Halothane…yes halothane!

Charles J. Cote’ MD FAAP and Myron Yaster MD

I’ve got to admit that I loved halothane and when sevoflurane was introduced in the early 1990s, I resisted halothane’s replacement with what I thought was an inferior drug.  When I anesthetized a kid with halothane, they lost consciousness very quickly and they were deep, and I do mean deep after just a few minutes of spontaneous ventilation.  Indeed, because the vaporizers allowed delivery of 5% halothane, one could achieve 4-5 MAC very quickly.  Thus, unlike sevoflurane, within a 2 or 3 minutes, there was no movement when the IV was inserted.  To achieve a similar depth of anesthesia, the sevoflurane vaporizer would have to be calibrated to allow 15% sevoflurane rather than the 8% on current vaporizers (see more on this in Charlie’s comments below).  Halothane was such a great, sweet smelling, easy to breathe, and inexpensive vapor anesthetic that I must admit I still miss it.  Further,  I used to jokingly tell my residents and fellows that halothane was an inhalational and titratable beta blocker (or calcium channel blocker).  Indeed, this property made it ideal in certain conditions like Tetralogy of Fallot or when trying to produce deliberate hypotension in large blood loss cases.  Of course there were problems, particularly cardiac depression and intraoperative cardiac arrests in very young children and its potential for hepatotoxicity.   

Most of you have never used halothane and know of it primarily because it is the basis of so many questions on the written anesthesia board examinations.  Today’s PAAD by Rob Friesen ¹ and its accompanying editorial by Kwinji² are simply terrific and I would urge all of you to read them in their entirety, particularly if you are in training. 

By the way, Rob Friesen is a very close friend and colleague who was a pioneer in the use of halothane in the newborn.  He is a Robert M. Smith award winner and has made many other contributions to our field.³ Today’s PAAD is a tour de force and provides foundational information on newborn cardiac physiology.

A final thought.  When halothane was removed from the Hopkins formulary, I took (Ok stole) one of the vaporizers and had a friend convert it into a desk lamp.  The vaporizer dial was turned into a rheostat that could control the light’s brightness.  Unfortunately, when I moved to Colorado I lost it in the move. Dr. David Polaner has one of these lamps and I’ll try to get a picture to share with all of you. Finally, if any of you have one of these old vaporizers let me know and I will be happy to buy it from you!  Myron Yaster MD

Original article

Friesen RH. The halothane era in pediatric anesthesia: The convergence of a cardiac depressant anesthetic with the immature myocardium of infancy. Paediatr Anaesth. 2024 Jul;34(7):592-596. doi: 10.1111/pan.14840. Epub 2024 Jan 17. PMID: 38231007

Editorial

Ndikontar Kwinji R. Halothane: Why we still use it. Paediatr Anaesth. 2024 Jul;34(7):590-591. doi: 10.1111/pan.14900. Epub 2024 Apr 15. PMID: 38619502

Today’s PAAD is a historical review of halothane’s pharmacology and the reasons for its replacement by sevoflurane in North America and other high income countries.¹ It is also accompanied by an editorial from an anesthesiologist from a low income country in Africa (Camaroon).²  Friesen provides a physiologic framework for the hypotension and  cardiac arrests that occur during halothane anesthesia, particularly in neonates. Conversely Dr. Kwinji points out that halothane is very, very inexpensive, just a fraction of the cost of sevoflurane. It is because it so much cheaper than sevoflurane making it the vapor anesthetic of choice in low income countries.

Let’s look more closely as to why the problem arose with halothane and why sevoflurane seems to have a better safety profile. The wash- in of anesthetic agents is determined by the inspired concentration, alveolar ventilation, functional residual capacity (these determine delivery of anesthetic to the lungs), and cardiac output, solubility and alveolar to venous partial pressure gradient (which determine uptake from the lungs).  Thus, due to  a larger alveolar ventilation to functional residual capacity ratio in infants (secondary to their greater metabolic rate), a more rapid uptake is likely with the more soluble halothane compared with less soluble sevoflurane and thus a more rapid pharmacologic response. The uptake of more soluble agents (halothane) will be more rapid than with less soluble agents (sevoflurane); this explains in part the rapid onset of myocardial depression in neonates compared with older patients, particularly during controlled or assisted ventilation.  This also means that the adjustment of anesthetic depth is more rapid with less soluble agents (sevoflurane) than more soluble agents (halothane). Additionally, since the blood solubility of halothane is less in neonates compared with adults vs sevoflurane, where it is nearly the same as adults, there is a more rapid anesthetic effect with halothane in neonates compared with sevoflurane. The net effect is that it takes longer to achieve a given depth of anesthesia with sevoflurane than with the more soluble halothane thus providing a “safety factor”.  Conversely, as anesthesia is deepened, spontaneous alveolar ventilation is depressed (negative feedback loop) which then reduces uptake of anesthetic agent providing another “safety factor”. When I  (CC) was still in practice, I used to teach my residents and fellows that with halothane one should never initiate controlled ventilation until an intravenous was in place which would allow administration of relaxant (and reduced inspired concentrations of inhalation agent) and/or the administration of atropine should bradycardia result.  In fact I used to say “controlled ventilation equals cardiac arrest when using halothane”.  This brings us back to the editorial by Dr. Kwinjii where he emphasized the importance of experience in pediatrics. Similarly, I (MY) would teach/preach that when the halothane vaporizer was cranked up to it maximum (5%), one had to keep their hands on the dial and once consciousness was lost to dial it back down to 2-3%.

Regarding hypotension it is interesting to look back at the original MAC papers for halothane and later sevoflurane by Lerman et al. In these studies the administration of inhalation agents was very slow and controlled.  Interestingly the incidence of hypotension at one MAC sevoflurane  in neonates ≤30 days of age was  8 out of 12 patients with systolic blood pressures reduced 34 ± 16%.⁴  In contrast, in his earlier study of halothane the incidence of hypotension defined as >30% decrease in systolic blood pressure from baseline was 4 out of 12 neonates.⁵  Thus, with carefully titrated doses of either agent the adverse effects on blood pressure were the same. In another study Holzman et al found a 12.5% reduction in systolic blood pressure at 1 MAC halothane and 7.5% with 1 MAC sevoflurane which returned to awake values at 1.5 MAC with both anesthetics.⁶  This observation again reflects the importance of a slow titrated administration of either agent or avoiding rapid administration of high doses. (I have done single breath inductions in older cooperative children but then rapidly reduce the inspired concentration as soon as consciousness is lost.)

Okay now let’s look at the real culprit: the design of the vaporizers.   A halothane vaporizer allows administration of up to 5% halothane which is about 5.75 MAC multiples but a sevoflurane vaporizer allows 8% sevoflurane which is about 2.42 MAC multiples.  So, if you put the petal to the metal and you control respirations cardiac arrest/death may result when using halothane!!

Halothane is a wonderful drug as Dr Kwinjii points out particularly for airway endoscopic procedures but you must understand its pharmacology and the nuances of the equipment we have available for its administration. Just remember don’t control ventilation until you have secured IV access and remember if you see ventricular arrhythmias, even ventricular tachycardia it is usually either due to light anesthesia or hypercarbia.  You do not need to change agents or administer antiarrhythmic medications, at this point simply deepening the anesthetic and reducing the ETCO2 will resolve the arrhythmia. ^{7 8}

Finally, why are the myocardial depressant effects of  halothane in the newborn and young infants so profound?  Friesen goes through a step by step analysis.  Essentially, “neonatal heart function is characterized by poor ventricular compliance, poor contractility due to fewer contractile elements and immature sympathetic innervation, and impaired mechanisms for storage and exchange of calcium in the sarcoplasmic reticulum. Halothane is a drug that depresses cardiac contractility, primarily through its effects on calcium ion flux in the sarcoplasmic reticulum.”¹  Further, as Kwinji reminds us, cardiac output in the newborn is very much heart rate dependent and halothane (as an inhalational beta blocker) slows the heart rate and blocks the baroreceptor response to falling blood pressure.  Thus (pre)treatment with atropine is a necessary component of safe administration of halothane.

I would love to hear your experiences with halothane. Send your thoughts and comments to Myron who will post in a Friday reader response.

References

1.            Friesen RH. The halothane era in pediatric anesthesia: The convergence of a cardiac depressant anesthetic with the immature myocardium of infancy. Paediatric anaesthesia. Jul 2024;34(7):592-596. doi:10.1111/pan.14840

2.            Ndikontar Kwinji R. Halothane: Why we still use it. Paediatric anaesthesia. Jul 2024;34(7):590-591. doi:10.1111/pan.14900

3.            Twite MD, Ing RJ, Nichols CS, Yaster M. Outstanding contribution to pediatric anesthesiology: An interview with Dr. Robert H. Friesen. Paediatric anaesthesia. Oct 2017;27(10):991-996. doi:10.1111/pan.13215

4.            Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology. 1994 1994;80(4):814-824. Not in File.

5.            Lerman J, Robinson S, Willis MM, Gregory GA. Anesthetic requirements for halothane in young children 0-1 month and 1-6 months of age. Anesthesiology. 1983 1983;59(5):421-424. Not in File.

6.            Holzman RS, van der Velde ME, Kaus SJ, et al. Sevoflurane depresses myocardial contractility less than halothane during induction of anesthesia in children. Anesthesiology. 1996 1996;85(6):1260-1267. Not in File.

7.            Rolf N, Coté CJ. Persistent cardiac arrhythmias in pediatric patients: effects of age, expired carbon dioxide values, depth of anesthesia, and airway management. Anesth Analg. Dec 1991;73(6):720-4. doi:10.1213/00000539-199112000-00008

8.            Anderson BJ, Lerman J, Coté CJ. Pharmacology of Drugs Used in Children. In: Coté CJ, Lerman J, Anderson BJ, eds. A Practice of Anesthesia for Infants and Children. 7th ed. Elsevier; 2024:chap 5.