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Seizures After Adult Cardiac Surgery and Interventional Cardiac Procedures
Author’s Accepted Manuscript Seizures after Adult Cardiac Interventional Cardiac Procedures
Surgery
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Ekaterina Pataraia, Rebekka Jung, Susanne AullWatschinger, Keso Skhirtladze-Dworschak, Martin Dworschak www.elsevier.com/locate/bios
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S1053-0770(17)31024-8 https://doi.org/10.1053/j.jvca.2017.12.036 YJCAN4489
To appear in: Journal of Cardiothoracic and Vascular Anesthesia Cite this article as: Ekaterina Pataraia, Rebekka Jung, Susanne AullWatschinger, Keso Skhirtladze-Dworschak and Martin Dworschak, Seizures after Adult Cardiac Surgery and Interventional Cardiac Procedures, Journal of Cardiothoracic and Vascular Anesthesia,doi:10.1053/j.jvca.2017.12.036 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Seizures after adult cardiac surgery and interventional cardiac procedures Ekaterina Pataraia, MD, PhD, MBA1, Rebekka Jung, MD1, Susanne Aull-Watschinger, MD1, Keso Skhirtladze-Dworschak, MD2, Martin Dworschak, MD, MBA2 1
Department of Neurology, Medical University of Vienna, Vienna, Austria
2
Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, Medical
University of Vienna, Vienna, Austria
Corresponding author: Ekaterina Pataraia, MD, PhD, MBA Department of Neurology Medical University of Vienna, 1090 Vienna, Austria Phone: +43 1 40400 34330 [email protected]
Abstract The aim of this narrative review is to evaluate the incidence of seizures after adult cardiac surgery or cardiac interventions, to describe risk factors, and to provide suggestions regarding diagnostic measures and proper management. Based on published peer-reviewed articles we demonstrate specific procedure-related risks for seizures. Early diagnosis and the identification of underlying causes as well as avoidance of amenable risk factors are crucial to reduce associated long-term morbidity and mortality. Methods of early recognition of
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seizures, particularly focusing on the initiation of appropriate diagnostic measures, their management, and their timely treatment, are presented in the article.
Introduction The western world currently sees a growing number of cardiac interventions and operations in adults. Epidemiological forecasts predict that it will further increase in the near future despite a decline in the incidence of heart disease.2 In spite of the rising number of cardiac surgeries and interventions that are carried out and the fact that more and more elderly patients and those with severe co-morbidities who have previously been excluded from surgical treatment are undergoing such procedures, postoperative mortality remained almost stable over the recent years.3 Nevertheless, all these procedures carry an inherent risk of complications and may be associated with neurological injury4-9. Neurological outcome is determined by underlying patient factors, the specific procedure and by perioperative management. Accordingly, some of these factors (e.g. administered pharmacologic agents, cerebral ischemia, hyperventilation, etc.) are amenable to modifications. Neurological symptoms vary depending on the type of injury and can be either transient or persistent. The most obvious central nervous system (CNS) injury continues to be stroke 10-14. Other more frequent complications are cognitive decline and encephalopathy that are usually not as easy to diagnose as thrombo-embolic stroke. 14-18 Postoperative seizures occur less commonly but may have significant consequences for the patient 4, 19, 20. They are presumably multifactorial and may result from focal or global cerebral ischemia due to hypoperfusion or emboli, metabolic disturbances or drug reactions (e.g. administration of contrast means 21, 22, drug overdose like for example with theophylline 23 or high dose of tranexamic acid (TXA) 24-26). In the past, most researchers investigating neurological injury post cardiac surgery mainly focused on ischemic injury and on cognitive decline. In contrast to perioperative stroke that has thoroughly been 2
investigated, there are much less data on the incidence, epidemiology, and outcome of seizures after cardiac surgery 4, 20. Early evaluation of such a complication requires a systematic approach in order to plan and initiate appropriate treatment in a timely manner. The present narrative review was performed by searching corresponding studies in PubMed using the key words ‘seizures’, ‘convulsive’, ‘non-convulsive’, ‘’status epilepticus’, ‘cardiac surgery’, ‘cardiac intervention’ and ‘anesthesia’. After assessing the most relevant studies a search of secondary sources including references of initially identified articles was done. Case reports and brief communication were also included. Only literature published in English language was selected.
Seizure types and their identification The International League against Epilepsy (ILAE) recently proposed an operational classification of seizure types with the purpose for appropriate assignment to seizures with focal of generalized onset, to include some missing seizure types and to adopt more transparent names. 27 Seizures are defined as transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain 28, 29. Different types of seizures have been observed postoperatively. Seizures, which can readily be recognized, are generalized tonic-clonic convulsions. Although this form causes great concern to medical staff, patients and their families, more disturbing are the non-convulsive seizures (NCS) and non-convulsive status epilepticus (NCSE) – a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures30. A great proportion of seizures in critically ill patients is non-convulsive. They are frequently missed or mistaken for something else so necessary management is consequently often delayed. Depending on the type and duration of seizures they can have long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks 30, 31. 3
The incidence of NCSE ranges from 8 to 40% in critically ill patients 24, 32, 33. It is still unknown for the cardiac surgical population since seizures can be missed or not being identified as such. In any case, the reported incidence of acute seizures varies between 0.5 and 1%, and for those of recurrent seizures was given as 0.5% 20. However, this data comes from an observational study on postoperative outcome and needs to be confirmed in larger prospective multicenter observational studies, which are laborious, challenging and timeconsuming. In addition, many investigations are retrospective in nature and lack a precise assessment of the occurrence of seizures. Often, the main problem is the correct identification of seizures. Shivering, tremor, dystonia, choreatic movements or myoclonus, misinterpretation of symptoms as postictal state, psychiatric disorders, stroke or metabolic encephalopathy – can lead to over-diagnosis of seizures 34. Clinical diagnosis, however, requires experienced personnel. Subtle clinical signs like nystagmus, eye-deviation, twitching of the hand, and subtle focal clonus of facial muscles must be carefully sought. Beyond clinical signs, the only confirmatory tool for the diagnosis particularly of NCSs and NCSE is electroencephalography (EEG)35. It can be performed intermittently or continuously36. Continuous EEG (cEEG) is very informative, but needs qualified personnel and expensive equipment. On the other hand, early identification of NCS or NCSE could mitigate brain injury and prevent prolonged intensive care stay30, 31. Several studies were conducted to compare intermittent vs. cEEG monitoring showing the superiority of cEEG in regard of seizure detection 35-37. Most of them were performed at neurological ICUs in patients with brain damage. Not surprisingly, the probability of seizure occurrence was high. In a prospective observational study of seizures after cardiac surgery Gofton et al. used a downgraded cEEG with a sub-hairline array of electrodes in a series of 101 consecutive patients to identify electrographic seizures without clear convulsive correlates 38. Although use of this device does not give complete information about the origin 4
of seizures, it could be very helpful in early identification of seizures. The authors observed that 3% of patients had early postoperative seizures (two patients had generalized and one an electrographic seizure). Since the number of potentially detrimental NCS was low, they concluded that use of cEEG after cardiac surgery would be unlikely to be cost-effective or improve long-term patient outcome. Nevertheless, prolongation of the duration of application (>24 hours) may improve seizure detection. Young et al found that a delay in seizure diagnosis of > 24 hours was associated with a 75% mortality rate due to prolonged NCS activity 33. However, it is still controversial which patients should be monitored by EEG and there are still no clear guidelines for applying a cEEG especially for the detection of NCS or NCSE 37. In a series of 2578 consecutive patients, who underwent cardiac surgery at a single institution, the predictors for developing seizures postoperatively were evaluated by Goldstone et al 4. The surgical procedures were standardized and all patients with exception of those with known hypercoagulable states received aminocapronic acid; aprotinin and TXA were not used. An attending neurologist classified the seizures based on clinical history and examination. The patients with ongoing seizures were subjected to computed tomography of the brain (CCT), which was not performed after a singular seizure and spontaneous resolution. Magnetic resonance imaging (MRI) was ordered only in patients with ongoing neurological deficits, where no pathologies could be ascertained in the previous CT scan. The authors found that 1.2% of patients had seizures in the postoperative period. Subgroup analysis identified 71% of cases with generalized tonic-clonic seizures, 26% with simple or complex partial seizures and 3% with NCSE. Thereby, the proportion of patients with NCSE was significantly lower than that with single seizures (either focal or generalized). The incidence of seizures further differed according to procedure. It was lowest in coronary artery bypass grafting (CABG) surgery (0.1%), 1% for isolated valve intervention, 3% for combined valve and bypass procedures, and 5% for aortic surgery (p<0.001). The researchers 5
also found that patients with seizures had more postoperative complications and a hospital mortality being five-fold greater than patients without seizures (29% vs. 6%). The type of seizure was not related to patient outcome. The authors also assessed the predictors of seizures. Only three (i.e. deep hypothermic circulatory arrest, aortic calcification or atheroma and critical postoperative state) of a total of 25 factors reached statistical significance. Suspected factors like body temperature and the duration of circulatory arrest were not significantly different between the seizure and the non-seizure group. Pre-existing cerebrovascular disease also had no influence on the occurrence of postoperative seizure. When seizures are detected postoperatively they may have a tendency to recur depending on the underlying cause and can thus worsen long-term morbidity and mortality. The risk factors and outcome of recurrent seizures following cardiac surgery has been assessed from data of 7280 patients 20. Patients with postoperative seizures were followed up by a median of 21 months. The incidence of postoperative seizures was 0.8%. Altogether, 59% of these patients had recurrent seizures either immediately after the first seizure or during their hospital stay. Only three patients (0.04%) had NCSE, which was suspected by decreased level of consciousness and confirmed by serial EEGs. The authors evaluated different predictors for seizure recurrence and found that higher preoperative creatinine (>120 mmol/L), procedures involving thoracic aortic surgery and early seizure onset after surgery (<4 hours) were associated with seizure recurrence. Preoperative seizure disorders or existence of cerebrovascular disease was not associated with postoperative seizures. Interestingly, there was no significant difference between patients with single or recurrent seizures in the longterm outcome regarding morbidity and mortality. However, the number of affected patients with recurrent seizures was low. Although the authors screened for preoperative cerebrovascular accidents, alterations in patients’ neurological status were not examined postoperatively. Unfortunately, the results from EEG, CT scan or MRI exams – if performed – were not presented in the paper. This, however, would be valuable information in regard of 6
understanding the mechanisms of origin and the prognosis of seizures and finally also determines the long-term treatment strategies.
Specific risks in different cardiac surgical procedures Cardiac catheterization and Percutaneous coronary interventions Seizures are not common after catheterization. In one study in adults a very low incidence of seizures of 0.06% was observed 5. These patients developed acute generalized seizures immediately after catheterization that resolved without sequelae. The authors do not comment on the results of brain imaging studies. Seizure etiology is unclear and might be attributable to direct toxic effects of the contrast medium on the central nervous system, which is doserelated. Idiosyncratic or non-idiosyncratic drug reactions have been described in case reports in the pediatric population 21, 22. Other possible mechanisms could be due to cerebral ischemia, air embolism or hemorrhage. Although no systematic publications exist in the adult population, it can be only speculated, that seizure activity would be more common in patients with underlying CNS pathology.
CABG Seizures may occur secondary to cerebral air embolism, brain ischemia, or as a result of adverse effects of concurrently administered medication. In one prospective multicenter observational study that included 2108 patients undergoing elective CABG surgery the independent predictive factors for stroke and encephalopathy were assessed to define their influence on the use of resources 8. The impact of seizures along with deterioration in intellectual function and memory deficits were classifies as type II injury and were considered as less incapacitating in comparison to type I neurological complications like e.g. stroke. Only 8 patients (0.4%) showed seizures postoperatively. Although the duration of intensive care and total hospital stay was prolonged for these patients, no independent risk
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factors associated with seizures were assessed. In another large series of CABG patients, only one patient (0.1%) developed postoperative seizures 4, 39. The underlying mechanisms of seizure activity and its association with other neurological complications like ischemia or air embolism had not been assessed. Valvular surgery According to Goldstone et al the incidence of seizures following valvular surgery is 1% and increases up to 3% in patients undergoing a combined valvular and CABG procedure 4. As in CABG surgery causal factors may be embolism of air, solid matter or thrombi with cerebral ischemia and putative pharmacological agents. Cardiac tumors The most common heart tumor, the atrial myxoma, frequently causes embolic stroke or – less often – seizures preoperatively that eventually lead to the final diagnosis. The proper timing of surgery after stroke with or without convulsions is still in debate. 40 An older study, however in patients with infective endocarditis, reported decreased mortality when surgery was delayed for at least four weeks after embolic stroke41 In addition to causes inherent to open heart surgery, convulsions in myxoma patients can also result from myxomateous embolic occlusion of brain vessels with consecutive focal cerebral ischemia or by metastatic spread into the brain42. It is unclear if the postoperative incidence is increased in these patients relative to the preoperative incidence. 40 Persistent or recurrent postoperative seizures may in this circumstance further be related to brain metastases or recurrent atrial myxoma42. Extracorporeal membrane oxygenation (ECMO) Veno-arterial ECMO is commonly used in the pediatric and adult population in instances of acute or acute-on-chronic left heart failure, either as a bridge to recovery or transplant, and also in the course of cardiopulmonary resuscitation. A considerable rate of neurological complications in association with the device has been published in the literature. Frequent neurological complications are intracranial hemorrhage, brain ischemia, and diffuse anoxic 8
brain injury leading to brain death. However, only few of these observational studies assessed the occurrence of seizures and their influence on outcome. In adult patients who undergo veno-venous ECMO for respiratory support the incidence of seizures is quoted to be 1%, in patients supported for primarily cardiac indications with veno-arterial ECMO 1.4% and in patients after extracorporeal cardiopulmonary resuscitation with ECMO even 2.3% (www.elsonet.org, ELCS Registry Report, January 2017)43. In a recent review on neurological complications of ECMO, 14 papers comprising data of almost 40000 patients were analyzed, and the clinical signs of neurologic injury were evaluated 9. Seizures were systematically evaluated in three prospective pediatric populations44-46 and one retrospective study including a total of 23951 patients (60% children and 40% adults)47. In the latter the observation period lasted over 10 years. Overall, seizures were documented in 4.1% of all patients (2.5% of adults aged 18-64 years and 0.3% of persons older than 65 years). Interestingly, postoperative outcome was not significantly different between patients with seizures and those without neurological complications. Although no coincidence of seizures with intracranial hemorrhage or cerebral infarction was presented, over one third of patients showed more than one neurological complication. There are no data available regarding the results of image-guided techniques or EEG. Left ventricular assist devices (LVAD) Seizure activity has also been reported in patients with ventricular assist devices secondary to brain injury. In a recent study, 69 patients after LVAD implantation were systematically screened for 30 days in regard of their postoperative neurological outcome 6. In 19 patients (28%) neurological complications were documented, seizures were described in only three patients, an additional six patients showed signs of ‘confusion’. In four of those patients brain imaging was performed, yet, in none of them was an EEG study conducted. Tranexamic acid and other pharmacologic agents
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Independent of the surgical procedures and the potentially associated cerebral injury, exposure to potentially epileptogenic medication, especially in cases of impaired renal clearance, can provoke seizures. Patients, who were exposed to the antifibrinolytic TXA showed a higher seizure incidence in the early postoperative period.48 In cardiac surgery these agents are used widely to reduce intraoperative blood loss. A recently published meta-analysis combining randomized and nonrandomized studies on seizures linked to TXA clearly confirmed that TXA administration in the course of adult cardiac surgery is associated with a 4.1-fold increase in the risk of seizures 25
. In a retrospective study in 669 patients without a history of seizures who were treated with
TXA 24 patients (3.6%) experienced postoperative seizures, on average, 4.7 hours after surgery. Only three of them showed evidence of recent minor cerebral infarction, which was not thought to have contributed to their seizures 24. In stark contrast, the seizure incidence in patients of the ATACAS trial was 0.7% in the TXA group, which is comparatively low in relation to other observations49, 50 . This may be explained by the fact that a certain proportion of postoperative seizures are non-convulsive, i.e. clinically difficult to detect. It can therefore be speculated if the incidence of postoperative seizures, which was a secondary outcome variable, has been underreported. In addition, it is well known that seizures occur more frequently in patients undergoing open-heart surgery. However, almost 80% of patients in the ATACAS trial had undergone isolated CABG procedures50-52. Another study on 11529 patients found a strong association between high-dose TXA and postoperative convulsions resulting in a 2.5-time higher in-hospital mortality rate and twice the length of hospital stay compared with patients without seizures.53 While some researchers described an increased incidence of seizures after high-dose (in excess of 80 – 100 mg/kg BW) TXA administration51, 54 others could not confirm such an association.50 It may nevertheless be prudent to administer the lowest dose possible that produces the desired effect. The proconvulsive action of TXA can be explained by a direct influence of TXA on neurons and glia 10
cells. As a lysine analog, TXA can easily cross the blood brain barrier and thus induce brain injury by acting as a competitive antagonist at the glycine receptor48. Additionally, TXA facilitates neuronal excitation by antagonizing the inhibitory effect of GABA-ergic neurotransmission.55 Both hypotheses, however, do not explain 1) why the seizure incidence is greater in open-heart procedures and in non-cardiac surgery and 2) why no difference was observed between patients who received TXA and those receiving placebo in the subgroup of patients undergoing CABG surgery50. Taken together, the occurrence and the severity of TXA-induced seizures appear to be related to multiple factors some potentially being related to patient-specific risk factors (e.g. ascending aortic disease, congestive heart failure, age, female sex, and renal failure). 20, 53 Beyond TXA, there are a great number of pharmacologic agents that may be administered in the course of cardiac surgical procedures, which have been implicated with seizure activity. Amongst these are volatile and intravenous anesthetics, opioids, atracurium, lidocaine, antibiotics (e.g. cephalosporins), atropine, antihistamines, propranolol, insulin, glucocorticosteroids, theophylline, haloperidol, salicylates, and many others.56 Procoagulants may also increase neuronal excitability indirectly either via formation of cerebral microthrombi with subsequent brain ischemia or via direct action of thrombin on neurons.57. Although the majority of drug-induced seizures are self-limited, some may require treatment usually in the form of IV administration of benzodiazepins, barbiturates or propofol.58
Management of postoperative seizures Of utmost importance is the timely and correct identification of seizures. Since they frequently appear immediately after or in the early postoperative phase (i.e. within the first two days after surgery), the personnel should be trained in recognizing typical clinical signs like abnormal movements, myoclonic muscle twitching, uncontrollable jerks of limbs (uni- or bilaterally), eye and head deviation, dystonic posturing of the hands or automatisms 59. 11
Usually, seizures -when they occur - do not last very long. In one third of cases a correct diagnosis of nonepileptic versus epileptic seizure can be established based on video data alone 60
. Therefore, the documentation of these movements by recording them, especially if they are
brief and recurrent, can be helpful in the diagnosis. If the duration of abnormal movements or behavior lasts longer than 2-3 minutes, management should be focused on stabilization of patient to prevent the development of status epilepticus 1. This includes insufflation of oxygen, administration of benzodiazepines (e.g. IV lorazepam, diazepam or midazolam), with repetition of an additional dosage if necessary and, if the seizure cannot be terminated, administration of second line drugs or even the sedation with continuous IV propofol 1. After stabilization, the underlying cause should be searched for. Structural brain imaging techniques (MRI, or, if not possible, CT scan) are inevitable studies to diagnose ischemic or hemorrhagic stroke, an easily identifiable cause for seizure activity. It should be performed soon after an event even in the case of singular and self-limiting seizures. Renal insufficiency, either preexistent or having developed acutely after surgery, may prolong the elimination of antibiotics, TXA, contrast agents, and other drugs that can induce seizures by concomitantly increased local brain tissue concentrations. Medical history should be carefully evaluated in regard of preoperative seizures and medication (i.e. antiepileptics, benzodiazepins) or alcohol as withdrawal can also trigger seizures. Identification of NCS or NCSE is, however, more difficult. The clinical signs - temporary confusion, loss of awareness or psychotic symptoms - are less prominent and can go unnoticed easily. In these instances, continuous video-EEG monitoring with simultaneous recordings of EEG and clinical behavior over hours to weeks is a helpful tool for their identification. Since it is cost-intensive and needs additional personnel, the sub-hairline 4derivation cEEG (9 sticker electrode system that is applied to the frontal and temporal areas
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and allows the seizure documentation) could alternatively be applied in conjunction with serial EEGs 61. The decision regarding long-term prescription of antiepileptic drugs should be made very cautiously. It should be based on the underlying cause for developing seizures and the results of additional tests, including the results of brain imaging and EEG. By choosing the appropriate drug its interaction potential, metabolism and elimination should be considered; the newer generation anticonvulsants should probably be preferred as fewer side effects are reported 62. After prescription, short-term evaluation should be performed to assess the necessity for long-term administration.
Conclusions The true incidence of postoperative seizures is probably under-reported since particularly detection of NCS is difficult and the diagnosis is frequently based solely on clinically apparent signs and symptoms that are typical of grand mal seizures. Sensitized and especially trained clinicians will consequently report seizure activity more accurately as someone who does not have this kind of clinical routine or a researcher who browses a hospital data base. As the number of patients with multiple co-morbidities who undergo cardiac surgical procedures will likely increase in the future it can be assumed that the incidence of neurological complications, including convulsions, will rise concomitantly. Not all mechanisms leading to seizure activity in adults after cardiac surgery have been clarified so far. Occurrence of postoperative seizures appears to be multi-factorial. There are risk factors associated with seizures most of which cannot - or only in part - be modified. These include long cardiopulmonary bypass time, open-chamber cardiac surgery, preoperative cardiac arrest, renal insufficiency, aortic calcification, deep hypothermic circulatory arrest, and critical preoperative state. Predisposing factors are also older age (>75 years) and pre-existing brain damage (i.e. stroke). Seizures further can be induced by 13
medication or alcohol withdrawal. Evidence concerning the benefit of certain pre-emptive measures is currently lacking. Nevertheless, exposure to TXA and the choice of its administered dosage for example, as well as avoidance of brain ischemia, certain pharmacologic agents and hyperventilation are some factors that can be modified, which may further translate into better outcome. Importantly, early diagnosis of seizures and identification of underlying causes is essential to reduce seizure-associated long-term morbidity and mortality of patients.
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Couture P, Lebon JS, Laliberte E, et al.: Low-Dose Versus High-Dose Tranexamic Acid Reduces the Risk of Nonischemic Seizures After Cardiac Surgery With Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth. 31:1611-1617, 2017.
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Koster A, Borgermann J, Zittermann A, et al.: Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth. 110:34-40, 2013.
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Management of postoperative seizures
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Surgery
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Ekaterina Pataraia, Rebekka Jung, Susanne AullWatschinger, Keso Skhirtladze-Dworschak, Martin Dworschak www.elsevier.com/locate/bios
PII: DOI: Reference:
S1053-0770(17)31024-8 https://doi.org/10.1053/j.jvca.2017.12.036 YJCAN4489
To appear in: Journal of Cardiothoracic and Vascular Anesthesia Cite this article as: Ekaterina Pataraia, Rebekka Jung, Susanne AullWatschinger, Keso Skhirtladze-Dworschak and Martin Dworschak, Seizures after Adult Cardiac Surgery and Interventional Cardiac Procedures, Journal of Cardiothoracic and Vascular Anesthesia,doi:10.1053/j.jvca.2017.12.036 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Seizures after adult cardiac surgery and interventional cardiac procedures Ekaterina Pataraia, MD, PhD, MBA1, Rebekka Jung, MD1, Susanne Aull-Watschinger, MD1, Keso Skhirtladze-Dworschak, MD2, Martin Dworschak, MD, MBA2 1
Department of Neurology, Medical University of Vienna, Vienna, Austria
2
Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, Medical
University of Vienna, Vienna, Austria
Corresponding author: Ekaterina Pataraia, MD, PhD, MBA Department of Neurology Medical University of Vienna, 1090 Vienna, Austria Phone: +43 1 40400 34330 [email protected]
Abstract The aim of this narrative review is to evaluate the incidence of seizures after adult cardiac surgery or cardiac interventions, to describe risk factors, and to provide suggestions regarding diagnostic measures and proper management. Based on published peer-reviewed articles we demonstrate specific procedure-related risks for seizures. Early diagnosis and the identification of underlying causes as well as avoidance of amenable risk factors are crucial to reduce associated long-term morbidity and mortality. Methods of early recognition of
1
seizures, particularly focusing on the initiation of appropriate diagnostic measures, their management, and their timely treatment, are presented in the article.
Introduction The western world currently sees a growing number of cardiac interventions and operations in adults. Epidemiological forecasts predict that it will further increase in the near future despite a decline in the incidence of heart disease.2 In spite of the rising number of cardiac surgeries and interventions that are carried out and the fact that more and more elderly patients and those with severe co-morbidities who have previously been excluded from surgical treatment are undergoing such procedures, postoperative mortality remained almost stable over the recent years.3 Nevertheless, all these procedures carry an inherent risk of complications and may be associated with neurological injury4-9. Neurological outcome is determined by underlying patient factors, the specific procedure and by perioperative management. Accordingly, some of these factors (e.g. administered pharmacologic agents, cerebral ischemia, hyperventilation, etc.) are amenable to modifications. Neurological symptoms vary depending on the type of injury and can be either transient or persistent. The most obvious central nervous system (CNS) injury continues to be stroke 10-14. Other more frequent complications are cognitive decline and encephalopathy that are usually not as easy to diagnose as thrombo-embolic stroke. 14-18 Postoperative seizures occur less commonly but may have significant consequences for the patient 4, 19, 20. They are presumably multifactorial and may result from focal or global cerebral ischemia due to hypoperfusion or emboli, metabolic disturbances or drug reactions (e.g. administration of contrast means 21, 22, drug overdose like for example with theophylline 23 or high dose of tranexamic acid (TXA) 24-26). In the past, most researchers investigating neurological injury post cardiac surgery mainly focused on ischemic injury and on cognitive decline. In contrast to perioperative stroke that has thoroughly been 2
investigated, there are much less data on the incidence, epidemiology, and outcome of seizures after cardiac surgery 4, 20. Early evaluation of such a complication requires a systematic approach in order to plan and initiate appropriate treatment in a timely manner. The present narrative review was performed by searching corresponding studies in PubMed using the key words ‘seizures’, ‘convulsive’, ‘non-convulsive’, ‘’status epilepticus’, ‘cardiac surgery’, ‘cardiac intervention’ and ‘anesthesia’. After assessing the most relevant studies a search of secondary sources including references of initially identified articles was done. Case reports and brief communication were also included. Only literature published in English language was selected.
Seizure types and their identification The International League against Epilepsy (ILAE) recently proposed an operational classification of seizure types with the purpose for appropriate assignment to seizures with focal of generalized onset, to include some missing seizure types and to adopt more transparent names. 27 Seizures are defined as transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain 28, 29. Different types of seizures have been observed postoperatively. Seizures, which can readily be recognized, are generalized tonic-clonic convulsions. Although this form causes great concern to medical staff, patients and their families, more disturbing are the non-convulsive seizures (NCS) and non-convulsive status epilepticus (NCSE) – a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures30. A great proportion of seizures in critically ill patients is non-convulsive. They are frequently missed or mistaken for something else so necessary management is consequently often delayed. Depending on the type and duration of seizures they can have long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks 30, 31. 3
The incidence of NCSE ranges from 8 to 40% in critically ill patients 24, 32, 33. It is still unknown for the cardiac surgical population since seizures can be missed or not being identified as such. In any case, the reported incidence of acute seizures varies between 0.5 and 1%, and for those of recurrent seizures was given as 0.5% 20. However, this data comes from an observational study on postoperative outcome and needs to be confirmed in larger prospective multicenter observational studies, which are laborious, challenging and timeconsuming. In addition, many investigations are retrospective in nature and lack a precise assessment of the occurrence of seizures. Often, the main problem is the correct identification of seizures. Shivering, tremor, dystonia, choreatic movements or myoclonus, misinterpretation of symptoms as postictal state, psychiatric disorders, stroke or metabolic encephalopathy – can lead to over-diagnosis of seizures 34. Clinical diagnosis, however, requires experienced personnel. Subtle clinical signs like nystagmus, eye-deviation, twitching of the hand, and subtle focal clonus of facial muscles must be carefully sought. Beyond clinical signs, the only confirmatory tool for the diagnosis particularly of NCSs and NCSE is electroencephalography (EEG)35. It can be performed intermittently or continuously36. Continuous EEG (cEEG) is very informative, but needs qualified personnel and expensive equipment. On the other hand, early identification of NCS or NCSE could mitigate brain injury and prevent prolonged intensive care stay30, 31. Several studies were conducted to compare intermittent vs. cEEG monitoring showing the superiority of cEEG in regard of seizure detection 35-37. Most of them were performed at neurological ICUs in patients with brain damage. Not surprisingly, the probability of seizure occurrence was high. In a prospective observational study of seizures after cardiac surgery Gofton et al. used a downgraded cEEG with a sub-hairline array of electrodes in a series of 101 consecutive patients to identify electrographic seizures without clear convulsive correlates 38. Although use of this device does not give complete information about the origin 4
of seizures, it could be very helpful in early identification of seizures. The authors observed that 3% of patients had early postoperative seizures (two patients had generalized and one an electrographic seizure). Since the number of potentially detrimental NCS was low, they concluded that use of cEEG after cardiac surgery would be unlikely to be cost-effective or improve long-term patient outcome. Nevertheless, prolongation of the duration of application (>24 hours) may improve seizure detection. Young et al found that a delay in seizure diagnosis of > 24 hours was associated with a 75% mortality rate due to prolonged NCS activity 33. However, it is still controversial which patients should be monitored by EEG and there are still no clear guidelines for applying a cEEG especially for the detection of NCS or NCSE 37. In a series of 2578 consecutive patients, who underwent cardiac surgery at a single institution, the predictors for developing seizures postoperatively were evaluated by Goldstone et al 4. The surgical procedures were standardized and all patients with exception of those with known hypercoagulable states received aminocapronic acid; aprotinin and TXA were not used. An attending neurologist classified the seizures based on clinical history and examination. The patients with ongoing seizures were subjected to computed tomography of the brain (CCT), which was not performed after a singular seizure and spontaneous resolution. Magnetic resonance imaging (MRI) was ordered only in patients with ongoing neurological deficits, where no pathologies could be ascertained in the previous CT scan. The authors found that 1.2% of patients had seizures in the postoperative period. Subgroup analysis identified 71% of cases with generalized tonic-clonic seizures, 26% with simple or complex partial seizures and 3% with NCSE. Thereby, the proportion of patients with NCSE was significantly lower than that with single seizures (either focal or generalized). The incidence of seizures further differed according to procedure. It was lowest in coronary artery bypass grafting (CABG) surgery (0.1%), 1% for isolated valve intervention, 3% for combined valve and bypass procedures, and 5% for aortic surgery (p<0.001). The researchers 5
also found that patients with seizures had more postoperative complications and a hospital mortality being five-fold greater than patients without seizures (29% vs. 6%). The type of seizure was not related to patient outcome. The authors also assessed the predictors of seizures. Only three (i.e. deep hypothermic circulatory arrest, aortic calcification or atheroma and critical postoperative state) of a total of 25 factors reached statistical significance. Suspected factors like body temperature and the duration of circulatory arrest were not significantly different between the seizure and the non-seizure group. Pre-existing cerebrovascular disease also had no influence on the occurrence of postoperative seizure. When seizures are detected postoperatively they may have a tendency to recur depending on the underlying cause and can thus worsen long-term morbidity and mortality. The risk factors and outcome of recurrent seizures following cardiac surgery has been assessed from data of 7280 patients 20. Patients with postoperative seizures were followed up by a median of 21 months. The incidence of postoperative seizures was 0.8%. Altogether, 59% of these patients had recurrent seizures either immediately after the first seizure or during their hospital stay. Only three patients (0.04%) had NCSE, which was suspected by decreased level of consciousness and confirmed by serial EEGs. The authors evaluated different predictors for seizure recurrence and found that higher preoperative creatinine (>120 mmol/L), procedures involving thoracic aortic surgery and early seizure onset after surgery (<4 hours) were associated with seizure recurrence. Preoperative seizure disorders or existence of cerebrovascular disease was not associated with postoperative seizures. Interestingly, there was no significant difference between patients with single or recurrent seizures in the longterm outcome regarding morbidity and mortality. However, the number of affected patients with recurrent seizures was low. Although the authors screened for preoperative cerebrovascular accidents, alterations in patients’ neurological status were not examined postoperatively. Unfortunately, the results from EEG, CT scan or MRI exams – if performed – were not presented in the paper. This, however, would be valuable information in regard of 6
understanding the mechanisms of origin and the prognosis of seizures and finally also determines the long-term treatment strategies.
Specific risks in different cardiac surgical procedures Cardiac catheterization and Percutaneous coronary interventions Seizures are not common after catheterization. In one study in adults a very low incidence of seizures of 0.06% was observed 5. These patients developed acute generalized seizures immediately after catheterization that resolved without sequelae. The authors do not comment on the results of brain imaging studies. Seizure etiology is unclear and might be attributable to direct toxic effects of the contrast medium on the central nervous system, which is doserelated. Idiosyncratic or non-idiosyncratic drug reactions have been described in case reports in the pediatric population 21, 22. Other possible mechanisms could be due to cerebral ischemia, air embolism or hemorrhage. Although no systematic publications exist in the adult population, it can be only speculated, that seizure activity would be more common in patients with underlying CNS pathology.
CABG Seizures may occur secondary to cerebral air embolism, brain ischemia, or as a result of adverse effects of concurrently administered medication. In one prospective multicenter observational study that included 2108 patients undergoing elective CABG surgery the independent predictive factors for stroke and encephalopathy were assessed to define their influence on the use of resources 8. The impact of seizures along with deterioration in intellectual function and memory deficits were classifies as type II injury and were considered as less incapacitating in comparison to type I neurological complications like e.g. stroke. Only 8 patients (0.4%) showed seizures postoperatively. Although the duration of intensive care and total hospital stay was prolonged for these patients, no independent risk
7
factors associated with seizures were assessed. In another large series of CABG patients, only one patient (0.1%) developed postoperative seizures 4, 39. The underlying mechanisms of seizure activity and its association with other neurological complications like ischemia or air embolism had not been assessed. Valvular surgery According to Goldstone et al the incidence of seizures following valvular surgery is 1% and increases up to 3% in patients undergoing a combined valvular and CABG procedure 4. As in CABG surgery causal factors may be embolism of air, solid matter or thrombi with cerebral ischemia and putative pharmacological agents. Cardiac tumors The most common heart tumor, the atrial myxoma, frequently causes embolic stroke or – less often – seizures preoperatively that eventually lead to the final diagnosis. The proper timing of surgery after stroke with or without convulsions is still in debate. 40 An older study, however in patients with infective endocarditis, reported decreased mortality when surgery was delayed for at least four weeks after embolic stroke41 In addition to causes inherent to open heart surgery, convulsions in myxoma patients can also result from myxomateous embolic occlusion of brain vessels with consecutive focal cerebral ischemia or by metastatic spread into the brain42. It is unclear if the postoperative incidence is increased in these patients relative to the preoperative incidence. 40 Persistent or recurrent postoperative seizures may in this circumstance further be related to brain metastases or recurrent atrial myxoma42. Extracorporeal membrane oxygenation (ECMO) Veno-arterial ECMO is commonly used in the pediatric and adult population in instances of acute or acute-on-chronic left heart failure, either as a bridge to recovery or transplant, and also in the course of cardiopulmonary resuscitation. A considerable rate of neurological complications in association with the device has been published in the literature. Frequent neurological complications are intracranial hemorrhage, brain ischemia, and diffuse anoxic 8
brain injury leading to brain death. However, only few of these observational studies assessed the occurrence of seizures and their influence on outcome. In adult patients who undergo veno-venous ECMO for respiratory support the incidence of seizures is quoted to be 1%, in patients supported for primarily cardiac indications with veno-arterial ECMO 1.4% and in patients after extracorporeal cardiopulmonary resuscitation with ECMO even 2.3% (www.elsonet.org, ELCS Registry Report, January 2017)43. In a recent review on neurological complications of ECMO, 14 papers comprising data of almost 40000 patients were analyzed, and the clinical signs of neurologic injury were evaluated 9. Seizures were systematically evaluated in three prospective pediatric populations44-46 and one retrospective study including a total of 23951 patients (60% children and 40% adults)47. In the latter the observation period lasted over 10 years. Overall, seizures were documented in 4.1% of all patients (2.5% of adults aged 18-64 years and 0.3% of persons older than 65 years). Interestingly, postoperative outcome was not significantly different between patients with seizures and those without neurological complications. Although no coincidence of seizures with intracranial hemorrhage or cerebral infarction was presented, over one third of patients showed more than one neurological complication. There are no data available regarding the results of image-guided techniques or EEG. Left ventricular assist devices (LVAD) Seizure activity has also been reported in patients with ventricular assist devices secondary to brain injury. In a recent study, 69 patients after LVAD implantation were systematically screened for 30 days in regard of their postoperative neurological outcome 6. In 19 patients (28%) neurological complications were documented, seizures were described in only three patients, an additional six patients showed signs of ‘confusion’. In four of those patients brain imaging was performed, yet, in none of them was an EEG study conducted. Tranexamic acid and other pharmacologic agents
9
Independent of the surgical procedures and the potentially associated cerebral injury, exposure to potentially epileptogenic medication, especially in cases of impaired renal clearance, can provoke seizures. Patients, who were exposed to the antifibrinolytic TXA showed a higher seizure incidence in the early postoperative period.48 In cardiac surgery these agents are used widely to reduce intraoperative blood loss. A recently published meta-analysis combining randomized and nonrandomized studies on seizures linked to TXA clearly confirmed that TXA administration in the course of adult cardiac surgery is associated with a 4.1-fold increase in the risk of seizures 25
. In a retrospective study in 669 patients without a history of seizures who were treated with
TXA 24 patients (3.6%) experienced postoperative seizures, on average, 4.7 hours after surgery. Only three of them showed evidence of recent minor cerebral infarction, which was not thought to have contributed to their seizures 24. In stark contrast, the seizure incidence in patients of the ATACAS trial was 0.7% in the TXA group, which is comparatively low in relation to other observations49, 50 . This may be explained by the fact that a certain proportion of postoperative seizures are non-convulsive, i.e. clinically difficult to detect. It can therefore be speculated if the incidence of postoperative seizures, which was a secondary outcome variable, has been underreported. In addition, it is well known that seizures occur more frequently in patients undergoing open-heart surgery. However, almost 80% of patients in the ATACAS trial had undergone isolated CABG procedures50-52. Another study on 11529 patients found a strong association between high-dose TXA and postoperative convulsions resulting in a 2.5-time higher in-hospital mortality rate and twice the length of hospital stay compared with patients without seizures.53 While some researchers described an increased incidence of seizures after high-dose (in excess of 80 – 100 mg/kg BW) TXA administration51, 54 others could not confirm such an association.50 It may nevertheless be prudent to administer the lowest dose possible that produces the desired effect. The proconvulsive action of TXA can be explained by a direct influence of TXA on neurons and glia 10
cells. As a lysine analog, TXA can easily cross the blood brain barrier and thus induce brain injury by acting as a competitive antagonist at the glycine receptor48. Additionally, TXA facilitates neuronal excitation by antagonizing the inhibitory effect of GABA-ergic neurotransmission.55 Both hypotheses, however, do not explain 1) why the seizure incidence is greater in open-heart procedures and in non-cardiac surgery and 2) why no difference was observed between patients who received TXA and those receiving placebo in the subgroup of patients undergoing CABG surgery50. Taken together, the occurrence and the severity of TXA-induced seizures appear to be related to multiple factors some potentially being related to patient-specific risk factors (e.g. ascending aortic disease, congestive heart failure, age, female sex, and renal failure). 20, 53 Beyond TXA, there are a great number of pharmacologic agents that may be administered in the course of cardiac surgical procedures, which have been implicated with seizure activity. Amongst these are volatile and intravenous anesthetics, opioids, atracurium, lidocaine, antibiotics (e.g. cephalosporins), atropine, antihistamines, propranolol, insulin, glucocorticosteroids, theophylline, haloperidol, salicylates, and many others.56 Procoagulants may also increase neuronal excitability indirectly either via formation of cerebral microthrombi with subsequent brain ischemia or via direct action of thrombin on neurons.57. Although the majority of drug-induced seizures are self-limited, some may require treatment usually in the form of IV administration of benzodiazepins, barbiturates or propofol.58
Management of postoperative seizures Of utmost importance is the timely and correct identification of seizures. Since they frequently appear immediately after or in the early postoperative phase (i.e. within the first two days after surgery), the personnel should be trained in recognizing typical clinical signs like abnormal movements, myoclonic muscle twitching, uncontrollable jerks of limbs (uni- or bilaterally), eye and head deviation, dystonic posturing of the hands or automatisms 59. 11
Usually, seizures -when they occur - do not last very long. In one third of cases a correct diagnosis of nonepileptic versus epileptic seizure can be established based on video data alone 60
. Therefore, the documentation of these movements by recording them, especially if they are
brief and recurrent, can be helpful in the diagnosis. If the duration of abnormal movements or behavior lasts longer than 2-3 minutes, management should be focused on stabilization of patient to prevent the development of status epilepticus 1. This includes insufflation of oxygen, administration of benzodiazepines (e.g. IV lorazepam, diazepam or midazolam), with repetition of an additional dosage if necessary and, if the seizure cannot be terminated, administration of second line drugs or even the sedation with continuous IV propofol 1. After stabilization, the underlying cause should be searched for. Structural brain imaging techniques (MRI, or, if not possible, CT scan) are inevitable studies to diagnose ischemic or hemorrhagic stroke, an easily identifiable cause for seizure activity. It should be performed soon after an event even in the case of singular and self-limiting seizures. Renal insufficiency, either preexistent or having developed acutely after surgery, may prolong the elimination of antibiotics, TXA, contrast agents, and other drugs that can induce seizures by concomitantly increased local brain tissue concentrations. Medical history should be carefully evaluated in regard of preoperative seizures and medication (i.e. antiepileptics, benzodiazepins) or alcohol as withdrawal can also trigger seizures. Identification of NCS or NCSE is, however, more difficult. The clinical signs - temporary confusion, loss of awareness or psychotic symptoms - are less prominent and can go unnoticed easily. In these instances, continuous video-EEG monitoring with simultaneous recordings of EEG and clinical behavior over hours to weeks is a helpful tool for their identification. Since it is cost-intensive and needs additional personnel, the sub-hairline 4derivation cEEG (9 sticker electrode system that is applied to the frontal and temporal areas
12
and allows the seizure documentation) could alternatively be applied in conjunction with serial EEGs 61. The decision regarding long-term prescription of antiepileptic drugs should be made very cautiously. It should be based on the underlying cause for developing seizures and the results of additional tests, including the results of brain imaging and EEG. By choosing the appropriate drug its interaction potential, metabolism and elimination should be considered; the newer generation anticonvulsants should probably be preferred as fewer side effects are reported 62. After prescription, short-term evaluation should be performed to assess the necessity for long-term administration.
Conclusions The true incidence of postoperative seizures is probably under-reported since particularly detection of NCS is difficult and the diagnosis is frequently based solely on clinically apparent signs and symptoms that are typical of grand mal seizures. Sensitized and especially trained clinicians will consequently report seizure activity more accurately as someone who does not have this kind of clinical routine or a researcher who browses a hospital data base. As the number of patients with multiple co-morbidities who undergo cardiac surgical procedures will likely increase in the future it can be assumed that the incidence of neurological complications, including convulsions, will rise concomitantly. Not all mechanisms leading to seizure activity in adults after cardiac surgery have been clarified so far. Occurrence of postoperative seizures appears to be multi-factorial. There are risk factors associated with seizures most of which cannot - or only in part - be modified. These include long cardiopulmonary bypass time, open-chamber cardiac surgery, preoperative cardiac arrest, renal insufficiency, aortic calcification, deep hypothermic circulatory arrest, and critical preoperative state. Predisposing factors are also older age (>75 years) and pre-existing brain damage (i.e. stroke). Seizures further can be induced by 13
medication or alcohol withdrawal. Evidence concerning the benefit of certain pre-emptive measures is currently lacking. Nevertheless, exposure to TXA and the choice of its administered dosage for example, as well as avoidance of brain ischemia, certain pharmacologic agents and hyperventilation are some factors that can be modified, which may further translate into better outcome. Importantly, early diagnosis of seizures and identification of underlying causes is essential to reduce seizure-associated long-term morbidity and mortality of patients.
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Management of postoperative seizures
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