The importance of bacterial sepsis in intensive care unit patients with acquired immunodeficiency syndrome: implications for future care in the age of increasing antiretroviral resistance.

OBJECTIVE: To describe the clinical characteristics and outcomes of patients with acquired immunodeficiency syndrome (AIDS) admitted to the intensive care unit (ICU). DESIGN: An observational cohort study with retrospective chart review. SETTING: ICU of an urban university medical center. PATIENTS: Consecutive ICU admissions of patients with AIDS at an urban university medical center between December 1993 and June 1996. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For each patient, we recorded ICU admission diagnosis, clinical characteristics, and outcome. Among 129 ICU admissions of patients with AIDS, 102 (79%) were admitted for infections, of which (45%) had infections caused by bacteria. Pseudomonas aeruginosa, Staphylococcus aureus, and other enteric pathogens were the most frequent isolates. Pneumonia accounted for 65% of 102 admissions for infections. Overall hospital mortality was 54%, but mortality was higher (68%) for patients with bacterial sepsis. Neutropenia was associated with differences in unadjusted survival rates, whereas CD4 counts were not. Independent predictors of hospital mortality included increasing acute physiology scores and severity of sepsis. CONCLUSIONS: In our ICU, among patients with AIDS, sepsis resulting from bacterial infection is now a more frequent cause of admission than Pneumocystis carinii pneumonia. Severity of illness and the presence of severe sepsis were the clinical predictors most associated with increased mortality. Patients who are not receiving or responding to highly active antiretroviral therapy may become as likely to be admitted to an ICU with a treatable bacterial infection as with classic opportunistic infections. Therefore, broad-spectrum empirical antibacterial therapy is particularly important when the etiology of infection is uncertain.

Intensive care unit length of stay: recent changes and future challenges.

OBJECTIVE: To compare case-mix adjusted intensive care unit (ICU) length of stay for critically ill patients with a variety of medical and surgical diagnoses during a 5-yr interval. DESIGN: Nonrandomized cohort study. SETTING: A total of 42 ICUs at 40 US hospitals during 1988-1990 and 285 ICUs at 161 US hospitals during 1993-1996. PATIENTS: A total of 17,105 consecutive ICU admissions during 1988-1990 and 38,888 consecutive ICU admissions during 1993-1996. MEASUREMENTS AND MAIN RESULTS: We used patient demographic and clinical characteristics to compare observed and predicted ICU length of stay and hospital mortality. Outcomes for patients studied during 1993-1996 were predicted using multivariable models that were developed and cross-validated using the 1988-1990 database. The mean observed hospital length of stay decreased by 3 days (from 14.8 days during 1988-1990 to 11.8 days during 1993-1996), but the mean observed ICU length of stay remained similar (4.70 vs. 4.53 days). After adjusting for patient and institutional differences, the mean predicted 1993-1996 ICU stay was 4.64 days. Thus, the mean-adjusted ICU stay decreased by 0.11 days during this 5-yr interval (T-statistic, 4.35; p < .001). The adjusted mean ICU length of stay was not changed for patients with 49 (75%) of the 65 ICU admission diagnoses. In contrast, the mean observed hospital length of stay was significantly shorter for 47 (72%) of the 65 admission diagnoses, and no ICU admission diagnosis was associated with a longer hospital stay. Aggregate risk-adjusted hospital mortality during 1993-1996 (12.35%) was not significantly different during 1988-1990 (12.27%, p = .54). CONCLUSIONS: For patients admitted to ICUs, the pressures associated with a decrease in hospital length of stay do not seem to have influenced the duration of ICU stay. Because of the high cost of intensive care, reduction in ICU stay may become a target for future cost-cutting efforts.

Molecular analysis of Drosophila eyes absent mutants reveals features of the conserved Eya domain.

The eyes absent (eya) gene is critical to eye formation in Drosophila; upon loss of eya function, eye progenitor cells die by programmed cell death. Moreover, ectopic eya expression directs eye formation, and eya functionally synergizes in vivo and physically interacts in vitro with two other genes of eye development, sine oculis and dachshund. The Eya protein sequence, while highly conserved to vertebrates, is novel. To define amino acids critical to the function of the Eya protein, we have sequenced eya alleles. These mutations have revealed that loss of the entire Eya Domain is null for eya activity, but that alleles with truncations within the Eya Domain display partial function. We then extended the molecular genetic analysis to interactions within the Eya Domain. This analysis has revealed regions of special importance to interaction with Sine Oculis or Dachshund. Select eya missense mutations within the Eya Domain diminished the interactions with Sine Oculis or Dachshund. Taken together, these data suggest that the conserved Eya Domain is critical for eya activity and may have functional subregions within it.

Functional analysis of an eye enhancer of the Drosophila eyes absent gene: differential regulation by eye specification genes.

Genes involved in eye development are highly conserved between vertebrates and Drosophila. Given the complex genetic network controlling early eye development, identification of regulatory sequences controlling gene expression will provide valuable insights toward understanding central events of early eye specification. We have focused on defining regulatory elements critical for Drosophila eyes absent (eya) expression. Although eya has a complex expression pattern during development, analysis of eye-specific mutations in the gene revealed a region selectively deleted in the eye-specific alleles. Here we have performed detailed analysis of the region deleted in the eye-specific eya(2) allele. This analysis shows that this region can direct early eya gene expression in a pattern consistent with that of normal eya in eye progenitor cells. Functional studies indicate that this element will restore appropriate eya transcript expression to rescue the eye-specific allele. We have examined regulation of this element during eye specification, both in normal eye development and in ectopic eye formation. These studies demonstrate that the element was activated upon ectopic expression of the eye specification genes eyeless and dachshund, but does not respond to ectopic expression of eya or sine oculis. The differential regulation of this element by genes involved during early retinal formation reveals new aspects of the genetic hierarchy of eye development.

Molecular genetic analysis of Drosophila eyes absent mutants reveals an eye enhancer element.

The eyes absent (eya) gene is critical for normal eye development in Drosophila and is highly conserved to vertebrates. To define regions of the gene critical for eye function, we have defined the mutations in the four viable eya alleles. Two of these mutations are eye specific and undergo transvection with other mutations in the gene. These were found to be deletion mutations that remove regulatory sequence critical for eye cell expression of the gene. Two other viable alleles cause a reduced eye phenotype and affect the function of the gene in additional tissues, such as the ocelli. These mutations were found to be insertion mutations of different transposable elements within the 5' UTR of the transcript. Detailed analysis of one of these revealed that the transposable element has become subject to regulation by eye enhancer sequences of the eya gene, disrupting normal expression of EYA in the eye. More extended analysis of the deletion region in the eye-specific alleles indicated that the deleted region defines an enhancer that activates gene expression in eye progenitor cells. This enhancer is responsive to ectopic expression of the eyeless gene. This analysis has defined a critical regulatory region required for proper eye expression of the eya gene.

Analysis of fluG mutations that affect light-dependent conidiation in Aspergillus nidulans.

Conidiation in Aspergillus nidulans is induced by exposure to red light but can also be induced by blue light in certain mutant strains. We have isolated a mutation in the fluG gene that abolishes responsiveness to red light but does not affect the response to blue light. It has been shown that the veA1 (velvet) mutation allows conidiation to occur in the absence of light. We have identified three other fluG mutations that suppress the veA1 phenotype; these double mutants do not conidiate in the dark. The mutations described here define two new phenotypic classes of fluG alleles that display abnormal responses to light. We have characterized these mutations with respect to their molecular identity and to their effect on fluG transcription. Although it has been shown that fluG is required for the synthesis of an extracellular factor that directs conidiation, we do not detect this factor under conditions that promote conidiation in the veA1 suppressors. Furthermore, extracellular rescue is not observed in fluG deletion strains containing the wild-type veA allele. We propose that a genetic interaction between fluG and veA influences the production of the extracellular signal and regulates the initiation of conidiation.

Evaluation of acute physiology and chronic health evaluation III predictions of hospital mortality in an independent database.

OBJECTIVE: To assess the accuracy and validity of Acute Physiology and Chronic Health Evaluation (APACHE) III hospital mortality predictions in an independent sample of U.S. intensive care unit (ICU) admissions. DESIGN: Nonrandomized, observational, cohort study. SETTING: Two hundred eighty-five ICUs in 161 U.S. hospitals, including 65 members of the Council of Teaching Hospitals and 64 nonteaching hospitals. PATIENTS: A consecutive sample of 37,668 ICU admissions during 1993 to 1996; including 25,448 admissions at hospitals with >400 beds and 1,074 admissions at hospitals with <200 beds. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used demographic, clinical, and physiologic information recorded during ICU day 1 and the APACHE III equation to predict the probability of hospital mortality for each patient. We compared observed and predicted mortality for all admissions and across patient subgroups and assessed predictive accuracy using tests of discrimination and calibration. Aggregate hospital death rate was 12.35% and predicted hospital death rate was 12.27% (p =.541). The model discriminated between survivors and nonsurvivors well (area under receiver operating curve = 0.89). A calibration curve showed that the observed number of hospital deaths was close to the number of deaths predicted by the model, but when tested across deciles of risk, goodness-of-fit (Hosmer-Lemeshow statistic, chi-square = 48.71, 8 degrees of freedom, p< .0001) was not perfect. Observed and predicted hospital mortality rates were not significantly (p < .01) different for 55 (84.6%) of APACHE III's 65 specific ICU admission diagnoses and for 11 (84.6%) of the 13 residual organ system-related categories. The most frequent diagnoses with significant (p < .01) differences between observed and predicted hospital mortality rates included acute myocardial infarction, drug overdose, nonoperative head trauma, and nonoperative multiple trauma. CONCLUSIONS: APACHE III accurately predicted aggregate hospital mortality in an independent sample of U.S. ICU admissions. Further improvements in calibration can be achieved by more precise disease labeling, improved acquisition and weighting of neurologic abnormalities, adjustments that reflect changes in treatment outcomes over time, and a larger national database.

Neurological intensive care admissions: identifying candidates for intermediate care and the services they receive.

OBJECTIVE: The high cost and scarcity of intensive care unit (ICU) beds has resulted in a need for improved utilization. This study describes the characteristics of patients who are admitted to the ICU for neurosurgical and neurological care, identifies patients who might receive all or most of their care in an intermediate care unit, and describes the services the patients would receive in an intermediate care unit. METHODS: We describe patients who received neurological care and who were part of a prospective study of 17,440 patients admitted to 42 ICUs at 40 United States hospitals. We identified patients who received only monitoring during ICU Day 1 and then used a previously validated equation to distinguish which patients were at low risk (< 10%) for subsequent active life-supporting therapy. We also describe the services these patients received during their ICU stay. RESULTS: Among 3000 patients admitted to the ICU for neurological care, 1350 received active therapy and 1650 (55%) underwent monitoring and received concentrated nursing care on ICU Day 1. After excluding those patients who received active therapy at admission, 1288 (78%) of the 1650 patients who underwent monitoring at admission were at low risk (< 10%) for subsequent active therapy; 95.8% received no active therapy. These patients who were at low risk for subsequent active therapy were significantly (P < 0.001) more often admitted postoperatively, were younger and less severely ill, and had lower ICU and hospital mortality rates (0.9 and 3.9%, respectively) than patients who received active treatment at admission. CONCLUSIONS: Patients receiving neurological care at an ICU who receive only monitoring during their 1st ICU day and have a less than 10% predicted risk of active treatment can be safely transferred to an intermediate care unit. Some of these patients may not require ICU admission. We suggest guidelines for equipping and staffing neurological intermediate care units based on the type and amount of therapy received by these patients.

Inositol 1,4,5-trisphosphate receptor expression in odontoblast cells.

The cellular distribution of inositol 1,4,5-trisphosphate receptors was examined in rodent maxillary incisor teeth. In situ hybridization studies with a transmembrane probe of type I inositol 1,4,5-trisphosphate receptor indicated that this receptor/channel was highly expressed in odontoblast cells of incisor teeth. In contrast, very low labeling was observed in dental pulp. Northern analysis showed a message size of approximately 9.5 kilobases for this receptor, and demonstrated that type III inositol 1,4,5-trisphosphate receptor was expressed in incisor teeth. Immunocytochemical studies confirmed that types I and III inositol 1,4,5-trisphosphate receptors were both highly expressed in odontoblasts while very low expression was detected in dental pulp. Finally, antibodies that recognized alpha subunits of the Gq class of GTP binding proteins also stained odontoblasts. These results indicate that receptor-mediated regulation of calcium release through inositol 1,4,5-trisphosphate receptors may occur in odontoblasts of rat incisor teeth. These findings also suggest that inositol 1,4,5-trisphosphate receptor/channels regulate calcium flux in odontoblasts during mineralization of dentin, or in growth and differentiation of incisor tissue.

Evaluating laboratory usage in the intensive care unit: patient and institutional characteristics that influence frequency of blood sampling.

OBJECTIVES: To develop a predictive equation to estimate the frequency of blood drawing for intensive care unit (ICU) laboratory tests and to evaluate variations in ICU blood sampling practices after adjusting for patient and institutional factors. DESIGN: Prospective, inception, cohort study. SETTING: Forty-two ICUs in 40 hospitals, including 20 teaching and 17 nonteaching ICUs. PATIENTS: A consecutive sample of 17,440 ICU admissions, in which 14,043 blood samples were drawn for laboratory testing on ICU days 2 to 7. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient demographic, physiologic, and treatment data were obtained on ICU day 1; the type and number of blood samples for laboratory testing were recorded on ICU days 1 to 7. In the 42 ICUs, a mean of 16.2 blood samples were drawn for tests on ICU days 2 to 7, but varied between 23 samples in the teaching ICUs and 9.9 samples in nonteaching ICUs. Using only ICU day 1 patient data, we predicted the subsequent number of samples drawn on ICU day 2 (R2 = .26 across individual patients) and on ICU days 2 to 7 (R2 = .26 across individual patients). The most important determinants of the number of blood samples drawn on ICU days 2 to 7 were the ICU day 1 Acute Physiology Score and admission diagnosis. After controlling for patient variables, hospital teaching status, number of beds, and location in the East and South were significantly (p < .05) associated with increased blood sampling on ICU day 2 and on ICU days 2 to 7. More frequent use of an arterial cannula and mechanical ventilation were also associated with increased blood sampling on subsequent days. CONCLUSIONS: The ability to adjust for patient and institutional variables and to predict the number of blood samples drawn for laboratory tests can allow ICUs to compare their practices with those of other units. When integrated into a continuous quality improvement process, this information can be used to identify and focus on opportunities for improving blood conservation and reducing excessive diagnostic testing.

Inositol 1,4,5-trisphosphate receptor expression in mammalian olfactory tissue.

Two cDNAs encoding inositol 1,4,5-trisphosphate (IP3) receptors were amplified from rat olfactory tissue, and both exhibited 100% sequence identity to the short (Segment II - ) variant of type I IP3 receptor. Type III IP3 receptor was also expressed in olfactory tissue. The distribution of IP3 receptors included the olfactory epithelium, lamina propria, and glandular tissue. These results demonstrate the co-expression of multiple IP3 receptor subtypes in olfactory cells, and suggest multiple functions for IP3 receptors in this tissue.

Cloning and characterization of two vertebrate homologs of the Drosophila eyes absent gene.

The Drosophila eyes absent (eya) gene plays an essential role in the events that lead to proper development of the fly eye and embryo. Here we report the analysis of two human and two mouse homologs of the fly eya gene. Sequence comparison reveals a large domain of approximately 270 amino acids in the carboxyl terminus of the predicted mammalian proteins that shows 53% identity between the fly sequence and all of the vertebrate homologs. This Eya-homology domain is of novel sequence, with no previously identified motifs. RNA hybridization studies indicate that the mouse genes are expressed during embryogenesis and in select tissues of the adult. Both mouse Eya genes are expressed in the eye, suggesting that these genes may function in eye development in vertebrates as eya does in the fly. The mouse Eya2 gene maps to chromosome 2 in the region syntenic with human chromosome 20q13, and the mouse Eya2 gene maps to chromosome 4 in the region syntenic with human chromosome 1p36. Our findings support the notion that several families of genes (Pax-6/eyeless, Six-3/sine oculis, and Eya) play related and critical roles in the eye for both files and vertebrates.

Variations in the use of do-not-resuscitate orders in ICUS. Findings from a national study.

STUDY OBJECTIVES: To describe the variation in frequency of do-not-resuscitate (DNR) orders in 42 US ICUs and to examine the relationship between published guidelines and qualitative observations about terminal care in 9 ICUs. DESIGN: Prospective inception cohort. SETTING: Forty-two ICUs in 40 US hospitals with more than 200 beds: 26 randomly selected and 14 large tertiary-care volunteers. PARTICIPANTS: A consecutive sample of 17,440 ICU admissions during 1988 to 1990. MEASUREMENTS AND RESULTS: We used age, race, comorbid conditions, disease, functional status, and acute physiology score on ICU day 1 to predict the likelihood of a DNR order for each patient. A cross-validated model was then used to predict variations in the risk of an ICU DNR order from 0 to 45% (area under receiver operating characteristic curve = 0.9). The model was then used to compare aggregate observed with predicted frequency of ICU DNR orders. Finally, we compared observations of DNR practices by a team of clinical and organizational researchers at 9 of the 42 ICUs with published guidelines and risk-adjusted DNR frequency: 1,577 admissions (9%) had DNR orders written in the ICU (range, 1.5 to 22%). The ICU site was a significant (p < 0.0001) predictor of variance in the patient level model. DNR orders were written significantly (p < 0.05) less frequently than predicted in 5 and more frequently than predicted in 3 of 42 ICUs. Nonwhite patients had significantly (p = 0.0001) fewer DNR orders after adjustment. The research team's implicit judgments following on-site analysis failed to distinguish ICUs with more or less DNR orders than predicted. Site-visited ICUs exhibited practices to emulate and practice to avoid. CONCLUSIONS: The frequency of ICU DNR orders can be predicted based on individual risk factors for groups of ICU patients. After adjusting for differences in patient characteristics, there is significant variation in the frequency of DNR orders in a national sample of ICUs. These variations may be due to unmeasured differences in patient characteristics such as treatment preferences, religious affiliation, educational level, or physician practices. We found no relationship between risk-adjusted DNR order frequency and adherence to published guidelines.

Planning patient services for intermediate care units: insights based on care for intensive care unit low-risk monitor admissions.

OBJECTIVE: To describe the technology and nursing services that would be required to care for intensive care unit (ICU) low-risk monitor admissions in an intermediate unit. DESIGN: Prospective, multicenter, inception cohort analysis. SETTING: Forty U.S. hospitals with > 200 beds, including 26 hospitals that were randomly selected and 14 that volunteered for the study. PATIENTS: A sample of 8,040 ICU patients admitted to the ICU for monitoring, who received no active life-support treatment on ICU day 1. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, physiologic, and treatment information were obtained during ICU days 1 to 7. A previously validated multivariate equation was used to identify 6,180 monitor admissions at low (< 10%) risk for receiving active treatment during their entire ICU stay. We used daily Therapeutic intervention Scoring System (TISS) data to identify the equipment, type and amount of nursing care, and the types of active treatment that would have been used had these ICU patients been admitted to an intermediate care unit. Mean day-1 ICU TISS scores were as follows: 16.4 for all patients; 18.3 for surgical patients; and 13.5 for medical admissions. Concentrated nursing care accounted for 89% and technologic monitoring for 11% of day-1 TISS points. Surgical admissions had a 2.8-day mean ICU length of stay and received an average of 16.5 TISS points per patient per day. Medical admissions had a 2.7-day mean ICU length of stay and received an average of 12.3 TISS points per patient per day. Subsequent active life-support therapy was received by 4.4% of these ICU low-risk monitor admissions. CONCLUSIONS: The services received by ICU low-risk monitor admissions provide insight regarding the equipment and nursing care that might be required, and the kinds of emergencies that might occur, if these patients were cared for in medical and surgical intermediate care units. Our data suggest that if ICU low-risk monitor patients were admitted to an intermediate care unit, they would mainly require concentrated nursing care (nurse/patient ratio of 1:3 to 1:4) and limited technologic monitoring.

A comparison of risks and outcomes for patients with organ system failure: 1982-1990.

OBJECTIVES: To compare the outcomes for patients with one or more organ system failures treated in 1988 to 1990 with those outcomes from 1979 to 1982; to document risk factors for developing organ system failure; and investigate the relationship of these factors to hospital survival. DESIGN: Prospective, multicenter, inception cohort analysis. SETTING: Sixty intensive care units (ICUs) at 53 U.S. hospitals. PATIENTS: A total of 17,440 ICU admissions treated in 1988 to 1990 and 5,677 ICU admissions treated in 1979 to 1982. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At the time of organ system failure, patients were classified by demographic, physiologic, and diagnostic information. The type and number of organ system failures and physiologic responses were recorded for < or = 7 days of ICU treatment, and all patients were followed for status at hospital discharge. Hospital survival and the prognostic value of assessing the number of organ system failures were compared with risk assessment, based on use of a prognostic scoring system that estimated the patient's probability of hospital mortality. The incidence of organ system failure (48%) among patients treated in 1988 to 1990 was similar (44%) to the occurrence rate in patients in 1979 to 1982; and an identical proportion (14%) developed multiple organ system failure. There was a significant (p < .0003) improvement in hospital mortality for patients with three or more organ system failures on day 4 or later of organ system failure. However, overall hospital mortality rates from multiple organ system failure were not different over this 8-yr period. The most important predictor of hospital mortality was the severity of physiologic disturbance on the initial day of failure. Discrimination of patients by risk of hospital mortality was better using the prognostic scoring system on day 1 of organ system failure (receiver operating characteristic curve = 0.88) than using a model based on the number of organ system failures (receiver operating characteristic curve = 0.68). CONCLUSIONS: Organ system failure remains a major contributor to death in patients in ICUs. The incidence and overall outcome have not significantly changed over the past 8 yrs, but there has been significant improvement in survival for patients with persistent severe organ system failure. A continuous measure of individual patient severity of illness is a more sensitive and accurate method for describing patients and estimating outcome than counting the number of organ system failures.

Reproducibility of MEG auditory evoked field source localizations in normal human subjects using a seven-channel gradiometer.

Magnetoencephalographic (MEG) auditory evoked fields (EF) were recorded from 12 normal adult subjects over both hemispheres on two separate occasions at least one week apart using a seven-channel second-order gradiometer. Stimuli were computer-generated at 25-msec duration, 1 kHz tone pips. Responses to 100 stimuli were averaged, and source estimates with confidence intervals were computed, for the 100-msec latency auditory EF component, termed M100. Root-mean-squared (rms) differences in x, y, and z locations were approximately 0.7 cm on the two occasions; strength and orientation differences were 18 nA-m and 11 degrees, respectively. This spatial accuracy using a seven-channel instrument, compares favorably with other currently available technologies for localization of brain function.

Predicting the duration of mechanical ventilation. The importance of disease and patient characteristics.

STUDY OBJECTIVE: To analyze the determinants of an individual patient's duration of mechanical ventilation and assess interhospital variations for average durations of ventilation. DESIGN: Prospective, multicenter, inception, cohort study. SETTING: Forty-two ICUs at 40 US hospitals. PATIENTS: A total of 5,915 patients undergoing mechanical ventilation on ICU day 1 selected from the acute physiology and chronic health evaluation (APACHE) III database of 17,440 admissions. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Utilizing APACHE III data collected on the 5,915 patients, multivariate regression analysis was performed on selected patients and disease characteristics to determine which variables were significantly associated with the duration of mechanical ventilation. An equation predicting duration of ventilation was then developed using the significant predictor variables and its accuracy was evaluated. Variables significantly associated with duration of ventilation included primary reason for ICU admission, day 1 acute physiology score (APS) of APACHE III, age, prior patient location and hospital length of stay, activity limits due to respiratory disease, serum albumin, respiratory rate, and PaO2/FIo2 measurements. Using an equation derived from these variables, predicted durations of ventilation were then calculated and compared with actual observed durations for each of the 42 ICUs. Average duration of ventilation for the 42 ICUs ranged from 2.6 to 7.9 days, but 60% of this variation was accounted for by differences in patient characteristics. CONCLUSIONS: For patients admitted to the ICU and ventilated on day 1, total duration of ventilation is primarily determined by admitting diagnosis and degree of physiologic derangement as measured by APS. An equation developed using multivariate regression techniques can accurately predict average duration of ventilation for groups of ICU patients, and we believe this equation will be useful for comparing ventilator practices between ICUs, controlling for patient differences in clinical trials of new therapies or weaning techniques, and as a quality improvement mechanism.