Cushing reflex
Encyclopedia
Cushing reflex is a physiological nervous system response to increased intracranial pressure
(ICP) that results in Cushing's triad
of widening pulse pressure
, irregular breathing, and a reduction of the heart rate
. It is usually seen in the terminal stages of acute head injury
and may indicate imminent brain herniation
. It can also be seen after the intravenous administration of epinephrine
and similar drugs. It was first described in detail by American neurosurgeon
Harvey Cushing
in 1901.
, reduction of the heart rate
(bradycardia
), and irregular respiration. It is caused by increased pressure inside the skull. These symptoms can be indicative of insufficient blood flow
to the brain (ischemia) as well as compression of arterioles.
In response to rising intracranial pressure (ICP), respiratory rate increases. The increase in ventilation
is exhibited as an increase in rate rather than depth of ventilation, so the Cushing reflex is often associated with slow, irregular breathing. Mayer waves
, which are waves in arterial blood pressure that can be seen in an electrocardiograph (ECG) register or blood pressure traces, are a symptom of a physiological response to falling blood flow. This often results in an increase in blood pressure
.
or bradycardia, the late phase of the reflex, to identify the ICP increase. Once the initial stage of the Cushing reflex (tachycardia combined with hypertension) was discovered, it offered a much more reliable and swift warning sign of high ICP. It was found that hypertension and tachycardia occurred 93% of the time when CPP dropped below 15 mmHg due to raised ICP. Also, the Cushing reflex is known to arise only from acute prolonged raises in ICP. Thus, it can be used as a tool by physicians to differentiate acute
and chronic
rises in ICP.
It has also reported that the presence of a Cushing reflex due to an ICP increase could allow one to conclude that ischemia has occurred in the posterior cranial fossa
. Finally, the Cushing reflex may be one of many ways to identify if a patient has rejected a transplanted organ. Aside from the innate autoimmune response, ischemia in the cranial region has been detected with a transplanted organ that is being rejected
. As such, the presence of a Cushing reflex due to ICP can indicate that ischemia may be occurring due to foreign organ rejection.
As first postulated by Harvey Cushing, raised intracranial pressure is the primary cause of the Cushing reflex. Furthermore, continued moderate increases in cranial pressure allows for the Cushing reflex to occur. In contrast, rapid and dramatic pressure rises do not allow for the mechanism of the reflex to sufficiently take place. Elevated intracranial pressure can result from numerous pathways of brain impairment, including: subarachnoid hemorrhages
, ischemia, trauma
, including concussions, hypoxia
, tumors, and stroke
. In one study, it was confirmed that raised ICP due to subarachnoid hemorrhaging causes mechanical distortion of the brainstem, specifically the medulla. Due to the mechanism of the Cushing reflex, brainstem distortion is then swiftly followed by sympathetic nervous system over activity. In addition, during typical neurosurgical procedures on patients, especially those involving neuroendoscopic techniques, frequent washing of the ventricles
have been known to cause high intracranial pressure. The Cushing reflex can also result from low cerebral perfusion pressure
(CPP), specifically below 15 mmHg. CPP normally falls between 70-90 mmHg in an adult human, and 60-90 mmHg in children.
Brain plateau wave changes are also associated with the Cushing reflex. These waves are characterized by acute rises of the ICP, and are accompanied by a decrease of the cerebral perfusion pressure. It has been found that if a Cushing reflex occurs, brain plateau wave changes can be erased due to disappearance of high ICP.
is located in an area which is surrounded by the skull, increased ICP consequently increases the pressure in the fluid itself. The pressure in the cerebral spinal fluid eventually rises to the point that it meets and gradually exceeds the mean arterial blood pressure
(MABP or MAP). When the ICP exceeds the MABP, arterioles
located in the brain's cerebrum become compressed. Compression then results in diminished blood supply to the brain, a condition known as cerebral ischemia
.
During the increase in ICP, both the sympathetic nervous system
and the parasympathetic nervous system
are activated. In the first stage of the reflex, sympathetic nervous system stimulation is much greater than parasympathetic stimulation.
The sympathetic response activates alpha-1 adrenergic receptors
, causing constriction of the body's arteries
. This constriction raises the total resistance of blood flow, elevating blood pressure to high levels, which is known as hypertension
. The body's induced hypertension is an attempt to restore blood flow to the damaged, ischemic brain. The sympathetic stimulation also increases the rate of heart contractions
and cardiac output
. Increased heart rate is also known as tachycardia
. This combined with hypertension is the first stage of the Cushing reflex.
Meanwhile, baroreceptors
in the carotid arteries
detect the increase in blood pressure and trigger a parasympathetic response via the vagus nerve
. This induces bradycardia, or slowed heart rate, and signifies the second stage of the reflex. Bradycardia may also be caused by increased ICP due to direct mechanical distortion of the vagus nerve. Mechanical distortion of the vagus nerve stimulates a parasympathetic response, which can in turn induce bradycardia. The blood pressure can be expected to stay higher than the pressure of the raised cerebral spinal fluid to continue to allow blood to flow to the brain. Similar to Korotkoff sounds
, the pressure will rise to the point where the artery which is compressed is pressurized such that the blood can provide oxygen to the hypoxic area of the brain by overcoming the resisting pressure. If the body is unable to compensate for the pressure on the artery, infarction
will occur.
Raised ICP, tachycardia, or some other endogenous stimulus can result in distortion and/or increased pressure on the brainstem. Since the brainstem controls involuntary breathing, changes in its homeostasis often results in irregular respiratory pattern and/or apnea
. This is the third and final stage of the reflex.
Commonly, in various pressor reflexes, the central chemoreceptors, which transform chemical signals into an action potentials, and the baroreceptors, which sense pressure changes, of the carotid sinuses
work together to increase or decrease blood pressure. However, chemoreceptors do not play a role in the Cushing reflex. Thus, even in the presence of sympathetic stimulation from the brain, which would normally produce tachycardia, there is in fact bradycardia.
in the brain
. It is widely accepted that the Cushing reflex acts as a baroreflex
, or homeostatic mechanism for the maintenance of blood pressure, in the cranial region. Specifically, the reflex mechanism can maintain normal cerebral blood flow and pressure under stressful situations such as ischemia or subarachnoid hemorrhages. A case report of a patient who underwent a spontaneous subarachnoid hemorrhage demonstrated that the Cushing reflex played a part in maintaining cerebral perfusion pressure (CPP) and cerebral blood flow. Eventually, the ICP drops to a level range where a state of induced hypertension in the form of the Cushing reflex is no longer required. The Cushing reflex was then aborted, and CPP was maintained. It has also been shown that an increase in mean arterial pressure due to hypertension, characteristic of the reflex, can cause the normalization of CPP. This effect is protective, especially during increased intracranial pressure, which creates a drop in CPP.
studying abroad with Emil Theodor Kocher
. A month into his trip, Cushing received a formal proposition from Emil Theodor Kocher
to begin testing how compression of the brain affected blood vessels. Cushing also enlisted the aid of Hugo Kronecker
, a known blood pressure researcher. Utilizing Kroenecker's
assistance and resources, Cushing began his research. Cushing left Bern in 1901 to work in Turin
, Italy
with Angelo Mosso
, a previous student of Kroenecker
. He continued to work on the same research project, while also simultaneously improving his methods of recording coincidence of blood pressure
and ICP
. In June of 1901 Cushing published his first paper through Johns Hopkins Hospital Bulletin entitled "Concerning a definite regulatory mechanism of the vasomotor centre which controls blood pressure during cerebral compression". Between 1901 and 1903, Cushing published five papers pertaining to his research on the vasopressor response. These papers were published in German
and English
, and one was authored by Emil Theodor Kocher
.
model to similarly test the effects of brain pressure on sinus pressure, cerebrospinal fluid pressure, arterial and venous blood pressure. Like Hill, Cushing used dogs for his experiments. To begin, Cushing monitorred the caliber and color of cortical vessels by fitting a glass window into the skull of the dog. Intracranial pressure was raised by filling an intracranial, soft, rubber bag with mercury. Cushing recorded the intracranial pressure along with blood pressure
, pulse rate, and respiratory rate
simultaneously. This three part effect is commonly referred to as Cushing's triad
. In later experiments performed by Mosso
, intrcranial pressure was induced by injecting physiological saline into the subarachnoid space
rather than increasing mercury content of an intracranial bag.
This research clearly displayed the cause and effect relationship between intracranial pressure and cerebral compression. Cushing noted this relationship in his subsequent publications. He also noted that there must exist a specific regulatory mechanism that increased blood pressure to a high enough point such that it did not create anemic conditions. Cushing's publications contain his observations and no statistical analysis. The sample size of the experiment is also not known.
, Henri Duret
, Friedrich Jolly
, and others experimented with intracranial pressure similarly to Cushing. Some of these researchers published similar findings concerning the relationship of intracranial pressure to arterial blood pressure before Cushing had begun experimenting. Cushing studied this relationship more carefully and offered an improved explanation of the relationship.
Some controversy concerning plagiarism does surround some of Cushing's research. Bernhard Naunyn
, a German pathologist and contemporary of Cushing, made remarks claiming that Cushing neither cited him in Cushing's research nor expanded on any of the results that he had found in his original experiments.
first expanded knowledge of what is now known as the Cushing reflex, there are still many aspects of the research that remain to be seen. The exact pathogenesis
of the disease has yet to be determined. The possibility that intracranial pressure (ICP) may not be the sole cause of the Cushing reflex per se came from an occurrence of Cushing blood pressure
response occurring before increased ICP. Some research observed symptoms of Cushing reflex, without the usual increased ICP and medullary anemia
, suggesting other causes that still require research. Axial brain stem
distortion could be the pathogenesis
of Cushing reflex.
The nature of receptors mediating the Cushing response is also unknown. Some research suggests the existence of intracranial baroreceptors to trigger specific Cushing baroreceptor reflex. Experiments by Schmidt and his fellow researchers showed that the Cushing reflex is directed by autonomic nervous system
, since its physiological change has to do with the balance of the sympathetic nervous system
and parasympathetic nervous system
. However, the specific relation between the autonomic nervous system
response and the Cushing reflex and its symptoms has yet to be identified.
It has been determined that rate of respiration
is affected by the Cushing reflex, though the respiratory changes induced are still an area which can use more research. Some researchers have reported apnea
, while others have reported increased respiratory rates. Other researchers have found that increases in respiratory rate follow ICP decreases, while others say it is a response to ICP increase. One must also take into account the use of anesthetics in early experimentation. Research was initially performed on animals or patients under anesthesia
. The anesthesia used in experiments have led to respiratory depression, which might have had effect on the results. Early experiments also put animal subjects under artificial ventilation, only allowing for limited conclusions about respiration in the Cushing reflex. The use of anesthetics proposes ideas for future research, since the creation of the Cushing response has been difficult to create under basal conditions or without anesthesia.
Some researchers have also suggested a long-term effect of the Cushing reflex. Thus far it has only been observed as an immediate acute response, but there has been some evidence to suggest that its effects could be prolonged, such as a long-term raise in blood pressure
. Heightened sensitivity of neurological response systems leading to arterial hypertension is also possible, but has not been examined.
Although the Cushing reflex was primarily identified as a physiological response when blood flow has almost ceased, its activity has also been seen in fetal life. This activity has not been thoroughly investigated, so there is a need for more research in this area.
The underlying mechanisms of the reflex on a cellular level are yet to be discovered, and will likely be the next area of research if scientists and/or doctors chose to do so.
Intracranial pressure
Intracranial pressure is the pressure inside the skull and thus in the brain tissue and cerebrospinal fluid . The body has various mechanisms by which it keeps the ICP stable, with CSF pressures varying by about 1 mmHg in normal adults through shifts in production and absorption of CSF...
(ICP) that results in Cushing's triad
Cushing's triad
Cushing's triad is a clinical triad variably defined as either hypertension, bradycardia, andirregular respiration , or less commonly as widened pulse pressure , irregular respiration, and bradycardia...
of widening pulse pressure
Pulse pressure
Pulse Pressure is most easily defined as being the amount of pressure required to create the feeling of a pulse. Measured in millimeters of mercury , the pressure difference between the systolic and diastolic pressures give you the amount of pressure change to create the pulse, which is the pulse...
, irregular breathing, and a reduction of the heart rate
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
. It is usually seen in the terminal stages of acute head injury
Head injury
Head injury refers to trauma of the head. This may or may not include injury to the brain. However, the terms traumatic brain injury and head injury are often used interchangeably in medical literature....
and may indicate imminent brain herniation
Brain herniation
Brain herniation, also known as cistern obliteration, is a deadly side effect of very high intracranial pressure that occurs when the brain shifts across structures within the skull...
. It can also be seen after the intravenous administration of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
and similar drugs. It was first described in detail by American neurosurgeon
Neurosurgery
Neurosurgery is the medical specialty concerned with the prevention, diagnosis, treatment, and rehabilitation of disorders which affect any portion of the nervous system including the brain, spine, spinal cord, peripheral nerves, and extra-cranial cerebrovascular system.-In the United States:In...
Harvey Cushing
Harvey Cushing
Harvey Williams Cushing, M.D. , was an American neurosurgeon and a pioneer of brain surgery, and the first to describe Cushing's syndrome...
in 1901.
Definition
The Cushing reflex classical presents as an increase in systolic and pulse pressurePulse pressure
Pulse Pressure is most easily defined as being the amount of pressure required to create the feeling of a pulse. Measured in millimeters of mercury , the pressure difference between the systolic and diastolic pressures give you the amount of pressure change to create the pulse, which is the pulse...
, reduction of the heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
(bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
), and irregular respiration. It is caused by increased pressure inside the skull. These symptoms can be indicative of insufficient blood flow
Blood flow
Blood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
to the brain (ischemia) as well as compression of arterioles.
In response to rising intracranial pressure (ICP), respiratory rate increases. The increase in ventilation
Ventilation (physiology)
In respiratory physiology, ventilation is the rate at which gas enters or leaves the lung. It is categorized under the following definitions:-Sample values:...
is exhibited as an increase in rate rather than depth of ventilation, so the Cushing reflex is often associated with slow, irregular breathing. Mayer waves
Mayer waves
Mayer waves are waves in arterial blood pressure brought about by oscillations in baroreceptor and chemoreceptor reflex control systems. The waves are seen both in the ECG and in blood pressure curves and have a frequency about 0.1 Hz...
, which are waves in arterial blood pressure that can be seen in an electrocardiograph (ECG) register or blood pressure traces, are a symptom of a physiological response to falling blood flow. This often results in an increase in blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
.
Differential diagnosis
Whenever a Cushing reflex occurs, there is a high probability that death will occur in the near future (seconds to minutes). As a result, when a Cushing reflex is detected, immediate care is needed. Since its presence is a good detector of high ICP, it is often useful in the medical field, particularly during surgery. During any neurosurgery being performed on the brain, there is always a likelihood that raised intracranial pressure may occur. Early recognition of this is crucial to the well being of the patient. Although direct measurement of ICP is possible, it is not always accurate. In the past, physicians and nurses have relied on hemodynamic changesHemodynamics
Hemodynamics, meaning literally "blood movement" is the study of blood flow or the circulation.All animal cells require oxygen for the conversion of carbohydrates, fats and proteins into carbon dioxide , water and energy in a process known as aerobic respiration...
or bradycardia, the late phase of the reflex, to identify the ICP increase. Once the initial stage of the Cushing reflex (tachycardia combined with hypertension) was discovered, it offered a much more reliable and swift warning sign of high ICP. It was found that hypertension and tachycardia occurred 93% of the time when CPP dropped below 15 mmHg due to raised ICP. Also, the Cushing reflex is known to arise only from acute prolonged raises in ICP. Thus, it can be used as a tool by physicians to differentiate acute
Acute
Acute may refer to:* Acute accent* Acute angle* Acute * Acute * Acute toxicity...
and chronic
Chronic
Chronic may refer to:* Chronic , a disease that is long-lasting and reoccurring.* Chronic toxicity, a substance with toxic effects after continuous or repeated exposure* The Chronic, a 1992 album by Dr. Dre...
rises in ICP.
It has also reported that the presence of a Cushing reflex due to an ICP increase could allow one to conclude that ischemia has occurred in the posterior cranial fossa
Posterior cranial fossa
The posterior cranial fossa is part of the intracranial cavity, located between the foramen magnum and tentorium cerebelli. It contains the brainstem and cerebellum.This is the most inferior of the fossae. It houses the cerebellum, medulla and pons....
. Finally, the Cushing reflex may be one of many ways to identify if a patient has rejected a transplanted organ. Aside from the innate autoimmune response, ischemia in the cranial region has been detected with a transplanted organ that is being rejected
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. As such, the presence of a Cushing reflex due to ICP can indicate that ischemia may be occurring due to foreign organ rejection.
As first postulated by Harvey Cushing, raised intracranial pressure is the primary cause of the Cushing reflex. Furthermore, continued moderate increases in cranial pressure allows for the Cushing reflex to occur. In contrast, rapid and dramatic pressure rises do not allow for the mechanism of the reflex to sufficiently take place. Elevated intracranial pressure can result from numerous pathways of brain impairment, including: subarachnoid hemorrhages
Subarachnoid hemorrhage
A subarachnoid hemorrhage , or subarachnoid haemorrhage in British English, is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain...
, ischemia, trauma
Trauma (medicine)
Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...
, including concussions, hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, tumors, and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. In one study, it was confirmed that raised ICP due to subarachnoid hemorrhaging causes mechanical distortion of the brainstem, specifically the medulla. Due to the mechanism of the Cushing reflex, brainstem distortion is then swiftly followed by sympathetic nervous system over activity. In addition, during typical neurosurgical procedures on patients, especially those involving neuroendoscopic techniques, frequent washing of the ventricles
Ventricular system
The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is continuous with the central canal of the spinal cord.-Components:The system comprises four ventricles:* right and left lateral ventricles* third ventricle...
have been known to cause high intracranial pressure. The Cushing reflex can also result from low cerebral perfusion pressure
Cerebral perfusion pressure
Cerebral perfusion pressure, or CPP, is the net pressure gradient causing blood flow to the brain . It must be maintained within narrow limits because too little pressure could cause brain tissue to become ischemic , and too much could raise intracranial pressure .-From resistance:CPP can be...
(CPP), specifically below 15 mmHg. CPP normally falls between 70-90 mmHg in an adult human, and 60-90 mmHg in children.
Brain plateau wave changes are also associated with the Cushing reflex. These waves are characterized by acute rises of the ICP, and are accompanied by a decrease of the cerebral perfusion pressure. It has been found that if a Cushing reflex occurs, brain plateau wave changes can be erased due to disappearance of high ICP.
Mechanism
The Cushing reflex is complex and seemingly paradoxical. The reflex begins when some event causes increased intracranial pressure (ICP). Since cerebrospinal fluidCerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
is located in an area which is surrounded by the skull, increased ICP consequently increases the pressure in the fluid itself. The pressure in the cerebral spinal fluid eventually rises to the point that it meets and gradually exceeds the mean arterial blood pressure
Mean arterial pressure
The mean arterial pressure is a term used in medicine to describe an average blood pressure in an individual. It is defined as the average arterial pressure during a single cardiac cycle.-Calculation:...
(MABP or MAP). When the ICP exceeds the MABP, arterioles
Arteriole
An arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.Arterioles have muscular walls and are the primary site of vascular resistance...
located in the brain's cerebrum become compressed. Compression then results in diminished blood supply to the brain, a condition known as cerebral ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
.
During the increase in ICP, both the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
and the parasympathetic nervous system
Parasympathetic nervous system
The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system . The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously...
are activated. In the first stage of the reflex, sympathetic nervous system stimulation is much greater than parasympathetic stimulation.
The sympathetic response activates alpha-1 adrenergic receptors
Alpha-1 adrenergic receptor
The alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
, causing constriction of the body's arteries
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
. This constriction raises the total resistance of blood flow, elevating blood pressure to high levels, which is known as hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
. The body's induced hypertension is an attempt to restore blood flow to the damaged, ischemic brain. The sympathetic stimulation also increases the rate of heart contractions
Contractility
Myocardial contractility is the intrinsic ability of the heart to contract independent of preload and afterload. Changes in the ability to produce force during contraction result from different degrees of binding between myosin and actin filaments...
and cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
. Increased heart rate is also known as tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
. This combined with hypertension is the first stage of the Cushing reflex.
Meanwhile, baroreceptors
Baroreceptor
Baroreceptors are sensors located in the blood vessels of several mammals. They are a type of mechanoreceptor that detects the pressure of blood flowing through them, and can send messages to the central nervous system to increase or decrease total peripheral resistance and cardiac output...
in the carotid arteries
Common carotid artery
In human anatomy, the common carotid artery is an artery that supplies the head and neck with oxygenated blood; it divides in the neck to form the external and internal carotid arteries. - Structure :...
detect the increase in blood pressure and trigger a parasympathetic response via the vagus nerve
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
. This induces bradycardia, or slowed heart rate, and signifies the second stage of the reflex. Bradycardia may also be caused by increased ICP due to direct mechanical distortion of the vagus nerve. Mechanical distortion of the vagus nerve stimulates a parasympathetic response, which can in turn induce bradycardia. The blood pressure can be expected to stay higher than the pressure of the raised cerebral spinal fluid to continue to allow blood to flow to the brain. Similar to Korotkoff sounds
Korotkoff sounds
Korotkoff are the sounds that medical personnel listen for when they are taking blood pressure using a non-invasive procedure. They are named after Dr. Nikolai Korotkoff, a Russian physician who described them in 1905, when he was working at the Imperial Medical Academy in St...
, the pressure will rise to the point where the artery which is compressed is pressurized such that the blood can provide oxygen to the hypoxic area of the brain by overcoming the resisting pressure. If the body is unable to compensate for the pressure on the artery, infarction
Infarction
In medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...
will occur.
Raised ICP, tachycardia, or some other endogenous stimulus can result in distortion and/or increased pressure on the brainstem. Since the brainstem controls involuntary breathing, changes in its homeostasis often results in irregular respiratory pattern and/or apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
. This is the third and final stage of the reflex.
Commonly, in various pressor reflexes, the central chemoreceptors, which transform chemical signals into an action potentials, and the baroreceptors, which sense pressure changes, of the carotid sinuses
Carotid sinus
In human anatomy, the carotid sinus is a localized dilation of the internal carotid artery at its origin, the common carotid artery.-Functions:...
work together to increase or decrease blood pressure. However, chemoreceptors do not play a role in the Cushing reflex. Thus, even in the presence of sympathetic stimulation from the brain, which would normally produce tachycardia, there is in fact bradycardia.
Function
Raised intracranial pressure can ultimately result in the shifting or crushing of brain tissue, which is detrimental to the physiological well being of patients. As a result, the Cushing reflex is a last ditch effort by the body to maintain homeostasisHomeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. It is widely accepted that the Cushing reflex acts as a baroreflex
Baroreflex
The baroreflex or baroreceptor reflex is one of the body's homeostatic mechanisms for maintaining blood pressure. It provides a negative feedback loop in which an elevated blood pressure reflexively causes heart rate to decrease therefore causing blood pressure to decrease; likewise, decreased...
, or homeostatic mechanism for the maintenance of blood pressure, in the cranial region. Specifically, the reflex mechanism can maintain normal cerebral blood flow and pressure under stressful situations such as ischemia or subarachnoid hemorrhages. A case report of a patient who underwent a spontaneous subarachnoid hemorrhage demonstrated that the Cushing reflex played a part in maintaining cerebral perfusion pressure (CPP) and cerebral blood flow. Eventually, the ICP drops to a level range where a state of induced hypertension in the form of the Cushing reflex is no longer required. The Cushing reflex was then aborted, and CPP was maintained. It has also been shown that an increase in mean arterial pressure due to hypertension, characteristic of the reflex, can cause the normalization of CPP. This effect is protective, especially during increased intracranial pressure, which creates a drop in CPP.
History
Cushing began his research in Bern, SwitzerlandSwitzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....
studying abroad with Emil Theodor Kocher
Emil Theodor Kocher
Emil Theodor Kocher was a Swiss physician, medical researcher, and Nobel laureate for his work in the physiology, pathology and surgery of the thyroid....
. A month into his trip, Cushing received a formal proposition from Emil Theodor Kocher
Kocher
The Kocher is a 168 km long right tributary of the Neckar in the north-eastern part of Baden-Württemberg, Germany. The name "Kocher" originates from its Celtic name "cochan" and probably means winding, meandering river. The Kocher rises in the eastern foothills of the Swabian Alb from two karst...
to begin testing how compression of the brain affected blood vessels. Cushing also enlisted the aid of Hugo Kronecker
Hugo Kronecker
Karl Hugo Kronecker was a German physiologist from Liegnitz, Prussian Silesia. He was the brother of Leopold Kronecker....
, a known blood pressure researcher. Utilizing Kroenecker's
Hugo Kronecker
Karl Hugo Kronecker was a German physiologist from Liegnitz, Prussian Silesia. He was the brother of Leopold Kronecker....
assistance and resources, Cushing began his research. Cushing left Bern in 1901 to work in Turin
Turin
Turin is a city and major business and cultural centre in northern Italy, capital of the Piedmont region, located mainly on the left bank of the Po River and surrounded by the Alpine arch. The population of the city proper is 909,193 while the population of the urban area is estimated by Eurostat...
, Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
with Angelo Mosso
Angelo Mosso
Angelo Mosso , 19th century Italian physiologist, who created the first crude neuroimaging technique by recording the pulsation of the human cortex in patients with skull defects following neurosurgical procedures...
, a previous student of Kroenecker
Hugo Kronecker
Karl Hugo Kronecker was a German physiologist from Liegnitz, Prussian Silesia. He was the brother of Leopold Kronecker....
. He continued to work on the same research project, while also simultaneously improving his methods of recording coincidence of blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
and ICP
ICP
-Business:* International Comfort Products Corporation, a company that manufactures and markets central air conditioning systems, gas and oil furnaces* Indonesian Crude Price...
. In June of 1901 Cushing published his first paper through Johns Hopkins Hospital Bulletin entitled "Concerning a definite regulatory mechanism of the vasomotor centre which controls blood pressure during cerebral compression". Between 1901 and 1903, Cushing published five papers pertaining to his research on the vasopressor response. These papers were published in German
German language
German is a West Germanic language, related to and classified alongside English and Dutch. With an estimated 90 – 98 million native speakers, German is one of the world's major languages and is the most widely-spoken first language in the European Union....
and English
English language
English is a West Germanic language that arose in the Anglo-Saxon kingdoms of England and spread into what was to become south-east Scotland under the influence of the Anglian medieval kingdom of Northumbria...
, and one was authored by Emil Theodor Kocher
Kocher
The Kocher is a 168 km long right tributary of the Neckar in the north-eastern part of Baden-Württemberg, Germany. The name "Kocher" originates from its Celtic name "cochan" and probably means winding, meandering river. The Kocher rises in the eastern foothills of the Swabian Alb from two karst...
.
Experimental setup and results
Cushing began experimenting once he obtained approval from Kocher. His experimental setup was a modified version of Leonard Hill'sLeonard Erskine Hill
Sir Leonard Erskine Hill was a British physiologist. He was elected a Fellow of the Royal Society in 1900 and was knighted in 1930. One of his sons was the epidemiologist and statistician Austin Bradford Hill...
model to similarly test the effects of brain pressure on sinus pressure, cerebrospinal fluid pressure, arterial and venous blood pressure. Like Hill, Cushing used dogs for his experiments. To begin, Cushing monitorred the caliber and color of cortical vessels by fitting a glass window into the skull of the dog. Intracranial pressure was raised by filling an intracranial, soft, rubber bag with mercury. Cushing recorded the intracranial pressure along with blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
, pulse rate, and respiratory rate
Respiratory rate
Respiratory rate is also known by respiration rate, pulmonary ventilation rate, ventilation rate, or breathing frequency is the number of breaths taken within a set amount of time, typically 60 seconds....
simultaneously. This three part effect is commonly referred to as Cushing's triad
Cushing's triad
Cushing's triad is a clinical triad variably defined as either hypertension, bradycardia, andirregular respiration , or less commonly as widened pulse pressure , irregular respiration, and bradycardia...
. In later experiments performed by Mosso
Angelo Mosso
Angelo Mosso , 19th century Italian physiologist, who created the first crude neuroimaging technique by recording the pulsation of the human cortex in patients with skull defects following neurosurgical procedures...
, intrcranial pressure was induced by injecting physiological saline into the subarachnoid space
Subarachnoid space
In the central nervous system, the subarachnoid cavity is the interval between the arachnoid membrane and pia mater....
rather than increasing mercury content of an intracranial bag.
This research clearly displayed the cause and effect relationship between intracranial pressure and cerebral compression. Cushing noted this relationship in his subsequent publications. He also noted that there must exist a specific regulatory mechanism that increased blood pressure to a high enough point such that it did not create anemic conditions. Cushing's publications contain his observations and no statistical analysis. The sample size of the experiment is also not known.
Other researchers
Several notable figures in the medical field, including Ernst von BergmannErnst von Bergmann
Ernst von Bergmann was a Baltic German surgeon. He is the beginner of aseptic surgery.Born in Riga, Livonia , in 1860 he earned his doctorate at the University of Dorpat, and later returned to Dorpat in 1871, where he was a professor of surgery until 1878...
, Henri Duret
Henri Duret
Henri Duret was a French neurologist whose contributions to the knowledge of cerebral circulation and the physiology of the brainstem were important for the early years of brain surgery. For thirty years he was associated with Faculté Libre de Médecine in Lille, France, and became dean of the...
, Friedrich Jolly
Friedrich Jolly
Friedrich Jolly was a German neurologist and psychiatrist who was a native of Heidelberg, and the son of physicist Philipp von Jolly ....
, and others experimented with intracranial pressure similarly to Cushing. Some of these researchers published similar findings concerning the relationship of intracranial pressure to arterial blood pressure before Cushing had begun experimenting. Cushing studied this relationship more carefully and offered an improved explanation of the relationship.
Some controversy concerning plagiarism does surround some of Cushing's research. Bernhard Naunyn
Bernhard Naunyn
Bernhard Naunyn was German pathologist who was born in Berlin. After receiving his degree at the University of Berlin in 1863, he became an assistant to pathologist Friedrich Theodor von Frerichs...
, a German pathologist and contemporary of Cushing, made remarks claiming that Cushing neither cited him in Cushing's research nor expanded on any of the results that he had found in his original experiments.
Research directions
Although a lot of progress has been made since 1901 when Harvey CushingHarvey Cushing
Harvey Williams Cushing, M.D. , was an American neurosurgeon and a pioneer of brain surgery, and the first to describe Cushing's syndrome...
first expanded knowledge of what is now known as the Cushing reflex, there are still many aspects of the research that remain to be seen. The exact pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of the disease has yet to be determined. The possibility that intracranial pressure (ICP) may not be the sole cause of the Cushing reflex per se came from an occurrence of Cushing blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
response occurring before increased ICP. Some research observed symptoms of Cushing reflex, without the usual increased ICP and medullary anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, suggesting other causes that still require research. Axial brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
distortion could be the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of Cushing reflex.
The nature of receptors mediating the Cushing response is also unknown. Some research suggests the existence of intracranial baroreceptors to trigger specific Cushing baroreceptor reflex. Experiments by Schmidt and his fellow researchers showed that the Cushing reflex is directed by autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
, since its physiological change has to do with the balance of the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
and parasympathetic nervous system
Parasympathetic nervous system
The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system . The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously...
. However, the specific relation between the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
response and the Cushing reflex and its symptoms has yet to be identified.
It has been determined that rate of respiration
Respiration (physiology)
'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...
is affected by the Cushing reflex, though the respiratory changes induced are still an area which can use more research. Some researchers have reported apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
, while others have reported increased respiratory rates. Other researchers have found that increases in respiratory rate follow ICP decreases, while others say it is a response to ICP increase. One must also take into account the use of anesthetics in early experimentation. Research was initially performed on animals or patients under anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
. The anesthesia used in experiments have led to respiratory depression, which might have had effect on the results. Early experiments also put animal subjects under artificial ventilation, only allowing for limited conclusions about respiration in the Cushing reflex. The use of anesthetics proposes ideas for future research, since the creation of the Cushing response has been difficult to create under basal conditions or without anesthesia.
Some researchers have also suggested a long-term effect of the Cushing reflex. Thus far it has only been observed as an immediate acute response, but there has been some evidence to suggest that its effects could be prolonged, such as a long-term raise in blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
. Heightened sensitivity of neurological response systems leading to arterial hypertension is also possible, but has not been examined.
Although the Cushing reflex was primarily identified as a physiological response when blood flow has almost ceased, its activity has also been seen in fetal life. This activity has not been thoroughly investigated, so there is a need for more research in this area.
The underlying mechanisms of the reflex on a cellular level are yet to be discovered, and will likely be the next area of research if scientists and/or doctors chose to do so.