The mental health of intensive care survivors may be poor. Patients may suffer from post-traumatic stress disorder (PTSD), depression or anxiety with poor quality of life in the months following intensive care [1–3]. It is not clear whether poor psychological outcomes are associated with the traumatic effects of critical illness, intensive care treatment and drugs (clinical risk factors), or mood and stress reactions in intensive care (acute psychological factors). Outcomes might be better explained by chronic physical conditions and psychological history (chronic health factors) or socio-demographic factors, such as low socio-economic position [4]. There is an urgent need to explore the relative effects of a broader set of risk factors than has previously been investigated on different psychosocial outcomes, within a fully-powered single study of mixed-diagnosis, general intensive care patients.

Psychological outcomes after intensive care include PTSD, an "anxiety disorder that often follows exposure to an extreme stressor that causes injury, threatens life or physical integrity" [5]. The person's immediate response involves intense fear, helplessness or horror. The disorder is characterised by three clusters of symptoms: re-experiencing, avoidance and hyper-arousal, that persist for more than a month and cause distress or impaired functioning. Another outcome of interest, depression, is characterised by low mood or loss of interest for more than two weeks, with a range of other symptoms. Anxiety is a normal emotion that may become persistent and inappropriate. In systematic reviews, the median point prevalence of PTSD among intensive care survivors was 22% [1] with 28% prevalence of depression [2]. Rates of anxiety after intensive care vary from 5% to 43% [3]. In a meta-analysis of quality of life, physical functioning was 20 points (0 to 100) and mental health 10 points below UK norms [3].

Patients are exposed to many stressors in the intensive care unit (ICU), including illness, pain, sleep deprivation, thirst, hunger, dyspnea, unnatural noise and light, inability to communicate, isolation and fear of dying; and they may show extreme emotional reactions in response [6–8]. Interventions, such as mechanical ventilation (MV) or invasive monitoring for cardiovascular support, may be difficult for patients to tolerate. Furthermore, the onset of delirium, including frightening psychotic symptoms, such as hallucinations and paranoid delusions, is common in intensive care [9, 10]. Delirium is associated with the pathophysiology of critical illness as well as drugs used in intensive care [11, 12]. The question is whether exposure to stressors, such as MV, or acute psychological reactions, such as stress, mood and hallucinations, are direct risk factors for PTSD and other adverse outcomes. It may be that patients' emotional reactions to stress in intensive care are early signs of psychological morbidity.

Consistent risk factors for post-ICU psychological morbidity have not been definitively established [13, 14], with associations mostly detected in very few studies. Socio-demographic risk factors for post-ICU PTSD include age [15, 16, 18], sex [17, 18] and unemployment [19]. Psychological history is a known chronic health risk factor [12, 15]. Acute psychological risk symptoms (extreme fear and agitation in the ICU) were found to be associated with PTSD in only one study to our knowledge [17]. Factual recall and memory of pain were associated with PTSD in one study [19], whereas delusional memories (of psychotic symptoms) following ICU discharge were more important in others [12, 20]. Clinical risk factors include aspects of sedation [12, 17, 18, 21] and duration of mechanical ventilation [15]. Two studies that found no association with mechanical ventilation and PTSD were small, with 41 [18] and 37 [22] participants. As mechanical ventilation is the most common intensive care intervention, replication of the positive result [15] is urgently needed.

The few risk factors identified for post-ICU depression and anxiety were mainly found in single or small studies or sub-groups of patients. Hypoglycemia [23] and benzodiazepine dosage [24] were associated with post-ICU depression in patients with acute lung injury. Pessimism was associated with subsequent depression and anxiety in one study [19]. A more consistent group of risk factors (age, illness severity, ICU length of stay and prior health) were identified in studies of post-ICU quality of life [3].

The aim of our study was to investigate a broader set of clinical, acute psychological, socio-demographic and chronic health risk factors than had previously been tested, for different psychosocial outcomes within a single study of mixed general ICU patients. We used multivariable analysis to determine relative contributions of risk factors in different domains. Furthermore, we aimed to identify modifiable clinical and acute psychological risk factors that might inform the development and evaluation of preventative interventions in intensive care.

A total of 157 level three patients were assessed before discharge from the ICU, and 100 patients (64%) were followed up at three months (see Figure 1). Most patients were mechanically ventilated for more than 24 hours, and most were sedated with benzodiazepines or anaesthetic agents (Table 1). Patients had elevated mean scores for mood disturbance and stress reactions in ICU (Table 2). Some 65 to 75% had hallucinations, agitation and nightmares. Memory impairment, including amnesia for time spent in ICU or unwanted intrusive memories of intensive care, were common.

Subsequently, the incidence of probable PTSD at three months was 27.1% (95%CI: 18.3%, 35.9%). Prevalence of probable depression was 46.3% (95% CI: 36.5%, 56.1%) and anxiety 44.4% (95% CI: 34.6%, 54.2%). In all, 55% of patients had psychological morbidity at three months. There were 16% of patients with prior history of psychological morbidity (depression in all cases). Mean mental quality of life was 43.9 (95% CI: 41.6, 46.3), six points below the population norm (50). Mean physical quality of life was 34.4 (95% CI: 32.3, 36.6), 16 points below the norm.

All psychological measures used had reliability (internal consistency), using Cronbach's alpha (0.91 for Profile of Mood States (POMS); 0.93 for PDS; O.91 for CES-D; and 0.88 for STAI). After principal components analysis, the ICU stress reactions scale was found to have four factors: physical stress, delirious symptoms, personal control and support. The total scale and three subscales were reliable (Cronbach's alphas: 0.83 (total); 0.78 (personal control); 0.74 (delirious symptoms); 0.75 (physical stress)). ICU stress reactions scores were highly correlated with POMS [28] scores (r = 0.73, P <0.01), suggesting concurrent validity. ICU stress reaction scores were also highly correlated with PTSD, depression and anxiety at three months, suggesting predictive validity.

In this prospective study, we found that level three patients with mixed diagnoses suffer considerable psychological distress both during and following a general ICU admission. Three months after being discharged, 27% had probable PTSD symptoms, 46% had probable depression and 44% had anxiety. Our PTSD estimate is broadly consistent with a systematic review in which median point prevalence of PTSD was 22% [1] and the expectation that 25 to 30% of people develop PTSD after a trauma [39]. Post-ICU depression and anxiety rates were high in this study, compared to 28% depression reported in a systematic review [2] and anxiety rates varying from 5 to 43% [3]. The varying rates of morbidity may be explained by differences in populations, admission criteria, and methods and timing of assessments. We believe our prevalence estimates are credible due to the high quality of questionnaires used to measure psychological morbidity and the representativeness of our level three samples.

Patients had high mean scores for mood disturbance and stress (see Table 2) in response to sleep deprivation, difficulty breathing, pain, inability to communicate, low control, hallucinations and nightmares. These stress reactions were measured during their ICU admission. Previous studies measured stress in ICU retrospectively [17] or in sub-groups, such as chronically critically ill [6] or terminally ill [8] patients. The presence of delirium has been well documented in intensive care patients [9, 40]. In this study, we were interested in measuring specific delirium symptoms, such as hallucinations, nightmares and agitation, which we found to be at high levels.

Acute psychological risk factors for PTSD, identified in univariable analysis, include higher intensive care stress and delirious symptom scores (measured using the ICUSS). Associations were also found between ICU stress and delirious symptoms, and subsequent depression. However, in spite of moderate to large effect sizes, ICU stress and delirious symptoms were confounded by the variable ICU mood in the first stage of multivariable analysis. ICU mood and stress may have been overlapping variables [41] with mood showing slightly larger effect sizes. As one sub-scale in the ICU stress reactions scale was found unreliable and did not correlate with outcomes, omitting this sub-scale might increase the scale's utility in future.

The strongest acute psychological risk factors for PTSD identified in multivariable analysis were mood in the ICU, the perceived timeline of illness and early intrusive memories of intensive care. The strongest acute psychological risk factor for depression was also mood in the ICU. This mood variable was composed of symptoms, such as anger, nervousness, low mood and confusion. The first three are common stress reactions while the latter is arguably related to hypoxia, sedation or delirium. The identification of ICU mood as one of the strongest risk factors in the study suggests that emotional stress reactions in intensive care may be a trigger for, or early manifestation of, future psychological morbidity.

It was of interest that early intrusive memories in intensive care were associated with memory loss. Patients who remembered little of their ICU stay were more likely to have early intrusive memories than those who remembered more. It is known that periods of unconsciousness do not preclude the development of intrusive memories [42]. Other ICU studies emphasise the relationship between "delusional" memories and PTSD [12, 20] but in our study there was no significant difference in outcomes between patients with factual or delusional intrusive memories. There is no consensus in the wider PTSD literature about the significance of early intrusive memories that immediately follow a trauma. Some studies predict successful recovery, but others predict a worse outcome [39].

Turning to clinical risk factors, it was of interest that many variables, such as TISS score [27], duration of mechanical ventilation and cardiovascular support, number of organs supported, drug groups given and length of sedation, were associated with PTSD in the univariable analysis. These results suggest that a level three admission, particularly when it involves multiple drugs and escalating invasive interventions, may be a traumatic stressor that can trigger PTSD symptoms if the patient survives.

During the first stage of multivariable analysis it emerged that the strongest clinical risk factors for PTSD were drug-related variables, particularly the number of days of sedation. In previous studies, PTSD was found to be associated with other aspects of sedation [12, 17, 18, 21]. Our study also found strong associations in the first stage of multivariable analysis between other ICU drugs and psychological outcomes, including benzodiazepines and depression; inotropes/vasopressors and anxiety; and both steroids and anaesthetic agents (mainly propofol) with improved physical quality of life.

It has been hypothesised that benzodiazepines trigger depression by reducing central monoamine activity [43]. The association between benzodiazepine use in the ICU and delirium [11, 12] also suggests pathways leading to long-term psychological morbidity. The association between inotropes and vasopressors in intensive care and subsequent anxiety has not previously been reported, although receiving noradrenaline or adrenaline was associated with short-term anxiety in medical patients [44]. These medications are known to enhance emotional memories [39], which are prominent in anxiety disorders. However, patients receiving inotropes and vasopressors are at risk for inadequate brain perfusion. Therefore, it should not be assumed the association is causal.

Regarding the association between corticosteroids and improved physical quality of life, it could be hypothesised that steroids offer protection by modifying the inflammatory response. In another study, patients receiving steroids in intensive care had a lower rate of PTSD [45]. However, caution is needed as the use of corticosteroids in intensive care has previously been associated with long-term physical impairments [46].

Few socio-demographic risk factors were identified in the analyses, perhaps suggesting that the stressful effects of intensive care transcend age or gender. However, lower socio-economic position was found to predict depression, anxiety and mental quality of life, although not PTSD. It may be that PTSD symptoms are directly triggered by traumatic experiences in intensive care, while depression and anxiety at three months are more affected by socio-economic factors. No previous studies of psychological outcomes after intensive care included a valid measure of socio-economic position, although this has been shown to predict mortality in ICU patients [4, 47].

The most important finding in this study was that acute psychological reactions were among the strongest risk factors for post-ICU psychological morbidity. The second stage of multivariable analysis demonstrated that associations between clinical factors, such as duration of sedation, and outcomes, such as PTSD, were weakened when acute psychological factors were added to the regression. This suggests that the effects of clinical factors on outcomes were partially explained (or mediated) by acute psychological reactions. It is important to note that the effects of acute stress reactions in the ICU on outcomes were not confounded by psychological history. Thus, stress in the ICU was found to contribute to future psychological morbidity independently of pre-existing psychological problems.

These results suggest that, as well as modifying clinical and sedation practices in the ICU, psychological interventions aiming to mitigate acute stress reactions in intensive care might have a positive impact on poor psycho-social outcomes.

The strengths of this study include the measurement of several important psychological outcomes with validated questionnaires, and of a comprehensive set of risk factors. The prospective design and participation of a representative sample of highest acuity "level three" general ICU patients, who are difficult to recruit, are also positive aspects of the study. The study was fully powered to detect associations between risk factors and outcomes using multiple regression models.

Limitations include the use of a single-centre. Another limitation was the necessary exclusion of patients who remained confused throughout the intensive care admission. Psychological questionnaires were used rather than clinician diagnosis of outcome. The ICU Stress Reactions Scale (ICUSS) was not validated before the study. However, this innovative instrument enables the measurement of ICU stress reactions in real time, not retrospectively, and preliminary validational data for the scale were collected. Records of patient's past medical history may not have been complete. The loss of 36% of participants to follow-up was due to death, homelessness, disability and hospitalisation. However, 90% of the patients who were able to participate in follow-up, completed the study.

This cohort study revealed that level three patients suffered considerable psychological morbidity after intensive care. We detected associations not found in previous studies: between inotropes/vasopressors and post-ICU anxiety; corticosteroids and better physical quality of life; and between delirious symptoms, early intrusive memories and memory loss with depression and PTSD. Our results lend weight to limited existing evidence that sedation is linked to depression and PTSD after intensive care. It was striking that different drug-related clinical risk factors were correlated with different outcomes, and further studies to assess mechanisms are warranted. The most important finding was that acute stress reactions in the ICU were stronger risk factors than clinical factors. This lends hope that modifying psychological as well as pharmacological risk factors may be possible, and preventative approaches to ICU stress could be developed and evaluated.