Safety, cost-effectiveness and feasibility of daycase paracentesis in the management of malignant ascites with a focus on ovarian cancer.

BACKGROUND: Paracentesis for malignant ascites is usually performed as an in-patient procedure, with a median length of stay (LoS) of 3-5 days, with intermittent clamping of the drain due to a perceived risk of hypotension. In this study, we assessed the safety of free drainage and the feasibility and cost-effectiveness of daycase paracentesis. METHOD: Ovarian cancer admissions at Hammersmith Hospital between July and October 2009 were audited (Stage 1). A total of 21 patients (Stage 2) subsequently underwent paracentesis with free drainage of ascites without intermittent clamping (October 2010-January 2011). Finally, 13 patients (19 paracenteses, Stage 3), were drained as a daycase (May-December 2011). RESULTS: Of 67 patients (Stage 1), 22% of admissions and 18% of bed-days were for paracentesis, with a median LoS of 4 days. In all, 81% of patients (Stage 2) drained completely without hypotension. Of four patients with hypotension, none was tachycardic or symptomatic. Daycase paracentesis achieved complete ascites drainage without complications, or the need for in-patient admission in 94.7% of cases (Stage 3), and cost £954 compared with £1473 for in-patient drainage. CONCLUSIONS: Free drainage of malignant ascites is safe. Daycase paracentesis is feasible, cost-effective and reduces hospital admissions, and potentially represents the standard of care for patients with malignant ascites.

Neuropathic pain in cancer.

Neuropathic pain in cancer arises following injury to peripheral or central neurons, in a similar manner to such pain arising from a non-cancer injury. Much of our knowledge of neuropathic pain is based on peripheral originating events with little known about central neuropathic pain. This article explores some of the similarities and differences between cancer and non-cancer-related neuropathic pain. The neural pathways, ion channels, receptors and neurotransmitters that potentially can be altered in both neuropathies are the same; however the nature of the injury, the timing, repeated injuries and the co-existence of simultaneous non-neuropathic pain states lead to potential unique constellations of neuroreceptor and neurotransmitter expression in the context of cancer pain. This in turn may lead to different clinical presentation of pain sensations and potentially lead to specific treatment options.

When does a human being die?

For most of human history there has been no particular importance of establishing the exact time of a person's death, only whether the person is alive or dead. With modern medical advances, however, more precise answers are looked for. For a definition of death to succeed is important that it is a universal definition and that under it, all human beings are correctly identified as alive or dead. This article initially examines the most commonly proposed positions on when a human being dies those of cardiopulmonary death, whole brain death, brainstem death and higher brain death and for each describes scenarios that provide counter-intuitive results. Intuition is used as a benchmark as this is what our patients most commonly use. The second part of the article seeks to establish a more robust definition of death. We argue that death is an event that takes place at a set point in time, when the collection of bodily processes that maintains homoeostasis finally cease. Based upon defining 'human being' as being in possession of human DNA and Olsen's Animalism, the model is applicable to a full lifespan and maintains personal identity throughout the course of life. That this conclusion will interfere with clinical practice concerning organ transplantation is considered, but countered with the argument that there has been a conflation of the normative question of timing of organ retrieval for transplantation with the metaphysical question of what is death.

Electrophysiological studies on the role of the NMDA receptor in nociception in the developing rat spinal cord.

The present study investigated the effects of spinally applied N-methyl-D-aspartate (NMDA) antagonists 2-amino-5-phosphonovaleric acid (AP5) and ketamine on convergent neurones in the deep dorsal horn of rats, in vivo at different postnatal ages (P) 14, 21, 28, and 56 days. AP5 inhibited the primary afferent fibre input, the C fibre, post-discharge and windup evoked responses in a dose-dependent manner at each age, and was significantly more effective in the pups than adult rats (P<0.03 at 100-microg dose). AP5 100 microg abolished windup almost completely in the pups, whilst the adults required 10-fold higher doses. In contrast there was no difference in ketamine potency between age groups. Windup in the ketamine groups was reduced in a dose-dependent manner equally across all the age groups. The differential inhibitory effects of AP5 and ketamine may be due to postnatal changes in density, localisation and receptor subunit composition, altering receptor affinity and kinetics.

Superficial dorsal horn neuronal responses and the emergence of behavioural hyperalgesia in a rat model of cancer-induced bone pain.

Animal models of cancer-induced bone pain have revealed a unique neurochemical reorganisation of segments of dorsal horn of the spinal cord receiving nociceptive input from the affected bone, and altered spinal neuronal response patterns. The aim of this investigation was determine correlations between the behavioural hyperalgesia and allodynia observed in these animals and the dorsal horn neuronal changes. The results show that in this rat model of cancer-induced bone pain, behavioural manifestations of pain emerge in parallel with the altered superficial dorsal horn neuronal response. Thus, in this model, the alterations in neuronal responses are a viable substrate for pharmacological studies on suprathreshold stimuli. In addition the clear temporal link between behavioural hyperalgesia and altered neuronal responses may provide an opportunity to investigate changes in dorsal horn gene expression in hyperalgesia.

In vivo single unit extracellular recordings from spinal cord neurones of rats.

A method for in vivo single unit extracellular recordings from the dorsal horn of rat or mouse spinal cords is described. This method allows the complex, dynamic and plastic circuitry of the dorsal horn to be explored in various models and situations. Briefly, the spinal cord is exposed in deeply anaesthetised animals and a recording electrode is inserted into the dorsal horn. To isolate a neurone the electrode is moved incrementally through the cord whilst the ipsilateral hindpaw (receptive field) is stimulated with a light tap. The neurone can then be characterised according to its depth, latency of Abeta-, Adelta- and C-fibre responses and its response to natural (brush, heat, pressure) and electrical stimulation. The neuronal response is captured, filtered, amplified and displayed via an oscilloscope and speakers, and fed through to a computer where the responses can be integrated and displayed in numerous formats. This basic technique can be adapted to record from animals of various ages, to investigate alterations in spinal processing, suprapsinal influences, receptive field size and so on, and to assess the impact of therapeutic or other interventions. A key issue is that this type of approach, unlike behavioural assessment that relies on threshold measures, allows quantitative measures of suprathreshold activity, closer to the clinical situation.

Neuronal nitric oxide synthase modulation of dorsal horn neuronal responses in the rat: a developmental study.

Nitric oxide (NO) is a diffusible chemical messenger functionally linked to N-methyl-D-aspartate (NMDA) receptor activity and has been shown to be involved in modulating numerous pathways in the central nervous system. In order to investigate the role of the neuronal NO synthase type I (nNOS)/NO system in the postnatal development of dorsal horn nociceptive pathways in rats, the specific nNOS inhibitor 7-nitroindazole sodium salt (7-NI) and the non-specific NOS inhibitor nitro-L-arginine methyl ester (L-NAME) were applied spinally at postnatal days (P) 14, 21, 28 and >56 (adult) and their effects on neuronal responses were compared. In response to a train of 16 noxious electrical stimuli, the wide dynamic range neurones in the deep dorsal horn showed a dose-dependent inhibition of C-fibre-evoked response, post-discharge and windup to both 7-NI and L-NAME. No difference between any age group was observed with either agent on these responses. However, the effect of both 7-NI and L-NAME on the primary evoked response, a measure of the events occurring pre-synaptic and intrinsic to the neurone recorded, was significantly different between the P14 and older age groups. nNOS is known to be expressed later in postnatal development than the NMDA receptor and from the results presented here, it is fully mature and functional from P14 onwards. The subtle differences in attenuation of the primary evoked response at P14 compared with older ages may reflect the immaturity of the dorsal horn and in particular the incomplete development of intrinsic and descending inhibitory controls.

A retrospective review of the use of alfentanil in a hospital palliative care setting.

Alfentanil is becoming an alternative to diamorphine when parental opioids are required, especially in the presence of renal insufficiency. Its pharmacokinetic properties suggest that tolerance may be rapidly induced, whilst concomitant administration of drugs that interfere with the cytochrome P450 system may alter its metabolism. This retrospective audit looked at the use of subcutaneous alfentanil in a palliative care setting over a 21-month period. Forty-eight out of the 81 notes identified were available for analysis. Alfentanil was used for a median of 9 days (range 1-81) with median increase in dose of 80% (range 0-1125%). No significant correlation was found between duration of infusion and dose escalation. In addition no significant correlation was found between dose escalation and concomitant drugs that either inhibited or induced the P450 system. This is the first study to investigate the use of relatively long-term use of parenteral alfentanil. The results suggest that neither tolerance nor concomitant drug administration is of clinical significance in the dose escalation.

Intra-thecal treatment of leptomeningeal lymphoma with immunotoxin.

An animal model has been established to investigate the effect of intra-thecal (i.t.) immunotoxins in the treatment of leptomeningeal metastases of acute lymphoblastic leukaemia (ALL). Direct inoculation of L2C lymphoma cells into the cisterna magna of guinea-pigs gives rise to a leptomeningeal pattern of growth, similar to that of human ALL, and to a systemic leukaemia which develops in approximately 14 days. In our model the systemic disease could be controlled with cyclophosphamide while the meningeal disease progressed and provided a target for i.t. immunotoxin. The immunotoxin used consisted of an anti-idiotypic antibody disulphide-bonded to the ribosome-inactivating protein saporin. It was highly cytotoxic to L2C cells in vitro, being around 30,000 times more potent than a control immunotoxin at inhibiting protein synthesis. In vivo, the maximum tolerated dose of i.t. immunotoxin was 10 micrograms. From the rate at which radiolabelled immunotoxins appeared in the plasma following i.t. injection, we were able to estimate that its half-life in the cerebrospinal fluid (CSF) was between 1 1/2 and 2 hr. Intrathecal treatment of guinea-pigs with immunotoxin 1 day after inoculation of L2C cells into the cisterna magna had a remarkable therapeutic effect. All guinea-pigs treated with 0.5 or 5 micrograms of immunotoxin survived, and remained tumour-free for more than 100 days after treatment, while control animals given cyclophosphamide alone or an irrelevant immunotoxin had a mean survival time of 28 days. Provided concerns over toxicity can be overcome, these results indicate that i.t. immunotoxins offer an alternative, highly specific form of treatment in leptomeningeal neoplasia.