Medication Summary
Pharmacologic therapy for necrotizing enterocolitis (NEC) includes agents to treat the developing disease and those to provide supportive and symptomatic relief.
As previously mentioned, placement of a central venous catheter for administration of pressors, fluids, antibiotics, and blood products is prudent because severely affected patients often have complications that include sepsis, shock, and disseminated intravascular coagulation (DIC).
The initial course of treatment in stage I or II NEC consists of stopping enteral feedings, performing nasogastric decompression, and initiating broad-spectrum antibiotics. Historically, antibiotic coverage has consisted of ampicillin, gentamicin, and either clindamycin or metronidazole, although the specific regimen used should be tailored to the most common nosocomial organisms found in the particular neonatal intensive care unit. Probiotics are emerging as a possible preventive therapy. [4, 41]
Antibiotics
Class Summary
Although no single infectious etiology is known to cause necrotizing enterocolitis (NEC), clinical consensus finds that antibiotic treatment is appropriate. Broad-spectrum parenteral therapy is initiated at the onset of symptoms after obtaining blood, spinal fluid, and urine for culture. Antibiotic coverage for staphylococcus should be considered in NICUs that have a high colonization rate. Antifungal therapy should be considered for premature infants with a history of recent or prolonged antibacterial therapy or for babies who continue to deteriorate clinically or hematologically despite adequate antibacterial coverage.
Various antibiotic regimens can be employed; one frequently used regimen includes ampicillin, aminoglycoside (eg, gentamicin) or third-generation cephalosporin (cefotaxime), and clindamycin or metronidazole. Vancomycin should be included if staphylococcus coverage is deemed appropriate. This combination provides broad gram-positive coverage (including staphylococcal species), excellent gram-negative coverage (with the exception of pseudomonads), and anaerobic coverage.
Doses are adapted from Neofax. [61] Postmenstrual age (PMA) is equivalent to gestational age plus postnatal age. Postnatal age is used as a secondary qualifier to determine dose.
Cefotaxime (Claforan)
Cefotaxime is a broad-spectrum, third-generation cephalosporin with excellent nonpseudomonal, gram-negative coverage at the expense of gram-positive effects. Its safety profile is more favorable than that for aminoglycosides. Cefotaxime penetrates cerebrospinal fluid to treat meningitis.
Ampicillin
Ampicillin is a broad-spectrum penicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. Ampicillin is an alternative to amoxicillin when medication cannot be taken orally. Previously, the HACEK bacteria were uniformly susceptible to ampicillin. However, beta-lactamase–producing strains of HACEK have been identified.
Gentamicin
Gentamicin is an aminoglycoside antibiotic for gram-negative coverage of bacteria, including Pseudomonas species. It is synergistic with beta lactamase against enterococci. Gentamicin interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits. Dosing regimens are numerous and are adjusted based on CrCl and changes in volume of distribution, as well as the body space into which the agent needs to distribute. Monitor gentamicin by serum levels obtained before the third or fourth dose (0.5 h before dosing); the peak level may be drawn 0.5 hour after a 30-minute infusion.
Vancomycin (Vancocin)
Vancomycin provides excellent gram-positive coverage, including of methicillin-resistant Staphylococcus species and Streptococcus species. The drug blocks bacterial cell wall synthesis. The parenteral formulation is widely bioavailable throughout all body tissues and fluids, including cerebrospinal fluid. Vancomycin is recommended for empiric use in patients with central lines and ventriculoperitoneal (VP) shunts, and for those with probable staphylococcal or streptococcal infection. Enteral administration is used for Clostridium difficile intoxication.
Clindamycin (Cleocin)
Clindamycin inhibits bacterial protein synthesis; it is bacteriostatic or bacteriocidal, depending on the drug concentration and organism. Coverage includes anaerobes commonly found in the intestinal tract and many staphylococcal and streptococcal species.
Metronidazole (Flagyl)
Metronidazole is used to treat susceptible anaerobic bacterial and protozoal intraabdominal, systemic, or central nervous system (CNS) infections.
Vasopressors
Class Summary
Babies with serious illness may progress to shock and require pharmacologic blood pressure support.
Dopamine
Dopamine is an adrenergic agonist that increases blood pressure by stimulating alpha-adrenergic vascular receptors, resulting in vasoconstriction. It has some inotropic effects via beta1 cardiac receptors and, at low doses, increases glomerular filtration via renal dopaminergic receptors. Dopamine is useful for babies with hypotension who are not responsive to volume repletion. It may be mixed in dextrose so that glucose delivery is not compromised.
Dobutamine
Dobutamine is an adrenergic agonist with specific effects on beta1-receptors in the heart, resulting in increased contractility. It has minimal alpha-adrenergic activity. Dobutamine can be used for babies in shock, usually adjunctively with dopamine, to increase cardiac output. It may be mixed in dextrose so that glucose delivery is not compromised.
Epinephrine (Adrenalin)
Epinephrine is a nonspecific adrenergic agonist that stimulates alpha receptors, beta1 receptors, and beta2 receptors. It can be used to support blood pressure in severe hypotension that is refractory to other treatment modalities.
Naloxone
Naloxone is an opioid receptor blocker. Experimental evidence suggests that it may increase blood pressure for babies in shock, perhaps by blocking the binding of endogenously produced endorphins released in sepsis, particularly from gram-negative organisms.
Volume Expanders
Class Summary
Patients with severe illness may experience fluid shifts to the extracellular space, resulting in intravascular depletion that requires expansion.
Albumin (5% and 25%)
Albumin is used to increase intravascular oncotic pressure in hypovolemia and helps to mobilize fluids from the interstitial to the intravascular space. The concentration can be either 5% (5 g/100 mL) or 25% (25 g/100 mL), depending on the desired effect.
Sodium chloride hypertonic, ophthalmic (Normal saline, NS, Isotonic saline)
Sodium chloride can be used as a volume expander and can be as effective as albumin in acute hypovolemia.
Fresh frozen plasma
Fresh frozen plaza is especially helpful as a volume expander in patients with concomitant coagulopathy.
Glucocorticosteroids
Class Summary
These agents correct the inappropriate adrenal response that is often present in very ill neonates. Once hydrocortisone therapy is initiated, hypotension typically resolves.
Hydrocortisone (Solu-Cortef)
Hydrocortisone elicits mineralocorticoid activity and glucocorticoid effects.
Opioid Analgesics
Class Summary
Although difficult to assess, premature infants presumably experience pain with severe illness and invasive procedures. Narcotic analgesics are safe and effective in premature infants and have a long history of clinical experience.
Morphine sulfate (Duramorph, Astramorph, Oramorph SR, MS Contin)
Morphine sulfate is an opioid analgesic with a long history of safe and effective use in neonates. It inhibits ascending pain pathways by binding to the opiate receptors in the CNS, causing generalized CNS depression. Morphine sulfate is used for sedation and analgesia.
Fentanyl (Onsolis, Fentora, Actiq, Duragesic)
Fentanyl is an opioid analgesic that is 50-100 times more potent than morphine. Its mechanism of action and indications for use are similar to those of morphine; however, fentanyl has less hypotensive effect than morphine does, because of minimal to no associated histamine release. Fentanyl is administered as an IV bolus or as a continuous infusion. Because of the small volumes used in neonates for bolus administration, it is not usually cost-effective to administer as a bolus.
Antifungal Agents
Class Summary
The mechanism of action in these agents may involve an alteration of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) metabolism or an intracellular accumulation of peroxide, which is toxic to the fungal cell.
If antifungal therapy is warranted, fluconazole can be initiated. Fluconazole is less toxic than amphotericin B, which is substituted if no clinical response to fluconazole occurs or if evidence of microbiologic resistance is present.
Fluconazole (Diflucan)
Fluconazole is an antifungal agent with good activity against Candida albicans. It is associated with less toxicity and is easier to administer than amphotericin B; however, fluconazole-resistant candidal species are being isolated with increasing frequency. This agent can be administered enterally or parenterally.
Probiotics
Class Summary
A meta-analysis of published studies showed that oral administration of nonpathogenic bacterial species may result in beneficial alteration of intestinal bacterial flora, reducing the risk and severity of disease. [62, 63, 64, 65, 66, 67, 68, 69, 70] However, data are insufficient regarding the optimal time of initiation, type and dose of bacteria to be used, duration of administration, and potential adverse effects.
Some probiotic formulations used in these studies are not available in the United States, and no regimen or available preparation can be issued based on the meta-analysis. Because of these unknown factors, this therapy is experimental and is not accepted as a standard of care.
Lactobacillus acidophilus/Bifidobacterium infantis (Floranex, Bacid, Dofus, Culturelle)
These lactic acid–producing organisms are thought to acidify the intestinal contents and to prevent selective bacterial growth. Probiotic live cultures are intended to restore or maintain healthy microbial flora. Data are currently emerging regarding their use in NEC. Various products are available and doses may vary between products. Infloran has specifically been studied in very low birth weight (VLBW) infants with NEC. It has completed phase II clinical trials.
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Normal (top) versus necrotic section of bowel. Photo courtesy of the Department of Pathology, Cornell University Medical College.
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Pneumatosis intestinalis. Photo courtesy of Loren G Yamamoto, MD, MPH, Kapiolani Medical Center for Women & Children, University of Hawaii, with permission.
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Pneumatosis intestinalis. Photo courtesy of Loren G Yamamoto, MD, MPH, Kapiolani Medical Center for Women & Children, University of Hawaii, with permission.
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Pneumatosis intestinalis. Photo courtesy of Loren G Yamamoto, MD, MPH, Kapiolani Medical Center for Women & Children, University of Hawaii, with permission.
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Pneumatosis intestinalis. Photo courtesy of Loren G Yamamoto, MD, MPH, Kapiolani Medical Center for Women & Children, University of Hawaii, with permission.
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Pneumoperitoneum. Photo courtesy of the Department of Pathology, Cornell University Medical College.
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Resected portion of necrotic bowel. Photo courtesy of the Department of Pathology, Cornell University Medical College.
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Micrograph of mucosal section showing transmural necrosis. Photo courtesy of the Department of Pathology, Cornell University Medical College.
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Histologic section of mucosal wall demonstrating pneumatosis. Photo courtesy of the Department of Pathology, Cornell University Medical College.
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Histologic section of bowel mucosa showing regeneration of normal cellular architecture. Photo courtesy of the Department of Pathology, Cornell University Medical College.
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Extensive pneumatosis intestinalis.
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Necrotizing enterocolitis totalis. Pneumatosis intestinalis and multiple areas of perforation were seen.
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Pneumatosis intestinalis.
