Re: Feasibility and Safety of Moderate Hypothermia After Massive Hemispheric Infarction
To the Editor:
We read with great interest the article by Schwab et al regarding hypothermia in acute ischemic stroke.1 The authors should be commended on their important work that possibly paves the way toward a randomized study exploring the efficacy of this mode of therapy in acute stroke. However, there are several points that merit further discussion before such a study could commence. Hypothermia is considered to be one of the most powerful methods of inducing cerebral protection in models of cerebral ischemia, hypoxia, and trauma.2–5⇓⇓⇓ Postulated mechanisms of action of hypothermia include lowering excitatory amino acid secretion and downregulation of glutamate receptors,5,6⇓ diminished production of reactive oxygen species,7 reduced consumption of tissue antioxidants, and reduced inflammatory response.8,9⇓ Other postulated mechanisms include a nonspecific lowering of cerebral metabolic rate,10 and changes in cerebral blood flow.11 However, as is the case with other potential neuroprotectants, mild hypothermia has long-term protective effects only when started either during or shortly after the injury.4 In their study, Schwab et al1 began to cool their patients relatively late after ischemic onset (mean 9±22 hours [range 4 to 75 hours]), which might have reduced the efficacy of this method of neuroprotection. We are told, however, that some of the patients were cooled relatively earlier than others, and it would therefore be important to learn whether these patients had better outcome parameters than those who were cooled at later time points following the injury. Moreover, since hypothermia is suggested to work by neuronal protection and not merely by reducing intracranial pressure, it would be interesting to learn whether the early institution of hypothermia resulted in smaller infarcts (as depicted by neuroimaging) as compared with the late onset of hypothermia and to historical controls.
It is not a secret that despite its protective capabilities, hypothermia may also lead to a number of important side effects as detailed by Schwab et al.1 At least a few of these side effects may be related to the depth of hypothermia. Thus, several authors have shown that mild hypothermia produced by lowering the core temperature to 33°C or 34°C suffices to produce neuroprotection.4 Nevertheless, Schwab et al have lowered the core temperature further and that might also have contributed to the relatively large number of complications observed in the current study.1 It is therefore possible that in future studies, use of milder degrees of hypothermia could reduce the complication rate and improve the efficacy.
Another point that needs more specific attention is that of the effect of rewarming on the final outcome. Previous experimental data have shown that too rapid rewarming may result in excess mortality and disability in animal models12 and human data.13 However, the patients in the current trial were passively rewarmed at a relatively rapid pace (11 to 24 hours), and this may have limited the clinical efficacy and led to a rebound rise in intracranial pressure as suggested by the authors. Therefore, we would suggest that in future larger trials exploring hypothermia as a possible neuroprotectant in stroke, the rewarming phase would be longer and rewarming should be much more gradual over a few days.
Thus, experimental data from animal studies have proven hypothermia to be a very promising method for establishing neuronal protection. It seems that in order for similar results to be obtained in humans, one needs to adhere more closely to the timing of hypothermia initiation and rewarming and the depth of hypothermia that would produce the best results in humans with the minimal number of side effects.
- ↵Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke. 2001; 32: 2033–2035.
- ↵Maier CM, Ahern K, Cheng ML, Lee JE, Yenari MA, Steinberg GK. Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke. 1998; 29: 2171–2180.
- ↵Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke. 1989; 20: 904–910.
- ↵Ishikawa M, Sekizuka E, Sato S, Yamaguchi N, Inamasu J, Bertalanffy H, Kawase T, Iadecola C. Effects of moderate hypothermia on leukocyte-endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke. 1999; 30: 1679–1686.
- ↵Yager JY, Asselin J. Effect of mild hypothermia on cerebral energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat. Stroke. 1996; 27: 919–925;discussion 926.
- ↵Verhaegen MJ, Todd MM, Hindman BJ, Warner DS. Cerebral autoregulation during moderate hypothermia in rats. Stroke. 1993; 24: 407–414.
We appreciate the interest of Drs Leker and Ovadia in our study. As they point out, many of the proposed mechanisms of hypothermia are beneficial only in a very narrow time window after the neuronal injury. In experimental stroke, this time window varies between 60 to 180 minutes after occlusion of the middle cerebral artery. Clearly, an ultra early treatment would be desirable. Still, this is currently not feasible. We would like to point out that, no matter how thrilling the prospect of hypothermia for neuroprotection may be, we applied this treatment only to reduce brain edema formation. The question of the effectiveness of hypothermia for neuronal protection cannot be answered on solid grounds. As we stated in our article, earliest induction of hypothermia was 10 hours after symptom onset, clearly a time window way beneath all experimental suggestions. Therefore it does not seem justified to analyze the difference between relative early or delayed induction of hypothermia. An ideal experiment to evaluate this in the clinical practice would be to look at the effect of very early cooling (<34°C attained within 6 hours of onset), using MR perfusion and DWI as each patient’s baseline predictor of the expected final infarct volume.
As stated in our article, target temperature in our patients was 33°C. A further decrease was not always avoidable. We recently reported our experience with an endovascular cooling catheter, an approach that may allow a better temperature control, thus avoiding significant deviations from target temperature.1 With the emerging catheter technology, it may allow more rapid cooling as well as more precise temperature control.
The two other points mentioned by Leker and Ovadia are well taken but difficult to answer. We have no data concerning the optimal temperature of hypothermia. So far, all studies have used target temperatures of 33°C to 34°C. It therefore seems prudent to choose similar target temperatures, in order to be able to compare effects and side effects. It is purely speculative whether milder degrees of hypothermia would produce fewer and less severe side effects. The same holds truth for the speed of rewarming. A recent study from our department illustrates the importance of slow and controlled rewarming.2 The technical feasibility, though, remains doubtful, unless we have potent cooling devices to achieve exact temperature control. We feel that additional hypothermia trials examining different depths of cooling are sure to follow in the coming years.
Overall, as is true for many facets of stroke care, it would be desirable to stick as close to the experimental evidence as possible, but as we had to learn in many negative neuroprotectant trials, men and mice are different.
- ↵Georgiadis D, Schwarz SD, Kollmar R, Schwab S. Endovascular cooling for patients with severe MCA infarction: first results of a novel approach. Stroke. 2001; 32: 2550–2553.
- ↵Steiner T, Friede T, Aschoff A, Schellinger PD, Schwab S, Hacke W. Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery. Stroke. 2001; 32: 2833–2835.