Correspondence  |   October 2012
Neurotoxicity: Rats versusNeonates
Author Affiliations & Notes
  • Maurice Lippmann, M.D.
  • *Harbor-University of California, Los Angeles Medical Center, Torrance, California.
Article Information
Correspondence   |   October 2012
Neurotoxicity: Rats versusNeonates
Anesthesiology 10 2012, Vol.117, 923-924. doi:10.1097/ALN.0b013e318267375d
Anesthesiology 10 2012, Vol.117, 923-924. doi:10.1097/ALN.0b013e318267375d
To the Editor: 
We just finished reading, in the March 2012 issue, the excellent editorial by Dr. Davidson entitled “Neurotoxicity and the Need for Anesthesia in the Newborn.”1 We wish to make a few comments. It is quite true; neonates have no explicit memory and when receiving no anesthesia for a particular surgical procedure (i.e.  , patent ductus arteriosis) will never remember what took place should they survive. These patients need to be immobile (muscle relaxant only) to suit the surgeon, but do they really need an analgesic to cloud their minds when the surgeon makes his incision? Is the central nervous system and brain at this moment really intact and mature to perceive pain sensation during an operation? Because neonates are very small, underweight, and not mature at this age, why make them totally unconscious or even semiconscious? The nervous system and brain are not developed to any great degree, so they won't feel anything. In the late 1960s and middle to late 1970s,2  4 neonates undergoing ligation of patent ductus arteriosus were semiconscious or totally conscious, had a muscle relaxant, had no narcotic for pain nor sedative and still survived with no neurotoxicity and no bad memories after growing up. These neonates showed no signs of distress during their procedure. One does not need a volatile anesthetic, potent narcotic, propofol, or other sedatives. If an anesthesia provider is worried about neurotoxicity of anesthetic drugs and agents, then the provider shouldn't administer the drugs. Performing research on animals such as rats and finding that certain medications and anesthetics cause neurotoxicity cannot or should not be extrapolated to humans. This research should be carried out in humans to confirm the hypothesis. It may be unpopular to say or suggest that neonates do not always need a hypnotic agent or such, but the fact remains many do not. Anesthesia providers (clinicians) must decide their technique based on factors such as patient height, weight, age, American Society of Anesthesiology class, surgical procedure, risk, and outcomes.
Again, data based on rat experiments5 should not be extrapolated automatically to humans. More research on humans is needed. The article3 was presented at the World Congress of Anesthesiology in 1976, Mexico City. The only question to arise was, “Did the neonate feel any pain?” The answer at the time was the same as now: “Does the neonate have a developed central nervous system and brain to perceive pain?” Is it developed? We do not know the exact answer to this very day. So the quandary still exists, and rat studies will not tell us emphatically, but if drugs and anesthetics are neurotoxic, then the clinician had better be careful in his decisions. The clinician must also be aware that administering an opioid to a very sick neonate could cause hypotension leading to a low pressure, which then leads to poor perfusion to vital organs, especially the heart and lungs, and poor perfusion to the central nervous system and brain. That is neurotoxicity.  Also poor perfusion to the intestinal tract, which could lead to bowel necrosis. Sedatives and potent volatile inhalation anesthetics might cause the same effect in sick neonates.
To reiterate, the author of the editorial is quite correct in stating that neonates may not need anesthetics or analgesics for various surgeries because of undeveloped central nervous system and brain functions, even though four6  9 of his references state the opposite. Those studies that led to publications took care of infants (babies) and not true neonates. Their papers6  9 plainly show on the day of surgery, their weight, gestation were all in the small baby stages and not true  neonates, which in the true sense is an infant within the first 4 weeks of life and not weighing more than 3–4 kg in some instances. The study by Gruber et al.  9 deals with babies 3–4 months old and weighing 4.5–5.1 kg. The Anand patients6  8 weighed approximately 3.5–3.6 kg, which is far from a neonate's weight. Gruber's patients9 had cardiac surgery via  cardiopulmonary bypass. No wonder they had general anesthesia. Therefore, these authors mixed up the definitions of neonates and babies like apples and oranges.
Davidson AJ: Neurotoxicity and the need for anesthesia in the newborn: Does the emperor have no clothes? ANESTHESIOLOGY 2012; 116:507–9
Cleveland RJ, Nelson RJ, Emmanoulides GC, Lippmann M, Bloomer WE: Surgical management of patent ductus arteriosus in infancy. Arch Surg 1969; 99:516–20
Lippmann M, Nelson RJ, Emmanouilides GC, Diskin J, Thibeault DW: Ligation of patent ductus arteriosus in premature infants. Br J Anaesth 1976; 48:365–9
Nelson RJ, Thibeault DW, Emmanouilides GC, Lippmann M: Improving the results of ligation of patent ductus arteriosus in small preterm infants. J Thorac Cardiovasc Surg 1976; 71:169–78
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Anand KJ, Sippell WG, Aynsley-Green A: Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: Effects on the stress response. Lancet 1987; 1(8527):243–8
Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A: Does halothan anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation? Br Med J (Clin Res Ed) 1988; 296:668–72
Anand KJ, Hickey PR: Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326:1–9
Gruber EM, Laussen PC, Casta A, Zimmerman AA, Zurakowski D, Reid R, Odegard KC, Chakravorti S, Davis PJ, McGowan FX Jr, Hickey PR, Hansen DD: Stress response in infants undergoing cardiac surgery: A randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg 2001; 92:882–90