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Systemic complications of status epilepticus — An update Sara Hocker ⁎ Division of Critical Care Neurology, Mayo Clinic, Rochester, MN, USA

a r t i c l e

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Article history: Revised 14 April 2015 Accepted 15 April 2015 Available online xxxx Keywords: Status epilepticus Treatment Cardiac Medical complications Intensive care unit

a b s t r a c t Systemic complications occur at every stage of status epilepticus, involve every organ system, and may worsen outcome. Initially, there is a massive catecholamine release and hyperadrenergic state that may result in neurocardiogenic, pulmonary, and, sometimes, musculoskeletal or renal injury. Further medical complications accompany the various treatments used to abort the seizures including the use of nonanesthetic antiseizure drugs and high-dose anesthetic infusions. Later, sequelae of prolonged immobility and critical illness occur and add to the cumulative morbidity of these patients. Clinicians should follow a protocol to guide screening for early markers of systemic injury, complications of specific pharmacologic and adjunctive treatments, and periodic surveillance for complications related to prolonged immobility. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.

1 . Introduction

2. Early systemic complications

Status epilepticus is truly a multisystem disorder. Management requires knowledge of physiologic and resultant end organ changes which occur during status epilepticus, anticipated and less common adverse effects of various treatment options, and the manifestations of prolonged critical illness. The metabolic demand of the brain is high during ongoing seizures. Compensatory mechanisms occur to meet the demand and prevent cerebral damage. These mechanisms are increased cerebral blood flow and metabolism, increased autonomic activity, and cardiovascular changes including increased cardiac output and central venous pressure. There is a catecholamine release which leads to tachycardia, hypertension, hyperpyrexia, hyperglycemia, and demargination of white blood cells resulting in a peripheral leukocytosis. During prolonged seizures, autonomic changes persist, and cardiopulmonary functions eventually fail to maintain hemodynamic and respiratory homeostasis (Fig. 1). The majority of early systemic complications result from this cascade and relate to mechanical injury from loss of consciousness, violent convulsions, massive catecholamine release, or tissue hypoperfusion. In nonconvulsive status epilepticus, or after control of convulsions during convulsive status epilepticus, a second set of complications can occur relating to the treatments used to control the seizures. In those with super refractory status epilepticus, additional systemic complications may result from prolonged immobility and exposure to pathogens (Table 1).

The typical metabolic profile of a patient arriving to the emergency department during or shortly after status epilepticus is that of a respiratory acidosis with or without metabolic acidosis. The respiratory acidosis results from a combination of increased production from the seizures and decreased removal by the lungs in the setting of decreased respiratory drive, diaphragmatic contraction during seizures, fatigue of respiratory muscles or increased upper airway resistance, and injury to the lung from aspiration. Metabolic acidosis is due to excessive muscular contraction causing depletion of the glycogen and anaerobic glycolysis which leads to production of lactic acid. Because the acidosis is not associated with potential life-threatening arrhythmias, bicarbonate is not recommended [1]. The acid–base abnormalities nearly always resolve within several hours after resolution of the seizures and do not require additional diagnostic or therapeutic interventions. Hypoxia, while common, is not well documented primarily because oxygen is administered during transfer to an emergency department or intensive care setting. Hypoxemia may result from apnea, upper airway obstruction, aspiration of gastric contents, mucous plugging, or neurocardiogenic pulmonary edema. Additionally, patients are invariably treated with benzodiazepines or other antiseizure drugs which may potentially depress the respiratory drive. Endotracheal intubation is commonly required. In a recent large multicenter study of patients with status epilepticus, 21% required endotracheal intubation. Intubation was more common among the elderly or those with refractory seizures and was associated with a higher mortality [2]. A catecholamine surge may result in a number of complications which require attention. Hyperglycemia and peripheral leukocytosis are common initially, are transient, and do not generally require

⁎ Mayo Clinic, Department of Neurology, Division of Critical Care Neurology, 200 First St SE, Rochester, MN 55905, USA. Tel.: +1 507 288 0320. E-mail address: [email protected].

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Please cite this article as: Hocker S, Systemic complications of status epilepticus — An update, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.04.024

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Fig. 1. Summary of systemic alterations and brain metabolism in status epilepticus. Figure from Lothman E. The biochemical basis and pathophysiology of status epilepticus. Neurology 1990; 40 (Suppl 2) Figure 1, page 15. Reprinted with permission.

intervention. Hyperpyrexia should be promptly controlled as it not only increases brain temperature but also is associated with the release of cytokines within the brain, contributes to neuronal hyperexcitability, and is, therefore, proconvulsant. Simple measures including scheduled antipyretics, cooling blankets, and ice packs under the axilla and over the femoral arteries are often sufficient. Fever occurring later in the course of refractory or super refractory status epilepticus may require other measures such as cold saline infusion or cold water circulated via pads adherent to the patient's skin. Perhaps, the most well-documented organ to be injured as a result of status epilepticus is the heart. Mechanisms of cardiac injury have been hypothesized to include catecholamine release, direct autonomic effects of seizures, cardiotoxic therapy, and electrolyte disturbances or acidosis resulting in arrhythmias. While excess catecholamine release [3,4] and direct autonomic effects of seizures [5] have been well documented, the acidosis associated with status epilepticus has not been shown to result in significant arrhythmias [1], and severe electrolyte imbalances resulting from status epilepticus are not commonly encountered. Excess sympathetic activation may result in a hyperadrenergic state associated with subendocardial necrosis, coagulation necrosis, and myocyte contraction band necrosis [6–8] and increase susceptibility to cardiac arrhythmias both in nonrefractory status epilepticus [9] and in refractory status

epilepticus [10]. An autopsy study in which clinical markers of cardiac injury were not reported, demonstrated that death from status epilepticus was significantly associated with the presence of cardiac contraction bands when compared with controls [6]. The clinical spectrum of neurocardiogenic injury in status epilepticus ranges from asymptomatic to shock, and the main manifestations include electrical conduction abnormalities and left ventricular stunning. Other manifestations include arrhythmias, cardiac troponin elevation, and ischemic electrocardiographic patterns. Abnormalities on electrocardiograms obtained within 24 h of status epilepticus, present in greater than half of patients in one study, have been associated with mortality [9]. Neurocardiogenic electrocardiographic changes are typically transient, improving within 24–48 h of the ictus and resolving within days or weeks [11]. Cardiac troponin elevations, when they occur in isolation, appear to be strongly related to the presence of underlying comorbid cardiovascular disease [12–14]. It is likely that in the presence of cardiovascular disease, a mismatch between oxygen and nutrient supply and demand occurs in the setting of status epilepticus, resulting in injury to the myocardium and leading to a troponin elevation and, in some cases, acute coronary syndrome [10]. The presence of cardiac troponin elevations have been strongly associated with increased mortality [12]. Status epilepticus may be accompanied by prolonged QTc, and this may be a marker of susceptibility to

Please cite this article as: Hocker S, Systemic complications of status epilepticus — An update, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.04.024

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ventricular arrhythmias [5,10]. While potentially detrimental in the setting of hypotension, which often occurs as a result of either antiseizure drugs or failure of physiologic compensatory mechanisms, there is experimental evidence that B-adrenergic blockade during status epilepticus may prevent the increased susceptibility to arrhythmias [6,15]. Patients may also present with a syndrome of reversible acquired cardiomyopathy due to neurogenic myocardial stunning, also known as stress cardiomyopathy, takotsubo cardiomyopathy (named for the similarity in appearance of the left ventriculogram in systole to the shape of a Japanese octopus trapping pot), or apical ballooning syndrome. This syndrome was originally described in patients with a sudden emotional stress and has been termed ‘the broken heart syndrome.’ It has been reported in patients with various types of acute intracranial events including seizures [16], focal [17] and convulsive [6,18] status epilepticus, and refractory status epilepticus [10]. In a study comparing patients with seizure-associated takotsubo cardiomyopathy with 974 patients with nonseizure-associated takotsubo, patients with seizure-associated takotsubo cardiomyopathy were younger, had less chest pain, were more likely to experience cardiogenic shock, and were more likely to have recurrent takotsubo cardiomyopathy during subsequent seizures [16]. Seizure-associated takotsubo cardiomyopathy manifests frequently as sudden hemodynamic deterioration accompanied by new transient electrographic changes; modest elevation of the cardiac troponin; and akinesis, hypokinesis, or dyskinesis of the left ventricle with or without apical dysfunction and extending beyond the territory of a single coronary distribution [16,19]. Some have theorized that cardiac toxicity occurs because of direct release of endogenous catecholamines into the myocardium from nerve terminals [4] because patients receiving high levels of exogenous catecholamines do not exhibit contraction band necrosis. Others have suggested that direct local release of catecholamines from cardiac sympathetic efferent neurons is unlikely given the higher norepinephrine content and higher density of sympathetic nerves at the base of the heart when compared with the apex. Because the apical myocardium is more responsive to sympathetic stimulation, it is thought to be more vulnerable to surges in circulating catecholamine levels [11]. It is possible that some cases of sudden unexpected death in epilepsy are attributable to takotsubo cardiomyopathy. Musculoskeletal injuries may initially go undetected, but should be screened for after control of convulsions. Injuries may include fractures of the long bones, rib fractures, vertebral body compression fractures, posterior shoulder dislocation, and tongue bites. Imaging is indicated when there is localized pain in these areas, and the tongue should be examined for ecchymosis or bleeding. Tongue bites are usually laterally located. Rhabdomyolysis caused by prolonged muscular contractions produces myoglobinuria and can result in acute kidney injury. Screening for this complication is accomplished by measuring serum creatine kinase and obtain serial measurements when elevated until there is a downward trend. When rhabdomyolysis is severe, the extremities should be monitored for compartment syndrome. 3. Complications relating to treatment The most concerning adverse effects of antiseizure drugs in the treatment of early stages of status epilepticus are sedation and respiratory depression. Benzodiazepines may suppress both the level of consciousness and respiratory drive; however, uncontrolled status epilepticus is more likely to cause hypoxemia and airway compromise compared with benzodiazepine administration [20,21]. With the exception of phenobarbital, medications used for benzodiazepine refractory status epilepticus are not respiratory depressants. While valproic acid and levetiracetam are well tolerated in hemodynamically tenuous patients, valproic acid has the theoretical risks of platelet and clotting dysfunction and hyperammonemia in predisposed patients, and levetiracetam may be sedating in the high doses required in status epilepticus. Lacosamide may cause PR prolongation but in a series of 92 patients with primarily nonconvulsive or focal motor status epilepticus treated with lacosamide, only 2 experienced

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asymptomatic PR prolongation, and 2 experienced dizziness [22]. Fosphenytoin, while commonly used as a second-line agent in status epilepticus, is less well tolerated primarily because of hypotension. Because the hypotension associated with fosphenytoin is dependent on the rate of infusion and intravascular volume status of the patient, initial reactions should include slowing the rate of infusion and administration of a fluid bolus. Still, 40% of patients receiving fosphenytoin loading doses develop hypotension, of whom half require temporary vasopressor support [unpublished data]. Guidelines and recommendations in several drug information sources recommend cardiac monitoring during and after administering intravenous fosphenytoin sodium because of hypotension and cardiac arrhythmias. This recommendation is supported by a 2006 review of the Food and Drug Administration's Adverse Event Reporting System databank for reports of possible fosphenytoin toxicity which found 29 reports of adverse cardiac events likely related to fosphenytoin infusion, including 10 cardiac deaths. Among survivors, there were four cases of high-grade atrioventricular block and five cases of transient sinus arrest [23]. The authors of a 2013 literature review questioned the need for continuous cardiac monitoring, at least in the case of phenytoin, after finding that intravenous phenytoin loading was not associated with an increased risk of cardiac rhythm abnormalities compared with other intravenous antiseizure drugs including phenobarbitone, diazepam, lorazepam, valproic acid, and levetiracetam [24]. Each anesthetic agent used for control of refractory and super refractory status epilepticus has a unique adverse effect profile, with side effects ranging from mild and easily managed to life-threatening. When used in high doses for 3 days or more, propofol can cause a syndrome of metabolic acidosis, rhabdomyolysis, lactic acidosis, lipemia, hyperkalemia, renal failure, and rapid cardiovascular collapse. Once the syndrome begins, there is no good treatment other than to stop the propofol and support the cardiopulmonary and renal systems with renal replacement therapy, cardiac pacing, and, sometimes, extracorporal membrane oxygenation [25]. The risk of this feared complication is higher at doses N5 mg/kg/h, and risk factors include younger age, high fat and low carbohydrate intake, concomitant catecholamine infusion, and concomitant corticosteroid use [26,27]. This has led some neurointensivists to either avoid the use of propofol in refractory status epilepticus, where high doses are often required for prolonged periods of time, or limit the use to lower doses and limit the days of infusion. Midazolam can cause prolonged sedation in the setting of obesity and renal failure. Profound cardiovascular depression and hypotension invariably accompany the use of barbiturate infusions, but all of the conventionally utilized anesthetic agents have the potential to produce hypotension which often requires vasopressor support. Barbiturates have the additional risk of paralytic ileus which, when severe, can result in microvascular ischemia and even bowel perforation [28]. Lingual edema has been reported to lead to airway obstruction and is self-limited upon discontinuation of the drug [29]. Another major but uncommon side effect is propylene glycol toxicity which occurs due to the vehicle in which barbiturates are delivered [30]. It manifests as a lactic acidosis, and diagnosis requires calculation of an osmolar gap. An elevated osmolar gap reflects elevated propylene glycol levels [31]. Propylene glycol toxicity was reported in one of thirty-one patients receiving continuous intravenous pentobarbital for super refractory status epilepticus [32]. In the same study, hypotension occurred in 29% and pneumonia in 32% of the patients. While uncommon, there is a risk of hepatic and pancreatic toxicity with prolonged high-dose barbiturate infusions, particularly in the elderly. The half-life of the most commonly used barbiturates, thiopental and pentobarbital, is very long; thus, prolonged sedation is expected. Ketamine has been increasingly used when first- or second-line anesthetic agents fail. Cumulative experience has demonstrated similar safety compared with the more conventional anesthetic agents. In a multicenter review of 60 patients treated with continuous intravenous infusions of ketamine, 5% developed tachyarrhythmias, requiring discontinuation of the drug. In one patient, the infusion was discontinued due to a probable adverse event that could not be reliably identified [33]. We have experienced prolonged

Please cite this article as: Hocker S, Systemic complications of status epilepticus — An update, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.04.024

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Table 1 Systemic complications of status epilepticus. Early systemic complications

Complications relating to treatment

Complications of prolonged intensive care unit care

Acidosis (respiratory N metabolic) • Increased CO2 production • Decreased CO2 removal • Depletion of glycogen stores

Nonanesthetic drugs • Benzodiazepine — respiratory depression, and sedation • Valproic acid — platelet and clotting dysfunction and hyperammonemia • Fosphenytoin/phenytoin — cardiac arrhythmias and hypotension • Levetiracetam — sedation • Lacosamide — PR prolongation, sedation, angioedema, and rash

Venous thromboembolic disease • Pulmonary embolism • Deep venous thrombosis

Hypoxia • Apnea • Upper airway obstruction • Aspiration of gastric contents • Mucous plugging • Neurocardiogenic pulmonary edema

Propofol • Propofol infusion syndrome • Hypotension

Pulmonary complications • Recurrent mucous plugging • Pleural effusions • Atelectasis • Tracheostomy Ventilator-associated pneumonia

Hyperadrenergic state • Hyperpyrexia • Hypertension • Tachycardia • Hyperglycemia • Peripheral leukocytosis

Midazolam • Accumulation in obesity and renal or hepatic dysfunction • Hypotension

Other infectious complications • Catheter-associated urinary tract infections • Sepsis • Bloodstream infections • Pseudomembranous colitis

Cardiac injury • Left ventricular stunning • Cardiac arrhythmias • Cardiac troponin elevation • Electrical conduction abnormalities • Cardiac contraction band necrosis

Barbiturates • Hypotension • Paralytic ileus • Increased risk of infection • Propylene glycol toxicity • Hepatic toxicity • Pancreatic toxicity • Lingual edema • Prolonged half-life

Skin complications • Skin breakdown • Yeast infections

Musculoskeletal injury • Tongue bites • Long bone fractures • Vertebral body compression fractures • Posterior shoulder dislocation Renal injury • Rhabdomyolysis and acute renal failure

Ketamine • Tachyarrhythmias

Intensive care unit acquired weakness • Critical illness myopathy • Critical illness neuropathy

Inhalational anesthetics • Hypotension • Increased risk of infection • Paralytic ileus Hypothermia • Acid base and electrolyte disturbances • Coagulopathy • Impaired immunity • Cardiac arrhythmias • Paralytic ileus • Thrombosis

sedation after the use of high-dose ketamine infusion for several days [unpublished observation]. Experience with the inhalational halogenated anesthetics including isoflurane and desflurane has been reported in individual case reports and case series. The largest series described 7 patients receiving inhalational anesthesia for a mean (range) of 11 (2–26) days. Complications during therapy included hypotension (100%), infections (71%), and paralytic ileus (43%). One patient died of acute hemorrhagic leukoencephalitis (autopsy proven) and another of bowel infarction [34]. Hypothermia, sometimes used as an adjunct to pharmacologic therapies in status epilepticus, is also not without risks. It can produce clinically significant acid–base and electrolyte disturbances, coagulopathy, impaired immunity, cardiac arrhythmias, paralytic ileus, and thrombosis or disseminated intravascular coagulation [35].

respiratory distress syndrome, atelectasis and pleural effusions resulting from third spacing, and immobility. Approximately 30% of patients will require tracheostomy, and this is often combined with percutaneous gastrostomy tube placement. Prolonged immobility may also lead to deep venous thrombosis and pulmonary embolism which may form spontaneously or be associated with central venous catheters. In addition to pneumonia, patients are at risk for catheter associated urinary tract infections, pseudomembranous colitis after repeated antibiotic exposures, sepsis, and infections with multidrug-resistant bacteria. While meticulous administration of special skin products and frequent turning and use of special air fluidized beds are essential to prevent skin breakdown, decubitus ulcers may still occur. Muscle atrophy and critical illness polyneuropathy may affect survivors, but the frequency of this complication is not known.

4. Complications of prolonged ICU care 5. Conclusions Many of the systemic complications encountered in super refractory status epilepticus result from prolonged immobility. Pulmonary sequelae include recurrent mucous plugging necessitating repeated therapeutic bronchoscopies, ventilator-associated pneumonias and associated acute

Systemic complications of status epilepticus are common and occur as a direct result of the hyperadrenergic state and, sometimes, violent muscular contractions induced by the seizures, the therapies used to

Please cite this article as: Hocker S, Systemic complications of status epilepticus — An update, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.04.024

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control the seizures, and prolonged immobility. Multiple markers of systemic injury have been independently associated with mortality in status epilepticus. Screening for early markers of injury with a serum lactate, arterial blood gas, creatine kinase, cardiac troponin, electrocardiogram, and chest X-ray is recommended. Meticulous attention to the medical complications of status epilepticus is indispensable and may lead to improved outcomes. Disclosures The author has no potential conflicts of interest. References [1] Wijdicks EF, Hubmayr RD. Acute acid–base disorders associated with status epilepticus. Mayo Clin Proc 1994;69:1044–6. [2] Vohra TT, Miller JB, Nicholas KS, Varelas PN, Harsh DM, Durkalski V, et al. Endotracheal intubation in patients treated for prehospital status epilepticus. Neurocrit Care 2015 (Jan 27. [Epub ahead of print]). [3] Meierkord H, Shorvon S, Lightman SL. Plasma concentrations of prolactin, noradrenaline, vasopressin and oxytocin during and after a prolonged epileptic seizure. Acta Neurol Scand 1994;90:73–7. [4] Simon RP, Aminoff MJ, Benowitz NL. Changes in plasma catecholamines after tonic– clonic seizures. Neurology 1984;34:255–7. [5] Bealer SL, Little JG, Metcalf CS, Brewster AL, Anderson AE. Autonomic and cellular mechanisms mediating detrimental cardiac effects of status epilepticus. Epilepsy Res 2010;91(1):66–73. [6] Shimizu M, Kagawa A, Takano T, Masai H, Miwa Y. Neurogenic stunned myocardium associated with status epileptics and postictal catecholamine surge. Intern Med 2008;47:269–73. [7] Manno EM, Pfeifer EA, Cascino GD, Noe KH, Wijdicks EF. Cardiac pathology in status epilepticus. Ann Neurol 2005;58(6):954–7. [8] Painter JA, Shiel FO, DeLorenzo RJ. Cardiac pathology findings in status epilepticus. Epilepsia 1993;34(Suppl. 6):30. [9] Boggs JG, Painter JA, DeLorenzo RJ. Analysis of electrocardiographic changes in status epilepticus. Epilepsy Res 1993;14(1):87–94. [10] Hocker S, Prasad A, Rabinstein AA. Cardiac injury in refractory status epilepticus. Epilepsia 2013;54(3):518–22. [11] Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352(6):539–48. [12] Soundarya N, Lawrence D, Samip J, Stacy A, Robert J, Leroy R, et al. Elevation of cardiac troponins in prolonged status epilepticus: a retrospective chart analysis. SOJ Neurol 2014;1(1):1–4. [13] Mehrpour M, Hajsadeghi S, Fereshtehnejad SM, Mehrpour M, Bassir P. Serum levels of cardiac troponin I in patients with status epilepticus and healthy cardiovascular system. Arch Med Res 2013;44(6):449–53. [14] Sieweke N, Allendörfer J, Franzen W, Feustel A, Reichenberger F, Pabst W, Krämer HH, Kaps M, Tanislav C. Cardiac troponin I elevation after epileptic seizure. BMC Neurol 2012;12:58. [15] Little JG, Bealer SL. β adrenergic blockade prevents cardiac dysfunction following status epilepticus in rats. Epilepsy Res 2012;99(3):233–9.

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Please cite this article as: Hocker S, Systemic complications of status epilepticus — An update, Epilepsy Behav (2015), http://dx.doi.org/10.1016/ j.yebeh.2015.04.024