Key Insights: The Pharmacology of Preventing Movement During Surgery

“My patient has no twitch during a train-of-four stimulus, but my patient is moving and the surgeon is yelling at me. My twitch monitor must not be working.”

Recently, we have witnessed a “perfect storm” impacting the pharmacology of immobility (preventing movement during anesthesia). With the availability of sugammadex, and the ability to reverse profound block, anesthesia providers have relied much more heavily on muscle relaxation to prevent movement than in the pre-sugammadex era, during which reversing profound block was not practical because of the limited effectiveness of neostigmine*. This was combined with fear of opioids because of the opioid use disorder epidemic. Some anesthesia providers have promoted the avoidance of opioids based on the unsubstantiated idea that the use of opioids during anesthesia will make postoperative opioid use disorder more likely (there is no evidence for this and in fact there is evidence to the contrary¹). Surgeons have encouraged the use of profound neuromuscular block because they believe it facilitates minimally invasive, port access surgery. Thus we see anesthesia providers struggling to prevent movement by overreliance on muscle relaxants, often with the use of little or no opioid. Many of these providers complain that their patients have “no twitch” (0/4 train-of-four twitches) but are moving anyway. They often don’t realize that their patients need to not only have no twitch in the train-of-four, but must also have a post-tetanic count of 0-2 (see below). These providers sometimes believe that their twitch monitor is not working, because their patient is moving, but has “no twitch”.

“Hey, the patient is waking up”—movement during surgery is undesirable

Preventing movement (also known as immobility) during a procedure performed under general anesthesia is a fundamental goal for anesthesia providers. Movement in response to a surgical stimulus can be troublesome for numerous reasons. Operating room staff may think that the moving patient is “waking up”, although movement can occur even when patients are deeply unconscious. We know from experience that movement during surgery is extremely common, while intraoperative awareness is much less common². Movement may interfere with the surgical procedure, and may even be dangerous if movement of the surgical field during a delicate procedure entails a risk of injury to the patient. The popularity of “minimally invasive surgery” performed through small incisions with the view of the surgical field provided by a video camera has made prevention of movement all the more important, since any movement can be more disruptive than when there is a traditional, larger “open” incision, viewed directly by the surgeon.

MAC Is an ED50: Movement and inhalational anesthetics

Interestingly, the most traditional measure of inhaled anesthetic potency focuses on the prevention of movement. The Minimum Anesthetic Concentration (MAC) is the end-tidal concentration of an inhaled anesthetic that will prevent movement in response to a surgical stimulus in 50% of people (or experimental animals)†. MAC is somewhat analogous to the Effective Dose 50% (ED50) for an intravenous anesthetic, the dose of the intravenous drug that produces a specific effect in 50% of people. While MAC and ED50 are useful for comparing the potencies of different inhaled or intravenous drugs, their clinical relevance is limited, since we are not looking for a 50% success rate during anesthesia. We are really looking for a 95 or even 99% success rate, so what we really would like to know is the ED95 or ED99!

Opioids are very effective for preventing movement

We tend to think of general anesthetics having their main site of action in the brain, but there is a fair amount of evidence suggesting that the anesthetic effects that prevent movement reside primarily in the spinal cord, rather than the brain‡.^3-5 This is actually quite important, because as we will see, when we use computerized electroencephalography (EEG) to measure the “depth of anesthesia”, we are measuring the effects of anesthetics on the brain (usually the frontal cortex to be specific), but not the spinal cord. Therefore, it should not be too surprising that an index of anesthetic depth based on EEG might not be predictive of whether a patient is going to move or not. This was demonstrated beautifully in a study by Sebel and his colleagues published in 1997⁶. They examined the probability of movement in response to a surgical stimulus using a variety of anesthetic techniques that included a range of doses of fentanyl, in relationship to the BIS number. When anesthesia consisted of an inhalational agent, without any fentanyl, there was a sigmoid relationship between the BIS number and the probability of movement. And the probability of movement was substantial, 50% at a BIS of 40, which is well within the recommended BIS range for general anesthesia. By contrast, when fentanyl was given in reasonable doses, the probability of movement declined dramatically to around 10%, and there was much less relationship between the BIS number and the probability of movement (Figure 1). 

Fig. 1: The probability of response to a surgical stimulus is plotted against the bispectral index for patients receiving isoflurane but no opioid, and another group of patients receiving isoflurane plus fentanyl analogs.  Note that there is a 50% chance of movement with a BIS in the low 40’s in the isoflurane group.  By comparison, the patients receiving opioid have a very low probability of movement that is not related to the BIS number (after Sebel et al).

Furthermore, the effect of fentanyl on movement was roughly dose related. From these and other data we can draw some very important and useful conclusions.  

• Opioids are very effective for preventing movement in response to a surgical stimulus
• Opioids are very effective for preventing voluntary breathing and diaphragmatic movement, often with incremental doses as small as 50-100 mcg
• Inhalational anesthesia is not very effective for preventing movement in response to a surgical stimulus
• The BIS number is useful for gauging anesthetic depth, but is less useful for predicting movement, unless we also consider what anesthetic drugs have been used to achieve a particular BIS number. Anesthetics that include opioids such as fentanyl, will have less risk of movement at any given BIS number than anesthetics that rely mostly or entirely on inhalational agents or intravenous anesthetics such as propofol.
  
  

The diaphragm is very resistant to neuromuscular blockade

Muscle relaxants, or so-called paralytic agents, such as rocuronium, are sometimes used to reduce the likelihood of movement. However, their effectiveness for this purpose is sometimes overestimated and misunderstood.

Here are some key points to remember:

• The diaphragm is very resistant to neuromuscular blockade.  Perhaps this was an evolutionary development to provide protection from naturally occurring muscle relaxants such as curare (d-tubocurarine is a plant alkaloid).  In any case, it is well established that in order to reliably prevent movement of the diaphragm based on muscle relaxation, profound neuromuscular blockade is necessary, resulting in a post-tetanic count of 0-2 at the adductor pollicis (Figure 2)^7,8.  
• Simply having no twitches in a train-of-four is not always adequate depth for preventing movement.  Unless the muscle relaxation is profound, the patient can still breath, cough and buck.  
• Movement during surgery is related to both the depth of neuromuscular blockade and the depth of anesthesia, and in particular, whether opioids are being used and in what dose (see above)

Fig. 2: The mean percent of cases with any response or “severe” response to a carinal stimulus plotted against post tetanic count.  The shaded area is the 95% confidence interval.  Note that “severe” response is only fully suppressed when the post tetanic count is 2 or less and that a post tetanic count of 0 is necessary to reliably prevent any response. Patients were anesthetized with thiopental, nitrous oxide and fentanyl (After Fernando et al).

Conclusions

The bottom line:

• If the intention is to prevent movement primarily with the use of neuromuscular blockade, there should be a post-tetanic count of approximately 0-2.  In such cases, quantitative monitoring to confirm reversal to a TOF ratio of ≥90% before extubation is critical to preventing residual paralysis and ensuring patient safety
• Opioids such as fentanyl are very effective for preventing movement, and in many situations are more efficient and effective than giving more rocuronium.  If opioids are used in combination with muscle relaxants, profound neuromuscular blockade may not be necessary to prevent movement
• Even when intending to prevent movement primarily by profound block, the addition of modest doses of fentanyl or other opioids will further decrease the likelihood of movement

* Neostigmine is only reliable for reversing shallow block, when there is a train-of-four ratio greater than about 0.4. More on this in a future post.

† MAC is actually a bit of a misnomer, because it is actually the MEDIAN anesthetic concentration, not the MINIMU anesthetic concentration that prevents movement in response to a surgical stimulus.

‡ Antognini et al demonstrated the importance of the spinal cord in mediating movement in response to surgical stimulus in an elegant complex experimental preparation with selective circulation to the brain and spinal cord of goats². Eger et al wrote a review on this topic³. Of note, Eger was the inventor of the concept of MAC.

ABOUT THE AUTHOR
Andrew Bowdle MD, PhD, FASE is a Professor of Anesthesiology and Pharmaceutics and the Laura Cheney Professor in Anesthesia Patient Safety at the University of Washington. Dr. Bowdle leads a multi-disciplinary group of investigators engaged in research related to anesthesia patient safety.

Reproduced with permission from Andrew Bowdle MD, PhD, FASE. Originally published on Dr. Bowdle's Substack A Higher Plane of Anesthesia.