Steroid Pretreatment Research Articles

Steroid Pretreatment of Deceased Donors Does Not Prevent Postischemic Acute Renal Failure

Steroid Pretreatment of Deceased Donors Does Not Prevent Postischemic Acute Renal Failure

Acute lymphoblastic leukemia masquerading as juvenile rheumatoid arthritis: no association with survival

Dear Editor, We read with interest the article by Marwaha and colleagues describing children with acute lymphoblastic leukemia (ALL) whose initial presentation mimics that of juvenile rheumatoid arthritis, or JRA [1]. This study provides a timely update on the subject, given the frequency with which osteoarticular manifestations are present at ALL diagnosis and the lack of previously published large studies exploring this topic. However, we have some reservations regarding the potentially misleading conclusion derived from the outcome data in patients with JRA-like disease, as measured by overall survival (OS). The authors state that ‘the 5 year OS was better than other patients with ALL (p=0.06, by log rank test)’ and as a result of this statement, conclude that ‘children with ALL mimicking JRA may belong to a subgroup of ALL with a better prognosis’. There is no evidence from the data provided to support these comments. Firstly, in the Materials and methods section, the article states that, for OS, ‘a p-value of <0.05 was taken as significant’. At 5 years, the OS was not significantly different, based on the authors’ own stated significance thresholds, and although only small numbers of patients are involved at later follow-up, the two Kaplan– Meier plots subsequently cross. Secondly, it remains a concern that children with ALL whose disease mimics JRA may initially receive prolonged non-steroidal antiinflammatory drugs (NSAIDs) and even cytotoxic agents such as steroids or methotrexate before the correct diagnosis is finally made [2]. There is some evidence to suggest that children who receive steroid pre-treatment for conditions including arthritis, prior to the correct diagnosis of ALL being established, have adverse outcomes [3]. In this series, although 32 of the 49 patients with ALL mimicking JRA received NSAIDs, only three (6%) received steroids and none were reported to have received other cytotoxic agents. This lack of pre-treatment may well explain why no difference in outcome was seen when this group was compared with those presenting without JRA. Finally, a number of features have been identified in these patients which are atypical for JRA, such as night pain which wakes the child from sleep [1, 2]. We advocate the continued policy of exclusion of leukemia by bone marrow examination in presumed cases of JRAwhere such atypical features exist [2]. In summary, the article by Marwaha and colleagues provides a useful insight into many of the clinico-pathological associations with this variant of childhood ALL. However, there is no difference in 5 year OS in JRA-mimicking leukemic patients, in whom only 6% have received prior cytotoxic agents. There is no evidence that these children belong to any ‘favorable’ subgroup and, furthermore, no evidence to refute the possibility that such cases, when pretreated with steroids or methotrexate, have a worse outcome. We suggest a high index of suspicion is maintained in such cases and that further biological studies are warranted to explore this specific presentation of childhood ALL in more detail.

Impaired metabolism in donor kidney grafts after steroid pretreatment

Summary We recently showed in a randomized control trial that steroid pretreatment of the deceased organ donor suppressed inflammation in the transplant organ but did not reduce the rate or duration of delayed graft function (DGF). This study sought to elucidate such of those factors that caused DGF in the steroid-treated subjects. Genome-wide gene expression profiles were used from 20 steroid-pretreated donor-organs and were analyzed on the level of regulatory protein-protein interaction networks. Significance analysis of microarrays (SAM) yielded 63 significantly down-regulated sequences associated with DGF that could be functionally categorized according to Protein ANalysis THrough Evolutionary Relationships ontologies into two main biologic processes: transport (P < 0.001) and metabolism (P < 0.001). The identified genes suggest hypoxia as the cause of DGF, which cannot be counterbalanced by steroid treatment. Our data showed that molecular pathways affected by ischemia such as transport and metabolism are associated with DGF. Potential interventional targeted therapy based on these findings includes peroxisome proliferator-activated receptor agonists or caspase inhibitors.

Mediastinal masses masquerading as common respiratory conditions of childhood: a case series

Leukaemia and lymphoma may present with symptoms and signs mimicking common respiratory conditions of childhood such as asthma or croup. The UK National Institute for Clinical Excellence guidelines for referral for suspected cancer state that "the primary healthcare professional should be ready to review the initial diagnosis in patients in whom common symptoms do not resolve as expected" and "must be alert to the possibility of cancer when confronted by unusual symptom patterns" (National Institute for Health and Clinical Excellence, 2005). A child with an undiagnosed mediastinal mass presenting with signs and symptoms suggestive of asthma or croup may be given oral systemic steroids. We report four such illustrative cases presenting to a single institution within the last 3 years. We highlight key points from the history and examination findings which should lead to review of the original diagnosis, the benefit of early chest X-ray in such cases and the dangers of steroid pretreatment.

Invited commentary

In this randomized prospective trial, Dr Angiletta and colleagues have shown that perioperative Dexamethasone (DEX) administration reduces the incidence of clinically apparent, temporary, carotid endarterectomy (CEA) associated cranial nerve (CN) dysfunction from 5.7% to 2.3% (P = .009). This benefit was achieved with no adverse effects attributable to the steroid. Interestingly, DEX administration had no effect on the incidence of permanent CN dysfunction in this study. The authors'conclusion that temporary CN dysfunction is often related to operative trauma induced perineural inflammation, which is mitigated by DEX treatment, is both novel and plausible. That DEX administration has no effect on the incidence of permanent CN dysfunction suggests that such injuries are the result of direct nerve trauma (transection or crush) not ameliorated by steroid pre-treatment. Two questions regarding the role of steroids in cranial nerve dysfunction remain unanswered by this study. First, in formulating their hypothesis and experimental design, the authors were influenced by the previously well-described beneficial effects of steroids in spinal cord injury patients. Their conviction that steroids were likely to be beneficial led the authors to a study design mandating postoperative steroid administration to all patients who showed signs of postoperative CN dysfunction. Since all patients with postoperative CN dysfunction were treated with steroids, the influence of postoperative steroids on recovery rate or in converting potentially permanent dysfunction to temporary dysfunction cannot be determined. Perhaps a better design would have included a secondary randomization of those with postoperative CN dysfunction to either no additional treatment or a 1-week course of DEX. Alternatively, the authors might now initiate a follow-up study testing the effects of postoperative DEX on recovery in patients with post-CEA CN dysfunction. However, given the low incidence of CEA-associated CN dysfunction, the number of subjects required to achieve a statistically robust study would be prohibitive in a single institution study. Second, the optimal dose and dosing regimen cannot be determined from this study. It is possible that a single lower pre-incisional steroid dose might be just as effective as the authors' regimen of six doses of 8 mg of DEX (1 hour prior to CEA, 6 and 12 hours post-CEA, every 12 hours on postoperative day #1, and once on the morning of postoperative day #2). This interesting and provocative study shows that the incidence of CEA-associated CN dysfunction can be markedly reduced with steroid pre-treatment with no adverse effects. Confirmatory studies elucidating the influence of postoperative steroids on the course of CN dysfunction and establishing the most practical and effective dosing regimen are now required. Dexamethasone minimizes the risk of cranial nerve injury during CEAJournal of Vascular SurgeryVol. 49Issue 1PreviewThe incidence of cranial and cervical nerve injury during carotid endarterectomy (CEA) ranges from less than 7.6% to more than 50%. Lesions are mainly due to surgical maneuvers such as traction, compression, tissue electrocoagulation, clamping, and extensive dissections. The use of dexamethasone (DEX) and its beneficial effects in spinal cord injuries have already been described. We investigated whether DEX could also be beneficial to minimize the incidence of cranial and cervical nerve injury during CEA. Full-Text PDF Open Archive

Lenalidomide Associated Tumor Flare Reaction Correlates with Clinical Response in Patients with Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia

INTRODUCTION: We have previously reported that in patients with B-CLL, lenalidomide induces a tumor flare reaction (TFR) that is clinically characterized by painful, tender enlargement of disease involved lymph nodes, spleen and/or liver along with low grade fever. The underlying mechanism as well as the impact of TFR on treatment outcomes remains unknown. We analyzed data from our phase II clinical trial in which the clinical efficacy of lenalidomide alone was investigated in patients with relapsed or refractory B-CLL and correlated the severity of TFR with clinical efficacy.METHODS: Forty five patients with relapsed refractory CLL, enrolled in a phase II study were divided into two groups; group A consisted of first 29 patients who were treated with 25 mg of lenalidomide for 21 days of a 28 day cycle without any prophylaxis for tumor flare reaction, group B consisted of subsequent 16 patients who received 10 mg per day of lenalidomide initially with subsequent escalations of 5 mg every 1–2 weeks to a maximum dose of 25 mg along-prednisone prophylaxis (20 mg/day for 5 days followed by 10 mg/day for 5 days) was given to this group during cycle 1 only.RESULTS: Thirty of the 45 patients (67%) developed clinically significant TFR. Of these 20 (67%) were grade I, 7 (23%) grade II and 3 (10%) grade III. The median time to TFR was 6 days (range 0–56 days). The median time to resolution was 14 days (95% CI: 10–26 days). In over 90% of cases flare occurred only during first treatment cycle. Median age for those who either developed or did not develop flare reaction was 61 and 71 years respectively (p=0.004, 2-sided, Wilcoxon test). Nineteen patients (66%) in group A and 11 (69%) in group B developed TFR. Grade II/III flare was observed in 9 (47%) and 1 (9%) patients in group A and B, respectively (p=0.05). The median time to onset of TFR was 4 days in group A and 9 days in group B (p=0.01). The median duration of TFR was 13 and 28 days in groups A and B respectively (p=0.16). A total of 8 patients achieved molecular complete remission (mCR). All but 1 patient who achieved mCR had a flare reaction (p=0.24). The median progression free survival of patients with or without TFR was 19.9 and 19.4 months, respectively. There was a trend to improvement of progression free survival in group A patients compared to group B patients, 23 vs. 17.8 months, respectively (p=0.74, log rank test), however, this difference did not reach statistical significance. TFR reaction was managed by non-steroidal anti-inflammatory agent with or without oral morphine. Eleven of the 30 patients with TFR required treatment and only 3 patients received supplemental morphine. None of patient required discontinuation of lenalidomide for TFR.CONCLUSION: Although the mechanism of TFR remains to be determined clinically it appears to be an immunologically mediated phenomenon that is uniquely seen in CLL patients. We observe that the occurrence and severity of TFR appears to correlate with clinical response to lenalidomide. Steroid prophylaxis decreases the severity but not the incidence of TFR. The effect on overall efficacy of steroid pre-treatment for prevention of TFR remains to be determined in larger cohort of patients.

Cytokines Induce an Early Steroid Resistance in Airway Smooth Muscle Cells

We have previously shown that long-term treatment of airway smooth muscle (ASM) cells with a combination of TNF-alpha and IFN-gamma impaired steroid anti-inflammatory action through the up-regulation of glucocorticoid receptor beta isoform (GRbeta) (Mol Pharmacol 2006;69:588-596). We here found that steroid actions could also be suppressed by short-term exposure of ASM cells to TNF-alpha and IFN-gamma (6 h) as shown by the abrogated glucocorticoid responsive element (GRE)-dependent gene transcription; surprisingly, neither GRalpha nuclear translocation nor GRbeta expression was affected by cytokine mixture. The earlier induction of CD38, a molecule recently involved in asthma, seen with TNF-alpha and IFN-gamma combination but not with cytokine alone, was also completely insensitive to steroid pretreatment. Chromatin-immunoprecipitation (IP) and siRNA strategies revealed not only increased binding of interferon regulatory factor 1 (IRF-1) transcription factor to CD38 promoter, but also its implication in regulating CD38 gene transcription. Interestingly, the capacity of fluticasone to completely inhibit TNF-alpha-induced IRF-1 expression, IRF-1 DNA binding, and transactivation activities was completely lost in cells exposed to TNF-alpha and IFN-gamma in combination. This early steroid dysfunction seen with cytokine combination could be reproduced by enhancing IRF-1 cellular levels using constitutively active IRF-1, which dose-dependently inhibited GRE-dependent gene transcription. Consistently, reducing IRF-1 cellular levels using siRNA approach significantly restored steroid transactivation activities. Collectively, our findings demonstrate for the first time that IRF-1 is a novel alternative GRbeta-independent mechanism mediating steroid dysfunction induced by pro-asthmatic cytokines, in part via the suppression of GRalpha activities.

Differential Effects of Dexamethasone on the Proximal and Distal Lung Response to Antigen Challenge in Allergic Cynomolgus Monkeys

The proximal and distal portions of the lungs may respond differently to antigen challenge and bronchodilator treatment. This difference may contribute to differences in actual and perceived efficacy of therapies. In this study we used the forced oscillation technique (FOT) to measure impedance in the pulmonary system and discern the effects of antigen challenge on proximal (large airway) and distal (small airway and lung parenchyma) portions of the lung. In addition we treated the animals with two i.m. injections of either a saline control or dexamethasone (0.5 mg/kg) 18 and 1 hour(s) before the antigen challenge. The FOT technique was used to measure indices of proximal airway status, Newtonian airway resistance (RN), and distal airway status, including tissue damping (G) and tissue elastance (H). Challenging the animals with Ascaris Suum antigen caused a significant increase in both the proximal and distal lung measures. Pretreatment with dexamethasone significantly reduced the peak increase in RN but not G or H. In addition, the area under the curve (AUC) of the FOT response over 60 minutes was significantly reduced for the RN but again, G and H were not significantly reduced. These data indicate that, using the FOT, we can dissociate the response of proximal and distal airways to an antigen challenge. Moreover, steroid pre-treatment can reduce the bronchoconstrictor response to inhaled antigen but this effect is primarily via effects on the proximal airways with little effect on the distal airways and parenchymal component of pulmonary impedance. These data may help to provide a mechanism for evaluation of novel therapies for small airway dysfunction.

Prospective randomized study of the benefits of preoperative corticosteroid administration on hepatic ischemia-reperfusion injury and cytokine response in patients undergoing hepatic resection

Background. Hepatic injury secondary to warm ischemia and reperfusion (I/R) remains an important clinical issue following liver surgery. The aim of this prospective, randomized study was to determine whether steroid administration may reduce liver injury and improve short-term outcome. Patients and methods. Forty-three patients undergoing liver resection were randomized to a steroid group or a control group. Patients in the steroid group received 500mg of methylprednisolone preoperatively. Serum levels of alanine aminotransferase (ALT), aspartate amminotransferase (AST), total bilirubin, anti-thrombin III (AT-III), prothrombin time (PT), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) were compared between the two groups. Length of stay and type and number of complications were recorded. Results. Postoperative serum levels of ALT, AST, total bilirubin, and inflammatory cytokines were significantly lower in the steroid group than in controls. The postoperative level of AT-III in the control group was significantly lower than in the steroid group (ANOVA p < 0.01). The incidence of postoperative complications in the control group tended to be significantly higher than that in the steroid group. Conclusion. These results suggest that steroid pretreatment represents a potentially important biologic modifier of I/R injury and may contribute to maintenance of coagulant/anticoagulant homeostasis.

Steroids in meningitis Part B: Clinical commentary

Steroids in meningitis Part B: Clinical commentary

A New Method To Evaluate the Prognostic Value of Response to Prednisone Pre-Treatment in Adult (15–60 Yrs) Patients with Acute Lymphoblastic Leukemia: Results of the GIMEMA LAL 2000 Study.

The prognostic significance of the response to initial prednisone treatment in adult ALL has been recently emphasized. Prednisone response is usually defined on the basis of the peripheral leukemic blast count. The threshold value for the defintion as good or poor prednisone response is 1000 blasts/mmc on day 8 of prednisone pre-treatment. The drawback of this definition is the difficulty of classifying patients with less than 1000 blasts at diagnosis. In the LAL2000 GIMEMA study we therefore evaluated whether the blast reduction rate, which is not affected by the initial blast level, could be a factor with comparable prognostic value. The protocol design provided a 7-day (−6 to 0) pre-treatment phase with an escalating dose of prednisone up to 60 mg/sqm. On day 1 before starting the induction the response was assessed both according to the absolute blast count (< versus ≥ 1000/mmc) (criterion 1) and according to the blast reduction rate ≥ 75% (criterion 2) in the peripheral blood. The induction included high dose Daunorubicin; for patients in complete remission (CR) this was followed by consolidation with high dose ARA-C, chemo and radio prophylaxis of the central nervous system, and periodical reinduction over a three years maintenance period. Patients with adverse cytogenetic features [i.e. t(9;22), t(4;11), t(1;19)] who achieved a CR were treated according to the HAM protocol that included high dose ARA-C and Mitoxantrone followed by Imatinib for Ph+ ALL and by allogeneic or autologous hemopoietic stem cells transplantation for the others. Between September 2000 and December 2003 a total of 368 patients were evaluable for response to induction. The median age was 35 years (15–60) and median WBC count 15′109/L (0.3–872); 72 (20%) were T ALL and 121 (33%) had cytogenetic high risk features (104 (86%) Ph+, 4 (3%) t(4;11) and 13 (11%) t(1;19)). Eighty-seven percent of the patients were evaluable for response to steroid pre-treatment: 'responders' were 75% according to criterion 1 (blast <1′109/L on day 0), and 80% according to criterion 2 (blast reduction rate ≤75% on day 0). The overall CR rate was 83%. The probability of response was significantly higher in prednisone responders with respect to non responders according to both criteria: 87% versus 63% (p<0.0001) according to criterion 1, 85% versus 68% (p=0.001) according to criterion 2. Also the post CR outcome was better in steroid responders, regardless of the definition. Using criterion 1, median disease-free survival (DFS) was 24 months in responders and 11 months in non responders; using criterion 2, median DFS was 23 months in responders and 12 months in non responders. Both criteria were significantly related to DFS in a multivariate analysis adjusted for cytogenetic risk and WBC count at diagnosis (>=/<50). In conclusion, our study confirms that the sensitivity to steroids is an independent prognostic factor for the outcome of adult ALL; moreover, we propose an alternative method of its evaluation with respect to the one currently used. This method has the advantage of allowing to classify all patients, regardless of the initial blasts level, and shows a comparable prognostic value.

ASGE Technology Status Evaluation Report: radiographic contrast media used in ERCP

ASGE Technology Status Evaluation Report: radiographic contrast media used in ERCP

Neuroactive steroids protect retinal pigment epithelium against oxidative stress

This study was undertaken to assess whether neuroactive steroids, 17beta-estradiol and dehydroepiandrosterone-sulfate, enhance survival and protect DNA of human retinal pigment epithelial cells challenged by oxidative stress, and to investigate the role of sigma1 receptors in the effects of neuroactive steroids. Retinal pigment epithelial cells were treated with various concentrations of neuroactive steroids and then exposed to hydrogen peroxide. Pretreatment with steroids resulted in significant increased viability in a dose-related manner. DNA damage induced by oxidative insult was significantly lower with steroid pretreatment. The effects of 17beta-estradiol and dehydroepiandrosterone-sulfate were antagonized by pretreatment with a sigma1 receptor antagonist. The results suggest that neuroactive steroids protect retinal cells from oxidative stress, and that this effect is mediated by sigma1 receptors.

Pilot Study of Rapid Steroid Elimination With Alemtuzumab Induction Therapy in Kidney and Pancreas Transplantation

This study evaluates our initial experience using alemtuzumab induction with rapid corticosteroid elimination in kidney (KTX) and pancreas transplant (PTX) patients. Data were collected retrospectively for all patients who received single-dose alemtuzumab (30 mg IV intraoperatively) with steroid pretreatment and a control group who received alternate day rabbit antithymocyte globulin (rATG) induction with a steroid-based regimen. Patients in both groups received tacrolimus (TAC) and mycophenolate mofetil (MMF). There were 16 patients in each group, including 9 deceased donor KTXs, 5 living donor KTXs, 1 simultaneous K-PTX, and 1 sequential PTX after KTX. Demographic, immunologic, and transplant characteristics were similar between groups. Nine patients (56%) in the alemtuzumab group compared to five (25%) in the control group developed neutropenia requiring MMF or valganciclovir dose reduction (or both). Absolute lymphocyte counts at 3 months were 340 ± 200/mm 3 and 890 ± 544/ mm 3 in the alemtuzumab and control groups, respectively ( P = .001). There were two biopsy-proven acute rejection episodes (12.5%) in each group, and no difference in the incidence of infection. Creatinine clearance at 6 months was 58 mL/min in each group. Patient and kidney graft survival rates were both 94% in the alemtuzumab group (one death from cardiac arrest), compared with 100% patient and kidney graft survival rates in the control group ( P = NS), with a mean follow-up of 9 and 11 months, respectively. The results of this pilot study suggest that similar short-term outcomes can be achieved using a rapid steroid elimination protocol with alemtuzumab induction therapy compared to rATG with steroids in patients receiving TAC and MMF maintenance therapy.

Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a major inflammatory disease of the premature human intestine that can be prevented by glucocorticoids if given prenatally before the 34th wk of gestation. This observation suggests that a finite period of steroid responsiveness exists as has been demonstrated in animal models. Human intestinal xenografts were used to determine whether a glucocorticoid responsive period exists in the developing human intestine. Developmental responsiveness was measured by lactase activity and inflammatory responsiveness by IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1) induction after an endogenous (IL-1 beta) or exogenous (LPS) proinflammatory stimulus, respectively. Functional development of ileal xenografts were monitored for 30 wk posttransplantation, and the lactase activity recapitulated that predicted by in utero development. Cortisone acetate accelerated the ontogeny of lactase at 20 wk (immature) but the effect was lost by 30 wk (mature) posttransplant. Concomitant with accelerated maturation, the IL-8 response to both IL-1 beta and LPS was significantly dampened (from 6- to 3-fold) by glucocorticoid pretreatment in the immature but not mature xenografts. The induction of IL-8 was reflected at the level of IL-8 mRNA, suggesting transcriptional regulation. The excessive activation of IL-8 in the immature gut was mediated by a prolonged activation of ERK and p38 kinases and nuclear translocation of NF-kappa B due to low levels of I kappa B. Steroid pretreatment in immature intestine dampens activation of all three signaling pathways in response to proinflammatory stimuli. Therefore, accelerating intestinal maturation by glucocorticoids within the responsive period by accelerating functional and inflammatory maturation may provide an effective preventive therapy for NEC.

Successful intrathecal administration of methotrexate following a prior adverse reaction to intravenous methotrexate

Rationale Adverse reactions to methotrexate are increasingly common and represent potential barriers to treatment options for oncologic diseases. There are no reports in the literature addressing intrathecal administration of methotrexate following adverse reactions to intravenous methotrexate. Methods A 6 year old, male patient developed hives and pruritus after intravenous infusion of 2 gm of methotrexate for Acute Lymphoblastic Leukemia as well as concomitant morphine infusion. Skin testing to methotrexate (skin prick 1 mg/ml, 10 mg/ml, intradermal 0.1 mg/ml, 1 mg/ml, 10 mg/ml) was negative. The patient required treatment with intrathecal methotrexate. Since the safety of intrathecal administration of methotrexate following desensitization is unknown, further assessment of the patient's sensitivity to methotrexate was determined by graded challenge (10% dose followed by 90% dose) in the Intensive Care Unit. Following two successful intravenous infusions, methotrexate was infused intrathecally, first with steroid pretreatment, then without steroid pretreatment. Results The patient tolerated the graded challenge to methotrexate and subsequent full dose infusions of methotrexate without complications, indicating no hypersensitivity to methotrexate. Methotrexate was subsequently administered intrathecally with steroid pretreatment followed by subsequent intrathecal infusions without steroid pretreatment. No adverse events occurred. Conclusions A combination of history, skin testing, and graded challenge may be utilized to elucidate the nature of adverse reactions to methotrexate. This information may help determinine the safety of future treatment options with methotrexate, including intrathecal administration.

ABI 007.

ABI 007.

Inflammatory response to cardiac bypass in ewe fetuses: effects of steroid administration or continuous hemodiafiltration

Objectives We sought to investigate the effectiveness of glucocorticoid administration or continuous venovenous hemodiafiltration on endothelin and corticotropin-releasing factor release or clearance during prolonged fetal cardiac bypass and on the overall performance of fetuses. Methods Circulating endothelin 1, 2, and 3 and corticotropin-releasing factor levels were measured in fetal ewes during a 60-minute cardiac bypass period performed with an inline axial flow pump. Blood samples were collected before, during, and 90 minutes after cardiac bypass. Animals were divided into 4 groups. The betamethasone group (n = 6) received maternal treatment with 12 mg of betamethasone 1 and 2 days before the experiment. The methylprednisolone group (n = 5) received fetal treatment with 40 mg/kg intravenous methylprednisolone at the beginning of cardiac bypass. The continuous venovenous hemodiafiltration group (n = 4) underwent continuous venovenous hemodiafiltration with a 0.3-m 2 polysulfone filter during cardiac bypass. The final group was the control group (n = 4). Results Maternal steroid pretreatment failed to decrease endothelin or corticotropin-releasing factor production when compared with levels in the control animals. Fetal treatment with methylprednisolone produced a significant decrease in endothelin 2 production during cardiac bypass ( P < .02) and endothelin 1 production at the end of the experiment ( P < .02). Continuous venovenous hemodiafiltration blocked completely the increase of endothelin and corticotropin-releasing factor levels during cardiac bypass ( P < .02), which was maintained 90 minutes after cardiac bypass. Acid-base balance was preserved during cardiac bypass by the continuous venovenous hemodiafiltration but worsened after disconnection of the extracorporeal circuit, whereas animals treated with methylprednisolone had better pH, Pa co 2, and bicarbonate levels by the end of the experiment. The overall tolerance of the procedure was better in the continuous venovenous hemodiafiltration group during cardiac bypass and in the methylprednisolone group at the end of the experiment. Conclusions Continuous venovenous hemodiafiltration provides sustained stability of endothelin levels during fetal cardiac bypass. This technique might help, in association with fetal steroid treatment, to contain the inflammatory response leading to postbypass placental dysfunction.

Timing of steroid treatment is important for cerebral protection during cardiopulmonary bypass and circulatory arrest: minimal protection of pump prime methylprednisolone.

The contact of cardiopulmonary bypass surface and patient's blood activates systemic inflammatory response which aggravates ischemia-reperfusion injury. This study evaluates the effects of cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) on cerebral protection using different steroid administration protocols. Eighteen (n=6/group) 4 week-old piglets were divided in three groups. Methylprednisolone (30 mg/kg) was administered intravenously 4 h prior to CPB in Group I, or added in pump prime in group II. Group III received no steroid. All animals were cooled to 15 degrees C followed by 100 min of DHCA, then rewarmed over 40 min and sacrificed 6 h after CPB. Post-operative weight gain, bioelectrical impedance, colloid oncotic pressure (COP) and interleukin-6 (IL-6) were evaluated. Determination of cerebral trypan blue and immunohistochemical assays of transforming growth factor (TGF)-beta1 and caspase-3 activities were performed. Post-operative % weight gain (13.0+/-3.8 (I) versus 26.4+/-9.9 (II) versus 22.6+/-6.4 (III), P=0.02); % bioimpedance reduction (14.5+/-8.0 (I) versus 38.3+/-13.3 (II) versus 30.5+/-8.0 (III), P=0.003); mean COP (mmHg) (14.9+/-1.8 (I) versus 10.9+/-2.0 (II) versus 6.5+/-1.8 (III), P=0.0001) and systemic IL-6 levels (pg/ml) (208.2+/-353.0 (I) versus 1562.1+/-1111.4 (II) versus 1712.3+/-533.2 (III), P=0.01) were significantly different between the groups. Spectrophotometric analysis of cerebral trypan blue (ng/g dry weight) was significantly different between the groups (0.0053+/-0.0010 (I) versus 0.0096+/-0.0026 (II) versus 0.0090+/-0.0019 (III), P=0.004). TGF-beta1 scores were 3.3+/-0.8 (I) versus 1.5+/-0.8 (II) versus 1.5+/-0.5 (III), P<0.05, groups I versus II and I versus III. Remarkable perivascular caspase-3 activity was observed in groups II and III. Different timing of steroid administration results in different inflammatory mediator response. Steroid in CPB prime is not significantly better than no steroid treatment, while systemic steroid pre-treatment significantly decreases systemic manifestation of inflammatory response and brain damage.

Myocardial and lung injury after cardiopulmonary bypass: role of interleukin (IL)-10

Background Proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-8 play a key role in the inflammatory cascade after cardiopulmonary bypass (CPB) and may induce cardiac and lung dysfunction. Antiinflammatory cytokines such as IL-10 may also significantly limit these complications. Corticosteroid administration before CPB increases blood IL-10 levels and prevents proinflammatory cytokine release. This study examined the association of increased release of IL-10, stimulated by steroid pretreatment, with reduced myocardial and lung injury after CPB. Methods Twenty patients undergoing coronary artery bypass grafting (CABG) received either preoperative steroid (n = 10, protocol group) or no steroid (n = 10, control group). Perioperative care was standardized, and all caregivers were blinded to treatment group. Seven intervals of blood samples were obtained and assayed for TNF-α, IL-6, IL-8, and IL-10. Various hemodynamic and pulmonary measurements were obtained perioperatively. Levels of MB isoenzyme creatine kinase (CK-MB) were also measured. Results In the protocol group, proinflammatory cytokines were significantly reduced while IL-10 levels were much higher after CPB. The protocol group had a lower alveolar-arterial oxygen gradient and higher ratio of arterial oxygen pressure to fraction of inspired oxygen after CPB. Creatine kinase (CK) and CK-MB were reduced in the patients treated with steroid. Correlations were found between plasma cytokines levels and cardiac index, and CK-MB. Conclusions This study confirms that corticosteroids abolish proinflammatory cytokines release and increase blood IL-10 levels after CPB. Our findings demonstrate a greater release of IL-10 induced by steroid pretreatment, and better heart and lung protection after CPB.