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Keywords:

  • Refractory;
  • Anesthetic;
  • Complications

Summary

  1. Top of page
  2. Summary
  3. Animal Data
  4. Application on Humans
  5. Conclusion
  6. Disclosures
  7. References

Patients with status epilepticus that proves refractory to anesthetic agents represent a daunting challenge for treating clinicians. Animal data support the neuroprotective action of brain hypothermia, and its efficacy in status epilepticus models. This approach, targeting a core temperature of about 33°C for at least 24 hours together with pharmacological sedation, has been described in adults and children. However, although relatively safe if concomitant barbiturates are avoided, it seems that mild hypothermia rarely allows a sustained control of ongoing status epilepticus, since seizures tend to recur in normothermia. Conversely, mild hypothermia has a high-evidence level and is increasingly used in postanoxic encephalopathy, both in newborns and adults. Due to the paucity of available clinical data, prospective studies are needed to assess the value of hypothermia in status epilepticus.

Although the beneficial effects of low body temperature on head injury were already recognized more than two millennia ago by Hippocrates [(Adams, 1939); cited in (Harris et al., 2002)], and despite several animal and clinical studies on various indications carried out in the last decades, the evidence-based use of therapeutic hypothermia (TH) has been only recently recommended in the setting of adult and pediatric postanoxic encephalopathy and reduction of intracranial pressure (Polderman, 2008). Its indication for the treatment of other acute brain disorders, including status epilepticus (SE) and traumatic brain injury, remains essentially anecdotic.

Animal Data

  1. Top of page
  2. Summary
  3. Animal Data
  4. Application on Humans
  5. Conclusion
  6. Disclosures
  7. References

A low brain temperature exerts several beneficial effects on the pathophysiologic cascades implicated in acute cerebral injuries; several seminal studies have been recently reviewed in (Polderman, 2008; Holzer, 2010). Globally, hypothermia reduces brain metabolism, oxygen utilization, and ATP consumption; furthermore, it leads to inhibition of glutamate release, mitochondrial dysfunction, and calcium overload. Conversely, brain-derived neurotrophic factor is increased. Following these changes, and reduction of free radical production and oxidative stress, apoptosis is inhibited. Other favorable modifications also corroborate the neuroprotective properties of hypothermia: mitigation of reperfusion injury, reduced permeability of the blood–brain barrier resulting in limitation of edema, and depression of proinflammatory reactions. Because several aforementioned mechanisms are implicated in neuronal suffering during SE (Lothman, 1990; Chen & Wasterlain, 2006), it would be straightforward to infer that TH is beneficial in this clinical indication.

Various rodent models of SE support the neuroprotective effects of TH. Hypothermia reduces seizure severity and epileptic discharges in SE triggered by electrical stimulation of the perforant path, especially if coadministered with diazepam (Schmitt et al., 2006); it reduces seizures, brain edema, and cognitive deficits in animals with kainate-induced SE (Wang et al., in press); and temperature lowering before pilocarpine injection in immature rats protects against SE and apoptosis in the hippocampus (Yu et al., 2011). Somewhat surprisingly, however, clinical observations are scarce.

Application on Humans

  1. Top of page
  2. Summary
  3. Animal Data
  4. Application on Humans
  5. Conclusion
  6. Disclosures
  7. References

TH may be applied with external devices and/or core cooling methods [infusion of cold fluids through peripheral or central approaches (Holzer, 2010)]. Deep hypothermia (15–22°C) leads to marked greater complications as compared to mild TH (30–35°C; Harris et al., 2002). Adverse effects may be related to the cooling devices or the low temperature itself. In 41 clinical trials using mild TH on postanoxic encephalopathy, complications related to the cooling device involved only 29 (1%) of 3,133 patients, with bleeding, infection, vein thrombosis, or pulmonary edema (Holzer, 2010). Conversely, in the few major comparative clinical trials in the same clinical setting, side effects were recorded in 223 of 300 patients treated with TH (74%) versus 201 of 285 controls (71%; p = 0.31; Holzer, 2010). These included pneumonia (probably related to mechanical ventilation), hyperglycemia, cardiac arrhythmias, and electrolyte disturbances.

A pioneer description published >25 years ago on three children with generalized SE successfully treated with TH (30–31°C) and thiopental (Orlowski et al., 1984) was followed by only a handful reported cases. Four adult patients with SE due to limbic encephalitis (two patients), hepatic encephalopathy (one patient), and of unknown origin (one patient) were treated with TH (31–35°C) together with midazolam; SE was controlled in all, but two subjects died subsequently (Corry et al., 2008). Shivering had to be controlled with neuromuscular blockade; other side effects included venous thrombosis and pulmonary embolism. One additional adult patient with cryptogenic SE was treated with TH (34°C) and thiopental, developing paralytic ileus that required emergency intestinal resection; she survived (Cereda et al., 2009). Finally, an infant with SE due to hemimegalencephaly had his ongoing seizures controlled by hypothermia at 35–36°C, together with ketamine; later, hemispherectomy was performed (Elting et al., 2010). Reported TH durations are markedly variable, ranging between 20 h and several days; clinical data are summarized in Table 1. Taking these reports into account, it seems that TH may help controlling ongoing seizures, but that its efficacy seems mostly to be only transient, that is, seizures tend to recur as soon as TH is reversed. TH represents thus a therapeutic option in severely refractory SE that may mostly help to bridge the time awaiting for the underlying etiology to be controlled, in line with several other anecdotic alternatives, such as volatile anesthetics, ketamine, lidocaine, verapamil, magnesium, paraldehyde, etomidate, ketogenic diet, immunomodulatory therapies, electroconvulsive treatment, vagus nerve stimulation, repetitive transcranial magnetic stimulation, or cerebrospinal fluid–air exchange (reviewed in Rossetti, 2009a). To achieve this goal, these options may be used in succession, alternating with common anesthetics (midazolam, propofol, barbiturates).

Table 1.   Parameters regarding the application of therapeutic hypothermia in status epilepticus described in the literature
Target temperatureDurationConcomitant sedationRisks
30–36°C20–96 hMidazolam/thiopental/propofol/ketamine Ileus with barbituratesCombination with neuromuscular blockade Coagulopathy

It has been increasingly recognized that postanoxic SE does not necessarily imply a poor outcome. In this setting, recent observations suggest that SE occurring during TH, mostly as a “seizure suppression” EEG pattern, represents a situation of extreme brain damage, and patients are extremely unlikely to survive (Rossetti et al., 2010b; Thenayan et al., 2010); conversely, SE arising after rewarming may be treated with antiepileptic drugs (AEDs) if the electroencephalography (EEG) background is reactive, and somatosensory evoked potentials and brainstem reflexes are preserved (Rossetti et al., 2009b). In those cases (representing about 10% of patients with postanoxic SE) survival with reasonable functional outcome may be obtained (Rossetti et al., 2010a). This suggests that TH (together with moderate midazolam or propofol doses) is sufficient to transitorily control “benign” postanoxic SE forms (illustrating its antiepileptic properties), whereas it does not prevent a dismal outcome in more severe forms.

Conclusion

  1. Top of page
  2. Summary
  3. Animal Data
  4. Application on Humans
  5. Conclusion
  6. Disclosures
  7. References

Considering the current lack of clinical evidence, it seems reasonable to reserve mild TH (32–35°C) for extremely refractory SE, on a patient by patient basis. Should this option be chosen, barbiturates should be avoided (thus favoring midazolam or propofol) and hypothermia duration should be limited to 24–48 h, in order to minimize potential side effects such as paralytic ileus. A routine check of cardiovascular indices, coagulation parameters and lactate counts (metabolic acidosis following intestinal necrosis or severe infections), and limbs inspections (vein thrombosis) is mandatory. A well-designed, prospective study would be necessary to implement an algorithm including TH in the treatment of SE.

Disclosures

  1. Top of page
  2. Summary
  3. Animal Data
  4. Application on Humans
  5. Conclusion
  6. Disclosures
  7. References

I have no conflicts of interest to declare. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Animal Data
  4. Application on Humans
  5. Conclusion
  6. Disclosures
  7. References