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Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical commentary
Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing Jessica McLellan BPsych a, Laurence A.G. Marshman b,c,⇑, Maria Hennessy a a
Department of Psychology, James Cook University, Douglas, Townsville 4810, Queensland, Australia Department of Neurosurgery, The Townsville Hospital, Douglas, Townsville 4810, Queensland, Australia c School of Medicine and Dentistry, James Cook University, Douglas, Townsville 4810, Queensland, Australia b
a r t i c l e
i n f o
Article history: Received 26 November 2016 Accepted 15 June 2017 Available online xxxx Keywords: Retrograde amnesia Opioids Disorientation Anterograde amnesia
a b s t r a c t The Glasgow Coma Scale (GCS) only assesses orientation after traumatic brain injury (TBI). ‘Posttraumatic amnesia’ (PTA) comprises orientation, anterograde amnesia (AA) and retrograde amnesia (RA). However, RA is often disregarded in formalized PTA assessment. Drugs can potentially confound PTA assessment: e.g. midazolam can cause AA. However, potential drug confounders are also often disregarded in formalized PTA testing. One study of medium-stay elective-surgery orthopaedic patients (without TBI) demonstrated AA in 80% taking opiates after general anesthesia. However, RA was not assessed. Opiates/opioids are frequently administered after TBI. We compared AA and RA in short-stay orthopaedic surgery in-patients (without TBI) taking post-operative opioids after opiate/opioid/benzodia zepine-free spinal anesthesia. In a prospective cohort, the Westmead PTA Scale (WPTAS) was used to assess AA (WPTAS < 12), whilst RA was assessed using the Galveston Orientation and Amnesia Test RA item. Results were obtained in n = 25 (60 ± 14 yrs, M:F 17:8). Surgery was uncomplicated: all were discharged by Day-4. All were taking regular oxycodone as a new post-operative prescription. Only one co-administered non-opioid was potentially confounding (temezepam, n = 4). Of 25, 14 (56%) demonstrated AA: five (20%) were simultaneously disorientated. Mean WPTAS was 11.08 ± 1.22. RA occurred in 0%. Conclusions: AA and disorientation, but not RA, were associated with in-patients (without TBI) taking opioids. Caution should therefore be applied in assessing AA/orientation in TBI in-patients taking opioids. By contrast, retrograde memory was robust and more reliable: even in older patients with iatrogenic AA and disorientation. RA assessment should therefore be integral to assessing TBI severity in all formalized PTA and GCS testing. Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
1. Introduction The Glasgow Coma Scale (GCS) is widely used to determine conscious level after traumatic brain injury (TBI) [1]. However, the GCS only assesses orientation [1]. The post-TBI syndrome, incompletely referred to as ‘post-traumatic amnesia’ (PTA) [2], comprises disorientation as well as retrograde amnesia (RA: defective memory of events prior to TBI) and anterograde amnesia (AA: defective memory subsequent to TBI). Noting that orientation usually recovered first [2], Russel and Symonds, two of the earliest pioneers in ⇑ Corresponding author at: Department of Neurosurgery, The Townsville Hospital, Douglas, Townsville 4810, Queensland, Australia. E-mail address: [email protected] (L.A.G. Marshman).
post-TBI assessment, emphasized the equal importance of both RA and AA testing in determining TBI recovery [2–9]. In particular, Russel opined that if, after TBI ‘‘..a patient is able to correctly describe events preceding the loss of consciousness by only a few minutes or seconds, then consciousness has returned in full” [3]. However, despite such emphasis, most current formalized PTA testing (i.e. in institutions using tests other than the Galveston Orientation and Amnesia Test [GOAT]) omits any RA assessment [2]. Instead, only resolution of orientation and AA is commonly used to determine recovery after TBI, to determine TBI severity, and to determine hospital discharge [2]. Thus, both the GCS and much formalized PTA testing are, potentially, incomplete. A recent review article also emphasized that the potential effect of concurrent medication, as a potentially confounding factor in
http://dx.doi.org/10.1016/j.jocn.2017.06.027 0967-5868/Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027
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J.McLellan BPsych et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
PTA assessment, is also often disregarded in much formalized PTA assessment after TBI [2]. This is despite the fact that Symonds, in 1942, had specifically cautioned that, for example, ‘‘..it is important to know whether the patient has been given morphia” when assessing PTA [8]. Indeed, it is now known that certain drugs (e.g. midazolam) can specifically elicit AA in patients without TBI [10]. This fact is exploited in day case procedures, such as endoscopy [10]. Opiates/opioids are frequently administered to TBI patients: either for headache, or for other concurrent injuries. Pertinently, a recent pilot study suggested that as many as 80% of medium-stay elective orthopaedic in-patients (without TBI) failed formalized PTA testing criteria whilst receiving opiates after general anesthesia (GA) [11]. However, in common with much formalized PTA practice, RA was not assessed in that study [11]. Thus, while AA may be overestimated, the potential effect of either opiates, or opioids, on RA currently remains unknown. In Australia, the Westmead PTA scale (WPTAS) is widely used to formally assess PTA after TBI. However, the WPTAS does not include a history of drug use, and it does not formally assess RA. We therefore aimed to compare AA and RA in short-stay orthopaedic surgery in-patients (without TBI) taking post-operative opioids after uncomplicated opiate/opioid-free and benzodiazepine-free spinal anesthesia. 2. Methods A convenience sample of in-patients on an orthopaedic ward in a major regional public hospital were prospectively studied after local ethics committee approval. All patients had undergone elective or semi-elective (typically joint replacement) surgery as a short stay (i.e. less than 4 days) procedure using opiate/opioidfree and benzodiazepine-free spinal anesthesia (bupivacaine combined with propofol sedation) of duration less than 3 h. Patients were included if they were older than 18 yrs and of ASA grade 1 or 2. Patients were excluded if they were regularly taking opioids other than codeine phosphate 15 mg as required, or any other recently prescribed potentially psycho-active drug including tramadol, anti-convulsants, major or minor tranquillizers, amitriptylline, or illicit or prescribed cannabinoids. Patients were also excluded if they had a history of current psychiatric disorder, substance abuse, alcohol abuse, recent or concurrent TBI, or any neurological disorder affecting cognition, memory or conscious level. Finally, patients were excluded if spinal anesthesia duration was greater than 3 h, or if surgery had been in any way complicated. All participants were given an information sheet detailing the study before signing a consent form in agreement to participate. The WPTAS was used to assess AA [12]. WPTAS < 12 was considered to indicate evidence of AA [12]. Since there is no evidence for three consecutive WPTAS day testing, and only evidence against it [2,13,14], WPTAS was recorded from only one day of testing. RA was assessed using the GOAT RA item [15]. RA was considered absent if patients could remember key events, in detail, immediately prior to the delivery of spinal anesthesia. All post-operative psychometric testing (WPTAS and GOAT-RA) was performed between 24-36 h after surgery (dependent upon the extent of surgery) in order to minimize any potentially confounding effects of drugs co-administered during surgery [16]. All patients were prescribed oral oxycodone on a regular basis immediately postoperatively as a new prescription in addition to non-steroidal anti-inflammatory agents and paracetomol. 3. Statistical analysis Normality of score distribution for dependent variables was examined using skewness, kurtosis, stem and leaf plots, and the
Shapiro-Wilks statistic. Assumptions of normality were confirmed for all dependent variables. Homogeneity of variance was considered using the Levene Test for Equality of Variance and were not violated. Analysis of variance (ANOVA) was therefore performed with statistical significance determined as P < 0.05. Effect sizes (eta squared, g2) were calculated. According to Cohen (1988) a small g2 effect size is 0.01, a medium g2 is 0.06, and a large g2 0.014 [17]. 4. Results Results were obtained in n = 25 (mean age 60 ± 14 yrs, M:F 17:8) (Table 1). Six (24%) had suffered recent trauma to the region operated: none of these cases, however, had been associated with alcohol. No case had suffered multiple trauma. Sixteen (64%) patients were discharged by Day 2 of surgery, 24 (96%) by Day3 and 100% by Day 4. All 25 patients (100%) studied were taking the opioid oral oxycodone on a regular basis post-operatively as a standard new prescription. The same treatment is standard for TBI in-patients on the neurosurgery ward. The most commonly co-administered drug was oral oxycodone/naloxone (10/25, 40%) (Table 1): six of these (40%) returned a WPTAS < 12/12. Temezepam was coadministered in four (WPTAS < 12/12 in all four cases). Subcutaneous fentanyl was co-administered in two (WPTAS = 12/12 in both). Buprenorphine was co-administered in one (with WPTAS < 12), whilst codeine (the only opiate) was coadministered in one other (WPTAS = 12/12). Two patients were taking non-tricyclic anti-depressants (Table 1). The opiate morphine was not administered in our study. The mean WPTAS total score was 11.08 ± 1.22. Those with an abnormal WPTAS were older than those with a normal WPTAS (65.8 ± 10.8 yrs v 55.6 ± 15.5 yrs): however, this was not statistically significant (P = 0.06, g2 = 0.141439). The mean WPTAS of patients with an abnormal score (WPTAS = 10.3 ± 1.1) was significantly reduced compared to those with a normal score (WPTAS = 12), (P < 0.0001, g2 = 0.517816). Of 25 patients without TBI, 14 (56%) demonstrated evidence of AA (Table 1). Whilst all 56% patients specifically failed memory testing, 5/14 (36%) of these also failed orientation testing: i.e. 5 (20%) were also disorientated. By contrast, 0/25 (0%) demonstrated evidence of RA. 5. Discussion Certain drugs (e.g. midazolam) can specifically elicit AA in patients without TBI [10]. A recent pilot study by Mc Carter et al. also suggested that, of medium-stay elective orthopaedic inpatients without TBI, as many as 80% failed WPTAS testing criteria whilst receiving opiates (i.e. morphine or codeine) [11]. Unfortunately, in keeping with much formalized PTA practice, RA was not assessed [11]. Furthermore, the latter study [11] comprised only 17 patients where some had been hospitalized for longer than in current elective orthopaedic practice [18], and where all had undergone GA [11]. It is therefore possible that some might have suffered confounders related either to a prolonged GA (with potentially significant ‘hang-over’) or to peri-operative complications. By contrast, all but one in our study had been discharged by Day 3; whilst all had been discharged by Day 4. All had therefore undergone uncomplicated elective or semi-elective surgery using opiate/opioid-free and benzodiazepine-free spinal anesthesia for less than 3 h. Psychometric testing was performed 24–36 h after commencement of regular post-operative analgesia [16]. In contrast to the study of McCarter et al. (where no single opiate was common to all), all our patients were regularly taking the opioid oxycodone as a standard new post-operative prescription.
Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027
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Table 1 WPTAS and GOAT-RA Scores and medication. Key: WPTAS Westmead Post Traumatic Amnesia Scale, GOAT-RA Galveston Orientation and Amnesia Test Retrograde Amnesia item. Maximal orientation item is 7/7, maximal memory item is 5/5: maximum total is 12/12. Opioid/opiate analgesia: O oral oxycodone, ON oral oxycodone/naloxone, F subcutaneous fentanyl, B oral buprenorphine, C oral codeine. Non-opioid/opiate analgesia: M meloxicam (non-steroid anti-inflammatory analgesia), T temazepam (benzodiazepine), E escitalopram (selective serotonin reuptake inhibitor), D duloxetine (serotonin–norepinephrine reuptake inhibitor). Participant
Age (yrs)
WPTAS Orientation, Memory (total)
GOAT-RA
Drugs
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
52 22 54 50 65 70 43 74 65 61 65 76 54 77 75 69 49 78 46 52 67 53 78 77 60
7, 7, 7, 7, 7, 7, 7, 7, 6, 7, 7, 6, 7, 5, 7, 7, 6, 7, 6, 7, 7, 7, 7, 7, 6,
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
O O O, F, C O O, T, E O, ON O, ON O O, ON O, F, D O, ON O, ON O O O O, ON, T O, ON, D O, T O, T ON, M O, B O, ON ON O O
5 5 5 5 4 5 5 4 4 5 5 5 5 2 4 4 4 4 4 4 4 5 4 5 3
(12) (12) (12) (12) (11) (12) (12) (11) (10) (12) (12) (10) (12) (7) (12) (11) (10) (11) (10) (11) (11) (12) (11) (12) (9)
The same treatment is standard for TBI in-patients on the neurosurgery ward. Opioids purportedly have less side effects than opiates. Notwithstanding, 56% of 25 patients demonstrated evidence of AA in our study. The overall mean WPTAS was reduced to 11.08 ± 1.22, but was significantly reduced in those affected (WPTAS: 10.3 ± 1.1 v 12, P < 0.0001, g2 = 0.517816). Whilst all 56% evidenced AA, 5/25 (20%) were simultaneously disorientated (Table 1). This contrasts with Mc Carter et al. where no disorientation was recorded [11]. Disorientation, but not AA or RA, reduces the GCS. Whilst opioids, as opposed to opiates, could have been responsible for disorientation, our study comprised older subjects. Indeed, those with an abnormal WPTAS were older than those with a normal WPTAS (65.8 ± 10.8 yrs v 55.6 ± 15.5 yrs, P = 0.06, g2 = 0.141439). However, whilst drug-related cognitive side-effects may be more likely in those with cerebral atrophy, atrophy is not an inevitable consequence of normal ageing. Instead, atrophy is determined by comorbid risk factors (at least under 70 yrs) [19]. All our patients were ASA grades 1 and 2, and did not have a disorder affecting cognition, memory or conscious level. Notwithstanding, despite AA and disorientation, no Patient evidenced RA in our older sample. Indeed, retrograde memory remained robust even in cases where other co-administered drugs (especially temezepam) could have been co-confounders. Our study is therefore the first to demonstrate that AA and disorientation, but not RA, are associated with in-patients (without TBI) taking opioids. Opioids therefore represented a potential confounder to PTA or GCS testing in our study, just as Symonds [8] and McCarter et al. [11] had concluded with opiates. Notably, this is additional to other defects previously outlined with routine WPTAS testing [2]: in particular, those associated with construct, criterion and externalization validity [2]. Had affected patients in our study have suffered a mild concurrent TBI (with uneventful recovery) they could have been falsely diagnosed with ‘PTA’ [11], or with ‘confusion’ (GCS = 14). Such misdiagnosis could have unnecessarily consumed hospital resources [2], risked litigation [11], and lead to excess social, financial and opportunity costs [2]: especially in regional
hospitals which service wide geographical regions [2]. Such costs would also have been exacerbated in those hospitals which continue the non-evidence-based practice [2,14] of three-day consecutive testing of WPTAS = 12/12 to ‘prove’ recovery after TBI. This is especially so where patients typically fluctuate about the maximal score on WPTAS: achieving a maximal score one day, only to regress on the next [2,14]. Participants in our study would potentially have suffered a comparable generalized stress response to that of TBI in-patients. However, unlike our patients, many TBI patients would also have undergone GA (with opiates and benzodiazepines) for several hours, if not days, prior to PTA testing. In our study, we minimized potentially confounding factors related to any history of a current psychiatric or neurological disorder affecting cognition, memory or conscious level; or to recently prescribed concurrent potentially psycho-active drugs. Furthermore, all psychometric testing was performed between 24–36 h after uncomplicated spinal anesthesia [16]. Notably, TBI in Australian adults is bimodal, with peaks in age groups 15–19 yrs, and over-85 yrs [20]. Our study therefore compliments that of Mc Carter et al. whose age range (18–55 yrs: mean 36.3 ± 13.2 yrs) tended toward the younger peak [11], whilst our study tended toward the older peak (22–78 yrs, mean 60 ± 14 yrs). Russel and Symonds, two of the earliest pioneers in post-TBI assessment, emphasized the equal importance of both RA and AA testing in determining recovery from TBI [2–9]. The results of our study are therefore relevant to routine PTA testing after TBI. Specifically, whilst caution should be applied in assessing orientation and AA in TBI in-patients taking either opiates or opioids, RA assessment is not so confounded. RA assessment is thus a potentially more reliable measure of TBI severity than AA or orientation assessment in in-patients taking commonly-used psycho-active analgesic drugs after TBI. In contrast to current practice, RA assessment should therefore form an integral part of routine post-TBI PTA testing. Further, since orientation was affected in 20%, and given its ease of administration, RA assessment should also be used to assess the GCS. Wherever RA is absent, and wherever drug confounders might be operative in in-patients, one might justifiably
Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027
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question the veracity of either AA or GCS = 14 (‘confused’) when these have been otherwise recorded. Our study is limited principally by its small sample size. However, this was largely due to the stringent inclusion/exclusion criteria, as detailed in the study Methodology; and effect sizes (eta squared, g2) were calculated. Notwithstanding, the rates of AA and disorientation observed were disturbingly significant. Furthermore, caution should be applied in that, whilst our study emphasized formalized PTA testing, ultimate clinical decision-making after TBI may often take into account the effect of potential drug confounders irrespective of any formalized PTA score obtained. Finally, our mean study sample age was older than a typical TBI population, and abnormal WPTAS scores were lower still in older patients within this sample. Although this may appear to signify that older subjects are more prone to drug confounders, our small study sample size precluded any definitive statement. 6. Conclusions AA and disorientation, but not RA, are associated with inpatients (without TBI) taking opioids. Caution should therefore be applied in assessing AA/orientation in TBI in-patients taking opioids. By contrast, retrograde memory appeared robust and more reliable: even in older patients with iatrogenic disorientation. RA assessment, as a reliable measure of TBI severity, should therefore be integral to routine PTA and GCS testing: in contrast to currentformalized practice. Wherever RA is absent, and wherever drug confounders might be operative, the veracity of either ‘AA’ or GCS = 14 (‘confused’) should be questioned. Funding No external funding was received. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement None. References [1] Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2(7872):81–4. http://dx.doi.org/10.1016/S01406736(74)91639-0. PMID 4136544. [2] Marshman L, Jakabek D, Hennessy M, Quirk F, Guazzo E. Review article: posttraumatic amnesia. J Clin Neurosci 2013;20(11):1475–81. http://dx.doi.org/ 10.1016/j.jocn.2012.11.022. Epub 2013 Jun 20.
[3] Russell WR. Cerebral involvement in head injury: a study based on the examination of two hundred cases. Brain 1932 Dec;55(4):549–603. http://dx. doi.org/10.1093/brain/55.4.549. [4] Symonds CP. Traumatic epilepsy. Lancet 1935 Nov;226(5857):1217–20. http:// dx.doi.org/10.1016/S0140-6736(00)47408-8. [5] Symonds CP. Disturbance of cerebral function in concussion. Lancet 1935 Mar;225(5818):486–8. http://dx.doi.org/10.1016/S0140-6736(01)00732-2. [6] Symonds CP. Mental disorder following head injury. Proc R Soc Med 1937;30:34–46. [7] Symonds CP. Concussion and contusion of the brain and their sequelae. In: Brock S, editor. Injuries of the skull, brain and spinal cord: Neuropsychiatric, surgical, and medico-legal aspects. Baltimore (US): Williams and Wilkins Co; 1940. p. 69–111. [8] Symonds CP. Discussion on differential diagnosis and treatment of postcontusional states [cited 14 May 2012] Available from:. Proc R Soc Med [Internet] 1942 Jul;35(9):601–14. http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1998300/pdf/procrsmed00629-0035.pdf. [9] Symonds CP, Russell WR. Accidental head injuries: prognosis in service patients. Lancet 1943;241(6227):7–10. http://dx.doi.org/10.1016/S0140-6736 (00)70687-8. [10] Hong YJ, Jang EH, Hwang J, Roh JH, Kwon M, Lee D, Lee JH. Effect of midazolam on memory during fiberoptic gastroscopy under conscious sedation. Clin Neuropharmacol 2015;38(2):47–51. http://dx.doi.org/10.1097/ WNF.0000000000000067. [11] McCarter RJ, Walton NH, Moore C, Ward A, Nelson I. PTA testing, the westmead post traumatic amnesia scale and opioid analgesia: a cautionary note. Brain Inj 2007;21(13–14):1393–7. http://dx.doi.org/10.1080/02699050701793793. [12] Shores EA, Marosszeky JE, Sandanam J, Batchelor J. Preliminary validation of a clinical scale for measuring the duration of post-traumatic amnesia [cited 14 May 2012] Available from:. Med J Aust [Internet] 1986 May;144(11):569–72. https://www.mja.com.au/journal/2003/178/6/4-rehabilitation-aftertraumatic-brain-injury. [13] Ponsford J, Facem P, Willmot C, Rothwell A, Kelly A-M, Nelms R, Ng KT. Use of the Westmead PTA scale to monitor recovery of memory after mild head injury. Brain Inj 2004;18(6):603–14. [14] Tate RL, Pfaff A, Baguley IJ, Marosszeky JE, Gurka JA, Hodgkinson AE, et al. A multicentre, randomised trial examining the effect of test procedures measuring emergence from post-traumatic amnesia. J Neurol Neurosurg Psychiatry 2006 Jul;77(7):841–9. http://dx.doi.org/10.1136/ jnnp.2005.074989. [15] Levin HS, O’Donnell VM, Grossman RG. The Galveston orientation and amnesia test: A practical scale to assess cognition after head injury. J Nerv Ment Dis 1979 Nov;167(11):675–84. http://dx.doi.org/10.1097/00005053-19791100000004. [16] Assessing fitness to drive. March 2012. Austroads. www.csanz.edu.au/wpcontent/uploads/2013/03/Assessing_Fitness_to_Drive.pdf. [17] Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988. [18] Salmon P, Hunt GR, Murthy BV, O’Brien S, Beverland D, Lynch MC, Hall GM. Patient evaluation of early discharge after hip arthroplasty: development of a measure and comparison of three centres with differing durations of stay. Clin Rehabil 2013 Sep;27(9):854–63. http://dx.doi.org/10.1177/ 0269215513481686. Epub 2013 Mar 29. [19] Lowe J, Mirra SS, Hyman BT, Dickson DW, Ageing and dementia. In: Love S, Louis DN, Ellison DW editor. Greenfield’s neuropathology, 8th ed., London: Hodder Arnold; 2008, Ch. 14. p. 1031–152. [20] Fortune N, Wen X. The definition, incidence and prevalence of acquired brain injury in Australia AIHW cat. no. DIS 15.. Canberra: Australian Institute of Health and Welfare; 1999. www.aihw.gov.au/WorkArea/DownloadAsset. aspx?id=6442455567.
Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical commentary
Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing Jessica McLellan BPsych a, Laurence A.G. Marshman b,c,⇑, Maria Hennessy a a
Department of Psychology, James Cook University, Douglas, Townsville 4810, Queensland, Australia Department of Neurosurgery, The Townsville Hospital, Douglas, Townsville 4810, Queensland, Australia c School of Medicine and Dentistry, James Cook University, Douglas, Townsville 4810, Queensland, Australia b
a r t i c l e
i n f o
Article history: Received 26 November 2016 Accepted 15 June 2017 Available online xxxx Keywords: Retrograde amnesia Opioids Disorientation Anterograde amnesia
a b s t r a c t The Glasgow Coma Scale (GCS) only assesses orientation after traumatic brain injury (TBI). ‘Posttraumatic amnesia’ (PTA) comprises orientation, anterograde amnesia (AA) and retrograde amnesia (RA). However, RA is often disregarded in formalized PTA assessment. Drugs can potentially confound PTA assessment: e.g. midazolam can cause AA. However, potential drug confounders are also often disregarded in formalized PTA testing. One study of medium-stay elective-surgery orthopaedic patients (without TBI) demonstrated AA in 80% taking opiates after general anesthesia. However, RA was not assessed. Opiates/opioids are frequently administered after TBI. We compared AA and RA in short-stay orthopaedic surgery in-patients (without TBI) taking post-operative opioids after opiate/opioid/benzodia zepine-free spinal anesthesia. In a prospective cohort, the Westmead PTA Scale (WPTAS) was used to assess AA (WPTAS < 12), whilst RA was assessed using the Galveston Orientation and Amnesia Test RA item. Results were obtained in n = 25 (60 ± 14 yrs, M:F 17:8). Surgery was uncomplicated: all were discharged by Day-4. All were taking regular oxycodone as a new post-operative prescription. Only one co-administered non-opioid was potentially confounding (temezepam, n = 4). Of 25, 14 (56%) demonstrated AA: five (20%) were simultaneously disorientated. Mean WPTAS was 11.08 ± 1.22. RA occurred in 0%. Conclusions: AA and disorientation, but not RA, were associated with in-patients (without TBI) taking opioids. Caution should therefore be applied in assessing AA/orientation in TBI in-patients taking opioids. By contrast, retrograde memory was robust and more reliable: even in older patients with iatrogenic AA and disorientation. RA assessment should therefore be integral to assessing TBI severity in all formalized PTA and GCS testing. Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
1. Introduction The Glasgow Coma Scale (GCS) is widely used to determine conscious level after traumatic brain injury (TBI) [1]. However, the GCS only assesses orientation [1]. The post-TBI syndrome, incompletely referred to as ‘post-traumatic amnesia’ (PTA) [2], comprises disorientation as well as retrograde amnesia (RA: defective memory of events prior to TBI) and anterograde amnesia (AA: defective memory subsequent to TBI). Noting that orientation usually recovered first [2], Russel and Symonds, two of the earliest pioneers in ⇑ Corresponding author at: Department of Neurosurgery, The Townsville Hospital, Douglas, Townsville 4810, Queensland, Australia. E-mail address: [email protected] (L.A.G. Marshman).
post-TBI assessment, emphasized the equal importance of both RA and AA testing in determining TBI recovery [2–9]. In particular, Russel opined that if, after TBI ‘‘..a patient is able to correctly describe events preceding the loss of consciousness by only a few minutes or seconds, then consciousness has returned in full” [3]. However, despite such emphasis, most current formalized PTA testing (i.e. in institutions using tests other than the Galveston Orientation and Amnesia Test [GOAT]) omits any RA assessment [2]. Instead, only resolution of orientation and AA is commonly used to determine recovery after TBI, to determine TBI severity, and to determine hospital discharge [2]. Thus, both the GCS and much formalized PTA testing are, potentially, incomplete. A recent review article also emphasized that the potential effect of concurrent medication, as a potentially confounding factor in
http://dx.doi.org/10.1016/j.jocn.2017.06.027 0967-5868/Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027
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PTA assessment, is also often disregarded in much formalized PTA assessment after TBI [2]. This is despite the fact that Symonds, in 1942, had specifically cautioned that, for example, ‘‘..it is important to know whether the patient has been given morphia” when assessing PTA [8]. Indeed, it is now known that certain drugs (e.g. midazolam) can specifically elicit AA in patients without TBI [10]. This fact is exploited in day case procedures, such as endoscopy [10]. Opiates/opioids are frequently administered to TBI patients: either for headache, or for other concurrent injuries. Pertinently, a recent pilot study suggested that as many as 80% of medium-stay elective orthopaedic in-patients (without TBI) failed formalized PTA testing criteria whilst receiving opiates after general anesthesia (GA) [11]. However, in common with much formalized PTA practice, RA was not assessed in that study [11]. Thus, while AA may be overestimated, the potential effect of either opiates, or opioids, on RA currently remains unknown. In Australia, the Westmead PTA scale (WPTAS) is widely used to formally assess PTA after TBI. However, the WPTAS does not include a history of drug use, and it does not formally assess RA. We therefore aimed to compare AA and RA in short-stay orthopaedic surgery in-patients (without TBI) taking post-operative opioids after uncomplicated opiate/opioid-free and benzodiazepine-free spinal anesthesia. 2. Methods A convenience sample of in-patients on an orthopaedic ward in a major regional public hospital were prospectively studied after local ethics committee approval. All patients had undergone elective or semi-elective (typically joint replacement) surgery as a short stay (i.e. less than 4 days) procedure using opiate/opioidfree and benzodiazepine-free spinal anesthesia (bupivacaine combined with propofol sedation) of duration less than 3 h. Patients were included if they were older than 18 yrs and of ASA grade 1 or 2. Patients were excluded if they were regularly taking opioids other than codeine phosphate 15 mg as required, or any other recently prescribed potentially psycho-active drug including tramadol, anti-convulsants, major or minor tranquillizers, amitriptylline, or illicit or prescribed cannabinoids. Patients were also excluded if they had a history of current psychiatric disorder, substance abuse, alcohol abuse, recent or concurrent TBI, or any neurological disorder affecting cognition, memory or conscious level. Finally, patients were excluded if spinal anesthesia duration was greater than 3 h, or if surgery had been in any way complicated. All participants were given an information sheet detailing the study before signing a consent form in agreement to participate. The WPTAS was used to assess AA [12]. WPTAS < 12 was considered to indicate evidence of AA [12]. Since there is no evidence for three consecutive WPTAS day testing, and only evidence against it [2,13,14], WPTAS was recorded from only one day of testing. RA was assessed using the GOAT RA item [15]. RA was considered absent if patients could remember key events, in detail, immediately prior to the delivery of spinal anesthesia. All post-operative psychometric testing (WPTAS and GOAT-RA) was performed between 24-36 h after surgery (dependent upon the extent of surgery) in order to minimize any potentially confounding effects of drugs co-administered during surgery [16]. All patients were prescribed oral oxycodone on a regular basis immediately postoperatively as a new prescription in addition to non-steroidal anti-inflammatory agents and paracetomol. 3. Statistical analysis Normality of score distribution for dependent variables was examined using skewness, kurtosis, stem and leaf plots, and the
Shapiro-Wilks statistic. Assumptions of normality were confirmed for all dependent variables. Homogeneity of variance was considered using the Levene Test for Equality of Variance and were not violated. Analysis of variance (ANOVA) was therefore performed with statistical significance determined as P < 0.05. Effect sizes (eta squared, g2) were calculated. According to Cohen (1988) a small g2 effect size is 0.01, a medium g2 is 0.06, and a large g2 0.014 [17]. 4. Results Results were obtained in n = 25 (mean age 60 ± 14 yrs, M:F 17:8) (Table 1). Six (24%) had suffered recent trauma to the region operated: none of these cases, however, had been associated with alcohol. No case had suffered multiple trauma. Sixteen (64%) patients were discharged by Day 2 of surgery, 24 (96%) by Day3 and 100% by Day 4. All 25 patients (100%) studied were taking the opioid oral oxycodone on a regular basis post-operatively as a standard new prescription. The same treatment is standard for TBI in-patients on the neurosurgery ward. The most commonly co-administered drug was oral oxycodone/naloxone (10/25, 40%) (Table 1): six of these (40%) returned a WPTAS < 12/12. Temezepam was coadministered in four (WPTAS < 12/12 in all four cases). Subcutaneous fentanyl was co-administered in two (WPTAS = 12/12 in both). Buprenorphine was co-administered in one (with WPTAS < 12), whilst codeine (the only opiate) was coadministered in one other (WPTAS = 12/12). Two patients were taking non-tricyclic anti-depressants (Table 1). The opiate morphine was not administered in our study. The mean WPTAS total score was 11.08 ± 1.22. Those with an abnormal WPTAS were older than those with a normal WPTAS (65.8 ± 10.8 yrs v 55.6 ± 15.5 yrs): however, this was not statistically significant (P = 0.06, g2 = 0.141439). The mean WPTAS of patients with an abnormal score (WPTAS = 10.3 ± 1.1) was significantly reduced compared to those with a normal score (WPTAS = 12), (P < 0.0001, g2 = 0.517816). Of 25 patients without TBI, 14 (56%) demonstrated evidence of AA (Table 1). Whilst all 56% patients specifically failed memory testing, 5/14 (36%) of these also failed orientation testing: i.e. 5 (20%) were also disorientated. By contrast, 0/25 (0%) demonstrated evidence of RA. 5. Discussion Certain drugs (e.g. midazolam) can specifically elicit AA in patients without TBI [10]. A recent pilot study by Mc Carter et al. also suggested that, of medium-stay elective orthopaedic inpatients without TBI, as many as 80% failed WPTAS testing criteria whilst receiving opiates (i.e. morphine or codeine) [11]. Unfortunately, in keeping with much formalized PTA practice, RA was not assessed [11]. Furthermore, the latter study [11] comprised only 17 patients where some had been hospitalized for longer than in current elective orthopaedic practice [18], and where all had undergone GA [11]. It is therefore possible that some might have suffered confounders related either to a prolonged GA (with potentially significant ‘hang-over’) or to peri-operative complications. By contrast, all but one in our study had been discharged by Day 3; whilst all had been discharged by Day 4. All had therefore undergone uncomplicated elective or semi-elective surgery using opiate/opioid-free and benzodiazepine-free spinal anesthesia for less than 3 h. Psychometric testing was performed 24–36 h after commencement of regular post-operative analgesia [16]. In contrast to the study of McCarter et al. (where no single opiate was common to all), all our patients were regularly taking the opioid oxycodone as a standard new post-operative prescription.
Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027
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Table 1 WPTAS and GOAT-RA Scores and medication. Key: WPTAS Westmead Post Traumatic Amnesia Scale, GOAT-RA Galveston Orientation and Amnesia Test Retrograde Amnesia item. Maximal orientation item is 7/7, maximal memory item is 5/5: maximum total is 12/12. Opioid/opiate analgesia: O oral oxycodone, ON oral oxycodone/naloxone, F subcutaneous fentanyl, B oral buprenorphine, C oral codeine. Non-opioid/opiate analgesia: M meloxicam (non-steroid anti-inflammatory analgesia), T temazepam (benzodiazepine), E escitalopram (selective serotonin reuptake inhibitor), D duloxetine (serotonin–norepinephrine reuptake inhibitor). Participant
Age (yrs)
WPTAS Orientation, Memory (total)
GOAT-RA
Drugs
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
52 22 54 50 65 70 43 74 65 61 65 76 54 77 75 69 49 78 46 52 67 53 78 77 60
7, 7, 7, 7, 7, 7, 7, 7, 6, 7, 7, 6, 7, 5, 7, 7, 6, 7, 6, 7, 7, 7, 7, 7, 6,
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
O O O, F, C O O, T, E O, ON O, ON O O, ON O, F, D O, ON O, ON O O O O, ON, T O, ON, D O, T O, T ON, M O, B O, ON ON O O
5 5 5 5 4 5 5 4 4 5 5 5 5 2 4 4 4 4 4 4 4 5 4 5 3
(12) (12) (12) (12) (11) (12) (12) (11) (10) (12) (12) (10) (12) (7) (12) (11) (10) (11) (10) (11) (11) (12) (11) (12) (9)
The same treatment is standard for TBI in-patients on the neurosurgery ward. Opioids purportedly have less side effects than opiates. Notwithstanding, 56% of 25 patients demonstrated evidence of AA in our study. The overall mean WPTAS was reduced to 11.08 ± 1.22, but was significantly reduced in those affected (WPTAS: 10.3 ± 1.1 v 12, P < 0.0001, g2 = 0.517816). Whilst all 56% evidenced AA, 5/25 (20%) were simultaneously disorientated (Table 1). This contrasts with Mc Carter et al. where no disorientation was recorded [11]. Disorientation, but not AA or RA, reduces the GCS. Whilst opioids, as opposed to opiates, could have been responsible for disorientation, our study comprised older subjects. Indeed, those with an abnormal WPTAS were older than those with a normal WPTAS (65.8 ± 10.8 yrs v 55.6 ± 15.5 yrs, P = 0.06, g2 = 0.141439). However, whilst drug-related cognitive side-effects may be more likely in those with cerebral atrophy, atrophy is not an inevitable consequence of normal ageing. Instead, atrophy is determined by comorbid risk factors (at least under 70 yrs) [19]. All our patients were ASA grades 1 and 2, and did not have a disorder affecting cognition, memory or conscious level. Notwithstanding, despite AA and disorientation, no Patient evidenced RA in our older sample. Indeed, retrograde memory remained robust even in cases where other co-administered drugs (especially temezepam) could have been co-confounders. Our study is therefore the first to demonstrate that AA and disorientation, but not RA, are associated with in-patients (without TBI) taking opioids. Opioids therefore represented a potential confounder to PTA or GCS testing in our study, just as Symonds [8] and McCarter et al. [11] had concluded with opiates. Notably, this is additional to other defects previously outlined with routine WPTAS testing [2]: in particular, those associated with construct, criterion and externalization validity [2]. Had affected patients in our study have suffered a mild concurrent TBI (with uneventful recovery) they could have been falsely diagnosed with ‘PTA’ [11], or with ‘confusion’ (GCS = 14). Such misdiagnosis could have unnecessarily consumed hospital resources [2], risked litigation [11], and lead to excess social, financial and opportunity costs [2]: especially in regional
hospitals which service wide geographical regions [2]. Such costs would also have been exacerbated in those hospitals which continue the non-evidence-based practice [2,14] of three-day consecutive testing of WPTAS = 12/12 to ‘prove’ recovery after TBI. This is especially so where patients typically fluctuate about the maximal score on WPTAS: achieving a maximal score one day, only to regress on the next [2,14]. Participants in our study would potentially have suffered a comparable generalized stress response to that of TBI in-patients. However, unlike our patients, many TBI patients would also have undergone GA (with opiates and benzodiazepines) for several hours, if not days, prior to PTA testing. In our study, we minimized potentially confounding factors related to any history of a current psychiatric or neurological disorder affecting cognition, memory or conscious level; or to recently prescribed concurrent potentially psycho-active drugs. Furthermore, all psychometric testing was performed between 24–36 h after uncomplicated spinal anesthesia [16]. Notably, TBI in Australian adults is bimodal, with peaks in age groups 15–19 yrs, and over-85 yrs [20]. Our study therefore compliments that of Mc Carter et al. whose age range (18–55 yrs: mean 36.3 ± 13.2 yrs) tended toward the younger peak [11], whilst our study tended toward the older peak (22–78 yrs, mean 60 ± 14 yrs). Russel and Symonds, two of the earliest pioneers in post-TBI assessment, emphasized the equal importance of both RA and AA testing in determining recovery from TBI [2–9]. The results of our study are therefore relevant to routine PTA testing after TBI. Specifically, whilst caution should be applied in assessing orientation and AA in TBI in-patients taking either opiates or opioids, RA assessment is not so confounded. RA assessment is thus a potentially more reliable measure of TBI severity than AA or orientation assessment in in-patients taking commonly-used psycho-active analgesic drugs after TBI. In contrast to current practice, RA assessment should therefore form an integral part of routine post-TBI PTA testing. Further, since orientation was affected in 20%, and given its ease of administration, RA assessment should also be used to assess the GCS. Wherever RA is absent, and wherever drug confounders might be operative in in-patients, one might justifiably
Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027
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question the veracity of either AA or GCS = 14 (‘confused’) when these have been otherwise recorded. Our study is limited principally by its small sample size. However, this was largely due to the stringent inclusion/exclusion criteria, as detailed in the study Methodology; and effect sizes (eta squared, g2) were calculated. Notwithstanding, the rates of AA and disorientation observed were disturbingly significant. Furthermore, caution should be applied in that, whilst our study emphasized formalized PTA testing, ultimate clinical decision-making after TBI may often take into account the effect of potential drug confounders irrespective of any formalized PTA score obtained. Finally, our mean study sample age was older than a typical TBI population, and abnormal WPTAS scores were lower still in older patients within this sample. Although this may appear to signify that older subjects are more prone to drug confounders, our small study sample size precluded any definitive statement. 6. Conclusions AA and disorientation, but not RA, are associated with inpatients (without TBI) taking opioids. Caution should therefore be applied in assessing AA/orientation in TBI in-patients taking opioids. By contrast, retrograde memory appeared robust and more reliable: even in older patients with iatrogenic disorientation. RA assessment, as a reliable measure of TBI severity, should therefore be integral to routine PTA and GCS testing: in contrast to currentformalized practice. Wherever RA is absent, and wherever drug confounders might be operative, the veracity of either ‘AA’ or GCS = 14 (‘confused’) should be questioned. Funding No external funding was received. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement None. References [1] Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2(7872):81–4. http://dx.doi.org/10.1016/S01406736(74)91639-0. PMID 4136544. [2] Marshman L, Jakabek D, Hennessy M, Quirk F, Guazzo E. Review article: posttraumatic amnesia. J Clin Neurosci 2013;20(11):1475–81. http://dx.doi.org/ 10.1016/j.jocn.2012.11.022. Epub 2013 Jun 20.
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Please cite this article in press as: BPsych JM et al. Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. J Clin Neurosci (2017), http://dx. doi.org/10.1016/j.jocn.2017.06.027