Clinical review: Post-extubation laryngeal edema and extubation failure in critically ill adult patients

Laryngeal edema is a frequent complication of intubation. It often presents shortly after extubation as post-extubation stridor and results from damage to the mucosa of the larynx. Mucosal damage is caused by pressure and ischemia resulting in an inflammatory response. Laryngeal edema may compromise the airway necessitating reintubation. Several studies show that a positive cuff leak test combined with the presence of risk factors can identify patients with increased risk for laryngeal edema. Meta-analyses show that pre-emptive administration of a multiple-dose regimen of glucocorticosteroids can reduce the incidence of laryngeal edema and subsequent reintubation. If post-extubation edema occurs this may necessitate medical intervention. Parenteral administration of corticosteroids, epinephrine nebulization and inhalation of a helium/oxygen mixture are potentially effective, although this has not been confirmed by randomized controlled trials. The use of non-invasive positive pressure ventilation is not indicated since this will delay reintubation. Reintubation should be considered early after onset of laryngeal edema to adequately secure an airway. Reintubation leads to increased cost, morbidity and mortality.     

Physiological effects of extracellular nucleotides in the inner ear

1. Electrochemical homeostasis, sound transduction and auditory neurotransmission in the cochlea are influenced by extracellular purines and pyrimidines. 2. Evidence that ATP and related nucleotides influence inner ear function arises from a considerable number of cellular, molecular and physiological studies in vitro and in vivo. 3. With a full understanding of these processes, which include ionotropic (P2X receptor) and metabotropic (P2Y receptor) signal transduction pathways, signal termination involving ecto-nucleotidases and recycling via nucleoside transporters, exciting possibilities emerge for treating hearing disorders, such as Meniere's disease, tinnitus and sensorineural deafness.     

ATP-gated ion channel expression in primary auditory neurones

Extracellular ATP acts via ionotropic P2X receptors to mediate fast neurotransmission in the central and autonomic nervous systems. Recent data, including identification of P2X2 receptor mRNA expression by spiral ganglion neurones, suggests that purinergic signalling may influence auditory neurotransmission via ATP-gated ion channels assembled from these subunits. Expression of the P2X2 receptor was localized to the region of the spiral ganglion neurone synapses with the inner hair cells using a P2X2 receptor specific antiserum. Whole-cell patch clamping of neurones cultured from post-natal day 3-5 spiral ganglia demonstrated a heterogeneity of ATP-activated conductances, consistent with the functional expression of P2X2 receptor subunit isoforms along with possible co-expression of additional P2X receptor subunits. These data provide substantive support for a purinergic transmission element at the peripheral auditory synapse.     

Evidence for alternative splicing of ecto-ATPase associated with termination of purinergic transmission

Ectonucleotidases provide the signal termination mechanism for purinergic transmission, including fast excitatory neurotransmission by ATP in the CNS. This study provides evidence for ectonucleotidase expression in the rat cochlea, brain and other tissues. In addition to detection of rat ecto-ATPase and ecto-ATPDase in these tissues, we identify a novel ecto-ATPase splice variant arising from the loss of a putative exon (193 bp) in the C-terminal coding region. This is the first evidence of alternative splicing in the ecto-ATPase gene family. Splicing of the 193-bp putative exon containing a stop codon extends the open reading frame and provides translation of an additional 50 amino acids compared with the isoform isolated earlier from the rat brain (rEATPase(A); GenBank accession #Y11835). The splice variant (rEATPase(B); GenBank accession #AF129103) encodes 545 amino acids with a predicted protein molecular mass of 60 kDa. rEATPase(B) contains a long cytoplasmic tail (62 amino acids) with three potential protein kinase CK2 phosphorylation sites not present in rEATPase(A). Co-expression of two ecto-ATPase isoforms with different regulatory sites suggests that the extracellular ATP signal levels may be differently influenced by intracellular feedback pathways.     

Distribution of the P2X2 receptor subunit of the ATP-gated ion channels in the rat central nervous system

The distribution of the P2X2 receptor subunit of the adenosine 5'-triphosphate (ATP)-gated ion channels was examined in the adult rat central nervous system (CNS) by using P2X2 receptor-specific antisera and riboprobe-based in situ hybridisation. P2X2 receptor mRNA expression matched the P2X2 receptor protein localisation. An extensive expression pattern was observed, including: olfactory bulb, cerebral cortex, hippocampus, habenula, thalamic and subthalamic nuclei, caudate putamen, posteromedial amygdalo-hippocampal and amygdalo-cortical nuclei, substantia nigra pars compacta, ventromedial and arcuate hypothalamic nuclei, supraoptic nucleus, tuberomammillary nucleus, mesencephalic trigeminal nucleus, dorsal raphe, locus coeruleus, medial parabrachial nucleus, tegmental areas, pontine nuclei, red nucleus, lateral superior olive, cochlear nuclei, spinal trigeminal nuclei, cranial motor nuclei, ventrolateral medulla, area postrema, nucleus of solitary tract, and cerebellar cortex. In the spinal cord, P2X2 receptor expression was highest in the dorsal horn, with significant neuronal labeling in the ventral horn and intermediolateral cell column. The identification of extensive P2X2 receptor immunoreactivity and mRNA distribution within the CNS demonstrated here provides a basis for the P2X receptor antagonist pharmacology reported in electrophysiological studies. These data support the role for extracellular ATP acting as a fast neurotransmitter at pre- and postsynaptic sites in processes such as sensory transmission, sensory-motor integration, motor and autonomic control, and in neuronal phenomena such as long-term potentiation (LTP) and depression (LTD). Additionally, labelling of neuroglia and fibre tracts supports a diverse role for extracellular ATP in CNS homeostasis.     

Extracellular adenosine 5′-triphosphate (ATP) in the endolymphatic compartment influences cochlear function

There is strong evidence for the presence of P₂ purinoceptors on cochlear tissues, but the role of extracellular ATP in cochlear function is still unclear. Our previous have determined the presence of ATP in the cochlear fluids and indicated that the purinoceptors are substantially localized to the tissues lining the endolymphatic compartment. This implies that extracellular ATP may have an humoral role confined to the endolymphatic space. In order to study the influence of extracellular ATP in the endolymphatic space, a series of studies were undertaken in which ATP (10 μM to 10 mM) in artificial endolymph (EL) (test solution: 2–12.5 nl) was injected into the scala media and the effect on the cochlear microphonic (CM) and endocochlear potential (EP) evaluated. A double-barrelled pipette, with one barrel containing the test solution and the other artificial EL (control solution) was inserted into scala media of the third turn of the guinea-pig cochlea. A known volume (2–12.5 nl) of test or control solution was then pressure-injected into the space. ATP had a significant dose-dependent suppressive effect on both EP and CM with a threshold of approximately 2×10⁻¹⁴ mol; the response was readily reversible, also in a dose-dependent fashion. Artificial EL of the same volume had no effect on EP and CM. The ATP effect on EP was blocked by the P₂ purinoceptor antagonists suramin and reactive blue 2 (RB2). Neither adenosine (2×10⁻¹³ to 2×10⁻¹¹ mol) nor suramin or RB2 on their own had any effect on EP and CM. This study provides the first evidence for an effect of extracellular ATP in the endolymphatic compartment on cochlear function which is mediated via P₂ purinoceptors. This provides supporting evidence for an humoral role for extracellular ATP in the modulation of cochlear function.     

The inactivating potassium currents of hair cells isolated from the crista ampullaris of the frog.

1. A-type outward currents were studied in sensory hair cells isolated from the semicircular canals (SCC) of the leopard frog (Rana pipiens) with whole-cell voltage- and current-clamping techniques. 2. There appear to be two classes of A-type outward-conducting potassium channels based on steady-state, kinetic, pharmacological parameters, and reversal potential. 3. The two classes of A-type currents differ in their steady-state inactivation properties as well as in the kinetics of inactivation. The steady-state inactivation properties are such that a significant portion of the fast channels are available from near the resting potential. 4. The inactivating channels studied do not appear to be calcium dependent. 5. The A-channels in hair cells appear to subserve functions that are analogous to IA functions in neurons, that is, modulating spike latency and Q (the oscillatory damping function). The A-currents appear to temporally limit the hair cell voltage response to a current injection.     

Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies

Citrobacter rodentium, a murine model pathogen for human enteropathogenic Escherichia coli, predominantly colonizes the lumen and mucosal surface of the colon and cecum and causes crypt hyperplasia and mucosal inflammation. Mice infected with C. rodentium develop a secretory immunoglobulin A (IgA) response, but the role of B cells or secretory antibodies in host defense is unknown. To address this question, we conducted oral C. rodentium infections in mice lacking B cells, IgA, secreted IgM, polymeric Ig receptor (pIgR), or J chain. Normal mice showed peak bacterial numbers in colon and feces at 1 week and bacterial eradication after 3 to 4 weeks. B-cell-deficient mice were equally susceptible initially but could not control infection subsequently. Tissue responses showed marked differences, as infection of normal mice was accompanied by transient crypt hyperplasia and mucosal inflammation in the colon and cecum at 2 but not 6 weeks, whereas B-cell-deficient mice had few mucosal changes at 2 weeks but severe epithelial hyperplasia with ulcerations and mucosal inflammation at 6 weeks. The functions of B cells were not mediated by secretory antibodies, since mice lacking IgA or secreted IgM or proteins required for their transport into the lumen, pIgR or J chain, cleared C. rodentium normally. Nonetheless, systemic administration of immune sera reduced bacterial numbers significantly in normal and pIgR-deficient mice, and depletion of IgG abrogated this effect. These results indicate that host defense against C. rodentium depends on B cells and IgG antibodies but does not require production or transepithelial transport of IgA or secreted IgM.