THERAPEUTIC HYPOTHERMIA EQUIPMENT «THE»

SHORT SUMMARY

BRAIN PROTECTION FOR ACTIVE LIFE

Director O. Shevelevtel: +7 916 532 61 41

For contacts: Repin V.e-mail: rvv7@inbox.rutel: +7 915 325 16 01

CryoTechnoMed

Purpose

Therapeutic hypothermia equipment

(«THE – 01») is designed for craniocerebral hypothermia induction (no lower than +27ºС) and mild general hypothermia

(no lower than +32ºС).

The THE-01 operating principle is based on the controlled cooling of helmets and cryoapplicators, providing contact heat removal from the scalp. THE-01 is designed for application on two patients simultaneously

(2 channels of cooling). «THE-02»* – is a single-channel, multipurpose

and small-size equipment of therapeutic hypothermia. It is technologically modernized and enhanced version of THE-01.

«THE-02P»* – modification of ATG-02 for installation in mobile intensive care units.* - is currently under development

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Hypothermia application in emergency care: Is an important method to ensure principle of «golden hour» while transportation of patients, express

diagnosis and emergency care provision. Can be used in case of stroke (European hypothermia Symposium, Brussels, 2010). Can be applied in cardio-pulmonary reanimation (Euroreanimation-2010); Allows to increase time or relatively safe total circulatory failure from 5-7 minutes up to 30-40 and more

without CPB (Meshalkin A.N., 2002); Is very important method of neuroprotection in neurosurgery (5-th Congress of RF neurosurgeons, 2009); Can be used in case of neurotrauma, including skull injury (SI) after car accident and in sport (RF Ministry of

Healthcare). Can be used in neonatology in case of trauma and asphyxia of newborn (Kopshev А.I., 1986); According to (American Society of Hypothermic Medicine, Intensive Cold Emergency Care, 2010)

hypothermia: Reduces death rate among patients in critical conditions (CPR, AICC, SI) by 20%, Reduces and slows down neurological consequences after emergency by 25%, Reduces rehabilitation by 2-3 times and prevents secondary diseases progression.

Hypothermia application in neurological system diseases therapy: In narcology and psychiatric help – neuroprotection, reduction of cerebral edema, reduction of period of

treatment (Bacherikov А.N., 2003, Kyatkin E., 2012, own experience); In sport medicine (selective CH) – prevention of complications after SI, regeneration(Nybo Y., 2012); In case of epilepsy or migrane (Horvath S., 2014) In case of fever (commonly acknowledged).

Current areas of hypothermia application

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The main concept of foreign analog equipment for induction of general hypothermia:

«blood temperature should be decrease by any means which will result in cooling of the brain».

However! Edema develops in the area of injury and perfusion volume drops sharply, which makes convection method of cooling highly inefficient.

Main concepts and ideas, which are implemented in the method of «THE» equipment series: «In case of brain edema and increase of intracranial pressure (ICP), cranial part of the scalp

should be cooled maximally (up to 0 - 5°С) with helmets, in order to increase heat removal through skull bones and soft tissues».

«In case satisfactory level of intracranial pressure and moderate brain edema, temperature of the cranial part of the scalp should not be decreased lower than 15°С in order to maintain and increase convectional heat removal».

«level of heat removal (Т°С scalp skin) must be considered with dynamics of patient’s condition monitoring (ICP), brain edema, cerebral hypothermia (CH), fever)».

Method of application of «THE» equipment takes into consideration change in priority of application of different kinds of heat removal (area of application, temperature, convection, heat removal) depending on clinical condition of the patient.

Technology – difference from the analogs

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Functionality due to flexibility of automated control programs:

possibility to induce local craniocerebral (CCH) and general therapeutic hypothermia (GTH);

possibility to use in patients being in consciousness, coma, or under medicament narcosis.

Heat removal efficiency (coolant temperature from -5 to -10⁰С).

User friendly – simplified technology of the procedure.

Safety:

control of body temperature and coolant leakage;

control of development of undesirable local or total body hypothermia;

Reduction of complications.

Possibility to use in a mobile intensive care unit/car*.

Wide specialization (obstetric aid, sports traumatology, arthrology , neurology, psychiatric support* and other).

Low cost.

* - for THE-02

Competitive advantage

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Disadvantages of foreign analogs

No full basal temperature and brain temperature monitoring function.

One model of equipment can only execute one method of hypothermia/normothermia with no consideration of clinical condition of the patient, nosology and dynamics of pathological process development.

Can not be applied to the conscious patients.

No options for flexible settings of heat removal including option of change of area of cooling.

Methods for hypothermia/normothermia induction do not take into consideration physiological mechanisms of temperature balance regulation and specifications of balance regulation disorders after cerebral stroke.

High probability of side effects and complications.

Large size of the equipment – can not be installed in emergency car units.

Can not be used in other fields, including arthrology, narcology, psychiatry, neurology, sport medicine and others.

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Experience in operational testing of the equipment «THE»

№ Medical Institution Number of THE Application

1 L.A. Polenov Institute of Neurosurgery, Saint Petersburg 1 Patients after neurosurgical correction of brain vessel aneurism rupture

2Russian University of People’s Friendship, кафедра анестезиологии-реаниматологии, Clinical base - City Clinical Hospital no.64

2Patients after cardiopulmonary resuscitation,cerebrovascular accidents and in the acute period if ischemia stroke

3 Moscow R&D Institute of Emergency Pediatric Surgery and Traumatology, Intensive Care Unit 1 Children with brain injuries

4 Vishnevsky Institute of Surgery 1 Patients after cardiopulmonary resuscitation

5 Hospital no.1 (Volynskaya), Moscow 1 Patients in the acute period of after ischemic stroke

6 Moscow Arterial Center 1 Patients with rheumatic arthritis and degenerative dystrophic diseases of large joints

7 R&D Institute of Sports Medicine of the Russian State University of Physical Education, Sport, Youth and Tourism 1 Sport and brain injuries, cerebral traumas.

8 Nizhnevartovsk Central regional hospital, resuscitation unit of psychiatric dispensary. 1

Patients after cardiopulmonary resuscitation,Neuro intoxication,FeverAbstinence Syndrome

9 Yaroslavl Central regional hospital, resuscitation unit of psychiatric dispensary. 2

10 Saransk regional hospital, resuscitation unit of psychiatric dispensary. 1

11 Kursk Central regional hospital, resuscitation unit 1

Patients after cardiopulmonary resuscitation,cerebrovascular accidents and in the acute period if ischemia stroke

12 Emergency care unit (Ufa) 1

13 Regional Clinical Hospital no.2 (Tyumen) 2

14 1-st Republic Clinical Hospital, resuscitation unit 1

Total: 17 7

More than 600 patients have been treated.

Allows for rapid regress of neurologic deficiency among patients with stroke on the first/second day of pathology.

Is effective against neurogenic fever and normalizes temperature in brain-cortex hypothermia area.

Contributes to increase of blood circulation speed in the required vessel pool without increase of vessel pressure.

Provides for decrease of ICP among patients with brain edema.

No side effects and complications (CCC reactions, increase in inflammation-septic complications).

Reduction of time spent in the Acute Impairment of Cerebral Circulation (AICC) unit for critical and highly critical patients by no less than 2 times, for average degree patients – reduced by 1,5 times.

Provides for reduction of usage of pharmacological support: antibiotics, anti-edematous, antioxidants, which proves high pharmacological and economic effectiveness of the equipment.

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Experience in operational testing of the equipment «THE»

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Hypothermia – commercialization

Narcology. Neurology. Rheumatology. Sport medicine.

Service duration: 60 - 120 minutes. Quantity of the procedures in the treatment: 8 -

10 Periodicity of procedures: daily – once in two

days.

As part of integrated therapy as the main method. As a subsidiary method which enhances therapy

(for instance pharmacological support).

Licensed as a physiotherapy (service)

Physiotherapy as part of medical healthcare in the following specialties: neurology, Orthopedic/trauma (arthrology), Psychiatry/narcology, Sport medicine.

Service parameters:

Classification of the service:

Hypothermia method specifications:

Commercialization:

Type of license:

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1) Therapeutic hypothermia equipment THE-01

2) SHF-radio thermometer РТМ-01-RES

3) Registration of brain temperature scheme

4) Temperature map of the brain after skull injury

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2

1

Craniocerebral hypothermia medical station equipment

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Thank you

LLC «CryoTechnoMed»

119607, Moscow, Ramenki street, house 17, building 1.

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Appendixes

Medical Problem 13

Mechanisms for support of thermal balance of the brain 15

Reasons for development of cerebral hypothermia 17

Technology - Principles 18

Neuroprotection effects of hypothermia 20

Technology – Temperature monitoring 21

Technology - «SHF-radiothermometry» 22

Technology - hypothermia induction scheme 23

Innovations 24

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Medical problematique - emergency care

Up to 3.7 million cases of newly detected cardiovascular diseases are revealed annually in the Russian Federation, including: more than 1 000 000 coronary heart diseases; about 450 000 people suffer an stroke

In 2013-2014 the mortality due to cardiovascular diseases in the RF equals to about 56% of overall death rate, which is 970 000 people per annum.

Traumatism: Traumas are 3rd cause of death (among men above 40 years old – 1-st cause) Average level of traumatism in RF - 12% of population per year Skull traumas (from overall number of traumas): 34% - on average; 91% - after car accidents In RF 2013 more than 204 thousand road traffic accidents were registered, where:

from 258 thousand people were injured, 27 thousand people died.

Traumatism specifications after car accidents: 30-40% of overall deaths from traumas. Mortality after car accident is 12 times higher Morbidity after car accident is 6 times higher Economic loss – 2,5% GDP (5,5 billion rubles)

Name USA Germany France Russia

Number of dead for 100 car accidents 1,9 2,5 6,4 20,4

Number of dead for 100 victims of car accidents 1,2 1,9 4,3 15,8

Number of vehicles per individual 0,65 0,46 0,53 0,18

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Medical problematique - other segments

Narcology (relieving the alcohol withdrawal syndrome and application during remission): RF FDCS: drug consumption market (2014) – (regular and episode consumption). Every month in RF 5000 people die as a result of drug consumption. Number of drug addicts under medical supervision in RF (2013) — 630 000 people.

Sport medicine (rehabilitation after sport trauma intense exercises): Sport skull trauma is considerable part of sport traumatism (18% - 232,6 thousand people). It is most

common in martial arts and contact/technical sports. Hypothermia can be used after intense exercises – martial arts (box, wrestling and others), athletics

(medium, long distance running, sport walking), skiing, football, hockey. Neurology (migraines):

Migraine is number 1 among neurological diseases and number 3 reason for prevalence of inability to work.

10-12% of RF population or 3,5 million men and 10,5 million women suffer from migraines. Early losses associated with migraine (direct and indirect expenditure) are equal to €111 billion.

Arthrology (rheumatoid arthritis) Cases in RF (2014 г.) - 28 842. Prevalence of the disease - 0,61% of RF adult population - 891 thousand people. $8,4 billion US dollars is spent yearly. Indirect losses equal to - $11 billion per year.

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Mechanisms for support of thermal balance of the brain

Human brain (2% of body weight) : Releases 20% of overall body heat during the process of metabolism, consumes :

20% oxygen, 25% glucose, 20% of 1 minute volume of blood flow

normally, at rest. OVERHEATING CAN HAVE NEGATIVE CONSEQUENCES FOR NEURONS!!! Main mechanisms of excess heat removal from the brain:

Convection:

1) Arterial blood flow in carotid arteries, cooled by the contact with vein system of respiratory system, face and head;

2) Inflow of skull skin vein blood to the veins of dura mater of brain; Heat removal:

3) Outside through flat bones of the skull;

4) Through orbital channel.

1, 2, 3

4

1

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Convection:

1) Vein blood of skull skin (1) and of nasal mucous membranes, which is cooled externally by the contact with artery vessels decreases the temperature of the blood, which flows to the brain through the carotid arteries (3).

2) Vein blood of skull skin spreads in the spongiform

substance in the flat bones of the skull (4)

and through the emmisarium veins it flows into

the dura mater of brain veins to the surface of

the brain (5). Heat removal:

3) The more Δt°С between the flat bones of the

skull, soft tissues of the head skin and surface

of the brain (6), the higher is heat removal through

these tissues.

4) Heat removal through orbital channel –

evaporation of fluid from the surface of

eyeballs (7).

Mechanisms for support of thermal balance of the brain

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5

1

2

3

6

7

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Reason / Disease Mechanism of hypothermia

Intellectual overload, emotional stress. Increase in metabolism activity of neurons during physiological excitement.

Increase of the temperature of the body during intense physical exercises professional sport, army).

Malfunction of convection heat removal. Physiological hypothermia.

Fever in case of inflammatory diseases and neurogenic fever in case of central nervous system affection.

Malfunction of convection mechanism.

Emotional distress, epilepsy, parkinsonism, convulsions.

Metabolic provision for hyper-synchronized activity of neurons.

Psychoactive medicine treatment, drugs and alcohol intake. Metabolic provision of excitement.

Migraine, «steal» syndrome, ischemic attack.Vessel cerebral dysfunction with identification of hypo-perfusion foci and activation of free radical processes.

After total termination of blood flow and cardio-pulmonary reanimation. Acute disorders of brain blood flow, brain failure.

Cerebral hypoxia, ischemia and reperfusion, neurogenic inflammation, excitotoxicity, lipid peroxidation.

Neurotrauma – all types of skull injury including car accidents, sport medicine and neurosurgeries.

Excitotoxicity, neurogenic inflammation, lipid peroxidation.

Reasons for development of cerebral hypothermia

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Limitation of main pathogenic mechanisms of secondary neuron damage is case of brain damage. Therapeutic hypothermia has positive influence on almost all steps of pathogenesis of the secondary

neuron damage in case of brain damage (excitotoxicity, inflammation, edema, apoptosis, hyperthermia).

Technology - Principles

hypothermia hypothermiahyperthermia

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Hypothermic-ischemia preconditioning. Neuron ischemia results in excitotoxicity and early reaction gene activation, which identifies

pathogenic reaction development of damage of secondary neurons (inflammation cytokines, apoptosis).

Intermitted, multiple sub-lethal ischemia of the cell results in increase in neuron stability against ischemia/hypoxia due to formation of sanogenetic reactions, (braking of excitement, inflammation and apoptosis inhibition, activation of reparation processes), and changes direction of the reactions, which are initiated by the genes of early reaction.

Cerebral hypothermia allows for safe ischemia, which is consistent with preconditioning conditions, is basis for therapeutic effects of low temperatures and can be used for prevention of consequences of impairment of cerebral circulation.

Technology - Principles

PATHOGENESIS

SANOGENESIS19

Role of cerebral hyperthermia in case of cerebral injury: Increase in t°С>40,5°С results in neuron damage (proteins denaturize, transmembrane potential

dysfunction, cell and organelles damage); Increase in t°С of neurons initiates free radical oxidation, which further increases brain t°С; Increase in t°С activates glutamate «cascade», forms effects of excitotoxicity, initiates metabolic activity

and further increase in t°С Fever and cerebral hyperthermia worsens the illness and further prognosis of vascular diseases of brain and

neurotrauma; Increase in t°С of the brain is an important pathogenic factor of neuron damage and facilitates formation

of «vicious circle» of pathology development. Neuroprotection effects of therapeutic hypothermia (Euroreanimation-2010):

Decrease of t°С of neurons: Deters effects of excitottoxicity (glutamate «cascade», Са-depolarization, peroxide oxidation, neurogen

inflammation, apoptosis); Neurons become more resistant to hypoxia/ischemia/reperfusion. Neurons require less oxygen and substrate. Slows down metabolism activity. Terminates effects of «vicious circle» formation of pathologies. Decrease in volume of secondary neuron damage. Decrease in number of complications of fever.

Neuroprotection effects of hypothermia

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THE-01 equipment is designed to register temperature with induction temperature sensors in 3 areas of human body: Axial temperature, Tympanic temperature, Scalp skin temperature in the areas of heat removal.

In the modernized THE-01 equipment there is technology of non-invasive SHF radio thermometry of human brain (additional option). Equipment allows to register temperature of the scalp skin in 18 areas and create map of cerebral heterogeneity temperature.

In the THE-02 equipment, which is currently being designed, there is option to register temperature in various parts of the human body: Axial (basal) Т°С – induction thermometry (1 area of measurement); Tympanic (correlate of dynamics of brain Т°С) – infrared thermometry (2 areas of measurement); Т°С in the area of heat removal (scalp skin) – induction termometry

(2 области измерения); Brain Т°С (SHF- radio thermometry) - (2 - 18 areas of measurment).

Full thermo-monitoring allows to measure and assess actual temperature balance of human organism and brain, identify if the patient is suitable TH procedure, effectiveness of heat removal and level of induction hypothermia.

Technology – Temperature monitoring

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Non invasive SHF radio thermometry allows to measure and evaluate level of brain temperature heterogeneity (bad prognosis predictor, suitability of hypothermia, evaluation of effectiveness of hypothermia).

Measurement is carried out 4-6 cm deep from the surface of the scalp skin (cortex of the brain), which allows to evaluate injury spot and severity of damage (temperature of deep tissues).

SHF-thermometry of deep tissues – high precision method, which is as accurate as direct measurements from the brain implanted induction thermo-sensors.a) Registration scheme of brain temperature; b) Temperature map of the brain after brain injury c) MRI figures of visualization of sensor location;d) Areas of registration of scalp temperature

(Т°С mapping).

(a)

Technology - «SHF-radiothermometry»

(c)

(b)

(d)

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Patient’s diagnosis and temperature monitoring allow for individual approach to the choice of heat removal regime:

For patients with defined brain edema and raised intracranial pressure (ICP) – higher than 25 mm, convectional type of hypothermia is not effective due to the decrease of brain perfusion.

Cooled blood will not reach damaged areas of the brain and decrease their temperature.

In case of raised ICP, it is advisable to increase effectiveness of heat removal by deep blood cooling in the area of scalp skin in order to increase Δt°С between cortex of the brain and scalp skin.

One should also consider, that in case of scalp skin temperature decrease lower than 10°С, blood flow in the skin terminates completely, vein blood does not provide for cooling of the surface of the brain through emissary veins and does not decrease temperature of artery blood, which inflows to the brain through the internal carotid arteries.

Patients with low ICP should be provided with convection type of cooling as well as by thermal conductivity.

In these cases temperature of the scalp skin should not be lower than 15°С, which allows to maintain vein outflow of the blood from the scalp skin and, therefore, provides cooling of brain surface and artery blood in the carotid arteries.

Technology - hypothermia induction scheme

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Innovations

Complex (equipment and method) provide for development of neuroprotection methods in case of acute brain damage (total and local ischemia/hypoxia, reperfusion and neurotrauma), which are based on temperature management of cerebral and overall temperature balance by regulation of the level of local and general heat removal (warming).

This will allow for: Controlled decrease in general and cerebral metabolism, decrease in requirement of oxigen and

increase of neuron stability against hypoxia, ischemia and reperfusion effects; Correction of temperature balance of the brain and heat center of the organism, which is

significant link of pathogenesis of development of secondary neuron damage in case of cerebral strokes;

Limitation of processing, release and engagement of signal molecules and receptor structures during the acute period of CNS damage development;

Early reaction genes activation in complex with endogenous reactions of neuron protection from damage (hypothermia-ischemic preconditioning);

Termination of neurogenic inflammation and prevention of increase of ICP. Method basis – selective management of cerebral and heat imbalance with provision of basal

normometria/hypothermia.

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