Pammi Mohan
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and in tracing unpublished ones
Pentoxifylline added to antibiotic treatment may reduce mortality from sepsis in newborn babies, but more research is needed
Sepsis is blood poisoning, caused by an infection reaching the bloodstream. It is often fatal when it occurs in newborn babies, especially those born preterm (before 37 weeks). The development of antibiotic resistance has made it more difficult to treat sepsis effectively. Pentoxifylline is an anti-inflammatory drug that may be able to reduce sepsis and complications from sepsis. The review found some evidence that pentoxifylline in combination with antibiotics reduces mortality from sepsis in newborns without adverse effects. More research is needed on pentoxifylline and other anti-inflammatory drugs that might be used for sepsis in newborns.
Two RCTs enrolled a total of 140 preterm (< 36 weeks) neonates with suspected late onset (> 7 days) sepsis to evaluate the effect of pentoxifylline on neonatal outcomes. However, the two studies reported outcomes of only the 107 randomised patients with confirmed sepsis. The results showed a reduction in 'all cause mortality during hospital stay' following pentoxifylline treatment [typical RR 0.14 (95% CI 0.03, 0.76), RD -0.16 (95% CI -0.27, - 0.04), NNT 6 (95% CI 4, 25)]. No adverse effects due to pentoxifylline were observed in the two included trials. No other outcomes of interest were reported.
Current evidence suggests that the use of pentoxifylline as an adjunct to antibiotics in neonatal sepsis reduces mortality without any adverse effects. But the number of neonates studied is small and considerable methodological weaknesses exist in the included trials. Hence these results should be interpreted with caution. Researchers are encouraged to undertake large well-designed trials to confirm or refute the effectiveness of pentoxifylline to reduce mortality and adverse outcomes in neonates with suspected or confirmed neonatal sepsis. Researchers might also compare pentoxifylline with other adjuncts to antibiotics which modulate inflammation (e.g. intravenous immunoglobulins, haematopoetic colony stimulating factors among others) in reducing mortality and morbidity due to neonatal sepsis.
The overall incidence of bacterial sepsis in the newborn has declined over the past decades but it still remains a significant cause of neonatal mortality and morbidity particularly in very low birth weight infants (VLBW). Incidence of neonatal sepsis in the developed world is reported to be between 0.6 to 1.2% of all live births (Philip 1994) but in the developing world it can be as high as 20 to 40 % of all live births (Bhutta 1997). In a study of 7861 VLBW (<1500g birth weight) infants from the National Institute of Child Health and Human Development (NICHD) network centres (1991-1993) 1.9% had culture proven sepsis in the first 72 hours of life, though almost 50% of the infants in this cohort were considered to have clinical sepsis and were treated with antibiotics for more than five days (Stoll 1996). Twenty six percent of these infants died. Survivors had a higher incidence of severe intra-ventricular haemorrhage, patent ductus arteriosus, prolonged assisted ventilation and longer hospital stay. In another cohort, of 6956 VLBW (401-1500 gm) neonates admitted to the NICHD neonatal network hospitals for the period 1998-2000 (Stoll 2002), 21% had one or more blood culture proven late onset (onset after 72 hours of life) sepsis. Mortality in the infected group was 18% (36% for those infected with gram-negative organisms) and co-morbidities like patent ductus arteriosus, prolonged ventilation, prolonged need for intravascular access, bronchopulmonary dysplasia, necrotising enterocolitis and length of hospital stay were all increased in the infected group. Neonatal sepsis has also been implicated in the development of cerebral palsy both in preterm and term infants. Sepsis in preterm infants increases the risk of cerebral palsy fourfold (Wheater 2000) and exposure to maternal infection during labour increases the risk of cerebral palsy nine fold in infants born at term (Grether 1997).
The mortality and morbidity for both early and late onset sepsis still remains high (Stoll 1996, Stoll 2002) despite the use of potent antimicrobials and there is a global emergence of antibiotic resistance (Levy 1998). This has led to the search for modalities to enhance neonatal host defence mechanisms, which could be used as adjuncts to antibiotics in treating neonatal sepsis. Some of these agents help to re-establish the balance between pro and anti inflammatory influences which may affect clinical outcome.
Pentoxifylline, a xanthine derivative and a phosphodiesterase inhibitor, has attracted fresh attention since the discovery that inhibition of tumor necrosis factor (TNF) gene transcription reduces mortality from sepsis. TNF acts as an early and important mediator of inflammation (Beutler 1990). Pentoxifylline has been shown to have numerous potential beneficial effects in human and animal models of sepsis. Pentoxifylline suppresses production of inflammatory mediators e.g. TNF, Interleukin-8 (IL-8) ( Zeni 1996, Mandi 1995). In adults and neonates it has been shown to decrease TNF alpha, IL-1, and IL-10 but not IL-6 or IL-8 (Zeni 1996, Bienvenu 1995). Pentoxifylline delays the release of endothelin-1, abolishes TNF burst and suppresses IL-6 and lactate whilst improving survival from abdominal sepsis in rats (Lundblad 1995). Pentoxifylline may prevent the development of necrotising enterocolitis by preserving small intestinal micro-vascular blood flow (Steeb 1992). Pentoxifylline also augments haemodynamic performance during sepsis (Zeni 1996, Bacher 1997), improving renal blood flow during bacteraemia (Krysztopik 1996) and preventing transition from hyperdynamic to hypodynamic response during sepsis (Yang 1999).
Pentoxifylline has been shown in human and animal studies to have a variety of physiological effects at cellular, endothelial and vascular levels. It prevents endothelial cell dysfunction in sepsis (Wang 1996), preserves endothelial thrombomodulin, protein C, and the protein S anticoagulant system (Boldt 1996a). Pentoxifylline stimulates fibrinolysis associated with the increased release of tissue plasminogen activator in sepsis (Schroer 1985). It also enhances prostacyclin release (Matzky 1982) and attenuates the release of thromboxane (Zheng 1991). Pentoxifylline may either up or down regulate circulating adhesion molecules (Boldt 1996b, Boldt 1996c) by inhibiting endothelial cell activation (Mandell 1988). Pentoxifylline does not impair platelet function (Boldt 1996d) or increase platelet adhesion (Schroer 1985). Pentoxifylline increases erythrocyte and leukocyte deformability (Betticher 1993). Interestingly, low doses of methylxanthines have been associated with suppression of neutrophil functions such as chemotaxis, super oxide anion production from respiratory burst, hydrogen peroxide production, deformability, phagocytosis and degranulation (Krause 1991, Mah 1993). These biological and cellular effects of pentoxifylline have been attributed to the inhibition of both cellular phosphodiesterase with resultant increase in cyclic adenosine monophosphate (cAMP) concentration. Therefore, the numerous potential beneficial effects make pentoxifylline an interesting modality for the treatment of sepsis. No significant adverse effects have been reported in either animal or human studies.
Primary objective:
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
Secondary objectives:
i) To determine the effect of pentoxifylline for treatment of neonatal
sepsis in reducing adverse neurological outcome at two years of age or later
ii) 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; gastro-intestinal disturbance,
increasing gastric residue, feed intolerance, thrombocytopenia, cholestatic
jaundice)
iii) 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 (within first 72hrs of life) or late onset sepsis (> 72 hrs of
life)
iv) To determine the effect of pentoxifylline for treatment of neonatal
sepsis on the duration of ventilation through endo-tracheal tube, development
of chronic lung disease and necrotising enterocolitis
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
Key subgroups of participants were based on
a) Gestational age
Preterm neonates (born before 37 completed weeks gestation)
Term infants (born at or after 37 completed weeks of gestation)
b) Time of onset of sepsis
Early onset sepsis (sepsis in the first 72 hrs of life, <=72hr )
Late onset sepsis (sepsis after the first 72 hrs of life, >72hr)
c) 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
Intravenous pentoxifylline at any dosage or duration used as adjunct to antibiotics to treat suspected or confirmed neonatal sepsis, compared with placebo, or no intervention, or other adjuncts to antibiotics.
Primary outcomes:
Please refer to Cochrane Neonatal Review Group's search strategy.
The following databases were searched in October 2002 and again in March
2003 and relevant trials in any language were identified through:
1. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane
Library, Issue 4, 2002)
2. Electronic journal reference databases: MEDLINE (1966 - present) and PREMEDLINE, EMBASE (1980 - present), CINAHL (1982 - present)
3. 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.
4. Relevant doctoral theses and dissertations through the British National Library and dissertation abstracts database were searched, but none were identified.
5. Authors who published in this field were contacted for possible unpublished articles, but none were identified.
6. 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.
# 1 explode 'sepsis' [all subheadings in MIME, MJME]
# 2 sepsis or septicemia
# 3 septic
# 4 # 1 or # 2 or # 3
# 5 explode 'infant - newborn' [all subheadings in MIME, MJME]
# 6 Neonat*
# 7 Newborn*
# 8 # 5 or # 6 or # 7
# 9 # 4 and # 8
# 10 "Pentoxifylline' [all subheadings on MIME, MJME]
# 11 pentoxif*
# 12 Trental or Torental
# 13 PTF or PTX or PTX F
# 14 agapurin or BL-191 or oxpentif*
# 15 # 10 or # 11 or # 12 or # 13 or # 14
# 16 # 9 and # 15
No language restriction was applied
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.
A- Adequate allocation concealment
B- Uncertainty about whether the allocation was adequately concealed
C- Inadequate allocation concealment
In addition, we have also reported on: blinding of intervention, blinding of outcome assessment and completeness of follow-up of all randomised infants. Each of these criteria were then rated as yes, no or unsure.
Analysis
Statistical analyses were performed according to the recommendations of the CNRG. Analyses were to be done for all infants, and for the sub-groups defined under 'Criteria for considering studies for this review '. All infants randomised were to be 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 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 (NTT) was calculated. A fixed effects model was used for meta-analysis.
Details of the included studies are provided in the table "Characteristics
of Included Studies".
Two studies (Lauterbach 1996 and Lauterbach 1999) met the inclusion criteria.
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 alpha 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 alpha, IL-6, IL-1, 2) mortality during hospital stay
and 3) adverse effects.
Excluded studies:
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.
Lauterbach 1996: Single centre randomised placebo controlled trail. 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 we are awaiting reply from the author re the outcomes of infants with suspected late-onset sepsis who were excluded from the analysis.
Two randomised controlled trails 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.
PRIMARY OUTCOMES:
1. All cause mortality during hospital stay
All infants with confirmed sepsis (2 trials, 107 infants, 10 events).
There is a significant reduction in all cause mortality during hospital
stay in neonates with 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.
Sub-group analyses:
Confirmed Gram negative sepsis (2 trials, 49 infants, 8 events).
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 sub-group analyses:
Both the included trials analysed preterm infants with confirmed, late onset sepsis only. Thus, the planned sub-group 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 sub-group analyses were not possible due to lack of data: term infants, early onset sepsis, suspected sepsis or fungal sepsis.
SECONDARY OUTCOMES:
No adverse effects due to pentoxifylline were observed in the two included trials. None of the other secondary outcomes were reported.
In our review we found a significant reduction in all cause mortality during hospital stay in neonates with sepsis who had pentoxifylline as an adjunct to antibiotics compared to neonates with sepsis who had placebo. In our sub-group analysis, we found 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. This sub-group 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, the mortality and morbidity from neonatal sepsis remains high (Stoll 2002). Multiple factors contribute to the increased susceptibility of neonates to infection. These include developmental, quantitative and qualitative neutrophil defects, decreased bone marrow neutrophil pool, and quantitative and qualitative deficiencies in immunoglobulins, among others. However, newborn infants including preterm infants are capable of mounting a significant proinflammatory response as well as counter anti-inflammatory responses to sepsis (Ng 2003). Recent evidence has also shown that inflammation plays an important role in cerebral (Grether 1997) and pulmonary injury (Speer 1999), especially in the preterm neonate. It is also recognised that pro-inflammatory cytokines such as TNF alpha and IL-6 play a pathophysiologic role in sepsis (Mancuso 1994). These findings have made researchers and clinicians recognise that some adjuvant modality in addition to antibiotic therapy is necessary to modulate inflammation and boost host defences. Immuno-modulatory agents may help not only in reducing mortality but also may help limit cerebral and pulmonary injury by limiting inflammation. Hubel et al (Hubel 2002) have shown that in various animal models of infection, therapeutic administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and interferon (IFN)-gamma enhance pathogen eradication and decrease mortality. However, clinical evidence for efficacy and benefit of these adjuncts in treating neonatal sepsis is poor (Bannerjea 2002) and currently there is insufficient evidence to recommend rhG-CSF or rhGM-CSF as routine adjunctive therapy for neonates with sepsis (Bernstein 2002).
Intravenous immunoglobulin (IVIG) administration provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity and improve neutrophilic chemo-luminescence (Baley 1988) amongst other modes of action (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. They encouraged researchers to undertake larger well designed trials. [Such a trial is underway funded by the Medical Research Council (UK) which aims to recruit 5000 neonates].
Pentoxifylline has been shown to have numerous potential beneficial effects by boosting host defences in human and animal models of sepsis, i.e. suppression of TNF alpha, IL-6 and IL-8, and a variety of physiological effects at cellular, vascular and endothelial level. Thus, it seems a promising adjunctive agent in the treatment of neonatal sepsis. 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, its routine use cannot be recommended.
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 undue adverse effects. However, these trials have considerable methodological weaknesses and the results of this meta-analysis should be interpreted with caution.
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. These trials should include neonates with suspected early and late onset sepsis. The trials should report on clinically important co-morbidities of sepsis (e.g; chronic lung disease, periventricular leukomalacia, duration of assisted ventilation, necrotising enterocolitis amongst 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.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Lauterbach 1996 | 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 patients were excluded from analysis. |
Single centre. Neonatal Unit, Jagiellonan 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, hepato-splenomegaly. Exclusions; major congenital malformation, Grade III and IV intra-ventricular 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 and in placebo group 1.86 Kg. Period of study 1st March to 30th July 1994. Only infants with positive blood culture were analysed. Treatment group 16/20 (4 negative culture), placebo group 13/20 (7 negative culture) |
Pentoxifylline (Trental; Boehring-Hoscht) 5 mg/kg/hour for 6
hours, repeated on 2nd and 3rd day ( n=20). Placebo: equal volume of normal saline (n=20). |
Outcomes reported were; 1) Mortality 2) TNF alpha levels before the first infusion and after the third infusion of the drug or placebo. 3) Adverse reactions to the drug. |
B | |
| Lauterbach 1999 | Randomised placebo controlled study. Concealment of randomisation: yes. Blinding of intervention: yes. Blinding of outcome assessment: cannot tell. Completeness of follow-up: no. 22/100 were excluded. |
Two centre study: Neonatal Unit, Medical College Jagiellonan,
University of Cracow, Poland and ITU at Polish Mother and Children Hospital,
Lodz, Poland. Preterm infants < 36 weeks of gestation, after first week of life with suspected sepsis. Criteria for sepsis: At least three 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 hepato-splenomegaly. Positive blood culture required for confirmation of sepsis. Period: 1st Jan 1995 to 30th July 1996. Exclusions: Congenital malformations, congenital infections and grade III and IV intra-ventricular haemorrhage. Total recruitment 100. 10/50 from the treatment group and 12/50 from placebo group excluded as sepsis was not confirmed. |
Pentoxifylline (Pentilin -KRKA Slovenia) 5 mg/kg/hour for 6 hours
for 6 successive days (n=50). Placebo: Equal volume of Normal saline (n=50). |
Outcomes reported were: 1) Mortality 2) Incidence and mortality of gram negative sepsis. 3) Plasma TNF alpha levels before and after the 1st and 3rd dose and before and after the 6th dose. 4) Adverse effects. |
A |
| Study | Reason for exclusion |
| Lauterbach 1994 | Not a randomised or a quasi-randomised trial |
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* indicates the primary reference for the study
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01.01 All cause mortality during hospital
stay
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Pentoxifylline versus placebo for the treatment of neonatal sepsis | ||||
| 01 All cause mortality during hospital stay | RR (fixed), 95% CI | Subtotals only | ||
| This review is published as a Cochrane review in
The Cochrane Library 2003, Issue 4, 2003 (see www.CochraneLibrary.net for
information). Cochrane reviews are regularly updated as new evidence
emerges and in response to comments and criticisms, and The Cochrane Library
should be consulted for the most recent version of the Review. |
