“A Retrospective Comparative Study on the Survival Outcome of Neoates with Early -Onset Sepsis with Sclerema Given Fresh Frozen Plasma at Davao Medical Centern Nursery-A One Year Review”
Objectives: To determine and compare the survival outcome of patients with early onset neonatal sepsis with sclerema given fresh frozen plasma plus standard therapy of neonatal sepsis to those who were only given standard therapy alone. Fresh Frozen plasma contains immunologic factors which is deficient in a neonate. This study would help us validate the role of FFP transfusion in a sick neonate with sclerema.
Design: Cohort Study design
Setting: Tertiary care hospital
Participants:All neonates presenting with clinical signs of neonatal sepsis with sclerema admitteded at Davao Medical Center nursery for the year 2008.
Results and Conclusion:
INTRODUCTION
Neonatal sepsis is a clinical syndrome of bacteremia characterized by systemic signs and symptoms of infection in the first month of life1. It has taken so many lives of newborn babies. The mortality rate continuously increases especially in the third world countries like the Philippines so that early recognition, diagnosis and treatment of infection is important because it is largely a preventable disease.
Neonatal Sepsis can be divided into two main classes depending on the onset of symptoms related to sepsis- early-onset and late-onset neonatal sepsis2. Early onset is mainly due to antepartum infections vertically transmitted while late-onset is the combination of the former and nosocomial infection.
The incidence of neonatal sepsis varies from one institution to another with higher rates in developing countries. In the United States , the incidence of a culture-proven sepsis is approximately 2 per 1000 livebirths and increases to 25 per 1000 livebirths in infants with birthweight less than 1500 grams3. It is considered to be a major cause of fatality during the first month of life contributing to 13-15% of all neonatal deaths with highest rates seen in premature infants and in small for gestational age infants. The mortality rate in neonatal sepsis may be as high as 50% for infants who are not treated3. A local study conducted at MCU-FDTMF Hospital nursery found the incidence of neonatal septicemia to be 9.6 %4 as compared to other studies at UP PGH which is 5.5%. At Davao Medical Center the incidence and the case fatality rate of neonatal sepsis for the year 2008 are about 5/1000 livebirths and 1.3% respectively5.
Considering the nonspecificity of the early clinical signs of neonatal sepsis and the neonate’s relative state of immunosuppression, early diagnosis and treatment is of utmost important. The mainstay of treatment is antibiotic. Supportive management is geared towards thermoregulation to prevent hypothermia or hyperthermia, ensuring good ventilation/oxygenation to vital tissues, provision of optimal nutrition preferably with enteral feeding or TPN, prevention of hypoglycemia and electrolyte imbalance by administration of parenteral fluids and vasopressors for hypotension. Adjunctive therapy includes fresh frozen plasma transfusion, exchange transfusion, immunoglobulin therapy, granulocyte-macrophage colony stimulating factor, and granulocyte transfusion.
Sclerema is the uniform hardening of the skin and subcutaneous tissues to the extent that the skin could not be pitted nor picked up or pinched into a fold6.It is considered as a sign of a potentially fatal underlying disease process like neonatal sepsis especially gram- negative sepsis. Neonatal septicemia is invariably fatal when associated with sclerema7. Its reported mortality rates range from 67-88% with death occurring hours to days after onset8.
Although literature about the benefits of Fresh Frozen Plasma transfusion in septic neonates with sclerema is scarce, our experienced at SPMC nursery suggests improved outcome from neonatal sepsis with sclerema when given FFP. We do not give FFP to septic neonates without sclerema. We are doing this study to validate if indeed our perception is correct and if this practice is valid.
The study will be limited to comparison of septic patients with sclerema only. This preselects the most seriously ill patients. By limiting the study to early onset neonatal sepsis, opportunistic infections from less virulent pathogens like candida and staphylococcus epidermides are likely to be excluded and infection is most likely vertically transmitted and not nosocomial. This is to limit the varaiables due to etiologic agents that may affect outcome and interpretation of the result.
Review of Related Literature
The defense system of the human body consists of three components: physical , cellular and humoral. Neonates are particularly deficient in all three so that a more aggressive management is mandatory to improve survival outcome when neonates develop septicemia.
The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. The skin of a preterm infant is only a few cell-layers thick and is poorly cornified hence can easily be damaged paving the way for infection. The protective fatty acid production is also low making them more vulnerable.
At 23 weeks gestational age the fetus possesses T and B lymphocytes, macrophages, monocytes, polymorphonuclear cells and the capacity to synthesize all known immune factors.
The ability of the T and B lymphocytes to produce cytokines is less in comparison to adults, however neonates are capable of generating appropriate adaptive immune responses. Langerhan’s cells are important in local infection and are present in the neonate at 18 weeks gestation.
Phagocytes from preterm neonates show normal activity when suspended in normal adult serum, however neonatal serum is deficient in immunoglobulin and complement so there is a marked reduction in adherence and chemotaxis. The neonatal neutrophil or polymorphonuclear (PMN) cell, which is vital for effective killing of bacteria is deficient in chemotaxis and killing capacity. Also neonatal PMNs are less deformable therefore they are less able to move through the extracellular matrix of tissues to reach the site of inflammation and infection. The limited ability of neonate for phagocytosis and killing of bacteria is further impaired when the infant is clinically ill. Lastly neutrophil reserves are easily depleted because of the diminished response of the bone marrow especially in the premature infant.
The neonate is capable of synthesizing IgM in utero at 10 weeks 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. During pregnancy IgG is transported actively and passively across the placenta from about the 20th week of gestation and at full term the neonate’s IgG levels are higher than his mother’s levels. The IgG in an infant’s plasma has a half-life of about three weeks.Until the infant is able to generate his own IgG, IgM and IgA there is a period of postnatal hypogammaglobulinemia. In a preterm neonate of 26 weeks gestation the plasma IgG levels are markedly lower and diminish to ineffective levels very quickly, increasing the risk of infection.
Complement protein production can be detected as early as 6 weeks gestation; however the concentration of the various components of the complement system widely varies among individual neonates. While some infants have had complement levels comparable with those in adults, deficiencies appear to be greater in the alternative pathway than in the classic pathway. The terminal cytotoxic components of the complement cascade that leads to killing of organisms, especially gram-negative bacteria are deficient. The deficiency is more marked in preterm infants. Mature complement activity is not reached until infants are aged 6-10 months. Neonatal sera have reduced opsonic deficiency against GBS, E. coli, and S pneumoniae because of decreased levels of fibronectin, a serum protein that assists with neutrophil adherence and has opsonic properties.
Most common organisms causing early- onset neonatal sepsis include group B streptococci, gram -negative enteric organisms like E. coli. Listeria monocytogenes and Klebsiella are also a common isolates. Less common organisms include staphylococcus, other streptococci, anaerobes, and Haemophilus influenza9.
The host-defence mechanism of neonates are immature. They have a markedly decrease levels of C3, Cy properdin and factor B which are very important in the alternative pathway of complement. Levels of IgM and IgA are also low at birth. Although IgG levels may be normal in term neonates, it is low in preterm infants. These relative deficiency of the neonate’s immune system complicated by low birthweight and decreasing age of gestation makes them more susceptible to life threatening infections10.
Sadana,et al mentioned that the incomplete development of the host defense system of the neonate is largely responsible for the high mortality in neonatal sepsis11.In his study an increase in the levels of IgG, IgM, IgA andC3 was noted after exchange transfusion.Exchange transfusion offers removal of bacteria and toxins, improves oxygenation and perfusion as well as decreases hemorrhagic complications. The relative immunodeficiency state and susceptibility to sepsis and complications is the impetus for exploring treatment modalities other than antibiotics.
There was an increase in the levels of IgG antibodies in septicemia patients with coagulase negative staphylococcus after FFP administration in the study made by Krediet, et al12
The neonate being deficient in both humoral and cellular immunity is more vulnerable to infection. There are literature that suggests the usage of Fresh Frozen Plasma in patients with neonatal sepsis to compensate for the immunologic deficiencies. FFP improves neonatal chemotaxis, provides humoral or cellular factors13 and increases the levels of immunoglobulin such as IgG, IgA and IgM. FFP remains the only approved source of factors V,XI, protein C, protein S and plasminogen14 and basically all the clotting factors. Others would say that FFP transfusion in neonatal sepsis is good because it increases levels of IgG, IgA and IgM15 that will increase chances of survival.
FFP contains immunoglobulins anc complement factors16.
Fresh frozen plasma, the plasma separated from a unit of whole blood and frozen at -18 oC within 8 hours of collection. It is a platelet-poor plasma17.Each bag has a volume of 175 to 250 ml and contains between 1 and 2 units of each coagulation factor per ml and 400 to 800 mg fibrinogen. It contains fibrinolytic and complement factors. It carries the same risks of viral transmission as other blood components and can cause allergic reactions and fluid overload.
Indications for fresh frozen plasma, once used routinely in the support of critically ill-infants and children, have become more specific as evolving evidence has confirmed or disproved the efficacy of plasma in various circumstances. Fresh frozen plasma is currently indicated to treat the coagulopathies of massive hemorrhage, liver failure, disseminated intravascular coagulation and sepsis18.
In an infant the fat has a higher saturated- to-unsaturated fatty acid ratio compared to adult fat and thus a higher melting point. Prematurity, hypothermia and shock and anatomic abnormalities have been postulated to further increase this ratio,possibly as a result of enzymatic alteration allowing precipitation of fatty acid crystals within the lipocytes. This condition has been suggested to result in the dramatic clinical findings in the affected skin. Xray diffraction techniques have confirmed that infants with sclerema have an increase in saturated fats and that the crystals within the fat cells are composed of triglycerides.
The exact incidence of sclerema neonatorum is unknown . All studies describe SN as extremely rare. The number of reported case in recent years have declined, probably as a result of a better neonatal care.
Because sclerema neonatorum invariably is associated with serious underlying disease process, the mortality rate is high. In different series, the reported mortality rates range from 67-88%, with death occuring hours to days after onset. If the underlying disease is treated successfuly, the skin softens and returns to normal.
Sclerema neonatorum shows a slight male preponderance, with an estimated male-to-female ratio of 1.5:1.
Sclerema neonatorum is a disease confined to the newborn period. It can present at birth, but onset within the first week of life is more common. The oldest reported infant presented with Pseudomonas septicemia is 106 days old.
According to literature one half of the affected infants are premature, , and the others are full term but have a serious underlying disease. They are often of low birth weight and have cyanosis and low apgar scores.In one series, 75% of the mothers were healthy, while 25% had preeclampsia, placenta previa, or infection. Labor is usually normal and the delivery is spontaneous and nontraumatic.
Physical findings appear suddenly, first on the thighs and on the buttocks and then spreading rapidly often affecting all parts of the body except the palms and the soles and the genitalia. The involved skin is pale, waxy, and firm to palpation. The skin cannot be pitted or pinched up because it is bound to the underlying tissues. The affected infant often dispalys flexion contractures at the elbows, knees and hips, temperature instability, restricted respiration, difficulty in feeding and decrease in spontaneous movement.17
Recognition and the prompt institution of therapy specific to the underlying disease process are mandatory such as antibiotics, steroids, exchange transfusions and FFP transfusion.
Definition of Terms
Neonatal sepsis-
It is a clinical syndrome of bacteremia characterized by systemic signs and symptoms of infection in the first month of life. Neonatal sepsis encompasses systemic infections of the newborn including septicemia, meningitis, pneumonia, arthritis, osteomyelitis and urinary tract infection of the newborn19.
Associated factors for early onset neonatal sepsis include lowbirthweight, PROM, foul smelling liquor, multiple vaginal examinations and maternal fever20
Early onset neonatal sepsis-
It usually presents within the first 48 hours of life. In severe cases, the neonate may be symptomatic in utero, (fetal tachycardia, poor beat to beat variability) or within the first few hours after birth. The source of the infection is generally in the maternal genital, gastrointestinal, urinary tract . Clinically neonates usually present with respiratory distress and pneumonia. Presence of some perinatal risk factors has been associated with an increased risk of early onset sepsis.
Frozen Frozen Plasma –
It is the plasma removed from a unit of whole blood and frozen at or below 55 degrees Fahrenheit within 8 hours of collection. It contains all the coagulation factors in normal amounts and is free of red cells, leukocytes and platelets. It is not a concentrate of clotting factors.
Sclerema Neonatorum-
It is derived from the Greek word “scleros”meaning hard. It is considered best as a sign of a potentially fatal underlying disease process in the newborn period. Physical findings appear suddenly first on the thighs and buttocks and then spreading rapidly, often affecting all parts of the body except the palms, soles and genitalia. The involved skin is pale, waxy and firm to palpation. The skin cannot be pitted or pinched up because it is bound to the underlying tissues.It can present at birth but onset within the first week of life is more common. Associated underlying conditions include septicemia, pneumonia, hypothermia, metabolic acidosis, respiratory distress syndrome, congenital heart defects, gastroenteritis and intestinal obstruction.
Clinical Signs of Neonatal Sepsis:
(At least 2 clinical signs supported by laboratory findings)
1.sclerema
2.hypoglycemia/hyperglycemia
3.temperature instability
4.tachypnea/respiratory distress
5.Apnea
6.Poor perfusion
Laboratory findings:
1..I/T ratio> 0.2
2.leukopenia <5000
3.Neutropenia <1500 ANC
4.Thrombocytopenia <150,000
Research Question
Will FFP transfusion improves the survival outcome of the sick neonates with early onset neonatal sepsis with sclerema given the standard therapy plus FFP?
Is the use of FFP justifiable in the treatment of neonatal sepsis with sclerema in terms of cost and survival outcome?
Significance of the study
Many studies have been done to improve the survival outcome of neonates with septicemia. The progress in terms of the available adjuctive therapies in the treatment of neonatal sepsis entail a higher cost which is an issue to our marginalized patients who cannot afford such expensive add on treatment hence inspired the researcher to study fresh frozen plasma transfusion which is much more affordable and readily available to the neonates with septicemia particularly with sclerema. FFP contains immunologic factors helping the immunologically deficient neonate in fighting serious infections.
This study aims to evaluate the effects of FFP transfusion in the subset of neonates with high case fatality rate. They are the candidates that would benefit from the terminal cytotoxic complement with the coagulation cascade that FFP may provide.
OBJECTIVES OF THE STUDY
General Objective:
To determine and compare the survival outcome of patients with early- onset neonatal sepsis with sclerema given the standard therapy (antibiotic + supportive care ) plus fresh frozen plasma to those with early -onset neonatal sepsis given only the standard therapy (antibiotic + supportive care ) at Southern Philippines Medical Center- Nursery for the year 2008 .
Specific Objectives:
Determine the incidence of sclerema in early onset neonatal sepsis in SPMC.
Determine the rate of early onset neonatal sepsis with sclerema in SPMC.
Determine the mortality rate of neonates with early onset sepsis with sclerema.
Identify the possible the maternal fetal/neonatal factors related to early neonatal sepsis with sclerema
Compare the outcome
1.resolution of sclerema
Chapter 2
METHODOLOGY
Study Design
This paper will be an observational descriptive and comparative study on the survival outcome of patients with neonatal sepsis with sclerema admitted at Southern Philippines Medical Center for the year 2008 using a Cohort study design.
Population
This study will include all neonates with early-onset neonatal sepsis with sclerema admitted at Southern Philippines Medical Center -Nursery for the year 2008.
Inclusion criteria:
All neonates admitted at Southern Philippines Medical Center -Nursery who presents with the clinical signs of early- onset neonatal sepsis with sclerema.
Exclusion criteria:
1.All neonates presenting with clinical signs of neonatal sepsis with sclerema occurring beyond 48 hours of life.
2. All non-institutional deliveries presenting with early onset neonatal sepsis with sclerema.
3. All neonates admitted at the NICU with obvious congenital anomalies like syndromic features, cleft lip and palate etc.
Data Collection
Data will be collected by the researcher through a retrospective chart review. The researcher will scan and evaluate each chart of the patient with neonatal sepsis for the presence of sclerema in the progress notes. A data sheet will be use for each patient.Research consultant will be asked for validation of diagnosis.
Independent variable -Fresh Frozen Plasma transfusion
Dependent variable- survival outcome of neonates with early onset sepsis with sclerema
Sample Size:
All neonates admitted at Southern Philippines Medical Center-Nursery who fulfilled the inclusion criteria for the year 2008 will be used as a sample in this study.
Data Analysis: correlation coefficient and odds ratio will be used to summarize the data for the comparative part. Means and standard deviation for the descriptive part and percentage and rates as per standard definition.
Ethical Consideration
The approval of the hospital research committee and the ethics committee will be sought before the conduct of the study. No identification data or marks will be placed in each patient included in the study. The data will be kept by the researcher for 5 years.
Table 1.Patient clinical profile
Name: AGA___SGA___LGA___
Age:
Weight:
AOG:
Sex:
Medical record number:
length of stay in the hospital: Date of admission : Date of discharge:
Diagnosis upon admission:
Final diagnosis:
OUTCOME: [ ] died [ ]survived [ ] HAMA [ ] transferred [ ]transout to blue area
Cause of death:
Age at onset of sepsis(hours)
Age at onset of sclerema(hours)
Antibiotics
Ampicillin/Gentamycin
Cefotaxime/Amikacin
Piperacillin + Tazobactam/Amikacin
Meropenem
Cefepime
Neonatal risk factors
Birthweight
1.VLBW<1.5 kg
2.LBW <2.5 kg
3.normal weight
4.LGA
APGAR SCORE (5 minute)
0-3
4-6
7-10
Ballard Scoring
<34 weeks
34-37
>37
Comorbidities
Neonatal pneumonia
Meconium aspiration
Intubation
Pulmonary hypertension
Pneumothorax
Others (specify)
MATERNAL RISK FACTORS
Premature labor and delivery
Prolong Rupture of membrane
Antenatal Steroid
Chorioamnionitis
Manipulative Operative Delivery
Maternal infection within 2 weeks of delivery
UTI
RTI
Preeclampsia/eclampsia
Placenta previa/ abruptio
Others (specify)
SCLEREMA
Hours first noted
FFP transfusion
Yes /hours before transfusion
No
Resolution of sclerema post FFP
Yes- number of hours first noted resolution
No-
OUTCOME
Died
Survived
COMPLICATIONS NOTED
Table 2. ANTIBIOTICS
Standard care+FFP
Standard care
Total
No.
%
No.
%
No.
%
Ampicillin+Gentamycin
Cefotaxime +Amikacin
Piptazo+Amikacin
Meropenem
Cefepime
Total
Table 2.BIRTHWEIGHT
Standard care+FFP
Standard care
Total
No.
%
No.
%
No.
%
VLBW <1.5kg
LBW <2.5kg
AGA
LGA
Total
Table 3. APGAR SCORE(5 MINUTE)
Standard care+FFP
Standard care
Total
No.
%
No.
%
No.
%
0-3
4-6
7-10
Total
Table 4. BALLARDS SCORE
Standard care+FFP
Standard care
Total
No.
%
No.
%
No.
%
<34 weeks
34-37 weeks
>37 weeks
Total
Table 5. Comorbidities
Standard care+FFP
Standard care
Total
No.
%
No.
%
No.
%
Neonatal pneumonia
Meconium aspiration
Intubation
Pulmonary hypertension
Pneumothorax
Others (specify)
Total
Table 6. Maternal Risk Factors
Antibiotic+Standard care+ FFP
Antibiotic +Standard care
Total
No.
%
No.
%
No.
%
Preterm labor/delivery
RBOW
Antenatal Steroid
Chorioamnionitis
Operative Delivery
Maternal infection
UTI
RTI
Preeclampsia/eclampsia
Placenta previa /abruptio
Others (specify)
Total
Table 7. Onset and Resolution of Sclerema
Antibiotic+Standard care+ FFP
Antibiotic +Standard care only
Onset
resolution
Total time of sclerema
Table 8. Outcome
Survived
Dead
Total
No.
%
No.
%
No.
%
Antibiotic+Standard care+ FFP
Antibiotic +Standard care
Total
Conceptual framework:
Babies admitted at DMC nursery 2008
No sepsis
Compare results
Sepsis with sclerema
Antibiotic+Standard care+ FFP
Antibiotic +Standard care
Sepsis without sclerema
Early-onset neonatal sepsis
COST/BUDGET:
COUPON BOND………………………………………………….P.400.00
PRINTING……………………………………………………………P700.00
RESEARCH MATERIALS ……………………………………..1,000.00
______________________
P 2,100.00
TIME TABLE (May 2009- December 2010)
May
PRESENTATION TO RESEARCH COMMITTEE
AND ETHICS
June -October
DATA GATHERING
November
PRESENTATION OF RESULTS
December
SUBMISSION OF HARD COPIES
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