Usability study of a new tool for nutritional and glycemic management in adult intensive care: Glucosafe 2.

The new decision support tool Glucosafe 2 (GS2) is based on a mathematical model of glucose and insulin dynamics, designed to assist caregivers in blood glucose control and nutrition. This study aims to assess end-user acceptance and usability of this bedside decision support tool in an adult intensive care setting. Caregivers were first trained and then invited to trial GS2 prototype on bedside computers. Data for qualitative analysis were collected through semi-structured interviews from twenty users after minimum three trial days. Most caregivers (70%) rated GS2 as convenient and believed it would help improving adherence to current guidelines (85%). Moreover, most nurses (80%) believed that GS2 would be timesaving. Nurses' risk perceptions and manual data entry emerged as central barriers to use GS2 in routine practice. Issues emerged from the caregivers were compiled into a list of 12 modifications of the GS2 prototype to increase end-user acceptance and usability. This usability study showed that GS2 was considered by ICU caregivers as helpful in daily clinical practice, allowing time-saving and better standardization of ICU patient's care. Important issues were raised by the users with implications for the development and deployment of GS2. Integrating the technology into existing IT infrastructure may facilitate caregivers' acceptance. Further clinical studies of the performance and potential health outcomes are warranted.

In vitro validation of indirect calorimetry device developed for the ICALIC project against mass spectrometry.

RATIONALE: Accurate evaluation of the energy needs is required to optimize nutrition support of critically ill patients. Recent evaluations of indirect calorimeters revealed significant differences among the devices available on the market. A new indirect calorimeter (Q-NRG®, Cosmed, Roma, Italy) has been developed by a group of investigators supporting the international calorimetry study initiative (ICALIC) to achieve ultimate accuracy for measuring energy expenditure while being easy to use, and affordable. This study aims to validate the precision and the accuracy of the Q-NRG® in the in-vitro setting, within the clinically relevant range for adults on mechanical ventilation in the ICU. Mass spectrometry is the reference method for the gas composition analysis to evaluate the analytic performances of the Q-NRG®. METHODS: The accuracy and precision of the O2 and CO2 measurements by the Q-NRG were evaluated by comparing the measurements of known O2 and CO2 gas mixtures with the measurements by the mass spectrometer (Extrel, USA). The accuracy and precision of the Q-NRG® for measurements of VO2 (oxygen consumption) and VCO2 (CO2 production) at clinically relevant ranges (150, 250 and 400 ml/min STPD) were evaluated by measuring simulated gas exchange under mechanically ventilated setting at different FiO2 settings (21-80%), in comparison to the reference measurements by the mass spectrometer-based mixing chamber system. RESULTS: The measurements of gas mixtures of predefined O2 and CO2 concentrations by the Q-NRG® were within 2% accuracy versus the mass spectrometer measurements in Passing Bablok regression analysis. In a mechanically ventilated setting of FiO2 from 21 up to 70%, the Q-NRG® measurements of simulated VO2 and VCO2 were within 5% difference of the reference mass spectrometer measurements. CONCLUSION: In vitro evaluation confirms that the accuracy of the Q-NRG® indirect calorimeter is within 5% at oxygen enrichment to 70%; i.e. maximum expected for clinical use. Further recommendations for the clinical use of the Q-NRG® by will be released once the ongoing multi-center study is completed.

Supplemental parenteral nutrition in intensive care patients: A cost saving strategy.

BACKGROUND & AIMS: The Swiss supplemental parenteral nutrition (SPN) study demonstrated that optimised energy provision combining enteral nutrition (EN) and SPN reduces nosocomial infections in critically ill adults who fail to achieve targeted energy delivery with EN alone. To assess the economic impact of this strategy, we performed a cost-effectiveness analysis using data from the SPN study. METHODS: Multivariable regression analyses were performed to characterise the relationships between SPN, cumulative energy deficit, nosocomial infection, and resource consumption. The results were used as inputs for a deterministic simulation model evaluating the cost-effectiveness of SPN administered on days 4-8 in patients who fail to achieve ≥60% of targeted energy delivery with EN by day 3. Cost data were derived primarily from Swiss diagnosis-related case costs and official labour statistics. RESULTS: Provision of SPN on days 4-8 was associated with a mean decrease of 2320 ± 338 kcal in cumulative energy deficit compared with EN alone (p < 0.001). Logistic regression analysis showed that each 1000 kcal decrease in cumulative energy deficit was associated with a 10% reduction in the risk of nosocomial infection (odds ratio 0.90; 95% confidence interval 0.83-0.99; p < 0.05). The incremental cost per avoided infection was -63,048 CHF, indicating that the reduction in infection was achieved at a lower cost. CONCLUSION: Optimisation of energy provision using SPN is a cost-saving strategy in critically ill adults for whom EN is insufficient to meet energy requirements.

Prescription and indication for oral nutritional supplements in a Swiss university hospital: a prospective survey.

AIMS OF THE STUDY: Patients with an acute or chronically negative nutritional balance are at nutritional risk. Oral nutritional supplements (ONS) are simple and effective medical treatments of nutritional risk. In the ambulatory setting, in Switzerland, ONS are reimbursed by public insurance under conditions defined by Swiss Society for Clinical Nutrition. The reimbursement requires a medical prescription for ONS and their delivery at the patient's home by a homecare service. The indication for the ONS, defined as a Nutritional Risk Screening-2002 (NRS-2002) score ≥3, must also be present. This survey aimed to document: (i) the existence of a medical prescription for ONS during hospitalisation and discharge for home, (ii) the adequacy of the indication for ONS during hospitalisation and at discharge for home, and (iii) the continuation or not of ONS treatment 1 month after discharge for home. METHODS: This prospective survey included adult patients hospitalised in the departments of surgery, medicine or rehabilitation and who were about to receive ONS for the first time. Patients already on ONS, with major consciousness disorders, who refused to take ONS or to participate to the survey were excluded. The existence of a medical prescription for ONS and the adequacy of the indication (Nutritional Risk Screening-2002 [NRS-2002] score ≥3) were evaluated at first ONS delivery and at hospital discharge. At home, the continuation of ONS consumption was evaluated by the homecare service 1 month after discharge. Results are presented as mean ± standard deviation or frequencies and percentages, and comparisons between patients with and without ONS at discharge for home. RESULTS: A total of 416 patients (age 71.7 ± 14.1 yr, 52.6% male, body mass index 23.6 ± 5.2 kg/m2) were included. At the first delivery of ONS, 44.5% (n = 185) of patients had no medical prescription for the supplements, and 82.7% (n = 344) had an NRS-2002 score ≥3. Out of 207 patients discharged for home, only 24.2% (n = 50) had an adequate homecare ONS prescription and 68% (n = 141) had a NRS-2002 score ≥3. One month after discharge for home, 76% (n = 29) were still taking ONS. CONCLUSIONS: In our survey, only few patients receiving ONS during the hospital stay had a medical prescription for ONS during the hospitalisation and at discharge for home. For most patients receiving ONS during hospitalisation and at discharge for home, an NRS-2002 score of ≥3 was present. If a medical prescription was provided, ONS were generally continued one month after discharge for home. CLINICAL TRIAL REGISTRATION NUMBER: NCT02476110.

Can proportional ventilation modes facilitate exercise in critically ill patients? A physiological cross-over study : Pressure support versus proportional ventilation during lower limb exercise in ventilated critically ill patients.

BACKGROUND: Early exercise of critically ill patients may have beneficial effects on muscle strength, mass and systemic inflammation. During pressure support ventilation (PSV), a mismatch between demand and assist could increase work of breathing and limit exercise. A better exercise tolerance is possible with a proportional mode of ventilation (Proportional Assist Ventilation, PAV+ and Neurally Adjusted Ventilatory Assist, NAVA). We examined whether, in critically ill patients, PSV and proportional ventilation have different effects on respiratory muscles unloading and work efficiency during exercise. METHODS: Prospective pilot randomized cross-over study performed in a medico-surgical ICU. Patients requiring mechanical ventilation >48 h were enrolled. At initiation, the patients underwent an incremental workload test on a cycloergometer to determine the maximum level capacity. The next day, 2 15-min exercise, at 60% of the maximum capacity, were performed while patients were randomly ventilated with PSV and PAV+ or NAVA. The change in oxygen consumption (ΔVO2, indirect calorimetry) and the work efficiency (ratio of ΔVO2 per mean power) were computed. RESULTS: Ten patients were examined, 6 ventilated with PSV/PAV+ and 4 with PSV/NAVA. Despite the same mean inspiratory pressure at baseline between the modes, baseline VO2 (median, IQR) was higher during proportional ventilation (301 ml/min, 270-342) compared to PSV (249 ml/min, 206-353). Exercise with PSV was associated with a significant increase in VO2 (ΔVO2, median, IQR) (77.6 ml/min, 59.9-96.5), while VO2 did not significantly change during exercise with proportional modes (46.3 ml/min, 5.7-63.7, p < 0.05). As a result, exercise with proportional modes was associated with a better work efficiency than with PSV. The ventilator modes did not affect patient's dyspnea, limb fatigue, distance, hemodynamics and breathing pattern. CONCLUSIONS: Proportional ventilation during exercise results in higher work efficiency and less increase in VO2 compared to ventilation with PSV. These preliminary findings suggest that proportional ventilation could enhance the training effect and facilitate rehabilitation.

Can calculation of energy expenditure based on CO2 measurements replace indirect calorimetry?

BACKGROUND: Methods to calculate energy expenditure (EE) based on CO2 measurements (EEVCO2) have been proposed as a surrogate to indirect calorimetry. This study aimed at evaluating whether EEVCO2 could be considered as an alternative to EE measured by indirect calorimetry. METHODS: Indirect calorimetry measurements conducted for clinical purposes on 278 mechanically ventilated ICU patients were retrospectively analyzed. EEVCO2 was calculated by a converted Weir's equation using CO2 consumption (VCO2) measured by indirect calorimetry and assumed respiratory quotients (RQ): 0.85 (EEVCO2_0.85) and food quotient (FQ; EEVCO2_FQ). Mean calculated EEVCO2 and measured EE were compared by paired t test. Accuracy of EEVCO2 was evaluated according to the clinically relevant standard of 5% accuracy rate to the measured EE, and the more general standard of 10% accuracy rate. The effects of the timing of measurement (before or after the 7th ICU day) and energy provision rates (<90 or ≥90% of EE) on 5% accuracy rates were also analyzed (chi-square tests). RESULTS: Mean biases for EEVCO2_0.85 and EEVCO2_FQ were -21 and -48 kcal/d (p = 0.04 and 0.00, respectively), and 10% accuracy rates were 77.7 and 77.3%, respectively. However, 5% accuracy rates were 46.0 and 46.4%, respectively. Accuracy rates were not affected by the timing of the measurement, or the energy provision rates at the time of measurements. CONCLUSIONS: Calculated EE based on CO2 measurement was not sufficiently accurate to consider the results as an alternative to measured EE by indirect calorimetry. Therefore, EE measured by indirect calorimetry remains as the gold standard to guide nutrition therapy.

Energy expenditure in mechanically ventilated patients: The weight of body weight!

BACKGROUND & AIMS: Optimal nutritional care for intensive care unit (ICU) patients requires precise determination of energy expenditure (EE) to avoid deleterious under- or overfeeding. The reference method, indirect calorimetry (IC), is rarely accessible and inconstantly feasible. Various equations for predicting EE based on body weight (BW) are available. This study aims at determining the best prediction strategy unless IC is available. METHODS: Mechanically ventilated patients staying ≥72 h in the ICU were included, except those with contraindications for IC measurements. IC and BW measurements were routinely performed. EE was predicted by the ESPEN formula and other predictive equations using BW (i.e. anamnestic (AN), measured (MES), adjusted for cumulated water balance (ADJ), calculated for a body mass index (BMI) of 22.5). Comparisons were made using Pearson correlation and Bland & Altman plots. RESULTS: 85 patients (57 ± 19 y, 61 men, SAPS II 43 ± 16) were included. Correlations between IC and predicted EE using the ESPEN formula with different BW (BWAN, BWMES, BWADJ, and BWBMI22.5) were 0.44, 0.40, 0.36, and 0.47, respectively. Bland & Altman plots showed wide and inconsistent variations. Predictive equations including body temperature and minute ventilation showed the best correlations, but when using various BWs, differences in predicted EE were observed. CONCLUSION: No EE predictive equation, regardless of the BW used, gives statistically identical results to IC. If IC cannot be performed, predictive equations including minute ventilation and body temperature should be preferred. BW has a significant impact on estimated EE and the use of measured BWMES or BW BMI 22.5 is associated with the best EE prediction. Clinical trial registration number on ClinicalTrial.gov: NCT02552446. Ethical committee number: CE-14-070.

Methods to validate the accuracy of an indirect calorimeter in the in-vitro setting.

INTRODUCTION: The international ICALIC initiative aims at developing a new indirect calorimeter according to the needs of the clinicians and researchers in the field of clinical nutrition and metabolism. The project initially focuses on validating the calorimeter for use in mechanically ventilated acutely ill adult patient. However, standard methods to validate the accuracy of calorimeters have not yet been established. This paper describes the procedures for the in-vitro tests to validate the accuracy of the new indirect calorimeter, and defines the ranges for the parameters to be evaluated in each test to optimize the validation for clinical and research calorimetry measurements. METHODS: Two in-vitro tests have been defined to validate the accuracy of the gas analyzers and the overall function of the new calorimeter. 1) Gas composition analysis allows validating the accuracy of O2 and CO2 analyzers. Reference gas of known O2 (or CO2) concentration is diluted by pure nitrogen gas to achieve predefined O2 (or CO2) concentration, to be measured by the indirect calorimeter. O2 and CO2 concentrations to be tested were determined according to their expected ranges of concentrations during calorimetry measurements. 2) Gas exchange simulator analysis validates O2 consumption (VO2) and CO2 production (VCO2) measurements. CO2 gas injection into artificial breath gas provided by the mechanical ventilator simulates VCO2. Resulting dilution of O2 concentration in the expiratory air is analyzed by the calorimeter as VO2. CO2 gas of identical concentration to the fraction of inspired O2 (FiO2) is used to simulate identical VO2 and VCO2. Indirect calorimetry results from publications were analyzed to determine the VO2 and VCO2 values to be tested for the validation. RESULTS: O2 concentration in respiratory air is highest at inspiration, and can decrease to 15% during expiration. CO2 concentration can be as high as 5% in expired air. To validate analyzers for measurements of FiO2 up to 70%, ranges of O2 and CO2 concentrations to be tested were defined as 15-70% and 0.5-5.0%, respectively. The mean VO2 in 426 adult mechanically ventilated patients was 270 ml/min, with 2 standard deviation (SD) ranges of 150-391 ml/min. Thus, VO2 and VCO2 to be simulated for the validation were defined as 150, 250, and 400 ml/min. CONCLUSION: The procedures for the in-vitro tests of the new indirect calorimeter and the ranges for the parameters to be evaluated in each test have been defined to optimize the validation of accuracy for clinical and research indirect calorimetry measurements. The combined methods will be used to validate the accuracy of the new indirect calorimeter developed by the ICALIC initiative, and should become the standard method to validate the accuracy of any future indirect calorimeters.

The burden of diarrhea in the intensive care unit (ICU-BD). A survey and observational study of the caregivers' opinions and workload.

BACKGROUND: Diarrhea as a common complication affects 14% patients in our intensive care unit. Risk factors for diarrhea and its clinical consequences for patients are well known, but the impact of diarrhea on caregivers' workload remains undocumented. OBJECTIVES: This study aims at establishing the impact of diarrhea on costs and human burden in intensive care unit caregivers. DESIGN: A survey and observational study. SETTINGS: A mixed 36-bed medical and surgical intensive care unit. PARTICIPANTS: All intensive care unit caregivers (nurses and nursing aides). METHODS: A questionnaire was designed by a multidisciplinary team and completed by intensive care unit caregivers analyzing the clinical and human impact of diarrhea on their workload. Time measurements for the management of liquid stools were performed. Human related costs of diarrhea were analyzed according to caregivers' years of clinical experience. RESULTS: Questionnaires were completed by 146 of 204 intensive care unit caregivers (75% nurses; 73% nursing aides). Dealing with diarrhea patients is a painful aspect of their work (69% nurses) with tiredness as main feeling and a source of conflict or misunderstanding among caregivers. The mean time measurement for managing one liquid stool in 50 diarrhea episodes was 17min and 33s, involving an average of 1.4 nurses and 0.8 nursing aides. Average human resources cost burden was 26.60 CHF per liquid stool. CONCLUSION: Dealing with diarrhea increases workload for intensive care unit caregivers with consequences on their well-being. Human related costs of diarrhea are substantial and highlight the economic burden of diarrhea episodes in the intensive care unit. A multidisciplinary approach and specific protocols could positively impact the burden of diarrhea in the intensive care unit. TRIAL REGISTRATION: Clinical Trials gov NCT01922570.

Evaluation of three indirect calorimetry devices in mechanically ventilated patients: which device compares best with the Deltatrac II(®)? A prospective observational study.

BACKGROUND & AIMS: Indirect calorimetry (IC) is the gold standard to measure energy expenditure (EE) in hospitalized patients. The popular 30 year-old Deltatrac II(®) (Datex) IC is no more commercialized, but other manufacturers have developed new devices. This study aims at comparing for the first time simultaneously, two new IC, the CCM express(®) (Medgraphics) and the Quark RMR(®) (Cosmed) with the Deltatrac II(®) to assess their potential use in intensive care unit (ICU) patients. METHODS: ICU patients on mechanical ventilation, with positive end-expiratory pressure <9 cm H2O and fraction of inspired oxygen <60%, underwent measurements by the three IC simultaneously connected during 20 min to the ventilator (Evita XL(®), Dräger). Patients' characteristics, VO2 consumption, VCO2 production, respiratory quotient and EE were recorded. Data were presented as mean (SD) and compared by linear regression, repeated measure one-way ANOVA and Bland & Altman diagrams. RESULTS: Forty patients (23 males, 60(17) yrs, BMI 25.4(7.0) kg/m(2)) were included. For the Deltatrac II(®), VO2 was 227(61) ml/min, VCO2 189(52) ml/min and EE 1562(412) kcal/d. VO2, VCO2, and EE differed significantly between Deltatrac II(®) and CCM express(®) (p < 0.001), but not between Deltatrac II(®) and Quark RMR(®). For EE, diagrams showed a mean difference (2SD) of 25.2(441) kcal between Deltatrac II(®) vs. the Quark RMR(®), and -273 (532) kcal between Deltatrac II(®) vs CCM express(®). CONCLUSION: Quark RMR(®) compares better with Deltatrac II(®) than CCM express(®), but it suffers an EE variance of 441 kcal, which is not acceptable for clinical practice. New indirect IC should be further improved before recommending their clinical use in ICU.

Comparison of three indirect calorimetry devices and three methods of gas collection: a prospective observational study.

BACKGROUND & AIMS: Indirect calorimetry was performed for a long time with the DeltatracII(®) device (Datex, Finland), considered as a reference but no longer produced. This study aims at comparing the energy expenditure (EE), the volume of oxygen (VO2) and carbon dioxide (VCO2) measured by two new available indirect calorimeters, the QuarkRMR(®) (Cosmed, Italy) and the CCMexpress(®) (MedGraphic,USA), using three different methods of gas collection, with the DeltatracII(®) in healthy subjects. METHODS: Twenty-four healthy subjects (15 women and 9 men, age 53 ± 15 yrs, mean BMI 25.5 ± 7.1 kg/m(2)) underwent measurements of EE with DeltatracII(®) using canopy, QuarkRMR(®) using canopy and CCMexpress(®) using canopy, face tent and facemask. All measurements were performed for 10 min in random order. Results are presented as mean ± SD and compared by linear regression, repeated measure one-way ANOVA with Bonferroni's post hoc test and Bland & Altman test. RESULTS: EE was 1630 ± 340 kcal for DeltatracII(®) and 1607 ± 307 kcal, 1741 ± 360 kcal, 1666 ± 315 and 1626 ± 336 kcal for QuarkRMR(®) and CCMexpress(®) with canopy, face tent and facemask, respectively (p = 0.001). Compared to DeltatracII(®), Bland & Altman test showed a mean EE difference (2SD) of 24(220)kcal for QuarkRMR(®), and -111(260) kcal, -36(304) kcal, 5(402) kcal for CCMexpress(®) with canopy, face tent and facemask, respectively. There was no systematic over- or underestimation with any device or gas collection method. CONCLUSION: Mean EE was similar between QuarkRMR(®) and DeltatracII(®) but not between CCMexpress(®), in any mode of gas collection, and DeltatracII(®). Bland & Altman test shows a large variability in EE differences with both devices compared to DeltatracII(®), highlighting the need for refining their accuracy.

Diarrhoea in the ICU: respective contribution of feeding and antibiotics.

INTRODUCTION: Diarrhoea is frequently reported in the ICU. Little is known about diarrhoea incidence and the role of the different risk factors alone or in combination. This prospective observational study aims at determining diarrhoea incidence and risk factors in the first 2 weeks of ICU stay, focusing on the respective contribution of feeding, antibiotics, and antifungal drugs. METHODS: Out of 422 patients consecutively admitted into a mixed medical-surgical ICU during a 2-month period, 278 patients were included according to the following criteria: ICU stay >24 hours, no admission diagnosis of gastrointestinal bleeding, and absence of enterostomy or colostomy. Diarrhoea was defined as at least three liquid stools per day. Diarrhoea episodes occurring during the first day in the ICU, related to the use of laxative drugs or Clostridium difficile infection, were not analysed. Multivariate and stratified analyses were performed to determine diarrhoea risk factors, and the impact of the combination of enteral nutrition (EN) with antibiotics or antifungal drugs. RESULTS: A total of 1,595 patient-days were analysed. Diarrhoea was observed in 38 patients (14%) and on 83 patient-days (incidence rate: 5.2 per 100 patient-days). The median day of diarrhoea onset was the sixth day, and 89% of patients had ≤4 diarrhoea days. The incidence of C. difficile infection was 0.7%. Diarrhoea risk factors were EN covering >60% of energy target (relative risk = 1.75 (1.02 to 3.01)), antibiotics (relative risk = 3.64 (1.26 to 10.51)) and antifungal drugs (relative risk = 2.79 (1.16 to 6.70)). EN delivery per se was not a diarrhoea risk factor. In patients receiving >60% of energy target by EN, diarrhoea risk was increased by the presence of antibiotics (relative risk = 4.8 (2.1 to 13.7)) or antifungal drugs (relative risk = 5.0 (2.8 to 8.7)). CONCLUSION: Diarrhoea incidence during the first 2 weeks in a mixed population of patients in a tertiary ICU is 14%. Diarrhoea risk factors are EN covering >60% of energy target, use of antibiotics, and use of antifungal drugs. The combination of EN covering >60% of energy target with antibiotics or antifungal drugs increases the incidence of diarrhoea.

Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial.

BACKGROUND: Enteral nutrition (EN) is recommended for patients in the intensive-care unit (ICU), but it does not consistently achieve nutritional goals. We assessed whether delivery of 100% of the energy target from days 4 to 8 in the ICU with EN plus supplemental parenteral nutrition (SPN) could optimise clinical outcome. METHODS: This randomised controlled trial was undertaken in two centres in Switzerland. We enrolled patients on day 3 of admission to the ICU who had received less than 60% of their energy target from EN, were expected to stay for longer than 5 days, and to survive for longer than 7 days. We calculated energy targets with indirect calorimetry on day 3, or if not possible, set targets as 25 and 30 kcal per kg of ideal bodyweight a day for women and men, respectively. Patients were randomly assigned (1:1) by a computer-generated randomisation sequence to receive EN or SPN. The primary outcome was occurrence of nosocomial infection after cessation of intervention (day 8), measured until end of follow-up (day 28), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00802503. FINDINGS: We randomly assigned 153 patients to SPN and 152 to EN. 30 patients discontinued before the study end. Mean energy delivery between day 4 and 8 was 28 kcal/kg per day (SD 5) for the SPN group (103% [SD 18%] of energy target), compared with 20 kcal/kg per day (7) for the EN group (77% [27%]). Between days 9 and 28, 41 (27%) of 153 patients in the SPN group had a nosocomial infection compared with 58 (38%) of 152 patients in the EN group (hazard ratio 0·65, 95% CI 0·43-0·97; p=0·0338), and the SPN group had a lower mean number of nosocomial infections per patient (-0·42 [-0·79 to -0·05]; p=0·0248). INTERPRETATION: Individually optimised energy supplementation with SPN starting 4 days after ICU admission could reduce nosocomial infections and should be considered as a strategy to improve clinical outcome in patients in the ICU for whom EN is insufficient. FUNDING: Foundation Nutrition 2000Plus, ICU Quality Funds, Baxter, and Fresenius Kabi.