A clinical practice guideline for the use of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers

BACKGROUND: The role of hyperbaric oxygen (HBO2) for the treatment of diabetic foot ulcers (DFUs) has been examined in the medical literature for decades. There are more systematic reviews of the HBO2/DFU literature than there have been randomized controlled trials (RCTs), but none of these reviews has resulted in a clinical practice guideline (CPG) that clinicians, patients and policy-makers can use to guide decision-making in everyday practice. METHODS: The Undersea and Hyperbaric Medical Society (UHMS), following the methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, undertook this systematic review of the HBO2 literature in order to rate the quality of evidence and generate practice recommendations for the treatment of DFUs. We selected four clinical questions for review regarding the role of HBO2 in the treatment of DFUs and analyzed the literature using patient populations based on Wagner wound classification and age of the wound (i.e., acute post-operative wound vs. non-healing wound of 30 or more days). Major amputation and incomplete healing were selected as critical outcomes of interest. RESULTS: This analysis showed that HBO2 is beneficial in preventing amputation and promoting complete healing in patients with Wagner Grade 3 or greater DFUs who have just undergone surgical debridement of the foot as well as in patients with Wagner Grade 3 or greater DFUs that have shown no significant improvement after 30 or more days of treatment. In patients with Wagner Grade 2 or lower DFUs, there was inadequate evidence to justify the use of HBO2 as an adjunctive treatment. CONCLUSIONS: Clinicians, patients, and policy-makers should engage in shared decision-making and consider HBO2 as an adjunctive treatment of DFUs that fit the criteria outlined in this guideline. The current body of evidence provides a moderate level of evidence supporting the use of HBO2 for DFUs. Future research should be directed at improving methods for patient selection, testing various treatment protocols and improving our confidence in the existing estimates.(AU)

Distribution of alpha 2-adrenergic receptor binding in the developing human brain stem.

Rapid and dramatic changes occur in cardiorespiratory function during early human life. Catecholamines within select brain stem nuclei are implicated in the control of autonomic and respiratory function, including in the nucleus of the solitary tract and the dorsal motor nucleus of X. Animal and adult human studies have shown high binding to alpha 2-adrenergic receptors in these regions. To determine the developmental profile of brainstem alpha 2-adrenergic binding across early human life, we studied brain stems from five fetuses at midgestation, three newborns (37-38 postconceptional weeks), and six infants (44-61 postconceptional weeks). We used quantitative tissue receptor autoradiography with [3H]para-aminoclonidine as the radioligand and phentolamine as the displacer. In the fetal group, binding was high (63-93 fmol/mg tissue) in the nucleus of the solitary tract, dorsal motor nucleus of X, locus coeruleus, and reticular formation; it was low (< 32 fmol/mg tissue) in the principal inferior olive and basis pontis. Binding decreased in all regions with age: in infancy, the highest binding was in the intermediate range (32-62 fmol/mg tissue) and was localized to the nucleus of the solitary tract and dorsal motor nucleus of X. The most substantial decrease in binding (75%-85%) between the fetal and infant periods occurred in the pontine and medullary reticular formation and hypoglossal nucleus. Binding remained low in the principal inferior olive and basis pontis. The decreases in binding with age remained significant after quench correction. These data suggest that rapid and dramatic changes occur in early human life in the brain stem catecholaminergic system in regions related to cardiorespiratory control.

Alpha2 receptor binding in the medulla oblongata in the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is the leading cause of postnatal infant mortality in the United States. Its etiology remains unknown. We propose that SIDS, or a subset of SIDS, is due to a failure of autoresuscitation, a protective brainstem response to asphyxia or hypoxia, in a vulnerable infant during a critical developmental period. Gasping is an important component of autoresuscitation that is thought to be mediated by the "gasping center" in the lateral tegmentum of the medulla, a region homologous in its cytoarchitecture and chemical anatomy to the intermediate reticular zone (IRZ) in the human. Since we found that [3H]para-aminoclonidine ([3H]PAC) binding to alpha2-adrenergic receptors localizes to this region in human infants and, thereby provides a neurochemical marker for it, we tested the hypothesis that [3H]PAC binding to alpha2-adrenergic receptors is decreased in the IRZ in SIDS victims. Using quantitative tissue autoradiography with [3H]PAC as the radioligand and phentolamine as the displacer, we analyzed alpha2-receptor binding density in the IRZ, as well as in 7 additional sites for comparison, in 10 SIDS and 10 control medullae. There were no significant differences in alpha2 receptor binding in the IRZ, vagal nuclei, or other medullary sites examined between SIDS and control cases. These results suggest that the putative gasping defect in the IRZ in SIDS victims is not related to [3H]PAC binding to alpha2-adrenergic receptors.

Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors.

The recently cloned CB2 cannabinoid receptor subtype was stably transfected into AtT-20 and Chinese hamster ovary cells to compare the binding and signal transduction properties of this receptor with those of the CB1 receptor subtype. The binding of [3H]CP 55,940 to both CB1 and CB2 was of similar high affinity (2.6 and 3.7 nM, respectively) and saturable. In competitive binding experiments, (-)-delta 9-tetrahydrocannabinol and CP 55,940 were equipotent at the CB1 and CB2 receptors, but WIN 55212-2 and cannabinol bound with higher affinity to the CB2 than the CB1 receptor. HU 210 had a higher affinity for the CB1 receptor. Anandamide, a recently identified endogenous cannabinoid agonist, was essentially equipotent at both receptor subtypes. The structurally related fatty acid ethanolamides dihomo-gamma-linolenylethanolamide and mead ethanolamide also bound with relatively equal affinity to both receptors, but adrenylethanolamide had a higher affinity for the CB1 receptor. The rank order of potency and efficacy for binding of the selected agonists to the CB1 and CB2 receptors was mimicked in functional inhibition of cAMP accumulation experiments for all compounds tested. Both CB1 and CB2 receptors couple to the inhibition of cAMP accumulation that was pertussis toxin sensitive. SR141716A, a CB1 receptor antagonist, was a poor antagonist at the CB2 receptor in both binding and functional inhibition of cAMP accumulation experiments. When expressed in AtT-20 cells, the CB1 receptor mediated an inhibition of Q-type calcium channels and an activation of inward rectifying potassium channels. In contrast, the CB2 receptor did not modulate the activity of either channel under identical assay conditions. Similar to results obtained for CB1 receptor, the CB2 receptor did not couple to the activation of phospholipases A2, C, or D or to the mobilization of intracellular Ca2+. Except for its inability to couple to the modulation of Q-type calcium channels or inwardly rectifying potassium channels, the CB1 and CB2 receptors display similar pharmacological and biochemical properties.

Mead ethanolamide, a novel eicosanoid, is an agonist for the central (CB1) and peripheral (CB2) cannabinoid receptors.

The recently discovered endogenous agonist for the cannabinoid receptor, anandamide (arachidonylethanolamide), can be formed enzymatically by the condensation of arachidonic acid with ethanolamine. 5Z,8Z,11Z-Eicosatrienoic acid (mead acid) has been found to substitute for arachidonic acid in the sn-2 position of phospholipids and accumulate during periods of dietary fatty acid deprivation in rats. In the present study, the chemically synthesized ethanolamide of mead acid was evaluated as a potential agonist at the two known subtypes of cannabinoid receptor: CB1 (central) and CB2 (peripheral). This compound was equipotent to anandamide in competing with [3H]CP55,940 binding to plasma membranes prepared from L cells expressing the human CB1 receptor and from ATt-20 cells expressing the human CB2 receptor. Mead ethanolamide was also equipotent to anandamide in inhibiting forskolin-stimulated cAMP accumulation in cells expressing the CB1 receptor. It inhibited N-type calcium currents with a lower potency than anandamide. Mead and arachidonic acid were equally efficacious as substrates for the enzymatic synthesis of their respective ethanolamides in rat and adult human hippocampal P2 membranes. Palmitic acid was not an effective substrate for the enzymatic synthesis of palmitoyl ethanolamide. Mead ethanolamide exhibits several characteristics of a novel agonist to CB1 and CB2 receptors and may represent another candidate endogenous ligand for the CB1 receptor. Due to the anticonvulsant properties of GABA and the positional similarity of L-serine to ethanolamine in membrane phospholipids, these compounds were synthetically coupled to arachidonic acid, and their resulting arachidonamides were tested as potential cannabinoid agonists. The arachidonamides of GABA and L-serine were inactive in both binding and functional assays at the CB1 receptor.