Ketamine Use for Palliative Care in the Austere Environment: Is Ketamine the Path Forward for Palliative Care.

The goal of palliative care is to focus on the holistic needs of the patient and their family versus the pathology of the patient's diagnosis to reduce the stress of illness. U.S. servicemembers deployed to austere environments worldwide have significantly less access to palliative care than in military treatment facilities in the U.S. Preparation for future conflicts introduces the concept of prolonged medical management for an environment where urgent casualty evacuation is impossible. Ketamine is currently widely used for analgesia and anesthesia in the care of military service members and its use has increased in combat zones of Iraq and Afghanistan due to the favorable preservation of respiratory function, minimal changes in hemodynamics, and lower pain scores compared to opioids. Ketamine acts as a non-competitive antagonist on N-methyl-D aspartate (NMDA) receptors. Its anesthesia and analgesic effects are complex and include both presynaptic and postsynaptic neurons in brain and spinal cord. The use of palliative care to minimize suffering should not be withheld due to the logistical boundaries of austere military environments or lack of guidelines for recommended use. The use of ketamine for palliative care is a new clinical management strategy to provide both sedation and pain management for an acute pain crisis or comfort measures for the terminally ill. This makes ketamine an attractive consideration for palliative care when managing critically wounded patients for an extended time.

Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging.

Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymphocyte-associated antigen, or CD11a expression by CD4(+) T cells or their physical capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject that results from decreased TNF-alpha secretion by macrophages. This prevents memory T cell entry into the skin after antigen challenge. However, isolated cutaneous macrophages from these subjects can be induced to secrete TNF-alpha after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro, indicating that the defect is reversible. The decreased conditioning of tissue microenvironments by macrophage-derived cytokines may therefore lead to defective immunosurveillance by memory T cells. This may be a predisposing factor for the development of malignancy and infection in the skin during aging.

The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo.

Naturally occurring CD4(+)CD25(hi)Foxp3(+) Tregs (nTregs) are highly proliferative in blood. However, the kinetics of their accumulation and proliferation during a localized antigen-specific T cell response is currently unknown. To explore this, we used a human experimental system whereby tuberculin purified protein derivative (PPD) was injected into the skin and the local T cell response analyzed over time. The numbers of both CD4(+)Foxp3(-) (memory) and CD4(+)Foxp3(+) (putative nTreg) T cells increased in parallel, with the 2 populations proliferating at the same relative rate. In contrast to CD4(+)Foxp3(-) T cell populations, skin CD4(+)Foxp3(+) T cells expressed typical Treg markers (i.e., they were CD25(hi), CD127(lo), CD27(+), and CD39(+)) and did not synthesize IL-2 or IFN-gamma after restimulation in vitro, indicating that they were not recently activated effector cells. To determine whether CD4(+)Foxp3(+) T cells in skin could be induced from memory CD4(+) T cells, we expanded skin-derived memory CD4(+) T cells in vitro and anergized them. These cells expressed high levels of CD25 and Foxp3 and suppressed the proliferation of skin-derived responder T cells to PPD challenge. Our data therefore demonstrate that memory and CD4(+) Treg populations are regulated in tandem during a secondary antigenic response. Furthermore, it is possible to isolate effector CD4(+) T cell populations from inflamed tissues and manipulate them to generate Tregs with the potential to suppress inflammatory responses.

Mantoux Test as a model for a secondary immune response in humans.

The Mantoux Test (MT) is a classical delayed-type hypersensitivity (DTH) response to the intradermal injection of tuberculin purified protein derivative (PPD). It represents a cutaneous T cell mediated memory recall immune response. The test is typically used to determine immunity to tuberculosis in humans and positive reactions develop in individuals previously exposed to Mycobacterium tuberculosis, and those immunised with the Bacillus of Calmette and Guérin (BCG) vaccine. In view of its relative accessibility human skin represents a convenient tissue for the investigation of human immune responses. Using the MT, we have been able to determine that significant cellular proliferation and clonal expansion occur at the site of antigen deposition in the skin. Furthermore, cells undergoing proliferation in the skin also undergo accelerated differentiation. Taken together with other studies, in humans and in mice, these observations shed new light on the importance of the microenvironment at the site of the immune response for the proliferation and differentiation of memory T cells.

Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo.

The extent of human memory T cell proliferation, differentiation, and telomere erosion that occurs after a single episode of immune challenge in vivo is unclear. To investigate this, we injected tuberculin purified protein derivative (PPD) into the skin of immune individuals and isolated responsive T cells from the site of antigenic challenge at different times. PPD-specific CD4+ T cells proliferated and differentiated extensively in the skin during this secondary response. Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals. Tissue fluid obtained from the site of PPD challenge in the skin inhibited the induction of the enzyme telomerase in T cells in vitro. Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition. Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro. Therefore, these results suggest that the rate of telomere erosion in proliferating, antigen-specific CD4+ T cells may be accelerated by type I IFN during a secondary response in vivo.

Taurine deficiency in dogs with dilated cardiomyopathy: 12 cases (1997-2001).

OBJECTIVE: To determine signalment, history, clinical signs, blood and plasma taurine concentrations, electrocardiographic and echocardiographic findings, treatment, and outcome of dogs with low blood or plasma taurine concentrations and dilated cardiomyopathy (DCM). DESIGN: Retrospective study. ANIMALS: 12 client-owned dogs with low blood or plasma taurine concentrations and DCM. PROCEDURE: Medical records were reviewed, and clinical data were obtained. RESULTS: All 12 dogs were being fed a commercial dry diet containing lamb meal, rice, or both as primary ingredients. Cardiac function and plasma taurine concentration improved with treatment and taurine supplementation. Seven of the 12 dogs that were still alive at the time of the study were receiving no cardiac medications except taurine. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that consumption of certain commercial diets may be associated with low blood or plasma taurine concentrations and DCM in dogs. Taurine supplementation may result in prolonged survival times in these dogs, which is not typical for dogs with DCM. Samples should be submitted for measurement of blood and plasma taurine concentrations in dogs with DCM, and taurine supplementation is recommended while results of these analyses are pending.