Advanced airway management--a medical emergency response team perspective.

OBJECTIVES: To determine the number of medical emergency response team (MERT) patients undergoing advanced airway management in the peri-evacuation phase and to determine the indications for airway interventions undertaken in flight. METHODS: This was a retrospective study. Data was collected from patient report and mission debrief forms completed after each MERT mission during Operation HERRICK 10 (April-October 2009). All patients that received advanced airway interventions before or during evacuation were identified. RESULTS: MERTs were involved in the primary transfer of 534 patients during the period studied, 56 (10.5%) underwent advanced airway management, of which 31 (5.8% of total) were initiated by the MERT in the peri-evacuation phase. Twenty five cases (4.7%) underwent advanced airway management by other pre-hospital providers prior to MERT arrival. Of the 31 advanced airway interventions undertaken in-flight, cardiac arrest was the primary indication in only nine cases. CONCLUSIONS: The figure of 56 patients requiring advanced airway management is at the higher end of the range expected from the study of historical military data. This may reflect the doctrine of "intelligent tasking", that is sending this physician-led team to the most seriously injured casualties.

Anaesthesia at Role 4.

The contribution of anaesthesia to the care of injured military personnel at Role 4 is described with particular emphasis on the working relationship between the Royal Centre for Defence Medicine and the civilian department of anaesthesia. The implications for operating theatre activity are discussed.

Traumatic pneumorrhachis.

Pneumorrhachis or intraspinal air is an increasingly encountered phenomenon in the management of severe trauma. The case of a 23-year-old soldier, who sustained a gunshot wound to the chest, is presented and the subsequent discussion illustrates that while often benign this phenomenon may indicate serious occult injury.

Cellular uptake of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA).

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA), a DNA intercalating dual topoisomerase I/II poison, has high experimental antitumour activity, is able to overcome several forms of multidrug resistance, and is undergoing clinical trial. We prepared 3H-labelled DACA and investigated its uptake using cultured Lewis lung carcinoma cells (LLTC), P388 leukaemia cells and P/DACT cells that were multidrug resistant. The kinetics of uptake and efflux were very rapid and equilibrium was obtained within seconds of drug addition. Fluorescence microscopy of LLTC cells treated with DACA showed punctate fluorescence in the cytoplasm, consistent with uptake into vesicles. To investigate the role of lipophilicity in drug uptake, a fluorimetric assay was developed to measure uptake of a more hydrophilic derivative, 9-amino-5-sulphonylmethyl-DACA (as-DACA). The calculated n-octanol-water partition coefficient for as-DACA was 20-fold lower than that for DACA. On the other hand, as determined by ethidium displacement from DNA, as-DACA bound DNA 16-fold more strongly than did DACA. Uptake and efflux of DACA and as-DACA were very rapid and the uptake ratios in LLTC cells were 550 for DACA and 54 for as-DACA. At equitoxic concentrations (corresponding to the IC50 values), LLTC cell association was estimated to be approximately 1.6 x 10(8) molecules per cell for DACA and 3.0 x 10(6) molecules per cell for as-DACA. It is argued that DACA binds predominantly to lipophilic sites such as proteins and cellular membranes, while as-DACA associates predominantly with DNA. The high affinity of DACA for membranes may contribute to the rapidity of its uptake and efflux, as well as to its ability to overcome multidrug resistance.

A comparison of the effects of aphidicolin and other inhibitors on topoisomerase II-directed cytotoxic drugs.

We have compared the effects of a number of inhibitors including aphidicolin, 2,4-dinitrophenol (DNP) and novobiocin on the in vitro cytotoxicity of several topoisomerase II (topo II)-directed agents, using cultured murine Lewis lung carcinoma cells. These agents comprised amsacrine, CI-921 (9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-N,5-dimethyl-4- acridinecarboxamide isethionate, isethionate, a derivative of amsacrine), DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride, a new DNA intercalator with high solid tumor activity), daunorubicin, doxorubicin, epirubicin, etoposide, mitoxantrone, and teniposide. Novobiocin, an antibiotic that affects topo II action, reduced the cytotoxic effect of DACA as well as that of amsacrine and doxorubicin, and reduced the extent of G2-phase arrest by DACA. DNP, an uncoupler of mitochondrial respiration, inhibited drug action in a manner similar to that of novobiocin but to a smaller extent. Aphidicolin, a specific inhibitor of DNA polymerase-alpha, reduced the cytotoxic effect of amsacrine, CI-921, etoposide, and teniposide but not that of DACA, daunorubicin, doxorubicin, epirubicin, or mitoxantrone. The immediate effect of each topo II-directed agent on the incorporation of thymidine into DNA was also measured at a drug concentration (D10) that killed 90% of cells. Susceptibility to aphidicolin reversal was strongly correlated with inhibition of thymidine incorporation (r = 0.91; p < or = 0.001). The results suggest that the involvement of DNA replication in the cytotoxic action of topo II-directed agents differs according to the agent used.

Cytokinetic differences in the action of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide as compared with that of amsacrine and doxorubicin.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-directed DNA intercalator with high experimental solid-tumour activity. The effect of DACA on the cytokinetics of cultured Lewis lung adenocarcinoma cells was compared with those of two clinical drugs of this class, doxorubicin and amsacrine. Cells were exposed to drugs for a 1-h period at concentrations that reduced viability by approximately 99% as measured by clonogenic assays. Subsequent progress through the cell cycle was monitored by propidium staining of fixed cells and flow cytometry. DACA, amsacrine and doxorubicin did not inhibit the G1- to S-phase transition but did delay progression through the S-phase. The effect was maximal in the late S-phase and, because of the differential rates of progress of cells in various cycle positions, led to the development of a synchronous S-phase peak. This peak moved to the G2/M-phase position at 11 h after the removal of DACA or at 14 h after the removal of amsacrine or doxorubicin. The effects of the drugs on cells initially in the G2-phase was measured by scoring mitotic cells in the presence and absence of colchicine. DACA had an immediate inhibitory effect on the progression of cells from the G2-phase to mitosis. This effect was much greater for DACA than for the other two drugs, consistent with the greater effect of DACA on the G2/M-phase to G1-phase transition. The results suggest that DACA causes cell-cycle changes expected for a DNA-damaging drug but differs from doxorubicin and amsacrine mainly by its effect on the transition of G2-phase cells to mitosis and the G1-phase.

Unusual dynamics of killing of cultured Lewis lung cells by the DNA-intercalating antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

The cytotoxicity of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601,316), a new experimental DNA-intercalating antitumor drug, against a cultured Lewis lung adenocarcinoma cell line was compared with that of the DNA-intercalating antitumor drug amsacrine. In contrast to amsacrine, AC demonstrated self-inhibition of cytotoxicity following short (3-9 h) incubation periods and exponential killing (with a shoulder) after long (24-72 h) periods of incubation. The difference between these drugs was best demonstrated using a constant concentration x time (C x T) exposure (AC, 12 mumol h l-1; amsacrine, 3 mumol h l-1). In contrast to amsacrine, AC was minimally effective over exposure periods of less than or equal to 1 h and maximally effective over intermediate periods (4-6 h). The results suggest the possibility of designing AC administration protocols that maximise the drug's cytotoxicity towards solid tumors, which, because of diffusion barriers, are subjected to longer drug exposures than are well-vascularised tumours.