Nimbex Is Dead. Long Live Sugammadex

I've been a lifelong fan of cisatracurium (Nimbex). It has been my neuromuscular blocker of choice ever since residency. Why do I love it so much? Let me count the ways.

I've found that Nimbex is very predictable in its metabolism. I've been burned badly before when I used another agent like rocuronium on a patient with renal insufficiency and the patient had incomplete reversal at the end of the case that necessitated reintubation. Not good for the patient or your reputation as an anesthesiologist.

Thanks to its Hoffman elimination, I don't have to worry about a patient's kidney or liver function. The drug just metabolizes at a very steady and predictable manner. This is particularly important when a patient may have an unknown issue with their renal or hepatic functions and suddenly you're wondering why the patient isn't waking up. Nimbex is also very easy to reverse. Neostigmine easily takes care of the drug and the patient emerges quickly. 

Sure you can't use Nimbex for rapid sequence induction but that's okay. Most cases don't require RSI anyway. Due to Nimbex's property of predictable reversal, I've stuck with it long after many of my colleagues switched to roc. But now that's all changed thanks to the miracle of sugammadex.

Sugammadex (Bridion) is a drug invented specifically to reverse the paralysis induced by rocuronium. But it also works with other aminosteroid compounds like vecuronium. I feel it has revolutionized NMB reversal the way propofol transformed the induction of anesthesia.

First of all, Bridion works very fast. I'm always amazed by how quickly a patient starts moving after it is given, even if there is still a fair amount of inhalational agents on board.

Rocuronium no longer needs to be carefully titrated in order for it to be reversible at the end of the case. This is especially relevant in procedures that finish rapidly like in ENT. Those cases always present the conundrum of the need for deep paralysis followed by a quick emergence. There's no greater predicament for the anesthesiologist than staring down at a patient with zero muscle twitches and an impatient surgeon wanting to get his next case started ASAP. Prior to sugammadex there was no way to reverse a deeply paralyzed patient effectively.

One can give roc to anybody with sugammadex. Before, I was always leery of using Bridion in dialysis patients because there was always a small chance that the reversal agent would wear off before the body has cleared the NMB. I have yet to see that happen. It's just as easy to wake up a patient with renal failure as a patient with normal kidney functions.

With all these advantages, rocuronium and sugammadex have become the combo of choice in our department. Nimbex use has practically disappeared. Bridion is in such high demand that our pharmacy is complaining about the high cost of the drug. Whereas one 200 mg vial of sugammadex costs about $100, one vial of neostigmine costs $10, and that can be used with multiple patients. Our sugammadex costs are now disrupting our pharmacy's budget because people are using it so often. In addition, the anesthesiologists frequently use more than one vial per patient as some are now becoming too lazy to titrate their NMBs properly.

Are there costs that are saved because we use so much sugammadex? One has to consider the cost benefit analysis for a weak patient in PACU that requires reintubation. What are the costs of prolonged OR use because the patient took a longer time than anticipated to wake up? What is the cost of the psychological trauma in a patient who is gasping for breath because he is too weak to breathe? Or the patient who is too weak to protect his own airway when extubated too early and she aspirates, requiring hospitalization for pneumonia? All these should be taken into consideration when calculating the cost of using sugammadex.

Are there downsides to sugammadex? I've already mentioned the exorbitant price of the drug. That hopefully will come down in a few years when the drug goes off patent and generics flood the market.

Worse than that though is that I think sugammadex makes anesthesiologists lazy and they lose an essential skill. It's a real art to titrate paralytic agents properly so it can be reversed quickly at the end of a case. It's not something that can be taught in a book since each patient is unique in their ability to metabolize NMBs and every surgical case is different. With sugammadex, it doesn't matter at all. This is particularly detrimental to the anesthesia residents. It is just as easy to wake up a patient with zero twitches as one with four twitches. There is no learning there. Just give more sugammadex! But they didn't learn anything about the art of controlling anesthesia.

This is all part of the long standing trend of making anesthesia ever faster and easier to use. From halothane to desflurane. Pentathol to propofol. Pancuronium to rocuronium. If we're not careful, anesthesia could become too easy to administer. There are plenty of people who would love to get anesthesiologists out of their procedure rooms. From gastroenterologists to cardiologists, having one less physician in the room would be a dream come true. If anybody ever makes reversal agent for propofol, anesthesiologists would soon be unemployed.

Your Inner Neanderthal May Be Causing You Pain

Are you the type of person who is sensitive to pain? Do you reach for the Percocet at the first sign of a headache? Perhaps it's not your fault that you are more acutely aware of pain than others. It maybe because of a Neanderthal gene you inherited eons ago.

Scientists who examined these ancient genes found a variant that alters an ion channel in nerve cells. This causes the channel to initiate pain perception more readily than those who don't have the gene. The Neanderthal genes are more commonly found in people of European and Central and South American descent.

So next time you tell your doctor that you need a refill of Norco along with a prescription of Dilaudid for breakthrough pain, tell her that it's not your fault. It's your Neanderthal genes making you sick.

Social Justice Anesthesia

Et tu Anesthesiology? Recently, medicine has come under fire for promoting ideas that are more akin to social justice ideology than medical facts. In a widely reported op-ed in the Wall Street Journal last year, Dr. Stanley Goldfarb, former associate dean of the University of Pennsylvania School of Medicine bemoaned the intrusion of topics like climate change and gun control into the already overburdened medical education system. This leaves less time for students to learn about actual disease processes and caring for the patients that are sitting in front of them.

Now the journal Anesthesiology has published a social justice article of its own. In the January 2020 issue, a paper by Angela Jerath, MD, et al, titled "Socialeconomic Status and Days Alive Out Of Hospital After Elective Noncardiac Surgery," the authors attribute  the environment that the patients come from for varying rates of successful care. Naturally those who live in the lowest quintile of median neighborhood household income had higher rates of postoperative complications and 30 day mortality. Sounds like something straight out of the Democratic party agenda.

I fail to see how this article has anything to do with anesthesiology. It reads more like something that should be published in Health Affairs. What am I supposed to do with this information? Am I supposed to accept that my poorer patients will have higher rates of complications and mortality? Am I supposed to lobby my Congressional representative to give everybody a basic universal income to lift them up to a different quintile of economic status? If Anesthesiology begins to pivot more to these social justice articles instead of publishing more information about how I can improve the anesthesia I administer to my patients, I'm going to find less need to read the journal.

How Does Anesthesia Work

This is a quick and surprisingly informative primer on how anesthesia works. Created by Dr. Steven Zheng, this cute animated video is a must see for any patient, and even medical students going through an anesthesiology rotation.

My favorite part is the illustration of an anesthesiologist mixing up drugs from a flask into a beaker like we are conducting chemistry experiments in the operating rooms every day. I only wish I was that smart. Some days I can barely get my electronic medical record to record properly.

I Heart Etomidate. And That's Alright.

I love etomidate. As our patient population gets older and sicker, I find myself using that drug more and more frequently. Unlike propofol, etomidate helps to maintain cardiac output and normal blood pressure upon induction. But we've been warned since residency that etomidate causes adrenal insufficiency and could potentially lead to an Addisonian crisis. Because of that, I've always been leery of administering the drug, with that caveat constantly in the back of my mind.

Now there is a new study that says it's okay to give etomidate for induction. In this month's issue of Anesthesiology, researchers from Vanderbilt University retrospectively examined over 3,000 patients undergoing cardiac surgery from 2007 to 2009. During that period, 62% were given etomidate as the induction drug. The study showed that etomidate was not associated with more hypotension, longer mechanical ventilation, longer hospital stay, or increased mortality.

Even though this study was based only on cardiac surgery patients, I find that the information will be useful for my every day practice. Many cardiac patients, with ejection fractions of 30% or lower, sometimes much lower, now undergo noncardiac procedures, like GI endoscopy, angiograms, pacemaker and defibrillator implants, and just plain old general surgery. As the life expectancy of heart patients increases with the use of devices like ICD's, ventricular assist devices, and even artificial heart implants, expect to see more of these tricky cases on the OR schedule for routine procedures like hernia repairs or lap chole's. Etomidate could become your new best pharmaceutical friend.

Masking A Patient. The Magic Number Is Fifteen.

In anesthesia residency, we were all taught how to gently induce anesthesia and intubate a patient. First we put the patient to sleep with the induction agent of choice, usually propofol. Once the patient was asleep we ventilated him with a face mask to be sure it could be done easily. When that was ascertained, then we gave our muscle relaxant to paralyze the patient for intubation. Masking the patient usually took about 90 to 120 seconds because we avoided using succinylcholine unless a rapid sequence intubation was desired. The reason we tried not to use sux was because of all its possible deleterious side effects, include hyperkalemia, malignant hyperthermia, and increased intracranial pressures. Plus patients frequently complained of whole body muscle aches during post op checks.

Now during those two minutes it took for the nondepolarizing muscle relaxants to work sufficiently for intubation, we had to mask the patient to prevent hypoxia. While doing this, we kept an eye on the peak airway pressure that was being applied to the patient. The magic number was 20 cm H2O. It was taught that using any more pressure to ventilate the lungs will also drive air into the stomach, distending it and possibly causing an aspiration. So we vigilantly looked at the pressure gauge to keep it just below the magical 20 line. Yet, no matter how careful I was, once the surgeon looked inside the abdomen during a procedure like a laparoscopic cholecystectomy, he would complain that the stomach is distended and I needed to drop in an orogastric tube to suction the air out. This isn't always easy to accomplish. The tube can be difficult to pass into the esophagus in the first place, coiling around itself in the mouth. Or it can get obstructed by a hiatal hernia in the lower esophagus. Or it can cause gastric mucosal bleeding from the suction during the case. Therefore placing an OG tube should not be taken lightly and, as with everything else we do, can be fraught with complications.

I always wondered how accurate that teaching of 20 cm H2O was. Now there is a study that lends credence to that age old dogma. In the February issue of Anesthesiology, researchers induced volunteers with propofol then ventilated them at peak airway pressures of 10, 15, 20, and 25 cm H2O. At the same time they used a stethoscope to listen for gastric air and an ultrasound to look for gastric distension and measure the size of the antrum.

What they found was that the stomach did distend in proportion to the pressures applied to the face mask. By listening to the stomach, the researchers found incidences of gastric insufflation ranging from 0% in the P10 group up to 41% in the P25 group. When visualized using the ultrasound, gastric insufflation went from 19% in P10 up to 59% in P25. The antral area when measured by the ultrasound did not significantly increase in size in the P10 and P15 groups while it was significantly increased in the P20 and P25 groups.

How well did the patients ventilate at these different pressures? As you would expect the greater the driving pressure, the higher the tidal volumes. With P10, the tidal volumes were only about 6 ml/kg. Tidal volumes were measured between 8 ml/kg and 12 ml/kg for the P15 and P20 volunteers. When the masking reached P25, the volumes shot up to 14 ml/kg.

Based on these results, the authors concluded that masking a patient up to 15 cm H2O gives a patient the greatest lung volumes with the smallest risk for gastric distension and aspiration. So my old attendings' lectures were not that far off. However, all of this would be moot if we could discover a nondepolarizing muscle relaxant that works as fast as sux without its side effects and dissipated just as quickly. Rocuronium currently comes the closest in rapidity of response. However it cannot be used in short cases due to its prolonged action. That is why the FDA's continued refusal to approve roc's reversal agent sugammedex is so disappointing. It has been used in Europe for years yet we can't get our gloves on it here. I wonder how many MH and other complications of sux could have been avoided in all these years if sugammedex had been approved for use in a timely manner. So in the meantime, keep masking those patients. Just keep it at 15 cm H2O or lower.

Anesthesia Exposure Will Make You A Bad Parent

At least that appears to be the case in laboratory mice. In this month's issue of Anesthesiology, researchers from Japan published a paper detailing their experience after giving six day old mice sevoflurane for six hours. Previous studies had demonstrated increased rates of neuronal deaths in young brains that have been exposed to general anesthesia.

After 7-9 weeks, the mice were then mated to other healthy mice and the resultant parental behaviors toward the new offsprings were documented. The results gave a rather stark demonstration of the latent effects of anesthesia on brain function. The control mice cared and fed their brood normally while the mice that were given sevoflurane showed a severe lack of maternal instincts. While 80% of the pups from the controls were well fed, only about 40% of the pups from sevo exposed mothers were fed.

The nesting instincts were also severely impaired. When the pups were randomly scattered around the cage, the control mice would retrieve all of them back to a central nest so they could be fed and kept warm. By contrast, the sevo mice took a much longer time to bring back the pups, frequently leaving them exposed throughout the bottom of the cage.

Consequently, as one can imagine, the survival of the pups were much different between the two groups. The pups from the control mice had an 80% rate of survival after 6 days. The sevo exposed mice had half of their pups die after only 2 days.

To test whether the effects of sevoflurane on maternal instincts can happen to adult mice, the researchers gave the anesthetic to mice who had just delivered one litter of pups. They found that the offsprings from subsequent pregnancies had no significant difference in care or survival compared to the controls. Thus it seems that sevo only made its impact on developing brains, not mature ones.

This study raises the potentially alarming question of the use of sevoflurane in human brain development. The anesthetic was first approved for use in the early 1990's. It quickly became the standard for inhalational induction in pediatric patients due to its rapid onset and low airway irritability. Many of those children are now young adults and of child bearing age. It will be interesting to follow up on the patients who received sevo for surgery twenty years ago and test them for their parenting skills and their children's developments. Will we see a surge of poorly raised or abandoned children in society? Only time will tell.

Can Anesthesia Prevent Dementia?

Patients often tell me after they have awakened from anesthesia, particularly propofol sedation, that it was the best sleep they ever had. They feel totally refreshed and often jokingly ask for some of the good stuff to take home with them. I always wondered what it is about propofol that makes patients feel so relaxed and carefree after its use.

Now in a fascinating Sunday Review article in the New York Times, researchers at the University of Rochester have identified a crucial neural cleansing function of the cerebral spinal fluid. It appears that the flow of CSF around the brain is significantly increased when the brain is in the sleep state. This is important because it is speculated that the byproducts of brain metabolism, like beta amyloids, if not removed from the nerve tissues and allowed to accumulate, can lead to long term dementia and Alzheimer's disease.

The researchers measured the CSF movement in mice using fluorescent markers. They then measured the flow of the fluids in sleeping mice. It turns out that when the mice were awake, the circulation was only five percent that of the sleep state. The amount of interstitial space between brain cells increased dramatically, allowing the CSF to penetrate deeper into brain tissue and extract the neuronal waste. The increased flow allowed the sleeping brain to be cleared out twice as quickly as the awake brain.

The interesting part is that this clearing mechanism also works when the mice are under anesthesia. The article doesn't specify the type of anesthetic used or how long the mice were anesthetized. But this should be a subject that the ASA and anesthesia researchers all over the world should be swarming over.

Imagine the implications this research could have if it pans out in humans. Dementia in the elderly is becoming an ever increasing burden in our society. Right now there is no treatment. The only things we can do to help these patients are to make sure they don't fall and break something or prevent them from aspirating. All that is a consequence of their worsening mental status which we are helpless to intervene. If anesthesia could lessen or eliminate the neural toxic waste that is thought to be the source of dementia, this would be a huge boon to mankind and a prestigious notch in the belt for anesthesiology, ranking right up there with Morton's first demonstration at MGH.

Imagine an office where patients with dementia would come to get anesthesia to help their brains get rid of its toxic waste. It would be similar to a dialysis clinic but staffed with anesthesiologists or anesthesia assistants. Patients would come a few times a week to get their scheduled anesthetic to prevent their Alzheimer's from deteriorating. The treatments would be expensive, but still cheaper than taking care of millions of debilitated patients that are currently draining our healthcare system. It would truly mark another golden age of anesthesia. I can't wait to see how this line of research works out.

Are We On The Threshold Of Perfect Anesthesia?

We are currently tantalizingly close to achieving perfect anesthesia. What is a perfect anesthetic? In my opinion, it should be a substance that has a rapid onset, zero to minimal side effects, and fast elimination. Several substances that are in the experimental stages are leading us toward this holy grail.

I recently mentioned the finding that methylphenidate, or Ritalin, has been discovered to quickly reverse the effects of propofol. The problem with giving propofol was that a patient's ability to regain consciousness depended on how quickly the drug is eliminated from the blood. Ritalin appears to stimulate the upper neural pathways that leads to more rapid emergence. Now with a combination of propofol and methylphenidate, a patient can be awakened at will without the anesthesiologist guessing how long the elimination time is for a particular person.

The next drug that will lead to the perfect anesthesia is Sugammadex. Even though Sugammadex has not been approved by the FDA for use in the United States, it has already been used in Europe for years. The drug rapidly reverses the paralyzing effects of rocuronium by wrapping itself around the rocuronium molecule, quickly making it unavailable to cause paralysis. Its effect works faster than even succinylcholine elimination, the current gold standard. The FDA denied Sugammadex approval because of some reported allergic reactions, which have been found to be minimal in medical studies. By contrast, succinylcholine is known to cause profound and feared complications, including hyperkalemia, muscle rigidity, cardiac arrhythmias, allergic reactions, and even death. Sux is one of those drugs that, if it had not been grandfathered in by the FDA decades ago, would never be approved today. But it is the only muscle relaxant that can achieve such rapid onset of paralysis required for emergency endotracheal intubation. Rocuronium can achieve similar onset of paralysis with none of the side effects of succinycholine. But its drawback has always been its prolonged effects. Now with Sugammadex, that will no longer be an issue and another dangerous drug can be taken out of the anesthesia cart and put into the museum of outdated drugs like ether and methoxyflurane.

With a combination of these two pairs of drugs, we can finally eliminate the expensive anesthesia machines and its complicated vaporizer system. Total IV anesthesia will be the way to go. Volatile agents such as sevoflurane and desflurane require vaporizers that are expensive to maintain. Refilling them can contaminate the air in the operating room. And they can fail leading to overdosage to the patient. Inhalational agents also cause malignant hyperthermia, the much dreaded nightmare of every anesthesiologist. Plus, what anesthesiologist hasn't walked into an operating room in the morning and found the the previous night's anesthesiologist forgot to turn off the vaporizer completely, gassing the OR all night? Vaporizers are difficult mechanical devices that can be easily removed and not missed at all with the use of TIVA.

What will be left is just a ventilator. By using TIVA, the OR can use the same ventilators as the ICU and eliminate the anesthesia machine. All we need is an Ambu bag to mask the patient then connect him to a regular ventilator with its myriad of vent settings at our disposal. This will save money by getting rid of the anesthesia machine and standardizing ventilators througout the hospital. If we ever get approval for injectable oxygen, conceivably the ventilator could be history too. Yes these are exciting times for anesthesia.

Injectable Oxygen. A Potential New Anesthesia Paradigm

Most medical research attempt to show incremental improvements to already proven treatments. But a team out of Boston Children's Hospital is working on a project that I believe will truly revolutionize anesthesia, and medicine in general: injectable oxygen. John Kheir, MD, et al, have been studying ways to bypass the lungs' oxygenation function and give the oxygen directly into the bloodstream ever since he and his colleagues had the misfortune to watch a pediatric patient die from severe respiratory distress and hypoxia in 2006.

Attempts at oxygenating blood directly have been tried for a century. Unfortunately the early experiments met with failure when patients developed air embolism instead. Later, machines such as the cardiopulmonary bypass machine and ECMO were invented that simulated lung function outside the body. While the machines are generally successful, they also carry high risk complications. First of all, they are highly invasive, requiring tricky cannulations of central vessels with large tubing. The machines are also bulky, tethering the patient in place with no possibility of mobility. Then there are all the complications associated with these devices. Patients have suffered air embolism, thrombotic embolism, bleeding catastrophes, and strokes when placed on these machines.

Dr. Kheir and his team changed the whole concept of oxygenating the blood by not trying to simulate the lungs. They used a machine called a sonicator that emits sound waves to mix together oxygen and lipids. The resultant emulsion carries three to four times the amount of oxygen that is carried by our own red blood cells. The lipid-O2 particles can be safely injected into the bloodstream without causing an embolism. They tested their creation on rabbit models which had their trachea occluded for up to 15 minutes. After injecting the rabbits with the emulsion, the rabbits' hypoxia immediately improved. Dr. Kheir states that currently only small amounts of the emulsion can be given. It cannot be infused over a prolonged period of time as the patient would likely get fluid overloaded receiving that much volume to maintain oxygenation. He envisions keeping small syringes of the emulsion in a crash cart for emergency situations.

I say he is being too modest. While the research team claims that the amount of emulsion that needs to be infused is currently too large to support more than a few minutes of oxygenation, I have confidence that they will refine and improve their technique to incorporate larger amounts of oxygen into their system. Once that happens, the product could truly change the practice of anesthesia. Imagine the potential of bypassing the lungs during an operation. Anything involving the use of the cardiopulmonary bypass machine would immediately become obsolete. Performing a double lung transplant would be a snap. Lung resections and pneumonectomies would no longer require the intricate placement of double lumen endotracheal tubes. We won't have to rush patients to the operating room for emergency tracheostomies because of foreign body or tumor occlusions of the airway. ENT can perform their laser surgeries in the oropharynx with little fear of causing an operating room fire because no oxygen will need to be blown into the lungs. Intubated ICU patients will suffer less barotrauma if they can give their lungs a rest for even a few hours a day. The possibilites are truly astounding.

The use of this oxygenated lipid reaches beyond the hospital walls. Firefighters would carry oxygenated lipids into a fire instead of pressurized oxygen. They can inject flame victims with the stuff to get them safely out of an inferno. Near drowning victims can be injected with oxygen instead of receiving the less efficient mouth to mouth or bag-mask resuscitation. The list goes on and on. I wish the Boston team the best of luck on improving their wondrous work.

Anesthesiologists are scientists too

What an amazing week this has been for science, and astronomy in particular. First we celebrated the 40th anniversary of the first manned lunar landing. Then there was the longest solar eclipse of this century over India and China yesterday. And late in the day was the amazing discovery by Australian amateur astronomer Anthony Wesley of a collision between Jupiter and a large space object, likely a comet or asteroid, producing a big black spot in the atmosphere.

What does all this have to do with anesthesiology? Well, we anesthesiologists are scientists too. We are not just "gasmen", "tube passers", or just "anesthesia". (That is one of my personal pet peeves, to be addressed as "are you anesthesia?" Anesthesia is a sensory state, not a profession or title. You never hear a nurse or resident ask a surgeon "are you the blade?" or "are you the skin cutter?") We all studied very hard in the sciences to get to where we are. And I bet most of us loved science as kids. You would not mistaken anesthesiology nerds for the jock orthopedic surgeons whose arms are the size of their heads.

I grew up watching all the science shows: Nova, Nature, Wild Kingdom. I saw every episode of Carl Sagan's "Cosmos" twice. I was so engaged and infatuated by that show that my best friend thought I was in the cult of Carl Sagan. I'll never forget the first time I looked at Saturn through a friend's telescope. The rings were even more spectacular than any of the books that I had read. It wasn't until much later that I bought my own telescope. And boy is it a good one, a Meade 8" Schmidt-Cassegrain. It weighs about 50 pounds in its case and that doesn't include the stand or the wedge. And everything was controlled manually, not like today's fancy computer guided scopes.

But as our jobs and lives get more hectic, the opportunity to indulge in our passions becomes more remote. That precious telescope has been stowed in the closet for years now. Last time I took it out was to watch Earth's close encounter with Mars a few years ago. Some of the neighborhood kids came out to watch. They were in awe of the Martian ice cap and the green and red blotches on the surface (alas no canals). I like to think that I instilled the love of science into at least a few of them. And in a few years, when my own children are older, I can share with them the joys of science and discovery that I made all those years ago.