Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates

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Authors

Mohan Pammi1, Khalid N Haque2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs


1Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [top]
2(Formerly) Division of Neonatology, Department of Child Health, Queen Mary's Hospital for Children, Wrythe Lane, Carshalton, UK [top]

Citation example: Pammi M, Haque KN. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD004205. DOI: 10.1002/14651858.CD004205.pub3. [top]

Contact person

Mohan Pammi

Section of Neonatology, Department of Pediatrics
Baylor College of Medicine
6621, Fannin, MC.WT 6-104
Houston TX 77030
USA

E-mail: mohanv@bcm.tmc.edu

Dates

Assessed as Up-to-date: 29 June 2014
Date of Search: 15 May 2014
Next Stage Expected: 15 May 2016
Protocol First Published: Issue 2, 2003
Review First Published: Issue 4, 2003
Last Citation Issue: Issue 3, 2015

What's new

Date / Event Description
29 June 2014
New citation: conclusions not changed

No changes to conclusions.

29 June 2014
Updated

We updated the search in May 2014 and added two new studies (Shabaan 2014 and Akdag 2014). We have revised the review by adding 'Summary of findings' table and changing the ongoing study (ZTB 2009) to the included study (Akdag 2014). We used the GRADE methods to rate quality of evidence as very low, low, moderate, or high.

History

Date / Event Description
08 July 2011
New citation: conclusions not changed

No change to conclusions.

08 July 2011
Updated

This updates the review 'Pentoxyfilline for treatment of sepsis and necrotizing enterocolitis in neonates' published in the Cochrane Database of Systematic Reviews (Haque 2003).

Search updated July 8, 2011. Two additional included trials and one additional ongoing study have been added to the review.

07 December 2010
Amended

Contact details updated.

21 February 2008
Amended

Converted to new review format

11 September 2007
Updated

This updates the review "Pentoxifylline for neonatal sepsis" published in the Cochrane Database of Systematic Reviews, Issue 2, 2003 (Haque 2003).

The updated search did not identify any new trials. Two ongoing trials using pentoxifylline in the treatment of necrotizing enterocolitis were identified.

The title and the review has been modified to include pentoxifylline treatment for necrotizing enterocolitis, in view of emerging evidence for potential benefits of the use of pentoxifylline for this condition.

28 January 2003
New citation: conclusions changed

Substantive amendment

Abstract

Background

Mortality and morbidity due to neonatal sepsis and necrotizing enterocolitis (NEC) remain high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline, a phosphodiesterase inhibitor, is one such agent.

Objectives

Our primary objectives were :

  1. To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis.
  2. To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with NEC.

Search methods

We searched the Cochrane Neonatal Review Group Specialized Register, CENTRAL (The Cochrane Library Issue 2, 2014), EMBASE (January 1980 to May 2014), PubMed (January 1966 to May 2014), CINAHL (January 1982 to May 2014), Science Citation Index (January 1990 to May 2014), and BIOSIS (January 1992 May 2014) in May 2014. We checked references and cross-references from identified studies. We handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings (from January 1990 to May 2014). We placed no restrictions on language.

Selection criteria

We included randomised or quasi-randomised trials assessing the efficacy of pentoxifylline as an adjunct to antibiotics for treatment of suspected or confirmed sepsis or NEC in neonates.

Data collection and analysis

We reported typical risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) using fixed-effect model for dichotomous outcomes and mean difference (MD) for continuous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB) if there was a statistically significant reduction in RD.

Main results

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis decreased all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-quality evidence). Subgroup analyses revealed decrease in mortality in preterm infants, infants with confirmed sepsis, and infants with gram-negative sepsis (low-quality evidence, four studies). Pentoxifylline decreased length of hospital stay (MD -7.59 days, 95% CI -11.65 to -3.52; 2 studies, 148 participants, low-quality evidence). Pentoxifylline did not change the risk of development of NEC, chronic lung disease, severe intraventricular haemorrhage, retinopathy of prematurity, or periventricular leukomalacia in neonates with sepsis (one to two studies, very low-quality evidence). Pentoxifylline therapy compared to pentoxifylline and immunoglobulin M-enriched intravenous immunoglobulin or immunoglobulin M-enriched intravenous immunoglobulin alone did not change mortality or development of NEC in neonates with sepsis (one study, very low-quality evidence). We noted no adverse effects due to pentoxifylline. We identified no trials evaluating pentoxifylline treatment for NEC.

Authors' conclusions

Low-quality evidence from six small studies suggests that pentoxifylline therapy as an adjunct to antibiotics in neonatal sepsis decreases mortality without any adverse effects. We encourage researchers to undertake large, well-designed multicentre trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.

Plain language summary

Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates

Review question

Does the use of intravenous pentoxifylline as an adjunct to antibiotic therapy prevent death and other serious complications in newborn babies with suspected or confirmed sepsis or necrotizing enterocolitis (NEC)?

Background

Sepsis is a bacterial or fungal infection of the blood. NEC is a condition with gastrointestinal tract injury and infection seen in premature babies. Modifying the body's response (inflammation) to infection may decrease deaths and tissue injury after sepsis or NEC. Pentoxifylline is a drug that decreases inflammation and possibly tissue injury. We reviewed the effects of pentoxifylline in newborn sepsis and NEC.

Study characteristics

Six randomised controlled trials met our inclusion criteria.

Results

We found low-quality evidence that pentoxifylline in combination with antibiotics decreases deaths and duration of hospital stay in newborn sepsis. Pentoxifylline treatment did not affect lung, eye, or brain injury as a result of sepsis (very low-quality evidence). We identified no adverse effects due to pentoxifylline. There were no completed studies looking at pentoxifylline treatment in NEC. We need better-quality evidence on the use of pentoxifylline in the treatment of sepsis or NEC in the newborn.

Background

Description of the condition

Neonatal sepsis is the most common cause of neonatal deaths worldwide (Lawn 2006). The incidence of neonatal sepsis in the developed world is reported to be between 1 to 4 cases per 1000 live births (Stoll 2004a), but in the developing world it is significantly higher (6.5 to 38 per 1000 live births) (Zaidi 2005). The incidence of neonatal sepsis is inversely proportional to gestational age and birth weight (Kaufman 2004). Early-onset sepsis (sepsis in infants less than 72 hours of life) occurs in 1.5% to 1.9% of very low-birth weight (VLBW) infants (birth weight 401 g to 1500 g) (Stoll 2005). In a cohort of 6956 VLBW infants admitted to the National Institute of Child Health and Human Development Neonatal Research Network hospitals for the period of 1998 to 2000, 21% had 1 or more blood culture-proven late-onset sepsis (onset after 72 hours of life) (Stoll 2002). Mortality of infants with late-onset sepsis was 18% (36% for those infected with gram-negative organisms), and morbidities (including patent ductus arteriosus, prolonged ventilation, prolonged need for intravascular access, bronchopulmonary dysplasia, NEC, and length of hospital stay) were significantly higher in infected infants. Sepsis significantly affects long-term neurodevelopmental outcomes, either by direct infection of the central nervous system or as a result of inflammatory injury. In a large cohort study of 6093 extremely low birth weight (ELBW) infants (birth weight less than 1000 g), infected infants had a significantly higher incidence of adverse neurodevelopmental outcomes at follow-up, characterized by cerebral palsy, low scores on Bayley Scales of Infant Development, and vision impairment when compared with uninfected infants (Stoll 2004b).

NEC occurs in about 1% to 5% of infants admitted to the neonatal intensive care unit. The most consistent risk factors are prematurity and low birth weight (Lin 2006). The pathogenesis of NEC is not entirely clear. Gastrointestinal immaturity, enteral feeding (especially formula feeding), presence of bacteria, and inflammation all play a part in the development of NEC (Lin 2006). Tumour necrosis factor alpha (TNF-α) and platelet-activating factor are the most important among pro-inflammatory cytokines that have been implicated in the development of NEC (Caplan 1990; Caplan 1990a). The pivotal role of TNF-α in NEC is supported by the fact that, in an animal model, monoclonal antibody to TNF-α reduced incidence of NEC from 80% to 17% (Halpern 2006). Mortality from NEC is high (15% to 30%), and 20% to 40% of infants with NEC undergo surgery. Infants who had NEC have delayed neurodevelopmental outcomes at 18 to 22 months corrected age (Stoll 2004b; Lin 2006).

Mortality and morbidity due to sepsis and NEC remain high despite the use of potent antimicrobial agents (Stoll 2002; Stoll 2005). Increased use of antimicrobials has led to a global emergence of antibiotic resistance (Levy 1998). Adjunct therapies may be important in increasing the efficacy of antimicrobial agents. Excessive or uncontrolled inflammatory response may be responsible for the multi-organ dysfunction and systemic inflammatory response seen in sepsis. The balance of pro- and anti-inflammatory cytokines may determine the severity and ultimate outcome in sepsis syndromes and NEC (Edelson 1999; Ng 2003; Harris 2005). Recent evidence has also shown that inflammation plays an important role in cerebral and pulmonary injury (Speer 1999; Adams-Chapman 2006), especially in the preterm neonate. When used in conjunction with antibiotics, immunomodulating agents may help to re-establish the balance between pro- and anti-inflammatory responses and may influence clinical outcome in neonatal sepsis and NEC.

Description of the intervention

Pentoxifylline, a xanthine derivative, is a phosphodiesterase inhibitor that suppresses TNF-α production by adenyl cyclase activation and increased cellular cyclic adenosine 3',5'-monophosphate concentration. Pentoxifylline has attracted increased interest since the discovery that inhibition of tumour necrosis factor gene transcription reduces mortality from sepsis. TNF-α increases peroxidation of arachidonic acid, activates polymorphonuclear leukocytes, increases eicosanoids, and increases its own production, thereby amplifying the inflammatory response (Vilcek 1991). Inhibition of TNF-α production by pentoxifylline negates this response and thereby may improve outcome. Pentoxifylline also has beneficial effects on endothelial cell function and coagulation in sepsis (Boldt 1996; Wang 1996).

How the intervention might work

Pentoxifylline has been shown to have beneficial effects in humans and animal models of sepsis and NEC. In sepsis, pentoxifylline has been shown to improve haemodynamics (including renal blood flow) and to prevent transition from a hyperdynamic to a hypodynamic response (Krysztopik 1996; Zeni 1996; Bacher 1997; Yang 1999). Pentoxifylline also ameliorates inflammatory lung injury after endotoxaemia (Michetti 2003). In adults and neonates, pentoxifylline has been shown to decrease serum levels TNF-α, interleukin-1, and interleukin-10, but not interleukin-6 or interleukin-8 (Bienvenu 1995; Zeni 1996). In a rat model of NEC, pentoxifylline reduced the incidence and severity of NEC (Travadi 2006). To date, no significant adverse effects have been reported in either animal or human studies.

Why it is important to do this review

The potential beneficial effects of pentoxifylline make it a promising agent for the treatment of sepsis and NEC in neonates. We performed this systematic review to determine the efficacy and safety of pentoxifylline as an adjunct to antibiotics in the treatment of sepsis or NEC in neonates.

Objectives

Primary objectives

  1. To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis.
  2. To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with NEC.

We performed separate comparisons for pentoxifylline treatment for neonatal sepsis and NEC.

Secondary objectives

  1. For treatment of neonatal sepsis:
    1. To determine the effect of pentoxifylline for treatment of neonatal sepsis on adverse neurological outcome at two years of age or later.
    2. To determine the effect of pentoxifylline for treatment of neonatal sepsis on the length of hospital stay before discharge in survivors and to determine adverse effects attributable to pentoxifylline (e.g. gastrointestinal disturbance, increasing gastric residue, feeding intolerance, thrombocytopenia, cholestatic jaundice).
    3. To determine the effect of pentoxifylline for treatment of neonatal sepsis in the following subgroups of neonates: term or preterm infants with suspected or confirmed sepsis, gram-negative sepsis, fungal sepsis, early-onset sepsis (within first 72 hours of life) or late-onset sepsis (greater than 72 hours of life).
    4. To determine the effect of pentoxifylline for treatment of neonatal sepsis on the duration of ventilation through endotracheal tube, development of chronic lung disease, and NEC.
  2. For treatment of NEC:
    1. To determine the effect of pentoxifylline for treatment of NEC on adverse neurological outcome at two years of age or later.
    2. To determine the effect of pentoxifylline for treatment of NEC on the length of hospital stay before discharge in survivors and to determine adverse effects attributable to pentoxifylline (e.g. gastrointestinal disturbance, increasing gastric residue, feeding intolerance, thrombocytopenia, cholestatic jaundice).
    3. To determine the effect of pentoxifylline for treatment of NEC in the following subgroups of neonates: term or preterm infants.
    4. To determine the effect of pentoxifylline for treatment of NEC on the duration of ventilation through endotracheal tube and development of chronic lung disease.

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised controlled trials

Types of participants

Neonates (less than 28 days old, at any gestational age or birth weight) with confirmed or suspected sepsis or neonates with NEC (Bell's stage 2 or 3) on antibiotics (Bell 1978).

We defined confirmed sepsis as clinical signs and symptoms consistent with infection and microbiologically proven with a positive blood culture, cerebrospinal fluid culture, urine culture (obtained by a suprapubic tap), or culture from a normally sterile site (for example pleural fluid, peritoneal fluid, or autopsy specimens) for bacteria or fungi.

We defined suspected sepsis as clinical signs and symptoms consistent with sepsis without isolation of a causative organism.

We defined NEC as an acute gastrointestinal disorder that manifests clinically with systemic signs (temperature instability, apnoea, bradycardia, lethargy, hypotension, metabolic acidosis, hyponatraemia, thrombocytopaenia, disseminated intravascular coagulation), intestinal signs (feed intolerance, gastrointestinal bleeding, abdominal tenderness, abdominal wall cellulitis, abdominal distension), radiological features (non-specific intestinal dilation and ileus in stage I, by pneumatosis intestinalis and air in the portal tree in stage II, or pneumoperitoneum in stage III), and pathologically by intestinal necrosis (Bell 1978; Walsh 1986).

Types of interventions

Intravenous pentoxifylline at any dosage or duration used as adjunct to antibiotics to treat suspected or confirmed neonatal sepsis or NEC, compared with placebo, no intervention, or other adjuncts to antibiotics.

Types of outcome measures

Primary outcomes
  1. All-cause mortality during hospital stay.
Secondary outcomes
  1. Neurological outcome at two years of age or more (neurodevelopmental outcome assessed by a validated test).
  2. Chronic lung disease in survivors (chronic lung disease defined as oxygen requirement at 36 weeks postmenstrual age).
  3. Adverse outcomes directly attributable to pentoxifylline: thrombocytopaenia (platelet count less than 100 x 109/L), increased gastric residue (gastric aspirate greater than 10% of oral feed), vomiting, cholestatic jaundice requiring therapy.
  4. Intraventricular haemorrhage.
  5. Periventricular leukomalacia (defined as necrosis of white matter in a characteristic distribution, i.e. in the white matter dorsal and lateral to the external angles of lateral ventricles involving particularly the centrum semiovale and optic and acoustic radiations and diagnosed by neuroimaging) (Volpe 1995).
  6. Duration of assisted ventilation through an endotracheal tube (days).
  7. Length of hospital stay in days for survivors to discharge.
  8. Outcome for neonates with sepsis only: NEC (definite NEC and perforated NEC, Bell's stage 2 or 3) (Bell 1978).
  9. Retinopathy of prematurity stages III and IV (ICROP 1984). (post-hoc analysis)

Search methods for identification of studies

We searched the following databases and identified relevant trials in any language through May 2014:

  1. The Cochrane Neonatal Review Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2014)
  2. Electronic journal reference databases: MEDLINE via PubMed (January 1966 to May 2014) and PREMEDLINE, EMBASE (January 1980 to May 2014), CINAHL (January 1982 to May 2014)
  3. Conference abstracts, including the proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research) and European Society for Paediatric Research from January 1990 in the journal Pediatric Research and 'Abstracts2view' online (January 2000 to May 2014).
  4. Conference abstracts in the database BIOSIS from January 1992 to May 2014 (none identified)
  5. Science Citation Index for all articles that cited 'Lauterbach 1996' from January 1990 to May 2014
  6. Ongoing trials with the search engines provided at the web sites www.clinicaltrials.gov, www.controlled-trials.com, and the Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au).

We contacted authors who published in the field for possible unpublished studies and identified one ongoing study (Patole 2006). We made additional searches from the reference lists of identified clinical trials and in the review authors' personal files up to May 2014.

MEDLINE and PREMEDLINE search strategy. We adapted this to suit the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and CINAHL.

  1. explode 'sepsis' [all subheadings in MIME, MJME]
  2. sepsis or septicemia
  3. septic
  4. NEC
  5. 'necrotizing enterocolitis'
  6. # 1 or # 2 or # 3 or # 4 or # 5
  7. explode 'infant - newborn' [all subheadings in MIME, MJME]
  8. Neonat*
  9. Newborn*
  10. # 7 or # 8 or # 9
  11. # 6 and # 10
  12. "Pentoxifylline' [all subheadings on MIME, MJME]
  13. pentoxif*
  14. Trental or Torental
  15. PTF or PTX or PTX F
  16. agapurin or BL-191 or oxpentif*
  17. # 12 or # 13 or # 14 or # 15 or # 16
  18. # 11 and # 17

We applied no language restriction.

We also searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).

Data collection and analysis

We employed the standard methods of the Cochrane Neonatal Review Group Guidelines in creating this update.

Selection of studies

We assessed the titles and abstracts of studies identified by the search strategy independently for eligibility for inclusion in this review. If we could not do this reliably by title and abstract, we obtained the full-text version for assessment. Any differences were resolved by mutual discussion. We obtained full-text versions of all eligible studies for quality assessment.

Data extraction and management

We designed forms for trial inclusion/exclusion, data extraction, and for requesting additional information from authors of the original reports. The review authors performed data extraction independently using specifically designed paper forms and compared for any differences, which we then resolved by discussion.

Assessment of risk of bias in included studies

We used the standardised review methods of the Cochrane Neonatal Review Group to assess the methodological quality of the studies. Review authors independently assessed the quality of the included studies using the standard criteria developed by The Cochrane Collaboration and the Cochrane Neonatal Review Group. We independently assessed the risk of bias for randomised trials using table 8.5a of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) based on the following six domains:

  1. Selection bias
    1. Method of sequence generation: Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.
    2. Concealment of allocation: Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
  2. Performance bias: Due to knowledge of the allocated interventions by participants and personnel during the study.
  3. Detection bias: Due to knowledge of the allocated interventions by outcome assessors.
  4. Attrition bias: Due to amount, nature, or handling of incomplete outcome data.
  5. Reporting bias: Due to selective outcome reporting.
  6. Any other sources of bias or important concerns not addressed in the previous domains.

We resolved all discrepancies by discussion and consensus. If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

In addition to the assessment of risk of bias, we rated evidence from included studies using the GRADE methodology as very low, low, moderate, or high. We used the five GRADE considerations to rate evidence: risk of bias, imprecision, inconsistency, indirectness, and publication bias (Higgins 2011).

Measures of treatment effect

We used the standard methods of the Cochrane Neonatal Review Group. We performed statistical analyses using Review Manager software (RevMan 2014). We analysed categorical data using risk ratio (RR), risk difference (RD), and the number needed to treat for an additional beneficial outcome (NNTB). We analysed continuous data using mean difference (MD). We reported the 95% confidence interval (CI) on all estimates.

Assessment of heterogeneity

We assessed heterogeneity of treatment effects between trials using the I2 statistic to check the appropriateness of pooling data and performing meta-analysis. We deferred meta-analysis if heterogeneity was high (greater than 75%). We used the following cut-offs to report on the degree of heterogeneity: less than 25% no heterogeneity; 25% to 49% low heterogeneity; 50% to 74% moderate heterogeneity; and greater than 75% high heterogeneity. If we detected statistical heterogeneity, we explored the possible causes (for example differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses. We used a fixed-effect model for meta-analysis.

Data synthesis

We performed the meta-analysis using Review Manager software (RevMan 2014), supplied by The Cochrane Collaboration. For estimates of typical risk ratio and risk difference, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed-effect model.

We analysed all infants including subgroups defined under Criteria for considering studies for this review on an intention-to-treat basis irrespective of whether or not they survived to complete their allocated treatment.

Subgroup analysis and investigation of heterogeneity

Planned subgroup analyses included:

  1. Gestational age:
    1. Preterm neonates (born before 37 completed weeks gestation)
    2. Term infants (born at or after 37 completed weeks of gestation)
  2. Time of onset of sepsis:
    1. Early-onset sepsis (sepsis in the first 72 hours of life)
    2. Late-onset sepsis (sepsis after the first 72 hours of life)
  3. Suspected or confirmed sepsis:
    1. Neonates with suspected sepsis (clinical signs and symptoms consistent with sepsis without isolation of causative organism treated with antibiotics)
    2. Neonates with confirmed sepsis
    3. Neonates with confirmed gram-negative sepsis
    4. Neonates with confirmed fungal sepsis

Results

Description of studies

We provided details of the included studies in the Characteristics of included studies table.

Six studies (Lauterbach 1996; Lauterbach 1999; Ali 2006; Adel 2010; Akdag 2014; Shabaan 2014) met the inclusion criteria.

Lauterbach 1996 randomised 40 preterm infants (less than 36 weeks gestation) with suspected late-onset sepsis to receive either pentoxifylline or placebo as adjunct to antibiotics. In 4 out of 20 infants in the treatment group and 7 out of 20 infants in the placebo group sepsis was not confirmed, and these infants were excluded from analysis. Outcomes were thus reported in only the 29 infants with confirmed sepsis (16 in treatment and 13 in placebo group). Of these, confirmed gram-negative sepsis occurred in 10 infants in the pentoxifylline group and 10 infants in the placebo group. The following outcomes were reported: i) plasma tumour necrosis factor alpha (TNF-α) levels, ii) mortality during hospital stay, and iii) adverse effects.

Lauterbach 1999 randomised 100 preterm infants (less than 36 weeks gestation) with suspected late-onset sepsis to receive either pentoxifylline or placebo as adjunct to antibiotics. In 10 out of 50 infants in the treatment group and 12 out of 50 infants in the placebo group sepsis was not confirmed, and these infants were excluded from analysis. Outcomes were thus reported for only the 78 infants with confirmed sepsis (40 in the pentoxifylline and 38 in the placebo group). Of these, confirmed gram-negative sepsis occurred in 15 infants in the pentoxifylline group and 14 infants in the placebo group. The following outcomes were reported: i) plasma levels of TNF-α, interleukin-6, and interleukin-1, ii) mortality during hospital stay, and iii) adverse effects.

Ali 2006 randomised 50 premature infants with culture-proven sepsis (less than 37 weeks gestational age) to pentoxifylline intravenously (5 mg/kg/h for 6 hours for 3 consecutive days, n = 25) as an adjunct to antibiotics or to control group, who received antibiotics alone (n = 25). The study reported the outcomes of mortality, development of NEC, length of hospital stay, duration of ventilation, and adverse effects.

Adel 2010 quasi-randomised 37 neonates with sepsis, based on the day of admission to the neonatal unit to intravenous pentoxifylline (5 mg/kg/h for 6 hours for 6 consecutive days) or placebo (equal volume of normal saline for 6 consecutive days) as adjuncts to antibiotics. Seventeen out of 37 received pentoxifylline and 20 out of 37 received placebo. The study reported outcomes of mortality, length of hospital stay, and multi-organ dysfunction in addition to coagulation profiles and C-reactive protein. Of the 37 neonates with suspected sepsis, 6 infants were culture negative but included in the analysis.

Akdag 2014 randomised 204 newborn infants with sepsis to 4 groups: pentoxifylline (6 mg/kg IV over 4 hours for 3 consecutive days), pentoxifylline and immunoglobulin M-enriched (IgM-enriched) intravenous immunoglobulin (IVIG) (pentaglobin, 250 mg/kg over 4 hours for 3 consecutive days), IgM-enriched IVIG (pentaglobin), or placebo (normal saline). The study reported outcomes of mortality, NEC, oliguria/anuria, hepatic failure, disseminated intravascular coagulation, pulmonary haemorrhage, and laboratory parameters of inflammation (white blood cell count, C-reactive protein, interleukin-6, TNF-α, and neutrophil CD64)

Shabaan 2014 randomised 120 preterm infants to intravenous pentoxifylline at 5 mg/kg/h for 6 hours on 6 successive days or normal saline (placebo). Of these infants 78 had confirmed sepsis and 52 had confirmed gram-negative sepsis. The primary outcome was death before hospital discharge, and secondary outcomes were length of hospital stay, duration of respiratory support, duration of antibiotic use, short-term morbidity (chronic lung disease, NEC, intraventricular haemorrhage, periventricular leukomalacia, and retinopathy of prematurity), TNF-α concentrations, C-reactive protein concentrations, and adverse effects of pentoxifylline.

Excluded studies

Lauterbach 1994: Seventeen preterm infants with sepsis were given pentoxifylline and compared with a historical control group of 13 septic infants who did not receive pentoxifylline. The study reported mortality and adverse effects. We excluded the study as it was neither randomised nor quasi-randomised.

Selim 2004: This non-randomised study included 20 neonates with sepsis; the first 13 infants received pentoxifylline and the next 7 participants constituted the control group. The study reported outcomes of mortality, leukocyte count, serum C-reactive protein level, TNF-α, and interleukin-6 levels. We excluded the study as it was non-randomised.

Ongoing studies

Patole 2006 and co-investigators plan in a pilot study to randomise 80 preterm (less than 32 weeks gestation) neonates with stage 2 or 3 NEC to intravenous pentoxifylline or an equal volume of placebo at 5 mg/kg/h for 12 hours a day (60 mg/kg/day) for 2 consecutive days, followed by infusion for 6 hours a day (30 mg/kg/day) for the next 4 consecutive days. The primary outcome is to assess the efficacy and safety of pentoxifylline in preventing the progression of NEC or death, or both. Secondary outcomes are reduction in plasma TNF-α levels, duration of hospital stay, duration of total parenteral nutrition support, and time to full enteral feeds. This study has not started recruiting yet as per communication with the primary investigator (as of June 2014).

Risk of bias in included studies

See: Characteristics of included studies.

Three trials (Lauterbach 1996; Ali 2006; Adel 2010) had high risk of selection bias due either to randomisation details not being available or absence of concealment of allocation. All included trials except one (Ali 2006) reported blinding of intervention. None of the included trials reported clearly on blinding of outcome assessment, hence detection bias could be an issue. Two trials (Lauterbach 1996; Lauterbach 1999) reported outcomes only in participants with culture-proven sepsis and suffered from attrition bias.

Effects of interventions

Pentoxifylline versus placebo for treatment of neonatal sepsis (Comparison 1)

Six randomised controlled trials where pentoxifylline was used for the treatment of neonatal sepsis were eligible for inclusion in the review (Lauterbach 1996; Lauterbach 1999; Ali 2006; Adel 2010; Akdag 2014; Shabaan 2014) and reported the following outcomes.

Primary outcomes
All-cause mortality during hospital stay (Outcome 1.1)
All infants with sepsis (Outcome 1.1.1)

All six studies reported on all-cause mortality in infants with sepsis. Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis decreased all-cause mortality during hospital stay compared to antibiotics alone (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants) (Figure 1). There was mild heterogeneity (I2 = 30%) among the six trials for this outcome. We downgraded evidence to low because four of the included studies had a high risk of bias, and the summary estimate was imprecise with wide confidence intervals.

Subgroup analyses
Confirmed sepsis (Outcome 1.1.2)

Four studies reported on all-cause mortality in infants with confirmed sepsis. Pentoxifylline used as an adjunct to antibiotics in neonates with confirmed sepsis decreased all-cause mortality during hospital stay (typical RR 0.37, 95% CI 0.19 to 0.73; typical RD -0.14, 95% CI -0.23 to -0.05; NNTB 7, 95% CI 4 to 20; 4 studies, 235 participants) (Figure 1). There was no heterogeneity (I2 = 0%) among the four trials for this outcome. We downgraded evidence to low because three of the included studies had a high risk of bias, and the summary estimate was imprecise with wide confidence intervals.

Confirmed gram-negative sepsis (Outcome 1.1.3)

Pentoxifylline used as an adjunct to antibiotics in neonates with confirmed gram-negative sepsis decreased all-cause mortality during hospital stay (typical RR 0.33, 95% CI 0.16 to 0.72; typical RD -0.19, 95% CI -0.31 to -0.07; NNTB 5, 95% CI 3 to 14; 4 studies, 143 participants) (Figure 1). There was no heterogeneity (I2 = 0%) among the four studies for this outcome. We downgraded evidence to low because three of the included studies had a high risk of bias, and the summary estimate was imprecise with wide confidence intervals.

Late-onset sepsis (Outcome 1.1.4)

Three studies reported on all-cause mortality in infants with late-onset sepsis. Pentoxifylline used as an adjunct to antibiotics in neonates with late-onset sepsis decreased all-cause mortality during hospital stay (typical RR 0.42, 95% CI 0.19 to 0.95; typical RD -0.12, 95% CI -0.23 to -0.02; NNTB 8, 95% CI 4 to 50; 3 studies, 169 participants) (Figure 1). There was no heterogeneity (I2 = 0) among the three trials for this outcome. We downgraded evidence to low because two of the included studies had a high risk of bias, and the summary estimate was imprecise with wide confidence intervals.

Preterm infants (Outcome 1.1.5)

A reduction in the risk of all-cause mortality during hospital stay was also seen in the subgroup of septic preterm infants (typical RR 0.38, 95% CI 0.20 to 0.71; typical RD -0.13, 95% CI -0.21 to -0.05; NNTB 8, 95% CI 5 to 20; 4 studies, 277 participants) (Figure 1). There was no heterogeneity (I2 = 0) among the three trials for this outcome. We downgraded evidence to low because two of the included studies had a high risk of bias.

Other planned subgroup analyses: Subgroup analyses were not possible for term infants, early-onset sepsis, suspected sepsis, and fungal sepsis due to lack of data.

Secondary outcomes
Chronic lung disease (Outcome 1.2)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of chronic lung disease compared to antibiotics alone (RR 1.50, 95% CI 0.45 to 5.05; RD 0.03, 95% CI -0.07 to 0.13; 1 study, 120 participants) (Figure 2). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

Severe intraventricular haemorrhage (Outcome 1.3)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of severe intraventricular haemorrhage compared to antibiotics alone (RR 0.75, 95% CI 0.28 to 2.03; RD -0.03, 95% CI -0.15 to 0.08; 1 study, 120 participants) (Figure 3). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

Periventricular leukomalacia (Outcome 1.4)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of periventricular leukomalacia compared to antibiotics alone (RR 0.50, 95% CI 0.10 to 2.63; RD -0.03, 95% CI -0.11 to 0.04; 1 study, 120 participants) (Figure 4). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

Length of hospital stay (Outcome 1.5)

The estimated MD for the outcome was -7.59 days (95% CI -11.65 to -3.52) (2 studies, 148 participants) (Figure 5). There was no heterogeneity (I2 = 0) between the two trials for this outcome. We downgraded evidence to low because only two studies were included studies and one had a high risk of bias.

Necrotizing enterocolitis (Outcome 1.6)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of NEC compared to antibiotics alone (typical RR 0.62, 95% CI 0.26 to 1.43; typical RD -0.04, 95% CI -0.10 to 0.02; 3 studies, 272 participants) (Figure 6). There was mild heterogeneity (I2 = 35%) among the three trials for this outcome. We downgraded the evidence to low because all three included studies had a high risk of bias, and the summary estimate was imprecise.

Retinopathy of prematurity (Outcome 1.7)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of retinopathy of prematurity compared to antibiotics alone (RR 0.40, 95% CI 0.08 to 1.98; RD -0.05, 95% CI -0.13 to 0.03; 1 study, 120 participants) (Figure 7). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

Secondary outcomes not reported

Neurological outcome at two years of age or more (neurodevelopmental outcome assessed by a validated test), adverse effects due to pentoxifylline and duration of assisted ventilation through an endotracheal tube (days) were reported from the included studies.

Pentoxifylline versus pentoxifylline and IgM-enriched IVIG for treatment of neonatal sepsis (Comparison 2)

One study was eligible for inclusion in this comparison (Akdag 2014).

Primary outcome: All-cause mortality during hospital stay (Outcome 2.1)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of all-cause mortality during hospital stay compared to pentoxifylline plus IgM-enriched IVIG (RR 0.71, 95% CI 0.24 to 2.10; RD -0.04, 95% CI -0.16 to 0.09; 1 study, 102 participants) (Figure 8). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

Secondary outcome: Necrotizing enterocolitis (Outcome 2.2)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of NEC compared to pentoxifylline plus IgM-enriched IVIG (RR 1.33, 95% CI 0.31 to 5.66; RD 0.02, 95% CI -0.08 to 0.12; 1 study, 102 participants) (Figure 9). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

None of the other secondary outcomes were reported for this comparison

Pentoxifylline versus IgM-enriched IVIG for treatment of neonatal sepsis (Comparison 3)

One study was eligible for inclusion in this comparison (Akdag 2014).

All-cause mortality during hospital stay (Outcome 3.1)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of all-cause mortality during hospital stay compared to IgM-enriched IVIG (RR 1.25, 95% CI 0.36 to 4.39; RD 0.02, 95% CI -0.09 to 0.13; 1 study, 102 participants) (Figure 10). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

Necrotizing enterocolitis (Outcome 3.2)

Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis led to no difference in the risk of NEC compared to IgM-enriched IVIG (RR 1.33, 95% CI 0.31 to 5.66; RD 0.02, 95% CI -0.08 to 0.12; 1 study, 102 participants) (Figure 11). We downgraded evidence to very low because only one study reported data, and the summary estimate was imprecise.

None of the other secondary outcomes were reported for this comparison

Other comparisons of pentoxifylline for the treatment of NEC were not possible because there were no randomised or quasi-randomised trials using pentoxifylline for the treatment of stage 2 or 3 NEC.

Discussion

Summary of main results

We identified six randomised controlled trials that reported on our prespecified neonatal outcomes. These trials randomised 416 newborn infants with sepsis to pentoxifylline, placebo, or IVIG. Low-quality evidence from these trials suggested a decrease in all-cause mortality during hospital stay, and the NNTB indicated that 13 infants need to be treated to prevent 1 neonatal death. In subgroup analyses of all-cause mortality during hospital stay, pentoxifylline therapy decreased neonatal deaths due to confirmed sepsis, confirmed gram-negative sepsis, in late-onset sepsis, and in preterm infants (low-quality evidence). Low-quality evidence from 2 trials (148 participants) suggested a decrease in length of hospital stay. Very low-quality evidence from one to three studies suggests that pentoxifylline therapy does not change the neonatal outcomes of development of NEC, chronic lung disease, severe intraventricular haemorrhage, retinopathy of prematurity, or periventricular leukomalacia.

One study reported on comparisons of pentoxifylline with pentoxifylline and IgM-enriched IVIG and IgM-enriched IVIG alone in 102 participants. There were no differences in all-cause mortality or development of NEC for those comparisons (very low-quality evidence).

Adverse effects of pentoxifylline including haematological adverse effects affecting platelet, leukocyte, and red cell function were not observed in the included trials.

Overall completeness and applicability of evidence

The six randomised controlled trials were performed in neonatal intensive care units in Poland, Egypt, Turkey, and India. Four of these studies suffered from a high risk of bias, namely selection, detection, and attrition biases. However, all these trials evaluated neonates with sepsis, including preterm infants and infants with proven sepsis. The small sample sizes and low evidence quality decrease generalisability and applicability of evidence.

Quality of the evidence

We rated four studies at high risk of bias and two studies at low risk of bias. We downgraded the evidence from six studies for the outcome 'all-cause mortality during hospital stay' to low quality based on GRADE methodology of evaluating evidence. The reasons for downgrading included high risk of bias in the included studies and the imprecision of the summary estimate. We also downgraded the evidence for the outcome 'length of hospital stay' to low because of evidence from only two studies, of which one had a high risk of bias. We downgraded the evidence for the outcomes of chronic lung disease, severe intraventricular haemorrhage, periventricular leukomalacia, and retinopathy of prematurity to very low because only a few studies reported this data, and the summary estimate was imprecise with large confidence intervals. Only one study reported comparisons of pentoxifylline with IVIG alone or with pentoxifylline plus IVIG, and the summary estimate was imprecise.

Potential biases in the review process

We strove to decrease biases in the review process. Two review authors performed the literature search using an inclusive search strategy and combined their results. Our search strategy identified six randomised clinical trials reporting neonatal outcomes. Our post-hoc analysis of retinopathy of prematurity did not change our conclusions. We pursued the investigators of published randomised controlled trials for data and missing information with limited success.

Agreements and disagreements with other studies or reviews

Harris, et al. reviewed the use of pentoxifylline in preterm neonates who had sepsis (two randomised controlled trials, one quasi-randomised study, and two observational studies) or NEC (one case series) (Harris 2010). The review authors also included cohort and observational studies and did not synthesize data into a meta-analysis. The review authors acknowledged that the included studies were small with significant methodological limitations, hence better-quality evidence is needed. There are no other systematic reviews on the use of pentoxifylline in sepsis in the neonatal or paediatric populations.

Authors' conclusions

Implications for practice

Low-quality evidence from six small randomised controlled trials suggests that pentoxifylline as an adjunct to antibiotic therapy in neonatal sepsis decreases mortality during hospital stay without adverse effects. Low-quality evidence from two trials suggests a decrease in the length of hospital stay. However, as the included trials have considerable methodological weaknesses, the results of this meta-analysis should be interpreted with caution. We identified no completed trial using pentoxifylline for the treatment of NEC.

Implications for research

Researchers should be encouraged to undertake adequately powered, well-designed, multicentre randomised controlled trials to confirm or refute the role of pentoxifylline in treatment of neonatal sepsis and NEC. The trials should report on clinically important comorbidities of sepsis (for example chronic lung disease, periventricular leukomalacia, and duration of assisted ventilation, among others) and long-term neurological outcomes. Researchers may consider comparing pentoxifylline with other adjunctive modalities that decrease inflammatory injury in the treatment of neonatal sepsis and NEC.

Acknowledgements

Ms. Nicola Bexon of the Institute of Health Sciences and Mr. Edward George of Hirson Library at St Helier Hospital for helping to formulate the literature search strategy.

Miss Natasha Haque for help with typing the manuscript.

Contributions of authors

Mohan Pammi:

  • Updated the review
  • Assisted in writing the protocol and review;
  • Independently assessed study methodology and extracted data from eligible studies;
  • Entered and checked data in RevMan for the updates;
  • Assisted in contacting authors for more information on published articles and in tracing unpublished ones.

Khalid Haque:

  • Searched the literature and identified trials for inclusion;
  • Assessed methodology;
  • Extracted relevant data from eligible studies;
  • Contacted prominent authors for more data on published and unpublished trials;
  • Wrote the text of the review;
  • Assisted in updating the review.

Declarations of interest

None known.

Differences between protocol and review

None

Characteristics of studies

Characteristics of included studies

Adel 2010

Methods

Single-centre quasi-randomised trial where neonates with suspected sepsis were randomised to pentoxifylline if they were admitted on Tuesday or Thursday and to the placebo if admitted on Monday or Wednesday.

No concealment of allocation.

Blinding of intervention - yes.

Blinding of outcome assessment - unclear.

Completeness of follow-up - yes.

Participants

Single-centre, at Ain Shams University, Cairo, Egypt.

Neonates with suspected sepsis with maternal and clinical risk factors.

Maternal risk factors: Fever ≥ 38°C or premature rupture of membranes > 36 hours, or both.

Neonatal risk factors: elevated C-reactive protein and abnormalities of complete blood count, deterioration of respiratory and cardiac functions, feeding intolerance, abdominal distension, temperature instability, lethargy or irritability, and hepatosplenomegaly.

The intervention and the placebo groups did not differ significantly in terms of gestational age, birth weight, or Apgar scores.

Interventions

Pentoxifylline (5 mg/kg/h for 6 hours for 6 consecutive days) or placebo (equal volume of normal saline for 6 consecutive days) as an adjunct to antibiotics.

Outcomes

Mortality, length of hospital stay, multi-organ dysfunction, coagulation profiles including platelet count and C-reactive protein.

Notes

6 of 37 neonates with sepsis were culture negative, and outcomes were not reported separately for this group.

Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) High risk

No allocation concealment.

Blinding (performance bias and detection bias) High risk

Test drug and placebo dispensed in similar syringes, but participants were quasi-randomised based on the day of admission. Hence the efficacy of the blinding unclear.

Blinding of participants and personnel (performance bias) High risk

Test drug and placebo dispensed in similar syringes, but participants were quasi-randomised based on the day of admission. Hence the efficacy of the blinding unclear.

Blinding of outcome assessment (detection bias) Unclear risk

Unclear.

Incomplete outcome data (attrition bias) Low risk

Outcomes for all infants reported.

Akdag 2014

Methods

Prospective double-blind controlled study

Participants

Newborn infants with sepsis

Interventions

Pentoxifylline (6 mg/kg IV over 4 hours for 3 consecutive days), pentoxifylline + IgM-enriched IVIG (pentaglobin, 250 mg/kg over 4 hours for 3 consecutive days), IgM-enriched IVIG (pentaglobin) or placebo (normal saline)

Outcomes

Mortality, NEC, oliguria/anuria, hepatic failure, disseminated intravascular coagulation, pulmonary haemorrhage, and lab parameters (white blood cell count, C-reactive protein, interleukin-6, TNF-α, and neutrophil CD64)

Notes

4-arm study comparing pentoxifylline, IgM-enriched IVIG, and both against placebo

Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) Low risk

Sealed, opaque envelopes containing the randomisation arm.

Blinding (performance bias and detection bias) Low risk

The infusions were covered with plastic covers, and infusion vials were identical for the different arms.

Blinding of participants and personnel (performance bias) Low risk

The infusions were covered with plastic covers.

Blinding of outcome assessment (detection bias) Low risk

The infusions were covered with plastic covers, and infusion vials were identical for the different arms.

Incomplete outcome data (attrition bias) Low risk

No loss to follow-up reported.

Ali 2006

Methods

Single-centre trial at Sher-i-Kashmir Institute of Medical Sciences (SKIMS).

Randomisation details not reported.

Concealment of allocation - unclear.

Blinding of intervention - no.

Blinding of outcome assessment - unclear.

Completeness of follow-up - yes.

Participants

50 premature infants with culture-proven sepsis (< 37 weeks gestational age).

Inclusion criteria: Culture-proven sepsis, gestation < 37 weeks, clinical signs of sepsis including cardiovascular and respiratory dysfunction, and written consent.

Exclusion criteria: Intraventricular haemorrhage, congenital infection, and culture negativity.

Gestational age in both the treatment and placebo groups ranged from 32 to 37 weeks.

Birth weight ranged from 950 g to 2580 g in the treatment group and 1000 g to 2650 g in the control group.

Interventions

Pentoxifylline intravenously (5 mg/kg/h for 6 hours for 3 consecutive days) in conjunction with antibiotics or control group who received antibiotics.

Outcomes

Mortality, development of NEC, length of hospital stay, duration of ventilation, and adverse effects were reported.

Notes

Although the mean length of hospital stay and duration of ventilation were reported, standard deviations were not.

Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) Unclear risk

No details of randomisation reported.

Blinding (performance bias and detection bias) High risk

None reported.

Blinding of participants and personnel (performance bias) High risk

None reported.

Blinding of outcome assessment (detection bias) Unclear risk

Unclear.

Incomplete outcome data (attrition bias) Low risk

Outcomes for all participants reported.

Lauterbach 1996

Methods

Single-centre, randomised, placebo-controlled trial. No details of randomisation given.
Blinding of intervention - yes.
Blinding of outcome - yes.
Completeness of follow-up - no.
11/40 participants were excluded from analysis.

Participants

Single centre. Neonatal Unit, Jagiellonian University Hospital, Poland.
Neonates < 36 weeks gestation with clinically suspected sepsis after the first week of life.
Criteria for sepsis: at least 2 of the following: feed intolerance, abdominal distention, lethargy, irritability, temperature instability, hyperbilirubinaemia, hepatosplenomegaly.
Exclusions: major congenital malformation, grades III and IV intraventricular haemorrhage, and congenital infections.
Mean gestational age in treatment group 31.5 weeks, in placebo group 32.3 weeks.
Mean birth weight in treatment group 1.75 kg, in placebo group 1.86 kg.
Period of study 1 March to 30 July 1994.
Only infants with positive blood culture were analysed. Treatment group 16/20 (4 negative culture), placebo group 13/20 (7 negative culture).

Interventions

Pentoxifylline (Trental; Boehring-Hoscht) 5 mg/kg/h for 6 hours, repeated on 2nd and 3rd day (n = 20).
Placebo: equal volume of normal saline (n = 20).

Outcomes

Outcomes reported were:

  1. mortality.
  2. plasma TNF-α levels before the first infusion and after the third infusion of the drug or placebo.
  3. adverse reactions to the drug.
Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) Unclear risk

Unclear.

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes.

Blinding of participants and personnel (performance bias) Low risk

Blinding of intervention - yes.

Blinding of outcome assessment (detection bias) Low risk

Yes.

Incomplete outcome data (attrition bias) High risk

11/40 participants were excluded from analyses.

Lauterbach 1999

Methods

Randomised, placebo-controlled study.
Concealment of randomisation - yes.
Blinding of intervention - yes.
Blinding of outcome assessment - unclear.
Completeness of follow-up - no.
22/100 were excluded.

Participants

Two-centre study: Neonatal Unit, Medical College Jagiellonian, University of Krakow, Poland and Intensive Therapy Unit at Polish Mother Memorial Hospital, Lodz, Poland.
Preterm infants < 36 weeks of gestation, after first week of life with suspected sepsis.
Criteria for sepsis: At least 3 of the following: feeding intolerance, abdominal distention, temperature instability, disordered peripheral circulation (as described by paleness, peripheral cyanosis, mottled skin, and capillary refill time > 3 seconds), lethargy, irritability and hepatosplenomegaly.
Positive blood culture required for confirmation of sepsis.
Period: 1 January 1995 to 30 July 1996.
Exclusions: Congenital malformations, congenital infections, and grades III and IV intraventricular haemorrhage.
Total recruitment 100.
10/50 from the treatment group and 12/50 from placebo group excluded as sepsis was not confirmed.

Interventions

Pentoxifylline (Pentilin; KRKA Slovenia) 5 mg/kg/h for 6 hours for 6 successive days (n = 50).
Placebo: equal volume of normal saline (n = 50).

Outcomes

Outcomes reported were:

  1. mortality
  2. incidence and mortality of gram-negative sepsis.
  3. plasma TNF-α, interleukin-1 and interleukin-6 levels before and after the 1st and 3rd dose and before and after the 6th dose.
  4. adverse effects.
Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) Low risk

Adequate.

Blinding (performance bias and detection bias) Low risk

Adequate.

Blinding of participants and personnel (performance bias) Low risk

Adequate.

Blinding of outcome assessment (detection bias) Unclear risk

Unclear.

Incomplete outcome data (attrition bias) High risk

22/100 were excluded.

Shabaan 2014

Methods

Double-blind randomised controlled trial

Participants

Preterm infants

Interventions

Intravenous pentoxifylline 5 mg/kg/h for 6 hours on 6 successive days or normal saline (placebo)

Outcomes

The primary outcome was death before hospital discharge.

Secondary outcomes were length of hospital stay, duration of respiratory support, duration of antibiotics use, short-term morbidity (chronic lung disease, severe intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity), TNF-α concentrations, C-reactive protein levels, and adverse effects of pentoxifylline.

Notes

Published and unpublished data

Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) Low risk

Randomisation by computer-generated numbers.

Blinding (performance bias and detection bias) Low risk

Double-blind controlled trial.

Blinding of participants and personnel (performance bias) Low risk

Double-blind controlled trial.

Blinding of outcome assessment (detection bias) Low risk

Double-blind controlled trial.

Incomplete outcome data (attrition bias) Low risk

No loss to follow-up.

Footnotes

IgM: immunoglobulin M
IVIG: intravenous immunoglobulin
NEC: necrotizing enterocolitis
TNF-α: tumour necrosis factor alpha

Characteristics of excluded studies

Lauterbach 1994

Reason for exclusion

Not a randomised or quasi-randomised trial.

Selim 2004

Reason for exclusion

Not a randomised or quasi-randomised trial.

Characteristics of studies awaiting classification

None noted.

Characteristics of ongoing studies

Patole 2006

Study name

Safety and efficacy of pentoxifylline as a treatment for preventing the progression of NEC in preterm neonates.

Methods

A randomised, placebo-controlled trial.

Participants

Premature neonates < 32 weeks gestation with stage 2 or 3 NEC.

Interventions

Pentoxifylline at 5 mg/kg/h for 12 hours for 2 days followed by the infusion for 6 hours a day for the next 4 days OR equal volume of placebo in controls.

Outcomes

Primary: Efficacy and safety of pentoxifylline in preventing the progression of NEC or death, or both.
Secondary: Reduction in plasma tumour necrosis factor alpha levels, extent of bowel resection at surgery, duration of hospital stay and total parenteral nutrition support, and duration to full enteral feeds.

Starting date

Late 2014

Contact information

Sanjay Patole, email: Sanjay.Patole@health.wa.gov.au

Notes

Not started recruiting yet (as of June 2014)

Footnotes

NEC: necrotising enterocolitis

Summary of findings tables

1 Summary of findings

Pentoxifylline compared with placebo for neonatal sepsis

Patient or population: Neonates with sepsis

Settings: Neonatal intensive care unit

Intervention: PTX

Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

PTX

All-cause mortality during hospital stay - All infants

36/207

20/209

RR 0.57 [0.35, 0.93]

416 participants
(6 studies)

⊕⊕⊝⊝
low

Evidence was downgraded to low because 4 of the included studies had a high risk of bias and the summary estimate was imprecise with wide confidence intervals.

All-cause mortality during hospital stay - Confirmed sepsis

25/116

9/119

RR 0.37 [0.19, 0.73]

235 participants
(4 studies)

⊕⊕⊝⊝
low

Evidence was downgraded to low because 3 of the included studies had a high risk of bias and the summary estimate was imprecise with wide confidence intervals.

All-cause mortality during hospital stay - Infants with confirmed gram-negative sepsis

19/67

7/76

RR 0.33 [0.16, 0.72]

143 participants
(4 studies)

⊕⊕⊝⊝
low

Evidence was downgraded to low because 3 of the included studies had a high risk of bias and the summary estimate was imprecise with wide confidence intervals.

All-cause mortality during hospital stay - Late-onset sepsis

17/84

7/85

RR 0.42 [0.19, 0.95]

169 participants
(3 studies)

⊕⊕⊝⊝
low

Evidence was graded low because 2 of the included studies had a high risk of bias and the summary estimate was imprecise.

All-cause mortality during hospital stay - Preterm infants

29/136

11/141

RR 0.38 [0.20, 0.71]

277 participants
(4 studies)

⊕⊕⊝⊝
low

Evidence was graded low because 2 of the included studies had a high risk of bias.

Chronic lung disease

4/60

6/60

RR 1.50 [0.45, 5.05]

120 participants
(1 study)

⊕⊝⊝⊝
very low

Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

Severe intraventricular haemorrhage

8/60

6/60

RR 0.75 [0.28, 2.03]

120 participants
(1 study)

⊕⊝⊝⊝
very low

Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

Periventricular leukomalacia

4/60

2/60

RR 0.50 [0.10, 2.63]

120 participants
(1 study)

⊕⊝⊝⊝
very low

Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

Length of hospital stay (LOS) in days

The mean LOS ranged across control groups from 33.8 to 38.3 days.

The mean LOS in the intervention groups was 22.6 to 33.3 days.

Mean difference

-7.59 [-11.65, -3.52]

148 participants
(2 studies)

low

⊕⊕⊕⊝

Evidence was graded low because of only 2 included studies and 1 with a high risk of bias.

Necrotizing enterocolitis

13/136

8/136

RR 0.62 [0.26, 1.43]

272 participants
(3 studies)

⊕⊝⊝⊝
very low

⊕⊕⊝⊝

Evidence was graded very low because all 3 included studies had a high risk of bias and the summary estimate was imprecise.

Retinopathy of prematurity

5/60

2/60

RR 0.40 [0.08, 1.98]

120 participants
(1 study)

⊕⊝⊝⊝
very low


Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; PTX: pentoxifylline; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

2 Summary of findings

PTX compared with PTX with IgM-enriched IVIG for neonatal sepsis

Patient or population: Neonates with sepsis

Settings: Neonatal intensive care unit

Intervention: PTX

Comparison: PTX with IgM-enriched IVIG

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

PTX with IgM-enriched IVIG

PTX

All-cause mortality during hospital stay

7/51

5/51

RR 0.71 [0.24, 2.10]

102 participants from 1 study

⊕⊝⊝⊝
very low

Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

Necrotizing enterocolitis

3/51

4/51

RR 1.33 [0.31, 5.66]

102 participants from 1 study

⊕⊝⊝⊝
very low

Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IgM: immunoglobulin M; IVIG: intravenous immunoglobulin; PTX: pentoxifylline; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

3 Summary of findings

PTX compared with IgM-enriched IVIG for neonatal sepsis

Patient or population: Neonates with sepsis

Settings: Neonatal intensive care unit

Intervention: PTX

Comparison: IgM-enriched IVIG

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

IgM-enriched IVIG

PTX

All-cause mortality during hospital stay

4/51

5/51

RR 1.25 [0.36, 4.39]

102 participants from 1 study

⊕⊝⊝⊝
very low

Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

Necrotizing enterocolitis

3/51

4/51

RR 1.33 [0.31, 5.66]

102 participants from 1 study

⊕⊝⊝⊝
very low

Evidence was graded very low because of only 1 study and the imprecision of the summary estimate.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IgM: immunoglobulin M; IVIG: intravenous immunoglobulin; PTX: pentoxifylline; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

References to studies

Included studies

Adel 2010

Adel M, Awad HA, Abdel-Naim AB, Al-Aziz MM. Effects of pentoxifylline on coagulation profile and disseminated intravascular coagulation incidence in Egyptian septic neonates. Journal of Clinical Pharmacy and Therapeutics 2010;35(3):257-65. [PubMed: 20831528]

Akdag 2014

Akdag A, Dilmen U, Haque K, Dilli D, Erdeve O, Goekmen T. Role of pentoxifylline and/or IgM-enriched intravenous immunoglobulin in the management of neonatal sepsis. American Journal of Perinatology 2014;31:905-12. [PubMed: 24515621]

Ali 2006

Ali W, Ahmed P, Bhat MA, Mushtaq AB, Mushtaq S. Pentoxifylline in treatment of sepsis of premature infants. JK Practitioner 2006;13(4):204-7.

Lauterbach 1996

Lauterbach R, Zembala M. Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis. European Journal of Pediatrics 1996;155(5):404-9. [PubMed: 8741040]

Lauterbach 1999

Lauterbach R, Pawlik D, Danuta K, Wieslaw K, Ewah K, Marek Z. Effect of immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebo controlled, double-blind trial. Critical Care Medicine 1999;27:807-14.

Shabaan 2014

Published and unpublished data

Shabaan AE, Nasef N, Shouman B, Nour I, Abd Elhamed A, Abdel-Hady H. In: Pentoxifylline therapy for late-onset sepsis in preterm infants: A randomized controlled trial. Pediatric Academic Societies Annual Meeting. Vancouver, 2014:Abstract 3570.20.

Excluded studies

Lauterbach 1994

Lauterbach R, Pawlik D, Tomaszcyk B, Cholewa B. Pentoxifylline treatment of sepsis of premature infants: preliminary clinical observations. European Journal of Pediatrics 1994;153(9):672-4. [PubMed: 7957428]

Selim 2004

Selim K, Hüseyin C, Ibrahim KH, Hasan BU, Kazim U, Hüseyin K. Effect of pentoxifylline on tumor necrosis factor-alpha and interleukin-6 levels in neonatal sepsis. The Medical Journal of Malaysia 2004;59(3):391-4. [PubMed: 15727386]

Studies awaiting classification

None noted.

Ongoing studies

Patole 2006

ACTRN12606000257561. Safety and efficacy of pentoxifylline as a treatment for preventing the progression of necrotising enterocolitis in preterm neonates – a randomised, placebo controlled pilot trial. http://apps.who.int/trialsearch/trial.aspx?trialid=ACTRN12606000257561 (accessed 15 May 2014).

Other references

Additional references

Adams-Chapman 2006

Adams-Chapman I, Stoll BJ. Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Current Opinion in Infectious Diseases 2006;19(3):290-7. [PubMed: 16645492]

Bacher 1997

Bacher A, Mayer N, Klimscha W, Oismüller C, Steltzer H, Hammerle A. Effects of pentoxifylline on haemodynamics and oxygenation in septic and non-septic patients. Critical Care Medicine 1997;25(5):795-800. [PubMed: 9187598]

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotising enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187(1):1-7. [PubMed: 413500]

Bienvenu 1995

Bienvenu J, Doche C, Gutowski MC, Lenoble M, Lepape A, Perdrix JP. Production of pro-inflammatory cytokines and cytokines involved in the Th2/Th3 balance is modulated by pentoxifylline. Journal of Cardiovascular Pharmacology 1995;25 Suppl 2:S80-4. [PubMed: 8699868]

Boldt 1996

Boldt J, Müller M, Heyn S, Welters I, Hempelmann G. Influence of long term continuous intravenous administration of pentoxifylline on endothelial related coagulation in critically ill patients. Critical Care Medicine 1996;24(6):940-6. [PubMed: 8681595]

Caplan 1990

Caplan MS, Hsueh W. Necrotizing enterocolitis: role of platelet activating factor, endotoxin, and tumor necrosis factor. Journal of Pediatrics 1990;117(1 Pt 2):S47-51. [PubMed: 2194011]

Caplan 1990a

Caplan MS, Sun XM, Hseuh W, Hageman JR. Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. Journal of Pediatrics 1990;116(6):960-4. [PubMed: 2348301]

Edelson 1999

Edelson MB, Bagwell CE, Rozycki HJ. Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 1999;103(4 Pt 1):766-71. [PubMed: 10103300]

Halpern 2006

Halpern MD, Clark JA, Saunders TA, Doelle SM, Hosseini DM, Stagner AM, et al. Reduction of experimental necrotizing enterocolitis with anti-TNF-alpha. American Journal of Physiology. Gastrointestinal and Liver Physiology 2006;290(4):G757-64. [PubMed: 16269520]

Harris 2005

Harris MC, D'Angio CT, Gallagher PR, Kaufman D, Evans J, Kilpatrick L. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing enterocolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. Journal of Pediatrics 2005;147(4):462-8. [PubMed: 16227031]

Harris 2010

Harris E, Schulzke SM, Patole SK. Pentoxifylline in preterm neonates. Pediatric Drugs 2010;12(5):301-11. [PubMed: 20799759]

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org.

ICROP 1984

The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Archives of Ophthalmology 1984;102(8):1130-4. [PubMed: 6547831]

Kaufman 2004

Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clinical Microbiology Reviews 2004;17(3):638-80. [PubMed: 15258097]

Krysztopik 1996

Krysztopik RJ, Bentley FR, Spain DA, Wilson MA, Garrison RN. Free radical scavenging by lazaroids improves renal blood flow during sepsis. Surgery 1996;120(4):657-62. [PubMed: 8862374]

Lawn 2006

Lawn JE, Wilczynska-Ketende K, Cousens SN. Estimating the causes of 4 million neonatal deaths in the year 2000. International Journal of Epidemiology 2006;35(3):706-18. [PubMed: 16556647]

Levy 1998

Levy SB. Antimicrobial resistance: Bacteria on the defence. Resistance stems from misguided efforts to try to sterilize our environment. BMJ 1998;317(7159):612-3. [PubMed: 9727983]

Lin 2006

Lin PW, Stoll BJ. Necrotizing enterocolitis. Lancet 2006;368(9543):1271-83. [PubMed: 17027734]

Michetti 2003

Michetti C, Coimbra R, Hoyt DB, Loomis W, Junger W, Wolf P. Pentoxifylline reduces acute lung injury in chronic endotoxemia. Journal of Surgical Research 2003;115(1):92-9. [PubMed: 14572778]

Ng 2003

Ng PC, Li K, Wong RP, Chui K, Wong E, Li G, et al. Proinflammatory and anti-inflammatory cytokine responses in preterm infants with systemic infections. Archives of Disease in Childhood. Fetal Neonatal Ed 2003;88(3):F209-13. [PubMed: 12719394]

RevMan 2014

Review Manager (RevMan). Version 5.3. [Computer program]. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Speer 1999

Speer CP. Inflammatory mechanisms in neonatal chronic lung disease. European Journal of Pediatrics 1999;158 Suppl 1:S18-22. [PubMed: 10592094]

Stoll 2002

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110(2 Pt 1):285-91. [PubMed: 12165580]

Stoll 2004a

Stoll BJ. Infections of the neonatal infant. In: Behrman RE, Kliegman RM, Jenson HB, editor(s). Nelson Textbook of Pediatrics. 17th edition. Philadelphia: Saunders, 2004:623-40.

Stoll 2004b

Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292(19):2357-65. [PubMed: 15547163]

Stoll 2005

Stoll BJ, Hansen NI, Higgins RD, Fanaroff AA, Duara S, Goldberg R, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003. Pediatric Infectious Disease Journal 2005;24(7):635-9. [PubMed: 15999007]

Travadi 2006

Travadi J, Patole S, Charles A, Dvorak B, Doherty D, Simmer K. Pentoxifylline reduces the incidence and severity of necrotizing enterocolitis in a neonatal rat model. Pediatric Research 2006;60(2):185-9. [PubMed: 16864701]

Vilcek 1991

Vilcek J, Lee TH. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. Journal of Biological Chemistry 1991;266(12):7313-6. [PubMed: 1850405]

Volpe 1995

Volpe JJ. Neurology of the Newborn. 3rd edition. Philadelphia, London: WB Saunders, 1995.

Walsh 1986

Walsh MC, Kliegman RM. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatric Clinics of North America 1986;33(1):179-201. [PubMed: 3081865]

Wang 1996

Wang P, Wood TJ, Ba ZF, Chaudry IH. Pentoxifylline maintains vascular endothelial cell function during hyperdynamic sepsis. Surgery 1996;120(2):367-73. [PubMed: 8751606]

Yang 1999

Yang S, Zhou M, Koo DJ, Chaudry IH, Wang P. Pentoxifylline prevents the transition from hyperdynamic to hypodynamic response during sepsis. American Journal of Physiology 1999;277(3 Pt 2):h2036-44. [PubMed: 10484426]

Zaidi 2005

Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldman DA. Hospital-acquired neonatal infections in developing countries. Lancet 2005;365(9465):1175-88. [PubMed: 15794973]

Zeni 1996

Zeni F, Pain P, Vindimian M, Gay JP, Gery P, Bertrand M, et al. Effects of pentoxifylline on circulating cytokine concentrations and haemodynamics in patients with septic shock: results from a double blind, randomized, placebo controlled study. Critical Care Medicine 1996;24(2):207-14. [PubMed: 8605790]

Other published versions of this review

Haque 2003

Haque K, Mohan P. Pentoxifylline for neonatal sepsis. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004205. DOI: 10.1002/14651858.CD004205.

Classification pending references

None noted.

Data and analyses

1 Pentoxifylline versus placebo for the treatment of neonatal sepsis

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 All cause mortality during hospital stay 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.1.1 All infants 6 416 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.35, 0.93]
  1.1.2 Confirmed sepsis 4 235 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.19, 0.73]
  1.1.3 Infants with confirmed gram negative sepsis 4 143 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.16, 0.72]
  1.1.4 Late-onset sepsis 3 169 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.19, 0.95]
  1.1.5 Preterm infants 4 277 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.20, 0.71]
1.2 Chronic lung disease 1 120 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.45, 5.05]
1.3 Severe Intraventricular haemorrhage (grade 3 and 4) 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.28, 2.03]
1.4 Periventricular leukomalacia 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.10, 2.63]
1.5 Length of hospital stay 2 148 Mean Difference (IV, Fixed, 95% CI) -7.59 [-11.65, -3.52]
1.6 Necrotizing enterocolitis 3 272 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.26, 1.43]
1.7 Retinopathy of prematurity 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.08, 1.98]
 

2 Pentoxifylline vs Pentoxifylline and IgM-enriched IVIG

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 All cause mortality 1 102 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.24, 2.10]
2.2 Necrotizing enterocolitis 1 102 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.31, 5.66]
 

3 Pentoxifylline vs IgM-enriched IVIG

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 All cause mortality 1 102 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [0.36, 4.39]
3.2 Necrotizing enterocolitis 1 102 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.31, 5.66]
 

Figures

Figure 1 (Analysis 1.1)

Refer to figure 1 caption below

Forest plot of comparison: 1 Pentoxifylline vs. placebo for the treatment of neonatal sepsis, outcome: 1.1 All-cause mortality during hospital stay (Figure 1 description).

Figure 2 (Analysis 1.2)

Refer to figure 2 caption below

Forest plot of comparison: 1 Pentoxifylline vs. placebo for the treatment of neonatal sepsis, outcome: 1.4 Chronic lung disease (Figure 2 description).

Figure 3 (Analysis 1.3)

Refer to figure 3 caption below

Forest plot of comparison: 1 Pentoxifylline vs. placebo for the treatment of neonatal sepsis, outcome: 1.5 Severe intraventricular haemorrhage (Figure 3 description).

Figure 4 (Analysis 1.4)

Refer to figure 4 caption below

Forest plot of comparison: 1 Pentoxifylline vs. placebo for the treatment of neonatal sepsis, outcome: 1.7 Periventricular leukomalacia (Figure 4 description).

Figure 5 (Analysis 1.5)

Refer to figure 5 caption below

Forest plot of comparison: 1 Pentoxifylline vs. placebo for the treatment of neonatal sepsis, outcome: 1.2 Length of hospital stay (Figure 5 description).

Figure 6 (Analysis 1.6)

Refer to figure 6 caption below

Forest plot of comparison: 1 Pentoxifylline vs. placebo for the treatment of neonatal sepsis, outcome: 1.3 Necrotizing enterocolitis (Figure 6 description).

Figure 7 (Analysis 1.7)

Refer to figure 7 caption below

Forest plot of comparison: 1 Pentoxifylline vs. placebo for the treatment of neonatal sepsis, outcome: 1.6 Retinopathy of prematurity (Figure 7 description).

Figure 8 (Analysis 2.1)

Refer to figure 8 caption below

Forest plot of comparison: 2 Pentoxifylline vs. Pentoxifylline and IgM-enriched IVIG, outcome: 2.1 Mortality (Figure 8 description).

Figure 9 (Analysis 2.2)

Refer to figure 9 caption below

Forest plot of comparison: 2 Pentoxifylline vs. Pentoxifylline and IgM-enriched IVIG, outcome: 2.2 Necrotizing enterocolitis (Figure 9 description).

Figure 10 (Analysis 3.1)

Refer to figure 10 caption below

Forest plot of comparison: 3 Pentoxifylline vs. IgM-enriched IVIG, outcome: 3.1 Mortality (Figure 10 description).

Figure 11 (Analysis 3.2)

Refer to figure 11 caption below

Forest plot of comparison: 3 Pentoxifylline vs IgM-enriched IVIG, outcome: 3.2 Necrotizing enterocolitis (Figure 11 description).

Sources of support

Internal sources

  • Epsom & St. Helier NHS Trust, UK
  • National Perinatal Epidemiology Unit, Headington, Oxford, UK

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2015 (see http://www.thecochranelibrary.com External Web Site Policy for information).  Cochrane reviews are regularly updated as new evidence emerges and in response to feedback.  The Cochrane Library should be consulted for the most recent version of the review.