Therapeutic Hypothermia (TH): Part 1

Therapeutic Hypothermia (TH): Part 1. Brain injury. Pathophysiology.



The use of therapeutic hypothermia (TH) over the past few years has increased worldwide. This technique has proven advantageous in a variety of clinical settings.  For several decades, TH had been used in an attempt to provide anesthesia in amputations, to prevent cancer cells from multiplying and during heart surgery.  The use of mild TH after cardiac arrest was first described in 1950s, but was soon abandoned without being formally tested. However, over the last decade, many animal and clinical trials have ascertained the beneficial effects of lowering the body’s core temperature in variety of situations.  In October 2002 and November 2005, the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association subcommittee recommended TH in unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest when the initial rhythm was ventricular fibrillation. The Committees encouraged further research to expand the indications for therapeutic hypothermia.

Hypothermia has been used for thousands of years for a variety of reasons. However, the use of low temperatures in modern clinical medicine has probably only 200 years old. The current evidence-based medicine, which requires a moderate degree of selective brain cooling, without instituted promptly, may protect against ischemic neuronal damage of the type that commonly occurs after cardiac arrest. The HT is now seen as a new neuroprotective strategy and is gaining ground as an emergency treatment.


El uso de la hipotermia terapéutica ( HT ) en los últimos años ha aumentado en todo el mundo. Esta técnica ha demostrado ser ventajosa en una variedad de situaciones clínicas. Durante varias décadas, la HT se había utilizado en un intento de proporcionar anestesia en amputaciones, para evitar que las células cancerosas se multipliquen y durante la cirugía cardiaca. El uso de la HT suave (entre 32-34ºC), después de un paro cardíaco fue descrita por primera vez en 1950 , pero pronto fue abandonado sin ser probado formalmente . Sin embargo, en la última década , muchos animales y ensayos clínicos han comprobado los efectos beneficiosos de la reducción de la temperatura central del cuerpo en una variedad de situaciones. En octubre de 2002 y noviembre de 2005, el Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association, a través del subcomité de HT, lo han recomendado en pacientes adultos inconscientes, con circulación espontánea tras el paro cardiaco, cuando el ritmo inicial fue fibrilación ventricular en paciente extrahospitalarios. Los Comités alienta una mayor investigación, para ampliar las indicaciones de la hipotermia terapéutica.

La hipotermia se ha usado durante miles de años para una variedad de razones. Sin embargo, el uso de bajas temperaturas en la medicina clínica moderna tiene probablemente sólo 200 años de edad. La medicina basada en la evidencia actual, que obliga a un moderado grado de enfriamiento cerebral selectivo, si instituirse rápidamente, puede proteger contra el daño neuronal isquémico del tipo que ocurre comúnmente tras un paro cardíaco. La HT se ve ahora como una nueva estrategia neuroprotectora y está ganando terreno como un tratamiento de emergencia.

DEFINITION OF ACUTE BRAIN INJURY: It’s any damage, affecting brain function independent of injury mechanism.

  • Ischemic or hemorrhagic stroke
  • SNC serious infection
  • POST ENCEPHALOPATHY cerebral anoxia after Cardiorespiratory Arrest.
  • Hypoxic – ischemic of the NEWBORN

We have to distinguish different mechanisms of brain injury

Mecanismo Lesional cerebral: Lesión Focal

Mecanismo Lesional cerebral: Lesión Focal

1 – Focal brain injury (for example): Ischemic stroke and cerebral hemorrhage. Here the injury is confined to a specific area of the brain that is damaged. That area is suffering from a loss of neuronal function. In the case of a cerebral hemorrhage, blood acumalada leads to decreased regional blood flow (ischemia called compression) and by another mechanism induce locally an area of ​​vasospasm. Cerebral vasospasm, as defined in 1951 by Ecker and Riemenschneider [1], is an abnormal narrowing (corroborated by thinning of cerebral blood flow in angiographic studies) focal, segmental or diffuse cerebral arteries of the base (Circle of Willis ).

This vasospasm will lead to cerebral edema or swelling

2 Focal or diffuse injury (for example): Swelling of the brain and / or head trauma. can coexist in this case two types of



injury, both locally and around the brain (diffuse). Herpes simplex encephalitis is a type of encephalitis associated herpes simplex virus. Herpes simplex encephalitis is a serious infection of the central nervous system. Is estimated to affect at least 1/500.000 individuals per year. Brain swelling from an injury usually located in the temporal lobe antlers. The electrical activity of the brain changes with the progression of the disease, first shown abnormalities in one of the temporal lobes of the brain, which spreads to other contralateral lobe 7-10 days later. The CT scan reveals a hypodense image temporal or frontotemporal level. In the MRI, which is more sensitive than CT in showing early lesions of the temporal lobe (see graph) [2].

In Trauma, injuries can behave either localized or diffuse, depending on the strength possibly traumatic injuries from trauma and also point at a distance by the slowdown of the same (kickback). Regardless of the lesion may be local (hematoma, cerebral contusions and lacerations) or diffuse lesions:

These are divided into 4 subgroups [3]:

Diffuse injury type I: Absence of visible intracranial pathology on CT scan (normal CT).

Diffuse Injury Type II: In this group we observed:

  • Cisterns present and unaltered perimesencephalic The midline shift is 0-5mm, if any.
  • In this category may be focal lesions (hyperdense or mixed density whose volume must be equal to or less than 25 cc). It is also acceptable to find bone fragments or foreign bodies. An important characteristic of this group of lesions detected are small isolated cortical contusion, a bruise on the brain stem, multiple injuries, bleeding, petechial, forming part of a diffuse axonal injury.
  • Diffuse Injury Type III: “swelling“: This category includes those patients in which:
  • Perimesencephalic tanks are compressed or absent.
  • The displacement of the midline is 0-5 mm.

There should be hyperdense lesions or mixed density with volume greater than 25 cc Although this category is classified as “BRAIN SWELLINGor inflammation, here refers to the brain turgor increased intravascular blood. In this category is the predominant edema, which is more than the increase in volume (liquid and blood, intracellular or extracellular).

Diffuse Injury Type IV: “Shift”: This category includes those patients in which:

  • The midline deviation is greater than 5 mm.
  • Focal lesions (hyperdense or mixed density less than 25 cc)

3 Not diffuse traumatic injury (for example): Sudden death, near-drowning and hypoxic – ischemic encephalopathy of the newborn. Diffuse injuries are related to brain neuronal affectation.


Diffuse injuries are related to brain neuronal affectation. Are caused by a global mechanism at the time of the injury as in sudden death (cardiac arrest), with the cessation of circulation brain being the first to be affected by the absence of oxygen from the circulation. In patients near drowning (if drowning, would be a complete death), the mechanism is due to lack of oxygen and then by the absence of circulation from cardiac arrest.

A case of special mention is the hypoxic-ischemic encephalopathy of the newborn (HIE)”. It is an aggression to fetus or the newborn and occurs as a result of the lack of O2 to the brain, either by arterial hypoxemia” or cerebral ischemia”, or by the concurrence of both.


Encefalopatía isquémico hipóxica del RN

Essential Criteria (EHIRN) [4, 5]
1. Evidence of intrapartum metabolic acidosis (pH <7.00 and DB 12 mmol / L).
2. Early onset of moderate or severe neonatal encephalopathy (see Table 2).
3. Cerebral palsy, spastic quadriplegia or dyskinetic cerebral palsy.

But no specific criteria taken together suggest an event perinatal

  1. Sentinel event occurring immediately before or during birth (eg placental abruption).
  2. Sudden deterioration or sustained fetal heart rate, usually after the sentinel event.
  3. Apgar score 0-6 after five minutes of life.
  4. Evidence of early organ dysfunction.
  5. Evidence of acute brain disorder by neuroimaging techniques.

Mechanism Encephalopathy: From injury to neuronal death
Regardless of the type of brain injury, we have to clarify pathophysiology that is what happens to you as the conditions of injury and sequelae limited life, but also could reach death.

Any condition involving injury to focal or diffuse level, generates the so-called primary lesion (unavoidable on the other hand) which depends on the intensity injurious:

  1.      Mild to severe head trauma
  2.      Time of shock and cerebral ischemia after ischemic stroke
  3.      Time duration of a cardiac arrest
  4.      Degree of cerebral haemorrhage
  5.      Overall degree of inflammation in an infection (meningitis, encephalitis, etc.)
  6.      Brain tumor (primary or metastatic)
  7.      Etc.

The PRIMARY INJURY, as I said, is inevitable and unpredictable and therefore can generate two types of damage:

1. Damage systemic (hypotension, hypoxemia, hypo-or hypercarbia by lowering or raising blood carbon dioxide [CO2], hypo-or hyperglycemia [lifting or lowering of blood glucose levels] and hyponatremia [serum sodium decrease tiered below 120 mEq / L].

2. Brain Damage (intracranial hypertension, vasospasm, cerebral edema and convulsions)

Both two types of damage are those that will generate the secondary injury that will lead to ischemia and neuronal death.

How is neuronal ischemia?


Mecanismo Lesional

From a very early ischemic excitotoxic cascade appears, that through enzyme induction by a change from a situation where oxygen conditional normalization, now lives in a situation anaerobic (without oxygen) and degradation product appears to be lactate levels that induce depletion of adenosine triphosphate (ATP). Consequently appear glutamate. Glutamic acid, or in its ionized form, glutamate (Glu or E abbreviated) is one of the 20 amino acids forming part of proteins. It is the quintessential excitatory neurotransmitter in the human cortex. His role as a neurotransmitter is mediated by stimulation of some receptors called glutamate receptors” which are classified as ionotropic (ion channels) and metabotropic glutamate receptors. All contain glutamate neurons, but only a few, which are used as a neurotransmitter. Is potentially excitotoxic (through enzymes excitatory (AMPA and NMDA), so the ability to depolarize through ion channel (influx of Na + and Ca +). Input Na + that determines the formation of the cell edema .

Glutamate excitotoxicity: From physiological role of glutamate, 8.isquemiaexcessive activation of its receptors can also cause neuronal dysfunction and even damage or neuronal necrosis. This cell death attributed to excessive activation of glutamate receptors has been called “excitotoxicity” and appears to occur in acute injuries such as stroke or trauma, but also in chronic neurodegenerative diseases such as Alzheimer’s Disease (AD).

  • A high frequency signal (or convergence of several signals) arrives at glutamatergic synapses, which leads to a massive release of glutamate.
  • Glutamate binds to the NMDA receptor so as AMPA receptor. However, only the latter is initially activated as the Mg2 + positively charged NMDA receptor channel blocker.
  • Continued activation of AMPA involves significant entry of Na + ions inside the cell, which, in turn, reduces the membrane potential (depolarization partial).
  • Depolarization removes this block by Mg2 + as the charge on the neuronal membrane is now much less negative (due to the influx of Na + ions of positive charge).
  • At this stage, Ca2 + ions can freely enter the cell through the NMDA receptor channel and initiating a series of enzymatic processes involved in the setting of a higher power synaptic (neuronal memory formation). Postsynaptic this change manifests as enhancing sensitivity and the number of AMPA receptors.

A standard calcium channel input (Ca + +) are activated unaserie of enzymes, such as lipase, protease, and DNA, which are able to stimulate the so-called “free radicals” (ROS reactive oxygen species) which in a very simple physiological conditions cell death. See below .
It is essential therefore that a balance between glutamate (NMDA) receptors and GABA [6]. Gamma-aminobutyric acid is an amino acid that is present in brain tissue [7]. GABA biosynthesis in neurons, because this neurotransmitter can not penetrate the blood brain barrier also any precursor in the periphery is known. This process is coupled into the Krebs cycle using alpha-ketoglutarate. GABA is formed by the irreversible decarboxylation of L-glutamate, which is catalysed by glutamate decarboxylase
(GAD), the enzyme that determines the rate of GABA synthesis.

During ischemia, there is a late phase orof darkness (penumbra), conditioned by the depletion of ATP, ROS, glutamate and Ca + + ions. It leads to cell death in two ways:

1. Extrinsic pathway (receiver) induces the formation of cytokines such as TNF (tumor necrosis factor) or tumor necrosis factor. TNF is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. Is produced mainly by activated macrophages (M1), although it can be produced by many other cell types such as neurons, NK cells, CD4 + and [8]

2. Or mitochondrial intrinsic pathway: through a family of proteins called apoptotic “as the Bcl-2 (B-cell lymphoma type 2. And BAX (deficient cells) resistant to all known stimuli of cell death pathway intrinsicTo a cell death signal is inserted in the BAX outer mitochondrial membrane and homooligómero shaped turn BAK suffers a conformational change which includes its oligomerization and permeabilization of the outer membrane with the release of mitochondrial intermembrane space factors such as cytochrome c.


9.isquemiaBoth of pathway, leading to the release of proteins that play a role in programmed cell death, necrosis and inflammation.

Caspases, or cysteine ​​proteases, aspartic acid, are a family of cysteine ​​proteases that play essential roles in apoptosis (programmed cell death), necrosis and inflammation. Caspases in cells are essential for apoptosis, development and many other stages of adult life, and have been termed “executioner proteinsfor their role in the cell. Some caspases are also required on the immune system maturation cytokines (mediators of inflammation). Failure of apoptosis is one of the major contributions to the development of tumors and autoimmune diseases, which together with the unwanted apoptosis that occurs with ischemia or Alzheimer‘s disease, has stimulated interest in caspases as potential therapeutic targets since they were discovered in the mid 1990s.

There are two types of apoptotic caspases: initiator caspases (apical) and effector caspases (executor). Initiator caspases (eg CASP2, CASP8, CASP9 and CASP10) cleave inactive pro-forms of the effector caspases, thereby activating them. Effector caspases (eg CASP3, CASP6, CASP7) in turn break other protein substrates into the cell, to activate the dying process. The initiation of this reaction cascade is regulated by caspase inhibitors.

Recent studies have shown that caspases are also regulatory functions unrelated to death, particularly if related to the maturation of a variety of cells such as red blood cells, and skeletal myoblasts.


We know that the primary lesion is inevitable and unpredictable and secondary injury is the one that determines the patient’s prognosis. There is also a third circumstance, whose impact is undervalued and is only cognitive dysfunction.

To modify the possible secondary injury, you must act immediately after the primary lesion (we will call or neuroresucitación neuroprotection treatment). Everything here we contribute, secondary injury ejerecerá less secondary damage and therefore prognosis.


Current research is controversial, since the path of neuroprotection has been uncertain and even ethical problems absent.

OBJETIVOS TERAPÉUTICOSHave been developed for many years model studies in vitro” and animal, but functional and histological results on neuroprotection have been little clarifiers. Also there have been studies and clinical trials are seeking long-term functional results and have not yet borne fruit.

We must clarify that all these studies have clear disagreements and have been exercised measures actually ineffective, test models in vitro” and in animals have not been adequate, nor the conditions of the same, as cerebral ischemic cell death is of great complexity. The nerve center despite being widely studied, has not yet managed to reproduce its network of tissue and connections. We know the centers of the senses and which houses awareness, but nevertheless, have not been reproduced in any study. Besides the Central Nervous System (CNS) is irreproducible. We only know that brain metabolism is well above logic, using drugs that can attenuate or modify certain places such as the connections between pathways and the appropriate receptors. In the treatment of seizures, many drugs have been found to attenuate the symptoms but do not reverse the condition. when there is a diffuse brain damage, all we can do is a treatment that somehow prevents the neuronal cells die by that insane metabolism triggered by ischemia and hypoxia. We can not cure, but we can delay death and that the prognosis is better, provided that the quality of life of the individual (prognosis) is sufficient to lead a dignified life. Will be many years yet to come to understand the network of neuronal life and to cure some harmful conditions.


12.opciones reales

Of all advertised currently only can act, practically in the Control of physiological variables and the use of hypothermia. The other measures although in our power would be feasible, have not proved useful.


Control of physiological variables and Hypothermia

Questions that we are trying to understand this:

  • In what way ? Classic Therapies on physiological variables .
  • Intensity measurement. Search strict body temperature management ( prevent fever , hyperglycemia , etc. ) measures do not help to get worse , but that will not change the prognosis .
  • Application time . After the right time of the injury ( including outpatient ) or at the time after the assessment of the primary lesion.
  • Duration of protection. How many hours will last neuroprotection ? 12, 24, 36 or 48 hour ….
  • Pathology and that population is targered.

      • Focal or diffuse .
      • To act on one or the other ? . At any rate both traumatic brain injury as traumatic ?
  • Our working environment
  • Research centers ? ( CI ) ? Do the CI are the only trained to develop models of neuroprotection ?
  • The medical practice. If I have a patient with an injury, I can innovate and act to prevent the progression of the patient is toward an increase and a worse prognosis , for doing nothing more ?
  • Is it compatible research and practice ? That line or boundary between research and medical practice ?

These logical questions are complicated to define. I think if we can understand the logic that the ” patient comes first ” , we also should be done more , given that the brain is the last frontier of human body. So it is lawful to treat a patient’s diseased heart with shock comprehensive measures , such as the brain , which is the center of the universe . If you have non-standard measures and at least do not induce more damage and instead can prevent disease progression indifferent type of brain injury , it is logical to do it, and my thought is that you should talk with families to make them understand , to “wait” is worse than ” act ” . Conventional medicine only moment acting on physiological variables and waits to see what happens (this is what everybody does ) . But medical practice , to be interpreted , we are not mere “observers” and that our goal is broader . this is what makes the medicine be innovative and attack the problem head on by using weapons that can change the fronts and change something vital prognosis . Therapeutic hypothermia is undoubtedly the most advanced weapon to reduce brain metabolism and slow the progression of the lesion. Unfortunately , not everyone uses this method , either by ignorance or by the ” follow pre-established guidelines as medical guidelines ” very challenged lately by the environment as the industry has to say about them.

Really, few centers in Spain , Therapeutic hypothermia is used outside or inside the only established CPR guidelines as the best neuroprotective mechanism , BUT , only a single indication , after Cardiorespiratory Stop by primary ventricular fibrillation , outpatient .


1.- Ecker A, Riemenschneider PA. Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms. J Neurosurg. 1951 Nov;8(6):660–667. [PubMed]

2.- Edelman RR, Warach S. Magnetic resonance imaging (1). N Engl J Med 1993; 328: 708-716. [PubMed]

3.- S. Yus Teruel y M. Cidoncha Gallego. Traumatismo Craneoencefálico (TCE). Manual de Medicina Intensiva. 2ª edición. (J.C. Montejo, A. García de Lorenzo, C. Ortiz Leyba, A. Bonet. Ed. Harcourt. 2ª edición, 2000

4.- Alastair MacLennan for the International Cerebral Palsy Task Force. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999; 319:1054-1059. [Link] [PubMed]

5.- Alfredo García-Alix, Miriam Martínez Biarge, Juan Arnaez, Eva Valverde, José Quero. Asfixia intraparto y encefalopatía hipóxico-isquémica. Hospital Universitario La Paz. © Asociación Española de Pediatría. Protocolos actualizados al año 2008. [Link to PDF]

6.- Alzaga AG, Cerdan M, Varon J: Resuscitation 2006; 70:369-380 [PubMed]

7.- A. Schousboe, H. S. Waagepetersen (2008). A. Lajtha. ed. Handbook of Neurochemistry and Molecular Neurobiology Neurotransmitter Systems. Springer US. pp. 214-221. ISBN 978-0-387-30382-6.

8.- Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010). “A meta-analysis of cytokines in Alzheimer’s disease”. Biol Psychiatry 68 (10): 930–941.


S Herrero, J varon, Robert E Fromm; Hipotermia Terapéutica (HT):1ª Parte. La lesión cerebral. Fisiopatología. Journal of Pearls in Intensive Care Medicine. Vol 62. 2013

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