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The effects of ibuprofen on sepsis parameters in preterm neonates
Early Human Development 88 (2012) 195–196
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
The effects of ibuprofen on sepsis parameters in preterm neonates Gamze Demirel ⁎, Istemi Han Celik, Fuat Emre Canpolat, Omer Erdeve, Serife Suna Oguz, Ugur Dilmen Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 23 June 2011 Received in revised form 22 July 2011 Accepted 26 July 2011 Keywords: Ibuprofen Patent ductus arteriosus Preterm infants Sepsis C-reactive protein Interleukin-6
a b s t r a c t Aim: To examine the effects of ibuprofen used for patent ductus arteriosus (PDA) treatment on the production of the proinflammatory cytokines C-reactive protein (CRP) and interleukin 6 (IL-6) in preterm septic newborns. Methods: Patients with acute phase reactant elevation were divided into two groups according to receiving ibuprofen (Group I, n = 51) or not (Group II, n = 38). Course of sepsis was evaluated by CRP and IL-6 levels. Results: CRP and IL-6 levels at the time of diagnosis were not different between two groups [16 ± 9.1 vs 16.4 ± 13.2 mg/dL (p = 0.43) for CRP and 124 ± 82 vs 119 ± 73 mg/dL (p = 0.517) for IL-6, respectively]. Similarly, they were statistically insignificant between the groups at the 2nd or 3rd days of ibuprofen treatment [14.3 ± 7.7 vs 13.7 ± 5.9 mg/dL (p = 0.21) for CRP and 83 ± 46 vs 86 ± 37 mg/dL (p = 0.29) for IL-6, respectively]. However, CRP and IL6 levels showed significant difference between groups in the following days; 6.03 ± 3.8 vs 9.1 ± 4.9 mg/dL (p = 0.025) for CRP and 42 ± 33.1 vs 58.9 ± 27.1 mg/dL (0.011) for IL-6 on 4th or 5th days of treatment and 2.3 ± 3.2 vs 4.1 ± 2.3 mg/dL (p = 0.032) for CRP and 16.1 ± 12.4 vs 21.3 ± 16.8 mg/dL (p = 0.016) for IL-6, on 7th to 10th days of treatment, respectively. Conclusions: IL-6 and CRP may decrease in infants receiving ibuprofen treatment more than infants who do not receive it. This decrease should be considered at the time of caring a preterm infant with both sepsis and PDA after ibuprofen treatment. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Patients and methods
Indomethacin and ibuprofen are commonly used as nonsteroidal anti-inflammatory drugs for the treatment of patent ductus arteriosus (PDA) in premature infants [1]. Reports on the effect of ibuprofen on the immune system revealed attenuation of certain sepsis-induced alterations [2], while others have found opposite results [3]. The proinflammatory cytokine interleukin-6 (IL-6), and C-reactive protein (CRP) are considered to be important mediators of the systemic host response to infection and are used commonly in neonatal intensive care units (NICU) for the diagnosis and follow up of sepsis and other neonatal infections. During neonatal sepsis, the serum level of these parameters is elevated [4]. The reports on the effect of ibuprofen on the cytokine production are controversial. Some investigators have reported an increased proinflammatory cytokine secretion [5,6], while others have found that it was reduced [2,7,8] or unchanged [9]. The purpose of the present study was to examine the clinical effects of ibuprofen on the production of the proinflammatory cytokine IL-6 and CRP in preterm septic newborns.
A total of 121 preterm newborns under 1250 g and 32 weeks of gestational age who were followed in our tertiary NICU between January 2010 and March 2011 were enrolled in the study. The main inclusion criteria were elevation of acute phase reactants such as IL-6 and CRP. Depending on our clinical protocol, we evaluate complete blood count and acute phase reactants of all inpatients of NICU at 6th hours of hospitalization, and begin prophylactic antibiotics to all patients who are b32 gestational week and b1250 g, preferably as Penicillin G and Netilmicin. If there is a suspicious or proven sepsis that does not respond to those therapy, we perform antibiotic changing according to culture results or clinical and laboratory status of the patient. Routine echocardiographic evaluation is performed to all patients below 32 gestational week and 1250 g between 72 and 96th hours of life. If echocardiography reveals one of the following criteria of a duct size N1.5 mm: a left atrium-to-aorta ratio N1.5, left-to-right shunting of blood, end-diastolic reversal of blood flow in the aorta, or poor cardiac function in addition to signs of PDA, medical therapy is performed. Ibuprofen is preferred for closure of PDA in our clinic because of lower side effects compared to indomethacin, and usually oral form is administered [1]. Exclusion criteria for PDA treatment are major congenital anomalies, right to left ductal shunting, life-threatening infections, urine output less than 1 mL/kg/h, serum creatinine level N1.6 mg/dL, platelet count b60,000/mm3, hyperbilirubinemia requiring exchange transfusion and grade 3 or 4 intraventricular hemorrhage. All enrolled patients in present
⁎ Corresponding author at: Zekai Tahir Burak Maternity Teaching Hospital, Division of Neonatology, Ankara, Turkey. Tel.: +90 3123065270. E-mail address: [email protected] (G. Demirel). 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.07.021
196
G. Demirel et al. / Early Human Development 88 (2012) 195–196
Table 1 Main characteristics and comparison of study groups. Preterm infants with sepsis, n = 89
Gestational age, week Birthweight, g CRP level at the time of diagnosis, mg/dL (CRP1) IL-6 level at the time of diagnosis (IL6-1) CRP level at the 2nd or 3rd days of diagnosis, mg/dL (CRP2) IL-6 level at the 2nd or 3rd days of diagnosis (IL6-2) CRP level at the 4th or 5th days of diagnosis, mg/dL (CRP3) IL-6 level at the 4th or 5th days of diagnosis (IL6-3) CRP level at the 7th or 10th days of diagnosis, mg/dL (CRP4) IL-6 level at the 7th or 10th days of diagnosis (IL6-4)
p values
PDA and ibuprofen received, n = 51
Non-PDA, n = 38
27.9 ± 1.8 1040 ± 280 16 ± 9.1 124 ± 82 14.3 ± 7.7 83 ± 46 6.03 ± 3.8 42 ± 33.1 2.3 ± 3.2 16.1 ± 12.4
28.2 ± 1.9 1084 ± 305 16.4 ± 13.2 119 ± 73 13.7 ± 5.9 86 ± 37 9.1 ± 4.9 58.9 ± 27.1 4.1 ± 2.3 21.3 ± 16.8
0.289 0.301 0.43 0.517 0.21 0.29 0.025⁎ 0.011⁎ 0.032⁎ 0.016⁎
PDA, patent ductus arteriosus; CRP, C-reactive protein; IL-6, interleukin-6. p b 0.05 considered significant, values are given as mean ± standard deviation. ⁎ Statistically significant.
study received oral ibuprofen (Pedifen, Atafarm, Istanbul, Turkey) at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48th hours. First evaluation for sepsis was done by complete blood count, blood culture, CRP and IL6 levels. This first values were named as CRP1 and IL6-1, respectively. If infants had CRP and IL6 on second or third days after the diagnosis, these parameters were classified as CRP2 and IL6-2. The classification continued as CRP3 and IL6-3 for 4th or 5th days and CRP4 and IL6-4 for 7th to 10th days of the treatment. We evaluated the levels of CRP and IL-6 before and after antibiotic treatment and divided the patients into two groups according to receiving ibuprofen for closure of PDA or not. Thirty two of these infants were excluded because of early death, missing data, congenital anomalies and additional surgical interventions which may affect CRP and IL-6 levels. Remaining 89 infants with sepsis were included in the study.
improve survival. Ibuprofen may decrease the levels of proinflammatory cytokines such as IL-1 and IL-6 and inflammatory parameters such as CRP because of its anti-inflammatory property [3]. Ibuprofen is widely used for PDA treatment in neonates and to the best of our knowledge, there is no report about the course of acute phase reactants of septic neonates after the ibuprofen treatment. In this study, we observed that sepsis parameters in preterm infants decreased by ibuprofen independently from antibiotic therapy. Our results indicate that this decrease should be considered at the time of caring a preterm infant with both sepsis and PDA after ibuprofen treatment. PDA can develop during the treatment of sepsis or both diseases may be observed in most preterm infants at the same time. Sepsis parameters (IL-6 and CRP) may decrease more in infants receiving ibuprofen in comparison to the ones who do not receive ibuprofen treatment. We conclude that this inconsequential but practicable data may be useful for clinicians who care preterm infants with sepsis and PDA.
3. Statistical analysis SPSS 17.0 was used for the analysis of data. T-test was used for statistical analysis.
Conflict of interest statement We have no conflict of interests.
4. Results CRP and IL-6 levels at the first day of life were not different between two groups (p N 0.05). Similarly, those acute phase reactants at the second or third days of the treatment (CRP2, IL6-2) were statistically insignificant between the groups. However, these parameters differed statistically between groups in the following days, presumably due to ibuprofen treatment. Main characteristics and mean CRP and IL-6 levels of study groups are summarized in Table 1. 5. Discussion PDA and sepsis are two main diseases in preterm neonates and ibuprofen has become one of the main drugs for PDA management [1]. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) working by inhibiting the enzyme cyclooxgenase (COX), which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2 is converted to several other prostaglandins that are mediators of pain, inflammation, and fever and to thromboxane A2 which stimulates platelet aggregation, leading to the formation of blood clots. NSAIDs, particularly ibuprofen have been used in the treatment of sepsis and have been shown to restore the normal hemodynamic pattern [10]. Coran et al. [11] showed that the administration of ibuprofen in septic shock in dogs did not reduce cytokine levels whereas Bernard et al. [3] reported that in patients with sepsis, treatment with ibuprofen reduced levels of prostacyclin and thromboxane and decreased fever, tachycardia, oxygen consumption and lactic acidosis but did not
References [1] Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr 2011;158:549–54. [2] Leeper-Woodford SK, Carey D, Byrne K, Walsh C, Fisher B, Sugerman HY, et al. Histamine receptor antagonists, cyclooxygenase blockade, and tumor necrosis factor during septic insult. Shock 1998;9:89–94. [3] Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis: The Ibuprofen in Sepsis Study Group. N Engl J Med 1997;336:912–8. [4] Celik IH, Demirel FG, Uras N, Oguz SS, Erdeve O, Biyikli Z, et al. What are the cut-off levels for IL-6 and CRP in neonatal sepsis? J Clin Lab Anal 2010;24:407–12. [5] Endres S, Whitaker RE, Ghorbani R, Meydani SN, Dinarello CA. Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and tumor necrosis factor-alpha ex vivo. Immunology 1996;87:264–70. [6] Mansilla-Rosello A, Ferron-Orihuela JA, Ruiz-Cabello F, Garrote-Lara D, FernandezMondejar E, Delgado-Carrasco ML. Differential effects of IL-1 beta and ibuprofen after endotoxic challenge in mice. J Surg Res 1997;67:199–204. [7] Qui HB, Pan JQ, Zhao YG, Chen DC. Effect of dexamethasone and ibuprofen on LPSinduced gene expression of TNF-, IL-1β and MIP-1 in rat lung. Chung Kuo Yao Li Hsueh Pao 1997;18:165–8. [8] Stuhlmeier KM, Li H, Kao JJ. Ibuprofen: new explanation for old phenomenon. Biochem Pharmacol 1999;57:313–20. [9] Mancuso G, Cusumano V, Cook JA, Smith E, Squadrito F, Blandino G, et al. Efficacy of tumor necrosis factor alpha and eicosanoid inhibitors in experimental models of neonatal sepsis. FEMS Immunol Med Microbiol 1994;9:49–54. [10] Fink MP, MacVittie TJ, Casey LC. Inhibition of prostaglandin synthesis restores normal hemodynamics in canine hyperdynamic sepsis. Ann Surg 1984;200(5): 619–26. [11] Coran AG, Drongowski RA, Paik JJ, Remick DG. Ibuprofen intervention in canine septic shock: reduction of pathophysiology without decreased cytokines. J Surg Res 1992;53(3):272–9.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
The effects of ibuprofen on sepsis parameters in preterm neonates Gamze Demirel ⁎, Istemi Han Celik, Fuat Emre Canpolat, Omer Erdeve, Serife Suna Oguz, Ugur Dilmen Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 23 June 2011 Received in revised form 22 July 2011 Accepted 26 July 2011 Keywords: Ibuprofen Patent ductus arteriosus Preterm infants Sepsis C-reactive protein Interleukin-6
a b s t r a c t Aim: To examine the effects of ibuprofen used for patent ductus arteriosus (PDA) treatment on the production of the proinflammatory cytokines C-reactive protein (CRP) and interleukin 6 (IL-6) in preterm septic newborns. Methods: Patients with acute phase reactant elevation were divided into two groups according to receiving ibuprofen (Group I, n = 51) or not (Group II, n = 38). Course of sepsis was evaluated by CRP and IL-6 levels. Results: CRP and IL-6 levels at the time of diagnosis were not different between two groups [16 ± 9.1 vs 16.4 ± 13.2 mg/dL (p = 0.43) for CRP and 124 ± 82 vs 119 ± 73 mg/dL (p = 0.517) for IL-6, respectively]. Similarly, they were statistically insignificant between the groups at the 2nd or 3rd days of ibuprofen treatment [14.3 ± 7.7 vs 13.7 ± 5.9 mg/dL (p = 0.21) for CRP and 83 ± 46 vs 86 ± 37 mg/dL (p = 0.29) for IL-6, respectively]. However, CRP and IL6 levels showed significant difference between groups in the following days; 6.03 ± 3.8 vs 9.1 ± 4.9 mg/dL (p = 0.025) for CRP and 42 ± 33.1 vs 58.9 ± 27.1 mg/dL (0.011) for IL-6 on 4th or 5th days of treatment and 2.3 ± 3.2 vs 4.1 ± 2.3 mg/dL (p = 0.032) for CRP and 16.1 ± 12.4 vs 21.3 ± 16.8 mg/dL (p = 0.016) for IL-6, on 7th to 10th days of treatment, respectively. Conclusions: IL-6 and CRP may decrease in infants receiving ibuprofen treatment more than infants who do not receive it. This decrease should be considered at the time of caring a preterm infant with both sepsis and PDA after ibuprofen treatment. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Patients and methods
Indomethacin and ibuprofen are commonly used as nonsteroidal anti-inflammatory drugs for the treatment of patent ductus arteriosus (PDA) in premature infants [1]. Reports on the effect of ibuprofen on the immune system revealed attenuation of certain sepsis-induced alterations [2], while others have found opposite results [3]. The proinflammatory cytokine interleukin-6 (IL-6), and C-reactive protein (CRP) are considered to be important mediators of the systemic host response to infection and are used commonly in neonatal intensive care units (NICU) for the diagnosis and follow up of sepsis and other neonatal infections. During neonatal sepsis, the serum level of these parameters is elevated [4]. The reports on the effect of ibuprofen on the cytokine production are controversial. Some investigators have reported an increased proinflammatory cytokine secretion [5,6], while others have found that it was reduced [2,7,8] or unchanged [9]. The purpose of the present study was to examine the clinical effects of ibuprofen on the production of the proinflammatory cytokine IL-6 and CRP in preterm septic newborns.
A total of 121 preterm newborns under 1250 g and 32 weeks of gestational age who were followed in our tertiary NICU between January 2010 and March 2011 were enrolled in the study. The main inclusion criteria were elevation of acute phase reactants such as IL-6 and CRP. Depending on our clinical protocol, we evaluate complete blood count and acute phase reactants of all inpatients of NICU at 6th hours of hospitalization, and begin prophylactic antibiotics to all patients who are b32 gestational week and b1250 g, preferably as Penicillin G and Netilmicin. If there is a suspicious or proven sepsis that does not respond to those therapy, we perform antibiotic changing according to culture results or clinical and laboratory status of the patient. Routine echocardiographic evaluation is performed to all patients below 32 gestational week and 1250 g between 72 and 96th hours of life. If echocardiography reveals one of the following criteria of a duct size N1.5 mm: a left atrium-to-aorta ratio N1.5, left-to-right shunting of blood, end-diastolic reversal of blood flow in the aorta, or poor cardiac function in addition to signs of PDA, medical therapy is performed. Ibuprofen is preferred for closure of PDA in our clinic because of lower side effects compared to indomethacin, and usually oral form is administered [1]. Exclusion criteria for PDA treatment are major congenital anomalies, right to left ductal shunting, life-threatening infections, urine output less than 1 mL/kg/h, serum creatinine level N1.6 mg/dL, platelet count b60,000/mm3, hyperbilirubinemia requiring exchange transfusion and grade 3 or 4 intraventricular hemorrhage. All enrolled patients in present
⁎ Corresponding author at: Zekai Tahir Burak Maternity Teaching Hospital, Division of Neonatology, Ankara, Turkey. Tel.: +90 3123065270. E-mail address: [email protected] (G. Demirel). 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.07.021
196
G. Demirel et al. / Early Human Development 88 (2012) 195–196
Table 1 Main characteristics and comparison of study groups. Preterm infants with sepsis, n = 89
Gestational age, week Birthweight, g CRP level at the time of diagnosis, mg/dL (CRP1) IL-6 level at the time of diagnosis (IL6-1) CRP level at the 2nd or 3rd days of diagnosis, mg/dL (CRP2) IL-6 level at the 2nd or 3rd days of diagnosis (IL6-2) CRP level at the 4th or 5th days of diagnosis, mg/dL (CRP3) IL-6 level at the 4th or 5th days of diagnosis (IL6-3) CRP level at the 7th or 10th days of diagnosis, mg/dL (CRP4) IL-6 level at the 7th or 10th days of diagnosis (IL6-4)
p values
PDA and ibuprofen received, n = 51
Non-PDA, n = 38
27.9 ± 1.8 1040 ± 280 16 ± 9.1 124 ± 82 14.3 ± 7.7 83 ± 46 6.03 ± 3.8 42 ± 33.1 2.3 ± 3.2 16.1 ± 12.4
28.2 ± 1.9 1084 ± 305 16.4 ± 13.2 119 ± 73 13.7 ± 5.9 86 ± 37 9.1 ± 4.9 58.9 ± 27.1 4.1 ± 2.3 21.3 ± 16.8
0.289 0.301 0.43 0.517 0.21 0.29 0.025⁎ 0.011⁎ 0.032⁎ 0.016⁎
PDA, patent ductus arteriosus; CRP, C-reactive protein; IL-6, interleukin-6. p b 0.05 considered significant, values are given as mean ± standard deviation. ⁎ Statistically significant.
study received oral ibuprofen (Pedifen, Atafarm, Istanbul, Turkey) at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48th hours. First evaluation for sepsis was done by complete blood count, blood culture, CRP and IL6 levels. This first values were named as CRP1 and IL6-1, respectively. If infants had CRP and IL6 on second or third days after the diagnosis, these parameters were classified as CRP2 and IL6-2. The classification continued as CRP3 and IL6-3 for 4th or 5th days and CRP4 and IL6-4 for 7th to 10th days of the treatment. We evaluated the levels of CRP and IL-6 before and after antibiotic treatment and divided the patients into two groups according to receiving ibuprofen for closure of PDA or not. Thirty two of these infants were excluded because of early death, missing data, congenital anomalies and additional surgical interventions which may affect CRP and IL-6 levels. Remaining 89 infants with sepsis were included in the study.
improve survival. Ibuprofen may decrease the levels of proinflammatory cytokines such as IL-1 and IL-6 and inflammatory parameters such as CRP because of its anti-inflammatory property [3]. Ibuprofen is widely used for PDA treatment in neonates and to the best of our knowledge, there is no report about the course of acute phase reactants of septic neonates after the ibuprofen treatment. In this study, we observed that sepsis parameters in preterm infants decreased by ibuprofen independently from antibiotic therapy. Our results indicate that this decrease should be considered at the time of caring a preterm infant with both sepsis and PDA after ibuprofen treatment. PDA can develop during the treatment of sepsis or both diseases may be observed in most preterm infants at the same time. Sepsis parameters (IL-6 and CRP) may decrease more in infants receiving ibuprofen in comparison to the ones who do not receive ibuprofen treatment. We conclude that this inconsequential but practicable data may be useful for clinicians who care preterm infants with sepsis and PDA.
3. Statistical analysis SPSS 17.0 was used for the analysis of data. T-test was used for statistical analysis.
Conflict of interest statement We have no conflict of interests.
4. Results CRP and IL-6 levels at the first day of life were not different between two groups (p N 0.05). Similarly, those acute phase reactants at the second or third days of the treatment (CRP2, IL6-2) were statistically insignificant between the groups. However, these parameters differed statistically between groups in the following days, presumably due to ibuprofen treatment. Main characteristics and mean CRP and IL-6 levels of study groups are summarized in Table 1. 5. Discussion PDA and sepsis are two main diseases in preterm neonates and ibuprofen has become one of the main drugs for PDA management [1]. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) working by inhibiting the enzyme cyclooxgenase (COX), which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2 is converted to several other prostaglandins that are mediators of pain, inflammation, and fever and to thromboxane A2 which stimulates platelet aggregation, leading to the formation of blood clots. NSAIDs, particularly ibuprofen have been used in the treatment of sepsis and have been shown to restore the normal hemodynamic pattern [10]. Coran et al. [11] showed that the administration of ibuprofen in septic shock in dogs did not reduce cytokine levels whereas Bernard et al. [3] reported that in patients with sepsis, treatment with ibuprofen reduced levels of prostacyclin and thromboxane and decreased fever, tachycardia, oxygen consumption and lactic acidosis but did not
References [1] Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr 2011;158:549–54. [2] Leeper-Woodford SK, Carey D, Byrne K, Walsh C, Fisher B, Sugerman HY, et al. Histamine receptor antagonists, cyclooxygenase blockade, and tumor necrosis factor during septic insult. Shock 1998;9:89–94. [3] Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis: The Ibuprofen in Sepsis Study Group. N Engl J Med 1997;336:912–8. [4] Celik IH, Demirel FG, Uras N, Oguz SS, Erdeve O, Biyikli Z, et al. What are the cut-off levels for IL-6 and CRP in neonatal sepsis? J Clin Lab Anal 2010;24:407–12. [5] Endres S, Whitaker RE, Ghorbani R, Meydani SN, Dinarello CA. Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and tumor necrosis factor-alpha ex vivo. Immunology 1996;87:264–70. [6] Mansilla-Rosello A, Ferron-Orihuela JA, Ruiz-Cabello F, Garrote-Lara D, FernandezMondejar E, Delgado-Carrasco ML. Differential effects of IL-1 beta and ibuprofen after endotoxic challenge in mice. J Surg Res 1997;67:199–204. [7] Qui HB, Pan JQ, Zhao YG, Chen DC. Effect of dexamethasone and ibuprofen on LPSinduced gene expression of TNF-, IL-1β and MIP-1 in rat lung. Chung Kuo Yao Li Hsueh Pao 1997;18:165–8. [8] Stuhlmeier KM, Li H, Kao JJ. Ibuprofen: new explanation for old phenomenon. Biochem Pharmacol 1999;57:313–20. [9] Mancuso G, Cusumano V, Cook JA, Smith E, Squadrito F, Blandino G, et al. Efficacy of tumor necrosis factor alpha and eicosanoid inhibitors in experimental models of neonatal sepsis. FEMS Immunol Med Microbiol 1994;9:49–54. [10] Fink MP, MacVittie TJ, Casey LC. Inhibition of prostaglandin synthesis restores normal hemodynamics in canine hyperdynamic sepsis. Ann Surg 1984;200(5): 619–26. [11] Coran AG, Drongowski RA, Paik JJ, Remick DG. Ibuprofen intervention in canine septic shock: reduction of pathophysiology without decreased cytokines. J Surg Res 1992;53(3):272–9.