Study title: A systematic review of RCTs to examine the risk of adverse cardiovascular events with nicotine use.

Associations between cigarette smoking and increased risk of cardiovascular disease are well established. However, it is unclear whether the association is mediated by exposure to nicotine and/or to other constituents in cigarette smoke. The objective of this systematic review and meta-analysis of randomized control trials (RCTs) was to identify any potential associations between exposure to nicotine and the risk of clinically diagnosed adverse cardiovascular events in adult current users and nonusers of tobacco products. Among 1,996 results, 42 studies, comparing nicotine and non-nicotine groups, were included and were both qualitatively and quantitatively synthesized across the outcomes of arrhythmia, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. The majority of studies evaluating nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death reported no events that occurred in either the nicotine or non-nicotine control groups. Among the studies that reported events, rates of adverse events were similarly low between both groups. Consistent with findings from previous systematic reviews and meta-analyses, pooled data showed that rates for arrhythmia, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death were not significantly different between nicotine and non-nicotine groups. The overall quality of the body of evidence for each of the four outcomes of interest was graded as "moderate," limited only by the imprecision of results. The findings of this systematic review and meta-analysis indicate that, with moderate certainty, there are no significant associations between the use of nicotine and the risk of clinically diagnosed adverse cardiovascular events-specifically, arrhythmia, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death.

A systematic review of preclinical studies evaluating the association between nicotine and the initiation and progression of cancer.

Background: The association between cigarette smoking and the increased risk of many cancers is well established. Conversely, epidemiological studies of smokeless tobacco demonstrate decreased risk, or no elevated risk, of certain cancers versus smoking. However, it is unclear what role, if any, nicotine plays in these associations. The objective of this systematic review was to synthesize the available evidence from preclinical studies that examined the potential association between nicotine and the initiation and/or progression of cancer. Methods: MEDLINE, Embase, PsychInfo, and Cochrane Database of Systematic Reviews were searched for articles published from inception until February 13, 2022. Studies were eligible for inclusion if they evaluated animal cancer or tumor models, compared nicotine and non-nicotine groups, and evaluated measures of cancer initiation or progression. Results: Among 1,137 identified articles, 61 were included in qualitative synthesis. Twelve studies reported data on tumor initiation, and 54 studies reported data on tumor progression. The majority of the tumor initiation studies did not identify an association between nicotine exposure and an increased risk of spontaneous tumor initiation. Results of tumor progression studies were inconsistent and varied across the reported measures, cancer type being evaluated, and animal cancer model used. Overall, the quality of reporting was poor, with many studies not demonstrating a high level of internal and/or external validity. Conclusions: In conclusion, although animal models have provided invaluable data for human health risk assessments of chemical exposures, the heterogeneity across the studies included in this systematic review make the interpretation and generalizability of the results difficult.

Characterization of end-of-life electroencephalographic surges in critically ill patients.

Neuromonitoring devices to assess level of sedation are now used commonly in many hospital settings. The authors previously reported that electroencephalicgraphic (EEG) spikes frequently occurred after the time of death in patients being neuromonitored at the time of cessation of circulation. In addition to the initial report, end-of-life electrical surges (ELES) have been subsequently documented in animal and human studies by other investigators. The frequency, character, intensity, and significance of ELES are unknown. Some have proposed that patients should not be declared dead for purposes of organ donation prior to the occurrence of an ELES. If clinical practice were altered to await the presence of an ELES, there could be detrimental consequences to donated organs and their recipients. To better characterize ELES, the authors retrospectively assessed the frequency and nature of ELES in serial patients. To better document ELES, they collected neuromonitoring, demographic, and clinical data on consecutive patients who expired while being actively monitored as part of their standard palliative care. These data were retrospectively collected when available as a convenience sample. The authors assessed 35 patients of which 7 were clinically confirmed as brain dead. None of the brain-dead patients displayed an ELES. Thirteen of the 28 remaining patients (46.4%) exhibited an ELES. The ELES observed were demonstrated to have high frequency EEG signal. The mean peak amplitude of ELES as measured by Patient State IndexTM (PSI) was 58.5 ± 25.7. In this preliminary assessment, the authors found that ELES are common in critically ill patients who succumb. The exact cause and significance of ELES remain unknown; further study is warranted.

Hemodynamic monitoring in the critical care environment.

Hemodynamic monitoring is essential to the care of the critically ill patient. In the hemodynamically unstable patient where volume status is not only difficult to determine, but excess fluid administration can lead to adverse consequences, utilizing markers that guide resuscitation can greatly affect outcomes. Several markers and devices have been developed to aid the clinician in assessing volume status with the ultimate goal of optimizing tissue oxygenation and organ perfusion. Early static measures of volume status, including pulmonary artery occlusion pressure and central venous pressure, have largely been replaced by newer dynamic measures that rely on real-time measurements of physiological parameters to calculate volume responsiveness. Technological advances have lead to the creation of invasive and noninvasive devices that guide the physician through the resuscitative process. In this manuscript, we review the physiologic rationale behind hemodynamic monitoring, define the markers of volume status and volume responsiveness, and explore the various devices and technologies available for the bedside clinician.

Neurogenic pulmonary edema: successful treatment with IV phentolamine.

Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant CNS insult. The cause is believed to be a surge of catecholamines that results in cardiopulmonary dysfunction. Although there are myriad case reports describing CNS events that are associated with this syndrome, few studies have identified specific treatment modalities. We present a case of NPE caused by an intracranial hemorrhage from a ruptured arteriovenous malformation. We uniquely document a rise and fall of serum catecholamine levels correlating with disease activity and a dramatic clinical response to IV phentolamine.

Are arterial blood gases necessary in the evaluation of acutely dyspneic patients?

Arterial blood gases (ABG) are obtained commonly in dyspneic persons presenting to emergency departments. The study by Burri and colleagues found that the information contained in ABG fails to distinguish between pulmonary and other causes of dyspnea. On the other hand, arterial pH was highly predictive of ICU admission and outcome. Until large clinical studies show equivalence between peripheral venous and ABG, we will continue to advocate the use of ABG in the evaluation of acute dyspnea.

Arterial pressure-based cardiac output monitoring: a multicenter validation of the third-generation software in septic patients.

PURPOSE: Second-generation FloTrac software has been shown to reliably measure cardiac output (CO) in cardiac surgical patients. However, concerns have been raised regarding its accuracy in vasoplegic states. The aim of the present multicenter study was to investigate the accuracy of the third-generation software in patients with sepsis, particularly when total systemic vascular resistance (TSVR) is low. METHODS: Fifty-eight septic patients were included in this prospective observational study in four university-affiliated ICUs. Reference CO was measured by bolus pulmonary thermodilution (iCO) using 3-5 cold saline boluses. Simultaneously, CO was computed from the arterial pressure curve recorded on a computer using the second-generation (CO(G2)) and third-generation (CO(G3)) FloTrac software. CO was also measured by semi-continuous pulmonary thermodilution (CCO). RESULTS: A total of 401 simultaneous measurements of iCO, CO(G2), CO(G3), and CCO were recorded. The mean (95%CI) biases between CO(G2) and iCO, CO(G3) and iCO, and CCO and iCO were -10 (-15 to -5)% [-0.8 (-1.1 to -0.4) L/min], 0 (-4 to 4)% [0 (-0.3 to 0.3) L/min], and 9 (6-13)% [0.7 (0.5-1.0) L/min], respectively. The percentage errors were 29 (20-37)% for CO(G2), 30 (24-37)% for CO(G3), and 28 (22-34)% for CCO. The difference between iCO and CO(G2) was significantly correlated with TSVR (r(2) = 0.37, p < 0.0001). A very weak (r(2) = 0.05) relationship was also observed for the difference between iCO and CO(G3). CONCLUSIONS: In patients with sepsis, the third-generation FloTrac software is more accurate, as precise, and less influenced by TSVR than the second-generation software.

Synthesis of 4-aryl- and 4-alkyl-2-silyl-1,3-butadienes and their Diels-Alder/cross-coupling reactions.

An ene-yne cross methasis of silyl-substituted alkynes and alkenes has been developed as a route to 4-aryl- and 4-alkyl-2-silyl-substituted 1,3-dienes. The dienes prepared were used to affect highly diastereoselective Diels-Alder reactions and then the silicon-substituted Diels-Alder cycloadducts were used in Hiyama cross-coupling reactions. The cross-coupling reactions enable these silicon dienes to be used as synthons for a variety of other dienes one might prepare and need access to. Two of the silicon-substituted Diels-Alder cycloadducts and one of the Hiyama cross-coupling products were also characterized by X-ray crystallography.

Utilization of base deficit and reliability of base deficit as a surrogate for serum lactate in the peri-operative setting.

BACKGROUND: Base deficit (BD) is commonly used in the operating room (OR) as an endpoint of resuscitation. BD is used as a surrogate marker for the accumulation of lactic acid(Lac). However, the BD can be affected by large amounts of saline. METHODS: We conducted a survey of anesthesiologists regarding the use of BD. We also studied the reliability of BD to determine the presence of hyperlactatemia (HL). Patients undergoing general anesthesia were eligible for enrollment if they were receiving an arterial line as part of their routine care. If an arterial blood gas was drawn by the operative team as part of the routine care, the remainder of the unused blood was also used to measure Lac. SURVEY: 73 staff anesthesiologists were surveyed. Over 70% of respondents used BD as an endpoint of resuscitation.Base Deficit Study: 35 patients were enrolled resulting in 88 arterial blood gases with corresponding Lac. Mean age was 61.4 ± 14.3 years, 43% were male. Mean pH was 7.39 ± 0.05, the mean bicarbonate was 23.0 ± 2.3 meq/L, the mean BD 1.34 ± 2.3, and the mean Lac was 1.58 ± 0.71 mmol/L. Mean ASA risk score was 3.16 ± 0.71. ROC area under the curve for base deficit to detect HL was 0.58. CONCLUSION: BD can often mislead the clinician as to the actual Lac. Lac can now be measured in the OR in real time. Therefore, if clinicians in the operative setting want to know the Lac, it should be measured directly.

Femoral-based central venous oxygen saturation is not a reliable substitute for subclavian/internal jugular-based central venous oxygen saturation in patients who are critically ill.

BACKGROUND: Central venous oxygen saturation (Scv(O(2))) has been used as a surrogate marker for mixed venous oxygen saturation (Sv(O(2))). Femoral venous oxygen saturation (Sfv(O(2))) is sometimes used as a substitute for Scv(O(2)). The purpose of this study is to test the hypothesis that these values can be used interchangeably in a population of patients who are critically ill. METHODS: We conducted a survey to assess the frequency of femoral line insertion during the initial treatment of patients who are critically ill. Scv(O(2)) vs Sfv(O(2)) STUDY: Patients with femoral and nonfemoral central venous catheters (CVCs) were included in this prospective study. Two sets of paired blood samples were drawn simultaneously from the femoral and nonfemoral CVCs. Blood samples were analyzed for oxygen saturation and lactate. RESULTS: One hundred and fifty physicians responded to the survey. More than one-third of the physicians insert a femoral line at least 10% of the time during the initial treatment of patients who were critically ill. Scv(O(2)) vs Sfv(O(2)) STUDY: Thirty-nine patients were enrolled. The mean Scv(O(2)) and Sfv(O(2)) were 73.1% +/- 11.6% and 69.1% +/- 12.9%, respectively (P = .002), with a mean bias of 4.0% +/- 11.2% (95% limits of agreement: -18.4% to 26.4%). The mean serum lactate from the nonfemoral and femoral CVCs was 2.84 +/- 4.0 and 2.72 +/- 3.2, respectively (P = .15). CONCLUSIONS: This study revealed a significant difference between paired samples of Scv(O(2)) and Sfv(O(2)). More than 50% of Scv(O(2)) and Sfv(O(2)) values diverged by > 5%. Sfv(O(2)) is not always a reliable substitute for Scv(O(2)) and should not routinely be used in protocols to help guide resuscitation.

Surges of electroencephalogram activity at the time of death: a case series.

Abstract Level of consciousness at the end of life in critically ill patients is poorly characterized. We report a case series of seven patients who were neurologically intact before the decision to withdraw care due to extensive systemic critical illness. As part of our end-of-life care protocol, bispectral index (BIS) monitor (Aspect Medical Systems, Newton, MA) or SEDline (Hospira, Lake Forest, IL) monitoring devices are placed on each patient to ensure adequate comfort. Both monitoring systems use an integer-based system (BIS or PSI, respectively) to reflect the level of consciousness/effect of anesthesia. In each case, loss of blood pressure, as monitored by indwelling arterial line, was followed by a decline is BIS/PSI activity followed by a transient spike in BIS/PSI activity that approached levels normally associated with consciousness. This spike in electroencephalogram (EEG) activity had short duration and the activity then declined to a level of activity associated with burst suppression. In one case of a patient who had a SEDLine device, we were able to capture and analyze the raw EEG signal, and confirm that the EEG waveform was not artifact, and in fact a high frequency waveform was present during the spike activity. We speculate that this level of BIS/SEDline activity is related to the cellular loss of membrane polarization due to hypoxemia. We further speculate that since this increase in electrical activity occurred when there was no discernable blood pressure, patients who suffer "near death" experiences may be recalling the aggregate memory of the synaptic activity associated with this terminal but potentially reversible hypoxemia.

Preparation of 2-silicon-substituted 1,3-dienes and their Diels-Alder/cross-coupling reactions.

2-Triethoxysilyl-substituted 1,3-butadiene has been prepared in 30-g quantities from chloroprene via a simple synthetic procedure. Silatrane- and catechol-substituted analogues of this main group element substituted diene were then prepared on a 10-g scale by ligand exchange and characterized by X-ray crystallography in addition to standard spectroscopic techniques. 2-Dimethylphenylsilyl-1,3-butadiene has also been prepared from chloroprene on an 8-g scale. Diels-Alder reactions of these dienes are reported as well as subsequent TBAF-assisted/Pd-catalyzed Hiyama cross-coupling reactions of those Diels-Alder adducts. Silicon-substituted cycloadducts and cross-coupled products were also characterized by NMR spectroscopy and, in two cases, by X-ray crystallography.

Variation in the TLR4 gene influences the risk of organ failure and shock posttrauma: a cohort study.

BACKGROUND: Genetic variation contributes to risk and outcomes of sepsis. We sought to determine whether variation in inflammation related genes is associated with severity of sepsis in trauma patients. METHODS: A cohort of severely injured Caucasian patients was studied and genotyped for candidate single nucleotide polymorphisms (SNPs). These were toll-like receptor 4 (TLR4) A896G, tumor necrosis factor-alpha G-308A, interleukin-6 G-174C, interleukin-1beta C-31T, and cluster of differentiation marker 14C-159T. SNP genotypes among patients with sepsis and complicated sepsis were analyzed by chi2 and logistic regression. Six haplotype-tagging SNPs in the TLR4 gene were subsequently examined to analyze their influence on TLR4 A896G SNPs relationship to sepsis severity. RESULTS: We enrolled 598 patients. Complicated sepsis developed in 147 (25%). Adjusting for independent risk factors, carriage of the variant TLR4 896 G allele was associated with decreased risk of complicated sepsis (odds ratio = 0.3, 95% confidence interval, 0.1-0.7, p = 0.008). Furthermore, two haplotypes seemed to better characterize this risk than the variant TLR4 896G allele. The variant TLR4 896G allele is linked to one common haplotype, which seems to confer a considerably reduced risk of complicated sepsis. (aOR = 0.2 95% confidence interval, 0.05-0.7, p = 0.01). CONCLUSIONS: Variation within TLR4 gene is associated with severity of posttraumatic sepsis. This risk may not be solely related to TLR4 A896G SNP. It is likely that other, uncharacterized variations in the TLR4 gene contribute to sepsis severity. A thorough evaluation of variability within the TLR4 gene is needed to characterize sepsis risk.

Anion gap, anion gap corrected for albumin, base deficit and unmeasured anions in critically ill patients: implications on the assessment of metabolic acidosis and the diagnosis of hyperlactatemia.

BACKGROUND: Base deficit (BD), anion gap (AG), and albumin corrected anion gap (ACAG) are used by clinicians to assess the presence or absence of hyperlactatemia (HL). We set out to determine if these tools can diagnose the presence of HL using cotemporaneous samples. METHODS: We conducted a chart review of ICU patients who had cotemporaneous arterial blood gas, serum chemistry, serum albumin (Alb) and lactate(Lac) levels measured from the same sample. We assessed the capacity of AG, BD, and ACAG to diagnose HL and severe hyperlactatemia (SHL). HL was defined as Lac > 2.5 mmol/L. SHL was defined as a Lac of > 4.0 mmol/L. RESULTS: From 143 patients we identified 497 series of lab values that met our study criteria. Mean age was 62.2 +/- 15.7 years. Mean Lac was 2.11 +/- 2.6 mmol/L, mean AG was 9.0 +/- 5.1, mean ACAG was 14.1 +/- 3.8, mean BD was 1.50 +/- 5.4. The area under the curve for the ROC for BD, AG, and ACAG to diagnose HL were 0.79, 0.70, and 0.72, respectively. CONCLUSION: AG and BD failed to reliably detect the presence of clinically significant hyperlactatemia. Under idealized conditions, ACAG has the capacity to rule out the presence of hyperlactatemia. Lac levels should be obtained routinely in all patients admitted to the ICU in whom the possibility of shock/hypoperfusion is being considered. If an AG assessment is required in the ICU, it must be corrected for albumin for there to be sufficient diagnostic utility.

Anion gap, anion gap corrected for albumin, and base deficit fail to accurately diagnose clinically significant hyperlactatemia in critically ill patients.

Anion gap, anion gap corrected for serum albumin, and base deficit are often used as surrogates for measuring serum lactate. None of these surrogates is postulated to predict hyperlactatemia in the critically ill. We prospectively collected data from September 2004 through August 2005 for 1381 consecutive admissions. Patients with renal disease, ketoacidosis, or toxic ingestion were excluded. Anion gap, anion gap corrected for albumin, and base deficit were calculated for all patients. We identified 286 patients who met our inclusion or exclusion criteria. The receiver-operating characteristic area under the curve for the prediction of hyperlactatemia for anion gap, anion gap corrected for albumin, and base deficit were 0.55, 0.57, and 0.64, respectively. Anion gap, anion gap corrected for albumin, and base deficit do not predict the presence or absence of clinically significant hyperlactatemia. Serum lactate should be measured in all critically ill adults in whom hypoperfusion is suspected.

Advances in critical care for the nephrologist: hemodynamic monitoring and volume management.

The monitoring of physiologic variables is an integral part of the diagnosis and management of the critically ill patient. Restoration of tissue perfusion and oxygen delivery is the ultimate goal for any state of circulatory collapse. Insight into a patient's intravascular volume status and cardiac performance, particularly in the early stages of shock, can help guide management and potentially change outcome. In the past 30 years, various bedside monitoring techniques and indices have been developed in an effort to determine and optimize a patient's cardiac performance. This article reviews the physiologic parameters that best predict intravascular volume status and volume responsiveness. We examine the controversies surrounding the pulmonary arterial catheter and describe the less invasive methods of measuring cardiac performance.

Identifying critically ill patients at high risk for developing acute renal failure: a pilot study.

BACKGROUND: Acute renal failure (ARF) occurs commonly in the intensive care unit (ICU), but predicting which patients will develop ARF is difficult. We set out to determine which risk factors would predict the development of ARF in critically ill patients who are admitted to the ICU without ARF. METHODS: From August 2002 to April 2003, we enrolled medical-surgical ICU admissions into a cohort using a sampling tool based on their risk factor (RF) profile. The risk factors we identified were separated into 3 categories: chronic major, chronic minor, and acute RFs. Combinations of these RFs were used to create a sampling tool and identify patients to enroll into our cohort. Patients with end-stage renal disease and ARF upon admission to the ICU were excluded. RESULTS: We enrolled 194 patients over a 14-month period. The mean age of the cohort was 64.6 +/- 14.7 years. The percentage of Caucasians, African Americans, and Hispanics was 40.7%, 50.5%, and 3.6%, respectively. In a univariate analysis of the entire cohort, increasing APACHE II quartile, increased A-a gradient, presence of systemic inflammatory response syndrome (SIRS), decreased levels of serum albumin, and presence of active cancer predicted ARF. In a multiple logistic regression analysis, decreased serum albumin (high levels of serum albumin were protective), increased A-a gradient, and cancer were associated with development of ARF (OR 2.17, 1.04, and 2.86, respectively). CONCLUSION: Decreased levels of serum albumin concentration, increased A-a gradient, and presence of active cancer predict which patients who are admitted to the ICU will develop ARF.

The influence of gender on human innate immunity.

BACKGROUND: Several experimental, clinical, and epidemiologic studies indicate a better prognosis in women after an infectious challenge. The monocyte/macrophage, as coordinators of the innate immune response to sepsis, secrete plasma inflammatory cytokines. Elevated plasma cytokine levels are inversely correlated with outcome. In addition, single-nucleotide polymorphisms related to these cytokine genes and in genes important for lipopolysaccharide (LPS) detection, particularly toll-like receptor-4, have been associated with variations in clinical outcome. We hypothesize that the gender differences in clinical outcome are due to measurable differences in cytokine responses and intracellular signaling, and these differences are independent of polymorphism carrier status. METHODS: Venous blood samples from healthy subjects (56 men, 23 women) were incubated with LPS, and supernatant cytokine levels were determined by enzyme-linked immunosorbent assay. In a randomly chosen subgroup, (8 men, 4 women), peripheral blood mononuclear cells were isolated, and LPS-mediated intracellular mitogen-activated protein kinase (MAPK) phosphorylation was assayed via Western blot analysis. Each subject was screened for the following SNPs: tumor necrosis factor alpha (TNF-alpha) -308G/A, interleukin (IL)-6 -174G/C, IL-1beta -31C/T, and toll-like receptor-4 (TLR4) +896A/G. RESULTS: Women produced significantly less LPS-induced TNF-alpha and IL-1beta but not IL-6. When the analysis was adjusted for the presence of each polymorphism, the differences in TNF-alpha and IL-1beta accumulation persisted. Female gender was associated with lower MAPK phosphorylation at each LPS concentration but was not statistically significant. CONCLUSIONS: Gender-specific differences in LPS-induced TNF-alpha and IL-1beta were observed, possibly attributed to alterations in MAPK phosphorylation. Furthermore, studies investigating the influence of genomic variation on the innate immune response should address potential gender-related differences.

A multicenter description of intermediate-care patients: comparison with ICU low-risk monitor patients.

STUDY OBJECTIVES: To describe the characteristics and outcomes of patients admitted to intermediate-care areas (ICAs) and to compare them with those of ICU patients who receive monitoring only on day 1 and are at a low risk (i.e., < 10%) for receiving subsequent active life-supporting therapy (i.e., low-risk monitor patients). DESIGN: Nonrandomized, retrospective, cohort study. SETTING: Thirteen US teaching hospitals and 19 nonteaching hospitals. PATIENTS: A consecutive sample of 8,971 patients at 37 ICAs and 5,116 low-risk (i.e., < 10%) monitor patients at 59 ICUs in 32 US hospitals. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We recorded demographic and clinical characteristics, resource use, and outcomes for the ICA and ICU low-risk monitor patients. Patient data and outcomes for this study were collected concurrently or retrospectively. ICA and ICU low-risk monitor patients were similar in regard to gender, race, and frequency of comorbitities, but ICA patients were significantly (p < 0.001) older, had fewer physiologic abnormalities (mean acute physiology score, 16.7 vs 19.8, respectively), and were more frequently admitted due to nonoperative diagnoses. The mean length of stay for ICA patients was significantly longer (3.9 days) than for ICU low-risk monitor patients (2.6 days; p < 0.001). The hospital mortality rate was significantly higher for ICA patients (3.1%) compared to ICU low-risk monitor patients (2.3%; p = 0.002). CONCLUSIONS: The clinical features of ICA patients are similar, but not identical to, those of less severely ill ICU monitor patients. Comparisons of hospital death rates and lengths of stay for these patients should be adjusted for characteristics that previously have been shown to influence these outcomes.