Early Cytokine Production Risk Stratifies Trauma Patients for Multiple Organ Failure
Shock is a prime inciting event for postinjury multiple organ failure (MOF), believed to induce a state of injurious systemic inflammation. In animal models of hemorrhagic shock, early (< 24 hours) changes in cytokine production are an index of the systemic inflammatory response syndrome. However, their predictive value in trauma patients remains to be fully elucidated.
In a prospective observational pilot study of > 1 year at an urban Level I trauma center, serial (every 4 hours) serum cytokine levels were determined during a 24-hour period using multiplex suspension immunoassay in patients with major torso trauma (excluding severe brain injury) who met criteria for standardized shock resuscitation. Temporal cytokine expression was assessed during shock resuscitation in severe trauma patients to predict risk for MOF. MOF was assessed with the Denver score.
Of 48 study patients (mean age 39 +/- 3 years, 67% men, 88% blunt mechanism, mean Injury Severity Score 25 +/- 2), MOF developed in 11 (23%). MOF patients had a considerably higher mortality (64% versus 3%) and fewer ICU-free days (3.5 +/- 2 versus 17.8 +/- 1.3 days) compared with non-MOF patients. Traditional predictors of MOF, including age (45 +/- 7 versus 38 +/- 3 years; p=0.21), Injury Severity Score (26 +/- 3 versus 25 +/- 2; p=0.67), admission hemoglobin (11.4 +/- 0.9 versus 12.1 +/- 0.5 g/dL; p=0.22), international normalized ratio (1.6 +/- 0.2 versus 1.4 +/- 0.06; p=0.17), and base deficit (9.0 +/- 2 versus 7.1 +/- 0.8; p=0.19), were not significantly different between MOF and non-MOF patients. Statistical analysis identified six candidate predictors of MOF: inducible protein 10, macrophage inflammatory protein-1beta, interleukin-10, interleukin-6, interleukin-1Ra, and eotaxin.
These data provide insight into cytokine expression during traumatic shock that can enable earlier identification of patients at risk for development of MOF.
Available from: Philippe Haouzi
- "Rather, the prognosis of a hemorrhagic shock is linked to a cascade of events, occurring during both the phase of bleeding and resuscitation, related to the magnitude of the oxygen deficit [3-6] and the resulting ischemic and post-ischemic inflammatory response [7,8]. Indeed, hemorrhagic shock precipitates inflammatory cascades that comprise the activation of stress transcriptional factors and up-regulation of cytokines synthesis [9,10] leading to multiple organ failure . Among the putative actors involved in the fatal course of an acute hemorrhage induced tissue ischemia/hypoxia, a novel candidate has been recently put forward: endogenous hydrogen sulfide [11,12]. "
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Hemorrhagic shock induced O2 deficit triggers inflammation and multiple organ failure (MOF). Endogenous H2S has been proposed to be involved in MOF since plasma H2S concentration appears to increase in various types of shocks and to predict mortality. We tested the hypothesis that H2S increases during hemorrhagic shock associated with O2 deficit, and that enhancing H2S oxidation by hydroxocobalamin could reduce inflammation, O2 deficit or mortality.
We used a urethane anesthetized rat model, where 25 ml/kg of blood was withdrawn over 30 minutes. O2 deficit, lactic acid, tumor necrosis factor (TNF)-alpha and H2S plasma concentrations (Siegel method) were measured before and after the bleeding protocol in control animals and animals that received 140 mg/kg of hydroxocobalamin. The ability to oxidize exogenous H2S of the plasma and supernatants of the kidney and heart homogenates was determined in vitro.
We found that withdrawing 25 ml/kg of blood led to an average oxygen deficit of 122 ± 23 ml/kg. This O2 deficit was correlated with an increase in the blood lactic acid concentration and mortality. However, the low level of absorbance of the plasma at 670 nm (A670), after adding N, N-Dimethyl-p-phenylenediamine, that is, the method used for H2S determination in previous studies, did not reflect the presence of H2S, but was a marker of plasma turbidity. There was no difference in plasmatic A670 before and after the bleeding protocol, despite the large oxygen deficit. The plasma sampled at the end of bleeding maintained a very large ability to oxidize exogenous H2S (high μM), as did the homogenates of hearts and kidneys harvested just after death. Hydroxocobalamin concentrations increased in the blood in the μM range in the vitamin B12 group, and enhanced the ability of plasma and kidneys to oxidize H2S. Yet, the survival rate, O2 deficit, H2S plasma concentration, blood lactic acid and TNF-alpha levels were not different from the control group.
In the presence of a large O2 deficit, H2S did not increase in the blood in a rat model of untreated hemorrhagic shock. Hydroxocobalamin, while effective against H2S in vitro, did not affect the hemodynamic profile or outcome in our model.
Critical care (London, England) 10/2012; 16(5):R178. DOI:10.1186/cc11661 · 4.48 Impact Factor
Available from: Carol L Wagner
- "Serum inflammatory proteins are readily measurable and may be useful biomarkers of phases of injury. Combinations of cytokines are beginning to be used as early, discriminating predictors of severe traumatic brain injury and multiorgan system failure in adults and children (Bogner et al, 2009; Berger et al, 2008; Kirchoff et al, 2008; Jastrow et al, 2009). In neonates with hypoxicischemic encephalopathy (HIE), elevated interleukin (IL)-6 and IL-8 in serum and cerebrospinal fluid have been associated with high lactate/choline ratios by magnetic resonance spectroscopy and more severe neurologic outcomes (Bartha et al, 2004; Savman et al, 1998; Nelson et al, 1998; Martin-Ancel et al, 1997). "
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ABSTRACT: Inflammatory cytokines may mediate hypoxic-ischemic (HI) injury and offer insights into the severity of injury and the timing of recovery. In our randomized, multicenter trial of hypothermia, we analyzed the temporal relationship of serum cytokine levels in neonates with hypoxic-ischemic encephalopathy (HIE) with neurodevelopmental outcome at 12 months. Serum cytokines were measured every 12 hours for 4 days in 28 hypothermic (H) and 22 normothermic (N) neonates with HIE. Monocyte chemotactic protein-1 (MCP-1) and interleukins (IL)-6, IL-8, and IL-10 were significantly higher in the H group. Elevated IL-6 and MCP-1 within 9 hours after birth and low macrophage inflammatory protein 1a (MIP-1a) at 60 to 70 hours of age were associated with death or severely abnormal neurodevelopment at 12 months of age. However, IL-6, IL-8, and MCP-1 showed a biphasic pattern in the H group, with early and delayed peaks. In H neonates with better outcomes, uniform down modulation of IL-6, IL-8, and IL-10 from their peak levels at 24 hours to their nadir at 36 hours was observed. Modulation of serum cytokines after HI injury may be another mechanism of improved outcomes in neonates treated with induced hypothermia.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2012; 32(10):1888-96. DOI:10.1038/jcbfm.2012.83 · 5.41 Impact Factor
Available from: PubMed Central
- "Future clinical studies need to be completed to evaluate Danger signals and their associations with outcomes in trauma. Jastrow et al.  provided insight into the predictive value of cytokine production as an index for developing future outcomes of multiple organ dysfunction or failure. As danger/alarmin signals are released in the acute setting after massive injury, they are the earliest markers of inflammation and may serve to predict outcomes earlier than other biomarkers. "
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ABSTRACT: Trauma is one of the leading causes of death in young adult patients. Many pre-clinical and clinical studies attempt to investigate the immunological pathways involved, however the true mediators remain to be elucidated. Herein, we attempt to describe the immunologic response to systemic trauma in the context of the Danger model.
A literature search using PubMed was used to identify pertinent articles describing the Danger model in relation to trauma.
Our knowledge of Danger signals in relation to traumatic injury is still limited. Danger/alarmin signals are the most proximal molecules in the immune response that have many possibilities for effector function in the innate and acquired immune systems. Having a full understanding of these molecules and their pathways would give us the ability to intervene at such an early stage and may prove to be more effective in blunting the post-injury inflammatory response unlike previously failed cytokine experiments.
Journal of Translational Medicine 06/2011; 9(1):92. DOI:10.1186/1479-5876-9-92 · 3.93 Impact Factor
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