Aims and objectivesEvaluate continuous vital sign surveillance as a tool to improve patient safety in the medical/surgical unit.BackgroundFailure‐to‐rescue is an important measure of hospital quality. Patient deterioration is often preceded by changes in vital signs. However, continuous multi‐parameter vital sign monitoring may decrease patient safety with an abundance of unnecessary alarms.DesignProspective observational study at two geographically disperse hospitals in a single hospital system.MethodsA multi‐parameter vital sign monitoring system was installed in a medical/surgical unit in Utah and one in Alabama providing continuous display of SpO2, heart rate, blood pressure and respiration rate on a central station. Alarm thresholds and time to alert annunciations were set based on prior analysis of the distribution of each vital sign. At the end of 4 weeks, nurses completed a survey on their experience. An average alert per patient, per day was determined retrospectively from the saved vital signs data and knowledge of the alarm settings.ResultsNinety‐two per cent of the nurses agreed that the number of alarms and alerts were appropriate; 54% strongly agreed. On average, both units experienced 10·8 alarms per patient, per day. One hundred per cent agreed the monitor provided valuable patient data that increased patient safety; 79% strongly agreed.ConclusionsContinuous, multi‐parameter patient monitoring could be performed on medical/surgical units with a small and appropriate level of alarms. Continuous vital sign assessment may have initiated nursing interventions that prevented failure‐to‐rescue events. Nurses surveyed unanimously agreed that continuous vital sign surveillance will help enhance patient safety.Relevance to clinical practiceNursing response to abnormal vital signs is one of the most important levers in patient safety, by providing timely recognition of early clinical deterioration. This occurs through diligent nursing surveillance, involving assessment, interpretation of data, recognition of a problem and meaningful response.

Protease inhibitors represent some of the most potent agents available for therapeutic strategies designed to inhibit human immunodeficiency virus type 1 (HIV-1) replication. Under certain circumstances the virus develops resistance to the inhibitor, thereby negating the benefits of this therapy. We have carried out selections for high-level resistance to each of three protease inhibitors (indinavir, ritonavir, and saquinavir) in cell culture. Mutations accumulated over most of the course of the increasing selective pressure. There was significant overlap in the identity of the mutations selected with the different inhibitors, and this gave rise to high levels of cross-resistance. Virus particles from the resistant variants all showed defects in processing at the NC/p1 protease cleavage site in Gag. Selections with pairs of inhibitors yielded similar patterns of resistance mutations. A virus that could replicate at near-toxic levels of the three protease inhibitors combined was selected. The pro sequence of this virus was similar to that of the viruses that had been selected for high-level resistance to each of the drugs singly. Finally, a molecular clone carrying the eight most common resistance mutations seen in these selections was characterized. The sequence of this virus was relatively stable during selection for revertants in spite of displaying poor processing at the NC/p1 site and having significantly reduced fitness. These results reveal patterns of drug resistance that extend to near the limits of attainable selective pressure with these inhibitors and confirm the patterns of cross-resistance for these three inhibitors and the attenuation of virion protein processing and fitness that accompanies high-level resistance.The evolution of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PI) represents a significant limitation to antiviral therapy. Resistance to protease inhibitors was initially shown by selection experiments carried out in vitro to be attributable to well-defined mutations in the pro gene encoding the viral protease. To a large extent, resistance mutations that were identified in the selections in cell culture overlap the mutations seen in subjects failing therapy (reviewed in reference 71).Therapeutic doses of PI are given at near-toxic levels to provide the maximal inhibitory effect. Even under these circumstances the number of resistance mutations present at the first time of apparent virus rebound is relatively small, although more mutations can accumulate over time under this constant level of selective pressure (11,13,22,45,50,62,74). Thus, the potential limit of selective pressure for these drugs has likely not been explored.One strategy for achieving higher selective pressure has been to use two PI together. This approach has three potential advantages. First, nonoverlapping toxicities allow for a higher combined inhibitory effect without the associated higher toxicity. Second, one PI can enhance the pharmacokinetic properties of a second inhibitor to p...

We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.Protease inhibitors (PIs) potently inhibit human immunodeficiency virus type 1 (HIV-1) replication, and their initial introduction into combination antiretroviral therapy was associated with a significant decrease of HIV-1-associated mortality and morbidity (41, 45). However, in clinical practice, virologic failure of protease inhibitor-containing therapy occurs in a significant fraction of the treated population (19,22,42,46,52,70). Virologic failure of protease inhibitor treatment is often due to the selection of HIV-1 strains with mutations in the pro gene, which encodes the viral protease (PR), and in specific protease cleavage sites encoded in the gag gene that collectively confer reduced drug susceptibility to the harboring strain (11,12,28,36,43,47,72).The resistance mutations are hypothesized to be largely preexisting, generated by the highly error-prone and rapid replication of HIV-1 in large virus populations (5, 10, 57). However, in PI-naïve subjects, some critical resistance mutations cannot be detected or can only be detected at very low levels, suggesting that these mutations may confer a selective disadvantage relative to wild-type HIV-1 strains (3,18,25,32,34,63). Indeed, it has been shown that the catalytic efficiency of protease is reduced by PI resis...

Rapidly evolving entities, such as viruses, can undergo complex genetic changes in the face of strong selective pressure. We have developed a modified heteroduplex tracking assay (HTA) capable of detecting the presence of single, specific mutations or sets of linked mutations. The initial application of this approach, termed multiple-site-specific (MSS) HTA, was directed toward the detection of mutations in the HIV-1 pro gene at positions 46, 48, 54, 82, 84, and 90, which are associated with resistance to multiple protease inhibitors. We demonstrate that MSS HTA is sensitive and largely specific to all targeted mutations. The assay allows the accurate and reproducible quantitation of viral subpopulations comprising 3% or more of the total population. Furthermore, we used MSS HTA in longitudinal studies of pro gene evolution in vitro and in vivo. In the examples shown here, populations turned over rapidly and more than one population was present frequently. To demonstrate the versatility of MSS HTA, we also constructed a probe sensitive to changes at positions 181 and 184 of the RT coding domain. Changes at these positions are involved in resistance to nevirapine and 2',3'-dideoxy-3'-thiacytidine (3TC), respectively. This assay easily detected the evolution of resistance to 3TC. MSS HTA provides a rapid and sensitive approach for detecting the presence of and quantifying complex mixtures of distinct genotypes, including genetically linked mutations, and, as one example, represents a useful tool for following the evolution of drug resistance during failure of HIV-1 antiviral therapy.

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