Module 3. Neonatology. Lesson 9. Topics:
Bacterial infection of the newborn: localized bacterial infections iewborns: skin diseases, subcutaneous fat diseases, and umbilical wound infection, neonatal pneumonia.
The localized forms of infections: skin diseases, subcutaneous fat diseases, and umbilical wound infection.
Problem of the newborns’ localized purulent infection is topical question because of frequent severe consequences. This pathology is more common in premature, low weight children, newborns with birth asphyxia, birth injury. The life prognosis depends on in time diagnosis and effective treatment. That’s why doctors of different specializations have to know this pathology.
The newborn infant is more vulnerable than the older child to certain infections. The preterm baby is even less able to withstand infection and more liable to suffer serious complications.
· Humoral antibodies
o IgG is transferred across the placenta especially in the last trimester, and protects the baby against specific infections to which the mother has been immunized, e.g. measles, mumps, polio, diphtheria, tetanus, typhoid.
o This passive immunity wanes after four to six months, but may persist to 9 months e.g. measles.
o Neither IgM nor IgA cross the placenta. They are normally only produced by the infant after birth. (Note: the fetus can produce IgM in response to an intra-uterine infection e.g. congenital syphilis)
· Cell-mediated immunity:
o Lymphocytes are involved in the killing of bacteria
o The lymphocytes have not been exposed previously to antigens
· Inflammatory reaction:
o In the newborn the inflammatory response is poor and phagocytosis of bacteria by leucocytes is inefficient (due to reduced opsonins and delayed chemotaxis)
· Antenatal:
o The placenta filters out most organisms but not rubella virus, HIV, Toxoplasma, CMV and Treponema pallidum
o amniotic fluid contains lysozymes and other antibacterial agents to reduce the risk of infection
· Postnatal:
· Breast feeding:
o breast milk has IgG, IgM, IgA, macrophages and lysozymes
o lactoferrin and transferrin protect against gram negative organisms
o breast feeding promotes growth of Lactobacilli and inhibits E.coli
· Nursery care:
o Infection may be prevented by hand-washing, bathing baby and cord and eye care.
· Antenatal:
o Syphilis, HIV, rubella, CMV, varicella and bacterial chorioamnionitis
· Intranatal:
o Herpes, Streptococci, Gonococci, Candida, Chlamydia (increased risk with prolonged labour)
· Postnatal:
o Cross-infection: hands, feeds, inhalation.
· Antenatal :
o Stillbirth, fetal anomalies (e.g. rubella), congenital infections (e.g. syphilis, amniotic fluid infection syndrome with pneumonia).
· Postnatal :
o Common: conjunctivitis, oral thrush.
o Less common: cord infection, skin sepsis.
o Uncommon: urinary infection, pneumonia, septicaemia, meningitis.
· Clinical:
o superficial infection: usually obvious
o generalised infections: may present with poor feeding, lethargy, failure to gain weight, jaundice, anaemia, rash, hepatosplenomegaly, diarrhoea, vomiting, etc
o The temperature may be raised but is more ofteormal or sub-normal.
· Viral infections:
o isolate the virus, or demonstrate a rise in antibody titre
o total or specific IgM levels
o demonstrate organism, e.g. Candida, on slide using Gram stain, or culture on special agar
o obtain cultures from mother
o gastric aspirate M/C/S
o white blood count (normal 5000 to 20 000)
o immature/total neutrophil ratio (normal 0-12%)
o C reactive protein
o pus, urine, CSF, blood culture
o x-rays of chest or bones
o ECG ( myocarditis)
Scalded skin syndrome (Ritter’s disease).
Conjunctivitis. Gonococcal conjunctivitis is a serious acute inflammation which may damage the cornea leading to blindness. The onset is often rapid with red swollen mucus membranes and a copious purulent discharge. The diagnosis can be made quickly with a Gram stain on a smear of pus (Gram negative diplococci in leucocytes). Small children may be susceptible to infective conjunctivitis, and they may develop severe forms of the condition because of poor immune defences.
This is particularly the case in babies, and conjunctivitis in an infant aged less than one month old is a notifiable disease in the UK.
This type of conjunctivitis (ophthalmia neonatorum) may be due to an infection that has been contracted during the passage through the mother’s birth canal and may include the sexually transmitted infections, such as gonococcal or chlamydial infection.
Small babies may develop conjunctivitis from other types of infection, but swabs should always be taken in order that appropriate treatment can be given.
Small babies often have poorly developed tear drainage passages (a condition known as nasolacrimal duct obstruction).
These children are susceptible to watering eyes and they may intermittently become sticky, but this is usually not serious and most of the time this settles down with no treatment.
Treatment involves the instillation of Penicillin eyedrops (20,000 units/ml), frequently enough to keep eye free of pus. Repeated irrigation of the eye with saline can be used if penicillin drops are not available.
It is essential to give an additional 100,000 units of intramuscular procaine penicillin daily for 3 days in severe gonococcal conjunctivitis. Don’t forget to also treat the mother and have her VDRL checked.
Gonococcal conjunctivitis can be prevented by putting chloromycetin eye ointment into both eyes routinely after delivery
Pic.1 Gonococcal conjunctivitis
Non-Gonococcal Conjunctivitis: Chloramphenicol ointment or drops applied 8 hourly for a week is usually sufficient for most infections aquired after delivery.
Use tetracycline or erythromycin ointment if Chlamydia infection is suspected or if inflammation recurs after chloramphenicol therapy. Proven Chlamydia infections should also be treated with oral erythromycin for 10 days.
Thrush:
Moniliasis is caused by the fungus Candida albicans and commonly affects the mouth or the nappy area. The source is usually mother’s vagina or nipples, or contaminated hands, bottles, etc.
Small numbers of Candida spp. commonly live on healthy skin and in a healthy mouth. They are usually harmless. However, an overgrowth of Candida spp. can occur in the mouth of some babies. This can cause a bout of oral thrush.
This overgrowth may happen because the baby’s immune system is still quite immature and so cannot control the Candida spp. levels. Another possible cause for oral thrush infection is if your baby has had a recent course of antibiotics. This is because the antibiotics can kill off healthy bacteria that live in your baby’s mouth. These healthy bacteria normally help to control the levels of Candida spp. in your baby’s mouth. If there are less healthy bacteria around, candidal overgrowth can occur. Also, if you are breast-feeding and you have recently been on antibiotics yourself, the levels of your healthy bacteria can be affected. This can make you, or your baby, more likely to develop thrush.
About
Small white patches are found on the tongue and may spread to the inside of the cheeks and lips. These white plaques resemble curds of milk but are difficult to dislodge. The underlying mucosa is inflammed and sucking is often painful. The diagnosis is proved by the identification of spores and hyphae on microscopy. In the nappy area, the insides of skin folds (groin) are affected.
Treatment:
Mycostatin suspension (Nystatin) 1 ml (100,000 units) after each feed for 7-10 days. If mother is breast feeding, mycostatin should be applied to the nipples while vaginal infection should be eradicated. Dummies, teats and bottle must be boiled.
Skin Infections: Mostly due to Staph. aureus and may present as one or more pustules, infected vesicles, abscesses, etc. The diagnosis is made on Gram stain and culture, the results of which will determine the form of treatment. Mild superficial infection may be treated with chlorhexidine (Hibiscrub). Abscesses need incision and drainage. More severe infections, e.g. cellulitis require systemic antibiotic therapy.
Physiologicoanatomical features of the skin in children
The skin in a newborn is velvety smooth, puffy and friable, especially around the eyes, the legs, the dorsal aspect of the hands and feet, and the scrotum or labia.
There are some peculiarities of the epidermis in the newborn and young children:
In the newborn the epidermis is thinner than in adults.
The basal layer is well developed and has 2 kinds of cells – basal and melenocytes. The last ones do not produce melanin until the infant is 6 month. That is why the skin in the newborn is lighter in the first days of life.
The grantilar layer is thinner, consists of 2-3 lines of cells It is poorly developed except soles and palms. The absence of keratogliadin protein makes the skin transparent considerably, because keratogliadin protein gives the skin a white hue.
The glassy layer is absent.
The corneal layer is poorly developed, thin, it has only 2-3 lines of flattened corneal cells. The structure of the corneal layer is friable and puffy.
The clinical significance. Iewborn and younger children the skin is susceptible to superficial bacterial infection, candidosis (oral moniliasis) and intertrigo with maceration, weeping and erosion.
The dermis comprises the major portion of the skin. It is firm, fibrous, and elastic connective tissue network containing an elaborate system of blood and lymphatics vessels, nerves. It varies throughout the body from 1 to
There are some peculiarities of the dermis in the newborn and young (little) children:
In the newborn the papillary layer is poorly developed. In the premature infant it is absent.
The dermis has an embryonic structure – it has a lot of cellular elements and a little amount of fibrous structures. Elastic fibres are absent. They first appear in 5-6 months of life.
Labrocytes (mast cells) have a high biological activity.
In the newborn the quantity of water is higher than in an adult (80 % and 6-8 % respectively) in the dermis.
The basal membrane is poorly developed. It leads to easy separation of the epidermis from the dermis, it results in epidermolysis.
Morphological maturity of the derma occurs by 6 years.
The clinical significance. A newborn and an infant more often show blistering (bullous) reactions caused by the poor adherence between the epidermis and the dermis and frequently affected by chronic atopic dermatitis (eczema).
Basic physiological functions of the skin
The protective function is an immature function, it occurs because of thin epidermis and dermis, immature basal membrane, a little amount of fibrous structures and a good developing of blood vessels network.
The bactericidal function is an immature function, it is due to pH of the newborn skin (6.1-6.7) in an adult pH is acidic (4.2-5.6)). This pH medium is favourable for developing microbes.
The thermoregulation is immature function as the result of high emission heat process and immature heat production. The high emission heat processes occur because of a thin skin, a later beginning of sweat glands functioning, a well developed superficial vessel network, the vessels are in physiological vasodilatation. Muscles of the hair bulbs are poor developed, so gooseflesh does not appear.
The respiratory function is well developed. It helps immature lungs to perform the respiratory function. The intensity of the respiratory function is more intensive by 8 times in a newborn than in an adult. Well developed respiratory functions are caused by puffy and thin skin, a well developed superficial vessel network, physiological vasodilatation of vessels.
The deposition function is well developed. The skin is the depot of blood and water.
The reception (receptor) function is well developed. There are a lot of nerves in the skin, so the skin is a peripheral analyzer that grasps endo– and exogenous stimuli.
The excretion function is provided by sweat glands. The skin excretes some products of metabolism of fat and carbohydrate and different medicaments. The excretion function of the skin begins with the beginning of functioning sweat and sebaceous glands (3-4 months).
The resorption is well developed. It is caused by puffy and thin skin, well developed superficial vessel network, a great number of sebaceous glands and hair follicles. But resorption depends on the chemical structure of the substance: liposoluble substances are well absorbed, water-soluble substances are nonabsorptive.
The buffer function is poor developed, because iewborn and young children pH of the skin is nearly neutral (pH 6.1-6.7) therefore the skin can’t neutralize acids and alkaline.
The pigmentation function is immature.
The synthesis of vitamins. The skin synthesizes vitamin D and other biologically active substances.
The secretation function. The skin secretes keratin, squalen, calcium and phosphorus. In a newborn the secretion of keratin and squalen is decreased, the secretion of calcium and phosphorus is increased.
The metabolic function is well developed, therefore newborns and young children have a high regeneration of the epidermis and d the ermis.
Physiologicoanatomical features of appendages of the skin in children
Appendages of the skin are sebaceous gland, sweat gland, hair.
Sebaceous glands are well developed, begin to function since 7-months of the intrauterine life. The quantity of sebaceous glands in 1 cm2 is relatively large in a newborn.
Millia is often seen in the newborn. That is the obstruction of the excretory duct of sebaceous glands. Millia localizes on the nose and cheeks, have yellow-roseate color, its size is 1×1 mm. Millia disappears by 2-3 month.
Sweat glands are poorly developed.
There are two types of sweat glands: eccrine and apocrine. In a newborn eccrine sweat glands are well formed, but their excretory ducts are feebly developed and obstructed. Eccrine sweat glands begin secretory function by 2 months.
Morphological and physiological maturity of eccrine sweat glands occurs by 5-7 years.
The formation of apocrine sweat glands finishes by one year but they begin to function only in the puberty period.
Hair. The hair covering the skin in a newborn falls gradually during the first year of life instead of permanent hair appearance. With age the hair becomes thicker.
Subcutaneous fat. In a newborn the thickness of subcutaneous fat is relatively larger than in an adult (12 % and 8 % in an adult). Distribution of the fat is not regular in a newborn. They have good subcutaneous fat all over the body except the abdomen where there is insensitive deposition during the first 6 months.
The subcutaneous fat has an embryonic structure; it gives the possibility to deposit fat and to perform the hemopoietic function.
If we look at the chemical structure of the subcutaneous fat we will see the predomination of saturated fatty acids. This gives a good turgor to the skin.
The next peculiarity of the subcutaneous fat in the newborn is the presence of a brown adipose tissue. It localizes in the back neck part, in the axillary area, around the thyroid gland and the kidneys, in the intrascupullar space and around great vessels. The main function of the brown fat is heat production without muscle contraction. In 5-6 months the brown fat disappears. The subcutaneous fat is absent in the abdomen, peritoneal and thoracic cavities, therefore the inner organs are movable.
The peculiarity of the skin iewborn
At birth the skin is covered with grayish-white, cheese-like substance called vernix caseosa. If it is not removed during the first bath, it will dry and disappear in 24 or 48 hours. It is thought to have insulating and bacteriostatic properties. A fine, downy hair called lanugo is present on the skin, especially on the forehead, cheeks, shoulders and back. It usually disappears spontaneously in a few weeks.
Phlegmona of the newborn: local signs + expressed intoxication.
There are 4 clinical stages: incidence, alterative-necrotic, declination, reparation.
This is a local hyperemia, infiltration with distinct margins, it enlarges quickly ® infiltration became cyanotic with softening in the center ® formation of the wound surface with digger margins ® granulations, epithelization with scars formation.
Localization: chest, back, buttocks, arms and legs.
Treatment: surgical + conservative (antibiotics, desintoxication, immune therapy, symptomatic).
Mastitis of the newborn
Neonatal mastitis typically occurs in full-term infants who are younger than
two months. It is usually unilateral and local iature. Characteristic clinical
features include marked erythema, tenderness, and induration of the affected
breast bud. Purulent nipple discharge and breast abscess may be present.
The axillary lymph nodes may be enlarged and tender. 25% of patients may
also have fever (>101ºF (38.3ºC)). Between 50 and 100 percent of neonatal
patients develop abscesses.
Systemic symptoms other than fever (eg, irritability, decreased appetite,
vomiting) are uncommon. Gastrointestinal symptoms may indicate
Salmonella or other gram-negative enteric pathogens. Bacteremia is rare.
Significant cerebrospinal (CSF) pleocytosis with sterile CSF culture may be
seen in association with mastitis with or without systemic symptoms in
patients infected with methicillin-resistant S. aureus. Cases of neonatal
mastitis complicated by extensive cellulitis, necrotizing fasciitis, and
osteomyelitis have been reported.
Diagnosis
Ieonates, particular attention should be given to the presence of abscess
formation, fever, and other systemic symptoms (eg, poor appetite, lethargy)
as these may indicate a serious systemic infection.
If the lesion is fluctuant, purulent material from aspiration (with or without
ultrasonographic guidance) or I&D also should be sent for Gram stain and
culture. If I&D are performed, it is important not to injure the underlying breast
bud; appropriately trained personnel (eg, a breast surgeon or pediatric
gynecologist) should be consulted when this procedure is necessary.
A CBC and blood culture should be obtained prior to antimicrobial therapy. If
present, nipple drainage should be sent for Gram stain and culture (aerobic
and anaerobic). Urine and cerebrospinal fluid cultures should be obtained if
these studies are clinically indicated (eg, if the infant is febrile, ill appearing,
younger than 28 days of age, or has leukocytosis).
Differential Diagnosis
It is important to distinguish mastitis from physiologic breast hypertrophy,
which resolves spontaneously. In contrast to mastitis, in physiologic
hypertrophy, the breast bud is neither red nor tender. The nipple discharge (if
present) in physiologic hypertrophy is milky rather than purulent and does not
contain polymorphonuclear white blood cells or bacteria on Gram stain.
Treatment
No randomized controlled studies have evaluated antibiotic regimens for
neonatal mastitis. Recommendations for treatment are based upon the
causative pathogens and the response to therapy. Because of the potential
for breast abscess, neonates should be treated with parenteral antibiotics
guided by Gram stain when available.
Neonatal mastitis be treated initially with parenteral antibiotics if the infant is
febrile, ill appearing, has leukocytosis, or is younger than 28 days of age. An
intial dose of parenteral antibiotics is also suggested in infants who are
afebrile, well appearing, without leukocytosis, and older than 28 days of age,
given the potential for progression to abscess in infants who are initially
treated orally and the increasing prevalence of community-associated
methicillin-resistant S. aureus. The empiric antibiotic choice should be guided
by local susceptibility patterns and the Gram stain, if one is available.
If gram-positive cocci are identified, empiric therapy should include coverage
for S. aureus eg Clindamycin or Vancomycin
If gram-negative organisms are identified, empiric therapy should include an
aminoglycoside (eg, gentamicin, amikacin) or third-generation cephalosporin
(eg, cefotaxime)
If the Gram stain is not available or if no organisms are seen, then therapy
should include coverage for S. aureus and gram-negative enteric organisms.
Therapy can be altered according to culture results once they are available.
Incision and drainage may be warranted if an abscess is present.
The duration of therapy depends upon the clinical response; a total of 7 to 14
days (parenteral and oral) is usually adequate if there are no complications.
Umbilical Infection (Omphalitis):
Causes: Omphalitis is a polymicrobial infection typically caused by a mixture of aerobic and anaerobic organisms. Associated risk factors include the following:
o Low birthweight (<
o Prior umbilical catheterization
o Septic delivery (as suggested by premature rupture of membranes, nonsterile delivery, or maternal infection)
o Prolonged rupture of membranes
Omphalitis occasionally manifests from an underlying immunologic disorder.
Rarely, an anatomic abnormality may be present, such as a patent urachus or patent omphalomesenteric duct.
Serous omphalitis: serous discharge from the umbilical stump, prolonged epithelization; symptoms from organs and systems, intoxication are absent.
Treatment: local (3% Hydrogen peroxide, Spiritus camphoratus, Viridis nitens, xerophormum).
Purulent omphalitis Local disease: Physical signs vary with the extent of disease. Signs of localized infection include the following:
o Purulent or malodorous discharge from the umbilical stump
o Periumbilical erythema
o Edema
o Tenderness
Extensive local disease: The following signs indicate more extensive local disease, such as fasciitis or myonecrosis. These signs also may suggest infection by both aerobic and anaerobic organisms and include the following:
o Periumbilical ecchymoses
o Crepitus
o Bullae
o Progression of cellulitis despite antimicrobial therapy
Fig. 1. Purulent omphalytis.
Lab Studies:
· Obtain specimens from umbilical infection routinely, and submit specimens for Gram stain and culture for aerobic and anaerobic organisms. If myonecrosis is suspected, obtain specimens from the involved muscle rather than the wound surface.
· Obtain a blood culture for aerobic and anaerobic organisms.
· Obtain a complete blood count with manual differential.
o Neutrophilia or neutropenia may be present in acute infection. An immature-to-total neutrophil ratio greater than 0.2 may be a useful indicator of systemic bacterial infection in the first few days of life.
o Thrombocytopenia may be present.
TREATMENT Medical Care: Treatment of omphalitis (periumbilical edema, erythema, and tenderness) in the newborn includes antimicrobial therapy and supportive care.
Antimicrobial therapy
o Include parenteral antimicrobial coverage for gram-positive and gram-negative organisms. A combination of an antistaphylococcal penicillin and an aminoglycoside antibiotic is recommended.
o Some believe that anaerobic coverage is important in all patients. Omphalitis complicated by necrotizing fasciitis or myonecrosis requires a more aggressive approach, with antimicrobial therapy directed at anaerobic organisms as well as gram-positive and gram-negative organisms.
§ Metronidazole may provide anaerobic coverage.
§ Clindamycin may be substituted for the antistaphylococcal penicillin.
§ As with antimicrobial therapy for other infections, consider local antibiotic susceptibility patterns.
§ Pseudomonas species have been implicated in particularly rapid or invasive disease.
o Expect erythema of the umbilical stump to improve within 12-24 hours after the initiation of antimicrobial therapy.
Supportive care: In addition to antimicrobial therapy, supportive care is essential to survival. These measures include the following:
o Provide ventilatory assistance and supplementary oxygen for hypoxemia or apnea unresponsive to stimulation.
o Administer fluid, vasoactive agents, or both for hypotension.
o Administration of platelets, fresh frozen plasma, or cryoprecipitate for DIC and clinical bleeding is suggested.
o Treat infants at centers capable of supporting cardiopulmonary function.
Management of necrotizing fasciitis and myonecrosis involves early and complete surgical debridement of the affected tissue and muscle.
Staphylococcus Aureus Infection
· Skin and soft tissue (impetigo) (Fig. 1, 2, 3, 4): Generally, this starts as a small area of erythema that progresses into bullae (filled with cloudy fluid) that rupture and heal with the formation of a crust, previously described as honey-colored. Although group A Streptococcus was considered the primary agent, S aureus has become the major pathogen since the 1980s. Bullous impetigo is caused exclusively by S aureus and is observed less frequently in the
· Initial appearance is a small area of erythema. Bullae, ie, blisterlike lesions filled with cloudy fluid, appear as the disease progresses. As bullae heal, a honey-colored crust develops.
Fig. 2. Impetigo in infant.
Fig. 3,4,5. Bullous impetigo.
Neonatal impetigo (Impetigo Neonatorum), also known as neonatal Pemphigus (Pemphigus Neonatorum), occurred in a newborn with bullae mainly suppurative acute infectious skin disease, rapid onset, infectious intensity.
Etiology and pathogenesis
First, the pathogen by the coagulase positive, phage type 71 group is transmitted due to Staphylococcus aureus. For delicate baby skin, weak resistance, the initial contact because of neonatal bacteria, the bacteria are particularly sensitive, plus wrapped with plastic sheeting, hot sweating, so that local skin temperature, high humidity, the skin vulnerable to dipping, to caused by pyogenic bacteria invasion and good conditions for breeding.
Second, the source of infection is often the maternal neonatal impetigo, infected from birth attendants and mothers, and some midwives are carriers. In the nursery, breastfeeding rooms, once discovered the disease, must be strictly sterilized and isolation.
Pathological changes
Pathological changes and is similar to impetigo, pustular located under the cuticle (or granular layer below) superficial dermal infiltration of inflammatory cells, neutrophils can be seen.
Clinical manifestations
First, the symptoms of the disease often occurs in infants born in 4-10 days, contagious. Most damage occurred in the face, hands and other exposed parts, but also occur widely in the trunk and limbs, palms and soles, often without damage, and sometimes damage also occurred in the mucosa or spread finger nail bed caused by inflammation or suppurative paronychia. The initial stage of the disease symptoms was not obvious, with the progress of the disease may include fever, body temperature as high as 39 diarrhea, pneumonia, nephritis, meningitis or septicemia, resulting in death in children.
Second, the lesions began to tip to the great big big red spots, blisters appeared on it quickly. Rapid expansion of blisters, from pea to a large walnut or larger, blister, blister and thin and break. A day or two, become turbid fluid bullae or blister before the end of some yellow pus, but most of the bullae will fester. Bullous be very full, after expanding and relaxation. After the blisters rupture, exposing flushing, smooth erosion surface, formed after the thin crust. Bullae can also occur elsewhere, but as you can into a piece of the general erosion of pemphigus.
Diagnosis and differential diagnosis
According to a large neonatal pustular impetigo subsequent diagnosis of systemic symptoms can be characterized, but the identification with the following diseases:
I. Staphylococcal scalded skin syndrome occurs mainly in infants after birth, 1-5 weeks, a few found in adults. Diffuse lesions characterized by flushing, erythema based on the occurrence of relaxation bullae, oral, nasal mucosa, conjunctiva may be involved. Nepal’s sign positive.
Second, genetic disease epidermolysis bullosa blisters occurred in the h
and, foot and other parts susceptible to trauma and friction, to clarify the content of bullae, often family history.
Treatment
First, support the treatment of attentioewborn’s skin clean, found that children should be immediately isolated, and the baby room, children’s clothing disinfected. Give supportive care, such as the transmission of whole blood or plasma or intramuscular injection of gamma globulin.
Second, the early application of sufficient quantities of anti-bacterial infection of sensitive antibiotics such as penicillin, a new penicillin, erythromycin, neomycin and other pioneers.
Third, the local treatment of locally under sterile conditions, cut broken blister wall, draw blister fluid, with a 1:10000 or 0.1% potassium permanganate solution rivanol wet packing, topical 2% gentian violet solution, or 0.5% 1% neomycin cream.
· Folliculitis/furuncle/carbuncle: This is a series of progressively severe staphylococcal skin infections. Folliculitis is a tender pustule that involves the hair follicle. A furuncle involves both the skin and the subcutaneous tissues in areas with hair follicles, such as the neck, axillae, and buttocks. They actually are small abscesses characterized by exuding purulent material from a single opening. A carbuncle is an aggregate of connected furuncles and has several pustular openings. Skin infections can be self-limited, but they can also disseminate hematogenously and cause life-threatening septicemia.
Fig. 6. The superficial pustule in axillar region.
· Folliculitis is the appearance of a tender pustule involving a hair follicle. Furuncle is an apparent small abscess that exudes purulent material from a single opening. Carbuncle is an aggregate of furuncles with several openings.
· Laboratory studies: Make the diagnosis based on clinical appearance and occasionally on results of aspiration and culture of purulent material from the lesion.
· Medical Care: Impetigo/folliculitis/furuncle/carbuncle: Treatment of impetigo and other minor skin infections (ie, superficial or localized infections) can be with a topical agent such as mupirocin. Treat more extensive skin disease and bullous impetigo with oral antistaphylococcal agents.
· Scalded skin syndrome (Ritter disease (Fig. 7): A relatively rare syndrome caused by exfoliative toxin takes the form of superficial fragile blisters that burst, leaving a tender base. The patient often is febrile and occasionally has mucopurulent eye discharge. Place special emphasis in making this diagnosis because it can often be mistaken for erythema multiforme and/or toxic epidermal necrolysis, which are treated with corticosteroids. Misdiagnosis delays treatment and allows exfoliation to progress, and corticosteroid therapy could potentiate bacterial superinfection. Although the mortality rate is low in children with this entity, most fatalities are caused by delays in diagnosis.
Fig. 7. Baby with Ritter’s disease.
· Examination shows superficial fragile blisters that burst, leaving a tender base. Skin sloughs easily when touched, called Nikolsky sign (Fig. 8). Fever is often present. A mucopurulent eye discharge may be present. As discussed above, it can often be mistaken for erythema multiforme and/or toxic epidermal necrolysis. Misdiagnosis must be avoided.
Fig. 8. Nikolsky sign.
· Therapy for this, as with any S aureus toxin–mediated disease, should be aimed at eradicating the focus of infection and ending toxin production. Administer large doses of intravenous antistaphylococcal agents, such as oxacillin (150 mg/kg/d) or a first-generation cephalosporin, such as cefazolin (100 mg/kg/d). In vitro, clindamycin has been shown to inhibit the synthesis of TSST-1, and personal experience has shown it to be extremely effective in combination with one of the above agents. Children with denuded skin should be touched as little as possible. Topical antimicrobial agents have little utility because skin damage is self-limited once systemic antibiotics are administered.
· Bone infections (osteomyelitis) Acute osteomyelitis, although a rare complication ieonates, is a diagnostic and therapeutic challenge. Due to their immature immune response neonates are more susceptible to osteomyelitis than are older children. Preterm infants are at high risk for osteomyelitis because of frequent blood drawing, invasive monitoring/procedures and intravenous drug administration [1,2]. Early diagnosis of neonatal osteomyelitis might be difficult because of the paucity of clinical signs and symptoms, but has to be included in the differential diagnosis when late-onset or prolonged neonatal sepsis is present, as outcome is dependent on rapid diagnosis and immediate start of treatment.
Epidemiology
In Western countries the incidence of osteomyelitis and septic arthritis is 5-12 per 100.000 infants . The overall incidence rate for bone and joint infections is 0.12 per 1000 live births and 0.67 per 1000 neonatal intensive care (NICU) admissions , with a mortality rate of 7.3% . Some recent studies have reported an estimated incidence of 1-7 per 1000 hospital admissions for neonatal osteomyelitis . In a review of more than 300 cases of neonatal osteomyelitis male infants are seen to predominate over females (1.6:1) and preterm infants to be at higher risk than term infants . Risk factors for osteomyelitis and septic arthritis in preterm infants are mostly iatrogenic, including invasive procedures, intravenous or intra-arterial catheters, parenteral nutrition, ventilatory support, and bacteremia with nosocomial pathogens. Two subgroups of neonates are affected: premature neonates with prolonged hospitalization and otherwise healthy newborns presenting within 2 to 4 weeks of discharge.
Neonatal osteomyelitis arises as a consequence of hematogenous spread of microorganisms, which is the most common route of infection. In preterm infants, neonatal osteomyelitis frequently results from directly inoculated bacteria (secondary to heel or venipuncture, umbilical catheterization, infected cephalhematoma, etc.) . Premature rupture of membranes and transplacental infection have also been described as risk factors for neonatal osteomyelitis .
The most common bacterial pathogen causing osteomyelitis in children is Staphylococcus aureus in all age groups. Group B streptococcus (Streptococcus agalactiae) and gram-negative organisms (E. coli and Klebsiella pneumonia) are also important bacteria in the neonatal period. Community-acquired strains of methicillin-resistant Staphylococcus aureus have emerged as being relevant in recent years and cause serious infections in the neonate .
Pathogenesis
Hematogenous infection of the long bones, which are most frequently affected, begins in the capillary loops of the metaphysic, adjacent to the cartilaginous growth plate (physis). These areas are very susceptible to hematogenous infection, because of its high vascularity and because the blood flow within the vessels is slow. Bacteria can pass through gaps from the sinusoidal veins to the capillaries into the tissue, where they are provided an ideal environment to grow, resulting in abscess formation. These abscesses frequently rupture into the joint. Ieonates acute hematogenous osteomyelitis and septic arthritis co-exist in up to 76% of all cases as a result of this unique vascular anatomy of the epiphysis; the bone marrow compartment is seldom involved. The epiphysis receives its blood supply directly from metaphyseal blood vessels (transphyseal vessels) and the adjacent cartilaginous growth plate is traversed by capillaries, allowing spread of the pathogenic bacteria to the physis, epiphysis and joint and resulting in slipped epiphyses, fractures, premature physeal closure and chronic infection.
Characteristics of the neonatal bone prevent many of the features of chronic osteomyelitis: cortical sequestra are often completely absorbed due to extensive bone blood supply in the newborn and, in addition, efficient vasculature of the inner layer of the periosteum encourages early development of new bone formation . Complete destruction of joints is rare, but serious growth disturbances may occur.
Children often present with a sudden onset of fever and bony tenderness or a limp. The pain can be throbbing and quite severe; however, presentation ieonates can be quite subtle. Infants can appear well except for failure to move an extremity or pain on movement. Redness or swelling indicates that infection has spread into the subperiosteal space. Rupture of a focus of osteomyelitis into a joint space can result in septic arthritis. This is often observed ieonates.
· Bone infections are indicated by fever and bony tenderness or limp. Infants can appear well except for failure to move an extremity or pain on movement. Children with vertebral osteomyelitis present with back pain, and those younger than 3 years present with refusal to walk or with a limp. Occasionally, children with vertebral osteomyelitis may have incontinence as a presenting symptom. Children with discitis tend to present with less fever and often appear less ill than those children with vertebral osteomyelitis.
· Laboratory studies: Blood cultures are positive only in 50% of pediatric patients. Therefore, cultures of bone aspirate are useful in obtaining the organism and planning for long-term therapy. In addition, C-reactive protein or erythrocyte sedimentation rate are generally elevated in acute disease.
Imaging techniques
Radiological investigations confirm the suspicion of neonatal osteomyelitis, define the infection site, differentiate between unifocal and multifocal disease patterns and identify secondary complications. Computed tomography, magnetic resonance imaging, ultrasound, radiography and bone scintigraphy scanning have been reported to be useful in detecting osteomyelitis. However, awareness of radiation exposure, need for sedation and transfer to another unit must be considered in the selection of technique.
Radiographs should be the first diagnostic assessment to be performed in patients with suspected osteomyelitis, because they may suggest the correct diagnosis and exclude other pathologic conditions. However, the specificity of plain radiographs for detecting osteomyelitis is greater (75% to 83%) than its sensitivity (43% to 75%). Plain radiography can show soft tissue swelling and destroyed fascial planes within days after onset of infection, but may be subtle and not obvious until day 5 to
Predominately in children, ultrasound can detect features of acute osteomyelitis several days earlier, than radiographs . Even though findings may not be specific and standardized reports for neonates with osteomyelitis are lacking, ultrasound should be taken into account as a useful additional diagnostic tool for the early detection and management of osteomyelitis ieonates as it has many advantages: it is non-invasive, readily accessible, performed bedside, of minimal discomfort for the patient, does not use ionizing radiation and does not need sedation. Even though ultrasound cannot exclude the diagnosis of osteomyelitis, its main value lies in its ability to identify involvement of the adjacent soft tissue (subperiosteal fluid collection or abscess formation), periosteal thickening or elevation, joint effusions and irregularities or interruptions of the cortical bone . Color Doppler imaging further supports the diagnostic assessment, showing coexisting presence of hyperemia surrounding the periost and soft tissue abscess formation. Ultrasound can also be used to image guided-needle aspiration of the subperiosteal fluid for pathogenic organism isolation or subperiosteal abscess drainage. Furthermore, ultrasound has been described as being helpful in differentiating between epiphyseal separation and subluxation following septic arthritis. However, ultrasound cannot exclude the diagnosis of acute osteomyelitis, and thus further imaging diagnostics may be required .
a
b
Pic.2 Acute osteomyelitis of the right humerus. a) periosteal elevation and soft tissue swelling b) joint effusion and synovial thickening
Magnetic resonance imaging (MRI) has high specificity (94%) and sensitivity (97%) for the diagnosis of acute osteomyelitis, showing changes as early as day 3 to 5 after the onset of infection. MRI gives excellent tissue characterization and high resolution, showing detailed anatomic presence of the inflammatory process and its complications (abscess formation, physeal involvement, septic arthritis), further allowing the assessment of involvement of the growth plate and epiphysis. MRI has been proven useful in the diagnosis of clinically suspected osteomyelitis in children , but for its use in neonatology it has several limitations: first and foremost the need for sedation and transfer to the MRI unit.
Three-phase bone imaging, using technetium 99m is very sensitive (90%-95%) for the detection of acute osteomyelitis in the early stages of disease and allows detection within 24 to 48 hours after onset of symptoms . Bone scintigraphy is especially useful for detecting multiple foci of infection or if the infection site is poorly localized. Technetium-99 methylene diphosphonate accumulates in areas of increased bone turnover and is for now the preferred agent of choice for radionuclide bone imaging. Ieonates bone scintigraphy is the subject of controversy: only a few reports support its use and have shown that sensitivity is much lower, than in older infants because of poor bone mineralization
· Differential diagnosis
|
Signs |
Osteomyelitis |
Dushen-Erb paralysis |
|
History |
Mother infections during pregnancy, delivery |
Birth trauma |
|
Time of appearing |
On the 3-5 day after birth |
From the birth |
|
Changes of the movements |
+ |
+ |
|
Intoxication |
+ |
– |
|
Local infiltration |
+ |
– |
|
Active movements in the arm |
absent |
absent |
|
Passive movements in the arm |
Very painful |
painless |
|
Blood count (leucocytosis, formula left shift) |
+ |
– |
|
Roentgenologic signes |
+ |
– |
· Therapy: Starting a semisynthetic penicillin, such as oxacillin (150 mg/kg/d), empirically is a good choice for most cases of community-acquired osteomyelitis. In patients with allergy to penicillin, a first-generation cephalosporin and lyncomycin (40 mg/kg/d) are both excellent alternatives. Cefuroxime (150 mg/kg/d) is a good alternative in younger children who are incompletely immunized because it covers H influenzae type B as well as S aureus. Only use vancomycin when the other drugs mentioned are absolutely not tolerated or when a possibility of a methicillin-resistant strain exists. The duration of therapy is a controversial topic in the literature, but the consensus among multiple authors is that the minimum effective treatment time is 4-6 weeks. A switch to oral therapy is acceptable if the child is able to take oral antibiotics, is afebrile, and if an etiologic agent is found after a good clinical response to parenteral antibiotics has been shown. Absorption of the antibiotic should be measured using serum bactericidal peaks and troughs.
· Surgical Care: Surgery is usually indicated to drain purulent material from the subperiosteal space or if infected foreign material is present.
Prognosis
Several studies have documented poor outcome even with modern treatment facilities. Ieonates the reported incidence of permanent sequelae varies from 6% to 50%. Neonatal osteomyelitis can lead to permanent joint disabilities, disturbances in bone growth secondary to damage to the cartilaginous growth plate, limb-length discrepancies, arthritis, decreased range of motion and pathologic fractures
· Septic arthritis: Typical findings include warmth, erythema, and tenderness of the joint together with constitutional symptoms and fever. An important exception to this is in infants (in whom the hip is the most commonly involved joint), where these signs may be absent. The child typically lies with the involved joint abducted and externally rotated. Because pain fibers are located within the joint capsule, movements, such as changing a diaper, that compress the head of the femur into the acetabulum cause pain. A portal of infection is almost never found, and the infection is nearly always unilateral. Patients with infection of the sacroiliac joint present with tenderness elicited during digital rectal examination and with pain during flexion, abduction, and external rotation of the hip.
· Examination shows warmth, erythema, and tenderness of the joint. Constitutional symptoms and fever are frequent. These findings may be absent in an infant. Children with infection of the sacroiliac joint present with tenderness elicited during digital rectal examination.
· Laboratory studies: Joint fluid, when obtained, is the primary means of diagnosis. The fluid should be Gram stained and cultured. In addition, the number and type of leukocytes should be determined. Median cell count in bacterial arthritis is 60.5 X 109 cells with a neutrophil predominance of greater than 75%.
· Imaging Studies: Plain radiographs show capsular swelling. They are most useful in identifying other causes of hip pain, such as Legg-Calve-Perthes disease. They should be obtained with the child in the frog leg position as well as with the legs extended and slightly internally rotated. Displacement of gluteal fat lines because of the swelling of the joint capsule is an early radiologic sign of septic arthritis. If a bone scan is performed, increased uptake on either side of the joint is visible. Pyogenic sacroiliitis is difficult to diagnose, and the radiologic method of choice is computerized tomography imaging.
· Therapy: As in osteomyelitis, start an appropriate antistaphylococcal drug (eg, oxacillin, which is penicillinase resistant; clindamycin; cefazolin) parenterally. These antibiotics reach joint fluid readily, and the concentration in the joint fluid is 30% the serum value. Therapy usually is for at least 4 weeks. Duration of parenteral therapy is often debated. Some authors have demonstrated efficacy with 1 week of parenteral therapy followed by 3 weeks of oral therapy. Make the decision to switch to oral therapy based on the ability to reliably administer a drug dosage with a peak bactericidal titer of at least 1:8. Any reaccumulation of joint fluid should be removed and cultured to assess the efficacy of therapy as well as to make the patient more comfortable.
· Surgical care: In an infant, septic arthritis of the hip and shoulder is a surgical emergency because these joints should be drained as soon as possible to prevent bony destruction. In addition, any joint should be surgically drained if a large amount of fibrin, tissue debris, or loculation is present, preventing adequate drainage by needle aspiration.
· Thrombophlebitis: Usually occurring in a hospitalized patient, the patient develops fever, pain, and sometimes erythema at the insertion site of an intravenous catheter. Occasionally, pus can be expressed. Severe suppurative thrombophlebitis can occur in burn patients, with fewer than half of diagnoses made while patients are alive.
· Patients usually have a fever and sometimes have cutaneous involvement such as erythema, induration, or tenderness. Occasionally, pus can be expressed at the insertion site of the catheter. Commonly, the exit site does not show signs of infection. Establishing infection of an intravascular device as the cause of fever in a hospitalized patient is a diagnosis of exclusion.
· Laboratory studies: Thrombophlebitis: Although management is sometimes controversial, obtaining a blood culture through the line and a peripheral blood culture is usually recommended.
· Therapy: Immediately remove the lines in any patient who is immunocompromised or severely ill. In mildly-to-moderately ill patients, a trial of antibiotic therapy, usually vancomycin and gentamicin, may be attempted. However, if the infecting organism is S aureus, such trials are usually unsuccessful.
· Surgical care: Remove the infected line in immunocompromised or severely ill patients or when infection is impossible to eradicate medically.
NECROTISING ENTEROLOCITIS Necrosis of the bowel wall may complicate bowel ischaemia after asphyxia, infection or shock iewborn infants.
Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) medical/surgical emergency occurring ieonates. An acute inflammatory disease with a multifactorial and controversial etiology, the condition is characterized by variable damage to the intestinal tract ranging from mucosal injury to full-thickness necrosis and perforation (see the image below). The clinical presentation of necrotizing enterocolitis (NEC) includes nonspecific aspects of the history, such as vomiting, diarrhea, feeding intolerance and high gastric residuals following feedings. More specific GI tract symptoms include abdominal distention and frank or occult blood in the stools.
With disease progression, abdominal tenderness, abdominal wall edema, erythema, crepitans, or palpable bowel loops indicating a fixed and dilated loop of bowel may develop. Systemic signs, such as apnea, bradycardia, lethargy, labile body temperature, hypoglycemia, and shock, are indicators of physiologic instability.
Epidemiologic studies demonstrate that demographics, risk factors, patient characteristics, and clinical course differ significantly between term and preterm infants with NEC.
Term baby
Compared with a preterm infant, a term baby with NEC presents at a younger age, with a reported median age of onset that ranges from 1-3 days of life in the immediate postnatal period but that may appear as late as age 1 month.
The term neonate who is immediately affected postnatally is usually systemically ill with other predisposing conditions, such as birth asphyxia, respiratory distress, congenital heart disease, or metabolic abnormalities, or has a history of abnormal fetal growth pattern.
Maternal risk factors that reduce fetal gut blood flow, such as placental insufficiency from acute disease (eg, pregnancy-induced hypertension), chronic disease (eg, diabetes), or maternal cocaine abuse, can increase the baby’s risk for developing NEC.
Specific signs and symptoms that may be part of the history include bilious vomiting or gastric aspirates, abdominal distention, passage of blood per rectum, abdominal radiographs that reveal dilated loops of bowel, pneumatosis intestinalis, free abdominal air, and other signs of systemic infection, including shock and acidosis.
Premature baby
Premature babies are at risk for developing necrotizing enterocolitis for several weeks after birth, with the age of onset inversely related to gestational age at birth.
Premature infants with patent ductus arteriosus are at higher risk for developing NEC earlier in life, particularly if they are treated with indomethacin for pharmacologic closure. However, patients with persistent patent ductus arteriosus who ultimately required surgical ligation were found to have a higher NEC-associated mortality rate than did patients whose patent ductus arteriosus was successfully closed without surgery.
Patients are typically advancing on enteral feedings or may have achieved full-volume feeds when symptoms develop.
Increased incidence in the posttransfusion period has been reported in otherwise healthy premature babies who are feeding enterally and undergo blood transfusion for asymptomatic anemia of prematurity.
Presenting symptoms may include subtle signs of feeding intolerance that progress over several hours to a day, subtle systemic signs that may be reported enigmatically by the nursing staff as “acting different,” and, in advanced disease, a fulminant systemic collapse and consumption coagulopathy.
Symptoms of feeding intolerance can include abdominal distention/tenderness, delayed gastric emptying as evidenced by increasing gastric residuals, and, occasionally, vomiting.
Systemic symptoms can insidiously progress to include nonspecific signs and symptoms, such as increased apnea and bradycardia, lethargy, and temperature instability, among the primary manifestation(s).
Patients with fulminant NEC present with profound apnea, rapid cardiovascular and hemodynamic collapse, and shock.
The baby’s feeding history can help increase the index of suspicion for early NEC. Babies who are breastfed have a lower incidence of NEC than do formula-fed babies.
Rapid advancement of formula feeding has been associated with an increased risk of NEC. However, multiple subsequent studies have failed to substantiate this finding.
Necrotizing enterocolitis represents a significant clinical problem and affects close to 10% of infants who weigh less than
NEC most commonly affects the terminal ileum and the proximal ascending colon. However, varying degrees of NEC can affect any segment of the small intestine or colon. The entire bowel may be involved and may be irreversibly damaged.
Numerous, vague reports in 19th-century literature report described infants who died from peritonitis in the first few weeks of life. The first half of the 20th century brought more reports of peritonitis with ileal perforation due to what was called infectious enteritis. In 1953, Scmid and Quaiser called this conditioewborn NEC. The first clear report of NEC did not appear until 1964, when Berdon from the New York Babies Hospital described the clinical and radiographic findings of 21 infants with the disease.
As neonatal intensive care has progressed an d as premature newborns have come to survive long enough for the disease to develop, the incidence of NEC ieonatal intensive care units (NICUs) has increased. NEC remains one of the most challenging diseases confronted by pediatric surgeons. It likely represents a spectrum of diseases with variable causes and manifestations, and surgical care must therefore be individualized.
NEC typically occurs in the second to third week of life in the infant who is premature and has been formula fed. Although various clinical and radiographic signs and symptoms are used to make the diagnosis, the classic clinical triad consists of abdominal distension, bloody stools, and pneumatosis intestinalis. Occasionally, signs and symptoms include temperature instability, lethargy, or other nonspecific findings of sepsis.
Although the exact etiology of necrotizing enterocolitis (NEC) remains unknown, research suggests that it is multifactorial; ischemia and/or reperfusion injury, exacerbated by activation of proinflammatory intracellular cascades, may play a significant role. Cases that cluster in epidemics suggest an infectious etiology. Gram-positive and gram-negative bacteria, fungi, and viruses have all been isolated from affected infants; however, many infants have negative culture findings.
Furthermore, the same organisms isolated in stool cultures from affected babies have also been isolated from healthy babies. Extensive experimental work in animal models suggests that translocation of intestinal flora across an intestinal mucosal barrier rendered vulnerable by the interplay of intestinal ischemia, immunologic immaturity, and immunological dysfunction may play a role in the etiology of the disease, spreading it and triggering systemic involvement. Such a mechanism could account for the apparent protection breast-fed infants have against fulminant NEC.
Animal model research studies have shed light on the pathogenesis of this disease. Regardless of the triggering mechanisms, the resultant outcome is significant inflammation of the intestinal tissues, the release of inflammatory mediators (eg, leukotrienes, tumor necrosis factor [TNF], platelet-activating factor [PAF]) and intraluminal bile acids, and down-regulation of cellular growth factors, all of which lead to variable degrees of intestinal damage.
Abnormal intestinal flora
In healthy individuals, the intestinal milieu is characterized by a predominance of bifidobacteria. Such colonization is enhanced by the presence of oligofructose, a component of human milk, in the intestinal lumen. Infants who receive formula feedings without oligofructose as a constituent have beeoted to have a predominance of clostridial organisms.
Infectious organisms are thought to play a key role in the development of NEC. Whether bacterial infection has a primary inciting role in NEC or whether an initial intestinal mucosal injury allows secondary bacterial invasion is unclear. Positive blood cultures are found in 30% of patients; the most commonly identified organisms are Escherichia coli and Klebsiella pneumoniae. Proteus mirabilis, Staphylococcus aureus, S epidermidis, Enterococcus species, Clostridium perfringens, and Pseudomonas aeruginosa have also been identified.
E coli, Klebsiella species, Enterobacter cloacae, P aeruginosa, Salmonella species, S epidermidis, C perfringens, C difficile, and C butyricum commonly grow in stool cultures. Klebsiella species, E coli, S epidermidis, and yeast are most commonly identified on peritoneal cultures. Fungal infection is believed to be an opportunistic infection in the presence of an altered host intestinal defense system.
The observation of an epidemic or cluster of cases in a short period in one nursery after sporadic cases supports the key role of infectious organisms in NEC. Nursery personnel are known to experience acute GI illnesses in association with these outbreaks, and the institution of infection control measures has accordingly reduced the rates of NEC.
Rat pups colonized with Staphylococcus aureus and Escherichia coli demonstrated increased incidence and severity of necrotizing enterocolitis compared with those whose intestines were populated with various bacterial species.Toll-like receptor signaling of intestinal mucosal transmembrane proteins is accomplished by binding of specific bacterial ligands that mediate the inflammatory response; the character of the intestinal bacterial milieu is thought to play a role in the up-regulation or down-regulation of intestinal inflammation via toll-receptor signaling.
Many preterm infants receive frequent exposure to broad-spectrum antibacterial agents, further altering the intra-intestinal bacterial environment.
Experimental and meta-analytical evidence suggests that exogenous administration of the probiotics bifidobacteria and lactobacilli (nondigestible substances that selectively promote the growth of beneficial, probioticlike bacteria normally present in the gut) may moderate the risk and severity of NEC in preterm infants.
Intestinal ischemia
Epidemiologically, some have noted that infants exposed to intrauterine environments marked by compromised placental blood flow (ie, maternal hypertension, preeclampsia, cocaine exposure) have an increased incidence of NEC. Similarly, infants with postnatally diminished systemic blood flow, as is found in patients with patent ductus arteriosus or congenital heart disease (both considered risk factors for NEC), also have an increased incidence. Infants with patent ductus arteriosus are at particularly high risk for developing NEC if pharmacologic closure is attempted.
A retrospective analysis compared outcomes of NEC in patients with congenital heart disease with outcomes of NEC in patients without congenital heart disease; the study demonstrated improved outcomes in patients with heart disease. This somewhat counterintuitive finding further emphasizes the multifactorial pathophysiology underlying NEC.
Animal models of induced intestinal ischemia have identified its significant role in the development of NEC. Pathologically, ischemia induces a local inflammatory response that results in activation of a proinflammatory cascade with mediators such as PAF, TNF-a, complement, prostaglandins, and leukotrienes such as C4 and interleukin 18 (IL-18).
Alterations in hepatobiliary cell junction integrity result in leakage of these proinflammatory substances and bile acids into the intestinal lumen, increasing intestinal injury. Cellular protective mechanisms such as epidermal growth factor (EGF), transforming growth factor β1 (TGF-β1), and erythropoietin are down-regulated, further compromising the infant’s ability to mount a protective response. Subsequent norepinephrine release and vasoconstriction result in splanchnic ischemia, followed by reperfusion injury.
Intestinal necrosis results in breach of the mucosal barrier, allowing for bacterial translocation and migration of bacterial endotoxin into the damaged tissue. The endotoxin then interacts synergistically with PAF and a multitude of other proinflammatory molecules to amplify the inflammatory response.
Activated leukocytes and intestinal epithelial xanthine oxidase may then produce reactive oxygen species, leading to further tissue injury and cell death. Experimental administration of PAF inhibitors in animal models has not been shown to mitigate intestinal mucosal injury. Many other modulators of the inflammatory response are being studied both in vivo in animal models and in vitro in an attempt to mitigate or prevent the morbidity and mortality caused by fulminant necrotizing enterocolitis.
Intestinal mucosal immaturity
NEC is principally a disease of premature infants. Although approximately 5-25% of infants with NEC are born full term, studies have found a markedly decreased risk of NEC with increasing gestational age. This finding suggests that maturation of the GI system plays an important role in the development of NEC.
The premature neonate has numerous physical and immunologic impairments that compromise intestinal integrity. Gastric acid and pepsin production are decreased during the first month of life. Pancreatic exocrine insufficiency is associated with low levels of enterokinase, the enzyme that converts trypsinogen to trypsin, which allows hydrolysis of intestinal toxins. Mucus secretion from immature goblet cells is decreased. Gut motility is impaired, and peristaltic activity is poorly coordinated. Finally, secretory immunoglobulin A (IgA) is deficient in the intestinal tract of premature infants not fed breast milk.
In the preterm infant, mucosal cellular immaturity and the absence of mature antioxidative mechanisms may render the mucosal barrier more susceptible to injury. Intestinal regulatory T-cell aggregates are a first-line defense against luminal pathogens and may be induced by collections of small lymphoid aggregates, which are absent or deficient in the premature infant.
Experimental and epidemiologic studies have noted that feeding with human milk has a protective effect; however, donor human milk that has been pasteurized is not as protective. Human milk contains secretory immunoglobulin A (IgA), which binds to the intestinal luminal cells and prohibits bacterial transmural translocation. Other constituents of human milk, such as IL-10, EGF, TGF-β1, and erythropoietin, may also play a major role in mediating the inflammatory response. Oligofructose encourages replication of bifidobacteria and inhibits colonization with lactose-fermenting organisms.
Human milk has been found to contain PAF acetylhydrolase, which metabolizes PAF; preterm human milk has higher PAF acetylhydrolase activity (as much as 5 times greater in one study ) than milk collected from women who delivered at term.
The initiation of early enteral feedings is associated with NEC. Some series have reported decreased rates of NEC when feeding volumes are reduced. In a prospective randomized trial, Book et al found a significant increase in the development of NEC among preterm infants fed a hyperosmolar elemental formula compared with those fed a milk formula.
Innate genetic predisposition
Twin studies have suggested susceptibility to NEC may be affected by a genetic component. Given the frequent subtle and nonspecific nature of presenting symptoms, identification of a biomarker for infants at higher risk of developing necrotizing enterocolitis could have significant impact on morbidity and mortality rates.
Animal models have focused on single-nucleotide polymorphisms (SNPs) that negatively affect innate immune responses to bacterial antigens. One such SNP, discovered in the gene that encodes carbamoyl-phosphate synthetase I (the rate-limiting enzyme for the production of arginine), has been reportedly associated with an increased risk of NEC.
Infants with distinct genotypes of various cytokines have also been associated with higher frequencies of NEC. Given the interplay of inherent, infectious, ischemic, inflammatory, iatrogenic, and environmental factors, alterations in expression of proinflammatory and/or anti-inflammatory mediators may play a role ieonatal susceptibility to the disease.
Epidemiology
Although some studies indicate a higher frequency of NEC in black babies than in white babies, other studies show no difference based on race. Most studies indicate that male and female babies are equally affected.
Occurrence in the United States
The frequency of necrotizing enterocolitis (NEC) varies among nurseries, without correlation with season or geographic location. Outbreaks of NEC seem to follow an epidemic pattern within nurseries, suggesting an infectious etiology, although a specific causative organism has not been isolated.
Population studies conducted in the United States over the past 25 years indicate a relatively stable incidence, ranging from 0.3-2.4 cases per 1000 live births. The disease classically presents among the smallest preterm infants. Although it is reported among term infants with perinatal asphyxia or congenital heart disease, differences in severity and outcome suggest presentation in this population may represent a distinct pathophysiologic entity.
International occurrence
Population-based studies from other countries suggest a frequency similar to the United States. However, nations with a lower rate of premature births than that in the United States generally have a lower rate of NEC as well. For example, a large study of NICUs in Japan identified a 0.3% incidence of NEC, which is significantly lower than that in similar patient populations in the United States.
An epidemiologic review of the disease in infants born at less than 32 weeks’ gestation who survived past 5 days of life in Canada reported an incidence of 6.4%.
Age-related demographics
NEC is more prevalent in premature infants, with incidence inversely related to birth weight and gestational age. Although specific numbers range from 4% to more than 50%, infants who weigh less than
The average age of onset in premature infants seems to be related to postconceptional age, with babies born earlier developing NEC at a later chronologic age. The average age of onset has been reported to be 20.2 days for babies born at less than 30 weeks’ estimated gestational age (EGA), 13.8 days for babies born at 31-33 weeks’ EGA, and 5.4 days for babies born after 34 weeks’ gestation.
Term infants develop necrotizing enterocolitis much earlier, with the average age of onset within the first week of life or, sometimes, within the first 1-2 days of life. Observational studies have suggested the etiology of the disease in term and near-term infants may be different than that postulated in the premature infant and could include entities such as cow’s milk protein–induced enterocolitis and glucose-6-phosphate dehydrogenase deficiency.
Stages of the necrotizing enterocolitis
|
Stage |
Clinical signs |
X-ray |
|
І – incidence |
Bad thermoregulation, poor sucking, loss of appetite, vomiting; Local signs: meteorism, defecation up to 10 per day with large amount of mucus. |
bowel wall thickening and bubbles of air in bowel |
|
ІІ – height |
General status is hard, often apneas, bradicardia, hypotonia, lethargy; blood in stools; Local signs: vomiting is often, edema of the anterior abdominal wall, sex organs. Abdomen is enlarged, lustering, peristalsis is depressed or absent |
Enlargement bubbles of air in bowel, levels of the fluid, bubbles of air in bowel wall |
|
ІІІ – progressive |
The same + increasing of the brease and cardiac defficiency, hypothermia, jaundice, DIC-syndrome; peritonitis, bowel inpassage, ascitis |
Fluid sequestration in the abdominal cavity, bowel wall necrosis |
|
ІV – complications |
Perforation, peritonitis, anuria, DIC–syndrom, septic shock. |
The same + pneumoperitoneum |
Approach Considerations
Initial presentation of necrotizing enterocolitis (NEC) usually includes subtle signs of feeding intolerance, such as gastric residuals, abdominal distention, and/or grossly bloody stools. Abdominal imaging studies are crucial at this stage. In fact, radiographic studies should be obtained if any concern about NEC is present.
Laboratory studies are pursued, especially if the abdominal study findings are worrisome or the baby is manifesting any systemic signs. Laboratory values can give insight into the severity of the disease and can aid in the provision of appropriate therapy.
However, although all of the initial laboratory studies taken together may aid in the diagnosis of NEC, they do not substitute for an appropriate appreciation of the clinical presentation and appearance of the infant.
Complete blood count
A complete blood count (CBC), with manual differential to evaluate the white blood cell (WBC), hematocrit, and platelet count, is usually repeated at least every 6 hours if the patient’s clinical status continues to deteriorate.
White blood cell count
Marked elevation may be worrisome, but leukopenia is even more concerning. Although elevated mature and/or immature neutrophil counts may not be good indicators of neonatal sepsis after the first 3 days of life, moderate to profound neutropenia (absolute neutrophil count [ANC] < 1500/μL) strongly suggests established sepsis.
Red blood cell count
Premature infants are prone to anemia due to iatrogenic blood draws, as well as anemia of prematurity; however, blood loss from hematochezia and/or a developing consumptive coagulopathy can manifest as an acute decrease in hematocrit.
An elevated hemoglobin level and hematocrit may mark hemoconcentration due to notable accumulation of extravascular fluid.
Platelet count
Platelets are an acute phase reactant, and thrombocytosis can represent physiologic stress to an infant, but acute NEC is more commonly associated with thrombocytopenia (< 100,000/μL). Thrombocytopenia may become more profound in severe cases that become complicated with consumption coagulopathy. Consumption coagulopathy is characterized by prolonged prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), and decreasing fibrinogen and increasing fibrin degradation products concentrations
Thrombocytopenia appears to be a reaction to gram-negative organisms and endotoxins. Platelet counts of less than 50,000 warrant platelet transfusion.
Blood culture
Obtaining a blood culture is recommended before beginning antibiotics in any patient presenting with any signs or symptoms of sepsis or NEC. Although blood cultures do not grow any organisms in most cases of NEC, sepsis is one of the major conditions that mimics the disease and should be considered in the differential diagnosis. Therefore, identification of a specific organism can aid and guide further therapy.
Serum electrolytes
Serum electrolytes can show some characteristic abnormalities. Obtain basic electrolytes (Na+, K+, and Cl–) during the initial evaluation, followed serially at least every 6 hours depending on the acuity of the patient’s condition.
Serum sodium
Hyponatremia is a worrisome sign that is consistent with capillary leak and “third spacing” of fluid within the bowel and peritoneal space. Depending on the baby’s age and feeding regimen, baseline sodium levels may be low normal or subnormal, but an acute decrease (< 130 mEq/dL) is alarming, and heightened vigilance is warranted.
Metabolic acidosis
Low serum bicarbonate (< 20) in a baby with a previously normal acid-base status is also concerning. It is seen in conjunction with poor tissue perfusion, sepsis, and bowel necrosis.
Other tests
Reducing substances may be identified in the stool of formula-fed infants because poorly digested carbohydrates are fermented in the colon and excreted in stool. Similarly, results from a breath hydrogen test may be positive with increased carbohydrate fermentation.
Imaging techniques
Reports from outside of the United States suggest that imaging techniques such as contrast radiography, magnetic resonance imaging (MRI), and radionuclide scanning may play a role in diagnosis the diagnosis of NEC. These techniques are not currently in common use.
GI tonometry is an infrequently used technique that may be helpful in distinguishing benign feeding intolerance from early NEC. The use of radiography and ultrasonography in the diagnosis of NEC is discussed in detail below.
Diagnostic Considerations
Necrotizing enterocolitis (NEC) is a clinical diagnosis that can be subtle at its onset. Early symptoms frequently mimic more common clinical conditions, such as poor gastric motility and benign feeding intolerance. Retrospective review of the earliest clinical signs once the diagnosis is apparent can seem misleadingly clear, even though the prospective assessment was much less straightforward. Laboratory and radiographic evidence can bolster a clinical impression of benign conditions.
Not infrequently, free air is noted on an abdominal radiograph of a premature infant, either as an incidental finding on imaging performed for other reasons or during an initial evaluation for abdominal pathology. Spontaneous intestinal perforation (SIP) can be distinguished from NEC by its lack of systemic involvement, absence of other clinical signs common to bowel perforation, and higher rate of survival.[SIP is further distinguished by its earlier onset in babies of smaller birth weight and more extreme prematurity. Associations have been identified between SIP and indomethacin, dexamethasone, and systemic candidiasis.
Conditions to consider in the differential diagnosis of NEC include the following:
- Hypoplastic left heart syndrome
- Intestinal malrotation
- Intestinal volvulus
- Bacterial meningitis
- Neonatal sepsis
- Omphalitis
- Prematurity
- Urinary tract infection
- Volvulus
Differential Diagnoses
- Acidosis, Metabolic
- Acidosis, Respiratory
- Apnea of Prematurity
- Bacteremia
- Candidiasis
- Coarctation of the Aorta
- Enteroviral Infections
- Gastroesophageal Reflux
- Hirschsprung Disease
- Hospital-Acquired Infections
· Complications:
o perforation, later – stenosis
Approach Considerations
As many as 50% of all premature infants manifest feeding intolerance during their hospital course, but less than one fourth of those infants develop necrotizing enterocolitis (NEC). As with all neonatal care, the risks and benefits of various clinical approaches to NEC must be considered carefully.
Patients with mild (Bell stage II) NEC require GI rest to facilitate resolution of the intestinal inflammatory process. These babies are traditionally kept on a diet of nothing by mouth (NPO) for 7-10 days, making parenteral hyperalimentatioecessary. Many of these babies have difficult intravenous (IV) access. Therefore, the need for prolonged parenteral nutrition frequently requires placing central venous catheters, which have attendant risks and complications that include thromboembolic events and nosocomial infections.
Cessation of feeding and initiation of broad-spectrum antibiotics in every baby with feeding intolerance impedes proper nutrition and exposes the baby to unnecessary antibacterials that may predispose to fungemia. On the other hand, failure to intervene appropriately for the baby with early NEC may exacerbate the disease and worsen the outcome. Clearly, managing this population requires a high degree of clinical suspicion for possible untoward events, tempered by cautious watching and waiting.
Placement of a peripheral arterial line may be helpful at the beginning of the patient’s treatment to facilitate serial arterial blood sampling and invasive monitoring.
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).
If the baby is rapidly deteriorating, with apnea and/or signs of impending circulatory and respiratory collapse, airway control and initiation of mechanical ventilation is indicated.
Abdominal decompression
Decompression is essential at the first sign of abdominal pathology. Abdominal decompression in infants with necrotizing enterocolitis is as follows:
- Use a large-bore catheter with multiple side holes and a second lumen to prevent vacuum attachment to the stomach mucosa (eg, Replogle tube)
- Set the catheter for low, continuous or intermittent suction and monitor output; the tube should be irrigated with several milliliters of normal saline to maintain patency
- If copious amounts of gastric/intestinal secretions are removed, consider IV replacement with a physiologically similar solution; maintaining electrolyte balance and intravascular volume is essential
Consultations
Consult with a pediatric surgeon at the earliest suspicion of developing necrotizing enterocolitis. This may require transferring the patient to another facility where such services are available.
Transfer
In the acute phase, patients with progressive NEC require pediatric surgical consultation. During refeeding, patients with or without previous surgical history may demonstrate signs of obstruction requiring surgical evaluation and/or intervention. Transfer the patient to a facility offering pediatric surgical expertise, if it is not available at the current location.
Future possibilities
Two Cochrane Database of Systematic Reviews studies discuss very promising but also very preliminary treatments.
One discusses lactoferrin supplementation in the milk of infants and suggests it shows promising preliminary results in reducing the incidence of late-onset sepsis in infants weighing less than
The other study found evidence that intravenous pentoxifylline as an adjunct to antibiotic therapy may reduce mortality and duration of hospitalization ieonates with sepsis; no completed studies were found confirming outcomes of treatment for patients with NEC. Although these results also are promising, more research is needed to validate the findings
The mainstay of treatment for patients with stage I or II necrotizing enterocolitis (NEC) is nonoperative management. The initial course of treatment 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 commoosocomial organisms found in the particular NICU.
Authors in some series have proposed the use of enteral aminoglycosides for the treatment of NEC, but several prospective trials have showo efficacy for this treatment. In addition, a strong index of suspicion for fungal septicemia must be maintained, especially in the infant with a deteriorating condition and negative bacterial cultures.
Bell stages IA and IB
The patient is kept on an NPO diet with antibiotics for 3 days. IV fluids are provided, including total parenteral nutrition (TPN).
Bell stages IIA and IIB
Treatment includes support for respiratory and cardiovascular failure, including fluid resuscitation, NPO, and antibiotics for 14 days. Surgical consultation should be considered. After stabilization, TPN should be provided during the period that the infant is NPO.
Bell stage IIIA
Treatment involves NPO for 14 days, fluid resuscitation, inotropic support, and ventilator support. Surgical consultation should be obtained. TPN should be provided during the period of NPO.
Bell stage IIIB
Surgical intervention, as outlined in the next section, is provided.
Indications
The principle indication for operative intervention iecrotizing enterocolitis (NEC) is perforated or necrotic intestine. Infants with necrotic intestine are identified based on various clinical, laboratory, and radiologic findings. The most compelling predictor of intestinal necrosis indicating a need for operative intervention is pneumoperitoneum (see the image below). Other relative indications for operative intervention are erythema in the abdominal wall, gas in the portal vein, and positive paracentesis.
Pneumoperitoneum.
Surgery is generally indicated in the medically treated patient whose clinical condition deteriorates. The signs of deterioration include worsening abdominal examination findings, signs of peritonitis, worsening and intractable acidosis, persistent thrombocytopenia, rising leukocytosis or worsening leukopenia, and hemodynamic instability.
Note that evaluation by a pediatric surgeon early in the course of NEC is important to avoid any delay in operative intervention. Many infants may have isolated perforations or necrotic tissue that wall off the abdominal cavity and do not show free intraperitoneal air. Knowing whether these infants may benefit from early operative intervention is difficult.
Contraindications
Contraindications to surgical intervention include patients with stage I or stage II disease, for whom nonoperative medical therapy is the treatment of choice. In addition, surgical intervention should be deferred in patients with more severe disease whose condition responds to initial medical management.
Patients who are extremely small and ill may not have the stability to tolerate laparotomy. If free air develops in such a patient, one may consider inserting a peritoneal drain under local anesthesia in the nursery.
Preoperative care
After the decision to proceed with surgery is made, the patient’s general physiologic condition should be optimized. Provide vigorous fluid replacement, correct any clinically significant anemia or coagulopathy, and ensure adequate urine output of at least 1 mL/kg/h. To minimize heat loss, place the infant on a heated air pad; in addition, a warmed operating room and warmed IV and irrigation fluids should be used. The use of heated and humidified oxygen and anesthetic gases may further minimize heat loss. Blood products should be available during surgery.
Intraoperative details
The abdomen can be entered via a right transverse incision just below the umbilicus by using electrocautery to ensure hemostasis. This incision provides adequate exposure away from a frequently large liver and decreases the risk of retractor injury to the liver. Care must be taken at the time of entry into the peritoneal cavity to avoid injury to dilated loops of intestine. If any free intraperitoneal fluid is identified, samples may be taken for aerobic, anaerobic, and fungal culture. Bloody peritoneal fluid is seen iecrosis and brown turbid fluid is found in perforation.
The abdominal cavity is then systematically inspected for evidence of necrosis and perforation. Particular attention is paid to the right lower quadrant because the terminal ileum and proximal ascending colon are most commonly involved. The guiding principle of surgery for NEC is to resect only perforated and unquestionably necrotic intestine and to make every effort to preserve the ileocecal valve. (See the images below.)
Normal (top) versus necrotic section of bowel
. Resected portion of necrotic bowel.
White or gray bowel indicates ischemic necrosis. Hemorrhagic or edematous areas of bowel may represent areas of mucosal ischemia and injury but do not necessarily indicate nonviable bowel. Saccular protrusions of bowel wall have undergone mucosal, submucosal, and muscularis necrosis and are covered only by a layer of serosa. These are areas of impending intestinal perforation.
Palpation may also be helpful, because resilient pliable bowel is typically viable, and lax and boggy bowel that indents on palpation is ofteecrotic. If the viability of remaining bowel is significantly questionable, a second-look operation can be performed in 24-48 hours to assess the viability of the remaining intestine.
If a single area of bowel is resected, a proximal ostomy and distal mucus fistula are created. The viability of the bowel at the cut margins can be ascertained by whether the cut edges bleed. The enterostomy and mucus fistula are brought out at opposite ends of the incision, with the serosa sutured to the abdominal wall fascia with interrupted sutures. About
Primary anastomosis is not generally advocated, because of the risk of ischemia at the anastomosis, leading to increased incidence of leakage, stricture, fistula, or breakdown. However, intestinal resection with primary anastomosis may be safely performed in select cases. Patients must demonstrate a clearly demarcated small segment of injured bowel with normal-appearing residual intestine and be in good general condition with no evidence of sepsis, coagulopathy, or physiologic compromise.
If multiple segments of intestine are involved because of necrosis or perforation, a decision must be made regarding the course of action. Historically, the individual segments of affected intestine are resected, and multiple ostomies are created. However, a number of other surgical options have been proposed. A single proximal stoma may be created and the distal bowel segments anastomosed in continuity, thus avoiding multiple stomas.
Moore proposes a technique of patch, drain, and wait, which involves transverse, single-layer repair of bowel perforations (patch); placement of 2 Penrose drains in the lower quadrants (drain), and initiation of long-term parenteral nutrition (wait); however, this technique is not widely advocated. The thin, distended bowel wall holds suture poorly, and the abdominal cavity does not drain freely with open gravity drainage. In addition, this technique does not address the source of intra-abdominal sepsis, because necrotic bowel is not resected.
In a small series, Vaughn describes a different technique of clip and drop-back. The unquestionably necrotic segments of intestine are resected and the transected ends are stapled closed. A second-look operation is performed in 48-72 hours when the clips are removed, and reanastomosis is performed without any ostomies.
NEC totalis occurs when less than 25% of the intestinal length is found to be viable at the time of operation; this finding results in a number of grim treatment options. Simple closure of the abdomen is supported by findings that show a 42-100% mortality rate in patients with pan involvement. Massive resection with excision of the ileocecal valve requires at least
Martin and Neblett describe a technique of enterostomy diversion proximal to the involved bowel without bowel resection. This technique may facilitate bowel healing by allowing bowel decompression, reducing intestinal bacterial load, and decreasing metabolic demand.
After intestinal resection, the length of remaining viable bowel should be sequentially measured along the antimesenteric border of the intestine and recorded.
Enterostomy closure
Timing of enterostomy closure to restore intestinal continuity is the principal follow-up issue for infants who are surgically treated for NEC. This procedure is generally performed 1-2 months after the original operation, depending on weight gain and ostomy output, among other factors. The argument against early ostomy closure is the difficulty of operating in a peritoneal cavity replete with adhesions and resolving inflammation; the ideal time is approximately 8 weeks.
If goal enteral feeds can be accomplished, there is some benefit in discharging the patient home and performing a reanastamosis after several months. This gives the infant a chance to grow and better tolerate an additional laparotomy.
Abnormally high ostomy output may indicate a need for early ostomy closure. A patient with a high jejunostomy may have substantial loss of fluid and electrolytes, with consequences such as failure to thrive and peristomal skin injury. These patients may benefit from early ostomy closure with attendant colonic water absorption.
However, infants with a high ostomy and extensive ileal resection who undergo ostomy closure may have considerable secretory diarrhea after the colon comes in contact with unabsorbed bile salts. They may require treatment with a bile salt–binding agent, such as cholestyramine. Sodium chloride supplementation (1-3 mcg/kg/day) has been recommended to optimize growth in infants with small-bowel stomas.
All patients who have any remaining large intestine after an initial operation for NEC must be examined with contrast-enhanced enema of the colon to identify any areas of stricture before the ostomy is closed. If any such areas are present, they are resected when the enterostomy is closed. In addition, some advocate a screening contrast enema study approximately 30 days after recovery in infants who have been nonoperatively treated for NEC. Symptomatic colonic strictures require treatment, whereas asymptomatic strictures may be observed.
Peritoneal drainage
Neonates who are extremely ill and unable to tolerate surgery may be treated by means of peritoneal drainage in a technique described by Ein et al. A right lower quadrant incision is made at the bedside under local anesthesia, and a Penrose drain is inserted. The procedure was initially intended as a means of temporizing with regard to surgical treatment, and indeed, some infants survived with this procedure alone and did not require subsequent laparotomy.
A multicenter, randomized clinical trial failed to show a significant difference in survival at 90 days between primary peritoneal drainage and laparotomy with resection for premature infants with very low birth weight (<
Critically ill newborns with a relative contraindication to formal operative exploration may be treated with the placement of a peritoneal drain. Although this is typically a temporizing measure, these extremely ill infants may recover with drain placement alone and do not require exploratory laparotomy.
Peritoneal drain placement may be the treatment of choice for extremely small (<
Postoperative details
After undergoing an operation for NEC, infants should continue to receive intravenous antibiotics and total parenteral nutrition for at least 2 weeks. Supportive care, including ventilatory support, fluid and electrolyte monitoring and replacement, and correction of anemia and coagulopathy, should continue.
During surgery infants with NEC often develop a coagulopathy that continues after surgery and can be difficult to manage. Blood can fill the abdominal cavity rapidly and create a compartment syndrome that requires drainage. Any infants with continued clinical deterioration must be evaluated for residual intestinal gangrene and possibly repeat surgical exploration. Infants who improve postoperatively should not resume enteral feedings for at least 10-14 days.
Parenteral Nutrition
In patients with necrotizing enterocolitis (NEC), prolonged parenteral nutrition is essential to optimize the baby’s nutrition while the GI tract is allowed enough time to recover and return to normal function. Central venous access is essential to facilitate parenteral delivery of adequate calories and nutrients to the recovering premature baby to minimize catabolism and promote growth.
Prolonged central venous access may be associated with an increased incidence of nosocomial infection, predominately with skin flora such as coagulase-negative Staphylococcus species, as well as methicillin-resistant S aureus (MRSA). A high degree of clinical suspicion must be maintained to detect the subtle signs of such infection as early as possible.
Parenteral administration of lipid formulations via central venous catheters is also associated with an increased incidence of catheter-related sepsis.
Lipids coat the catheter’s interior, allowing ingress of skin flora through the catheter lumen. A high degree of clinical suspicion is required for early detection of such an infection.
If line infection is suspected, obtain a blood culture through the central line and from a peripheral vein or artery. Antibiotics effective against skin flora, such as vancomycin, should be administered (although prolonged broad-spectrum antibacterial therapy increases the premature infant’s risk for fungal sepsis). Persistently positive cultures require removal of the central line. Remove the central line once sepsis and bacteremia are confirmed, because eradication is almost impossible when the central line is kept in place.
Prolonged parenteral nutrition may be associated with cholestasis and direct hyperbilirubinemia. This condition resolves gradually following initiation of enteral feeds.
Restarting enteral feedings
Enteral feedings are traditionally restarted 10-14 days after findings on abdominal radiographs normalize in the case of nonsurgical NEC. However, balancing the risks and benefits of NPO versus enteral feeds may alter this timeline. Reinitiating enteral feeds in postsurgical babies may take longer and may also depend on issues such as the extent of surgical resection, return of bowel motility, timing of reanastomosis, and preference of the consulting surgical team.
Because of the high incidence of postsurgical strictures, some clinicians prefer to evaluate intestinal patency via contrast studies prior to initiating enteral feeds. When feeds are restarted, if human milk is not available, formulas containing casein hydrolysates, medium-chain triglycerides, and safflower/sunflower oils (eg, Alimentum, Pregestimil, Nutramigen) may be better tolerated and absorbed than standard infant formulas.
Feeding strategies
Breastfed babies have a lower incidence of necrotizing enterocolitis (NEC) than do formula-fed infants. Much anecdotal evidence details the role of feeding regimens in the etiology of NEC, but clinical research does not demonstrate definitive evidence for either causation or prevention. Although conventional wisdom recommends slow initiation and advancement of enteral feeds for premature infants, random trials do not show an increased incidence of NEC in babies in whom feeds have been started early in life versus after 2 weeks’ chronologic age.
In 1992, McKeown et al reported that rapid increase in feeding volume (>20 mL/kg/d) was associated with higher risk of NEC. In 1999, however, Rayyis et al showed no difference in the occurrence of NEC Bell stage II or greater in patients advanced at 15 mL/kg/day compared with those advanced at 35 mL/kg/day
A systematic review published by the Cochrane Collaboration in 1999 reported no effect on NEC from rapid feeding advancement for low birth weight infants.
Antenatal and postnatal conditions that diminish intestinal blood flow may increase an infant’s risk of developing NEC. Antenatal conditions causing placental insufficiency, such as hypertension, preeclampsia, or cocaine use, may justify a more cautious and vigilant approach to enteral feeding in these infants. Similarly, postnatal conditions that diminish splanchnic blood flow, such as patent ductus arteriosus (particularly when associated with reversed aortic diastolic flow demonstrated on echocardiography), other cardiac disease, or general hypotension/cardiovascular compromise, may increase the risk.
Because early presentation of NEC can be subtle, high clinical suspicion is important when evaluating any infant with signs of feeding intolerance or other abdominal pathology. In general, continuing to feed a baby with developing NEC worsens the disease.
Pharmacologic strategies
Efforts to reduce the incidence of NEC may target infection control in the newborursery, augmentation of premature host defenses, stimulation of GI tract maturation, inhibition of inflammatory mediators, and reduction of enteric bacterial load.
Enteral immunoglobulin A (IgA) is deficient in the premature GI system, and oral IgA supplementation reduces the incidence of NEC in rat models. In addition, a series in human infants found that patients who received an oral IgG-IgA preparation were significantly less likely to develop NEC than were control subjects.
The administration of prenatal glucocorticoids to mothers for fetal pulmonary maturation significantly reduces the incidence of NEC. In addition, postnatal treatment decreases the incidence of NEC, although not as effectively as prenatal treatment.
In laboratory models PAF antagonists reduced bowel injury. However, their role in the prevention and treatment of NEC in humans has not been well established.
Nonabsorbable oral antibiotics have been used in attempts to reduce the intestinal bacterial load and presumably inhibit the progression of NEC. However, several investigators found no significant difference in outcome between infants receiving oral antibiotics and control subjects.
Long-Term Monitoring
Following hospital discharge, caring for premature infants has shifted away from neonatologists at regionalized centers to general pediatricians and other health care providers in the community. Adequate interaction between subspecialists and community providers and formulation of well-communicated health care plans for these vulnerable babies are crucial to serving their best interest and to optimizing their health outcome.
If a baby goes home with a colostomy, parents need thorough instruction regarding the baby’s care. Having the parent(s) room with the baby at the hospital for several days prior to discharge is advisable so that they can learn and demonstrate adequate caregiving skills.
Babies who have undergone intestinal resection may experience short-gut syndrome. These babies require vigilant nutritional regimens to maintain adequate calories and vitamins for optimum growth and healing.
MENINGITIS
History and Physical Examination
Regardless of the specific pathogen involved, neonatal meningitis is most often caused by vertical transmission during labor and delivery. It occurs most frequently in the days following birth and is more common in premature infants than in term infants.It is closely associated with sepsis.
Risk factors for the development of meningitis include low birth weight (<
In evaluating a neonate for meningitis, the following 3 key points should be kept in mind:
- It is important to remain vigilant for maternal infection “setups” (eg, prolonged rupture of membranes, fever, and chorioamnionitis) while remembering that asymptomatic maternal infection is always a possibility even with screening
- Early-onset and late-onset bacterial infections have distinctive clinical courses (see below)
- In herpes simplex virus (HSV) infections, the presence of skin lesions in a meningitic neonate is the exception rather than the rule
Bacterial meningitis
Early onset
Symptoms appearing in the first 48 hours of life are referable primarily to systemic illness rather than to meningitis. Such symptoms include temperature instability, episodes of apnea or bradycardia, hypotension, feeding difficulty, hepatic dysfunction, and irritability alternating with lethargy. Respiratory symptoms can become prominent within hours of birth in group B streptococcal (GBS) infection; however, the symptom complex also is seen with infection by E coli or Listeria species.
Late onset
Late-onset bacterial meningitis (ie, symptom onset after 48 hours of life) is more likely to be associated with neurological symptoms. Most commonly seen are stupor and irritability, which Volpe describes in more than 75% of affected neonates. Between 25% and 50% of neonates will exhibit the following neurological signs:
Seizures
Bulging anterior fontanel
Extensor posturing or opisthotonos
Focal cerebral signs including gaze deviation and hemiparesis
Cranial nerve palsies
Nuchal rigidity is the least common sign ieonatal bacterial meningitis, occurring in fewer than 25% of affected neonates.[
HSV meningitis
Early features of HSV meningitis may mimic those associated with bacterial meningitis, including pallor, irritability, high-pitched cry, respiratory distress, fever, or jaundice, progressing to pneumonitis, seizures, hepatic dysfunction, and disseminated intravascular coagulopathy (DIC).
Complications
Regardless of etiology, meningitis ieonates can progress rapidly to serious complications, including cerebral edema, hydrocephalus, hemorrhage, ventriculitis (especially with bacterial infection), abscess formation, and cerebral infarction.
Cerebral edema, hydrocephalus, and hemorrhage each may cause increased intracranial pressure, with potential for secondary ischemic injury to the brain because of decreased brain perfusion:
Cerebral edema results from vasogenic changes, cytotoxic cell injury, and, at times, inappropriate antidiuretic hormone (ADH) secretion
Hydrocephalus results from debris obstructing the flow of cerebrospinal fluid (CSF) through the ventricular system or from dysfunction of arachnoid villi; it occurs in as many as 24% of neonates with bacterial meningitis
Hemorrhage occurs in regions of infarction or necrosis and should be suspected in a neonate with new focal neurological findings or clinical deterioration
Ventriculitis results in sequestration of infection to areas that are poorly accessible to systemic antimicrobial drugs. Inflammation of the ependymal lining of ventricles often obstructs CSF flow. Thus, all of these complications are interactive, making effective management difficult. Ventriculitis occurs in as many as 20% of infected neonates. Failure to respond to appropriate antibiotic therapy and signs of elevated intracranial pressure (ICP) may suggest the diagnosis.Intraventricular administration of antibiotics may be necessary in cases of ventriculitis.
Cerebral abscess occurs in as many as 13% of neonates with meningitis. New seizures, signs of elevated ICP, or new focal neurological signs suggest the diagnosis. Brain imaging with contrast is essential for making the definitive diagnosis. Surgical intervention may be required.
Cerebral infarction, both focal (arterial) and diffuse (venous), may complicate recovery. Autopsy studies have found evidence of infarction in 30-50% of specimens studied. Imaging studies suggest that the actual incidence of infarction may be even higher. Meningitis has been shown to be associated with 1.6% of all cases of neonatal arterial stroke and 7.7% of venous infarcts.
Necrotizing lesions secondary to HSV meningitis can be deleterious to the developing brain.
Other, longer-term complications that may develop include residual epilepsy, cognitive impairment, hearing loss, visual impairment, spastic paresis, and microcephaly. Some of these disorders may be difficult to detect during infancy.
Hearing, for example, is difficult to evaluate without the child’s cooperation, and even then, assessment may be limited to behavioral response to sounds. Brainstem auditory evoked response (BAER) testing does not evaluate all dimensions of hearing, but this test, which can be performed reliably in sedated infants, only slightly overestimates hearing loss, which occurs in 30% of survivors of bacterial meningitis and 14% of survivors of nonbacterial meningitis. Subtle impairment of sound discrimination may not be readily apparent.
Similarly, cognitive impairment may not be evident until the child has started school or advanced into higher grades where more complex analysis of information is necessary. Careful screening for neurological, cognitive, and developmental deficits must be conducted as part of routine pediatric care over a period of many years, and the responsible physician should be attentive to possible problems with perception, learning, or behavior that may result from neonatal infection
Diagnostic Considerations
Bacterial meningitis ieonates almost always occurs with sepsis but is difficult to distinguish clinically from sepsis alone; both present with a constellation of symptoms that indicate systemic illness. Therefore, treatment is started on the basis of presumed infection rather than proven infection. Because the goal in the neonate is to manage any life-threatening condition that will respond to intervention, the differential diagnosis includes disorders of cardiac, pulmonary, and metabolic functions.
Other central nervous system (CNS) problems may present in a manner that simulates meningitis. These include hemorrhage, ischemic stroke, and hypoxic-ischemic encephalopathy. Cerebral edema associated with nonhemorrhagic trauma may present a confounding picture.
In addition, bacterial or viral meningitis always should be considered among the disorders that cause shock, disseminated intravascular coagulation (DIC), or hepatic failure ieonates. However, by the time these conditions develop, the opportunity for successful intervention may have passed. Therefore, prompt consideration of meningitis remains prudent whenever a neonate demonstrates even slight lethargy or irritability.
Other conditions that should be considered are drug withdrawal, inborn errors of metabolism (including aminoacidopathies, organic acidurias, urea cycle disorders, and mitochondrial disease), and gastrointestinal problems such as necrotizing enterocolitis or perforated bowel. The possibility of nonaccidental trauma (ie, shaken baby syndrome) should be taken into account as well.
Differential Diagnoses
- Abnormal Neonatal EEG
- Aseptic Meningitis
- Benign Neonatal Convulsions
- Cerebellar Hemorrhage
- Cerebral Aneurysms
- Cerebral Venous Thrombosis
- Haemophilus Meningitis
- Head Trauma
- Inherited Metabolic Disorders
- Intracranial Epidural Abscess
- Intracranial Hemorrhage
- Meningococcal Meningitis
- Neonatal Seizures
- Viral Encephalitis
- Viral Meningitis
Approach Considerations
Delayed diagnosis of neonatal meningitis is a potentially critical pitfall. Failure to perform a lumbar puncture and detect infection in a neonate with mild fever and minimal, nonspecific clinical findings is problematic; all neonates in whom meningitis might be the cause of symptoms should undergo CSF examination. Delay in treatment because of equivocal laboratory screening tests or because findings are altered by prior partial treatment may cause significant harm.
In a 2001 survey of pediatricians, “meningitis or other infectious disease” and “newborn conditions other than congenital vision/hearing loss” were the 2 most frequent bases reported for malpractice suits. In this survey, “the most prevalent condition for which claims were filed against pediatricians was neurological impairment of an infant. Thirty percent of claims paid were for this condition alone. However, the second most prevalent condition, meningitis, resulted in a higher percentage of paid claims (46%) and a higher total and average indemnity.”
Laboratory Studies
Suspected bacterial infection is often, but not uniformly, confirmed by positive results from cultures of cerebrospinal fluid (CSF) or blood. CSF cultures should be obtained in all symptomatic infants; despite the close relationship between bacterial sepsis and meningitis, it has been estimated that 15-30% of infants with CSF-proven meningitis will have negative blood cultures.
A study from Duke emphasized that with the exception of CSF culture, no single CSF value can be relied upon to exclude neonatal meningitis. The onus is on the clinician to justify initiation of antimicrobial and antiviral therapy, regardless of the CSF values.
Polymerase chain reaction (PCR) assay is a powerful diagnostic tool with excellent sensitivity and specificity. It permits identification of group B streptococcal (GBS) antigen in urine or CSF, and it is the standard for identification of herpes simplex virus (HSV) and enterovirus in CSF. Ieonates, PCR is 71-100% sensitive for HSV but 98-99% specific. If initial HSV PCR is negative and HSV meningitis is suspected, a repeat lumbar puncture 5-7 days later may be useful. Blood in the CSF can also lead to false-negative results.
As PCR becomes more widely available, recognition of enteroviral infections has increased. Additionally, PCR for human parechovirus-3 is becoming more widely available.
Rapid screening is available with latex particle agglutination (LGA) testing of urine, which can be performed for GBS, E coli, and Streptococcus pneumoniae. Unfortunately, the presence of GBS antigen does not prove invasive disease.
If vesicles are present on the skin, evaluation for HSV infection should include cultures of fluid from these vesicles. Swabs of the nasopharynx, conjunctiva, and rectum have also been used to identify viral agents. DNA from HSV or enteroviruses can be identified from either vesicles or CSF by using PCR.
It should be kept in mind that interpretation of CSF findings is more difficult ieonates than in older children, especially in premature infants whose more permeable blood-brain barrier causes higher levels of glucose and protein.
The classic finding of decreased CSF glucose, elevated CSF protein, and pleocytosis is seen more with gram-negative meningitis and with late gram-positive meningitis; this combination also is suggestive of viral meningitis, especially HSV. Only if all 3 parameters are normal does the lumbar puncture provide evidence against infection; no single CSF parameter exists that can reliably exclude the presence of meningitis in a neonate.
The number of white blood cells (WBCs) found in the CSF in healthy neonates varies according to gestational age. Many authors use a cutoff value of 20-30/µL. Bacterial meningitis commonly causes CSF pleocytosis greater than 100/µL, with predominantly polymorphonuclear leukocytes (PMNs) gradually evolving to lymphocytes. In neonates with viral meningitis, the picture may be similar but with a less dramatic pleocytosis. HSV meningitis may be particularly associated with a large number of red blood cells (RBCs) in the CSF.
If the mother is symptomatic, maternal investigation may be warranted; bacterial or viral cultures can provide valuable adjunctive information.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is the neuroimaging modality of choice for identifying focal areas of infection, infarction, secondary hemorrhage, cerebral edema, hydrocephalus, or, rarely, abscess formation. It should be considered in the context of focal neurological abnormalities, persistent infection, or clinical deterioration. Sinovenous occlusions, ventriculitis, and subdural collections are best diagnosed with MRI.
Follow-up MRI scans are useful for following the resolution of the infection, as well as for contributing to prognostication. If available, magnetic resonance spectroscopy can add important information on the metabolic function of the neonatal brain.
Several studies have documented periventricular white matter abnormalities on MRI in infants with neonatal meningitis. Newer MRI technologies, including diffusion-weighted and diffusion tensor imaging, have allowed this association to be evaluated in more detail, and such evaluation may prove to have prognostic implications.
Other Imaging Modalities
Although computed tomography (CT) carries the risk of exposing the neonatal brain to radiation, the rapidity and ease with which it can be obtained (in comparison with MRI) makes it useful in decision-making for potential neurosurgical interventions, such as ventriculostomy for hydrocephalus or surgical drainage of empyema or abscess. It may be particularly appropriate for a critically ill neonate being considered for neurosurgery.
Cranial ultrasonography provides an alternative imaging modality for critically ill neonates, but it does not provide optimal detail in all circumstances. However, it is a low-risk and thus is useful in monitoring ventricular size for hydrocephalus during the acute phase of meningitis.
Chest radiography provides important information about the lung parenchyma and the cardiac silhouette. Meningitis or sepsis may occur with pneumonia but may be indistinguishable from surfactant deficiency, pulmonary hypertension, and obstructive cardiac disease.
Electroencephalography
Electroencephalography (EEG) is not an essential part of the initial diagnostic process. However, in neonates who are unresponsive or have seizures presenting as episodes of apnea, bradycardia, or rhythmic focal movements, EEG monitoring provides useful information to guide treatment with anticonvulsant drugs.
EEG also has some prognostic utility. In a study by Klinger et al, infants with normal or mildly abnormal EEGs had better outcomes, whereas those with moderately-to-markedly abnormal EEGs were more likely to die or to suffer adverse outcomes. In a study by Poblano et al, EEG was predictive of microcephaly and spasticity at 9-month follow-up.
Lumbar Puncture
Lumbar puncture is indicated for evaluation of the CSF in all neonates suspected of having sepsis or meningitis, even in the absence of neurological signs.
Many clinicians are reluctant to perform this procedure on a critically ill infant. Although the theoretical complications of lumbar puncture include trauma, brain-stem herniation, introduction of infection, and hypoxic stress, none of these complications were reported in a meta-analysis of more than 10,000 infants who underwent lumbar puncture.
Meningitis, however, increases the risk of death ieonates. Stoll et al reported a mortality of 23% in babies with CSF-proven meningitis, compared with a mortality of 9% ieonates whose lumbar puncture results were not consistent with meningitis. Additionally, many infants who had negative blood cultures had positive CSF cultures, suggesting that cases of meningitis may be missed.
In cases of bacterial meningitis, repeat lumbar puncture should be performed 24-48 hours after initiation of therapy to ensure sterilization of the CSF. After a full course of therapy for PCR-proven HSV, repeat lumbar puncture should be undertaken to rule out incompletely treated infections.
Pharmacologic and Supportive Therapy
Although evaluation and treatment of perinatal infection often begins before birth, discussion of antenatal interventions is beyond the scope of this review. However, early initiation of antimicrobial drugs is essential; a confirmed diagnosis of meningitis seldom is established before treatment is started.
Aggressive antimicrobial intervention is lifesaving ieonates with suspected meningitis. Because distinguishing viral from bacterial meningitis is difficult early in the clinical course, a combination of agents is ofteecessary, providing coverage for both types of infection. The duration of therapy for bacterial and herpes simplex virus (HSV) meningitis with an appropriate agent is typically 14-21 days.
Although there is a consensus that acyclovir is the preferred antiviral therapy, there remains some disagreement with respect to what constitutes optimal antibacterial therapy. The combination of ampicillin and gentamicin is a common regimen. Resistance of E coli to ampicillin has been reported; this may be related to increased use of intrapartum antibiotic prophylaxis.
In treating meningitis, many centers administer cefotaxime in addition to or instead of gentamicin, particularly when gram-negative infections are suspected. Cefotaxime is also often used rather than gentamicin when there are concerns regarding renal function, given the potential nephrotoxicity of the latter. However, the use of cefotaxime has been linked to the emergence of cephalosporin-resistant strains of several gram-negative species. Antimicrobial resistance may be even more problematic in developing countries; resistance of E coli and Klebsiella species to ampicillin, gentamicin, and cephalosporins is on the rise.
The choice of an antibiotic regimen should be based on the likely pathogen, the local patterns of antibacterial drug sensitivities, and the policies of the hospital.
Corticosteroids have been shown to reduce long-term sequelae, particularly hearing loss, in older infants with Haemophilus influenzae type B meningitis and S pneumoniae infection. However, use of corticosteroids is not recommended for neonates with meningitis.
Supportive care is focused on supporting blood pressure to maintain adequate cerebral perfusion and preventing secondary brain injury. Meticulous fluid management is important to minimize cerebral edema and to respond to inappropriate antidiuretic hormone (ADH) secretion. The syndrome of inappropriate ADH secretion (SIADH) may cause hyponatremia and hypo-osmolality, which may increase lethargy and seizures while further increasing intracranial pressure (ICP).
Management of seizures is a common challenge ieonates with meningitis. Phenobarbital and phenytoin remain the current drugs of choice, with benzodiazepines utilized as adjunctive therapy. Respiratory dysfunction, disseminated intravascular coagulation (DIC), and nutritional deficiencies should be managed by experienced neonatologists.
Assessment of response to therapy
Lumbar puncture, especially for cerebrospinal fluid (CSF) culture and sensitivity, should be repeated 24-48 hours after the initial study to monitor the course of the infection and guide further treatment decisions. If the patient has persistent infection in the lumbar CSF or clinical deterioration that is not explained by other complications, imaging studies to investigate for abscess formation should be performed. A diagnostic tap of the lateral ventricle should be considered to assess for ventriculitis if no focal abscess is noted on imaging. Ventriculitis may occur, especially with gram-negative bacteria, in the absence of pleocytosis in the lumbar CSF or with sterile CSF.
Given the high sensitivity and specificity of polymerase chain reaction (PCR) assay for HSV, a negative HSV-PCR result in the initial CSF sample is an acceptable end point for discontinuance of empiric acyclovir treatment. However, if any clinical data continue to suggest HSV, consider a full course of treatment despite the negative HSV-PCR result. At some centers, lumbar puncture is repeated 3 weeks after completion of therapy for PCR-proven HSV meningitis to confirm that the virus has been eradicated.
Infants with partially treated bacterial meningitis should be managed on a case-by-case basis in accordance with their clinical presentation. These infants should be observed for at least 48 hours after treatment is discontinued.
C-reactive protein levels can be useful in identifying the presence of a systemic anti-inflammatory response and can be used serially to track the response to treatment.
Ventriculostomy
Ventriculostomy with external drainage may be required in cases where acute hydrocephalus develops secondary to obstruction of CSF flow.
Administration of intraventricular antibiotics is recommended in cases of ventriculitis, but is no longer recommended as a routine treatment for gram-negative meningitis.
Prevention
The use of intrapartum antibiotic prophylaxis in pregnant mothers who are positive for group B streptococcal (GBS) colonization on screening or have risk factors for GBS colonization has reduced the incidence of neonatal early-onset GBS meningitis from approximately 1.8 cases to 0.3 cases per 1000 live births. Screening and risk factor assessment should be included universally in routine prenatal care.
Cesarean delivery decreases, but does not eliminate, transmission of HSV from the mother’s genital tract to the neonate in cases of known infection. Suppressive antiviral therapy for HSV-infected women during the third trimester may prevent recurrent infectious episodes and thereby minimize the infant’s exposure to the virus during delivery.
Long-Term Monitoring
Because of the potential for hearing loss, neonates with meningitis should undergo brainstem auditory evoked response (BAER) testing at 4-6 weeks after discharge. Survivors of neonatal meningitis require long-term surveillance not only for disorders of hearing but also for disorders of vision, motor, or cognitive function.
Developmental delay is a frequent complication of neonatal meningitis. Early intervention services should be employed to maximize developmental gains.
Medication Summary
Aggressive antimicrobial intervention is lifesaving ieonates with suspected meningitis. Because distinguishing viral from bacterial meningitis is difficult early in the clinical course, a combination of agents is ofteecessary, providing coverage for both types of infection.
In most institutions, acyclovir is the preferred antiviral therapy, but the best antibacterial therapy remains subject to debate. The combination of ampicillin and gentamicin is a common regimen. Many centers use cefotaxime in addition to or instead of gentamicin, particularly when gram-negative infections are suspected. Selection of antibiotics should be based on likely pathogens, local patterns of antibacterial drug sensitivities, and hospital policies.
In addition to the medications listed below, pleconaril is an experimental agent that interferes with attachment, entry, and uncoating of enteroviruses. It was shown to be well tolerated by neonates in a single, small, double-blinded study. Data supporting the efficacy of pleconaril are limited, although a larger clinical trial is currently under way. At present, this drug is available only for compassionate use or in clinical trials.
Acyclovir (Zovirax)
Acyclovir is the preferred treatment for herpes simplex virus (HSV) meningitis. Intravenous (IV) therapy is treatment of choice for neonatal HSV infection, regardless of clinical presentation. Acyclovir is activated by herpes-specific thymidine kinase; it prevents viral replication by inhibiting viral DNA polymerase. Because it is excreted primarily by the kidneys, dosing must be modified in patients with renal impairment.
Antibiotics, Other
Class Summary
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Either gram-positive or gram-negative organisms may cause bacterial sepsis and meningitis. Combination therapy is necessary.
Ampicillin
Ampicillin has bactericidal activity against susceptible organisms. The combination of ampicillin with an aminoglycoside is the initial treatment of choice for neonates with presumptive group B streptococcal (GBS) meningitis and for most other suspected bacterial infections of the central nervous system (CNS).
Penicillin G (Pfizerpen)
Penicillin G interferes with synthesis of cell-wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. It can be given alone to treat GBS meningitis when susceptibility of CSF isolates to the drug has been demonstrated.
Cefotaxime (Claforan)
Cefotaxime is a third-generation cephalosporin with a gram-negative spectrum of activity; it has lower efficacy against gram-positive organisms. It arrests bacterial cell-wall synthesis, which, in turn, inhibits bacterial growth.
Whereas ampicillin plus an aminoglycoside remains the initial treatment of choice for bacterial meningitis, some investigators recommend ampicillin plus a cephalosporin (eg, cefotaxime) as initial treatment. The rapid emergence of cephalosporin-resistant strains limits the use of the latter combination, unless gram-negative bacterial meningitis strongly suspected. Treatment typically lasts 21 days, with most authorities recommending 14-21 days from the first negative CSF culture.
Gentamicin
Gentamicin is the prototypical aminoglycoside for combining with ampicillin to treat neonatal meningitis, but organism sensitivities and hospital protocols vary widely. Evolving bacterial resistance may necessitate the use of higher doses.
Anticonvulsants, Other
Class Summary
Anticonvulsants prevent seizure recurrence and terminate clinical and electrical seizure activity.
Phenobarbital
Phenobarbital increases the activity of gamma-aminobutyric acid, an inhibitory neurotransmitter in the central nervous system. This medication is typically used as the first-line agent in the treatment of neonatal seizures. An IV dose may require approximately 15 minutes to attain peak levels in the brain. Typically, a loading dose of 20 mg/kg IV is given initially, with additional bolus doses of 5-10 mg/kg if seizure activity persists, to a maximum total dose of 40 mg/kg.
Fosphenytoin (Cerebyx)
Fosphenytoin is the diphosphate ester salt of phenytoin and acts as a water-soluble prodrug of that agent. After administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin, in turn, stabilizes neuronal membranes and decreases seizure activity.
To eliminate the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses, express the dose in terms of phenytoin sodium equivalents (PE). Although fosphenytoin can be administered either IV or IM, IV administration is preferable and should be used in emergency situations.
Fosphenytoin is typically considered the second choice of anticonvulsants ieonates if phenobarbital does not control seizures.
Lorazepam (Ativan)
Lorazepam is a benzodiazepine anticonvulsant that is used in cases that are refractory to phenobarbital and phenytoin. By increasing the action of gamma-aminobutyric acid (GABA) the major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including the limbic system and the reticular formation.
URINARY TRACT INFECTION: Infection usually blood-borne. Commonest pathogen E.coli. Predisposed to by urinary tract anomalies e.g. pelvi-ureteric junction obstruction, vesico-ureteric reflux. Signs of infection are usually non-specific. The kidneys may be enlarged.
· Diagnosis:
o made by obtaining a pure growth of more than 105 orgs/ml (“clean catch” specimen), suprapubic aspiration is useful when the diagnosis is in doubt.
· Treatment:
o Cefotaxime or Ceftriaxone or an aminoglycoside. Modify once sensitivities are known.
Frequent follow-up urine examinations are advisable. An ultrasound examination and micturating cystogram should be considered at a later stage to exclude an underlying abnormality.
Prophylaxis
· Sanation and treatment of future mother
· Saving of health of healthy woman
· Hygiene of the family and sex life
In the postnatal period:
· Early breast feeding;
· Mother and her child should be together after birth;
· Natural breast feeding.
The major antibiotics active against the staphylococcal organism are presented here.
|
Drug Name |
Cephalexin (Biocef, Keflex, Keftab) |
|
Pediatric Dose |
25-100 mg/kg/d |
|
Drug Name |
Cefuroxime (Ceftin oral, Kefurox injection, Zinacef) injection |
|
Pediatric Dose |
Serious infections: 150 mg/kg/d IV divided q8h |
|
Drug Name |
Nafcillin (Nafcil injection, Nallpen injection, Unipen injection/oral) |
|
Pediatric Dose |
Neonates: |
|
Drug Name |
Cefazolin (Ancef, Kefzol, Zolicef) |
|
Pediatric Dose |
50-100 mg/kg/d IV divided q8h; not to exceed 6 g/d |
|
Drug Name |
Vancomycin (Lyphocin, Vancocin, Vancoled) |
|
Pediatric Dose |
Neonates: |
|
Drug Name |
Rifampin (Rifadin injection/oral, Rimactane oral |
|
Pediatric Dose |
S aureus: 15 mg/kg/d PO/IV divided q12h with other antibiotics |
|
Drug Name |
Mupirocin (Bactroban) — For elimination of S aureus. Inhibits bacterial growth by inhibiting RNA and protein synthesis. |
|
Adult Dose |
Apply small amount topically to affected area 2-5 times per d for 5-14 d |
|
Pediatric Dose |
Administer as in adults |
|
Contraindications |
Documented hypersensitivity; hypersensitivity to polyethylene glycol |
|
Interactions |
Concurrent intranasal administration of other medicatioot studied |
|
Pregnancy |
B – Usually safe but benefits must outweigh the risks. |
|
Precautions |
For topical use only; avoid contact with eyes; polyethylene glycol can be absorbed to toxic levels in patients with burns or open wounds; may irritate mucous membranes; overgrowth of nonsusceptible organisms can result with prolonged use |
|
Drug Name |
Amoxicillin and clavulanate (Augmentin) |
|
Pediatric Dose |
<3 months: 30 mg (based on amoxicillin component) per kg/d PO divided q12h Use 125 mg/5 mL |
|
Drug Name |
Oxacillin (Bactocill) |
|
Pediatric Dose |
Postnatal age <7 days: |
|
Drug Name |
Clindamycin (Cleocin) — Used to treat infections caused by anaerobic bacteria. |
|
Pediatric Dose |
Postnatal age <7 days: |
|
|
Other medicine to treat omphalitis |
|
Drug Name |
Metronidazole IV (Flagyl) |
|
Pediatric Dose |
Postnatal age <7 days: |
|
Drug Name |
Gentamicin (Garamycin) |
|
Pediatric Dose |
Postconception and postnatal age: |
Background: Neonatal sepsis may be categorized as early or late onset. Eighty-five percent of newborns with early-onset infection present within 24 hours, 5% present at 24-48 hours, and a smaller percentage of patients present between 48 hours and 6 days of life. Onset is most rapid in premature neonates. Early-onset sepsis syndrome is associated with acquisition of microorganisms from the mother. Transplacental infection or an ascending infection from the cervix may be caused by organisms that colonize in the mother’s genitourinary tract. The infant may acquire the microbe by passage through a colonized birth canal at delivery. The microorganisms most commonly associated with early-onset infection include group B Streptococcus (GBS), Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes.
Late-onset sepsis syndrome occurs at 7-90 days of life and is acquired from the caregiving environment. Organisms that have been implicated in causing late-onset sepsis syndrome include coagulase-negative staphylococci, Staphylococcus aureus, E coli, Klebsiella, Pseudomonas, Enterobacter, Candida, GBS, Serratia, Acinetobacter, and anaerobes. The infant’s skin, respiratory tract, conjunctivae, gastrointestinal tract, and umbilicus may become colonized from the environment, leading to the possibility of late-onset sepsis from invasive microorganisms. Vectors for such colonization may include vascular or urinary catheters, other indwelling lines, or contact from caregivers with bacterial colonization.
Pneumonia is more common in early-onset sepsis, whereas meningitis and/or bacteremia are more common in late-onset sepsis. Premature and ill infants have an increased susceptibility to sepsis and subtle nonspecific initial presentations; therefore, they require much vigilance so that sepsis can be identified and treated effectively.
Pathophysiology: The infectious agents associated with neonatal sepsis have changed over the past 50 years. S aureus and E coli were the most common infectious hazards for neonates in the 1950s in the
Meningoencephalitis and neonatal sepsis syndrome can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Additionally, sexually transmitted diseases and viral diseases, such as gonorrhea, syphilis, herpes simplex virus (HSV), cytomegalovirus (CMV), hepatitis, HIV, rubella, toxoplasmosis, Trichomonas vaginalis, and Candida species, have all been implicated ieonatal infection. Bacterial organisms with increased antibiotic resistance have also emerged and have further complicated the management of neonatal sepsis. The colonization patterns iurseries and personnel are reflected in the organisms currently associated with nosocomial infection. Infants with lower birth weight and infants who are less mature in today’s neonatal intensive care units (NICUs) have increased susceptibility to these organisms.
Staphylococcus epidermidis, or coagulase-negative Staphylococcus is increasingly seen as a cause of nosocomial or late-onset sepsis, especially in the premature infant. It is considered the leading cause of late-onset infections for this population.
The neonate is unable to respond effectively to infectious hazards because of deficits in the physiological response to infectious agents.
Fig. 7. Spread of Infection Via the Blood to the Entire Body in an Infant.
The fetus has some preimmune immunoglobulin present; however, preimmune immunoglobulin is relatively limited in fetuses compared to adults. The infant receives immunoglobulin G (IgG) prenatally after 16 weeks of gestation; however, the infant born prematurely has less IgG due to the shorter period of placental transmission of immunoglobulin.
Additionally, if the mother is immunosuppressed, it is possible that less IgG can be transmitted to the infant. The neonate is capable of synthesizing immunoglobulin M (IgM) in utero at 10 weeks of gestation; however, IgM levels are generally low at birth, unless the infant was exposed to an infectious agent during the pregnancy, thereby stimulating increased IgM production. IgG and immunoglobulin E (IgE) may be synthesized in utero; however, only traces are found in cord blood at delivery. The neonate may receive immunoglobulin A (IgA) from breastfeeding but does not secrete IgA until 2-5 weeks after birth. Response to bacterial polysaccharide antigen is diminished and remains so during the first 2 years of life.
The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. Skin and mucus membranes are broken down easily in the premature infant. Neonates who are ill and/or premature are additionally at risk because of the invasive procedures that breach their physical barriers to infection. Because of the interdependence of the immune response, these individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation for the neonate exposed to infectious threats.
Scheme of sepsis pathogenesis
pathogen, toxins, ferments
distortion of hemostasis, changes of immunogenesis
macrophages endothelial thrombocytes complement T, В–lymphocytes coagulation
cells system system
mediators of inflammation: ТNА, interleukins– IL 1,6,8, NO, prostaglandins, thromboxan А2, prostacyclin
increase of penetrate ability, vasodilatation, blood depot, hypovolemia, metabolic disorders
polyorganic insufficiency
septic shock
Mortality/Morbidity: The mortality rate ieonatal sepsis may be as high as 50% for infants who are not treated. Infection is a major cause of fatality during the first month of life, contributing to 13-15% of all neonatal deaths. Neonatal meningitis, a serious morbidity of neonatal sepsis, occurs in 2-4 cases per 10,000 live births and significantly contributes to the mortality rate ieonatal sepsis; it is responsible for 4% of all neonatal deaths.
Age: Studies have shown that premature infants have an increased incidence of sepsis. The incidence of sepsis is significantly higher in infants with very low birth weight (<
1. Time of beginning:
· antenatal
· postnatal
o early
o late
· nosocomeal
2. Etiology: streptococcal, staphylococcal, Klebsiella’s, Escherichia’s, Candida’s, mixed etiology.
3. Clinical forms: septicemia, septicopyemia.
4. Entrance region: umbilical, pulmonary, bowel, otogenic, cryptogenic.
5. Duration:
o fulminant – few hours–1-3 days
o acute – 4-8 weeks
o prolonged – more than 8 weeks
6. Periods: initial, significant clinical signs, recovery, period of rehabilitation.
7. Complications: DIC–syndrome, thrombosis, hypotrophy, endomyocarditis, renal failure etc.
Diagnosis example: postnatal umbilical, staphylococcal sepsis, septicopyemia: (omphalitis, bilateral pneumonia with cardiovascular syndrome, respiratory failure ІІ grade, right shoulder proximal epiphysial osteomyelitis), acute duration, DIC–syndrome.
The risk factors that are associated most highly with neonatal sepsis include:
1. maternal GBS colonization (especially if untreated during labor),
2. premature rupture of membranes (PROM),
3. preterm rupture of membranes,
4. prolonged rupture of membranes,
5. prematurity,
6. and chorioamnionitis.
Predisposing risk factors also are associated with neonatal sepsis. They include:
1. maternal urinary tract infection, maternal fever greater than
2. poor maternal nutrition, low socioeconomic status,
3. poor prenatal care,
4. maternal substance abuse,
5. recurrent abortion,
6. difficult delivery,
7. low Apgar score (<6 at 1 or 5 min), birth asphyxia,
8. meconium staining,
9. low birth weight, and congenital anomalies.
An awareness of the myriad of risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment, thereby reducing mortality and morbidity.
Physical: The clinical signs of neonatal sepsis are nonspecific and are associated with characteristics of the causative organism and the body’s response to the invasion.
· Congenital pneumonia and intrauterine infection: Inflammatory lesions are observed postmortem in the lungs of infants with congenital and intrauterine pneumonia. This may not be caused by the action of the microorganisms themselves but may be caused by aspiration of amniotic fluid containing maternal leukocytes and cellular debris. Tachypnea, irregular respirations, moderate retracting, apnea, cyanosis, and grunting may be observed. Neonates with intrauterine pneumonia may also be critically ill at birth and require high levels of ventilatory support. The chest radiograph may depict bilateral consolidation or pleural effusions.
· Congenital pneumonia and intrapartum infection: Neonates who are infected during the birth process may acquire pneumonia through aspiration of the microorganisms during the delivery process. The colonization may lead to infection with pulmonary changes, infiltration, and destruction of bronchopulmonary tissue. This damage is partly due to the granulocytes’ release of prostaglandins and leukotrienes. Fibrinous exudation into the alveoli leads to inhibition of pulmonary surfactant function and respiratory failure with an RDS-like presentation. Vascular congestion, hemorrhage, and necrosis may occur.
o Klebsiella species and S aureus are especially capable of considerably damaging the lungs, producing microabscesses and empyema.
o Infectious pneumonia is also characterized by pneumatoceles within the pulmonary tissue. Coughing, grunting, costal and sternal retractions, nasal flaring, tachypnea and/or irregular respiration, rales, decreased breath sounds, and cyanosis may be observed.
o On radiography, segmental or lobar atelectasis or a diffuse reticulogranular pattern may exist, much like what is observed in RDS.
o Pleural effusions may be observed in advanced disease.
· Congenital pneumonia and postnatal infection: Postnatally acquired pneumonia may occur at any age. Because these infectious agents exist in the environment, the likely cause depends heavily on the infant’s recent environment. If the infant has remained hospitalized in an NICU environment, especially with endotracheal intubation and mechanical ventilation, the organisms may include Staphylococcus or Pseudomonas species. Additionally, these hospital-acquired organisms frequently demonstrate multiple antibiotic resistances. Therefore, the choice of antibiotic agents in such cases requires knowledge of the likely causative organisms and the antibiotic-resistance patterns of the hospital.
· Cardiac signs: In overwhelming sepsis, an initial early phase characterized by pulmonary hypertension, decreased cardiac output, and hypoxemia is postulated to occur. These cardiopulmonary disturbances may be due to the activity of granulocyte biochemical mediators, such as hydroxyl radicals and thromboxane B2, an arachidonic acid metabolite. These biochemical agents have vasoconstrictive actions that result in pulmonary hypertension when released in pulmonary tissue. A toxin derived from the polysaccharide capsule of type III Streptococcus has also been shown to cause pulmonary hypertension. The early phase of pulmonary hypertension is followed by further progressive decreases in cardiac output with bradycardia and systemic hypotension. The infant manifests overt shock with pallor, poor capillary perfusion, and edema. These late signs of shock are indicative of severe compromise and are highly associated with mortality.
· Metabolic signs: Hypoglycemia, metabolic acidosis, and jaundice all are metabolic signs that commonly accompany neonatal sepsis syndrome. The infant has an increased glucose requirement because of sepsis. The infant may also have impaired nutrition from a diminished energy intake. Metabolic acidosis is due to a conversion to anaerobic metabolism with the production of lactic acid. When infants are hypothermic or they are not kept in a neutral thermal environment, efforts to regulate body temperature can cause metabolic acidosis. Jaundice occurs in response to decreased hepatic glucuronidation caused by both hepatic dysfunction and increased erythrocyte destruction.
· Neurologic signs: Meningitis is the common manifestation of infection of the central nervous system. It is primarily associated with GBS (36%), E coli (31%), and Listeria species (5-10%) infections, although other organisms such as S pneumoniae, S aureus, Staphylococcus epidermis, Haemophilus influenzae, and species of Pseudomonas, Klebsiella, Serratia, Enterobacter, and Proteus may cause meningitis. Acute and chronic histologic features are associated with specific organisms.
o Ventriculitis is the initiating event with inflammation of the ventricular surface. Exudative material usually appears at the choroid plexus and is external to the plexus. Then, ependymitis occurs with disruption of the ventricular lining and projections of glial tufts into the ventricular lumen. Glial bridges may develop by these tufts and cause obstruction, particularly at the aqueduct of Sylvius. The lateral ventricles may become multiloculated, which is similar to forming abscesses. Multiloculated ventricles can isolate organisms in an area, making treatment more difficult. Meningitis is likely to arise at the choroid plexus and extend via the ventricles through aqueducts into the arachnoid to affect the cerebral and cerebellar surfaces. The high glycogen content in the neonatal choroid plexus provides an excellent medium for the bacteria. Ventricular origination of meningitis causes significant treatment problems because the areas are inaccessible. Ventricular obstruction causes an additional problem.
o Arachnoiditis is the next phase and is the hallmark of meningitis. The arachnoid is infiltrated with inflammatory cells producing an exudate that is thick over the base of the brain and more uniform over the rest of the brain. Early in the infection, the exudate is primarily PMNs, bacteria, and macrophages. Exudate is prominent around the blood vessels and extends into the brain parenchyma. In the second and third weeks of infection, the proportion of PMNs decreases; the dominant cells are histiocytes, macrophages, and some lymphocytes and plasma cells. Exudate infiltration of cranial roots 3-8 occurs. After this period, the exudate decreases. Thick strands of collagen form, and arachnoid fibrosis occurs, which is responsible for obstruction. Hydrocephalus results. Early-onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis.
o Vasculitis extends the inflammation of the arachnoid and ventricles to the blood vessels surrounding the brain. Occlusion of the arteries rarely occurs; however, venous involvement is more severe. Phlebitis may be accompanied with thrombosis and complete occlusion. Multiple fibrin thrombi are especially associated with hemorrhagic infarction. This vascular involvement is apparent within the first days of meningitis and becomes more prominent during the second and third weeks.
o Cerebral edema may occur during the acute state of meningitis. The edema may be severe enough to greatly diminish the ventricular lumen. The cause is unknown, but it is likely related to vasculitis and the increased permeability of blood vessels. It may also be related to the cytotoxins of microorganisms. Herniation of edematous supratentorial structures does not occur ieonates because of the cranium’s distensibility.
o Infarction is a prominent and serious feature of neonatal meningitis. It occurs in 30% of infants who die. Lesions occur because of multiple venous occlusions, which are frequently hemorrhagic. The loci of infarcts are most often in the cerebral cortex and underlying white matter but may also be subependymal within the deep white matter. Neuronal loss occurs, especially in the cerebral cortex, and periventricular leukomalacia may subsequently appear in areas of neuronal cell death.
o Meningitis due to early-onset neonatal sepsis usually occurs within 24-48 hours and is dominated by nonneural signs. Neurologic signs may include stupor and irritability. Overt signs of meningitis occur in only 30% of cases. Even culture-proven meningitis may not demonstrate white cell changes in the CSF. Meningitis due to late-onset disease is more likely to demonstrate neurologic signs (80-90%). Impairment of consciousness (ie, stupor with or without irritability), coma, seizures, bulging anterior fontanel, extensor rigidity, focal cerebral signs, cranial nerve signs, and nuchal rigidity occur.
o The CSF findings in infectious neonatal meningitis are an elevated WBC count (predominately PMNs), an elevated protein level, a decreased CSF glucose concentration, and positive cultures. The decrease in CSF glucose concentration does not necessarily reflect serum hypoglycemia. Glucose concentration abnormalities are more severe in late-onset disease and with gram-negative organisms. The CSF WBC count is within the reference range in 29% of GBS meningitis infections; in gram-negative meningitis, it is within the reference range in only 4%. Reference range CSF protein and glucose concentrations are found in about 50% of patients with GBS meningitis; however, in gram-negative infections, reference range CSF protein and glucose concentrations are found in only 15-20%.
o Temperature instability is observed with neonatal sepsis and meningitis, either in response to pyrogens secreted by the bacterial organisms or from sympathetic nervous system instability. The neonate is most likely to be hypothermic. The infant is also floppy, lethargic, and disinterested in feeding. Signs of neurologic hyperactivity are more likely when late-onset meningitis occurs.
· Hematologic signs
o The platelet count in the healthy newborn is rarely less than 100,000 per mm3 in the first 10 days of life. Thrombocytopenia with counts less than 100,000 may occur ieonatal sepsis in response to the cellular products of the microorganisms. These cellular products cause platelet clumping and adherence leading to platelet destruction. Thrombocytopenia is generally observed after sepsis has been diagnosed and usually lasts 1 week, though it can last as long as 3 weeks. Only 10-60% of infants with sepsis have thrombocytopenia. Because of the appearance of newly formed platelets, mean platelet volume (MPV) and platelet distribution width (PDW) are shown to be significantly higher ieonatal sepsis after 3 days. Because of the myriad of causes of thrombocytopenia and its late appearance ieonatal sepsis, the presence of thrombocytopenia does not aid the diagnosis of neonatal sepsis.
o WBC counts and ratios are more sensitive for determining sepsis than platelet counts, although normal WBC counts may be observed in as many as 50% of cases of culture-proven sepsis. Infants who are not infected may also demonstrate abnormal WBC counts related to the stress of delivery. A differential may be of more use in diagnosing sepsis. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). Abnormal neutrophil counts, taken at the time of symptom onset, are only observed in two thirds of infants; therefore, the neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is observed with maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage.
o Neutrophil ratios have been more useful in diagnosing or excluding neonatal sepsis; the immature-to-total (I/T) ratio is the most sensitive. All immature neutrophil forms are counted, and the maximum acceptable ratio for excluding sepsis during the first 24 hours is 0.16. In most newborns, the ratio falls to 0.12 within 60 hours of life. The sensitivity of the I/T ratio has ranged from 60-90%, and elevations may be observed with other physiological events; therefore, when diagnosing sepsis, the elevated I/T ratio should be used in combination with other signs.
· Gastrointestinal signs: The gut can be colonized by organisms in utero or at delivery by swallowing infected amniotic fluid. The immunologic defenses of the gut are not mature, especially in the preterm infant. Lymphocytes proliferate in the gut in response to mitogen stimulation; however, this proliferation is not fully effective in responding to a microorganism because antibody formation and cytokine formation is immature until approximately 46 weeks. Necrotizing enterocolitis (NEC) has been associated with the presence of a number of species of bacteria in the immature gut, and bacterial overgrowth of these organisms in the neonatal lumen is a component of the multifactorial pathophysiology of NEC.
Lab Studies:
Blood, CSF, and urine cultures
· Aerobic cultures are appropriate for most of the bacterial etiologies associated with neonatal sepsis; however, anaerobic cultures are indicated ieonates with abscess formation, processes with bowel involvement, massive hemolysis, and refractory pneumonia.
· A Gram stain provides early identification of the gram-negative or gram-positive status of the organism for preliminary identification.
· Bacterial cultures should generally reveal the organism of infection within 36-48 hours; the subsequent initial identification of the organism occurs within 12-24 hours of the growth.
· Urine cultures are most appropriate when investigating late-onset sepsis.
· Blood and CSF cultures are appropriate for early and late-onset sepsis.
· Because of the low incidence of meningitis in the newborn infant with negative cultures, clinicians may elect to culture the CSF of only those infants with documented or presumed sepsis.
A CBC and differential may be ordered serially to determine changes associated with the infection, such as thrombocytopenia or neutropenia, or to monitor the development of a left shift or an elevated I/T ratio. Such serial monitoring of the CBC may be useful in aiding the differentiation of sepsis syndrome from nonspecific abnormalities due to the stress of delivery.
· The platelet count in the healthy newborn is rarely less than 100,000 per mm3 in the first 10 days of life. Thrombocytopenia with counts less than 100,000 may occur ieonatal sepsis, although this sign is usually observed late in the infection. MPV and PDW have been shown to be significantly elevated in infants with sepsis after 2-3 days of life. These measures may assist in determining the etiology of thrombocytopenia.
· WBC counts and ratios are more sensitive in determining sepsis, although normal WBC counts may be observed in culture-proven sepsis in as many as 50% of cases. Infants who are not infected may also have abnormal WBC counts related to the stress of delivery. A differential may be of more use in diagnosing sepsis. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). Abnormal neutrophil counts at the time of symptom onset are only observed in two thirds of infants; therefore, neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is also observed with maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage.
· Neutrophil ratios have been more useful in diagnosing neonatal sepsis; the I/T ratio is the most sensitive. All immature neutrophil forms are counted, and the maximum acceptable ratio for excluding sepsis in the first 24 hours is 0.16. In most newborns, the ratio falls to 0.12 within 60 hours of life. The sensitivity of the I/T ratio has ranged from 60-90%, and elevations may be observed with other physiological events; therefore, when diagnosing sepsis, the elevated I/T ratio should be used in combination with other signs.
The CSF findings in infectious neonatal meningitis are an elevated WBC (predominately PMNs), an elevated protein level, a depressed glucose level, and positive cultures. The decrease in glucose is not reflective of serum hypoglycemia. The CSF abnormalities are more severe in late onset and with gram-negative organisms. The WBC is within the reference range in 29% of GBS meningitis infections; in gram-negative meningitis, it is within the reference range in only 4%. Reference range protein and glucose concentrations are found in about 50% of patients with GBS meningitis; however, in gram-negative infections, reference range protein and glucose concentration are found in only 15-20%.
C-reactive protein, an acute phase protein associated with tissue injury, is eventually elevated in 50-90% of infants with systemic bacterial infections. This is especially true of infections with abscesses or cellulitis of deep tissue. C-reactive protein usually rises within 24 hours of infection, peaks within 2-3 days, and remains elevated until the inflammation is resolved. The C-reactive protein level is not recommended as a sole indicator of neonatal sepsis, but it may be used as part of a sepsis workup or as a serial study during infection to determine response to antibiotics, duration of therapy, and/or relapse of infection.
IgM concentration in serum may be helpful in determining the presence of an intrauterine infection, especially if present over a period of time.
Imaging Studies:
· Chest radiographs may depict segmental or lobar atelectasis, but they more commonly reveal a diffuse, fine, reticulogranular pattern, much like what is observed in RDS. Hemothorax and pleural effusions may also be observed.
·
scan may be needed late in the course of complex neonatal meningitis to document any occurrence of blocks to CSF flow, the site where the blocks are occurring, and occurrence of major infarctions or abscesses. Signs of chronic stage disease, such as ventricular dilation, multicystic encephalomalacia, and atrophy, are also demonstrated on CT scan.
· Head ultrasonograms ieonates with meningitis show evidence of ventriculitis, abnormal parenchymal echogenicities, extracellular fluid, and chronic changes. Serially, head ultrasonograms can demonstrate the progression of complications.
Procedures: Lumbar puncture is warranted for early- and late-onset sepsis, although clinicians may be unsuccessful in obtaining sufficient or clear fluid for all the studies. Infants may be positioned on their side or sitting with support, but adequate restraint is needed to avoid a traumatic tap. Because the cord is lower in the spinal column in infants, the insertion site should be between L3 and L4. If positive cultures are demonstrated, a follow-up lumbar puncture is often performed within 24-36 hours after antibiotic therapy to document CSF sterility. If organisms are still present, modification of drug type or dosage may be required to adequately treat the meningitis. An additional lumbar puncture within 24-36 hours is necessary if organisms are still present.
Complications
1. Septic shock is sepsis with uncorrected hypotension, hypoperfusion of tissues, acidosis, oliguria, conscious changes.
o Early septic shock is sepsis with hypotension, hypoperfusion of capillaries; which may be corrected in the short period of time by fluids or/and medicine.
o Refractive septic shock is sepsis with hypotension, hypoperfusion of capillaries; which is not corrected by fluids or/and medicine more than 1 hour; need dopamine, adrenalin or noradrenalin correction.
Septic shock’s stages: І – decreasing of blood circulation; ІІ – early decompensation; ІІІ – late decompensation; IV – irreversible (agonizing).
2. DIC–syndrome, stages: І – hypercoagulation; ІІ – hypocoagulation; ІІІ – consume coagulopathy; IV – restoring.
DIFFERENTIALS These nonspecific clinical signs of early sepsis syndrome are also associated with other neonatal diseases, such as Respiratory Distress Syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a traumatic delivery. Therefore, diagnose neonatal sepsis by excluding other disease processes
|
Criteria |
Meningitis |
Localized forms of infection |
Congenital infections |
Birth trauma |
|
1. Anamnesis: |
|
|
|
|
|
Acute and chronic maternal diseases during the pregnancy |
+ |
–– |
+ |
–– |
|
Mastitis during breastfeeding period |
+ |
–– |
–– |
–– |
|
Umbilical late epithelization |
+ |
+ |
–– |
–– |
|
Purulent changes of the skin |
+ |
+ |
–– |
–– |
|
Rapid delivery |
–– |
–– |
–– |
+ |
|
Complicated delivery of shoulders |
–– |
–– |
–– |
+ |
|
Using of forceps, vacuum extraction |
–– |
–– |
––– |
+ |
|
2.Prolonged intoxication: |
+ |
–– |
+ |
–– |
|
-increased body temperature |
+ |
–– |
–– |
–– |
|
–loss of appetite |
+ |
+ |
+ |
+ |
|
–vomiting, |
+ |
– |
+ |
+ |
|
–skin color: |
|
|
|
|
|
–pale-pink |
–– |
+ |
–– |
–– |
|
–pallor |
+ |
–– |
–– |
+ |
|
–pale-grey |
+ |
–– |
+ |
–– |
|
–yellow |
+ |
–– |
+ |
+ |
|
–weight gain: –slow |
–– |
+ |
–– |
+ |
|
–absent |
+ – |
–– |
+ |
–– |
|
– jaundice: |
+ |
–– |
+ |
+ |
|
–conjugated |
–– |
–– |
–– |
+ |
|
–parenchimatous |
+ |
–– |
+ |
–– |
|
З.Presence of hematogenous methastatic sites of infection |
+ |
–– |
+ |
–– |
|
–hepatosplenomegaly |
+ |
–– |
+ |
–– |
|
4.Positive cultures |
|
|
|
|
|
–blood |
+ |
–– |
+ |
–– |
|
–from sites of infection |
+ |
+ |
+ |
–– |
|
5. CSF: |
|
|
|
|
|
– transparent |
–– |
+ |
–– |
–– |
|
–muddy – hemorrhagic – pleocytosis – proteinorrhachia 6. Disappearance of the clinical signs during treatment: – slow – rapid – absent |
+ –– ++ + + –– –– –– |
–– –– –– –– –– + –– –– |
+ –– + + + –– + + |
–– + –– –– + –– –– –– |
TREATMENT Medical Care: Initiate treatment immediately because of the neonate’s immunologic weaknesses for fighting infection. Begin antibiotics as soon as diagnostic tests are performed. Additional therapies have been investigated for the treatment of neonatal sepsis; however, no unequivocal proof that these treatments are beneficial exists. These additional therapies include granulocyte transfusion, intravenous immune globulin (IVIG) replacement, exchange transfusion, and the use of recombinant cytokines.
Antibiotic therapy In the
· If infection appears to be nosocomial, direct coverage at organisms implicated in hospital-acquired infections, including S aureus, S epidermis, and Pseudomonas species. Most strains of S aureus produce beta-lactamase, which makes them resistant to penicillin G, ampicillin, carbenicillin, and ticarcillin. Vancomycin has been favored for this coverage; however, concern exists that overuse of this drug may lead to vancomycin-resistant organisms, thereby eliminating the best response to these resistant organisms. Cephalosporins are attractive in the treatment of nosocomial infection because of their lack of dose-related toxicity and adequate serum and CSF concentration; however, resistance by gram-negative organisms has occurred with their use. Do not use ceftriaxone in infants with hyperbilirubinemia because it displaces bilirubin from serum albumen. Resistance and sensitivities for the organism are used to indicate the most effective drug.
· Aminoglycosides and vancomycin are both ototoxic and nephrotoxic; have caution when using them. Check the serum level after 48 hours of treatment to determine if levels are above those required for a therapeutic effect. The dosage amount or interval may need to be changed to ensure adequate but nontoxic coverage. A serum level may be warranted when the infant’s clinical condition has not improved to ensure that a therapeutic level has been reached. In addition, perform renal function and hearing screening to determine any short- or long-range toxic effects of these drugs.
· If cultures are negative but the infant has significant risk for sepsis and/or clinical signs, the clinician must decide whether to provide continued treatment. Three days of negative cultures should provide confidence in the data; however, a small number of infants with proven sepsis at postmortem had negative cultures during their initial sepsis workup. Management is further complicated if the mother received antibiotic therapy before delivery, especially close to delivery. This may result iegative cultures in the infant who is still ill. Review all diagnostic data, including cultures, maternal and intrapartal risk factors, CSF results, the CBC and differential radiographs, and the clinical picture to determine the need for continued therapy. Treatment for 7-10 days may be appropriate, even if the infant has negative cultures at 48 hours.
· The clinician may require different antibiotic choice, dosage, and/or treatment time if the infant has bacterial meningitis. Perform a follow-up lumbar puncture within 24-36 hours after antibiotic therapy has been initiated to determine if the CSF is sterile. If organisms are still present, modification of drug type or dosage is required to adequately treat the meningitis. Continue antibiotic treatment for 2 weeks after sterilization of the CSF or for a minimum of 2 weeks for gram-positive meningitis and 3 weeks for gram-negative meningitis, whichever period is longest. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis.
Granulocyte transfusion has been shown to be suitable for infants with significant depletion of the storage neutrophil pool; however, the documentation of storage pool depletion requires a bone marrow aspiration, and the granulocyte transfusion must be administered quickly to be beneficial. The number of potential adverse effects, such as graft versus host reaction, transmission of CMV or hepatitis B, and pulmonary leukocyte sequestration, is considerable. Therefore, this therapy remains an experimental treatment.
Intravenous immune globuline has been considered for neonatal sepsis to provide type-specific antibodies to improve opsonization and phagocytosis of bacterial organisms and to improve complement activation and chemotaxis of neonatal neutrophils; however, difficulties with IVIG therapy for neonatal sepsis exist. The effect has been transient, and adverse effects associated with the infusion of any blood product can occur. Dose-related problems with this therapy decrease its usefulness ieonatal populations.
Recombinant human cytokine administration to stimulate granulocyte progenitor cells has been studied as an adjunct to antibiotic therapy. These therapies have shown promise in animal models, especially for GBS sepsis, but require pretreatment or immediate treatment to demonstrate efficacy. The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) has been studied in clinical trials, but their use in clinical neonatology remains experimental.
The infant with sepsis may require treatment aimed at the overwhelming systemic effects of the disease. Cardiopulmonary support and intravenous nutrition may be required during the acute phase of the illness until the infant’s condition stabilizes. Monitoring of blood pressure, vital signs, hematocrit, and platelets is vital.
Surgical Care: If hydrocephalus associated with neonatal meningitis occurs, and progressive accumulation of CSF is present, placing a ventriculoperitoneal (VP) shunt may be necessary to drain off the excess fluid. The immediate complications of shunt placement are overdrainage, equipment failure, disconnection, migration of catheter, or shunt infection. Abdominal obstruction, omental cysts, and perforation of the bladder, gall bladder, or bowel occur infrequently. The VP shunt may cause long-term neurologic complications, including slit-ventricle syndrome, seizures, neuro-ophthalmological problems, and craniosynostosis; however, the outcome for children with VP shunt placement is generally good with careful follow-up.
Diet: The neonate may need to be giveothing by mouth (NPO) during the first days of treatment because of gastrointestinal symptoms or poor feeding. Consider parenteral nutrition to ensure that the patient’s intake of calories, protein, minerals, and electrolytes is adequate during this period. Feeding may be restarted via a nasogastric tube for the infant with serious compromise. Encourage that breast milk be given because of the immunologic protection it provides.
Activity: The infant with temperature instability needs thermoregulatory support with a radiant warmer or incubator. Also, encouraging parental contact is important to ease the stress for parents and continue the bonding between the parents and child.
|
Drug Name |
Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin) |
|
Pediatric Dose |
<7 days and <2000 g: 50 mg/kg/dose IV/IM q12h |
|
Drug Name |
Gentamicin (Garamycin) |
|
Pediatric Dose |
0-4 weeks and <1200 g: 2.5 mg/kg/dose IV/IM q18h |
|
Drug Name |
Cefotaxime (Claforan) |
|
Pediatric Dose |
<7 days: 50 mg/kg/dose IV/IM q12h |
|
Drug Name |
Vancomycin (Lyphocin, Vancocin, Vancoled) — |
|
Pediatric Dose |
<1 month: |
|
Drug Name |
Metronidazole (Flagyl) — Antimicrobial that has shown effectiveness against anaerobic infections, especially Bacteroides fragilis meningitis. |
|
Pediatric Dose |
<4 weeks and <1200 g: 7.5 mg/kg/dose PO/IV q2d |
|
Drug Name |
Erythromycin (E-Mycin, Erythrocin) –. |
|
Pediatric Dose |
<7 days and <2000 g: 5 mg/kg/dose PO/IV/IM q12h |
|
Drug Name |
Piperacillin (Pipracil) |
|
Pediatric Dose |
<7 days and 1200-2000 g: 75 mg/kg IV/IM q12h |
Drug Category: Antifungals — Fungal infections can masquerade as bacterial infections and/or may appear at the end of prolonged antibacterial therapy.
|
Drug Name |
Fluconazole (Diflucan) — Used to treat susceptible fungal infections, including oropharyngeal, esophageal, and vaginal candidiasis. Also used for systemic candidal infections and cryptococcal meningitis. |
|
Pediatric Dose |
0-14 days: Oropharyngeal candidiasis: 6 mg/kg PO/IV initial dose; after 3 d, 3 mg/kg q3d for a total of 14 d |
|
Drug Name |
Amphotericin B (Amphocin, Fungizone) |
|
Pediatric Dose |
Test dose: 0.1 mg/kg/dose IV; not to exceed 1 mg/dose infused over 20-60 min or 0.25 mg/kg infused over 6 h; if tolerated, administer 0.25 mg/kg/d; gradually increase dose by 0.25-mg/kg/d increments until desired daily dose reached |
Deterrence/Prevention: The Committee on Infectious Diseases of the AAP recommends that obstetric care include a strategy to manage early-onset GBS disease. Treat women with GBS bacteriuria during pregnancy when it is diagnosed and at delivery. The committee also recommends that women who have previously given birth to an infant with GBS disease be intrapartally treated. Practitioners should use either a strategy based on screening the mother or a strategy based on the presence of intrapartum risk factors to minimize the risk of early-onset GBS disease.
Prognosis: With early diagnosis and treatment, infants are not likely to experience long-term health problems associated with neonatal sepsis; however, if early signs and/or risk factors are missed, the mortality rate increases. Residual neurologic damage occurs in 15-30% of neonates with septic meningitis. Infants with meningitis may acquire hydrocephalus and/or periventricular leucomalacia. They may also have complications associated with the use of aminoglycosides, such as hearing loss and/or nephrotoxicity.
References:
1. Avery‘s neonatology: pathophysiology and management of the newborn / G. B. Avery, M. G. MacDonald, M. M. K. Seshia [et al.]. – 6th ed. –
2. Nelson Textbook of Pediatrics, 19th Edition. – Expert Consult Premium Edition – Enhanced Online Features and Print / by Robert M. Kliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD and Richard E. Behrman, MD. – 2011. – 2680 p.
3. Pediatrics / Edited by O.V. Tiazhka, T.V. Pochinok, A.M. Antoshkina/ – Vinnytsa: Nova Knyha Publishers, 2011. – 584 p.
4. Faden H. Mastitis in children from birth to 17 years. Pediatr Infect Dis J 2005; 24:1113
WEB–adresses
http://www.neonatology.org/neo.clinical.html
