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Home , Autonomic dysreflexia, Dysautonomia, Stroke recovery

BRAIN , VOL. 18, NO.5(MAY 2004), 409–417

Pharmacological management of following traumatic brain injury

IAN J. BAGULEYyz, IAN D. CAMERON}, ALISA M. GREENy, SHAMERAN SLEWA- YOUNANy, JENO E. MAROSSZEKYzô and JOSEPH A. GURKAy y Brain Injury Rehabilitation Service, Westmead Hospital, Wentworthville, NSW, Australia z Department of Rehabilitation , University of Sydney, Sydney, NSW, Australia } Rehabilitation Studies Unit, University of Sydney, Sydney, NSW, Australia ô Department of Rehabilitation Medicine, Westmead Hospital, Wentworthville, NSW, Australia (Received 21 November 2002; accepted 31 March 2003)

Primary objective: To document and critically evaluate the likely effectiveness of pharmacological treatments used in a sample of patients with Dysautonomia and to link these findings to previously published literature. Research design: Retrospective case control chart review. Methods and procedures: Data were collected on age, sex and GCS matched subjects with and without Dysautonomia (35 cases and 35 controls). Data included demographic and injury details, physiological parameters, medication usage, clinical progress and rehabilitation outcome. Descriptive analyses were

For personal use only. undertaken to characterize the timing and frequency of CNS active medications. Main outcomes and results: Dysautonomic patients were significantly more likely to receive neuro- logically active medications. A wide variety of drugs were utilised with the most frequent being /midazolam and . Cessation of morphine/midazolam produced significant increases in rate and respiratory rate but not temperature. Chlorpromazine may have modified respiratory rate responses, but not temperature or . Conclusions: The features of Dysautonomia are similar to a number of conditions treated as medical emergencies. Despite this, no definitive treatment paradigm exists. The best available evidence is for morphine (especially intravenously), benzodiazepines, propanolol, bromocriptine and possibly intrathecal . Barriers to improving management include the lack of a standardized nomen- clature, formal definition or accepted diagnostic test. Future research needs to be conducted to improve understanding of Dysautonomia with a view to minimizing disability. Brain Inj Downloaded from informahealthcare.com by George Washington University on 03/23/11

Introduction Dysautonomia is a syndrome of episodic dysfunction and increased muscle tone affecting a small but significant sub-group of survivors

Correspondence to: Dr Ian J. Baguley, Research Team Leader, Brain Injury Rehabilitation Service, Westmead Hospital, PO Box 533, Wentworthville, NSW 2145, Australia. e-mail: ianb@ biru.wsahs.nsw.gov.au

Brain Injury ISSN 0269–9052 print/ISSN 1362–301X online # 2004 Taylor & Francis Ltd http://www.tandf.co.uk/journals DOI: 10.1080/02699050310001645775 410 I. J. Baguley et al.

of severe traumatic brain injury (TBI). Dysautonomia has a dramatic presentation characterized by extreme, paroxysmal changes in , heart rate, respira- tory rate, temperature and/or sweating. To date, it has been poorly reported in the medical literature where it is variously referred to as Dysautonomia, Autonomic Dysfunction Syndrome, autonomic or sympathetic ‘storming’, hyperpyrexia associ- ated with muscle contraction, hypothalamic-midbrain dysregulation syndrome, acute midbrain syndrome or diencephalic epilepsy. Despite this, research has shown statistically significant physiological differences between survivors of severe TBI with and without the condition [1]. Dysautonomia-like syndromes have been reported in a range of other (CNS) disorders including cerebral tumours [2], hydrocephalus [3–6], intracerebral and subarachnoid haemorrhage [3, 7], hypoxic encephalopathy [8] and on discontinuation of [9] and GABA-ergic drugs [10]. One of the more concerning syndromes that Dysautonomia mimics is Neuroleptic Malignant Syndrome (NMS) [3, 11]. NMS is characterized by hyper- thermia and muscle rigidity along with other features such as sweating, , , blood pressure changes, leucocytosis, elevated Creatinine Kinase (CK) levels and altered consciousness (DSM-IV). NMS is thought to result from CNS dopamine blockade and has a 15–30% mortality rate [12]. Dysautonomia is also similar to another potentially fatal syndrome resulting from abrupt intrathecal baclofen withdrawal [13, 14]. This syndrome is characterized by fever, tachycardia, variable blood pressure, exaggerated rebound , muscle rigidity, altered mental state and increased CK levels. There are further similarities evident between Dysautonomia and (AD). In AD, non- specific noxious stimuli in people with a above T6 can result in severe , increased spasticity, profuse sweating and vasodilatation above

For personal use only. the spinal lesion. This association between noxious stimuli and increased symptoms has also been reported in Dysautonomia [15]. Unlike Dysautonomia, AD is usually associated with due to intact reflexes mediated by the vagal [16]. Given the clinical similarities between Dysautonomia and a range of potentially fatal syndromes, it could be argued that Dysautonomia also warrants the aggressive clinical management seen with NMS and AD. Taken alone, the increased core tem- peratures following acute TBI represent a potentially preventable cause of secondary brain injury [17]. The extent of these temperature increases are significantly higher and more prolonged in patients with Dysautonomia [1].

Brain Inj Downloaded from informahealthcare.com by George Washington University on 03/23/11 Despite the above, there is little or no systematic evidence available to optimize clinical management. Most of the published literature has concentrated on anecdote, individual case studies or small case series reporting medication effects. Some of these latter publications are difficult to interpret given that some patients were simultaneously trialled on multiple drugs and few studies published their criteria for determining efficacy. The aims of this study are to document medications used in a large published sample of patients with Dysautonomia [1], to critically evaluate the likely effective- ness of some of these medications based on observed physiological changes and to link these findings with a review of the published literature to suggest a tentative treatment protocol for this syndrome. Pharmacological management of dysautonomia 411

Method Subjects A retrospective case control methodology was used. For the purposes of this study, Dysautonomia was defined as simultaneous, paroxysmal increases in at least five out of the seven reported features of Dysautonomia (heart rate (HR), respiratory rate (RR), blood pressure, temperature, posturing, and sweating). File reviews of 35 age, sex and GCS matched subjects with and without Dysautonomia were performed. Control cases were taken from a database of 121 consecutive rehabilitation inpatients with a severe TBI on GCS criteria (maximum GCS 8 in the first 24 hours) and without evidence of Dysautonomia on file review. Data recorded were demographic and injury details, CT scan findings, physiological parameters (HR, RR, temperature), evidence of infections over the first 28 days, clinical progress and rehabilitation outcome. The dates that medica- tions, particularly antibiotics, sedatives and centrally acting drugs, were commenced or ceased were also recorded. Approval was obtained from the relevant human research ethics committee.

Statistical analyses Descriptive analyses were undertaken to characterize the study participants. The timing and frequency of use of CNS active medications were reported descriptively. The data for the most frequently used medications (morphine/ midazolam infusions and chlorpromazine) were further evaluated. Dependent vari- ables included the mean of the maximum daily temperature, HR and RR during the pre-, on or off phase of Dysautonomia for each subject. Morphine/midazolam infusions were commenced on arrival in ICU and, thus, the effect of morphine/ For personal use only. midazolam infusions were investigated via a repeated measures t test. Chlorpromazine was utilized later during the ICU admission, allowing pre-commencement variables to be analysed. The effect of chlorpromazine status (pre-commencement, on chlor- promazine, off chlorpromazine) was analysed via a one-way repeated measures ANOVA. In the latter analysis, only cases with seven consecutive days of data were analysed.

Results

Brain Inj Downloaded from informahealthcare.com by George Washington University on 03/23/11 Demographic and injury related variables for the Dysautonomia and control groups appear in table 1. Records of medications used in the early intensive care management were available for 32 and 31 subjects in the Dysautonomia and control groups, respectively. Significantly more Dysautonomic patients received neurologically active medi- cations compared to controls (27/32 (84%) vs 9/31 (29%), (w2 ¼ 19.69, p < 0.001)). The only exceptions to this pattern were that there were no significant differences in the number of people managed with morphine/midazolam infusions ( p ¼ 0.773) or phenobarbital ( p ¼ 0.753) between the two groups (table 2). The average interval before morphine/midazolam infusions were replaced with PRN bolus doses was 4.1 days post-injury (range 1–12). Excluding these drugs, medication use varied dramatically between the two groups. 412 I. J. Baguley et al.

Table 1. Demographic and injury data for Dysautonomia and control groups

Dysautonomia Control Significance

n 35 35 Mean age (years) 20.5 20.7 n.s. GCS score (median) 4.0 3.0 n.s. Male/female ratio 25/10 25/10 n.s. Injury mode MVA/other 25/10 22/13 n.s.

Table 2. Drug utilization and timing in the control and Dysautonomia groups

Neuro- Control Dysautonomia Median Median transmitter Class Drug group group day started day ceased

Opiates Agonist Morphine 28 28 1 4.0 GABA A Agonist Midazolam 27 20 1 4.0 7 5 5.5 9.0 Clonazepam 3 2.0 41.0 GABA B Agonist Baclofen (oral) 3 31.5 > 150 Baclofen (IT) Alpha Agonist Prazosin 1 Antagonist 1 8 12.0 16.5 Beta Antagonist Propanolol 4 29.0 63.0 Dopamine Agonist Bromocriptine 6 17.0 102.0 Amantadine 1 Antagonist Chlorpromazine 3 13 6.0 16.5 Haloperidol 2 Other 7 39.5 > 150 Phenobarbital 4 5

For personal use only. Hydrallazine 1 Methyldopa 1 Patient ICU data unavailable 3 4

Note: The median day drugs were started and ceased refers to subjects in the Dysautonomia group only.

The frequency and type of medications used in the Dysautonomia and control groups are listed in table 2. In the control group, medications included diazepam (7 patients), chlorpromazine (3), haloperidol (2) and clonidine (1). In the Dysautonomia group, the most commonly used neurotransmitter agonists were

Brain Inj Downloaded from informahealthcare.com by George Washington University on 03/23/11 the benzodiazepines (8), dopamine agents (7) and baclofen (3). The most commonly used neurotransmitter antagonists were chlorpromazine (13), clonidine (8) and propanolol (4). Dantrolene was used in seven subjects. Of the 26 patients with early data, neurotransmitter agonists were the sole agent in nine subjects, antagonists in seven and both classes used (often simultaneously) in 10. In the Dysautonomia group, the median interval from injury to drug onset varied considerably. The introduction of chlorpromazine and benzodiazepines was usually within the Intensive Care setting (days 2–6 post-injury). The median interval until propanolol, bromocriptine and the oral antispasticity agents baclofen and dantrolene were started was much later ( 3–4 weeks post-injury), usually following admission to inpatient rehabilitation. Dopamine antagonists were used more frequently in the acute post-trauma period, whereas agonists were more Pharmacological management of dysautonomia 413

Table 3. Mean physiological variables for the Dysautonomia group during early treatment

Pre On Off

Morphine/Midazolam Temp (C) 38.5 38.3 HR (/min) 108.8 120.2 RR (/min) 13.8 27.7 Chlorpromazine Temp (C) 38.0 38.6 37.7 HR (/min) 112.6 123.1 113.4 RR (/min) 15.0 19.7 22.7

Note: ‘Pre’ refers to the interval before commencement of the drug. Morphine/Midazolam infusions commenced on admission to hospital so that pre data is unavailable. ‘On’ data refers to the period that the drug was utilized, whereas ‘Off ’ data is the period following cessation of the drug.

common in the sub-acute period (table 2). Chlorpromazine usage tended to decrease during the later years of the study. Analysis of the morphine and midazolam infusion data revealed significant increases in heart rate (t(1, 12) ¼3.65, p < 0.005) and respiratory rate (t(1, 10) ¼ 7.30, p < 0.005), but not temperature following their cessation (table 3). Chlorpromazine data revealed a rise and fall pattern in temperature and heart rate. This pattern was not apparent in RR, which showed a significant linear relationship ( p < 0.01), suggestive of a drug effect. Five patients in the Dysautonomia group had CK levels measured during their acute management. None of these patients were given dopamine antagonists and only one patient had associated musculoskeletal trauma. Of these patients, all had abnormally high CK levels. CKs were noted to be abnormal between days 1–10 For personal use only. post-trauma, with a mean maximum increase to 2380 IU/L (median 1920, range 1184–5478).

Discussion The results from this study demonstrated that the Dysautonomia group was signifi- cantly more likely to be prescribed neurologically active medications compared to controls. The difference in treatments offered to the two groups implies clinician awareness of the syndrome in most cases. Treatment attempts sought to modify CNS responsiveness via changes to , , GABA, dopamine and/or opiate receptors.

Brain Inj Downloaded from informahealthcare.com by George Washington University on 03/23/11 There was also an observed difference in the timing of the introduction of the various medications (table 2), with chlorpromazine and benzodiazepines used in Intensive Care and propanolol, bromocriptine and the oral antispasticity agents used later during rehabilitation. The majority of medications used to treat subjects in this study have anecdotal support in previous literature, namely morphine [1, 3, 18, 19], or blockers [20–23], dopamine agonists [3, 4, 18, 19, 23, 24] and benzodiazepines [8, 22, 23]. A number of drugs were utilized which do not have support in the literature (table 4). In particular, phenobarbital [3, 8, 15, 18] and chlorpromazine [8] have not been reported to be useful in this condition. Due to the natural history of TBI and Dysautonomia, it would be expected that physiological variables would peak following the cessation of morphine and 414 I. J. Baguley et al.

Table 4. Literature reports and effects of drugs used in the treatment of Dysautonomia

Neurotransmitter Class Drug Unhelpful Beneficial

Opiates Agonist Morphine [1, 3, 18, 19] Methadone [3, 22] GABA A Agonist Diazepam [22] Clonazepam [3, 22] [8] Lorazepam [22] [23] GABA B Agonist Baclofen (oral) [22] Baclofen (IT) [32, 33] Alpha Antagonist Clonidine [24] [23] Beta Antagonist Propanolol [3] [15, 20–23] Dopamine Agonist Carbi/levodopa [23] [4, 23] Bromocriptine [4, 22] [3, 18, 19, 24] Antagonist Chlorpromazine [4] Other Dantrolene [22] [3] Phenobarbital [3, 8, 15, 18] Phenytoin [3, 5, 18] Carbamazepine [8] Acetominophen [22]

Note: Each reference denotes one literature report of drug efficacy. Baclofen (IT) refers to the intrathecal mode of drug delivery.

midazolam. This pattern was found to occur with significant increases noted in HR and RR while maximum daily temperature remained constant at 38.5C. In determining the efficacy of chlorpromazine, the early use of the medication (median onset day 6 post-injury) would mean that physiological measurements should be highest during the ‘on’ phase and be lower during the ‘off ’ phase, For personal use only. even if chlorpromazine was ineffective. A significant drug effect can only be inferred if a differing pattern was found. The expected rise and fall pattern was found for HR and temperature. However, the linear nature of the change in RR over the three time points suggests that chlorpromazine may have had some clinical effect on this variable. However, despite this finding, the data revealed a decrease in the use of chlorpromazine in patients during the later years of the study. By its design, this study was unable to determine whether morphine/midazolam or chlorpromazine significantly modified the outcome of Dysautonomia. Although frequently used in this study, chlorpromazine would be expected to further impair dopaminergic pathways in the damaged brain [25]. This has been reported to

Brain Inj Downloaded from informahealthcare.com by George Washington University on 03/23/11 impair cognitive function while on the drug [26] and has been proposed to cause a permanent reduction in overall cognitive recovery [27]. Furthermore, dopamine blockade is central to the aetiology of NMS, the symptoms and signs of which are almost identical to Dysautonomia. In the current study, it could be argued that the use of chlorpromazine induced NMS in the patients in this study. However, only 13 of the 35 patients received a dopamine antagonist. The clinical progress for patients in this study was also different to the published case reports of NMS following TBI [12, 25, 28, 29]. These subjects were treated with neuroleptics for agitation 2, 12, 6 and 2 days post-injury, respectively. All four patients had regained consciousness prior to the commencement of NMS symptoms, with CK levels rising to a maximum of between 842–16 230 IU/L. Pharmacological management of dysautonomia 415

However, other case histories have reported patients with NMS-like syndromes and documented CK rises without neuroleptic medication. The clinical presenta- tion of each of these patients would also be consistent with a diagnosis of Dysautonomia. In a case following TBI [8], CK levels rose to 2685 IU/L in associ- ation with posturing and a patient with acute hydrocephalus had CK rises to 50 000 IU/L [6]. In another paper, a patient had an ‘NMS-like syndrome’ following TBI with minimal neuroleptic medication (a single 10 mg dose of ) with a concomitant CK rise to 61 842 IU/L [11]. In the current study, only five patients had CK levels checked. None of these patients had been given dopamine antagonists and all had raised CK levels. This suggests that factors other than the neuroleptic medication are the cause of CK rises seen in NMS. The overlap between NMS, intrathecal baclofen withdrawal and Dysautonomia complicates an already difficult management problem. NMS and intrathecal baclofen withdrawal result from reduced neurotransmitter availability (dopamine [30] and GABA B [13] agonists, respectively) are treated as medical emergencies and have a literature base to optimize treatment. The limited drug literature for Dysautonomia suggests that the clinical syndrome can be moderated by both of these agents (dopamine and GABA B) as well as and GABA A agonists and non-selective -blockers. This finding may hint at other potential avenues to explore for managing acute intrathecal baclofen withdrawal. The rationale behind Dysautonomia treatment should be aimed at controlling the variables that have potential to increase morbidity. Given the association between Dysautonomia and noxious stimuli, the first stage of any clinical manage- ment paradigm should be to focus on minimizing noxious stimuli such as infection, , decubitus ulceration, heterotopic ossification or undiagnosed fractures. The possibility of concomitant NMS also needs to be considered. Some patients

For personal use only. with severe TBI are provided minimal narcotic analgesia in the early recovery period and the need to control pain and Dysautonomia should be balanced against the risk of further impairing the patient’s cognitive reserve. In addition to control- ling pain, intravenous morphine adequately controls the extremes of physiological changes and . Most of the available literature reports that propanolol is beneficial in treating Dysautonomia. From a theoretical perspective, it should be advantageous to decrease the patient’s thermal load by reducing heart rate, core temperature and muscle tone. In one study [20], acute intravenous propanolol decreased hyper- metabolism by 25% through reductions in HR and temperature. Propanolol

Brain Inj Downloaded from informahealthcare.com by George Washington University on 03/23/11 also decreases circulating catecholamines and reduces cardiac work following TBI [31]. These studies help to explain the widespread anecdotal use of propanolol and suggest that propanolol could assist in minimizing secondary brain injury in this patient sub-group. At present, a definitive treatment paradigm for Dysautonomia remains elusive. While there is no incontrovertible evidence re efficacy, the best available evidence is for morphine (especially intravenously), benzodiazepines, propanolol and bromo- criptine. More recently, a number of case studies have been published showing promising results with intrathecal baclofen [32, 33]. Providing better management of Dysautonomia will require appropriate research. Barriers to achieving this include the ongoing lack of a standardized nomenclature and the lack of a formal definition or accepted diagnostic test for the condition. Future research needs to be conducted 416 I. J. Baguley et al.

to improve understanding of the causes of and management for Dysautonomia with a view to minimizing disability.

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