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In a 71 year old male case study, it was concluded that the physiological conditions brought on by ischemia alone caused a Cushing reflex response. <ref name=Nielsen>{{cite journal | last = Nielsen| first = EW| authorlink = | coauthors = Alstadhaug KB, Hugaas KA, et al| title = A 71-year-old man with Cushing reflex.| journal = Tidsskr Nor Laegeforen| volume = 124| issue = 7| pages = 943-5| publisher = | date = 2004 Apr 1| url = | doi = | pmid = 15088604}}</ref> Induced subarachnoid hemorrhage studies on cats via injection of autologous blood into the cisterna magna of the brain confirmed that ICP causes mechanical distortion of bulbar sensors in the medulla.<ref name=Kosieradzki>{{cite journal | last = Kosieradzki| first = M| authorlink = | coauthors = W Rowinski| title = Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention.| journal = Transplant. Proc.| volume = 40| issue = 10| pages = 3279-88| publisher = | date = 2008 Dec| url = | doi = | pmid = 19100373}}</ref><ref name=Woodman>{{cite journal | last = Woodman| first = OL| authorlink = | coauthors = 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| publisher = | date = 1987 Aug| url = | doi = | pmid =2887122}}</ref> This was then followed by sympathetic nervous system over activity, characteristic of the reflex (2).
In a 71 year old male case study, it was concluded that the physiological conditions brought on by ischemia alone caused a Cushing reflex response. <ref name=Nielsen>{{cite journal | last = Nielsen| first = EW| authorlink = | coauthors = Alstadhaug KB, Hugaas KA, et al| title = A 71-year-old man with Cushing reflex.| journal = Tidsskr Nor Laegeforen| volume = 124| issue = 7| pages = 943-5| publisher = | date = 2004 Apr 1| url = | doi = | pmid = 15088604}}</ref> Induced subarachnoid hemorrhage studies on cats via injection of autologous blood into the cisterna magna of the brain confirmed that ICP causes mechanical distortion of bulbar sensors in the medulla.<ref name=Kosieradzki>{{cite journal | last = Kosieradzki| first = M| authorlink = | coauthors = W Rowinski| title = Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention.| journal = Transplant. Proc.| volume = 40| issue = 10| pages = 3279-88| publisher = | date = 2008 Dec| url = | doi = | pmid = 19100373}}</ref><ref name=Woodman>{{cite journal | last = Woodman| first = OL| authorlink = | coauthors = 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| publisher = | date = 1987 Aug| url = | doi = | pmid =2887122}}</ref> This was then followed by sympathetic nervous system over activity, characteristic of the reflex (2).

==Signs and Symptoms==

The Cushing reflex is characterized by increased intracranial pressure. <ref name=Fodstad>{{cite journal |author=Fodstad H, Kelly PJ, Buchfelder M |title=History of the cushing reflex |journal=Neurosurgery |volume=59 |issue=5 |pages=1132–7; discussion 1137 |year=2006 |month=November |pmid=17143247 |doi=10.1227/01.NEU.0000245582.08532.7C |url=}}</ref>. Its classical symptoms are an increase in [[systolic]] and [[pulse pressure]], [[bradycardia]], and irregular respiration . <ref name = Fodstad></ref> These physiological symptoms can be indicative of [[cerebral ischemia]] as well as compression of [[arterioles]]. <ref name=Fodstad></ref>

In response to rising [[ICP]], respiratory rate increases. <ref name=Grady>{{cite journal |author=Grady PA, Blaumanis OR |title=Physiologic parameters of the Cushing reflex |journal=Surg Neurol |volume=29 |issue=6 |pages=454–61 |year=1988 |month=June |pmid=3375974 |doi= |url=}}</ref> The increase in [[ventilation]] is exhibited as an increase in rate rather than depth of ventilation <ref name=Dickinson></ref>, so the Cushing reflex is often associated with slow, irregular breathing. <ref name=Fox>{{cite journal |author=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 Suppl 47 |issue= |pages=9–16 |year=1986 |pmid=3813470 |doi= |url=}}</ref>[[Mayer waves]] are also a sign of the Cushing reflex, as can be observed from [[blood pressure]] traces or [[ECG]]s <ref name=Dickinson>{{cite journal |author=Dickinson CJ |title=Reappraisal of the Cushing reflex: the most powerful neural blood pressure stabilizing system |journal=Clin. Sci. |volume=79 |issue=6 |pages=543–50 |year=1990 |month=December |pmid=2176941 |doi= |url=}}</ref>. [[Mayer waves]] are the symptoms of a physiological response to falling blood flow, responding with an increase in [[blood pressure]]. <ref name=Dickinson></ref>


==Physiological Significance==
==Physiological Significance==
Line 42: Line 48:


Wan et al. also reported that the presence of a CR due to an ICP could allow one to conclude that ischemia has occurred in the posterior cranial fossa.<ref name=Wan></ref> 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. <ref name=Kosieradzki>{{cite journal |last = Kosieradzki|first = M|authorlink = |coauthors = W Rowinski|title = Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention.|journal = Transplant. Proc.|volume = 40|issue = 10|pages = 3279-88|publisher = |date = 2008 Dec|url = |doi = |pmid = 19100373}}</ref> As such, the presence of a CR due to ICP can indicate that ischemia may be occurring due to foreign organ rejection.
Wan et al. also reported that the presence of a CR due to an ICP could allow one to conclude that ischemia has occurred in the posterior cranial fossa.<ref name=Wan></ref> 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. <ref name=Kosieradzki>{{cite journal |last = Kosieradzki|first = M|authorlink = |coauthors = W Rowinski|title = Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention.|journal = Transplant. Proc.|volume = 40|issue = 10|pages = 3279-88|publisher = |date = 2008 Dec|url = |doi = |pmid = 19100373}}</ref> As such, the presence of a CR due to ICP can indicate that ischemia may be occurring due to foreign organ rejection.

==Research==
Though 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 has yet to be determined <ref name=Fox>{{cite journal |author=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 Suppl 47 |issue= |pages=9–16 |year=1986 |pmid=3813470 |doi= |url=}}</ref> The possibility that [[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></ref> 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></ref> Axial [[brain stem]] distortion could be the [[pathogenesis]] of Cushing reflex. <ref name=Fox></ref>

The nature of [[receptors]] mediating the Cushing response is also unknown. <ref name=Reis>{{cite journal |author=Reis DJ, Nathan MA, Doba N |title=Two specific brainstem systems which regulate the blood pressure |journal=Clin. Exp. Pharmacol. Physiol. |volume=Suppl 2 |issue= |pages=179–83 |year=1975 |pmid=1102170 |doi= |url=}}</ref> Some research suggests the existence of intracranial [[baroreceptors]] to trigger specific Cushing baroreceptor reflex. <ref name=Schmidt>{{cite journal |author=Schmidt EA, Czosnyka Z, Momjian S, Czosnyka M, Bech RA, Pickard JD |title=Intracranial baroreflex yielding an early cushing response in human |journal=Acta Neurochir. Suppl. |volume=95 |issue= |pages=253–6 |year=2005 |pmid=16463859 |doi= |url=}}</ref> Experiments by Schmidt et al. showed that Cushing reflex directed by [[autonomic nervous system]], since its physiological change has to do with the [[sympathetic nervous system]] and [[parasympathetic nervous system]] balance. <ref name=Schmidt></ref> 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></ref>

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. <ref name=Grady></ref> Some researchers have reported [[apnea]], while others have reported increased respiratory rates. <ref name=Grady></ref> Other researchers have found that increases in respiratory rate follow [[ICP]] decrease, while others say it is a response to [[ICP]] increase. <ref name=Grady></ref> One must also take into account the use of [[anesthetics]] in early experimentation. <ref name=Grady></ref> Research was initially performed on animals or patients under [[anesthesia]]. <ref name=Dickinson></ref> The [[anesthesia]] used led to respiratory depression, which might have had effect on the results. <ref name=Grady></ref> Early experiments also put animal subjects under artificial [[ventilation]], only allowing for limited conclusions about respiration in the Cushing reflex. <ref name=Dickinson></ref> 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></ref>

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

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></ref> This activity has not been thoroughly investigated, so there is a need for more research in this area.


==See also==
==See also==

Revision as of 05:00, 25 March 2011

The 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. It results in Cushing's triad of widening pulse pressure, irregular breathing, and bradycardia.[1] 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.[2] It was first described by American neurosurgeon Harvey Cushing in 1901.

Mechanism

The Cushing reflex is complex and seemingly paradoxical.[3] The reflex begins when some event causes increased intracranial pressure (ICP). This increases the hydrostatic pressure of cerebrospinal fluid to the point that it meets and gradually exceeds mean arterial pressure (MAP). As the ICP exceeds the MAP, the cerebral arterioles become compressed, diminishing blood supply to the brain, a condition known as cerebral ischemia.[4]

Both the sympathetic system and the parasympathetic system are both activated, but sympathetic stimulation is much greater than parasympathetic stimulation.[5] This renders the response of the parasympathetic system to be almost nonexistent. The sympathetic response activates alpha-1 adrenergic receptors within the arteries, causing vasoconstriction.[6] This constriction raises the total peripheral resistance of blood flow and elevates blood pressure causing hypertension in an attempt to restore perfusion to the ischemic brain. The sympathetic stimulation also increases heart contractility and cardiac output.[7] 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 vagal stimulation. This induces bradycardia, and signifies the second stage of the reflex.[8] Bradycardia may also be caused by increased ICP impinging on the vagal nerve, mechanically stimulating a parasympathetic response. An irregular respiratory pattern and/or apnea is typically the result of herniation or increased pressure on the brainstem.[9] This is the third and final stage of the reflex.

Commonly, in various pressor reflexes, the central chemoreceptors of the brain and the baroreceptors 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.[8]

History

Background

Cushing began his research in Bern, Switzerland studying abroad with Emil Theodor Kocher. After 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, but had improved his methods of recording coincidence of blood pressure and ICP during this time. 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".[10] Between 1901 and 1903, Cushing had five papers published pertaining to his research on the vasopressor response. The papers were published in German and English, and one was authored by Emil Theodor Kocher.[11]

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. [12]

Experimental Setup and Results

Cushing began experimenting once he obtained approval from Kocher. His experimental setup was a modified version that used by Leonard Hill to similarly test the effects of brain pressure on sinus pressure, cerebrospinal fluid pressure, arterial and venous blood pressure. [11][13] 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 with Mosso induced the ICP by injecting physiological saline into the subarachnoid space rather than increasing mercury content of an intracranial bag.[11]

This research clearly displayed the cause and effect relationship between intracranial pressure and cerebral compression.[14] 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.[10] Cushing's publications contain his observations and no statistical analysis. The sample size of the experiment is also not known.[14]

Other Researchers

Several notable figures in the medical field, including Ernst von Bergmann [15], Henri Duret [16], Friedrich Jolly [17] , and others experimented with intracranial pressure similarly to Cushing. Some of these researchers published similar findings concerning the relationship of ICP to arterial blood pressure before Cushing had begun experimenting. Cushing studied this relationship more carefully and offered an improved explanation of the relationship.[11]

Causes

As first postulated by Harvey Cushing, raised intracranial pressure (ICP) is the primary cause of the Cushing Reflex. [10] Furthermore, sustained moderate increases in cranial pressure, as opposed to rapid and large ones, allows for the Cushing Reflex to occur. These dramatic pressure rises do not allow for the mechanism of the reflex to sufficiently take place. [18] This elevated intracranial pressure can occur due to numerous pathways of brain impairment such as subarachnoid hemorrhages, ischemia, trauma, including concussions, hypoxia, tumors, and stroke. In addition, during typical neurosurgical procedures on patients involving neuroendoscopic techniques, frequent washing of the ventricles have been known to cause high ICP.[4] Induced subarachnoid hemorrhage studies on cats via injection of autologous blood into the cisterna magna of the brain confirmed that ICP causes mechanical distortion of the medulla, and is followed by sympathetic nervous system over activity.[5] The Cushing Reflex can also result from low cerebral perfusion pressure, specifically below 15 mmHg. [19] Raised ICP was also found in combination with a drop in cerebral perfusion pressure (CPP), which preceded the emergence of brain plateau waves. These plateau waves were subsequently erased after a Cushing Reflex response occurred 10-15 seconds prior to this. [20]

In a 71 year old male case study, it was concluded that the physiological conditions brought on by ischemia alone caused a Cushing reflex response. [21] Induced subarachnoid hemorrhage studies on cats via injection of autologous blood into the cisterna magna of the brain confirmed that ICP causes mechanical distortion of bulbar sensors in the medulla.[22][6] This was then followed by sympathetic nervous system over activity, characteristic of the reflex (2).

Signs and Symptoms

The Cushing reflex is characterized by increased intracranial pressure. [23]. Its classical symptoms are an increase in systolic and pulse pressure, bradycardia, and irregular respiration . [23] These physiological symptoms can be indicative of cerebral ischemia as well as compression of arterioles. [23]

In response to rising ICP, respiratory rate increases. [24] The increase in ventilation is exhibited as an increase in rate rather than depth of ventilation [25], so the Cushing reflex is often associated with slow, irregular breathing. [26]Mayer waves are also a sign of the Cushing reflex, as can be observed from blood pressure traces or ECGs [25]. Mayer waves are the symptoms of a physiological response to falling blood flow, responding with an increase in blood pressure. [25]

Physiological Significance

Raised ICP 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 CR 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. [20] Specifically, the reflex mechanism can maintain normal CBP and CBF under stressful situations such as ischemia or subarachnoid hemorrhages. A case report on a patient who underwent a spontaneous subarachnoid hemorrhage demonstrated that the CR played a part in maintaining CPP and CBF as evidenced by the absence of neurological deterioration during neurological stress. [20] Eventually, the CPP drops to a level range where a state of induced hypertension in the form of the CR is no longer required. The CR 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.[4] This effect is protective, especially during increased ICP, which creates a drop in CPP.

Clinical Importance

One of the more prominent warning signs of the CR is that patient death will likely occur, sooner rather than later. As a result, when a CR is detected, immediate care is needed for the patient to survive. Unfortunately, death may be inevitable if the cause of a CR and ICP is unknown. Since the presence of a Cushing Reflex is a good detector of high ICP, it is often useful in the medical field, particularly during surgery or other emergency situations. [1] 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 changes or bradycardia, the late phase of the CR. Once the initial stage of the CR was discovered, tachycardia combined with hypertension, it offered a much more reliable and swift warning sign of high ICP. [20] It was found that hypertension and tachycardia occurred 93% of the time when CPP dropped below 15 mmHg due to raised ICP. Also, the CR 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. [27]

Wan et al. also reported that the presence of a CR due to an ICP could allow one to conclude that ischemia has occurred in the posterior cranial fossa.[20] 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. [22] As such, the presence of a CR due to ICP can indicate that ischemia may be occurring due to foreign organ rejection.

Research

Though 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 has yet to be determined [26] The possibility that 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. [26] Some research observed symptoms of Cushing reflex, without the usual increased ICP and medullary anemia, suggesting other causes that still require research. [26] Axial brain stem distortion could be the pathogenesis of Cushing reflex. [26]

The nature of receptors mediating the Cushing response is also unknown. [28] Some research suggests the existence of intracranial baroreceptors to trigger specific Cushing baroreceptor reflex. [29] Experiments by Schmidt et al. showed that Cushing reflex directed by autonomic nervous system, since its physiological change has to do with the sympathetic nervous system and parasympathetic nervous system balance. [29] However, the specific relation between the autonomic nervous system response and the Cushing reflex and its symptoms has yet to be identified. [29]

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. [24] Some researchers have reported apnea, while others have reported increased respiratory rates. [24] Other researchers have found that increases in respiratory rate follow ICP decrease, while others say it is a response to ICP increase. [24] One must also take into account the use of anesthetics in early experimentation. [24] Research was initially performed on animals or patients under anesthesia. [25] The anesthesia used led to respiratory depression, which might have had effect on the results. [24] Early experiments also put animal subjects under artificial ventilation, only allowing for limited conclusions about respiration in the Cushing reflex. [25] 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. [25]

Some researchers have also suggested a long-term effect of the Cushing reflex. [25] 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. [25] The possibility that heightened sensitivity of neurological response system leading to arterial hypertension is possible, but has not been examined. [28]

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. [25] This activity has not been thoroughly investigated, so there is a need for more research in this area.

See also

References

  1. ^ a b Ayling, J (2002). "Managing head injuries". Emergency Medical Services. 31 (8): 42. PMID 12224233. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
  2. ^ Ogilvy, CS (1987). "Effect of increased intracranial pressure on blood pressure, heart rate, respiration and catecholamine levels in neonatal and adult rabbits". Biology of the Neonate. 52 (6): 327–336. PMID 3435736. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ Beiner, JM. "Cerebral blood flow changes in response to elevated intracranial pressure in rabbits and bluefish: a comparative study". Biochem Physiol A Physiol. 116 (3): 245–52. PMID 9102186. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ a b c Dickinson, CJ (1990). "Reappraisal of the Cushing reflex: the most powerful neural blood pressure stabilizing system". Clin Sci. 79: 543–50. PMID 2176941. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
  5. ^ a b Pasztor, E. "Activity of peripheral sympathetic efferent nerves in experimental subarachnoid haemorrhage. Part 1: Observations at the time of intracranial hypertension". Acta Neurochir. 79: 125–31. PMID 3962742. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ a b Woodman, OL (1987 Aug). "Coronary vasoconstriction mediated by α1- and α2-adrenoceptors in conscious dogs". Am. J. Physiol. 253 ((2 Pt 2)): H388-93. PMID 2887122. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Per Brodal (2004). The Central Nervous System: Structure and Function. Oxford University Press US. pp. 369–396.
  8. ^ a b Hackett, J.G. "Coronary vascular responses to stimulation of chemoreceptors and baroreceptors". Circ. Res. 31 (1): 8–17. PMID 4402639. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ P Barash, B Cullen, R Storlting (1992). Clinical Anesthesia. Philadelphia: JB Lippincott. p. 520.{{cite book}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b c Cushing, H (1901). "Concerning a definite regulatory mechanism of the vasomotor centre which controls blood pressure during cerebral compression". Bull Johns Hopkins Hosp. 126: 289–292. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
  11. ^ a b c d Fodstad, H (2006). "History of the Cushing Reflex". Neurosurgery. 59 (5): 1132–7. PMID 17143247. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help) Cite error: The named reference "fodstad" was defined multiple times with different content (see the help page).
  12. ^ JF Fulton (1946). Harvey Cushing. A biography. Springfield: Charles C. Thomas. pp. 176–193.
  13. ^ Leonard Hill (1896). Physiology and Pathology of the Cerebral Circulation. London: J & A Churchill.
  14. ^ a b Mitchell Fink; Michelle Hayes; Neil Soni (2008). Classic Papers in Critical Care. London, England: Springer. pp. 89–90.{{cite book}}: CS1 maint: multiple names: authors list (link)
  15. ^ Hanigan, WC (1992). "Neurological surgery in the nineteenth century: the principles and techniques of Ernst von Bergmann". Neurosurgery. 30 (5): 750–7. PMID 1584389. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ Duret H (1878). Anatomic Studies of the Cerebral Circulation. Paris, Bailliere. p. 642.{{cite book}}: CS1 maint: location missing publisher (link)
  17. ^ Friedrich Jolly (1871). About Intracranial Pressue and Blood Circulation Inside the Cranium. Medical Thesis. Wurzburg, Germany.{{cite book}}: CS1 maint: location missing publisher (link)
  18. ^ Marshman, LA (1997). "Cushing's 'variant' response (acute hypotension) after subarachnoid hemorrhage. Association with moderate intracra- nial tension and subacute cardiovascular collapse". Stroke. 28 (7): 1445–50. PMID 9227698. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
  19. ^ Kalmar, AF (2005). "Value of Cushing Reflex as warning sign for brain ischemia during neuroendoscopy". Br J Anaes. 94 (6): 791–9. PMID 15805143. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ a b c d e Wan, WH (2008 Jan 7). "The cushing response: A case for a review of its role as a physiological reflex". J Clin Neurosci. 15 (3): 223–8. PMID 18182296. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  21. ^ Nielsen, EW (2004 Apr 1). "A 71-year-old man with Cushing reflex". Tidsskr Nor Laegeforen. 124 (7): 943–5. PMID 15088604. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  22. ^ a b Kosieradzki, M (2008 Dec). "Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention". Transplant. Proc. 40 (10): 3279–88. PMID 19100373. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help) Cite error: The named reference "Kosieradzki" was defined multiple times with different content (see the help page).
  23. ^ a b c Fodstad H, Kelly PJ, Buchfelder M (2006). "History of the cushing reflex". Neurosurgery. 59 (5): 1132–7, discussion 1137. doi:10.1227/01.NEU.0000245582.08532.7C. PMID 17143247. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ a b c d e f Grady PA, Blaumanis OR (1988). "Physiologic parameters of the Cushing reflex". Surg Neurol. 29 (6): 454–61. PMID 3375974. {{cite journal}}: Unknown parameter |month= ignored (help)
  25. ^ a b c d e f g h i Dickinson CJ (1990). "Reappraisal of the Cushing reflex: the most powerful neural blood pressure stabilizing system". Clin. Sci. 79 (6): 543–50. PMID 2176941. {{cite journal}}: Unknown parameter |month= ignored (help)
  26. ^ a b c d e Fox JL, Ransdell AM, Al-Mefty O, Jinkins JR (1986). "The Cushing reflex in the absence of intracranial hypertension". Ann. Clin. Res. 18 Suppl 47: 9–16. PMID 3813470.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Jones, JV (1989 Feb 2). "Differentiation and investigation of primary versus secondary hypertension (Cushing reflex)". 63 (6): 10C–13C. PMID 2643847. {{cite journal}}: Check date values in: |date= (help); Cite has empty unknown parameter: |coauthors= (help); Cite journal requires |journal= (help)
  28. ^ a b Reis DJ, Nathan MA, Doba N (1975). "Two specific brainstem systems which regulate the blood pressure". Clin. Exp. Pharmacol. Physiol. Suppl 2: 179–83. PMID 1102170.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ a b c Schmidt EA, Czosnyka Z, Momjian S, Czosnyka M, Bech RA, Pickard JD (2005). "Intracranial baroreflex yielding an early cushing response in human". Acta Neurochir. Suppl. 95: 253–6. PMID 16463859.{{cite journal}}: CS1 maint: multiple names: authors list (link)


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