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Experiments by Manucher Javid, Paul Settlage Made Modern Neurosurgery Possible

Madison, Wisconsin - Neurosurgeons operating on the brain 50 years ago often confronted a serious problem: "fungus cerebri," a condition in which pressure forces the brain to mushroom out of a hole in the skull. 


But two University of Wisconsin-Madison scientists changed all that when they pushed past the skepticism of some peers and developed the first successful solution to reduce intracranial pressure during surgery. Their discovery made modern neurosurgery possible.


Manucher JavidThe pioneering work of Dr. Manucher Javid, past chairman of neurosurgery at the University of Wisconsin School of Medicine and Public Health, and UW research scientist Paul Settlage, is recounted in the May edition of the journal Neurosurgery.


Author Dr. Brandon Rocque, chief resident in UW Hospital's neurosurgery department, recounts how, in 1954, Javid made time in his busy day at the old State of Wisconsin General Hospital to attend a research lecture. Another doctor presented the work of Settlage, a member of the anatomy faculty, who had success using a solution of urea to reduce cerebrospinal fluid (CSF) pressure in monkeys.


Other scientists as far back as 1919 had worked on creating the correct cocktail, but earlier solutions were abandoned because they caused potentially fatal side effects in patients.


"For Javid, it immediately represented a potential solution to the problem of fungus cerebri with cortical rupture, one of the most vexing problems in neurosurgery," Rocque writes.


The two met with a UW pharmacologist, who proposed a solution of 50 milligrams of urea per kilogram of patient body weight, "but Javid, whose pharmacist father (in Iran) had always told him that pharmacologists were too conservative," decided to double the concentration.


Javid almost immediately tried the urea solution on patients. (There was no Institutional Review Board or informed consent in those days.) The second patient was a sheriff and bartender from northern Wisconsin who had severe headaches due to a malignant brain tumor. An infusion of the urea solution resolved the man's headache immediately. By 1957, after bedside experiments on more than two dozen patients, urea was used in the operating theater at Wisconsin for the first time and was an immediate success.


But first, the innovation faced controversy. One biochemist on a national committee said he could think of "a myriad of reasons why only a pathetic oaf would suggest anything so ludicrous (as) putting back into the body the final waste product of protein metabolism." (Urea is a waste product excreted by the body in urine.)


The discovery finally took off after Javid gave a talk at the American College of Surgeons in late 1956. The Wisconsin Alumni Research Foundation (which owned the rights to the discovery) was so deluged by demand for urea solution that it contracted with a lab in Illinois to manufacture the product for widespread distribution.


Tragically, Settlage died in a canoe accident on Lake Wingra in April 1957, just as the importance of his work was being noticed.


In 1958, the New York Times reported that the solution "has saved the lives of many patients suffering from increased brain pressure cause by concussions, fractures and other head and brain injuries." When Nobel Prize-winning Soviet physicist Lev Landau suffered a head injury in a car accident, Soviet authorities used Khruschev's private plane to fly urea solution from England to the Soviet Union to save Landau's life. Urea had a heyday of about a decade before it was replaced by mannitol and other solutions that were easier to prepare and store.


Rocque says he initially researched Dr. Javid's discovery in a History of Medicine class that he took while working on his master's degree in clinical investigations. A highlight, he says, was getting to meet and interview Dr. Javid, adding,  "He just turned 90, still lives in Madison and is quite sharp."


"Today, most young neurosurgeons have never heard of this history, and I have received quite a few good comments on the article," Dr. Rocque says. "Nowadays, we only see the fungus cerebri condition after the most severe brain injuries."

Date Published: 05/09/2012

News tag(s):  neurosurgery

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Experiments by Manucher Javid, Paul Settlage Made Modern Neurosurgery Possible

Last updated: 05/09/2012
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