Tokmakov K.A., Gorbachev V.I., Unzhakov V.V., Gorbacheva S.М.

 Russian Medical Academy of Continuous Professional Education, Irkutsk, Russia,
Regional Clinical Hospital No.2, Khabarovsk, Russia

Institute of Postgraduate Education for Healthcare Specialists, Khabarovsk, Russia


Increasing body temperature is a quite common symptom in critically ill patients. According to the literature data, 26-70 % of adult patients have the elevated body temperature in ICU [1-4]. The incidence is even higher among patients of neurocritical unit [5]. So, the body temperature > 37.5°C is noted in 60 % of patients with traumatic brain injury (TBI) in ICU [6]. The causes of elevated body temperature are different. All causes can be divided into two groups: infectious and non-infectious. The patients with primary cerebral injury may have the so called centrogenous hyperthermic response (neurogenic fever in English literature) as one of the non-infectious causes of fever (in 4-37 % of cases with traumatic brain injury) [7]. The pathogenesis of centrogenous hyperthermia is not studied enough [8]. A cadaveric study showed that hypothalamus injuries were in 42.5 % of TBI cases in combination with hyperthermia [9].
There are some conclusive evidences that the hyperthermic response increases the possibility of lethal outcome in patients with cerebral injury [10-13]. Therefore, the necessity of correcting the elevated body temperature does not raise doubts. However the studies showed that centrogenous hyperthermic responses are more or less resistant to conventional pharmacological therapy [9, 14]. Only 7 % of the patients with TBI demonstrated the decreasing body temperature at the background of antipyretics administration [15].

There is not a uniform technique for correcting centrogenous hyperthermic responses. Considering the fact that the centrogenous hyperthermic response is the exclusion diagnosis, then early differential diagnostics and appropriate intensive care of this condition are necessary for patients with traumatic brain injury and improving clinical outcomes in such patients.

The presented case of treatment corresponded to the standards of the ethical committee of Institute of Postgraduate Education for Healthcare Specialists and Helsinki Declare of World Medical Association.

The patient, age of 20, was transported by the emergency medical team to the admission unit of Khabarovsk City Clinical Hospital No.2. The patients had some complaints for headache, nausea and vomiting. From the disease history it was known that the patient suffered from a knife injury to the head after quarrel with his fellow student. The life history and the general examination did not find any significant notes.

The neurological status: clear consciousness, GCS = 15, the pupils were equal, the photoreaction was weak to the right. Right-sided ptosis, depressed corneal reflex to the right. The face was asymmetrical. No paresis in the extremities. Meningeal signs including rigidity of occipital muscles up to 4 cm. Some pathological plantar signs were on both sides. Tendon reflexes were equal and weak. No signs of urinary incontinence.
After the local examination, the neurosurgeon of the admission unit made a record: “a lineal skin incision of 3 cm in the zygomatic region to the right, with a knife penetrating up to the deep of 10 cm”.

Cerebral computer tomography identified a lamellar subdural hematoma to the right, a knife with its blade penetrating the pterygopalatine fossa, with penetration upwards, through the basis of the middle cranial fossa; the knife tip is near the Turkish saddle (Fig. 1).

Figure 1. Cerebral CT on the day of admission (reconstruction)


The diagnosis was made on the basis of the primary examination: “Opened penetrating TBI, severe brain contusion, stab incised wound of the head with the middle cranial fossa damage”.
After making the diagnosis, the patient was transported to the surgery room. Decompressive cranial trepanation was conducted in the right frontotemporal region during the surgery. Acute subdural hematoma (about 80 ml) was removed. The brain was moderately edematous (with pulsation) in the region of the removed hematoma. The approach to the cavernous sinus was made. The knife blade was found there. Arterial and venous bleeding was in the region of the sinus injury. The injury to the cavernous region of the internal carotid artery (ICA) was suspected. The tourniquet was applied to ICA. The knife was removed from the wound under the visual control of the sinus. Intensive arterial bleeding initiated from the sinus defect. Later ICA was ligated, and bleeding intensity significantly decreased, but it was not arrested completely. There was an unsuccessful attempt of packing for the sinus defect. Successful packing was performed later: plastics for sinus wall with use of medical felt, with further ICA opening. The time of ICA cross-clamping was two times per 5 minutes with 3 minutes intervals. Bleeding was arrested. The total intrasurgical blood loss was about 500 ml. The plastic surgery of the skull base was performed with use of Tachocomba plate. The general duration of the surgery was 4 hours. During the surgery, hemotransfusion for correcting volume of circulating red blood cells (566 ml) was without complications. The anesthesia included total intravenous anesthesia with tracheal intubation. The anesthesia components were the main anesthetic (propofol), the analgetic (fentanyl), myorelaxant (pipecuronium bromide). The hemodynamically stable course of anesthesia was observed with short time elevation of arterial pressure (AP) and increasing heart rate (HR) at the stage of removal of the foreign body. After the surgery, the patient was transported to the intensive care unit.

Cerebral CT was conducted in the early postsurgical period for postsurgical controlling. No hematomas were found. There were some air bubbles and minimal hemorrhagic impregnation in the right middle cranial fossa. The course of the cerebral vessels and their caliber were without changes. There were not any signs of carotid cavernous inosculation. The region of the bone defect included the muscle saturated with bleed, with moderate extensive influence on the right frontal and temporal lobes. The median structures displaced by 2 mm leftwards. The subarachnoidal spaces were without changes (Fig. 2).

Figure 2. Cerebral CT on the second day after removal of a foreign body

The patient’ condition was critical and stable during two days after the surgical management. The condition severity was determined by cerebral insufficiency.
The neurological status: GCS = 6. Pupils D > S. Photoreactions were persistent. The face was symmetrical. No meningeal signs. Equal tendon reflexes. No pathologic plantar signs and paresis. Sensitivity was normal. Vegetative disorders were absent.
The hemodynamics was stable. The synchronization with the artificial lung ventilation device was performed. Normothermia persisted. The laboratory values were within the normal range.
Some negative trends were observed on the third day. At the background of persistent coma, the patient demonstrated febrile hyperthermia, sinus tachycardia, arterial hypertension. The patient was desynchronized with the ALV device. It was accompanied by hyperventilation. Sibazon infusion (15-20 mg/h) was initiated for correcting the changes. Cerebral CT was conducted over time.
On the third day after hospital admission, cerebral CT found that the cerebral structures had displaced by 3 mm leftwards. There were no hematomas. The small amount of the air was identified in the middle cranial fossa to the right. Some remains of the lamellar subdural hematoma were in the right parietal region. The lateral ventricles were narrowed. The embracing cistern was deformed. The fourth ventricle was narrowed. Bilateral semispheric edema was found (Fig. 3).

Figure 3. Cerebral CT on the third day

The complex of the diagnostic procedures for identifying a possible cause of fever was used owing to development of the hyperthermic response with persistence to the antipyretic (metamizole sodium) and more than 24 hours duration at the level of febrile and pyretic values, the non-stable condition with such clinical manifestation as sinus tachycardia, arterial hypertension, desynchronization with ALV device with development of hyperventilation at the background of consciousness depression with transition to coma. First of all, the diagnosis of systemic inflammatory response syndrome (febrile hyperthermia with tachycardia and hyperventilation) was made, procalcitonin test was made (negative result), and blood culturing for sterility (the result was sterility) was carried out. For excluding possible bronchopulmonary infectious pathology, the chest radiography (frontal view, no pathology), diagnostic fiberoptic bronchoscopy (sputum with mucous pattern, no signs of endobronchitis). Cerebrospinal fluid puncture was made (clear and clean liquor).
The antibiotic therapy was initiated simultaneously with the diagnostic procedures (ceftriaxone, 1 g, 2 times per day). Pharmacological antipyretic therapy was continued (metamizole sodium).

Considering persistent hyperthermia at the background of antibacterial therapy and absent reliable data after examinations of the infectious cases of fever, the diagnostic search was redirected to the non-infectious causes. The pharmaceutical and allergic anamnesis was collected with help of the patient’s mother. As result, a possible source of hyperthermia was not found. The patient had not any signs of drug fever such as relative bradycardia, skin rash, eosinophilia. The ultrasonic examination of the lower extremity veins was carried out. Thrombosis was excluded.
The diagnosis “centrogenous hyperthermic response” was made after exclusion of possible infectious and non-infectious causes of fever, its persistence during antibiotic therapy and non-efficient traditional antipyretic.

Non-invasive hypothermia with use of controlled hyper/hypothermia and the active cooling technology Blanketrol II CZN with water basis and the microprocessor control and patient feedback was initiated on the fourth day for correcting centrogenous hyperthermic response. Sibazon sedation (15-20 mg/h) was continued for preventing and correcting shivering. The targeted body temperature of 35 °C was achieved within two hours after initiation of the procedure. The temperature was measured in the axillary cavity.

Cerebral CT was conducted on the fifth day. There were some positive trends in comparison with the previous CT examination on the third day in ICU. Semispheric edema decreased. The middle structures shifter by 2 mm leftwards. The lateral ventricles are normally visualized. The embracing cistern and the fourth ventricle are deformed and sharply narrowed (Fig. 4).

Figure 4. Cerebral CT on the fifth day

Considering the clinical data, the complex ultrasonic examination of the cerebral brachiocephalic vessels was carried out for identification of possible causes of the centrogenous hyperthermic response, despite of positive time course according to CT examination. A cerebral angiospasm was not found (the table).

Table. Complex ultrasonic examination of cerebral brachiocephalic vessels on the fifth day


To the right

To the left

LBFV max/min cm/sec


LBFV max/min cm/sec






















Lindegard’s index



Note: ICA – internal carotid artery, MCA – medial cerebral artery, ACA – anterior cerebral artery, PCA – posterior cerebral artery, LBFV – linear blood flow velocity, TPRI – total peripheral resistance index.

The phase of targeted temperature maintenance (35 °C) lasted for 4 days. The interesting fact is temperature variability +/-1 ° in comparison with the targeted value. The long term myorelaxant was used for correcting shivering within a day.

Cerebral magnetic resonance imaging was conducted. There was a focus of abnormal MR signal in the region of subcortical nuclei. The signal was hyperintensive in the mode of diffusion weighted imaging (DWI). It could correspond to lacunary stroke (Fig. 5).

Figure 5. Cerebral MRI on the seventh day after admission

Therefore, cerebral MRI examination identified some possible structural cases of the centrogenous hyperthermic response.
The phase of maintaining the controlled hypothermia lasted up to 19 day of ICU stay. Owing to the stable condition of the patient, the controlled hypothermia was attempted to stop two times on the days 12 and 16 after the surgery (on the days 8 and 12 after initiation of controlled hypothermia). The phase of warming was conducted with the rate of 0.1 °C within an hour with reaching 36.6 °C. It was accompanied by discontinuation of sibazon sedation. But owing to appearance of febrile hyperthermia, controlled general non-invasive hypothermia was restarted (Fig. 6).

Figure 6. Temperature changes during ICU stay

Tracheostomy was carried out on 7th day from the injury moment owing to need for long term respiratory support and continuous sanitation of the tracheobronchial tree.
One should notice that polyuria developed from 6th day of ICU stay (and from 3rd day after initiation of controlled hypothermia), and it was considered as a result of hypothalamus injury. After prescribing desmopressin and selecting the dosage, the diuresis rate normalized by 14th day. It is interesting that the patients demonstrated the increasing diuresis rate and febrile hyperthermia, despite of continuous administration of titrate dose of desmopressin, on 17th day after withholding the controlled hypothermia. The diuresis rate restored after restarting hardware hypothermia (Fig. 7).

Figure 7. Diuresis time course

The plasma levels of К+ and Na+ electrolytes, urea, creatinine, bilirubin and glucose remained within the normal range during controlled hypothermia.
If an infectious source of hyperthermia was not identified at the moment of initiation of controlled hypothermia, then, on the day 13, the general blood analysis showed leukocytosis with leftward shift to myelocytes, and the chest X-ray examination showed the decreasing pneumatitization by the infiltration type in the right region in the plane of the lower lobe, resulting in confirming the diagnosis “ventilator-associated right-sided lower lobe pneumonia”. The results of sputum inoculation showed that Acinetobacter baumannii was a possible causative agent. After prescription of imipenem and cilastatin (Acinetobacter baumannii was sensitive to them), the positive time course of the laboratory and instrumental values was observed. There were not any ventilation disorders during the follow-up.

Cerebral CT was conducted on 26th day of hospital stay. The cranial trepanation was carried out on the right side and showed some hydromes in the trepanation field (subdurally, the layer up to 1.2 cm, the volume up to 40 ml), a subcutaneous hydrome (the layer up to 1.4 ml). Some cystic changes were in the base of the temporal lobe to the right. The signs of atrophy (extension of subarachnoidal spaces) were in the right hemisphere. The middle structures were not displaced. There were not any mass lesions or hematomas. The ventricles were easily extended, the basal cisterns with satisfactory differentiation (Fig. 8).

Figure 8. Cerebral CT on the 26th day of hospital stay

The general controlled hypothermia and sibazon infusion were arrested on 29th day of ICU stay. The body temperature did not exceed the subfebrile values during those and subsequent days in ICU.
The consciousness restored on 34th day. The independent breathing was on 36th day. The patient was transported to the neurosurgery unit on 39th day, where decanulation was performed. The patient was discharged for outpatient treatment on 47th day of hospital stay. His condition was satisfactory. The final clinical diagnosis: “Severe opened penetrating traumatic brain injury; severe brain contusion; penetrating stab wound of the middle cranial fossa; incised wound of the right zygomatic region; syndromes: psychoorganic, vestibular atactic, general cerebral; traumatic damage of the right oculomotor nerve”.


The use of general controlled non-invasive hypothermia in complex management of the centrogenous hyperthermic response in patients with severe traumatic brain injury is an efficient technique of decreasing body temperature, considering the fact that the conventional techniques of fever arrest has the low efficiency in this case. The results of neurovisualizing techniques showed that the technique of controlled hypothermia promoted the decrease in intensity of cerebral edema.
The technique was safe. It was supported by the results of the laboratory and clinical examinations. However development of pneumonia during treatment at the background of the controlled hypothermia system suggests that for further use of the technique, the special attention should be given to prevention of hospital infections and researching whether this technique is a predisposing factor of the infections, for example, by means of depressing the immune response of the patient.

Information about financing and conflict of interests:
The study was conducted without sponsorship.
The authors declare the absence of clear and potential conflicts of interests relating to the publication of this article.


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