Cushing reflex 1

Cushing reflexCushing reflex (also referred to as the vasopressor response, the Cushing effect, the Cushing reaction, theCushing phenomenon, the Cushing response, or Cushing's Law) is a physiological nervous system response toincreased intracranial pressure (ICP) that results in Cushing's triad of widening pulse pressure, irregular breathing,and a reduction of the heart rate.[1] It is usually seen in the terminal stages of acute head injury and may indicateimminent brain herniation. It can also be seen after the intravenous administration of epinephrine and similardrugs.[2] It was first described in detail by American neurosurgeon Harvey Cushing in 1901.[3]

Definition

Defect of the bloodbrain barrier after strokeshown in MRI. T1-weighted images, left image

without right image with contrast mediumadministration showing evidence of brain

ischemia

The Cushing reflex classically presents as an increase in systolic andpulse pressure, reduction of the heart rate (bradycardia), and irregularrespiration.[4] It is caused by increased pressure inside the skull.[4]

These symptoms can be indicative of insufficient blood flow to thebrain (ischemia) as well as compression of arterioles.[4][5]

In response to rising intracranial pressure (ICP), respiratory rateincreases.[6] The increase in ventilation is exhibited as an increase inrate rather than depth of ventilation, so the Cushing reflex is oftenassociated with slow, irregular breathing.[7][8] Mayer waves, which arewaves in arterial blood pressure that can be seen in anelectrocardiograph (ECG) register or blood pressure traces, are asymptom of a physiological response to falling blood flow. This oftenresults in an increase in blood pressure.[7]

Differential diagnosis

Subarachnoid hemorrhage as shown on a CTscan. It is denoted by the arrow. This type ofinjury may result in damage to the brainstem

which could initiate or worsen the symptoms ofthe Cushing reflex

Whenever a Cushing reflex occurs, there is a high probability thatdeath will occur in the near future (seconds to minutes). As a result,when a Cushing reflex is detected, immediate care is needed. Since itspresence is a good detector of high ICP, it is often useful in the medicalfield, particularly during surgery.[1] During any neurosurgery beingperformed on the brain, there is always a likelihood that raisedintracranial pressure may occur. Early recognition of this is crucial tothe well being of the patient. Although direct measurement of ICP ispossible, it is not always accurate. In the past, physicians and nurseshave relied on hemodynamic changes or bradycardia, the late phase ofthe reflex, to identify the ICP increase. Once the initial stage of theCushing reflex (tachycardia combined with hypertension) wasdiscovered, it offered a much more reliable and swift warning sign ofhigh ICP.[9] It was found that hypertension and tachycardia occurred93% of the time when CPP dropped below 15 mmHg due to raisedICP. Also, the Cushing reflex is known to arise only from acuteprolonged raises in ICP. Thus, it can be used as a tool by physicians todifferentiate acute and chronic rises in ICP.[10]

Cushing reflex 2

It has also reported that the presence of a Cushing reflex due to an ICP increase could allow one to conclude thatischemia has occurred in the posterior cranial fossa.[9] Finally, the Cushing reflex may be one of many ways toidentify if a patient has rejected a transplanted organ. Aside from the innate autoimmune response, ischemia in thecranial region has been detected with a transplanted organ that is being rejected.[11] As such, the presence of aCushing 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.[3]

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.[12] Elevatedintracranial 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 ICPdue to subarachnoid hemorrhaging causes mechanical distortion of the brainstem, specifically the medulla. Due tothe mechanism of the Cushing reflex, brainstem distortion is then swiftly followed by sympathetic nervous systemover activity.[13] In addition, during typical neurosurgical procedures on patients, especially those involvingneuroendoscopic techniques, frequent washing of the ventricles have been known to cause high intracranialpressure.[7] The Cushing reflex can also result from low cerebral perfusion pressure (CPP), specifically below 15mmHg.[14] 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 risesof the ICP, and are accompanied by a decrease of the cerebral perfusion pressure. It has been found that if a Cushingreflex occurs, brain plateau wave changes can be erased due to disappearance of high ICP.[9]

MechanismThe Cushing reflex is complex and seemingly paradoxical.[15] The reflex begins when some event causes increasedintracranial pressure (ICP). Since cerebrospinal fluid is located in an area which is surrounded by the skull, increasedICP consequently increases the pressure in the fluid itself. The pressure in the cerebral spinal fluid eventually rises tothe point that it meets and gradually exceeds the mean arterial blood pressure (MABP or MAP). When the ICPexceeds the MABP, arterioles located in the brain's cerebrum become compressed. Compression then results indiminished blood supply to the brain, a condition known as cerebral ischemia.[7]

During the increase in ICP, both the sympathetic nervous system and the parasympathetic nervous system areactivated. In the first stage of the reflex, sympathetic nervous system stimulation is much greater thanparasympathetic stimulation.[13] The sympathetic response activates alpha-1 adrenergic receptors, causingconstriction of the body's arteries.[16] This constriction raises the total resistance of blood flow, elevating bloodpressure to high levels, which is known as hypertension. The body's induced hypertension is an attempt to restoreblood flow to the damaged, ischemic brain. The sympathetic stimulation also increases the rate of heart contractionsand cardiac output.[17] Increased heart rate is also known as tachycardia. This combined with hypertension is the firststage of the Cushing reflex.Meanwhile, baroreceptors in the carotid arteries detect the increase in blood pressure and trigger a parasympatheticresponse via the vagus nerve. This induces bradycardia, or slowed heart rate, and signifies the second stage of thereflex.[18] 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 inducebradycardia. The blood pressure can be expected to stay higher than the pressure of the raised cerebral spinal fluid tocontinue to allow blood to flow to the brain. Similar to Korotkoff sounds, the pressure will rise to the point where theartery, which is compressed is pressurized such that the blood, can provide oxygen to the hypoxic area of the brainby overcoming the resisting pressure. If the body is unable to compensate for the pressure on the artery, infarctionwill occur.[19]

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

Cushing reflex 3

respiratory pattern and/or apnea.[20] This is the third and final stage of the reflex.Commonly, in various pressor reflexes, the central chemoreceptors, which transform chemical signals into an actionpotentials, and the baroreceptors, which sense pressure changes, of the carotid sinuses work together to increase ordecrease blood pressure. However, chemoreceptors do not play a role in the Cushing reflex. Thus, even in thepresence of sympathetic stimulation from the brain, which would normally produce tachycardia, there is in factbradycardia.[18]

FunctionRaised intracranial pressure can ultimately result in the shifting or crushing of brain tissue, which is detrimental tothe physiological well being of patients. As a result, the Cushing reflex is a last-ditch effort by the body to maintainhomeostasis in the brain. It is widely accepted that the Cushing reflex acts as a baroreflex, or homeostaticmechanism for the maintenance of blood pressure, in the cranial region.[9] Specifically, the reflex mechanism canmaintain normal cerebral blood flow and pressure under stressful situations such as ischemia or subarachnoidhemorrhages. A case report of a patient who underwent a spontaneous subarachnoid hemorrhage demonstrated thatthe Cushing reflex played a part in maintaining cerebral perfusion pressure (CPP) and cerebral blood flow.[9]

Eventually, the ICP drops to a level range where a state of induced hypertension in the form of the Cushing reflex isno longer required. The Cushing reflex was then aborted, and CPP was maintained. It has also been shown that anincrease in mean arterial pressure due to hypertension, characteristic of the reflex, can cause the normalization ofCPP.[7] This effect is protective, especially during increased intracranial pressure, which creates a drop in CPP.

History

Harvey Cushing, Doris Ulmann 1920s

Cushing began his research in Bern, Switzerland studying abroad withEmil Theodor Kocher. A month into his trip, Cushing received aformal proposition from Emil Theodor Kocher to begin testing howcompression of the brain affected blood vessels. Cushing also enlistedthe aid of Hugo Kronecker, a known blood pressure researcher.Utilizing Kroenecker's assistance and resources, Cushing began hisresearch. Cushing left Bern in 1901 to work in Turin, Italy with AngeloMosso, a previous student of Kroenecker. He continued to work on thesame research project, while also simultaneously improving hismethods of recording coincidence of blood pressure and ICP. In June1901 Cushing published his first paper through Johns Hopkins HospitalBulletin entitled "Concerning a definite regulatory mechanism of thevasomotor centre which controls blood pressure during cerebralcompression".[3] Between 1901 and 1903, Cushing published fivepapers pertaining to his research on the vasopressor response. Thesepapers were published in German and English, and one was authoredby Emil Theodor Kocher.[4]

Experimental setup and resultsCushing began experimenting once he obtained approval from Kocher. His experimental setup was a modified version of Leonard Hill's model to similarly test the effects of brain pressure on sinus pressure, cerebrospinal fluid pressure, arterial and venous blood pressure.[4][21] 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

Cushing reflex 4

intracranial pressure along with blood pressure, pulse rate, and respiratory rate simultaneously. This three part effectis commonly referred to as Cushing's triad. In later experiments performed by Mosso, intrcranial pressure wasinduced by injecting physiological saline into the subarachnoid space rather than increasing mercury content of anintracranial bag.[4]

This research clearly displayed the cause and effect relationship between intracranial pressure and cerebralcompression.[22] Cushing noted this relationship in his subsequent publications. He also noted that there must exist aspecific regulatory mechanism that increased blood pressure to a high enough point such that it did not create anemicconditions.[3] Cushing's publications contain his observations and no statistical analysis. The sample size of theexperiment is also not known.[22]

Other researchersSeveral notable figures in the medical field, including Ernst von Bergmann,[23] Henri Duret,[24] Friedrich Jolly,[25]

and others experimented with intracranial pressure similarly to Cushing. Some of these researchers published similarfindings concerning the relationship of intracranial pressure to arterial blood pressure before Cushing had begunexperimenting. Cushing studied this relationship more carefully and offered an improved explanation of therelationship.[4]

Some controversy concerning plagiarism does surround some of Cushing's research. Bernhard Naunyn, a Germanpathologist and contemporary of Cushing, made remarks claiming that Cushing neither cited him in Cushing'sresearch nor expanded on any of the results that he had found in his original experiments.[26]

Research directionsAlthough a lot of progress has been made since 1901 when Harvey Cushing first expanded knowledge of what isnow known as the Cushing reflex, there are still many aspects of the research that remain to be seen. The exactpathogenesis of the disease has yet to be determined.[8] The possibility that intracranial pressure (ICP) may not bethe sole cause of the Cushing reflex per se came from an occurrence of Cushing blood pressure response occurringbefore increased ICP.[8] Some research observed symptoms of Cushing reflex, without the usual increased ICP andmedullary anemia, suggesting other causes that still require research.[8] Axial brain stem distortion could be thepathogenesis of Cushing reflex.[8]

The nature of receptors mediating the Cushing response is also unknown.[27] Some research suggests the existence ofintracranial baroreceptors to trigger specific Cushing baroreceptor reflex.[28] Experiments by Schmidt and his fellowresearchers showed that the Cushing reflex is directed by autonomic nervous system, since its physiological changehas to do with the balance of the sympathetic nervous system and parasympathetic nervous system.[28] However, thespecific relation between the autonomic nervous system response and the Cushing reflex and its symptoms has yet tobe identified.[28]

It has been determined that rate of respiration is affected by the Cushing reflex, though the respiratory changesinduced are still an area which can use more research.[6] Some researchers have reported apnea, while others havereported increased respiratory rates.[6] Other researchers have found that increases in respiratory rate follow ICPdecreases, while others say it is a response to ICP increase.[6] One must also take into account the use of anestheticsin early experimentation.[6] Research was initially performed on animals or patients under anesthesia.[7] Theanesthesia used in experiments have led to respiratory depression, which might have had effect on the results.[6]

Early experiments also put animal subjects under artificial ventilation, only allowing for limited conclusions aboutrespiration in the Cushing reflex.[7] The use of anesthetics proposes ideas for future research, since the creation of theCushing response has been difficult to create under basal conditions or without anesthesia.[7]

Some researchers have also suggested a long-term effect of the Cushing reflex.[7] 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

Cushing reflex 5

as a long-term raise in blood pressure.[7] Heightened sensitivity of neurological response systems leading to arterialhypertension is also possible, but has not been examined.[27]

Although the Cushing reflex was primarily identified as a physiological response when blood flow has almostceased, its activity has also been seen in fetal life.[7] This activity has not been thoroughly investigated, so there is aneed 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 areaof research if scientists and/or doctors chose to do so.

References[1] Ayling, J (2002). "Managing head injuries". Emergency Medical Services 31 (8): 42. PMID12224233.[2] Ogilvy, CS; Dubois AB (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): 327336. PMID3435736.[3] Cushing, H (1901). "Concerning a denite regulatory mechanism of the vasomotor centre which controls blood pressure during cerebral

compression". Bull Johns Hopkins Hosp. 126: 289292.[4] Fodstad H, Kelly PJ, Buchfelder M (November 2006). "History of the cushing reflex". Neurosurgery 59 (5): 11327; discussion 1137.

doi:10.1227/01.NEU.0000245582.08532.7C. PMID17143247.[5] Dagal, A; Lam AM (April 2011). "Cerebral blood flow and the injured brain: how should we monitor and manipulate it?". Curr Opin

Anaesthesiol. 24 (2): 1317. doi:10.1097/ACO.0b013e3283445898. PMID21386665.[6] Grady PA, Blaumanis OR (June 1988). "Physiologic parameters of the Cushing reflex". Surg Neurol 29 (6): 45461. PMID3375974.[7] Dickinson, CJ (1990). "Reappraisal of the Cushing reex: the most powerful neural blood pressure stabilizing system.". Clin Sci 79 (6):

54350. PMID2176941.[8] 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: 916. PMID3813470.[9] Wan, WH; BT Ang, E Wang (2008 Jan 7). "The cushing response: A case for a review of its role as a physiological reflex.". J Clin Neurosci.

15 (3): 2238. doi:10.1016/j.jocn.2007.05.025. PMID18182296.[10] Jones, JV (1989-02-02). "Differentiation and investigation of primary versus secondary hypertension (Cushing reflex)". Am. J. Cardiol. 63

(6): 10C-13C. PMID2643847.[11] Kosieradzki, M; W Rowinski (2008 Dec). "Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention.". Transplant.

Proc. 40 (10): 327988. doi:10.1016/j.transproceed.2008.10.004. PMID19100373.[12] Marshman, LA (1997). "Cushings variant response (acute hypotension) after subarachnoid hemorrhage. Association with moderate

intracra- nial tension and subacute cardiovascular collapse.". Stroke 28 (7): 144550. PMID9227698.[13] Pasztor, E; Fedina L, Kocsis B, et al. (1986). "Activity of peripheral sympathetic eerent nerves in experimental subarachnoid haemorrhage.

Part 1: Observations at the time of intracranial hypertension.". Acta Neurochir 79 (2-4): 12531. PMID3962742.[14] Kalmar, AF; JV Aken, J Caemaert, et. al. (2005). "Value of Cushing Reex as warning sign for brain ischemia during neuroendoscopy". Br

J Anaes 94 (6): 7919. doi:10.1093/bja/aei121. PMID15805143.[15] Beiner, JM; CS Olgiyy, AB DuBois (March 1997). "Cerebral blood ow changes in response to elevated intracranial pressure in rabbits and

bluesh: a comparative study.". Biochem Physiol A Physiol 116 (3): 24552. PMID9102186.[16] Woodman, OL; SF Vatner (1987 Aug). "Coronary vasoconstriction mediated by 1- and 2-adrenoceptors in conscious dogs.". Am. J.

Physiol. 253 ((2 Pt 2)): H388-93. PMID2887122.[17] Per Brodal (2004). The Central Nervous System: Structure and Function. Oxford University Press US.. pp.369396.[18] Hackett, J.G.; F. M. Abboud, A. L. Mark, P. G. Schmid, and D. D. Heistad. (July 1972). "Coronary vascular responses to stimulation of

chemoreceptors and baroreceptors.". Circ. Res. 31 (1): 817. PMID4402639.[19] Guyton, Arthur; Hall, John (2006). "Chapter 18: Nervous Regulation of Circulation, and a Rapid Control of Arterial Pressure". In Gruliow,

Rebecca (Book). Textbook of Medical Physiology (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc.. p.213. ISBN0-7216-0240-1.[20] P Barash, B Cullen, R Storlting (1992). Clinical Anesthesia. Philadelphia: JB Lippincott. pp.520.[21] Leonard Hill (1896). Physiology and Pathology of the Cerebral Circulation.. London: J & A Churchill.[22] Mitchell Fink; Michelle Hayes; Neil Soni (2008). Classic Papers in Critical Care.. London, England: Springer. pp.8990.[23] Hanigan, WC; W. Ragen, M. Ludgera (1992). "Neurological surgery in the nineteenth century: the principles and techniques of Ernst von

Bergmann.". Neurosurgery 30 (5): 7507. doi:10.1227/00006123-199205000-00017. PMID1584389.[24] Duret H (1878). Anatomic Studies of the Cerebral Circulation. Paris, Bailliere. pp.642.[25] Friedrich Jolly (1871). About Intracranial Pressue and Blood Circulation Inside the Cranium. Medical Thesis. Wurzburg, Germany.[26] JF Fulton (1946). Harvey Cushing. A biography. Springfield: Charles C. Thomas. pp.176193.[27] Reis DJ, Nathan MA, Doba N (1975). "Two specific brainstem systems which regulate the blood pressure". Clin. Exp. Pharmacol. Physiol.

Suppl 2: 17983. PMID1102170.[28] 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: 2536. PMID16463859.

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Cushing reflexDefinition Differential diagnosisMechanismFunction

HistoryExperimental setup and resultsOther researchers

Research directionsReferences

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