Furosemide, which increases renal prostaglandin synthesis, has been suggested to

help prevent indomethacin-associated renal toxicity. However, by increasing

prostaglandins, furosemide may theoretically decrease ductal closure. Currently,

studies do not support the routine use of furosemide in preterm neonates who receive

indomethacin for the treatment of PDA. Furosemide is also contraindicated in

patients who are dehydrated.

58

In addition to monitoring renal function and serum

electrolytes, serum concentrations of aminoglycosides, digoxin, and other renally

eliminated drugs should be monitored carefully. Indomethacin therapy may decrease

renal drug clearance and cause accumulation of these agents, which may require a

dosage reduction.

59

A platelet count should also be obtained from T.S. before therapy because

indomethacin may decrease platelet aggregation. Thrombocytopenia (platelet count

<50,000/μL) is a contraindication to indomethacin therapy.

51

In cases of

thrombocytopenia, indomethacin may be withheld temporarily until platelets can be

transfused. Other potential contraindications to indomethacin therapy include active

bleeding and clinical evidence of NEC because GI bleeding, perforation, and NEC

have been reported with indomethacin use.

49 These GI effects may be related to

decreases in intestinal blood flow usually seen with rapid IV infusions. Grades II to

IV IVH also are frequently quoted as contraindications to indomethacin therapy;

however, indomethacin treatment probably is not associated with progression of

IVH. In fact, prophylactic treatment with indomethacin may be associated with a

decrease in the incidence of severe IVH (grades III and IV).

49,50

CASE 105-3, QUESTION 7: When is the best time to initiate an NSAID for symptomatic treatment of

T.S.’s PDA?

Conflicting data exist on when to initiate indomethacin or ibuprofen therapy for the

treatment of symptomatic PDA. Some centers may opt to treat within the first 2 to 3

days of life (early symptomatic PDA) when infants initially present with clinical

signs of PDA (i.e., murmur, widened pulse pressures, tachycardia). Others may not

treat until clinical signs of congestive heart failure are present (late symptomatic

PDA; 7–10 days of life).

50 Both treatment strategies (early and late) significantly

decrease the incidence of PDA, but both cause significant transient reduction of urine

output and SCr elevation. In some studies, infants receiving early treatment of

indomethacin had significant reductions in the incidence of BPD and NEC and the

need for surgical ligation.

50

In contrast, one study found that final PDA closure rates

and the need for surgical ligation were comparable in early versus late indomethacintreated neonates. In fact, spontaneous closure was observed in 43% of the late

treatment group, which may indicate unnecessary treatment in the early group. In

addition, renal adverse effects and ventilatory requirements were higher in the infants

treated early.

60 Thus, early administration of indomethacin should not be used

routinely; however, it may be given to preterm neonates at high risk for having a large

PDA. Clinically, these recommendations can also be applied to ibuprofen. Because

T.S. is an ELBW neonate with RDS, she is at high risk for exhibiting a large PDA.

She also has clinical signs of a PDA and, thus, should be treated as soon as possible.

CASE 105-3, QUESTION 8: The physicians were able to decrease T.S.’s ventilator support within the first

12 to 24 hours after starting indomethacin treatment. After 3 to 4 days of gradual and consistent ventilator

weaning, the ventilator settings could not be decreased further. During the next 2 to 3 days, T.S.’s respiratory

status deteriorates, and she requires increased ventilator support. T.S. now has tachycardia, a widened pulse

pressure, bounding pulses, and a hyperactive precordium. Repeat echocardiogram shows a small-to-moderate

PDA. Current data include the following:

BUN, 10 mg/dL

SCr, 1.1 mg/dL

Sodium, 134 mEq/L

Potassium, 4.9 mEq/L

Chloride, 97 mEq/L

Urine output, 2.3 mL/kg/hour

Fluid intake, 130 mL/kg/day

Platelets, 180,000/μL

Why did PDA recur in T.S., and how should it be managed?

Successful closure of the PDA with indomethacin occurs in 70% to 90% of infants;

however, ductal reopening or recurrence can occur in 20% to 35% of infants who

initially respond to indomethacin.

61 Recurrence of PDA occurs especially in lowerbirth-weight infants. Several reasons might explain T.S.’s transient response to

indomethacin. Recurrence of PDA is inversely proportional to gestational age; the

incidence of ductal reopening is significantly higher in infants with 26 weeks’

gestational age or younger compared with infants born at 27 weeks’ gestation or

more (37% vs. 11%, respectively).

62 The higher recurrence in younger gestational

age neonates may be related to resumption of PGE2 production after indomethacin

serum concentrations decline and heightened sensitivity of the immature ductus

arteriosus to the dilating effects of PGE2

.

49,61 This is particularly important in

ventilator-dependent patients such as T.S. because mechanical ventilation increases

circulating vasodilating prostaglandins.

Furthermore, the rate of ductal reopening is independent of indomethacin serum

concentrations, but seems to be related to the timing of indomethacin therapy, PNA,

and the amount of fluid intake 24 hours before indomethacin treatment.

62 The rate of

recurrence is lower in infants who were treated with indomethacin earlier in life

compared with those who receive treatment later.

49 Because anatomic closure of a

PDA may be delayed for a couple of weeks, it is not surprising that the ductus

arteriosus reopened in T.S. after her initial response to indomethacin.

p. 2180

p. 2181

Although controversial, prolonged indomethacin therapy may prevent recurrences

and allow for permanent closure of the ductus arteriosus. Several prolonged

treatment regimens have been successful in preventing ductal reopening.

49,61 One such

regimen (indomethacin 0.2 mg/kg/dose IV every 12 hours for three doses, followed

by 0.2 mg/kg/dose every 24 hours for five doses) was able to significantly decrease

the recurrence of PDA from 47% to 10% in neonates less than 1,500 g without

increasing toxicity. The need for surgical ligation also was decreased significantly.

61

However, some studies report an increased mortality in infants receiving prolonged

therapy (5 to 7 days) compared with those receiving the short course (three doses).

49

Furthermore, a recent meta-analysis demonstrated that prolonged therapy (six to eight

doses) did not improve PDA closure, retreatment, reopening, or surgical ligation

rates. Although prolonged courses were shown to decrease transient renal

dysfunction, a significantly higher incidence of NEC was observed. Thus, the routine

use of prolonged courses of indomethacin is not currently recommended.

63 Select use

of prolonged therapy may be used. Individual patient response needs to be

considered, especially in ELBW neonates. The optimal duration of indomethacin

therapy and dosing regimen need to be identified.

T.S. remains ventilator-dependent and is at increased risk for exhibiting BPD.

Because she has no contraindications to indomethacin therapy, a second course of

indomethacin (0.1–0.2 mg/kg/dose every 12–24 hours for three to five doses) should

be considered.

61,63

If the PDA fails to respond to this prolonged regimen or if it

recurs again after an initial response, and T.S. remains ventilator-dependent, surgical

ligation most likely will be required to permanently close the PDA.

Prophylactic Administration

CASE 105-3, QUESTION 9: Could prophylactic NSAID administration have prevented the development of a

symptomatic PDA in T.S.?

Prophylactic indomethacin therapy is defined as the administration of

indomethacin within 24 hours of life to newborns who are at risk of experiencing a

symptomatic PDA.

64 However, routine prophylaxis would unnecessarily expose a

large number of newborns to indomethacin (and its adverse effects), because PDA

closure may occur spontaneously without treatment. Prophylactic use of indomethacin

has short-term benefits; it significantly decreases the incidence of PDA and IVH

(grades III and IV) and the need for PDA surgical ligation.

64 Unfortunately, most

studies have not shown that prophylactic ductal closure with indomethacin decreases

the incidence of death, BPD, NEC, or neurodevelopmental disabilities. Additionally,

infants receiving prophylactic therapy have a higher incidence of severe oliguria or

anuria, albeit transient.

64 Therefore, routine prophylactic administration is usually not

warranted. It may be considered, however, in some neonatal units that do not have

easy access to cardiac diagnostic and therapeutic services or that have a high

incidence of IVH. Typically, preterm neonates, particularly those at high risk for

experiencing a large PDA (e.g., ELBW neonates), are treated as soon as clinical

signs appear.

Prophylactic ibuprofen therapy (administered at <24 hours of life) significantly

decreases the incidence of PDA and the need for rescue pharmacologic treatment and

surgical ligation.

65 However, it does not appear to decrease BPD, IVH, NEC, or

mortality, and may increase the risk of renal dysfunction and sepsis. Because of the

lack of long-term follow-up studies with the current ibuprofen lysine product,

prophylactic ibuprofen therapy for the prevention of PDA is not recommended at this

time.

65

Treatment with Acetaminophen

CASE 105-3, QUESTION 10: During multidisciplinary NICU rounds, the advanced nurse practitioner

mentions that acetaminophen has been used to treat PDA and may be safer than NSAIDs. Should

acetaminophen, rather than indomethacin, have been used to treat the symptomatic PDA in T.S.? What is the

evidence to support its use?

The advanced nurse practitioner is partially correct and should be informed of the

following information. Several case reports suggest that acetaminophen may be used

for the treatment of PDA in neonates who fail or have contraindications to NSAID

therapy.

66–68 Similar to NSAIDs, acetaminophen inhibits prostaglandin synthesis.

However, in contrast to NSAIDs that inhibit cyclooxygenase-1 and -2 (steps that

occur early in the synthesis of prostaglandins), acetaminophen is thought to affect a

subsequent step in prostaglandin synthesis by inhibiting the peroxidase site of the

enzyme, prostaglandin synthetase. Others suggest that acetaminophen inhibits a yetunidentified cyclooxygenase-3. Due to the different mechanisms of actions,

acetaminophen would be expected to have less serious side effects than NSAIDs.

Two randomized controlled trials compared acetaminophen to ibuprofen for the

treatment of PDA in preterm neonates.

67,68 Both trials used acetaminophen doses of

15 mg/kg every 6 hours for 3 days. A recent meta-analysis of these studies found no

significant difference in the failure rates for PDA closure or risk of reopening the

PDA between the two drugs.

68 No significant differences in secondary outcomes or

adverse effects were observed, with two exceptions: The duration of required

supplemental oxygen was shorter, and the incidence of hyperbilirubinemia was lower

in patients who received acetaminophen. Although these results appear promising, an

association of postnatal use of acetaminophen with autism or autism spectrum

disorder has recently been identified.

68

In addition, animal studies suggest

acetaminophen may affect cognitive function when administered during neonatal

brain development. Therefore, further research, including long-term follow-up

studies of neurodevelopment, is needed before acetaminophen can be recommended

for PDA closure in routine clinical practice.

68 Due to these concerns, acetaminophen

should not have been used in place of indomethacin to treat the symptomatic PDA in

T.S. After weighing all potential risks and benefits, some clinicians may use

acetaminophen before surgical ligation, in select neonates with a significant PDA,

who have failed or who have contraindications to NSAID therapy.

67

NECROTIZING ENTEROCOLITIS

CASE 105-4

QUESTION 1: C.D., a 15-day-old female neonate, was born at 28 weeks’ gestational age with a birth weight

of 908 g. Her postnatal course has been complicated by RDS, sepsis, and a large PDA for which she required

intubation and mechanical ventilation, one dose of beractant, a 7-day course of ampicillin and gentamicin, and

indomethacin. Enteral feedings with a standard preterm 24-cal/ounce formula were started on day 4 of life at 5

mL every 3 hours (44 mL/kg/day). Feedings were increased by 5 mL/feed on days 5 through 7 to 20 mL/feed

every 3 hours on day 7 of life (176 mL/kg/day). This morning, C.D. exhibited a distended abdomen, bloody

stools, multiple episodes of apnea that required reintubation and assisted ventilation, and metabolic acidosis.

ABG results revealed the following:

pH, 7.15

PCO2

, 67 mm Hg

p. 2181

p. 2182

PO2

, 55 mm Hg

Base deficit, 10

An abdominal radiograph revealed pneumatosis intestinalis (the presence of gas in the intestinal submucosa).

C.D. is to take nothing by mouth (NPO), and gentamicin 4 mg/kg IV infusion every 36 hours and ampicillin 100

mg/kg IV push every 12 hours are restarted. What clinical signs of NEC does C.D. have? What is the

pathogenesis of NEC, and what risk factors for NEC does C.D. have?

NEC, a type of acute intestinal necrosis, is the most common neonatal lifethreatening nonrespiratory condition. The incidence of NEC ranges from 3% to 11%

and is inversely proportional to gestational age and birth weight.

69 Approximately

90% to 95% of NEC occurs in premature infants; however, NEC can infrequently

occur in full-term neonates.

70 The age of onset of NEC is also inversely related to

gestational age and birth weight; the greater the gestational age at birth, the sooner the

onset of NEC. Although NEC is less common in term infants, it usually develops

within 3 to 4 days of birth. In contrast, infants born at approximately 30 weeks’

gestation acquire NEC at a mean PNA of 20 days. Thus, preterm infants are at a risk

for NEC for a longer time.

71,72 Although C.D. is extremely premature, she

experienced NEC early (at 15 days of age), most likely because of the aggressive

advancement of feedings. The rate of hospitalization associated with NEC is 1.1 per

1,000 live births.

73 The mortality rate of NEC can be as high as 40% to 50%, and

approximately 25% of survivors experience long-term complications.

70,71,73

In

addition, infants with NEC required longer hospitalizations (60 days longer if

surgery is needed and 20 days longer if surgery is not needed) compared with infants

without NEC. For infants with medically managed NEC, the estimated hospital cost

is $60,000 to $70,000 compared to $200,000 for infants with surgically managed

NEC.

70,74

C.D. has several clinical signs of NEC, including abdominal distension, bloody

stools, apnea, metabolic acidosis, and pneumatosis intestinalis on abdominal

radiograph. Gastric retention of feedings, respiratory distress, occult blood in stools,

lethargy, temperature instability, thrombocytopenia, and neutropenia also may occur.

NEC may progress to bowel perforation, peritonitis, sepsis, disseminated

intravascular coagulopathy (DIC), and shock. On an abdominal radiograph, the

presence of gas in the intestinal mucosa or in the portal venous system is diagnostic

of NEC, and free air in the abdomen is observed with bowel perforation. (For

images of NEC go to https://image.slidesharecdn.com/necrotizingenterocolitis-

150719105818-lva1-app6892/95/necrotizing-enterocolitis-8-638.jpg?

cb=1437303559.) Although these radiographic findings confirm the diagnosis of

NEC, a lag time may occur between the initial clinical signs of NEC and radiologic

confirmation.

NEC can evolve slowly during a period of 24 to 48 hours, from a clinically benign

course to an advanced stage of shock, peritonitis, and widespread intestinal necrosis.

Although NEC can affect any part of the GI tract, most of the disease is confined to

the ileum and colon. A staging system, which categorizes severity according to

systemic, intestinal, and radiologic signs, has been developed to permit a more

consistent evaluation and treatment of patients.

75 Stages IA and IB NEC include

neonates and infants with suspected disease or rule out NEC. These patients may

have mild GI problems such as delayed gastric emptying and emesis, temperature

instability, apnea, bright red blood from the rectum, or a mild ileus. Infants with

stages IIA and IIB have definite NEC and usually present with abdominal distension,

bloody stools, and the presence of pneumatosis intestinalis on radiograph. Infants in

stage IIB NEC may also exhibit metabolic acidosis and thrombocytopenia. Infants

with stages IIIA and IIIB (advanced disease) are severely ill with clinical signs,

including peritonitis, ascites, shock, severe metabolic and respiratory acidosis, and

DIC. Those with stage IIIB have intestinal perforation. Pneumatosis intestinalis,

caused by hydrogen production from bacterial translocation into the bowel wall, is a

classic and diagnostic radiographic finding of NEC. Because pneumatosis intestinalis

may be hard to detect on radiographs, some infants can experience severe NEC

needing surgery without having radiographic findings. Therefore, new criteria

including biomarkers of NEC may be needed to help diagnose NEC sooner and

prevent its progression. C.D.’s presentation is most consistent with stage IIB NEC.

The pathogenesis of NEC is unknown, but seems to be multifactorial. Most likely,

NEC results from the effects of intestinal bacteria and other factors on injured

intestinal mucosa. Inflammatory mediators such as platelet-activating factor, tumor

necrosis factor-α, interleukin 1β, and interleukin 8 may also contribute to mucosal

damage.

70,72 The neonatal intestinal mucosa is prone to injury for the following

reasons: (a) increased permeability to potentially harmful substances, such as

bacteria and proteins; (b) decreased immunologic host defenses, including low

concentrations of immunoglobulin A in intestinal mucosa; and (c) decreased

nonimmunologic defenses, such as decreased concentrations of proteases and gastric

acid. Furthermore, inappropriate initial microbial colonization may also contribute to

the pathogenesis of NEC in preterm neonates, especially because NEC does not

occur until after 1 week of life, at a time when the gut has been colonized with

anaerobic bacteria. In addition, numerous factors (both prenatal and postnatal) can

cause injury to the neonatal intestinal mucosa and increase the risk for NEC.

72,75

Prenatal maternal factors include eclampsia, prolonged rupture of membranes, fetal

distress, maternal cocaine use, and cesarean section. Postnatal factors include

prematurity, low birth weight, ischemia or hypoxemia, asphyxia, hypothermia,

hypotension, respiratory distress, apnea, malnutrition, infection, hemodynamically

significant PDA, congenital GI anomalies, cyanotic heart disease, toxins,

hyperosmolar substances (e.g., feedings, medications), rapid advancement of enteral

feedings, exchange transfusions, blood transfusions, and the presence of umbilical

catheters.

72,74,75 Medications such as corticosteroids, indomethacin, and H2

-blockers

and prolonged empiric IV antibiotic use have also been associated with an increased

risk of NEC.

72,74,75 However, the most significant clinical risk factor for NEC is

prematurity.

75

C.D. has several risks for developing NEC, which include prematurity, ELBW,

history of infection, and RDS requiring mechanical ventilation. Furthermore, C.D. not

only was given a hyperosmolar formula (24 cal/ounce instead of 20 cal/ounce), but

her feedings were advanced aggressively. These two factors may also contribute to

the development of NEC. More than 90% of infants with NEC have received enteral

feedings, although NEC also occurs in infants who have never been fed.

70 Enteral

feedings (breast milk or formulas) serve as substrates for bacterial proliferation in

the gut. As a result, reducing substances, organic acids, and hydrogen gas are

produced by bacterial fermentation of these nutrients. Although studies have shown

that rapid advancements in the volume of feeds (30 mL/kg/day vs. 15–20 mL/kg/day)

were associated with an increased risk of NEC, a systematic review reported that

infants advanced at a rate of 30 to 35 mL/kg/day reach full enteral intake and regain

birth weight significantly earlier than infants advanced at 10 to 20 mL/kg/day without

increasing the risk of NEC or NEC with perforation.

73 Similarly, older studies

reported that early initiation of feeds might increase the risk of NEC; however, a

recent review failed to confirm these findings. In fact, infants who were fed earlier

(within 4 days of birth) had a significant reduction in the number of days on

parenteral nutrition.

73 C.D. was started at a much higher initial feeding volume (44

mL/kg/day) and aggressively increased by 44 mL/kg/day, which may have increased

the risk

p. 2182

p. 2183

of NEC. If C.D. were appropriately fed, she would have reached full feedings in 7

to 14 days instead of 4 days. Last, the presence of PDA and the use of indomethacin

for the treatment of PDA may also have contributed to NEC in C.D. through

decreased mesenteric blood flow with resultant ischemia and intestinal mucosal

injury.

71

Treatment

CASE 105-4, QUESTION 2: How should C.D. be managed?

Significant abdominal distension may compromise respiratory function and blood

flow to the intestines. Therefore, as soon as NEC is suspected, feedings should be

stopped immediately and an orogastric tube with low intermittent suction placed to

decompress the abdomen. C.D.’s vital signs and abdominal circumference should be

closely monitored for disease progression. A complete blood count and platelet

count should be obtained frequently to monitor for neutropenia and

thrombocytopenia. Blood and urine cultures should be obtained, and parenteral

antibiotics should be started as soon as possible; 20% to 30% of infants with NEC

have associated bacteremia. Radiographic examinations should be routinely

performed at least every 4 to 8 hours or as needed to evaluate the progression of the

disease. In infants with stage I NEC, antibiotic therapy is usually given for 3 days

pending culture results and clinical signs. Once the diagnosis of NEC is ruled out,

antibiotics may be discontinued. Enteral feedings can then be initiated slowly.

However, if the diagnosis of NEC is made (i.e., stages II or III), antibiotics are

continued and parenteral nutrition is initiated at that time. Infants require bowel rest

(NPO) for at least 7 to 14 days. The length of antibiotic therapy and bowel rest in

infants with documented NEC is determined by the severity of systemic illness (e.g.,

metabolic acidosis, thrombocytopenia). In general, infants with NEC stage II require

at least 7 to 10 days of antibiotic therapy and bowel rest whereas those with NEC

stage III may require at least 10 to 14 days. C.D. has stage IIB disease and needs to

be NPO for at least 7 to 10 days; she requires total parenteral nutrition during that

time, and the surgery team should be notified at this point. Infants with stage III

disease may also require fluid resuscitation, administration of inotropic agents such

as dopamine and dobutamine, and surgical intervention, especially for those with

perforated NEC.

70,71 Up to 40% of infants treated for medically managed NEC may

require surgical intervention (either primary peritoneal drainage or exploratory

laparotomy), with the absolute indication for surgery being intestinal perforation.

73

Despite the type of surgical intervention, up to 50% of ELBW infants who require

surgery will die.

72

CASE 105-4, QUESTION 3: C.D. just completed a 7-day course of ampicillin and gentamicin. Is it

appropriate to restart these antibiotics?

The selection of antibiotics for NEC depends on the common microorganisms

observed in an individual neonatal unit and their sensitivities. Many organisms have

been implicated in NEC, including Enterobacteriaceae (e.g., Escherichia coli,

Klebsiella species), Pseudomonas, Staphylococcus aureus (in rare cases, methicillin

resistant), Staphylococcus epidermidis, Clostridium, enteroviruses, and rotaviruses.

76

For most cases of NEC, treatment with a broad-spectrum penicillin, such as

ampicillin, and an aminoglycoside (e.g., gentamicin) is appropriate.

Due to an increase in S. epidermidis-associated NEC, vancomycin and an

aminoglycoside may be used as routine treatment in some nurseries or in specific

patients at risk for Staphylococcus infections (e.g., neonates with central catheters or

prolonged ICU stays). Vancomycin may be more appropriate than ampicillin because

vancomycin has coverage against methicillin-resistant S. epidermidis, as well as

enterococcal and streptococcal species. Because C.D. has been hospitalized for

longer than 1 week and weighs less than 1,000 g, vancomycin and gentamicin may be

more appropriate, especially if her neonatal ICU has a high incidence of

staphylococcal nosocomial infections. C.D. should be treated with parenteral

antibiotics for 7 to 10 days.

Other antibiotic combinations used to treat NEC include cefotaxime and

vancomycin, and cefotaxime and ampicillin. The combination of cefotaxime and

vancomycin has been shown to prevent severe peritonitis and death and reduce the

need for surgery in less than 2,200-g birth-weight neonates with NEC, whereas

gentamicin and ampicillin have not. Suppression of aerobic fecal flora by the

combination of cefotaxime and vancomycin, but not by ampicillin and gentamicin,

may explain these findings.

76 Therefore, if C.D. is not responding to vancomycin and

gentamicin, consideration should be made to replace gentamicin with cefotaxime.

CASE 105-4, QUESTION 4: Two days later, C.D. exhibits peritonitis with ascites (NEC stage III),

hypotension, worsening metabolic acidosis, neutropenia, and DIC. IV fluids and dopamine are administered for

the hypotension, fresh-frozen plasma and whole blood are given to treat the coagulopathy, and a fentanyl

continuous infusion at 1 mcg/kg/hour is started for pain control. Free air in the abdomen is observed on

abdominal radiograph. Blood and urine cultures have had no growth for 48 hours. What additional antimicrobial

coverage should be provided?

The use of empiric anaerobic coverage in infants with definite NEC, stage II or III,

remains controversial; however, many institutions have added anaerobic coverage to

routine antibiotic regimens.

76 The two most commonly used agents are clindamycin

and metronidazole. Routine use of clindamycin in the treatment of NEC has not

decreased the incidence of intestinal gangrene, perforation, or death. In addition, it

has been associated with an increased incidence of abdominal strictures.

76 There are

no studies to demonstrate the efficacy of metronidazole in this patient population, but

the lack of reports documenting adverse effects in preterm infants has made it the

agent of choice in some hospitals. A recent study reported no significant difference in

the incidence of the combined outcome of death or intestinal strictures in infants with

NEC stages II and III treated with or without anaerobic coverage.

77 Furthermore,

anaerobic antibiotic therapy did not prevent the progression to death within 7 days of

NEC diagnosis or to surgical NEC. However, a higher risk of strictures was found in

all infants receiving anaerobic antibiotic therapy. Furthermore, in those with surgical

NEC, a lower mortality rate was found in the anaerobic antibiotic-exposed infants.

77

Based on this study, it might be prudent to consider weighing the risk versus benefit

when deciding to add anaerobic antibiotic therapy in the treatment of medically

managed NEC. In contrast, infants with peritonitis secondary to intestinal perforation

(i.e., those needing surgery) require both aerobic and anaerobic coverage. Therefore,

an antimicrobial agent with anaerobic activity such as metronidazole should be

added to C.D.’s current regimen.

Complications and Prognosis

CASE 105-4, QUESTION 5: C.D. is taken urgently to the operating room, and 40 cm of necrotic ileum is

removed along with the ileocecal valve. What long-term nutritional problems is C.D. likely to have?

The most common postoperative complications of NEC are intestinal strictures (up

to 25%) and short-bowel syndrome (11%).

70

p. 2183

p. 2184

C.D. is at risk of experiencing short-bowel syndrome, a condition of

malabsorption and malnutrition that results from surgical removal of a significant

portion of the small intestine. The most important factors that determine short-bowel

syndrome are the length of the remaining small intestine and the presence of the

ileocecal valve. Because C.D. has had a majority of her ileum and her ileocecal

valve removed, she most likely will suffer from short-bowel syndrome.

Because the terminal ileum is an important site for absorption of vitamins, trace

minerals, and nutrients, C.D. will be at risk for decreased absorption of these

substances. C.D. also will have a faster GI transit time and diarrhea because her

ileocecal valve was removed. (The ileocecal valve plays a major role in controlling

intestinal transit time.) Absorption of enterally administered medications also may be

decreased in patients with short-bowel syndrome. When C.D. starts to receive most

of her nutrition enterally, she should be monitored for fat malabsorption and other

nutritional deficiencies (e.g., deficiencies in vitamins A, B12

, D, E, and K), and

supplemented accordingly.

Despite advances in earlier diagnosis and aggressive treatment, approximately

15% to 50% of all infants with NEC die, with the highest mortality in those with birth

weight <750 g and with surgical NEC.

69,70,74,75 Furthermore, infants with NEC are

significantly more likely to have neurodevelopmental impairment (e.g., CP); those

requiring surgical management are at higher risk.

73

Prevention

CASE 105-4, QUESTION 6: What could have been done to prevent NEC in C.D.?

Several interventions may decrease the incidence of NEC. Enteral feedings in

preterm infants can be withheld for several weeks and parenteral nutrition initiated.

Intestinal priming or trophic feeding (i.e., using a small amount of full-strength

formula or breast milk for several days to stimulate GI mucosal development) has

been shown to decrease the incidence of NEC compared with infants with

advancement of feedings.

73 Because breast milk provides antibodies, growth factors,

and cellular immune factors, it may reduce the incidence of NEC. Infants fed with

human milk had a significantly lower incidence of NEC than those fed with

formula.

74,75

In a recent study, a significant decrease in the incidence of NEC and

surgical NEC was observed in infants who were exclusively fed with a human milkbased diet compared with a combination of human milk- and formula-based diets.

74

In contrast, the use of hyperosmolar formulas or medications can cause osmotic

injury to the bowel and may result in NEC. Maternal steroids (commonly used to

accelerate fetal lung maturation) can decrease the incidence of NEC owing to a

maturational effect on the microvillous membranes.

Although prophylactic enteral administration of antibiotics (i.e., gentamicin or

vancomycin) has been shown to decrease the incidence of NEC, its routine use is not

recommended.

74

In addition, prophylactic use of these antibiotics has been associated

with the emergence of resistant organisms, especially with long and repeated

courses.

72,74

Probiotics are live, nonpathogenic microbial preparations that colonize the

intestine and have a beneficial effect on the health of the host. Probiotic

microorganisms commonly used are strains of Lactobacillus and Bifidobacterium. In

a recent Cochrane review, enteral administration of probiotics significantly

decreased the risk of severe NEC and death and shortened the time to full feedings in

VLBW infants.

78 Furthermore, recent studies evaluating the long-term effects of

probiotics (assessed at 18–22 months up to 3 years corrected age) reported no

adverse effects on growth or neurodevelopmental outcomes.

78 One major concern is

that exposing immunologically immature VLBW infants to probiotics may potentially

increase the risk for infections. Although the Cochrane review did not find an

increased risk for infections in neonates receiving probiotics, cases of systemic

infections, especially in ELBW neonates, have been reported.

78 The lack of

probiotic-associated sepsis could be due to failure of the laboratory to isolate these

strains in blood cultures by the use of conventional culture-based techniques. Other

controversies exist. Most studies did not evaluate the effects of probiotics in ELBW

infants, the population at greatest risk for NEC. The optimal type of probiotic

(species, strains, single or combined, live or killed) and the timing, dosage, and

duration of therapy are still unknown. Little is known regarding the benefits of

probiotics in infants who are exclusively or partially fed breast milk. Furthermore,

none of the studies were conducted in the United States and most of the trials did not

utilize US commercially available probiotics. Lastly, currently no product in the

United States has the appropriate regulatory mechanisms in place to ensure the

quality of the product. Therefore, clinical studies are needed to address these issues,

and if probiotics are administered to VLBW infants for the prevention of NEC,

careful surveillance of mortality, NEC, and emergence of resistant strains will be

necessary. When C.D. is ready to be fed, breast milk (if available) should be used in

place of formula to help prevent future risk of NEC. Although probiotics have been

shown to significantly decrease the incidence of NEC, their use cannot be

recommended for C.D. at this time.

NEONATAL SEPSIS AND MENINGITIS

CASE 105-5

QUESTION 1: J.E., a 28-week gestation, 850-g male, was born to a mother with prolonged rupture of

membranes (>72 hours). The newborn’s mother is diagnosed with chorioamnionitis. J.E. had Apgar scores of 3

at 1 minute, 4 at 5 minutes, and 7 at 10 minutes after birth. Mechanical ventilation was instituted, and J.E. was

admitted to the neonatal ICU. Vitalsigns on admission were as follows:

HR, 190 beats/minute

Temperature, 35.8°C

BP, 56/33 mm Hg

Blood and urine cultures are pending. Significant laboratory data include the following:

WBC 2,400 cells/μL with a differential of 25% segmented neutrophils, 15% bands, 45% lymphocytes, 10%

monocytes, 4% eosinophils, and 1% basophils

Platelets, 45,000/μL

C-reactive protein (CRP), 5 mg/dL

What is the etiology and pathogenesis of neonatal sepsis? What risk factors for sepsis does J.E. have? What

clinicalsigns and laboratory evidence of sepsis are apparent in J.E.?

Bacterial sepsis significantly contributes to neonatal morbidity and mortality.

Neonates, especially preterm newborns, are at increased risk for infections and

should be considered immunocompromised. The neonate’s decreased immune

function (e.g., immature function of neutrophils, lower amounts of immunoglobulin)

also results in a reduced ability to localize infections. Once a tissue site becomes

infected, bacteria can spread easily, resulting in disseminated disease. In addition,

the lack of opsonic antibodies in preterm infants such as J.E. increases the

susceptibility to infections caused by bacteria with polysaccharide capsules (e.g.,

group B streptococcus, E. coli, Haemophilus influenzae type B).

79

p. 2184

p. 2185

The incidence of neonatal sepsis is inversely proportional to birth weight and

gestational age, and ranges from 6 to 9 cases per 1,000 live births. However, the

incidence is much higher in VLBW neonates (~25%).

80 Risk factors (as demonstrated

in J.E.) include prematurity, low birth weight, male sex, and predisposing maternal

conditions (e.g., prolonged rupture of membranes, maternal fever, elevated maternal

WBC or left shift, chorioamnionitis, and urinary tract infection).

81,82 Despite

treatment, mortality rates for neonatal sepsis can be as high as 30% to 50%, with the

highest mortality observed in newborns less than 1,500 g.

83 Meningitis occurs as a

complication of bacterial sepsis in 10% to 30% of septic neonates

83 and has a

mortality rate of 20% to 50%, depending on the pathogen.

81 Long-term sequelae of

meningitis have been reported in about 20% to 60% of survivors and include hearing

loss, abnormal behavior, developmental delay, cerebral palsy, focal motor disability,

seizure disorders, and hydrocephalus.

79,84