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Dehydroepiandrosterone an Inexpensive Steroid Hormone That Decreases the Mortality Due to Sepsis Following Trauma-Induced Hemorrhage

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Dehydroepiandrosterone an Inexpensive Steroid Hormone That Decreases the Mortality Due to Sepsis Following Trauma-Induced Hemorrhage PAPER Dehydroepiandrosterone An Inexpensive Steroid Hormone That Decreases the Mortality Due to Sepsis Following Trauma-Induced Hemorrhage Martin K. Angele, MD; Robert A. Catania, MD; Alfred Ayala, PhD; William G. Cioffi, MD; Kirby I. Bland, MD; Irshad H. Chaudry, PhD Background: Recent studies suggest that male sex ste- hemorrhage and resuscitation, the animals were killed roids play a role in producing immunodepression follow- and blood, spleens, and peritoneal macrophages were har- ing trauma-hemorrhage. This notion is supported by stud- vested. Splenocyte proliferation and interleukin (IL) 2 ies showing that castration of male mice before trauma- release and splenic and peritoneal macrophage IL-1 and hemorrhage or the administration of the androgen receptor IL-6 release were determined. In a separate set of experi- blocker flutamide following trauma-hemorrhage in non- ments, sepsis was induced by cecal ligation and punc- castrated animals prevents immunodepression and im- ture at 48 hours after trauma-hemorrhage and resusci- proves the survival rate of animals subjected to subse- tation. For those studies, the animals received vehicle, a quent sepsis. However, it remains unknown whether the single 100-µg dose of DHEA, or 100 µg/d DHEA for 3 most abundant steroid hormone, dehydroepiandros- days following hemorrhage and resuscitation. Survival terone (DHEA), protects or depresses immune functions was monitored for 10 days after the induction of sepsis. following trauma-hemorrhage. In this regard, DHEA has been reported to have estrogenic and androgenic proper- Results: Administration of DHEA restored the de- ties, depending on the hormonal milieu. pressed splenocyte and macrophage functions at 24 hours after trauma-hemorrhage. Moreover, daily administra- Objective: To determine whether administration of tion of DHEA for 3 days significantly increased the sur- DHEA after trauma-hemorrhage has any salutary or del- vival of animals subjected to subsequent sepsis (P = .01). eterious effects on immune responses, and whether it im- proves the survival of animals subjected to subsequent Conclusion: The finding that DHEA markedly im- sepsis. proves the depressed immune functions and survival of animals subjected to subsequent sepsis suggests that short- Design: Male C3H/HeN mice underwent laparotomy (ie, term treatment with DHEA after trauma-hemorrhage is trauma-induced) and hemorrhagic shock (blood pres- a safe and novel approach for preventing immunode- sure, 35 ± 5 mm Hg for 90 minutes) followed by fluid pression and for decreasing the mortality rate due to sub- resuscitation, or sham operation. The animals then re- sequent sepsis. ceived 100 mg of DHEA (4 mg/kg) or propylene glycol (hereafter referred to as vehicle). At 24 hours after trauma- Arch Surg. 1998;133:1281-1288 EVERAL STUDIES indicate ies that showed that depletion of testos- that cell-mediated immune terone by castration of male mice before responses are markedly de- trauma-hemorrhage prevents the depres- pressed in male patients fol- sion of splenocyte immune functions.5 lowing trauma and hemor- Alternatively, administration of a testos- Srhagic shock, and that these changes terone receptor antagonist, eg, flu- persist for as long as 10 days after resus- tamide, in normal male animals follow- citation.1,2 Moreover, these depressed im- ing trauma-hemorrhage restores the mune responses have been associated with depressed immune responses and in- an increased susceptibility to and mortal- creases the survival rate of animals sub- ity due to subsequent sepsis.3,4 Recent stud- jected to subsequent sepsis. In contrast to ies have suggested that male sex steroid male mice, female mice in the proestrus From the Center for Surgical hormones play a significant role in pro- state of the estrus cycle demonstrate en- Research and Department of ducing immunodepression following hanced immune responses following 7 Surgery, Brown University trauma-induced hemorrhage (hereafter trauma-hemorrhage. Thus, it appears that School of Medicine, Rhode referred to as trauma-hemorrhage).4-6 Sup- elevated levels of female sex hormones, ie, Island Hospital, Providence. port for this assertion comes from stud- prolactin and estrogen, in the proestrus ARCH SURG/ VOL 133, DEC 1998 1281 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 MATERIALS AND METHODS solution (4 times the shed blood volume for 30 minutes) to provide adequate fluid resuscitation. Lidocaine hydrochloride ANIMALS was applied to the groin incision sites, the catheters were re- moved, the vessels were ligated, and the groin incisions were InbredmaleC3H/HeNmice(CharlesRiverLaboratories,Wilm- closed. Animals undergoing sham operation underwent the ington, Mass), 7 weeks of age (body weight, 24-27 g) were used. same groin dissection, which included ligation of both fem- All procedures were performed in accordance with the guide- oral arteries; however, neither hemorrhage nor fluid resusci- lines set forth in the Animal Welfare Act and the Guide for the tationwasperformed.Nomortalitywasobservedinthistrauma- Care and Use of Laboratory Animals by the National Institutes hemorrhage model. of Health, Bethesda, Md. This project was approved by the In- stitutional Animal Care and Use Committee of Rhode Island CECAL LIGATION AND PUNCTURE Hospital and Brown University, Providence. Polymicrobial sepsis was induced at 48 hours after hemorrhage EXPERIMENTAL GROUPS and resuscitation using the model of CLP described by Baker et al.13 Briefly, mice were lightly anesthetized with methoxy- Male mice were randomized into 4 groups (6-8 mice per flurane, and a 2.0-cm midline incision was made. The cecum group). Mice in groups 3 and 4 were subjected to trauma- was isolated, a 6-0 silk ligature was placed around it, and the hemorrhage, whereas the mice in groups 1 and 2 under- cecum was ligated just below the ileocecal valve. The cecum went the sham procedure. Groups 1 and 3 received 0.1 was then punctured twice with a 22-gauge needle, a small mL subcutaneous propylene glycol injection (hereafter amount of bowel contents was extruded through the punc- referred to as vehicle) following experimental treatment, ture holes, and the cecum was returned to the peritoneal cav- whereas groups 2 and 4 received subcutaneous injection ity. After application of lidocaine (Xylocaine) on the incision of DHEA, 100 µg per mouse (4 mg/kg). This dose of site, the abdominal incision was closed in 2 layers (using 6-0 DHEA has been reported to produce an immunoenhanc- Ethilon sutures). Isotonic sodium chloride solution (20 mL/ ing effect on the depressed immune functions in mice fol- kg body weight) was administered subcutaneously at that time. lowing thermal injury.12 In additional studies, following Previous studies have demonstrated that blood cultures taken trauma-hemorrhage and resuscitation, mice were ran- from rats or mice following CLP are positive for gram-positive domized into 3 groups (15 mice per group) and were sub- (eg,Streptococcus bovis) and gram-negative (eg,Bacteroides fra- jected to subsequent sepsis. Group 1 received vehicle after gilis, Escherichia coli, Klebsiella species, and Proteus mirabilis) resuscitation and again on the first and second postopera- bacteria as early as 1 hour after CLP.13 tive days. Group 2 received a single subcutaneous injec- tion of DHEA, 100 µg, immediately after resuscitation. BLOOD-, TISSUE-, AND CELL-HARVESTING Group 3 was treated with DHEA after resuscitation and PROCEDURES again on the first and second postoperative days. In all experimental groups, polymicrobial sepsis was induced by The animals were killed with methoxyflurane overdose 24 cecal ligation and puncture (CLP) 48 hours after trauma- hours after the completion of the experiment to obtain the hemorrhage and resuscitation. The survival rate was spleen, peritoneal macrophages, and whole blood samples. monitored for up to 10 days after the induction of sepsis. The mice were killed at the same time of the day to avoid fluctuations due to circadian rhythm. TRAUMA-HEMORRHAGE PROCEDURE Whole blood was obtained using cardiac puncture and placed in microcentrifuge tubes (Microtainer; Becton Mice were lightly anesthetized with methoxyflurane (Meto- Dickinson and Co, Rutherford, NJ). The tubes were then fane, Pitman-Moore, Mundelein, Ill) and restrained in a su- centrifuged at 16 000g for 15 minutes at 4°C. Plasma was pine position, and a 2.5-cm midline laparotomy (ie, trauma- separated, placed in pyrogen-free microcentrifuge tubes, induced) was performed. This was then closed aseptically in immediately frozen, and stored (−80°C) until assay. 2layersusingcommerciallyavailablesutures(6-0Ethilon,Ethi- con, Inc, Somerville, NJ). Following this, both femoral arter- DETERMINATION OF PLASMA DHEA LEVELS ies were aseptically cannulated with polyethylene 10 tubing (Clay-Adams,Parsippany,NJ)usingaminimaldissectiontech- Plasma DHEA levels were determined using a commercially nique. Blood pressure was constantly monitored by attaching available radioimmunoassay (Diagnostics Systems Labora- 1 of the catheters to a blood pressure analyzer (Digi-Med, Lou- tory, Webster, Tex) as described by the manufacturer. isville, Ky). On awakening, the animals were bled rapidly through the other catheter to a mean arterial blood pressure PREPARATION OF SPLENOCYTE CULTURE of 35 ± 5 mm Hg (prehemorrhage blood pressure, 95 ± 5mm Hg), which was maintained for 90 minutes. At the endof that The spleens were removed aseptically and placed
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