Age and mortality after injury: is the association linear?

INTRODUCTION: Multiple studies have demonstrated a linear association between advancing age and mortality after injury. An inflection point, or an age at which outcomes begin to differ, has not been previously described. We hypothesized that the relationship between age and mortality after injury is non-linear and an inflection point exists. METHODS: We performed a retrospective cohort analysis at our urban level I center from 2007 through 2009. All patients aged 65 years and older with the admission diagnosis of injury were included. Non-parametric logistic regression was used to identify the functional form between mortality and age. Multivariate logistic regression was utilized to explore the association between age and mortality. Age 65 years was used as the reference. Significance was defined as p < 0.05. RESULTS: A total of 1,107 patients were included in the analysis. One-third required intensive care unit (ICU) admission and 48 % had traumatic brain injury. 229 patients (20.6 %) were 84 years of age or older. The overall mortality was 7.2 %. Our model indicates that mortality is a quadratic function of age. After controlling for confounders, age is associated with mortality with a regression coefficient of 1.08 for the linear term (p = 0.02) and a regression coefficient of -0.006 for the quadratic term (p = 0.03). The model identified 84.4 years of age as the inflection point at which mortality rates begin to decline. CONCLUSIONS: The risk of death after injury varies linearly with age until 84 years. After 84 years of age, the mortality rates decline. These findings may reflect the varying severity of comorbidities and differences in baseline functional status in elderly trauma patients. Specifically, a proportion of our injured patient population less than 84 years old may be more frail, contributing to increased mortality after trauma, whereas a larger proportion of our injured patients over 84 years old, by virtue of reaching this advanced age, may, in fact, be less frail, contributing to less risk of death.

Rethinking bicycle helmets as a preventive tool: a 4-year review of bicycle injuries.

INTRODUCTION: Traumatic brain injury is a leading cause of disability in bicycle riders. Preventive measures including bicycle helmet laws have been highlighted; however, its protective role has always been debated. The aim of this study was to determine the utility of bicycle helmets in prevention of intra-cranial hemorrhage. We hypothesized that bicycle helmets are protective and prevent the development of intra-cranial hemorrhage. METHODS: We performed a 4-year (2009-2012) retrospective cohort analysis of all the patients who presented with traumatic brain injury due to bicycle injuries to our level 1 trauma center. We compared helmeted and non-helmeted bicycle riders for differences in the patterns of injury, need for intensive care unit admissions and mortality. RESULTS: A total of 864 patients were reviewed of which, 709 patients (helmeted = 300, non-helmeted = 409) were included. Non-helmeted bicycle riders were more likely to be young (p < 0.001) males (p = 0.01). There was no difference in the median ISS between the two groups (p = 0.3). Non-helmeted riders were more likely to have a skull fracture (p = 0.01) and a scalp laceration (p = 0.01) compared to the helmeted riders. There was no difference in intra-cranial hemorrhage between the two groups (p = 0.1). Wearing a bicycle helmet was not independently associated (p = 0.1) with development of intra-cranial hemorrhage. CONCLUSION: Bicycle helmets may have a protective effect against external head injury but its protective role for intra-cranial hemorrhage is questionable. Further studies assessing the protective role of helmets for intra-cranial hemorrhage are warranted.

Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat.

Understanding catecholamine metabolism is crucial for elucidating the pathogenesis of hereditary hypertension. Here we integrated transcriptional and biochemical profiling with physiologic quantitative trait locus (eQTL and pQTL) mapping in adrenal glands of the HXB/BXH recombinant inbred (RI) strains, derived from the spontaneously hypertensive rat (SHR) and normotensive Brown Norway (BN.Lx). We found simultaneous down-regulation of five heritable transcripts in the catecholaminergic pathway in young (6 weeks) SHRs. We identified cis-acting eQTLs for Dbh, Pnmt (catecholamine biosynthesis) and Vamp1 (catecholamine secretion); enzymatic activities of Dbh and Pnmt paralleled transcripts, with pQTLs for activities mirroring eQTLs. We also detected trans-regulated expression of Vmat1 and Chga (both involved in catecholamine storage), with co-localization of these trans-eQTLs to the Pnmt locus. Pnmt re-sequencing revealed promoter polymorphisms that result in decreased response of the transfected SHR promoter to glucocorticoid, compared with BN.Lx. Of physiological pertinence, Dbh activity negatively correlated with systolic blood pressure in RI strains, whereas Pnmt activity was negatively correlated with heart rate. The finding of such cis- and trans-QTLs at an age before the onset of frank hypertension suggests that these heritable changes in biosynthetic enzyme expression represent primary genetic mechanisms for regulation of catecholamine action and blood pressure control in this widely studied model of hypertension.

Different preconditioning stimuli invoke disparate electromechanical and energetic responses to global ischemia in rat hearts.

One hypothesized mechanism of the cardioprotection provided by preconditioning is decreased utilization of ATP during ischemia. Although ATP levels in preconditioned heart during ischemia have been previously studied, contractile activity during ischemia has not been investigated. Contractile activity accounts for significant ATP consumption during ischemia. We hypothesized that preconditioning stimuli may conserve energy during the ischemic period by decreasing myocardial contractile energy expenditure prior to asystolic cardiac arrest. We studied three preconditioning stimuli: (i) four cycles of 5-min periods of ischemia (4 x 5' CI), (ii) 2 min of alpha 1-adrenergic stimulation (phenylephrine; PE), and (iii) 2 min of P1-purinergic stimulation (adenosine). The effects of these stimuli on myocardial ATP, ventricular contractility, and the time to cessation of electromechanical function (asystole) during the sustained ischemic period were then examined. Preconditioning stimuli (4 x 5' CI, phenylephrine, and adenosine) improved postischemic functional recovery compared with nonpreconditioned controls. Myocardial ATP contents at the end of 20 min of global ischemia were higher for adenosine-treated (9.0 +/- 1.5 mumol/g dry weight; p < 0.05) and PE-treated (9.9 +/- 1.9 mumol/g dryweight; p < 0.05) hearts than for controls (6.6 +/- 1.2 mumol/g dry weight). The CI hearts began with lower myocardial ATP levels (9.9 +/- 1.2 mumol/g dry weight; p < 0.05) than other groups prior to the sustained ischemic period (control 13.4 +/- 1.0 mumol/g dry weight). As a result of a lower rate of ATP depletion, ATP levels in the CI group were similar to the untreated control after 20 min of sustained ischemia (5.5 +/- 0.7 mumol/g dry weight). Preconditioning with 4 x 5' CI or adenosine (but not PE) led to earlier ventricular arrest. Only adenosine-treated hearts demonstrated a more rapid decline in ventricular contractility during sustained ischemia than did nonpreconditioned control hearts. We conclude that while the final recovery of ventricular contractility after asystolic arrest and reperfusion is improved by preconditioning with different stimuli (4 x 5' CI, adenosine, or PE), each stimulus conferred a characteristic electromechanical and energy conservation strategy during sustained ischemia. Adenosine conserved myocardial ATP content and reduced total cardiac work (developed pressure and heart beats). CI conserved myocardial ATP and minimized the number of ischemic cardiac beats. PE preserved myocardial ATP during ischemia without changing contractile behavior. Thus, energy conservation strategies during ischemia could contribute to the protection afforded by preconditioning stimuli, but the mechanisms appear to differ among stimuli.

Impairment of endothelial-dependent pulmonary vasorelaxation after mesenteric ischemia/reperfusion.

BACKGROUND: A major hemodynamic feature of acute lung injury is pulmonary hypertension caused by pulmonary vasoconstriction. Impairment of the mechanisms of pulmonary vasorelaxation may contribute to this pulmonary vasoconstriction. This study examined the effect of mesenteric ischemia/reperfusion (I/R) on lung neutrophil accumulation and endothelial-dependent and -independent cyclic 3'-5' guanosine monophosphate-mediated pulmonary vasorelaxation in rats. METHODS: Rats were studied after 1 hour of superior mesenteric artery occlusion and 2 hours of reperfusion. Lung neutrophil accumulation was determined by myeloperoxidase assay (MPO). The following mechanisms of pulmonary vasorelaxation were studied in isolated pulmonary artery rings by generating dose response curves (10(-9) to 10(-6)mol/L): (1) receptor-dependent, endothelial-dependent relaxation (response to acetylcholine), (2) receptor-independent, endothelial-dependent relaxation (response to the calcium ionophore, A23187), and (3) endothelial-independent relaxation (response to sodium nitroprusside [SNP]). RESULTS: Lung MPO activity was significantly increased from 2.4 +/- 0.2 units/gm lung weight in controls to 10.3 +/- 0.4 after mesenteric I/R (p < 0.05). The vasorelaxation response to SNP was not different after mesenteric I/R, but vasorelaxation by both acetylcholine and A23187 were significantly impaired. CONCLUSIONS: Endothelial-dependent pulmonary vasorelaxation is significantly impaired after mesenteric I/R. Such impairment of pulmonary vasorelaxation may help tip the net balance of pulmonary vasomotor tone toward vasoconstriction and contribute to the pulmonary hypertension seen in acute lung injury.

Inhaled nitric oxide prevents pulmonary endothelial dysfunction after mesenteric ischemia-reperfusion.

This study examined the effect of inhaled nitric oxide (NO) on lung neutrophil accumulation and endothelial-dependent and -independent guanosine 3',5'-cyclic monophosphate (cGMP)-mediated mechanisms of pulmonary vasorelaxation after mesenteric ischemia-reperfusion (I/R) in mechanically ventilated rats. Inhaled NO (20 ppm) was administered in two protocols: 1) throughout mesenteric I/R and 2) during mesenteric reperfusion alone. Concentration-response curves were generated (10(-9) to 10(-8) M) for acetylcho-line (ACh), A23187, and sodium nitroprusside (SNP) in isolated pulmonary arterial rings preconstricted with phenylephrine. Lung neutrophil accumulation [myeloperoxidase assay (MPO)] was significantly increased from 2.4 +/- 0.2 units/g lung wt in controls to 10.3 +/- 0.4 after 1 h of superior mesenteric artery occlusion and 2 h of reperfusion. Lung MPO activity was not different from controls in rats receiving inhaled NO either 1) during mesenteric I/R or during mesenteric reperfusion alone. The concentration-response curves demonstrated significant impairment of pulmonary vasorelaxation by endothelial-dependent mechanisms (response to ACh and A23187) but not endothelial-independent pulmonary vasorelaxation (response to SNP) after mesenteric I/R. This pulmonary vasomotor dysfunction was prevented by administration of inhaled NO during either mesenteric I/R or during mesenteric reperfusion alone. We conclude that inhaled NO prevents lung neutrophil accumulation and pulmonary vascular endothelial dysfunction after mesenteric I/R.

NO prevents neutrophil-mediated pulmonary vasomotor dysfunction in acute lung injury.

The purpose of this study was to examine the effect of administration of inhaled nitric oxide (NO) on lung neutrophil accumulation and pulmonary vascular endothelial cell function in endotoxin-induced acute lung injury. Mechanically ventilated rats were studied 4 hr after endotoxin (0.5 mg/kg IP). Inhaled NO (20 ppm) was administered for either the entire 4 hr after endotoxin (continuous group) or for only the first 2 of 4 hr after endotoxin (abbreviated group). Endothelial-dependent (acetylcholine, ACh) and -independent cGMP-mediated relaxation (nitroprusside, SNP) pulmonary vasorelaxation were studied in isolated pulmonary arterial rings. Lung neutrophil accumulation was determined by myeloperoxidase assay (MPO). Inhaled NO prevented endotoxin-induced lung neutrophil accumulation as well as pulmonary endothelial cell dysfunction. However, this protection required continuous administration of inhaled NO. We conclude that inhaled NO prevents neutrophil-mediated pulmonary vascular endothelial cell dysfunction in acute lung injury.

Alpha-adrenergic preservation of myocardial pH during ischemia is PKC isoform dependent.

alpha-adrenergic stimulation of patients with ischemic heart disease should intuitively impose a destructive stress. However, therapeutic alpha1-adrenergic receptor mediated cardioadaptation prior to myocardial ischemia protects ventricular mechanical function, promotes electrophysiologic stability, and preserves myocyte viability. Prior to an anticipated cardiac ischemic insult, alpha1-adrenergic preconditioning attenuates ischemic myocardial acidosis by a protein kinase C-(PKC) dependent mechanism. The alpha1-adrenoceptor can directly stimulate calcium-independent nPKC isoforms via diacylglycerol (DAG) or indirectly stimulate calcium-dependent cPKC isoforms through the release of intracellular calcium via inositol triphosphate, (IP3). We hypothesized that alpha1-adrenergic limitation of ischemic acidosis is mediated by the family of calcium-dependent PKC isoforms. [31P]NMR spectra were obtained in isolated, buffer perfused rat hearts treated with alpha1-adrenergic stimulation [phenylephrine (PE) 50 microM, 2 min]; PKC blockade [chelerythrine chloride, (Chel) 20 microM]; or stearoyl-arachidonoyl glycerol (SAG, a DAG analogue, 100 microM, 2 min) administered 10 min prior to ischemia. Control hearts were perfused under normoxic conditions for 20 min. All hearts were then subjected to global ischemia (20 min, 37.5 degrees C). Developed pressure (DP) and heart rate were recorded continuously. pHi was obtained from chemical shift of inorganic phosphate. Immunohistochemical staining was utilized to delineate the translocation and activation profiles of specific PKC profiles established with each stimulus. Pre-ischemic alpha1-adrenergic stimulation did attenuate the myocellular hydrogen ion accumulation during sustained normothermic ischemia (6.90 +/- 0.13 vs control 6.54 +/- 0.10; P < 0.05). General PKC inhibition abrogated this effect (end-ischemic pH 6.17 +/- 0.10; P < 0.05 vs control and PE). Ischemic acidosis was not attenuated following selective nPKC stimulation (SAG, 6.48 +/- 0.08; NS vs control). Myocellular immunohistochemical staining revealed translocation of the calcium-independent PKC-epsilon isoform in the calcium-dependent PKC (SAG) group, but not in response to alpha1-adrenergic stimulation. The results suggest that (1) alpha1-adrenoceptor stimulation limits ischemic acidosis, (2) alpha1-adrenergic stimulated attenuation of ischemic acidosis is PKC dependent, (3) direct nPKC stimulation with SAG does not limit ischemic acidosis, and (4) SAG stimulates nPKC-epsilon isoform activation where alpha1-adrenergic stimulation does not. We conclude that alpha1-adrenergic stimulation limits ischemic acidosis by a cPKC-dependent mechanism and that the mobilization of the IP3 arm by receptor stimuli suppresses PKC-epsilon thus permitting the limitation of ischemic acidosis.

Clinically accessible cell signaling: second messengers in sepsis and trauma.

Inflammatory mediators of trauma and sepsis transduce cellular events through cell surface receptors initiating intricate membrane and cytosolic reaction cascades that funnel through surprisingly few checkpoints in order to provoke a cellular response. As critical care surgeons, we can explore these cell signalling systems. The purpose of this article is to delineate the six known second messenger pathways relevant to surgical sepsis and trauma. Our comprehension of these signaling systems may offer us an opportunity to blunt post-traumatic cellular injury and promote a constructive response.

Cardiac preconditioning protects against irreversible injury rather than attenuating stunning.

The purpose of this experiment was to determine if cardiac preconditioning (PC) mediates protection by attenuating stunning or preventing irreversible injury. Inherent in the definition of myocardial stunning is the ability to respond to catechol stimulation after ischemia/reperfusion (I/R). Irreversibly injured myocardium cannot respond to catechols. We hypothesized that alpha 1-adrenergic-stimulated PC is mediated through a functional protection against reversible injury. We investigated this hypothesis in the isolated, buffer-perfused rat heart subjected to global ischemia (20 min, 37.5 degrees C) and reperfusion (40 min). The PC group received an alpha 1-adrenergic stimulus (norepinephrine, 0.5-1.0 microM, 2 min) 10 min prior to ischemia. Control hearts were perfused normoxically for 80 min. Developed pressure (DP) and heart rate were recorded continuously. To determine maximal myocellular function, all hearts received a beta-adrenergic pathway stimulus (forskolin (FSK), 100 microM bolus) at end reperfusion. The ability to improve DP in response to FSK was indicative of reversible dysfunction (stunning). Failure to attain the maximal DP established in normoxic controls was utilized as a measure of irreversible dysfunction. Recovery was assessed as a percentage of initial DP. The results suggest that (1) PC protects against an I/R injury (recovery: I/R, 50.1%; PC + I/R, 76.0%; P < 0.05); (2) all groups exhibit reversible dysfunction (all increased DP in response to FSK); (3) when maximally stimulated, I/R hearts are unable to develop pressures similar to those of normoxic controls, suggesting irreversible injury; and (4) PC hearts, however, attained similar maximal pressures compared to controls. We conclude that alpha 1-adrenergic PC improves postischemic cardiac function by preventing irreversible injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Trauma primes cells.

Trauma induces many dramatic and complex changes in host cellular response. This complexity arises from the constellation of signals induced by stress, infection, and injury. Cellular priming, defined as altered response to an agonist induced by an antecedent stimulus, appears to be operative after trauma. If the interaction between two signalling pathways is such that one augments (or depresses) the other, subsequent stimulation of the second "primed" pathway can result in an exaggerated (or attenuated) response. Thus, trauma can prime cells in either a constructive or destructive fashion. Receptor stimulation by priming agents results in the activation of receptor-specific cell signalling pathways. These intracellular signalling pathways can "crosstalk" modifying each other in either a positive of negative fashion. The positive or negative character of interpathway crosstalk eventually manifests itself physiologically as constructive or destructive priming. Could the characteristics of the initial priming predict the sense of the final cellular message? Although the magnitude of both the priming stimulus and subsequent stimuli are important, the temporal relationship between the two stimuli as well as the positive or negative character of their interacting signal pathways need to be considered. It is unclear whether any one characteristic alone determines the sense of the priming effect. In general, it is the interaction of two stimuli with a cell at all three levels (magnitude, character, and temporal relationship) that dictates the final cellular response.