Original Article

905

Role of Pentoxifylline and/or IgM-Enriched Intravenous Immunoglobulin in the Management of Neonatal Sepsis Khalide Haque, MD2

1 Department of Neonatology, Zekai Tahir Burak Maternity and

Teaching Hospital Ankara, Turkey 2 Department of Paediatrics, Taibah University, Taibah University Medina, Medina, Saudi Arabia

Dilek Dilli, MD1

Omer Erdeve, MD1

Address for correspondence Dilek Dilli, MD, Talatpaşa Bulvarı, Zekai Tahir Burak Maternity Teaching Hospital, Hamamönü, Ankara 06111, Turkey (e-mail: [email protected]).

Am J Perinatol 2014;31:905–912.

Abstract

Keywords

► ► ► ►

sepsis newborn pentoxifylline IgM-enriched intravenous immunoglobulin

Objective To investigate the effectivity of pentoxifylline (PTX) and immunoglobulin M (IgM)-enriched intravenous immunoglobulin (IVIG) therapy in the treatment of neonatal sepsis (NS), alone or in combination. Study design This was a prospective, double-blind, controlled study. Newborns with suspicion of sepsis were enrolled in the study. The patients were separated into four groups according to treatment protocol: Group 1 ¼ placebo, Group 2 ¼ pentoxifylline, Group 3 ¼ IgM-enriched IVIG, and Group 4 ¼ pentoxifylline þ IgM-enriched IVIG. Blood samples were taken for C-reactive protein, interleukin-6, neutrophil CD64 expression, and tumor necrosis factor-alfa measurements immediately before treatment (1st day), and measurements were repeated on the 2nd and 4th days of the therapy. Results A total of 204 patients, 51 in each group, were recruited into the study. There were no significant differences for symptoms of sepsis among groups, except lethargy. No significant differences were observed among the groups according to laboratory data. Overall mortality rate was 8.8%. The rates of morbidities and mortality among study groups were similar. Conclusion PTX and IgM-enriched IVIG therapies, either alone or in combination, did not reduce the rates of morbidities and mortality in NS.

Neonatal sepsis (NS) is a major cause of morbidity and mortality all over the world both in term and preterm infants.1–4 Despite advances in neonatal care and the use of newer generation of antibiotics, mortality from NS is still unacceptably high; assuming combined rates of mortality and major morbidity around 10 to 20% for all infants and 20 to 30% for very low birth weight (VLBW) infants.5–7 It has been suggested that two major reasons for the high mortality in NS are both lack of effective antibiotics to resistant bacteria

and the poor host defense mechanism of the newborn.8–10 Thus, for effective treatment of sepsis, boosting the host defense mechanisms of the newborn appears to be essential. Various adjuvant therapies offer important additional strategy.9,11 The most promising of these are intravenous immunoglobulin (IVIG) and pentoxifylline (PTX). Clinical trials on polyclonal IVIG as adjuvant therapy in sepsis have yielded contradicting results, in part because of the varying study design and varying microbiological etiologies.12–15 A

received October 4, 2013 accepted after revision November 15, 2013 published online February 10, 2014

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0033-1363771. ISSN 0735-1631.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Arzu Akdag, MD1 Ugur Dilmen, MD1 Tuelin Goekmen, MD1

Adjuvant Treatments in NS

Akdag et al.

recent large study performed on 3,493 infants showed that therapy with IVIG had no effect on the outcomes of suspected or proven NS.16 On the contrary, the efficacy of immunoglobulin M (IgM)enriched IVIG as adjunct therapy in sepsis has been shown in both adults and newborns.8,17,18 PTX, a methylxanthine derivative, inhibits production of tumor necrosis factor-alfa (TNF-α), preserves microvascular blood flow, prevents circulatory failure and intestinal vasoconstriction, and improves survival.19,20 There are two small randomized-controlled trials on the effectivity of PTX in preterm infants with NS.20,21 However, to the best of our knowledge, there is no study on the combined use of PTX and IgM-enriched IVIG in NS. Therefore, in this study, we aimed to investigate the role of adjuvant therapies on the reduction of the rates of morbidities and mortality in NS.

Design and Setting This was a prospective, double-blind, controlled study conducted in the neonatal intensive care unit (NICU) of Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey, between August, 2009, and October, 2010. This trial was

Fig. 1 Randomization, follow-up, and data analyses.

Vol. 31

Patients Inclusion and Exclusion Criteria During the study period, the newborns with suspicion of sepsis were enrolled in the study. Exclusion criteria were major congenital abnormalities, intraventricular hemorrhage (grade 3 or grade 4), symptoms of a congenital infection, and inborn errors of metabolism. The patients who previously received PTX or IgM-enriched IVIG were also excluded (►Fig. 1).

Diagnosis of Sepsis

Patients and Methods

American Journal of Perinatology

approved by the local ethics committee. The infants were enrolled in the study after written parental consent. Consent process was included potential adverse effects of pentaglobulin such as fever, edema, flushing of the face, hypotension, tachycardia, vomiting, and hyperglycemia secondary to IVIGs.

No. 10/2014

Sepsis was diagnosed with physical and laboratory signs of infection.22 Physical signs of sepsis were lethargy or irritability, temperature instability, feeding intolerance,23 abdominal distension, disordered peripheral circulation, and hepatosplenomegaly. Respiratory dysfunction was established by presence of tachypnea (> 60 breaths/min) plus grunting/

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

906

Adjuvant Treatments in NS

Grouping The patients were separated into four groups according to treatment protocol. Group 1: Standard treatment plus placebo (5 mL/kg of normal saline IV, over 4 hours), daily for three consecutive days. Group 2: Standard treatment plus PTX (6 mg/kg/h IV, over 4 hours) (Trental, Sanofi-Aventis, Istanbul, Turkey), daily for three consecutive days.27 Group 3: Standard treatment plus IgM-enriched IVIG (250 mg/kg IV, over 4 hours) (Pentaglobin, Biotest Pharma, GmbH, Dreieich, Germany), daily for three consecutive days.28 Group 4: Standard treatment plus PTX (first) (6 mg/kg/h IV, over 4 hours) plus IgM-enriched IVIG (250 mg/kg IV, over 4 hours), daily for three consecutive days.

Randomization Informed and written parental consents were obtained before randomization. The investigators (U.D. and O.E.) who perform group assignment and analyze the data of the study did not take care of the patients in the nursery. The nurses who were in care of the infants were blinded to the group assignment. The parents and other investigators were also blinded to the group assignment. Patients were assigned randomly to treatment groups by using cards in sealed opaque envelopes and sequentially numbered. The solutions were prepared by the

907

unblinded pharmacist (Gülgün Altınok) and delivered to vertical the clinical unit in bottles with special plastic covers. Infusions vials were identical. A small slit allowed the nurse to watch the level of infusion without seeing the bubbles of the infusion.

Study Protocol As soon as infection was suspected, blood samples were taken according to current protocol for diagnosis and confirmation of sepsis. Laboratory studies included complete blood count, CRP, IL-6, neutrophil CD64 expression, TNF-α, culture from blood, and other sites (CSF, urine, and catheter), if necessary. Antibiotic and fluid therapies were initiated according to our clinic protocol just after the laboratory sampling. Antibiotics were changed according to culture and sensitivity results obtained usually with 48 hours.

Laboratory Analyses Blood samples were taken for CRP, IL-6, CD64, and TNF-α measurements immediately before treatment (1st day), and tests were repeated on the 2nd and 4th days of the therapy. Blood specimens were obtained immediately, transported to the laboratory and processed upon arrival. For TNF-α determination, plasma was separated from blood within 30 minutes and aliquots were stored at –70°C until assayed. The volume of plasma required for each cytokine analysis was 100 µL. Serum concentrations of CRP were measured by a Tina-quant CRP (latex) high sensitive immunoturbidimetric assay on the Roche Modular P analyzer according to the manufacturer’s instructions (CRP latex HS, Roche kit, Roche Diagnostics, Mannheim, Germany). Plasma levels of IL-6 were analyzed by IL-6 solid phase, enzyme labeled, chemiluminescent sequential immunometric assay on IMMULITE 1000 analyzer, according to the manufacturer’s instructions (Siemens Diagnostic Product Corporation, Los Angeles, CA). The expression of CD64 in neutrophils was analyzed by flow cytometry. Flow cytometric analysis was performed using FACSCalibur (Becton Dickinson, Biosciences, Erembodegem, Belgium). Data analysis was quantified as mean fluorescence intensity (MFI). TNF- α was determined by immunoenzymatic test (Hu TNF-α ELISA; Invitrogen, Camarillo, CA). The minimum detectable dose of Hu TNF-α is 1.7 pg/mL. This was determined by adding two standard deviations to the mean OD obtained when the zero standard was assayed 20 times.

Evaluation of Infant’s Clinical Condition in the Course of Sepsis Daily data (e.g., systemic arterial pressure, heart and respiratory rates, and skin temperature) for each neonate were recorded continuously. Acute renal insufficiency is defined as an abrupt reduction in kidney function and blood urea nitrogen greater than 20 mg/dL on two separate occasions at least 24 hours apart. Oliguria was defined if the urine output was less than 1 mL/kg/h.29 Neonates with abdominal distension had a radiographic examination. Necrotizing enterocolitis (NEC) was diagnosed according to modified Bell staging criteria.30 Criteria for disseminated intravascular coagulation (DIC) included generalized hemorrhagic diathesis with bleeding from venipuncture sites, hypofibrinogenemia (< 150 mg/dL), American Journal of Perinatology

Vol. 31

No. 10/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

retraction or desaturation.24 Tachycardia (heart rate 180 breaths/min) or bradycardia (100 beats/min) plus disordered peripheral circulation were regarded as symptoms of circulatory dysfunction (defined as paleness or peripheral cyanosis and mottled skin with delayed capillary refill > 3 second). Criteria for septic shock were defined as sepsis with hypotension25 (mean arterial pressure below the fifth percentile for age) requiring fluid resuscitation or inotropic support. Glucose instability such as severe hypoglycemia (< 40 mg/dL) or hyperglycemia (> 140 mg/dL) was also noted.26 The following laboratory measurements were determined in all infants with suspicion of sepsis: leukocyte count, concentration of C-reactive protein (CRP), interleukine-6 (IL-6), neutrophil CD64 expression (CD64), and TNF-α. Laboratory signs of sepsis were as follows: total leukocyte count of either less than 4,000 or more than 34,000 cells/mm3; CRP level above 10 mg/L, IL-6 level above 70 pg/mL. Infants with negative blood or cerebrospinal fluid (CSF) culture but with significant clinical signs and symptoms of sepsis plus supporting laboratory parameters were classed as “suspected sepsis”. Neonates with a positive blood or CSF culture were considered to have “proven sepsis.” Infection that occurred within the first 72 hours was designated as “early onset sepsis” and that after 72 hours as “late onset sepsis.”21 Staphylococcus epidermidis was considered as the causative organism only when it was the only isolate from two blood culture specimen from separate sites (usually taken at the same time) and was accompanied by supporting laboratory parameters along with clinical signs and symptoms of sepsis.

Akdag et al.

Adjuvant Treatments in NS

Akdag et al.

elevated fibrin split products (>10 µg/mL), thrombocytopenia (< 100  103/mm3) and prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT) for age.31 Hepatic failure was diagnosed when increased serum concentrations of alanine aminotransferase and aspartate aminotransferase (>100 U/L) and significantly elevated aPTT and PT were present.32 Essential parts of the management of septic shock were as follows: obligatory mechanical ventilation, improvement of blood perfusion by volume resuscitation (crystalloid and colloid solutions), and/or vasopressors (dopamine and dobutamine or epinephrine), and compensation of acid–base balance disturbances. When DIC developed, infants were additionally treated with infusions of fresh frozen plasma, administration of vitamin-K, and packed red blood cells transfusions. Steroid and granulocyte transfusions were not given. The criteria either for artificial ventilation or for weaning from the ventilator were comparable. Primary outcome of the study was death. Secondary outcomes were level of proinflammatory biomarkers.

(p > 0.05) (►Table 2). The alterations in plasma CRP, IL-6, CD-64, and TNF-α levels in four groups during the 4 days course of the study are shown in ►Fig. 2A–D. A total of 89 patients (43.6%) were diagnosed as proven sepsis. Among these patients, gram-positive, gram-negative, and fungal infection rates were 55.0, 42.6, and 22.4%, respectively. In terms of Gram staining, there was no significant difference among the groups (p > 0.05). Isolated microorganisms according to groups are shown in ►Table 3. Coagulasenegative staphylococcus, being responsible for nearly 50% of the isolates, was the leading microorganism. Comparison of the incidence of NEC, renal and hepatic failure, DIC, and mortality among study groups are presented in ►Table 4. Overall mortality rate was 8.8% (n ¼ 18). Of the total patients, 11 babies died within the first 72 hours of the study without completion of the treatment schedule. Causes of deaths were septic shock, DIC, advanced NEC, and pulmonary hemorrhage. Groups did not differ in terms of mortality rates (p > 0.05).

Sample Size Calculation and Statistics

Discussion

According to our previous NICU experience, the rate of mortality of NEC among infants with NS is 12%. Power analysis showed that setting the error 0.05 and β error 0.30 (two-tailed) and an absolute reduction of rate of mortality by approximately 50%, the total number needed to verify our hypothesis was 204 (51 in each group) (https://www.dssresearch.com). According to intention-to-treat analysis, every subject who was randomized was included. Statistical Package for Social Sciences 17.0 was used for statistical analyses (SPSS, Chicago, IL). Data are expressed as the arithmetic mean  standard deviation, median (min– max), or interquartile ranges (IQR), as appropriate. Because the most hematologic parameters follow a log-normal distribution, all subsequent analyses were performed on log transformed scales and geometric mean values were used. Nonparametric tests were performed, if normal distribution could not be obtained despite log transformation of the data. Differences among four groups were analyzed by variance analysis or Kruskal–Wallis test, if appropriate. Chi-square test was performed for categorical variables. Variance analyses were used in comparison of repeated measurements. The level of significance was set at 5% for all comparisons.

The high rates of mortality and morbidity for both early and late onset sepses despite the use of potent antimicrobials have led to research for modalities to augment neonatal host defense mechanisms. In this context, various adjuvant therapies have been used in the treatment of sepsis.9,11 Some of these are IVIG, IgM-enriched IVIG, and PTX. Clinical trials on the efficacy of these adjutants have yielded contradicting results.12–18,33 Furthermore, there is no study comparing PTX and IgM-enriched IVIG alone or in combination. In this study, we investigated the effectivity of PTX and IgM-enriched IVIG therapy in the treatment of NS and our results demonstrated that adjuvant therapies either alone or in combination did not reduce mortality in NS. Newborn infants, particularly small preterms, are deficient in IgG, which provides opsonic activity and can improve neutropenia by enhancing the release of stored neutrophils.34 IVIG is therefore a theoretically attractive strategy, with multiple mechanisms of action. There are multiple studies evaluating the efficacy of IVIG as prophylaxis or treatment for infection in neonates. A meta-analysis showed a reduction in mortality when IVIG was used in the acute treatment of NS.12 Another meta-analysis showed a very modest reduction in development of late-onset sepsis following IVIG prophylaxis in preterm neonates but did not reduce mortality in this situation.13 In the most recent systematic review, routine administration of IVIG to prevent mortality in infants with suspected or proven neonatal infection was not recommended.14 As the benefit of IVIG seemed to have limited value we used IgM-enriched IVIG, not IVIG. The use of IgM-enriched IVIG as adjuvant therapy in the treatment of sepsis has been described.8,16 IgM-enriched IVIG has been postulated to confer superior toxin neutralization and bacterial agglutination and to reduce mortality in gramnegative septic shock in all age groups.17,18,35 However, Erdem et al33 suggested that IgM-enriched IVIG did not reduce mortality in neonates with sepsis. We also observed

Results A total of 204 patients included in the study were randomized into four groups, 51 in each group. Overall prematurity and VLBW rates were 84.3% (n ¼ 172) and 66.8% (n ¼ 115), respectively. Early sepsis (72 hours) and late sepsis (> 72 hours) were detected in 42 (20.5%) and 162 (79.4%) patients. ►Table 1 shows the characteristics of all 204 study subjects included in the study according to groups. There were no significant differences for symptoms of sepsis among groups, except lethargy. No significant differences were observed among the groups according to laboratory data American Journal of Perinatology

Vol. 31

No. 10/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

908

Adjuvant Treatments in NS

Akdag et al.

909

Placebo group (n ¼ 51)

Pentoxifylline group (n ¼ 51)

Pentaglobin group (n ¼ 51)

Pentoxifylline þ pentaglobin Group (n ¼ 51)

p value

Birth weight (g), median (range)

1,410 (620–4,300)

1,490 (620–4,580)

1,320 (620–3,860)

1,330 (540–4,100)

NS

Gestational age weeks, median (range)

31 (25–40)

31 (24–42)

30 (24–41)

30 (24–40)

NS

Male gender, n (%)

33 (64.7)

29(56.8)

27(52.9)

36(70.6)

NS

Age at sepsis evaluation, median (d) (IQR)

5.5 (3–10)

9 (5–13)

8 (4–13)

9 (5–17)

NS

Antenatal steroid, n (%)

28 (54.9)

28 (54.9)

30 (58.8)

29 (56.8)

NS

Premature rupture of membrane > 18 h, n (%)

4 (7.8)

6 (11.7)

4 (7.8)

3 (5.9)

NS

Cesarean delivery, n (%)

35 (68.6)

38 (74.5)

41 (80.4)

33 (64.7)

NS

5-minute Apgar score (< 6), n (%)

5 (9.8)

5 (9.8)

3 (5.9)

3 (5.9)

NS

Prematurity, n (%)

41 (80.3)

41 (80.3)

44 (86.2)

46 (90.1)

NS

Very low birth weight, n (%)

27 (52.9)

25 (49.1)

30 (58.8)

34 (66.7)

NS

Catheter, n (%)

22 (43.1)

20 (39.2)

14 (27.4)

27 (52.9)

NS

Late sepsis, n (%)

36 (70.5)

41 (80.3)

40 (78.4)

45 (88.2)

NS

Temperature instability, n (%)

12 (23.5)

8 (15.6)

14 (27.4)

13 (25.4)

NS

Lethargy, n (%)

27 (52.9)

28 (54.9)

30 (58.8)

38 (74.5)

0.004

Glucose instability, n (%)

12 (23.5)

7 (13.7)

13 (25.4)

13 (25.4)

NS

Recurrent apnea, n (%)

10 (19.6)

13 (25.4)

10 (19.6)

17 (33.3)

NS

Feeding intolerance, n (%)

28 (54.9)

33 (64.7)

27 (52.9)

34 (66.6)

NS

Symptoms of shock, n (%)

5 (9.8)

3 (5.8)

5 (9.8)

5 (25.4)

NS

Length of hospital, median (d) (range)

27 (1–168)

28 (5–246)

32 (5–136)

38 (5–119)

NS

Abbreviations: IQR, interquartile range; NS, nonsensitive.

Table 2 Laboratory evaluation of the study subjects according to groups Placebo group (n ¼ 51)

Pentoxifylline group (n ¼ 51)

Pentaglobin group (n ¼ 51)

Pentoxifylline þ pentaglobin Group (n ¼ 51)

p value

White blood cell count, cells/mm3, mean  SD

4,000  250

4,004  230

4,130  230

4,040  280

NS

Plasma CRP level (mg/L), mean  SD

1.24  0.43

1.32  0.45

1.35  0.33

1.18  0.53

NS

Plasma IL-6 level (pg/mL), mean  SD

1.89  0.76

1.92  0.77

2.19  0.74

2.01  0.88

NS

Neutrophil CD64 (MFI), mean  SD

2.17  0.31

2.19  0.28

2.18  0.31

2.17  0.28

NS

Plasma TNF level (pg/mL), mean  SD

2.27  0.18

2.24  0.27

2.23  0.22

2.25  0.21

NS

Positive blood culture, n (%)

19 (37.2)

20 (39.2)

23 (45)

27 (52.9)

NS

Positive urinary tract culture, n (%)

1 (2)

1 (2)

5 (10.5)

6 (23.2)

NS

Positive CSF culture, n (%)

2 (4)

4 (8.1)

2 (4.2)

4 (8.8)

NS

Positive catheter culture, n (%)

4 (20)

2 (9.6)

5 (8.8)

5 (23.8)

NS

Abbreviations: CRP, C-reactive protein; CSF, cerebrospinal fluid; IL-6, interleukin-6; MFI, mean fluorescence intensity; NS, nonsensitive; SD, standard deviation; TNF, tumor necrosis factor. American Journal of Perinatology

Vol. 31

No. 10/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Table 1 Comparison of the study subjects at randomization according to study groups

Adjuvant Treatments in NS

Akdag et al.

Fig. 2 (A) Serum C-reactive protein (mg/L), (B) plasma interleukine-6 (pg/mL), (C) plasma CD64 (mean fluorescence intensity), and (D) plasma tumor necrosis factor (pg/mL) levels according to groups on the 1st, 2nd, and 4th days of the study. (Log-transformed values are presented in graphs). CRP, C-reactive protein; IL-6, interleukine-6; TNF, tumor necrosis factor.

Table 3 Microorganisms isolated from the study subjects according to the groups

Coagulase-negative staphylococci

Placebo group (n ¼ 18)

Pentoxifylline group (n ¼ 20)

Pentaglobin group (n ¼ 26)

Pentoxifylline þ pentaglobin group (n ¼ 29)

12 (2)

10 (2)

11 (1)

13 (2)

Staphylococcus aureus

1

Klebsiella pneumoniae

6

8 (1)

7

9 (2)

Pseudomonas aeruginosa







3

Enterobacteriaceae





1



Enterococcus faecalis





1



Escherichia coli

1

1

1(1)

Stenotrophomonas maltophilia







1

Candida species



1



1

Group B Streptococcus

1 (1)

Note: Figures in parentheses indicate positive cerebrospinal fluid. American Journal of Perinatology

Vol. 31

No. 10/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

910

Adjuvant Treatments in NS

Akdag et al.

911

Placebo group (n ¼ 51)

Pentoxifylline group (n ¼ 51)

Pentaglobin group (n ¼ 51)

Pentaglobin þ pentoxifylline group (n ¼ 51)

p value

Oliguria/anuria, n (%)



2 (3.9)

4 (7.8)

1 (1.9)

NA

Hepatic failure, n (%)



1 (1.9)

1 (1.9)

1 (1.9)

NA

Necrotizing enterocolitis, n (%)

2 (3.9)

4 (7.8)

3 (5.8)

3 (5.8)

NA

Disseminated intravascular coagulation, n (%)

1 (1.9)

3 (5.8)

5 (9.8)

2 (3.9)

NA

Pulmonary hemorrhage, n (%)







2 (3.9)

NA

Mortality, n (%)

2 (3.9)

5 (9.8)

4 (7.8)

7 (13.7)

NS

Abbreviations: NA, nonapplicable; NS, nonsensitive.

that mortality rate was not reduced when IgM-enriched IVIG was used in the management of NS. It was found that PTX decreased TNF-α production,36 lowered circulating cytokine concentrations,30 and preserved small intestine microvascular blood flow37 during bacteremia in patients with sepsis. Lauterbach and Zembala20 in a pilot study of 17 premature infants with sepsis showed that standard therapy plus PTX 5 mg/kg/hour for 6 hours on three consecutive days significantly reduced mortality from sepsis. These studies are limited by the small number of patients and differ in entry criteria. In a Cochrane systematic review, Haque and Mohan reported that the use of PTX as an adjunct to antibiotics in NS reduced mortality without any adverse effects.38 On the contrary to previous reports, we did not find any difference for mortality rates among the four groups. We also observed that the incidence of NEC in patients treated by PTX was similar to other groups. PTX has been showed to be of great benefit in different models of animal sepsis, including both gram-positive and gram-negative bacteria.39 In a clinical trial, investigators showed that PTX significantly affected the synthesis of TNF and IL-6 as well as reduced the mortality rate in premature infants with sepsis. In their study, the frequency of gramnegative sepsis was similar in both groups (37.5 and 36.8%).21 An in vitro assay study revealed that infusion of IgM-enriched IVIG might be beneficial for patients with severe infections.40 In a recent review, Norrby-Teglund et al41 stated that the results of the many studies suggested that patients most likely to benefit from IgM-enriched IVIG therapy were those with gram-negative septic shock. In this study, PTX or IgM-enriched IVIG did not change the outcome in NS. However, the most of our patients had gram-positive infections. This may cause difference between the previous research and our results. In neonates, there are some studies which have shown that PTX significantly decreased serum levels of TNF-α, IL-6 but not IL-1.21 In this study, the decreasing trend of proinflammatory markers (TNF-α, IL-6, and CD64) from the 1st to 4th day of evaluation was similar in newborns treated with PTX or not; however, CD64 response pattern was different in patients treated with IgM-enriched IVIG compared with ones in other groups. There is a substantial increase in CD64 expression on the surface of neutrophils in response to bacterial

infection in neonates. Expression of CD64 has been found to be a highly specific and sensitive (95–97%) indicator of NS with a high negative predictive value (97–99%) for early- and late-onset NS. In our study, IgM-enriched IVIG when given either on its own or along with PTX significantly reduced CD-64 levels suggesting a significant trend toward reduction in infection. This effect needs to be studied further with larger number of patients. To the best our knowledge, this is the first study investigating the effectiveness of PTX and IgM-enriched IVIG therapy in the treatment of NS, alone or in combination. However, we recognize several limitations of our study. First, our study has a moderate power (70%). The sample size required in future studies should be higher than 326 to reach 85% power. In addition, we have not evaluated whether PTX or IgMenriched IVIG affect or not long-term neurologic development of the patients. We plan to report the results of neurodevelopmental evaluation of these infants in a future study.

Conclusion PTX and IgM-enriched IVIG therapies either alone or in combination as used in this study have no effect on mortality in NS. Early diagnosis of sepsis, effective antibiotic, and fluid treatment with respiratory and circulatory support remain the main stay in the treatment of NS. Funding There is no any funding from any foundation.

Conflict of Interest There is no any conflict of interest.

References 1 Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely

preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126(3):443–456 2 Lawn JE, Wilczynska-Ketende K, Cousens SN. Estimating the causes of 4 million neonatal deaths in the year 2000. Int J Epidemiol 2006;35(3):706–718 American Journal of Perinatology

Vol. 31

No. 10/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Table 4 The incidence of morbidities in the course of sepsis according to the groups

Adjuvant Treatments in NS

Akdag et al.

3 Grether JK, Nelson KB. Maternal infection and cerebral palsy in 4

5 6

7

8

9

10

11 12

13

14

15

16

17

18

19 20

21

infants of normal birth weight. JAMA 1997;278(3):207–211 Stoll BJ, Hansen NI, Adams-Chapman I, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292(19):2357–2365 Tiskumara R, Fakharee SH, Liu CQ, et al. Neonatal infections in Asia. Arch Dis Child Fetal Neonatal Ed 2009;94(2):F144–F148 Talbert AW, Mwaniki M, Mwarumba S, Newton CR, Berkley JA. Invasive bacterial infections in neonates and young infants born outside hospital admitted to a rural hospital in Kenya. Pediatr Infect Dis J 2010;29(10):945–949 Bader D, Kugelman A, Boyko V, et al. Risk factors and estimation tool for death among extremely premature infants: a national study. Pediatrics 2010;125(4):696–703 Haque KN, Zaidi MH, Bahakim H. IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child 1988;142(12):1293–1296 Cohen-Wolkowiez M, Benjamin DK Jr, Capparelli E. Immunotherapy in neonatal sepsis: advances in treatment and prophylaxis. Curr Opin Pediatr 2009;21(2):177–181 Wynn J, Cornell TT, Wong HR, Shanley TP, Wheeler DS. The host response to sepsis and developmental impact. Pediatrics 2010; 125(5):1031–1041 Tarnow-Mordi W, Isaacs D, Dutta S. Adjunctive immunologic interventions in neonatal sepsis. Clin Perinatol 2010;37(2):481–499 Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev 2010;3(3):CD001239 Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev 2004;1(1):CD000361 Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev 2013;7: CD001239 Haque KN, Zaidi MH, Haque SK, Bahakim H, el-Hazmi M, elSwailam M. Intravenous immunoglobulin for prevention of sepsis in preterm and low birth weight infants. Pediatr Infect Dis 1986; 5(6):622–625 Brocklehurst P, Farrell B, King A, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med 2011;365(13): 1201–1211 Haque KN, Remo C, Bahakim H. Comparison of two types of intravenous immunoglobulins in the treatment of neonatal sepsis. Clin Exp Immunol 1995;101(2):328–333 Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 2007;35(12):2677–2685 Harris E, Schulzke SM, Patole SK. Pentoxifylline in preterm neonates: a systematic review. Paediatr Drugs 2010;12(5):301–311 Lauterbach R, Zembala M. Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis. Eur J Pediatr 1996;155(5):404–409 Lauterbach R, Pawlik D, Kowalczyk D, Ksycínski W, Helwich E, Zembala M. Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebocontrolled, double-blind trial. Crit Care Med 1999;27(4):807–814

American Journal of Perinatology

Vol. 31

No. 10/2014

22 Haque KN. Definitions of bloodstream infection in the newborn.

Pediatr Crit Care Med 2005;6(3, Suppl):S45–S49 23 Ng E, Shah V. Erythromycin for feeding intolerance in preterm

infants. Cochrane Database Syst Rev 2001;(2):CD001815 24 Rajesh VT, Singhi S, Kataria S. Tachypnoea is a good predictor of

25 26

27

28

29 30

31

32

33

34 35

36

37

38 39

40

41

hypoxia in acutely ill infants under 2 months. Arch Dis Child 2000; 82(1):46–49 Marik PE, Lipman J. The definition of septic shock: implications for treatment. Crit Care Resusc 2007;9(1):101–103 Hebson CL, Chanani NK, Rigby MR, et al. Safe and effective use of a glycemic control protocol for neonates in a cardiac ICU. Pediatr Crit Care Med 2013;14(3):284–289 Pawlik MT, Schreyer AG, Ittner KP, et al. Early treatment with pentoxifylline reduces lung injury induced by acid aspiration in rats. Chest 2005;127(2):613–621 Haque KN, Remo C, Bahakim H. Comparison of two types of intravenous immunoglobulins in the treatment of neonatal sepsis. Clin Exp Immunol 1995;101(2):328–333 Mathur NB, Agarwal HS, Maria A. Acute renal failure in neonatal sepsis. Indian J Pediatr 2006;73(6):499–502 Ahmad I. Necrotizing enterocolitis and spontaneous intestinal perforation. In: Fred KA, Lebowitz H, eds. Lange Neonatalogy: Management, Procedures, On-Call Problems, Diseases, and Drugs. 6th ed. New York: McGraw-Hill Companies, Inc; 2009:590–595 Woods WG, Luban NL, Hilgartner MW, Miller DR. Disseminated intravascular coagulation in the newborn. Am J Dis Child 1979; 133(1):44–46 Tarcan A, Tiker F, Güvenir H, Gürakan B. Hepatic involvement in perinatal asphyxia. J Matern Fetal Neonatal Med 2007;20(5): 407–410 Erdem G, Yurdakök M, Tekinalp G, Ersoy F. The use of IgM-enriched intravenous immunoglobulin for the treatment of neonatal sepsis in preterm infants. Turk J Pediatr 1993;35(4):277–281 Werdan K. Supplemental immune globulins in sepsis. Clin Chem Lab Med 1999;37(3):341–349 Haque KN. Use of Intravenous Immunoglobulin in the Treatment of Neonatal Sepsis: A Pragmatic Review and Analysis. J Med Sci 2010; 3(3):160–167 Zeni F, Pain P, Vindimian M, et al. Effects of pentoxifylline on circulating cytokine concentrations and hemodynamics in patients with septic shock: results from a double-blind, randomized, placebo-controlled study. Crit Care Med 1996;24(2):207–214 Steeb GD, Wilson MA, Garrison RN. Pentoxifylline preserves smallintestine microvascular blood flow during bacteremia. Surgery 1992;112(4):756–763, discussion 763–764 Haque K, Mohan P. Pentoxifylline for neonatal sepsis. Cochrane Database Syst Rev 2003;(4):CD004205 Schönharting MM, Schade UF. The effect of pentoxifylline in septic shock—new pharmacologic aspects of an established drug. J Med 1989;20(1):97–105 Lissner R, Struff WG, Autenrieth IB, Woodcock BG, Karch H. Efficacy and potential clinical applications of Pentaglobin, an IgM-enriched immunoglobulin concentrate suitable for intravenous infusion. Eur J Surg Suppl 1999;584(584):17–25 Norrby-Teglund A, Haque KN, Hammarström L. Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis. J Intern Med 2006;260(6):509–516

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

912

Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

or IgM-enriched intravenous immunoglobulin in the management of neonatal sepsis.

To investigate the effectivity of pentoxifylline (PTX) and immunoglobulin M (IgM)-enriched intravenous immunoglobulin (IVIG) therapy in the treatment ...
261KB Sizes 2 Downloads 0 Views