A Randomized, Double-Blind, Placebo-Controlled Trial (TAURCAT Study) of Citrate Lock Solution for Prevention of Endoluminal Central Venous Catheter Infection in Neutropenic Hematological Patients.

Infection of long-term central venous catheters (CVCs) remains a challenge in the clinical management of cancer patients. We aimed to determine whether a lock solution with taurolidine-citrate-heparin would be more effective than placebo for preventing nontunneled CVC infection in high-risk neutropenic hematologic patients. We performed a prospective, multicenter, randomized (1:1), double-blind, parallel, superiority, placebo-controlled trial involving 150 hematological patients with neutropenia carrying nontunneled CVCs who were assigned to receive CVC lock solution with taurolidine-citrate-heparin or heparin alone. The primary endpoint was bacterial colonization of the CVC hubs. Secondary endpoints were the incidence of catheter-related bloodstream infection (CRBSI), CVC removal, adverse events related to the lock solution, and the 30-day case fatality rate. CVC lock solution with taurolidine-citrate-heparin was associated with less colonization of the CVC hubs than that with placebo, with no statistically significant differences: 4.1%, versus 10.1% (relative risk [RR] = 0.41, 95% confidence interval [CI] = 0.11 to 1.52), with a cumulative incidence of 4.17 (95% CI = 0.87 to 11.70) and 10.14 (95% CI = 4.18 to 19.79), respectively. There were no significant differences regarding the secondary endpoints. Only three episodes of CRBSI occurred during the study period. No adverse events related to the administration of the lock solution occurred. In this trial involving high-risk patients carrying nontunneled CVCs, the use of taurolidine-citrate-heparin did not show a benefit over the use of placebo. Nevertheless, the safety of this prevention strategy and the trend toward less hub colonization in the taurolidine-citrate-heparin group raise the interest in assessing its efficacy in centers with higher rates of CRBSI. (This study has been registered in ISRCTN under identifier ISRCTN47102251.).

Behavioral and pathological effects in the rat define two groups of neurotoxic nitriles.

Adult male Long-Evans rats (250-350 g) received control vehicles, 3,3'-iminodipropionitrile (IDPN, 400 mg kg(-1) day(-1)), allylnitrile (50 mg kg(-1) day(-1)), cis-crotononitrile (110 mg kg(-1) day(-1)), trans-crotononitrile (250 mg kg(-1) day(-1)), or 2,4-hexadienenitrile (300 mg kg(-1) day(-1)), i.p., for 3 consecutive days. Rats treated with IDPN, allylnitrile, and cis-crotononitrile developed the ECC (excitation with circling and choreiform movements) syndrome, whereas those treated with trans-crotononitrile and hexadienenitrile exhibited a different syndrome, characterized by faltering movements. On quantitative analysis, IDPN, allylnitrile, and cis-crotononitrile induced high scores in a test battery for vestibular dysfunction and hyperactivity in the open field, but they did not significantly decrease stride length. Hexadienenitrile and trans-crotononitrile did not increase the vestibular scores or the locomotor activity, but they caused a marked decrease in stride length; they also decreased holding time on a vertical ladder. In brain and spinal cord tissue from rats exposed to IDPN, allylnitrile, or cis-crotononitrile, Fluoro-Jade B, a selective stain for degenerating neurons, did not reveal any labeling other than that of nerve terminals in the glomeruli of the olfactory bulbs, indicating degeneration of the olfactory mucosa. With the same stain, rats exposed to trans-crotononitrile or hexadienenitrile showed a common pattern of selective neurotoxicity; major targets were the inferior olive and the piriform cortex. Hexadienenitrile did not cause hair cell degeneration in the vestibular and auditory sensory epithelia. Present and previous data indicate that neurotoxic nitriles induce one or the other of two different motor syndromes, through either vestibular hair cell degeneration or neuronal degeneration of the inferior olive.

The targets of acetone cyanohydrin neurotoxicity in the rat are not the ones expected in an animal model of konzo.

Konzo is a neurotoxic motor disease caused by excess consumption of insufficiently processed cassava. Cassava contains the cyanogenic glucoside linamarin, but konzo does not present the known pathological effects of cyanide. We hypothesized that the aglycone of linamarin, acetone cyanohydrin, may be the cause of konzo. This nitrile rapidly decomposes into cyanide and acetone, but the particular exposure and nutrition conditions involved in the emergence of konzo may favor its stabilization and subsequent acute neurotoxicity. A number of preliminary observations were used to design an experiment to test this hypothesis. In the experiment, young female Long-Evans rats were given 10mM acetone cyanohydrin in drinking water for 2 weeks, and then 20mM for 6 weeks. Nutrition deficits associated with konzo were modeled by providing tapioca (cassava starch) as food for the last 3 of these weeks. After this period, rats were fasted for 24h in order to increase endogenous acetone synthesis, and then exposed to 0 (control group) or 50 micromol/kg-h of acetone cyanohydrin for 24h (treated group) through subcutaneous osmotic minipump infusion (n=6/group). Motor activity and gait were evaluated before exposure (pre-test), and 1 and 6 days after exposure. Brains (n=4) were stained for neuronal degeneration by fluoro-jade B. Rats exposed to 50 micromol/kg-h of acetone cyanohydrin showed acute signs of toxicity, but no persistent motor deficits. Two animals showed fluoro-jade staining in discrete thalamic nuclei, including the paraventricular and the ventral reuniens nuclei; one also exhibited labeling of the dorsal endopiriform nucleus. Similar effects were not elicited by equimolar KCN exposure. Therefore, acetone cyanohydrin may cause selective neuronal degeneration in the rat, but the affected areas are not those expected in an animal model of konzo.