Information

Does antidromic conduction occur in the brain under normal conditions?


So I am reading a book on neuroscience and they mentioned in passing that the action potential is capable of travelling in either direction along the axon (orthodromic vs antidromic), The wikipedia antidromic article states that the effect is often used to confirm connections in laboratory experiments.

What I'm now wondering is if the phenomenon has been observed with normally behaving neurons in situ (as normal as a neuron under experimental observation can be anyway) and therefore possibly needs to be factored in when modelling neurons in software or is it safe/justified to treat the information as only flowing in one direction (orthodromic)?


Under physiological conditions, action potentials are generally assumed to travel one-way. Action potentials are generated in the dendritic region, and travel from the soma to the axon terminal. Because voltage-gated sodium channels are inactivated after having been active during action potential generation, the action potential cannot travel backwards because the tail-end of the action potential is basically temporarily shut down (Fig. 1). The duration of inactivation of sodium channels determines how fast a neuron can fire, i.e., it determines the refractory period of neurons (Purves et al., 2001).


Fig. 1. Action potential conduction and refractoriness. Source: Zoology.

When neural tissue is artificially electrically stimulated, however, action potentials can be generated anywhere along the neuron. When an axon is activated somehwere in the middle with an electrical stimulus, an action potential will travel both ways, i.e. normally to the axon terminal, but also antiodromically to the cell body.

However, it has been noted in vivo that some neurons do show antidromic action potentials under physiological conditions (Jansen et al., 1996). For modeling purposes I would not bother too much about this, though, because antidromic action potentials are generally only observed under artificial conditions.

References
- Jansen et al., J Neurophysiol; 76(6): 4206-9
- Purves et al., ed. Neuroscience. 2nd ed. Sunderland (MA): Sinauer Associates; 2001


General Anesthesia Causes Telltale Brain Activity Patterns

Emery N. Brown and Francisco J. Flores
Mar 1, 2019

B efore the advent of general anesthesia in the mid-19th century, surgery was a traumatic experience for everyone involved—the patient, of course, but also the medical staff and anyone who happened to walk by the surgery room and could hear the screams. The practice of putting patients in a reversible coma-like state changed surgery to a humane and often life-saving therapy. Because general anesthesia was such a game changer in medicine, these drugs were implemented in the operating room many decades before researchers understood how they worked.

Nowadays, researchers and anesthesiologists know much more about the mechanisms underlying the effects of anesthetic drugs and how they produce the profound change in behavioral state that implies a total lack of perception. Anesthetics primarily act on receptors located in the brain and produce oscillations in the brain’s circuits, leading to a state of consciousness that it is much more similar to a coma than to sleep. Anesthesiologists typically used vital signs, such as heart rate and blood pressure, to assess the adequacy of the anesthetized state and the processing of pain signals. However, the effects of anesthetics in brain circuits result in conspicuous oscillations in the brain’s electrical activity, which prompted the addition of electroencephalography (EEG) measurements to monitor the brain state of an anesthetized patient.

  • Unconsciousness, lack of awareness of sensory input
  • Analgesia, lack of pain
  • Akinesia, lack of movement
  • Amnesia, lack of recall
  • Physiological stability, the preservation of normal levels of all vital physiological functions, such as respiration, heart rate, blood pressure, and temperature

Starting in the 1990s, researchers developed algorithms to consolidate the signals recorded from several EEG electrodes into a single number that provided a simplified measurement of arousal level. More recently, direct observation of the raw EEG signals and their breakdown in time by frequencies, the spectrogram, is gaining traction for monitoring patients during general anesthesia. Learning to interpret the raw brain activity and its spectrogram, rather than relying on a single-number summary, has allowed anesthesiologists to assess how different anesthetics affect brain activity and produce the anesthetic state. 1

By tracking brain activity during general anesthesia, researchers are also uncovering a wealth of new information that helps them understand the biological basics of how brain function is altered in an anesthetized state. In addition, general anesthesia has provided new options to treat a range of ailments, from sleep problems to depression.


Antidromic propagation of action potentials in branched axons: implications for the mechanisms of action of deep brain stimulation

Electrical stimulation of the central nervous system creates both orthodromically propagating action potentials, by stimulation of local cells and passing axons, and antidromically propagating action potentials, by stimulation of presynaptic axons and terminals. Our aim was to understand how antidromic action potentials navigate through complex arborizations, such as those of thalamic and basal ganglia afferents—sites of electrical activation during deep brain stimulation. We developed computational models to study the propagation of antidromic action potentials past the bifurcation in branched axons. In both unmyelinated and myelinated branched axons, when the diameters of each axon branch remained under a specific threshold (set by the antidromic geometric ratio), antidromic propagation occurred robustly action potentials traveled both antidromically into the primary segment as well as “re-orthodromically” into the terminal secondary segment. Propagation occurred across a broad range of stimulation frequencies, axon segment geometries, and concentrations of extracellular potassium, but was strongly dependent on the geometry of the node of Ranvier at the axonal bifurcation. Thus, antidromic activation of axon terminals can, through axon collaterals, lead to widespread activation or inhibition of targets remote from the site of stimulation. These effects should be included when interpreting the results of functional imaging or evoked potential studies on the mechanisms of action of DBS.

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The Nervous System

The nervous system is made up of a complex collection of nerves and specialised cells which allow us to response to our environment. Whenever two nerve cells (neurones) meet, they form a synapse. Our brains form so many synapses that they outnumber the number of stars in the galaxy. It’s this that allows us to carry out complex behaviours and be just so bloody brilliant..

How the nervous system works

The nervous system detects changes in our environment (known as stimuli) through cells called receptors. Receptors are sensitive to a number of different aspects of our environment, such as light, pressure (touch) and chemicals in the air (smell). When receptors detect certain stimuli, they signal to the central nervous system (CNS) through initiating an electrical impulses through a neuron (nerve cell). The neuron which sends an electrical impulse from the receptor within the sense organ and the coordination centre is called the sensory neuron. The coordination centre receives impulses from various receptors around the body, processes the information and coordinates a response by signalling to other parts of the body. Coordination centres include the brain, spinal cord and pancreas. These organs will signal to an effector (a muscle or gland) by releasing an electrical impulse along a motor neuron. Stimulation of an effector will produce a response such as muscle contraction or hormonal release.

Receptors

Our nervous system uses receptors to detect stimuli (changes in the environment) and pass on this information to the CNS. Receptors can either be whole cells (e.g. photoreceptors are cells which are sensitive to light) or proteins molecules which are found on the cell surface membrane. Each receptor is specific to a single type of stimulus, such as light, temperature or glucose concentration. When a receptor is not stimulated, there is a charge difference between the inside and outside of the membrane and it is said to be polarised. When the receptor detects a stimulus, the permeability of its cell membrane changes which changes the charge difference (potential difference) across the membrane. If the change in potential difference is large enough (i.e. it exceeds the threshold level), it will trigger an action potential (an electrical impulse) in a sensory neuron.

We contain the following receptors in our sense organs:

Chemoreceptors - receptors which detect chemicals

Thermoreceptors - receptors which detect heat

Mechanoreceptors - receptors which detect pressure (see the Pacinian corpuscle below)

Photoreceptors - receptors which detect light (e.g. rods and cones)

Photoreceptors

Photoreceptors are receptors which detect light and are found in the retina of the eye. There is an area of the retina called the fovea which contains a cluster of photoreceptor cells. Photoreceptors detect light as it hits the retina and send nerve impulses to the brain along the optic nerve. The region of the eye containing the optic nerve is called the blind spot since there are no photoreceptors in this region so light can’t be detected. Photoreceptors are connected to the optic nerve through a bipolar neurone.

The human eye has two types of photoreceptors - rods and cones. Rods are mostly located along the outside of the retina while cones are clustered together in the fovea. Rods are responsible for black-and-white vision and can function in lower light levels than cones. They are much more sensitive than cones, so are the type of photoreceptor used for visualising objects in the dark. Cones are responsible for colour vision and are sensitive to either blue, green or red light. Different cones are stimulated in different proportions, so that we see different colours. Cone cells provide good visual acuity (the ability to distinguish between two points which are close together) because each cone cell has its own synapse via a bipolar neurone which connects to the optic nerve.

In dark conditions, the membrane of rod cells is depolarised, which means there is not much difference in charge between the inside and outside of the membrane. This is because the rod cells actively transport sodium ions out of the cell, which flow straight back into the cell through sodium ion channels. Depolarisation of the rod cell membrane triggers the release of neurotransmitters which inhibit the bipolar neurone. The bipolar neurone cannot fire an action potential which means that no information is sent to the brain. However, when light is present, light energy causes a pigment called rhodopsin to split apart into two proteins, retinal and opsin. This process is referred to as the bleaching of rhodopsin and it causes sodium ion channels in the cell surface membrane to close. Sodium ions continue to be actively transported out of the rod cells but they cannot flow back into the cell through the ion channels, creating a difference in charge across the membrane. The inside of the membrane is now much more negative compared to the outside and the rod cell is said to be hyperpolarised. When the rod cell is hyperpolarised it stops releasing neurotransmitters. This means that inhibition of the bipolar neurone stops and it can now become depolarised. If depolarisation exceeds a threshold level, information is passed onto the brain via the optic nerve and the presence of light is detected.

Pacinian corpuscles

Pacinian corpuscles are receptors which respond to changes in pressure - they are a type of mechanoreceptor. They are found deep in the skin and are abundant in the feet, fingers, external genitalia and in our joints. The Pacinian corpuscle consists of a single sensory neurone, surrounded by layers of tissue which are each separated by a gel, forming an onion-like structure.

The Pacinian corpuscle contains stretch-mediated sodium ion channels in the cell surface membrane. Under normal conditions these channels are closed but when pressure is applied these channels become deformed and open, allowing a rapid influx of sodium ions. This makes the membrane potential in the neurone less negative (depolarisation), producing a generator potential which can then produce an action potential.

Types of neurone

Neurones are cells which carry information to and from the central nervous system, in the form of electrical impulses called action potentials. There are three different types of neurone, with slightly different structures. What they all have in common, however, is a cell body containing a nucleus, dendrites which carry an action potential towards the cell body and an axon which carries the action potential away from the cell body.

Sensory neurones carry action potentials from receptors to the central nervous system. They consist of one long dendron and a short axon.

Relay neurons carry action potentials between the sensory and motor neurons and are found within the CNS. They have lots of short dendrites.

Motor neurones carry action potentials from the CNS to an effector. They have lots of short dendrites and one long axon.

Resting potential

When a neurone is not firing (i.e. it is not transmitting an action potential), there is a difference in charge between the inside and the outside of the membrane (it is polarised). This charge difference is referred to as the resting potential and is usually around -70 mV. Polarisation of neuronal cell membranes at rest occurs due to the action of sodium-potassium ion pumps. These pumps are found within the cell membrane and actively transport sodium and potassium ions into and out of the neurone. For every three sodium ions that the proteins pump out of the cell, they pump two potassium ions into the cell. This ensures that there are always more positive ions out of the cell compared to inside the cell and makes sure there is a charge difference across the membrane.

Action potential

When a neurone is stimulated, the charge difference between the inside and outside of the cell membrane is lost and the membrane is depolarised. If enough charge is lost and depolarisation exceeds -55 mV, an action potential will occur in that neurone. The -55 mV ‘limit’ is known as the threshold potential - any depolarisation above this number will result in an action potential whereas anything less than that will result in nothing. We therefore refer to action potentials as an “all-or-nothing” response.

Depolarisation during an action potential occurs because sodium ion channels open up in the membrane. Remember that the sodium-potassium ion pump has been actively transporting sodium ions out of the neurone, creating a sodium ion concentration gradient. This means that when sodium ion channels open, sodium ions flood into the neuron by facilitated diffusion. The potential difference across the membrane is reduced until is reaches a voltage of around +30 mV.

Sodium ion channels close and potassium ion channels open, which causes potassium ions to move out of the neurone down their concentration gradient. The movement of positive ions out of the cell means that there is a charge difference again across the membrane - this is called repolarisation. However, the charge difference exceeds the resting potential and becomes ‘hyperpolarised’. This is because the potassium ion channels are slow to close and too many potassium ions diffuse out of the neurone. The action of the sodium-potassium ion pump restores the balance between sodium and potassium ions on either side of the membrane and returns the neurone to its resting potential of -70 mV.

Immediately after an action potential is a brief period called the refractory period. During the refractory period, the neurone cannot be stimulated and an action potential cannot occur. This is because the ion channels are recovering and they cannot be made to open. The refractory period is important because it ensures that action potentials do not overlap (i.e. they pass along the neurone as separate impulses) and that action potentials are unidirectional.

Once an action potential occurs in one part of the neuron, it will stimulate an action potential in the adjacent part of the neuron, creating a kind of ‘Mexican wave’ of depolarisation. This wave of depolarisation occurs because the sodium ions which diffuse into the neuron diffuse sideways, causing voltage-gated ion channels in the next portion of the neurone to open, so sodium ions move into the neurone further along the membrane. The wave moves away from the part of the neurone which has just fired an action potential because that part of the neurone will be in the refractory period and cannot be stimulated.

Saltatory conduction

Some neurones are insulated with a fatty layer along the axon. This fatty layer is called a myelin sheath and is made up of a type of cell called a Schwann cell. The myelin sheath acts as an electrical insulator, which means that ions cannot move into or out of the myelinated portions of the neurone. However, there are gaps in the myelin sheath called nodes of Ranvier, where sodium ion channels and potassium ion channels are concentrated. Action potentials occur only at the nodes of Ranvier - when one node is stimulated this triggers depolarisation of the next node, causing the impulse to ‘jump’ from node to node. This type of nervous transmission is called saltatory conduction and is much faster than transmission along non-myelinated neurones, where the action potential has to travel along the entire length of the neurone in a wave of depolarisation. The speed at which an action potential moves along a neurone is known as the conduction velocity - the higher the conduction velocity, the faster the action potential is travelling. This means that action potentials along myelinated neurones have a higher conduction velocity compared to those travelling along non-myelinated neurones.

Size of the stimulus

We’ve seen how an action potential is an ‘all-or-nothing’ response. If the threshold potential is reached, an action potential will occur. This action potential is always of the same voltage (depolarisation to +30 mV) regardless of whether the stimulus that initiated the action potential is small (e.g. a pinprick) or large (e.g. a sledgehammer). If the threshold isn’t reached then an action potential will not be fired. The difference between action potentials resulting from stimuli of different sizes is the frequency that action potentials are firing - the bigger the stimulus, the more often an action potential will occur along the neurone.

Anaesthetics

Anaesthetics are drugs which create a numbing sensation and are used in medicine to prevent patients from feeling pain (e.g. during an operation). They work by binding to sodium ion channels in the neurone and preventing them from opening. If sodium ions cannot move into the neurone, then the membrane cannot depolarise and an action potential cannot occur. This prevents neurone from sending a pain impulse to the brain, so the brain doesn’t register anything.

Synapses

A synapse is a gap found between neurones (or between a motor neurone and an effector). Electrical impulses cannot pass through the gap, so neurones release neurotransmitters from one neurone to the next to stimulate an action potential in the next neurone. The neurone before the synapse is called the presynaptic neurone and the one after the synapse is called the postsynaptic neurone. The space between them is called the synaptic cleft. This means that action potentials will travel along the presynaptic neurone, through the synaptic cleft (via neurotransmitters) then along the postsynaptic neurone. The presynaptic neurone has a swelling at the end which is called the synaptic knob.

Synaptic transmission takes place in the following stages:

An action potential arrives at the end of the presynaptic neurone (at the synaptic knob) and triggers the opening of voltage-gated calcium ion channels.

Calcium ions move into the synaptic knob by facilitated diffusion and trigger the movement of vesicles containing neurotransmitters (such as acetylcholine or dopamine) towards the presynaptic membrane.

The vesicles fuse with the presynaptic membrane and their contents is released by exocytosis.

The neurotransmitters diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic membrane.

This triggers the opening of sodium ion channels in the postsynaptic membrane. Sodium ions move into the postsynaptic neurone, causing depolarisation and triggering an action potential if the excitation exceeds the threshold potential of -55 mV.

The neurotransmitter is removed from the synaptic cleft which prevents the continuous stimulation of an action potential in the postsynaptic neurone. The neurotransmitter is either reabsorbed by the presynaptic neurone (and recycled) or broken down by enzymes in the synaptic cleft (and the products are reabsorbed).


Related Biology Terms

  • Sympathetic Nervous System (SNS) – Controls “fight or flight” bodily actions, such as increasing heart rate and raising blood pressure.
  • Autonomic Nervous System (ANS) – Controls the mostly unconscious actions of internal organs, and consists of the parasympathetic and sympathetic nervous systems.
  • Somatic Nervous System (SoNS) – Controls voluntary body movements of the skeletal muscles.
  • Peripheral Nervous System (PNS) – Parts of the nervous system that are not the brain and spinal cord, such as the nerves and ganglia found throughout the body.

1. Which is NOT a function of the parasympathetic nervous system?
A. Lowering blood pressure
B. Lowering heart rate
C. Dilating pupils
D. Increasing digestive activities

2. What divisions of the nervous system are parts of the parasympathetic nervous system classified as?
A. The somatic nervous system
B. The autonomic nervous system
C. The peripheral nervous system
D. Both B and C

3. Why is the parasympathetic nervous system called the “rest and digest” system?
A. It solely controls the actions of sleeping and digesting.
B. It controls activities that take place when the body is at rest and not deciding whether to face an opponent or run from it.
C. It increases the heart rate and activates the adrenal glands, which allow the body to digest more efficiently.
D. It begins immediately after eating and ends immediately after resting.


Brain Temperature: Physiology and Pathophysiology after Brain Injury

The regulation of brain temperature is largely dependent on the metabolic activity of brain tissue and remains complex. In intensive care clinical practice, the continuous monitoring of core temperature in patients with brain injury is currently highly recommended. After major brain injury, brain temperature is often higher than and can vary independently of systemic temperature. It has been shown that in cases of brain injury, the brain is extremely sensitive and vulnerable to small variations in temperature. The prevention of fever has been proposed as a therapeutic tool to limit neuronal injury. However, temperature control after traumatic brain injury, subarachnoid hemorrhage, or stroke can be challenging. Furthermore, fever may also have beneficial effects, especially in cases involving infections. While therapeutic hypothermia has shown beneficial effects in animal models, its use is still debated in clinical practice. This paper aims to describe the physiology and pathophysiology of changes in brain temperature after brain injury and to study the effects of controlling brain temperature after such injury.

1. Introduction

Many popular figures of speech connect brain activity with temperature. It is now well known that, while brain temperature is largely dependent on the metabolic activity of brain tissue, the regulation of these two parameters is complex. The relationship between temperature and metabolism is always interactive. While brain cell metabolism is a major determinant of brain temperature, minor changes in brain temperature can result in significant changes in neural cell metabolism and therefore in brain function. Tight control of brain temperature is critical for optimal brain function under different physiological conditions such as intense physical activity or complete rest.

In intensive care clinical practice, continuous monitoring of core temperature in patients with brain injury is highly recommended [1]. It has been shown that, in cases of trauma, the brain is extremely sensitive and vulnerable to small temperature variations. Indeed, fever is considered a secondary injury to the brain in neurosurgical patients with severe traumatic brain injury [2], subarachnoid hemorrhage [3], or stroke [4], in whom hyperthermia is a frequent phenomenon. In these cases, guided, directed normothermia can be used to limit secondary brain injury. This paper aims to describe the physiology and pathophysiology associated with changes in brain temperature, with particular focus on acutely ill patients suffering from severe traumatic brain injury, stroke, or subarachnoid hemorrhage.

2. Physiology of Brain Temperature

Energy production in humans derives from glucose, protein, and fat metabolism. The end products of aerobic metabolism are carbon dioxide (CO2) and water. The production of adenosine triphosphate (ATP), the main intracellular energy storage molecule, is accompanied by heat (Figure 1). The energy lost during electron transport and oxidative phosphorylation is largely converted into heat and contributes to maintaining body temperature at 37°C. The combustion of glucose and protein produces 4.1 kcal/kg, while fat combustion yields 9.3 kcal/kg. Heat production depends, therefore, on energy metabolism [5].


Although the brain represents only from 2 to 3% of human body weight, it uses 20% and 25% of the body’s total consumption of oxygen and glucose, respectively. Even at rest, the metabolic activity of brain tissue is high. Energy metabolism in the brain is mainly aerobic 95% of the glucose used by the brain undergoes oxidative metabolism. Approximately 40% of the energy provided by glucose is used to produce ATP the remainder (approximately 60%) is converted into heat [5]. Under normal conditions, production of heat within the brain is balanced by its dissipation. In contrast to other organs such as muscles, the heat produced within the brain is not easily dispersed due to the protection of the brain by the skull. Brain temperature depends primarily on three factors: local production of heat, temperature of the blood vessels, and cerebral blood flow. Dissipation of generated heat is improved by vascular anatomical specializations that permit heat exchange.

2.1. Heat Exchangers

Heat exchangers vary across species. In felids, arterial blood for the brain flows through a vascular network at the base of the skull. In these species, the carotid artery is very close to the cavernous or pterygoid sinus, which receives cool blood from the mucosal surfaces of the nose. This heat exchange produces selective brain cooling (SBC) that depends on sympathetic activity [6]. In canids, the carotid rete is rudimentary [7]. However, the large surface of the cavernous sinus, which is in close contact with the base of the brain, allows direct cooling of the rostral brain stem. Similar regional SBC has been found in other mammals. In humans, the face and the mucosal surfaces of the nose, which are sources of cool venous blood, are small in relation to the mass of the brain. Moreover, a specialized heat exchanger similar to the carotid rete does not exist in humans, and a substantial fraction of the blood supply to the brain is provided by the vertebral arteries, which have no direct contact with cool venous blood [6]. Cool blood from the skin of the head can flow into the cranium and cool the brain via the emissary veins of the temporal and parietal bones [8]. Moreover, brain cortical arteries can cover distances of 15 to 20 cm in fissures and sulci on the brain surface before reaching their final destinations in the cortex and adjacent white matter [9]. Perforating veins that connect the skin of the head with the venous sinuses in the dura mater allow the venous sinuses to receive cool blood. Thus, the temperature of the blood in the sinuses depends on the relative contributions of extracranial and intracranial inflows. The scalp-sinus pathway may be a source of regional SBC. Another source of regional SBC is the upper respiratory tract. The nasal cavities help to cool arterial blood through heat exchange between inhaled air and blood of the nasal mucosa. The thickness of the bone between the nose and the floor of the anterior cranial fossa permits heat exchange and allows the frontal lobes to be cooled [10]. When these heat exchangers are short-circuited, such as during mechanical ventilation with tracheal intubation, venous blood from the nasal cavities is no longer cooled by ventilation. The high respiratory rate observed in association with body temperature increase most likely functions to increase heat transfer in the nasal cavities, resulting in protection of the brain by decreasing the temperature of the blood supplying the brain.

2.2. Thermal Compartments

In humans, two thermal compartments have been described: a central and a peripheral ones [11]. The central compartment includes tissues that are highly perfused under all conditions. Heat exchanges are rapid in this compartment, and, in theory, its temperature is relatively homogeneous. The trunk, head, and also the brain make up the central compartment. The peripheral compartment includes tissues in which the temperature is variable and inhomogeneous (lower limbs, hands, and skin). The temperature in the peripheral compartment is generally 2–4°C lower than in the central compartment and is highly dependent on vascular tonus.

An integrative center that regulates core temperature is located in the hypothalamus [12]. Although the response mechanisms of this center are still not completely known, they are likely to involve neurotransmitters such as norepinephrine, dopamine, acetylcholine, neuropeptides, and prostaglandins such as PGE2. Core temperature undergoes circadian variation that is controlled by the release of melatonin from the suprachiasmatic nucleus. The hypothalamic center also regulates the temperature of the central compartment in response to information from thermoreceptors (monosynaptic pathway), feeding, locomotor activity, or secretion of corticosteroids (plurisynaptic pathway).

Temperature regulation, or homeothermy, remains a highly active area of research. Two neuronal models of temperature regulation in mammals have been described: the set-point model and the null-zone model. The set-point model includes an adjustable set point and signals from peripheral and/or central temperature-sensitive neurons that are integrated and compared with a set point at the level of the hypothalamus. Thermogenic or thermolytic responses can correct the core temperature toward the set point level [13, 14]. Fever or hypothermia are here considered to result from a shift in the set point [15]. An alternative view is that body core temperature is defended around a “set level” or “null zone” rather than a set point [16]. The existence of this “null zone” has been demonstrated in several species, including humans [16]. The null-zone model is based on the interaction of two variables rather than on the comparison of a variable to a constant set point. Reciprocal cross inhibition between a cold sensor and a heat production effector pathway and a warm sensor and a heat loss effector pathway, with the goal of defending a null zone of core temperature, is the basis of this model [17].

2.3. Physiological Fluctuations in Brain Temperature
2.3.1. Brain Activity

Neuronal energy metabolism is primarily used for the restoration of membrane potential after cell depolarization [18]. This suggests a relationship between cellular metabolism and electrical activity. Considering that a large part of the energy used for neuronal metabolism is finally transformed into heat, heat production by the brain is therefore an important characteristic of cerebral metabolic activity. In animals, significant changes of 2 to 3°C in brain temperature have been observed after behavioral stimuli [19, 20]. Increase in intracerebral heat production seems to be the primary cause of the brain hyperthermia observed during behavioral stimuli in animals. Indeed, brain temperature increases first, followed by an increase in blood temperature [21, 22]. In awake subjects (or animals) under these conditions, blood going to the brain is therefore cooler than the brain itself, and the temperature gradient between brain and arterial blood increases with the intensity of behavioral stimuli.

Increased brain activity and metabolism is therefore accompanied by an increase in temperature. Concomitantly, in both animals and humans, there is an increase in cerebral blood flow (CBF). The increase in local cerebral temperature resulting from an increase in local metabolism could be considered one of the causes of local blood flow increase that contributes to the coupling between CBF and metabolism.

2.3.2. General Anesthesia

As previously described, in awake conditions, the brain is warmer than the arterial blood. Depression of cerebral metabolism induced by general anesthesia could affect brain temperature. In rats anesthetized with pentobarbital, urethane, or alpha-chloralose, brain temperature decreases more rapidly than rectal temperature [23]. Under general anesthesia, a healthy brain could therefore be cooler than the blood as was shown in these animal studies.

2.4. Where Should We Measure Temperature?

Core temperature can be estimated by measuring the temperature of the lower esophagus, pulmonary artery, nasopharynx, or tympanum [24]. Brain temperature is usually considered a “central” temperature, and in the absence of intracranial pathology, it can be estimated by measuring tympanic or esophageal temperatures. These temperatures are easy to measure and are often used to monitor changes in brain temperature. However, in cases of severe cerebral injury, the estimates yielded by such measurements may be inaccurate [25, 26].

In humans, the center of the brain is from 0.5 to 1°C warmer than the epidural space [27]. The brain’s surface temperature is always lower than its core temperature, but it is also more variable. For these reasons, it is recommended that temperature sensors are inserted to a depth of at least 1.5 to 2 cm in the brain parenchyma [28]. Several temperature sensors are currently available, all of which use thermocouple technology. Some are designed for intraparenchymal and others for intraventricular use. Analysis of the literature does not allow recommendation of one probe over another. Intraparenchymal probes are the most commonly used [29].

More recently, techniques for the noninvasive measurement of brain temperature with magnetic resonance spectroscopy (MRS) have been developed [30, 31]. Experimental studies in phantoms [31] and experimental models [32] have shown close correlation between temperatures measured by MRS and temperatures measured using implanted probes. MRS has been used to measure temperature in healthy adult human volunteers, during head cooling, in children, in patients with brain tumors, and in patients with ischemic stroke [33].

3. Physiological Cerebral Changes Induced by Variations in Brain Temperature

Changes in brain temperature significantly affect vascular, metabolic, and neuronal parameters. Because they have a major impact on cerebral physiology, an understanding of these changes is essential.

3.1. Cerebral Metabolism

The relationship between temperature and brain activity has been extensively studied using electrophysiology. Animal studies have shown a close relationship between brain temperature and cerebral metabolic rate of oxygen (CMRO2) [34]. Previous studies in rats and dogs reported that temperature changes of more than 1°C significantly altered both functional neurologic outcome and histopathology [35]. Cerebral metabolism changes linearly with brain temperature, with 6 to 8% changes in metabolism per degree Celsius of temperature [36, 37]. In anesthetized dogs at 28°C, cerebral metabolism represents only 50% of that at 37°C [38]. Brain oxygen consumption is therefore dramatically reduced at these temperature levels. It has also been shown that all energy-production pathways in the brain, including the cerebral metabolic rates for glucose (CMRglu) and lactate, are reduced by a factor of 2 to 4 with each 10°C decrease in temperature [39].

In vitro, temperature influences the passive properties of the neuronal membrane and synaptic responses (post-potential). Synaptic transmission is temperature dependent. The effect of temperature on the release of neurotransmitters (excitatory postsynaptic potential) seems more pronounced than the effect of temperature on the synaptic response itself [40, 41]. These temperature-dependent changes in electrophysiological properties can be related to effects on neuronal ion channels. Indeed, some calcium or voltage-gated sodium channels are regulated by temperature [42, 43]. Moreover, glutamate diffusion and toxicity rise in temperature [44]. Temperature changes alter brain neurotransmitter release, reuptake, and diffusion. In animal models of ischemia or focal brain injury, brain temperatures above 39°C are associated with increased levels of extracellular excitatory amino acids, opening of the blood-brain barrier, and an increase in proteolysis of the neuronal cytoskeleton [45]. Excitotoxicity is dependent on brain temperature.

3.2. Cerebral Blood Flow

Cerebral blood flow (CBF) also changes with temperature, and these changes are proportional to the changes in cerebral metabolism induced by temperature variations [46]. Due to the physiological coupling between CBF and metabolism, decreased brain temperature induces a concomitant decrease in metabolism and blood flow [47], leading to decreased intracerebral vascular volume and intracranial pressure [48]. However, some studies suggest that the coupling between CMRO2 and CBF is nonlinear [49]. During mild hypothermia after cardiac arrest in humans, CBF is low [47]. Rewarming for 24 hours increases CBF to normal values. A recent study of 10 comatose patients who were successfully resuscitated following out-of-hospital cardiac arrest reported an effect of mild therapeutic hypothermia on CBF and cerebral oxygen extraction. The median core temperature at the start of the study was 34.3°C, and this temperature was maintained between 32 and 34°C for 72 hours. The median mean flow velocity in the middle cerebral artery (MFVMCA) was low at admission and significantly increased at 72 hours [50]. Median jugular bulb oxygenation (SjbO2) was normal in the majority of patients throughout the study. The observation of normal SjbO2 together with low MFVMCA strongly suggests that there was decreased cerebral metabolism during the first 24–48 hours of mild therapeutic hypothermia. However, the fact that SjbO2 reached a plateau 24–30 hours after admission indicates relatively low cerebral oxygen extraction. These findings suggest that cerebral metabolic coupling may be lost during hypothermia.

3.3. Carbon Dioxide, pH, and Oxygen

The level of gaseous carbon dioxide (CO2), or CO2 partial pressure (PaCO2), in arterial blood depends on the solubility coefficient of this gas, which is itself dependent on temperature. As the temperature decreases, the amount of gaseous CO2 decreases. In other words, there are fewer bubbles in a champagne bottle when the bottle is cold. Moreover, cellular energetic metabolism, the end products of which are water and CO2, decreases with temperature. CO2 production is therefore reduced by hypothermia. Thus, for both physical and metabolic reasons, PaCO2 decreases with temperature [51]. Similarly, pH is modified by temperature due to changes in PaCO2: hyperthermia is accompanied by acidosis, and hypothermia by alkalosis [52]. The CO2 gas crosses the blood-brain barrier and transmits the induced modifications (e.g., alkalosis in hypothermia) to the extracellular environment, which regulates the state of arteriolar vascular tone. This explains why hypothermia-induced hypocapnia may cause arteriolar vasoconstriction and a decrease in intracranial pressure [53].

The decrease in PaCO2 is partly the result of decreased oxygen consumption (O2) [53]. This reduction could be beneficial in areas with high ischemic risk. However, the effect is counteracted by an increase in hemoglobin affinity for oxygen that occurs with the decrease in temperature (Figure 2). The increased affinity of hemoglobin for oxygen impedes the diffusion of oxygen to tissues.


Relationship between oxygen partial pressure (PO2) and oxygen saturation of hemoglobin (SO2). Hypothermia increases the affinity of hemoglobin for oxygen, according to Tremey and Vigué [51].
3.4. Brain Inflammation and Blood-Brain Barrier

In animals, after focal trauma (fluid percussion), the inflammatory response of contused and noncontused brain areas is temperature dependent. Accumulation of leukocytes increases with temperature [54]. These changes in inflammatory processes may play a major role in the posttraumatic cascade. Moreover, the permeability of the blood-brain barrier also seems to depend on brain temperature. An increase in brain temperature can damage the endothelial cells of the brain and spinal cord, leading to diffusion of serum proteins through the blood-brain barrier and contributing to the occurrence of cerebral edema [55]. Even if hyperthermia occurs after a period of four days following trauma (animal model of fluid percussion), brain hyperthermia worsens mortality and increases lesions of the blood-brain barrier and axonal injury [56].

4. Changes in Brain Temperature in Neurointensive Care

After major brain injury, brain temperature is often higher than systemic temperature and can vary independently, making the extrapolation of brain temperature from “central” temperature difficult. Rossi et al. [25] found that the number of temperature measurements >38°C in the brain was 15% higher than core body temperature measured simultaneously at the pulmonary artery. The difference between brain and core temperature has been found to be as much as 2°C depending on the characteristics of the patient, probe placement, and interactions with other physiologic variables [25, 57]. As patients become hyperthermic, the difference between brain and core temperature increases, which may indicate that the true incidence of febrile episodes in the brain is even higher than that reported in large observational studies that measured only core body temperature.

4.1. Severe Traumatic Brain Injury

Traumatic brain injury (TBI) produces focal or multiple brain injuries, blood-brain barrier disruption, ischemia and reperfusion, diffuse axonal injury and development of cerebral microbleeding, intracranial hematomas, or contusion areas [58]. The primary injury can be followed by secondary injuries that lead to increased cell death and poor neurological outcome [58, 59].

Two studies conducted in sedated patients suffering from severe TBI reported an average brain temperature that was higher by approximately 1°C than the average rectal temperature in the first posttraumatic days [25, 60]. This difference is accentuated when patients become febrile. In the absence of an infectious cause, one explanation of this phenomenon could be a “resetting” of the hypothalamic thermoregulatory center. Autopsies have indeed found a high frequency (42%) of hypothalamic lesions in patients who died after severe TBI [61]. However, other causes could produce an increase in “intracerebral” temperature after TBI. The observed elevation in brain temperature could be related to posttraumatic changes in brain metabolism (hyperglycolysis) [62], in CBF (hyperemia) [63], or in the local inflammatory response (e.g., increased intracerebral interleukin-1β) [64]. Decoupling of energy metabolism in cases of brain injury could also contribute to the production of heat in such cases, ATP synthesis can indeed be short-circuited. The reduction in the proton gradient and the mitochondrial membrane potential accelerates cellular respiration, and respiration is no longer coupled to the phosphorylation of adenosine diphosphate (ADP), becoming a purely thermogenic process (Figure 1).

Inversion of the brain/body temperature gradient, in which the brain temperature falls below the “general” body temperature, is associated with poor neurological prognosis in severe TBI [65]. This phenomenon is also observed during progression to brain death [66]. The decrease in CBF associated with increased intracranial pressure most likely causes a decrease in brain temperature to below the core temperature. Variations in this gradient could therefore reflect the occurrence of cerebral ischemia.

On the other hand, early fever is frequent after TBI and is associated with higher severity at presentation and with the presence of diffuse axonal injury, cerebral edema on the initial head computed tomography scan, systolic hypotension, hyperglycemia, and leukocytosis [2]. Elevations in temperature within the first 24 hours after TBI are attributed to an acute phase response [67]. Other studies have reported that the presence of blood within the cerebrospinal fluid, especially within the intraventricular spaces, may stimulate hypothalamic thermoregulatory centers and lead to increased body temperature [68]. As with all other brain injuries, fever after TBI can be related to the development of infection, to the occurrence of inflammatory responses, and to hypothalamic dysfunction following the injury. Observational studies have found that the occurrence of fever in the first week after injury is associated with increased intracranial pressure, neurologic impairment, and prolonged length of stay in intensive care [69, 70]. Jiang et al. reported a strong relationship between fever and outcome in a study of 846 patients with TBI [71]. Childs et al. suggested that patients who had the highest and lowest average brain temperatures during the first 48 hours after injury were more likely to have a worse outcome and to die [72]. Soukup et al. also reported poor outcome at 3 months in patients with TBI who showed extremes of brain temperature [65]. Recently, Sacho et al. conducted a study in which intraparenchymal brain temperature was measured in severe TBI patients during the first 5 days in the intensive care unit. Brain temperatures within the range of 36.5°C to 38°C during the first 24 hours were associated with a lower probability of death (10–20%). Brain temperature outside this range was associated with a higher probability of death and with poor 3-month neurological outcomes [73]. Evidence for the adverse effects of a small increase in brain temperature on secondary neuronal damage [74] and mortality [4, 56] is now extensive. Hyperthermia causes the release of excitatory amino acids and free radicals, aggravates blood-brain barrier breakdown, amplifies cytoskeletal proteolysis, and increases cerebral metabolic rate [75–77]. Recently, Stocchetti et al. described impact of pyrexia on neurochemistry and cerebral oxygenation after acute brain injury in humans [78]. During the onset of fever, cerebral oxygenation was preserved, and no signs of anaerobic metabolism (stable concentrations of glucose, lactate, pyruvate and glutamate, and lactate to pyruvate ratio) were recorded, possibly because of a concomitant increase in CBF.

Therapeutic cooling or targeted temperature management has been proposed as a neuroprotective treatment for TBI. From a historical perspective, Fay first introduced neurological therapeutic hypothermia in 1943 in a case of severe TBI [79]. The primary neuroprotective benefit of therapeutic hypothermia has been attributed to reduction of CMRO2, which is strongly linked to oxygen and glucose consumption and lactate production in neurons [80, 81]. However, many neuroprotective effects of hypothermia have been described, including reduced metabolism (permitting a decrease in interstitial lactate accumulation and the maintenance of physiological tissue pH balance) [82], reduced intracranial pressure (ICP) [83], stabilized blood-brain barrier, reduced free radical production, decreased accumulation of lactic acid and other neurotoxins, enhanced glucose utilization, facilitaed antiinflammatory responses and anti-apoptotic pathways, and reduced release of excitotoxic neurotransmitters such as glutamate [82, 84–87]. The intracranial pressure decrease induced by hypothermia occurs through multiple mechanisms: decrease in CMRO2 and thus in CBF and cerebral blood volume, decrease in ischemic edema, and decrease in PaCO2.

A number of studies with animal models have shown that hypothermia can improve outcome after experimental TBI [84, 88, 89]. These results have led to clinical trials. Studies including patients with refractory raised ICP showed a decrease in ICP during cooling [84, 90–93]. One prospective multicentric randomized study did not find any beneficial effect on outcome [48]. However, in a subgroup of patients who were hypothermic on admission, 52% of those assigned to the hypothermia group had poor outcomes, while 76% of those assigned to the normothermia group had poor outcomes. A recent meta-analysis suggests that treatment with hypothermia may decrease mortality and improve neurologic outcome if treatment is maintained more than 48 hours [94]. Guidelines for the management of severe TBI have limited prophylactic hypothermia recommendations to level III because of potential confounding factors [95].

Therapeutic hypothermia appears to be an attractive tool, but its handling requires experienced teams. In our neurointensive care unit, we recommend its use in severe TBI patients presenting hypothermia on arrival at the hospital and as a third-line option for the treatment of raised intracranial pressure (target temperature 33°C for at least 48 hours).

Fever can also be regarded as an adaptive response that enhances the ability to control infection. Induction of normothermia may impair this adaptive response. In fact, the use of antipyretics has been reported to prolong the evolution of certain types of bacterial and viral infections [96, 97]. Studies have shown a correlation between febrile response and increased survival rate in patients with community-acquired pneumonia, Escherichia coli, Streptococcus pneumonia, and Pseudomonas aeruginosa sepsis [98–101]. Fever also has the direct effect of inhibiting the replication of some microorganisms, and it enhances the antibacterial effect of a variety of antibiotics [102, 103]. Schulman et al. reported higher mortality rates in critically ill patients with aggressive treatment (treatment when temperature was >38.5°C) compared to a permissive group (treatment when temperature was >40°C) [104]. Recently, however, Schortgen et al. described the effect of external cooling for fever control during septic shock in a multicenter-randomized controlled trial. Body temperature was lower in the cooling group after 2 hours (36.8°C versus 38.4°C), resulting in a significant decrease in vasopressor dosage and better shock reversal. Moreover, day 14 mortality rate was better in the cooling group (19% versus 34%) [105]. Therefore, in this study, fever control during septic shock was demonstrated to be safe. However, several important points of this study should be emphasized. First, the main source of infection was the lung and not the abdomen in cases involving the latter, deleterious effects of fever control have been shown in experimental models [106, 107]. Second, most of the patients in Schortgen’s study have received appropriate antimicrobial therapy, thereby mitigating the potential negative effect of fever control on host defenses [102]. Further, it is important to emphasize that the goal in this study was fever control and not induction of hypothermia. Of note, in several previous studies, an increased risk of acquisition of infection after mild therapeutic hypothermia was demonstrated [108, 109].

4.2. Severe Subarachnoid Hemorrhage

Nontraumatic subarachnoid hemorrhage (SAH) primarily occurs due to intracranial aneurysm rupture [110]. Sudden internal bleeding causes high ICP. Bleeding in subarachnoid spaces, sometimes with intraventricular hemorrhage or intraparenchymal hematoma, follows rupture of an aneurysm. Brain tissue hypoxia can occur in relation to significant CBF decrease and edema formation [111]. After a severe SAH, brain temperature is usually higher than core temperature [112]. An attractive hypothesis involves the potential role of the degradation products of heme. The heme molecule is degraded by heme oxygenase to biliverdin, iron, and carbon monoxide (CO) [113]. In rats, intraventricular injection of CO increases body temperature by more than 1°C [114].

A prospective study in patients admitted for severe SAH found a relationship between brain temperature and survival [112]. In TBI, when the measured brain temperature is lower than the body temperature (bladder), the prognosis is very poor. This temperature decrease could also be related to a significant decrease in CBF.

In the acute phase of SAH, alterations in body temperature regulation are common. Fever, defined as body temperature >38.3°C, occurs in up to 72% of aneurysmal SAH patients [115, 116]. Noninfectious fever, usually beginning in the first 3 days, is common in patients with SAH [117]. In patients with intraventricular hemorrhage, body temperature is persistently increased (plateau) instead of presenting spikes [68]. Refractory fever during the first 10 days after SAH is associated with increased mortality, severe functional disability, and cognitive impairment among survivors [3]. Cumulative fever burden, defined as the sum of time at body temperature >38.3°C in the first 13 days, is associated with worse outcome and with later and often incomplete recovery in good-grade patients and potential late recovery in poor-grade patients [118]. Moreover, fever induces cerebral metabolic distress, and elevated lactate/pyruvate ratios have been documented using microdialysis during febrile episodes. In acohort study, Oddo et al. found an association between fever and cerebral metabolic distress and showed that cerebral metabolic distress can be reduced with fever control independently of intracranial pressure management [119]. Induced normothermia was related to significant reduction in the lactate/pyruvate ratio and fewer episodes of cerebral metabolic crisis, supporting the view that fever control may be “neuroprotective.” This evidence suggests that fever could be detrimental and that its control could reduce metabolic distress.

A recent review describes fever incidence, impact, and treatment in patients with SAH [120]. In SAH, fever is associated with worse outcome and increased length of stay [121] and has detrimental effects independent of vasospasm. Fever has also been linked to symptomatic vasospasm independent of hemorrhage severity or the presence of infection [113, 122]. This association could be due to inflammatory activation after SAH [123], which might be implicated in the development of both phenomena. In addition to disease severity and to the amount of blood in the subarachnoid space, the presence of intraventricular hemorrhage is a strong risk factor for fever development [3, 68]. Fever exacerbates ischemic injury [75], worsens cerebral edema, increases intracranial pressure [25], and may lead to a decreased level of consciousness.

Hypothermia has not been studied in severe SAH patients being treated in intensive care units. Deep intraoperative hypothermia has been proposed to protect brain tissue from surgery-related ischemic damage. A recent review by the Cochrane collaboration evaluated the effect of intraoperative mild hypothermia on postoperative death and neurological deficits in patients with intracranial aneurysms [124]. The authors concluded that there were insufficient data to draw any conclusions and that therapeutic hypothermia should therefore not be recommended during surgery in patients with poor-grade aneurysmal SAH. Recently, guidelines for the management of aneurysmal SAH have proposed recommendations on anesthetic management during surgical and endovascular treatment. Induced hypothermia during aneurysm surgery is not routinely recommended but may be a reasonable option in selected cases (Class III, level of evidence B) [125]. The IHAST study compared 499 patients randomly assigned to an intraoperative hypothermia group during surgery for intracranial aneurysm (target temperature 33°C) versus 501 patients in a normothermia group (36.5°C) [126]. The aim of the study was to determine whether intraoperative cooling during open craniotomy resulted in improved outcome among patients with acute aneurysmal SAH. The results did not show any significant differences between the two groups. Other studies have not shown any benefit of hypothermia on cognitive function or neuropsychological outcome after SAH [127, 128].

Therapeutic hypothermia is not routinely used or recommended in severe SAH. In practice, we do not use intraoperative cooling because of lack of evidence for its use.

4.3. Stroke

Ischemic stroke is one of the major causes of adult disability in industrialized countries [129]. Stroke causes permanent brain damage and long-term impairment. In the central core regions of the insult, neuronal cells undergo death within minutes. Surrounding this core, CBF levels may fall below functional thresholds but above the threshold for cell death this area has been called the penumbra [130]. The penumbral zone permits cell survival only for a period of time, but at least some of the tissue in this zone is potentially salvageable.

After ischemic stroke, the temperature in the areas of the brain affected by ischemia is higher than the temperature in the unaffected parts of the brain and the rest of the body [33]. Clinical trials of therapeutic hypothermia in patients with ischemic stroke have been conducted based on observations that in animal models hypothermia reduces the size of cerebral infarcts by more than half [131]. Furthermore, in stroke patients, higher body temperature is associated with poorer outcome [4].

The processes that determine brain temperature after human ischemic stroke are not fully understood. There may be dissociation between metabolic activity and heat generation in ischemic brain. A systemic response to the increase in systemic inflammatory cytokines after stroke could also increase brain temperature. Interleukin-6 (IL-6) triggers the release of other proinflammatory cytokines, and its presence is important for the generation of fever [132]. Higher levels of IL-6 and acute phase proteins are associated with poorer functional outcome after stroke [133, 134], and one potential mechanism for the association with poor outcome is an increase in brain temperature. Whiteley et al. recently studied 44 patients with acute ischemic stroke and found an association between levels of IL-6, as well as downstream acute-phase proteins such as C-reactive protein and fibrinogen, and changes in brain or body temperatures over the first 5 days after stroke [135]. In this study, brain temperature was recorded at hospital admission and 5 days after stroke using multivoxel magnetic resonance spectroscopic imaging of normal-appearing brain and of the acute ischemic lesion, which was defined by diffusion-weighted imaging [35]. The mean temperature in DWI-ischemic brain soon after admission was 38.4°C (95% confidence interval (CI) 38.2–38.6), while in DWI-normal brain the mean temperature was 37.7°C (95% CI 37.6–37.7). The mean body temperature was 36.6°C (95% CI 36.3–37.0). Higher levels of interleukin-6, C-reactive protein, and fibrinogen were associated with higher temperature in DWI-normal brain at admission and at 5 days.

Therapeutic hypothermia has been proposed as a neuroprotective strategy after ischemic stroke. In patients suffering from cerebral ischemia, therapeutic hypothermia may minimize the extent of injury by modulating various steps of the ischemic cascade [136]. Target temperature management reduces neuronal excitotoxicity by blocking glutamate and dopamine release, leading to reduced calcium influx and lipid peroxidation and thus attenuating free radical production [85]. Temperature-related reduction of free radical production has been associated with decreased neuronal damage during both the ischemic and reperfusion phases [137]. Another hypothesis is that therapeutic hypothermia may favor the upregulation of stress response genes that produce antiapoptotic proteins. These gene products are translocated into the nuclei, where they regulate gene expression favoring cell survival [138, 139].

In experimental stroke studies, mild hypothermia (32–34°C) seemed to be superior to other temperatures tested for example, it resulted in a larger reduction in infarct volume than 27°C [140] and better tolerance than 30°C [141]. A number of studies suggest that hypothermia is neuroprotective when applied early after the stroke, and that it remains beneficial if the duration of cooling is prolonged [142–144]. It should be noted that in many animal studies therapeutic hypothermia is initiated before or at the onset of ischemic stroke, whereas in clinical situations, patients typically reach the hospital several hours after the onset of the injury. Furthermore, most patients receive hypothermia for several days, whereas animal models use hypothermia only for short cooling periods. The rewarming phase after therapeutic hypothermia is also crucial because rapid rewarming may enhance deleterious ischemic effects. Berger et al. have shown that slow rewarming significantly reduces the infarct volume compared to fast rewarming [145].

A recent review found 17 relevant clinical studies of the use of hypothermia after ischemic stroke (4 observational studies, 5 self-controlled clinical trials, and 8 parallel-controlled clinical trials) [129]. The observational studies show that admission temperature is a prognostic factor for poor neurological outcome and mortality in ischemic stroke [146–148]. The self-controlled studies suffer from lack of a proper control group, and their results are not sufficiently robust to justify the conclusion that hypothermia influences stroke outcome [149–153]. Of the parallel-controlled clinical trials that have been conducted to date, only one showed improvement in NIHSS (National Institutes of Health Stroke Scale) and significant differences in mortality rate with hypothermia and craniectomy combination compared to craniectomy alone [154]. Two randomized double blind studies have been completed. One did not report any difference between hypothermia and normothermia for mortality or NIHSS at 24 hours or 72 hours in patients undergoing craniectomy [155]. Mortality has been found to be similar between hypothermia and control groups in all randomized blinded clinical trials [155, 156].

The literature suffers from lack of evidence supporting the use of mild therapeutic hypothermia on ischemic stroke patients.

5. Conclusion

After severe brain injury, brain temperature is usually not measured, although several studies have shown that it may differ significantly from core temperature. Measurement of body temperature often underestimates brain temperature, especially in situations in which the central nervous system is vulnerable. Dissociation between brain and body temperature could be a sign of poor prognosis. After major brain injury, brain temperature, similarly to intracranial pressure, should be continuously monitored using in situ measurement such measurement should most likely be a part of the multimodal monitoring of patients to prevent secondary injury to the brain.

Fever management should take into consideration the protection of the brain from secondary insults as well as the capacity to fight against infections. Fever should most likely be treated aggressively in the first days of TBI, SAH, or stroke, but randomized controlled trials are needed to assess the risk-benefit ratio. Therapeutic hypothermia has yielded promising results in animal models of TBI, SAH, or stroke, but its usefulness in clinical practice is still debated. In severe TBI, therapeutic hypothermia permits control of intracranial pressure elevation, but its effects on outcome and mortality have not been conclusively demonstrated. In patients with poor-grade aneurysmal SAH, therapeutic hypothermia is not recommended during aneurysmal surgery. The benefit of hypothermia in reducing infarct size in humans after ischemic stroke is not clear.

References

  1. M. Shigemori, T. Abe, T. Aruga et al., “Guidelines for the Management of Severe Head Injury, 2nd edition guidelines from the Guidelines Committee on the Management of Severe Head Injury, the Japan Society of Neurotraumatology,” Neurologia Medico-Chirurgica, vol. 52, no. 1, pp. 1–30, 2012. View at: Google Scholar
  2. C. J. Cairns and P. J. Andrews, “Management of hyperthermia in traumatic brain injury,” Current Opinion in Critical Care, vol. 8, no. 2, pp. 106–110, 2002. View at: Google Scholar
  3. A. Fernandez, J. M. Schmidt, J. Claassen et al., “Fever after subarachnoid hemorrhage: risk factors and impact on outcome,” Neurology, vol. 68, no. 13, pp. 1013–1019, 2007. View at: Publisher Site | Google Scholar
  4. D. M. Greer, S. E. Funk, N. L. Reaven, M. Ouzounelli, and G. C. Uman, “Impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive meta-analysis,” Stroke, vol. 39, no. 11, pp. 3029–3035, 2008. View at: Publisher Site | Google Scholar
  5. B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter, Molecular Biology of the Cell, Garland Science, 4th edition, 2002.
  6. C. Jessen, “Selective brain cooling in mammals and birds,” Japanese Journal of Physiology, vol. 51, no. 3, pp. 291–301, 2001. View at: Publisher Site | Google Scholar
  7. M. A. Baker, “Brain cooling in endotherms in heat and exercise,” Annual Review of Physiology, vol. 44, pp. 85–96, 1982. View at: Publisher Site | Google Scholar
  8. M. Cabanac and H. Brinnel, “Blood flow in the emissary veins of the human head during hyperthermia,” European Journal of Applied Physiology and Occupational Physiology, vol. 54, no. 2, pp. 172–176, 1985. View at: Google Scholar
  9. W. Zenker and S. Kubik, “Brain cooling in humans𠅊natomical considerations,” Anatomy and Embryology, vol. 193, no. 1, pp. 1–13, 1996. View at: Google Scholar
  10. Z. Mariak, M. D. White, J. Lewko, T. Lyson, and P. Piekarski, “Direct cooling of the human brain by heat loss from the upper respiratory tract,” Journal of Applied Physiology, vol. 87, no. 5, pp. 1609–1613, 1999. View at: Google Scholar
  11. D. I. Sessler, “Perioperative heat balance,” Anesthesiology, vol. 92, no. 2, pp. 578–596, 2000. View at: Google Scholar
  12. C. B. Saper, J. Lu, T. C. Chou, and J. Gooley, “The hypothalamic integrator for circadian rhythms,” Trends in Neurosciences, vol. 28, no. 3, pp. 152–157, 2005. View at: Publisher Site | Google Scholar
  13. H. T. Hammel, D. C. Jackson, J. A. Stolwijk, J. D. Hardy, and S. B. Stromme, “Temperature regulation by hypothalamic proportional control with an adjustable set point,” Journal of Applied Physiology, vol. 18, pp. 1146–1154, 1963. View at: Google Scholar
  14. J. A. Boulant, “Neuronal basis of Hammel's model for set-point thermoregulation,” Journal of Applied Physiology, vol. 100, no. 4, pp. 1347–1354, 2006. View at: Publisher Site | Google Scholar
  15. M. Cabanac, “Adjustable set point: to honor Harold T. Hammel,” Journal of Applied Physiology, vol. 100, no. 4, pp. 1338–1346, 2006. View at: Publisher Site | Google Scholar
  16. I. B. Mekjavic, C. J. Sundberg, and D. Linnarsson, “Core temperature ‘null zone’,” Journal of Applied Physiology, vol. 71, no. 4, pp. 1289–1295, 1991. View at: Google Scholar
  17. J. Bligh, “A theoretical consideration of the means whereby the mammalian core temperature is defended at a null zone,” Journal of Applied Physiology, vol. 100, no. 4, pp. 1332–1337, 2006. View at: Publisher Site | Google Scholar
  18. L. Sokoloff, “Energetics of functional activation in neural tissues,” Neurochemical Research, vol. 24, no. 2, pp. 321–329, 1999. View at: Publisher Site | Google Scholar
  19. R. M. Abrams, J. A. J. Stolwijk, H. T. Hammel, and H. Graichen, “Brain temperature and brain blood flow in unanesthetized rats,” Life Sciences, vol. 4, no. 24, pp. 2399–2410, 1965. View at: Google Scholar
  20. J. M. Delgado and T. Hanai, “Intracerebral temperatures in free-moving cats,” The American Journal of Physiology, vol. 211, no. 3, pp. 755–769, 1966. View at: Google Scholar
  21. E. A. Kiyatkin and P. L. Brown, “Brain and body temperature homeostasis during sodium pentobarbital anesthesia with and without body warming in rats,” Physiology and Behavior, vol. 84, no. 4, pp. 563–570, 2005. View at: Publisher Site | Google Scholar
  22. E. A. Kiyatkin, P. L. Brown, and R. A. Wise, “Brain temperature fluctuation: a reflection of functional neural activation,” European Journal of Neuroscience, vol. 16, no. 1, pp. 164–168, 2002. View at: Publisher Site | Google Scholar
  23. M. Zhu, D. Nehra, J. J. H. Ackerman, and D. A. Yablonskiy, “On the role of anesthesia on the body/brain temperature differential in rats,” Journal of Thermal Biology, vol. 29, no. 7-8, pp. 599–603, 2004. View at: Publisher Site | Google Scholar
  24. R. C. Cork, R. W. Vaughan, and L. S. Humphrey, “Precision and accuracy of intraoperative temperature monitoring,” Anesthesia & Analgesia, vol. 62, no. 2, pp. 211–214, 1983. View at: Google Scholar
  25. S. Rossi, E. Roncati Zanier, I. Mauri, A. Columbo, and N. Stocchetti, “Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage,” Journal of Neurology Neurosurgery and Psychiatry, vol. 71, no. 4, pp. 448–454, 2001. View at: Publisher Site | Google Scholar
  26. L. McIlvoy, “Comparison of brain temperature to core temperature: a review of the literature,” Journal of Neuroscience Nursing, vol. 36, no. 1, pp. 23–31, 2004. View at: Google Scholar
  27. P. Mellergård, “Intracerebral temperature in neurosurgical patients: intracerebral temperature gradients and relationships to consciousness level,” Surgical Neurology, vol. 43, no. 1, pp. 91–95, 1995. View at: Publisher Site | Google Scholar
  28. J. G. Stone, R. R. Goodman, K. Z. Baker, C. J. Baker, and R. A. Solomon, “Direct intraoperative measurement of human brain temperature,” Neurosurgery, vol. 41, no. 1, pp. 20–24, 1997. View at: Publisher Site | Google Scholar
  29. B. Alessandri, B. M. Hoelper, R. Behr, and O. Kempski, “Accuracy and stability of temperature probes for intracranial application,” Journal of Neuroscience Methods, vol. 139, no. 2, pp. 161–165, 2004. View at: Publisher Site | Google Scholar
  30. E. B. Cady, P. C. D'Souza, J. Penrice, and A. Lorek, “The estimation of local brain temperature by in vivo 1H magnetic resonance spectroscopy,” Magnetic Resonance in Medicine, vol. 33, no. 6, pp. 862–867, 1995. View at: Publisher Site | Google Scholar
  31. R. J. T. Corbett, A. R. Laptook, G. Tollefsbol, and B. Kim, “Validation of a noninvasive method to measure brain temperature in vivo using 1H NMR spectroscopy,” Journal of Neurochemistry, vol. 64, no. 3, pp. 1224–1230, 1995. View at: Google Scholar
  32. K. Kuroda, N. Takei, R. V. Mulkern et al., “Feasibility of internally referenced brain temperature imaging with a metabolite signal,” Magnetic Resonance in Medical Sciences, vol. 2, no. 1, pp. 17–22, 2003. View at: Google Scholar
  33. B. Karaszewski, J. M. Wardlaw, I. Marshall et al., “Measurement of brain temperature with magnetic resonance spectroscopy in acute ischemic stroke,” Annals of Neurology, vol. 60, no. 4, pp. 438–446, 2006. View at: Publisher Site | Google Scholar
  34. J. D. Michenfelder and J. H. Milde, “The relationship among canine brain temperature, metabolism, and function during hypothermia,” Anesthesiology, vol. 75, no. 1, pp. 130–136, 1991. View at: Google Scholar
  35. D. S. Warner, C. McFarlane, M. M. Todd, P. Ludwig, and A. M. McAllister, “Sevoflurane and halothane reduce focal ischemic brain damage in the rat: possible influence on thermoregulation,” Anesthesiology, vol. 79, no. 5, pp. 985–992, 1993. View at: Google Scholar
  36. W. L. Lanier, “Cerebral metabolic rate and hypothermia: their relationship with ischemic neurologic injury,” Journal of Neurosurgical Anesthesiology, vol. 7, no. 3, pp. 216–221, 1995. View at: Google Scholar
  37. H. L. Rosomoff and D. A. Holaday, “Cerebral blood flow and cerebral oxygen consumption during hypothermia,” The American Journal of Physiology, vol. 179, no. 1, pp. 85–88, 1954. View at: Google Scholar
  38. J. D. Michenfelder and J. H. Milde, “The effect of profound levels of hypothermia (below 14ଌ) on canine cerebral metabolism,” Journal of Cerebral Blood Flow and Metabolism, vol. 12, no. 5, pp. 877–880, 1992. View at: Google Scholar
  39. T. C. Glenn, D. F. Kelly, W. J. Boscardin et al., “Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism,” Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 10, pp. 1239–1250, 2003. View at: Google Scholar
  40. M. Volgushev, T. R. Vidyasagar, M. Chistiakova, and U. T. Eysel, “Synaptic transmission in the neocortex during reversible cooling,” Neuroscience, vol. 98, no. 1, pp. 9–22, 2000. View at: Publisher Site | Google Scholar
  41. M. Volgushev, I. Kudryashov, M. Chistiakova, M. Mukovski, J. Niesmann, and U. T. Eysel, “Probability of transmitter release at neocortical synapses at different temperatures,” Journal of Neurophysiology, vol. 92, no. 1, pp. 212–220, 2004. View at: Publisher Site | Google Scholar
  42. A. D. Rosen, “Temperature modulation of calcium channel function in GH3 cells,” American Journal of Physiology, vol. 271, no. 3, part 1, pp. C863–C868, 1996. View at: Google Scholar
  43. A. D. Rosen, “Nonlinear temperature modulation of sodium channel kinetics in GH3 cells,” Biochimica et Biophysica Acta, vol. 1511, no. 2, pp. 391–396, 2001. View at: Publisher Site | Google Scholar
  44. E. Suehiro, H. Fujisawa, H. Ito, T. Ishikawa, and T. Maekawa, “Brain temperature modifies glutamate neurotoxicity in vivo,” Journal of Neurotrauma, vol. 16, no. 4, pp. 285–297, 1999. View at: Google Scholar
  45. W. D. Dietrich, “The importance of brain temperature in cerebral injury,” Journal of Neurotrauma, vol. 9, supplement 2, pp. S475–S485, 1992. View at: Google Scholar
  46. J. Sahuquillo and A. Vilalta, “Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury,” Current Pharmaceutical Design, vol. 13, no. 22, pp. 2310–2322, 2007. View at: Publisher Site | Google Scholar
  47. L. L. A. Bisschops, C. W. E. Hoedemaekers, K. S. Simons, and J. G. van der Hoeven, “Preserved metabolic coupling and cerebrovascular reactivity during mild hypothermia after cardiac arrest,” Critical Care Medicine, vol. 38, no. 7, pp. 1542–1547, 2010. View at: Publisher Site | Google Scholar
  48. G. L. Clifton, E. R. Miller, S. C. Choi et al., “Lack of effect of induction of hypothermia after acute brain injury,” The New England Journal of Medicine, vol. 344, no. 8, pp. 556–563, 2001. View at: Google Scholar
  49. M. Sakoh and A. Gjedde, “Neuroprotection in hypothermia linked to redistribution of oxygen in brain,” American Journal of Physiology, vol. 285, no. 1, pp. H17–H25, 2003. View at: Google Scholar
  50. L. L. Bisschops, J. G. van der Hoeven, and C. W. Hoedemaekers, “Effects of prolonged mild hypothermia on cerebral blood flow after cardiac arrest,” Critical Care Medicine, vol. 40, no. 8, pp. 2362–2367, 2012. View at: Google Scholar
  51. B. Tremey and B. Vigué, “Changes in blood gases with temperature: Implications for clinical practice,” Annales Francaises d'Anesthesie et de Reanimation, vol. 23, no. 5, pp. 474–481, 2004. View at: Publisher Site | Google Scholar
  52. A. K. Ream, B. A. Reitz, and G. Silverberg, “Temperature correction of PCO2 and pH in estimating acid-base status: an example for the emperor's new clothes?” Anesthesiology, vol. 56, no. 1, pp. 41–44, 1982. View at: Google Scholar
  53. B. Vigué, C. Ract, N. Zlotine, P. E. Leblanc, K. Samii, and B. Bissonnette, “Relationship between intracranial pressure, mild hypothermia and temperature-corrected PaCO2 in patients with traumatic brain injury,” Intensive Care Medicine, vol. 26, no. 6, pp. 722–728, 2000. View at: Google Scholar
  54. K. Chatzipanteli, O. F. Alonso, S. Kraydieh, and W. D. Dietrich, “Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies,” Journal of Cerebral Blood Flow and Metabolism, vol. 20, no. 3, pp. 531–542, 2000. View at: Google Scholar
  55. H. S. Sharma and P. J. Hoopes, “Hyperthermia induced pathophysiology of the central nervous system,” International Journal of Hyperthermia, vol. 19, no. 3, pp. 325–354, 2003. View at: Publisher Site | Google Scholar
  56. W. D. Dietrich, O. Alonso, M. Halley, and R. Busto, “Delayed posttraumatic brain hyperthermia worsens outcome after fluid percussion brain injury: a light and electron microscopic study in rats,” Neurosurgery, vol. 38, no. 3, pp. 533–541, 1996. View at: Publisher Site | Google Scholar
  57. R. A. Henker, S. D. Brown, and D. W. Marion, “Comparison of brain temperature with bladder and rectal temperatures in adults with severe head injury,” Neurosurgery, vol. 42, no. 5, pp. 1071–1075, 1998. View at: Publisher Site | Google Scholar
  58. K. H. Polderman, “Induced hypothermia and fever control for prevention and treatment of neurological injuries,” The Lancet, vol. 371, no. 9628, pp. 1955–1969, 2008. View at: Publisher Site | Google Scholar
  59. N. Bruder, L. Velly, and J. L. Codaccioni, “Hypothermia for intracranial hypertension,” Annales Francaises d'Anesthesie et de Reanimation, vol. 28, no. 4, pp. 365–370, 2009. View at: Publisher Site | Google Scholar
  60. C. S. Rumana, S. P. Gopinath, M. Uzura, A. B. Valadka, and C. S. Robertson, “Brain temperature exceeds systemic temperature in head-injured patients,” Critical Care Medicine, vol. 26, no. 3, pp. 562–567, 1998. View at: Publisher Site | Google Scholar
  61. M. R. Crompton, “Hypothalamic lesions following closed head injury,” Brain, vol. 94, no. 1, pp. 165–172, 1971. View at: Publisher Site | Google Scholar
  62. J. C. Goodman, A. B. Valadka, S. P. Gopinath, M. Uzura, and C. S. Robertson, “Extracellular lactate and glucose alterations in the brain after head injury measured by microdialysis,” Critical Care Medicine, vol. 27, no. 9, pp. 1965–1973, 1999. View at: Publisher Site | Google Scholar
  63. D. W. Marion, J. Darby, and H. Yonas, “Acute regional cerebral blood flow changes caused by severe head injuries,” Journal of Neurosurgery, vol. 74, no. 3, pp. 407–414, 1991. View at: Google Scholar
  64. J. R. Goss, S. D. Styren, P. D. Miller et al., “Hypothermia attenuates the normal increase in interleukin 1β RNA and nerve growth factor following traumatic brain injury in the rat,” Journal of Neurotrauma, vol. 12, no. 2, pp. 159–167, 1995. View at: Google Scholar
  65. J. Soukup, A. Zauner, E. M. R. Doppenberg et al., “The importance of brain temperature in patients after severe head injury: relationship to intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and outcome,” Journal of Neurotrauma, vol. 19, no. 5, pp. 559–571, 2002. View at: Google Scholar
  66. K. N. Fountas, E. Z. Kapsalaki, C. H. Feltes et al., “Disassociation between intracranial and systemic temperatures as an early sign of brain death,” Journal of Neurosurgical Anesthesiology, vol. 15, no. 2, pp. 87–89, 2003. View at: Publisher Site | Google Scholar
  67. A. B. Young, L. G. Ott, D. Beard, R. J. Dempsey, P. A. Tibbs, and C. J. McClain, “The acute-phase response of the brain-injured patient,” Journal of Neurosurgery, vol. 69, no. 3, pp. 375–380, 1988. View at: Google Scholar
  68. C. Commichau, N. Scarmeas, and S. A. Mayer, “Risk factors for fever in the neurologic intensive care unit,” Neurology, vol. 60, no. 5, pp. 837–841, 2003. View at: Google Scholar
  69. N. Stocchetti, S. Rossi, E. R. Zanier, A. Colombo, L. Beretta, and G. Citerio, “Pyrexia in head-injured patients admitted to intensive care,” Intensive Care Medicine, vol. 28, no. 11, pp. 1555–1562, 2002. View at: Publisher Site | Google Scholar
  70. P. A. Jones, P. J. D. Andrews, S. Midgley et al., “Measuring the burden of secondary insults in head-injured patients during intensive care,” Journal of Neurosurgical Anesthesiology, vol. 6, no. 1, pp. 4–14, 1994. View at: Google Scholar
  71. J. Y. Jiang, G. Y. Gao, W. P. Li, M. K. Yu, and C. Zhu, “Early indicators of prognosis in 846 cases of severe traumatic brain injury,” Journal of Neurotrauma, vol. 19, no. 7, pp. 869–874, 2002. View at: Google Scholar
  72. C. Childs, A. Vail, P. Leach, T. Rainey, R. Protheroe, and A. King, “Brain temperature and outcome after severe traumatic brain injury,” Neurocritical Care, vol. 5, no. 1, pp. 10–14, 2006. View at: Publisher Site | Google Scholar
  73. R. H. Sacho, A. Vail, T. Rainey, A. T. King, and C. Childs, “The effect of spontaneous alterations in brain temperature on outcome: a prospective observational cohort study in patients with severe traumatic brain injury,” Journal of Neurotrauma, vol. 27, no. 12, pp. 2157–2164, 2010. View at: Publisher Site | Google Scholar
  74. R. Busto, W. D. Dietrich, M. Globus, I. Valdes, P. Scheinberg, and M. D. Ginsberg, “Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury,” Journal of Cerebral Blood Flow and Metabolism, vol. 7, no. 6, pp. 729–738, 1987. View at: Google Scholar
  75. M. D. Ginsberg and R. Busto, “Combating hyperthermia in acute stroke: a significant clinical concern,” Stroke, vol. 29, no. 2, pp. 529–534, 1998. View at: Google Scholar
  76. D. W. Busija, C. W. Leffler, and M. Pourcyrous, “Hyperthermia increases cerebral metabolic rate and blood flow in neonatal pigs,” American Journal of Physiology, vol. 255, no. 2, part 2, pp. H343–H346, 1988. View at: Google Scholar
  77. G. A. Mickley, B. L. Cobb, and S. T. Farrell, “Brain hyperthermia alters local cerebral glucose utilization: a comparison of hyperthermic agents,” International Journal of Hyperthermia, vol. 13, no. 1, pp. 99–114, 1997. View at: Google Scholar
  78. N. Stocchetti, A. Protti, M. Lattuada et al., “Impact of pyrexia on neurochemistry and cerebral oxygenation after acute brain injury,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 76, no. 8, pp. 1135–1139, 2005. View at: Publisher Site | Google Scholar
  79. T. Fay, “Observations on generalized refrigeration in cases of severe cerebral trauma,” Research Publications𠅊ssociation for Research in Nervous and Mental Disease, no. 24, pp. 611–619, 1943. View at: Google Scholar
  80. D. I. Sessler, “Complications and treatment of mild hypothermia,” Anesthesiology, vol. 95, no. 2, pp. 531–543, 2001. View at: Google Scholar
  81. L. Liu and M. A. Yenari, “Therapeutic hypothermia: neuroprotective mechanisms,” Frontiers in Bioscience, vol. 12, no. 3, pp. 816–825, 2007. View at: Publisher Site | Google Scholar
  82. J. Varon and P. Acosta, “Therapeutic hypothermia: past, present, and future,” Chest, vol. 133, no. 5, pp. 1267–1274, 2008. View at: Publisher Site | Google Scholar
  83. F. Sadaka and C. Veremakis, “Therapeutic hypothermia for the management of intracranial hypertension in severe traumatic brain injury: a systematic review,” Brain Injury, vol. 26, no. 7-8, pp. 899–908, 2012. View at: Google Scholar
  84. J. Y. Jiang, B. G. Lyeth, M. Z. Kapasi, L. W. Jenkins, and J. T. Povlishock, “Moderate hypothermia reduces blood-brain barrier disruption following traumatic brain injury in the rat,” Acta Neuropathologica, vol. 84, no. 5, pp. 495–500, 1992. View at: Publisher Site | Google Scholar
  85. T. Miyazawa, A. Tamura, S. Fukui, and K. A. Hossmann, “Effect of mild hypothermia on focal cerebral ischemia. Review of experimental studies,” Neurological Research, vol. 25, no. 5, pp. 457–464, 2003. View at: Publisher Site | Google Scholar
  86. T. S. Olsen, U. J. Weber, and L. P. Kammersgaard, “Therapeutic hypothermia for acute stroke,” Lancet Neurology, vol. 2, no. 7, pp. 410–416, 2003. View at: Publisher Site | Google Scholar
  87. H. B. van der Worp, M. R. MacLeod, and R. Kollmar, “Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials,” Journal of Cerebral Blood Flow and Metabolism, vol. 30, no. 6, pp. 1079–1093, 2010. View at: Publisher Site | Google Scholar
  88. H. M. Bramlett, E. J. Green, W. D. Dietrich, R. Busto, M. Y. T. Globus, and M. D. Ginsberg, “Posttraumatic brain hypothermia provides protection from sensorimotor and cognitive behavioral deficits,” Journal of Neurotrauma, vol. 12, no. 3, pp. 289–298, 1995. View at: Google Scholar
  89. W. D. Dietrich, C. M. Atkins, and H. M. Bramlett, “Protection in animal models of brain and spinal cord injury with mild to moderate hypothermia,” Journal of Neurotrauma, vol. 26, no. 3, pp. 301–312, 2009. View at: Publisher Site | Google Scholar
  90. K. H. Polderman, R. Tjong Tjin Joe, S. M. Peerdeman, W. P. Vandertop, and A. R. J. Girbes, “Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury,” Intensive Care Medicine, vol. 28, no. 11, pp. 1563–1573, 2002. View at: Publisher Site | Google Scholar
  91. D. W. Marion, L. E. Penrod, S. F. Kelsey et al., “Treatment of traumatic brain injury with moderate hypothermia,” The New England Journal of Medicine, vol. 336, no. 8, pp. 540–546, 1997. View at: Publisher Site | Google Scholar
  92. G. L. Clifton, S. Allen, P. Barrodale et al., “A phase II study of moderate hypothermia in severe brain injury,” Journal of Neurotrauma, vol. 10, no. 3, pp. 263–271, 1993. View at: Google Scholar
  93. D. W. Marion, W. D. Obrist, P. M. Carlier, L. E. Penrod, and J. M. Darby, “The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report,” Journal of Neurosurgery, vol. 79, no. 3, pp. 354–362, 1993. View at: Google Scholar
  94. K. Peterson, S. Carson, and N. Carney, “Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis,” Journal of Neurotrauma, vol. 25, no. 1, pp. 62–71, 2008. View at: Publisher Site | Google Scholar
  95. S. L. Bratton, R. M. Chestnut, J. Ghajar et al., “Guidelines for the management of severe traumatic brain injury. III. Prophylactic hypothermia,” Journal of Neurotrauma, supplement 1, pp. S21–S25, 2007. View at: Google Scholar
  96. E. D. Stanley, G. G. Jackson, and C. Panusarn, “Increased virus shedding with aspirin treatment of rhinovirus infection,” Journal of the American Medical Association, vol. 231, no. 12, pp. 1248–1251, 1975. View at: Publisher Site | Google Scholar
  97. T. F. Doran, C. De Angelis, R. A. Baumgardner, and E. D. Mellits, “Acetaminophen: more harm than good for chickenpox?” Journal of Pediatrics, vol. 114, no. 6, pp. 1045–1048, 1989. View at: Google Scholar
  98. A. Kuikka, A. Sivonen, A. Emelianova, and V. V. Valtonen, “Prognostic factors associated with improved outcome of Escherichia coli bacteremia in a Finnish university hospital,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 16, no. 2, pp. 125–134, 1997. View at: Publisher Site | Google Scholar
  99. A. Kuikka and V. V. Valtonen, “Factors associated with improved outcome of Pseudomonas aeruginosa bacteremia in a Finnish university hospital,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 17, no. 10, pp. 701–708, 1998. View at: Publisher Site | Google Scholar
  100. S. Ahkee, L. Srinath, and J. Ramirez, “Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis,” Southern Medical Journal, vol. 90, no. 3, pp. 296–298, 1997. View at: Publisher Site | Google Scholar
  101. S. Jefferies, M. Weatherall, P. Young, S. Eyers, and R. Beasley, “Systematic review and meta-analysis of the effects of antipyretic medications on mortality in Streptococcus pneumoniae infections,” Postgraduate Medical Journal, vol. 88, no. 1035, pp. 21–27. View at: Google Scholar
  102. P. A. Mackowiak, M. Marling-Cason, and R. L. Cohen, “Effects of temperature on antimicrobial susceptibility of bacteria,” Journal of Infectious Diseases, vol. 145, no. 4, pp. 550–553, 1982. View at: Google Scholar
  103. P. A. Mackowiak, “Direct effects of hyperthermia on pathogenic microorganisms: teleologic implications with regard to fever,” Reviews of Infectious Diseases, vol. 3, no. 3, pp. 508–520, 1981. View at: Google Scholar
  104. C. I. Schulman, N. Namias, J. Doherty et al., “The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study,” Surgical Infections, vol. 6, no. 4, pp. 369–375, 2005. View at: Publisher Site | Google Scholar
  105. F. Schortgen, K. Clabault, S. Katsahian et al., “Fever control using external cooling in septic shock: a randomized controlled trial,” American Journal of Respiratory and Critical Care Medicine, vol. 185, no. 10, pp. 1088–1095, 2012. View at: Google Scholar
  106. Q. Jiang, A. S. Cross, I. S. Singh, T. T. Chen, R. M. Viscardi, and J. D. Hasday, “Febrile core temperature is essential for optimal host defense in bacterial peritonitis,” Infection and Immunity, vol. 68, no. 3, pp. 1265–1270, 2000. View at: Publisher Site | Google Scholar
  107. F. Su, D. N. Nam, Z. Wang, Y. Cai, P. Rogiers, and J. L. Vincent, “Fever control in septic shock: beneficial or harmful?” Shock, vol. 23, no. 6, pp. 516–520, 2005. View at: Publisher Site | Google Scholar
  108. N. Mongardon, S. Perbet, V. Lemiale et al., “Infectious complications in out-of-hospital cardiac arrest patients in the therapeutic hypothermia era,” Critical Care Medicine, vol. 39, no. 6, pp. 1359–1364, 2011. View at: Google Scholar
  109. A. Kurz, D. I. Sessler, and R. Lenhardt, “Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization,” The New England Journal of Medicine, vol. 334, no. 19, pp. 1209–1215, 1996. View at: Publisher Site | Google Scholar
  110. J. I. Suarez, R. W. Tarr, and W. R. Selman, “Aneurysmal subarachnoid hemorrhage,” The New England Journal of Medicine, vol. 354, no. 4, pp. 387–396, 2006. View at: Publisher Site | Google Scholar
  111. G. F. Prunell, T. Mathiesen, N. A. Svendgaard et al., “Experimental subarachnoid hemorrhage: cerebral blood flow and brain metabolism during the acute phase in three different models in the rat,” Neurosurgery, vol. 54, no. 2, pp. 426–437, 2004. View at: Google Scholar
  112. Y. Otawara, K. Ogasawara, Y. Kubo, N. Tomitsuka, A. Ogawa, and M. Suzuki, “Brain and systemic temperature in patients with severe subarachnoid hemorrhage,” Surgical Neurology, vol. 60, no. 2, pp. 159–164, 2003. View at: Publisher Site | Google Scholar
  113. K. E. Wartenberg, J. M. Schmidt, J. Claassen et al., “Impact of medical complications on outcome after subarachnoid hemorrhage,” Critical Care Medicine, vol. 34, no. 3, pp. 617–623, 2006. View at: Publisher Site | Google Scholar
  114. A. A. Steiner and L. G. S. Branco, “Carbon monoxide is the heme oxygenase product with a pyretic action: evidence for a cGMP signaling pathway,” American Journal of Physiology, vol. 280, no. 2, pp. R448–R457, 2001. View at: Google Scholar
  115. M. M. Kilpatrick, D. W. Lowry, A. D. Firlik, H. Yonas, and D. W. Marion, “Hyperthermia in the neurosurgical intensive care unit,” Neurosurgery, vol. 47, no. 4, pp. 850–855, 2000. View at: Google Scholar
  116. M. M. Todd, B. J. Hindman, W. R. Clarke et al., “Perioperative fever and outcome in surgical patients with aneurysmal subarachnoid hemorrhage,” Neurosurgery, vol. 64, no. 5, pp. 897–908, 2009. View at: Publisher Site | Google Scholar
  117. A. A. Rabinstein and K. Sandhu, “Non-infectious fever in the neurological intensive care unit: Incidence, causes and predictors,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 11, pp. 1278–1280, 2007. View at: Publisher Site | Google Scholar
  118. A. M. Naidech, B. R. Bendok, R. A. Bernstein et al., “Fever burden and functional recovery after subarachnoid hemorrhage,” Neurosurgery, vol. 63, no. 2, pp. 212–217, 2008. View at: Publisher Site | Google Scholar
  119. M. Oddo, S. Frangos, A. Milby et al., “Induced normothermia attenuates cerebral metabolic distress in patients with aneurysmal subarachnoid hemorrhage and refractory fever,” Stroke, vol. 40, no. 5, pp. 1913–1916, 2009. View at: Publisher Site | Google Scholar
  120. V. Scaravilli, G. Tinchero, and G. Citerio, “Fever management in SAH,” Neurocritical Care, vol. 15, no. 2, pp. 287–294, 2011. View at: Publisher Site | Google Scholar
  121. M. N. Diringer, N. L. Reaven, S. E. Funk, and G. C. Uman, “Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients,” Critical Care Medicine, vol. 32, no. 7, pp. 1489–1495, 2004. View at: Publisher Site | Google Scholar
  122. J. Oliveira-Filho, M. A. Ezzeddine, A. Z. Segal et al., “Fever in subarachnoid hemorrhage relationship to vasospasm and outcome,” Neurology, vol. 56, no. 10, pp. 1299–1304, 2001. View at: Google Scholar
  123. Y. Yoshimoto, Y. Tanaka, and K. Hoya, “Acute systemic inflammatory response syndrome in subarachnoid hemorrhage,” Stroke, vol. 32, no. 9, pp. 1989–1993, 2001. View at: Google Scholar
  124. L. R. Li, C. You, and B. Chaudhary, “Intraoperative mild hypothermia for postoperative neurological deficits in intracranial aneurysm patients,” Cochrane Database Syst Rev, vol. 2, Article ID CD008445, 2012. View at: Google Scholar
  125. E. S. Connolly Jr., A. A. Rabinstein, J. R. Carhuapoma et al., “Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association,” Stroke, vol. 43, no. 6, pp. 1711–1737, 2012. View at: Google Scholar
  126. M. M. Todd, B. J. Hindman, W. R. Clarke, and J. C. Torner, “Mild intraoperative hypothermia during surgery for intracranial aneurysm,” The New England Journal of Medicine, vol. 352, no. 2, pp. 135–145, 2005. View at: Google Scholar
  127. S. W. Anderson, M. M. Todd, B. J. Hindman et al., “Effects of intraoperative hypothermia on neuropsychological outcomes after intracranial aneurysm surgery,” Annals of Neurology, vol. 60, no. 5, pp. 518–527, 2006. View at: Publisher Site | Google Scholar
  128. S. K. Samra, B. Giordani, A. F. Caveney et al., “Recovery of cognitive function after surgery for aneurysmal subarachnoid hemorrhage,” Stroke, vol. 38, no. 6, pp. 1864–1872, 2007. View at: Publisher Site | Google Scholar
  129. S. E. Lakhan and F. Pamplona, “Application of mild therapeutic hypothermia on stroke: a systematic review and meta-analysis,” Stroke Research and Treatment, vol. 2012, Article ID 295906, 12 pages, 2012. View at: Publisher Site | Google Scholar
  130. C. Xing, K. Arai, E. H. Lo, and M. Hommel, “Pathophysiologic cascades in ischemic stroke,” International Journal of Stroke, vol. 7, no. 5, pp. 378–385, 2012. View at: Google Scholar
  131. H. B. van der Worp, E. S. Sena, G. A. Donnan, D. W. Howells, and M. R. Macleod, “Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis,” Brain, vol. 130, no. 12, pp. 3063–3074, 2007. View at: Publisher Site | Google Scholar
  132. C. Gabay and I. Kushner, “Acute-phase proteins and other systemic responses to inflammation,” The New England Journal of Medicine, no. 6, pp. 448–454, 1999. View at: Google Scholar
  133. W. Whiteley, W. L. Chong, A. Sengupta, and P. Sandercock, “Blood markers for the prognosis of ischemic stroke: a systematic review,” Stroke, vol. 40, no. 5, pp. e380–e389, 2009. View at: Publisher Site | Google Scholar
  134. W. Whiteley, C. Jackson, S. Lewis et al., “Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6,” PLoS Medicine, vol. 6, no. 9, Article ID e1000145, 2009. View at: Publisher Site | Google Scholar
  135. W. N. Whiteley, R. Thomas, G. Lowe et al., “Do acute phase markers explain body temperature and brain temperature after ischemic stroke?” Neurology, vol. 79, no. 2, pp. 152–158, 2012. View at: Google Scholar
  136. A. Faridar, E. M. Bershad, T. Emiru, P. A. Iaizzo, J. I. Suarez, and A. A. Divani, “Therapeutic hypothermia in stroke and traumatic brain injury,” Frontiers in Neurology, vol. 2, article 80, 2011. View at: Google Scholar
  137. C. M. Maier, G. H. Sun, D. Cheng, M. A. Yenari, P. H. Chan, and G. K. Steinberg, “Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia,” Neurobiology of Disease, vol. 11, no. 1, pp. 28–42, 2002. View at: Publisher Site | Google Scholar
  138. H. Zhang, C. Ren, X. Gao et al., “Hypothermia blocks β-catenin degradation after focal ischemia in rats,” Brain Research, vol. 1198, pp. 182–187, 2008. View at: Publisher Site | Google Scholar
  139. W. J. Nelson and R. Nusse, “Convergence of Wnt, β-Catenin, and Cadherin pathways,” Science, vol. 303, no. 5663, pp. 1483–1487, 2004. View at: Publisher Site | Google Scholar
  140. P. W. Huh, L. Belayev, W. Zhao, S. Koch, R. Busto, and M. D. Ginsberg, “Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia,” Journal of Neurosurgery, vol. 92, no. 1, pp. 91–99, 2000. View at: Google Scholar
  141. C. M. Maier, K. V. B. Ahern, M. L. Cheng, J. E. Lee, M. A. Yenari, and G. K. Steinberg, “Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation,” Stroke, vol. 29, no. 10, pp. 2171–2180, 1998. View at: Google Scholar
  142. T. Zgavc, A. G. Ceulemans, S. Sarre, Y. Michotte, and S. Hachimi-Idrissi, “Experimental and clinical use of therapeutic hypothermia for ischemic stroke: opportunities and limitations,” Stroke Research and Treatment, vol. 2011, Article ID 689290, 2011. View at: Google Scholar
  143. H. Ohta, Y. Terao, Y. Shintani, and Y. Kiyota, “Therapeutic time window of post-ischemic mild hypothermia and the gene expression associated with the neuroprotection in rat focal cerebral ischemia,” Neuroscience Research, vol. 57, no. 3, pp. 424–433, 2007. View at: Publisher Site | Google Scholar
  144. C. M. Maier, Guo Huan Sun, D. Kunis, M. A. Yenari, and G. K. Steinberg, “Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size,” Journal of Neurosurgery, vol. 94, no. 1, pp. 90–96, 2001. View at: Google Scholar
  145. C. Berger, F. Xia, M. Köhrmann, and S. Schwab, “Hypothermia in acute stroke-Slow versus fast rewarming. An experimental study in rats,” Experimental Neurology, vol. 204, no. 1, pp. 131–137, 2007. View at: Publisher Site | Google Scholar
  146. L. P. Kammersgaard, H. S. Jørgensen, J. A. Rungby et al., “Admission body temperature predicts long-term mortality after acute stroke: the Copenhagen Stroke Study,” Stroke, vol. 33, no. 7, pp. 1759–1762, 2002. View at: Publisher Site | Google Scholar
  147. J. Reith, H. S. Jørgensen, P. M. Pedersen et al., “Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome,” The Lancet, vol. 347, no. 8999, pp. 422–425, 1996. View at: Publisher Site | Google Scholar
  148. Y. Wang, L. L. Y. Lim, C. Levi, R. F. Heller, and J. Fisher, “Influence of admission body temperature on stroke mortality,” Stroke, vol. 31, no. 2, pp. 404–409, 2000. View at: Google Scholar
  149. R. Kollmar, P. D. Schellinger, T. Steigleder, M. Köhrmann, and S. Schwab, “Ice-cold saline for the induction of mild hypothermia in patients with acute ischemic stroke: a pilot study,” Stroke, vol. 40, no. 5, pp. 1907–1909, 2009. View at: Publisher Site | Google Scholar
  150. S. Martin-Schild, H. Hallevi, H. Shaltoni et al., “Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia,” Journal of Stroke and Cerebrovascular Diseases, vol. 18, no. 2, pp. 86–96, 2009. View at: Publisher Site | Google Scholar
  151. E. Keller, T. Steiner, J. Fandino, S. Schwab, and W. Hacke, “Changes in cerebral blood flow and oxygen metabolism during moderate hypothermia in patients with severe middle cerebral artery infarction,” Neurosurgical Focus, vol. 8, no. 5, article e4, 2000. View at: Google Scholar
  152. S. Schwab, S. Schwarz, M. Spranger, E. Keller, M. Bertram, and W. Hacke, “Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction,” Stroke, vol. 29, no. 12, pp. 2461–2466, 1998. View at: Google Scholar
  153. S. Schwab, S. Schwarz, A. Aschoff, E. Keller, and W. Hacke, “Moderate hypothermia and brain temperature in patients with severe middle cerebral artery infarction,” Acta Neurochirurgica, Supplement, vol. 1998, no. 71, pp. 131–134, 1998. View at: Google Scholar
  154. D. Georgiadis, S. Schwarz, A. Aschoff, and S. Schwab, “Hemicraniectomy and moderate hypothermia in patients with severe ischemic stroke,” Stroke, vol. 33, no. 6, pp. 1584–1588, 2002. View at: Publisher Site | Google Scholar
  155. B. J. Hindman, M. M. Todd, A. W. Gelb et al., “Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial,” Neurosurgery, vol. 44, no. 1, pp. 23–32, 1999. View at: Publisher Site | Google Scholar
  156. T. M. Hemmen, R. Raman, K. Z. Guluma et al., “Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results,” Stroke, vol. 41, no. 10, pp. 2265–2270, 2010. View at: Publisher Site | Google Scholar

Copyright

Copyright © 2012 Ségolène Mrozek et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Relation of EOG magnitude and spike suppression

We studied the relation between the EOG size and amount of spike suppression by varying the flow rate for three odorants of different physiochemical properties. Methyl benzoate is very polar and evokes large EOGs in the dorsal epithelium but only does so at high flow rates. Vinyl cyclohexane is very nonpolar and evokes much smaller dorsal EOG responses, but those responses change very little with flow rate. Isoamyl acetate evokes large dorsal EOG responses, and its flow dependency is intermediate between that of methyl benzoate and vinyl cyclohexane. Figure 10 shows examples of mean EOG and spike suppression responses to these odorants for one animal. Note that the spike suppression is detectable over much the same range as the EOG. The shape of the spike suppression waveform is not the same as the waveform of the EOG. The spike suppression waveform lags as though it is related to the EOG by at least one decay process. As noted above, the recovery of spike size is also slower than the EOG, probably because of axon fatigue.

FIG. 10.The average EOGs and corresponding spike suppression records are plotted for 3 odorants at a series flow rates from a single animal. All records have the same time base. All responses were all evoked by 1.5-s odor stimuli, indicated by the bars at the bottom of the figure. The calibration for the EOGs and spike suppression plots are shown in the top right. Significance tests for the spike suppression records were one-tailed t-tests with a criterion of P < 0.01 for the sums of the degree of suppression against the corresponding blank records.

The size of the peak EOG and spike suppression responses are compared in Fig. 11 from three experiments in which we varied the flow rates over a nominal range of 5 to 1,000 ml/min. These were three experiments for which there were strong EOG responses with a peak for isoamyl acetate at 10 −1 of 10 mV or more at a high flow rate. There is a high correlation between the EOG size and the degree of spike suppression. Because the minimum spike size is limited, the relation between the EOG peak and peak spike suppression seems to be better fit by a function of the square root of the EOG. However, both linear and curvilinear fits give correlation coefficients above 0.94 for the plot in Fig. 11, and it would take much more data to establish whether the relationship is significantly nonlinear. Because Fig. 11 is based primarily on variations in flow rate, we included some experiments where we manipulated odor concentration by altering the concentration in the odor stimulus bottles in addition to manipulating flow rate. One of these experiments is shown in Fig. 12A. Very similar curves were seen if we compared the area under the curves for EOG and spike suppression for the experiments of Figs. 11 and 12 (data not shown). In contrast to the apparent nonlinear shape of the relation between the EOG and the degree of spike suppression, the relation between the EOG peak and antidromic spike latency appears linear. One example is shown in Fig. 12B. Although the greater linearity would seem to make peak latency a better measure, latency is difficult to measure with strong stimuli because the spikes are strongly suppressed.

FIG. 11.Peak EOG and peak spike suppression from 3 experiments. The fitted line is −0.06 + 0.3 × sqrt (EOG). The correlation with the fitted line is 0.97 and the linear correlation is 0.94. The relationship seems independent of the odor.


FIG. 12.A: results from an experiment in which response size was manipulated by varying both flow rate and isoamyl acetate concentration. The result is very similar to that of Fig. 9. The fitted line is −0.09 + 0.32 × sqrt(EOG). The correlation for the fitted line is 0.95 and the linear correlation is 0.92. The nonlinearity occurs because the spike suppression ratio cannot go beyond 100%. However, some of the response did approach 100% spike suppressio. B: spike latency data from the same experiment as Fig. 10 showing that the spike latencies are also very sensitive to odor stimulation. In this case the relationship is clearly linear.


AVNRT for two

A 56 year old year old woman presents to the Emergency Department with a referral from her General Practitioner for “assessment and management of severe tachycardia and possible myocardial infarction” following a sudden onset of palpitations. Objectively she was found to have a regular tachycardia with no overt signs of cardiovascular compromise.

  • The patient described experiencing the sudden onset of palpitations whilst cleaning at 10:30am that morning. She stated that the palpitations came on without warning and had not gone away after she ceased cleaning to lie down – they were ‘regular and extremely fast’. There were no associated symptoms of shortness of breath, dizziness or chest pain. Five hours later, upon her presentation to the Emergency Department, the rapid heart rate is still continuing.
  • She describes to you a five year history of occasional episodes of suddenly increased heart rate, but in all cases, they self-resolved within one minute and she did not seek medical investigation or treatment.
  • On examination in the emergency department, her heart rate is 160bpm and regular, RR 20bpm and BP 134/75. She was apyrexial and saturating at 97% on room air. Cardiovascular and respiratory examination revealed no abnormalities aside from the tachycardia.

On the history, examination and ECG findings, the patient was diagnosed with ‘Slow-Fast AVNRT’ (Atrioventricular Nodal Reentrant Tachycardia) and successfully treated with 6mg of adenosine.

What is AVNRT?

Atrioventricular Nodal Reentrant Tachycardia is a type of supraventricular tachycardia (ie it originates above the level of the Bundle of His) and is the commonest cause of palpitations in patients with hearts exhibiting no structurally abnormality.

Clinical Features of AVNRT
  • AVNRT is typically paroxysmal and may occur spontaneously in patients or upon provocation with exertion, coffee, tea or alcohol. It is more common in women than men (
Pathophysiology and types of AVNRT
  • AVNRT is caused by a reentry circuit in or around the AV node.
  • The circuit is formed by the creation of two pathways forming the re-entrant circuit, namely the slow and fast pathways.
  • The fast pathway is usually anteriorly situated along septal portion of tricuspid annulus with the slow pathway situated posteriorly, close to the coronary sinus ostium.
  • Sustained reentry occurs over a circuit comprising the AV node, His Bundle, ventricle, accessory pathway and atrium.
  • The various forms of AVNRT can be described in terms of ECG appearance such as R-P intervals or Slow/Fast pathway dominance.
Descriptive Terminology

The ‘descriptive’ terminology regarding AVNRT classification can be confusing…and I am still confused!

Slow-Fast AVNRT (Common AVNRT)

  • Accounts for 80-90% of AVNRT
  • Associated with Slow AV nodal pathway for anterograde conduction and Fast AV nodal pathway for retrograde conduction.
  • The retrograde P wave is obscured in the corresponding QRS or occurs at the end of the QRS complex as pseudo r’ or S waves
  • ECG:
    • P waves are often hidden – being embedded in the QRS complexes.
    • Pseudo r’ wave may be seen in V1
    • Pseudo S waves may be seen in leads II, III or aVF.

    Cardiac rhythm strips demonstrating (top) sinus rhythm and (bottom) paroxysmal supraventricular tachycardia. The P wave is seen as a pseudo-R wave (circled in bottom strip) in lead V1during tachycardia. By contrast, the pseudo-R wave is not seen during sinus rhythm (it is absent from circled area in top strip). This very short ventriculoatrial time is frequently seen in typical Slow-Fast Atrioventricular Nodal Reentrant Tachycardia.

    Fast-Slow AVNRT (Uncommon AVNRT)

    • Accounts for 10% of AVNRT
    • Associated with Fast AV nodal pathway for anterograde conduction and Slow AV nodal pathway for retrograde conduction.
    • The retrograde P wave appears after the corresponding QRS
    • ECG
      • QRS -P-T complexes
      • P waves are visible between the QRS and T wave

      Slow-Slow AVNRT (AtypicalAVNRT)

      • 1-5% AVNRT
      • Associated with Slow AV nodal pathway for anterograde conduction and Slow left atrial fibres approaching the AV node as the pathway for retrograde conduction.
      • ECG: Tachaycardia with a P-wave seen in mid-diastole… effectively appearing ‘before the QRS complex’…
      • Confusing as a P wave appearing before the QRS complex in the face of a tachycardia might honestly be read as a sinus tachycardia…

      • Left Panel: Anterograde conduction from the atrium (ATR) to the ventricle (VTR) over both slow and fast pathways. The ventricle is activated initially in sinus rhythm by the fast pathway.
      • Centre Panel: The effect of a premature atrial complex (PAC). Although the fast pathway conducts rapidly, it repolarizes slowly. In this hypothetical scenario, the fast pathway is refractory to the PAC, allowing the PAC to proceed via the slow pathway, which has a shorter refractory period.
      • Right Panel: Anterograde conduction of the PAC occurs via the slow pathway, with subsequent recovery of the fast pathway. These conditions allow retrograde conduction into the atrium via the fast pathway, thereby creating the first beat of typical slow-fast atrioventricular nodal reentrant tachycardia.
      Investigations

      The ECG will typically show a tachycardia of 140-280 bpm with normal and regular QRS complexes. There will be either

      • No visible P-waves (hidden within the QRS complex) or
      • P-waves immediately before the QRS or
      • P-waves immediately after the QRS complex

      For recurrent episodes of palpitations, a Holter monitor and EPS may be useful in identifying rhythms typical of AVNRT. An echocardiogram may be useful in evaluating for structural heart disease and electrophysiological studies may be necessary if considering ablative therapy. Blood tests that may be appropriate in patients experiencing palpitations include cardiac markers (to investigate for myocardial infarction), urea and electrolytes (to identify imbalances in potassium, magnesium or calcium) or thyroid function tests (hyperthyroidism may trigger AVNRT or other arrhythmias).

      Management

      Patients may be instructed to undertake vagal manoeuvres upon the onset of symptoms which can be effective in stopping the AVNRT. This may involve carotid sinus massage or valsalva manoeuvres, which will both stimulate the vagus nerve. Alternative strategies include:


      BIO 140 - Human Biology I - Textbook

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      Chapter 32

      The Urinary System and Homeostasis

      • Describe the role of the kidneys in vitamin D activation
      • Describe the role of the kidneys in regulating erythropoiesis
      • Provide specific examples to demonstrate how the urinary system responds to maintain homeostasis in the body
      • Explain how the urinary system relates to other body systems in maintaining homeostasis
      • Predict factors or situations affecting the urinary system that could disrupt homeostasis
      • Predict the types of problems that would occur in the body if the urinary system could not maintain homeostasis

      All systems of the body are interrelated. A change in one system may affect all other systems in the body, with mild to devastating effects. A failure of urinary continence can be embarrassing and inconvenient, but is not life threatening. The loss of other urinary functions may prove fatal. A failure to synthesize vitamin D is one such example.

      Vitamin D Synthesis

      In order for vitamin D to become active, it must undergo a hydroxylation reaction in the kidney, that is, an &ndashOH group must be added to calcidiol to make calcitriol (1,25-dihydroxycholecalciferol). Activated vitamin D is important for absorption of Ca ++ in the digestive tract, its reabsorption in the kidney, and the maintenance of normal serum concentrations of Ca ++ and phosphate. Calcium is vitally important in bone health, muscle contraction, hormone secretion, and neurotransmitter release. Inadequate Ca ++ leads to disorders like osteoporosis and osteomalacia in adults and rickets in children. Deficits may also result in problems with cell proliferation, neuromuscular function, blood clotting, and the inflammatory response. Recent research has confirmed that vitamin D receptors are present in most, if not all, cells of the body, reflecting the systemic importance of vitamin D. Many scientists have suggested it be referred to as a hormone rather than a vitamin.

      Erythropoiesis

      EPO is a 193-amino acid protein that stimulates the formation of red blood cells in the bone marrow. The kidney produces 85 percent of circulating EPO the liver, the remainder. If you move to a higher altitude, the partial pressure of oxygen is lower, meaning there is less pressure to push oxygen across the alveolar membrane and into the red blood cell. One way the body compensates is to manufacture more red blood cells by increasing EPO production. If you start an aerobic exercise program, your tissues will need more oxygen to cope, and the kidney will respond with more EPO. If erythrocytes are lost due to severe or prolonged bleeding, or under produced due to disease or severe malnutrition, the kidneys come to the rescue by producing more EPO. Renal failure (loss of EPO production) is associated with anemia, which makes it difficult for the body to cope with increased oxygen demands or to supply oxygen adequately even under normal conditions. Anemia diminishes performance and can be life threatening.

      Blood Pressure Regulation

      Due to osmosis, water follows where Na + leads. Much of the water the kidneys recover from the forming urine follows the reabsorption of Na + . ADH stimulation of aquaporin channels allows for regulation of water recovery in the collecting ducts. Normally, all of the glucose is recovered, but loss of glucose control (diabetes mellitus) may result in an osmotic dieresis severe enough to produce severe dehydration and death. A loss of renal function means a loss of effective vascular volume control, leading to hypotension (low blood pressure) or hypertension (high blood pressure), which can lead to stroke, heart attack, and aneurysm formation.

      The kidneys cooperate with the lungs, liver, and adrenal cortex through the renin&ndashangiotensin&ndashaldosterone system. The liver synthesizes and secretes the inactive precursor angiotensinogen. When the blood pressure is low, the kidney synthesizes and releases renin. Renin converts angiotensinogen into angiotensin I, and ACE produced in the lung converts angiotensin I into biologically active angiotensin II (Figure 1). The immediate and short-term effect of angiotensin II is to raise blood pressure by causing widespread vasoconstriction. angiotensin II also stimulates the adrenal cortex to release the steroid hormone aldosterone, which results in renal reabsorption of Na + and its associated osmotic recovery of water. The reabsorption of Na + helps to raise and maintain blood pressure over a longer term.

      Regulation of Osmolarity

      Blood pressure and osmolarity are regulated in a similar fashion. Severe hypo-osmolarity can cause problems like lysis (rupture) of blood cells or widespread edema, which is due to a solute imbalance. Inadequate solute concentration (such as protein) in the plasma results in water moving toward an area of greater solute concentration, in this case, the interstitial space and cell cytoplasm. If the kidney glomeruli are damaged by an autoimmune illness, large quantities of protein may be lost in the urine. The resultant drop in serum osmolarity leads to widespread edema that, if severe, may lead to damaging or fatal brain swelling. Severe hypertonic conditions may arise with severe dehydration from lack of water intake, severe vomiting, or uncontrolled diarrhea. When the kidney is unable to recover sufficient water from the forming urine, the consequences may be severe (lethargy, confusion, muscle cramps, and finally, death) .

      Recovery of Electrolytes

      Sodium, calcium, and potassium must be closely regulated. The role of Na + and Ca ++ homeostasis has been discussed at length. Failure of K + regulation can have serious consequences on nerve conduction, skeletal muscle function, and most significantly, on cardiac muscle contraction and rhythm.

      PH Regulation

      Recall that enzymes lose their three-dimensional conformation and, therefore, their function if the pH is too acidic or basic. This loss of conformation may be a consequence of the breaking of hydrogen bonds. Move the pH away from the optimum for a specific enzyme and you may severely hamper its function throughout the body, including hormone binding, central nervous system signaling, or myocardial contraction. Proper kidney function is essential for pH homeostasis.

      Everyday Connection

      Stem Cells and Repair of Kidney Damage

      Stem cells are unspecialized cells that can reproduce themselves via cell division, sometimes after years of inactivity. Under certain conditions, they may differentiate into tissue-specific or organ-specific cells with special functions. In some cases, stem cells may continually divide to produce a mature cell and to replace themselves. Stem cell therapy has an enormous potential to improve the quality of life or save the lives of people suffering from debilitating or life-threatening diseases. There have been several studies in animals, but since stem cell therapy is still in its infancy, there have been limited experiments in humans.

      Acute kidney injury can be caused by a number of factors, including transplants and other surgeries. It affects 7&ndash10 percent of all hospitalized patients, resulting in the deaths of 35&ndash40 percent of inpatients. In limited studies using mesenchymal stem cells, there have been fewer instances of kidney damage after surgery, the length of hospital stays has been reduced, and there have been fewer readmissions after release.

      How do these stem cells work to protect or repair the kidney? Scientists are unsure at this point, but some evidence has shown that these stem cells release several growth factors in endocrine and paracrine ways. As further studies are conducted to assess the safety and effectiveness of stem cell therapy, we will move closer to a day when kidney injury is rare, and curative treatments are routine.

      Chapter Review

      The effects of failure of parts of the urinary system may range from inconvenient (incontinence) to fatal (loss of filtration and many others). The kidneys catalyze the final reaction in the synthesis of active vitamin D that in turn helps regulate Ca ++ . The kidney hormone EPO stimulates erythrocyte development and promotes adequate O2 transport. The kidneys help regulate blood pressure through Na + and water retention and loss. The kidneys work with the adrenal cortex, lungs, and liver in the renin&ndashangiotensin&ndashaldosterone system to regulate blood pressure. They regulate osmolarity of the blood by regulating both solutes and water. Three electrolytes are more closely regulated than others: Na + , Ca ++ , and K + . The kidneys share pH regulation with the lungs and plasma buffers, so that proteins can preserve their three-dimensional conformation and thus their function.