Spiros G. Frangos

Clinical review: Acid–base abnormalities in the intensive care unit – part II

Acid–base abnormalities are common in the critically ill. The traditional classification of acid–base abnormalities and a modern physico-chemical method of categorizing them will be explored. Specific disorders relating to mortality prediction in the intensive care unit are examined in detail. Lactic acidosis, base excess, and a strong ion gap are highlighted as markers for increased risk of death.

Nicotine: a review of its role in atherosclerosis.

Overwhelming evidence is available associating cigarette smoking and several pathologic conditions, including cardiopulmonary disease and malignancies (Table 1). In the United States, one in six deaths is related to tobacco smoking. Extensive research has been done over the past few decades aimed at understanding the pathophysiology of tobacco-related disease and elucidating the mechanisms by which tobacco smoke causes disease. The Framingham study is the best-known prospective investigation that established the risk factors for coronary heart disease and peripheral vascular disease. Five factors were shown to be predictors of atherosclerosis: hypertension, serum cholesterol level above 297 mg/ 100mL, glucose intolerance, left ventricular hypertrophy on electrocardiography, and smoking. Of these factors smoking history was the most predictive of the development of intermittent claudication. Cigarette smoking especially accelerates atherosclerosis in the coronary arteries, the aorta, the carotid and cerebral arteries, and the large arteries in the peripheral circulation. Smoking is associated with an increased risk of acute cardiovascular events, including acute myocardial infarction, sudden death, and stroke. Other effects include aggravation of stable angina pectoris, intermittent claudication and vasospastic angina, rethrombosis after thrombolysis, and restenosis after angioplasty. Cigarette smoke is a complex mixture of more than 4,000 chemical constituents distributed in particulate and gaseous phases. The most important constituents includenicotine,aromatichydrocarbons, sterolsandoxygenated isoprenoid compounds, aldehydes, nitriles, cyclic ethers, and sulfur compounds (Table 2). PHARMACOLOGY AND METABOLISM Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring (Table 3). Tobacco contains both a levorotatory S-nicotine and an R-isomer in quantities up to 10% of the total nicotine present. Nicotine is a weak base with a pKa of 8.0. At a physiologic pH, approximately 30% of nicotine is nonionized and can readily cross cell membranes. Nicotine binds stereospecifically to acetylcholine receptors at the autonomic junctions and the brain. Nicotine cholinergic receptors have been detected in the brain, autonomic ganglia, and the neuromuscular junction. The diversity of nicotinic cholinergic receptors may explain the varied effects of nicotine in humans. Nicotine is distilled from burning tobacco, carried proximally, and deposited in the small airways and alveoli. On inhalation, nicotine is rapidly absorbed from cigarette smoke, from which it enters the arterial circulation and is rapidly distributed to body tissues. It takes 10 to 20 seconds for nicotine to pass through the brain. Nicotine levels than fall, owing to uptake by peripheral tissues and later to elimination of nicotine from the body. Arteriovenous differences during cigarette smoking are substantial, with arterial levels exceeding venous levels 6to 10-fold. The rapid delivery of nicotine results in an intense pharmacologic response, owing both to higher arterial levels entering the brain and effects occurring rapidly, before there is adequate time for the development of tolerance. Nicotine plasma concentrations in smokers range between 10 mol/L and 10 mol/L.22 The elimination half-life of nicotine during the use of tobacco or nicotine products averages 2 to 3 hours. Nicotine levels accumulate over 6 to 8 hours during regular smoking. But there is a very long terminal half-life, 20 hours or more, reflecting the slow release of nicotine from body tissues. Nicotine crosses the placenta freely and has been found in amniotic fluid and the umbilical cord blood of neonates. Nicotine is metabolized extensively, primarily by the liver, but also to a lesser extent by the lung (Fig. 1). The No competing interests declared.

Collective reviewNicotine: a review of its role in atherosclerosis1

Overwhelming evidence is available associating cigarette smoking and several pathologic conditions, including cardiopulmonary disease and malignancies (Table 1). In the United States, one in six deaths is related to tobacco smoking. Extensive research has been done over the past few decades aimed at understanding the pathophysiology of tobacco-related disease and elucidating the mechanisms by which tobacco smoke causes disease. The Framingham study is the best-known prospective investigation that established the risk factors for coronary heart disease and peripheral vascular disease. Five factors were shown to be predictors of atherosclerosis: hypertension, serum cholesterol level above 297 mg/ 100mL, glucose intolerance, left ventricular hypertrophy on electrocardiography, and smoking. Of these factors smoking history was the most predictive of the development of intermittent claudication. Cigarette smoking especially accelerates atherosclerosis in the coronary arteries, the aorta, the carotid and cerebral arteries, and the large arteries in the peripheral circulation. Smoking is associated with an increased risk of acute cardiovascular events, including acute myocardial infarction, sudden death, and stroke. Other effects include aggravation of stable angina pectoris, intermittent claudication and vasospastic angina, rethrombosis after thrombolysis, and restenosis after angioplasty. Cigarette smoke is a complex mixture of more than 4,000 chemical constituents distributed in particulate and gaseous phases. The most important constituents includenicotine,aromatichydrocarbons, sterolsandoxygenated isoprenoid compounds, aldehydes, nitriles, cyclic ethers, and sulfur compounds (Table 2). PHARMACOLOGY AND METABOLISM Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring (Table 3). Tobacco contains both a levorotatory S-nicotine and an R-isomer in quantities up to 10% of the total nicotine present. Nicotine is a weak base with a pKa of 8.0. At a physiologic pH, approximately 30% of nicotine is nonionized and can readily cross cell membranes. Nicotine binds stereospecifically to acetylcholine receptors at the autonomic junctions and the brain. Nicotine cholinergic receptors have been detected in the brain, autonomic ganglia, and the neuromuscular junction. The diversity of nicotinic cholinergic receptors may explain the varied effects of nicotine in humans. Nicotine is distilled from burning tobacco, carried proximally, and deposited in the small airways and alveoli. On inhalation, nicotine is rapidly absorbed from cigarette smoke, from which it enters the arterial circulation and is rapidly distributed to body tissues. It takes 10 to 20 seconds for nicotine to pass through the brain. Nicotine levels than fall, owing to uptake by peripheral tissues and later to elimination of nicotine from the body. Arteriovenous differences during cigarette smoking are substantial, with arterial levels exceeding venous levels 6to 10-fold. The rapid delivery of nicotine results in an intense pharmacologic response, owing both to higher arterial levels entering the brain and effects occurring rapidly, before there is adequate time for the development of tolerance. Nicotine plasma concentrations in smokers range between 10 mol/L and 10 mol/L.22 The elimination half-life of nicotine during the use of tobacco or nicotine products averages 2 to 3 hours. Nicotine levels accumulate over 6 to 8 hours during regular smoking. But there is a very long terminal half-life, 20 hours or more, reflecting the slow release of nicotine from body tissues. Nicotine crosses the placenta freely and has been found in amniotic fluid and the umbilical cord blood of neonates. Nicotine is metabolized extensively, primarily by the liver, but also to a lesser extent by the lung (Fig. 1). The No competing interests declared.

The Integrin-Mediated Cyclic Strain-Induced Signaling Pathway in Vascular Endothelial Cells

The irregular distribution of plaque in the vasculature results from the interaction of local hemodynamic forces with the vessel wall. One well-characterized force is cyclic circumferential strain, the repetitive pulsatile pressure distention on the arterial wall. This review summarizes current research, which has aimed to elicit the signal transduction pathway by which cyclic strain elicits functional and structural responses in endothelial cells; specifically, it summarizes the signaling pathway that begins with the reorganization of integrins. One method by which these extracellular matrix receptors affect signal transduction is through their ability to initiate the process of phosphorylation on tyrosine residues of cytoplasmic protein kinases, including focal adhesion kinase. The strain-induced pathway appears to also involve ras and the mitogen-activated protein kinase family of enzymes, and preliminary data suggests a role for src as well. Ultimately, it is the regulation of gene expression through the modulation of transcription factors that allows endothelial cells to respond to changes in local hemodynamics.

Alcohol use by pedestrians who are struck by motor vehicles: How drinking influences behaviors, medical management, and outcomes

BACKGROUND Injuries to pedestrians struck by motor vehicles represent a significant public health hazard in large cities. The purpose of this study is to investigate the demographics of alcohol users who are struck by motor vehicles and to assess the effects of alcohol on pedestrian crossing patterns, medical management, and outcomes. METHODS Data were prospectively collected between December 2008 to September 2010 on all pedestrians who presented to a Level I trauma center after being struck by a motor vehicle. Variables were obtained by interviewing patients, scene witnesses, first responders, and medical records. RESULTS Pedestrians who used alcohol were less likely to cross the street in the crosswalk with the signal (22.6% vs. 64.7%) and more likely to cross either in the crosswalk against the signal (22.6% vs. 12.4%) or midblock (54.8% vs. 22.8%). Alcohol use was associated with more initial computed tomography imaging studies compared with no alcohol involvement. Alcohol use was associated with a higher Injury Severity Score (8.82 vs. 4.85; p < 0.001) and hospital length of stay (3.89 days vs. 1.82 days; p < 0.001) compared with those with no alcohol involvement. Patients who used alcohol had a lower average Glasgow Coma Scale score (13.80 vs. 14.76; p < 0.001) and a higher rate of head and neck, face, chest, abdomen, and extremity/pelvic girdle injuries (based on Abbreviated Injury Scale) than those with no alcohol involvement. CONCLUSION Alcohol use is a significant risk factor for pedestrians who are struck by motor vehicles. These patients are more likely to cross the street in an unsafe manner and sustain more serious injuries. Traffic safety and injury prevention programs must address irresponsible alcohol use by pedestrians.

U.S. surgeon and medical student attitudes toward organ donation.

BACKGROUND Nearly 100,000 people await an organ transplant in the U.S. Improved utilization of potential organ donors may reduce the organ shortage. Physician attitudes toward organ donation may influence donation rates; however, the attitudes of U.S. physicians have not been formally evaluated. METHODS Anonymous questionnaires were distributed to surgical attendings, surgical residents, and medical students at two academic medical centers. Willingness to donate ones own organs and family members organs was examined, as well as experience with transplant procedures and religious views regarding organ donation. RESULTS A total of 106 surveys were returned. Sixty-four percent of responders were willing to donate their own organs, and 49% had signed an organ donor card. Willingness to donate inversely correlated with professional experience. Eighty-four percent of those surveyed would agree to donate the organs of a family member, including 55% of those who refused to donate their own organs. Experience on the transplant service influenced 16% of those refusing donation, with the procurement procedure cited by 83% of this group. Sixteen percent refused organ donation on the basis of religious beliefs. CONCLUSIONS The surveyed U.S. physicians are less willing to donate their organs compared with the general public. Despite understanding the critical need for organs, less than half of physicians surveyed had signed organ donor cards. Previous experiences with the procurement procedure influenced several responders to refuse organ donation. As the lay public traditionally looks to physicians for guidance, efforts must be made to improve physician attitudes toward organ donation with the hope of increasing donation rates.

Bicycle helmets are highly protective against traumatic brain injury within a dense urban setting.

BACKGROUND New York City (NYC) has made significant roadway infrastructure improvements, initiated a bicycle share program, and enacted Vision Zero, an action plan to reduce traffic deaths and serious injuries. The objective of this study was to examine whether bicycle helmets offer a protective advantage against traumatic brain injury (TBI) within a contemporary dense urban setting with a commitment to road safety. METHODS A prospective observational study of injured bicyclists presenting to a Level I trauma centre was performed. All bicyclists arriving within 24 h of injury were included. Data were collected between February, 2012 and August, 2014 and included demographics, imaging studies (e.g. computed tomography (CT)), injury patterns, and outcomes including Glasgow Coma Scale (GCS) and Injury Severity Score. RESULTS Of 699 patients, 273 (39.1%) were wearing helmets at the time of injury. Helmeted bicyclists were more likely to have a GCS of 15 (96.3% [95% Confidence Interval (CI), 93.3-98.2] vs. 87.6 [95% CI, 84.1-90.6]) at presentation. Helmeted bicyclists underwent fewer head CTs (40.3% [95% CI, 34.4-46.4] vs. 52.8% [95% CI, 48.0-57.6]) and were less likely to sustain intracranial injury (6.3% [95% CI, 2.6-12.5] vs. 19.7% [14.7-25.6]), including skull fracture (0.9% [95% CI, 0.0-4.9] vs. 15.3% [95% CI, 10.8-20.7]) and subdural hematoma (0.0% [95% CI, 0.0-3.2] vs. 8.1% [95% CI, 4.9-12.5]). Helmeted bicyclists were significantly less likely to sustain significant TBI, i.e. Head AIS ≥3 (2.6% [95% CI: 0.7-4.5] vs.10.6% [7.6-12.5]). Four patients underwent craniotomy while three died; all were un-helmeted. A multivariable logistic regression model showed that helmeted bicyclists were 72% less likely to sustain TBI compared with un-helmeted bicyclists (Adjusted Odds Ratio 0.28, 95% CI 0.12-0.61). CONCLUSIONS Despite substantial road safety measures in NYC, the protective impact of simple bicycle helmets in the event of a crash remains significant. A re-assessment of helmet laws for urban bicyclists is advisable to most effectively translate Vision Zero from a political action plan to public safety reality.

Traumatic injury in the United States: In-patient epidemiology 2000–2011

BACKGROUND Trauma is a leading cause of death and disability in the United States (US). This analysis describes trends and annual changes in in-hospital trauma morbidity and mortality; evaluates changes in age and gender specific outcomes, diagnoses, causes of injury, injury severity and surgical procedures performed; and examines the role of teaching hospitals and Level 1 trauma centres in the care of severely injured patients. METHODS We conducted a retrospective descriptive and analytic epidemiologic study of an inpatient database representing 20,659,684 traumatic injury discharges from US hospitals between 2000 and 2011. The main outcomes and measures were survey-adjusted counts, proportions, means, standard errors, and 95% confidence intervals. We plotted time series of yearly data with overlying loess smoothing, created tables of proportions of common injuries and surgical procedures, and conducted survey-adjusted logistic regression analysis for the effect of year on the odds of in-hospital death with control variables for age, gender, weekday vs. weekend admission, trauma-centre status, teaching-hospital status, injury severity and Charlson index score. RESULTS The mean age of a person discharged from a US hospital with a trauma diagnosis increased from 54.08 (s.e.=0.71) in 2000 to 59.58 (s.e.=0.79) in 2011. Persons age 45-64 were the only age group to experience increasing rates of hospital discharges for trauma. The proportion of trauma discharges with a Charlson Comorbidity Index score greater than or equal to 3 nearly tripled from 0.048 (s.e.=0.0015) of all traumatic injury discharges in 2000 to 0.139 (s.e.=0.005) in 2011. The proportion of patients with traumatic injury classified as severe increased from 22% of all trauma discharges in 2000 (95% CI 21, 24) to 28% in 2011 (95% CI 26, 30). Level 1 trauma centres accounted for approximately 3.3% of hospitals. The proportion of severely injured trauma discharges from Level 1 trauma centres was 39.4% (95% CI 36.8, 42.1). Falls, followed by motor-vehicle crashes, were the most common causes of all injuries. The total cost of trauma-related inpatient care between 2001 and 2011 in the US was

Helmet use is associated with safer bicycling behaviors and reduced hospital resource use following injury

240.7 billion (95% CI 231.0, 250.5). Annual total US inpatient trauma-related hospital costs increased each year between 2001 and 2011, more than doubling from

Acute Care Surgery Survey: Opinions of Surgeons About a New Training Paradigm

12.0 billion (95% CI 10.5, 13.4) in 2001 to 29.1 billion (95% CI 25.2, 32.9) in 2011. CONCLUSIONS Trauma, which has traditionally been viewed as a predicament of the young, is increasingly a disease of the old. The strain of managing the progressively complex and costly care associated with this shift rests with a small number of trauma centres. Optimal care of injured patients requires a reappraisal of the resources required to effectively provide it given a mounting burden.