UNIVERSITY OF MAKATI COLLEGE OF ALLIED HEALTH STUDIES

J.P. RIZAL EXTENSION, WEST REMBO, MAKATI CITY

Neonatal Sepsis
A Case Study in Partial Fulfilment of the Requirements in NEWBORN SERVICES UNIT (NSU) DUTY (James L. Gordon Memorial Hospital) Submitted by: Amparo, Roxanne Azul, Deneice Patricia Balbarono, Mary Ann Castro, Roger Dayao, Irish Grace de Guerto, Camille Anne Dionisio, Errica Joice Formaran, Kevin Manila, Ciara Alyssa Nichole Simangan, Precious Anne Serad, Donna Usman, Amal Villar, Michael Vincent Yu, Arnilyn

October 24-26, 2011

I.

INTRODUCTION Septic shock is a syndrome in which a potentially lethal drop in blood pressure occurs as

a result of an overwhelming bacterial infection. Septic shock is a possible consequence of bacteremia, which is also called sepsis. Bacterial toxins, and the immune system's response to them, can cause a dramatic drop in blood pressure and may result in under-perfusion to various organs. Septic shock can lead to multiple organ failure, including respiratory failure, and may cause rapid death. In 1914, Schottmueller wrote, Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes sign of illness. The definition did not change much over the years, because the terms sepsis and septicemia referred to several ill-defined clinical conditions present in a patient with bacteremia. In practice, the terms often were used interchangeably; however, fewer than half the patients with signs and symptoms of sepsis have positive results on blood culture. Furthermore, not all patients with bacteremia have signs of sepsis; therefore, sepsis and septicemia are not identical. In the past few decades, the discovery of endogenous mediators of the host response has led to the recognition that the clinical syndrome of sepsis is the result of excessive activation of host defense mechanisms rather than the direct effect of microorganisms. Sepsis and its sequelae represent a continuum of clinical and pathophysiologic severity. Serious bacterial infections at any site, with or without bacteremia, are usually associated with important changes in the function of every organ system in the body. These changes are mediated mostly by elements of the host immune system against infection. Shock is deemed present when volume replacement fails to increase blood pressure to acceptable levels and associated clinical evidence indicates inadequate perfusion of major organ systems, with progressive failure of organ system functions. Multiple organ dysfunctions, the extreme end of the continuum, are incremental degrees of physiologic derangements in individual organs (ie, processes rather than events). Alteration in organ function can vary widely from a mild degree of organ dysfunction to frank organ failure.

During an infection, certain bacteria can release complex molecules, called endotoxins, which may provoke a dramatic response by the body's immune system. Endotoxins are particularly dangerous; as they become widely dispersed, they cause arteries and the smaller arterioles to dilate. At the same time, the walls of the blood vessels become leaky, allowing fluid to seep into the tissues, lowering intravascular volume (the amount of fluid left in circulation). This combination, of arterial dilation and decreased intravascular volume, causes a dramatic decrease in blood pressure and impaired blood flow to multiple organs. Other changes seen in septic shock are disseminated intravascular coagulation (DIC), which can further impair organ perfusion (blood flow). Septic shock is seen most often in patients with impaired host defenses (patients who are immunosuppressed), and is often due to nosocomial (hospitalacquired) infections. The immune system is suppressed by drugs used to treat cancer, autoimmune disorders, organ transplants, and diseases of immune deficiency such as AIDS. Malnutrition, chronic drug abuse, and long-term illness also increase the likelihood of succumbing to bacterial infection. Bacteremia is more likely with preexisting infections such as urinary or gastrointestinal tract infections, or skin ulcers. Bacteria may be introduced to the blood stream by surgical procedures, catheters, or intravenous equipment. Toxic shock syndrome (TSS) is a potentially fatal disorder resulting from infection with Staphylococcus aureus, a toxin-producing strain of bacteria. When it was first reported about 25 years ago, toxic shock syndrome was associated with menstruation and linked to super-absorbent tampon use. Today, it is recognized that use of super-absorbent tampons does increase the risk of TSS, as the use of a contraceptive sponge or diaphragm. Postpartum patients (women who have just given birth) and patients with wound infections, or recovering from nasal surgery also are at risk for TSS. The illness appears suddenly, with fever, rash, low blood pressure, and episodes of fainting. Survival has improved since the 1980s, approximately 25% of patients die from this dis-order. Patients recovering from TSS face increased risk of recurrence. To prevent TSS, menstruating women are advised to avoid use of super-absorbent tampons.

Septic shock is most likely to develop in the hospital, since it frequently results from hospital-acquired infection. Close monitoring and early, aggressive therapy can minimize the likelihood of progression. Nonetheless, death occurs in at least 25% of all cases. The likelihood of recovery from septic shock depends on many factors, including the degree of immunosuppression of the patient, underlying disease, timeliness of treatment, and type of bacteria responsible. Mortality is highest in the very young and the elderly, those with persistent or recurrent infection, and those with compromised immune systems. Generally, care for the septic patient is delivered by hospital-based health care professionals in the hospital ICU (intensive care unit). Physicians, intensive care nurses, and other nursing personnel closely monitor patients' vital signs and administer antibiotics and fluids. Laboratory technologists perform necessary blood tests, and respiratory therapists may provide oxygen to patients in respiratory distress.

II.

ETIOLOGY Most patients who develop sepsis and septic shock have underlying circumstances that

interfere with the local or systemic host defense mechanisms. Sepsis is seen most frequently in elderly persons and in those with comorbid conditions that predispose to infection, such as diabetes or any immunocompromising disease. The most common disease states predisposing to sepsis are malignancies, diabetes mellitus, chronic liver disease, chronic renal failure, and the use of immunosuppressive agents. In addition, sepsis also is a common complication after major surgery, trauma, and extensive burns. Patients with indwelling catheters or devices are also at high risk. In most patients with sepsis, a source of infection can be identified, with the exception of patients who are immunocompromised with neutropenia, where an obvious source often is not found. Multiple sites of infection may occur in 6-15% of patients.

Before the introduction of antibiotics in clinical practice, gram-positive bacteria were the principal organisms causing sepsis. More recently, gram-negative bacteria have become the key pathogens causing severe sepsis and septic shock. Anaerobic pathogens are becoming less important as a cause of sepsis. In one institution, the incidence of anaerobic bacteremia declined by 45% over a 15-year period. Fungal infections are the cause of sepsis in 0.8-10.2% of patients with sepsis, and their incidence appears to be increasing. Respiratory tract infection and urinary tract infection are the most frequent causes of sepsis, followed by abdominal and soft tissue infections. Each organ system tends to be infected by a particular set of pathogens (see below). Lower respiratory tract infections are the cause of septic shock in 25% of patients, and the following are the common pathogens:
y y y y y y y y y

Streptococcus pneumoniae Klebsiella pneumoniae Staphylococcus aureus Escherichia coli Legionella species Haemophilus species Anaerobes Gram-negative bacteria Fungi Urinary tract infections are the cause of septic shock in 25% of patients, and the following are the common pathogens:

y y y y y y

E coli Proteus species Klebsiella species Pseudomonas species Enterobacter species Serratia species

Soft tissue infections are the cause of septic shock in 15% of patients, and the following are the common pathogens:
y y y y y y

S aureus Staphylococcus epidermidis Streptococci Clostridia Gram-negative bacteria Anaerobes GI tract infections are the cause of septic shock in 15% all patients, and the following are the common pathogens:

y y y y y y y

E coli Streptococcus faecalis Bacteroides fragilis Acinetobacter species Pseudomonas species Enterobacter species Salmonella species Infections of the male and female reproductive systems are the cause of septic shock in 10% of patients, and the following are the common pathogens:

y y y y

Neisseria gonorrhoeae Gram-negative bacteria Streptococci Anaerobes Foreign bodies leading to infections are the cause of septic shock in 5% of patients, and S aureus, S epidermidis, and fungi/yeasts (eg, Candidaspecies) are the common pathogens. Risk factors Risk factors for severe sepsis and septic shock include the following:

Extremes of age ( < 10 y and >70 y)

Primary diseases (eg, liver cirrhosis, alcoholism, diabetes mellitus, cardiopulmonary diseases, solid malignancy, hematologic malignancy)

Immunosuppression (eg, neutropenia, immunosuppressive therapy, corticosteroid therapy, IV drug abuse [see the image below], complement deficiencies, asplenia)

y y

Major surgery, trauma, burns Invasive procedures (eg, catheters, intravascular devices, prosthetic devices, hemodialysis and peritoneal dialysis catheters, endotracheal tubes)

y y y

Previous antibiotic treatment Prolonged hospitalization Other factors, such as childbirth, abortion, and malnutrition

III. PATHOPHYSIOLOGY

MODIFIABLE FACTORS Sterility of the environment Exposure to Bacteria Sterility of delivery

NON-MODIFIABLE FACTORS Malnutrition Premature newborn Birth weight <1500g Immune system(leukopenia)

Organism invades the bloodstream and multiply Triggers pro-inflammatory mediators

Leukotrienes Lipoxygenase Histamine Bradykinin

Results in negative feedback mechanism

Interleukin 4-10

Arteries and arterioles dilate

Production of micro thrombi

Impaired removal of CO2 and waste products Epithelial cells of tubules slough
Loss of functions of nephrons

Inability to retain IVF

Impairs O2 absorption of epithelial cells

Filing of fluids in the lungs

Collapse alveoli Inability for O2 and CO2 exchange Lung Failure Hypoxia of the heart Irritability and exhaustion of the heart muscles Heart failure

Acute renal failure Decrease blood supply to brain Gross hypoxia Brain dysfunction Coma Septic shock

IV.

CLINICAL MANIFESTATION 1. Acute inflammation present throughout the entire body. 2. Temperature instability (hypothermia or hyperthermia) 3. Elevated white blood cell count (leukocytosis) 4. Vomiting 5. Bradycardia/tachycardia 6. Resp rate > 60/minute 7. Diminished spontaneous activity 8. Less vigorous sucking 9. Yellow skin and whites of the eyes (jaundice) 10. Breathing problems 11. Seizures

V.

DIAGNOSTIC PROCEDURES CBC, differential, and smear: The normal WBC count in neonates varies, but values < 4,000/ L or > 25,000/ L are abnormal. The absolute band count is not sensitive enough to predict sepsis, but a ratio of immature:total polymorphonuclear leukocytes of < 0.2 has a high negative predictive value. A precipitous fall in a known absolute eosinophil count and morphologic changes in neutrophils (eg, toxic granulation, Dhle bodies, intracytoplasmic vacuolization in noncitrated blood or ethylenediaminetetraacetic acid [EDTA]) suggest sepsis. The platelet count may fall hours to days before the onset of clinical sepsis but more often remains elevated until a day or so after the neonate becomes ill. This fall is

sometimes accompanied by other findings of DIC (eg, increased fibrin degradation products, decreased fibrinogen, prolonged INR). Because of the large numbers of circulating bacteria, organisms can sometimes be seen in or associated with polymorphonuclear leukocytes by applying Gram stain, methylene blue, or acridine orange to the buffy coat. Regardless of the results of the CBC or LP, in all neonates with suspected sepsis (eg, those who look sick or are febrile or hypothermic), antibiotics should be started after cultures (eg, blood, urine, and CSF [if possible]) are taken. Lumbar puncture: There is a risk of increasing hypoxia during an LP in already hypoxemic neonates. However, LP should be done in neonates with suspected sepsis as soon as they are able to tolerate the procedure (see also Infections in Neonates: Diagnosis under Neonatal Bacterial Meningitis). Supplemental O2 is given before and during LP to prevent hypoxia. Because GBS pneumonia manifesting in the first day of life can be confused with respiratory distress syndrome, LP is often done routinely in neonates suspected of having these diseases. Blood cultures: Umbilical vessels are frequently contaminated by organisms on the umbilical stump, especially after a number of hours, so blood cultures from umbilical lines may not be reliable. Therefore, blood for culture should be obtained by venipuncture, preferably at 2 peripheral sites, each meticulously prepared by applying an iodine-containing liquid, then applying 95% alcohol, and finally allowing the site to dry. Blood should be cultured for both aerobic and anaerobic organisms. If catheter-associated sepsis is suspected, a culture specimen should be obtained through the catheter as well as peripherally. In > 90% of positive bacterial blood cultures, growth occurs within 48 h of incubation. Because bacteremia in neonates is associated with a high density of organisms and delayed clearance, a small amount of blood (eg, 1 mL) is usually sufficient for detecting organisms. Data on capillary blood cultures are insufficient to recommend them.

Candida grows in blood cultures and on blood agar plates, but if other fungi are suspected, a fungal culture medium should be used. For species other than Candida, fungal blood cultures may require 4 to 5 days of incubation before becoming positive and may be negative even in obviously disseminated disease. Proof of colonization (in mouth or stool or on skin) may be helpful before culture results are available. If disseminated candidiasis is suspected, indirect ophthalmoscopy with dilation of the pupils is done to identify retinal candidal lesions. Renal ultrasonography is done to detect renal mycetoma. Urinalysis and culture: Urine should be obtained by catheterization or suprapubic aspiration, not by urine collection bags. Although only culture is diagnostic, a finding of 5 WBCs/high-power field in the spun urine or any organisms in a fresh unspun gramstained sample is presumptive evidence of a UTI. Absence of pyuria does not rule out UTI. Other tests for infection and inflammation: Numerous tests are often abnormal in sepsis and have been evaluated as possible early markers. In general, however, sensitivities tend to be low until later in illness, and specificities are suboptimal. Acute-phase reactants are proteins produced by the liver under the influence of IL-1 when inflammation is present. The most valuable of these is quantitative C-reactive protein. A concentration of 1 mg/dL (measured by nephelometry) has both a falsepositive and a false-negative rate of about 10%. Elevated levels occur within a day, peak at 2 to 3 days, and fall to normal within 5 to 10 days in neonates who recover. The ESR is often elevated in sepsis. The micro-ESR correlates well with the standard Wintrobe method but has the same high false-negative rate (especially early in the course and with DIC) and a slow return to normal, well beyond the time of clinical cure. IL-6 and other inflammatory cytokines are being investigated as markers for sepsis. VI. MANAGEMENT Nursing Management

Prior: y y Verify with the doctors order. Explain the indication to the mother.

During: y Label the IVF bottle and tubings indicating the date and time it was started with the ordered regulation. y y y After: y Check the site for any signs/symptoms of infection. Maintain and regulate at the rate prescribed. Handle IVF site aseptically. Change solution and IVF tubings as per hospital policy.

Surgical Management If an abscess is present, surgical drainage may be necessary because intravenous antibiotic therapy cannot adequately penetrate an abscess and because antibiotic treatment alone is ineffective. Surgical consultation for central line placement may be necessary in infants who require prolonged IV antimicrobial therapy for sepsis, if peripheral IV access cannot be maintained. If hydrocephalus associated with neonatal meningitis occurs, and progressive accumulation of CSF is present, 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, gallbladder, or bowel are uncommon. 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.

Medical Management When neonatal sepsis is suspected, treatment should be initiated immediately because of the neonate's relative immunosuppression. Begin antibiotics as soon as diagnostic tests are performed. Additional therapies have been investigated for the treatment of neonatal sepsis; however, no substantial clinical trials have shown that these treatments are beneficial. These additional therapies include granulocyte transfusion, intravenous immune globulin (IVIG) replacement, exchange transfusion, and the use of recombinant cytokines. If an infection appears to be nosocomial, antibiotic coverage should be directed 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. Oxacillin therapy is preferred by some clinicians because of this. Cephalosporins are attractive in the treatment of nosocomial infection because of their lack of dose-related toxicity and adequate serum and cerebrospinal fluid (CSF) concentration; however, resistance by gram-negative organisms has occurred with their use. Ceftriaxone displaces bilirubin from serum albumin and should be used with caution in infants with significant hyperbilirubinemia. Resistance and sensitivities for the organism isolated from cultures are used to select the most effective drug. Aminoglycosides and vancomycin both have the potential to produce ototoxicity and nephrotoxicity and should therefore be used with caution. The serum drug level is assessed around the third dose or at 48 hours after starting treatment to determine if levels

are within the therapeutic range. The drug dosage or interval may need to be adjusted to optimize the drug serum levels. A serum level may also be warranted if the infant's clinical condition has not improved to ensure that a therapeutic level has been reached. In addition, renal function and hearing screening should be considered after completion of the therapeutic course to determine if any short- or long-range toxic effects of these drugs have occurred. If culture results are negative but the infant has significant risk or clinical signs for sepsis, the clinician must decide whether to provide continued treatment. Two to three days of negative culture results should provide confidence in the data; however, a small number of infants documented to have had sepsis by postmortem examination had negative culture results during their initial sepsis evaluation. Management is further complicated if the mother received antibiotic therapy before delivery, especially if she received the therapy within several hours of delivery. This may result in negative culture results in an infant who actually has bacteremia or sepsis. With this in mind, the need for continued therapy should be based not on a single test, but on a review of all diagnostic data, including culture results, maternal and intrapartal risk factors, CSF results, the CBC count and differential, C-reactive protein (CRP) trends, radiographs, and clinical progress. Treatment for 7-10 days may be appropriate, even if culture results remain negative at 48-72 hours. Infants with bacterial meningitis often require different dosages of antibiotics and longer courses of treatment. These infants may also require an antimicrobial that has better penetration of the blood-brain barrier to achieve therapeutic drug concentrations in the CSF. A follow-up lumbar puncture within 24-36 hours after antibiotic therapy has been initiated to determine if the CSF is sterile is recommended. 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.

Meningitis complicated by seizures or persistent positive cultures may require extended IV antimicrobial therapy. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. Trimethoprim-sulfamethoxazole should not be used if hyperbilirubinemia and kernicterus are of concern in the newborn. 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 cytomegalovirus (CMV) or hepatitis B, and pulmonary leukocyte sequestration, is considerable. Therefore, this therapy remains an experimental treatment. IVIG infusion has been studied as a possible therapy 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, clinically available IVIG solutions do not contain type-specific antibody and adverse effects associated with the infusion of any blood product can occur. Dose-related problems with this therapy decrease its usefulness in neonatal populations. At present, the data do not support the routine use of IVIG in neonatal sepsis.[13] 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, platelets, and coagulation studies is vital. The need for blood product transfusion including packed RBCs (PRBCs), platelets, and fresh frozen plasma (FFP) is not uncommon.