Plasma arginine correlations in trauma and sepsis.

Arginine (ARG) is an amino acid (AA) with unique properties and with a key-role in the metabolic, immune and reparative response to trauma and sepsis. This study has been performed to characterize the correlations between plasma levels of ARG, of other AA and of multiple metabolic variables in trauma and sepsis. Two-hundred and sixty-three plasma amino-acidograms with a large series of additional biochemical and blood variables were obtained consecutively in 9 trauma patients who developed sepsis, undergoing total parenteral nutrition with dextrose, fat and a mixed AA solution containing 10.4% arginine. ARG was low soon after trauma, then it increased with increasing distance from trauma and with the development of sepsis. ARG was also directly related to the AA infusion rate (AAIR) and for any given AAIR, was lower after trauma than after the development of sepsis. ARG was also related directly to the plasma levels of most of the other AA, the best correlation being that with lysine (r(2) = 0.81, p < 0.001). These correlations were often shifted downwards (showing lower ARG for any given level of the other AA) in measurements performed after trauma, compared to those performed after development of sepsis; this effect was more pronounced for the correlations with branched chain AA. Correlations between ARG and non-AA variables were not particularly relevant. The best simultaneous correlates of ARG, among variables involved in plasma ARG availability, were citrulline level, AAIR and urinary 3-methylhistidine excretion (accounting for the effect of endogenous proteolysis) (multiple r(2) = 0.70, p < 0.001). Plasma ornithine (ORN), the AA more specifically linked to ARG metabolism, correlated with AAIR better than ARG and, for any given AAIR, was lower after trauma than after the development of sepsis. Correlations of ORN with other AA levels were poorer than those found for ARG, however ORN was directly related to white blood cell and platelet count, fibrinogen, transferrin, cholesterol and many AA clearances. These data show that changes in ARG in trauma and sepsis are correlated with changes in other AA and, within these correlations, reconfirm a tendency to lower ARG in trauma compared to sepsis. The strong correlation with lysine warrants a deeper assessment of the practical implications of interdependency between these two AA. The data also suggest that changes in plasma ORN in trauma and sepsis may reflect adequacy of AA substrate to support acute-phase and other synthetic processes.

The relationship between plasma cholesterol, amino acids and acute phase proteins in sepsis.

The purpose of the study was to correlate degree of hypocholesterolemia to changes in plasma levels of amino acids and other metabolic variables in severely injured septic patients. Measurements included plasma cholesterol, full amino-acidograms, acute phase proteins, complementary variables and blood cell counts. The Fischer plasma molar amino acid ratio (leucine+isoleucine+valine)/(phenylalanine+tyrosine) was calculated. Plasma cholesterol for all measurements (n=145) was 3.1+/-1.1 mmol/L and, upon entry in the study, it was correlated inversely with sepsis severity score (p<0.05). Along the clinical course, changes in cholesterol were clearly paralleled by opposite changes in C-reactive protein, which was the best correlate of cholesterol (r2=0.70, p<0.0001). Furthermore cholesterol was inversely related to phenylalanine, fibrinogen, lactate and white blood cell count, and directly to the Fischer molar amino acid ratio, cystathionine, methionine, glycine and transferrin (r2 between 0.36 and 0.15, p<0.0001 for all). Within this pattern of correlations, cholesterol was also directly related to alkaline phosphatase, which accounted for the effect of cholestasis, when present. For any given value of the other variables, cholesterol increased significantly with increase in alkaline phosphatase (p<0.0001). C-reactive protein (CRP, mg/dl) and alkaline phosphatase (ALKPH, U/L) together in the same regression explained 79% of the variability of cholesterol (CHOL, mmol/L): CHOL=5.90-0.74[Log(e)CRP]+0.004[ALKPH]; multiple r2=0.79, p<0.0001. Inclusion in this regression of other variables did not increase the r2. By using only amino acid variables, the best fit was provided by a regression including the Fischer ratio and cystathionine, which explained 55% of the variability of cholesterol (multiple r2=0.55 p<0.0001), and this result was not improved by the inclusion of other amino acids. These data show that severity of hypocholesterolemia in sepsis is quantifiably related to changes in plasma amino acids, and to severity of acute phase response and metabolic decompensation. More study is needed to understand whether hypocholesterolemia in sepsis has only diagnostic or prognostic implications, or that it may also contribute actively to worsening of the disease.

Co-variation of plasma sodium, taurine and other amino acid levels in critical illness.

This study investigates the relationship between changes in plasma sodium and changes in amino acid levels in a patient with post-traumatic sepsis and prolonged critical illness. Ninety-two consecutive measurements were performed at regular intervals over a period of many weeks; these consisted in the determination of full amino-acidograms, plasma sodium and complementary variables. A unique, highly significant inverse correlation between taurine and plasma sodium was found (r(2) = 0.48, p < 0.001). All other amino acids were unrelated, or much more weakly related, to sodium. Taurine was also strongly and directly related to phosphoethanolamine, glutamate and aspartate. Changes in sodium and in levels of these amino acids explained up to 86% of the variability of taurine. Besides, levels of these amino acids maintained a high degree of co-variation, remaining reciprocally related one to each other, directly, with r(2) ranging between 0.33 and 0.59 (p < 0.001 for all). There were similar findings for beta-alanine, which however was measured inconsistently. These data provide gross clinical evidence of a specific link binding plasma sodium and taurine levels, and may be consistent with occurrence of opposite and interdependent shifts of sodium and taurine between intravascular and extravascular space, to maintain osmoregulation. Co-variation of taurine with the other amino acids may be related to the same phenomenon, and/or to similarities in transport systems and chemical structure, or true metabolic interactions.

Factors influencing the patterns of injuries and outcomes in car versus car crashes compared to sport utility, van, or pick-up truck versus car crashes: Crash Injury Research Engineering Network Study.

BACKGROUND: Data using crash dummies suggest that motor vehicle crashes (MVCs) involving passenger sedans (S) vs sport utility, vans, or light trucks (SUVTs) produce more severe injuries than those involving two sedans (SvS). However, no detailed data regarding pattern of injuries or force mechanisms involved have been presented in real patients. METHODS: The relationship of injury patterns and severities with MVC reconstruction data were obtained in 412 MVC patients, drivers or front seat passengers. Crashes were examined with regard to impact direction, frontal (F) or lateral (L) crashes, vehicle mass ratio, ISS, DELTA V, seat belt use, and airbag deployment (AB). RESULTS: In 309 F-MVC, AB reduced overall ISS (24.3 to 17.9) with a reduction in the mean severity of traumatic brain injury (TBI) GCS < or = 12, from 48% to only 28%. This AB protection from TBI was preserved as DELTA V increased to > 30 mph even though non-AB protected body areas (thorax, lung, liver, and lower extremity injuries) all increased. When vehicles of incompatible size and mass (SUVT) had F-MVC with sedans the incidence of severe TBI rose as did face lacerations despite AB or belt use. In L-MVC between SUVT and sedans compared with SvS MVC, there was a cephalad shift in body injuries with increased thorax, but decreased lower extremity injuries. The incidence of TBI increased. Analysis of injury contact sites (hits) showed more hits and a wider distribution of contract sites in SUVT vs sedan MVC. These appeared due to the greater mass excess and larger mass ratio, hood height, and width in the F-SUVT vs S crashes. All of these factors plus the increased bumper height above the body frame side-door sill were injury causal factors in the L-SUVT vs S MVCs. CONCLUSION: Both F and L crashes between sedans and SUVT with a high mass ratio shift the pattern of injury cephalad with increased thorax and intrathoracic organ injuries, and more severe TBI. These data suggest that improved head and thorax side-impact buffering and design features which transmit MVC forces from the higher front end of the larger mass SUVT to the frame of the sedan may better protect sedan occupants from side-impacts.

Augmented TNF-alpha and IL-10 production by primed human monocytes following interaction with oxidatively modified autologous erythrocytes.

The presence of dysfunctional/damaged red blood cells (RBCs) has been associated with adverse clinical effects during the inflammatory response. The aim of this study was to elucidate whether oxidatively modified, autologous RBCs modulate monocyte cytokine responses in humans. Monocyte tumor necrosis factor alpha (TNF-alpha) and IL-10 production was measured in whole blood from healthy volunteers using ELISA and flow cytometry. Oxidatively modified RBCs (15 mM phenylhydrazine, 1 h, OX-RBC) or vehicle-treated RBCs (VT-RBC) opsonized by autologous serum were administered alone or in combination with one of three priming agents: E. coli lipopolysaccharide (LPS, 0.2 ng/ml), zymosan A (1 mg/ml), or phorbol 12-myristate 13-acetate (PMA, 50 ng/ml). OX-RBC or VT-RBC alone did not result in the release of TNF-alpha or IL-10. LPS, zymosan, and PMA caused marked and dose-dependent increases in TNF-alpha and IL-10 production. Addition of OX-RBC augmented the LPS-, zymosan-, and PMA-induced TNF-alpha release by approximately 100%. OX-RBC augmented LPS- and zymosan-induced IL-10 release by 400-600%. Flow cytometry analyses showed that monocytes were responsible for TNF-alpha and IL-10 production in whole blood. The presence of OX-RBC alone increased the complexity of CD14+ monocytes but caused no cytokine production. LPS alone induced cytokine production without altering cell complexity. After the combined (OX-RBC+LPS) treatment, monocytes of high complexity were responsible for TNF-alpha production. The presence of mannose or galactose (at 10-50 mM) did not alter the observed augmentation of cytokine production by OX-RBC, suggesting that lectin receptors are not involved in the response. These studies indicate that the interaction between damaged autologous erythrocytes and monocytes has a major impact on the cytokine responses in humans. An augmented cytokine production by the mononuclear phagocyte system may adversely affect the clinical course of injury and infections especially in genetic or acquired RBC diseases or after transfusions.

Endoscopic retrograde cholangiopancreatography and the pancreas: when and why?

Historically, endoscopic retrograde cholangeopancreatography (ERCP) has played a unique role as a diagnostic and therapeutic modality for diseases of the pancreas. Despite the advent of new imaging techniques, ERCP continues to play a central role in the evaluation and treatment of pancreatitis of various causes. Endoscopic cholangiography and stenting remain mainstays in the palliation of inoperable obstructive jaundice in patients with cancer of the pancreas.

Endoscopic therapy for chronic pancreatitis.

Endoscopic therapy for chronic pancreatitis is feasible and effective in selected patients. The management of pain and ductal obstruction is most effective if reversal of the obstructive process--stricture or stone--is successful and durable. Multiple endoscopic modalities are available, and new technologies will continue to advance the capabilities of therapeutic pancreatic endoscopists. Adjunctive treatments, such as ESWL, enhance the success of these techniques. These varied therapies, although attractive and theoretically sensible, have not been compared in a randomized, controlled fashion with standard surgical therapies. In this sense, they remain experimental. Nonetheless, these techniques are widely applied in advanced endoscopy centers worldwide, and uncontrolled individual series are expected to continue to expound on and demonstrate the effectiveness of these minimally invasive interventions until randomized, prospective studies become available.

Pancreas divisum: endoscopic therapy.

Pancreas divisum is a common congenital variation that can be associated with pancreatic disease. Symptomatic patients with divisum must be classified according to clinical presentation and morphologic findings. Response to endoscopic therapy is best in patients with ARP, of whom 75% benefit. Results in patients with chronic pancreatitis and pain but without objective pancreatitis are mixed, and patients should be carefully selected.

Increased incidence of sepsis and altered monocyte functions in severely injured type A- glucose-6-phosphate dehydrogenase-deficient African American trauma patients.

OBJECTIVE: To determine whether trauma patients with the common, type A- glucose-6-phosphate dehydrogenase (G6PD) deficiency have an aggravated inflammatory response, increased incidence of septic complications, and/or more profound alterations in leukocyte functions compared with nondeficient trauma patients. SETTINGS: Intensive and surgical care units of a trauma center and flow cytometry and experimental laboratories at a teaching university hospital. DESIGN: Prospective cohort clinical study with measurements on days 2 and 5 postinjury. Monocyte and neutrophil oxidant content, apoptosis, and CD11b expression and plasma cytokine levels were compared between G6PD-deficient and nondeficient patients. PATIENTS: A total of 467 male African American trauma patients were screened for the deficiency. Forty-four type A-202/376 G6PD-deficient patients were identified and enrolled in the study; 43 nondeficient patients were also enrolled and were matched by age, clinical criteria of injury severity, and type of trauma. MAIN RESULTS: After severe injury (Injury Severity Score, > or =16), 50% of the deficient and 6.2% of nondeficient patients developed sepsis with positive bacterial blood cultures. In deficient patients, the frequency of bronchial (75%) and wound infections (25%) was also increased compared with nondeficient patients (32% and 0%). The durations of systemic inflammatory response syndrome, Sepsis Syndrome, and days on antibiotics were three times longer in deficient than in nondeficient individuals. However, adult respiratory distress syndrome occurred in 37% of both groups. Anemia was more severe in the deficient than nondeficient patients from day 10 posttrauma. On day 5, the peroxide content was doubled, apoptosis was decreased, and CD11b expression was increased in monocytes from deficient patients compared with cells from nondeficient patients. On day 5, the plasma interleukin (IL)-10 concentration was significantly lower in deficient than nondeficient patients, whereas tumor necrosis factor-alpha, IL-6, and IL-8 levels were similar. After moderate injuries (Injury Severity Score, 9-16), the deficiency was not associated with adverse clinical effects, and the trauma-induced changes in leukocyte function were similar in deficient and nondeficient patients. CONCLUSIONS: The common type A- G6PD deficiency predisposes septic complications and anemia in trauma patients after severe injuries as defined by an Injury Severity Score of > or =16. This adverse clinical course is accompanied by altered monocyte functions manifested as augmented oxidative stress, a decreased apoptotic response, increased cell adhesion properties, and a diminished IL-10 response.

Distortion-product otoacoustic emissions measured at high frequencies in humans.

Distortion-product otoacoustic emissions (DPOAEs) elicited with stimulus frequencies less than or equal to 8 kHz have been used in hearing clinics to assess whether the middle ear and cochlea are normal, but high-frequency hearing (>4 kHz) is most vulnerable to cochlear pathology. It might prove useful to measure DPOAEs with even higher frequency stimuli (>8 kHz), but there have been few reports of such studies in humans. DPOAEs have been measured in other mammals to the upper range of hearing sensitivity. The purpose of this study was to compare some characteristics of DPOAEs in human subjects elicited with high-frequency stimuli with those that have been extensively measured with lower-frequency stimuli. The primary goal was to establish if the same phenomenon responsible for the behavior of low-frequency DPOAEs is responsible for the behavior of high-frequency DPOAEs. Specifically, the DPOAE level with stimuli varied from 2 to 20 kHz, growth functions of DPOAEs, effects of varying the primary frequency ratio (f2/f1) on the DPOAE level, and DPOAE group delay were determined. Because the behaviors appeared to vary smoothly with stimulus frequency, the study suggests that emissions measured from 2 to 20 kHz were the product of the same biological process.

Metabolic correlates of oxygen debt predict posttrauma early acute respiratory distress syndrome and the related cytokine response.

BACKGROUND: The purpose of this study was to quantify the relationship between negative base excess (base deficit) and lactate as correlates of oxygen debt and the probability of the early acute respiratory distress syndrome (ARDS) response and with regard to the mediator and metabolic response characteristic of this disease. METHODS: Eighty patients with multiple trauma were studied (514 samples) during their intensive care unit courses (Injury Severity Score 27.6+/-8.8, 36% deaths). Simultaneous samples of arterial base excess and lactate as correlates of oxygen debt, and enzyme-linked immunosorbent assay-measured mixed venous cytokines were obtained daily. At each sample period, the patient was categorized as having ARDS or non-ARDS. RESULTS: Twenty-nine patients (36%; 19 deaths) developed ARDS over the period studied: 17 in postinjury days 1 to 4 (EARLY ARDS) and 12 in postinjury days 5 or later (LATE ARDS). Patients subsequently developing ARDS had evidence of ischemic acidosis on or within the first 24 hours after hospital admission (lower base excess -7.1 mmol/L and higher lactate 5.2 mmol/L in ARDS versus base excess -3.8 mmol/L and lactate 3.6 mmol/L in non-ARDS; p < 0.05). Patients with EARLY ARDS showed even lower (p < 0.05) initial 24 hour mean base excess and higher lactate (base excess -9.1 mmol/L and lactate 6.4 mmol/L) compared with LATE ARDS (base excess -4.3 mmol/L and lactate 3.3 mmol/L). In EARLY ARDS, this degree of ischemic acidosis was followed by a greater mean IL-6 response in the postinjury days 1 to 4 (323 pg/mL) compared with the LATE ARDS response (141 pg/mL) (p < 0.05) or compared with the non-ARDS IL-6 response (67 pg/mL; p < 0.001). In addition, in EARLY ARDS, mean IL-8 levels in postinjury days 1 to 4 (264 pg/mL) were higher than in LATE ARDS (168 pg/mL) (p < 0.05) and the mean IL-1 response in postinjury days 1 to 4 of EARLY ARDS (65 pg/mL) was greater than non-ARDS (32 pg/mL) (p < 0.05). Derivation of probability curves suggests a critical threshold of base excess -6.6 mmol/L or greater for an increased risk of EARLY ARDS. CONCLUSION: These data suggest that the maximum posttrauma oxygen debt (quantified by the ischemia correlates of negative base excess and lactate) is a critical primary determinant of the later fulminant autoinflammatory EARLY ARDS response mediated by the host's endogenous cytokine mediators.

The relationship between plasma taurine and other amino acid levels in human sepsis.

Although reports of decreased plasma taurine in trauma, sepsis and critical illness are available, very little is known about the relationships among changes in plasma taurine, other amino acid levels and metabolic variables. We analyzed a large series of plasma amino acid profiles obtained in trauma patients with sepsis who were undergoing total parenteral nutrition. The correlations between plasma taurine, other amino acid levels, parenteral substrate doses and metabolic and cardiorespiratory variables were assessed by regression analysis. Post-traumatic hypotaurinemia was followed by partial recovery toward less abnormal values when sepsis developed. Levels of taurine were directly and significantly related to levels of glutamate, aspartate, beta-alanine and phosphoethanolamine (and unrelated to other amino acids). Levels of these amino acids increased simultaneously with increasing doses of leucine, isoleucine and valine in total parenteral nutrition. Decreasing taurine was associated with increasing lactate, arteriovenous O(2) concentration difference and respiratory index, and with decreasing cholesterol and cardiac index. These results characterize the relationships between plasma taurine and other amino acid levels in sepsis, provide evidence of amino acid interactions that may support taurine availability and show more severe decreases in plasma taurine with the worsening of metabolic and cardiorespiratory patterns.

Taurine and pulmonary hemodynamics in sepsis.

This study has been performed to characterize the relationship between changes in plasma taurine (TAU) and hemodynamic patterns in sepsis. Analysis of 249 plasma aminoacidograms (AA-grams) and associated measurements in a group of critically ill, mechanically ventilated septic patients, showed that decreases in TAU were significantly correlated with increases in pulmonary artery pressure and pulmonary vascular resistance, and with worsening of pulmonary dysfunction. All cases requiring positive end-expiratory pressure greater than 10cmH2O had TAU lower than 50 microM/L. Low TAU was paralleled by decreases in other sulfur-containing AA, phosphoethanolamine, beta-alanine, glutamate and aspartate, within a pattern of greater metabolic dysregulation. These data provide evidence of a link between severity of pulmonary dysfunction and reduced TAU availability in clinical sepsis. The implications relate also to the need for specific investigations of the clinical effect of exogenous TAU on proinflammatory mediator-induced pulmonary dysfunction.

The utility of venous lactate to triage injured patients in the trauma center.

BACKGROUND: Field triage criteria for trauma patients results in over-triage rates of 30% to 50% to achieve under-triage rates of 10%. This large number of patients may stress trauma center resources. Elevated arterial lactate (ALAC) levels have been shown to be a marker of serious injury but the need for arterial sampling limits the utility of the determination. The goal of this study was: 1) to determine the correlation between venous lactate (VLAC) and ALAC; 2) to determine whether VLAC could identify those patients with serious injuries; and 3) to compare an elevated VLAC level against standard triage criteria (STC) in their ability to identify major injury. STUDY DESIGN: Arterial and venous samples for blood gas and lactate analyses were obtained in 375 patients within 10 minutes of patient arrival to the trauma center. Arterial and venous samples were drawn within 2 minutes of each other, placed on ice, and analyzed within 10 minutes of sampling. The location of sampling was left to physician discretion. Data collected included injury mechanism, demographics, admission vital signs, emergency department disposition, length of stay, and injury severity scores (ISS). Admission to the ICU, need for emergency operation, length of stay, and death were noted. Emergency medical service staff were queried to determine which standard triage criteria (STC) were fulfilled. RESULTS: The mean ALAC was 3.11 mmol/L (SD 3.45, 95% confidence interval [CI] 2.67 to 3.55) and mean VLAC was 3.43 mmol/L (SD 3.41, 95% CI 2.96 to 3.90). There was no significant difference between ALAC and VLAC. The correlation between ALAC and VLAC was 0.94 (95% CI 0.94 to 0.96, p = 0.0001). An elevated VLAC predicted moderate to severe injury and there was a significant association between an increased lactate and maximum Abbreviated Injury Score (AIS) of 4 and 5 (ANOVA, F = 8.26, p < 0.001). Patients with VLAC > or =2 mmol/L had significantly increased relative risks of ISS > or = 13, death, admission to the ICU, and length of stay > 2 days. In comparison with STC, a VLAC > or = 2 mmol/L decreased undertriage in patients with ISS > or = 13 by one half (11% versus 24%) for patients with ISS > or = 13 and decreased over-triage by 28% (46% versus 64%). These data were most pronounced for patients injured in motor vehicle collisions. CONCLUSIONS: VLAC is an excellent approximation for ALAC. A VLAC > or = 2 mmol/L appears to predict an ISS > or = 13, the need for ICU resources, and prolonged hospital stays. VLAC was significantly better than STC in all patients and was most useful in victims of blunt trauma, especially motor vehicle collisions.

Effect of change in velocity on the development of medical complications in patients with multisystem trauma sustained in vehicular crashes.

Medical complications such as sepsis or multiple organ system failure increase the morbidity and mortality associated with injuries sustained in car crashes. This study addresses the question of the association, if any, between one crash characteristic, i.e. change in velocity (delta v), and subsequent medical complications. Data on seventy-six severely injured patients were obtained as part of an in-depth, trauma-center-based study of the biomechanics of vehicular trauma. Factors found to be predictive of the development of complications included patient age > or = 36 years, delta v > or = 30 mph, and injury severity score > or = 25. Vehicle occupants involved in crashes with a delta v > or = 30 mph had a risk of complications more than five times greater than for those in the lower delta v group. Better knowledge of the dynamics and severity of the crash could help clinical staff anticipate the development of complications and initiate timely prevention strategies.