Matthew M. Carrick

Sepsis, oxidative stress, and hypoxia: Are there clues to better treatment?

Abstract Sepsis is a clinical syndrome characterized by systemic inflammation, usually in response to infection. The signs and symptoms are very similar to Systemic Inflammatory Response Syndrome (SIRS), which typically occur consequent to trauma and auto-immune diseases. Common treatments of sepsis include administration of antibiotics and oxygen. Oxygen is administered due to ischemia in tissues, which results in the production of free radicals. Poor utilization of oxygen by the mitochondrial electron transport chain can increase oxidative stress during ischemia and exacerbate the severity and outcome in septic patients. This course of treatment virtually mimics the conditions seen in ischemia–reperfusion disorders. Therefore, this review proposes that the mechanism of free radical production seen in sepsis and SIRS is identical to the oxidative stress seen in ischemia–reperfusion injury. Specifically, this is due to a biochemical mechanism within the mitochondria where the oxidation of succinate to fumarate by succinate dehydrogenase (complex II) is reversed in sepsis (hypoxia), leading to succinate accumulation. Oxygen administration (equivalent to reperfusion) rapidly oxidizes the accumulated succinate, leading to the generation of large amounts of superoxide radical and other free radical species. Organ damage possibly leading to multi-organ failure could result from this oxidative burst seen in sepsis and SIRS. Accordingly, we postulate that temporal administration with anti-oxidants targeting the mitochondria and/or succinate dehydrogenase inhibitors could be beneficial in sepsis and SIRS patients.

Cerebral salt wasting after traumatic brain injury: a review of the literature.

Electrolyte imbalances are common among patients with traumatic brain injury (TBI). Cerebral salt wasting (CSW) is an electrolyte imbalance characterized by hyponatremia and hypovolemia. Differentiating the syndrome of inappropriate antidiuretic hormone and CSW remains difficult and the pathophysiological mechanisms underlying CSW are unclear. Our intent was to review the literature on CSW within the TBI population, in order to report the incidence and timing of CSW after TBI, examine outcomes, and summarize the biochemical changes in patients who developed CSW. We searched MEDLINE through 2014, hand-reviewed citations, and searched abstracts from the American Association for the Surgery of Trauma (2003–2014). Publications were included if they were conducted within a TBI population, presented original data, and diagnosed CSW. Publications were excluded if they were review articles, discussed hyponatremia but did not differentiate the etiology causing hyponatremia, or presented cases with chronic disease. Fifteen of the 47 publications reviewed met the selection criteria; nine (60xa0%) were case reports, five (33xa0%) were prospective and 1 (7xa0%) was a retrospective study. Incidence of CSW varied between 0.8 - 34.6xa0%. The populations studied were heterogeneous and the criteria used to define hyponatremia and CSW varied. Though believed to play a role in the development of CSW, increased levels of natriuretic peptides in patients diagnosed with CSW were not consistently reported. These findings reinforce the elusiveness of the CSW diagnosis and the need for strict and consistent diagnostic criteria.

The epidemiology of do-not-resuscitate orders in patients with trauma: a community level one trauma center observational experience

BackgroundDo-Not-Resuscitate (DNR) orders in patients with traumatic injury are insufficiently described. The objective is to describe the epidemiology and outcomes of DNR orders in trauma patients.MethodsWe included all adults with trauma to a community Level I Trauma Center over 6 years (2008–2013). We used chi-square, Wilcoxon rank-sum, and multivariate stepwise logistic regression tests to characterize DNR (established in-house vs. pre-existing), describe predictors of establishing an in-house DNR, timing of an in-house DNR (early [within 1 day] vs late), and outcomes (death, ICU stay, major complications).ResultsIncluded were 10,053 patients with trauma, of which 1523 had a DNR order in place (15%); 715 (7%) had a pre-existing DNR and 808 (8%) had a DNR established in-house. Increases were observed over time in both the proportions of patients with DNRs established in-house (pu2009=u20090.008) and age ≥65 (pu2009<u20090.001). Over 90% of patients with an in-house DNR were ≥65 years. The following covariates were independently associated with establishing a DNR in-house: age ≥65, severe neurologic deficit (GCS 3–8), fall mechanism of injury, ED tachycardia, female gender, and comorbidities (pu2009<u20090.05 for all). Age ≥65, female gender, non-surgical service admission and transfers-in were associated with a DNR established early (pu2009<u20090.05 for all). As expected, mortality was greater in patients with DNR than those without (22% vs. 1%), as was the development of a major complication (8% vs. 5%), while ICU admission was similar (19% vs. 17%). Poor outcomes were greatest in patients with DNR orders executed later in the hospital stay.ConclusionsOur analysis of a broad cohort of patients with traumatic injury establishes the relationship between DNR and patient characteristics and outcomes. At 15%, DNR orders are prevalent in our general trauma population, particularly in patients ≥65 years, and are placed early after arrival. Established prognostic factors, including age and physiologic severity, were determinants for in-house DNR orders. These data may improve physician predictions of outcomes with DNR and help inform patient preferences, particularly in an environment with increasing use of DNR and increasing age of patients with trauma.

Anti-Inflammatory Activity in the Low Molecular Weight Fraction of Commercial Human Serum Albumin (LMWF5A)

The innate immune system is increasingly being recognized as a critical component in osteoarthritis (OA) pathophysiology. An ex vivo immunoassay utilizing human peripheral blood mononuclear cells (PBMC) was developed in order to assess the OA anti-inflammatory properties of the low molecular weight fraction (<5 kDa) of commercial human serum albumin (LMWF5A). PBMC from various donors were pre-incubated with LMWF5A before LPS stimulation. TNFα release was measured by ELISA in supernatants after an overnight incubation. A ≥ 30% decrease in TNFα release was observed. This anti-inflammatory effect is potentially useful in assessing potency of LMWF5A for the treatment of OA.

The epidemiology, prognosis, and trends of severe traumatic brain injury with presenting Glasgow Coma Scale of 3

Purpose: To characterize trends and prognosis of severe traumatic brain injury (TBI). Methods: This 5‐year multicenter retrospective study included patients with TBI and Glasgow Coma Scale of 3. We analyzed demographic and clinical characteristics and mortality using Pearson χ2 tests, Cochran‐Armitage trend tests, and stepwise logistic regression. Analyses were stratified by vehicular and fall etiologies; other etiologies were excluded (24%). Results: Included were 481 patients. Fall‐related injuries increased 58% (P = .001) but vehicular etiology did not change (P = .63). The characteristics of the populations changed over time; with falls, the population became older and increasingly presented with normal vital signs, whereas with vehicular etiology, the population became younger, with more alcohol‐related injury (P < .05 for all). Mortality from falls increased substantially from 25% to 63% (P < .001), whereas death from vehicular injures remained statistically unchanged but with a downward trend (50%‐38%, P = .28). Predictors of mortality included injury severity and age at least 65 years for both groups. Additional variables that were prognostic were abnormal vital signs and subdural hematoma for vehicular injuries, and sex for fall injuries. Conclusions: The epidemiology of severe TBI is changing. These epidemiologic data may be used for management and resource decisions, monitoring, and directing injury prevention measures. HighlightsSevere TBI resulting from fall etiology increased by 59% (26%‐41%, P = .001), whereas the severe TBI from vehicular injury did not change over time (49%‐44%, P = .63). There were significant changes in the make‐up of both the vehicular and fall population over time.Overall mortality with TBI and Glasgow Coma Scale 3 was 43% and did not differ by etiology. However, mortality from falls increased substantially from 25% to 63% (P < .001), whereas death from vehicular etiology remained statistically unchanged but with a downward trend.A key prognostic indicator of mortality for vehicular etiology was abnormal emergency department vital signs, increasing the odds of mortality 2.7‐fold. On the contrary, mortality with a fall etiology was identical with normal and abnormal emergency department vital signs (48% for both).

The low molecular weight fraction of human serum albumin upregulates production of 15d-PGJ2 in Peripheral Blood Mononuclear Cells

Activation of the innate immune system involves a series of events designed to counteract the initial insult followed by the clearance of debris and promotion of healing. Aberrant regulation can lead to systemic inflammatory response syndrome, multiple organ failure, and chronic inflammation. A better understanding of the innate immune response may help manage complications while allowing for proper immune progression. In this study, the ability of several classes of anti-inflammatory drugs to affect LPS-induced cytokine and prostaglandin release from peripheral blood mononuclear cells (PBMC) was evaluated. PBMC were cultured in the presence of dexamethasone (DEX), ibuprofen (IBU), and the low molecular weight fraction of 5% albumin (LMWF5A) followed by stimulation with LPS. After 24xa0h, TNFα, PGE2, and 15d-PGJ2 release was determined by ELISA. Distinct immunomodulation patterns emerged following LPS stimulation of PBMC in the presence of said compounds. DEX, a steroid with strong immunosuppressive properties, reduced TNFα, PGE2, and 15d-PGJ2 release. IBU caused significant reduction in prostaglandin release while TNFα release was unchanged. An emerging biologic with known anti-inflammatory properties, LMWF5A, significantly reduced TNFα release while enhancing PGE2 and 15d-PGJ2 release. Incubating LMWF5A together with IBU negated this observed increased prostaglandin release without affecting the suppression of TNFα release. Additionally, LMWF5A caused an increase in COX-2 transcription and translation. LMWF5A exhibited a unique immune modulation pattern in PBMC, disparate from steroid or NSAID administration. This enhancement of prostaglandin release (specifically 15d-PGJ2), in conjunction with a decrease in TNFα release, suggests a switch that favors resolution and decreased inflammation.

Lights and siren transport and the need for hospital intervention in trauma patients

Abstract Emergent ambulance transportation is associated with increased risk of collision, injury, and death for EMS professionals, patients, and the general public. Time saved using lights and siren (L&S) is typically small, and often provides minimal clinical benefit. Our objective was to investigate the frequency of L&S transports, describe the precision of the decision to employ L&S to predict the need for a time critical hospital intervention (TCHI) within 15 minutes of hospital arrival, identify clinical predictors of a TCHI, and compare clinical outcomes in patients transported by Emergency Medical Services (EMS) with and without L&S in a trauma-specific population. EMS patient care reports and trauma registry data were retrospectively reviewed for trauma patients consecutively transported from the field by three EMS agencies to three trauma centers within urban and suburban settings over a two-year period. TCHIs were collaboratively developed by the study team. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were utilized to report the precision of the decision to employ L&S to predict the need of a TCHI. Univariate and multivariate analyses determined predictors of a TCHI and compared clinical outcomes. 2,091 patients were included in the study. Of the 19.8% of patients transported with L&S, 22.9% received a TCHI. The most common TCHI was airway or respiratory procedures (87.2% of all TCHIs). The sensitivity and specificity of L&S to predict the need for a TCHI was 87.2% (95% CI 79.4–92.8) and 84.0% (95% CI 82.2–85.5), respectively. PPV was 23.0% (95% CI 23.53–38.01); NPV was 99.2% (95% CI 98.6–99.6). L&S was predictive for the need for a TCHI (p < 0.001), as was abnormal Glasgow Coma Score (p < 0.001), abnormal systolic blood pressure and age (p < 0.05 for all). Among patients that received a TCHI, over a third that were transported with L&S (36.8%) expired, compared with two of 14 patients (14.3%) not transported L&S. EMS professionals in this study demonstrated a high ability to discern which trauma patients did not require L&S. Nevertheless, L&S transport resulted in a TCHI less than one quarter of the time, suggesting an opportunity for further reduction of L&S transports in trauma patients.

Aggressive operative neurosurgical management in patients with extra-axial mass lesion and Glasgow Coma Scale of 3 is associated with survival benefit: A propensity matched analysis

INTRODUCTIONnPrognosis in patients with traumatic brain injury (TBI) and Glasgow Coma Scale (GCS) score of 3 is poor, raising concern regarding the utility of aggressive operative neurosurgical management. Our purpose was to describe outcomes in a propensity matched population with TBI and GCS3 treated with operative neurosurgical procedures of craniotomy or craniectomy (CRANI).nnnMETHODSnWe conducted a five-year, multicenter retrospective cohort study of patients with an ED GCS 3 and a positive head CT identified by ICD-9CM diagnosis codes. Two populations were examined: (1) patients with extra-axial mass lesion (subdural or epidural haematoma), (2) patients without mass lesion (subarachnoid and intraparenchymal haemorrhage including contusion, other intracerebral haemorrhage or intracranial injury including diffuse axonal injury). In patients with extra-axial mass lesion, propensity score techniques were used to match patients 1:1 by CRANI, and the following outcomes were analysed with conditional logistic regression: survival, favourable hospital disposition to home or rehabilitation, and development of complications.nnnRESULTSnThere were 541 patients with TBI and GCS3; 19% had a CRANI, 83% were initiated within 4h. In those with mass lesion, 27% (91/338) had a CRANI; after matching, a significant survival benefit was observed with CRANI vs. without CRANI (65% vs. 34% survival, OR: 3.9 (1.6-10.5) p<0.001). There was borderline increased odds of favourable disposition (43% vs. 26%, OR: 2.4 (0.99-6.3, p=0.052) with CRANI vs. without CRANI, and no difference in developing a complication (58% vs. 48%, OR: 1.5 (0.7-3.4), p=0.30).nnnCONCLUSIONSnSurvival was achieved in 65% of patients that underwent surgical intervention for subdural and epidural haematoma, despite a presenting GCS of 3. These results demonstrate prompt operative neurosurgical management of mass lesion is warranted for selected patients with a GCS of 3, contributing to a significant 4-fold survival benefit. In the absence of mass lesion the effect of immediate neurosurgery on outcomes is inconclusive.

Does diabetes type increase the odds of venous thromboembolism following traumatic injury

Background Venous thromboembolism (VTE) remains a clinically significant complication after trauma even though screening and prophylaxis strategies for at-risk patients have substantially reduced incidence. Our study sought to determine if diabetes, a condition that promotes thrombi formation, is associated with developing a VTE in trauma patients. Methods The registries of 2 level I and a level II trauma centers were retrospectively reviewed for consecutively admitted trauma patients over a 6-year period. Demographics, VTE risk factors, injury characteristics, and VTE incidence were univariately compared between patients with insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), and no diabetes. Stepwise logistic regression was performed to identify independent predictors of VTE; results were further stratified by age (<65 and ≥65u2005years) and presented as adjusted ORs (AOR). Results Of the 26u2005934 total patients, 779 (2.9%) had IDDM, 2052 (7.6%) had NIDDM, and the remaining 89.5% were without diabetes. VTE incidence was 3.6%, 2.4%, and 2.2%, in IDDM, NIDDM, and non-diabetes, respectively (p=0.02). After adjustment for established and significant risk factors, neither IDDM (AOR=1.43, 95% CI 0.95 to 2.15, p=0.09) nor NIDDM (AOR=1.03, 95% CI 0.75 to 1.40, p=0.88) was associated with increased odds of developing a VTE. Patients ≥65u2005years developed VTE more frequently than those <65u2005years (2.5% vs 2.1%, p=0.04). Among patients <65u2005years, IDDM was significantly predictive of VTE (AOR=1.86, 95% CI 1.01–3.41, p=0.045), but NIDDM was not. For patients ≥65u2005years, neither type of diabetes was predictive of VTE. Conclusions VTE incidence was ∼2 times higher among injured patients <65u2005years with IDDM versus no diabetes. Overall, we did not find an increased risk of VTE in patients with any diabetes. Additional studies are needed before a recommendation on VTE screening or prophylaxis in IDDM can be made. Level of evidence Level III, therapeutic/care management.