The American Society of Regional Anesthesia and Pain Medicine's Third Practice Advisory on local anesthetic systemic toxicity is an interim update from its 2010 advisory. The advisory focuses on new ...information regarding the mechanisms of lipid resuscitation, updated frequency estimates, the preventative role of ultrasound guidance, changes to case presentation patterns, and limited information related to local infiltration anesthesia and liposomal bupivacaine. In addition to emerging information, the advisory updates recommendations pertaining to prevention, recognition, and treatment of local anesthetic systemic toxicity. WHAT'S NEW IN THIS UPDATE?: This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning. Since the previous practice advisory, epidemiological data have emerged that suggest a lower frequency of LAST as reported by single institutions and some registries, nevertheless a considerable number of events still occur within the general community. Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions. Small patient size and sarcopenia are additional factors that increase potential risk for LAST. An increasing number of reported events occur outside of the traditional hospital setting and involve non-anesthesiologists.
Cancer is the second cause of death worldwide. Chemotherapy and radiotherapy are the most common modalities for the treatment of cancer. Experimental studies have shown that inflammation plays a ...central role in tumor resistance and the incidence of several side effects following both chemotherapy and radiotherapy. Inflammation resulting from radiotherapy and chemotherapy is responsible for adverse events such as dermatitis, mucositis, pneumonitis, fibrosis, and bone marrow toxicity. Chronic inflammation may also lead to the development of second cancer during years after treatment. A number of anti‐inflammatory drugs such as nonsteroidal anti‐inflammatory agents have been proposed to alleviate chronic inflammatory reactions after radiotherapy or chemotherapy. Curcumin is a well‐documented herbal anti‐inflammatory agents. Studies have proposed that curcumin can help management of inflammation during and after radiotherapy and chemotherapy. Curcumin targets various inflammatory mediators such as cyclooxygenase‐2, inducible nitric oxide synthase, and nuclear factor κB (NF‐κB), thereby attenuating the release of proinflammatory and profibrotic cytokines, and suppressing chronic production of free radicals, which culminates in the amelioration of tissue toxicity. Through modulation of NF‐κB and its downstream signaling cascade, curcumin can also reduce angiogenesis, tumor growth, and metastasis. Low toxicity of curcumin is linked to its cytoprotective effects in normal tissues. This protective action along with the capacity of this phytochemical to sensitize tumor cells to radiotherapy and chemotherapy makes it a potential candidate for use as an adjuvant in cancer therapy. There is also evidence from clinical trials suggesting the potential utility of curcumin for acute inflammatory reactions during radiotherapy such as dermatitis and mucositis.
The experimental use of lipid emulsion for local anesthetic toxicity was originally identified in 1998. It was then translated to clinical practice in 2006 and expanded to drugs other than local ...anesthetics in 2008. Our understanding of lipid resuscitation therapy has progressed considerably since the previous update from the American Society of Regional Anesthesia and Pain Medicine, and the scientific evidence has coalesced around specific discrete mechanisms. Intravenous lipid emulsion therapy provides a multimodal resuscitation benefit that includes both scavenging (eg, the lipid shuttle) and nonscavenging components. The intravascular lipid compartment scavenges drug from organs susceptible to toxicity and accelerates redistribution to organs where drug (eg, bupivacaine) is stored, detoxified, and later excreted. In addition, lipid exerts nonscavenging effects that include postconditioning (via activation of prosurvival kinases) along with cardiotonic and vasoconstrictive benefits. These effects protect tissue from ischemic damage and increase tissue perfusion during recovery from toxicity. Other mechanisms have diminished in favor based on lack of evidence; these include direct effects on channel currents (eg, calcium) and mass-effect overpowering a block in mitochondrial metabolism. In this narrative review, we discuss these proposed mechanisms and address questions left to answer in the field. Further work is needed, but the field has made considerable strides towards understanding the mechanisms.
To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell ...therapy.
A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021.
The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus.
The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell-associated neurotoxicity syndrome should be managed with corticosteroids and supportive care.Additional information is available at www.asco.org/supportive-care-guidelines.
Although analgesics are initiated on hospital discharge in millions of adults each year, studies quantifying the risks of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) among older adults ...during this transition are limited. We sought to determine the incidence and risk of post-discharge adverse events among older adults with an opioid claim in the week after hospital discharge, compared to those with NSAID claims only.
We performed a retrospective cohort study using a national sample of Medicare beneficiaries age 65 and older, hospitalized in United States hospitals in 2016. We excluded beneficiaries admitted from or discharged to a facility. We derived a propensity score that included over 100 factors potentially related to the choice of analgesic, including demographics, diagnoses, surgeries, and medication coadministrations. Using 3:1 propensity matching, beneficiaries with an opioid claim in the week after hospital discharge (with or without NSAID claims) were matched to beneficiaries with an NSAID claim only. Primary outcomes included death, healthcare utilization (emergency department ED visits and rehospitalization), and a composite of known adverse effects of opioids or NSAIDs (fall/fracture, delirium, nausea/vomiting, complications of slowed colonic motility, acute renal failure, and gastritis/duodenitis) within 30 days of discharge. After propensity matching, there were 13,385 beneficiaries in the opioid cohort and 4,677 in the NSAID cohort (mean age: 74 years, 57% female). Beneficiaries receiving opioids had a higher incidence of death (1.8% versus 1.1%; relative risk RR 1.7 1.3 to 2.3, p < 0.001, number needed to harm NNH 125), healthcare utilization (19.0% versus 17.4%; RR 1.1 1.02 to 1.2, p = 0.02, NNH 59), and any potential adverse effect (25.2% versus 21.3%; RR 1.2 1.1 to 1.3, p < 0.001, NNH 26), compared to those with an NSAID claim only. Specifically, they had higher relative risk of fall/fracture (4.5% versus 3.4%; RR 1.3 1.1 to 1.6, p = 0.002), nausea/vomiting (9.2% versus 7.3%; RR 1.3 1.1 to 1.4, p < 0.001), and slowed colonic motility (8.0% versus 6.2%; RR 1.3 1.1 to 1.4, p < 0.001). Risks of delirium, acute renal failure, and gastritis/duodenitis did not differ between groups. The main limitation of our study is the observational nature of the data and possibility of residual confounding.
Older adults filling an opioid prescription in the week after hospital discharge were at higher risk for mortality and other post-discharge adverse outcomes compared to those filling an NSAID prescription only.
Pharmacogenetics offers the potential to improve health outcomes by identifying individuals who are at greater risk of harm from certain medicines. Routine adoption of pharmacogenetic tests requires ...evidence of their cost effectiveness.
The present review aims to systematically review published economic evaluations of pharmacogenetic tests that aim to prevent or reduce the incidence of ADRs.
We conducted a systematic literature review of economic evaluations of pharmacogenetic tests aimed to reduce the incidence of adverse drug reactions. Literature was searched using Embase, MEDLINE and the NHS Economic Evaluation Database with search terms relating to pharmacogenetic testing, adverse drug reactions, economic evaluations and pharmaceuticals. Titles were screened independently by two reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed.
We identified 852 articles, of which 47 met the inclusion criteria. There was evidence supporting the cost effectiveness of testing for HLA-B*57:01 (prior to abacavir), HLA-B*15:02 and HLA-A*31:01 (prior to carbamazepine), HLA-B*58:01 (prior to allopurinol) and CYP2C19 (prior to clopidogrel treatment). Economic evidence was inconclusive with respect to TPMT (prior to 6-mercaptoputine, azathioprine and cisplatin therapy), CYP2C9 and VKORC1 (to inform genotype-guided dosing of coumarin derivatives), MTHFR (prior to methotrexate treatment) and factor V Leiden testing (prior to oral contraception). Testing for A1555G is not cost effective before prescribing aminoglycosides.
Our systematic review identified robust evidence of the cost effectiveness of genotyping prior to treatment with a number of common drugs. However, further analyses and (or) availability of robust clinical evidence is necessary to make recommendations for others.
Rapamycin (sirolimus) is a macrolide immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) protein kinase and extends lifespan in model organisms including mice. Although ...rapamycin is an FDA-approved drug for select indications, a diverse set of negative side effects may preclude its wide-scale deployment as an antiaging therapy. mTOR forms two different protein complexes, mTORC1 and mTORC2; the former is acutely sensitive to rapamycin whereas the latter is only chronically sensitive to rapamycin in vivo. Over the past decade, it has become clear that although genetic and pharmacological inhibition of mTORC1 extends lifespan and delays aging, inhibition of mTORC2 has negative effects on mammalian health and longevity and is responsible for many of the negative side effects of rapamycin. In this review, we discuss recent advances in understanding the molecular and physiological effects of rapamycin treatment, and we discuss how the use of alternative rapamycin treatment regimens or rapamycin analogs has the potential to mitigate the deleterious side effects of rapamycin treatment by more specifically targeting mTORC1. Although the side effects of rapamycin are still of significant concern, rapid progress is being made in realizing the revolutionary potential of rapamycin-based therapies for the treatment of diseases of aging.
Tumor mutational burden (TMB) has emerged as a potential predictive biomarker for clinical response to ICI therapy, but whether TMB also predicts toxicity remains unknown. We investigated the ...relationship between TMB, objective response rate (ORR), overall survival (OS), and toxicity for ICI therapy across multiple cancer types.
We searched MEDLINE, PubMed, and ASCO/ESMO/AACR meetings for clinical trials of anti-PD(L)1, CTLA-4, or combination in 29 cancer types. We assessed ICI administered, responses (complete or partial response), median OS, OS HR, and grade 3/4 toxicity. We conducted a systematic review, meta-analysis and meta-regression using tumor level TMB data from Foundation Medicine.
One hundred seventeen clinical trials, which included 12,450 patients treated with ICI therapy were analyzed. Meta-regression analysis revealed that TMB was significantly associated with ORR for anti-PD(L)1, anti-CTLA-4, and combination (
< 0.0001 for all), but not associated with toxicity in all treatment groups. OS data were unavailable for most studies included in our meta-analysis, and the relationship between TMB and OS in this subset was not significant (
= 0.26). In high TMB tumor types (≥10 mut/megabase) the improvement of ORR and increase in grade 3/4 toxicity with combination ICI therapy as compared with PD(L)1 monotherapy were 21.13% and 25.41%, respectively, as compared with 3.73% and 18.78% in low TMB tumor types (<10 mut/megabase).
There is a positive association between TMB and clinical response with anti-PD(L)1, anti-CTLA-4, and combination ICIs, but no association between TMB and toxicity. These results imply a favorable risk/benefit ratio for ICIs in tumors with a higher TMB.
Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events ...(irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients.
Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab.
Twenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8–786) and from irAE onset to tocilizumab 32 days (range 1–192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1–93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3–99), at the onset of irAE 49.5 mg/L (range 0.3–251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3–18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9–18.8) and median overall survival was not reached.
Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.
•Anti-IL6 (interleukin-6) was effective for management of immunotherapy-related toxicities.•In pre-existing auto-immune disorders, anti-IL6 could prevent flare during immune checkpoint inhibitor.•Clinical improvement/benefit was demonstrated in 21/22 patients (96%).•Anti-IL6 was well-tolerated in 21 patients, with transient toxicities in 50%.•Caution is required in patients with underlying bowel disease (bowel perforation).
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