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A brief history of ketamine (Ketalar®)

My advocacy of the routine use of ketamine (Ketalar®) in adults for day surgery cases has made me a lightning rod for enormous criticism since 1993. If you are not familiar with the controversies around the use of ketamine, here is a quick history

In the 1950s, postoperative pain was treated with morphine or meperidine (Pethidine® or Demerol®), often under-treated for 2 reasons:

  1. the unfounded fear of producing opioid addiction
  1. the all-too-real problem of over-treatment, apnea and death

N.B. There was no naloxone (Narcan®) or pulse oximetry until much later than the 1950s.

The researchers of the day postulated that, if another class of drugs could be developed that would ameliorate pain without respiratory depression, patients could be better treated for postop pain without under or over treatment.

The first class of drugs explored was the phencyclidines. The parent compound, phencyclidine phosphate, was marketed as Serenyl® by ParkeDavis in 1958 but was quickly withdrawn from the market because of undesirable side effects; i.e. hallucinations. Later, phencyclidine phosphate became better known by the initials, PCP.

The researchers did not give up quickly on this class of compounds and about 6 years later they began experimenting with a modified PCP molecule, ketamine, which received FDA approval in humans in 1971.

The drug, like its predecessor, was introduced as the 'silver bullet,' the complete, total IV agent. Meaning no other agents were needed.

Unfortunately, some of the first patients to receive ketamine for their anesthesia were women having elective termination of pregnancy, as abortions were delicately referred to then. Can you even begin to imagine the horrific dysphorias and hallucinations these poor patients experienced and how the recovery room nurses felt about ketamine?

Ketamine quickly gained a reputation as a safe drug but one not too good for adult patients. It did become popular in children's burn units, especially for the extremely painful dressing changes.

During my residency at Stanford 1975-7, I was introduced to using ketamine in small doses (10-20 mg) prior to positioning elderly patients to get spinal anesthesia for pinning their fractured hips.

It turns out that neither the very young nor the very old were particularly susceptible to ketamine associated hallucinations or dysphorias.

The veterinarians also picked up on ketamine, quickly realizing that it was nearly impossible to kill an animal, even if the per body weight dose was more than 2X the recommended amount. Also, the animals did not complain about hallucinations.

Bottom line: ketamine, a safe drug but one that 2 generations of anesthesiologists had given a wide berth to for use in adult day surgery.

Sometime during the mid-1970s, a Las Vegas plastic surgeon, Charles Vinnik, began tiring of listening to his patients cry out when he injected local anesthesia under diazepam (Valium®) and meperidine IV sedation. Even though the patients had amnesia for the experience, the cries were distressing to the OR staff. He asked his anesthesiologist if there was anything else he could use that would eliminate the distressing reactivity of the patients. Ketamine was suggested.

Through trial and error, Vinnik came upon the initial dose of 75 mg independent of body weight to prevent the patients from either moving or crying out after they were rendered sleepy from incremental doses of intravenous Valium.

Although Vinnik published his ‘secret’ to using ketamine (i.e. sleep first, then dissociation) without the dreaded hallucinations or dysphorias, the 1981 paper appeared in the plastic surgery literature. Vinnik’s ‘secret’ lay largely unnoticed in the anesthesia community until I heard him speak in Newport Beach in December 1991 and subsequently visited his office operating room in March 1992.

I considered Vinnik’s use of ketamine productive but ruled out Valium as a useful drug for day cases. I thought that propofol might be a better fit for this purpose but could find nothing in the anesthesia literature to support what I thought was a reasonable extension of Vinnik’s concept of ‘sleep first, then dissociation.’ see Friedberg BL: Hypnotic doses of propofol block ketamine induced hallucinations. Plastic & Reconstructive Surgery 91:196,1993.

In the 1990s, ketamine became a drug of abuse, a 'rave' drug and later lumped together with Rohypnol & GHB as 'date rape' drugs.

If you haven't given up on my narrative, are you beginning to get a sense of the large pile of excrement into which I stepped by trying to promote the use of propofol & ketamine for office-based cosmetic surgery?

After five years of performing propofol ketamine (PK) intravenous sedation, I learned about the bispectral index (BIS) monitor for measuring propofol effect. My surgeons kept clamoring for a less expensive way to give propofol. The BIS monitor appeared to offer more promise than my previous efforts with midazolam premedication. see Friedberg BL, Sigl JC: Bispectral (BIS) index monitoring decreases propofol usage in propofol-ketamine office based anesthesia. Anesthesia & Analgesia 1999;88: S54. & Friedberg BL, Sigl JC: Clonidine premedication decreases propofol consumption during bispectral (BIS) index monitored propofol-ketamine technique for office based surgery. Dermatologic Surgery 2000:26; 848-852.

In many third world countries, ketamine infusions are still to be found as the drug was originally marketed. However, as propofol has become very inexpensive, more anesthesia providers from third world countries have accessed my web site to obtain information with which to execute my paradigm for PK.

Ketamine, ironically, turned out to be the perfect adjuvant drug, not the complete and total intravenous agent its makers originally intended it to be, at least in the western world.

Brain monitored PK IV sedation is less expensive, safer, simpler and gives better outcomes (i.e. no PONV & minimal postop pain).

With ability to stratify anesthesia outcomes by depth of anesthesia, the negative effects of routine anesthesia over-medication (i.e. BIS <45), studies have demonstrated more apparent negative effects from this practice. most recently Leslie K, Myles PS, Forbes A, Chan MTV: The Effect of Bispectral Index Monitoring on Long-Term Survival in the B-Aware Trial. Anesthesia & Analgesia 2010;110 816-822.

Postoperative cognitive dysfunction (POCD) is the sterile name for the pseudo-Alzheimer’s type of confusion seen more often in elderly patients. Sometimes this lasts hours, day weeks or months. Sometimes the effects are not transitory.

The brain monitored PK IV sedation technique also gives providers the ability to refrain from the nefarious practice of routinely over-medicating patients for fear of under-medicating them.

VIDEO: Dr Barry L. Friedberg' s speach at the Biennal Pan Pacific Surgeon’s Meeting in January, 2010
PK Anesthesia: Making Your Office/Outpatient Anesthesia Practice Safest

 

Author:
Dr. Barry L. Friedberg M.D., A.M.C

    
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