Easing Suffering for ICU Patients and Their Families: Evidence and Opportunities for Primary and Specialty Palliative Care in the ICU.

Intensive care unit (ICU) admissions are often accompanied by many physical and existential pressure points that can be extraordinarily wearing on patients and their families and surrogate decision makers (SDMs). Multidisciplinary palliative support, including physicians, advanced practice nurses, nutritionists, chaplains and other team members, may alleviate many of these sources of potential suffering. However, the palliative needs of ICU patients undoubtedly exceed the bandwidth of current consultative specialty palliative medicine teams. Informed by standard-of-care palliative medicine domains, we review common ICU symptoms (pain, dyspnea and thirst) and their prevalence, sources and their treatment. We then identify palliative needs and impacts in the domains of communication, SDM support and transitions of care for patients and their families through their journey in the ICU, from discharge and recovery at home to chronic critical illness, post-ICU disability or death. Finally, we examine the evidence for strategies to incorporate specialty palliative medicine and palliative principles into ICU care for the improvement of patient- and family-centered care. While randomized controlled studies have failed to demonstrate measurable improvement in pre-determined outcomes for patient- and family-relevant outcomes, embracing the principles of palliative medicine and assuring their delivery in the ICU is likely to translate to overall improvement in humanistic, person-centered care that supports patients and their SDMs during and following critical illness.

Hospitalisations for heart failure: increased palliative care referrals - a veterans affairs hospital initiative.

OBJECTIVES: Heart failure (HF) portends significant morbidity and mortality. Integrating palliative care (PC) with HF management improves quality of life and preparedness planning. At a Veterans Affairs hospital, PC was used in 6.5% of patients admitted for HF from October 2019 to September 2020. We sought to increase the percentage of referrals to PC to 20%. METHODS: PC referral guidelines were developed and used to screen all HF admissions between October 2020 and May 2021. Point-of-care education on the benefits of PC was delivered to teams caring for patients who met PC referral criteria. Changes were tested using Plan-Do-Study-Act (PDSA) cycles. Results were analysed using run charts. RESULTS: During the study period, there were 109 HF admissions in patients who were not already followed by PC. Thirty-one (28%) received a new PC consult. The mean age was 81±9.5 years, median B-type natriuretic peptide was 1202 pg/mL, and mean length of stay was 8±5 days. After our intervention, there was an upward shift in the percentage of new referrals to PC with 6 values above the baseline median, which represents a significant change. CONCLUSIONS: Through multiple PDSA cycles, referrals to PC for patients admitted with HF increased from 6.5% to 28%. Point-of-care education was an effective tool to teach medical teams about the benefits of PC. Inpatient teams more consistently and independently considered PC for patients with HF, representing a cultural shift. This quality improvement model may serve as a paradigm to improve the care of HF patients.

Feasibility of Safe Opioid Prescribing in Outpatient Palliative Care: A Quality Improvement Project.

BACKGROUND: No guidelines for safe opioid prescribing in palliative care exist, which contributes to limited monitoring of opioid misuse in palliative care. MEASURES: Feasibility of a safe opioid prescribing standard operating protocol (SOP) was determined by assessing the percentage of patients in an outpatient cancer center who completed each component of a five-component SOP. INTERVENTION: A five-component SOP included: risk stratification for misuse, consent form, prescription drug monitoring program review, urine drug testing, and Naloxone for high-risk individuals. OUTCOMES: After one year, compliance rates on four of the of the five-component SOP were greater or equal to 93%. Naloxone co-prescription for high-risk patients never reached over 78%, largely due to clinical decision not to co-prescribe if transition to hospice was imminent. CONCLUSIONS/LESSONS LEARNED: Safe opioid prescribing measures are feasible in outpatient palliative care and can facilitate identification of individuals at risk for opioid misuse and prompt early interventions for misuse.

Specialized Palliative and Hospice Care and the Importance of Mourning Our Nation's Veterans.

One aspect of palliative medicine that has been underexplored is the perspective of veterans either facing critical life-limiting illness or at the end of life. The needs of veterans differ not only because military culture affects how veterans cope with their illness but also because exposure-related factors (combat and environmental) differ between military branches. In this paper, we describe two cases involving end-of-life care for veterans with combat trauma and describe individualized approaches to their care.

Conformational changes at cytoplasmic intersubunit interactions control Kir channel gating.

The defining structural feature of inward-rectifier potassium (Kir) channels is the unique Kir cytoplasmic domain. Recently we showed that salt bridges located at the cytoplasmic domain subunit interfaces (CD-Is) of eukaryotic Kir channels control channel gating via stability of a novel inactivated closed state. The cytoplasmic domains of prokaryotic and eukaryotic Kir channels show similar conformational rearrangements to the common gating ligand, phosphatidylinositol bisphosphate (PIP2), although these exhibit opposite coupling to opening and closing transitions. In Kir2.1, mutation of one of these CD-I salt bridge residues (R204A) reduces apparent PIP2 sensitivity of channel activity, and here we show that Ala or Cys substitutions of the functionally equivalent residue (Arg-165) in the prokaryotic Kir channel KirBac1.1 also significantly decrease sensitivity of the channel to PIP2 (by 5-30-fold). To further understand the structural basis of CD-I control of Kir channel gating, we examined the effect of the R165A mutation on PIP2-induced changes in channel function and conformation. Single-channel analyses indicated that the R165A mutation disrupts the characteristic long interburst closed state of reconstituted KirBac1.1 in giant liposomes, resulting in a higher open probability due to more frequent opening bursts. Intramolecular FRET measurements indicate that, relative to wild-type channels, the R165A mutation results in splaying of the cytoplasmic domains away from the central axis and that PIP2 essentially induces opposite motions of the major ß-sheet in this channel mutant. We conclude that the removal of stabilizing CD-I salt bridges results in a collapsed state of the Kir domain.

Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids.

Inward rectifier potassium (Kir) channel activity is controlled by plasma membrane lipids. Phosphatidylinositol-4,5-bisphosphate (PIP2) binding to a primary site is required for opening of classic inward rectifier Kir2.1 and Kir2.2 channels, but interaction of bulk anionic phospholipid (PL(-)) with a distinct second site is required for high PIP2 sensitivity. Here we show that introduction of a lipid-partitioning tryptophan at the second site (K62W) generates high PIP2 sensitivity, even in the absence of PL(-) Furthermore, high-resolution x-ray crystal structures of Kir2.2[K62W], with or without added PIP2 (2.8- and 2.0-Å resolution, respectively), reveal tight tethering of the C-terminal domain (CTD) to the transmembrane domain (TMD) in each condition. Our results suggest a refined model for phospholipid gating in which PL(-) binding at the second site pulls the CTD toward the membrane, inducing the formation of the high-affinity primary PIP2 site and explaining the positive allostery between PL(-) binding and PIP2 sensitivity.

Secondary anionic phospholipid binding site and gating mechanism in Kir2.1 inward rectifier channels.

Inwardly rectifying potassium (Kir) channels regulate multiple tissues. All Kir channels require interaction of phosphatidyl-4,5-bisphosphate (PIP2) at a crystallographically identified binding site, but an additional nonspecific secondary anionic phospholipid (PL(-)) is required to generate high PIP2 sensitivity of Kir2 channel gating. The PL(-)-binding site and mechanism are yet to be elucidated. Here we report docking simulations that identify a putative PL(-)-binding site, adjacent to the PIP2-binding site, generated by two lysine residues from neighbouring subunits. When either lysine is mutated to cysteine (K64C and K219C), channel activity is significantly decreased in cells and in reconstituted liposomes. Directly tethering K64C to the membrane by modification with decyl-MTS generates high PIP2 sensitivity in liposomes, even in the complete absence of PL(-)s. The results provide a coherent molecular mechanism whereby PL(-) interaction with a discrete binding site results in a conformational change that stabilizes the high-affinity PIP2 activatory site.

Structural rearrangements underlying ligand-gating in Kir channels.

Inward rectifier potassium (Kir) channels are physiologically regulated by a wide range of ligands that all act on a common gate, although structural details of gating are unclear. Here we show, using small molecule fluorescent probes attached to introduced cysteines, the molecular motions associated with gating of KirBac1.1 channels. The accessibility of the probes indicates a major barrier to fluorophore entry to the inner cavity. Changes in fluorescence resonance energy transfer between fluorophores, attached to KirBac1.1 tetramers, show that phosphatidylinositol-4,5-bisphosphate-induced closure involves tilting and rotational motions of secondary structural elements of the cytoplasmic domain that couple ligand binding to a narrowing of the cytoplasmic vestibule. The observed ligand-dependent conformational changes in KirBac1.1 provide a general model for ligand-induced Kir channel gating at the molecular level.