End-of-life practices in Hong Kong intensive care units: results from the Ethicus-2 study.

INTRODUCTION: The need for end-of-life care is common in intensive care units (ICUs). Although guidelines exist, little is known about actual end-of-life care practices in Hong Kong ICUs. The study aim was to provide a detailed description of these practices. METHODS: This prospective, multicentre observational sub-analysis of the Ethicus-2 study explored end-of-life practices in eight participating Hong Kong ICUs. Consecutive adult ICU patients admitted during a 6-month period with life-sustaining treatment (LST) limitation or death were included. Follow-up continued until death or 2 months from the initial decision to limit LST. RESULTS: Of 4922 screened patients, 548 (11.1%) had LST limitation (withholding or withdrawal) or died (failed cardiopulmonary resuscitation/brain death). Life-sustaining treatment limitation occurred in 455 (83.0%) patients: 353 (77.6%) had decisions to withhold LST and 102 (22.4%) had decisions to withdraw LST. Of those who died without LST limitation, 80 (86.0%) had failed cardiopulmonary resuscitation and 13 (14.0%) were declared brain dead. Discussions of LST limitation were initiated by ICU physicians in most (86.2%) cases. Shared decision-making between ICU physicians and families was the predominant model; only 6.0% of patients retained decision-making capacity. Primary medical reasons for LST limitation were unresponsiveness to maximal therapy (49.2%) and multiorgan failure (17.1%). The most important consideration for decision-making was the patient's best interest (81.5%). CONCLUSION: Life-sustaining treatment limitations are common in Hong Kong ICUs; shared decision-making between physicians and families in the patient's best interest is the predominant model. Loss of decision-making capacity is common at the end of life. Patients should be encouraged to communicate end-of-life treatment preferences to family members/surrogates, or through advance directives.

End-of-life practices in 11 German intensive care units : Results from the ETHICUS-2 study.

BACKGROUND: End-of-life care is common in German intensive care units (ICUs) but little is known about daily practice. OBJECTIVES: To study the practice of end-of-life care. METHODS: Prospectively planned, secondary analysis comprising the German subset of the worldwide Ethicus­2 Study (2015-2016) including consecutive ICU patients with limitation of life-sustaining therapy or who died. RESULTS: Among 1092 (13.7%) of 7966 patients from 11 multidisciplinary ICUs, 967 (88.6%) had treatment limitations, 92 (8.4%) died with failed CPR, and 33 (3%) with brain death. Among patients with treatment limitations, 22.3% (216/967) patients were discharged alive from the ICU. More patients had treatments withdrawn than withheld (556 [57.5%] vs. 411 [42.5%], p < 0.001). Patients with treatment limitations were older (median 73 years [interquartile range (IQR) 61-80] vs. 68 years [IQR 54-77]) and more had mental decision-making capacity (12.9 vs. 0.8%), advance directives (28.6 vs. 11.2%), and information about treatment wishes (82.7 vs 33.3%, all p < 0.001). Physicians reported discussing treatment limitations with patients with mental decision-making capacity and families (91.3 and 82.6%, respectively). Patient wishes were unknown in 41.3% of patients. The major reason for decision-making was unresponsiveness to maximal therapy (34.6%). CONCLUSIONS: Treatment limitations are common, based on information about patients' wishes and discussion between stakeholders, patients and families. However, our findings suggest that treatment preferences of nearly half the patients remain unknown which affects guidance for treatment decisions.

H2AX phosphorylation screen of cells from radiosensitive cancer patients reveals a novel DNA double-strand break repair cellular phenotype.

BACKGROUND: About 1-5% of cancer patients suffer from significant normal tissue reactions as a result of radiotherapy (RT). It is not possible at this time to predict how most patients' normal tissues will respond to RT. DNA repair dysfunction is implicated in sensitivity to RT particularly in genes that mediate the repair of DNA double-strand breaks (DSBs). Phosphorylation of histone H2AX (phosphorylated molecules are known as gammaH2AX) occurs rapidly in response to DNA DSBs, and, among its other roles, contributes to repair protein recruitment to these damaged sites. Mammalian cell lines have also been crucial in facilitating the successful cloning of many DNA DSB repair genes; yet, very few mutant cell lines exist for non-syndromic clinical radiosensitivity (RS). METHODS: Here, we survey DNA DSB induction and repair in whole cells from RS patients, as revealed by gammaH2AX foci assays, as potential predictive markers of clinical radiation response. RESULTS: With one exception, both DNA focus induction and repair in cell lines from RS patients were comparable with controls. Using gammaH2AX foci assays, we identified a RS cancer patient cell line with a novel ionising radiation-induced DNA DSB repair defect; these data were confirmed by an independent DNA DSB repair assay. CONCLUSION: gammaH2AX focus measurement has limited scope as a pre-RT predictive assay in lymphoblast cell lines from RT patients; however, the assay can successfully identify novel DNA DSB repair-defective patient cell lines, thus potentially facilitating the discovery of novel constitutional contributions to clinical RS.

Hyperthermia and irradiation of head and neck squamous cancer cells causes migratory profile changes of tumour infiltrating lymphocytes.

PURPOSE: CD4(+)CD25(+)FoxP3(+) regulatory T-cells (Treg) are responsible for immunoevasion mechanisms induced by cancer. Specific chemokines such as CCL22 are presumed to mediate active Treg trafficking into the tumour site. In this context, the effects of irradiation and hyperthermia of tumour cells on Treg migration and the CCL22 concentration in the tumour cell supernatants after treatment were studied. Moreover, the relationship between CCL22 concentration and Treg cell migration was also examined. MATERIALS AND METHODS: Treg and CD4(+)CD25(-) T-cells were isolated from human peripheral blood. Supernatants were obtained from primary cell cultures derived from head and neck carcinoma patients. Tumour cell cultures were treated with a dose of 2 Gy and hyperthermia (41.5 degrees C) or with hyperthermia or irradiation alone. Cancer cell culture supernatants were then used for a transmigration assay. RESULTS: Treg and CD4(+)CD25(-) T-cells showed an increased transmigration towards supernatants of hyperthermia-treated tumour cells. After combined application of hyperthermia and irradiation, Treg migration was similar to control levels, but CD4(+)CD25(-) migration was still enhanced. Irradiation caused a significantly decreased Treg influx, whereas the CD4(+)CD25(-) T-cell migration was not altered after the same treatment. Changes of Treg chemotaxis could be attributed to a treatment-associated escalation of the CCL22 in the tumour cell supernatants. CONCLUSION: The combination of irradiation and hyperthermia is able to modify transmigration of tumour infiltrating lymphocytes beneficially and individually. In this in vitro system hyperthermia alone negatively impacts the immune response by selectively recruiting Treg, whereas hyperthermia with the addition of irradiation negates this effect.

Detection and monitoring of biofilm formation in water treatment systems by quartz crystal microbalance sensors.

Investigations are presented for the development and testing of a sensor for the early stage detection and monitoring of biofilm formation. The sensor is based on the well known quartz crystal microbalance technology (QCM). The QCM detectors are integrated into the water flow system and provide continuous in-situ signals. The main objectives of the research are the evaluation of optimal operation conditions and the modification of the quartz resonator surface promoting a preferred cell attachment onto the quartz sensor surface. The miniaturization degree of the mass sensitive detector modules permits the integration into industrial plants, e.g., in order to control and ensure perfect hygienic conditions. First results of the lab study using Pseudomonas putida cultures are presented and discussed.

The status of intensive care medicine research and a future agenda for very old patients in the ICU.

The "very old intensive care patients" (abbreviated to VOPs; greater than 80 years old) are probably the fastest expanding subgroup of all intensive care unit (ICU) patients. Up until recently most ICU physicians have been reluctant to admit these VOPs. The general consensus was that there was little survival to gain and the incremental life expectancy of ICU admission was considered too small. Several publications have questioned this belief, but others have confirmed the poor long-term mortality rates in VOPs. More appropriate triage (resource limitation enforced decisions), admission decisions based on shared decision-making and improved prediction models are also needed for this particular patient group. Here, an expert panel proposes a research agenda for VOPs for the coming years.

Holy consent--a dilemma for medical staff when maternal consent is withheld for emergency caesarean section.

A parturient (grand multipara) developed arrested labour complicated by severe fetal heart rate decelerations. Senior physicians explained the need for a caesarean section, but she chose to deliver vaginally since rabbinical blessing could not be obtained. Forcing the mother to have a cesarean section without consent is considered "civil battery." The dilemma faced by medical staff and the implications of her refusal for the treating medical staff are described.

Increased risk of bloodstream and urinary infections in intensive care unit (ICU) patients compared with patients fitting ICU admission criteria treated in regular wards.

Critically ill patients, eligible for admission into intensive care units (ICUs), are often hospitalized in other wards due to a lack of ICU beds. Differences in morbidity between patients managed in ICUs and elsewhere are unknown, specifically the morbidity related to hospital-acquired infection. Patients fitting ICU admission criteria were identified by screening five entire hospitals on four separate days. Hospital infections within a 30-day follow-up period were compared in ICU patients and in patients on other wards using Kaplan-Meier curves. Residual differences in the patients' case mix between ICUs and other wards were adjusted for utilizing multivariate Cox models. Of 13415 patients screened, 668 were critically ill. The overall infection rates (per 100 patient-days) were 1.2 for bloodstream infection (BSI) and 1.9 for urinary tract infection (UTI). The adjusted hazard ratios in ICU patients compared with patients on regular wards were 3.1 (P<0.001) for BSI and 2.5 (P<0.001) for UTI. This increased risk persisted even after adjusting for the disparity in the number of cultures sent from ICUs compared with ordinary wards. No interdepartmental differences were found in the rates of pneumonia, surgical wound infections and other infections. Minimizing the differences between characteristics of patients hospitalized in ICUs and in other wards, and controlling for the higher frequency of cultures sent from ICUs did not eliminate the increased risk of BSI and UTI associated with admission into ICUs.

Positive and negative thyroid hormone response elements are composed of strong and weak half-sites 10 nucleotides in length.

The steroid-thyroid hormone receptors bind to imperfect repeats of two or more half-sites. It is generally accepted that a T3 response element (TRE) half-site consists of a six-nucleotide core motif (5'-AGGT(C/A)A-3'). It is less widely appreciated that the nucleotides flanking this core motif also have a major influence on the affinity of T3 receptor (TR) for its response element. We analyzed TR-DNA interactions under conditions in which the affinity of receptor monomers for individual TRE half-sites of the rat GH (rGH) gene was measured. These studies avoided the effects of half-site spacing and orientation on receptor binding. Variations in the nucleotides flanking the core sequence can modulate receptor binding by more than 15-fold. Systematic mutational analysis of TRE half-site structure demonstrated that at least two nucleotides flanking either side of the half-site core motif strongly influence TR binding affinity and activity, indicating that half-sites are approximately 10 nucleotides long. Thus, the half-sites of most TREs overlap, and mutations in one half-site may affect the activity of its partner. The TRE half-site sequence 5'-CTGAGGTAACG-3' was bound with highest affinity by TRs. The negatively T3-responsive promoter of the rGH gene was used to investigate the functional significance of the nucleotides flanking the core motif in vivo. A promoter consisting of only 22 rGH nucleotides, containing two functional TRE half-sites which overlap the rGH TATA box, directed T3-inhibited transcription. Mutation of nucleotides flanking the core sequence of the weaker half-site dramatically reduced the activity of the element, demonstrating that the flanking sequences of the half-sites can profoundly affect TRE activity.

Living related donation in lung transplantation. Ethical considerations.

Lung transplantation has become an established rescue therapy for patients with end-stage disease. The major problem, however, is the shortage of organ donors. Living related donation has been successful in kidney and liver transplantation and, recently, in lobar lung transplantation as well. The main ethical dilemma is whether we should risk a parent family member in order to save a child or relative. This dilemma can be taken to the extreme in a case in which pneumonectomy from a live donor can save a patient who is in need of single lung transplantation, a procedure that has not yet been performed, although technically feasible. We discuss the ethical aspects of such a procedure from the perspectives of the donor, the recipient, and the medical team.

Predictors of bacteremia and gram-negative bacteremia in patients with sepsis. The Veterans Affairs Systemic Sepsis Cooperative Study Group.

BACKGROUND: We analyzed data from the Department of Veterans Affairs trial of steroid therapy for systemic sepsis to identify predictors of bacteremia and gram-negative bacteremia. METHODS: Of the 2568 patients screened for entry in the trial, 465 met the following criteria: presence of four of seven clinical signs of sepsis; blood cultures at the time of screening; and complete data on nine clinical parameters. The multivariate logistic regression model was used to identify predictors of bacteremia and gram-negative bacteremia. Predicted probabilities of having these types of infections were calculated using the identified predictors. Patients were then classified into groups with and without bacteremia (and gram-negative bacteremia) based on the predicted probability. Misclassification error rates were calculated for each method of categorization by comparing the true with the predicted grouping of patients. RESULTS: Three factors were independently predictive of bacteremia and gram-negative bacteremia: elevated temperature, low systolic blood pressure, and low platelet count. Using these three factors, classification methods were identified that predicted blood infection better than chance, but misclassification was also high. For predicting bacteremia, the maximum predicted positive rate was 83%, with a specificity of nearly 100% and a sensitivity of only 5%. For predicting gram-negative bacteremia, the maximum predicted positive accuracy was 100%, with a specificity also of 100% and a sensitivity of almost 0%. CONCLUSIONS: Using simple clinical parameters, we could not predict either bacteremia or gram-negative bacteremia with sufficient accuracy to be clinically meaningful; however, our approach represents a step in the direction of forecasting the bacterial organism responsible for sepsis in advance of culture results.

The metabolic and respiratory alterations of heat stroke.

The metabolic and respiratory changes of 21 patients with heat stroke were studied. Admission arterial blood gas levels were measured, and serum bicarbonate, lactate, calcium, phosphorus, and anion gap determinations were performed. Seven patients had a metabolic acidosis (pH 7.20 +/- 0.04, PCO2 32 +/- 2 mm Hg, and bicarbonate 12 +/- 1 mEq/L), seven a combined metabolic acidosis and respiratory alkalosis (pH 7.39 +/- 0.01, PCO2 25 +/- 1 mm Hg, and bicarbonate 15 +/- 1 mEq/L), four a respiratory alkalosis (pH 7.45 +/- 0.01, PCO2 30 +/- 1 mm Hg, and bicarbonate 20 +/- 1 mEq/L), one a metabolic and respiratory acidosis (pH 7.13, PCO2 52 mm Hg, and bicarbonate 17 mEq/L), and one a respiratory acidosis (pH 7.30, PCO2 56 MM Hg, and bicarbonate 27 mEq/L). The 15 patients with a metabolic acidosis had a pH of 7.28 +/- 0.03, PCO2 of 30 +/- 2 mm Hg, bicarbonate level of 14 +/- 1 mEq/L, lactate concentration of 6.5 +/- 1.0 mEq/L, and an anion gap of 26 +/- 4 mEq/L. Nine patients were hypocalcemic (7.8 +/- 0.3 mg/dL), and five patients were hypophosphatemic (2.0 +/- 0.2 mg/dL). The predominant metabolic change in heat stroke is a metabolic acidosis secondary to increased lactate content and/or a respiratory alkalosis. Hypocalcemia is common and hypophosphatemia is not infrequent.

The enigma of underdrainage in shunting with hydrostatic valves and possible solutions.

OBJECTIVE: Hydrostatic devices have considerable advantages compared to "conventional" differential-pressure-valves concerning overdrainage, but are thought to imply a tendency to underdrain or to clog. The aim of this study was to evaluate the ability of the hydrostatic gravitational Dual-Switch-Valve (DSV) to minimize overdrainage-related complications without increasing the danger of underdrainage. RESULTS: In a series of 202 adult patients with different etiologies treated with a ventriculo-peritoneal shunt including the hydrostatic Dual-Switch-valve (DSV), 21 cases were suspected of suffering from underdrainage. Using a new algorithm we were able to differentiate obstruction in 6 patients from functional underdrainage in 15 cases, thus we saw an indication to reimplant a DSV with a lower opening pressure in the latter. CONCLUSION: The reasons for functional underdrainage were multifold in our series, especially the intraperitoneal pressure is still a "black box". Despite the ability of the DSV to avoid clogging and to minimize overdrainage by its high-pressure-chamber, it remains difficult to determine the optimal opening pressure of the low-pressure-chamber of the DSV for ideal clinical improvement. Therefore a new hydrostatic gravitational "programmable" valve (proGAV), entitled on avoiding the disadvantages of other adjustable devices, has been developed and implanted in 16 patients with promising results.

Evidence for increased permeability in reexpansion pulmonary edema.

Concurrent analyses of the colloid osmotic pressure of pulmonary edema fluid and serum were performed in two patients with reexpansion pulmonary edema. In addition, pulmonary artery wedge pressure was measured during pulmonary edema in one patient. The colloid osmotic pressure of the pulmonary edema fluid was 73 and 81 percent of the serum value. The pulmonary arterial wedge pressure in one patient was within normal limits (8 mm Hg). Reexpansion pulmonary edema appears to be due to increased pulmonary capillary permeability rather than to hemodynamic mechanisms.

Uremic pulmonary edema.

Pulmonary edema fluid analyses and hemodynamic evaluations were performed in two uremic patients with acute pulmonary edema. The colloid osmotic pressure of the pulmonary edema fluid ranged from 57 per cent to 93 per cent that of the serum. Although cardiac function was normal in both patients, the serum colloid osmotic pressure--pulmonary artery wedge pressure gradients were markedly reduced. Uremic pulmonary edema is the result of alterations of pulmonary intravascular Starling forces and increases in pulmonary capillary membrane permeability, allowing for the efflux of protein-rich fluid from the capillaries into the lung.

Prophylactic use of lidocaine to prevent advanced ventricular arrhythmias during pulmonary artery catheterization. Prospective double-blind study.

To determine whether prophylactic lidocaine could decrease the incidence of advanced ventricular arrhythmias, 62 patients undergoing 67 pulmonary artery catheterizations were given lidocaine or placebo before and during catheterization. Advanced ventricular arrhythmias occurred in 42 of the 67 catheterizations (63 percent). In 18 of 31 patients receiving lidocaine (58 percent) arrhythmias developed, whereas 24 of 36 patients who received placebo (67 percent) had evidence of arrhythmias. These differences were not significant. However, patients with catheterization times of less than 20 minutes who were treated with lidocaine had less ectopy (25 percent) than patients treated with placebo (68 percent) (p less than 0.05). Two patients has sustained ventricular tachycardia and both were receiving placebo. No complications of lidocaine prophylaxis were noted. Prophylactic lidocaine appears to decrease the incidence of mechanically induced arrhythmias in critically ill patients undergoing catheterization that is not prolonged.

Advanced ventricular arrhythmias during bedside pulmonary artery catheterization.

To determine the incidence of advanced arrhythmias and acute right bundle branch block during beside pulmonary artery catheterization, 119 critically ill patients undergoing 150 pulmonary artery catheterizations were prospectively studied using continuous electrocardiographic monitoring with permanent recordings. Ventricular arrhythmias other than isolated premature ventricular contractions, couplets or bigeminy occurred during 80 of the 150 catheterizations (53 percent). These included ventricular salvos (three to five consecutive premature ventricular contractions) in 30 percent, nonsustained ventricular tachycardia (five to 30 premature ventricular contractions) in 20 percent and sustained ventricular tachycardia (more than 30 consecutive premature ventricular contractions) in 3 percent. In two patients, ventricular fibrillation developed; in another three patients, lidocaine or precordial thump was required to terminate the episodes of ventricular tachycardia. The incidence of advanced ventricular arrhythmias was statistically correlated with either the presence of predisposing risk factors for ventricular ectopy (p less than 0.05) or prolonged catheterization time (p less than 0.01). A new right bundle branch block developed in seven patients (5 percent) and persisted for a mean of 9.5 hours.

Promoter independent down-regulation of the firefly luciferase gene by T3 and T3 receptor in CV1 cells.

We report that the activity of the firefly luciferase (LUC) reporter gene is down-regulated by T3 and T3 receptor (TR) in the CV1 mammalian cell line, which is widely used for studies of TR action. Repression was highly reproducible, T3 and TR dependent, promoter independent, and observed regardless of whether an internal control for transfection efficiency was used. Cotransfections with normal and mutant TRs indicate that the negative T3 response is mediated by sequences within the LUC gene coding region, and is not due to the interaction of TR with a limiting transcription factor. Negative regulation of the LUC reporter was overcome by a strong, cis-linked T3 response element (TRE), but continued in the presence of a TRE of moderate strength. The results described here demonstrate that conclusions drawn from studies of TRE structure and activity performed using the LUC reporter in CV1 cells should be interpreted with caution.

Hemodynamic alterations of heat stroke in the elderly.

Serial hemodynamic alterations were investigated in seven elderly patients with heat stroke. Their mean age was 72 +/- 6 years. The circulatory response to heat stroke was either hyperdynamic of hypodynamic. Two patients had increased cardiac index (4.3 and 4.4 L/min/m2), increased right atrial pressure (10 and 12 mm Hg), normal pulmonary capillary wedge pressure (10 and 12 mm Hg), and decreased systemic vascular resistance (542 and 738 dyne.sec.cm-5). Five patients had decreased cardiac index (mean 2.3 +/- 0.2 L/min/m2), decreased right atrial pressure (mean 2 +/- 1 mm Hg), normal pulmonary capillary wedge pressure (mean 6 +/- 3 mm Hg), and increased systemic vascular resistance (mean 2020 +/- 204 dyne.sec.cm-5). Circulatory failure appears to be secondary to peripheral pooling of blood or hypovolemia. The inability to compensate hemodynamically when stressed by heat may predispose certain elderly individuals to develop heat stroke.

Pulmonary edema; a complication of diabetic ketoacidosis.

Hemodynamic evaluation in two patients and analysis of pulmonary edema fluid in one patient with diabetic ketoacidosis and acute pulmonary edema were performed. Pulmonary arterial wedge pressures in both patients were low or normal (1 and 9 mm Hg). In one patient the colloid osmotic pressure of the pulmonary edema fluid was 68 percent of the value of the serum. The serum colloid osmotic pressure-pulmonary arterial wedge pressure gradient in the second patient was markedly reduced. Pulmonary edema complicating diabetic ketoacidosis may be the result of increased permeability of pulmonary capillary membranes and altered intravascular colloid-hydrostatic forces.