Abstract
Summary Despite antiviral treatment and advances in critical care, the Herpes simplex encephalitis (HSE) still has a poor outcome in a significant portion of patients. In severe cases of HSE, reduced carbon dioxide reactivity is usually present and these patients don't respond to the usual treatment of brain edema and intracranial hypertension. We present case series of patients with severe form of HSE treated with therapeutic hypothermia (TH) and describe in detail the indications, methods, and the rationale for its use.
Abstract
In this case series, patients presented with severely impaired consciousness and very high predicted death rate as measured by Glasgow coma scale and Acute Physiology and Chronic Health Evaluation (APACHE II) score respectively. According to our findings, TH in carefully selected patients with HSE holds promise as an adjunctive to the antiviral treatment.
Introduction
Despite antiviral treatment and advances in critical care Herpes simplex encephalitis (HSE) still has poor outcome in 35 % of patients, with mortality of 9 % [1] .
Introduction
Antiviral treatment in HSE is well defined and consists of acyclovir in a dose of 30 mg/kg daily by intravenous route. However, during the early course of the disease, the treatment of intracranial hypertension (ICH) caused by brain edema with the possibility of brain herniation is of utmost importance for satisfactory outcome.
Introduction
It has been proven that in patients with brain edema and reduced carbon dioxide reactivity (CO 2 R), the usual treatment options such as administration of hyperosmolar solutions, hyperventilation, barbiturate-induced coma, and steroids are of humble efficacy or completely useless [2] . Furthermore, in traumatic brain injury and central nervous system infections, reduction in CO 2 R was a single most accurate predictor variable for poor outcome [2, 3] . Consequently, in patients with HSE, reduced CO 2 R, and severe focal or diffuse brain edema, the useful treatment options are still lacking while the death and brain herniation may ensue rapidly. Introduction of new treatment methods in such patients are desirable.
Introduction
Of particular interest is therapeutic hypothermia (TH). It has well documented neuroprotective effects and may have a potential use in selected patients with inflammatory central nervous system (CNS) diseases [4] [5] [6] [7] .
Introduction
In patients with transtentorial brain herniation, lifesaving decompressive craniectomy has been successfully employed. However, this surgical procedure has well documented adverse effects such as meningitis and brain abscess. Furthermore, in these patients, the cranioplasty is usually performed after 6 months and during that time the brain is not bone-protected while the patients are prone to seizures and thus to possible deleterious brain trauma. Cranioplasty alone is fraught with complications such as epidural or subdural hematoma, wound healing disturbance, abscess, hygroma, or cerebrospinal fluid fistula formation.
Introduction
Single case of HSE treated with TH has been reported in the literature thus far [8] . We present case series of patients with severe form of HSE with reduced CO 2 R. One patient had evident subfalcine and incipient transtentorial brain herniation TH. The indications, methods, and the rationale for the use of the TH are described in detail.
Case reports
In the period between February 2009 and January 2011, three patients suffering from severe HSE had TH as an adjunctive treatment. All patients were mechanically ventilated, deeply sedated, and relaxed using midazolam and vecuronium, respectively. For all invasive procedures, fentanyl was given for analgesia as 0.2 mg bolus. Furthermore, if the patient were to show any signs of distress (relative tachycardia or arterial hypertension) fentanyl would be added in continuous infusion to provide analgesia.
Case reports
The major indication for TH in these patients was reduced CO 2 R and one patient had subfalcine and transtentorial brain herniation detected on computed tomography (CT) scan of the brain. The following treatment protocol was applied in all patients: mild hypothermia (32-34° C) accompanied with daily assessment of cerebrovascular CO 2 R, jugular bulb oximetry and optic nerve sheath diameter (ONSD). CT scan of the brain was indicated if worsening was detected on the TCD, jugular bulb oximetry, and/or ONSD measurements in order to have timely neurosurgical consultation and decompressive craniectomy if indicated.
Transcranial Doppler ultrasound (TCD)
TCDmeasurement of CO 2 R was performed by using a Multidop 4 X (DWL, Sipplingen, Germany) with two 2-MHz pulsed wave probes 1.7 cm in diameter. The software used was TCD-8 for MDX (Version 8.0, Aaslid Rune).
Transcranial Doppler ultrasound (TCD)
The left and right middle cerebral arteries (MCA) were insonated simultaneously through the temporal bone windows at a depth of 50-55 mm. The probes were secured to the head of the patient with a specially designed spectacle frame that permitted a constant angle of insonation. The mean blood flow velocities (MBFV) were continuously recorded during normal ventilation and during interventions (induced hypercapnia, norepinephrine or urapidil infusion and hyperventilation). CO 2 R was assessed using the breath-holding method (disconnection from the ventilator for 30 s in a deeply sedated and relaxed patient). BHI was calculated by dividing the percentage of MBFV increase during breath holding by the time (in seconds) of apnea.
Optic nerve sheath diameter (ONSD)
ONSD measurements were made using a B-scan ultrasound with a 10 MHz linear probe (Accuson CV70, Siemens Medical Solutions Inc., WA, USA) before and during the induced hypothermia. Optic nerve sheath diameter has been shown to be a very reliable measure of intracranial pressure (ICP). In adults, the ONSD greater than 5.8 mm correlates with a mean cerebrospinal fluid (CSF) pressure of more than 20 mmHg.
Jugular bulb oximetry
The jugular bulb catheter placement offers an opportunity for the measurement of SjO 2 and calculation of lactate-oxygen index (LOI) using paired arterial and venous blood samples. The measurements were made twice daily during the period of hypothermia in order to detect desaturation of jugular bulb venous blood (SjO 2 < 55 %) or increased cerebral LOI > 0.08 (derived from arteriojugular venous oxygen content difference and arteriojugular venous lactate concentration difference) as reliable markers of cerebral hypoperfusion.
Therapeutic hypothermia
We used an internal protocol designed to achieve mild hypothermia (rectal temperature of 32-34° C). Hypothermia was induced by intravenous infusion of cold (4-8° C) isotonic saline (2,000 ml/h) and maintained with continuous veno-venous hemofiltration (CVVHF) by using a Prismaflex (Gambro Dasco S.p.A., Medolla, Italy) machine for 72-120 h [9] . Duration of therapeutic hypothermia was determined by the recovery of CO 2 R, improvement in LOI measurements and normalization of ONSD. This method of cooling was chosen because it allows stable temperatures during hypothermia as well as gradual rewarming. The patients were cooled at the fastest rate possible and rewarming rate was approximately 0.3 °C/h. The blood flow rate was set to 150 ml/ min, ultrafiltration rate (UFR) to 0 ml/h and the replacement solution rate was set to 2,000 ml/h. Enoxaparin was used for anticoagulation of the circuit. TH procedure underwent without significant side-effects occurring in all the patients. Sinus bradycardia was noted in two patients without any repercussion to the blood pressure.
Therapeutic hypothermia
The hospital Ethics Committee approved the treatment protocol and informed consent was obtained from the relatives of all patients.
Therapeutic hypothermia
In presented patients, the polymerase chain reaction detected Herpes simplex 1 virus DNA in the cerebrospinal fluid. The patient with subfalcine and transtentorial brain herniation was too severely ill to be transferred to neurosurgery. One patient had an absent acoustic window. Jugular bulb oximetry parameters remained stable during TH, and the LOI actually improved when target temperature was achieved. The ICU stay of our patients ranged from 16 to 19 days and the outcome was favorable in all patients considering the severity of the disease (Glasgow Outcome Scale score (GOS) 4-5 and Glasgow Coma Scale score (GCS) 14-15). Acute Physiology and Chronic Health Evaluation (APACHE II) score in our patients at admission predicted high mortality and GCS at admission revealed severely impaired consciousness. Demographic and clinical data of the patients are summarized in Table 1 .
Discussion
We present three patients with severe HSE and impaired CO 2 R with presumable treatment failure of the standard treatment regimen for ICH that consists of hyperosmolar solutions, hyperventilation, and barbiturate induced coma. One patient with an absent acustic window had subfalcine and incipient transtentorial brain herniation detected on the CT scan of the brain. Urgent treatment options were required in order to avoid lethal outcome.
Discussion
According to the literature as well as our own experience, TH is highly effective in reducing intracranial pressure and has been used in one patient with similar presentation of HSE [4] [5] [6] [7] [8] .
Discussion
Our patients had severely impaired consciousness and very high predicted death rate as measured by GCS and APACHE II score respectively. However, despite the severity of illness, all the patients had a good outcome after treatment with TH.
Discussion
According to our, although limited, experience, it seems prudent to employ TH in patients with severe HSE and reduced CO 2 R. However, during TH, the patients should be carefully monitored and if any increment in intracranial pressure (ICP) is detected in comparison to the pre-TH ICP, a CT scan of the brain should be obtained and a neurosurgeon should be consulted. We used noninvasive ICP monitoring with ONSD and TCD as well as jugular bulb oximetry since neurosurgery is stationed outside our premises. Furthermore, in patients with severe HSE and evident brain herniation, TH seems effective and is indicated if decompressive craniectomy cannot be performed for some reason.
Discussion
Even though TH procedure requires experience, it is available at the bedside, therapeutic temperature range can be achieved rather quickly, and efficacy in this indication is favorable. Our protocol for TH as well as monitoring during the procedure is effective in temperature management, graduate rewarming, and in detecting complications, thus we can advocate its use in other centers as well. Of course, invasive ICP monitoring can be used as well with even more precision and compatible success.
Discussion
Despite successful treatment intervention with TH in described patients, its use in this indication requires further investigation before definite conclusions can be drawn. 

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