Seizures damage not only the brain but also other organs. Status epilepticus results in a dramatic physiologic response, some of which causes an unstable medical condition. There is a need for rapid seizure control, and that involves the transition to a large dose of an intravenously administered antiepileptic drug (or a combination of drugs); such an approach often is at the expense of serious side effects (Smith, 2011). In patients with superrefractory status epilepticus who are held in a pharmacologic coma (and frighteningly close to suspended animation), long-term mechanical ventilation and immobilization may collectively lead to a multitude of systemic complications requiring complex critical care (Shorvon & Ferlisi, 2012). This brief review touches on some of the major medical issues.
After seizures have been controlled, long-term care of status epilepticus may be needed and collectively involves every major organ. First, as a result of rapid escalation of antiepileptic drugs, there are initial concerns with hypotension, acid-base abnormalities, and cardiac arrhythmias. Second, refractory status epilepticus and the continuous need for intravenous administration of anesthetic drugs will lead to a multitude of systemic complications that require long-term complex care. Most anticipated problems are infectious complications with a high risk of pneumonia and sepsis, but thromboembolism due to immobilization and catheter placement are also common. If a good outcome is possible or anticipated in a patient with refractory status epilepticus, physicians should plan for a surveillance and treatment protocol to adequately support these patients.
Side Effects of Anesthetic Drugs
The medical problems may start early, and some of the used drugs have side effects within days after their administration. These side effects are usually easily handled, but some are severe or even life-threatening. An example is the so-called propofol infusion syndrome and is usually found only in patients treated with a high dose—starting at >5 mg/kg/h—or an infusion time of 3 days or more. Risk factors are young age, any critical illness, high fat and low carbohydrate intake, concomitant catecholamine infusion, and concomitant corticosteroid use (Diedrich & Brown, 2011). Many neurointensivists have become cautious with using the drug after experiencing this syndrome that often results in rapid cardiovascular collapse (Iyer et al., 2009). It is therefore unsettling that many reviews on status epilepticus still allow a high dose of propofol, up to 10 mg/kg/h. There is no good treatment for propofol infusion syndrome other than stopping propofol, improving gas exchange, and sometimes cardiac pacing and renal replacement therapy. Extracorporal membrane oxygenation may be the only option in some cases.
Another major and immediately noted side effect is propylene glycol toxicity (Bledsoe & Kramer, 2008). Propylene glycol is a vehicle in lorazepam, barbiturates, and etomidate, and its absorption peaks within an hour in most patients. The diagnosis is suspected in any patient who has developed lactic acidosis, but this potentially worrisome acid-base imbalance is often misattributed to ongoing seizures (Miller et al., 2008) and not detected because it requires calculation of an osmolar gap—measured serum osmolality minus calculated osmolality. There is a good correlation between osmolar gap and propylene glycol levels (Barnes et al., 2006).
Long-term effects of prolonged use of anesthetic drugs are not precisely known, and if found they may be difficult to separate from brain injury associated with the excitotoxic state. Inhaled anesthetic agents such as isoflurane can be demonstrable toxic, but with disappearance of MRI abnormalities when it is discontinued (Fugate et al., 2010).
Systemic Manifestations of Status Epilepticus
Metabolic acidosis occurs because of excessive muscular contraction, which results in glycogen depletion and anaerobic glycolysis, thereby promoting lactic acid formation from pyruvic acid. Metabolic acidosis—but mostly with pH values of about 7.2—was not significantly associated with potential life-threatening cardiac arrhythmias in one study (Wijdicks & Hubmayr, 1994). However, a pH value of 6.8 has been recorded soon after a generalized seizure, and most physicians may feel compelled to administer sodium bicarbonate. In many patients respiratory acidosis is found, and increased arterial PCO2 can be caused from lung injury from aspiration, but may also result from decreased respiratory drive and increased mechanical load of respiratory muscles. Mechanical ventilation (reducing hypercarbia) and bronchoscopy (clearing secretions) will correct this abnormality. Many of the initial concerns in super refractory status epilepticus are pulmonary, and physicians must continuously correct episodes of pulmonary effusions and consolidation. Both rapid development of atelectasis and mucous plugging of a main bronchus are common. Acute atelectasis is basically an airless part of the lung created by resorption after obstruction. Pleural effusions develop frequently in acutely ill neurologic patients and may require thoracocentesis.
Health-acquired pneumonia or ventilator-associated pneumonia is increasingly caused by multidrug-resistant or extremely drug-resistant pathogens. This includes Pseudomonas aeruginosa, Acinetobacter species, Klebsiella pneumoniae, and carbapenems containing Enterobacteriaceae (Sutter et al., 2012). The use of oral gastric decontamination in combination with parenteral antibiotics is often considered, but there is a great likelihood that this will lead to more antibiotic resistance in the ICU.
Another major systemic manifestation after refractory status epilepticus is fever. Any combination of fever and seizures is underappreciated by clinicians who should find ways to effectively cool the patient (Corry et al., 2008). Cooling can be achieved in controlled hospital settings with well-designed practice protocols, but quick cooling can also be achieved by large-volume (20 ml/kg), cold (refrigerator cold; 4°C) saline, but its effect is short (<30 min) and may need to be repeated (with 10 ml/kg) until more long-lasting effective measures are available. Cooling may lead to shivering, and if it occurs, the best intervention is dexmedetomidine titrating up to 1.5 µg/kg/h.
Cardiac arrhythmias are common after any status epilepticus, and more than two thirds require cardiac intervention (Hocker et al., 2013a,b). Moreover, any use of a high dose of intravenous anesthetic drugs will result in hypotension, and in some patients this may become refractory. Causes other than the intravenous drugs must be considered, and apical ballooning cardiomyopathy (i.e., Takotsubo cardiomyopathy) described in >50 cases after status epilepticus may be the cause of hypotension in refractory status epilepticus (Weeks et al., 2007; Lemke et al., 2008; Stollberger et al., 2011; Shah et al., 2012). Echocardiography will easily characterize the disorder and will show a significant reduction in ejection fraction.
Most of Takotsubo cardiomyopathy can be treated with inotropes, which may include dobutamine or milrinone, but intraarterial balloon pump has been needed in some cases. Damage to the heart has been further corroborated by cardiac pathology studies in patients who died after refractory status epilepticus. Microscopy showed contraction bands and coagulative necrosis in a high proportion of samples, suggesting a massive hyperadrenergic response during seizures (Manno et al., 2005). Whether this cardiomyopathy can be predicted by electrocardiography (ECG) abnormalities is unlikely.
Other clinical concerns result from the massive increase in catecholamine that can lead to hyperglycemia and damages the brain through worsening lactate acidosis. Glucose control is standard ICU practice, preferably with insulin infusion starting at a threshold not higher than 180 mg/dl and—at least—maintaining a blood glucose target between 140 and 180 mg/dl. A blood glucose of <110 mg/dl is not considered safe.
Tonic–clonic seizures may damage muscle. A slight increase in serum creatine kinase concentration is invariably found after a single seizure, but creatine kinase levels may reach enormous proportions within a day. Some laboratory values may already point to rhabdomyolysis. These are metabolic acidoses not entirely explained by lactate accumulation, hyperkalemia, increased serum aldolase, hypocalcemia, and certainly myoglobinuria. Most cases associated with status epilepticus reported in the literature are mild and temporary. Acute nonoliguric renal failure from rhabdomyolysis may become apparent with acutely rising serum creatinine, hyperkalemia, and hyperphosphatemia. Initial treatment is to change intravenous fluids from normal saline to D5W (5% dextrose in water) with three ampules of bicarbonate at 200 ml/h to maintain urinary output of >100 ml/h. Phosphate binders (calcium acetate) are needed until laboratory values normalize.
Long-Term Medical Issues with Induced Coma
Approximately 30% of the patients with status epilepticus will require tracheostomy, but this decision is often already made 2–3 weeks after treatment. Tracheostomy is often also combined with a gastrostomy to facilitate nutrition.
Any patient who is in a prolonged immobilized state is at risk of multiple systemic complications. Most noticeable are infectious complications that include high risk of pneumonia, sepsis, pseudomembranous colitis, and urinary tract infections. Gastrointestinal problems may be seen and often lead to adynamic ileus. Many of the drug effects can produce significant colonic standstill that would lead to temporary parenteral nutrition.
The risk of deep venous thrombosis is markedly increased in these immobilized patients. Antithrombotic and thrombotic therapy includes the use of subcutaneous heparin, low molecular-weight heparin, or intermitted compression devices. Deep venous thrombosis and pulmonary emboli and thrombus may form spontaneously or at central lines. Each of these complications would require heparinization, often invariably in patients who have been treated for several months for refractory status epilepticus.
The most common problems are skin lesions. We have found massive tongue swelling with barbiturates, and the skin is often at high risk of breakdown in patients who have been on long-term barbiturates (Ji et al., 2009). Skin might also become abnormal as a result of drug rashes with polypharmacy during the management of these complex patients. Skin care has a high priority in immobilized patients. Decubital ulcers or, more often, patches of demarcated painful erythema indicative of developing ulcers may appear, even with meticulous care. Two thirds of the patients with pressure sores acquire them within the first week of admission and therefore frequent turning in bed, lanolin creams, and dry patting of the skin are essential. Use of air-fluidized mattresses is critical. Oral candidiasis, recognized as creamy white patches on the pharynx or tongue, should be anticipated in patients receiving broad-spectrum antibiotics, corticosteroids, or total parenteral nutrition, but the probability is increased in any preceding debilitating state. Fluconazole, 100 mg orally per day, may treat this infection rapidly before it becomes invasive.
With every minute that passes there must be an urge to quickly control seizures. Such an approach is necessary, but it may lead to more side effects of these drugs, and some are substantial. After seizures are temporarily controlled, the care of these patients is complex and multifaceted and involves virtually every major organ. Poor outcome is often seen in patients with prolonged mechanical ventilation, pneumonia at any time, or cardiac arrhythmias. There are many laboratory abnormalities, including acid-base abnormalities, seen throughout the course of treatment of these patients. A carefully designed treatment protocol is warranted to better support these patients.
The author has no conflict of interest to disclose. The author confirms that he has read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.