Thanh N. Huynh

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.

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.

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.

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.

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.