver failure
	Prochlorperazine: cholestasis
	Risperidone: hepatocellular
	Thiazide diuretics (hydrochlorothiazide, chlorothiazide, chlorthalidone): cholestasis
	Trazodone: hepatocellular, cholestasis
	Tricyclic antidepressants (amitriptyline, imipramine): cholestasis
Chemotherapy and immunosuppressants	Azathioprine: hepatitis, hepatic veno-occlusive disease
	Busulfan: hepatic veno-occlusive disease
	Chlorambucil: cirrhosis, fibrosis, (rare)
	Cyclosporine: cholestasis
	Dacarbazine: acute hepatic failure
	Dactinomycin (in combination with radiotherapy): hepatitis
	Erlotinib: hepatitis, hepatorenal syndrome
	Fluorouracil (when given intra-arterially): hepatitis, sclerosing cholangitis
	Flutamide: cholestasis
	Gemcitabine: hepatitis
	Interleukin-2: hepatitis
	L-asparaginase, pegaspargase: liver steatosis, hepatitis, necrosis, fibrosis
	Megestrol acetate: cholestasis
	Mercaptopurine, azathioprine: hepatitis, cholangitis
	Methotrexate: cirrhosis, fibrosis, steatosis
	Natalizumab: hyperbili
	Nitrosoureas (carmustine, lomustine, streptozotocin): hepatitis, hepatic veno-occlusive disease
	Paclitaxel, docetaxel: hepatitis
	Plicamycin: hepatitis, necrosis	Plicamycin: most hepatotoxic chemotherapy agent commercially available
	Recombinant α-interferon: hepatitis
	Tamoxifen: cholestasis
	Thioguanine: hepatic veno-occlusive disease
Anesthetics	Halothane: hepatitis, necrosis
Anti-infectives	ANTIBIOTICS
	Amoxicillin and amoxicillin/clavulanic acid: cholestasis, hepatitis
	Oxacillin, cloxacillin, dicloxacillin, flucloxacillin: cholestasis
	Erythromycin: cholestasis, necrosis, hepatitis
	Tetracycline, minocycline: microvesicular steatosis, hepatitis
	FLUOROQUINOLONES
	Ciprofloxacin, ofloxacin, levofloxacin, norfloxacin: hepatitis
	Rifampin: hepatitis
	SULFONAMIDES
	Sulfamethoxazole and trimethoprim, sulfamethoxazole: hepatitis, cholestasis, granulomas
	Nitrofurantoin: cholestasis, granulomas, chronic hepatitis
	ANTIFUNGALS
	Fluconazole, itraconazole, ketoconazole, flucytosine, terbinafine: cholestasis, hepatitis, necrosis
	ANTIRETROVIRALS
	Nucleoside analogue reverse transcriptase inhibitors (didanosine, stavudine): hepatic steatosis and lactic acidosis
	Nevirapine: hepatitis	Nevirapine: monitor liver enzymes for first 18 weeks of therapy
	PROTEASE INHIBITORS
	Ritonavir, tipranavir: acute liver failure, hepatitis, cholestasis
	ANTITUBERCULOUS AGENTS
	Isoniazid: hepatocellular necrosis
	Pyrazinamide + rifampin or isoniazid	Rifampin + pyrazinamide combination use is discouraged by the CDC and ISDA because of severe liver injury
Miscellaneous	Allopurinol: hepatitis, fulminant hepatic failure
	Amatoxin, found in wild mushrooms: acute liver failure
	Cocaine: ischemic liver necrosis
	Designer drugs of amphetamine (ecstasy): resemble acute viral hepatitis, acute liver failure requiring transplant
	Estrogens: cholestasis
	Marijuana and hashish: alterations in liver enzymes
	Ondansetron: hepatitis
	Propylthiouracil: hepatitis
	Tolcapone: acute liver failure
	Vitamin A (dose dependent): fibrosis, portal hypertension
	Zafirlukast: hepatitis, necrosis
Herbals	Camphor: necrolytic hepatitis
	Cascara sagrada: cholestasis
	Chaparral leaf, germander: acute and chronic hepatitis, cholestasis, cirrhosis, fulminant liver failure
	Greater celandine: chronic hepatitis, cholestasis, fibrosis
	Kava kava: acute and chronic hepatitis, fulminant liver failure
	Ma huang: acute hepatitis, autoimmune hepatitis
	Mistletoe: chronic hepatitis
	Pyrrolizidine alkaloids (found in herbal and bush teas): veno-occlusive disease, dose-dependent hepatotoxicity
	Sassafras: hepatocarcinogen
	Saw palmetto: mild hepatitis
	Usnic acid (lichen alkaloid): fulminant liver failure
	Valerian: mild hepatitis

HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; CDC, Centers for Disease Control and Prevention; ISDA, Infectious Disease Society of America.

∗ Withdrawn from market.

Treatment

Various pharmacological agents may be started to manage the wide-ranging adverse effects that arise from liver failure.

Cerebral Edema and Hepatic Encephalopathy

Protein restriction to 2 to 3 g/kg/day may help lessen excessive ammonia production,¹⁰⁰ whereas fluid restriction to 75% of maintenance may prevent cerebral edema and reduce encephalopathy.¹⁰¹ Intravenous mannitol, continuous furosemide infusions, and tight glucose control have also been used for treatment of cerebral edema.¹⁰¹ Oral antibiotics, in particular neomycin, have been effective in reducing ammonia production in adults with hepatic encephalopathy by suppressing ammonia-forming bacteria in the gut.^94,¹⁰⁰ However, neomycin should be used cautiously in children because of potential renal toxicity and deafness. Synthetic disaccharides such as lactulose are metabolized by bacteria in the colon to form organic acids that lower the colonic stool pH and trap diffusible ammonia, thus decreasing serum ammonia levels. Lactulose forms the basis of therapy in children with hepatic encephalopathy and elevated serum ammonia levels, although the bulk of research surrounding its use is in adults.¹⁰⁰ Levocarnitine may offer another option for reduction of ammonia levels in the brain, whereas albumin infusions have been used to reduce plasma ammonia levels.¹⁰¹ Sodium benzoate has been used in adults with cirrhosis, and may provide an alternative option in children.^94,^101,¹⁰³

Ascites

Ascites is the accumulation of fluid in the peritoneal cavity. Although liver transplantation is the only definitive treatment for refractory ascites, many pharmacologic and nonpharmacologic options exist for acute management of ascites. Diagnostic abdominal paracentesis can help in directing therapy. Traditionally, bed rest has been recommended, however a lack of scientific evidence and difficulty enforcing in children may limit its role.¹⁰⁴ Dietary restriction of sodium, such as restriction to 1 to 2 mEq/kg/day for infants and children and 1 to 2 g/day in adolescents, may help increase diuresis.^104,¹⁰⁵ Diuretics are used to increase urinary sodium excretion, leading to a negative fluid balance and weight loss. The target negative fluid balance in children of approximately 10 ml/kg/day is often used.¹⁰⁴ Conflicting approaches to initiation of diuretics exist. Spironolactone typically is added first, with thiazide and loop diuretics (mainly furosemide in children) added if maximal doses of spironolactone are insufficient. Spironolactone acts to inhibit aldosterone at the distal renal tubule, thus inhibiting reabsorption of sodium, whereas furosemide inhibits sodium reabsorption in the ascending limb of the loop of Henle. Initial doses can be given once or twice daily, and titrated upwards as necessary.^94,^101,¹⁰⁴ Another approach is to initiate both spironolactone and furosemide upfront in a ratio of 5:2, with subsequent change to spironolactone monotherapy once a desired diuresis occurs.¹⁰⁵ Monitoring of serum electrolytes, acid base status, urine output and serum creatinine is necessary with all diuretic use, especially when using spironolactone and furosemide in combination. Potassium supplementation may be necessary. In patients with hypoalbuminemia, albumin infusion followed by furosemide may offer a brief, brisk diuresis.^101,¹⁰⁴ Fluid restriction is typically not necessary in children. In refractory ascites, other options may include large volume paracentesis, transjugular intrahepatic shunts, although unlike with adults have limited use in children, peritoneovenous shunts, and ultimately liver transplantation.¹⁰⁴ The most significant complication of ascites is spontaneous bacterial peritonitis.¹⁰⁵ E. coli and Klebsiella pneumoniae are the most common causes, hence an intravenous, third-generation cephalosporin such as cefotaxime is often used for empiric therapy as it covers 95% of the associated flora.^100,¹⁰⁵ A β-lactam and β-lactamase combination agent, such as ampicillin/sulbactam, may offer an alternative,¹⁰⁴ as well as once-daily norfloxacin in cirrhotic patients with ascites for prevention of spontaneous bacterial peritonitis.¹⁰⁵ Trimethoprim-sulfamethoxazole has been considered a therapeutic alternative to fluoroquinolones given safety concerns in pediatrics.¹⁰⁰

Coagulopathy and Hemorrhagic Complications

As both procoagulant and anticoagulant proteins are reduced in acute liver failure, clinically relevant bleeding rarely occurs. Intravenous vitamin K can be used to control coagulopathy, whereas severe cases may be treated with fresh frozen plasma and cryoprecipitate.¹⁰¹ Recombinant factor VII offers another alternative for correction of prothrombin time/INR abnormalities when active bleeding is present, although its high cost may preclude its use.⁹⁴ Prophylaxis with H₂ receptor blockers, PPIs, or sucralfate is started to prevent any GI bleeding.^94,¹⁰¹ Infection may precipitate bleeding in this population; thus initiation of antibiotics should be considered if bleeding develops.⁹⁴ The use of nonselective β-blockers in children, while successfully used in both primary and secondary prevention of variceal hemorrhage in adults with portal hypertension, is controversial. Insufficient data exist to demonstrate its use in this population; however, use may be considered as related to a risk reduction in bleeding. Both endoscopic injection sclerotherapy and endoscopic variceal ligation for variceal bleeding have been shown to be effective in treating varices in children and preventing future bleeding, thus these options are considered first-line, with beta blocker use adjunctive therapy.¹⁰⁰ For emergent treatment of variceal bleeding in children, intravenous octreotide or continuous vasopressin is often initiated in an attempt to lower splanchnic vascular tone, thus decreasing portal venous pressure.^100,¹⁰¹ However, approximately 30% of children treated with octreotide will still have a persistent hemorrhage despite conservative management and octreotide.¹⁰⁰

Pruritus

Pruritus may be a result of prolonged cholestasis or noncholestatic liver disease. Treatment of underlying cholestatic disease should improve pruritus. Cholestyramine, an anion exchange resin, is widely used.¹⁰⁶ Other agents that have been used and may offer benefit include ursodiol, opioid antagonists such as naloxone and naltrexone, rifampin, antihistamines, dexamethasone, and ondansetron.^98,¹⁰⁶ Trials have also evaluated prednisolone, cyclosporine, methotrexate, exposure to ultraviolet light, s-adenosyl methionine, antioxidants, macrolide antibiotics, and plasmapheresis with varying results.¹⁰⁶

Cholangitis

Primary care consists of fasting, adequate intravenous hydration and broad spectrum antibiotics such as a third-generation cephalosporin and/or aminoglycoside to cover gram-negative bacilli, mainly Enterobacter spp.¹⁰⁷

Miscellaneous

Acetaminophen is a widely used over the counter medication and the most common cause of DILI in children in the United States. DILI can occur after ingestion of therapeutic doses of acetaminophen over several days to treat clinical symptoms or a single overdose. Interventions for toxic acetaminophen ingestion include inhibiting drug absorption (i.e., gastric lavage), dialysis,¹⁰⁸ prevention of the conversion to the toxic intermediate metabolite N-acetyl-p-benoquin imine (i.e., through use of cimetidine), replenishment of glutathione stores to prevent hepatotoxicity, and liver transplant. Methionine, cysteamine and N-acetylcysteine (NAC) are available agents to detoxify N-acetyl-p-benoquin imine.¹⁰⁹ NAC is available either oral or intravenously in the United States and is the antidote of choice with fewer GI and central nervous system adverse effects compared with these other agents.^109,¹¹⁰

It has been proposed that NAC may be useful therapy in other types of liver failure because of its ability to enhance hepatosplanchnic perfusion, to improve oxygen supply and demand, and its presumed cytoprotective and antioxidant effects. NAC may offer benefit in this patient population; however, many unanswered questions regarding dose, duration, and timing still remain.^111,¹¹²

Dose Adjustments for Hepatic Dysfunction

Drugs absorbed via the GI tract undergo hepatic metabolism via a Phase I reaction (i.e., oxidation, reduction or hydrolysis) mediated be the CYP450 family of enzymes. These enzymes are found primarily in the liver.^96,¹⁰⁵ These reactions cause the biotransformation of the parent compound to a more polar compound, that is more readily excreted.^99,¹¹³ Many adverse drug reactions and therapeutic failures can be attributed to genetically based differences in drug metabolism and elimination. Individuals can be divided into three groups: poor metabolizers, intermediate metabolizers, and extensive metabolizers. Average doses of medications given to poor metabolizers leads to higher drug exposure and greater risks of adverse drug reactions and drug toxicity.⁹⁹ The CYP3A subfamily makes up the largest group of CYP enzymes in the liver, with CYP3A4 the most important for post natal metabolism.^103,¹¹⁴^–¹¹⁶ Consideration of the activity of the CYP450 isoenzymes, with specific focus on age differences, may aide in accurate drug dosing. For example, children require doses 50% to 100% higher than adults of drugs metabolized primarily by CYP2C9, whereas CYP3A4 activity is low at birth and reaches 72% of adult values at 1 year of age.¹¹⁵ However, age-related changes in the pharmacokinetics of various drugs may be difficult to separate from altered enzyme activity due to altered liver mass, liver blood flow, and changes in plasma drug binding.¹¹³

There are no specific diagnostic tests or pathological findings to diagnose liver dysfunction. Routine laboratory tests to assess liver function are helpful in identifying a hepatic insult; however, these findings are not specific to viral, autoimmune, metabolic disorders or drug-related causes, nor do they identify the extent that hepatic metabolism may be impaired.¹¹⁷ When hepatotoxicity is attributed to a dose-dependent hepatotoxin such as acetaminophen, blood levels of the suspected agent should be drawn.

The Child-Pugh score, adapted from the original Child score proposed in 1964, has been extensively used in adults as a user-friendly classification system for liver disease. This score is used as a prognosis of liver disease and as an indicator of a patient’s ability to metabolize drugs eliminated by the liver.¹¹⁸ However, this tool does not have the ability to predict the liver’s ability to metabolize individual drugs.¹¹⁶ Although various recent tools exist to classify liver disease, such as the Model for End-Stage Liver Disease (i.e., MELD) score widely used in adult liver transplantation ranking, the Child-Pugh score is the classic standard.^116,¹¹⁹ Patients are divided into three risk groups, based on their degree of liver dysfunction. Class A is low risk/mild disease, class B is intermediate risk/moderate disease, and class C is high risk hepatic dysfunction/severe disease (Table 87-4). Even with the wide acceptance and use of the Child-Pugh score, there are a limited number of medications containing specific recommendations for dosage adjustment based on hepatic function as categorized by the Child-Pugh score.¹¹⁶ In 2005, a review of all Food and Drug Administration-approved medications found that only 23 included guidance for dosage adjustment based on Child-Pugh. Dose adjustments were typically recommended starting with Class B liver dysfunction, with many agents suggesting nonuse in patients with Class C rankings.¹²⁰

Table 87–4 The Child-Pugh Score

Rectal Administration of Medication

Many drugs otherwise approved for oral and/or intravenous use have been administered rectally, in both adults and children. Rationale for using the rectal route varies. Rectal administration allows for avoidance of the orogastric route when necessary or avoidance of the intravenous route when access is an issue or when parenteral dosage forms are not available. The rectal route allows for a higher local concentration of drug in situations where limited systemic absorption is desired. Administration via this route may afford a less-costly alternative to a considerably more expensive parenteral product, and may offer an alternative when a parenteral product is unavailable. Although generally well accepted amongst patients and their families ^121,¹²² clinicians may need to overcome resistance to rectal administration from patients and families because of personal perceptions.

Interpatient variability surrounding rectal administration is a key factor for clinicians to consider. Drug absorption may be accelerated or delayed. The rate of rectal transmucosal absorption is affected by various factors. First, the formulation of the product itself varies, causing differences in the time to liquefaction with suppositories, the volume of liquid administered and the concentration of the drug. The length of the rectal catheter helps determine the site of absorption. Drugs administered high in the rectum, which is drained by the superior rectal veins, typically are carried to the liver via the portal vein, thus subject to first-pass hepatic metabolism. Drugs administered low in the rectum are delivered into the venous circulation by the inferior and middle rectal veins before passing through the liver. Presence of stool in the rectum and rectal pH can alter drug absorption. Rectal pH affects absorption by ionizing varying amounts of drug. The rectal mucosa in children typically has a more alkaline pH.¹²³ Nonionized drugs have greater lipid solubility, causing enhanced absorption across biological membranes. The rectal retention of the drug administered also affects absorption.¹²⁴

The rectal route has been commonly studied with the use of rectal diazepam gel (Diastat). This commercially available product is used for prolonged or repetitive seizures in children and has approval by the FDA for at-home administration by a trained nonprofessional caregiver. Clinical trials and postmarketing data have reported a low rate of serious respiratory adverse events,¹²⁵ a major concern of many clinicians surrounding at-home use; however, cases have been reported in chronic, high-dose users of fluctuating effects of rectal diazepam, including reappearance of seizure activity.¹²⁶ This product may offer an alternative to other oral and intravenous benzodiazepine options available in a critical care setting, especially in emergent situations if access cannot be readily achieved. The controlled environment of a critical care unit can easily recognize adverse effects as opposed to home administration.

Clinically, successful rectal administration of medication in children has dealt mainly with anticonvulsants such as diazepam, lorazepam, and oxcarbazepine for status epilepticus ¹²⁷; sedatives such as diazepam, midazolam, and ketamine in varying uses^124,¹²⁸; localized treatment for irritable bowel disease using mesalamine¹²⁹^–¹³¹; vancomycin for pseudomembranous colitis¹³²; antibacterial agents such as erythromycin¹³³; antiemetics¹³⁴; cardiovascular agents such as nifedipine and metoprolol¹³⁵^–¹³⁸; and analgesics, specifically acetaminophen, nonsteroidal antiinflammatory drugs, and tramadol, for temperature reduction and postoperative pain control.^121,^122,^139,¹⁴⁰ Although the American Academy of Pediatrics dissuades the rectal use of acetaminophen without consultation with a health care provider,¹⁴¹ it has been widely used and studied.^139,^140,^142,¹⁴³ In addition, rectally administered nonsteroidal anti-inflammatory medications, opioid analgesics, antiseizure medications, antiemetics, anticholinergic medications, antidepressants, psychostimulants, and antibiotics have been used with success in the hospice and palliative care settings.¹⁴⁴