Updates on multimodal analgesia and regional anesthesia for total knee arthroplasty patients.

The subspecialty of regional anesthesiology and acute pain medicine (RAAPM) is in a position to lead changes that may impact the current opioid crisis. At the hospital level, RAAPM experts can implement evidence-based multimodal analgesic clinical pathways featuring regional anesthesia. Multimodal analgesia consists of using two or more analgesic modalities targeting pain pathways at various levels to improve pain control, while also aiming to reduce opioid utilization and related adverse effects. These types of pathways or protocols have been widely applied in the joint replacement population. This review focuses on the current state of the evidence regarding individual elements of a multimodal analgesic pathway for patients with total knee arthroplasty including new regional anesthesia techniques like the IPACK (Infiltration between the Popliteal Artery and Capsule of the Knee) block and suggests future research directions to improve the clinical care of this surgical population in the future.

Implementation of the IPACK (Infiltration between the Popliteal Artery and Capsule of the Knee) block into a multimodal analgesic pathway for total knee replacement.

BACKGROUND: The Infiltration between the Popliteal Artery and Capsule of the Knee (IPACK) block is a new anesthesiologist- administered analgesic technique for controlling posterior knee pain that has not yet been well studied in total knee arthroplasty (TKA) patients. We compared pain outcomes in TKA patients before and after implementation of the IPACK with the hypothesis that patients receiving IPACK blocks will report lower pain scores on postoperative day (POD) 0 than non-IPACK patients. METHODS: With Institutional Review Board approval, we retrospectively reviewed data for consecutive TKA patients by a single surgeon 4 months before (PRE) and after (POST) IPACK implementation. All TKA patients received adductor canal catheters and peri-operative multimodal analgesia. The primary outcome was pain on POD 0. Other outcomes were daily pain scores, opioid consumption, ambulation distance, length of stay, and adverse events within 30 days. RESULTS: Post-implementation, 48/50 (96%) of TKA patients received an IPACK block, and they were compared with 32 patients in the PRE group. On POD 0, the lowest pain score (median [10th-90th percentiles]) was significantly lower for the POST group compared to the PRE group (0 [0-4.3] vs. 2.5 [0-7]; P = 0.003). The highest patient-reported pain scores on any POD were similar between groups with no differences in other outcomes. CONCLUSIONS: Within a multimodal analgesic protocol, addition of IPACK blocks decreased the lowest pain scores on POD 0. Although other outcomes were unchanged, there may be a role for new opioid-sparing analgesic techniques, and changing clinical practice change can occur rapidly.

Emergency department-initiated palliative care for advanced cancer patients: protocol for a pilot randomized controlled trial.

BACKGROUND: For patients with advanced cancer, visits to the emergency department (ED) are common. Such patients present to the ED with a specific profile of palliative care needs, including burdensome symptoms such as pain, dyspnea, or vomiting that cannot be controlled in other settings and a lack of well-defined goals of care. The goals of this study are: i) to test the feasibility of recruiting, enrolling, and randomizing patients with serious illness in the ED; and ii) to evaluate the impact of ED-initiated palliative care on health care utilization, quality of life, and survival. METHODS/DESIGN: This is a protocol for a single center parallel, two-arm randomized controlled trial in ED patients with metastatic solid tumors comparing ED-initiated palliative care referral to a control group receiving usual care. We plan to enroll 125 to 150 ED-advanced cancer patients at Mount Sinai Hospital in New York, USA, who meet the following criteria: i) pass a brief cognitive screen; ii) speak fluent English or Spanish; and iii) have never been seen by palliative care. We will use balanced block randomization in groups of 50 to assign patients to the intervention or control group after completion of a baseline questionnaire. All research staff performing assessment or analysis will be blinded to patient assignment. We will measure the impact of the palliative care intervention on the following outcomes: i) timing and rate of palliative care consultation; ii) quality of life and depression at 12 weeks, measured using the FACT-G and PHQ-9; iii) health care utilization; and iv) length of survival. The primary analysis will be based on intention-to-treat. DISCUSSION: This pilot randomized controlled trial will test the feasibility of recruiting, enrolling, and randomizing patients with advanced cancer in the ED, and provide a preliminary estimate of the impact of palliative care referral on health care utilization, quality of life, and survival. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT01358110 (Entered 5/19/2011).

Barriers to palliative care research for emergency department patients with advanced cancer.

BACKGROUND: Patients with advanced cancer often visit the emergency department (ED). Little is known about their willingness or ability to engage in palliative care research, although enrollment in clinical trials of other seriously ill ED patients—those with stroke, for example—has been shown to be feasible. OBJECTIVE: To identify barriers to the enrollment of ED patients with advanced cancer in palliative care research. METHODS: We prospectively tracked factors that affected patient accrual into a trial of palliative care for adults with metastatic solid tumors at an urban, academic ED. Research staff screened the electronic medical records for patients admitted to the hospital with metastatic solid tumors 8-12 hours a day, Monday through Friday. The ED attending of record and the patient's medical oncologist had to agree before research staff invited the patient to participate. Informed consent was obtained at the bedside in the ED, and patients were offered a $20 incentive to participate. RESULTS: Attempts were made to enroll 150 eligible patients in the study, and 73 were enrolled (49% enrollment rate). Barriers to enrollment for the 77 patients who did not participate were deduced from the field notes and placed into the following categories: patient refusal (n = 38, 49%), diagnostic uncertainty regarding cancer stage (n = 11, 14%), symptom burden (n = 9, 12%), family refusal (n = 7, 9%), physician refusal (n = 7, 9%), and/or patient unaware of illness or stage (n = 5, 7%). LIMITATIONS: The findings are descriptive and do not test predetermined hypotheses. CONCLUSION: Patient refusal, symptom burden, and diagnostic disparities are common barriers encountered when recruiting ED patients with advanced cancer. Despite the barriers, recruitment was feasible for such ED patients. FUNDING/SPONSOR: This study was funded by a Mentored Research Scholar Grant from the American Cancer Society (Dr Grudzen), a Medical Student Training in Aging Research Grant from the American Federation on Aging (Mr Kandarian), and by a Mid- Career Investigator Award in Patient Oriented Research (K24 AG022345) from the National Institute on Aging (Dr Morrison).

Hospital administrators' views on barriers and opportunities to delivering palliative care in the emergency department.

STUDY OBJECTIVE: We identify hospital-level factors from the administrative perspective that affect the availability and delivery of palliative care services in the emergency department (ED). METHODS: Semistructured interviews were conducted with 14 key informants, including hospital executives, ED directors, and palliative care directors at a tertiary care center, a public hospital, and a community hospital. The discussions were digitally recorded and transcribed to conduct a thematic analysis using grounded theory. A coding scheme was iteratively developed to subsequently identify themes and subthemes that emerged from the interviews. RESULTS: Barriers to integrating palliative care and emergency medicine from the administrative perspective include the ED culture of aggressive care, limited knowledge, palliative care staffing, and medicolegal concerns. Incentives to the delivery of palliative care in the ED from these key informants' perspective include improved patient and family satisfaction, opportunities to provide meaningful care to patients, decreased costs of care for admitted patients, and avoidance of unnecessary admissions to more intensive hospital settings, such as the ICU, for patients who have little likelihood of benefit. CONCLUSION: Though hospital administration at 3 urban hospitals on the East coast has great interest in integrating palliative care and emergency medicine to improve quality of care, patient and family satisfaction, and decrease length of stay for admitted patients, palliative care staffing, medicolegal concerns, and logistic issues need to be addressed.

The medicinal leech genome encodes 21 innexin genes: different combinations are expressed by identified central neurons.

Gap junctional proteins are important components of signaling pathways required for the development and ongoing functions of all animal tissues, particularly the nervous system, where they function in the intracellular and extracellular exchange of small signaling factors and ions. In animals whose genomes have been sufficiently sequenced, large families of these proteins, connexins, pannexins, and innexins, have been found, with 25 innexins in the nematode Caenorhabditis elegans Starich et al. (Cell Commun Adhes 8: 311-314, 2001) and at least 37 connexins in the zebrafish Danio rerio Cruciani and Mikalsen (Biol Chem 388:253-264, 2009). Having recently sequenced the medicinal leech Hirudo verbana genome, we now report the presence of 21 innexin genes in this species, nine more than we had previously reported from the analysis of an EST-derived transcriptomic database Dykes and Macagno (Dev Genes Evol 216: 185-97, 2006); Macagno et al. (BMC Genomics 25:407, 2010). Gene structure analyses show that, depending on the leech innexin gene, they can contain from 0 to 6 introns, with closely related paralogs showing the same number of introns. Phylogenetic trees comparing Hirudo to another distantly related leech species, Helobdella robusta, shows a high degree of orthology, whereas comparison to other annelids shows a relatively low level. Comparisons with other Lophotrochozoans, Ecdyzozoans and with vertebrate pannexins suggest a low number (one to two) of ancestral innexin/pannexins at the protostome/deuterostome split. Whole-mount in situ hybridization for individual genes in early embryos shows that ∼50% of the expressed innexins are detectable in multiple tissues. Expression analyses using quantitative PCR show that ∼70% of the Hirudo innexins are expressed in the nervous system, with most of these detected in early development. Finally, quantitative PCR analysis of several identified adult neurons detects the presence of different combinations of innexin genes, a property that may underlie the participation of these neurons in different adult coupling circuits.

Activity of recombinant cysteine-rich domain proteins derived from the membrane-bound MUC17/Muc3 family mucins.

BACKGROUND: The membrane-bound mucins, MUC17 (human) and Muc3 (mouse), are highly expressed on the apical surface of intestinal epithelia and have cytoprotective properties. Their extracellular regions contain two EGF-like Cys-rich domains (CRD1 and CRD2) connected by an intervening linker segment with SEA module (L), and may function to stimulate intestinal cell restitution. The purpose of this study was to determine the effect of size, recombinant host source, and external tags on mucin CRD1-L-CRD2 protein activity. METHODS: Four recombinant Muc3-CRD proteins and three MUC17-CRD proteins were generated using Escherichiacoli or baculovirus-insect cell systems and tested in colonic cell cultures for activity related to cell migration and apoptosis. RESULTS: N-terminal glutathione-S-transferase (GST) or C-terminal His(8) tags had no effect on either the cell migration or anti-apoptosis activity of Muc3-CRD1-L-CRD2. His-tagged Muc3-CRD1-L-CRD2 proteins with truncated linker regions, or the linker region alone, did not demonstrate biologic activity. The human recombinant MUC17-CRD1-L-CRD2-His(8) was shown to have anti-apoptotic and pro-migratory activity, but did not stimulate cell proliferation. This protein showed similar in vitro biologic activity, whether produced in E. coli or a baculovirus-insect cell system. CONCLUSIONS: Recombinant mucin proteins containing a bivalent display of Cys-rich domains accelerate colon cell migration and inhibit apoptosis, require a full-length intervening Linker-SEA segment for optimal biologic activity, and are functional when synthesized in either E. coli and insect cell systems. GENERAL SIGNIFICANCE: These results indicate that an Escherichiacoli-derived full-length His(8)-tagged human MUC17 CRD1-L-CRD2 recombinant protein is a biologically active candidate for further development as a therapeutic agent.