To the Editor:
Takeda et al.1 are to be congratulated for carrying out a series of experiments in monkeys and man in developing and evaluating a minimally invasive technique to selectively lower brain temperature. There are, however, a number of questions concerning the methodology and experimental design, which should be mentioned.
It should be noted that 10 monkeys were involved in this study, five of which were subjected to 30 min of cooling after cardiac arrest and resuscitation, whereas the remaining five served as the controls and arrested, resuscitated but not cooled for 30 min. Because pharyngeal cooling was the principal variable, would it not have been more appropriate to include a third arm to this animal study to carry out anesthesia, no cardiac arrest and resuscitation but use pharyngeal cooling for 30 min. This would give a control with the brain being cooled without arrest and further test the efficacy of cooling in the normal brain.
The article noted the use of laser Doppler flowmetry for monitoring cerebral blood flow with the cerebral blood flow more pronounced in the pharyngeal cooling group than in the control. In absolute terms, namely mmHg/100 qbrain/min what flows were calculated? Were upper and lower limits of antoregulation of cerebral blood flow also determined before arrest and after resuscitation?
The small decreases in tympanic temperature in the clinical cases may in part be due to the measurement error inherent in the tympanic membrane technique, but is also possibly due to the inadequate thermal exchange using a flow rate of 500 ml/min with water entering at 5°C. With the monkey weighing on the average of 8.9 kg, the brain having a weight of about 0.36 kg, and accepting a cerebral blood flow of 50 ml/100g/brain/min, the caloric interchange was adequate to achieve the decrease noted. However, with the human brain weighing at an average of 1,200 grams, the blood volume going into the brain is in the order of approximately 5–6 l/min, making the caloric gradients on the negative side when 500 ml/min perfusate at 5°C was employed. This writer is familiar with this problem in that he participated in experiments related to direct cooling of the spinal cords of Rhesus monkeys2 and found that a normal saline perfusate bathing the cord at a flow rate of 100 ml/min entering between 2° and 5°C was able to reduce intrinsic spinal cord temperatures to 10°C within 20 min. In the human spinal cord, because of its larger mass and vascularity, flow rates of 1.0 l/min with perfusate at 2.0°–5.0°C was needed to overcome the higher caloric gradient to reach 10°C in the spinal cord.
This writer feels that with the apparent demonstration of minimal side effects resulting from this technology, and the ability to lower brain temperature while keeping body core at or near normothermia, the authors should design and carry out another subhuman primate study that would determine the lowest temperature levels in brain, whichmight be achieved with this technique without impinging seriously on body core temperatures.
No mention was made as to the clinical background of the three patients treated with pharyngeal hypothermia. How long before pharyngeal cooling were the patients in the intensive care unit and what were their Glasgow Coma Scale levels?
A major concern with this article is the lack of thoroughness in the bibliographic review. The area of experimental and therapeutic hypothermia is indeed rich with extraordinary information waiting for the patient investigator to mine it. Interestingly, from a historic perspective, 47 yr ago, Brown et al.3 produced a striking brain-body temperature gradient in canines by naso-oral perfusion and head immersion using cold saline as the hypothermic medium. Within 20–38 min (median time, 32 min), intracerebral temperatures less than 20°C were reached with right atrial temperatures stabilizing between 30° and 33°C. Termination of perfusion allowed for rewarming of the brain from the warmer body core without eye injuries or neurological deficits.
In 1973, Albin et al.4 reported on differential brain cooling using cephalic immersion similar to the method reported by Brown et al. in six canines and five Rhesus monkeys. In both species, a brain target temperature of 30°–31°C was reached in less than 15 min, with the core temperature at or near normothermia. In two monkeys, cerebral blood flow was measured using Xe 133 injected through a catheter placed in the common carotid artery after ligation of the external carotid, with a marked decrease in cerebral blood flow occurring from preperfusion levels on reaching 30°C in brain. No behavioral or neurological deficits were noted in these two monkeys after 6 weeks of observation.
Another more recent publication not cited in the report of Takeda et al., was published in 2011 by Abu-Chebl et al.5 in which they described yet another technique to produce pharyngeal and brain cooling. They achieved this by the insertion of nasal catheters that spray a perfluorocarbon-oxygen mixture into the nasopharynx to achieve cooling. This technique was used in a safety and feasibility study of intubated brain-injured patients for whom temperature reduction was indicated. The aim of reducing core temperatures by 1.0°C within 1 h was met in 14 of the 15 cases, with hypertension occurring in one patient leading to discontinuation of therapy. The authors noted that there were no nasal complications with this modality.
This writer is forced to add that in spite of the very sophisticated information technology we have today, science did exist earlier than the 21st century. Winston Churchill once noted, “The farther backward you can look, the farther forward you are likely to see.”