This systematic review of PTSD in general ICU survivors highlights three important issues. First, the prevalence of substantial post-ICU PTSD symptoms is high, and symptoms appear to persist over time. Across studies, the median point prevalence of questionnaire-ascertained substantial PTSD symptoms was 22%, and the median point prevalence of clinician-diagnosed PTSD was 19%. These figures are quite a bit higher than the 3.5% one-year prevalence of PTSD in a recent study of US adults that utilized non-clinicians administering a structured interview [26
]. In addition, these figures are as high as, or higher than, the median point prevalences of substantial PTSD symptoms in survivors of myocardial infarction (16%) or cardiac surgery (17%) in a recent review of studies that used three of the same PTSD measures [27
]. Also, these figures are only slightly lower than the median point prevalence of substantial PTSD symptoms in ALI/ARDS survivors (28%) in a recent systematic review of studies that used two of the same PTSD questionnaires [9
]. Importantly, since pre-ICU psychopathology appears a potent risk factor for post-ICU PTSD, and several of the studies reviewed here excluded patients with prior psychopathology, our prevalence estimates for post-ICU PTSD are very likely underestimates for the population of all ICU survivors.
Second, consistent predictors of post-ICU PTSD include pre-ICU psychopathology, greater ICU benzodiazepine administration, and post-ICU memories of in-ICU frightening and/or psychotic experiences. Female sex and younger age were less consistent predictors, and severity of critical illness was consistently not
a predictor. Pre-trauma psychopathology, female sex, and younger age appear to be general risk factors for PTSD [28
]. We note that, though we previously speculated that durations of mechanical ventilation and ICU length of stay may increase risk for post-ICU PTSD [9
], we found little evidence for this here.
Third, post-ICU PTSD may have a substantial impact on quality of life. Though only two of the included studies addressed this issue, the results are consistent with findings in ALI/ARDS survivors [9
] and the general PTSD literature [29
The existing literature has several important limitations. First, most of the studies relied exclusively on questionnaires (i.e., screening instruments) to estimate the burden of PTSD symptoms in ICU survivors. Only three of the fifteen studies utilized expert clinicians and diagnostic interviews, and, of the questionnaires employed, only the PTSS-10 has been validated against clinician diagnoses in the post-ICU setting [31
]. Future studies of PTSD in general ICU survivors should utilize expert clinicians to conduct diagnostic interviews in larger cohorts, to more definitively estimate prevalence and incidence, and to evaluate the psychometric properties of other existing questionnaires, such as the IES, in this setting; as noted in the Results section, different investigators employed different thresholds in their studies.
Second, additional research is required to understand risk factors for post-ICU PTSD. We first consider patient-specific risk factors. Only one study related personality traits to PTSD symptoms [11
], and, in that study, patients rated trait anxiety and PTSD symptoms simultaneously, so it remains unclear whether patients’ symptom states affected their self-reports of traits [32
]. Nevertheless, the results are consistent with the general PTSD literature, which suggests that high neuroticism (a more general tendency to experience negative emotions) is a risk factor for PTSD [33
]. State-related recall could also have biased patients’ reports of pre-ICU psychopathology, as it appears the latter was assessed after the ICU stay in each case; i.e., patients with more acute stress disorder or PTSD symptoms may have recalled pre-ICU psychiatric illness more readily.
ICU-related risk factors also require clarification. First, it remains unclear to what extent and through what mechanism benzodiazepine sedation might relate causally to post-ICU PTSD. That is, benzodiazepine administration might reflect clinicians’ management
of patients’ in-ICU anxiety/agitation, the latter of which may be a marker of risk for, or prodrome of, PTSD. Notably, one study found that pre-ICU anxiety or depression was associated with more in-ICU benzodiazepine administration [13
]. Of the studies reviewed, the closest approximation to a clinical trial was a small study with a low follow-up proportion (n = 32, 40% of survivors) on the effects of sedative interruption during mechanical ventilation on subsequent psychopathology [21
]. If benzodiazepines are
a cause of post-ICU PTSD, an intermediate mechanism may be delirium with associated frightening psychotic experiences. That is, since psychotic symptoms and nightmares are common in delirious patients, and post-ICU memories of in-ICU psychotic experiences are strong predictors of PTSD, delirium may be a true risk factor for PTSD in the ICU setting. Only one of the eligible studies explicitly examined delirium as a risk factor for post-ICU PTSD [18
]; although no significant association was evident, this could be due to a lack of statistical power (n = 43) or insensitivity of delirium operationalization or measurement (i.e., number of days of delirium measured with a daily clinical exam). Interestingly, a history of anxiety and/or depressive disorders prior to ICU admission predicted post-ICU memories of in-ICU psychotic experiences in two of two studies in which this was assessed [11
]; also, a growing number of studies provide evidence that pre-hospital depression is a risk factor for in-hospital delirium [36
]. Thus, patients with a history of anxiety or depression may be particularly prone to in-ICU delirium and associated psychotic experiences, as well as subsequent PTSD, and the causal mechanisms remain unclear. Clarification of these issues is an important goal for future research that could facilitate prevention. For example, if delirium itself is causally related to post-ICU PTSD, minimization of delirium – e.g., via use of alternative sedatives [39
] – would have important longer-term mental health benefits. We note that some form/level of sedation is required for mechanically ventilated patients, not just for humane practice but also to reduce oxygen demands and promote synchronous breathing with ventilators [40
Additionally, how, and in what circumstances, systemic corticosteroid administration may prevent PTSD is also unclear. The small studies (n = 20–54) reviewed here suggest that stress-dose hydrocortisone is preventative in the context of septic shock [23
]. The authors speculated that administration of corticosteroids may have resulted in less endogenous catecholamine release (through an endogenous feedback mechanism) and less need for exogenous catecholamine administration in order to maintain adequate blood pressure; indeed, there was some evidence for the latter in the one reviewed study in which this was assessed [23
]. Another mechanism the authors considered is that hydrocortisone (and minimization of catecholamines) could have advantageously affected memory formation and retrieval. We note that corticosteroids may also be preventative via minimization of systemic inflammation; i.e., some evidence suggests that inflammatory cytokines are associated with general medical illness-related psychopathology [41
]; to our knowledge, this potential mechanism has not been studied in the ICU setting. Importantly, though Schelling et al. have reported that stress-dose hydrocortisone was similarly beneficial in the context of cardiac surgery [43
], we know of no studies of PTSD-preventative effects of stress-dose corticosteroids in general ICU patients. Also, a recent study of surgical abdominal peritonitis patients did not find that ICU corticosteroid administration prevented later PTSD in survivors [45
]. Thus, it is unclear whether administration of stress-dose corticosteroids would have PTSD-preventative effects in most critically ill patients.
Studies that integrate patient-specific and ICU-related risk factors are needed. Taking a step in this direction, Jones et al. developed a structural equation model of risk factors for post-ICU PTSD [13
]; their model suggests that pre-ICU anxiety or depressive disorders, sedation and physical restraint, and recall of in-ICU nightmares/psychotic experiences have individual and combined effects on the development of post-ICU PTSD. More research is needed to understand the role that these and other potential etiologic factors (e.g., sepsis, hypoxia, delirium, and corticosteroid/catecholamine administration) may play. We feel that critical illness/ICU treatment is promising as a model to investigate the development of psychopathology in the context of extreme stress, as intensive monitoring of clinical state, physiology, hormones, and catecholamines are possible at the time of the stress
. Though knowledge regarding the neurobiology of PTSD is increasing, inconsistent findings are common, and consideration of context (within and outside individuals) appears vital [46
There are several potentially important limitations to this systematic review. First, confidence regarding the precision and validity of our findings should be tempered given the methodological issues described above. Second, though the results suggest some stability in levels of PTSD symptoms over the first 6–12 months post-ICU, we did not feel we could draw strong conclusions regarding the effect of time on prevalence of substantial PTSD symptoms, given heterogeneity in instruments (for which thresholds may not be equivalent), in thresholds within instrument (i.e., the IES), and in sample compositions. Notably, the studies of septic shock survivors had much longer follow-up periods than the other studies, and the prevalences of substantial PTSD symptoms were as high as those in studies with shorter follow-up periods. Though it is possible that septic shock is associated with a particularly high prevalence and/or persistence of substantial PTSD symptoms, we are unable to draw strong conclusions without additional data. Third, although we did not include studies that focused exclusively on survivors from trauma, neurological, coronary, or surgical ICUs, individual patients in the reviewed studies did have other potential risk factors for PTSD, including trauma, surgery, and heart disease; thus, we cannot conclude that the high prevalences reported are specific to critical illness/ICU treatment itself. Finally, despite a comprehensive search of 16,301 citations, potentially eligible studies may have been missed due to inconsistent indexing in electronic databases.
We conclude that, in general ICU survivors, substantial PTSD symptoms are common and may negatively impact HRQOL. Risk factors for post-ICU PTSD appear to include pre-ICU psychopathology, greater in-ICU benzodiazepine sedation, and in-ICU frightening/psychotic experiences, though further work is necessary to clarify causal mechanisms. In the meantime, clinicians should recognize that PTSD is common following intensive care, necessitating collaboration between intensivists, primary care physicians, and psychiatrists to ensure prompt, comprehensive evaluations and treatment.