Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates
Khalid N Haque1, Pammi Mohan2
1Division of Neonatology, Department of Child Health, Queen Mary's Hospital for Children, Wrythe Lane, Carshalton, UK
2Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, USA
Pediatrics, Section of Neonatology
Baylor College of Medicine
6621, Fannin, MC.WT 6-104
Houston Texas 77030
|Assessed as Up-to-date:||11 September 2007|
|Date of Search:||30 May 2007|
|Next Stage Expected:||11 September 2009|
|Protocol First Published:||Issue 2, 2003|
|Review First Published:||Issue 4, 2003|
|Last Citation Issue:||Not specified|
|Date / Event||Description|
|11 September 2007
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.
|13 February 2008
Converted to new review format.
|Date / Event||Description|
|28 January 2003
New citation: conclusions changed
Mortality and morbidity due to neonatal sepsis and necrotizing enterocolitis (NEC) is high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcome. Pentoxifylline, a phosphodiesterase inhibitor, is one such agent.
The primary objectives were to assess the. Effect on mortality and the safety of intravenous pentoxifylline as an adjunct to antibiotic therapy in neonates with
- suspected or confirmed sepsis
The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE, EMBASE and CINAHL, Science Citation Index for articles referencing Lauterbach 1996, proceedings of the Pediatric Academic Societies (1980 - 2006), BIOSIS (1992-2007), conference proceedings (1992 - 2007), ongoing trials and reference lists of identified RCTs were searched in May 2007.
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 and reporting at least one of the following outcomes: all cause mortality during initial hospital stay, neurological development at two years of age or later, length of hospital stay, duration of ventilation via endotracheal intubation, chronic lung disease in survivors, periventricular leukomalacia, necrotising enterocolitis, or adverse events were eligible.
Data collection and analysis
Two reviewers independently abstracted information for the outcomes of interest. Typical Relative Risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using fixed effects model are reported for dichotomous outcomes. NNT was calculated for outcomes for which there was a statistically significant reduction in RD.
Two randomized controlled trials that enrolled a total of 140 preterm (< 36 weeks gestation) neonates with suspected late onset (> 7 days) sepsis were identified. Outcomes were reported for only 107 randomised patients with confirmed sepsis. A reduction was noted in 'all cause mortality during hospital stay' following pentoxifylline treatment [typical RR 0.14 (95% CI 0.03, 0.76), typical RD -0.16 (95% CI -0.27, - 0.04), NNT 6 (95% CI 4, 25)]. No adverse effects due to pentoxifylline or other outcomes of interest were reported. No completed trial of treatment with pentoxifylline for NEC was identified.
Current evidence from two small studies suggests that the use of pentoxifylline as an adjunct to antibiotics in neonatal sepsis reduces mortality without any adverse effects. Researchers are encouraged to undertake large well-designed trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and adverse outcomes in neonates with suspected or confirmed neonatal sepsis and NEC.
Plain language summary
Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates
Pentoxifylline added to antibiotic treatment may reduce mortality from sepsis in newborn babies, but more research is needed. Sepsis is a bacterial or fungal infection of the bloodstream. Necrotizing enterocolitis (NEC) is a condition in premature babies where the gastrointestinal tract is damaged. NEC is often associated with infection. Sepsis and NEC may cause death and adversely affect development. Modulating the body's response to infection (inflammation) may reduce death and tissue injury after sepsis and NEC. Pentoxifylline is a drug that affects inflammation. This review found some evidence that pentoxifylline in combination with antibiotics reduces deaths from sepsis in the newborn. No adverse effects due to pentoxifylline were identified. Although two ongoing studies were found, there were no completed studies looking at treatment of NEC with pentoxifylline. More research is needed on pentoxifylline and other anti-inflammatory drugs that might be useful the treatment of sepsis and NEC in the newborn.
Neonatal sepsis is the most common cause for neonatal deaths worldwide (Lawn 2006). The incidence of neonatal sepsis in the developed world is reported to be between 0.6 to 1.2% (Philip 1994; Stoll 2004a). In the developing world, the incidence of sepsis is significantly higher (20 to 40 % of all live births) (Bhutta 1997). The incidence of neonatal sepsis is inversely proportional to gestational age and birth weight (Kaufman 2004). Early onset sepsis (sepsis in infants < 72 hrs of life) occurs in 1.5 to 1.9% of very low birthweight infants (VLBW, birthweight 401 - 1500 gm) (Stoll 2005). In a cohort of 6956 VLBW infants admitted to the NICHD Neonatal Network hospitals for the period 1998-2000, 21% had one 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, necrotizing enterocolitis 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 infants (ELBW, birth weight < 1000 g), infected infants had a significantly higher incidence of adverse neurodevelopmental outcomes at follow-up, characterized by cerebral palsy, low Bayley's scores of infant development and vision impairment when compared with uninfected infants (Stoll 2004b).
Necrotizing enterocolitis (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 birthweight (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). 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% - 17% (Halpern 2006). Mortality from NEC is high (15 - 30%) and 20 - 40% of infants with NEC undergo surgery. Infants who had NEC have delayed neurodevelopmental outcomes at 18 - 22 months corrected age (Lin 2006, Stoll 2004b).
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 (SIRS) seen in sepsis. The balance of pro and anti-inflammatory cytokines may determine the severity and the 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 (Adams-Chapman 2006) and pulmonary injury (Speer 1999), 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.
Pentoxifylline (PTX), a xanthine derivative, is a phosphodiesterase inhibitor that suppresses TNF-α production by adenylcyclase activation and increased cellular cyclic AMP concentration. PTX has attracted increased interest since the discovery that inhibition of tumor 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 and thereby amplifies the inflammatory response (Jaattela 1991; Vilcek 1991). Inhibition of TNF-α production by PTX negates this response and thereby may improve outcome. PTX also has beneficial effects on endothelial cell function and coagulation in sepsis (Wang 1996; Boldt 1996).
Pentoxifylline has been shown to have beneficial effects in humans and animal models of sepsis and necrotizing enterocolitis. In sepsis, PTX has been shown to improve haemodynamics (including renal blood flow) and to prevent transition from a hyperdynamic to a hypodynamic response (Zeni 1996; Bacher 1997; Krysztopik 1996; Yang 1999). Inflammatory lung injury after endotoxemia is also ameliorated by PTX (Michetti 2003). In adults and neonates, PTX has been shown to decrease serum levels TNF-α, IL-1, and IL-10 but not IL-6 or IL-8 (Zeni 1996; Bienvenu 1995). In a rat model of NEC, PTX reduces the incidence and severity of NEC (Travadi 2006).
To date, no significant adverse effects have been reported in either animal or human studies. The potential beneficial effects make pentoxifylline a promising agent for the treatment of sepsis and NEC in neonates. This systematic review evaluates the effect of pentoxifylline as an adjunct to antibiotics for the treatment of sepsis and NEC in neonates.
- To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis
- To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with NEC
Separate comparisons will be made for pentoxifylline treatment for neonatal sepsis and NEC.
- For treatment of neonatal sepsis:
- To determine the effect of pentoxifylline for treatment of neonatal sepsis on adverse neurological outcome at two years of age or later
- To determine the effect of pentoxifylline for treatment of neonatal sepsis on the length of hospital stay in survivors to discharge and to determine adverse effects attributable
- to pentoxifylline (e.g. gastrointestinal disturbance, increasing gastric residue, feeding intolerance, thrombocytopenia, cholestatic jaundice)
- 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 hrs of life) or late onset sepsis (> 72 hrs of life)
- 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 necrotising enterocolitis
- For treatment of NEC:
- To determine the effect of pentoxifylline for treatment of NEC on adverse neurological outcome at two years of age or later
- To determine the effect of pentoxifylline for treatment of NEC on the length of hospital stay in survivors to discharge and to determine adverse effects attributable to pentoxifylline (e.g. gastrointestinal disturbance, increasing gastric residue, feeding intolerance, thrombocytopenia, cholestatic jaundice)
- To determine the effect of pentoxifylline for treatment of NEC in the following subgroups of neonates; term or preterm infants
- To determine the effect of pentoxifylline for treatment of NEC on the duration of ventilation through endotracheal tube and development of chronic lung disease
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials
Types of participants
Neonates (< 28 days old, at any gestational age or birthweight) with confirmed or suspected sepsis or neonates with NEC [Bell's Stage II or III (Bell 1978)] on antibiotics
Confirmed sepsis was defined as clinical signs and symptoms consistent with infection and microbiologically proven, with a positive blood culture, CSF culture, urine culture (obtained by a suprapubic tap) or culture from a normally sterile site (e.g. pleural fluid, peritoneal fluid or autopsy specimens) for bacteria or fungi
Suspected sepsis was defined as clinical signs and symptoms consistent with sepsis without isolation of a causative organism
NEC was defined as an acute gastrointestinal disorder that manifests clinically with systemic signs (temperature instability, apnea, bradycardia, lethargy, hypotension, metabolic acidosis, hyponatremia, thrombocytopenia, disseminated intravascular coagulation), intestinal signs (feed intolerance, GI 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).
Planned subgroup analyses included
- Gestational age
- Preterm neonates (born before 37 completed weeks gestation)
- Term infants (born at or after 37 completed weeks of gestation)
- Time of onset of sepsis
- Early onset sepsis (sepsis in the first 72 hrs of life)
- Late onset sepsis (sepsis after the first 72 hrs of life)
- Suspected or confirmed sepsis
- Neonates with suspected sepsis (clinical signs and symptoms consistent with sepsis without isolation of causative organism treated with antibiotics).
- Neonates with confirmed sepsis
- Neonates with confirmed gram negative sepsis
- Neonates with confirmed fungal sepsis
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, or no intervention, or other adjuncts to antibiotics.
Types of outcome measures
- All cause mortality during hospital stay
- Neurological outcome at two years of age or more (neurodevelopmental outcome assessed by a validated test)
- Chronic lung disease (CLD) in survivors (CLD defined as oxygen requirement at 36 weeks postmenstrual age)
- Adverse outcomes directly attributable to pentoxifylline: thrombocytopenia, (platelet count less than 100, 000 x 109/L) increased gastric residue (gastric aspirate greater than 10% of oral feed), vomiting, cholestatic jaundice requiring therapy
- 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 semi ovale, optic and acoustic radiations and diagnosed by neuroimaging) (Volpe 1995)
- Duration of assisted ventilation through an endotracheal tube in days.
- Length of hospital stay in days for survivors to discharge
- Outcome for neonates with sepsis only: Necrotising enterocolitis (NEC) (definite NEC and perforated NEC, Bell's stage II or III) (Bell 1978)
Search methods for identification of studies
Please refer to Cochrane Neonatal Review Group's search strategy.
The following databases were searched again in May 2007 and relevant trials in any language were identified through:
- The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007)
- Electronic journal reference databases: MEDLINE (1966 - present) and PREMEDLINE, EMBASE (1980 - present), CINAHL (1982 - present)
- Abstract of conferences - proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research) and European Society for Paediatric Research were searched from 1990 in the journal Pediatric Research and 'Abstracts online' (2000-2006).
- Biological abstracts in the database BIOSIS and conference abstracts from 'Proceedings First' from 1992-2007 were searched but none were identified.
- Science citation index was searched for all articles that cited ' Lauterbach 1996'.
- Ongoing trials were searched with the search engines provided at the web sites www.clinicaltrials.gov and www.controlled-trials.com. One ongoing trial (Hammerman 2005) was identified with the search word 'pentoxifylline'.
- Authors who published in this field were contacted for possible unpublished studies and one ongoing study was identified (Patole 2006).
- Additional searches were made from the reference lists of identified clinical trials and in the reviewer's personal files.
MEDLINE and PREMEDLINE search strategy. This was adapted to suit EMBASE, CINAHL and the Cochrane Controlled Trials Register.
- explode 'sepsis' [all subheadings in MIME, MJME]
- sepsis or septicemia
- 5 'necrotizing enterocolitis'
- # 1 or # 2 or # 3 or # 4 or # 5
- explode 'infant - newborn' [all subheadings in MIME, MJME]
- # 7 or # 8 or # 9
- # 6 and # 10
- "Pentoxifylline' [all subheadings on MIME, MJME]
- Trental or Torental
- PTF or PTX or PTX F
- agapurin or BL-191 or oxpentif*
- # 12 or # 13 or # 14 or # 15 or # 16
- # 11 and # 17
No language restriction was applied
Data collection and analysis
The titles and the abstracts of studies identified by the search strategy were assessed independently for eligibility for inclusion in this review by the two reviewer authors. If this could not be done reliably by title and abstract, then the full text version was obtained for assessment. Any differences were resolved by mutual discussion. Full text versions of all eligible studies were obtained for quality assessment. Forms were designed for trial inclusion/exclusion, data extraction and for requesting additional information from authors of the original reports. Data extraction was done independently by the authors using specifically designed paper forms and compared for any differences which were then resolved by discussion.
Assessment of the quality of studies:
The standardized review methods of the Cochrane Neonatal Review Group (CNRG) were used to assess the methodological quality of the studies. An assessment of the concealment of allocation in the included studies was done by the two reviewers independently using the standard criteria developed by the CNRG.
- Adequate allocation concealment
- Uncertainty about whether the allocation was adequately concealed
- Inadequate allocation concealment
In addition, blinding of intervention, blinding of outcome assessment and completeness of follow-up of all randomised infants is reported. Each of these criteria were then rated as yes, no or unsure.
Statistical analyses were performed according to the recommendations of the CNRG. Analyses were done for all infants, and for the subgroups defined under 'Criteria for considering studies for this review '. All infants randomised were analysed on 'an intention to treat basis' irrespective of whether or not they survived to receive their allocated treatment completely. Treatment effects in the individual trials were analysed. Heterogeneity of treatment effects between trials was assessed to check the appropriateness of pooling data and performing meta-analysis. The statistical package (RevMan 4.1) provided by the Cochrane Collaboration was used. Relative risk (RR) and risk difference (RD) with 95% confidence interval (CI) are reported for dichotomous outcomes. If there was a statistically significant reduction in RD then the number needed to treat (NNT) was calculated. A fixed effects model was used for meta-analysis.
Description of studies
Details of the included studies are provided in the table "Characteristics of Included Studies".
Lauterbach 1996 randomised 40 preterm infants (< 36 weeks gestation) with suspected late onset sepsis to receive either pentoxifylline or placebo as adjunct to antibiotics. In 4/20 infants in the treatment group and 7/20 infants in the placebo group sepsis was not confirmed, and these infants were excluded from analysis in the report of this trial. Thus, outcomes were 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 in 10 infants in the placebo group. The following outcomes were reported: 1) plasma TNF-α levels, 2) mortality during hospital stay, and 3) adverse effects.
Lauterbach 1999 randomised 100 preterm infants (< 36 weeks gestation) with suspected late onset sepsis to receive either pentoxifylline or placebo as adjunct to antibiotics. 10/50 infants in the treatment group and 12/50 in the placebo group were excluded from analysis in the report of this trial as sepsis was not confirmed in these infants. Thus, outcomes were 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: 1) plasma levels of TNF-α, IL-6 and IL-1, 2) mortality during hospital stay and 3) adverse effects.
Lauterbach 1994: 17 preterm infants with sepsis were given pentoxifylline and compared with a historical control group of 13 septic infants who did not receive pentoxifylline. Mortality and adverse effects were reported. The study was excluded as it was neither a randomised nor a quasi-randomised study.
Hammerman 2005 and coworkers plan to randomise 50 premature neonates with a birthweight less than 1750 g and with clinical and radiological diagnosis of NEC to pentoxifylline (5 mg/kg/hr for 6 hr for 6 days) or an equal volume of 1/2 normal saline. Infants with abdominal perforation will be excluded. This study started in January 2005 and scheduled to conclude in March 2009.
In a pilot study, Patole 2006 and coworkers plan to randomise 80 preterm (< 32 weeks gestation) neonates with Stage II or III NEC. Enrolled neonates will be randomised to intravenous pentoxifylline or an equal volume of placebo at 5 mg/kg/hour for 12 hours a day (60 mg/kg/day) for two consecutive days, followed by infusion for six hours a day (30 mg/kg/day) for the next four consecutive days. The primary outcome is to assess the efficacy and safety of pentoxifylline in preventing the progression of NEC and or death. Secondary outcomes are reduction in plasma TNF-α levels, duration of hospital stay, duration of TPN support and time to full enteral feeds. This study is scheduled to be conclude in 2009 or 2010.
Risk of bias in included studies
See: Table of included studies.
Lauterbach 1996: Single centre randomised placebo controlled trial. No details of randomisation are available, thus blinding of randomisation is unclear. Physicians were blinded to the intervention. Blinding of outcome assessment unclear. 11/40 were excluded from analysis as they did not have confirmed sepsis.
Lauterbach 1999: A two centre randomised placebo controlled trial. Randomisation was done using computer generated random numbers centrally. There was concealment of randomisation. Physicians were blinded to the intervention and outcome. 22/100 were excluded from analysis as they did not have confirmed sepsis.
In both the above trials, information has been requested from the author regarding the outcomes of infants with suspected late onset sepsis who were excluded from the analysis.
Effects of interventions
I. PENTOXIFYLLINE VERSUS PLACEBO FOR TREATMENT OF NEONATAL SEPSIS (COMPARISON 01):
Two randomised controlled trails where pentoxifylline was used for the treatment of neonatal sepsis were eligible for inclusion in the review.
A total of 140 preterm infants with suspected neonatal sepsis (Lauterbach 1996, Lauterbach 1999) have been enrolled in RCTs to evaluate the effect of pentoxifylline on important clinical outcomes. A total of 107 neonates with subsequently confirmed sepsis were analysed in the reports of these trials.
1. All cause mortality during hospital stay (Outcome 01.01):
All infants with confirmed sepsis (2 trials, 107 infants, 10 events) (Outcome 01.01.01):
There is a significant reduction in all cause mortality during hospital stay in neonates with confirmed sepsis who had pentoxifylline as an adjunct to antibiotics compared to neonates with sepsis who had placebo [typical RR 0.14 (95% CI 0.03, 0.76), typical RD -0.16 (95% CI -0.27, -0.04), NNT 6 (95%CI 4, 25)]. There was no significant heterogeneity in this result for the two trials.
Confirmed gram negative sepsis (2 trials, 49 infants, 8 events) (Outcome 01.01.02):
There is a reduction of borderline statistical significance in all cause mortality during hospital stay in neonates with confirmed gram negative sepsis who had pentoxifylline as an adjunct to antibiotics compared to neonates with confirmed gram negative sepsis who had placebo. [typical RR 0.19 (95% CI 0.04, 1.02), typical RD -0.25 (95% CI -0.46, -0.04), NNT 4 (95% CI 2, 25)]. There was no significant heterogeneity in this result for the two trials.
Other planned subgroup analyses:
Both the included trials analysed preterm infants with confirmed, late onset sepsis only. Thus, the planned subgroup analyses based on preterm infants, infants with confirmed sepsis or infants with late onset sepsis are in fact identical to the analyses reported in this review for all infants. The following subgroup analyses were not possible due to lack of data: term infants, early onset sepsis, suspected sepsis or fungal sepsis.
No adverse effects due to pentoxifylline were observed in the two included trials. None of the other secondary outcomes were reported.
II. PENTOXIFYLLINE FOR TREATMENT OF NEC (COMPARISON 02):
No completed randomised or quasi-randomised trials using pentoxifylline for the treatment of stage II or III NEC were identified.
This review identified only two eligible RCT's using pentoxifylline for the treatment of neonatal sepsis. Both studies were performed by the same principal investigator in Poland. The two studies included 140 preterm neonates with suspected late onset sepsis. Of these, 33 (23%) of the enrolled subjects were excluded because of unconfirmed sepsis. Thus, the analysis was not based on 'intention to treat'. The trials did not include sample size calculations and studied a very small number of neonates with sepsis. Two ongoing trial using pentoxifylline for NEC that will be completed in 2009 or 2010 were identified (Hammerman 2005, Patole 2006).
In this review, a significant reduction in all cause mortality during hospital stay in neonates with sepsis who were treated with pentoxifylline as an adjunct to antibiotics compared to placebo was noted. In the subgroup analysis, a reduction of borderline statistical significance in all cause mortality during hospital stay in neonates with confirmed gram negative sepsis who had pentoxifylline as an adjunct to antibiotics compared to neonates with confirmed gram negative sepsis who had placebo was noted. This subgroup analysis only included 49 neonates. There was no significant heterogeneity between the results of the included studies (p > 0.10).
Possible haematological adverse effects of pentoxifylline affecting platelet, leukocyte and red cell function were not observed in the included trials. However, pentoxifylline is currently not licensed for use in neonates in many countries and thus may not be widely available.
Despite advances in neonatal care and use of potent antimicrobials, the mortality and morbidity from neonatal sepsis and NEC remain high (Stoll 2005; Stoll 2002; Lin 2006). Adjuvants that modulate inflammation, in conjunction with antibiotics, have the potential to reduce mortality and limit cerebral and pulmonary injury. Intravenous immunoglobulin (IVIG) is one of the agents that modulates inflammation and used to treat or prevent sepsis (Haque 1998). In seven trials (n = 262) of neonates with confirmed sepsis, treatment with IVIG resulted in a statistically significant reduction in mortality; however, Ohlsson and Lacy in their Cochrane review (Ohlsson 2002) concluded that there was insufficient evidence to support the routine administration of IVIG for neonatal sepsis. A large trial (approximately 3500 infants) evaluating IVIG in sepsis (International Neonatal Immunotherapy Study) and funded by the Medical Research Council (UK) which recruited approximately 3500 neonates has recently concluded.
Pentoxifylline has been shown to have numerous potential benefits by modulating inflammation in human and animal models of sepsis and NEC, i.e. suppression of TNF-α, IL-6 and IL-8, and a variety of physiological effects at cellular, vascular and endothelial levels. Thus, it appears to be a promising adjunct in the treatment of neonatal sepsis and NEC. The results from the two studies identified in the this review show a statistically significant reduction in mortality and a trend towards earlier correction of metabolic and haemodynamic derangements in preterm neonates with confirmed late onset sepsis. However, because of the methodological weaknesses of the studies highlighted earlier, the routine use of pentoxifylline cannot be recommended.
Implications for practice
Current evidence from two small RCT's suggests that pentoxifylline as an adjunct to antibiotic therapy in late onset neonatal sepsis significantly reduces mortality during hospital stay without adverse effects. However, these trials have considerable methodological weaknesses and the results of this meta-analysis should be interpreted with caution. No completed trial using pentoxifylline for the treatment of NEC was identified.
Implications for research
Researchers should be encouraged to undertake large well designed RCT's to confirm or refute the role of pentoxifylline in treatment of confirmed or suspected early and late onset neonatal sepsis as well as NEC. The trials should report on clinically important co-morbidities of sepsis (e.g. chronic lung disease, periventricular leukomalacia, duration of assisted ventilation, among others) and long term neurological outcome. Researchers may consider comparing pentoxifylline with other adjunctive modalities to treat neonatal sepsis such as colony stimulating factors or intravenous immunoglobulins.
- Ms. Nicola Bexon of the Institute of Health Sciences for helping to formulate the literature search strategy
- Mr. Edward George of Hirson Library at St Helier Hospital for assisting to formulate the literature search strategy
- Miss Natasha Haque for help with typing the manuscript
Contributions of authors
Searched the literature and identified trials for inclusion
Extracted relevant data from eligible studies
Verified and entered data in RevMan
Contacted prominent authors for more data on published and unpublished trials
Wrote the text of the review
Is the corresponding author
Assisted in updating the review
Assisted in writing the protocol and review
Independently assessed study methodology and extracted data from eligible studies
Assisted in entering and checking data in RevMan
Assisted in contacting authors for more information on published articles and in tracing unpublished ones
Updated the review
Potential conflict of interest
- None noted.
Characteristics of studies
Characteristics of Included Studies
Single centre, randomised placebo controlled trial. No details of randomisation given.
Single centre. Neonatal Unit, Jagiellonan University Hospital, Poland.
Pentoxifylline (Trental; Boehring-Hoscht) 5 mg/kg/hour for 6 hours, repeated on 2nd and 3rd day ( n=20).
Outcomes reported were;
Risk of bias table
B - Unclear
Randomised placebo controlled study.
Two centre study: Neonatal Unit, Medical College Jagiellonan, University of Cracow, Poland and ITU at Polish Mother and Children Hospital, Lodz, Poland.
Pentoxifylline (Pentilin -KRKA Slovenia) 5 mg/kg/hour for 6 hours for 6 successive days (n=50).
Outcomes reported were:
Risk of bias table
A - Adequate
Characteristics of excluded studies
|Reason for exclusion||
Not a randomised or a quasi-randomised trial
Characteristics of studies awaiting classification
- None noted.
Characteristics of ongoing studies
Pentoxifylline in the treatment of NEC in premature neonates
Premature neonates (< 1750g birthweight) with clinical suspicion of NEC and abdominal X-ray consistent with NEC
Pentoxifylline IV at 5mg/kg/hr to run over 6hr for 6 days or an equal volume of 1/2 normal saline as placebo
To be confirmed with the principal investigator.
Cathy Hammerman- email - firstname.lastname@example.org
Finishes in March 2009
Safety and efficacy of pentoxifylline as a treatment for preventing the progression of necrotising enterocolitis in preterm neonates– A randomised, placebo controlled pilot trial
Premature neonates < 32 weeks gestation with Stage II or III NEC
Pentoxifylline at 5mg/kg/hr for 12hrs for 2 days followed by the infusion for 6 hours a day for the next 4 days OR equal volume of placebo in controls
Primary: Efficacy and safety of pentoxifylline in preventing the progression of NEC and or death.
To finish in 2009 or 2010
References to studies
Lauterbach R, Zembala M. Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis. European Journal of Pediatrics 1996;155:404-9.
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.
Lauterbach R, Pawlik D, Tomaszcyk B, Cholewa B. Pentoxifylline treatment of sepsis of premature infants: preliminary clinical observations. European Journal of Pediatrics 1994;153:672-74.
Studies awaiting classification
- None noted.
Adams-Chapman I, Stoll BJ. Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Current Opinion in Infectious Disease 2006;19:290-7.
Bacher A, Mayer N, Klimscha W, et al. Effects of pentoxifylline on haemodynamics and oxygenation in septic and non-septic patients. Critical Care Medicine 1997;25:795-800.
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotising enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgert 1978;187:1-7.
Bhutta ZA. Neonatal infections. Current Opinion in Paediatrics 1997;9:133-40.
Bienvenu J, Doche C, Gutowski MC, Lenoble M, Lepape A, Perdrix JP. Production of pro-inflamatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline. Journal of Cardiovascular Pharmacology 1995;25:S80-4.
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Other published versions of this review
Haque K, Mohan P. Pentoxifylline for neonatal sepsis. Cochrane Database of Systematic Reviews 2003, Issue 4.
Data and analyses
1 Pentoxifylline versus placebo for the treatment of neonatal sepsis
|Outcome or Subgroup||Studies||Participants||Statistical Method||Effect Estimate|
|1.1 All cause mortality during hospital stay||2||Risk Ratio (M-H, Fixed, 95% CI)||Subtotals only|
|1.1.1 All infants||2||107||Risk Ratio (M-H, Fixed, 95% CI)||0.14 [0.03, 0.76]|
|1.1.2 Infants with confirmed gram negative sepsis||2||49||Risk Ratio (M-H, Fixed, 95% CI)||0.19 [0.04, 1.02]|
Sources of support
- Epsom & St. Helier NHS Trust, UK
- National Perinatal Epidemiology Unit, Headington, Oxford, UK
- No sources of support provided.
This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2008 (see http://www.thecochranelibrary.com 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.