Learning objectives.
By reading this article, you should be able to:
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Describe the known risk factors for accidental awareness under general anaesthesia (AAGA).
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Recall the stress disorders associated with AAGA.
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Detail the American Psychiatric Association's practice guidelines for psychopharmacological and psychotherapeutic interventions for post-traumatic stress disorder (PTSD).
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Recount recommendations for management of patients with AAGA.
Key points.
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Patients that experience distress during AAGA are prone to PTSD.
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Evidence-based therapeutic management strategies for AAGA-induced PTSD have been constrained by the relatively low incidence of AAGA.
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Treatment with antidepressants in combination with cognitive behavioural therapy is frequently used to treat PTSD.
Accidental awareness during general anaesthesia (AAGA) is a rare but severe complication of anaesthetic care. Despite advances in physiological monitoring and an improved understanding of the neural mechanisms underlying anaesthesia, the incidence of AAGA has remained steady for several decades.1 At present, there is a disparity between reports of AAGA from patients (1–2 in 1000 general anaesthetics) and from anaesthesia care providers (1 out of 15,000 general anaesthetics).2 The 5th National Audit Project (NAP5) of the Royal College of Anaesthetists, the largest patient-centred report on AAGA to date, examined more than 400 individual experiences of AAGA and found considerable variation in the incidence of AAGA across anaesthetic techniques.3
The long-term health-related consequences of AAGA can be devastating. We note that 43% (15/35) of patients with history of definite or possible AAGA in three major AAGA trials including the B-Unaware (Anaesthesia Awareness and the Bispectral Index) trial, the BAG-RECALL (BIS or Anaesthesia Gas to Reduce Explicit Recall) trial, and the MACS (Michigan Awareness Control Study) trial, met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for the diagnosis of post-traumatic stress disorder (PTSD).4, 5, 6, 7
It is important to understand the risk factors that predispose to AAGA. This knowledge is expected to guide our clinical practice, given that 73.6% (81/110) of the certain/probable reports of AAGA cases examined by NAP5 were considered preventable.8 Because studies of AAGA have typically focused on risk factors and prevention strategies, insights into the pathophysiology of AAGA-induced stress disorders are limited. Studies to inform evidence-based management of AAGA-induced stress disorders have also been limited by the relatively low-frequency occurrence of AAGA.
This review explores the psychological implications of AAGA and summarises current recommendations for management of AAGA. The American Psychiatric Association's practice guidelines for psychopharmacological and psychotherapeutic interventions that have been extrapolated to patients who have experienced AAGA are discussed. Lastly, current recommendations for anaesthetists on the immediate management of patients who have experienced AAGA are addressed.
Incidence
Although the reported incidence of AAGA has been consistent at 1–2 out of 1000 general anaesthetics for the past decades, there are substantial variations between subspecialties and groups of patients. It is well established that the incidence of AAGA is significantly higher in paediatric, obstetric, and cardiac anaesthesia.9, 10, 11 Interestingly, the incidence of AAGA is also heavily skewed towards women. A review of litigations related to AAGA in the UK showed that 117 out of 159 (74%) of AAGA claims were from women, and two thirds were related to obstetric care.12 Similarly, in the USA, closed claims data of AAGA revealed that 61 out of 79 (77%) claims were also from women.13 These numbers indicate that there may be a sex susceptibility to AAGA or possibly, a reporting bias. Genetic predisposition to AAGA has also been suggested. For example a secondary analysis of 26,490 patients in the B-Unaware trial, BAG-RECALL trial, and MACS trial revealed that patients with a history of AAGA were five times more likely to experience AAGA again (relative risk=5.0; 95% CI, 1.3–19.9).14 Table 1 summarises the key findings and limitations of five major studies of AAGA.
Table 1.
Summarizes the key findings and limitations of 5 major AAGA trials. BIS (Bispectrial index), CI (Confidence interval), ARR (Absolute risk reduction), NMB (Neuromuscular Blockade), NNTB (Number-needed-to-treat in order to benefit one person), MAC (Minimum alveolar concentration).
| Trials | Number of patients | Target population | Incidence of AAGA | Study design | Statistical finding (95% CI) | Findings/Limitations |
|---|---|---|---|---|---|---|
| B-Aware (2004)15 | 2463 | High risk for AAGA | BIS group: 1/1225 (0.17%) Routine care group: 11/1238 (0.91%) |
|
Fisher's exact test, P=0.03 ARR 0.14%–1.4%16 NNTB 697 to7016 |
|
| B-Unaware (2008)4 | 1941 | High risk for AAGA | BIS group: 2/974 (0.21%) MAC group: 2/967 (0.21%) |
|
No difference ARR -0.57%–0.56%16 NNTB ∞ to 17916 |
|
| BAG-RECALL (2011)5 | 5713 | High risk for AAGA | BIS group: 8/2861 (0.28%) MAC group: 2/2852 (0.0.07%) |
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No difference ARR –0.49%–0.02%16 NNTB ∞ to 467316 |
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| MACS (2012)6 | 18,836 of 30,000 goal reached | All surgical patients |
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No difference |
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| NAP5 (2014)3 | 300 | Individuals who experienced AAGA and volunteered to report their experience | ∼1:19,000 in all anaesthetics ∼1:8600 when NMB was used ∼1:8600 in cardiothoracic anaesthesia ∼ 1:670 Caesarean section |
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The incidence of certain/probable and possible accidental awareness cases was ∼1:19,600 anaesthetics |
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AAGA, accidental awareness under general anaesthesia; ARR, ; BIS, bispectral index; MAC, ; NMB, ; NNTB.
The incidence of AAGA in NAP5 (∼1 out of 19,600) was remarkably lower than in previous reports. Patients in the NAP5 study actively sought to report their personal experience of AAGA via a secure online portal. The authors of NAP5 argued that the occurrence of AAGA reported to NAP5 may be more relevant in clinical practice, as patients chose to report the event spontaneously. Even if differences in the incidence of AAGA from NAP5 and the Brice interview cannot be explained easily, the importance of patient-reported and thoroughly investigated incidences of AAGA should not be undervalued.17
Risk factors
To obtain comparator data, NAP5 used information from a nationwide activity survey as denominator data for AAGA cases. The NAP5 investigators reported a 10-fold increase in the incidence of AAGA in obstetric patients and a 2.5-fold increase in cardiothoracic patients. It appeared that female sex increased susceptibility as 91 out of 141 (65%) cases of AAGA involved female patients. Obese patients were three times more likely to experience AAGA, and the use of total intravenous anaesthesia was overrepresented in patients who experienced AAGA (18% in AAGA cases vs 8% overall).
The anaesthetic drug type, or perhaps the use of anaesthetic drugs that are typically reserved for emergencies, increased the risk of AAGA. Ketamine, etomidate and thiopental were used most often in the AAGA activity survey cohort, with ratios of 17.2, 14.3, and 8.2, respectively, whereas propofol's ratio of use was 0.9. The incidence of AAGA increased from 1 out of 135,000 general anaesthetics to 1 out of 8200 general anaesthetics when neuromuscular blocking drugs were used. Importantly, monitoring and reversal of neuromuscular block were less frequent in those with AAGA. Processed electroencephalogram (pEEG) monitoring was used in only 2.8% of all general anaesthetics in the activity survey, and AAGA occurred despite use of pEEG monitor in 6 out of 141 (4.3%) cases of AAGA. However, it is unclear whether the anaesthetists had access to the raw EEG or spectrogram for anaesthetic state monitoring. Owing to limited usage, the NAP5 investigators were not able to derive a meaningful statistical analysis between pEEG use and AAGA.
The patient’s experience of accidental awareness during general anaesthesia
Spontaneous reports of AAGA did not occur routinely after the precipitating event. Only 47 out of 141 (33%) reports were made on the day of the surgery and less than half within the first 24 h. Interestingly, only 35 out of 141 (25%) reports were made to the anaesthetist who took care of the patient. Many patients first reported AAGA during preparations for a subsequent procedure, as patients became understandably anxious about having general anaesthesia. These findings highlight the need to perform postoperative checks on patients and may explain the disparity between patients' and anaesthetists' reports of AAGA. Twelve patients (11%) submitted a formal complaint to the hospital, and 8 (6%) initiated legal action.
Patients' experiences of AAGA varied. NAP5 found that in 47% of AAGA cases, the recall of AAGA was described in a neutral way, involving few isolated aspects of the experience, such as auditory and tactile memory. However, the other 53% of the AAGA events were associated with distress. The primary causes of distress were paralysis and pain. Not surprising, all forms of distress were strongly associated with long-term psychological consequences, such as flashbacks, insomnia, fear of future surgery, and PTSD.
Psychophysiological mechanisms of PTSD
The alert, non-stressed brain benefits from a top–down management system, such that the medial prefrontal cortex (mPFC) down-regulates amygdala-driven fear conditioning through axonal stimulation of inhibitory γ-aminobutyric interneurones in the basolateral region of the amygdala.18 In contrast, the stressed brain is marked by a diminished capacity of the mPFC and the hippocampus to act as checkpoints on the excitatory flow that emerges from the amygdala. This leads to a bottom–up system, characterised by more reflexive and habitual responses by the primitive brain circuits in the limbic system.19 Neuroimaging data on PTSD neurocircuitry supports the importance of the inhibitory control of the mPFC over the amygdala by showing that a diminution in mPFC function is associated with the heightened amygdala activity seen in PTSD.20 To our knowledge, changes in neural structure and functional connectivity have not yet been investigated in subjects with AAGA compared with matched controls using neuroimaging. Figure 1 illustrates the neural circuitry involved in fear conditioning and PTSD.
Fig 1.
Schematic diagram of neural circuitry Involved in fear conditioning and post-traumatic stress disorder. A, Primary brain regions involved in regulating fear and threat responses are the amygdala, the hippocampus, and the medial prefrontal cortex, which comprises dorsal (dmPFC) and ventral (vmPFC) subdivisions; the orbitofrontal cortex (OFC); and the anterior cingulate cortex (ACC). B, Amygdala-specific circuits that are involved in fear conditioning. The sensory information representing the conditioned stimulus (e.g. previously neutral stimulus such as driving a car) is integrated within the amygdala with the unconditioned stimulus information (e.g. a traumatic event such as an explosion in a car). The amygdala is central in the neural circuit involved in regulating fear conditioning. In general, input to the lateral nucleus (LA) of the amygdala leads to learning about fear, whereas the central amygdala (lateral [CeL] and medial [CeM] subdivisions) is responsible for sending output signals about fear to the hypothalamus and brainstem structures. The intercalated cell masses (ITC) are thought to regulate inhibition of information flow between the basal nucleus (BA) and central amygdala. C and D, Interactions between components of the mPFC and the hippocampus constantly regulate the amygdala's output to subcortical brain regions activating the fear reflex. The mPFC (in particular, the vmPFC) is classically thought to inhibit amygdala activity and reduce subjective distress, while the hippocampus plays a role both in the coding of fear memories and also in the regulation of the amygdala. The hippocampus and mPFC also interact in regulating context and fear modulation. Figure 1 adapted from Ross et al.21
General anaesthesia and neural circuitry of PTSD
Inhibition of long-term potentiation of the γ-aminobutyric acid type A receptor in the hippocampus and other parts of the medial temporal lobe memory system – amygdala and the hippocampal region including perirhinal, entorhinal, and parahippocampal cortices – are associated with amnesia during anaesthesia.22 AAGA may result in a net effect summarised by a failure to downregulate glutamatergic and norepinephrine pathways emanating from the amygdala. Moreover, painful stimuli may further increase amygdala activity. A putative downstream effect of increased amygdala output leads to activation of hypothalamic and brainstem circuits underlying high arousal fight–flight–freeze and behavioural inflammatory response syndromes. Hence, the amygdalar activity surge during AAGA may lay down a permanent emotionally traumatic memory (PTSD) through excitotoxic long-term potentiation. 23
Psychological assessment and diagnosis
Patients who experience AAGA are often traumatised. Patients in the NAP5 study described feelings of panic, extreme fear, dissociation, suffocation, and fear of dying. In some, the distress persisted with long-term symptoms of post-traumatic stress. The distress of AAGA may emerge soon after the event, qualifying it as an acute stress disorder (ASD).
The presence of nine symptoms or more from the five categories of intrusion, negative mood, dissociation, avoidance, and arousal is required to make the diagnosis of ASD, with symptoms beginning or worsening after the traumatic event(s) occurred. The diagnosis of ASD ranges between 3 days and 1 month after exposure to the traumatic event. Sleep disturbance (e.g. difficulty falling or staying asleep, restless sleep), irritable behaviour, and angry outbursts (with little or no provocation) that are typically expressed as verbal or physical aggression toward people or objects are seen in ASD. In addition, patients may display hypervigilance, concentration difficulties, and an exaggerated startle response.
Post-traumatic stress disorder is diagnosed when these symptoms last for more than 1 month after a traumatic event. Some patients do not initially present with PTSD, making the diagnosis challenging. The exposure scenario for PTSD is the same as in ASD. However, the traumatic event is persistently re-experienced with upsetting memories, nightmares, flashbacks, distress after traumatic reminders, and physical reactivity after exposure to trauma reminders.
The Psychological Sequelae of Surgery Study (Psych SOS) was a prospective 2 yr cohort study involving participants of three AAGA prevention trials: B-Unaware trial, BAG-RECALL trial, and MACS trial. 24 The study confirmed that experiencing AAGA substantially increased the risk of PTSD. The risk factors for post-surgical PTSD included poor social support; history of PTSD; prior mental health treatment; dissociation related to the surgery; perceiving that one's life was in danger during surgery; and intraoperative awareness. Recognising these risk factors during patient screening can be useful for promoting early diagnosis and treatment referrals.
Management
To our knowledge, there are no specific treatment guidelines for AAGA. Instead, treatment recommendations have been extrapolated from our current understanding of general PTSD. The American Psychiatric Association published treatment guidelines for ASD and PTSD in 2004 with updates in 2014. 25 There is no evidence-based psychopharmacological recommendation that prevents ASD and PTSD in patients at risk. Treatment with selective serotonin reuptake inhibitors (SSRIs) can be used for both ASD and PTSD. SSRIs are recommended as first-line medication for PTSD because they can reduce symptoms of re-experiencing, avoidance, numbing, and hyperarousal. SSRIs are also effective for psychiatric disorders that frequently coexist with PTSD (e.g. depression, panic disorder, social phobia, and obsessive-compulsive disorder). They may reduce symptoms such as suicidality, impulsivity, and aggression that complicate the management of PTSD. They also are generally well tolerated, although with continued use, adverse effects may occur on discontinuation. Other antidepressants can also be beneficial. Benzodiazepines may reduce acute anxiety and help with sleep, but they have not been establised to prevent ASD or PTSD, or treat the core symptoms of PTSD. Caution is warranted given their potential for abuse. Anticonvulsants such as divalproex, carbamazepine, topiramate, and lamotrigine may help treat re-experiencing symptoms of nightmares and flashbacks. The atypical antipsychotic medications including olanzapine, quetiapine, and risperidone may be helpful in some patients. These drugs may be also indicated for patients with comorbid psychotic disorders or when first-line approaches have been ineffective in controlling symptoms. Alpha2-adrenergic agonists and α1-adrenergic blockers may also provide symptomatic relief.
Early supportive psychotherapeutic interventions, along with psychoeducation and case management that encourage reliance on inherent resilience and good sound judgement, can be very beneficial after acute trauma. This is because they promote engagement in ongoing care and can lead to the use of appropriate treatments. Patients diagnosed with ASD and PTSD may also benefit from cognitive behavioural therapy with an exposure component. Eye movement desensitisation and reprocessing, which includes a brief, interrupted exposure-based therapy, directed eye movements, along with recall and venting of traumatic memories in the setting of relaxation response elicitation, may also be helpful. Stress inoculation, imagery rehearsal, and prolonged exposure techniques may reduce PTSD-associated anxiety and avoidance symptoms. Present-centred and trauma-focused group therapies may also reduce the severity of symptoms. Psychological debriefing is not recommended as there is no evidence to suggest it is effective in preventing PTSD.
There have been three recent meta-analyses of data on the management of PTSD. The first focused on psychological interventions for adults with PTSD.26 The second focused on pharmacological treatment.27 The third compared outcomes and acceptability of psychotherapeutic and pharmacological treatments and their combination in adults with PTSD.28 According to these meta-analyses, patients with PTSD clearly benefit from psychological interventions, although there is no evidence that one intervention is superior to another. Desipramine, fluoxetine, paroxetine, phenelzine, risperidone, sertraline, and venlafaxine were more effective than placebo for symptomatic PTSD. Thus, evidence supports a choice of psychotherapeutic approaches as first-line treatments for PTSD. It is notable that treatment combining both psychotherapy and psychopharmacology was superior in the long term. Table 2 summarises the key findings and limitations of these meta-analyses.
Table 2.
Summarises the key findings and limitations of the meta-analyses on management of PTSD. RCTs (Randomised controlled trials), SMD CI, confidence interval; PTSD, post-traumatic stress disorder; RCTs, Randomised controlled trials; SMD, Standardised mean difference.
| Meta-analysis | Method | Data | Findings | Limitations |
|---|---|---|---|---|
| Psychological interventionsGerger and colleagues26 | RCTs that involved psychological interventions for adults with PTSD | 4190 patients 66 trials Intervention categories
|
|
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| Pharmacological InterventionsCipriani and colleagues27 | RCTs that involved any pharmacological intervention or placebo as oral therapy for adults with PTSD | 6189 patients 51 trials Pharmacological medications: Desipramine, fluoxetine, paroxetine, phenelzine, risperidone, sertraline, venlafaxine, phenelzine, mirtazapine, olanzapine, brofaromine, amitriptyline, topiramate, imipramine, nefazodone, NK1R antagonist, guanfacine, tiagabine, prazosin, bupropion, divalproex, citalopram, lamotrigine, nefazodone |
|
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| Comparison of psychotherapeutic, pharmacological and combination treatmentMerz and colleagues28 | RCTs that compares outcomes and acceptability of psychotherapeutic and pharmacological treatments and their combination in adults with PTSD | 922 patients 12 RCTs 23 direct comparisons between psychotherapeutic and pharmacological treatments or their combinations Outcome analysis:
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The NAP5 awareness support pathway emphasises the importance of: (i) face-to-face postoperative meeting with patients that experience AAGA; (ii) early consultation with a psychiatrist or psychologist and early assessment of flashbacks, nightmares, new level of anxiety, and depressed mood; and (iii) active follow-up at 2 weeks to assess for new or ongoing needs for treatment referrals.
The NAP5 was a large-scale survey that characterised the incidence of AAGA in the UK and Ireland. Thus, extrapolating the findings of NAP5 outside of the UK and Ireland warrants careful consideration.29 This is because cultural and societal norms, which can fundamentally shape patients' expectations of care may vary between different populations.
Conclusions
Accidental awareness under general anaesthesia is associated with ASD and PTSD in patients who experience distress, such as paralysis and pain during the event. However, evidence-based therapeutic management strategies for ASD and PTSD have been constrained by the relatively low incidence of AAGA. Thus, treatment strategies are based on extrapolations from patients with PTSD that is not associated with AAGA. Because significant depression affects 30–50% of patients diagnosed with PTSD, drug treatment with antidepressants in combination with cognitive behavioural therapy can be especially helpful.30 All reports of AAGA should be taken very seriously and institutional guidelines should be in place to follow the NAP5 awareness support pathway. Anaesthetists should be aware of the risk factors for AAGA and choose their anaesthetic plan carefully, especially regarding use of neuromuscular blocking drugs and TIVA. Future prevention research might study the effects of targeted psychological therapies in patients at risk for post-surgical PTSD.
Declaration of interests
The authors declare that they have no conflicts of interest.
Biographies
Meerim Cindy Kim MD is an attending anaesthetist at Massachusetts General Hospital, and an instructor in anaesthesia at Harvard Medical School. Her major clinical and research interests are anaesthesia for neurosurgery and EEG monitoring for anaesthesia.
Gregory Fricchione MD is associate chief of psychiatry at the Department of Psychiatry, Massachusetts General Hospital. He is also the director for the Division of Psychiatry and Medicine and Benson-Henry Institute for Mind Body Medicine at the McCance Center for Brain Health.
Oluwaseun Akeju MD MMSc is the anaesthetist-in-chief at the Massachusetts General Hospital and the Henry Isaiah Dorr Associate Professor of Research and Teaching in Anaesthetics and Anaesthesia at Harvard Medical School.
Matrix codes: 1E06, 2A04, 3J02
MCQs
The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.
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