Correspondence

Lack of Effect of Induction of Hypothermia after Acute Brain Injury

N Engl J Med 2001; 345:66July 5, 2001

Article

To the Editor:

The study by Clifton et al. (Feb. 22 issue)1 has two shortcomings. First, brain temperature was not monitored. Second, the types of injuries were neither described nor analyzed. Hypothermia might be beneficial in patients with specific types or areas of injury in the brain — for example, areas of edema or areas of focal contusions. In such injured but potentially viable areas, cerebral perfusion may be diminished or even absent. Cooling the blood in the systemic circulation to the predetermined level of 33°C (as measured by bladder temperature), as in the study by Clifton et al., may have a limited effect in lowering the temperature in areas of injured brain tissue.

Damianos E. Sakas, M.D.
Ioanna Dimopoulou, M.D.
University of Athens School of Medicine, Athens 106 75, Greece
sakasde@cc.uoa.gr

1 References

1. 1

   Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556-563
   Full Text | Web of Science | Medline

To the Editor:

Clifton et al. reported that mild hypothermia (33°C) after traumatic brain injury had no effect on outcome. We believe that the study results were negative at least in part because hypothermia was not initiated soon after injury. Furthermore, in randomized clinical trials, numerous variables that can affect outcome cannot be accounted for in the randomization nor controlled during the trial. For example, in this study, patients with spontaneous hypothermia were included in the normothermia group. In addition, the beneficial effects of hypothermia can be offset by suboptimal life support, and life support may have varied greatly among the participating hospitals.

Peter Safar, M.D.
Patrick M. Kochanek, M.D.
University of Pittsburgh, Pittsburgh, PA 15260
safarp@anes.upmc.edu

Author/Editor Response

Dr. Clifton replies:

To the Editor: Devices approved by the Food and Drug Administration (FDA) that measure brain temperature concurrently with intracranial pressure were not available until the study was near completion. We did not think that we should use non–FDA-approved devices in a trial in which consent was waived for many patients. Although it would have been useful to measure brain temperature in the study, the limiting factor in the depth of hypothermia is the core temperature, because at core temperatures below 30°C there is a risk of ventricular arrhythmias.1 As stated in the article, we used the standard classification system based on computed tomography to examine for subgroup effects and found none.2

Patients were not stratified according to the presence or absence of spontaneous hypothermia, and therefore the treatment groups were not balanced with respect to this variable. Spontaneous hypothermia was not known beforehand to affect outcome. There were no other imbalances between the treatment groups with respect to any variable known to affect the outcome of brain injury, and therefore there is no reason to believe that such imbalances could have affected the outcome. We agree that the overall negative results were probably due to the initiation of hypothermia too long after injury. This may account for the apparent benefit of the maintenance of hypothermia in patients with spontaneous hypothermia.

Although management of the patients' cerebral perfusion pressure varied among the hospitals within the boundaries defined by the protocol, there were no differences between the treatment groups with respect to cerebral perfusion pressure3,4 (and unpublished data). There are no data to support the supposition that differences between the groups in management influenced the outcome of the study.

Guy L. Clifton, M.D.
University of Texas–Houston Medical School, Houston, TX 77006
guy.l.clifton@uth.tmc.edu

4 References

1. 1

   Clifton GL, Allen SJ, Berry J, Koch SM. Systemic hypothermia in treatment of brain injury. J Neurotrauma 1992;9:Suppl 2:S487-S495
   Web of Science | Medline

2. 2

   Marshall LF, Marshall SB, Klauber MR, et al. A new classification of head injury based on computerized tomography. J Neurosurg 1991;75:Suppl:S14-S20
   Web of Science

3. 3

   Polderman KH, Girbes ARJ, Peerdeman SM, Vandertop WP. Hypothermia. J Neurosurg 2001;94:853-858
   Web of Science | Medline

4. 4

   Clifton GL. Hypothermia. J Neurosurg 2001;94:855-858
   Web of Science

Citing Articles (3)

Citing Articles

1. 1

   Salvatore Chibbaro, Fedreico Di Rocco, Giuseppe Mirone, Marco Fricia, Orphee Makiese, Paolo Di Emidio, Antonio Romano, Eric Vicaut, Alina Menichelli, Alisha Reiss, Joaquim Mateo, Didier Payen, Jean Pierre Guichard, Bernard George, Damien Bresson. (2011) Decompressive Craniectomy and Early Cranioplasty for the Management of Severe Head Injury: A Prospective Multicenter Study on 147 Patients. World Neurosurgery 75:3-4, 558-562
   CrossRef

2. 2

   Harald G. Fritz, Reinhard Bauer. (2004) Secondary Injuries in Brain Trauma: Effects of Hypothermia. Journal of Neurosurgical Anesthesiology 16:1, 43-52
   CrossRef

3. 3

   T. Frietsch, A. Piepgras, P. Krafft, S. Schwab, W. Kuschinsky, K. F. Waschke. (2002) Acid-base management - is it relevant for the study design of hypothermic neuroprotection?. European Journal of Anaesthesiology 19:6, 389-394
   CrossRef