Associations between urinary 3-indoxyl sulfate, a gut microbiome-derived biomarker, and patient outcomes after intensive care unit admission.

PURPOSE: 3-indoxyl sulfate (3-IS) is an indole metabolism byproduct produced by commensal gut bacteria and excreted in the urine; low urinary 3-IS has been associated with increased mortality in bone marrow transplant recipients. This study investigated urinary 3-IS and patient outcomes in the ICU. MATERIALS AND METHODS: Prospective study that collected urine samples, rectal swabs, and clinical data on 78 adult ICU patients at admission and again 72 h later. Urine was analyzed for 3-IS by mass spectrometry. RESULTS: Median urinary 3-IS levels were 17.1 µmol/mmol creatinine (IQR 9.5 to 26.2) at admission and 15.6 (IQR 4.2 to 30.7) 72 h later. 22% of patients had low 3-IS (≤6.9 µmol/mmol) on ICU admission and 28% after 72 h. Low 3-IS at 72 h was associated with fewer ICU-free days (22.5 low versus 26 high, p = 0.03) and with death during one year of follow-up (36% low versus 9% high 3-IS, p < 0.01); there was no detectable difference in 30-day mortality (18% low versus 5% high, p = 0.07). CONCLUSIONS: Low urinary 3-IS level 72 h after ICU admission was associated with fewer ICU-free days and with increased one-year but not 30-day mortality. Further studies should investigate urinary 3-IS as an ICU biomarker.

The effect of short-course antibiotics on the resistance profile of colonizing gut bacteria in the ICU: a prospective cohort study.

BACKGROUND: The need for early antibiotics in the intensive care unit (ICU) is often balanced against the goal of antibiotic stewardship. Long-course antibiotics increase the burden of antimicrobial resistance within colonizing gut bacteria, but the dynamics of this process are not fully understood. We sought to determine how short-course antibiotics affect the antimicrobial resistance phenotype and genotype of colonizing gut bacteria in the ICU by performing a prospective cohort study with assessments of resistance at ICU admission and exactly 72 h later. METHODS: Deep rectal swabs were performed on 48 adults at the time of ICU admission and exactly 72 h later, including patients who did and did not receive antibiotics. To determine resistance phenotype, rectal swabs were cultured for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). In addition, Gram-negative bacterial isolates were cultured against relevant antibiotics. To determine resistance genotype, quantitative PCR (qPCR) was performed from rectal swabs for 87 established resistance genes. Within-individual changes in antimicrobial resistance were calculated based on culture and qPCR results and correlated with exposure to relevant antibiotics (e.g., did ß-lactam antibiotic exposure associate with a detectable change in ß-lactam resistance over this 72-h period?). RESULTS: Of 48 ICU patients, 41 (85%) received antibiotics. Overall, there was no increase in the antimicrobial resistance profile of colonizing gut bacteria during the 72-h study period. There was also no increase in antimicrobial resistance after stratification by receipt of antibiotics (i.e., no detectable increase in ß-lactam, vancomycin, or macrolide resistance regardless of whether patients received those same antibiotics). This was true for both culture and PCR. Antimicrobial resistance pattern at ICU admission strongly predicted resistance pattern after 72 h. CONCLUSIONS: Short-course ICU antibiotics made little detectable difference in the antimicrobial resistance pattern of colonizing gut bacteria over 72 h in the ICU. This provides an improved understanding of the dynamics of antimicrobial resistance in the ICU and some reassurance that short-course antibiotics may not adversely impact the stewardship goal of reducing antimicrobial resistance.

Impact of Fiber-Based Enteral Nutrition on the Gut Microbiome of ICU Patients Receiving Broad-Spectrum Antibiotics: A Randomized Pilot Trial.

OBJECTIVES: Dietary fiber increases the abundance of bacteria that metabolize fiber into short-chain fatty acids and confers resistance against gut colonization with multidrug-resistant bacteria. This pilot trial estimated the effect of fiber on gut short-chain fatty acid-producing bacteria in the ICU. DESIGN: Randomized, controlled, open label trial. SETTING: Medical ICU. PATIENTS: Twenty ICU adults receiving broad-spectrum IV antibiotics for sepsis. INTERVENTION: 1:1 randomization to enteral nutrition with mixed soy- and oat-derived fiber (14.3 g fiber/L) versus calorie- and micronutrient-identical enteral nutrition with 0 g/L fiber. MEASUREMENTS: Rectal swabs and whole stools were collected at baseline and on study Days 3, 7, 14, and 30. The primary outcome was within-individual change in the cumulative relative abundance of short-chain fatty acid-producing taxa from baseline to Day 3 based on 16S sequencing of rectal swabs. The secondary outcome was Day 3 cumulative short-chain fatty acid levels based on mass spectrometry of whole stools. Analyses were all intent to treat. MAIN RESULTS: By Day 3, the fiber group received a median of 32.1 g fiber cumulatively (interquartile range, 17.6-54.6) versus 0 g fiber (interquartile range, 0-4.0) in the no fiber group. The median within-individual change in short-chain fatty acid producer relative abundance from baseline to Day 3 was +61% (interquartile range -51 to +1,688) in the fiber group versus -46% (interquartile range, -78 to +13) in the no fiber group (p = 0.28). Whole stool short-chain fatty acid levels on Day 3 were a median of 707 µg short-chain fatty acids/g stool (interquartile range, 190-7,265) in the fiber group versus 118 µg short-chain fatty acids/g stool (interquartile range, 22-1,195) in the no fiber group (p = 0.16). CONCLUSIONS: Enteral fiber was associated with nonsignificant trends toward increased relative abundance of short-chain fatty acid-producing bacteria and increased short-chain fatty acid levels among ICU patients receiving broad-spectrum IV antibiotics. Larger studies should be undertaken and our results can be used for effect size estimates.

Reorganizing a Medicine Residency Program in Response to the COVID-19 Pandemic in New York.

The COVID-19 pandemic has been particularly severe in New York City, resulting in a rapid influx of patients into New York-Presbyterian Hospital/Columbia University Irving Medical Center. The challenges precipitated by this pandemic have required urgent changes to existing models of care. Internal medicine residents are at the forefront of caring for patients with COVID-19, including the critically ill. This article describes the exigent restructuring of the New York-Presbyterian Hospital/Columbia University Internal Medicine Residency Program. Patient care and educational models were fundamentally reconceptualized, which required a transition away from traditional hierarchical team structures and a significant expansion in the program's capacity and flexibility to care for large numbers of patients with disproportionately high levels of critical illness. These changes were made while the residency program maintained the priorities of patient care and safety, resident safety and well-being, open communication, and education. The process of adapting the residency program to the demands of the pandemic was iterative given the unprecedented nature of this crisis. The goal of this article is to share the experiences and lessons learned from this crisis, communicate the solutions that were designed, and inform others who may be facing the prospect of creating similar disaster response measures.

Relationship Between Dietary Fiber Intake and Short-Chain Fatty Acid-Producing Bacteria During Critical Illness: A Prospective Cohort Study.

BACKGROUND: Dietary fiber increases short-chain fatty acid (SCFA)-producing bacteria yet is often withheld in the intensive care unit (ICU). This study evaluated the safety and effect of fiber in ICU patients with gut microbiome sampling. METHODS: This was a retrospective study nested within a prospective cohort. Adults were included if newly admitted to the ICU and could receive oral nutrition, enteral feedings, or no nutrition. Rectal swabs were performed at admission and 72 hours later. The primary exposure was fiber intake over 72 hours, classified in tertiles and adjusted for energy intake. The primary outcome was the relative abundance (RA) of SCFA producers via 16S RNA sequencing and the tolerability of fiber. RESULTS: In 129 patients, median fiber intake was 13.4 g (interquartile range 0-35.4 g) over 72 hours. The high-fiber group had less abdominal distension (11% high fiber vs 28% no fiber, P < .01) and no increase in diarrhea (15% high fiber vs 13% no fiber, P = .94) or other adverse events. The median RA of SCFA producers after 72 hours was 0.40%, 0.50%, and 1.8% for the no-, low-, and high-fiber groups (P = .05 for trend). After correcting for energy intake, the median RA of SCFA producers was 0.41%, 0.32%, and 2.35% in the no-, low-, and high-corrected-fiber categories (P < .01). These associations remained significant after adjusting for clinical factors including antibiotics. CONCLUSIONS: During the 72 hours after ICU admission, fiber was well tolerated, and higher fiber intake was associated with more SCFA-producers.

Association Between State-Mandated Protocolized Sepsis Care and In-hospital Mortality Among Adults With Sepsis.

Importance: Beginning in 2013, New York State implemented regulations mandating that hospitals implement evidence-based protocols for sepsis management, as well as report data on protocol adherence and clinical outcomes to the state government. The association between these mandates and sepsis outcomes is unknown. Objective: To evaluate the association between New York State sepsis regulations and the outcomes of patients hospitalized with sepsis. Design, Setting, and Participants: Retrospective cohort study of adult patients hospitalized with sepsis in New York State and in 4 control states (Florida, Maryland, Massachusetts, and New Jersey) using all-payer hospital discharge data (January 1, 2011-September 30, 2015) and a comparative interrupted time series analytic approach. Exposures: Hospitalization for sepsis before (January 1, 2011-March 31, 2013) vs after (April 1, 2013-September 30, 2015) implementation of the 2013 New York State sepsis regulations. Main Outcomes and Measures: The primary outcome was 30-day in-hospital mortality. Secondary outcomes were intensive care unit admission rates, central venous catheter use, Clostridium difficile infection rates, and hospital length of stay. Results: The final analysis included 1 012 410 sepsis admissions to 509 hospitals. The mean age was 69.5 years (SD, 16.4 years) and 47.9% were female. In New York State and in the control states, 139 019 and 289 225 patients, respectively, were admitted before implementation of the sepsis regulations and 186 767 and 397 399 patients, respectively, were admitted after implementation of the sepsis regulations. Unadjusted 30-day in-hospital mortality was 26.3% in New York State and 22.0% in the control states before the regulations, and was 22.0% in New York State and 19.1% in the control states after the regulations. Adjusting for patient and hospital characteristics as well as preregulation temporal trends and season, mortality after implementation of the regulations decreased significantly in New York State relative to the control states (P = .02 for the joint test of the comparative interrupted time series estimates). For example, by the 10th quarter after implementation of the regulations, adjusted absolute mortality was 3.2% (95% CI, 1.0% to 5.4%) lower than expected in New York State relative to the control states (P = .004). The regulations were associated with no significant differences in intensive care unit admission rates (P = .09) (10th quarter adjusted difference, 2.8% [95% CI, -1.7% to 7.2%], P = .22), a significant relative decrease in hospital length of stay (P = .04) (10th quarter adjusted difference, 0.50 days [95% CI, -0.47 to 1.47 days], P = .31), a significant relative decrease in the C difficile infection rate (P < .001) (10th quarter adjusted difference, -1.8% [95% CI, -2.6% to -1.0%], P < .001), and a significant relative increase in central venous catheter use (P = .02) (10th quarter adjusted difference, 4.8% [95% CI, 2.3% to 7.4%], P < .001). Conclusions and Relevance: In New York State, mandated protocolized sepsis care was associated with a greater decrease in sepsis mortality compared with sepsis mortality in control states that did not implement sepsis regulations. Because baseline mortality rates differed between New York and comparison states, it is uncertain whether these findings are generalizable to other states.

Rapid gastrointestinal loss of Clostridial Clusters IV and XIVa in the ICU associates with an expansion of gut pathogens.

Commensal gastrointestinal bacteria resist the expansion of pathogens and are lost during critical illness, facilitating pathogen colonization and infection. We performed a prospective, ICU-based study to determine risk factors for loss of gut colonization resistance during the initial period of critical illness. Rectal swabs were taken from adult ICU patients within 4 hours of admission and 72 hours later, and analyzed using 16S rRNA gene sequencing and selective culture for vancomycin-resistant Enterococcus (VRE). Microbiome data was visualized using principal coordinate analyses (PCoA) and assessed using a linear discriminant analysis algorithm and logistic regression modeling. 93 ICU patients were analyzed. At 72 hours following ICU admission, there was a significant decrease in the proportion of Clostridial Clusters IV/XIVa, taxa that produce short chain fatty acids (SCFAs). At the same time, there was a significant expansion in Enterococcus. Decreases in Cluster IV/XIVa Clostridia were associated with loss of gut microbiome colonization resistance (reduced diversity and community stability over time). In multivariable analysis, both decreased Cluster IV/XIVa Clostridia and increased Enterococcus after 72 hours were associated with receipt of antibiotics. Cluster IV/XIVa Clostridia, although a small fraction of the overall gastrointestinal microbiome, drove distinct clustering on PCoA. During initial treatment for critical illness, there was a loss of Cluster IV/XIVa Clostridia within the distal gut microbiome which associated with an expansion of VRE and with a loss of gut microbiome colonization resistance. Receipt of broad-spectrum antibiotics was associated with these changes.

Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection.

PURPOSE: Loss of colonization resistance within the gastrointestinal microbiome facilitates the expansion of pathogens and has been associated with death and infection in select populations. We tested whether gut microbiome features at the time of intensive care unit (ICU) admission predict death or infection. METHODS: This was a prospective cohort study of medical ICU adults. Rectal surveillance swabs were performed at admission, selectively cultured for vancomycin-resistant Enterococcus (VRE), and assessed using 16S rRNA gene sequencing. Patients were followed for 30 days for death or culture-proven bacterial infection. RESULTS: Of 301 patients, 123 (41%) developed culture-proven infections and 76 (25%) died. Fecal biodiversity (Shannon index) did not differ based on death or infection (p = 0.49). The presence of specific pathogens at ICU admission was associated with subsequent infection with the same organism for Escherichia coli, Pseudomonas spp., Klebsiella spp., and Clostridium difficile, and VRE at admission was associated with subsequent Enterococcus infection. In a multivariable model adjusting for severity of illness, VRE colonization and Enterococcus domination (≥ 30% 16S reads) were both associated with death or all-cause infection (aHR 1.46, 95% CI 1.06-2.00 and aHR 1.47, 95% CI 1.00-2.19, respectively); among patients without VRE colonization, Enterococcus domination was associated with excess risk of death or infection (aHR 2.13, 95% CI 1.06-4.29). CONCLUSIONS: Enterococcus status at ICU admission was associated with risk for death or all-cause infection, and rectal carriage of common ICU pathogens predicted specific infections. The gastrointestinal microbiome may have a role in risk stratification and early diagnosis of ICU infections.

Efficient Simultaneous Reconstruction of Time-Varying Images and Electrode Contact Impedances in Electrical Impedance Tomography.

OBJECTIVE: In electrical impedance tomography (EIT), we apply patterns of currents on a set of electrodes at the external boundary of an object, measure the resulting potentials at the electrodes, and, given the aggregate dataset, reconstruct the complex conductivity and permittivity within the object. It is possible to maximize sensitivity to internal conductivity changes by simultaneously applying currents and measuring potentials on all electrodes but this approach also maximizes sensitivity to changes in impedance at the interface. METHODS: We have, therefore, developed algorithms to assess contact impedance changes at the interface as well as to efficiently and simultaneously reconstruct internal conductivity/permittivity changes within the body. We use simple linear algebraic manipulations, the generalized singular value decomposition, and a dual-mesh finite-element-based framework to reconstruct images in real time. We are also able to efficiently compute the linearized reconstruction for a wide range of regularization parameters and to compute both the generalized cross-validation parameter as well as the L-curve, objective approaches to determining the optimal regularization parameter, in a similarly efficient manner. RESULTS: Results are shown using data from a normal subject and from a clinical intensive care unit patient, both acquired with the GE GENESIS prototype EIT system, demonstrating significantly reduced boundary artifacts due to electrode drift and motion artifact.

Critical Care Beds and Resource Utilization: Current Trends and Controversies.

Recent studies have shown a dramatic increase in the number of intensive care unit (ICU) beds in recent decades. As technologies have become more complex, ICUs continue to grow in size and in specialization. The driving forces behind ICU bed expansion include not only the incorporation of advanced technologies but also other factors such as the increased utilization of ICU beds for patients who previously were not offered ICU care--those who may be terminally ill and those who are not critically ill. This expansion of ICU care in the United States sets it apart from other industrialized nations with comparably fewer ICU beds in relation to other hospital beds. The consequences of this expansion are now being felt in the form of unused beds, workforce shortages, and overuse of ICUs for patients who previously were not cared for in ICUs. ICUs are also now commonly used in the care of dying patients. In coming decades it is likely that changes will need to take place to forestall exorbitant costs and labor shortages. In addition to bringing in new forms of medical staff such as hospitalists and physician assistants, recent opinion papers have suggested that a de-escalation of ICU growth and a new tiered system of ICU care will be necessary in the United States.

Acute brain failure in severe sepsis: a prospective study in the medical intensive care unit utilizing continuous EEG monitoring.

PURPOSE: Investigate the prevalence, risk factors and impact of continuous EEG (cEEG) abnormalities on mortality through the 1-year follow-up period in patients with severe sepsis. METHODS: Prospective, single-center, observational study of consecutive patients admitted with severe sepsis to the Medical ICU at an academic medical center. RESULTS: A total of 98 patients with 100 episodes of severe sepsis were included; 49 patients (50%) were female, median age was 60 (IQR 52-74), the median non-neuro APACHE II score was 23.5 (IQR 18-28) and median non-neuro SOFA score was 8 (IQR 6-11). Twenty-five episodes had periodic discharges (PD), of which 11 had nonconvulsive seizures (NCS). No patient had NCS without PD. Prior neurological history was associated with a higher risk of PD or NCS (45 vs. 17%; CI 1.53-10.43), while the non-neuro APACHE II, non-neuro SOFA, severity of cardiovascular shock and presence of sedation during cEEG were associated with a lower risk of PD or NCS. Clinical seizures before cEEG were associated with a higher risk of nonconvulsive status epilepticus (24 vs. 6%; CI 1.42-19.94) while the non-neuro APACHE II and non-neuro SOFA scores were associated with a lower risk. Lack of EEG reactivity was present in 28% of episodes. In the survival analysis, a lack of EEG reactivity was associated with higher 1-year mortality [mean survival time 3.3 (95% CI 1.8-4.9) vs. 7.5 (6.4-8.7) months; p = 0.002] but the presence of PD or NCS was not [mean survival time 3.3 (95% CI 1.8-4.9) vs. 7.5 (6.4-8.7) months; p = 0.592]. Lack of reactivity was more frequent in patients on continuous sedation during cEEG. In patients with available 1-year data (34% of the episodes), 82% had good functional outcome (mRS ≤ 3, n = 27). There were no significant predictors of functional outcome, late cognition, and no patient with complete follow-up data developed late seizure or new epilepsy. CONCLUSIONS: NCS and PD are common in patients with severe sepsis and altered mental status. They were less frequent among the most severely sick patients and were not associated with outcome in this study. Lack of EEG reactivity was more frequent in patients on continuous sedation and was associated with mortality up to 1 year after discharge. Larger studies are needed to confirm these findings in a broader population and to further evaluate long-term cognitive outcome, risk of late seizure and epilepsy.

New cost-effective treatment strategies for acute emergency situations.

In an era of ever-increasing healthcare costs, new treatments must not only improve outcomes and quality of care but also be cost-effective. This is most challenging for emergency and critical care. Bigger and better has been the mantra of Western medical care for decades, leading to costlier but not necessarily better care. Recent advances focused on new implementation processes for evidence-based best practices such as checklists and bundles have transformed medical care. We outline recent advances in medical practice that have positively affected both the quality of care and its cost-effectiveness. Future medical care must be smarter and more effective if we are to meet the increasing demands of an aging patient population in the context of ever more limited resources.

ICU occupancy and mechanical ventilator use in the United States.

OBJECTIVES: Detailed data on occupancy and use of mechanical ventilators in U. S. ICU over time and across unit types are lacking. We sought to describe the hourly bed occupancy and use of ventilators in U.S. ICUs to improve future planning of both the routine and disaster provision of intensive care. DESIGN: Retrospective cohort study. We calculated mean hourly bed occupancy in each ICU and hourly bed occupancy for patients on mechanical ventilators. We assessed trends in overall occupancy over the 3 years. We also assessed occupancy and mechanical ventilation rates across different types and sizes of ICUs. SETTING: Ninety-seven U.S. ICUs participating in Project IMPACT from 2005 to 2007. PATIENTS: A total of 226,942 consecutive admissions to ICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over the 3 years studied, total ICU occupancy ranged from 57.4% to 82.1% and the number of beds filled with mechanically ventilated patients ranged from 20.7% to 38.9%. There was no change in occupancy across years and no increase in occupancy during influenza seasons. Mean hourly occupancy across ICUs was 68.2% ± 21.3% (SD) and was substantially higher in ICUs with fewer beds (mean, 75.8% ± 16.5% for 5-14 beds vs 60.9% ± 22.1% for 20+ beds, p = 0.001) and in academic hospitals (78.7% ± 15.9% vs 65.3% ± 21.3% for community not-for-profit hospitals, p < 0.001). More than half of ICUs (53.6%) had 4+ beds available more than half the time. The mean percentage of ICU patients receiving mechanical ventilation in any given hour was 39.5% (± 15.2%), and a mean of 29.0% (± 15.9%) of ICU beds were filled with a patient on a ventilator. CONCLUSIONS: Occupancy of U.S. ICUs was stable over time, but there is uneven distribution across different types and sizes of units. Only three of 10 beds were filled at any time with mechanically ventilated patients, suggesting substantial surge capacity throughout the system to care for acutely critically ill patients.

Evaluation of medication list completeness, safety, and annotations.

Clinical documents frequently contain a list of a patient's medications. Missing information about the dosage, route, or frequency of a medication impairs clinical communication and may harm patients. We examined 253 medication lists. There were 181 lists (72%) with at least one medication missing a dose, route, or frequency. Missing information was judged to be potentially harmful in 47 of the lists (19% of 253) by three physician reviewers (kappa=0.69). We also observed that many lists contained additional information included as annotations, prompting a secondary thematic analysis of the annotations. Fifty-five of the 253 lists (22%) contained one or more annotations. The most frequent types of annotations were comments about the patient's medical history, the clinician's treatment plan changes, and the patient's adherence to a medication. Future development of electronic medication reconciliation tools to improve medication list completeness should also support annotating the medication list in a flexible manner.

Reduction in hospital-wide mortality after implementation of a rapid response team: a long-term cohort study.

INTRODUCTION: Rapid response teams (RRTs) have been shown to reduce cardiopulmonary arrests outside the intensive care unit (ICU). Yet the utility of RRTs remains in question, as most large studies have failed to demonstrate a significant reduction in hospital-wide mortality after RRT implementation. METHODS: A cohort design with historical controls was used to determine the effect on hospital-wide mortality of an RRT in which clinical judgment, in addition to vital-signs criteria, was widely promoted as a key trigger for activation. All nonprisoner patients admitted to a tertiary referral public teaching hospital from 2003 through 2008 were included. In total, 77, 021 admissions before RRT implementation (2003 through 2005) and 79, 013 admissions after RRT implementation (2006 through 2008) were evaluated. The a priori primary outcome was unadjusted hospital-wide mortality. A Poisson regression model was then used to adjust for hospital-wide mortality trends over time. Secondary outcomes defined a priori were unadjusted out-of-ICU mortality and out-of-ICU cardiopulmonary-arrest codes. RESULTS: In total, 855 inpatient RRTs (10.8 per 1, 000 hospital-wide discharges) were activated during the 3-year postintervention period. Forty-seven percent of RRTs were activated for reasons of clinical judgment. Hospital-wide mortality decreased from 15.50 to 13.74 deaths per 1, 000 discharges after RRT implementation (relative risk, 0.887; 95% confidence interval (CI), 0.817 to 0.963; P = 0.004). After adjusting for inpatient mortality trends over time, the reduction in hospital-wide mortality remained statistically significant (relative risk, 0.825; 95% CI, 0.694 to 0.981; P = 0.029). Out-of-ICU mortality decreased from 7.08 to 4.61 deaths per 1, 000 discharges (relative risk, 0.651; 95% CI, 0.570 to 0.743; P < 0.001). Out-of-ICU cardiopulmonary-arrest codes decreased from 3.28 to 1.62 codes per 1, 000 discharges (relative risk, 0.493; 95% CI, 0.399 to 0.610; P < 0.001). CONCLUSIONS: Implementation of an RRT in which clinical judgment, in addition to vital-signs criteria, was widely cited as a rationale for activation, was associated with a significant reduction in hospital-wide mortality, out-of-ICU mortality, and out-of-ICU cardiopulmonary-arrest codes. The frequent use of clinical judgment as a criterion for RRT activation was associated with high RRT utilization.