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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.

Measurement of the nutrient oxidation rate with 13C as a tracer requires knowledge of the value of its coefficient of fractional recovery in the expired gas (FR). We measured FR in nine intensive care patients who were mechanically ventilated and received total parenteral nutrition. NaH13CO3 was administered at a priming dose (3.75 mumol.kg-1.min-1) followed by a continuous infusion (0.05 mumol.kg-1.min-1). Metabolic rate and pulmonary carbon dioxide elimination (VCO2) were measured by using a mass-spectrometer system. The 13C-12C ratio was measured in the expired gas with an isotopic-ratio mass spectrometer and FR was calculated by using standard equations. The average value of FR was 0.899 +/- 0.026 (means +/- SE) and remained stable for each patient on 2 consecutive days. Between patients, the coefficient of variation of FR was 8.6%. Metabolic rate was the only physiological factor found to affect the FR value.

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, P0.001). 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.

Early somatosensory (SEP) and auditory (BAEP) evoked potentials, when recorded within the first seven days of the course of anoxic coma, appear to be reliable to evaluate anoxic ischemic cortical or under-cortical lesions. Prognosis depends especially on cortical SEP (N20-P25): the lack of SEP is a good outcome predictor of death (abnormal BAEP) or of vegetative status (normal BAEP); the presence of normal and bilateral cortical SEP (with normal BAEP) allows to predict awakening, without prejudging of neurologic sequelae, even if they are severe.

We report a case with focal neurological deficits suggesting vertebro-basilar system ischemia, in the course of pre-eclampsia. An early CT scan showed a large hypodensity throughout the midbrain. Brainstem auditory evoked potentials initially showed an abolition of III and V pikes suggesting brainstem injury. Two days later both neurological examination and brain stem auditory evoked potentials returned to normal. A CT scan performed three weeks after the onset was normal. These findings suggest a vasospasm which may have been due to sympathomimetic agents given two weeks before the onset of toxemia for preterm labor.

Early somatosensory (ESEP) and auditory (EAEP) evoked potentials were recorded in 27 patients with severe coma (Glasgow score less than 5) following cardiorespiratory arrest, within the first 7 days of its course. Somatosensory responses were elicited by stimulation of the median nerve. ESEP were abolished in 17 patients due to a parietal thalamo-cortical lesion. Among these, 6 patients died within one month and 11 presented with a persistent vegetative state. In all patients EAEP were obtained, showing functional brainstem activity. Low-voltage EAEP, especially for peak V (inferior colliculus or upper part of the brainstem), was sometimes observed. One patient, in whom ESEP and EAEP were initially abolished, died rapidly. In 9 other patients scalp-recorded ESEP and EAEP were normal; all emerged from coma including 5 with good neurological recovery and 4 with neurological sequelae. Clinical, electroencephalographic and computerized tomographic data appeared to be devoid of predictive value at the same initial period. In view of their sensitivity to anoxia and to cerebral oedema, even with neurosedative drugs, ESEP seemed to be reliable in predicting outcomes and in evaluating central nervous system lesions at cortical and subcortical levels (basal ganglia and brainstem) after cardiorespiratory arrest.

The pharmacokinetics of alfentanil were studied in 11 patients with alcoholic cirrhosis and 10 control patients during general anesthesia. All patients received 50 micrograms . kg-1 alfentanil as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 10 h, using a specific radioimmunoassay technique. Protein binding was measured by equilibrium dialysis. Patients with cirrhosis had a significantly lower (P less than 0.01) plasma clearance of alfentanil of 1.6 +/- 1.0 ml . min-1 . kg-1 (mean +/- SD) instead of 3.1 +/- 1.6 ml . min-1 . kg-1 in the controls. The total apparent volume of distribution was similar in the two groups. The elimination half-life was prolonged from 90 +/- 18 min in the controls to 219 +/- 128 min in the cirrhotics (P less than 0.01). Patients with cirrhosis had a higher (P less than 0.01) alfentanil plasma-free fraction (18.6 +/- 9.4%) compared with the control patients (11.5 +/- 3.9%). When kinetic parameters were corrected for protein binding, the unbound volume of distribution and the free drug clearance were decreased significantly in patients with cirrhosis. Since the concentration alpha 1-glycoprotein to which alfentanil mainly is bound in plasma did not differ in the two groups, it is suggested that the increase in the free fraction is caused by an alteration of binding sites of this protein in patients with cirrhosis. Owing to its delayed elimination and increased free fraction, alfentanil will exert a prolonged and pronounced effect in patients with cirrhosis.

Seven cases of acute ajmaline overdose admitted over a 3 year period to a polyvalent intensive care unit are reported. The severity of this condition is related to the membrane stabilising and depolarising effects of ajmaline on the myocardium. The dose ingested varied from 10 to 40 mg/kg. The delay between ingestion and hospital admission ranged from 3 to 6 1/2 hours. The first cardiac disturbances can appear one hour after ingestion. Three cardiac arrests and one hypovolemic shock occurred. Three atrioventricular blocks, six intraventricular blocks, three ventricular tachycardias, and six prolongations of the QT interval were observed. Serum ajmaline levels varied from 0,8 to 6 mg/l. Symptomatic therapy was mainly based on sodium, temporary cardiac pacing, external DC shock, sympathomimetics and external cardiac massage with assisted ventilation. Cardiac bypass should be a part of the therapeutic arsenal. Elimination of the drug is assisted by a complete digestive evacuation. Renal or extrarenal dialysis is not indicated. One of the seven patients died. Prophylaxis is based on the non-prescription of ajmaline for benign cardiac disturbances.

Twenty mechanically ventilated patients with acute renal failure were studied on 31 occasions to determine their energy expenditure (EE) during a 2 h period before a hemodialysis. Oxygen consumption and CO2 elimination were measured continuously with a mass spectrometer system. EE (1660 +/- 48 kcal day-1) was close to the total caloric intake (1682 +/- 83 kcal day-1) and represented 1.19 +/- 0.03 times the predicted resting energy expenditure (PREE) with large inter-individual variations (0.7-1.7 PREE). EE/PREE was higher when sepsis was present (1.31 +/- 0.03 versus 1.14 +/- 0.02; p less than 0.05). Glucose oxidation rate (4.35 mg kg-1 min-1) exceeded glucose intake (2.6 mg kg-1 min-1). Respiratory quotient was 1.02 +/- 0.01. Nitrogen loss was 17.3 +/- 1.7 g day-1 and nitrogen balance -11.9 +/- 1.9 g day-1. In conclusion, EE values were scattered but never exceeded 1.7 times the PREE. Sepsis increased EE. With a nutritional support covering EE, nitrogen balance remained markedly negative and a preferential utilisation of glucose and lipogenesis occurred.

Between 1977 and 1982, fifty cases of post-traumatic fat embolism were treated in a general intensive care unit. Average age of patients was 25.5 +/- 13 years; there was no male majority. Mean free interval was 39 +/- 27 h. 12 cases (24%) had single fractures and 38 (76%) multiple fractures. Forty-four patients had a fractured femur. Thirty-two patients presented the complete clinical syndrome with general, respiratory, neurological and cutaneous signs. Thrombocytopaenia and hypocholesterolaemia were the biological signs most often seen. In forty-four patients, orthopaedic treatment consisted of immediate immobilization, usually with traction. Twenty-six patients were reoperated on: intramedullary nail for twenty patients, plate for the other six. Fat embolism appeared in spite of surgery in six cases; it worsened after surgery in six others. Seven patients had per- or postanaesthetic problems. Fourteen per cent of patients died. The decrease in mortality was mainly due to an improvement in mechanical ventilation techniques. Early surgical fixation remained the rule if there was no serious respiratory distress or haemodynamic instability, although it did not seem to change the mortality rate in this group of patients.

The neurological signs, the cerebral CAT scan aspects and the ocular problems seen in five cases of acute methanol poisoning are reported; these were, respectively, coma requiring assisted ventilation, convulsions, hypotonicity, hypodensity of the putamen, and amaurosis and papillary oedema. The simplified acute physiologic score varied from 11 to 26; the value of 26 was observed in the only death of the series. Pathogenesis of the metabolic acidosis, as well as the different parts played by formic acid, lactic acid and ketone bodies are discussed. A normal or lowered serum potassium in a case of unexplained metabolic acidosis associated with an osmotic gap should make one think of the diagnosis. Macrocytosis, an indirect sign of folic acid deficiency, was in favour of a poor prognosis. The treatment included early gastric lavage, alkalinization, blocking of the metabolism of methanol by ethanol and haemodialysis with a bicarbonate dialysate enriched in ethanol; this corrected the acidosis and permitted the elimination of the toxic metabolites (clearance of methanol: 159 ml X min-1; half-life of methanol during purification: 3.46 +/- 1.32 h; quantity extracted: 246 g). The possible advantages of 4-methyl-pyrazol and alkyldiol derivatives need further confirmation.

A new case of oxytocin-induced water intoxication is reported in a 30 year old gravid woman. The severe symptoms of this uncommon complication are principally neurological; biological signs are a hyponatraemia with low plasma osmolality. Usually, biological and clinical signs are rapidly cleared up by treatment, but maternal death or neonatal water intoxication may occur. Such accidents must be prevented by clinical monitoring, watching out for alarm signals (oliguria is always found, resulting from the effect of oxytocin on the kidney), minimum fluid and proportional salt intakes, careful monitoring of oxytocin infusion rates, facilitated by the use of a constant flow-rate pump.

Among the 94 tricyclic antidepressant intoxications received in 3 years in the intensive care unit of Edouard Herriot Hospital, 16 with cardio-vascular manifestations are studied. The criteria of selection is the presence on the electrocardiogram (ECG) of a ventricular trouble in conduction excitability or automaticity. Eight times, the ingested dose exceeds 20 mg/kg. 10 times several toxics are taken explaining the severity of coma and the rarity of convulsions. 2 collapses, 1 shock, 1 cardiac arrest occur. The most frequent ECG abnormalities are: T modifications, (90 p. 100), prolongation of QT interval (60 p. 100), right bundle branch block (50 p. 100) or left one (25 p. 100). Only one death occurs; (1 p. 100 of this series). Ventricular dysrythmia or myocardial failure represent the main criteria in the evaluation of severity of the tricyclic antidepressant intoxication. For the treatment, a complete digestive evacuation is needed, Hemodialysis, plasmapheresis, or hemoperfusion cannot be actually recommended. The treatment of cardiac troubles involves essentially sodium. and eventually intra-cardiac pace maker.

This clinical investigation examined deep venous thrombosis with clinical signs indicating superior vena caval involvement, secondary to installation of central venous catheters. Thrombophlebitis was rare, but very dangerous if of septic origin.