Recommendations for triage to intensive care units (ICUs) have been issued but not evaluated.
In this prospective, multicenter study, all patients granted or refused admission to 26 ICUs affiliated ...with the French Society for Critical Care were included during a 1-month period. Characteristics of participating ICUs and patients, circumstances of triage, and description of the triage decision with particular attention to compliance with published recommendations were recorded.
During the study period, 1,009 patients were and 283 were not admitted to the participating ICUs. Refused patients were more likely to be older than 65 yrs (odds ratio OR, 3.53; confidence interval CI, 1.98-5.32) and to have a poor chronic health status (OR, 3.09; CI, 2.05-4.67). An admission diagnosis of acute respiratory or renal failure, shock, or coma was associated with admission, whereas chronic severe respiratory and heart failure or metastatic disease without hope of remission were associated with refusal (OR, 2.24; CI, 1.38-3.64). Only four (range, 0-8) of the 20 recommendations for triage to ICU were observed; a full unit and triage over the phone were associated with significantly poorer compliance with recommendations (0 0-2 vs. 6 2-9, p =.0003; and 1 0-6 vs. 6 1-9, p <.0001; respectively).
Recommendations for triage to intensive care are rarely observed, particularly when the unit is full or triage is done over the phone. These recommendations may need to be redesigned to improve their practicability under real-life conditions, with special attention to phone triage and triaging to a full unit.
Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends ...life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials.
The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software.
Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine.
These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.
Phosphorylation of cytosine analogs by deoxycytidine kinase (dCK) and deamination by cytidine deaminase (CDA) are two important processes in the activation and elimination of these drugs. We have ...investigated the kinetic parameters of 2',2'-difluorodeoxycytidine (dFdC) using purified enzymes from human cells. Deoxycytidine (CdR) and dFdC had Km values of 1.5 and 4.6 microM for dCK, respectively. Feedback inhibition of dCK by deoxycytidine 5'-triphosphate (dCTP) was also studied. Our results show that dCTP produced a greater inhibition of the phosphorylation of dFdC than CdR with concentrations of dCTP ranging from 1 to 25 microM. dFdC was a good substrate for CDA. Kinetic studies with this enzyme gave Km values for CdR and dFdC of 46.3 and 95.7 microM, respectively. The effect of competitive inhibitors of CDA on the deamination of dFdC was also investigated. Diazepinone riboside was a more potent inhibitor than tetrahydrouridine using either CdR or dFdC as the substrate. Inhibitors of CDA could be useful in clinical trials in patients with cancer to increase the chemotherapeutic effectiveness of dFdC.
Continuous monitoring of cardiac output during liver transplantation is essential to evaluate the patient's haemodynamic tolerance to acute volume variations. The aim of this study was to compare the ...cardiac output values obtained with a transoesophageal echo-Doppler and those obtained with a continuous thermodilution cardiac output pulmonary artery catheter.
Twenty adult patients were prospectively studied during a 5 min hepatic vascular exclusion test performed at the end of the dissection phase. Echo-Doppler and continuous thermodilution cardiac output, mean arterial pressure and end-tidal CO2 were measured before and at the end of the test.
Before the test, echo-Doppler cardiac output was 7.0 +/- 2.7 L min(-1) and thermodilution was 9.4 +/- 3.1 L min(-1), (R = 0.85, P < 0.001). The end test values were, respectively, 3.5 +/- 2.7 and 7.8 +/- 3.5 L min(-1) (R = 0.23, P = 0.34). Bland and Altman analysis showed a bias of -2.2 before the test, which increased to -4.4 at the end of the test. Mean arterial pressure decreased from 85.5 +/- 15 to 66.8 +/- 16 mmHg, end-tidal CO2 from 31.4 +/- 2.3 to 23.8 +/- 2.7 mmHg.
Echo-Doppler cardiac output values are different from those measured by thermodilution cardiac output in these patients. Echo-Doppler cardiac output monitoring seems to detect the output changes, which can occur during acute haemodynamic changes more rapidly than thermodilution cardiac output in the course of liver transplantation.
5-Aza-2'-deoxycytidine (5-AZA-CdR, Decitabine) is a nucleoside analog and an active drug for the therapy of acute leukemia. The incorporation of 5-AZA-CdR into DNA blocks DNA methylation and can ...result in the activation of specific genes, such as tumor suppressor genes. This novel mechanism of action of 5-AZA-CdR stimulated our interest in its potential for cancer therapy in patients with lung cancer. Using a colony assay we observed that 5-AZA-CdR showed a potent antineoplastic effect against two human lung carcinoma cell lines. The objective of this preliminary phase I-II study was to evaluate the toxicity and clinical efficacy of 5-AZA-CdR in patients with stage IV non-small cell lung carcinoma. There were 15 patients that entered the clinical study. For nine assessable patients that received 5-AZA-CdR by a single 8 h i.v. infusion of 200-660 mg/m2 for one or more cycles, the median survival duration was 6.7 months, with three patients surviving more than 15 months. The steady-state plasma concentration of 5-AZA-CdR during the infusion was estimated in some patients and was in the same range that produced activation of a tumor suppressor gene in human lung tumor cell lines as reported by other investigators. The major side effect of 5-AZA-CdR was hematopoietic toxicity which required a 5-6 week recovery period before the next cycle of therapy. This study suggests that 5-AZA-CdR may have some clinical activity against metastatic lung carcinoma using this type of dose schedule.
Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show ...that a tetrahydrofuran phosphonate analogue of guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl) tetrahydrofuran (BCH-1868), previously reported as having antiviral activity, also displays antitumor activity. In vitro, BCH-1868 inhibited the proliferation of several murine and human cancer cell lines with IC50s in the microM range independently of the tissue type or the presence of multidrug resistance protein MRP/gp190. In vivo, BCH-1868 was active against a variety of human tumor xenograft models (Caki-1, HT-29, DU 145, COLO 205, and CCRF-CEM). In all tumors tested, a significant tumor growth inhibition was noted at 40-50 mg/kg (daily x 5), but no tumor regression was observed in the settings used. To better understand these results, we partially characterized, at the cellular level, the mechanism of action of this new cyclic nucleoside phosphonate and investigated its pharmacokinetic characteristics in mice. We showed that BCH-1868 exerts its antitumor activity by an inhibitory mechanism at the level of DNA polymerase a, resulting in arrest of DNA synthesis and a block of cell division at the S phase of the cell cycle. Low-circulating plasma concentration (Cmax = 87 microM; area under the curve = 1138 micromol x min/liters; after a bolus i.v. injection of 10 mg/kg) and rapid clearance of the drug (terminal half-life, t1/2 = 16 min) may contribute to the modest antitumor efficacy observed in vivo.
To evaluate a monitor of pulmonary gas exchange (Deltatrac, Datex) in a clinical setting.
After in vitro evaluation, comparison over 2 min between VO2 and VCO2 values measured by the Deltatrac and ...the Douglas bag technique. Comparisons were also achieved over 8 h periods between the Deltatrac and a system using a mass-spectrometer.
Polyvalent intensive care unit (ICU 15 beds) in a 1200 bed general hospital.
Comparison with the Douglas bag technique in 10 patients undergoing controlled ventilation. Comparison with the mass-spectrometer system in 25 other patients undergoing controlled or pressure support ventilation.
Compared to the results obtained by the Douglas bag technique, the bias (+/- 2 SD) for VO2 and VCO2 was -3.5 +/- 26.6 and 6.1 +/- 12.7 ml.min-1, respectively. By comparison with the mass-spectrometer system, the bias for VO2 and RQ was -5.8 +/- 16.0 ml.min-1 and 0.018 +/- 0.048, respectively. No drift between the two systems was observed over time.
The Deltatrac appears suitable for VO2 and VCO2 measurements in ventilated patients and equivalent to a mass-spectrometer system for long term measurements.
To evaluate the opinions of intensive care unit staff and family members about family participation in decisions about patients in intensive care units in France, a country where the approach of ...physicians to patients and families has been described as paternalistic.
Prospective multiple-center survey of intensive care unit staff and family members.
Seventy-eight intensive care units in university-affiliated hospitals in France.
We studied 357 consecutive patients hospitalized in the 78 intensive care units and included in the study starting on May 1, 2001, with five patients included per intensive care unit.
We recorded opinions and experience about family participation in medical decision making. Comprehension, satisfaction, and Hospital Anxiety and Depression Scale scores were determined in family members.
Poor comprehension was noted in 35% of family members. Satisfaction was good but anxiety was noted in 73% and depression in 35% of family members. Among intensive care unit staff members, 91% of physicians and 83% of nonphysicians believed that participation in decision making should be offered to families; however, only 39% had actually involved family members in decisions. A desire to share in decision making was expressed by only 47% of family members. Only 15% of family members actually shared in decision making. Effectiveness of information influenced this desire.
Intensive care unit staff should seek to determine how much autonomy families want. Staff members must strive to identify practical and psychological obstacles that may limit their ability to promote autonomy. Finally, they must develop interventions and attitudes capable of empowering families.
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