Christopher G. Hughes

Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study

Background Critical illness is associated with cognitive impairment, but mental health and functional disabilities in general intensive care unit (ICU) survivors are inadequately characterized and there are a paucity of data regarding the relationship between age and delirium and these outcomes.BACKGROUND Critical illness is associated with cognitive impairment, but mental health and functional disabilities in survivors of intensive care are inadequately characterised. We aimed to assess associations of age and duration of delirium with mental health and functional disabilities in this group. METHODS In this prospective, multicentre cohort study, we enrolled patients with respiratory failure or shock who were undergoing treatment in medical or surgical ICUs in Nashville, TN, USA. We obtained data for baseline demographics and in-hospital variables, and assessed survivors at 3 months and 12 months with measures of depression (Beck Depression Inventory II), post-traumatic stress disorder (PTSD, Post-Traumatic Stress Disorder Checklist-Event Specific Version), and functional disability (activities of daily living scales, Pfeffer Functional Activities Questionnaire, and Katz Activities of Daily Living Scale). We used linear and proportional odds logistic regression to assess the independent associations between age and duration of delirium with mental health and functional disabilities. This study is registered with ClinicalTrials.gov, number NCT00392795. FINDINGS We enrolled 821 patients with a median age of 61 years (IQR 51-71), assessing 448 patients at 3 months and 382 patients at 12 months after discharge. At 3 months, 149 (37%) of 406 patients with available data reported at least mild depression, as did 116 (33%) of 347 patients at 12 months; this depression was mainly due to somatic rather than cognitive-affective symptoms. Depressive symptoms were common even among individuals without a history of depression (as reported by a proxy), occurring in 76 (30%) of 255 patients with data at 3 months and 62 (29%) of 217 individuals at 12 months. Only 7% of patients (27 of 415 at 3 months and 24 of 361 at 12 months) had symptoms consistent with post-traumatic distress disorder. Disabilities in basic activities of daily living (ADL) were present in 139 (32%) of 428 patients at 3 months and 102 (27%) of 374 at 12 months, as were disabilities in instrumental ADL in 108 (26%) of 422 individuals at 3 months and 87 (23%) of 372 at 12 months. Mental health and functional difficulties were prevalent in patients of all ages. Although old age was frequently associated with mental health problems and functional disabilities, we observed no consistent association between the presence of delirium and these outcomes. INTERPRETATION Poor mental health and functional disability is common in patients treated in intensive-care units. Depression is five times more common than is post-traumatic distress disorder after critical illness and is driven by somatic symptoms, suggesting approaches targeting physical rather than cognitive causes could benefit patients leaving critical care. FUNDING National Institutes of Health AG027472 and the Geriatric Research, Education and Clinical Center (GRECC), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System.

Epidemiology and risk factors for delirium across hospital settings.

Delirium is one of the most common causes of acute end-organ dysfunction across hospital settings, occurring in as high as 80% of critically ill patients that require intensive care unit (ICU) care. The implications of this acute form of brain injury are profound. Across many hospital settings (emergency department, general medical ward, postoperative and ICU), a patient who experiences delirium is more likely to experience increased short- and long-term mortality, decreases in long-term cognitive function, increases in hospital length of stay and increased complications of hospital care. With the development of reliable setting-specific delirium-screening instruments, researchers have been able to highlight the predisposing and potentially modifiable risk factors that place patients at highest risk. Among the large number of risk factors discovered, administration of potent sedative medications, most notably benzodiazepines, is most consistently and strongly associated with an increased burden of delirium. Alternatively, in both the hospital and ICU, delirium can be prevented with the application of protocols that include early mobility/exercise. Future studies must work to understand the epidemiology across settings and focus upon modifiable risk factors that can be integrated into existing delirium prevention and treatment protocols.

Statins and Delirium during Critical Illness: A Multicenter, Prospective Cohort Study

Objective:Since statins have pleiotropic effects on inflammation and coagulation that may interrupt delirium pathogenesis, we tested the hypotheses that statin exposure is associated with reduced delirium during critical illness, whereas discontinuation of statin therapy is associated with increased delirium. Design:Multicenter, prospective cohort study. Setting:Medical and surgical ICUs in two large tertiary care hospitals in the United States. Patients:Patients with acute respiratory failure or shock. Interventions:None. Measurements and Main Results:We measured statin exposure prior to hospitalization and daily during the ICU stay, and we assessed patients for delirium twice daily using the Confusion Assessment Method for the ICU. Of 763 patients included, whose median (interquartile range) age was 61 years (51–70 yr) and Acute Physiology and Chronic Health Evaluation II was 25 (19–31), 257 (34%) were prehospital statin users and 197 (26%) were ICU statin users. Overall, delirium developed in 588 patients (77%). After adjusting for covariates, ICU statin use was associated with reduced delirium (p < 0.01). This association was modified by sepsis and study day; for example, statin use was associated with reduced delirium among patients with sepsis on study day 1 (odds ratio, 0.22; 95% CI, 0.10–0.49) but not among patients without sepsis on day 1 (odds ratio, 0.92; 95% CI, 0.46–1.84) or among those with sepsis later, for example, on day 13 (odds ratio, 0.70; 95% CI, 0.35–1.41). Prehospital statin use was not associated with delirium (odds ratio, 0.86; 95% CI, 0.44–1.66; p = 0.18), yet the longer a prehospital statin user’s statin was held in the ICU, the higher the odds of delirium (overall p < 0.001 with the odds ratio depending on sepsis status and study day due to significant interactions). Conclusions:In critically ill patients, ICU statin use was associated with reduced delirium, especially early during sepsis; discontinuation of a previously used statin was associated with increased delirium.

Association between Endothelial Dysfunction and Acute Brain Dysfunction during Critical Illness

Background:Acute brain dysfunction (delirium and coma) during critical illness is prevalent and costly, but the pathophysiology remains unclear. The relationship of acute brain dysfunction with endothelial function, which is impaired in critical illness and may contribute to alterations in cerebral blood flow and blood–brain barrier permeability, has not been studied. This study sought to determine whether systemic endothelial dysfunction is associated with acute brain dysfunction during critical illness. Methods:In this prospective cohort study, adult medical/surgical intensive care unit patients in shock and/or respiratory failure were enrolled. Endothelial function was assessed at enrollment using peripheral artery tonometry to calculate the reactive hyperemia index, with lower reactive hyperemia index indicative of worse endothelial function. Patients were assessed for coma and delirium with the Richmond Agitation–Sedation Scale and Confusion Assessment Method for the Intensive Care Unit. Multivariable linear regression was used to analyze the association between reactive hyperemia index and (1) delirium/coma-free days among all patients and (2) delirium duration among survivors, both over a 14-day period. Results:One hundred forty-seven patients with median age of 57 yr and median Acute Physiology and Chronic Health Evaluation II score of 26 were enrolled. After adjusting for age, severity of illness, severe sepsis, preexisting cognitive function, medical versus surgical intensive care unit admission, and prehospital statin use, lower reactive hyperemia index (worse systemic endothelial function) was associated with fewer delirium/coma-free days (P = 0.02) and more delirium days (P = 0.05). Conclusions:In this study, critically ill patients with lower vascular reactivity indicative of worse systemic endothelial function had increased duration of acute brain dysfunction.

Intraoperative risk factors for acute respiratory distress syndrome in critically ill patients.

BACKGROUND: Risk factors for the development of acute respiratory distress syndrome (ARDS) in the intensive care unit (ICU) include positive fluid balance, high tidal volumes (TVs), high airway pressures, and transfusion of blood products. However, research examining intraoperative factors such as fluid resuscitation, mechanical ventilation strategies, and blood administration on the postoperative development of ARDS is lacking. METHODS: We assessed patients admitted to the ICU with postoperative hypoxemic respiratory failure requiring mechanical ventilation for the development of ARDS in the first 7 postoperative days using established clinical and radiological criteria. Data on risk factors for ARDS were obtained from the electronic anesthetic and medical records. Logistic regression was used to examine the independent association between fluid resuscitation, TV per ideal body weight, and number of blood products transfused during surgery and the postoperative development of ARDS, adjusting for important clinical covariates. RESULTS: Of the 89 patients with postoperative respiratory failure, 25 developed ARDS. Compared with those who received <10 mL/kg/h fluid resuscitation in the operating room, patients receiving >20 mL/kg/h fluid resuscitation had a 3.8 times higher adjusted odds of developing ARDS (P = 0.04), and those receiving 10 to 20 mL/kg/h had a 2.4 times higher adjusted odds of developing ARDS (P = 0.14). TV per ideal body weight and the number of blood units transfused were not associated with ARDS development in this study. CONCLUSIONS: This cohort study provides evidence to suggest a relationship between intraoperative fluid resuscitation and the development of ARDS. Larger prospective trials are required to confirm these findings.

Balanced Crystalloids versus Saline in Critically Ill Adults

BACKGROUND Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU). METHODS We conducted a single‐center, pragmatic, multiple‐crossover trial comparing balanced crystalloids (lactated Ringers solution or Plasma‐Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16‐month trial. The primary outcome was hospital‐free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days — a composite of death from any cause, new renal‐replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) — all censored at hospital discharge or 30 days, whichever occurred first. RESULTS A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital‐free days did not differ between the balanced‐crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01). CONCLUSIONS Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital‐free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT‐ED ClinicalTrials.gov number, NCT02614040.)

Pathophysiology of acute brain dysfunction: what's the cause of all this confusion?

Purpose of reviewTo survey the recent medical literature examining the pathophysiology of acute brain dysfunction (delirium and coma) in the ICU. Recent findingsClinical risk factors for brain dysfunction in the ICU continue to be elucidated and prediction models developed. Multiple studies have identified sedatives, especially benzodiazepines, as modifiable risk factors for delirium. Imaging studies examining global brain disorders have demonstrated white matter lesions and brain atrophy to be associated with delirium. Endothelial dysfunction, increased blood–brain barrier permeability, and reduced blood flow have also been implicated in cerebral perfusion abnormalities associated with brain dysfunction. The response of the brain to inflammation, including activation of microglia and neuronal apoptosis, leads to synaptic and neurochemical disturbances. Decreased availability of acetylcholine during critical illness leads to decreased counter-regulatory activity in response to inflammatory disease states, likely causing additional injury and further neurotransmitter imbalances. Dopamine, norepinephrine, and serotonin excess and their respective amino acid precursors have also been associated with brain dysfunction. SummaryThe multifactorial pathophysiology of acute brain dysfunction remains incompletely understood. Multiple clinical risk factors have been identified and numerous pathophysiologic pathways have been hypothesized. Future research is required to investigate the roles of these pathways on differing clinical presentations, potential therapeutic options, and patient outcomes.

Statins and Brain Dysfunction: A Hypothesis to Reduce the Burden of Cognitive Impairment in Patients Who Are Critically Ill

Delirium is a frequent form of acute brain dysfunction in patients who are critically ill and is associated with poor clinical outcomes, including a critical illness brain injury that may last for months to years. Despite widespread recognition of significant adverse outcomes, pharmacologic approaches to prevent or treat delirium during critical illness remain unproven. We hypothesize that commonly prescribed statin medications may prevent and treat delirium by targeting molecular pathways of inflammation (peripheral and central) and microglial activation that are central to the pathogenesis of delirium. Systemic inflammation, a principal mechanism of injury, for example, in sepsis, acute respiratory distress syndrome, and other critical illnesses, can cause neuronal apoptosis, blood-brain barrier injury, brain ischemia, and microglial activation. We hypothesize that the known pleiotropic effects of statins, which attenuate such neuroinflammation, may redirect microglial activation and promote an antiinflammatory phenotype, thereby offering the potential to reduce the public health burden of delirium and its associated long-term cognitive injury.

Daily sedation interruption versus targeted light sedation strategies in ICU patients.

Objective:The updated clinical practice guidelines for the management of pain, agitation, and delirium recommend either daily sedation interruption or maintaining light levels of sedation as methods to improve outcomes for patients who are sedated in the ICU. We review the evidence supporting both methods and discuss whether one method is preferable or if they should be used concurrently. Data Source:Original research articles identified using the electronic PubMed database. Study Selection and Data Extraction:Randomized controlled trials and large prospective cohort studies of mechanically ventilated ICU patients requiring sedation were selected. Data Synthesis:The methods of daily sedation interruption and targeting light sedation levels (including avoidance of deep sedation) are safe in critically ill patients with no increase, and a potential decrease, in long-term psychiatric disturbances. Randomized trials comparing these methods with standard care, which has traditionally involved moderate to heavy sedation, found that both methods reduced duration of mechanical ventilation and ICU length of stay. Additionally, one trial noted that daily sedation interruption paired with spontaneous breathing trials improved 1-year survival, whereas a large observational study found that deep sedation was associated with decreased 180-day survival. Two common characteristics of these interventions in trials showing benefits were avoidance of deep levels of sedation and significant reductions in sedative doses, especially benzodiazepines. Thus, combining targeted light sedation with daily sedation interruption may be more beneficial than either method alone if sedative doses are reduced and arousal and mobility are facilitated during the ICU stay. Conclusion:Daily sedation interruption and targeting light sedation levels are safe and proven to improve outcomes for sedated ICU patients when these approaches result in reduced sedative exposure and facilitate arousal. It remains unclear as to whether one approach is superior, and further studies are needed to evaluate which patients benefit most from either or both techniques.

Emergence from general anaesthesia and evolution of delirium signs in the post-anaesthesia care unit

BACKGROUND Emergence from anaesthesia is often accompanied by signs of delirium, including fluctuating mental status and inattention. The evolution of these signs of delirium requires investigation since delirium in the post-anaesthesia care unit (PACU) may be associated with worse outcomes. METHODS Adult patients emerging from anaesthesia were assessed for agitated emergence in the operating room using the Richmond Agitation-Sedation Scale (RASS). The Confusion Assessment Method for the Intensive Care Unit was then used to evaluate delirium signs at PACU admission and during PACU stay at 30 min, 1 h, and discharge. Signs consistent with delirium were classified as hyperactive vs hypoactive based upon a positive CAM-ICU assessment and the concomitant RASS score. Multivariable logistic regression was utilized to assess potential risk factors for delirium during PACU stay including age, American Society of Anesthesiologists classification, and opioid and benzodiazepine exposure. RESULTS Among 400 patients enrolled, 19% had agitated emergence. Delirium signs were present at PACU admission, 30 min, 1 h, and PACU discharge in 124 (31%), 59 (15%), 32 (8%), and 15 (4%) patients, respectively. In patients with delirium signs, hypoactive signs were present in 56% at PACU admission and in 92% during PACU stay. Perioperative opioids were associated with delirium signs during PACU stay (P=0.02). CONCLUSIONS A significant proportion of patients develop delirium signs in the immediate postoperative period, primarily manifesting with a hypoactive subtype. These signs often persist to PACU discharge, suggesting the need for structured delirium monitoring in the PACU to identify patients potentially at risk for worse outcomes in the postoperative period.