Susan Jeffrey

November 16, 2014

CHICAGO — The combination of prehospital hypoxia and hypotension, each known to increase mortality in the setting of traumatic brain injury (TBI), has a synergistic negative effect, boosting mortality risk by three or more times than either alone, a new study shows.

The results from a preliminary analysis of the Excellence in Prehospital Injury Care (EPIC) study showed that while hypoxia and hypotension increased mortality by four- and threefold respectively, the combination increased mortality by 14-fold.

The largest previous study had suggested the combination didn't make a significant difference vs either condition alone, Dr Daniel W. Spaite, professor and distinguished chair, department of emergency medicine, and director of emergency medical services (EMS) research, College of Medicine, University of Arizona, Tucson, told Medscape Medical News. "It turns out that after severity adjustment, it's really dramatic; the combination gets to really high mortality rates."

Their findings support current EMS TBI treatment guidelines that call for the prevention and treatment of both hypoxia and hypotension, that to date have not been widely implemented in the United States, Dr Spaite said. "So the first thing to say is, do what the guidelines say."

The EPIC trial is now moving into a prospective phase, during which researchers are examining whether implementing the guidelines will affect outcomes. "That's not the focus of today — this is just the retrospective — but it's very powerful data showing that if you don't prevent these things, the likelihood of the patient dying goes way up."

The findings were presented here at the American Heart Association 2014 Scientific Sessions Resuscitation Science Symposium.

EPIC Study

Dr Daniel W. Spaite

Although it's well known that hypoxia and hypotension occurring during prehospital emergency management of TBI reduce survival in these patients, little is known about the effect of the combination of these factors. Studies that have looked at this have had only a small number of cases with both hypoxia and hypotension — the largest to date included only 14 such cases, Dr Spaite noted.

"The problem historically is that it's very, very difficult to link the trauma center data to the data that's in the prehospital environment, the [emergency medical services] EMS environment," he said. "The advantage of the EPIC study is we believe we're going to have about 27,000 patients in the study, and this gives us a huge retrospective cohort to look at this question, and the linkage rate is very high, so we have the prehospital data now in over 10,000 retrospective patients."

For this analysis, they reviewed all moderate to severe TBI cases, defined as type 1 using the Centers for Disease Control and Prevention Barell matrix, enrolled in the EPIC trial, a statewide "before-and-after" study that looked at implementation of TBI treatment guidelines between January 1, 2008 and June 30, 2012.

Cases were excluded if they were under age 10, died prior to arrival in the emergency department, EMS oxygen saturation was less than 11%, EMS systolic blood pressure was less than 40 mm Hg or greater than 200 mm Hg, or either of these measures was not recorded.

The relationship between mortality and hypoxia, defined as oxygen saturation less than 90% and/or hypotension, defined as systolic blood pressure less than 90 mm Hg, was assessed with crude and multivariate odds ratios, adjusted for important confounders including age, sex, ethnicity, payment source, and accounting for clustering by trauma center.

In this analysis, 9194 cases were included. Patients were a mean age of 46 years (interquartile range, 26–65 years), and about 70% were men.

Most patients (8109, 88.2%) had neither hypotension nor hypoxia, 535 (5.8%) had only hypoxia, 419 (4.6%) had only hypotension, and 131 (1.4%) had both hypoxia and hypotension.

Prehospital hypoxia and hypotension were both associated with significantly increased mortality, Dr Spaite reported. However, the combination had a "profoundly negative effect on survival," even after adjustment, with a risk roughly threefold greater than either factor alone.

Finally, they explored what might be the ideal blood pressure and found that in this analysis it was about 144 mm Hg, he said. "Well, everybody on the planet before this has been thinking maybe it's 90, maybe 95, maybe 100, but nobody has been thinking 130s, 140s is where we want them to be," Dr Spaite noted. It's not enough to change practice based on these retrospective data, but may be something of a "wake-up call" that the best threshold may be higher than currently thought and will be the subject of some of their prospective analyses in EPIC, he added.

In the prospective interventional part of the study, researchers will aggressively treat hypoxia and hypotension to see whether outcomes can be affected. Patients with hypoxia will receive treatment using a high-flow nonrebreather mask at 100% oxygen, and those with hypotension — systolic BPs dropping and approaching 90 mm Hg — will receive fluids. If the patient requires intubation, hyperventilation should be avoided, he said. "It's the three H-bombs:" hypoxia, hypotension, and hyperventilation.

Mortality Risk With Hypoxia, Hypotension, or Both in TBI

Endpoint Mortality (%) Adjusted Odds Ratio
Neither Hypoxia nor Hypotension 6.5 1.0 (reference)
Hypoxia Only 29.7 4.1
Hypotension Only 21.8 3.0
Hypoxia Plus Hypotension 50.6 13.8

"When you manually hyperventilate — all of us bag at about 30 times a minute — it closes off the vessels to the brain," Dr Spaite said. "So ironically, you're giving them more oxygen, but because you're dropping in the CO2 levels, you literally lose flow to the brain."

Important Initiative

Asked to comment, session comoderator Dr Theresa M. Olasveengen, Olso University Hospital, Norway, noted the EPIC study will yield important information.

"The EPIC project is such an important healthcare-services initiative, translating evidence-based medicine into evidence-based implementation and practice," Dr Olasveengen told Medscape Medical News. "Both as a researcher and provider of prehospital care for TBI patients, I am very excited to follow their work in the time to come."

The current results presented here on the association between hypoxia and hypotension and negative outcome is "not surprising," she notes, "but the sheer volume and quality of the data are impressive.

"The remaining question will be to assess to what extent hypoxia/hypotension is a marker for severely injured patients, or represents a real opportunity for interventions to improve patient outcomes," she concluded.

For more information on the ongoing EPIC trial, go to

The EPIC study is funded by the National Institutes of Health/National Institute for Neurological Disorders and Stroke. The authors and report no they have no relevant financial relationships.

American Heart Association Scientific Sessions 2014 Resuscitation Science Symposium. Abstract 4. Presented November 15, 2014.


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