The opportunity cost of futile treatment in the ICU*.

OBJECTIVE: When used to prolong life without achieving a benefit meaningful to the patient, critical care is often considered "futile." Although futile treatment is acknowledged as a misuse of resources by many, no study has evaluated its opportunity cost, that is, how it affects care for others. Our objective was to evaluate delays in care when futile treatment is provided. DESIGN: For 3 months, we surveyed critical care physicians in five ICUs to identify patients that clinicians identified as receiving futile treatment. We identified days when an ICU was full and contained at least one patient who was receiving futile treatment. For those days, we evaluated the number of patients waiting for ICU admission more than 4 hours in the emergency department or more than 1 day at an outside hospital. SETTING: One health system that included a quaternary care medical center and an affiliated community hospital. PATIENTS: Critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Boarding time in the emergency department and waiting time on the transfer list. Thirty-six critical care specialists made 6,916 assessments on 1,136 patients of whom 123 were assessed to receive futile treatment. A full ICU was less likely to contain a patient receiving futile treatment compared with an ICU with available beds (38% vs 68%, p < 0.001). On 72 (16%) days, an ICU was full and contained at least one patient receiving futile treatment. During these days, 33 patients boarded in the emergency department for more than 4 hours after admitted to the ICU team, nine patients waited more than 1 day to be transferred from an outside hospital, and 15 patients canceled the transfer request after waiting more than 1 day. Two patients died while waiting to be transferred. CONCLUSIONS: Futile critical care was associated with delays in care to other patients.

Factors associated with palliative withdrawal of mechanical ventilation and time to death after withdrawal.

BACKGROUND: In imminently dying patients, mechanical ventilation withdrawal is often a comfort measure and avoids prolonging the dying process. OBJECTIVE: The aim of the study was to identify factors associated with palliative withdrawal of mechanical ventilation and time to death after extubation. METHODS: Logistic regression models were used to identify factors associated with palliative withdrawal of mechanical ventilation. Cox proportional hazards models were used to determine factors associated with time to death after extubation. We retrospectively evaluated 322 patients who died on mechanical ventilation or after palliative ventilator withdrawal at a single tertiary care center. RESULTS: Of the 322 ventilated deaths, 159 patients had palliative withdrawal of mechanical ventilation and 163 patients died on the ventilator. Clinical service was associated with palliative withdrawal of mechanical ventilation: Patients withdrawn from the ventilator were less likely to be on the surgery service and more likely to be on the neurology/neurosurgical service. The median time to death was 0.9 hours (range 0-165 hours). Fraction of inspired oxygen (FIO2) greater than 70% (hazard ratio [HR] 1.92, 95% confidence interval [CI ]1.24-2.99) and a requirement for vasopressors (HR 2.06, 95% CI 1.38-3.09) were associated with shorter time to death. Being on the neurology/neurosurgical service at the time of ventilator withdrawal was associated with a longer time to death (HR 0.60, 95% CI 0.39-0.92). CONCLUSIONS: Palliative withdrawal of mechanical ventilation was performed in only half of dying mechanically ventilated patients. Because clinical service rather than physiologic parameters are associated with withdrawal, targeted interventions may improve withdrawal decisions. Considering FIO2 and vasopressor requirements may facilitate counseling families about anticipated time to death.

The frequency and cost of treatment perceived to be futile in critical care.

IMPORTANCE: Physicians often perceive as futile intensive care interventions that prolong life without achieving an effect that the patient can appreciate as a benefit. The prevalence and cost of critical care perceived to be futile have not been prospectively quantified. OBJECTIVE: To quantify the prevalence and cost of treatment perceived to be futile in adult critical care. DESIGN, SETTING, AND PARTICIPANTS: To develop a common definition of futile care, we convened a focus group of clinicians who care for critically ill patients. On a daily basis for 3 months, we surveyed critical care specialists in 5 intensive care units (ICUs) at an academic health care system to identify patients whom the physicians believed were receiving futile treatment. Using a multivariate model, we identified patient and clinician characteristics associated with patients perceived to be receiving futile treatment. We estimated the total cost of futile treatment by summing the charges of each day of receiving perceived futile treatment and converting to costs. MAIN OUTCOME AND MEASURE: Prevalence of patients perceived to be receiving futile treatment. RESULTS: During a 3-month period, there were 6916 assessments by 36 critical care specialists of 1136 patients. Of these patients, 904 (80%) were never perceived to be receiving futile treatment, 98 (8.6%) were perceived as receiving probably futile treatment, 123 (11%) were perceived as receiving futile treatment, and 11 (1%) were perceived as receiving futile treatment only on the day they transitioned to palliative care. The patients with futile treatment assessments received 464 days of treatment perceived to be futile in critical care (range, 1-58 days), accounting for 6.7% of all assessed patient days in the 5 ICUs studied. Eighty-four of the 123 patients perceived as receiving futile treatment died before hospital discharge and 20 within 6 months of ICU care (6-month mortality rate of 85%), with survivors remaining in severely compromised health states. The cost of futile treatment in critical care was estimated at $2.6 million. CONCLUSIONS AND RELEVANCE: In 1 health system, treatment in critical care that is perceived to be futile is common and the cost is substantial.

Prognostic factors and outcomes of patients with pulmonary hypertension admitted to the intensive care unit.

PURPOSE: Patients with pulmonary hypertension (PH) can decompensate to the point where they require care in the intensive care unit (ICU). Our objective is to examine the outcomes and characteristics of patients with PH admitted to the ICU. METHODS: This is a retrospective study of 99 patients with PH who were admitted to the medical ICU of a single tertiary care center. Baseline characteristics, interventions during ICU admission, and ICU and 6-month outcome were documented. Univariate and multivariate logistic regressions were used to evaluate association of patient characteristics with mortality. RESULTS: Intensive care unit mortality was 30%, and 6-month mortality was 40%. Acute Physiology and Chronic Health Evaluation II score, World Health Organization Group 3 PH, and preexisting treatment with a prostacyclin at time of ICU admission were associated with worse outcome. Patients who received cardiopulmonary resuscitation had 100% mortality. The requirement for mechanical ventilation and dialysis was also associated with increased mortality. Pulmonary artery catheter placement was associated with reduced mortality, specifically if it was placed early during ICU admission and if associated with a change in the present management. CONCLUSIONS: Mortality is high in critically ill patients with PH. The identification of prognostic baseline characteristics and interventions in the ICU is important and warrants further investigation.

Fusion of concentrically layered tubular tissue constructs increases burst strength.

Tubular tissue constructs prepared from neonatal human dermal fibroblasts entrapped in fibrin gel were incubated on a mandrel for three weeks to allow for initial fibrin remodeling into tissue before being concentrically layered and incubated for an additional three weeks on the mandrel. Upon harvest, double layer constructs were not statistically different from single layer control constructs in terms of length, collagen density, cell density, tensile modulus, or ultimate tensile strength. However, the thickness and burst pressure were both approximately twice the single layer control values. Metabolically active cells were detected at the interface, and scanning electron microscopy revealed fiber structures bridging the two layers, co-localizing with the cells, which exhibited minimal migration across the layers. In contrast, double layer constructs where tissue fusion was prohibited by mechanical distraction of the layers showed no increase in burst pressure despite having increased thickness and the same collagen and cell densities of the single layer control constructs; moreover, the burst failure occurred sequentially in the layers in contrast to simultaneous failure for the fused double layer constructs. This study provides insight into the nature of the interface and the role of cell behavior when tissue fusion occurs between two layers of bioartificial tissue in vitro. It also suggests a method for improving the burst strength of fibrin-based tubular tissue constructs by increasing the construct thickness via concentrically layering and fusing two constructs.

Fibronectin-based isolation of valve interstitial cell subpopulations: relevance to valve disease.

Myxomatous mitral valves (MVs) contain elevated proportions of unique cell populations such as myofibroblasts. Without a reliable technique to isolate such cell populations, however, it has been difficult to study the role of these cells. The goal of this study was to use fibronectin (FN) to isolate distinct cell subpopulations from normal porcine MVs. Cells from porcine posterior MV leaflets were separated based on time-dependent adhesion to either tissue culture plastic (TCP) flasks or FN-coated flasks. The resultant "FAST" and "SLOW" adhering subpopulations from each technique were phenotyped using flow cytometry and immunocytochemistry to detect expression of myofibroblast markers, enzymes for collagen synthesis, and MAP kinases. Compared with FN SLOW, FN FAST showed significantly higher expression of prolyl 4-hydroxylase, heat shock protein-47 (HSP47), smooth muscle alpha-actin (SMalphaA), nonmuscle myosin (Smem), extracellular-related signaling kinase (ERK) 1, ERK2, and phosphorylated-ERK. In contrast, TCP FAST showed higher expression of only HSP47, SMalphaA, and Smem compared with TCP SLOW. In conclusion, differential adhesion to FN successfully separated a myofibroblast-like subpopulation from the posterior leaflet of the MV. This subpopulation may be useful in studying myxomatous MV disease, although additional studies remain to verify that this myofibroblast-like population resembles that observed in myxomatous MV disease.

Outcome and prognostic indicators of patients with hematopoietic stem cell transplants admitted to the intensive care unit.

The prognosis of patients with hematopoietic stem cell transplants (HSCTs) who require admission to the intensive care unit (ICU) has been regarded as extremely poor. We sought to re-evaluate recent outcomes and predictive factors in a retrospective cohort study. Among the 605 adult patients that received an HSCT between 2001 and 2006, 154 required admission to the ICU. Of these, 47% were discharged from the ICU, 36% were discharged from the hospital, and 19% survived 6 months. Allogeneic transplant, mechanical ventilation, vasopressor-use, and neutropenia were each associated with increased mortality, and the mortality of patients with all four characteristics was 100%. Hemodialysis was also associated with increased mortality in a Kaplan-Meier analysis but did not appear important in a multivariate tree analysis. A final Cox model confirmed that allogeneic transplant, mechanical ventilation, and vasopressor-use were each independent risk factors for mortality in the 6 months following ICU admission.

Mitral valvular interstitial cells demonstrate regional, adhesional, and synthetic heterogeneity.

BACKGROUND/AIMS: Because various regions of the mitral valve contain distinctive extracellular matrix enabling the tissues to withstand diverse mechanical environments, we investigated phenotype and matrix production of porcine valvular interstitial cells (VICs) from different regions. METHODS: VICswere isolated from the chordae (MCh), the center of the anterior leaflet (AlCtr), and the posterior leaflet free edge (PlFree), then assayed for metabolic, growth, and adhesion rates; collagen and glycosaminoglycan (GAG) production, and phenotype using biochemical assays, flow cytometry, and immunocytochemistry. RESULTS: The AlCtr VICs exhibited the fastest metabolism but slowest growth. PlFree cells grew the fastest, but demonstrated the least smooth muscle alpha-actin, vimentin, and internal complexity. AlCtr VICs secreted less collagen into the culture medium but more 4-sulfated GAGs than other cells. Adhesion-based separation resulted in altered secretion of sulfated GAGs by MCh and AlCtr cells but not by the PlFree cells. CONCLUSIONS: VICs isolated from various regions of the mitral valve demonstrate phenotypic differences in culture, corresponding to the ability of the mitral valve to accommodate the physical stresses or altered hemodynamics that occur with injury or disease. Further understanding of VIC and valve mechanobiology could lead to novel medical or tissue engineering approaches to treat valve diseases.

Effects of venous needle turbulence during ex vivo hemodialysis on endothelial morphology and nitric oxide formation.

Arteriovenous grafts used for hemodialysis frequently develop intimal hyperplasia (IH), which ultimately leads to graft failure. Although the turbulent jet from the dialysis needle may contribute to vessel wall injury, its role in the pathogenesis of IH is relatively unexplored. In the current study, using bovine aortic endothelial cells (BAEC) cultured on the inner surface of a compliant tube, we evaluated the effects of simulated hemodialysis conditions on morphology and nitric oxide (NO) production. The flows via the graft and needle were 500 ml/min (Reynolds number=819) and 100ml/min (Reynolds number=954), respectively. In the presence of the needle jet for 6h, 19.3% (+/-1.53%) of BAEC were sheared off, whereas no loss of BAEC was observed in the presence of graft flow alone (P<0.05). In the presence of graft flow alone, assessment of cell orientation by the Saltykov method revealed that BAEC were oriented along the flow direction. This alignment, however, was lost in the presence of needle flow. Finally, NO production was also significantly decreased in the presence of the needle flow compared to the presence of graft flow alone (16+/-3.1 vs 34.7+/-1.9 nmol/10(6)cells/h, P<0.05). NO is a key player in vascular homeostasis mechanisms modulating vasomotor tone, inhibiting inflammation and smooth muscle cell proliferation. Thus, the loss of NO signaling and the loss of endothelial integrity caused by needle jet turbulence may contribute to the cascade of events leading to IH formation during hemodialysis.

The role of histone acetylation in SMN gene expression.

Increasing survival motor neuron 2 (SMN2) gene expression may be an effective strategy for the treatment of spinal muscular atrophy (SMA). Histone deacetylase (HDAC) inhibitors have been shown to increase SMN transcript and protein levels, but the specific role of histone acetylation in regulating SMN gene expression has not been explored. Using chromatin immunopreciptation, we investigated the levels of acetylated H3 and H4 histones and HDACs associated with different regions of the human and mouse SMN genes in both cultured cells and tissues. We show that the SMN gene has a reproducible pattern of histone acetylation that is largely conserved among different tissues and species. A limited region of the promoter surrounding the transcriptional start site has relatively high levels of histone acetylation, whereas regions further upstream or downstream have lower levels. After HDAC inhibitor treatment, acetylated histone levels increased, particularly at upstream regions, correlating with a 2-fold increase in promoter activity. During development in mouse tissues, histone acetylation levels decreased and associated HDAC2 levels increased at the region closest to the transcriptional start site, correlating with a 40-60% decrease in SMN transcript and protein levels. These data indicate that histone acetylation modulates SMN gene expression and that pharmacological manipulation of this epigenetic determinant is feasible. HDAC2, in particular, may be a future therapeutic target for SMA.

Turbulent flow evaluation of the venous needle during hemodialysis.

Arteriovenous (AV) grafts and fistulas used for hemodialysis frequently develop intimal hyperplasia (IH) at the venous anastomosis of the graft, leading to flow-limiting stenosis, and ultimately to graft failure due to thrombosis. Although the high AV access blood flow has been implicated in the pathogenesis of graft stenosis, the potential role of needle turbulence during hemodialysis is relatively unexplored. High turbulent stresses from the needle jet that reach the venous anastomosis may contribute to endothelial denudation and vessel wall injury. This may trigger the molecular and cellular cascade involving platelet activation and IH, leading to eventual graft failure. In an in-vitro graft/needle model dye injection flow visualization was used for qualitative study of flow patterns, whereas laser Doppler velocimetry was used to compare the levels of turbulence at the venous anastomosis in the presence and absence of a venous needle jet. Considerably higher turbulence was observed downstream of the venous needle, in comparison to graft flow alone without the needle. While turbulent RMS remained around 0.1 m/s for the graft flow alone, turbulent RMS fluctuations downstream of the needle soared to 0.4-0.7 m/s at 2 cm from the tip of the needle and maintained values higher than 0.1 m/s up to 7-8 cm downstream. Turbulent intensities were 5-6 times greater in the presence of the needle, in comparison with graft flow alone. Since hemodialysis patients are exposed to needle turbulence for four hours three times a week, the role of post-venous needle turbulence may be important in the pathogenesis of AV graft complications. A better understanding of the role of needle turbulence in the mechanisms of AV graft failure may lead to improved design of AV grafts and venous needles associated with reduced turbulence, and to pharmacological interventions that attenuate IH and graft failure resulting from turbulence.

Valproic acid increases SMN levels in spinal muscular atrophy patient cells.

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7-containing SMN transcript and SMN protein in type I SMA patient-derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA.