Shawn G. Rhind

The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: a randomized, controlled, double-blinded trial.

Objective:To investigate the potential immunologic and anti-inflammatory effects of hypertonic saline plus dextran (HSD) in hemorrhagic trauma patients. Background:Unbalanced inflammation triggered by shock has been linked to multiorgan dysfunction (MOD) and death. In animal and cellular models, HSD alters the inflammatory response to shock, attenuating MOD and improving outcome. It remains untested whether HSD has similar effects in humans. Methods:A single 250-mL dose of either HSD (7.5% NaCl, 6% dextran-70) or placebo (0.9% NaCl) was administered to adult blunt trauma patients in hemorrhagic shock. The primary outcome was to measure changes in immune/inflammatory markers, including neutrophil activation, monocyte subset redistribution, cytokine production, and neuroendocrine changes. Patient demographics, fluid requirements, organ dysfunction, infection, and death were recorded. Results:A total of 27 patients were enrolled (13 HSD) with no significant differences in clinical measurements. Hyperosmolarity was modest and transient, whereas the immunologic/anti-inflammatory effects persisted for 24 hours. HSD blunted neutrophil activation by abolishing shock-induced CD11b up-regulation and causing CD62L shedding. HSD altered the shock-induced monocyte redistribution pattern by reducing the drop in “classic” CD14++ and the expansion of the “pro-inflammatory” CD14+CD16+ subsets. In parallel, HSD significantly reduced pro-inflammatory tumor necrosis factor (TNF)-α production while increasing anti-inflammatory IL-1ra and IL-10. HSD prevented shock-induced norepinephrine surge with no effect on adrenal steroids. Conclusions:This first human trial evaluating the immunologic/anti-inflammatory effects of hypertonic resuscitation in trauma patients demonstrates that HSD promotes a more balanced inflammatory response to hemorrhagic shock, raising the possibility that similar to experimental models, HSD might also attenuate post-trauma MOD.

Abnormal Coagulation Tests Are Associated With Progression of Traumatic Intracranial Hemorrhage

BACKGROUND Intracranial hemorrhage (ICH) is common in traumatic brain injury (TBI) and a major determinant of death and disability. ICH commonly increases in size and coagulopathy has been implicated in such progression. We investigated the association between coagulopathy diagnosed by routine laboratory tests and ICH progression. METHODS Subgroup post hoc analysis from a randomized controlled trial including adult patients with blunt severe TBI (Glasgow Coma Scale score <or=8) and repeat computerized tomography scans in 48 hours. Coagulopathy was defined as international normalized ratio >or=1.3, activated partial thromboplastin time >or=35, or platelet count (PLT) <or=100 x 10/L any time in the first 24 hours. Progression was any size increase or new ICH. TBI-associated coagulopathy was investigated measuring soluble tissue factor (TF) and d-dimer. RESULTS The ICH progressed in 37 of 72 patients (51%), in 80% if any abnormal laboratory test (coagulopathic patients) versus 36% in noncoagulopathic (p = 0.0004). Abnormal international normalized ratio (odds ratio [OR] = 4.09; 95% confidence interval [CI] = 1.29-12.95; p = 0.017), PLT (OR = 12.59; 95% CI = 1.52-108.57; p = 0.019), head Abbreviated Injury Scale (AIS) (OR = 1.82; 95% CI = 1.15-2.88; p = 0.011) were significantly associated with progression (univariate analysis). In a multiple logistic regression, only head AIS (OR = 1.81; 95% CI 1.10-2.98; p = 0.0198) and PLT (OR = 11.8; 95% CI = 1.38-101.23; p = 0.024) correlated with progression. All patients with abnormal partial thromboplastin time experienced progression. ICH progression carried a 5-fold higher odds of death; 32% with progression died versus 8.6% without. Age, head AIS, Injury Severity Score, and d-dimer were also associated with mortality. Tissue factor was not associated with progression or mortality. CONCLUSION This study demonstrates an association between coagulopathy, diagnosed by routine laboratorial tests in the first 24 hours, with ICH progression; and ICH progression with mortality in patients with severe TBI. The causal relationship between coagulopathy and ICH progression will require further studies.

Mild endotoxemia, NF-κB translocation, and cytokine increase during exertional heat stress in trained and untrained individuals

This study examined endotoxin-mediated cytokinemia during exertional heat stress (EHS). Subjects were divided into trained [TR; n=12, peak aerobic power (VO2peak)=70+/-2 ml.kg lean body mass(-1).min(-1)] and untrained (UT; n=11, VO2peak=50+/-1 ml.kg lean body mass(-1).min(-1)) groups before walking at 4.5 km/h with 2% elevation in a climatic chamber (40 degrees C, 30% relative humidity) wearing protective clothing until exhaustion (Exh). Venous blood samples at baseline and 0.5 degrees C rectal temperature increments (38.0, 38.5, 39.0, 39.5, and 40.0 degrees C/Exh) were analyzed for endotoxin, lipopolysaccharide binding protein, circulating cytokines, and intranuclear NF-kappaB translocation. Baseline and Exh samples were also stimulated with LPS (100 ng/ml) and cultured in vitro in a 37 degrees C water bath for 30 min. Phenotypic determination of natural killer cell frequency was also determined. Enhanced blood (104+/-6 vs. 84+/-3 ml/kg) and plasma volumes (64+/-4 vs. 51+/-2 ml/kg) were observed in TR compared with UT subjects. EHS produced an increased concentration of circulating endotoxin in both TR (8+/-2 pg/ml) and UT subjects (15+/-3 pg/ml) (range: not detected to 32 pg/ml), corresponding with NF-kappaB translocation and cytokine increases in both groups. In addition, circulating levels of tumor necrosis factor-alpha and IL-6 were also elevated combined with concomitant increases in IL-1 receptor antagonist in both groups and IL-10 in TR subjects only. Findings suggest that the threshold for endotoxin leakage and inflammatory activation during EHS occurs at a lower temperature in UT compared with TR subjects and support the endotoxin translocation hypothesis of exertional heat stroke, linking endotoxin tolerance and heat tolerance.

Normal range values for thromboelastography in healthy adult volunteers

Thromboelastography (TEG) provides a functional evaluation of coagulation. It has characteristics of an ideal coagulation test for trauma, but is not frequently used, partially due to lack of both standardized techniques and normal values. We determined normal values for our population, compared them to those of the manufacturer and evaluated the effect of gender, age, blood type, and ethnicity. The technique was standardized using citrated blood, kaolin and was performed on a Haemoscope 5000 device. Volunteers were interviewed and excluded if pregnant, on anticoagulants or having a bleeding disorder. The TEG parameters analyzed were R, K, alpha, MA, LY30, and coagulation index. All volunteers outside the manufacturers normal range underwent extensive coagulation investigations. Reference ranges for 95% for 118 healthy volunteers were R: 3.8-9.8 min, K: 0.7-3.4 min, alpha: 47.8-77.7 degrees, MA: 49.7-72.7 mm, LY30: -2.3-5.77%, coagulation index: -5.1-3.6. Most values were significantly different from those of the manufacturer, which would have diagnosed coagulopathy in 10 volunteers, for whom additional investigation revealed no disease (81% specificity). Healthy women were significantly more hypercoagulable than men. Aging was not associated with hypercoagulability and East Asian ethnicity was not with hypocoagulability. In our population, the manufacturers normal values for citrated blood-kaolin had a specificity of 81% and would incorrectly identify 8.5% of the healthy volunteers as coagulopathic. This study supports the manufacturers recommendation that each institution should determine its own normal values before adopting TEG, a procedure which may be impractical. Consideration should be given to a multi-institutional study to establish wide standard values for TEG.

The value of serum biomarkers in prediction models of outcome after mild traumatic brain injury.

BACKGROUND To determine, using a civilian model of mild traumatic brain injury (TBI), the added value of biomarker sampling upon prognostication of outcome at 1 week and 6 weeks postinjury. METHODS The Galveston Orientation and Amnesia test was administered, and blood samples for serum protein S100B and neuron-specific enolase (NSE) were collected from 141 emergency department patients within 4 hours of a suspected mild TBI (mTBI). The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) was administered via telephone 3 days postinjury. Patients were assessed by a physician at 1 week (n = 113; 80%) and 6 weeks (n = 95; 67%) postinjury. Neurocognitive and postural stability measures were also administered at these follow-ups. RESULTS Levels of S100B and NSE were found to be abnormally elevated in 49% and 65% of patients with TBI, respectively. Sixty-eight percent and 38% of the patients were considered impaired at 1 week and 6 weeks postinjury, respectively. Stepwise logistic regression modeling identified admission Galveston Orientation and Amnesia test score, S100B level, and RPQ score at day 3 postinjury to be predictive of poor outcome at 1 week postinjury (c-statistic 0.877); female gender, loss of consciousness, NSE level, and RPQ score at day 3 postinjury were predictive of poor outcome at 6 weeks postinjury (c-statistic 0.895). The discriminative power of the biomarkers alone was limited. CONCLUSIONS Biomarkers, in conjunction with other readily available determinants of outcome assessed in the acute period after injury, add value in the early prognostication of patients with mTBI. Our findings are consistent with the notion that S100B and NSE point to biological mechanisms underlying poor outcome after mTBI.

Cytokine induction during exertional hyperthermia is abolished by core temperature clamping: neuroendocrine regulatory mechanisms.

The immunomodulatory effects of physiological temperature change remain poorly understood and inter-relationships between changes in core temperature, stress hormones and cytokines during exertional hyperthermia are not well established. This experimental study was designed to examine how cytokine (tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-12 and IL-1ra (receptor antagonist)) and hormone (epinephrine (Epi), norepinephrine (NE), growth hormone (GH) and cortisol (CORT)) responses are modified when the exercise-induced rise in core temperature is attenuated or exacerbated by immersion in a water bath. Ten men ((mean ± SD) age: 26.9 ± 5.7 years; height 1.75 ± 0.07 m; body mass 76.0 ± 10.9 kg; O2 peak: 48.0 ± 12.4 mL kg−1 min−1) completed two 40-min cycle ergometer exercise trials at 65% O2 peak while immersed to mid-chest. Rectal temperature (Tre) peaked at 39.1 ± 0.03 and 37.5 ± 0.13°C during the hot (39°C) and cold (18°C) conditions, respectively. Blood samples were collected before, during (20- and 40-min) and after (30- and 120-min) exercise. Increases in circulating NE (>350%), Epi (>500%), GH (>900%), IL-12 (>150%) and TNF-α (>90%) were greatest after 40-min exercise in the heat. Substantial elevations of CORT (80%), IL-1ra (150%) and IL-6 (>400%) did not occur until after exercise was complete. Core temperature clamping decreased the rise in circulating stress hormone concentrations and abolished increases in plasma cytokine concentrations. These findings suggest that exercise-associated elevations of Tre mediate increases of circulating stress hormones, which subsequently contribute to induction of circulating cytokine release.

Exercise and the immune system. Natural killer cells, interleukins and related responses.

SummaryThe main methods for the evaluation of natural killer (NK, CD16+ CD56+) cells, interleukins and related subsets of lymphocytes are briefly described. Moderate endurance exercise causes either no change or an increase in lymphocyte and NK cell counts, total T cell (CD3+) count, the ratio of T helper (CD3+ CD4+) to T suppressor (CD3+ CD8+) cells, mitogen-induced lymphocyte proliferation, serum immunoglobulin levels and in vitro immunoglobulin production. Plasma levels of interleukin-1 increase but interleukin-2 (IL-2) levels generally fall. Decreases in plasma IL-2 levels reflect increased expression of β (CD122) receptors for IL-2, and thus increased binding of IL-2, changes in cell distribution or a lesser production of IL-2 by peripheral blood mononuclear cells. Exercise to exhaustion induces adverse changes in many of these indices of immune function, particularly if the physical activity is accompanied by psychological or environmental stress. Moderate, appropriately graded training reduces the adverse reactions initially associated with a given bout of exhausting exercise, and cross-sectional comparisons show an increased expression of β IL-2 receptors on the peripheral blood mononuclear cells of trained individuals. However, excessive training, nutrient deficiency and/or muscle damage has adverse consequences for both the production of interleukins and the response of the immune system to these cytokines.

Effects of moderate endurance exercise and training on in vitro lymphocyte proliferation, interleukin-2 (IL-2) production, and IL-2 receptor expression

AbstractThis study was designed to examine immunological responses to an acute bout of cycle ergometry exercise before and after moderate endurance training. Previously sedentary males were randomly assigned to matched training (n=9) or control (n=6) groups. Training comprised 12 weeks during which supervised cycle ergometer exercise took place [30 min at 65–70% of maximal oxygen intake

Resuscitation with hypertonic saline-dextran reduces serum biomarker levels and correlates with outcome in severe traumatic brain injury patients.

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