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ZZZ�ZZZFFFFFF����Sepsis- induced refractory status epilepticus: a case report 




Katarina Tomulic Brusich, M.D. *1; Ivana Acan, M.D. 1; Natasa Viskovic Filipcic, M.D. 1 
1 Department of Anesthesiology and Intensive Care, University Hospital Merkur, Zagreb, Zajceva 19, Croatia 


*Corresponding author: 
Katarina Tomulic Brusich * 
Department of Anesthesiology and Intensive Care 
University Hospital Merkur 
Zajceva 19 
10 000 Zagreb 
Croatia. 
Phone: +385 (0)99 4888 256 
Fax: +385 (0)1 2431 402 
E-mail: HYPERLINK "mailto:ktomulic@gmail.com"ktomulic@gmail.com


Ivana Acan:  HYPERLINK "mailto:acan.ivana@gmail.com"acan.ivana@gmail.com 
Natasa Viskovic Filipcic: HYPERLINK "mailto:natashav7@gmail.com"natashav7@gmail.com 




Abstract:
Background: Sepsis is often accompanied by various degrees of mental status deterioration. It can range from slight confusion to coma and can be, although rarely, accompanied by focal
neurological signs. Presentation as status epilepticus requires early recognition and treatment due to the fact that it carries a significant amount of complications and mortality. 
Methods: We here present a case of a patient with sepsis who developed generalized convulsions: epi grand-mal progressing to refractory status epilepticus. 
Results: A 24- year old female underwent colon cancer surgery with liver metastasis already present. Her course was complicated by bleeding from resected part of the liver and afterwards by sepsis, causing multiorgan failure. Treatment required mechanical ventilation, vasopressors, antibiotics, corticosteroids and coagulopathy support. Mental status deterioration presented as refractory status epilepticus, which was rapidly treated with combination of benzodiazepine and barbiturate administration and anticonvulsive drugs, all together resulting in no present neurological and cognitive complications at the time of hospital discharge. 
Conclusion: This is most uncommon presentation of the underlying disease which involved multidisciplinary approach to the successful treatment. The treatment of the seizures must be immediate with sedatives, anticonvulsant drugs and anesthetics, if needed. Global patient management is based mainly on infection control, organ system failure management and reestablishing metabolic homeostasis, according to the protocol for Surviving Sepsis Campaign.




Key words: 
Sepsis  
Sepsis associated encephalopathy 
Status epilepticus 
Barbiturates 
Infection control 



Abbreviations: 
SE- status epilepticus  
SAE- sepsis associated encephalopathy  
ASA- American Society of Anesthesiologists physical status classification system 
BMI- body mass index
ICU- Intensive Care Unit  
POD- postoperative day  
MSCT- multislice computed tomography 
DIC- disseminated intravascular coagulopathy  
BIS EEG- bispectral index electroencephalography
PRIS- propofol infusion syndrome  
NMDA receptor - N-methyl-D-aspartate receptor




Introduction: 
Sepsis is often complicated with acute and reversible deterioration of mental status, which is associated with increased mortality. It usually presents as delirium, but it can also manifest as focal neurologic signs. Febrile convulsions are unusual in adults and their presentation as status epilepticus (SE) is uncommon. SE is a neurological emergency that requires early recognition and treatment and carries a significant amount of complications and mortality [1]. Annual incidence in population-based studies ranges from 10 to 61 cases per 100 000 persons per year [2]. Initial treatment typically consists of benzodiazepines followed by a standard intravenous anticonvulsant drug. Convulsion cessation is considered to be a neuroprotective measure. 


Case report: 
A 24- year old Caucasian female, ASA status 1H (BMI 16.0 kg/m2) was admitted to the Intensive Care Unit (ICU) after emergency operation due to the pelveoperitonitis. During surgical exploration multiple colon polyps were found and suspected for carcinoma on two locations together with metastatic lesions on the liver. Subtotal colectomy was performed along with retroperitoneal lymphatic nodes and metastatic liver lesions removal. On the 2nd postoperative day (POD) she was well and discharged to the surgical ward. Patohistological findings of the specimen collected intraoperatively were characterized as familial adenomatous polyposis (adenocarcinomas Dukes A and C with present liver metastasis) and supported by the fact that patient's mother already underwent colon carcinoma surgery two years before. 
On the 7th POD she underwent another emergency operation due to hemorrhagic shock. Bleeding was found to origin from resected part of the liver together with signs of biliary leak. After surgical hemostasis patient was admitted to the ICU sedated, mechanically assist- ventilated, hemodynamicaly stable, with adequate urine output and satisfactory laboratory findings.
Three hours after surgery she developed generalized convulsions: epi grand-mal progressing to status epilepticus and accompanied with hyperthermia 39.5 �C and hemodynamic instability (invasive arterial blood pressure 80/45 mmHg, HR 140 bpm). According to previous medical history, patient didn�t suffer from epilepsy. 
Treatment started with volume load and vasopressore therapy (norepinephrine drip up to 2.5 mcg/kg/min). Anticonvulsive therapy was administered immediately, starting with diazepam 10 mg iv and repeated up to 40 mg due to second grand-mal attack, along with 200 mg of  iv thiopental, and antiedematous therapy with 200 ml of 10 % mannitol infusion as well. 
Thiopental was continued with infusion pump up to 2.5 mg/kg/min. Emergency MSCT scan of the head was performed and showed no signs of abnormalities. Four hours after last seizure, patient experienced another (fourth) seizure, in spite the fact that she was fully sedated with thiopental. Additional midazolam infusion was administrated up to 7 mcg/kg/min which lead to convulsion cessation. 
Her condition was rapidly deteriorating causing additional hemodynamic instability, and multiorgan failure. Blood, urine, tracheal aspiration and abdominal secretion samples were obtained for microbiological screening. Broad spectrum antibiotics were administrated (iv piperacillin + tazobactam 13.5 g and cefepime 2.0 g/ daily). Hydrocortisone 300 mg iv was administered to restore hemodynamic stability in septic shock. There were no signs of meningisam present. Lumbar punction was not performed. Signs of disseminated intravascular coagulopathy (DIC) developed and were treated accordingly. 
The next day she was still sedated and mechanically ventilated but with improved hemodynamic parameters and no vasopressor requirements. Microbiological sampling tests showed intraabdominal origin of infection, isolating Acinetobacter baumanii and Enterococcus faecium. Antibiotic therapy was reassessed and treatment continued with piperacillin + tazobactam 13.5 g and ampicillin + sulbactam 4.5 g/ daily.  
After four days of convulsion-free period, continuous sedation has been slowly discontinued. During withdrawal of anesthetic therapy, topiramate and phenobarbital were additionally implemented in therapy to ensure an adequate baseline of antiepileptic medication and to prevent the recurrence of status epilepticus. Control MSCT showed no pathological findings, and she regained consciousness with no evident neurological deficit.
Due to long-lasting infection with multidrug- resistant bacteria, weaning from mechanical ventilation was difficult resulting in percutaneous tracheotomy formation. As the sepsis resolved, patient become respiratory sufficient and was spontaneously breathing by the 15th POD. Patient was discharged to the ward on the 22nd day and went home on the 34th day in good condition. She underwent chemotherapy and is doing well 2 years after the surgery, with no neurological or cognitive deficit. 



Discussion: 
Sepsis is often accompanied by various degrees of mental status deterioration, which is reversible as the infection resolves. The cerebral dysfunction may be present even before signs of other organ failure. The literature describes it as a separate entity called ''Sepsis Associated Encephalopathy'' (SAE) in order to point out the absence of direct infection of the central nervous system as cause of this state [3]. This is general term that is used to describe various disorders of mental functioning in sepsis that can range from slight confusion to coma and can be accompanied by focal neurological signs. 
Pathophysiology of SAE is still not completely understood and it is probably multifactorial. It may be directly related to action of micro-organisms toxins, inflammatory mediators involved in sepsis and the indirect effects of hyperthermia, hypoxia and cerebral hypoperfusion [4]. Hepatic, uremic, or respiratory encephalopathy and metabolic disturbances must be ruled out to establish the diagnosis of SAE [5]. 
Although the incidence of brain metastases in patients with colorectal carcinoma is low and reported to be approximately 1.2% [6], our patient was in advanced phase of the disease and therefore also suspected for their existence at first. Accordingly, we must have in mind that brain metastases can, among symptoms of increased intracranial pressure, induce seizures. It is advised to do CT or MRI scan of the brain. With those imaging techniques we can ensure adequate diagnostic which can lead to adequate treatment of the patients. 
In the presence of meningismus, cerebrospinal fluid analysis is recommended. In our case lumbar puncture was not obtained due to the lack of meningeal signs, but also present signs of DIC in order to avoid possible subdural hematoma. 
After the pharmacologically induced deep sedation and seizure cessation, a neurologist performed examination not indicating additional specific medical testing. BIS EEG monitoring was applied during the deep sedation. 
At this moment a specific treatment for SAE does not exist and outcome relies upon prompt and appropriate treatment of sepsis as a whole. Patient management is based mainly on infection control, organ system failure management and reestablishing metabolic homeostasis, according to the protocol for Surviving Sepsis Campaign, as it was done with our patient [7]. At the same time we must have in mind to avoid the use of neurotoxic drugs. 
There have been reports of SE and encephalopathy with the use of cefepime which was used in our patient�s treatment. However, the main characteristic that distinguishes those reports from ours is that they were all nonconvulsive SE [8]. 
Focal neurological signs of SAE, especially SE, are extremely rare. However, SE has the most dramatic clinical presentation which is encountered by emergency room physicians, neurologists, neurosurgeons and intensive care specialists. Diagnosis of SAE is established after ruling out all other possible causes of mental status deterioration. Nevertheless, the treatment of the seizures must be immediate. Treatment implies sedation and neuroprotection. 
Refractory SE is defined as SE unresponsive to initial standard antiepileptic medications (benzodiazepine + iv anticonvulsant drug). Refractory cases still carry significant morbidity and mortality rates, leading to poor cognitive outcomes [9,10]. 
Barbiturate anesthetics (i.e. pentobarbital and thiopental sodium) are the most frequently used agents and are highly effective for refractory SE both in children and adults. Indeed, they remain the only way to stop seizure activity with certainty in severely refractory cases. Other options are midazolam for adults and children and propofol for adults only. 
According to Claassen et al. barbiturates were associated with less treatment failure, breakthrough seizures, or need to change to another anticonvulsive drug compared with midazolam or propofol [11]. This is the main reason why we chose barbiturates over propofol and also due to the concern of hypotension and propofol infusion syndrome (PRIS). 
Some recent articles review the use of steroids and immunotherapy in patients with highly refractory SE [1]. There is the increasing evidence of the role of inflammation on epileptogenesis, due to the recognition of antibody- mediated causes of SE involving NMDA receptors. In our case we administered hydrocortisone due to septic shock and we can only speculate that it also contributed in seizure cessation. 




Conclusion: 
SAE can present in many ways; from delirium to status epilepticus. SE is rarely reported among critically ill patients, probably due to the fact that its diagnosis is often delayed or missed, in part because it is mistaken for other causes of altered mental status. This diagnosis should be sought more often in ICU patients with abnormal mental status. 
SE is a neurological emergency that requires early recognition and seizure control. Barbiturates still remain the drug of choice in refractory SE. When SE is a part of SAE, we must treat the underlying disease. Patient management should be based on infection control, organ system failure support and metabolic homeostasis reestablishment.  




Conflict of interest: 
All authors declare that they have no conflict of interest. 

Acknowledgement: 
We are grateful to the patient, who agreed to the publication of the case report and provided all information needed. Also, we wish to thank all the staff in the ICU for their good co-operation and participation in treatment and recovery of the patient.





Reference: 
Fernandez A, Claassen J (2012) Refractory status epilepticus. Curr Opin Crit Care 18(2):127-31. 
Rosenow F, Hamer HM, Knake S (2007) The epidemiology of convulsive and nonconvulsive status epilepticus. Epilepsia 48 (Suppl 8):82�84. 
Consales G, De Gaudio AR (2005) Sepsis associated encephalopathy. Minerva Anestesiol 71(1-2):39-52. 
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