Critical Care and the Postintensive Care Syndrome

Abstract

Critical care generally focuses on short- and intermediate-term outcomes by providing urgent interventions to enhance the chance of meaningful survival. As lifesaving interventions and avoidance of harmful approaches have improved, clinicians and investigators have increasingly appreciated the profound implications of critical illness for neurocognitive and psychiatric outcomes after recovery from critical illness. Williams Roberson et al1 bring both of these considerations to the forefront in their study by addressing neurocognitive and psychological outcomes at 6 months after participation in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial. This trial evaluated the effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis who presented with respiratory or cardiovascular dysfunction.1 Williams Roberson et al1 hypothesized that neurocognitive outcomes would improve secondary to vitamin C–, thiamine-, and steroid-induced reductions in oxidative stress and neuroinflammation during septic shock. Unexpectedly, the trial revealed lower immediate memory scores (adjusted odds ratio [aOR], 0.49; 95% CI, 0.26-0.89), higher posttraumatic stress disorder (PTSD) odds (aOR, 3.51; 95% CI, 1.18-10.4), and less use of mental health care (aOR, 0.38; 95% CI, 0.16-0.87) in the intervention group.1 The analysis by Williams Roberson et al1 highlights a long-term outcome after critical illness: postintensive care syndrome (PICS). This syndrome is characterized by new or worsening disorders in mental, physical, or neurocognitive outcomes that adversely affect daily function and quality of life in survivors of critical illness.2 Sequelae can include neuromuscular weakness; loss of independence in home care or activities of daily living; anxiety; depression; PTSD; and other neurocognitive changes, including alterations in personality, memory, or executive function.2 Despite relatively brief windows of critical illness in participants in the VICTAS trial, with a median respiratory-support duration of 0 days and intensive care unit (ICU) stay of 3 days, approximately 20% of patients received a positive screening result for PTSD, and approximately 35% of patients received a positive screening result for depression at the 6-month follow-up.1 While distressing, these percentages are less than those in other reports, including a landmark 2015 meta-analysis that revealed a pooled prevalence of 25% to 44% for clinically important PTSD symptoms occurring 1 to 6 months and 17% to 34% at 7 to 12 months after critical illness.3 Postintensive care syndrome occurs more frequently in patients who receive benzodiazepines, have frightening ICU memories, and/or have comorbid psychiatric illness.3 While risks are actively being defined and described, it is clear that socioeconomic risk factors play a role.4 Severity of illness and delirium are also factors in PICS, particularly affecting cognitive outcomes.2 Given these features, it is likely that core care pathways and bundles, including exercise, nutrition, and light sedation, may be associated with reduced incidence of PICS, along with other approaches, such as ICU diaries and flexible visiting hours for family and familiar contacts.2 While light sedation and sedation holidays are broadly agreed to be of marked patient benefit, these are often foregone and deep sedation is used even in the face of protocolized plans for light sedation.5 Thus, both establishing sedation care bundles and shifting clinical approaches to sedation and analgesia are necessary. Vitamin C is a pleiotropic vitamin that is an antioxidant with additional broad activity at the endothelium, in mitochondria, and as a cofactor for various biochemical reactions. Vitamin C facilitates dopamine-to-norepinephrine metabolism and can increase endogenous norepinephrine levels. While the VICTAS trial showed no difference between the intervention and control groups in vasopressor-free days, brain metabolism of norepinephrine may not be entirely reflected in macrocirculatory effects.1 In the brain, vitamin C–induced increase in norepinephrine levels could enhance activity in brain areas involved in the physical and emotional stress response and in consolidation of aversive memories.1 Increased adrenergic agents have long been recognized to be associated with increasing traumatic memories in critically ill patients, potentially increasing PTSD.6 Stress-steroid administration, however, may mitigate traumatic memory retrieval, producing a divergent impact. Nonetheless, depth and choice of sedative agents are also associated with traumatic memory formation, consolidation, and retrieval via interactions between multiple pathways, including the endocannabinoid system and the noradrenergic and glucocorticoid receptors in the brain.6 In addition, administration of vitamin C, an antioxidant, should be appropriately timed to the hyperacute oxidative burst of septic shock. An even slightly delayed administration, such as in the VICTAS trial wherein the interventions were administered approximately 15 hours after organ dysfunction, may adversely affect oxidant signaling, a core component of the (healthy) stress response. Taken together, neurocognitive and neuropsychological symptoms occur with high frequency after critical illness and warrant follow-up in the same way that cardiac and pulmonary recovery is assessed. Socioeconomic distress also seems to increase the risk of PICS, particularly its psychological components. This factor, plus the avoidant symptoms inherent in PTSD, may limit patients' willingness and ability to use health care and/or mental health resources. This observation is consistent with the finding by Williams Roberson et al1 that the intervention group had lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.87). Highlighted by this unexpected finding, planned research interventions in the ICU should ideally include longitudinal assessment for PICS. To this end, a core outcome set should be delineated and a consistent and validated battery of tests and approach to testing is warranted, including standardized score cutoffs and validation of surrogate-completed forms.2,7 Defining at-risk patients based on history, including socioeconomic and psychological considerations, and current medical and treatment considerations should be combined with ICU or hospital neurocognitive assessments to identify high-risk patients who can benefit from closer follow-up for PICS. It is important to recognize that well-intentioned therapies may have durable, clinically meaningful adverse effects well after recovery from critical illness. Ongoing efforts and studies of interventions in the ICU must focus on the entire continuum of critical care, including longitudinal outcomes. Postintensive care syndrome occurs frequently and is greatly associated with the quality of life of ICU survivors. Prevention and follow-up are crucial, particularly for interventions that may directly or indirectly alter the disorder. The association found between increased PTSD and the intervention of hydrocortisone, vitamin C, and thiamine1 draws attention to the importance of establishing biological plausibility between an intervention and unexpected outcomes. Although the association of vitamin C, thiamine, and corticosteroids with worsened neurocognitive outcomes can be confounded by several factors (eg, imbalance in socioeconomic status, loss of follow-up, and preillness psychological or psychiatric status), this clinical observation should foster a careful investigation of the potential underlying mechanisms, linking bench and bedside research while illustrating the concept of serendipity, an important trigger of major scientific discoveries.