Comfort and patient-centred care without excessive sedation:the eCASH concept

We propose an integrated and adaptable approach to improve patient care and clinical outcomes through analgesia and light sedation, initiated early during an episode of critical illness and as a priority of care. This strategy, which may be regarded as an evolution of the Pain, Agitation and Delirium guidelines, is conveyed in the mnemonic eCASH—early Comfort using Analgesia, minimal Sedatives and maximal Humane care. eCASH aims to establish optimal patient comfort with minimal sedation as the default presumption for intensive care unit (ICU) patients in the absence of recognised medical requirements for deeper sedation. Effective pain relief is the first priority for implementation of eCASH: we advocate flexible multimodal analgesia designed to minimise use of opioids. Sedation is secondary to pain relief and where possible should be based on agents that can be titrated to a prespecified target level that is subject to regular review and adjustment; routine use of benzodiazepines should be minimised. From the outset, the objective of sedation strategy is to eliminate the use of sedatives at the earliest medically justifiable opportunity. Effective analgesia and minimal sedation contribute to the larger aims of eCASH by facilitating promotion of sleep, early mobilization strategies and improved communication of patients with staff and relatives, all of which may be expected to assist rehabilitation and avoid isolation, confusion and possible long-term psychological complications of an ICU stay. eCASH represents a new paradigm for patient-centred care in the ICU. Some organizational challenges to the implementation of eCASH are identified.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Tuning Activity of Antimicrobial Peptides by Lipidation

Antimicrobial peptides (AMPs) are amino acid-based bioactive molecules that specifically target microbes. As such, they are a potent class of antibiotics, especially against bacterial infections. Naturally occurring AMPs are usually too long to be considered for therapeutic applications. To solve this, short sequences that mimic the activity of AMPs are designed. However, such endeavors are often accompanied with a reduction in antibacterial activity. To counter this, lipophilic molecules can be attached that function as a lipid anchor and target the short sequence to the bacterial membrane. For a range of short AMPs, this strategy has proven to lead to more active constructs. Although these lipidated short AMPs often work as complex target specific surfactants, more delicate modes of action that do not deviate too much from the nonlipidated counterparts are also known. This is readily observed by the large differences in activities that are detected when alterations in the lipid chain length and chirality of the amino acids residues are implemented. It is not uncommon to see that inactive or poorly active short AMPs can be turned into potent antibacterial agents. Importantly, selectivity of the short lipidated AMPs (lipoAMPs) for the bacterial membrane can be enhanced by alteration of the amino acid chirality. This strategy has led to lipoAMPs with submicromolar activities; in fact, activities that rival that of vancomycin have been observed for several short AMPs. Future research needs to determine (i) the effect of lipidation on the formation of lipid rafts in the bacterial membrane, (ii) if structural complications like branched lipids or chiral substituents on the lipid chain can be used to further increase the activity and selectivity of the conjugates, and (iii) if additional functionalities other than a membrane-anchoring ability can be bestowed on the lipid chain, e.g., redox activity or scavenger for small molecular components that traverse the lipid membrane. The interplay between degree of lipophilicity and the chirality of the amino acids of the AMP also needs further exploration, especially to see if more potent and selective (lipo)AMPs can be obtained that can be applied systemically. It may also be advisable to measure the most potent lipoAMPs in a centralized facility in order to obtain objective and comparable antibacterial activities

Bovine and human lactoferricin peptides: chimeras and new cyclic analogs

Lactoferrin (LF) is an important antimicrobial and immune regulatory protein present in neutrophils and most exocrine secretions of mammals. The antimicrobial activity of LF has been related to the presence of an antimicrobial peptide sequence, called lactoferricin (LFcin), located in the N-terminal region of the protein. The antimicrobial activity of bovine LFcin is considerably stronger than the human version. In this work, chimera peptides combining segments of bovine and human LFcin were generated in order to study their antimicrobial activity and mechanism of action. In addition, the relevance of the conserved disulfide bridge and the resulting cyclic structure of both LFcins were analyzed by using "click chemistry" and sortase A-catalyzed cyclization of the peptides. The N-terminal region of bovine LFcin (residues 17-25 of bovine LF) proved to be very important for the antimicrobial activity of the chimera peptides against E. coli, when combined with the C-terminal region of human LFcin. Similarly the cyclic bovine LFcin analogs generated by "click chemistry" and sortase A preserved the antimicrobial activity of the original peptide, showing the significance of these two techniques in the design of cyclic antimicrobial peptides. The mechanism of action of bovine LFcin and its active derived peptides was strongly correlated with membrane leakage in E. coli and up to some extent with the ability to induce vesicle aggregation. This mechanism was also preserved under conditions of high ionic strength (150 mM NaCl) illustrating the importance of these peptides in a more physiologically relevant system