Local Anesthetic Peripheral Nerve Block Adjuvants for Prolongation of Analgesia: A Systematic Qualitative Review

<div><p>Background</p><p>The use of peripheral nerve blocks for anesthesia and postoperative analgesia has increased significantly in recent years. Adjuvants are frequently added to local anesthetics to prolong analgesia following peripheral nerve blockade. Numerous randomized controlled trials and meta-analyses have examined the pros and cons of the use of various individual adjuvants.</p><p>Objectives</p><p>To systematically review adjuvant-related randomized controlled trials and meta-analyses and provide clinical recommendations for the use of adjuvants in peripheral nerve blocks.</p><p>Methods</p><p>Randomized controlled trials and meta-analyses that were published between 1990 and 2014 were included in the initial bibliographic search, which was conducted using Medline/PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Only studies that were published in English and listed block analgesic duration as an outcome were included. Trials that had already been published in the identified meta-analyses and included adjuvants not in widespread use and published without an Investigational New Drug application or equivalent status were excluded.</p><p>Results</p><p>Sixty one novel clinical trials and meta-analyses were identified and included in this review. The clinical trials reported analgesic duration data for the following adjuvants: buprenorphine (6), morphine (6), fentanyl (10), epinephrine (3), clonidine (7), dexmedetomidine (7), dexamethasone (7), tramadol (8), and magnesium (4). Studies of perineural buprenorphine, clonidine, dexamethasone, dexmedetomidine, and magnesium most consistently demonstrated prolongation of peripheral nerve blocks.</p><p>Conclusions</p><p>Buprenorphine, clonidine, dexamethasone, magnesium, and dexmedetomidine are promising agents for use in prolongation of local anesthetic peripheral nerve blocks, and further studies of safety and efficacy are merited. However, caution is recommended with use of any perineural adjuvant, as none have Food and Drug Administration approval, and concerns for side effects and potential toxicity persist.</p></div

Mycobacterium tuberculosis Requires Phosphate-Responsive Gene Regulation To Resist Host Immunity

Mycobacterium tuberculosis persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-gamma). We identified the M. tuberculosis phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-gamma-dependent immunity. A Delta pstA1 mutant was fully virulent in IFN-gamma(-/-) mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-gamma-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that Delta pstA1 bacteria are sensitized to an IFN-gamma-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In M. tuberculosis, we found that Delta pstA1 bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the regX3 gene suppressed the replication and virulence defects of Delta pstA1 bacteria in NOS2(-/-) mice, suggesting that M. tuberculosis requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate in vivo. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling M. tuberculosis gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response

Summary of findings and recommendations.

<p>¹Attestation: Referenced in textbooks and/or multiple (>5) peer-reviewed research publications; Harm: Not Food and Drug Administration (FDA)-approved and balance of evidence suggests harm with perineural use; FDA: FDA-approved for regional anesthesia; IND: Investigational New Drug status (or international equivalent) granted or waived for in at least one reviewed study.</p><p>²a: Studies with Jadad score III+ or higher/total number of studies; b: % of studies with positive results; c: clinical significance of positive results (extent of prolongation of analgesia or sensory block).</p><p>³Agency for HealthCare Research and Quality Levels of Evidence and Grades of Recommendations: Grade A: based directly on Level 1 evidence; Level 1a: evidence from meta-analysis of clinical trials; Level 1b: evidence from at least 1 randomized controlled trial.</p><p>Abbreviations: PNB = peripheral nerve block; PONV = postoperative nausea and vomiting; ISB = interscalene block; FNB = femoral nerve block; GI = gastrointestinal.</p><p>Summary of findings and recommendations.</p

Clinical findings for most extensively studied agents not covered by recent meta-analyses.

<p>Abbreviations: SCB = supraclavicular block; ISB = interscalene block; PN = perineural; IM = intramuscular; IV = intravenous; BP = blood pressure; HR = heart rate; saph = saphenous; POD = postoperative day; SQ = subcutaneous; GI = gastrointestinal; TAP = transversus abdominis plane; epi = epinephrine; PONV = postoperative nausea and vomiting; pts: patients.</p><p>*Time to first analgesic;</p><p>**Time to first reported pain;</p><p>***Time to pinprick or restoration of sensation.</p><p>Clinical findings for most extensively studied agents not covered by recent meta-analyses.</p

PRISMA flowchart.

<p>Details regarding records that were identified, screened, and assessed for eligibility are provided, according to the PRISMA guidelines.</p

Summary of meta-analyses analyzing adjuvants for analgesia/block duration.

<p>Abbreviations: LA = local anesthetic; OR = odds ratio</p><p>Summary of meta-analyses analyzing adjuvants for analgesia/block duration.</p

Spontaneous Phthiocerol Dimycocerosate-Deficient Variants of Mycobacterium tuberculosis Are Susceptible to Gamma Interferon-Mediated Immunity▿

Onset of the adaptive immune response in mice infected with Mycobacterium tuberculosis is accompanied by slowing of bacterial replication and establishment of a chronic infection. Stabilization of bacterial numbers during the chronic phase of infection is dependent on the activity of the gamma interferon (IFN-γ)-inducible nitric oxide synthase (NOS2). Previously, we described a differential signature-tagged mutagenesis screen designed to identify M. tuberculosis “counterimmune” mechanisms and reported the isolation of three mutants in the H37Rv strain background containing transposon insertions in the rv0072, rv0405, and rv2958c genes. These mutants were impaired for replication and virulence in NOS2−/− mice but were growth-proficient and virulent in IFN-γ−/− mice, suggesting that the disrupted genes were required for bacterial resistance to an IFN-γ-dependent immune mechanism other than NOS2. Here, we report that the attenuation of these strains is attributable to an underlying transposon-independent deficiency in biosynthesis of phthiocerol dimycocerosate (PDIM), a cell wall lipid that is required for full virulence in mice. We performed whole-genome resequencing of a PDIM-deficient clone and identified a spontaneous point mutation in the putative polyketide synthase PpsD that results in a G44C amino acid substitution. We demonstrate by complementation with the wild-type ppsD gene and reversion of the ppsD gene to the wild-type sequence that the ppsD(G44C) point mutation is responsible for PDIM deficiency, virulence attenuation in NOS2−/− and wild-type C57BL/6 mice, and a growth advantage in vitro in liquid culture. We conclude that PDIM biosynthesis is required for M. tuberculosis resistance to an IFN-γ-mediated immune response that is independent of NOS2

Identification of Mycobacterium tuberculosis Counterimmune (cim) Mutants in Immunodeficient Mice by Differential Screening

Tuberculosis (TB) is characterized by lifetime persistence of Mycobacterium tuberculosis. Despite the induction of a vigorous host immune response that curtails disease progression in the majority of cases, the organism is not eliminated. Subsequent immunosuppression can lead to reactivation after a prolonged period of clinical latency. Thus, while it is clear that protective immune mechanisms are engaged during M. tuberculosis infection, it also appears that the pathogen has evolved effective countermechanisms. Genetic studies with animal infection models and with patients have revealed a key role for the cytokine gamma interferon (IFN-gamma) in resistance to TB. IFN-gamma activates a large number of antimicrobial pathways. Three of these IFN-gamma-dependent mechanisms have been implicated in defense against M. tuberculosis: inducible nitric oxide synthase (iNOS), phagosome oxidase (phox), and the phagosome-associated GTPase LRG-47. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of differential signature-tagged transposon mutagenesis. Using this approach we have identified three M. tuberculosis genes that are essential for progressive M. tuberculosis growth and rapid lethality in iNOS-deficient mice but not in IFN-gamma-deficient mice. We propose that these genes are involved in pathways that allow M. tuberculosis to counter IFN-gamma-dependent immune mechanisms other than iNOS