Emergency surgery during the COVID-19 pandemic: what you need to know for practice.

INTRODUCTION: Several articles have been published about the reorganisation of surgical activity during the COVID-19 pandemic but few, if any, have focused on the impact that this has had on emergency and trauma surgery. Our aim was to review the most current data on COVID-19 to provide essential suggestions on how to manage the acute abdomen during the pandemic. METHODS: A systematic review was conducted of the most relevant English language articles on COVID-19 and surgery published between 15 December 2019 and 30 March 2020. FINDINGS: Access to the operating theatre is almost exclusively restricted to emergencies and oncological procedures. The use of laparoscopy in COVID-19 positive patients should be cautiously considered. The main risk lies in the presence of the virus in the pneumoperitoneum: the aerosol released in the operating theatre could contaminate both staff and the environment. CONCLUSIONS: During the COVID-19 pandemic, all efforts should be deployed in order to evaluate the feasibility of postponing surgery until the patient is no longer considered potentially infectious or at risk of perioperative complications. If surgery is deemed necessary, the emergency surgeon must minimise the risk of exposure to the virus by involving a minimal number of healthcare staff and shortening the occupation of the operating theatre. In case of a lack of security measures to enable safe laparoscopy, open surgery should be considered.

Erratum to: The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections.

[This corrects the article DOI: 10.1186/s13017-017-0141-6.].

Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

Interleukin-6 suppression of neutrophil apoptosis is neutrophil concentration dependent.

Apoptosis of polymorphonuclear leukocytes (PMNs) is a critical step in the resolution of tissue inflammation. PMN apoptosis has been studied extensively in vitro, and diverse inflammatory mediators have been shown to modulate the process. The reported effects of interleukin-6 (IL-6) on PMN apoptosis are inconsistent; however, analysis of published studies reveals at least one discriminating factor--the use of varied concentrations of PMNs in the experimental design. Consequently, we hypothesized that the in vitro effects of IL-6 on PMN apoptosis varied with the concentration of PMNs in culture. PMNs isolated from healthy human donors were cultured at concentrations from 1 to 20 x 10(6)/mL, and incubated with IL-6 doses from 1 to 100 ng/mL. PMNs cultured at 1-5 x 10(6)/mL were unaffected by IL-6; in contrast, IL-6 inhibited apoptosis in PMNs cultured at 10-20 x 10(6)/mL, compared with untreated similarly concentrated PMNs. These data suggest caution in interpreting in vitro studies of apoptosis; on the other hand, appropriately designed experiments may help elucidate the regulation of apoptosis in vivo.

Interleukin-6 stimulates neutrophil production of platelet-activating factor.

Interleukin-6 (IL-6) is an integral mediator of the acute phase response to injury and infection; an exaggerated IL-6 response has been associated with adverse clinical events. The precise role of IL-6 is unclear, but it appears capable of modulating the functional repertoire of mature neutrophils (PMNs). Our previous work demonstrated that IL-6 -stimulated PMNs are primed by lower concentrations of platelet-activating factor (PAF) than nonstimulated PMNs. Recently, we have found that IL-6 suppresses PMN apoptosis via a PAF-like mechanism. We hypothesized that IL-6 stimulates PMNs to produce PAF. PMNs isolated from healthy human donors were incubated with IL-6 (0.1-100 ng/ml) at 37 degrees C. Lipid production was measured by use of thin-layer chromatography, and PAF quantitated with a scintillation proximity assay. IL-6 (1 and 10 ng/ml) stimulated PMNs to produce increase quantities of PAF. PAF production was associated with an increase in PMN cytosolic calcium. These data may provide mechanistic insight into IL-6 regulation of PMN-mediated cytotoxicity and the role of PAF in mediating IL-6 effects on PMNs.

Reduced PAF-acetylhydrolase activity is associated with postinjury multiple organ failure.

Our basic laboratory work has identified the postischemic gut as a source of platelet-activating factor (PAF), which primes circulating neutrophils for the production of reactive oxygen metabolites (ROMs) leading to distant organ injury. Circulating PAF-acetylhydrolase (PAF-AH) hydrolyzes PAF to lyso-PAF. Recently, ROMs have been shown to rapidly and irreversibly inactivate human PAF-AH. Consequently, our study hypothesis was that reduced levels of PAF-AH in severely injured patients would be associated with the development of multiple organ failure (MOF). Over a 16 mo period, 26 patients at known risk for MOF (Injury Severity Score (ISS) > or = 25 or an ISS > 15 with > or = 6 U of blood transfused within the first 6 h) had blood sampled on postinjury days 0, 1, 2, 3, and 5. PAF-AH activity was assessed by measuring the percentage of 3H-labeled PAF hydrolyzed. MOF was defined by a standard score. The mean age of the 26 study patients was 34 +/- 2 yr; 19 (73%) were male. The injury mechanism was blunt in 18 (69%), and the mean ISS was 31 +/- 2. Eight patients (31%) developed MOF. In the MOF patients, plasma PAF-AH activity was significantly lower on the day of injury and remained depressed throughout the ensuing 5 days compared with the non-MOF patients. Reduced PAF-AH activity is associated with the development of postinjury MOF. With the recent molecular cloning of human plasma PAF-AH, repleting this circulating, anti-inflammatory enzyme may represent useful therapy for these high risk patients.

Stored red blood cells selectively activate human neutrophils to release IL-8 and secretory PLA2.

Packed red blood cell (PRBC) transfusion has been invoked previously with immunosuppression and increased infections, but it has now been demonstrated that stored PRBCs (>14 days) can prime PMNs and provoke multiple organ failure. Recently, the role of PMNs in the genesis of MOF has been extended to their release of inflammatory cytokines, notably IL-1, IL-8, TNFalpha, and secretory phospholipase A2 (sPLA2). We hypothesize that stored PRBCs can act as a second event via stimulating the release of inflammatory cytokines from PMNs. Isolated human PMNs were incubated for 24 h in RPMI with either 20% fresh plasma or plasma from 42 day old PRBC (day of outdate) and release of IL-8, IL-1beta, TNFalpha, and sPLA2 were measured. Plasma from stored PRBCs contained small amounts of IL-8, sPLA2, and TNFalpha (102.1 +/-5.6 pg/ml, 87.6+/-6.0 pg/ml and 9.7+/-.7 pg/ml). Levels of IL-1beta were below detection (<1 pg/ml). Day 42 PRBC plasma stimulated significant PMN release of both IL-8 and sPLA2 as compared to both control and day 0 plasma (*P < .05), but PRBC plasma did not stimulate PMN release of either IL-1beta or TNFalpha. Transfused blood is emerging as an inflammatory agent that is capable of producing PMN priming. In this study we have demonstrated that PRBC plasma selectively activates PMNs to release both IL-8 and sPLA2. Thus, transfusion of PRBCs may represent a preventable inflammatory insult via modification of both blood banking and transfusion practices.

Hypertonic saline inhibits neutrophil (PMN) priming via attenuation of p38 MAPK signaling.

Priming of the neutrophil cytotoxic response is central to the pathogenesis of early postinjury multiple organ failure (MOF). Platelet-activating factor (PAF) has been implicated as a key inflammatory mediator in postinjury neutrophil priming and requires p38 MAPK signaling to produce its biologic effects. Hypertonic saline (HTS) resuscitation decreases the postinjury inflammatory response following shock in animals and decreases receptor-mediated neutrophil (PMN) cytotoxic functions in vitro. We hypothesized that HTS attenuates PAF priming of the PMN cytotoxic response by interfering with PAF-mediated p38 MAPK signal transduction. Isolated PMNs were preincubated in isotonic buffer or HTS (Na+ = 180 mM), then primed with PAF. Neutrophil CD11b/CD18 expression was measured by flow cytometry. Receptor-dependent (fMLP), N-formyl-methionyl-leucyl-phenylalanine, fMLP) and receptor-independent (PMA) O2- production was measured by reduction of cytochrome c in resting and PAF primed PMNs. Total p38 MAPK protein PAF-mediated p38 MAPK activation was assessed by western blot of PMN lysates. Clinically relevant levels of HTS attenuated PAF-mediated beta2-integrin expression. While HTS attenuated receptor-dependent (fMLP and PAF/fMLP) O2- production, receptor-independent (PMA) O2- production was unaffected. Conversely, HTS attenuated PAF priming of PMA-mediated O2- production. PAF and HTS did not alter total cellular p38 MAPK content. Clinically relevant levels of HTS alone did not activate p38 MAPK but inhibited PAF mediated p38 MAPK activation. HTS attenuates PAF priming of the PMN cytotoxic response by altering intracellular signal transduction. Therefore, HTS resuscitation may attenuate postinjury PMN priming and ultimately the risk of developing MOF.

The lipid fraction of post-hemorrhagic shock mesenteric lymph (PHSML) inhibits neutrophil apoptosis and enhances cytotoxic potential.

Dysfunctional neutrophil (PMN) apoptosis facilitates hyperinflammatory tissue injury. Previous work has demonstrated that post-hemorrhagic shock mesenteric lymph (PHSML) provokes PMN-mediated acute lung injury in animal models, but the mechanism remains unclear. We have documented that the lipid fraction of PHSML is responsible for PMN priming of the respiratory burst. In this study, we hypothesized that PHSML lipids delay PMN apoptosis and thereby further enhance PMN cytotoxic potential. Mesenteric lymph was collected from rats (n = 5) before (control), during non-lethal hemorrhagic shock (MAP 40 mmHg, 30 min), and during resuscitation (shed blood + 2x crystalloid). Human PMNs were incubated with control, PHSML, PHSML lipid extracts, and heat-treated PHSML (60 degrees C, 30 min.) at 1-10% (v:v) in RPMI 1640 for 24 h. Apoptosis was assessed using acridine orange/ethidium bromide staining and fluorescence microscopy. Priming of the respiratory burst was evaluated by incubating PMNs with (a) control PHSML or (b) PHSML lipid extracts for 24 h and by activating with fMLP (1 micromol/L). PHSML and PHSML lipid extracts (5-10%) inhibited PMN apoptosis. Heat denaturing the PHSML (to eliminate cytokines and complement) had no effect on the inhibition of PMN apoptosis. Similarly, incubation with polymixin B at a concentration that binds endotoxin had no effect. Both the PHSML and PHSML lipids (5%) following 24-h incubation primed the fMLP-activated oxidase. At physiologic concentrations, both PHSML and the lipid fraction of PHSML delay PMN apoptosis and prime the NADPH oxidase. These data further implicate the lipid components of mesenteric lymph as central in the pathogenesis of hemorrhagic shock induced PMN-mediated acute lung injury.

Postinjury suppression of human neutrophil cytokine production results from the stabilization of inhibitory kappaB.

UNLABELLED: Postinjury neutrophil (PMN) dysfunction is a well recognized event that may be responsible for increased infections. PMN cytokine production is an important component of their bactericidal capacity. When PMNs are stimulated, inhibitory factor kappaB (IkappaB) is degraded, allowing nuclear factor kappaB (NFkappaB) to translocate to the nucleus and promotes genes for the transcription of the interleukin-8 (IL-8) and tumor necrosis factor (TNF) genes. We hypothesize that similar to their late postinjury depressed superoxide production, postinjury PMNs manifest suppressed cytokine production, which is mediated by stabilization of IkappaB levels. METHODS: Twelve severely injured patients with an injury severity score (ISS) of 24 (+/-4.6) were studied as well as 10 elective surgical patients as a control. PMNs were isolated and incubated for 24 h in RPMI. PMNs were stimulated with lipopolysaccharide (LPS; 100 ng) or PAF (200 nm) and fMLP (1 microM) and release of IL-8, TNF, and interleukin-1 receptor antagonist (IL-1ra) were measured. Postinjury PMNs were also stimulated with LPS (100 ng), and IkappaB breakdown was measured at 0, 30, and 60 min using gel electrophoresis. RESULTS: Postinjury PMNs displayed a significant suppression of both IL-8 and TNF on postinjury Days 1-3, while the release of IL-1ra was preserved throughout the entire study period. In contrast, elective surgical patients demonstrated no decrease in IL-8 or TNF. Furthermore, IkappaB levels were preserved in the postinjury PMNs as compared with normal control PMNs. CONCLUSION: Postinjury PMNs have a suppressed release of both IL-8 and TNF following injury that did not occur in elective surgical patients. Furthermore, the NFkappaB/IkappaB-independent IL-1ra did not show suppression of release. In addition, stabilization of IkappaB following severe injury leads to decreased PMN IL-8 and TNF production. This genetic reprogramming may help explain PMN dysfunction and subsequent infections seen in severely injured patients.

Hypertonic saline activation of p38 MAPK primes the PMN respiratory burst.

Investigation of hypertonic saline (HTS) modulation of neutrophils (PMN) cytotoxic responses has generated seemingly contradictory results. Clinically relevant levels of HTS attenuate receptor-mediated p38 MAPK signaling, whereas higher levels activate p38 MAPK. Concurrently, HTS exerts a dose-dependent attenuation of the PMN respiratory burst, most notably at concentrations where p38 MAPK is activated. We hypothesized that HTS-mediated p38 MAPK activation augments the PMN respiratory burst on return to normotonicity. We found that although clinically relevant levels of HTS (Na+ > or = 200 mM) did not activate p38 MAPK, higher concentrations (Na+ > or = 300 mM) resulted in activation comparable with that after PAF stimulation. Transient stimulation with high levels of HTS primed the PMN respiratory burst in response to fMLP and PMA. This effect was attenuated by pretreatment with SB 203580, a p38 MAPK specific inhibitor. We conclude that severe osmotic shock primes the respiratory burst via p38 MAPK signaling, further supporting the role of this signaling cascade in PMN priming.

Post-hemorrhagic shock mesenteric lymph lipids prime neutrophils for enhanced cytotoxicity via phospholipase A2.

Hemorrhagic shock induced mesenteric hypoperfusion has long been implicated as a key event in the pathogenesis of the adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF). Previous work links post-hemorrhagic shock mesenteric lymph (PHSML) lipids and neutrophil (PMN) priming in the pathogenesis of ARDS. We hypothesize that gut phospholipase A2 (PLA2) liberates proinflammatory lipids following hemorrhagic shock, which are responsible for enhanced PMN cytotoxicity. Mesenteric lymph was collected from rats (n > or = 5) before hemorrhagic shock, during hemorrhagic shock (MAP 40 mm Hg x 30 min), and after resuscitation (shed blood + 2x lactated Ringers). PMNs were incubated with physiologic concentrations (1-5%, v:v) of (a) buffer control, (b) sham (c) pre-shock lymph, (c) PHSML, (d) PHSML lipid extracts, (e) heat-denatured PSHML, and (f) PHSML harvested after i.v. pretreatment with a known PLA2 inhibitor (quinacrine, 10 mg/kg). PMNs were activated with fMLP (1 micromol), and the maximal rate of superoxide production measured by reduction of cytochrome c. Gut morphology was assessed histologically using hematoxalin and eosin (HE) staining. PHSML and PHSML lipid extracts (5%, v:v) primed for enhanced superoxide production compared to buffer controls (2.5-fold and 3.6-fold), sham (2.5-fold) and pre-shock lymph (2.0-fold). Lymph collected after systemic PLA2 inhibition, in contrast, abrogated the PMN priming response. Gut mucosal morphology, at end-resuscitation, was intact on HE staining both with and without PLA2 inhibition. Heat denaturing the PHSML (eliminating cytokines and complement), on the other hand, did not reduce PMN priming. Physiologic concentrations of PHSML lipids prime the PMN respiratory burst. Lymph priming is diminished with systemic PLA2 inhibition, implicating gut PLA2 as a source of proinflammatory lipids that may be central in the pathogenesis of hemorrhagic shock induced ARDS/MOF.

Soluble intercellular adhesion molecule-1 provokes polymorphonuclear leukocyte elastase release by CD18.

BACKGROUND: Elevated levels of soluble intercellular adhesion molecule-1 (sICAM-1) correlate with the development of postinjury multiple organ failure. Soluble ICAM-1 secretion is known to be induced in endothelial cells and monocytes by diverse inflammatory stimuli. We have found that incubation of quiescent polymorphonuclear leukocytes (PMNs) with sICAM-1 elicits elastase release and, more recently, that cross-linking CD18 receptors on PMNs also produces elastase release. Consequently, our study hypothesis was that sICAM-1 provokes PMN elastase release through its interaction with CD18. METHODS: To obtain sICAM-1, Chinese hamster ovarian cells transfected with human ICAM-1 were lysed and centrifuged at 150,000 g for 1 hour; the supernatant was passed over an ICAM-1 affinity column, eluted with 0.1 mmol/L glycine HCl, and concentrated with dialysis filter. Human PMNs (2.5 x 10(5)) were saturated with specific monoclonal antibodies for the beta 2 subunits (CD11a, CD11b, CD18) or nonspecific monoclonal antibodies for 30 minutes on ice before a 1-hour incubation with sICAM-1 (75 ng/ml) at 37 degrees C. Elastase activity was measured by the cleavage of n-methoxysuccinyl-A-A-P-V-p-nitroanilide. RESULTS: Neutrophil incubation with sICAM-1 resulted in 19.2% +/- 2.8% of total PMN elastase, compared with 2.4% +/- 0.5% in the controls. Blockade of CD18 abrogated sICAM-1 provoked elastase release with monoclonal antibodies to CD18 (TS1/18, 31H8) resulting in 4.3% +/- 1.0% and 5.5% +/- 1.4% elastase release, respectively. Blockade of CD11a, CD11b, and nonspecific antibody controls had no effect on sICAM-1 induced elastase release. CONCLUSIONS: In vitro, sICAM-1 provokes PMN elastase release through CD18. This may represent a mechanism by which elevated levels of circulating sICAM-1, released from local injury sites, provoke distal organ dysfunction.

Hypertonic saline attenuation of the neutrophil cytotoxic response is reversed upon restoration of normotonicity and reestablished by repeated hypertonic challenge.

BACKGROUND: Hypertonic saline (HTS) resuscitation, in addition to enhancing hemodynamic recovery, modulates postinjury hyperinflammation in the critically injured. The polymorphonuclear neutrophil (PMN) cytotoxic response, a key element in the pathogenesis of postinjury organ dysfunction, is attenuated under hypertonic conditions. Although plasma Na(+) rises to 180 mmol/L after HTS infusion, baseline levels are reestablished within 24 hours. We hypothesized that HTS attenuation of the PMN cytotoxic response (beta2-integrin expression, elastase release, and O2- production) is reversed upon return to normotonicity, but can be reestablished by repeated HTS challenge. METHODS: Isolated human PMNs were incubated in HTS (Na(+) = 180 mmol/L) for 5 minutes at 37 degrees C then returned to normotonicity by centrifugation and resuspension in isotonic buffer. Stimulated (PAF) beta2-integrin expression was measured by flow cytometry. Stimulated (PAF/fMLP) elastase release and O2- production were measured by cleavage of N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide and reduction of cytochrome c (Cyt c). Protein tyrosine phosphorylation in PMN cell lysates was assessed by Western blot. RESULTS: Clinically relevant levels of HTS induced tyrosine phosphorylation in resting PMNs and attenuated cytotoxic responses. Reestablishment of normotonicity returned these functions to baseline. A repeated HTS challenge after restoration of normotonicity also induced tyrosine phosphorylation and suppressed the cytotoxic response. CONCLUSIONS: HTS attenuation of the PMN cytotoxic response is reversible but can be reestablished by repeated HTS treatment. This phenomenon may provide the unique opportunity to selectively and temporarily decrease the postinjury inflammatory response when patients are at greatest risk for PMN-mediated tissue damage.

Intercellular adhesion molecule-1 promotes neutrophil-mediated cytotoxicity.

BACKGROUND: Interaction of the CD11/CD18 complex on polymorphonuclear neutrophils (PMNs) and intercellular adhesion molecule (ICAM)-1 on endothelium is a critical event in PMN-mediated tissue injury. In addition, increased expression of ICAM-1 on type I pneumocytes has been identified in a variety of pulmonary disorders associated with PMN-induced inflammation. We hypothesized that ICAM-1 up-regulation is sufficient to promote cytotoxicity via activated PMNs. METHODS: The complementary DNA for human ICAM-1 was transfected into Chinese hamster ovarian (CHO) cells, which do not inherently express this adhesion receptor, by using the expression vector CD1.8. Fluorescence-activated cell sorter analysis revealed 62% CHO cell surface expression of ICAM-1. Wild type and transfected CHO cells were labeled with chromium 51 and exposed to quiescent or activated (1 mumol/L phorbol myristate acetate) PMNs for 4 hours. Subsets were pretreated with a monoclonal antibody to ICAM-1. PMN cytotoxicity was determined by specific percent 51Cr release. RESULTS: Incubation of quiescent PMNs with wild type and transfected CHO cells produced nominal cell lysis, 0.5% +/- 0.3% and 0.2% +/- 0.2%, respectively. Activated PMNs produced 13.6% +/- 3.2% versus 1.4% +/- 0.7% cell lysis, comparing transfected with wild type CHO cells, and 0.5% +/- 0.2% cell lysis after pretreatment with a monoclonal antibody to ICAM-1, p < 0.01. CONCLUSIONS: ICAM-1 up-regulation is sufficient to promote cytotoxicity via activated PMNs. This may represent a potential target for attenuating PMN-mediated injury to endothelial and other cell lines, including parenchyma.

Neutrophils are primed for cytotoxicity and resist apoptosis in injured patients at risk for multiple organ failure.

BACKGROUND: Postinjury multiple organ failure (MOF) is the result of a dysregulated systemic inflammatory response in which primed neutrophils (PMNs) are sequestered in tissues, vulnerable to activation through secondary insults. Apoptosis is critical to the normal clearance of these sequestered PMNs. Conversely, dysfunctional apoptosis prolongs the PMN functional life span, potentially exacerbating PMN-mediated tissue injury and the development of MOF. We hypothesized that severe trauma, in addition to priming PMNs, provokes dysfunctional PMN apoptosis. METHODS: Neutrophils were harvested daily from 12 severely injured patients at high risk for MOF, cultured for 24 hours, and assessed for apoptosis with use of acridine orange-ethidium bromide staining and fluorescence microscopy. Priming for elastase release was measured in freshly isolated patient PMNs. Plasma from patients was assessed for its ability to delay apoptosis of normal PMNs. RESULTS: Four patients (33%) had MOF. Neutrophil apoptosis was profoundly delayed in severely injured patients throughout the 5-day study period. Priming for elastase release was augmented concomitantly. Patients' plasma delayed apoptosis of normal PMNs. CONCLUSION: In patients at high risk for postinjury MOF, PMNs are not only primed for cytotoxicity but also resist apoptosis. The dysfunctional apoptosis is attributed, at least in part, to a plasma-borne mediator. The net effect may facilitate hyperinflammatory organ injury.

Phospholipase A(2)--derived neutral lipids from posthemorrhagic shock mesenteric lymph prime the neutrophil oxidative burst.

BACKGROUND: Our previous work identified posthemorrhagic shock mesenteric lymph (PHSML) lipids as key elements in polymorphonuclear neutrophil (PMN)--provoked acute lung injury. We hypothesize that gut phospholipase A(2) (PLA(2)) is responsible for the generation of proinflammatory lipids in PHSML that primes circulating PMNs for enhanced oxidative burst. METHODS: Mesenteric lymph was collected from rats (n = 5) before (preshock), during the induction of hemorrhagic shock (mean arterial pressure, 40 mm Hg x 30 minutes), and at resuscitation (shed blood + 2x lactated Ringer's solution). PLA(2) inhibition (quinacrine, 10 mg/kg, intravenously) was given before shock was induced. Extracted lipids were separated by normal phase high-pressure liquid chromatography and resuspended in albumin. PMNs were exposed to a 5% vol:vol concentration of eluted lipids and activated with N-formyl-methionyl-leucyl-phenylalanine (1 micromol/L). Superoxide production was assessed by cytochrome C reduction. RESULTS: High-pressure liquid chromatography--extracted neutral lipids of lymph collected before hemorrhagic shock did not prime the PMN oxidase, whereas isolated neutral lipids of postshock lymph primed PMNs 2.6- +/- 0.32-fold above baseline (P <.05). PLA(2) inhibition returned PHSML neutral lipid priming to baseline levels. CONCLUSIONS: PLA(2) inhibition before hemorrhagic shock abrogates the neutrophil priming effects of PHSML through reduction of the accumulation of proinflammatory neutral lipids. Identification of these PLA(2)-dependent lipids provides a mechanistic link that may have therapeutic implications for postshock acute lung injury.

Male gender is a risk factor for major infections after surgery.

BACKGROUND: Accumulating clinical and epidemiological evidence suggests significant gender differences in the incidence of and outcome following major infection. In a rodent model of hemorrhagic shock, investigators have shown that males manifest depressed cell-mediated immunity that is reversed by castration or pharmacologic testosterone receptor blockade. Female rats, in contrast, show enhanced immune function that is reduced to male levels by testosterone administration. This sexual dimorphism is believed responsible for the improved outcome in female mice following septic challenge. HYPOTHESIS: Male gender is a risk factor for major infections following severe injury. DESIGN: Five-year prospective cohort study ending October 1998. SETTING: Urban level I regional trauma center. PATIENTS AND METHODS: A total of 545 trauma patients older than 15 years with an Injury Severity Score greater than 15 and survival more than 48 hours were prospectively identified and studied. Collected data included age, injury mechanism, and Injury Severity Score. Major infections, defined as pneumonia, abdominal and pelvic abscess, wound infection requiring operative debridement, and meningitis, were tabulated. The occurrence of major infections in males and females was compared using multiple logistic regression analysis. MAIN OUTCOME MEASURE: Postinjury major infectious complications. RESULTS: Of the 545 patients, 135 (24.8%) were female and 410 (75.2%) were male. Major infections occurred in 219 (40.2%) patients. Logistic regression confirmed that male gender is an independent risk factor for major infections (P=.04) after controlling for age and Injury Severity Score. Males had a 58% greater risk of developing a major infection (odds ratio, 1.58; 95% confidence interval, 1.01-2.48). CONCLUSIONS: Male gender is associated with a dramatically increased risk of major infections following trauma. This effect is most significant following injuries of moderate severity (Injury Severity Score 16-25) and persists in all age groups.

Interleukin-6 delays neutrophil apoptosis.

BACKGROUND: Neutrophil (PMN) apoptosis promotes the phagocytosis of PMNs without inciting an inflammatory response or local cytotoxic effect. This is important in the normal resolution of inflammatory processes and the control of tissue injury. Conversely, a delay in PMN apoptosis may facilitate PMN-mediated organ dysfunction by extending PMN functional integrity at an inflammatory site. Elevated circulating and tissue levels of interleukin-6 (IL-6) have been associated with postinjury organ dysfunction, and IL-6 appears to augment PMN cytotoxic functions. Therefore, we hypothesized that IL-6 delays PMN apoptosis, thereby enhancing PMN-mediated cytotoxicity. METHODS: Neutrophils isolated from healthy human donors were incubated for 24 hours in enriched RPMI 1640 cell culture medium at 37 degrees C in 5% carbon dioxide. Subgroups were incubated with IL-6, heat-denatured IL-6, or buffer alone. Apoptosis was assessed morphologically using acridine orange-ethidium bromide stain, and biochemically by DNA gel electrophoresis. Functional capacity of PMNs was assessed by superoxide generation after activation with phorbol myristate acetate or platelet-activating factor plus formyl-methionyl-leucyl-phenylalanine. RESULTS: Treatment with IL-6 resulted in a greater population of surviving (nonapopototic) PMNs after 24 hours. In addition, the IL-6-treated population produced more superoxide after 24 hours than did the untreated or heat-denature IL-6-treated groups, after either activating stimulus. CONCLUSIONS: Interleukin-6 delays PMN apoptosis, resulting in a larger population of surviving PMNs with a greater collective capacity for superoxide production. This could potentially facilitate PMN-mediated tissue injury and may be a mechanism whereby IL-6 contributes to organ dysfunction.