Editing Cushing reflex

{{Short description|Physiological nervous system response to increased intracranial pressure}}
'''Cushing reflex''' (also referred to as the '''vasopressor response''', the '''Cushing effect''', the '''Cushing reaction''', the '''Cushing phenomenon''', the '''Cushing response''', or '''Cushing's Law''') is a physiological nervous system response to increased [[intracranial pressure]] (ICP) that results in [[Cushing's triad]] of increased blood pressure, irregular breathing, and [[bradycardia]].<ref name=ayling>{{cite journal | last =Ayling | first = J| title =Managing head injuries| journal =Emergency Medical Services | volume =31 | issue = 8| pages =42 | year =2002 | pmid =12224233 }}</ref> 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.<ref name=Ogilvy>{{cite journal | last =Ogilvy | first = CS|author2=Dubois AB| title =Effect of increased intracranial pressure on blood pressure, heart rate, respiration and catecholamine levels in neonatal and adult rabbits. | journal =Biology of the Neonate | volume =52 | issue = 6| pages =327–336 | year =1987 | doi = 10.1159/000242728| pmid =3435736 }}</ref> It was first described in detail by American [[neurosurgery|neurosurgeon]] [[Harvey Cushing]] in 1901.<ref name=Cushing>{{cite journal | last =Cushing | first = H| title = Concerning a definite regulatory mechanism of the vasomotor centre which controls blood pressure during cerebral compression | journal = Bull Johns Hopkins Hosp.| volume =12 | pages =290–2 | year =1901 | url =http://babel.hathitrust.org/cgi/pt?id=coo.31924069247447;view=1up;seq=336 }}</ref>

== Definition ==
[[File:Bluthirnschranke nach Infarkt nativ und KM.png|thumb|Defect of the blood–brain barrier after stroke shown in T1-weighted MRI images. Left image without, right image with contrast medium administration showing evidence of [[brain ischemia]] ]]
The Cushing reflex classically presents as an increase in [[systole (medicine)|systolic]] and [[pulse pressure]], reduction of the [[heart rate]] ([[bradycardia]]), and irregular respiration.<ref name =Fodstad /> It is caused by increased pressure inside the skull.<ref name=Fodstad /> These symptoms can be indicative of insufficient [[blood flow]] to the brain ([[brain ischemia|ischemia]]) as well as compression of [[arterioles]].<ref name=Fodstad /><ref name= Dagal>{{cite journal | last = Dagal| first = A|author2=Lam AM| title = Cerebral blood flow and the injured brain: how should we monitor and manipulate it?| journal = Current Opinion in Anesthesiology| volume = 24| issue = 2| pages = 131–7| doi = 10.1097/ACO.0b013e3283445898| pmid =21386665 |date=April 2011 | s2cid = 6025444}}</ref>

In response to rising intracranial pressure (ICP), respiratory cycles change in regularity and rate. Different patterns indicate a different location of the brain where the injury occurred.<ref name=Grady>{{cite journal |vauthors=Grady PA, Blaumanis OR |title=Physiologic parameters of the Cushing reflex |journal=Surg Neurol |volume=29 |issue=6 |pages=454–61 |date=June 1988 |pmid=3375974 |doi= 10.1016/0090-3019(88)90140-1}}</ref> The increase in [[ventilation (physiology)|ventilation]] is exhibited as an increase in rate rather than depth of ventilation, so the Cushing reflex is often associated with slow, irregular breathing.<ref name=Dickinson /><ref name=Fox>{{cite journal |vauthors=Fox JL, Ransdell AM, Al-Mefty O, Jinkins JR |title=The Cushing reflex in the absence of intracranial hypertension |journal=Ann. Clin. Res. |volume=18 |pages=9–16 |year=1986 |issue=Suppl 47 |pmid=3813470 }}</ref> As a result of the now-defective regulation of heart rate and blood pressure, the physiologic response is decreased blood flow peripherally, which can present as [[Mayer waves]].  These are simply pathologic waves seen in HR tracings (i.e., arterial lines, electrocardiograph ([[ECG]], etc.), which reflect decreased intravascular blood flow. This decreased flow often causes reflexive [[vasoconstriction]], which leads to an overall increase in [[blood pressure]] despite the actual decrease in intravascular volume.<ref name=Dickinson />

==Differential diagnosis==
[[File:SubarachnoidP.png|thumb|Subarachnoid hemorrhage as shown on a CT scan. It is denoted by the arrow. This type of injury may result in damage to the brainstem, which could initiate or worsen the symptoms of the Cushing reflex]]
Whenever a Cushing reflex occurs, there is a high probability of death in seconds to minutes. As a result, a Cushing reflex indicates a need for immediate care. Since its presence is a good detector of high ICP, it is often useful in the medical field, particularly during surgery.<ref name="ayling"/> 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 [[hemodynamics|hemodynamic changes]] or bradycardia, the late phase of the reflex, to identify the ICP increase. Once the initial stage of the Cushing reflex (bradycardia combined with hypertension) was discovered, it offered a much more reliable and swift warning sign of high ICP.<ref name=Wan /> It was found that hypertension and bradycardia occurred 93% of the time when [[cerebral perfusion pressure]] (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 (medicine)|acute]] and [[Chronic (medicine)|chronic]] rises in ICP.<ref name=JonesJV>{{cite journal | last = Jones| first = JV| title = Differentiation and investigation of primary versus secondary hypertension (Cushing reflex)| journal = Am. J. Cardiol.| volume = 63| issue = 6| pages = 10C–13C| date = 1989-02-02| doi = 10.1016/0002-9149(89)90398-6 | pmid =2643847}}</ref>

It has also been 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]].<ref name=Wan /> Finally, the Cushing reflex may be one of many ways to identify if a patient has rejected a [[Organ transplantation|transplanted organ]]. Aside from the innate [[autoimmune]] response, ischemia in the cranial region has been detected with a transplanted organ that is being [[Transplant rejection|rejected]].<ref name=Kosieradzki>{{cite journal |last = Kosieradzki|first = M|author2=W Rowinski|title = Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention.|journal = Transplant. Proc.|volume = 40|issue = 10|pages = 3279–88|date = December 2008|doi = 10.1016/j.transproceed.2008.10.004|pmid = 19100373}}</ref> As such, the presence of a Cushing reflex due to ICP can indicate that ischemia may be occurring due to foreign organ rejection.{{cn|date=March 2021}}

As first postulated by Harvey Cushing, raised intracranial pressure is the primary cause of the Cushing reflex.<ref name="Cushing"/> 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.<ref name=Marshman>{{cite journal | last = Marshman| first = LA| title = Cushing's 'variant' response (acute hypotension) after subarachnoid hemorrhage. Association with moderate intracra- nial tension and subacute cardiovascular collapse.| journal = Stroke| volume = 28| issue = 7| pages = 1445–50| year = 1997| doi = 10.1161/01.str.28.7.1445| pmid = 9227698}}</ref> Elevated intracranial pressure can result from numerous pathways of brain impairment, including: [[subarachnoid hemorrhage]]s, ischemia, meningitis, [[Trauma (medicine)|trauma]], including [[concussion]]s, [[Hypoxia (medical)|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.<ref name=Pasztor>{{cite journal | last = Pasztor| first = E|author2=Fedina L |author3=Kocsis B | title = Activity of peripheral sympathetic efferent nerves in experimental subarachnoid haemorrhage. Part 1: Observations at the time of intracranial hypertension. | journal = Acta Neurochir | volume = 79| issue = 2–4| pages = 125–31| doi = 10.1007/bf01407456| pmid = 3962742 | year=1986| s2cid = 1449385|display-authors=etal}}</ref> In addition, during typical neurosurgical procedures on patients, especially those involving neuroendoscopic techniques, frequent washing of the [[Ventricular system|ventricles]] have been known to cause high intracranial pressure.<ref name=Dickinson /> The Cushing reflex can also result from low CPP, specifically below 15 mmHg.<ref name=Kalmar>{{cite journal | last = Kalmar| first = AF|author2=JV Aken |author3=J Caemaert | title = Value of Cushing Reflex as warning sign for brain ischemia during neuroendoscopy | journal = Br J Anaesth | volume = 94| issue = 6| pages = 791–9| year = 2005| doi = 10.1093/bja/aei121| pmid = 15805143|display-authors=etal| citeseerx = 10.1.1.507.1734}}</ref> CPP normally falls between 70-90 mmHg in an adult human, and 60-90 mmHg in children.{{cn|date=March 2021}}

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.<ref name=Wan />

==Mechanism==
The Cushing reflex is complex and seemingly paradoxical.<ref name= Beiner>{{cite journal | last = Beiner| first = JM|author2=CS Olgiyy |author3=AB DuBois | title = Cerebral blood flow changes in response to elevated intracranial pressure in rabbits and bluefish: a comparative study | journal =  Comparative Biochemistry and Physiology Part A: Physiology| volume = 116| issue = 3| pages = 245–52| doi = 10.1016/s0300-9629(96)00206-x| pmid =9102186 |date=March 1997 | doi-access = free}}</ref> The reflex begins when some event causes increased intracranial pressure (ICP). Since [[cerebrospinal fluid]] is located in an area 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 pressure|mean arterial blood pressure]] (MAP). When the ICP exceeds the MAP, [[arteriole]]s located in the brain's [[cerebrum]] become compressed. Compression then results in diminished blood supply to the brain, a condition known as cerebral [[ischemia]].<ref name=Dickinson>{{cite journal | last = Dickinson| first = CJ| title = Reappraisal of the Cushing reflex: the most powerful neural blood pressure stabilizing system | journal = Clinical Science| volume = 79| issue = 6| pages = 543–50| year = 1990| doi = 10.1042/cs0790543| pmid = 2176941}}</ref>

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.<ref name=Pasztor/> The sympathetic response activates [[alpha-1 adrenergic receptor]]s, causing constriction of the body's [[Artery|arteries]].<ref name=Woodman>{{cite journal | last = Woodman| first = OL|author2=SF Vatner| title = Coronary vasoconstriction mediated by α1- and α2-adrenoceptors in conscious dogs. | journal = Am. J. Physiol.| volume = 253| issue = 2 Pt 2| pages = H388–93| date = August 1987| doi = 10.1152/ajpheart.1987.253.2.H388| pmid =2887122}}</ref> 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 ischemic brain. The sympathetic stimulation also increases the rate of heart [[contractility|contractions]] and [[cardiac output]].<ref name=Brodal>{{cite book |author= Per Brodal| title= The Central Nervous System: Structure and Function| publisher= Oxford University Press US.| year= 2004| pages=369–396}}</ref>  Increased heart rate is also known as [[tachycardia]]. This combined with hypertension is the first stage of the Cushing reflex.{{cn|date=March 2021}}

Meanwhile, [[baroreceptor]]s in the [[aortic arch]] 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.<ref name=Hacket>{{cite journal | last = Hackett| first = J.G.|author2=F. M. Abboud |author3=A. L. Mark |author4=P. G. Schmid |author5=D. D. Heistad| title = Coronary vascular responses to stimulation of chemoreceptors and baroreceptors.| journal = Circ. Res.| volume = 31| issue = 1| pages = 8–17| doi = 10.1161/01.res.31.1.8| pmid =4402639 |date=July 1972 | doi-access = free}}</ref> Bradycardia may also be caused by increased ICP due to direct mechanical distortion of the vagus nerve and subsequent parasympathetic response.{{citation needed|date=June 2011}} Furthermore, this reflexive increase in parasympathetic activity is thought to contribute to the formation of [[Cushing ulcer]]s in the stomach, due to uncontrolled activation of the [[parietal cell]]s. The blood pressure can be expected to remain higher than the pressure of the raised cerebral spinal fluid to continue to allow blood to flow to the brain. The pressure rises to the point where it overcomes the resisting pressure of the compressed artery, and blood is allowed through, providing oxygen to the hypoxic area of the brain. If the increase in blood pressure is not sufficient to compensate for the compression on the artery, [[infarction]] occurs.<ref>{{cite book |last1=Guyton |first1=Arthur |last2=Hall |first2=John |editor1-first=Rebecca |editor1-last=Gruliow |title=Textbook of Medical Physiology |type=Book |edition=11th |year=2006 |publisher=Elsevier Inc. |location=Philadelphia, Pennsylvania |isbn=978-0-7216-0240-0 |page=213  |chapter=Chapter 18: Nervous Regulation of Circulation, and a Rapid Control of Arterial Pressure}}</ref>

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]].<ref name=Barash>{{cite book |author1=P Barash |author2=B Cullen |author3=R Storlting | title= Clinical Anesthesia|url=https://archive.org/details/clinicalanesthes00bara |url-access=registration | publisher= JB Lippincott| location= Philadelphia| year= 1992| pages=[https://archive.org/details/clinicalanesthes00bara/page/520 520]|isbn=9780397511600 }}</ref>  This is the third and final stage of the reflex.

The role of the [[central chemoreceptors]] in the Cushing reflex is unclear. In most normal pressure responses the chemoreceptors and baroreceptors work together to increase or decrease blood pressure. In the Cushing reflex, the central chemoreceptors are likely involved in the detection of ischemia, contributing to the sympathetic surge and hypertension in the first phase of the reflex, and work in opposition to the baroreceptors, contributing to the combined high sympathetic and parasympathetic activation.<ref>{{Citation|last=Hall|first=John|title=Nervous Regulation of the Circulation and Rapid Control of Arterial Pressure|date=2012|url=https://www.clinicalkey.com/#!/content/book/3-s2.0-B9781455770052000184?scrollTo=%23hl0000379|work=Guyton and Hall Textbook of Medical Physiology|pages=215–255|publisher=Elsevier|isbn=9781455770052|access-date=2019-11-10}}</ref>

===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 [[homeostasis]] 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.<ref name=Wan /> 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.<ref name=Wan>{{cite journal | last = Wan| first = WH|author2=BT Ang |author3=E Wang | title = The cushing response: A case for a review of its role as a physiological reflex.| journal = J Clin Neurosci| volume = 15| issue = 3| pages = 223–8| date = Jan 7, 2008| doi = 10.1016/j.jocn.2007.05.025| pmid = 18182296| s2cid = 43225467}}</ref> 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.<ref name=Dickinson /> This effect is protective, especially during increased intracranial pressure, which creates a drop in CPP.<ref>{{Cite journal |last1=Wittenberg |first1=Philippa |last2=McBryde |first2=Fiona D. |last3=Korsak |first3=Alla |last4=Rodrigues |first4=Karla L. |last5=Paton |first5=Julian F. R. |last6=Marina |first6=Nephtali |date=March 6, 2025 |title=On the regulation of arterial blood pressure by an intracranial baroreceptor mechanism |journal=The Journal of Physiology |doi=10.1113/JP285082 |pmid=39924875 |url=https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP285082|doi-access=free |pmc=7617620 }}</ref>

=== Cushing's triad {{anchor|Cushing's_Triad}} ===
'''Cushing's triad''' refers to when all of these symptoms are seen together:<ref>{{Cite book |last=Blumenfeld |first=Hal |title=Neuroanatomy through clinical cases |publisher=Sinauer Associates |year=2022 |isbn=978-1-60535-962-5 |edition=3rd |location=Sunderland, MA, USA |pages=143 |language=en}}</ref>
*Irregular, decreased respirations (caused by impaired brainstem function)
*Bradycardia
*Systolic hypertension (with widening pulse pressure)<ref>{{cite book|last1=Caroline|first1=Nancy|title=Emergency Care in the Streets|date=2013|publisher=Jones and Bartlett Learning|isbn=978-1-4496-4151-1|page=1665|edition=7th}}</ref>
It is associated with an increase in [[intracranial pressure]].

==History==
[[File:Harvey Cushing, Doris Ulmann 1920s.jpg|thumb|[[Harvey Cushing]], Doris Ulmann 1920s]]
Cushing's reflex is named after [[Harvey Williams Cushing]] (1869–1939), an [[United States|American]] [[neurosurgeon]]. Cushing began his research in [[Bern]], [[Switzerland]] studying abroad with [[Emil Theodor Kocher]]. A month into his trip, Cushing received a formal proposition from [[Kocher|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 [[Hugo Kronecker|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 [[Hugo Kronecker|Kroenecker]]. He continued to work on the same research project, while also simultaneously improving his methods of recording coincidence of [[blood pressure]] and [[Intracranial pressure|ICP]]. In June 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".<ref name=Cushing /> Between 1901 and 1903, Cushing published five papers pertaining to his research on the vasopressor response. These papers were published in [[German language|German]] and [[English language|English]], and one was authored by [[Kocher|Emil Theodor Kocher]].<ref name=Fodstad>{{cite journal |vauthors=Fodstad H, Kelly PJ, Buchfelder M |title=History of the cushing reflex |journal=Neurosurgery |volume=59 |issue=5 |pages=1132–7; discussion 1137 |date=November 2006 |pmid=17143247 |doi=10.1227/01.NEU.0000245582.08532.7C }}</ref>

===Experimental setup and results===
Cushing began experimenting once he obtained approval from Kocher. His experimental setup was a modified version of  [[Leonard Erskine Hill|Leonard Hill's]] model to similarly test the effects of brain pressure on sinus pressure, cerebrospinal fluid pressure, [[arterial blood pressure|arterial]] and venous blood pressure.<ref name=Fodstad /><ref name=HillL>{{cite book |author=Leonard Hill |title= Physiology and Pathology of the Cerebral Circulation. |url=https://archive.org/details/cu31924024799110 |publisher= J & A Churchill |location=London |year=1896 }}</ref>  Like Hill, Cushing used dogs for his experiments. To begin, Cushing monitored 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 [[Angelo Mosso|Mosso]], intracranial pressure was induced by injecting physiological saline into the [[subarachnoid space]] rather than increasing mercury content of an intracranial bag.<ref name=Fodstad />

This research clearly displayed the cause and effect relationship between intracranial pressure and cerebral compression.<ref name=FinkM>{{cite book |author1=Mitchell Fink |author2=Michelle Hayes |author3=Neil Soni |title= Classic Papers in Critical Care.  |publisher= Springer |location=London, England |year=2008 |pages= 89–90 }}</ref>  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.<ref name="Cushing"/> Cushing's publications contain his observations and no statistical analysis. The sample size of the experiment is also not known.<ref name="FinkM"/>

===Other researchers===
Several notable figures in the medical field, including [[Ernst von Bergmann]],<ref name=Hanigan>{{cite journal | last =Hanigan | first = WC|author2=W. Ragen |author3=M. Ludgera | title =Neurological surgery in the nineteenth century: the principles and techniques of Ernst von Bergmann.| journal =Neurosurgery | volume =30 | issue = 5| pages =750–7 | year =1992 | doi = 10.1227/00006123-199205000-00017| pmid =1584389}}</ref> [[Henri Duret]],<ref name=duret>{{cite book |author=Duret H |title=Anatomic Studies of the Cerebral Circulation |location=Paris, Bailliere|year=1878 |pages=642 }}</ref> [[Friedrich Jolly]],<ref name=JollyF>{{cite thesis |author=Friedrich Jolly |title= About Intracranial Pressure and Blood Circulation Inside the Cranium. Medical Thesis |location=Wurzburg, Germany |year=1871 }}</ref> 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.<ref name=Fodstad />

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.<ref name=FultonJF>{{cite book |author=JF Fulton |title= Harvey Cushing. A biography |url=https://archive.org/details/in.ernet.dli.2015.179766 |publisher= Charles C. Thomas |location=Springfield |year=1946 |pages=[https://archive.org/details/in.ernet.dli.2015.179766/page/n103 176]–193 }}</ref>

==Research directions==

Although a lot of progress has been made since 1901 when [[Harvey Cushing]] 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 remains undetermined.<ref name="Fox"/> 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.<ref name=Fox /> Some research observed symptoms of Cushing reflex, without the usual increased ICP and medullary [[anemia]], suggesting other causes that still require research.<ref name=Fox />  Axial [[brain stem]] distortion could be the [[pathogenesis]] of Cushing reflex.<ref name=Fox />

The nature of [[Receptor (biochemistry)|receptors]] mediating the Cushing response is also unknown.<ref name=Reis>{{cite journal |vauthors=Reis DJ, Nathan MA, Doba N |title=Two specific brainstem systems which regulate the blood pressure |journal=Clin. Exp. Pharmacol. Physiol. |volume=Suppl 2 |pages=179–83 |year=1975 |pmid=1102170 }}</ref> Some research suggests the existence of intracranial baroreceptors to trigger specific Cushing baroreceptor reflex.<ref name=Schmidt>{{cite book |vauthors=Schmidt EA, Czosnyka Z, Momjian S, Czosnyka M, Bech RA, Pickard JD |title=Intracranial Pressure and Brain Monitoring XII |chapter=Intracranial baroreflex yielding an early cushing response in human |journal=Acta Neurochir. Suppl. |volume=95 |pages=253–6 |year=2005 |pmid=16463859 |doi= 10.1007/3-211-32318-x_51|series=Acta Neurochirurgica Supplementum |isbn=978-3-211-24336-7 }}</ref> 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]].<ref name=Schmidt /> However, the specific relation between the [[autonomic nervous system]] response and the Cushing reflex and its symptoms has yet to be identified.<ref name=Schmidt />

It has been determined that rate of [[Respiration (physiology)|respiration]] is affected by the Cushing reflex, though the respiratory changes induced are still an area that needs more research.<ref name=Grady /> Some researchers have reported [[apnea]], while others have reported increased respiratory rates.<ref name=Grady /> Other researchers have found that increases in respiratory rate follow ICP decreases, while others say it is a response to ICP increase.<ref name=Grady /> One must also take into account the use of [[anesthetics]] in early experimentation.<ref name=Grady /> Research was initially performed on animals or patients under [[anesthesia]].<ref name=Dickinson /> The anesthesia used in experiments have led to respiratory depression, which might have had effect on the results.<ref name=Grady /> Early experiments also put animal subjects under artificial ventilation, only allowing for limited conclusions about respiration in the Cushing reflex.<ref name=Dickinson />  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.<ref name=Dickinson />

Some researchers have also suggested a long-term effect of the Cushing reflex.<ref name=Dickinson /> 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]].<ref name=Dickinson /> Heightened sensitivity of neurological response systems leading to arterial hypertension is also possible, but has not been examined.<ref name=Reis />

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.<ref name=Dickinson /> 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.{{cn|date=March 2021}}

==See also==
* [[Traumatic brain injury]]
* [[Bainbridge reflex]]

==References==
{{reflist|2}}
{{Nervous system symptoms and signs}}
{{Reflex}}
{{Respiratory physiology}}

{{DEFAULTSORT:Cushing Reflex}}
[[Category:Cardiovascular physiology]]
[[Category:Reflexes]]
[[Category:Medical triads]]