User:Sean Dikdan/The Cushing Reflex

Cushing Reflex: One Page Proposal  

The goal of this project is to modify the existing Wikipedia article of 'Cushing Reflex' to the standing of a Good Article. Cushing Reflex is a nervous system response to an increase in intracranial pressue. This reflex was discovered by Harvey Cushing, a doctor who worked in both endocrinology and neurology. Cushing observed a distinct relationship between increasing cerebral compression and increasing blood pressure. This increase of pressure has been shown to affect both the sympathetic and parasympathetic portions of the autonomic nervous system. The primary three effects of the Cushing Reflex have been dubbed Cushing's Triad. This refers to the increase in blood pressure, irregular breathing, and bradycardia. This nervous system reflex is relevant in instances ranging from severe head trauma to using it as a warning sign during neurosurgery.

Outline

Here is our general outline of subtopics that is subject to change as additional references are acquired:

1. Introduction (with a picture included) 2. History/Discovery 3. Anatomy and Location of Structures involved 1. Brainstem 4. Mechanism 1. How it occurs (ICP etc.) 5. Importance of Reflex 1. Warning sign for brain ischemia particularly during an neuroendoscopy 2. Concussions 3. Hemorrhages 6. Symptoms/Signs of the reflex 1. Cushing's Triad 7. Current Research/Where future research is headed 8. See also 9. References

The work will be divided as follows: Sean Dikdan will research History and Anatomy, Philip Johnson will research the Mechanism and its Importance, and Cynthia Cepeda will research the Signs and Symptoms of the Cushing Reflex along with Current Research. These will all be compiled together as is seen in the preliminary outline above. This should offer a broad and thorough overview of the Cushing Reflex.

References

Cushing H. "Concerning a deﬁnite regulatory mechanism of the vasomotor centre which controls blood pressure during cerebral compression." Bull Johns Hopkins Hosp. 126 (1901): 289–92.

Dickinson, C. "REAPPRAISAL OF THE CUSHING REFLEX THE MOST POWERFUL NEURAL BLOOD PRESSURE STABILIZING SYSTEM." Clinical science 79.6 (1990): 543-50.

Erol, Demet. "A Risk during an Elective Repair of Craniosynostosis: The Cushing Reflex." Paediatric anaesthesia 17.5 (2007): 496-7.

Fodstad, H., P. Kelly, and M. Buchfelder. "History of the Cushing Reflex." Neurosurgery 59.5 (2006): 1132-7.

Fox, J., et al. "THE CUSHING REFLEX IN THE ABSENCE OF INTRACRANIAL HYPERTENSION." Annals of clinical research.Supplement.47 (1986): 9-16.

Grady, P., and O. Blaumanis. "PHYSIOLOGIC PARAMETERS OF THE CUSHING REFLEX." Surgical neurology 29.6 (1988): 454-61.

Kalmar, A., et al. "Value of Cushing Reflex as Warning Sign for Brain Ischaemia during Neuroendoscopy." British journal of anaesthesia 94.6 (2005): 791-9.

Meyer, G., T. Ducker, and L. Kempe. "THE CUSHING REFLEX." Transactions of the American Neurological Association 94 (1969): 358-9.

---. "THE CUSHING REFLEX." International Congress Series (1969): 103.

Molnr, Csilla, et al. "Harvey Cushing, a Pioneer of Neuroanesthesia." Journal of anesthesia 22.4 (2008): 483-6.

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''. 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. (5)

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. (7)

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. (5)(6) 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. (5)

This research clearly displayed the cause and effect relationship between intracranial pressure and cerebral compression (8). 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. (8)

Other Researchers
Several notable figures in the medical field, including Ernst von Bergmann(1), Henri Duret(2), Friedrich Jolly(3), Bernhard Naunyn(4), 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(5).

Mechanism
The Cushing reflex is complex and seemingly paradoxical. 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. Both the sympathetic system and the parasympathetic system are both activated, but sympathetic stimulation is much greater than parasympathetic stimulation. 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. 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. 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. 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. 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.

Causes
As first postulated by Harvey Cushing, raised intracranial pressure (ICP) is the primary cause of the Cushing Reflex. 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. 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. 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. The Cushing Reflex can also result from low cerebral perfusion pressure, specifically below 15 mmHg. 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.

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. 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. This was then followed by sympathetic nervous system over activity, characteristic of the reflex (2).

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. 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. 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. 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. 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. 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.

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. 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 CR due to ICP can indicate that ischemia may be occurring due to foreign organ rejection.