Improving care for intensive care survivors and their families requires collaboration between practitioners and researchers in both the inpatient and outpatient settings. Strategies were developed to address the major themes arising from the conference to improve outcomes for survivors and families.

Raising awareness of post-intensive care syndrome for the public and both critical care and non-critical care clinicians will inform a more coordinated approach to treatment and support during recovery after critical illness. Continued conceptual development and engagement with additional stakeholders is required.

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As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

Membranes from rabbit aorta and from rabbit and rat kidney cortex possess high-affinity (Kd = 10-10 M) specific binding sites for atrial natriuretic factor (ANF). Similar high-affinity sites are present in an established cell line from pig kidney, LLC-PK,. Results of fractionation studies indicate that the receptors are localized in the plasma membrane of these tissues. The binding is time-dependent and saturable. An excellent quantitative correlation was found between the affinity of synthetic ANF and analogs of intermediate activity to aorta membranes and the half-maximal concentration needed for relaxation of rabbit aorta rings contracted by addition of serotonin. Furthermore, the binding affinity of the receptor in kidney membranes is consistent with the concentration required for in vivo natriuresis in the rat. Biologically inactive synthetic ANF fragments and other peptide hormones such as angiotensin II and vasopressin do not significantly inhibit binding. These data suggest that the receptors for ANF in vascular and renal tissues are responsible for mediating the physiological actions of this peptide in these target tissues.A possible role for the cardiac atria in the regulation of extracellular fluid volume and electrolyte concentration has been shown by the induction of sodium and water excretion in response to changes in intraatrial pressure and stretch of the atrial wall (1). The cardiac atria possess granules that have the appearance of secretory granules (2-4) and whose number can be altered by manipulation of the water-electrolyte balance in experimental animals (5). Crude extracts of atria from several species have been shown to possess potent diuretic and natriuretic activity when given intravenously to rats (6). Subcellular fractionation (7) and immunocytochemistry (8) indicated that these granules are storage sites for an atrial natriuretic factor (ANF). Furthermore, in vitro, atrial extracts were shown to be potent vasorelaxants (9-14). As little as 0.0006 atrial equivalent per milliliter gave 50% relaxation of precontracted aorta tissues (12). In vivo, ANF caused lowering of mean arterial blood pressure in normal and hypertensive animals (6,15,16). Recently, a family of peptides has been isolated from acidic extracts of rat (10,11,(19)(20)(21)(22) and human (23) atria and sequenced independently by several laboratories. From rat atria, the longest peptide that has been reported contains 33 amino acids, 1, and was isolated as the free COOH-terminal tyrosine acid (20,21). Shorter rat ANF peptides are truncated at either the NH2 or COOH terminus.5 10 H-Leu -Ala-Gly-Pro -Arg-Ser -Leu-Arg-Arg-Ser-Ser-15 20Cys-Phe-Gly-Gly-Arg-Ile -Asp-Arg-Ile -Gly-Ala--30Gln -Ser-Gly-Leu-Gly-Cys -Asn-Ser-Phe-Arg-Tyr-OH 1 A peptide consisting of residues 8-33, designated sANF, has been synthesized (21, 24) and shown to possess full biological activity (12,16,21,24). The IC50 of sANF for relaxation of precontracted rabbit aorta rings is 550 pM (12). The amount of sANF required for half-maximal natriuresis wh...

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